REGULATORY ASSISTANCE CORPORATION 

17 Clearview Circle 

Hopewell Junction, New York 12533 

PLEASE NOTE 845-896-4340 

NEW AREA CODE 845-8964341 (FAX #) 

November 11, 2009 

Document Control Officer 

Office of Pollution Prevention 

And Toxic Substances 7407 

U.S. EPA 

1200 Pennsylvania Avenue NW 

Washington, D.C. 20460 

RE: PMN P 10-0009 

Gentlemen: 

Company Sanitized 

We recently filed the subject PMN but were only recently informed that a 28 Day 

Repeated-Dose Oral Toxicity Study in Rats study had been conducted, the results of 

which were also just received. 

We are, therefore, submitting herewith the full text of the 28 day repeat dose study - 3 

copies of full text version, one copy of non confidential version. 

We apologize for the delay in sending the study but as indicated above, we have just 

become aware of its availability and promptly submitting it to EPA upon its availability . 

If you have any questions, please contact the undersigned. 

GSD/dk 

Enclosure 

Company Sanitized 

II I I i II!I I Ilii~ II !' II'i~ II i~ II'I~ li II II i ! ! .I I ~i II 5 0 , U 0 0 0 0 i 1 0 , 

3 P-2;a ~~oa 
STUDY CODE: ~ 

Receipt No. 

~-9 

~: 03 

Company Sanitized 

FINAL REPORT 

TWENTY-EIGHT-DAY REPEATED-DOSE 

ORAL TOXICITY STUDY OF 

IN RATS 

September 2009 

Hita Laboratory 

Chemicals Evaluation and Research Institute 

Japan 
STATEMENT 

I, the undersigned, hereby declare that this report provides correct English translation of the final 

report (Study Code 40M, issued on September 28, 2009). 

,~Ozt_' ('-~ v t ~fo~.~ Z ~ zob ~ 

Katsumi Miyata, M.S ., JA.C.L .C .T. Date 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 
GLP STATEMENT 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 

Sponsor: 

Title : Twenty-Eight-Dav Repeated-Dose Oral Toxicity Study o~ in Rats 

Study Code: 

I, the undersigned, hereby declare that this study was conducted in compliance with "Concerning 

Standard of the Testing Facilities Conducting the Test Relating to the New Chemical Substances" 

[Notification No. 1121003 of the Pharmaceutical and Food Safety Bureau, MHLW, No. 3 (November 

17, 2003) of the Manufacturing Industries Bureau, METI & No. 031121004 of the. Environmental 

Health Department, MOE (November 21, 2003)]" and "OECD Principles of. Good Laboratory 

Practice" (November 26, 1997). 

And, I confirmed that this report accurately reflects the raw data obtained and that data of the study 

has reliability. 

Study Director: Signed in original September 28, 2009 

Katsumi Miyata, M.S ., J.A .C .L.C.T. 
4UALTTY ASSURANCE STATEMENT 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 

Sponsor: Uft 

Title : Twenty-Eight-Day Repeated-Dose Oral Toxicity Study of dM in Rats 

Study Code: 

This study was audited and inspected by Quality Assurance Section of Hita Laboratory, Chemicals 

Evaluation and Research Institute, Japan. The dates audited and/or inspected and the dates reported 

of these results to the study director and management are as follows. 

Items of Inspections 

and Audits 

Dates of Inspections 

__ and Audits 

Dates of Inspections and 

Audits Reports 

Protocol May 18, 2009 May 18, 2009 

Assessment of response (protocol) May 22, 2009 May 22 2009 

Amendment to protocol May 22, 2009 May 22 2009 

Preparation of test substance May 27, 2009 May 27 2009 

Assessment of response 

(amendment to protocol) May .29, 2009 May 29 2009 

Administration and clinical 

observation May 29, 2009 May 29 2009 

Blood sampling June 26, 2009 June 26 2009 

Dissection, necropsy and organ 

weight measurements June 26, 2009 June 26 2009 

Clinical chemistry data September 8, 2009 September 8, 2009 

Animal data September 8, 2009 September 8, 2009 

Documents of test substance and 

housing conditions September 8, 2009 September 8, 2009 

Pathological data September 14, 2009 September 14, 2009 

Re-inspection of documents of test 

substance and housing conditions 

_ 

September 14, 2009 September 14, 2009 

Draft of final report September 16, 2009 September 16, 2009 

Re-inspection of draft final report _September 17, 2009 September 17, 2009 

Draft of final report (2 September 24, 2009 September 24, 2009 

(~-inspection of draft final report September 28, 2009 September 28, 2009 

Final report September 28, 2009 September 28, 2009 
Following items were reported to the study director and management on the basis of the audit of 

facility oraudit-iesults 'ni other studies. -" 

Items of Audits Dates of Audits Dates of Audits Reports 

Preparation investigation June 4, 2008 September 24, 2009 

Animal receipt April 14, 2009 September 24, 2009 

Quarantine and acclimatization April 14, 2009 September 24, 2009 

Animal care April 14, 2009 September 24, 2009 

Allocation and nimal 

identification April 1, 2009 September 24, 2009 

Body weight measurements April 1, 2009 September 24, 2009 

Food intake measurements April 1, 2009 September 24, 2009 

Detailed clinical observation and 

sensorimotor function test April 27, 2009 September 24, 2009 

Urine sampling April 16, 2009 September 24, 2009 

Hematology April 30, 2009 September 24, 2009 

Blood chemistry April 30, 2009 September 24, 2009 

Urinalysis April 30, 2009 

_ 

September 24, 2009 

Pathological preparation May 7, 12 and 13, 2009 September 24, 2009 

~ Microscopic examinations June 4, 2009 September 24, 2009 

I, the undersigned, hereby declare that this report provides an accurate description of the methods and 

procedures used in this study and that the reported results accurately reflect the raw data obtained . 

Section Chief, Quality Assurance: Signed in original _ September 28, 2009 

Masakazu Yoshida, B.S . 
TABLE OF CONTENTS 

IITI;F .-: . . . :: . . . .. . . . . . . . . . . . . . . . . . . . . . . . : . :. . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . :. .. .. . . . . . . . . . . . . . . . . . .. . . . . . .. . . .. . . . .. .. . 

SPONSOR . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 

TESTING FACILITY . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 

PURPOSE OF THE STUDY. . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . . .. .. . . . .. . . . . . . . . . . . . .. . . . . . . . . . .. . . . 

TESTING METHOD. . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 

GLP COMPLIANCE . . . . . . . . . . . . . . . . . . . .. .. . . .. . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

PERIOD OF THE STUDY . . . . . . . . . . .. .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 

LOCAT10N AND PERIOD FOR RETENTION OF RAW DATA AND 

SPECIMENS . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . . .. .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . 

RETENTION OF THE ORIGINAL PROTOCOL AND FINAL REPORT °~~°~°~°~~~~~~ 

AUTHOR AND PERSONNEL CONCERNED WITH THE STUDY . . .. .. . . .. . . . . . . . . . . . . . . . . 

AUTHOR APPROVAL . . . . . .. . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. .. . . .. . . . . . . . . . . . . . . . . 

SUIVIMARY. . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . .. . . . . . . 

MATERIALS AND METHODS . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . 

1. 

2. 

3. 

4. 

5. 

6. 

7. 

TEST SUBSTANCE . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . .. . 

ANIMALS . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . 

HOUSING CONDITIONS . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . .. .. . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . 

GROUPING . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . .. . . . . . . :. . . . . . . . . . . . . . . . . .. . . . .. . . ... . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . 

STABILITY OF THE TEST SUBSTANCE . . . . . . . .. .. . . . . . .. . . . . . . . . . .. . . . . . . . . . . .. . . .. . . . . . 

PREPARATION OF FORMULATIONS . . . . . . . . . . .:. . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

ADMINISTRATION-. . .. . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . 

8. OBSERVATIONS . . . .. . . .. . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . 

9. STATISTICAL ANALYSIS . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . . .. . . . . . . 

ENVIRONMENTAL FACTORS THAT MIGHT HAVE AFFECTED 

THE RELIABILITY OF THE STUDY RESULTS . . . . .. . . .. . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 

RESULTS . .. . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . .. . . . .. . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . 

1. 

2. 

3. 

4. 

5. 

6. 

7. 

8. 

9. 

10. 

11 . 

CLINICAL SIGNS . . . . . . . . . . . . . . . . .. . . . .. .. .. . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . 

DETAILED CLINICAL OBSERVATIONS . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . " .. . . . . . . . . .. . . 

SENSORIMOTOR FUNCTION . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. .. . . . .. . . 

BODY WEIGHTS . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. .. . . . .. . . . . . . . .. . . 

FOOD INTAKES . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . .. . . . .. . . . .. . . .. . . 

HEMATOLOGICAL EXAMINATIONS . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . 

BLOOD CHENIICAL EXAMINATIONS . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

URINALYSES-. . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . .. . . . . . . . . . . .. . . . 

ORGAN WEIGHTS . . . . . . . .. . . . .. . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . . . . . 

NECROPSY. . . .. . . . . . . . . . . . . . . . . . . . . .. .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 

HISTOPATHOLOGICAL EXAMINATIONS . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . 

vi - 
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . :. . . . . . . . . . . . . . . . . . . . . 

REFERENCE- :.-. .: . :: . . . . . . . . . . . . . . . . . . . . . . . . . . . . : :. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .: . . . . . . . . . . . . . . . . . . . . . 

FIGURES 

1 Body weights . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . 

2 Food intakes . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . 

23 

25 

26 

28 

TABLES 

1 Summary of clinical signs . . . . . . .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . .. . . .. .. . . . . . . . . . . . . .. . . . . . . 30 

2 Summary of detailed clinical observations . . . .. . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. .. . . . . 31 

3 Summary of reflex . .. . . . . . . . . . . . . . .. .. .. . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . .. . . . . . . . . .. . . . . 56 

4 Summary of grip strength . . . . . .. .. .. . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . 59 

~' 5 Summary of motor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

. . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .. . . . .. . . .. . . . . 60 

6 Summary of body weights . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . .. . 61 

Summary of food intakes . . .. . . . . . . . . . .. . . . . . . . . . .. .. . . . . . . . .. . . . . . . . . . . . . : . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 63 

8 Summary of hematological examinations . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 65 

9 Summary of blood chemical examinations . . . . . . . . . . . . . . . . . . . . . . . .. .. .. . . . . . . . . . . . . . . .. . . . . . . . . 67 

10 Summary of urinalyses . . . . . . . . . . . .. .. . . . . . . . . . . . . . . .. . . .. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . .. . . . . 69 

11 Summary of absolute organ weights . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . 72 

12 Summary of relative organ weights . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . 74 

13 Summary of macroscopic examinations . . . . . . . . . . . . .. . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 76 

14 Summary of histopathological examinations . . . .. .. . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . 77 

ADDENDA 

1 Clinical signs of individual animals . . . . . . .. . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . 82 

2 Detailed clinical observations of individual animals . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . 94 

3 Reflex of individual animals . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 164 

4 Grip strength of individual animals . . .. . . .. . . . .. .. . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . .. . . . .. . . . . . . . . . . . 166 

5 Motor activity of individual animals .. . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . 168 

6 Body weights of individual animals . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .. . .. .. . . . . . .. . . . . 170 

Food intakes of individual animals . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . 173 

8 Hematological data of individual animals . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 176 

9 Blood chemical data of individual animals . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . 180 

10 Urinalytic data of individual animals . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . 184 

1 ~ Absolute organ weights of individual animals . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . .. . . . . . . . . . . 190 

1 4 Relative organ weights of individual animals . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 

13 Pathological findings of individual animals . . . . . . . . . . . . . . . . . . . .. .. . . . . . .. . . . . . . . . . .. . . . . . . . . . . 198 

APPENDIX 1 Photos (Histopathological examinations) 

APPENDIX 2 "STABILITY ANALYSIS OF d1so HOMOGENEITY, STABILITY AND 

CONCENTRATION ANALYSES OF THE TEST SUBSTANCE FORMULATION 

(Study code: 40W) 
p. 9 

Study Code: i ; 

- - --- Test Substance Code: 

Sponsor Code: 

TITLE 

Twenty-Eight-Day Repeated-Dose Oral Toxicity Study ofeW in Rats 

SPONSOR 

TESTING FACILITY 

Hita. Laboratory 

Chemicals Evaluation and Research Institute, Japan 

822, 3-chome, Ishii-machi, Hita, Oita 877-0061, Japan 

PURPOSE OF THE STUDY 

The purpose of this study is to define the type, severity and reversibility of toxicological signs of the 

test substance by observing the functional and morphological changes in animals receiving repeated 

doses orally for 28 days. 

TESTING METHOD 

This study was conducted in accordance with "28-day Repeated Dose Toxicity Study in Mammalian 

Species" prescribed in "Concerning Testing Methods Relating to the New Chemical Substances" 

[Notification No. 1121002 of the Pharmaceutical and Food Safety Bureau, MHLW, No. 2 (November 

13, 2003) of the Manufacturing Industries Bureau, METI & No. 031121002 of the Environmental 

Health Department, MOE (November 21, 2003)]" and "Repeated Dose 28-day Oral Toxicity Study in 

Rodents (No. 407, Adopted: October 3, 2008)" prescribed in "OECD Guideline for the Testing of 

Chemicals". 

GLP COMPLIANCE 

This study was conducted in conformity "Concerning Standard of the Testing Facilities Conducting 

the Test Relating to the New Chemical Substances" [Notification No. 1121003 of the Pharmaceutical 

and Food Safety Bureau, MHLW, No. 3 (November 17, 2003) of the Manufacturing Industries 

Bureau, METI & No. 031121004 of the Environmental Health Department, MOE (November 21, 

2003)]" and "OECD Principles of Good Laboratory Practice" (November 26, 1997). 
PERIOD OF THE STUDY 

Commencbmentofthe Study: -

Animal Receipt: 

Initiation of Examination (Initiation of Dosing) : 

Terminal Necropsy of Dosing Period: 

Initiation of Recovery Period: 

Terminal Necropsy of Recovery Period: 

Termination of Examination (Termination of Histology): 

Completion of the Study: 

May 14, 2009 

May 19, 2009 

May 29, 2009 

June 26, 2009 

June 26, 2009 

July 10, 2009 

August 20, 2009 

September 28, 2009 

LOCATION AND PERIOD FOR RETENTION OF RAW DATA AND SPECIMENS 

The raw data, protocol and amendment, study contract documents, test substance information, final 

report, iother record documents and specimens will be stored in the archive of the Hita Laboratory of 

our organization, and samples of every lot of the test substance will be stored in the test substance 

storage room, for a period of 10 years from the date of receipt of the notification that they are 

applicable to Article 4, Paragraphs 1 or 2, Article 4-2, Paragraphs 2, 3 or 8, Article 5-4, Paragraph 2, 

Article 24, Paragraph 2 or Article 25-3, Paragraph 2 of the Japanese Chemical Substances Control 

Law No. 117 (1973) . The sponsor will inform the Hita Laboratory of our organization of the date .of 

receipt of the notification. After termination of the retention period, any measures taken will be 

done so with the approval of the sponsor. Samples and specimens that are liable to deteriorate 

markedly will be retained for 10 years after receipt of the notification or only for as long as the 

quality of the preparation permits evaluation, and they will be disposed with approval of the sponsor. 

RETENTION OF THE ORIGINAL PROTOCOL AND FINAL REPORT 

The original protocol and protocol amendments and final report will be retained at Hita Laboratory. 

A copy of the document will be retained by the sponsor. 
AUTHOR AND PERSONNEL CONCERNED WITH THE STUDY , 

-Study~Duector:- --Katsumi IVIiyata, M:S., J.A.C.L.C.T. 

(Planning and management of the study, evaluation of ~ e 

results, report creation, and over all responsible for the technial 

conduct of the study) 

Study Staff Saori Takakura, J.L.A.T. 

(Quarantine, acclimation and housing management of animals, 

preparation and administration of the test substance, clini¢al 

observation, detailed clinical observation, sensorimotor 

Function, body weights and food intakes measurements, and 

responsible for the animal examination) 

Person in charge of Pathologic Examination: 

Satsuki Hoshuyama, Ph.D:, D.V.M. 

(Necropsy, collection of tissues, organ weight measurements, 

histopathological examinations, and responsible for the 

histopathology) 

Person in charge of Clinical Chemistry: 

Nobuhiko Higasihara, B.S . 

(Hematological and blood chemical examinations, urinalysis, 

and responsible for the biochemistry of the specimens) 

, 

AUTHOR APPROVAL 

Study Director: Signed in original September 28, 2009 

Katsumi Miyata, M.S ., J .A.C.L.C.T. 

Section 2 (Toxicology area) 

Hita Laboratory 
SUMMARY 

A 28-day repeated-dose oral toxicity study of4MjW was performed in groups of five male and five 

female Cr1:CD(SD) rats at 5 weeks of age . The high dose was set at 300 mg/kg/day, and altogether 

four doses including 100, 30 and 10 mg/kg/day were employed. Recovery groups were also set for 

the 300 mg/kg and vehicle control groups to investigate the reversibility of the effects . 

Due to treatment with the test substance, changes suggesting effects on the blood was observed. 

Red blood cell count (RBC) was decreased in males and females in the 300 mg/kg group. 

Hemoglobin conc. and hematocrit value were decreased in females in the 100 mg/kg and higher 

group and males in the 300 mg/kg group. Mean corpuscular volume was increased in males in 

the 300 mg/kg group. In addition, recitulocytes were increased in females in the 100 mg/kg and 

highergroup and males in the 300 mg/kg group. 

On blood chemistry, aspartate aminotransferase and alanine aminotransferase were increased in 

males in the 300 mg/kg group. 

Anemia related changes were noted in the spleen. Absolute and relative spleen weights were 

increased in males in the 100 mg/kg and higher group and females in the 300 mg/kg group. 

Blackish change in females in the 100 mg/kg and higher group and males in the 300 mg/kg group, 

and enlargement in males in the 300 mg/kg group were noted macroscopy. Congestion in males 

and females in the 300 mg/kg group, hemosiderin deposition in females in the 100 mg/kg and 

higher~ group and males in the 300 mg/kg group, and increased extramedullary hematopoiesis in 

males Iand females in the 100 mg/kg and higher group were noted histopathologically . In the 

liver, an increase in relative liver weight .and increased extramedullary hematopoiesis were 

observed in males and females in the 300 mg/kg group. Hemosiderin deposition in the Kupffer 

cells was noted in females in the 300 mg/kg group. 

These changes suggested a hemolytic anemia due to test substance tretament . 

After the recovery period, although RBC was decreased in females in the 300 mg/kg recovery 

group, the severity was decreased and suggested to be a reversible change . , 

In addlition, post-dose salivation was observed in males and females in the 100 mg/kg and higher 

group. Food intakes were increased in females in the 300 mg/kg group on day 28 of treatment. 

, 

On henmatology, lymphocytes were decreased in males in the 100 mg/kg and higher group. On 

blood chemistry, alkaline phosphatase was increased in males in the 300 mg/kg group. 

Albumin was increased .in females in the 100 mglkg and higher group. 

-4- 
p. 13 

Detailed clinical observation, sensorimotor function, body weights and urinalysis showed no 

-beatftfent reT-ated changes. 

Based on these results, the No-Observed-Adverse-Effect Level (NOAEL) of 40M under ~e 

conditions tested was considered to be 30 mg/kg/day because of increased extramedullary 

hematopoiesis in the spleen in males and females, increases in absolute and relative spleen weights in 

males, decreases in Hb and Ht, increases in reticulocytes and albumin, and blackish change and 

hemosiderin deposition in the spleen in females in the 100 mg/kg and higher group. 

The No-Observed-Effect Level (NOEL) was considered to be 30 mg/kg/day because of salivation 'in 

males and females of the 100 mg/kg and. higher group. 
p. 14 
p. 15 

1.7 Physicochemical Properties 

- --- Appiwance at Ordinary Temperature : 

Molecular Weight: 

Stability: 

Melting point: 

Degree of Solubility : 

1.8 Storage Conditions ; 

The test substance was sent cryogenically and stored in the freezer No. 1 temporary. The test 

substance was stored at room temperature (19.5-22.2°C from obtaining storage information to 

the final preparation of the dosing formulations, cabinet No. 5 or 1 in the test substance storage 

room). 

1.9 Handling Precaution ' 

Glove, mask, cap, protective glasses and lab coat were put on. The test substance was 

warmed up at 40°C when precipitation of the test substance was observed. 

2. ANIIVIALS 

Cr1:CD(SD) rats (SPF) of 38 males and 38 females were obtained from Charles River Japan 

Hino Breeding Center at 4 weeks old. Animals were acclimatized for 10 days including 6 

days quarantine. No abnormalities were noted in all animals during the quarantine and 

acclimation periods. The animals were allocated to groups to ensure homogeneity of mean 

body weights using body weight-stratified randomization on two days before the start, of 

administration. The animals not treated were excreted from the study and used for treatment 

training . At the onset of treatment, the animals were five weeks old with body weight ranges 

of 148 .7-175 .0 g and 121.1-148 .7 g for males and females, respectively. 

Animals were identified by means of a marker on the tail before grouping, and ear-tags after 

grouping . However, the detailed clinical examinations, reflex and grip strength 

measurements were performed on a blind test bases. Racks and cages were identified by 

individual cards. 
3. HOUSING CONDTTIONS ° 

A-li-animalgweie bred at the barrier-system animal rooms (quarantine room No. 1 during the 

quarantine period and room No. 5 after the quarantine), which were maintained at a stable 

temperature (21-25°C) and relative humidity (40-70%) with 10-15 sir changes per hour and 

artificial light-dark cycle of 12-12 hours (light on: 7:00 and light off. 19:00) throughout the 

whole feeding period including the quarantine and' acclimation periods. The actual 

temperature and humidity were 21.7-23.4°C and 46.6-64.0%, respectively . 

The rats were housed in hanging stainless steel cages with wire-mesh floor at three or five 

animals age (260 Wx380 Dx180 H mm, TOKIWA KAGAKU KIKAI) for quarantine and 

acclimation, and at one animal/cage (165 WX300 DX150 H mm, TOKIWA KAGAKU KIKAI) 

for after grouping. 

Undertrays were changed once before grouping, and twice weekly after grouping. Feeders, 

cages and racks were changed once at the grouping, and once at the termination of the dosing 

period for the recovery group. The animals had free access to an MF pelleted diet (Lot No. 

090119, Oriental Yeast) and chlorinated water from Hita City supply via automatic watering 

system with sipper tubes. 

The diet and housing materials were autoclaved at 121 °C for 30 min prior to use. Analysis of 

the. diet was performed in Japan Food Research laboratories, and the analytical data were 

provided by the manufacturer. The tested parameters met the requirements in our laboratory 

according to the "Toxic Substances Control Act of US-EPA". Contaminants in drinking 

water were analyzed twice yearly in Oita Prefecture Pharmaceutical Association according to 

the water regulations of the "Notification No. 101 of Environmental Health Bureau, MHLW ' 

except for test of the taste and residual chlorine in our Hita Laboratory . Contaminants in the 

water were in the stated ranges in our laboratory. 

4. GROUPING 

Range finding study of 7 days repeated oral treatment was performed with male and female 

Crl:CD(SD) rats at 0, 25, 250, 500 and 1,000 mg/kg/day. As a result, suppressed body weight 

gains or decreased body weights and enlargement of the liver were observed in males in the 

~00 mg/kg and higher group and females in the 1,000 mg/kg group. Orange urine was 

6bserved in males and females in the 1,000 mg/kg group. Blackish change of the spleen was 

bbserved in the same dose group, and hemolytic anemia was suggested. 

The high dose in the present study was set at 300 mg/kg/day at highest dose level, considering 

elongation of the dosing period compared to the range finding study, and death had been 
p. 17 

concerned at 500 mg/kg/day where the treatment effects were observed in the 7 days study. 

_Tfie lower doses were set at 100, 30 and 10 mg/kg./day in consideration for hematologiyal 

effects to the low dose levels . Recovery groups were also set for the 300 mg/kg and vehi~le 

control groups. 

Group 

Dose Volume Concentration Number of Animals (Animal No.) 

(mg/kg/day) (mL/kg) (w/v%) Male Female 

Vehicle control 0 10 0 5 ( 1 - 5 ) 5 ( 36 - 40 ) 

Vehicle control (recovery) 0 10 0 5 ( 6 - 10 ) 5 ( 41 - 45 ) 

Low dose 10 10 0.100 5 ( 11 - 15 ) 5 ( 46 - 50 ) 

Intermediate (1) dose 30 10 0.300 5 ( 16 - 20 ) 5 ( 51 - 55 ) 

Intermediate (2) dose 100 10 1 .00 5 ( 21 - 25 ) 5 ( 56 - 60 ) 

High dose 300 10 3.00 5 ( 26 - 30 ) 5 ( 61 - 65 ) 

High dose (recovery) 300 10 3.00 5 ( 31 - 35 ) 5 ( 66 - 70 ) 

5. STABILITY OF THE TEST SUBSTANCE (see attached physicochemical report) 

Stability of the test substance during the dosing period was confirmed with infrared (IR) 

spectrophotometer in Hita Laboratory (See APPENDIX 2, Study code: ~. IR 

spectrum of the test substance within was compared with that provided by 

the sponsor before dosing to determine the identity. The test substance was also analyzed to 

confirm the stability before and after the dosing period to confirm the stability . 

6. PREPARATION OF FORMULATIONS 

6.1 Vehicle + 

In preparation investigation of the dosing formulations at 10.0 w/v%, the test substance did not 

dissolved in purified water. However, the test substance was suspended successfully with 

olive oil. Therefore, olive oil (Lot No. 0470YH, Fujimi Pharmaceutical) was selected as the 

vehicle. 

6.2 Preparation and Storage 

The test substance was accurately weighed and mixed with olive ail to prepare 3.00 w/v%. 

The lower concentrations of 1 .00, 0.300 and 0.100 w/v% were diluted from 3.00 w/v% with 

olive oil by stirring with a magnetic stirrer. The formulations including olive oil for the 

vehicle control were divided into an aliquot for each administration day, and stored at room 

temperature (20-23°C, in the test substance formation storage container in the reagent storage 

room) until treatment. , 
Concentration Test substance weights Volume 

.-Preparation-days 

(w/v%) and dilution methods (ML) 

May 27, 2009 3 .00 18.00 g 600 

(Concentration analysis) 1 .00 Diluted with 100 mL of 3.00 w/vO/o 300 

0.300 Diluted with 30 mL of 3.00 w/vO/o 300 

0.100 Diluted with 10 mL of 3.00 w/vO/o 300 

June 5, 2009 3.00 18.00 g 600 

1 .00 Diluted with 100 mL of 3.00 w/vO/o 300 

0.300 Diluted with 30 mL of 3.00 w/vO/o 300 

0.100 Diluted with 10 mL of 3.00 w/vO/o 300 

June 12, 2009 3.00 18 .00 g 600 

(warmed up to 40°C 1 .00 Diluted with 100 mL of 3.00 w/vO/o 300 

because of precipitation 0.300 Diluted with 30 mL of 3.00 w/v% 300 

of the test substance) 0.100 Diluted with 10 mL of 3.00 w/vO/o 300 

June 19, 2009 3.00 18.00 g 600 

1 .00 Diluted with 100 mL of 3.00 w/vO/o 300 

0.300 Diluted with 30 mL of 3 .00 w/v% 300 

0.100 Diluted with 10 mL of 3 .00 w/v% 300 

6.3 Homogeneity and Stability Analyses 

The homogeneity and stability tests were performed in Hita Laboratory (see APPENDIX 2, 

,Study code: 400M. In the homogeneity test, top, middle and bottom layers of 10.0 and 

;0.1 w/v% formulations were taken immediately after preparation. These samples were 

quantitatively analyzed by a high performance liquid chromatography. In the stability test, 

the formulations for homogeneity samples were stored at room temperature and analyzed after 

4 and 10 days. The test substance in formulations was confirmed to be stable for 9 days. 

6.4 1 Concentration Analyses 

Concentration of the test substance was confirmed in Hita Laboratory (see APPENDIX 2, 

Study code: 41111IM The concentrations of 3 .00, 1 .00, 0.300 and 0.100 w/vO/o 

formulations were confirmed to be within 100t10% of each nominal concentration at the first 

; preparation of the dosing period. 
7. ADMINISTRATION 

--Me -ormulations were taken with mixing by a magnetic stirrer and repeatedly administerpd 

daily in the morning (9:05-11 :18) by oral gavage using a syringe (Terumo) connected tol a 

Nelaton catheter (Terumo) for 28 days. 

8. OBSERVATIONS 

Concerning the numbering of day and week, the day of the initiation of dosing was regarded as 

day 1, and the week of initiation of dosing as week 1. The day after the last dosing was 

regarded as day 1 (recovery period) and the week of the initiation of recovery as week! 1 

(recovery period). 

8.1 Clinical Signs 

During the dosing period, animals were observed three times a day, i.e., before dosing (in the 

morning), during and just after dosing, and in the afternoon, daily from day 1 to day 28. 

During the recovery period, observation was performed once daily . 

8.2 Detailed Clinical Observations 

The detailed examination in all animals was performed ad blind tests before dosing and once 

weekly thereafter. 

1) Removal from cage 

Animal reactions such as excitement from external stimuli (holding animals or bringing a 

hand close to animals to hold, etc.) were observed. 

Ease of removal and vocalization. 

2) Handling observations 

Muscle tone, subnormal temperature, piloerection, hair appearance (staining ahd 

unkempt hair), skin color and mucous (paleness, reddening and cyanosis), eyes 

(lacrimation, exophthalmos and pupillary size), salivation and secretion. 

3) Observation in arena 

Animals were placed in a standard arena (on an observation platform) and observed for 1 

min or more, and the frequencies of defecation (number of feces) and urination (number 

of pools) were recorded for 1 min. 

Posture, motor activity level, respiration, lid closure, gait characteristics, tremor, 

twitch, convulsion, stereotypes and abnormal behavior. 

8.3 Sensorimotor Function 

All animals were -examined in week 4 of the dosing period, but not in the recovery period, 

since no abnormalities werq noted in week 4 of the dosing period. 

1) Reflex 

Reactions of animals were observed and made a score when proper stimuli were given 

-11- 
their test subjected sensory organs. The examinations wdre also performed on a blind 

test-basis- - - 

(1) Approach contact/touch response 

A blunt probe was bought approximately 3 cm from the animal's nose for 4 

seconds . 

(2) Pinna response 

The animal's response to a sudden sound of finger snap was assessed. 

(3) Pain response 

The animal's tail was pinched with a clothespin between one-third and base of the 

tail. 

(4) Pupillary reflex 

Following darkness adaptation of the animal's eyes, pupil constriction in response to 

a bright beam of penlight was observed. 

(5) Air righting reflex 

The animal was held ventral surface uppermost approximately 30 cm height from 

the flat surface and released. 

2) Grip strength 

Forelimbs and hindlimbs grip strengths were measured with automated grip strength meter 

(FGC-2, MATYS) ad blind tests. Two trials were performed, and the mean values were 

calculated. 

3) . Locomotor activity counts 

Locomotor activity level of each animal was counted with activity monitoring system for 

rats (ACTIMO-10, SHINTECHNO) by the number of crossing IR beam for 1 hr at 10 min 

intervals. 

8.4 Body Weights 

Body weight was measured at allocation to groups, and on days 1, 3, 8, 12, 17, 21, 26 and 28 

Ouring the dosing period and on days 1., 5, 10 and 14 during the recovery period. In addition, 

immediately before necropsy, body weights were measured for calculation of the relative organ 

weights. 

8.5 Food Intakes 

I ood consumption was measured at allocation to groups, and on days 1, 3, 8, 15, 22 and 28 

during the dosing period and on days 1, 4, 8 and 14 during the recovery Period. Mean food 

'intakes per day were calculated from their remainders for each period. 
8.6 Hematological Examinations 

-- Tlood or plasma samples ob~ained by blood sampling from the abdominal aorta under ether 

anesthesia after overnight fasting (16 to 20 hr) at completion of the dosing period (excl " g 

the recovery groups) and at completion of the recovery period were determined for t e 

following items. In addition, the blood smears stained with Wright staining were ma~e; 

however, these were not used for the examinations . 

As an anticoagulant, 3.2% sodium citrate aqueous solution (Lot No. PEQ4430, Wako Pure 

Chemical Industries) was used for the determination of prothrombin time and activated partial 

thromboplastin time, and EDTA-2K (Lot No. G7039, Sysmex) for other measurements. 

Parameters 

1) Red blood cell count (RBC) NO 

4 

/11L) 

2) White blood cell count (WBC) (X 102/uL) 

3) Hemoglobin conc. (Hb) (g/dL) 

4) Hematocrit value (Ht) (%) 

5) Mean corpuscular volume (MCV) (ff,) 

6) Mean corpuscular hemoglobin (MCH) (pg) 

7) Mean corpuscular hemoglobin cona. (MCHC) (g/dL) 

8) Platelet count (Platelet) (x 104/AL) 

9) Reticulocyte ratio (Reticulo) (%) 

10) Prothrombin time (PT) (sec) 

11) Activated partial thromboplastin time (APTT) (sec) 

12) Differentiation of leukocytes (%) 

Neutrophils (Neutro) 

Eosinophils (Eosino) 

Basophils (Baso) 

Lymphocytes (Lymph) 

Monocytes (Mono) 

Large unstained cells (LUC) 

Method 

Electrical resistance detection 

Electrical resistance detection 

Noncyanhemoglobin method 

RBC x MCV 

103 

Electrical resistance detection 

Rb 

x 103 

RBC 

Hb 

x 102 Ht 

Electrical resistance detection 

RNA staining 

Magnetic sensor , 

Magnetic sensor 

Flow cytometry technique 

1)-8) CELL-DYN3500, Abbott Laboratories 

9),12) ADVIA 120, SIEMENS 

10),11) KC-10A, AMELUNG 
8.7 Blood Chemical Examinations 

Sercun sampies-were separated from-blood samples collected at the same times as those 

described in section 8.6, and the following items were determined in the obtained serum 

samples. 

Parameters 

1) 

2) 

3) 

4) 

5) 

Aspartate aminotransferase (AST) 

Alanine aminotransferase (ALT) 

Alkaline phosphatase (ALP) 

Cholinesterase (ChE) 

y-Glutamyl transpeptidase (y-GTP) 

(IUIL) 

(IU2) 

) 

2) 

(IU2) 

6) Total cholesterol (T-Cho) (mg/dL) 

7) Triglyceride (TG) (mg/dL) 

8) Glucose (mg/dL) 

9) Total protein (T-Protein) (g/dL) 

10) Albumin (g/dL) 

11) A/G ratio 

12) Blood urea nitrogen (BUN) (mg/dL) 

13) Crealznine (mg/dI,) 

14) Total bilirubin (T-Bil) (mg/dL) 

1'5) Calcium (Ca) (mg/dL) 

1'6) Inorganic phosphorus (IP) (mg/dL) 

17) Sodium (Na) ( 

18) Potassium (K) 

I 

1'9) Chloride (Cl) 

l)-10),12)-16) 

17)-19) 

(mEq2) 

(mE1[L) 

7170 Automatic Analyzer, Hitachi 

PVA-EXII, A & T 

Method 

UV method (method based on JSCC) 

UV method (method based on JSCC) 

p-Nitrophenyl phosphate method , 

Butyrylthiocholine iodide method 

L-y-glutamyl-3-carboxy-4-nitroanilide 

method 

COD~ADPS method 

GPO~ADPS glycerol blocking method 

Hexokinase~G-6-PDH method 

Biuret method 

Bromocresol green method 

Albumin (Calculated value) 

T -Protein -Albumin 

Urease~GIDH method 

Creatininase-F-DAOS method 

Enzyme method 

OCPC method 

Fiske-Subbarow method 

Crown-Ether membrane 

electrode method 

Crown-Ether membrane 

electrode method 

Coulometric titration method 
8.8 Urinalyses , 

-_ ---iTnnaTysis was performed once (on day-28) during the dosing period (excluding the recovery 

groups) and once (on day 14) during the recovery period. Urine samples (accumulated for 

15-17 hr) collected in individual metabolic cages (150 WX200 Dx263 H mm) were determi*d 

with drinking water ad lib. The urine sediments was stained and examined in males and 

females of the vehicle control and 300 mg/kg groups at the end of the dosing period . 

Parameters 

1) Urine volume (m/L) 

2) Color 

3) Turbidity 

4) Urine osmotic pressure (Uosm) (m0sm/L) 

5) pH 

6) Protein 

7) Glucose 

8) Occult blood 

9) Urinary sediments 

4) 

5)-8) 

9) 

8.9 

OM-6040, ARKRAY 

Hema-Combistix, SIEMENS 

Biological microscope, BX41, OLYMPUS 

Method 

Volumetric method 

Macroscopy 

Macroscopy 

Freezing-point depression method 

Test paper 

Test paper 

Test paper 

Test paper 

Sternheimer modified 

Pathological Examinations 

1) Necropsy 

2) 

All animals were subjected to the detailed gross necropsy including body surface, % all 

orifices, subcutis, cranial, thoracic, abdominal and pelvic cavities, and the contents. 

Organ weights 

The weights of the following organs were measured in all animals . Prostate and seminal 

vesicles were weighed with urethra partly . Uterus was measured the weights including 

its content fluid . The relative organ weight was calculated based on the body weight at 

the time of necropsy. 

*=Left and right organs were measured totally . 

Liver (g), heart (g), kidneys* (g), testes* (g), epididymides* (g), prostate and seminal 

vesicles (g), ovaries* (mg), uterus (g), brain (g), spleen (g), thymus (mg) and adrenals* 

(mg) 
3) Histopathological examinations 

-(r) -The fo~owing organs and tissues were taken. Trachea, lungs and urinary bladder 

were filled with 10% neutralized buffered formalin before taken. Stomach and 

intestines were filled and fixed with 10% neutralized buffered formalin and were 

washed with water. All organs/tissues were preserved in 10% neutralized buffered 

formalin. However, testes and epididymides were fixed in Bouin's solution. 

Category 

Respiratory system 

Digestive system 

Cardiovascular system 

%Urinary system 

Reproductive system 

Nervous system 

Hematopoietic and lymphatic 

systems 

Endocrine system 

Special sense organ 

Muscle and skeletal system 

Skin and adnexa 

(2) 

Organ " j tissue 

Trachea 

Lungs 

Organs and Tissues 

Trachea, lungs 

Stomach, intestine (duodenum to rectum with Peyer's 

patches), liver 

Heart 

Kidneys, urinary bladder 

Testes, epididymides, prostate (ventral and 

dorsolateral lobes), seminal vesicles (with coagulation 

gland), ovaries, uterus (with cervical region), vagina 

Brain (cerebrum, cerebellum and pons), spinal cord, 

sciatic nerve 

Bone marrow (femur), axillar and mesenteric lymph 

nodes, spleen, thymus 

Pituitary gland, thyroid (with parathyroids), adrenals 

Eye balls 

Skeletal muscle (femoral region), bone (femur) 

Mammary gland 

Light microscopic examinations were performed for the organs and tissues of the 

following groups after embedding in paraffin, sectioning and hematoxylin and eosin 

(BE) staining . Decalcification was done for the bone marrow (femur) with 10% 

formic acid formalin before cutting. In the table, "a/?" show groups which were. 

examined and "-" shows examinations were not done. . 

Vehicle 

control 

group 

Vehicle 

control 

recovery 

group 

10 30 100 300 

mg/kg mg/kg mg/kg mg/kg 

group group group group 

a~ - = - - a~ 

a~ - - - - _ a~ 

300 

mg/kg 

recovery 

group 

-16- 
Forestomach a` ~ - - - - a ~ 

Glandular stomach - a' ~ f- - - - - a ~ 

Duodenum-ileum a' ~ - - - - 

Cecum- rectum a' ~ - - - _ 

Liver*1 a~ a~ a~ a~ a~ a~ ~ a~ 

Heart a` ~ - - - - a ~ -

Kidneys a ~ - - - - a ~ - 

Urinary bladder a~ - - - - a~ -

Testes a - - - - a ~ -

Epididymides a - - - - a - 

Prostate (ventral and 

dorsolateral) a - - - a -

Seminal vesicle a' - - - - a -

Ovaries ~ - - _ _ ~ -

Uterus (horn and cervix) ~ - _ - - 

Vagina ~ - - _ -

Cerebrum, cerebellum, 

Pons a ~ - - - - a ~ -

Spinal cord a' ~ - - - - a ~ -

Sciatic nerve 

Bone marrow* 1 a~ a~ a~ a~ a~ ay 69 

Axillar lymph nodes a`~ - - - - a9 -

Mesenteric lymph nodes 69 - 

Spleen* 1 a~ a~ a~ a~ ay ay ~ 69 

Thymus a~ - - - - 69 - 

Pituitary gland 

Thyroid 69 

Parathyroid 69 

Adrenals 69 

Eye ball 

69 

69 

a ~ 

Skeletal muscle a`~ - - - - a~ -

Bone a`~ - - - - 

Mammary gland a~ - - - - a~ 

* 1 Since changes suspected to be effects of the test substance were observed in males and females of the 300 mg/kg 

group, histopathological examinations for both sexes of all groups including the recovery groups were done. 
(3) Gross lesions in the kidney (animal No. 6 and 7) in the vehicle control recovery group 

--- -were examined histopathologically . 

(4) Brown pigments were observed in HE stained spleen in males and females in the 300 

mg/kg group and was suggestive of hemosiderin deposition. Berlin blue stain was 

performed in one male (No. 1) in the vehicle control group and one male (No. 28) in 

the 300 mg/kg group. Berlin blue positive substance was increased in the 300 mg/kg 

group compared to the vehicle control group, and brown pigments were confirmed to 

be hemogiderin. 

Brown pigments or greenish brown pigments were observed in HE stained liver in 

females in the 300 mg/kg group and suggested hemosiderin or biliary pigments. 

Berlin blue stain and Hall process were performed in one female (No. 38) in the 

vehicle control group and one female (No. 62) in the 300 mg/kg group. Althouhg 

Berlin blue positive substance was observed in the Kupffer cells, positive substance 

was not noted in Hall process . Brown pigments or greenish brown pigments were 

confirmed to be hemogiderin . 

9. STATISTICAL ANALYSIS " 

Data regarding body weights (excluding those at the time of necropsy), food intakes, 

hematological examinations, blood chemical examinations, urine volume, urine osmotic 

pressure, organ weights and FOB metrical data (grip strength and locomotor activity count) 

were analyzed using the Bartlett's test for homogeneity of variance. If the variances were 

homogeneous at a significance level of 5%, one way analysis of variance was performed. If 

~there was a significant difference in this analysis, the difference between the vehicle control 

group and each of the treatment groups was analyzed by the Dunnett's test. If the variances 

were not homogeneous, the Kruskal-Wallis's test was used. If there was a significant 

difference in this analysis, the difference between the vehicle control group and each of the 

~reatment groups was analyzed by the nonparametric Dunnett's test. 

FOB numerical data (defecation and urination) was analyzed using the Kruskal-Wallis's test. 

ENVIRONMENTAL FACTORS THAT NIIGHT HAVE AFFECTED THE RELIABILITY OF 

I THE STUDY RESULTS 

There 'were no factors which might have affected the reliability of the test data or deviation from 

the protocol. 
RESULTS 

1. CLINICAL SIGNS (Table 1, Addendum 1) i 

1.1 During Dosing Period 

In males, post-dose salivation was observed sporadically or continuously in three animals 'in 

the 100 mg/kg group on day 21 and later, and nine animals in the 300 mg /kg group after day 5. 

No abnormalities were observed in the vehicle control, 10 or 30 mg/kg groups . 

In females, post-dose salivation was observed sporadically or continuously in two animals lin 

the 100 mg/kg group on day 17 and later and all animals in the 300 mg/kg group .on day 5 and 

later . Salivation was also observed immediately before dosing in one animal in the 300 

mg/kg group on days 14, 15, 16, 20 and 21 . In addition, staining lower abdomen was 

observed in three animals on day 27 and in one animal on day 28.. Vehicle control, 10 and 30 

mg/kg showed no abnormalities . ' 

1.2 During Recovery Period 

All signs disappeared during the recovery period. No abnormal changes were observed in the 

vehicle control recovery group. 

2. DETAILED CLINICAL OBSERVATIONS (Table 2, Addendum 2) 

2.1 During Dosing Period 

No abnormalities were noted in males or females of any treatment groups . 

2.2 During Recovery Period , 

No abnormalities were noted in either sex of the vehicle control and 300 mg/kg recovery 

groups. 

3. SENSORIMOTOR FUNCTION (Tables 3,4 and 5, Addenda 3,4 and 5) 

3.1 During Dosing Periodi 

In males, grip strength of the hind limbs was increased without dose relationship in the 100 

mg/kg group. Sensorimotor function had no abnormal signs in the vehicle control, 10, 30 or 

300 mg/kg groups. 

No abnormal changes were noted in females in any treatment groups including the vehicle 

control group. 
3.2 During Recovery Period = 

Males and--females were not examined-since no abnormalities attributable to the test substance 

were noted during the dosing period . 

4. BODY WEIGHTS (Fig.l, Table 6, Addendum 6) 

4.1 During Dosing Period 

No statistically significant changes of body weight were noted in any treated males or females. 

4.2 During Recovery Period 

No statistically significant changes of body weights were noted in males or females in the 

recovery group. 

5. FOOD INTAKES (Fig.2, Table 7, Addendum 7) 

5.1 During Dosing Period 

In males, no significant changes were noted in any groups. 

In females, a significant increase was observed in the 300 mg/kg group on day 28, and 

significant changes were not noted in the 10, 30 or 100 mg/kg groups. 

5.2 During Recovery Period 

No, significant changes were noted in males or females . 

6. HEMATOLOGICAL EXAD'IINATIONS (Table 8, Addendum 8) 

6.1 At Termination of Dosing Period 

In males, RBC, Hb and Ht were decreased in the 300 mg/kg group. MCV and reticulocytes 

were increased in the same group. Neutrohpiles were increased in the 100 mg/kg group 

without dose relationship . In addition, a dose-related increase in WBC and a decrease in 

}ymphocytes with unclear dose relationship were observed in the 100 mg/kg and higher group. 

No statistically significant changes of hematological parameters were noted in the 10 or 30 

mg/kg groups. 

In females, decreases in Hb and Ht, and an increase in reticulocytes were observed in the 100 

mg/kg and higher group. RBC was decreased in the 300 mg/kg group. No abnormalities 

~vere noted in the 10 or 30 mg/kg groups . 

I 

6.2 *t Termination of Recovery Period 

In males, All of RBC, Hb, Ht, MCV, reticulocytes, WBC and lymphocytes showed recovery. 

Although no abnormalities were noted at the end of the dosing period, increases of platelet and 

-20- 
_ p.29 

- 

basophils were newly noted in the 300 mg/kg recovery group. 

In females, RBC was decreased in the 300 mg/kg recovery group; however, the severity wjas 

decreased compared to those at the dosing period. The changes of Hb, Ht and reticulocyle~ s 

disappeared during the recovery period . Increases of MCV and MCH and a decrease 'in 

neutrophils were newly observed in the 300 mg/kg recovery group, although no abnormal 

signs were noted in these parameters at the end of the dosing period. 

7. BLOOD CHENIICAL EXAMINATIONS (Table 9, Addendum 9) 

7.1 At Termination of Dosing Period 

AST, ALT, ALP and IP were increased in males of the 300 mg/kg group. No statistically 

significant changes were noted in males of the 10, 30 or 100 mg/kg groups . 

In females, albumin was increased in the 100 mg/kg and higher group and the values in the 100 

mg/kg and 300 mg/kg showed the same levels. Total cholesterol was increased in the 300 

mg/kg group. No significant changes were noted in females in the 10 or 30 mg/kg groups . 

7.2 At Termination of Recovery Period 

In males, AST, ALT, ALP and IP did not show abnormal changes. Although no 

abnormalities were noted at the end of the dosing period, an increase in total protein and a 

decrease in A/G ratio were newly observed in males of the 300 mg/kg recovery group. 

No abnormal albumin or cholesterol levels were noted in females. ALP and A/G ratio were 

newly decreased in females in the 300 mg/kg recovery group. 

8. URINALYSES (Table 10, Addendum 10) 

8.1 At Termination of Dosing Period 

No abnormalities were noted in males or females in any treatment groups. 

8.2 At Termination of Recovery Period 

No abnormalities were noted in the 300 mg/kg recovery group. 

9. ORGAN WEIGHTS (Tables 11 and 12, Addenda 11 and 12) 

9.1 At Termination of Dosing Period 

In males, absolute and relative spleen weights were increased dose-dependently in the 100 

mg/kg and higher dose gro,up . Relative weights of liver and kidneys were increased in the 

300 mg/kg group. No statistically significant changes were noted in males in the 10 or 30 

mg/kg groups. 

-21- 
In females, an increase in relative liver weight, increases in `absolute and relative spleen 

i -f ghts -iHU idecrease in relative adrenal weight were noted in the 300 mg/kg group. Organ 

weights in the 10, 30 and 100 mg/kg group showed no abnormalities. 

9.2 At Termination of Recovery Period 

In males, although relative spleen weight was increased in the 300 mg/kg recovery group, the 

severity was decreased and absolute weight of the spleen did not have changes . There were 

no abnormal signs in the weights of the liver or kidneys . 

The changes of the liver, spleen and adrenal weights disappeared in females in the 300 mg/kg 

recovery group. 

10. NECROPSY (Table 13, Addendum 13) 

10.1 At Termination of Dosing Period 

In males, blackish change in four animals and enlargement in two animals were observed in 

the spleen in the 300 mg/kg group. No abnormal changes were noted in the 10, 30 or 100 

mg/kg groups. 

In females, blackish change of the spleen was observed in one animal in the 100 mg/kg group 

and four animals in the 300 mg/kg group. Vehicle control, 10 and 30 mg/kg groups have no 

abnormal changes . 

10.2 At Termination of Recovery Period 

Spleen lesions as shown at the end of the dosing period were not observed in any males or 

females at the end of the recovery period. Deformity and recessed region were observed in 

the kidneys in one male in the vehicle control recovery group although females did not show 

any abnormal signs. 

I 

11. HISTOPATHOLOGICAL EXAMINATIONS (Table 14, Addendum 13) 

11.1 At Termination of Dosing Period 

In males, increased extramedullary hematopoiesis was noted in the spleen in one animal in the 

100 mg/kg group. Increased extramedullary hematopoiesis in the liver in one animal, 

lincreased hematopoiesis in the bone marrow in three animals, and congestion in four animals, 

! 1hemosiderin deposition and increased extramedullary hematopoiesis in all animals in the 

spleen were observed in the 300 mg/kg group. In addition, microgranuloma in the liver and 

idilatation of the ventricle in the cerebrum in one animal each were noted in the vehicle control 

group. Focal necrosis of the hepatocytes was noted in one animal in the 300 mg/kg group. 
In females, hemosiderin deposition in all animals and increased extramedullary hematopoiesis 

--in one animal were observe3'm the spleen in the 100 mg/kg group. Hemosiderin depositipn 

in the Kupffer cells and increased extramedullary hematopoiesis in the liver in one anim~l, 

increased hematopoiesis in the bone marrow in two animals, congestion in the spleen in 40 

animals and hemosiderin deposition and increased extramedullary hematopoiesis in the spleen 

in all animals were noted in the 300 mg/kg group. In addition, microgranuloma was observed 

in the liver in one animal in the vehicle control group. 

11.2 At Termination of Recovery Period 

Although hemosiderin deposition was observed in the spleen in males and females in the 300 

mg/kg recovery group, liver and bone marrow lesions disappeared. In males in the vehicle 

control recovery group solitary cyst in cortex in the kidney was noted in one animal. No 

abnormal changes were noted in the females in the vehicle control recovery group. 

DISCUSSION 

Treatment-related effects were mainly observed in the blood, especially the erythrocytes. Anemic 

findings such as decreases in the RBC, Hb and Ht were namely observed. Increased hemosiderin 

deposition in the spleen and liver and increases in AST and ALT were considered to be changes 

suggestive of erythrocyte destruction. Increased hematopoiesis in the liver, bone marrow and spleen 

and increases in the reticulocyte rate and MCV were considered to be compensational changes for the 

anemia . Increased spleen weight was considered to be due to splenic congestion with hemolysis and 

increased extra.medullary hematopoiesis, and increased WBC was considered to be a secondary 

change due to hematopoiesis. It was not clear whether the decreased lymphocytes observed in males 

in the 100 mg/kg and higher dose group was related to the anemia. 

These changes were observed in the 100 mg/kg and higher group, and animals in the 30 mg/kg group 

did not showed abnormalities . 

With N-ethylaniline, which has an aniline moiety in its structure like the test substance, increased 

methemoglobin levels and hemolytic anemia with Heinz bodies in the erythrocytes were observed 

and it was accompanied by hemosiderin deposition in the spleen due to the anemia (Ito, Japan 

Existing Chemical Data Base). Thus, it was considered that the changes due to the test article were 

similar to hemolytic anemia commonly induced by aniline (SIDS, 1993). . 

These changes recovered or tended to recover after the 14-day recovery period and were thus 

reversible. However, in females in the 300 mg/kg recovery group, MCV was newly increased, but 

the change was not observed at the completion of the dosing period. 

-23- 
As other changes, salivation was observed in males and females in the 100 mg/kg and higher dose 

group, buf it was mostly observed immediately after dosing and was different from the continuous 

salivation caused by neurotoxicity. In addition, no animals showed any abnormalities on detailed 

clinical observation or sensorimotor function, and there were no changes suggestive of irritation due 

to the test substance such as thickening of the forestomach mucosa. Therefore, this change was 

considered to be due to the taste of the test article (Matsuo, 2000) and to be of no toxicological 

significance . Salivation was also observed immediately before dosing in one female in the 300 

mg/kg group, and it was considered that a conditioned reflex was established by repeated dosing. 

Staining of the lower abdomen was observed in females in the 300 mg/kg group on days 27 and 28 of 

dosing and deterioration in the condition of these animals was suggested. However, no 

abnormalities were noted in any animals on detailed clinical observation and sensorimotor function, 

and the cause was not clear. In this group, food consumption increased on day 28, but the change 

was not accompanied by any effects on body weight, and was considered to be of no toxicological 

importance . 

On blood chemistry, ALP was increased in males in the 300 mg/kg group, but no clear changes such 

as increased bilirubin were noted. Therefore, it was suggested that bilirubin metabolism in the 

hepatocytes was enhanced (Tanimoto, 1988). Albumin was also increased in females in the 100 

mg/kg and higher dose group, and the relative weight of the liver increased in males and females in 

the 300 mg/kg group. These changes were considered to support hypermetabolism in the liver . 

Total cholesterol was increased in females in the 300 mg/kg group, and a relation with the liver was 

suspected, but the cause could not be specified . Inorganic phosphorus and relative kidney weight 

increased in males in the 300 mg/kg group, and relative adrenal weight decreased in females in the 

300 mg/kg group. These findings were not accompanied by any histopathological changes and were 

considered to be of no toxicological importance. 

These Ichanges disappeared during the recovery period or at the recovery period. 

Based on these results, the No-Observed-Adverse-Effect Level (NOAEL) of 1W under the 

conditions tested was considered to be 30 mg/kg/day because of increased extramedullary 

hematQpoiesis in the spleen in males and females, increases in absolute and relative spleen weights in 

males,j decreases in Hb and Ht, increases in reticulocytes and albumin, and blackish change and 

hemos,iderin deposition in the spleen in the 100 mg/kg and higher group. 

The Nb-Observed-Effect Level (NOEL) was considered to be 30 mg/kg/day because of salivation in 

males and females of the 100 mg/kg and higher group. 
REFERENCES 

Ito Y. Twenty-eight-day Repeated Dose Oral Toxicity Test of N-Ethylaniline in Rats . Japan Existif ng 

Chemical Data Base (in Japanese). 

Tanimoto Y. (1988) Laboratory Animal Series 5, Biochemistry of Blood and Urine in Experimental 

Animals. 92, Soft Science Inc., Tokyo, Japan (in Japanese). 

Matsuo R (2000) Role of saliva in the maintenance of taste sensitivity . Crit. Rev. Oral Biol. Njed. 

11(2): 216-229. 

(SIDS) Screening Information Data Set for High Volume Chemicals (1993) Aniline, SIAM. 10, 

October, Germany. 
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Table 1 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of clinical signs -- 

Sex Signs Administration period Recovery period 

mg/kg/day VC 

VC 10 30 100 300 300 VC 300 

ta ta ta ta ta ta ta ta ta 

5') 5 5 5 5 5 5 5 5 

No abnormalities detected 5 5 5 5 2 1 5 5 

Salivation 

(just after dosing) 3 4 5 

Female ta ta ta ta ta ta ta ta ta 

5° 5 5 5 5 " 5 5 5 5 

No abnormalities detected 5 5 5 5 3 5 5 

Salivation 

(just after dosing) 2 5 5 

(just before dosing to just after dosing) 1 

Staining,lower abdomen 

a) Number of animals examined. 

VC, Vehicle control; (R), Recovery. 

ta, terminal autopsy . 
Table 2 Twepty-eight-day repeated-dose oral toxicity study in rats 

--- Summary-of-detailed clinical observations (scoring scale for detailed clinical observations) 

REMOVAL FROM CAGE 

Ease of removal 

-2 No reaction 

-1 Very easy 

0 Easy (slight resistance) 

+1 Difficult 

+2 Very difficult 

Vocalization 

0 . None 

+1 Vocalization during handling 

+2 Continuous vocalization 

HANDLING OBSERVATIONS 

Muscle tone ' 

-1 Decreased 

0 Normal 

, +1 Increased 

Subnormal temperature 

Absent 

Present 

Piloerection 

Staining hair 

Unkempt hair 

Paleness 

Reddening 

Cyanosis . 

Lacrimation 

- Absent 

+ Present 

Absent 

Present 

Absent 

+ Present 

- Absent 

+ . Present 

- Absent 

+ Present 

- Absent 

+ Present 

- Absent 

+ :Present 
Table 2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed-clinical observations (scoring-scale for detailed clinical observations) 

HANDLING OBSERVATIONS-continued 

Exophthaimos 

Pupillary size 

Salivation 

Secretion 

- Absent 

+ Present 

-1 Miosis 

0 Normal 

+1 Mydriasis 

- Absent 

+ Present 

- Absent 

+ Present 

OBSERVATIONS 1N ARENA 

Posture 

0 Normal 

+1 Crouching position or hunchback position 

+2 Prone position or lateral position 

Motor activity 

-2 Significantly decreased 

-1 Decreased 

0 Normal 

+1 Increased 

+2 Significantly increased 

Respiration 

0 Normal 

+1 Slightly insufficiency 

' +2 Moderately insufficiency 

+3 Severely insufficiency 

Lid closure 

- Absent 

+ Present 

Gait 

- Normal 

S Staggering gait 

T Tip toe gait 

P Shuffling (paralytic) gait 

GD Gait disturbance 
Table 2 Twenty-eight-day repeated-dose oral toxicity study in rats 

-. S>?mmApLof d Ai ed clinical observations (scoring scale for detailed clinical observations) 

OBSERVATIONS IN ARENA-continued 

Tremor/twitch/convulsion 

0 

+1 

+2 

+3 

Stereotypic behavior 

C 

G 

S 

H 

Abnormal behavior 

S 

B 

C 

R 

W 

V 

ST 

T 

None 

Tremor 

Twitch or convulsion 

Systematic tonic convulsion (opisthotonus or episthotonus etc.) 

None 

Circling 

Grooming 

Sniffing 

Head bobbing 

None 

Self-biting 

Backing 

Circling 

Rolling 

Writhing 

Vocalization 

Straub tail 

Tail ~lashing behavior 
Table 2-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations - _ 

Removal from cage 

Sex Period Exp. group Number of Ease of removal Vocalization 

(mg/kg/day) animals -2 -1 0 +1 +2 0 +1 +2 

Vehicle control 10 0 0 10 0 0 9 1 0 

10 5 0 0 5 0 0 5 0 0 

Predosing 30 5 0 0 5 0 0 5 0 0 

100 5 0 0 5 0 0 5 0 0 

300 10 0 0 10 0 0 9 1 0 

Vehicle control , 10 0 0 10 0 0 9 1 0 

10 5 0 0 5 0 0 4 1 0 

week 1 30 5 0 0 5 0 0 3 2 0 

100 5 0 ~ 0 5 0 0 5 0 0 

300 10 0 0 10 0 0 10 0 0 

Vehicle control ' 10 0 0 10 0 0 8 ' 2 0 

10 5 0 0 5 0 0 4 1 0 

week 2 30 5 0 0 5 0 0 3 2 0 

100 5 0 0 5 0 0 5 0 0 

Male 300 10 0 0 10 0 0 10 0 0 

Vehicle control 10 0 0 10 0 0 10 0 0 

10 5 0 0 5 0 0 4 1 - 0 

week 3 30 5 0 0 5 0 0 4 1 0 

100 5 0 0 5 0 0 5 0 0 

300 10 . 0 0 10 0 0 9 1 0 

Vehicle control 10 0 0 10 0 0 6 4 0 

10 5 0 0 5 0 0 4 l 0 

week 4 30 5 0 0 5 0 0 5 0 0 

100 5 0 0 5 0 0 5 0 0 

300 10 0 0 10 0 0 8 2 0 

Recovery Vehicle control 5 0 0 5 0 0 3 2 0 

week 1 300 5 0 0 5 0 0 5 0 0 

Recovery Vehicle control 5 0 0 5 0 0 4 1 0 

" 2 300- 5 0 0 5 0 0 5 0 0 
Table 2-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

S-u_rwnKy-af detailed clinical observations 

Removal from cage 

Sex Period Exp. group Number of Ease of removal 

- 

Vocalftn 

(mg/kg(day) animals -2 -1 0 +1 +2 0 +1 ~ +2 

Vehicle control 10 0 0 10 0 0 10 0 ' 0 

10 5 0 0 5 0 0 5 0 0 

Predosing 30 5 0 0 5 0 0 5 0 0 

100 5 0 0 5 0 0 4 1 0 

300 10 0 0 10 0 0 10 0 0 

Vehicle control 10 0 0 10 0 0 9 1 j 0 

10 5 0 0 5 0 0 3 2 0 

week 1 30 5 0 0 5 0 0 5 0 0 

100 5 0 0 5 0 0 4 1 0 

300 10 0 0 10 0 0 8 2 0 

Vehicle control 10 0 0 10 0 0 8 2 0 

10 5 0 0 5 0 0 4 1 , 0 

week 2 30 5 0 0 5 0 0 5 0 ' 0 

100 5 0 0 5 0 0 4 1 0 

Female 300 10 0 0 10 0 0 10 0 0 

Vehicle control 10 0 0 10 0 0 8 2 0 

10 5 0 0 5 0 0 5 0 0' 

week 3 30 5 0 0 5 0 0 5 0 0 

100 5 0 0 5 0 0 5 0 0 

300 10 0 0 10 0 0 10 0 0 

Vehicle control 10 0 0 10 0 0 8 2 0 

10 5 0 0 5 0 0 5 0 0 

week 4 30 5 0 0 5 0 0 4 1 0 

100 5 0 0 5 0 0 5 0 , 0 

300 10 0 0 10 0 0 10 0 0 

Recovery Vehicle control 5 0 0 5 0 0 5 0 0 

week 1 300 5 0 0 5 0 0 4 1 0 

Recovery Vehicle control 5 0 0 5 0 0 5 0 0 

week 2 300 5 0 0 5 0 0 5 . 0 0 
p. 44 

dMINOWA 

Table 2-3 Twenty-eight-day repeated-dose oral toxicity study in rats 

Sunnmary of detaile"irlical observations - 

Handling observations 

Sex Period Exp. group Number of Muscle tone Subnormal temperature Piloerection 

(mg/kg(day) animals -1 0 +1 - + - + 

Vehicle control 10 0 10 0 10 0 ' 10 0 

10 5 0 5 0 5 0 5 0 

Predosing . 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 1 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 2 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

Male 300 10 0 10 0 10 0 10 0 

Vehicle control . 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 3 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

-week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

week 1 300 5 0 5 0 5 0 5 0- 

Recovery Vehicle control 5 0 5 0 5 . 0 5 0 

1w'eek 2 300 5 0 5 0 5 0 5 0 
p. 45 

Table 2-4 Twenty-eight-day repeated-dose oral toxicity study in rats 

S.ummarl-of detailed clinical observations 

Handling observations 

Sex Period Exp. group Number of Muscle tone Subnormal temperature Piloereoon 

(mg/kg/day) animals -1 0 +1 - + - ~ + 

Vehicle control 10 0 10 0 10 0 10 ' 0 

10 5 0 5 0 5 0 5 0 

Predosing 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 ' 

Vehicle control 10 0 10 0 10 0 10 I 0 

10 5 0 5 0 5 0 5 0 

week 1 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

l 300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 2 30 5 0 5 0 5 0 5 ' 0 

100 5 0 5 0 . 5 0 5 0 

Female 300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 3 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 , 0 

300 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

week 1 300 5 0 5 0 5 0 5 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

~'~ 2 ~ 300 5 0 5 0 5 0 5 0 
Table 2-5 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailedr.linical observations -- - 

Handling observations 

Sex Period Exp. group Number of Staining hair Unkempt hair Paleness Reddening 

(mg/kglday) animals - + - + - + - + 

Vehicle control 10 10 0 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 5 0 

Predosing 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 5 0 

week 1 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 10 0 

, Vehicle control 10 10 0 10 0 10 0 10 0 

10 . 5 5 0 5 0 5 0 5 0 

week 2 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

Male 300 10 10 0 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 5 0 

week 3 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 5 0 

week 4 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 5 0 5 0 5 0 5 0 

week 1 300 5 5 0 5 0 5 0 5 0 

Recovery Vehicle control 5 5 0 5 0 5 0 5 0 

Iweek 2 300 5 5 0 5 0 5 0 5 0 
* 

Table 2-6 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summarysof-detailed clinical observations _ 

Handl ing observations 

p. 47 

Sex Period Exp. group Number of Staining hair Unkempt hair Paleness Rodening 

(mg/kg/day) animals - + - + - + - ~ + 

Vehicle control 10 10 0 10 0 10 0 10' 0 

10 5 5 0 5 0 5 0 5 0 

Predosing 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 1q 0 

10 5 5 0 5 0 5 0 5 0 

week 1 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5: 0 

300 10 10 0 10 0 10 0 10 0 

. Vehicle control 10 10 0 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 5~ 0 

week 2 30 5 5 0 5 0 5 0 5' 0 

100 5 5 0 5 0 5 0 5 0 

Female 300 10 10 0 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 

10 5 5 1 0 5 0 

week 3 30 5 5 0 5 0 

100 5 5 0 5 0 

300 10 10 0 10 0 

10 0 10 0 

5 0 5 0 

5 0 5 0 

5 0 5 0 

10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 10 0 

- 10 5 5 0 5 0 5 0 5 0 

week 4 30 5 5 0 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 5, 0 

300 10 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 5 0 5 0 5 0 5 0 

week 1 300 5 5 0 5 0 5 0 5 0 

Recovery Vehicle control . 5 5 0 5 0 5 0 5 0 

week 2 300 5 5 0 5 0 5 0 5 0 
Table 2-7 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summery ofddailed_clinical observations - - 

Handling observations 

Sex Period Exp. group Number of Cyanosis Lacrimation Exophthalmos 

(mg/kg/day) animals - + - + - + 

Vehicle control 10 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 

Predosing 30 5 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 

week 1 30 5 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 

week 2 30 5 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 

Male 300 10 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 

week 3 30 5 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 

Vehicle control 10 10 0 10 0 10 0 

10 5 5 0 5 0 5 0 

week 4 30 ' 5 5 0 5 0 5 0 

100 5 5 0 5 0 5 0 

300 10 10 0 10 0 10 0 

Recovery Vehicle control 5 5 0 5 0 5 0 

week 1 300 5 5 0 5 0 5 , 0 

Recovery Vehicle control 5 5 0 5 0 5 0 

~week 2 300 5 5 0 5 0 5 0 

Table 2-9 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary afdeYailed-clinical observations - - -- 

Handling observations 

Sex Period Exp. group Number of Pupillary size Salivation Secretion 

(mg/kg/day) animals -1 0 +l - + - + 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

Predosing 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10. 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 1 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 2 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

Male 300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 3 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

week 1 300 5 0 5 0 5 0 5 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

1week 2 300 5 0 5 0 5 0 5 0 
Table 2-10 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ Su_mm_ ar of detailed clinical obsery4tions 

Handling observations 

Sex Period Exp. group Number of Pupillary size Salivation Secretion 

(mg/kg/day) animals -1 0 +1 - + - + 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

Predosing 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 j 

10 5 0 5 0 5 0 5 0 

week 1 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 2 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

Female 300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 l0 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 3 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 , 

300 10 0 10 0 10 0 10 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

week 1 300 5 0 5 0 5 0 5 0 

Recovery Vehicle control 5 0 5 0 5 0 5 0 

week 2 300 5 0 . 5 0 5 0 5 0 
Table 2-11 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of dcUdedc_linical observat ions _ 

Observations in arena 

Sex Period Exp. group Number of Posture - Motor activity 

(mg/Wday) animals 0 +1 +2 -2 -1 0 +1 +2 

Vehicle control 10 10 0 0 0 0 10 0 0 

10 5 5 0 0 0 0 5 0 0 

Predosing 30 5 5 0 0 0 0 5 0 0 

100 5 5 0 0 0 0 5 0 0 

300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 0 9 1 0 

10 5 5 0 0 0 0 4 1 0 

week 1 30 5 5 0 0 0 0 4 1 0 

100 5 5 0 0 0 0 5 0 0 . 

300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 0 10 0 0 

10 5 5 0 0 0 0 5 0 0 

week 2 30 5 5 0 0 0 . 0 5 0 0 

100 5 5 0 0 0 1 4 0 0 

Male 300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 1 8 1 0 

10 5 5 0 0 " 0 0 5 0 0 

week 3 30 5 5 0 0 0 1 ,4 0 0 

100 5 5 0 0 0 0 4 1 0 

300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 0 9 1 0 

10 5 5 0 0 0 0 5 Q 0 

week 4 30 5 5 0 0 0 0 4 1 0 

100 5 5 0 0 0 0 5 0 0 

300 10 10 0 0 0 0 10 0 0 

Recovery Vehicle control 5 5 0 0 0 0 4 1 0 

week 1 300 5 5 0 0 0 0 5 0 0 

Recovery Vehicle control 5 5 0 0 0 0 4 1 0 

Feek 2 300 5 5 0 0 0 0 4 1 0 
Table 2-12 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Posture Motor activity 

(mg/kg/day) animals 0 +1 +2 -2 -1 0 +1 ~2 

Vehicle control 10 10 0 0 0 0 10 0 0 

10 5 5 0 0 0 0 5 0 0 

Predosing 30 5 5 0 0 0 0 5 0 0 

100 . 5 5 0 0 0 0 5 0 0 

300 10 10 0 0 0 0 9 1 0 

Vehicle control 10 10 0 0 0 0 9 1 ~ 0 

10 5 5 0 0 0 0 5 0 0 

week 1 30 5 5 0 0 0 0 5 0 0 

100 5 5 0 0 0 0 5 0 0 

300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 0 10 0 0 

10 5 5 0 0 0 0 5 0 0 

week 2 30 5 5 0 0 0 0 5 0 ' 0 

100 5 5 0 0 0 0 4 1 0 

Female 300 10 10 0 0 0 0 10 0 0 

Vehicle control 10 10 0 0 0 0 9 1 0 

10 5 5 0 0 0 0 4 1 0 

week 3 30 5 5 0 0 0 0 5 0 0 

100 5 5 0 0 0 0 5 0 0 

300 10 10 0 0 0 0 7 3 0 

Vehicle control 10 10 0 0 0 0 9 1 0 

10 5 5 0 0 0 0 4 1 0 

week 4 30 5 5 0 0 0 0 5 0 0 

100 5 5 0 0 0 0 4 1 , 0 

300 . 10 10 0 0 0 0 9 1 0 

Recovery Vehicle control 5 5 0 0 0 0 4 1 0 

week 1 300 5 5 0 0 0 0 4 1 0 

Recovery Vehicle control 5 5 0 0 0 0 3 2 0 

week 2 300 5 5 ' 0 0 0 0 5 0 0 
Table 2-13 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Respiration Lid closure 

(mg/kg/day) animals 0 +1 +2 +3 - + 

Vehicle control , 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

Predosing . 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 1 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 2 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

Male - 300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 3 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 4 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Recovery Vehicle control 5 5 0 0 0 5 0 

week 1 300 5 5 0 0 0 5 0 

Recovery Vehicle control . 5 5 0 0 0 5 0 

~'I eek 2 -- 300 5 5 0 0 0 5 0 
Table 2-14 Twenty-eight-day repeated-dose oral toxicity study in rats 

-Summaryof detailed clinical observations 

Observations in arena 

'Sex Period Exp. group Number of Respiration Lid closure 

(mg/kg/day) animals 0 +1 +2 +3 - + 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

Predosing 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 1 30 5 5 0 0 0 5 0 

- 

100 5 5 0 0 0 5 0 

- 300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 2 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

Female 300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 3 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Vehicle control 10 10 0 0 0 10 0 

10 5 5 0 0 0 5 0 

week 4 30 5 5 0 0 0 5 0 

100 5 5 0 0 0 5 0 

300 10 10 0 0 0 10 0 

Recovery Vehicle control 5 5 0 0 0 5 0 

week 1 300 5 5 0 0 0 5 0 

Recovery Vehicle control 5 5 0 ~ 0 0 5 0 

week 2 300 5 5 0 0 0 5 0 
Table 2-15 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Gait 

(mg/kg/day) animals - S T P GD 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

Predosing 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 1 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

- 10 5 5 0 0 0 0 

week 2 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

Male 300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 3 30 5 5 0 0 0 0 

100 5 5 0 0 0 .0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

,week 4 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

week 1 300 5 5 0 0 0 0 

Recovery Vehicle control 5 5 _ 0 0 0 0 

1 week 2 300 5 5 0 0 0 0 
Table 2-16 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Gait 

(mg/kg/day) animals - S T P GD 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

Predosing 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 1 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

( . 300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 2 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

Female 300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 3 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 4 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

week 1 300 5 5 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

week 2 300 5 5 0 0 0 0 
Table 2-17 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Tremorhwitch/convulsion Defecation Urination 

(mg/kg/day) animals 0 +1 +2 +3 (count/min)°I (count/min)") 

Vehicle control 10 10 0 0 0 0.1 f0.32 1 .0 f1.41 

10 5 5 0 0 0 0.2 t0.45 0.8 f0.84 

Predosing 30 5 5 0 0 0 0.2 t0.45 0.6 f1.34 

100 5 5 0 0 0 0.2 f0.45 3.6 f2.70 

300 10 10 0 0 0 0.2 f0.63 2.4 f2.91 

Vehicle control 10 10 0 0 0 ` 0.0 t0.00 1 .6,+2.99 

10 5 5 0 0 0 0.2 t0.45 0.6 f0.55 

week 1 30 5 5 0 0 0 0.2 f0.45 1 .4 f2.07 

100 5 6 U 0 0 1 .4 f2.19 1 .6 f1.95 

300 10 10 0 0 0 0.1 f0.32 1 .8 f1.48 

Vehicle control 10 10 0 0 0 0.2 f0.42 0.6 t0.84 

10 5 5 0 0 0 0.2 f0.45 0.6 i-0 .55 

week 2 30 5 5 0 0 0 0.0 t0.00 0.4 f0.89 

100 5 5 0 0 0 0.8 t1.30 1 .8 t1.30 

Male 300 10 10 0 0 0 0.3 f0.67 0.8 f0.92 

Vehicle control 10 10 0 0 0 0.0 f0.00 0.3 f0.67 

10 _ 5 5 0 0 0 0.0 t0.00 0.4 f0.89 

week 3 30 5 5 0 0 0 0.0 t0.00 0.4 f0.89 

100 5 5 0 0 0 0.4 0.55 1 .6 f1 .14 

300 10 10 0 0 0 0.3 f0.95 0.4 f0.84 

Vehicle control 10 10 0 0 0 0.0 f0.00 0 .0 10.00 

10 5 5 0 0 0 0.2 f0.45 0 .2 f0.45 

week 4 30 5 5 0 0 0 0.0 t0.00 0 .4 t0.55 

100 5 5 0 0 0 0.0 t0.00 0.0 f0.00 

300 10 10 0 0 0 0.0 t0.00 0.0 i-0.00 

Recovery Vehicle control 5 5 0 0 0 0.0 f0.00 0.2 f0.45 

week 1 300 5 5 0 0 0 0 .0 f0.00 0.0 f0.00 

Recovery Vehicle control 5 5 0 0 0 0.0 f0.00 0.4 f0.89 

reek 2 300 5 5 0 0 0 0.0 f0.00 0.6 f1 .34 

a) Mean fS.D. 

* Significantly different from vehicle control at P<0.05. 

** Significantly different from vehicle control at P<0.01 . 
p. 59 

Table 2-18 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Tretnorhwitch/convulsion Defecation Urinition 

(mg/kglday) animals 0 + 1 +2 +3 (count/~n)'~ (coun t~min)') 

Vehicle control 10 10 0 0 0 0.1 f0.32 0.8 f1.40 

10 5 5 0 0 0 0 .0 f0.00 2.0 f4.47 

Predosing 30 " 5 5 0 0 0 0.4 f0.89 0.4 f0.55 

100 5 5 0 0 0 0.0 i-0.00 1 .0 f1.22 

300 10 10 0 0 0 0.2 t0.63 0.5 f0.85 

Vehicle control 10 10 0 0 0 0.0 f0.00 0.2 4.42 

10 5 5 0 0 0 0.0 i-0 .00 0.0 f0.00 

week 1 30 5 5 0 0 0 0.4 t0.89 0.0 f0.00 

100 5 5 0 0 0 0.0 i-0.00 0.2 i-0.45 

300 10 10 0 0 0 0.0 t0.00 0.6 f0.97 

Vehicle control 10 10 0 0 0 0.0 1-0.00 0.4 f1 .26 

10 5 5 0 0 0 0.0 f0.00 0.0 f0.00 

week 2 30 5 5 0 0 0 0.6 f1.34 0.0 f0.00 

100 5 5 0 0 0 0 .0 10.00 0.2 f0.45 

Female 300 10 10 0 0 0 0.0 t0.00 0.4 t0.52 

Vehicle control 10 10 0 0 0 0 .0 10.00 0.0 f0.00 

10 5 5 0 0 0 0.0 f0.00 0.0 f0.00 

week 3 30 5 5 0 0 0 0.2 f0.45 0.0 t0.00 

100 5 5 0 0 0 0.0 f0.00 0 .0 f0.00 

300 10 10 0 0 0 0.0 f0.00 0.0 f0.00 

Vehicle control 10 10 0 0 0 0.0 i-0 .00 0.0 f0.00 

10 5 5 0 0 0 0.0 f0.00 0.0 f0.00 

week 4 30 5 5 0 0 0 0.0 i-0.00 0.0 f0.00 

100 5 5 0 0 0 0.0 f0.00 0.0 f0.00 

300 10 10 0 0 0 0.0 f0.00 0.0 f0.00 

Recovery Vehicle control 5 5 0 0 0 0.0 f0.00 0.0 i-0 .00 

week 1 300 5 5 0 0 0 0.0 t0.00 0.2 f0.45 

Recovery Vehicle control 5 5 0 0 0 0.0 f0.00 0.0 +-0 .00 

week 2 300 5 5 0 0 0 0.0 f0.00 0.0 f0.00 

a) Mean fS.D. 

* Significantly different from vehicle control at P<0.05. 

** Significantly different from vehicle control at P<0.01 . 
Table 2-19 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Stereotypic behavior 

(mg/kg/day) animals - C 0 S H 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

Predosing 30 5 5 0. 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 1 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 2 . 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

Male 300 10 10 . 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 3 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 4 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

week 1 300 5 5 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

7,ek .2 - 300 5 5 0 0 0 0 
Table 2-20 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Period Exp.group 

Observations in arena 

Number of Stereotypic behavior 

(mglkgJday) animals - C G S H 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

Predosing 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 1 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 2 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

Female 300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 3 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Vehicle control 10 10 0 0 0 0 

10 5 5 0 0 0 0 

week 4 30 5 5 0 0 0 0 

100 5 5 0 0 0 0 

300 10 10 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 , 

week 1 300 5 5 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 

week 2. 300 5 5 0 0 0 0 
i 

Table 2-21 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Abnormal behavior 

(mg/kglday) animals - S B - C R W V ST T 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

Predosing 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 U 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 1 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 . 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 2 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 b 0 

Male 300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 3 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 4 30 5 5 0 0 0 0 0 0 0 0 

' 100 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 0 0 0 0 

week 1 300 5 5 0 0 0 0 0 . 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 0 0 0 0 

week 2 300 5 5 0 0 0 0 0 0 0 0 
p. 63 

Table 2-22 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of detailed clinical observations 

Observations in arena 

Sex Period Exp. group Number of Abnormal behavior 

(mFJkg/day) animals - S B C R W V STI T 

Vehicle control 10 10 0 0 0 0 0 0 0 ' 0 

10 5 5 0 0 0 0 ~0 0 0 0 

Predosing 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0, 0 

Vehicle control 10 10 0 0 0 0 0 0 01 0 

10 5 5 0 0 0 0 0 0 0 0 

week 1 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 2 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

Female 300 10 10 0 0 0 0 0 0 0 0 

. Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 3 30 5 5 0 0 0 0 0 0 0 0 

100 ' 5 5 0 0 0 0 0 0 0 0 

300 10 10 0 0 0 0 0 0 0 0 

Vehicle control 10 10 0 0 0 0 0 0 0 0 

10 5 5 0 0 0 0 0 0 0 0 

week 4 30 5 5 0 0 0 0 0 0 0 0 

100 5 5 0 0 0 0 0 0 0 0 

1 

300 10 10 0 0 0 0 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 0 0 0 0 

week 1 300 5 5 0 0 0 0 0 0 0 0 

Recovery Vehicle control 5 5 0 0 0 0 0 0 0 . 0 

week 2 300 5 5 0 0 0 0 0 0 0 0 
Table 3 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of reflex (scoring scale for reflex) 

SENSORIMOTOR FUNCTION 

Approach contactltouch response 

-1 No reaction 

0 Normal 

+1 Hyper reaction 

Pinna response 

-1 No reaction 

0 Normal 

+1 Hyper reaction 

Pain response (tail pinch) 

-1 No reaction 

0 Normal 

, +1 Hyper reaction 

Pupillary reflex 

+ Normal 

- Abnormal reaction . 

Air righting reflex 

+ Normal 

- Abnormal reaction 
Table 3-1 Twenty-eigbt-day repeated-dose oral toxicity study in rats 

Summary of reflex 

Sensorimotor function 

Sex Period Exp. group Number of Approach contact/ Pinna response 

(mg/kg/day) animals touch response 

-1 0 +1 -1 0 +1 

Vehicle control 10 0 10 0 0 10 0 

10 5 0 5 0 0 5 0 

Male week 4 30 5 0 5 0 0 5 0 

100 5 0 5 0 0 5 0 

300 10 0 10 0 0 10 0 

Vehicle control 10 0 10 0 0 10 0 

10 5 0 5 0 0 5 0 

Female week 4 30 5 0 5 0 0 5 0 

100 5 0 5 0 0 5 0 

300 10 0 10 0 0 10 0 
Table 3-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of reflex 

Sensorimotor function 

Sex Period Exp. group Number of Pain response (tail pinch) Pupillary reflex Air righting reflex 

(mg/kg/day) animals -1 0 +1 + - + - 

Vehicle control 10 0 10 0 10 0 10 0 

10 5 0 5 0 5 0 5 0 

Male week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 . 0 -

300 10 0 10 . 0 10 0 10 0 

Vehicle control 10 0 10 0 10` 0 10 0 

10 5 0 5 0 5 ' 0 5 0 

Female week 4 30 5 0 5 0 5 0 5 0 

100 5 0 5 0 5 0 5 0 

300 10 0 10 0 10 0 10 0 
Table 4 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of grip strength 

Sex~ Period Exp. group Number of Forelimb Hindlanb 

(mg/kg/day) animals (g) (g) 

Vehicle control 10 434 ±35 411 dk34 

10 5 467 f21 432 f25 

Male week 4 30 5 462 ±33 409 f18 

100 5 459 f27 467 f45 

300 10 447+30 441 4:15 

Vehicle control 10 370 f27 370 f20 

10 5 381 f37 361 f26 

Female week 4 ' 30 5 385 f22 388+-30 

100 5 369+37 373 f9 

300 10 372+29 379-08 

Mean fS.D . 

* Significantly different from vehicle control at P<0.05. 

** Significantly different from vehicle control at P<0.01. 
Table 5 Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of xmoor_~Cdvlty 

Sex Period Exp. group Number of Intexval (min) 

(mg/kg/day) animals 0-10 10-20 20-30 30-40 40-50 50-60 Total 

Vehicle control 10 216 135 85 61 39 23 557 

f43 f58 f53 t52 :L40 f35 f160 

10 5 169 96 62 42 52 57 477 

f93 4:46 f51 128 141 172 f158 

Male week 4 30 5 219 91 75 29 5 16 435 

f42 f59 +-54 t24 f5 f23 t165 

100 5 206 63 51 79 46 12 457 

f50 02 f50 f36 f35 f17 t130 

300 10 187 120 79 27 61 15 490 

f71 f40 +-53 f32 f43 f31 t150 

Vehicle control 10 234 135 75 33 28 34 539 

f60 f61 f51 +31 +-33 +51 f178 

10 5 260 158 75 60 46 24 624 . 

+50 f75 f18 f25 f36 125 t162 

Female week 4 30 5 228 146 72 43 14 2 507 

f91 183 f41 +36 t16 f5 f189 

100 5 251 87 26 44 68 45 521 

f75 t72 +-30 :b43 f55 144 f213 

300 10 240 122 55 26 52 38 533 

f76 175 f47 f51 f83 +54 4-229 

Mean fS.D. 

* Significiantly different from vehicle control at P<0.05. 

** Significantly different from vehicle control at P<0.01. 
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Addendum 2-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

. --Detailed-elieieal observations of individual animals (Predosing) -- 

Sex 

Exp,group AnimalNo 

Removal from cage 

. 

(mglkg/day) Ease of removal Vocalization 

1 0 0 

2 0 0 

3 0 0 

4 0 0 

Vehicle 5 0 0 

control 6 0 0 

7 0 0 

8 0 +1 

9 0 0 

10 0 0 

11 0 0 

` 12 0 0 

10 13 0 0 

14 0 0 

15 0 0 

16 0 0 

17 0 0 

Male 30 18 0 0 

19 0 0 

20 0 0 

21 0 0 

22 0 0 

100 23 0 0 

24 0 0 

25 0 0 

300 

26 0 0 

27 0 0 

28 0 0 

29 0 0 

30 0 0 

31 0 0 

32 0 +1 

33 0 0 

34 0 0 

35 0 0 
Addendum 2-2 'Itwenty-eight-day repeated-dose oral toxicity study in rats 

_ _ -- --Detailed clinical observations-ef individual-animals (Predosing) 

Sex 

Exp.group 

Animal No. 

Removal from cage 

. 

(mg/kg/day) Ease of removal Vocalization 

36 0 0 

37 0 0 

38 0 0 

39 0 0 

Vehicle 40 0 0 

control 41 0 0 

42 0 0 

43 0 0 

44 0 0 

45 0 0 

46 0 0 

47 0 0 

10 48 0 0 

49 0 0 

50 0 0 

51 0 0 

52 0 0 

Feniale 30 53 0 0 

54 0 0 

55 0 0 

56 0 0 

57 0 0 

100 58 0 0 

59 0 +1 

60 0 0 

300 

61 0 0 

62 0 0 

63 0 0 

64 0 0 

65 0 0 

66 0 0 

67 0 0 

68 0 0 

69 0 0 

70 0 0 
Addendum 2-3 Twenty-eight-day repeated-dose oral toxicity study in rats 

--Detailed-ctimcal observatio ns of individual animals (week 1) 

Sex Animal No. 

Exp.group Rmnoval from cage 

(mg/kg/day) Ease of removal Vocalization 

1 0 0 

2 0 0 

3 0 0 

4 0 0 

Vehicle 5 0 +1 

control 6 0 0 

7 0 0 

8 0 0 

9 0 0 

10 0 0 

11 0 +1 

12 0 0 

10 13 0 0 

14 0 0 

15 0 , 0 

16 0 +1 

17 0 0 

Male 30 18 0 +1 

19 0 0 

20 0 0 

21 , 0 0 

22 0 0 

100 23 0 0 

24 0 0 

25 0 0 

300 

26 0 0 

27 0 0 

28 0 0 

29 0 0 

30 0 0 

31 0 . 0 

32 0 0 

33 0 0 

34 0 0 

35 0 0 
Addendum 2-4 Twenty-eight-day repeated-dose oral toxicity study in rats 

-~- -I3~etailed clinical observaYions of in dividual animals (week 1 ) 

Sex Exp'gr°up Animal No. 

Removal from cage . 

(mg/kg/day) Ease of removal Vocalization 

36 0 +1 

37 0 0 

38 0 0 

39 0 0 

Vehicle 40 0 0 

control 41 0 0 

42 0 0 

43 0 0 

44 0 0 

45 0 0 

46 0 0 

47 0 +1 

10 48 0 +1 

49 0 0 

50 0 . 0 

51 0 0 

52 0 0 

Female 30 53 0 0 

54 0 0 

55 0 0 

56 0 0 

57 0 0 

100 58 0 0 

59 0 +1 

60 0 0 

300 

61 0 0 

62 0 +1 

63 0 0 

64 0 +1 

65 0 0 

66 0 0 

67 0' 0 

68 0 0 

69 0 0 

70 0 0 
Addendum 2-5 Twenty-eight-day-repeated-dose oral toxicity study in rats 

- Detail&Mllnic`1a observations of indivi du-la animals (week 2) 

Sex 

ExP~grouP 

Animal No. 

Removal from cage 

(mg/kg/day) Ease of removal Vocalization 

1 '0 0 

2 0 0 

3 0 0 

4 0 0 

Vehicle 5 0 +1 

control 6 0 0 

7 0 0 

8 0 +1 

9 0 0 

10 0 0 

11 0 +1 

12 0 0 

10 13 0 0 

14 0 0 

15 0 0 

16 0 +1 

17 0 0 

Male 30 18 0 +1 

19 0 0 

20 0 0 

21 0 0 

22 0 0 

100 23 0 0 

. 24 0 0 

25 0 0 

300 

26 0 0 

27 0 0 

28 0 0 

29 0 0 

30 0 0 

31 0 0 

32 0 0 

33 0 0 

34 0 0 

35 0 0 
Addendum 2-6 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ _ _ Detailed clinical observations-of individual anirnals (week 2) 

Sex 

Exp.group 

Animal No. 

Removal from cage 

(mB4Wday) Ease of removal Vocalization 

36 0 0 

37 0 +1 

38 0 +1 

39 0 0 

Vehicle 40 0 0 

control 41 0 0 

42 0 0 

43 0 0 

44 0 0 

45 0 0 

46 0 0 

47 0 0 

10 48 0 +1 

49 0 0 

50 0 0 

51 0 0 

52 0 0 

Female 30 53 0 0 

54 0 0 

55 0 0 

56 0 0 

57 0 0 

100 58 0 0 

59 0 +1 

60 0 0 

61 0 0 

62 0 0 

63 0 0 

64 0 0 

300 65 0 0 

66 0 0 

67 0 0 

68 0 0 

69 0 0 

- 70 0 0 
Addendum 2-7 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -Detadrled-elfnkM Observations of individua animals (Week 3) 

Sex No. 

Ease ofremoval Vocalization 

Exp.group Removal from cage Animal . 

1 0 0 

2 0 0 

3 0 0 

4 0 0 

Vehicle 5 0 0 

control 6 0 0 

7 0 0 

8 0 0 

9 0 0 

10 0 0 

11 0 +1 

12 0 0 

10 13 0 0 

14 0 0 

15 0 0 

16 0 0 

17 0 0 

Male 30 18 0 +1 

19 0 0 

20 0 0 

21 0 0 

22 0 0 

100 23 0 0 

24 0 0 

25 0 0 

300 

26 0 0 

27 0 0 

28 0 0 

29 0 0 

30 0 0 

31 0 0 

32 0 +1 

33 0 0 

34 0 . 0 

35 0 0 
Addendum 2-8 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- ------Detailed clinical observations-af individual animals (week 3) 

Sex 

Exp.group 

Animal 

No. Removal from cage 

(mg/kg/day) Ease of removal Vocalization 

36 0 +1 

37 0 0 

38 0 +1 

39 0 . 0 

Vehicle 40 0 0 

control 41 0 0 

42 0 0 

43 0 0 

44 0 0 

45 0 0 

46 0 0 

47 ' 0 0 

10 48 0 0 

49 0 0 

50 0 0 

51 0 0 

52 0 0 

Female 30 53 0 0 

54 0 0 

55 0 0 

56 0 0 

57 0 0 

100 58 0 0 

59 0 0 

60 0 0 

300 

61 0 0 

62 0 0 

63 0 0 

64 0 0 

65 0 0 

66 0 0 

67 0 0 

68 0 0 

69 0 0 

70 0 0 
Addendum 2-9 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -Detailed-clinical observations of individual animals (week 4) 

Sex Exp-group, Anima( No. 

Removal from cage 

(mg/kg/day) Ease of removal Vocalization 

1 0 0 

2 0 0 

3 0 0 

4 0 0 

Vehicle 5 0 +1 

control 6 0 +1 

7 0 0 

8 0 +1 

9 0 0 

10 0 +1 

11 0 +1 

12 0 0 

10 13 0 0 

14 0 0 

15 0 0 

16 0 0 

17 0 0 

Male 30 18 0 0 

19 0 0 

20 0 0 

21 0 0 

22 0 0 

100 23 0 0 

24 0 0 

25 0 0 

300 

26 0 0 

27 0 +1 

28 0 0 

29 0 0 

30 0 0 

31 0 0 

32 0 +1 

33 0 0 

34 0 0 

35 0 0 
Addendum 2-10 Twenty-eight-day repeated-dose oral toxicity study in rats 

__ _ -___-DcWled clinical observations-of individual-animals (week 4) 

Sex Animal No. 

Exp.group Removal from cage 

(mg/kg(day) Ease of removal Vocalization 

36 0 +1 

37 0 0 

38 0 +1 

39 0 0 

Vehicle 40 0 0 

control 41 0 0 

42 0 0 

43 0 0 

44 0 0 

45 0 0 

( 46 0 0 

47 0 0 

10 48 0 0 

49 0 0 

50 0 0 

51 0 0 

52 0 0 

Female 30 53 0 0 

54 0 +1 

55 0 0 

56 0 0 

57 0 0 

100 58 0 0 

59 0 0 

60 0 0 , 

300 

61 0 0 

62 0 0 

63 0 0 

64 0 0 

65 0 0 

66 0 0 

67 0 0 

68 0 0 

69 0 0 

70 0 0 
Addendum 2-11 Twenty-eight-day repcated-dose oral toxicity study in rats 

-Detaiied-cliaicai observations of individual animals (Recovery week 1) 

Sex Animal No. 

Exp.gronp Removal from cage 

(mg/kglday) Ease ofremoval Vocalization 

6 0 +1 

7 0 0 

Male 

Vehicle 8 0 +1 control 

9 0 0 

10 0 0 

31 0 0 

32 0 0 

300 33 0 0 

34 0 0 

35 0 0 
Addendum 2-12 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ --------Detailed clinical observations-of individual animals (Recovery week 1) 

Sex 

Exp.group 

Animal No. 

Removal from cage 

- 

(mg/kg/day) Ease of removal Vocalization 

,41 0 0 

42 0 0 

Vehicle 

43 0 0 control 

44 0 0 

Female 

45 0 0 

66 0 0 

67 0 0 

300 68 0 0 

69 0 +1 

, 70 0 0 
Addendum 2-13 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -Detaired-cUueal-observations of indiviual animals (ltecovery week 2) 

Sex 

Exp.group 

Animal No. 

Removal from cage 

(mg/kg/day) Ease of removal Vocalization 

6 0 +1 

7 0 0 

Male 

Vehicle g 0 0 

control 

9 0 0 

10 0 0 

31 0 0 

32 0 0 

300 33 0 0 

34 0 0 

35 0 0 
Addendum 2-14 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- - -----Detailed clinical observations-Df individual-animals (Recovery week 2) 

Female 

(mglk¬Jday) 

Exp.group 

Animal No. 

Removal from cage 

Ease of removal Vocalization 

41 0 0 

42 0 0 

Vehicle 

43 0 0 control 

44 0 0 

45 0 0 

66 0 0 

67 0 0 

300 68 0 0 

69 0 0 

70 0 0 
p. 116 

Addendum 2-15 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- --Detailed-clinical-observations of individual animals (Predosing) 

Handling observations 

Sex Exp.group Animal No. Muscle Subnormal Piloereotion Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

1 0 - - - - - -

2 0 - - - - - - 

. 3 0 - - - - - -

4 0 - - - - - -

Vehicle 5 0 

control 6 0 

7 0 - - - - - -

8 0 

9 0 

10 0 

11 0 

12 0 

10 13 0 

14 0 

15 0 

16 0 

17 0 

Male 30 18 0 

19 0 

20 0 

21 0 

22 0 

100 23 0 

24 0 

25 0 

300 

26 0 

27 0 

28 0 

29 0 

30 0 

31 0 

32 0 

33 0 

34 0 

35 0 
Addendum 2-16 Twenty-eight-day repeated-dose oral toxicity study in rats 

- - -----Het~led clinical obseryetion~f individual animals (Predosing) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Palen s Reddening 

(mg/kg/day) tone temperature hair hair 

36 0 

37 0 

38 0 

39 0 

Vehicle 40 0 

control 41 0 

42 0 

43 0 

44 0 

45 0 

46 0 

47 0 

10 48 0 

49 0 

50 0 

51 0 

52 0 

Female 30 53 0 

54 _ 0 

55 ' 0 

56 0 

57 0 

100 58 0 

59 0 

60 0 

300 

61 0 

62 0 

63 0 

64 . 0 

65 0 

66 0 

67 0 

68 0 

69 0 

70 0 
Addendum 2-17 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detailed-clin1W -observations of individual animals (week 1) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/Icglday) tone temperature hair hair 

1 0 

2 0 

3 0 

4 0 

Vehicle 5 0 

control 6 0 

7 0 

8 0 

9 0 

( 10 0 

11 0 

12 0 

10 13 0 

14 0 

15 0 

16 0 

17 0 

30 18 0 

19 0 

20 0 

21 0 

22 0 

100 23 0 

24 0 

25 0 

300 

26 0 

27 0 

28 0 

29 0 

30 0 

31 0 

32 0 

33 0 

34 0 

35 0 
p. 119 

Addendum 2-18 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ -cisiled clinical observatio ns-of individual animals (week 1) 

Handling observations ; 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Palen s Reddening 

(mg/kg/day) tone temperature hair hair 

36 0 

37 0 

38 0 

39 0 

Vehicle 40 0 

control 41 0 

42 0 

43 0 

44 0 

45 0 

46 0 

47 0 

10 48 0 

49 0 

50 0 

51 0 

52 0 

Female 30 53 0 

54 0 . 

55 0 

56 0 

57 0 

100 58 0 

59 0 

60 0 

61 0 

62 0 

63 0 

64 0 

300 

65 0 

66 0 

67 0 

68 0 

69 0 

70 0 

- 
p. 120 

COMM 

Addendum 2-19 Twenty-eight-day repeated-dose oral toxicity study in rats 

' -Detailed clinical observations of individual animals (week 2) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

1 0 

2 0 

3 0 

4 0 

Vehicle 5 0 

control 6 0 

7 0 

8 0 

9 0 

10 0 

11 0 

12 0 

10 13 0 

14 0 

15 0 

16 0 

17 0 

Male 30 18 0 

19 0 

20 0 

21 0 

22 0 

100 23 0 

24 0 

25 0 

300 

26 0 

27 0 

28 0 

29 0 

30 0 

31 0 

32 0 

33 0 

34 0 

35 0 
Addendum 2-20 Twenty-eight-day repeated-dose oral toxicity stltdy in rats 

Detailed clinical observations of individual animals (week 2) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Palen~ss Reddening 

(mpJkg/day) tone temperature hair hair I 

36 0 

37 0 

38 0 

39 0 

Vehicle 40 0 

control 41 0 

42 0 

43 0 

44 0 

45 0 

46 0 

47 0 

10 48 0 

49 0 

50 0 

51 0 

52 0 

Female 30 53 0 

54 0 

55 0 

56 0 

57 0 

100 58 0 

59 0 

60 0 

300 

61 0 

62 0 

63 0 

64 0 

65° 0 

66 0 

67 0 

68 0 

69 0 

70 0 
p. 122 

Addendum 2-21 Twenty-eight-day repeated-dose oral toxicity study in rats 

Detailed clinical observations of individual animals (week 3) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

1 0 

2 0 

3 0 

4 0 

Vehicle 5 0 

control 6 0 

7 0 

8 0 

9 0 

10 0 

11 0 

. 12 0 

10 13 0 

14 0 

15 0 

16 0 

17 0 

Male 30 18 0 

19 0 

20 0 

21 0 

22 0 

100 23 0 

24 0 

25 0 

300 

26 0 

27 0 

28 0 

29 0 

30 0 

31 0 

32 0 

33 0 

34 0 

35 0 

- - ~ - - - 
Addendum 2-22 Twenty-eight-day repeated-dose oral toxicity study in rats 

Detailed clinical observations of individual animals (week 3) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Pa(en~ss Reddening 

(mg/kg/day) tone temperature hair -7- hair I 

36 0 

37 0 

38 0 

39 0 

Vehicle 40 0 

control 41 0 

42 0 

43 0 

44 0 

45 0 

46 0 

47 0 

10 48 0 

49 0 

50 0 

51 0 

52 0 

Female 30 53 0 

54 0 

55 0 

56 0 

57 0 

100 58 0 

. 59 0 

60 0 

300 

61 0 

62 0 

63 0 

64 0 

65' 0 

66 0 

67 0 

68 0 

69 0 

70 0 
p. 124 

Addendum 2-23 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detailed clinical observations of individual animals_ (wsek 4) _ 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

2 0 

3 0 

4 0 

Vehicle 5 0 

control 6 0 

7 0 

S 0 

9 0 

10 0 

11 0 

12 0 

10 13 0 

14 0 

15 0 

16 0 

17 0 

Male 30 18 0 

19 0 

20 0 

21 0 

22 0 

100 23 0 

24 0 

25 0 

300 

26 0 

27 0 

28 0 

29 0 

30 0 

31 0 

32 0 

33 0 

34 0 

35 0 
p. 125 

Addendum 2-24 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ _______a?tWlad clinical observations-of individual -animals (week 4) 

Handling observarions 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Palen Reddening 

(mg/kg/day ) tone temperature hair hair 

36 0 

37 0 

38 0 

39 0 

Vehicle 40 0 

control 41 0 

42 0 

43 0 

44 0 

45 0 

46 0 

47 0 

10 48 0 

49 .0 

50 0 

51 0 

52 0 

Female 30 53 0 

54 0 

55 0 

56 0 

57 0 

100 58 0 

59 0 

60 0 

300 

61 0 

62 0 

63 0 

64 0 

65 0 

66 0 ~ 

67 0 

68 0 

69 0 

70 0 
p. 126 

Addendum 2-25 Twenty-eight-day repeated-dose oral toxicity study in rats . 

--Detaiied olinical observations of individual animals (Recovery week 1)- 

Handling observations 

Sex Exp.group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

6 0 

7 0 

Male 

Vehicle 8 0 

control 

9 0 

10 0 

31 0 

32 0 

300 33 0 

34 0 

35 0 
Addendum 2-26 Twenty-eight-day repeated-dose oral toxicity study in rats 

- - ------Detailed clinical observations-of individual animals (Recovery week 1) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleniss Reddening 

(mg/kg/day) tone temperature hair hair 

41 0 

42 0 

Vehicle 

43 0 control 

44 0 

45 0 - - - ~ - - - -

Female 

66 0 

67 0 

300 68 0 

69 0 

70 0 
Addendum 2-27 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- Detailed-Ctinfml observations of individual animals (Recovery week 2) 

Handling observations 

Sex Exp.group Animal No. Muscle Subnormal Piloerection Staining Unkempt Paleness Reddening 

(mg/kg/day) tone temperature hair hair 

6 0 

7 0 

Vehicle 

control 8 0 

' 9 0 

10 0 Male 

31 0 

32 0 

300 33 0 

34 0 

35 0 
p. 129 

Addendum 2-28 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -- -----Heteikd clinical observation" f individual-animals (Recovery week 2) 

Handling observations 

Sex Exp. group Animal No. Muscle Subnormal Piloerection Staining Unkempt Palen~s Reddening 

(mg/kg/day) tone temperature hair hair 

41 0 

42 0 

Vehicle 

43 0 control 

44 0 

Female 

45 0 

66 0 

67 0 

300 68 0 

69 0 

70 0 
Addendum 2-29 Twenty-eight-day repeated-dose oral toxicity study in rats 

--Detaited-cllttirff observations of individuV animals (Predosing) 

Handling observations 

Sex Exp.group Animal No. Cyanosis Lacrimation Exophthalmos Pnpillary Salivation Secretion 

(,ngtkg/day) size 

1 - - - 0 

2 - - - 0 

3 - - - 0 

4 - - - 0 

Vehicle 5 - - - 

control 6 - - ~ - 0 

7 - - - 0 

8 - - - 0 

9 - - - 0 

10 - - - 0 

11 

12 

10 13 

14 

15 

0 

0 

0 

0 

0 

16 - - - 0 

17 - - - 0 

Male 30 18 - - - 0 

19 - - - 0 

20 - - - 0 

21 - - - 0 - -

22 - - - 0 - - 

100 23 - - - 0 - -

24 - - - 0 - -

25 - - - 0 - - 

300 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-30 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- -- -Detailed clinical observations-of individual animals (Predosing) 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophtha(mos Pupillary Salivation Sec+tion 

(mP,/kg/day) ~ size 

36 

37 

38 

39 

Vehicle 40 

control 41 

42 

43 

44 

45 

46 

47 

10 48 

49 

50 

51 

52 

Female 30 53 

54 

55 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

56 - - - 0 - -

57 0 - - 

100 58 0 - _ 

59 0 

60 - - - 0 - - 

300 

61 

62 

63 

64 

65 

66 

67 

68 

69 

70 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-31 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detailsd-sliakal observations of individual animals (week 1) 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Secretion 

(mP,/kg/day) size 

1 

2 

3 

4 

Vehicle 5 

control 6 

7 

8 

9 

10 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

11 - - - 0 

12 - - - 0 

10 13 - - - 0 

14 - - - 0 

15 - - - 0 

16 - - - 0 

17 - - - 0 

Male 30 18 0 

19 - - - 0 

20 - - - 0 

21 

22 

100 23 

24 

25 

300 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-32 Twenty-eight-day repeated-dose oral toxicity study in rats 

- _ __- Detailed clinical observations-of individual animals (week 1) 

Handling observations 

- - Sex Exp. group Animal No. Cyanosis Lacrimation Exophthelmos Fupillary Salivation Secr~tion 

(mg/kg(day) size I 

36 - - - 0 

37 - - - 0 

38 - - - 0 -

39 - - - 0 - 

Vehicle 40 - - - 0 _ 

control 41 - - - 0 -

42 - - _ 0 _ 

43 - - - 0 -

44 - - - 0 -

45 - - - 0 - 

46 - - - 0 

47 - - - 0 

10 48 - . - 0 

49 - - - 0 

50 - - - 0 

51 - - - 0 

52 - - - 0 

Female 30 53 - - - 0 

54 - - - 0 

55 - - - 0 

56 

57 

100 58 

59 

60 

300 

61 

62 

63 

64 

65 

66 

67 

68 

69 

70 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-33 Twenty-eight-day repeated-dose oral toxicity study in rats 

__ Detailed rlinical observations of individual animals (week 2) - 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimatiqn Exophthalmos Pupillary Salivation Secretion 

(mglkg/day) size 

1 - - - 0 

2 - - - 0 

3 - - - 0 

4 - - - 0 

Vehicle 5 

control 6 - - - 0 

7 - - - 0 

8 - - - 0 

9 - - - 0 

10 - - - 0 

11 

12 

10 13 

14 

15 

0 

0 

0 

0 

0 

16 - - - 0 

17 - - - 0 

Male 30 18 - - - 0 

19 - - - 0 

20 - - - 0 

21 - - - 0 

22 - - - 0 

100 23 - - - 0 

24 - - - 0 

25 - - - 0 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
p. 135 

Addendum 2-34 Twenty-eight-day repeated-dose oral toxicity study in rats 

____-Dotaikd clinical observations-of individual-animals (week 2) 

Handling observations 

Sex Exp.group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Se tion 

(mSA*day) size 1. 

36 

37 

38 

39 

Vehicle 40 

control 41 

42 

43 

.44 

45 

46 

47 

10 48 

49 

50 

51 

52 

Female 30 53 

54 

55 

56 

57 

100 58 

59 

60 

300 

61 

62-

63 

64 

65 

66 

67 

68 

69 

70 

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 
Addendum 2-35 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detailed-clinical observations of individual animals (week 3) 

Handling observations 

Sex Exp. group Animal No. Cyanosis l,acrimation Exophthahnos Pupillary Salivation Secretion 

(mg/kg/day) size 

1 

2 

~3 

4 

Vehicle 5 

control 6 

7 

8 

9 

10 

11 

12 

10 13 

14 

15 

16 

17 

Male 30 18 

19 

20 

21 

22 

100 23 

24 

25 

300 

26 

27 

28 

29 . 

30 

31 

32 

33 

34 

35 

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 
p. 137 

Addendum 2-36 Twenty-eight-day repeated-dose oral toxicity study in rats 

--- ---Detailed clinical observations-of individual-animals (week 3) 

Handling-observations 

Sex Exp. group Animal No. Cyanosis Laximation Exophthalmos Pupillary Salivation Secr4tion 

(mg/kg/day) size 

36 - - - 0 

37 - - - 0 

38 - - - 0 

39 - - - 0 -

Vehicle 40 - - - 0 -

control 41 - - - -

. 0 

42 - - - 0 -

43 - - - 0 -

44 - - - 0 . -

45 - - - 0 - 

46 - - - 0 

47 - - - 0 

10 48 - - _ 0 

49 - - - 0 

50 - - - 0 

51 - - - 0 

52 - - - 0 

Female 30 53 - - - 0 

54 - - - 0 

55 - - - 0 

56 

57 

100 58 

59 

60 

300 

61 

62 

63 

64 

65 

66 

67 

68 

69 

70 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-37 Twenty-eight-day repeated-dose oral toxicity study in rats 

-Detailed-eli:ricxl observ ations of individual animals (week 4) 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophtttatmos Pupillary Salivation Secretion 

(a'g/kgIday) size 

1 

2 

3 

4 

Vehicle ' 5 

control 6 

7 

8 

9 

10 

11 

12 

10 13 

14 

15 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

16 - - - 0 

17 0 

Male 30 18 0 

19 - - - 0 

20 ` - - - 0 

21 

22 

100 23 

24 

25 

300 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
Addendum 2-38 Twenty-eight-day repeated-dose oral toxicity study in rats 

_.__ -----Detailed clinical observations-0f individual animals (week 4) 

Handling observ ations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophthalmos Pupiltary Salivation Sccr~tion 

(mSlWdxy) size I 

36 

37 

38 

39 

Vehicle 40 

control 41 

42 

43 

44 

45 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

46 - - - 0 

47 - - - 0 

10 48 - - - 0 

49 - - - 0 

50 , - - - 0 

51 - - - 0 

52 - - - 0 

Female ~ 30 53 - - - 0 

54 - - - 0 

55 - - - 0 

56 - - - 0 

57 - - - 0 

100 ' 58 - - - 0 

59 - - - 0 

60 - - - 0 

300 

61 

62 

63 

64 

65 

66 

67 

68 

69 

70 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 
- 

Addendum 2-39 Twenty-eight-day repeated-dose oral toxicity study in rats 

--Detai7-ed cl`uridd observations of individnff animals (Recovery week 1) 

Handling observations 

Sex Exp.group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Secretion 

(m&g1day) size 

Vehicle 

control 

Male 

- - - 0 

- - - 0 

- - - 0 

- - - 0 

10 - - - 0 

31 - - - 0 

32 - - - 0 

300 33 0 

34 - - - 0 

( 35 - - - 0 
p. 141 

Addendum 2-40 Twenty-eight-day repeated-dose oral toxicity study in rats 

_.____-Djetailed clinical observations -of individual animals (Recovery week 1) 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Secr~don 

(mg/kg/day) size 

Vehicle 

control 

Female 

41 - - - 0 

42 - - - 0 

43 - - - 0 

44 - - - 0 

45 - - - 0 

66 

67 

300 68 

69 

70 

0 

0 

0 

0 

0 
Addendum 2-41 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- Detailed-clinical observations of individual animals (Recovery week 2) 

Handling observations 

Sex Exp.group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Secretion 

(mWWday) size 

Vehicle 

control 

Male 

- - - 0 

- - - 0 

- - - 0 

- - - 0 

10 - - - 0 

31 

32 

300 33 

34 

35 

0 

0 

0 

0 

0 
p. 143 

Addendum 2-42 Twenty-eight-day repeated-dose oral toxicity study in rats 

---- ------ DetaHed clinical observations-of individual animals (Recovery week 2) 

Handling observations 

Sex Exp. group Animal No. Cyanosis Lacrimation Exophthalmos Pupillary Salivation Se ;Won 

(mg/kg/day) size 

Vehicle 

41 - - - 0 - -

42 0 - - 

control 43 - - ' 0 - 

44 - - - 0 - - 

Female 45 - - - 0 

66 - - - 0 

67 - - - 0 

300 68 - - - 0 

69 - - - 0 

7 0 - - - 0 
Addendum 2-43 Twenty-eight-day repeated-dose oral toxicity study in rats 

-Detailsd-Winical observations of i ndividual-animals -(Predosing) 

Observations in arena 

Sex Exp.goup Animal No. Posture Motor Respiration Lid Gait ' 

(mg/kgtday) activity closure 

1 0 0 0 

2 0 0 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control 6 0 0 0 

7 0 0 0 

8 0 0 0 

9 0 0 0 

10 0 0 0 

I1 0 0 . 0 

12 0 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

16 0 0 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 0 

20 0 0 0 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 0 0 

25 0 0 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 , 0 

29 0 0 0 

30 0 0 . 0 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-44 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -- ---------i ~~aed clinical observations-of individual animals (Predosing) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mB4*day) activity ' closure 

36 0 0 0 

37 0 0 0 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 0 0 

43 0 0 0 

44 0 0 0 

( 45 0 0 0 

, 46 0 0 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0 0 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64, 0 0 0 

65 0 0 0 

66 0 0 0 

67 0 0 0 

68 0 0 0 

69 0 +1 0 

70 0 0 0 
Addendum 2-45 Twenty-eight-day repeated-dose oral toxicity study in rats 

--Detaiied-clinM observations of individual animals (week 1) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mg/kg/day) activity closure 

1 0 +1 0 

2 0 0 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control 6 0 0 0 

7 0 0 0 

8 0 0 0 

9 0 0 0 

( 10 0 0 0 

11 0 0 0 

12 0 0 0 

10 13 0 0 0 

14 0 +1 0 

15 0 0 0 

16 0 +1 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 0 

20 0 0 0 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 0 0 

25 0 0 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 0 

30 0 0 0 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-46 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- - ------Detailed clinical observations-of individual animals (week 1) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(m&kg/day) activity closure 

36 0 0 0 

37 0 0 0 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 +1 0 

43 0 0 0 

44 0 0 0 

45 0 0 0 

46 0 0 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0 0 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 0 0 

65 0 0 0 

66 0 0 0 

67 0 0 0 

68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-47 Twenty-eight-day repeated-dose oral toxicity study in rats 

-Hetail~eal observations of individual- animals (week 2) 

' Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mgf 1cg/day) activity closure 

1 0 0 0 

2 0 0 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control 6 0 0 0 

7 0 0 0 

8 0 0 0 

9 0 0 0 

10 0 0 0 

11 0 0 0 

12 0 . 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

' 16 0 0 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 0 

20 0 0 0 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 -1 0 

25 0 0 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 0 

30 0 0 0 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-48 Twenty-eight-day repcated-dose oral toxicity study in rats 

__ ._ ___ . _ nPtaHed clinical observationsof individual animals (week 2) 

Observations in arena 

Sex Exp: group Animal No. Posture Motor Respiration Lid Gait 

(mglkg(day) activity closure 

36 0 0 0 - -

37 0 0 0 - -

38 0 0 0 - -

39 0 0 0 - - 

Vehicle 40 0 0 0 - -

control 41 0 0 0 - -

42 0 0 0 - -

43 0 0 0 - -

44 0 0 0 - -

45 0 0 0 - -

46 0 0 0 - -

47 0 0 0 - - 

10 48 0 0 0 - -

49 0 0 0 - -

50 0 0 0 - - 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0 +1 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 . 0 0 

65 0 0 0 

66 0 0 0 

67 0 0 0 

68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-49 Twenty-eight-day repeated-dose oral toxicity study in rats ° 

--Detailed clini cai observations of individuia animals (week 3) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mglkg/day) activity closure 

1 0 0 , 0 

2 0 -1 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control 6 0 +1 0 

7 0 0 0 

8 0 0 0 

9 0 0 0 

_ 10 0 0 0 

11 0 0 0 

12 0 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

16 0 -1 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 0 

20 0 0 0 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 0 0 

25 0 +1 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 0 

30 0 0 0 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-50 Twenty-eight-day repeated-dose oral toxicity study in rats 

--- ----- ----D°}~..~'.,° ed clinical observationsof individual animals (week 3) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mg/kg/day) ' activity closure 

36 0 0 0 . -

.37 0 0 0 - -

38 0 0 0 - _ 

_ 39 0 0 0 . -

Vehicle 40 0 +1 0 - _ 

control 41 0 0 0 - _ 

42 0 0 0 - -

43 0 0 0 - -

44 0 0 0 - -

45 0 0 0 - - 

46 0 +1 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0' 0 0 - _ 

57 0 0 0 - _ 

100 58 0 0 0 _ -

59 0 0 0 - - , 

60 0 0 0 _ - 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

6,4 , 0 0 0 

65 0 0 0 

66 0 +1 0 

67 0 +1 0 

68 0 +1 0 

69 0 0 0 

70 0 0 0 
Addendum 2-51 Twenty-eight-day repeated-dose oral toxicity study in rats 

__ Detailed cli`m-c--la observations of individiuaI animals (week 4) 

Observations in arena 

Sex Exp- group Animal No. Posture Motor Respiration Lid Gait 

(mg/kg/day) activity closure 

1 0 0 0 

2 0 0 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control (, .0 0 0 

7 0 0 0 

8 0 0 0 

9 0 +1 0 

10 0 0 0 

11 0 0 0 

12 0 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

16 0 0 0 

17 0 0 0 

Male 30 18 0 +1 0 

19 0 0 0 

--- 20 0 0 0 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 0 0 

25 0 0 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 0 

30 0 0 0 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-52 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -- -- --Detailed clinical observations-of individual animals (weak 4) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mVIcg(day) activity closure 

36 0 0 0 

37 0 0 0 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 +1 0 

43 0 0 0 

44 0 0 0 

45 0 0 0 

46 0 +1 0 

47 0 0 0 

10 , 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female . 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0 +1 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 0 0 

65 0 0 0 

66 0 0 0 

67 0 +1 0 

68 0 . 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-53 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detat}ed-atinicai observations of individual animals (Recovery week 1) 

Observations in arena 

Sex Bxp.group Animal No. Posture Motor Respiration Lid Gait 

--- -(mg/kg/day) activity closure 

Vehicle 

Male 

6 0 0 0 

7 0 0 0 

control 8 0 +1 0 

9 0 0 0 

10 0 0 0 

31 0 0 0 

32 0 0 0 

300 33 0 0 0 

34 0 0 0 

35 0 0 0 
'Addendum 2-54 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -- ----Hetailed clinical observations-of individual-animals (Recovery week 1) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mg/Wday) activity closure 

Female 

41 0 +1 0 

42 0 0 0 

control 43 0 0 0 

Vehicle 

44 0 0 0 

45 0 0 0 

66 0 0 0 -

67 0 0 0 - 

300 68 0 0 0 -

69 0 +1 0 -

70 0 0 0 - 
Addendum 2-55 Twenty-eight-day repeated-dose oral toxicity study in rats 

- Detailed-cltnical observations of individual animals (Recovery week 2Y 

Observations in arena 

Sex Exp.group Animal No. Posture Motor Respiration Lid Gait 

(mBIkBlday) activity closure ' 

Vehicle 

6 0 0 0 

7 0 0 0 

control g 0 +1 0 

9 0 0 0 

Male 

10 0 0 0 

31 0 0 0 

32 0 0 0 

300 33 0 0 0 

34 0 0 0 

35 0 +1 0 
Addendum 2-56 Twenty-eight-day repeated-dose oral toxicity study in rats 

- - ----Hetailed clinical observations-of individual animals (Recovery week 2) 

Observations in arena 

Sex Exp. group Animal No. Posture Motor Respiration Lid Gait 

(mgVday) activity closure 

Female 

41 0 +1 0 

42 0 +1 0 

control 43 0 0 0 

Vehicle 

44 0 0 0 

45 0 0 0 

66 0 0 0 

67 0 0 0 

300 68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-57 Twenty-eight-day repeated-dose oral toxicity study in rats 

- -Detall®d-slinie.$1 observations of individual animals (Predosing) -- 

Observations in arena 

Sex Exp.group Animal No. Tremor/twitch/ . Defecation Urination Stereotypic Abnormal 

(m8/kBlday) convulsion (count/min) (count/min) behavior behavior 

1 0 0 0 

2 0 0 0 

3 0 0 4 

4 0 0 0 

Vehicle 5 0 0 2 

control 6 0 0 2 

7 0 0 2 

8 0 1 0 

9 0 0 0 

10 0 0 0 

11 0 1 1 

12 0 0 0 

10 13 0 0 0 

14 0 0 2 

15 0 0 1 

16 0 0 3 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 0 

20 0 1 0 

21 0 0 5 _ 

22 0 1 7 - 

100 23 0 0 0 -

24 0 0 4 -

25 0 0 2 - 

300 

26 0 0 0 

27 0 0 2 

28 0 0 1 

29 0 0 3 

30 0 2 3 

31 0 0 10 

32 0 0 1 

33 0 0 3 

34 0 0 1 

35 0 0 0 
p. 159 

ONNO 

Addendum 2-58 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _ ___-Detailed clinical observations-of individual. animals (Predosing) 

Observations in arena i 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count/min) behavior behavior 

36 0 1 0 - -

37 0 0 2 - -

38 0 0 4 - -

39 0 0 0 - - 

Vehicle 40 0 0 0 - _ 

control 41 0 0 0 . - I 

42 0 0 0 - _ 

43 0 0 0 - _ 

44 0 0 2 _ . 

45 0 0 0 - . 

46 0 0 0 

47 0 0 0 

10 48 0 0 10 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 1 

54 0 2 1 

55 0 0 0 

56 0 0 3 

57 0 0 1 

100 58 0 0 0 

59 0 0 0 

60 0 0 1 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 ' 0 0 

65 0 2 2 

66 0 0 0 

67 0 0 2 

68 0 0 1 

69 0 0 0 

70 0 0 0 
Addendum 2-59 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- -Detailed-cli-ric`al observations of individual animals (week 1) 

Observations in arena 

Sex Exp. group Animal No. Tremorflwitch/ Defecation Urination Stereotypic Abnormal 

(mSVday) convulsion (count/min) (count/min) behavior behavior 

1 0 0 0 - _ 

2 0 0 0 - . 

3 0 0 4 - _ 

4 0 0 0 _ - 

Vehicle 5 0 0 0 - _ 

control 6 0 0 0 - _ 

7 0 0 9 - _ 

8 0 0 0 - _ 

9 0 0 3 _ _ 

10 0 0 0 _ _ 

11 0 1 1 

12 0 0 0 

10 13 0 0 1 

14 0 0 1 

15 0 0 0 

16 0 0 1 

17 0 0 0 

Male 30 18 0 0 0 

19 0 1 5 

20 0 0 1 

21 0 0 1 

22 0 2 5 

100 23 0 0 1 

24 0 0 1 

25 0 5 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 4 

30 0 1 3 

31 0 0 3 

32 0 0 1 

33 0 0 2 

34 0 0 3 

35 0 0 2 
Addendum 2-60 Twenty-eight-day repeated-dose oral toxicity study in rats 

__-Detailed clinical observations-of individual-animals (week 1) 

Observations in arena 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count(min) (count/min) behavior' behavior 

36 0 0 0 

37 0 0 1 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 0 0 

43 0 0 0 

44 0 0 1 

45 0 0 0 

46 0 0 0 

47 0 0 0 

10 48 0 . 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 2 0 

55 0 0 0 

56 0 0 0 

57 0 0 1 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 1 

62 0 0 1 

63 0 0 0 

64 0 0 0 

65 0 0 0 

66 0 0 0 

67 0 0 3 

68 0 0 1 

69 0 0 0 

70 0 0 0 
Addendum 2-61 Twenty-eight-day repeated-dose oral toxicity study in rats 

-Detailed-elirrieal observations of individual animals (week 2) 

Observations in arena 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count(min) behavior behavior 

1 0 0 0 - _ 

2 0 0 0 _ _ 

3 0 0 2 - - 

. 4 0 0 0 - -

Vehicle 5 0 0 1 

control . 6 0 0 1 - -

7 0 1 2 _ 

8 0 1 0 _ -

9 0 0 0 - _ 

10 0 0 0 - - 

11 0 1~ 1 

12 0 0 0 

10 13 0 0 1 

14 0 0 0 

15 0 0 1 

30 

16 0 0 0 

17 0 0 0 

18 0 0 0 

19 0 0 0 

20 0 0 2 

21 0 0 1 

22 0 1 1 

100 23 0 0 2 

24 0 0 4 

25 b 3 1 

300 

26 0 1 1 

27 0 0 0 

28 0 0 1 

29 0 0 2 

30 0 2 0 

31 0 0 2 

32 0 0 0 

33 0 0 2 

34 0 0 0 

35 0 0 0 
Addendum 2-62 Twenty-eight-day repeated-dose oral toxicity study in rats 

.___-.Detailed clinical observations of individual animals (week 2) 

Observations in arena 

Sex Exp. group Animal No. Tremorltwitch/ Defecation Urination Stereotypic Abnormal 

(mglkg/day) ' convulsion (count!min) (count/min) behavior behavior 

36 0 0 0 

37 0 0 4 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 0 0 

43 0 0 0 

44 0 0 0 

45 0 0 0 

46 0 0 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

' 54 0 3 0 

55 0 0 0 

56 0 0 1 

57 0 0 0 

.100 58 0 0 0 

59 0 0 0 

60 0 0 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 1 

64 0 0 1 

65 0 0 1 

66 0 0 0 

67 0 0 - 1 

68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-63 Twenty-eight-day repeated-dose oral toxicity study in rats 

Detailed clinical observations of individual animals (weelc 3) 

' Observations in arena - 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count/min) behavior behavior 

1 0 0 0 

2 0 0 0 

3 0 0 2 

4 0 0 0 

Vehicle 5 0 0 0 

' control 6 0 0 0 

7 0 0 1 

8 0 0 0 

9 0 0 0 

10 0 0 0 

' 11 0 0 2 

12 0 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

16 0 0 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 2 

20. 0 0 0 

21 0 1 2 

22 0 1 1 

100 23 0 0 3 

24 . 0 0 2 

25 0 0 0 

300 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 2 

30 0 3 0 

31 0 0 2 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
p. 165 

mom 

Addendum 2-64 Twenty-eight-day repeated-dose oral toxicity study in rats 

_-D&tailed clinical observations of individual_ animals (week 3) 

Observations in arena i 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count/min) behavior behavior 

36 0 0 0 - - ' 

37 0 0 0 - -

38 0 0 0 - 

39 0 0 0 - -

Vehicle 40 0 0 0 - -

control 41 0 0 0 - - 

42 0 0 0 - -

43 0 0 0 - -

44 0 0 0 - -

45 0 , 0 0 - - 

46 0 0 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 1 0 

55 0 0 0 

56 0 0 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 0 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 0 0 

300 65 0 0 0 

66 0 0 0 

67 0 0 0 

68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-65 Twenty-eight-day repeated-dose oral toxicity study in rats 

__ _Detailssi. .clinical observations of individual animals (week 4) 

Observations in arena 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count(min) (countlmin) behavior behavior 

1 0 0 0 

2 0 0 0 

3 0 0 0 

4 0 0 0 

Vehicle 5 0 0 0 

control 6 0 0 0 

7 0 0 0 

8 0 0 0 

9 0 0 0 

10 0 0 0 

11 0 1 1 

12 0 0 0 

10 13 0 0 0 

14 0 0 0 

15 0 0 0 

16 0 0 0 

17 0 0 0 

Male 30 18 0 0 0 

19 0 0 1 

20 0 0 1 

21 0 0 0 

22 0 0 0 

100 23 0 0 0 

24 0 0 0 

25 0 0 0 

26 0 0 0 

27 0 0 0 

28 0 0 0 

29 0 0 0 

30 0 0 0 

300 

31 0 0 0 

32 0 0 0 

33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-66 Twenty-eight-day repeated-dose oral toxicity study in rats 

Detailed clinical observations of individual_ animals (week 4) 

Observations in arena 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count(min) (count/min) behavior behavior 

36 0 0 0 

37 0 0 0 

38 0 0 0 

39 0 0 0 

Vehicle 40 0 0 0 

control 41 0 0 0 

42 0 0 0 

43 0 0 0 

44 0 0 0 

45 0 0 0 

46 0 0 0 

47 0 0 0 

10 48 0 0 0 

49 0 0 0 

50 0 0 0 

51 0 0 0 

52 0 0 0 

Female 30 53 0 0 0 

54 0 0 0 

55 0 0 0 

56 0 0 0 

57 0 0 0 

100 58 0 0 0 

59 0 0 0 

60 0 0 ' 0 

300 

61 0 0 0 

62 0 0 0 

63 0 0 0 

64 0 0 0 

650 0 0 

66 0 0 0 

67 0 0 0 

68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-67 Twenty-eight-day repeated-dose oral toxicity study in rats 

-.Detailod-slisisal observations of individual animals (Recovery week 1)- 

Observations in arena 

Sex Exp.group AnimalNo . Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count/min) behavior behavior 

6 0 0 0 

7 0 0 0 

Male 

Vehicle g 0 0 0 control 

9 0 0 1 

10 0 0 0 

31 0 0 0 

32 0 0 0 

300 33 0 0 0 

34 0 0 0 

35 0 0 0 
Addendum 2-68 Twenty-eight-day repeated-dose oral toxicity study in rats 

- - ---~-DeTaired clinical observations -of individual-animals (Recovery week l ) 

Observations in arena 

Sex Exp. group Animal No.' Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/Wday) convulsion (count/min) (count(min) behavior behavior 

41 0 0 0 

42 0 0 0 

Female 

Vehicle 

43 0 0 0 

control 

44 0 0 0 

45 0 0 0 

66 0 0 0 

67 0 0 1 

300 68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 2-69 Twenty-eight-day repeated-dose oral toxicity study in rat 

_ _Detailedr.linical-observations of individual animals (Recovery week 2) 

Observations in arena 

Sex Exp.group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count(min) behavior behavior 

6 0 ~0 0 

7 0 0 2 

Male 

Vehicle g 0 0 0 

control 

9 0 0 0 

10 0 0 0 

31 0 0 0 

32 0 0 0 

300 33 0 ' 0 3 

34 0 0 0 

35 0 0 0 
Addendum 2-70 Twenty-eight-day repeated-dose oral toxicity study in rats 

Detailed clinical observations-0f individual animals (Recovery week 2) 

Observations in arena 

Sex Exp. group Animal No. Tremor/twitch/ Defecation Urination Stereotypic Abnormal 

(mg/kg/day) convulsion (count/min) (count/min) behavior behavior 

41 0 0 0 

42 0 0 0 

Vehicle 

43 0 0 0 control 

44 0 0 0 

Female 

45 0 0 0 

66 0 0 0 

67 0 0 0 

300 68 0 0 0 

69 0 0 0 

70 0 0 0 
Addendum 3-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

--Reflex-afiatilvtdual animals (week 4J -- 

Sensorimotor function 

Sex Exp. group Animal No. Approach contact/ Pinna Pain response Pupillary Air righting 

(mg/kg/day) touch response response (tail pinch) reflex reflex 

1 0 0 0 + + 

2 0 0 0 + + 

3 0 0 0 + + 

4 0 0 0, + + 

Vehicle 5 0 0 0 , + + 

control 6 0 0 0 + + 

7 0 0 0 + + 

8 0 0 0 + + 

9 0 0 0 + + 

10 0 0 0 + + 

11 0 0 0 + + 

12 0 0 0 . + + 

10 13 0 0 0 + + 

14 0 0 0 + + 

15 0 0 0 + + 

16 0 0 0 + + 

17 0 0 0 + + 

Male 30 18 0 0 0 + + 

19 0 0 0 + + 

20 0 0 0 + + 

21 0 0 0 + + 

22 0 0 0 + + 

100 23 0 0 0 + + 

24 0 0 0 + + 

25 0 0 0 + + 

300 

26 0 0 0 + + 

27 0 0 0 + + 

28 0 0 0 + + 

29 0 0 0 + + 

30 0 0 0 ' + + 

31 0 0 0 + + 

32 0 0 . 0 + + 

33 0 0 0 + + 

34 0 0 0 + + 

35 0 0 0 + + 
p. 173 

Addendum 3-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

- - - ---Reflmof individual animals {week 4) - 

Sensorimotor function 

Sex Exp. group Animal No. Approach contact/ Pinna Pain response Pupillary Air righ ing 

(mgVday) touch response response (tail pinch) reflex refle4 

. 36 0 0 0 + + ' 

37 0 0 0 + + 

38 0 0 0 + + 

39 0 0 0 + + 

Vehicle 40 0 0 0 + + 

control 41 0 0 0 + + i 

42 0 0 0 + + 

43 0 0 0 + + 

44 0 0 0 + + ' 

45 0 0 0 + + 

46 0 0 0 + + 

47 0 0 0 + + 

10 48 0 0 0 + + 

49 0 0 0 + + 

50 0 0 0 + + 

51 0 0 0 + + 

52 0 0 0 + + 

Female 30 53 0 0 0 + + 

54 0 0 0 + + 

55 0 0 0 + + 

56 0 0 0 + + 

57 0 0 0 + + 

100 58 0 0 0 + + 

300 

59 0 0 0 + +t 

60 0 0 0 + + 

61 0 0 0 + + 

62 0 0 0 + + 

63 0 0 0 + + 

64 0 0 0 + + 

65 0 0 0 + + 

66 0 .0 0 + + 

67 0 0 0 + + 

68 0 0 0 + + 

69 0 0 0 + + 

70 0 0 0 + + 
Addendum 4-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ Grip_greeth nf9ndividual animals (weelc4) 

Sex Exp.group Animal No. Forelimb (g) Hindlimb (g) 

(m&Wday) Trial l Trial 2 Mean Trial l Trial 2 Mean 

1 433 462 448 435 412 424 

2 451 421 436 432 398 415 

3 406 469 438 491 466 479 

4 412 392 402 399 372 386 

Vehicle 5 408 507 458 422 411 417 

control 6 481 496 489 397 377 387 

7 392 400 396 350 348 349 

8 410 404 407 389 420 405 

9 370 409 390 440 401 421 

10 488 465 477 406 444 425 

11 495 440 468 405 444 425 

12 513 459 486 384 494 439 

10 13 519 459 489 452 464 458 

14 454 423 439 439 452 446 

15 423 483 453 416 372 394 

16 444 . 446 445 419 403 411 

17 460 412 436 395 369 382 

Male 30 18 ' 516 484 500 376 435 406 

19 411 459 435 444 417 431 

20 506 484 495 419 413 416 

21 394 480 437 418 436 427 

22 466 515 491 453 472 463 

100 23 499 467 483 509 378 444 

300 

24 428 434 431 497 415 456 

25 446 464 455 564 521 543 

26 455 477 466 441 389 415 

27 536 432 484 419 469 444 

28 449 483 466 448 462 455 

29 421 494 458 447 422 435 

30 519 452 486 462 453 458 

31 432 416 424 444 465 455 

32 419 391 405 432 407 420 

33 390 428 409 421 447 434 

34 394 454 424 493 394 444 

35 446 457 452 495 413 454 
Addendum 4-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

_-_- Grip strengrth of individual-animals (week.4) - 

Sex Exp.group Animal No. Forelimb (g) Hindlimb (g) 

(mg/kgIday) Trial l Trial 2 Mean Trial l Trial 2 Mean 

36 392 453 423 375 416 396 

37 392 . 349 371 379 393 386 

38 463 342 403 343 396 370 

39 399 354 377 428 313 371 

Vehicle 40 317 380 349 358 330 344 

control 41 319 333 326 323 405 364 

42 365 341 353 421 373 397 

43 392 331 362 337 331 334 

44 312 427 370 336 389 363 

45 390 347 369 355 401 378 

46 302 355 329 319 399 359 

47 323 387 355 400 326 363 

10 48 389 422 406 334 347 341 

49 417 403 410 337 342 340 

50 361 448 405 428 377 403 

51 354 422 388 337 405 371 

52 358 374 366 378 363 371 

Female 30 53 342 460 401 441 440 441 

54 462 358 410 366 402 384 

55 347 371 359 401 342 ' 372 

56 377 475 426 355 384 370 

57 397 319 358 345 384 365 

100 58 362 365 364 379 396 388 

59 313 336 325 416 323 370 

60 333 407 370 386 359 373 

300 

61 319 370 345 403 382 393 

62 349 355 352 410 420 415 

63 382 405 394 390 389 390 

64 370 412- 391 324 353 339 

65 338 361 350 320 400 360 

66 360 382 371 364 438 401 

67 438 425 432 340 353 347 

68 326 347 337 447 365 406 

69 316 404 360 325 367 346 

70 391 374 383 409 367 388 
Addendum 5-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

_ _MotQr-actiYity-of individual animals (week 4) _ 

Sex Exp. group Animal No. Interval (min) 

(mg/kg/day) 0-10 10-20 20-30 30-40 40-50 50-60 Total 

1 109 49 , 20 136 4 34 352 

2 199 46 0 12, 80 0 337 

3 217 199 108 21 95 110 750 

4 238 104 94 38 l 0 475 

Vehicle 5 240 192 158 92 51 50 783 

control 6 222 148 82 162 _ . 35 1 650 

7 255 167 147 33 4 3 609 

8 212 127 82 41 102 21 585 

9 262 203 122 47 1 1 636 

10 202 113 32 24 18 8 397 

F 11 217 40 31 43 53 0 384 

12 18 87 139 41 16 173 474 

10 13 261 150 83 84 96 75 749 

14 196 70 50 35 5 4 360 

15 151 135 7 6 90 31 420 

16 240 25 63 40 12 54 434 

17 177 77 23 23 2 0 302 

Male 30 18 276 172 136 65 4 22 675 

19 178 54 26 1 0 4 263 

20 223 126 126 18 5 2 . 500 

21 239 93 60 59 94 38 583 

22 131 9 10 122 27 22 321 

100 23 240 100 134 104 14 0 592 

300 

24 242 87 25 80 21' 1 456 

25 179 27 26 30 72 0 334 

26 136 95 44 9 62 0 346 

27 139 . 109 73 22 5 4 352 

28 275 99 4 0 68 0 446 

29 200 81 137 51 88 9 566 

30 165 139 .170 64 142 4 684 

31 96 66 71 0 67 21 321 

32 245 206 140 91 20 0 702 

33 307 152 29 31 101 0 620 

34 194 126 58 . 0 50 102 530 

35 113 131 66 4 10 7 331 
p. 177 

' 

Addendum 5-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Motor activity of individual animals (week 4) _ _ 

Sex Exp. group Animal No. Interval (min) i 

(mg/kg/day) 0-10 10-20 20-30 30-40 40-50 50-60 TIw 

36 190 236 71 29 106 127 f59 

37 170 102 5 60' 37 46 420 

38 248 101 116 11 26 26 528 

39 346 203 138 24 5 3 719 

Vehicle 40 193 162 85 42 8 0 490 

control 41 170 40 0 48 14 10 282 

42 239 97 119 15 . 0 0 470 

43 202 116 15 0 62 0 395 

44 288 195 113 103 18 126 843 

45 296 102 87 2 1 0 488 

46 248 162 82 25 91 56 664 

47 322 224 60 86 76 1 769 

10 48 195 30 54 57 6 3 345 

49 239 195 98 83 28 18 661 

50 296 178 . 82 51 30 44 681 

51 98 68 6 32 28 0 232 

52 248 131 104 13 34 11 541 

Female 30 53 181 87 60 86 0 0 414 

54 282 170 99 76 10 0 637 

55 331 276 93 9 0 0 709 

56 276 88 6 88 42 99 599 

57 286 72 76 49 0 0 483 

100 58 332 202 29 82 118 35 798 

59 133 1 16 0 49 9 ,208 

60 230 74 1 0 129 83 517 

300 

61 286 182 9 0 26 0 503 

62 223 65 70 1 0 5 364 

63 290, 151 23 27 0 0 491 

64 237 104 3 0 4 105 453 

653 149 4 107 164 37 1 462 

66 322 174 61 25 253 133 968 

67 81 20 1 0 1 105 208 

68 254 151 47 0 43 30 525 

69 236 127 89 0 10 2 464 

70 319 243 140 46 147 0 895 
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p. 206 

Addendum 13-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Ezp-group -No aFate -Macroscopic findings 

Male Vehicle control 

Histopathological findings') 

1 ta No abnormalities detected No abnormalities detected 

- - 2 ------ ~W 'Ro no. s d ---------------- ~Wo ;!~o- . . . . . . . . 

. . . . . . . . . . . . . . . . . . . . . . . . . . . E 

3 

n 

s er 

Microgranuloma + 

ta 

11 

i~ 

.. . . . .. .. . .. 

--------------- 6ei;~j;~; --------------------------------

Dilatation of ventricle + 

----------------------------------------------------------------------------=----------------------- 

5 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: trachea, lungs, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, 

colon, rectum, liver, 4art, kidneys, urinary bladder, testes, epididymides, ventral prostate, dorsolateral prostate, 

coagulating gland, seminal vesicle, cerebrum, cerebellum, pons, spinal cord, sciatic nerve, bone marrow, axillar lymph node, 

mesenteric lymph node, spleen, thymus, pituitary gland, thyroid, parathyroid, adrenals, eye ball, skeletal muscle, bone and 

mammary gland. 

ta, terminal autopsy-

+, slight 
' p. 207 

Addendum 13-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals i 

Sex - -----Exp .g~oup 

Animal No. Fate Macroscopic findings Histopatiiological ~ndings°) 

6 ta Kidney Kidney 

Recessed region (right, 4, 2 mm) Solitary cyst in cortex ~. . ..----------- . ---- ;~------~ --~ -------- ---------------------------- . Kidney No abnormalities detected 

Vehicle control Deformity (left) Kidney 

(Recovery) . . . .. .. .. . . .. . .. . No abnormalities detected 

--------------------------------------------------------------------------------- . . . . 8 ta No abnormalities detected No abnormalities detected ------ . .

.---------------------------------------------------------------------- . . .. .--- .. .---------- 

. . . . . 

9 ta No abnormalities detected No abnormalities detected - . . . .. .. .. . . . . . . . .. .. ... .. . .. .. .. . .. .. .. .. .. .. . . . . . .. .. . . . . . . .. .. .----------- . . .. . .. .. .. . . . .. . . . . . .. .. . . .. . . .----------------- 10 ta No abnormalities detected No abnormalities detectqd 

a) Organs/tissues examined as follows: liver, bone marrow,. spleen and macroscopic lesion . 

ta, terminal autopsy. 

+, slight. 
p. 208 

Addendum 13-3 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findin~s of individual animals 

sex E~'~°~---~m~ Fate -Macroscopic findings (ing/lcg/day) No. Histopathological findings) 

11 ta No abnormalities detected No abnormalities detected 

---------------------------------------------------------------------------------------------------- . . 

---------- 

12 ta No abnormalities detected No abnormalities detected ------------------------- . . .-------------- .. .-------------- . . .. . . . Male 10 13 .-------------------------

. .. . . . . .. . . .

ta . .. .. No 

----

abnormalities 

. .. .. .. . .. .. .. . 

detected No abnormalities detected 

-------- . .. .. .. .. . .. . 

---- 

---------------" ----

.. .------- . 14 

----- 

ta 

--

. 

No 

. ----- .. .-----------------

abno~alities-detected 

. .

No abnormalities detected 

.------------ 

------------- . 

---------------------------------------- 15 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy. 

'Y 
p. 209 

Addendum 13-4 'Itwenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals i 

x - ---~'~oup Animal Se 

m da No. 

Fate Macroscopic findings

. HistoPathological' rmdjngs°) 

"

16 ta No abnormalities detected No abnormalities dete ---------------------------------------------------------- ------------------------ ------------- 

-------

17 

.._ . ..

ta No abnormalities detected No abnormalities detect~d .---------------------------------- . . . .

Male 30 18 .-------------------------------- .___ . ta No abnormalities detected _ No abnormalities detecte~d 

----------- 

--

---------------------------------------------------------- -------------------------------------- . . 

------- 

19 

----- 

ta No abnormalities detected No abnormalities detected ----------------;;----------------------------------------------------------- ._ .. .---

. . 20 ta 

--- 

No abnormaht<es detected No abnormalities detected 

a) Organs/tissues examined as follows: liver, bone marrow and spleen . 

ta, terminal autopsy. 
p. 210 

Addendum 13-5 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp'group---knimal Fate --Macroscopic findings (mg/kg/day) No. 

Histopathological findings`) 

.

21 ta No abnormalitles detected No abnormalities detected 

.-----------------------------------------------------------------------=-------------------------- 22 ta No abnormalities detected No abnormalities detected -------------------------------------------- .. ..

.----------------------------- .. . . . . .-----

. ..--- . . 23 ta 

--- 

No 

- 

abnormalities detected Spleen 

Male 100 Increased extramedullary 

hematonoiesis + 

a) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy. 

+, slight. 

--- ---------- - ----- - --- ----------------- - -- ------ . . . ._ . .. 

----------; ;----- .. . . .----------------------------------------- .._ . .--------- . .. . 

----------- 24 ta No abnormalities detected No abnormalities detected 

25 ta No abnormalities detected No abnormalities detected 
p. 211 

Addendum 13-6 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals -- ---- 

Sex -----Exp-group 

(mg/k¬~day) 

~~ Fate Macroscopic findings . Histopathological fin.dings`) 

ta Spleen Spleen 

Blackish change Hemosiderin depositiori + 

Increased cxumedullary 

h 4-4- to 

Male 300 

26 

iesxs 

. .------------------- "---- " -" ------------= -----. ._- 

ema po 

-___ .___ . . -- .- . ..------" ------==------------- " 

27 ta Spleen Liver 

Blackish change Increased extramedullary 

hematopoiesis + 

Spleen 

Congestion + 

Hemosiderin deposition + 

Increased extramedullary 

.-_---------- " ---- ------------------- . ..--------------- 

hematopoiesis ~!------------ . ..--------" 

28 ta Spleen Liver 

Enlargement Focal necrosis of hepatocytes + 

Bone marrow 

Increased hematopoiesis 4 -

Spleen 

Congestion + 

Hemosiderin deposition + 

Increased extramedullary 

- hematopoiesis ++ 

-------------------------- " ------------ "----- . . .. . .-------- ---------------------------------___- 

29 ta Spleen Bone marrow 

Blackish change Increased hematopoiesis f 

Enlargement Spleen 

Congestion + 

Hemosiderin deposition + 

Increased extramedullary 

.- .. .-------------------------- " ----- hemato oiesis++ 

-------------------------------~ ------------------------------

30 ta Spleen Bone marrow 

Blackish change Increased hematopoiesis t 

Spleen 

Congestion + 

' Hemosiderin deposition + 

Increased extr°amedullary 

hematopoiesis ++ 

a) Organs/tissues examined as follows: trachea, lungs, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, 

colon, rechnn, liver, heart, kidneys, urinary bladder, testes, epididym.ides, ventral prostate, dorsolateral prostate, 

coagulating gland, seminal vesicle, cerebrum, cerebellum, pons, spinal cord, sciatic nerve, bone marrow, axillar lymph node, 

mesenteric lymph node, spleen, thymus, pituitary gland, thyroid, parathyroid, adrenals, eye ball, skeletal muscle, bone and 

mammary gland. 

ta, terminal autopsy. 

f, very slight; +, slight; ++, moderate. 
p. 212 

Addendum 13-7 'l~ven"ight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals ° 

Sex 

Exp.group Animal Fate Macroscopic findings Histopathological findinge 

(mg/kg1day) No. 

31 ta No abnormalities detected Spleen 

Hemosiderin deposition + 

------------------------------------------------

. . . .. .----------------------------------------------- 

32 ta No abnormalities detected Spleen 

Male 

------------- .----~o-

;~n-o- 

--------------------------- Heanosiderin deposition + 

-------- ------------------------------------- 

300 33 ta rmalities detected Spleen 

(Recovery) Hemosiderin deposition + 

-----------------------------------------------------------------------------------------------------

34 ta No abnormalities detected Spleen 

` Hemosiderin deposition + 

. .---. ..---------------------------------------------------------------------------------------------

35 ta No abnonnalities detected Spleen 

Hemosiderin deposition + 

a) Organs/tissues examined as follows: liver, bone marrow and spleen . 

ta, terminal autopsy- 

+, slight. 
p. 213 

Addendum 13-8 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals . 

-- -- ----- - --

Sex Exp.group N~ al Fate Macroscopic fiadings Histopathological ~ndings'~ 

Female Vehicle control 

36 ta No abnormahhes detected __-.----------No abnormalities detecte~d---------- ._ .-, . . . .----------------- . .. .. .. .. . . . .. - .. .. .

. . . .. . . . .. .. ... .. . . .. . 

------- ----37 ta No abnormalities detected -------------- No abnormalities ~~!# ------------ ---

38 

.. . . .. . .. . . .. . . . . . .. .. .... . .. .. . .. .. . . . .. . . . .. .. .. ... .. . . .. . ------- ------------- 

38 ta No abnormalities detected No abnormalities detected 

-------------------------------------------------------------------------------- .- .- . . .------------ 39 ta No abnormalities detected No abnormalities detected 

----------------------------------------------------------------------------------------------------- 

40 ta No abnor-malities detected Liver 

Microgranuloma + 

a) Organs/tissues examined as follows: trachea, lungs, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, 

colon, rectum, liver, heart, kidneys, urinary bladder, ovaries, uterus (horn and cervix), vagina, cerebrum, cerebellum, pons, 

spinal cord, sciatic nerve, bone marrow, axillar lymph node, mesenteric lymph node, spleen, thymus, pituitary gland, thyroid, 

parathyroid, adrenals, eye ball, skeletal muscle, bone and mammary gland. 

ta, terminal autopsy. 

+, slight- 
p. 214 

Addendum 13-9 Twenty-eight-day repeated dose oral toxicity study in rats 

_ Pathological find9ngof individual animals 

Sex E-xp.groiip-----Animal No. Fate --Macroscopic findings Histopatbological findings 

41 ta No abnormalities detected No abnormalities detected 

--------------------- . . .. . . . ..---------------------------------------------------------------------- . . 

Vehicle control ---- 

42 

----- 

ta 

--- 

No 

- 

abnormalities 

. 

detected 

.. . . . . . . .. .. . . . 

No abnormalities 

- 

detected 

---------- ; :----------- . .. . . . .. . .. . . . . Female (R=very) ._ . 43 . . . .. 

ta No abnormalities detected No abnormalities detected 

------------------- . .. ... .. . . .. . . . . . . . .. .. . . . .. .. . . . . .. . . . .. . . . . . .. .. .. . . . .. . . . .. ... . . . . ----

44 ta No abnormalities detected No abnormalities detected 

--------------------------------------------

. . .------------------------------------ . . .--------------

45 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy. 
p. 215 

Addendum 13-10 Twenty-eight day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

set- --J--Exp4oW 

~~ Fate Macroscopic findings Histopathological ~ndings°~ 

_46 ta No abnormalities detected No abnormalities detee 

. .-_47-----ta-.-No abnormalities detected _.--. .------- .No abnormalities detec * 

Female 10 48 ta No abnormalities detected No abnormalities detecte'd 

-------- ._ .----- . .--4--9 -------t-a ---N--o --a-h--n-o-r-m "

-a-li--t-ie-s 

--d-e-t-e-c--te-d----------------No --a-b-n-o--n-~---i-t-ie--'d--e-t-e-c-t-e-d 

-----------------=------------------------- " ------------------------- "------s--------------------- 

50 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: liver, bone marrow and spleen . 

ta, terminal autopsy. 
p. 216 

Addendum 13-11 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals " 

Sex Exp'group---Anima1 

mgkgday) No Fate Macroscopic findings Histopathological findings") . 

Female 30 

------------ -------------------------------------------------------------------- -- - ---- - -- 53 ta No abaormalities detected No abnormalities detected 

------------------------------------------------------------------- ----------- 

52, ta No abnormahhes detected No abnormaliti d tected 

51 ta No abnormalities detected No abnormalities detected 

-----; ;--.. .---.---------------------------------------------- .. . .----------- 

54 ta No abnormalities detected No abnormalities detected 

- __ es e 

-------------------------------;;------------------------------------------------------------- . . . . . .. . 55 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy- 
p. 217 

AddenduYn 13-12 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex- -"-~m~ y ) N~ pate lVtacroscopic findings Histopathological findings" 

56 ta No abnormalities detected . Spleen 

Hemosiderin depositio + 

----------------------------------------------p --------------------

.~ . .. . . . . .. . . . .. . . 

57 ta- No abnormalittes detected S leen 

Hemosiderin deposition+ . .--------- .._ . .----------------------------------------------------------------------

. ..-----------. . 

58 ta No abnormalities detected Spleen 

Female 100 Hemosiderin deposition + 

Increased extremedullary 

, 

------

. . . . . . .. .. . . . . . ... .. .. . . . . . . .. .. . .. . . .... .. . . . . .. . . .. . 

hematap~fiesis + 

- ------------ " ------- r . . . . .. . . . .. .. . .. 

59 ta No abnormalities detected Spleen , 

Hemosiderin deposition + 

---------------------------------------------------------------------------------------

. . . .-------. . .. 

60 ta Spleen Spleen 

Blackish change Hemosiderin deposition + 

s) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy. , 

+, slight. ' 

- 
p. 218 

Addendum 13-13 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals " 

Sex Exp'group---_-Aaimal 

Fate - -Macroscopic findings (mg/kg/day) No. Histopathological findings) 

61 ta Spleen Spleen 

Blackish change Congestion + 

Hemosiderin deposition ++ 

Increased extramedullary 

------------------------ "---------------------------- 

hematopoiesis + ------- 

---------------------------------. . . . 62 ta Spleen Liver 

Blackish change Hemosiderin deposition in Kupffer 

` cells + 

Increased extramedullary . 

hematopoiesis + 

Spleen 

Congestion + 

Hemosiderin deposition ++ 

Increased extramedullary 

---- ~ hematopoiesis + 

Female 300 --S -~~ "-- " .- ._ .-_------------------------ --__---------------------------- p Spleen 

Blackish change Hemosiderin deposition ++ 

Increased extramedullary 

----------------- ----- " -_ .- hemiesis + 

------------------------ ---------atopo----------------------------_-- P Bone marrow 

Blackish change Increased hematopoiesis f 

Spleen 

Hemosiderin deposition ++ 

Increased extramedullary 

hematopoiesis + ------------------------------- " ----------------------_- ._ .- . .-------------- "---- . .

65 .----------- ta No abnormalities detected Bone marrow 

Increased hematopoiesis t 

Spleen 

Hemosiderin deposition ++ 

Increased extramedullary 

hematopoiesis + a) Organsftissue,s examined as follows: trachea, lungs, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectund, liver, heart, kidneys, urinary bladder, ovaries, uterus (horn and cervix), vagina, cerebrum, cerebellum, pons, spinal cord, sciatic nerve, bone marrow, axillar lymph node, mesenteric lymph node, spleen, thymus, pituitary gland, thyroid, parathyroid, adrenals, eye ball, skeletal muscle, bone and mammary gland. ta, terminal autopsy. 

t, very slight; +, slight; ++, moderate. 
p. 219 

Addendum 13-14 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals -T- ! 

Sex - -~--V'Uoup m1 (mg/lcg/day) No. Fate Macroscopic findings Histopathological pndings`) 

66 ta No abnormalities detected Spleen 

---_- .-____ . . Hemosiderin depositio- ~++ 

------------------------- ------------- . . .---------- ..-------p ---------------------~--- 

67 - ta No abnormahties detected S leen 

Hemosiderin deposition -+-+ 

------------------------- " ---------------------------------------------------------------------------- 

Female 300 68 ta No abnormalities detected Spleen 

(Recovery) ' Hemosiderin deposition ++ 

. .------------------------------------------------------------------------------------ " ------ " -----

69 ta No abnormalities detected Spleen ' 

_---- Hemosiderin depositio +~-

---- .. .. . .. .. .. .. . .. . . . .. . . . .. .. . . . . .. .. .. ... .. .. . . . . " - . . ..--------------------------

ta No abnormalities .70 detected Spleen 

Hemosiderin deposition ++ 

a) Organs/tissues examined as follows: liver, bone marrow and spleen. 

ta, terminal autopsy. 

i-+, moderate. 
APPENDIX 

PHOTOS 

HISTOPATHOLOGICAL EXAMIIdATIONS 

(Study code: 4~) 
Photo. 1 Spleen of a male rat from vehicle control group. 

Normal. 

No. 1 animal . HE. x 187.5 . 

Photo. 2 Spleen of a male rat from 300 mg/kg/day group. 

Congestion and increased extramedullary hematopoiesis. 

No. 28 animal. HE. x 187.5 . 
Photo. 3 Spleen of a male rat from vehicle control group. 

Normal . 

No. 1 animal. Berlin blue . x 187.5 . 

i 

Photo. 4 Spleen of a male rat from 300 mg/kg/day group. 

Hemosiderin deposition . 

No. 28 animal . Berlin blue . x187.5 . 
_ APPENI?IXZFINAL REPORT 

STABILITY ANALYSIS OF(IM, HOMOGENEITY, STABILITYAND CONCENTRATION 

ANALYSES OF THE TEST SUBSTANCE FORMULATION 

(Study code: jlmb) 
CER~ 

I Receipt No. 

STUDY CODE: 4~ 

FINAL REPORT 

STABILITY ANALYSIS OI~, HOMOGENEITY, STABILITY AND 

CONCENTRATION ANALYSES OF THE TEST SUBSTANCE WSk1VIULATION 

September 2009 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 
p. 225 

STATEMENT 

I, the undersigned, hereby declare that this report provides a correct English translation of the 

final report (Study Code: ~, issued on September 25, 2009). 

. 

Y1MI~ 'Lvuae Oetbey 20 , 2tvl 

Yuji Kusune, M.S. Date 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 
GLP STATEMENT 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 

Sponsor: 

Title : Stabili y Analysis of ~ Homogeneity, Stability and Concentration 

Analyses of the Test Substance Formulation 

Study Code: 

1, the iKndersigned, hereby declare that this study was conducted in compliance with "Concerning 

Standard of the Testing Facilities Conducting the Test Relating to the New Chemical 

Substances" on Japanese GLP [Notification No. 1121003 of the Pharmaceutical and Food Safety 

Bureau, MHLW, No. 3 (November 17, 2003) of the Manufacturing Industries Bureau, METI & 

No. 031121004 of the Environmental Health Department, MOE (November 21, 2003)] and 

"OECD Principles of Good Laboratory Practice (November 26, 1997)". 

I also ,confirmed that this report accurately reflected the raw data and the test data were valid. 

Study Director: Signed in ori ig-al September 25, 2009 

~ Yuji Kusune, M.S . 
p. 227 

i 

QUALITY ASSURANCE STATEMENT 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 

Sponsor: 

Title : Stability Analysis of ~ Homogeneity. Stability and Concentration 

Analyses of the Test Substance Formulation ! 

Study Code: 4~ 

This study was inspected by Quality Assurance Unit of Hita Laboratory, Chemicals Evaluation 

and Research Institute, Japan The dates inspected and the dates reported these results to the 

study director and management are as follows 

Item of Inspections/Audits Dates of Dates of Report of 

Inspections/Audits Inspections/Audits 

Protocol April 22, 2009 April 22, 2009 

Confirmation of the answer from study April 23, 2009 April 23, 2009 director (protocol) 

IR spectrum of test substance April 24, 2009 April 24, 2009 

Homogeneity and stability analyses of April 27, 2009 April 27, 2009 test substance formulation 

Amendment to protocol May 15, 2009 May 15, 2009 

Confirmation of the answer from study May 15, 2009 May 15, 2009 director (amendment to protocol) ' 

Amendment to protocol (No. 2) May 15, 2009 May 15, 2009 

Amendment to protocol (No. 3) May 22, 2009 May 22, 2009 

Concentration analysis of test substance May 27, 2009 May 27 2009 formulation , 

Raw data and draft final report September 24, 2009 September 24, 2009 

Reinspection of raw data and draft final September 24, 2009 September 24, 2009 report 

I Final report September 25, 2009 September 25, 2009 

I, the undersigned, hereby declare that this report provides an accurate description of the methods 

and procedures used in this study, and that the reported results accurately reflect obtained raw 

data. 

Head, Quality Assurance Unit: - Signed in original September 25, 2009 

Masakazu Yoshida, B.S . 

-iv- 
TABLE OF CONTENTS 

Page 

, 

TITLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 3 

SPONSOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

TESTING FACILITY . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

PURPOSE OF STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

GLP COMPLIANCE . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

PERIOD OF STUDY . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 

STORAGE AND RETENTION PERIOD OF DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 4 

RETENTION OF ORIGINAL DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 4 

STUDY DIRECTOR AND PERSONS CONCERNED WITH THE STUDY AND THE 

OPERATION . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

APPRIOVAL BY AUTHOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

MATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

1 . TEST SUBSTANCE . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 6 

METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 

1 . SUBJECT STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . 7 

2. STABILITY ANALYSIS OF THE TEST SUBSTANCE . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 

3. HOMOGENEITY, STABILITY AND CONCENTRATION ANALYSES OF THE 

TEST SUBSTANCE FORMULATION . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . g 

THE ENVIRONMENTAL FACTORS THAT MIGHT HAVE AFFECTED THE 

RELIABILITY OF THE STUDY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 

RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 

1 . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 

2. DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 
TABLES 

-- --- - -- -

-1 I~omogeneity and stability analyses of the test substance formulation . . . . . . . . . . .

. . . . . . . . . . 14 , 

, 

2 Concentration analysis of the dose formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 14 I 

I 

FIGURES 

1 IR spectrum measured prior to the administration period . . . . . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 15 

2 IR spectrum measured.after the end of the administration period . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 

REFERENCE 

1 IR spectrum provided by the sponsor . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 
Study Code: 

Test Substance Code: 

Sponsor Code: 

TITLE 

Stability Analysis of 1~ Homogeneity, Stability and Concentration Analyses of the Test 

Substance Formulation 

SPONSOR 

TESTING FACILITY 

Hita Laboratory 

Chemicals Evaluation and Research Institute, Japan 

822, 3-chome, Ishii-machi, Hita, Oita 877-0061, Japan 

PURPOSE OF STUDY 

The purpose of this study is to determine the stability of the test substance during the dosing 

period, and homogeneity, stability and concentration of the test substance in formulation in 

"Twenty-Eight-Day Repeated-Dose Oral Toxicity Study MOW in Rats" (Study Code: 

GLP COMPLIANCE 

This ~tudy was conducted in compliance with "Concerning Standard of the Testing Facilities 

Conducting the Test Relating to the New Chemical Substances" on Japanese GLP [Notification 

No. 1121003 of the Pharmaceutical and Food Safety Bureau, MHLW, No. 3 (November 17, 

2003) of the Manufacturing Industries Bureau, METI & No. 031121004 of the Environmental 

Health Department, MOE (November 21, 2003)] and "OECD Principles of Good Laboratory 

Practice (November 26, 1997)". 
p. 231 

PERIOD OF STUDY 

- -Coinmencement of Study: 

Initiation of Examination (Initiation of Analysis) : 

Termination of Examination (Termination of Analysis) : 

Completion of Study: 

April 22, 2009 , 

April 24, 2009 

July 10, 2009 I 

September 25, 2009 

STORAGE AND RETENTION PERIOD OF DATA 

The raw data, protocol, amendments to protocol, study contract documents, test substance 

information, final report and other record documents will be retained in the archive of the Hita 

Laboratory of our organization for the same period of JIM paper data. After termination 

of the retention period, any measures taken will be done so with the approval of the sponsor. 

RETENTION OF ORIGINAL DOCUMENTS 

An original protocol, original amendments to protocol and an original fmal report will be 

retained at Hita Laboratory. The copies of their original that the study director will be 

recognized to be accurate copy will be sent to the sponsor . 

STUDY DIRECTOR AND PERSONS CONCERNED WITH THE STUDY AND THE 

OPERATION 

Study director: Yuji Kusune, M.S . 

Study staff Hiroko Sugimoto, B.S . 

Tomoko Kajiwara, B.S. 

(Analysis of the test substance) 

Saori Takakura, J.L.A.T., J.A.C.L.C.T. 

(Preparation of the test substance formulation) 

APPROVAL BY AUTHOR 

Study director: Signed in original September 25, 2009 

Yuji Kusune, M.S . 

Analytical Chemistry Section 

Hita Laboratory 
SUMMARY 

The test substance 40M was stable during the dosing period of subject study (Study Code: 

The test substance in 10.0 and 0.1 w/v°/a formulations was stable for 9 days after preparation at 

room temperature and showed good homogeneity . The concentration of test substance in 3.00, 

1 .00, 0.300 and 0.100 w/v% dose formulations for subject study was acceptable level. 
~oNFDENiul 

CONFIDENTIAL 
Melting point: 

Degree of solubility 

DMSO: 

Acetone: 

1.8 Storage Conditions 

The test substance was sent cryogenically and stored in the freezer No. 1 temporary. The 

test substance was stored at room temperature in the test substance storage room under a 

light shielding condition (actual temperature: 19.5-22.2°C, tolerance temperature: 

10-30°C) after obtaining storage information at room temperature . . 

Storage place and period : Cabinet No. 5, from March 19, 2009 to March 31, 2009 

Cabinet No. 1, from March 31, 2009 to July 10, 2009 

1.9 Handling Precaution 

`Gloves, mask, cap, protective glasses and lab coat were worn. 

The test substance was warmed up at about 40°C when precipitation of the test substance 

was observed. 

METHODS 

1. SUBJECT STUDY 

Twenty-Eight-Day Repeated-Dose Oral Toxicity Study of 410 in Rats (Study Code: 

loom 

2. STABILITY ANALYSIS OF THE TEST SUBSTANCE 

The infrared (IR) spectrum was measured by IR spectrophotometer before and after the 

dosing period of subject study. 

2.1 Measurement of IR 

' 1) Instrument 

IR spectrophotometer : FT-720 (HORIBA, Ltd.) 

2) Condition 

Wave number: 4000 cm"' - 500 cm"' 

,3) Pre-Treatment 

Potassium bromide neat 

2.2 i Criteria for Judgment 

IR spectrum of the test substance that measured prior to dosing in our laboratory should be 

~ identical with provided from the sponsor. The test substance was judged to be stable 

when there are no differences in the IR spectrums at before and after dosing period . 
CONFIDENTIAL 

PC-Ckes ,5? - t5 

TNFIDENTIA'