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## 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: PMNP10-0009 Gentlemen

: 

# Company Sanitized

We recently filed the subject PMNbut were only recently informed that a 28 Day Repeated-Dose Oral Toxicity Study in Rats study had been conducted, the results of which were alsojust received. We are, therefore, submitting herewith the full text ofthe 28 day repeat dose study - 3 copies of full text version, one copy ofnon confidential version . We apologize for the delay in sending the study but as indicated above, we havejust become aware of its availability and promptly submitting it to EPAupon its availability. 

## Ifyou have any questions, please contact the undersigned.

GSD/dk Enclosure 

# Company Sanitized 

# IIIIi II!I I Ilii~II!'II'i~IIi~II'I~liII IIi!! .II~iII 5 0 , U 0 0 0 0 i 1 0 , 

# 3P-2;a~~oa

### STUDY CODE: ~ Receipt No. 

# ~-9

~: 03 

# Company Sanitized FINAL REPORT

TWENTY-EIGHT-DAY REPEATED-DOSE ORAL TOXICITY STUDY OF



### INRATS

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_' ('-~t v ~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 ofthe 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 ofthe 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 ofdM in Rats Study Code: This study was audited and inspected by Quality Assurance Section ofHita Laboratory, Chemicals Evaluation and Research Institute, Japan. The dates audited and/or inspected and the dates reported ofthese results to the study director and management are as follows.

Items ofInspections andAudits Dates of Inspections

__ andAudits Dates ofInspections and Audits Reports 

### Protocol May 18, 2009 May 18, 2009 Assessment ofresponse (protocol) M ay22, 2009 May 222009 Amendmentto protocol May 22, 2009 May 222009 Preparation oftest 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 June26, 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 housingconditions _ September 14, 2009 September 14, 2009 

### Draft offinal report September 16, 2009 September 16, 2009 Re-inspection ofdraft final report _September 17, 2009 September 17, 2009 Draft offinal 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 ofAudits Dates ofAudits Dates ofAudits Rep orts 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 A pril 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 ofthe methods and procedures used in this study and that the reported results accurately reflect the raw data obtained. Section Chief, QualityAssurance: Signed in original _ September 28, 2009 Masakazu Yoshida, B

.S.

### TABLE OF CONTENTS IITI ;F.-: .. . :: .. ... .. .. .. .. ... .. .. .. ... .. .: .: .. ... .. .. ... .. .. . ... .. .. .. ... .. .. . : ... .. .. .. ... .. .. ... .. ... .. .. ... .. .. .. ... .. . SPONSOR .. .. .. .. ... .. .. .. ... .. .. .. .. .. ... .. ... . .. ... .. .. ... .. .. . ... .. .. ... .. .. .. .. ... .. ... . .. ... .. ... .. ... .. .. ... .. .. ... .. .. . TESTINGFACILITY ... .. .. .. .. ... .. .. ... . .. .. ... .. .. .. ... . ... .. .. ... .. .. .. .. ... .. .. .. .. ... .. ... .. .. ... .. .. ... .. ... .. .. . PURPOSE OF THE STUDY.. .. .. .. ... . ... .. .. .. ... .. .. .. .. .. ... .. .. .. ... .. .. .. ... .. .. ... . ... .. ... .. ... .. .. .. ... .. .. . TESTINGMETHOD

. .. .. .. .. .. .. ... .. .. ... . ... .. .. .. ... .. .. .. .. .. ... .. .. .. .. ... .. .. ... .. .. .. ... .. .. ... .. .. ... .. .. ... .. .. . GLP COMPLIANCE. .. .. .. .. .. ... .. .. ... .. . ... .. .. .. ... .. .. .. ... .. .. .. .. .. .. ... .. .. ... .. .. .. ... .. .. ... .. .. ... .. .. ... .. .. . PERIOD OF THE STUDY... .. .. .. ... .. .. .. .. .. ... .. .. .. .. .. .. ... .. .. ... .. .. .. .. ... .. .. ... .. .. .. ... .. ... .. .. .. ... .. .. . LOCAT10NAND PERIOD FORRETENTIONOF RAW DATA AND SPECIMENS .. .. .. ... .. .. .. ... . ... .. .. ... .. .. .. ... .. . .. ... .. .. ... .. .. .. ... . .. ... .. .. ... .. .. ... .. .. .. ... .. .. ... .. .. ... .. .. .. ... RETENTIONOF THE ORIGINAL PROTOCOL ANDFINAL REPORT °~~°~°~°~~~~~~ AUTHOR

ANDPERSONNEL CONCERNEDWITHTHE STUDY. ... .. .. .. .. ... .. .. .. ... .. AUTHOR

APPROVAL .. .. ... . .. ... .. .. ... .. .. .. ... . ... .. .. .. ... .. .. ... . ... .. .. .. ... .. .. .. ... .. ... .. . ... .. ... .. .. .. ... .. SUIVIMARY. .. .. .. .. .. ... .. .. .. .. ... .. .. .. .. .. ... .. .. .. ... .. .. .. .. .. ... .. .. ... . ... .. .. .. ... .. .. .. ... .. ... .. .. ... . ... .. ... . ... .. MATERIALSANDMETHODS.. .. .. .. .. .. ... .. .. .. .. .. ... .. .. ... .. .. .. .. .. ... .. .. ... .. .. ... .. .. ... . ... .. ... . ... .. 1 . 2 . 3. 4. 5. 6 . 7. 

### TEST SUBSTANCE . ... .. .. .. ... .. .. .. ... . .. ... .. .. .. ... .. .. .. .. ... .. .. .. ... .. .. ... .. .. ... .. .. .. ... .. ... . ANIMALS . .. ... . ... .. ... . ... .. .. .. ... .. .. ... .. . .. ... .. .. ... .. .. .. ... . ... .. ... . ... .. ... .. .. .. ... .. ... .. ... . ... . HOUSING CONDITIONS . ... .. ... .. .. .. .. .. .. ... .. .. .. ... .. .. .. .. ... .. ... .. .. .. .. ... .. .. ... .. ... . ... . GROUPING. .. .. .. .. ... .. .. .. .. .. ... .. .. ... .. .. .. :. .. .. ... .. .. .. ... .. .. ... . .... . ... .. .. .. ... .. .. .. ... ... .. .. .. . STABILITY OF THE TEST SUBSTANCE .. .. .. ... .. .. .. ... . ... .. .. ... .. .. .. ... ... .. .. ... .. PREPARATIONOF 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. . .. ... .. .. ... .. .. .. ... .. .. .. .. .. .. ... .. .. ... .. .. .. ... .. .. ... .. .. .. ... .. .. ... .. .. ... . ... . DETAILEDCLINICAL OBSERVATIONS . .. .. .. .. .. ... .. .. ... .. .. .. ... .. .." .. .. .. ... ... . . SENSORIMOTOR FUNCTION .. .. .. .. .. ... .. .. .. ... .. .. ... . ... .. .. ... .. .. .. ... .. ... .. ... .. .. ... . . BODYWEIGHTS .. ... .. . ... .. .. .. ... .. .. .. ... .. .. .. .. ... .. .. .. ... .. ... . ... .. .. .. ... .. ... .. .. ... .. .. .. ... .. FOOD INTAKES . .. .. .. .. ... .. .. .. ... .. .. .. ... .. .. .. .. .. ... .. .. ... .. ... . ... .. .. .. ... .. .. ... .. ... .. ... . ... .. HEMATOLOGICAL EXAMINATIONS .. .. .. .. ... .. .. ... .. .. .. .. ... .. .. ... .. .. ... .. ... .. ... . BLOODCHENIICAL EXAMINATIONS . .. .. ... .. .. .. ... .. .. ... .. .. .. .. ... .. ... .. .. ... .. ... . URINALYSES- . .. .. ... .. ... .. .. .. .. .. .. ... .. .. .. ... .. .. .. ... .. .. .. ... .. .. .. ... .. .. ... .. .. .. ... .. .. .. ... ... .. . ORGANWEIGHTS .. ... .. .. .. ... . ... .. ... .. .. .. .. .. .. ... .. .. .. ... .. .. .. ... ... .. .. .. ... . ... .. .. ... .. ... .. . NECROPSY.. ... . .. ... .. .. ... .. .. .. ... .. .. .. ... .. .. .. .. ... .. .. .. .. .. ... .. ... .. .. ... .. .. .. ... . ... .. .. ... ... .. .. . HISTOPATHOLOGICAL EXAMINATIONS .. .. .. .. ... .. .. ... .. .. .. ... . .... . ... .. ... .. .. . vi -

### DISCUSSION . . .. .. . .. .. . .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. . .. .. .. .. .. . .. . .. .. . .. . : .. . .. .. .. .. .. . .. .. .. .

REFERENCE-: .-

. .: . : : .. .. .. . .. .. . .. .. .. . .. .. .. . ..: : . ... .. . .. . .. .. . .. .. .. .. . .. .. . .. .. . .. .: .. .. . .. .. .. .. . .. .. .. . FIGURES 1 Body weights . ... .. .. .. . ... .. .. ... .. .. .. .. .. .. ... .. .. ... .. .. ... . .. ... .. .. .. .. ... .. .. .. .. ... .. .. .. .. ... .. ... . ... 2 Food intakes . .. ... .. .. .. .. .. .. .. .. ... .. ... . .. ... .. .. .. ... .. .. ... . .. ... .. .. .. ... .. .. .. .. .. ... .. .. .. .. ... .. ... .. .. 23 25 26 28 TABLES 1 Summaryof clinical signs . . . . . . .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . .. . . .. .. . . . . . . . . . . . . .. . . . . . . 30 2 Summaryof detailed clinical observations . . . .. . . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. .. . . . . 31 3 Summaryof reflex . .. . . . . . . . . . . . . . .. .. .. . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . .. . . . . . . . . .. . . . . 56 4 Summaryof 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 Summaryof blood chemical examinations. . . . . . . . . . . . . . . . . . . . . . . .. .. .. . . . . . . . . . . . . . . .. . . . . . . . . 67 10 Summaryof urinalyses . . . . . . . . . . . .. .. . . . . . . . . . . . . . . .. . . .. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . .. . . . . 69 11 Summaryof absolute organweights . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . 72 12 Summaryof relative organweights . . . . . . . . . . .. . . . . . . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . . . 74 13 Summaryof macroscopic examinations . . . . . . . . . . . . .. . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 76 14 Summary of histopathological examinations . . . .. .. . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . 77 

### ADDENDA 1 Clinical signs ofindividual animals. .. .. ... .. .. .. ... .. .. .. .. .. ... .. .. .. .. ... .. .. .. .. ... .. .. ... .. .. . 82 2 Detailed clinical observations ofindividual 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 ofindividual animals . .. .. .. .. ... .. .. .. ... .. . .. ... .. ... .. .. .. ... .. .. ... . 180 10 Urinalytic data of individual animals ... .. .. ... .. .. .. .. .. ... .. .. .. ... .. . ... .. .. ... .. .. ... .. .. .. ... . 184 1 ~ Absolute organ weights ofindividual animals . .. .. ... .. .. .. ... .. .. .. .. .. ... .. .. ... .. .. .. ... . 190 1 4 Relative organweights of individual animals . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 13 Pathological findings ofindividual animals . . . . . . . . . . . . . . . . . . . .. .. . . . . . .. . . . . . . . . . .. . . . . . . . . . . 198 APPENDIX 1 Photos (Histopathological examinations) APPENDIX 2 "STABILITY ANALYSIS OF d1so HOMOGENEITY, STABILITY AND

CONCENTRATIONANALYSES 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

TESTINGFACILITY 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. TESTINGMETHOD This studywas 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 ofthe 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 ofthe 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 "OECDPrinciples of Good Laboratory Practice" (November 26, 1997) .

### PERIODOF THE STUDY

CommencbmentoftheStudy: - Animal Receipt: Initiation ofExamination (Initiation ofDosing) : Terminal Necropsy ofDosing Period: Initiation ofRecovery Period: Terminal Necropsy ofRecovery Period: Termination of Examinati on (Termination ofHistology) : Completion ofthe 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 LOCATIONANDPERIOD FORRETENTION OF RAW DATAANDSPECIMENS 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 ofthe 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 fromthe 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 ofour organization ofthe 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 ofthe preparation permits evaluation, and they will be disposed with approval ofthe sponsor. RETENTIONOF THE ORIGINAL PROTOCOL ANDFINAL REPORT 

### The original protocol and protocol amendments and final report will be retained at Hita Laboratory. A copy ofthe document will be retained by the sponsor.

### AUTHORAND PERSONNEL CONCERNEDWITHTHE 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 ofthe 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 examinati on) Person in charge ofPathologic Examina tion: Satsuki Hoshuyama, Ph.D:, D .V .M . (Necropsy, collection of tissues, organ weight measurements, histopathological examinations, and responsible for the histopathology) Person in charge ofClinical Chemistry: Nobuhiko Higasihara, B .S. 

### (Hematological and blood chemical examinations, urinalysis, and responsible for the biochemistry ofthe specimens)

, AUTHORAPPROVAL 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 offive 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 ofthe 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 300mg/kg group. On blood chemistry, aspartate aminotransferase and alanine aminotransferase were increased in males in the 300mg/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 100mg/kg and higher group and males in the 300 mg/kg group, and enlargement in males in the 300 mg/kg groupwere 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 100mg/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 substancewas sent cryogenically and stored in the freezer No. 1 temporary. The test substance was stored at roomtemperature (19.5-22 .2°C fromobtaining storage information to the final preparation ofthe 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 thetest substance was observed. 

### 2 . ANIIVIALS Cr1 :CD(SD) rats (SPF) of 38 males and 38 females were obtained fromCharles 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 treatedwere excreted from the study and used for treatment training. At the onset oftreatment, the animals were five weeks old with body weight ranges of 148.7-175.0 g and 121 .1-148.7 gfor 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-systemanimal rooms (quarantine roomNo . 1 during the quarantine period and roomNo . 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 Hmm, TOKIWA KAGAKUKIKAI) 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 ofthe dosing period for the recovery group. The animals had free access to an MF pelleted diet (Lot No. 090119, Oriental Yeast) and chlorinated water fromHita City supply via automatic watering systemwithsipper 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 ofthe "Notification No. 101 of Environmental Health Bureau, MHLW ' except for test ofthe taste and residual chlorine in our Hita Laboratory. Contaminants in the waterwere in thestated 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, 500and 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 ofthe spleen was bbserved in the same dose group, and hemolytic anemia wassuggested . 

### 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 ofAnimals (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 ofthe 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 . PREPARATIONOF FORMULATIONS 6 .1 Vehicle + In preparation investigation ofthe 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 3.00w/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 3.00w/vO/o 300 0.300 Diluted with 30 mL of3.00 w/vO/o 300 0.100 Diluted with 10 mL of3.00 w/vO/o 300 June 5, 2009 3.00 18 .00 g 600 1 .00 Diluted with 100 mL of3.00 w/vO/o 300 0.300 Diluted with 30mL of3.00w/vO/o 300 0.100 Diluted with 10 mL of3.00w/vO/o 300 June 12, 2009 3.00 18.00 g 600 (warmed up to 40°C 1 .00 Diluted with 100mL of3.00w/vO/o 300 because of precipitation 0 .300 Diluted with 30 mL of 3 .00 w/v% 300 

### ofthe test substance) 0 .100 Diluted with 10 mL of3.00 w/vO/o 300 June 19, 2009 3.00 18.00 g 600 1 .00 Diluted with 100 mL of 3.00w/vO/o 300 0 .300 Diluted with 30 mL of3.00 w/v% 300 0 .100 Dilutedwith 10 mL of3.00 w/v% 300 6 .3 Homogeneity and StabilityAnalyses 

### The homogeneity and stability tests were performed in Hita Laboratory (see APPENDIX 2, ,Study code: 400M

. In the homogeneity test, top, middle and bottomlayers 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 roomtemperature and analyzed after 4 and 10 days. The test substance in formulations was confirmed to be stable for 9 days. 6.4 1ConcentrationAnalyses 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 ofthedosing 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 28days. 8. OBSERVATIONS Concerning the numbering of day andweek, the day ofthe 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 examinati on 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 ofremoval 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 ofpools) 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 ofthe 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 cmfrom the animal's nose for 4 seconds. (2) Pinna response The animal's response to a sudden sound offinger snapwas 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 ofthe animal's eyes, pupil constriction in response to a bright beamofpenlight 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) . Locomotoractivity counts 

### Locomotor activity level of each animal was counted with activity monitoring systemfor rats (ACTIMO-10, SHINTECHNO) by the number of crossing IRbeamfor 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 ofthe 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 --Tloodorplasma samples ob~ained by blood sampling fromthe 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% sodiumcitrate 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 ofleukocytes (%) Neutrophils (Neutro) Eosinophils (Eosino) Basophils (Baso) Lymphocytes (Lymph) Monocytes (Mono) Large unstained cells (LUC) Method Electrical resistance detection Electrical resistance detection Noncyanhemoglobin method RBCx MCV 103 Electrical resistance detection Rb x 103 RBC Hb x102 

# 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/Gratio 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 AutomaticAnalyzer, Hitachi PVA-EXII, A&T 

### Method UV method (method based onJSCC) UVmethod (method based onJSCC) 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 

### OCPCmethod Fiske-Subbarowmethod 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 WX200Dx263 H mm) were determi*d with drinking water ad lib. The urine sediments was stained and examined in males and females ofthe vehicle control and 300mg/kggroups 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 ofthe 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 ofnecropsy. *=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 (duodenumto rectumwith 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/?" showgroups 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 ofthe test substance were observed in males and females ofthe 300 mg/kg group, histopathological examinations for both sexes ofall groups including the recovery groups were done.

### (3) Gross lesions in the kidney (animal No . 6 and 7) in the vehicle control recovery group --- -wereexamined 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 FACTORSTHAT NIIGHT HAVE AFFECTEDTHE RELIABILITY OF I THE STUDY RESULTS There'were no factors which might have affected the reliability ofthe test data or deviation from the protocol .

### RESULTS 1. CLINICAL SIGNS (Table 1, Addendum1) 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 300mg /kg group after day 5. No abnormalities were observed in the vehicle control, 10 or 30mg/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 3,4and 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 300mg/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, Addendum6) 4 .1 During Dosing Period Nostatistically significant changes ofbody 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, Addendum7) 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/kggroups. 5 .2 During Recovery Period 

### No, significant changes were noted in males or females. 6 . HEMATOLOGICAL EXAD'IINATIONS (Table 8, Addendum8) 6 .1 At Termination of Dosing Period In males, RBC, Hb and Ht were decreased in the 300 mg/kg group. MCVand 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/kggroups. 

### 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 30mg/kg groups. 

## I 6 .2 *t Termination of Recovery Period In males, All of RBC, Hb, Ht, MCV, reticulocytes, WBCand lymphocytes showed recovery. Although no abnormalities were notedat theendofthe dosing period, increases ofplatelet and -20-

### _ p.29

- basophils were newly noted in the 300 mg/kg recovery group . In females, RBCwas 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 ofthe dosing period. 7. BLOODCHENIICAL EXAMINATIONS (Table 9, Addendum 9) 7.1 At Termination ofDosing Period AST, ALT, ALP and IP were increased in males of the 300 mg/kg group. No statistically significant changes were noted in males ofthe 10, 30 or 100mg/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 inA/Gratio were newly observed in males ofthe 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 300mg/kg recovery group. 8. URINALYSES (Table 10, Addendum10) 8.1 At Termination of Dosing Period Noabnormalities 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/kggroups. 

### -21-

### In females, an increase in relative liver weight, increases in `absolute and relative spleen ghts idecrease in relative adrenal weightwere noted in the 300 mg/kg group. Organ i -f -iHU weights in the 10, 30 and 100 mg/kggroup 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 ofthe 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, Addendum13) 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/kggroups. 

### 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 Terminationof 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, Addendum13) 11 .1 At Termination of DosingPeriod 

### 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 ofthe ventricle in the cerebrumin one animal each were noted in the vehicle control group . Focal necrosis ofthe 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'mthe 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 marrowlesions 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 thevehicle 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 andspleen and increases in the reticulocyte rate and MCVwere considered to be compensational changes for the anemia. Increased spleen weight was considered to be dueto 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 100mg/kgand higher dose group was related to theanemia. 

### 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, MCVwas newly increased, but the change was not observed at the completion ofthe 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 fromthe 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 ofthe lower abdomenwas 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 metabolismin 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 ofnotoxicological 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 ofthe 100mg/kg and higher group.

### REFERENCES Ito Y . Twenty-eight-day Repeated Dose Oral Toxicity Test of N-Ethylaniline in Rats. Japan Existifng Chemical Data Base (inJapanese) . Tanimoto Y

. (1988) Laboratory Animal Series 5, Biochemistry of Blood and Urine in Experimental Animals. 92, Soft Science Inc., Tokyo, Japan (inJapanese) . 

### Matsuo R (2000) Role of saliva in the maintenance oftaste 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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~ ~ 8 p ~ ~ 8 d ~ ~Table 1 Twenty-eight-day repeated-dose oral toxicity study in rats Summary ofclinical 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 (justbeforedosing to just after dosing) 1 Staining,lower abdomen a) Number ofanimals 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 ofremoval

-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 HANDLINGOBSERVATIONS



### 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-doseoral toxicity study in rats

Summary ofdetailed-clinical observations (scoring-scale for detailed clinical observations) HANDLINGOBSERVATIONS-continued

Exophthaimos Pupillary size
Salivation Secretion 

### - Absent

+ Present -1 Miosis 0 Normal +1 Mydriasis

- Absent + Present

- Absent + Present OBSERVATIONS 1NARENA

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-doseoral toxicity study in rats

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

### OBSERVATIONS INARENA-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 

### Systematictonic 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-doseoral toxicity study inrats

Summaryofdetailed cli nical observations - _ Removal from cage Sex Period Exp. group Number of Ease ofremoval 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 0Table 2-2 Twenty-eight-day repeated-dose oral toxicity study in rats S-u_rwnKy-afdetailed clinical observations Removal from cage Sex Period Exp. group Number of Ease ofremoval 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 ofdetaile"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 -week4 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-doseoral toxicity study in rats

S .ummarl-ofdetailed 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 0Table 2-5 Twenty-eight-day repeated-dose oral toxicity study in rats Summary o

fdetailedr.linical observations -- - 

### Handling observations Sex Period Exp. group Number of Staininghair Unkempthair 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 week3 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 0Table 2-7 Twenty-eight-day repeated-dose oral toxicity study inrats Summery ofddailed_clinical observations - - 

### Handling observations Sex Period Exp . group Number of Cyanosis Lacrimation Exophthal mo s (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 0Table 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 0Table 2-10Twenty-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 0Table 2-11 Twenty-eight-day repeated-dose oral toxicity study in rats Summary o

fdcUdedc_li nical 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 week2 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 2-12Twenty-eight-day repeated-doseoral toxicity study in rats Summaryofdetail ed 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 Vehiclecontrol 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-doseoraltoxicity study in rats

Summary ofdetailed 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 2-14Twenty-eight-day repeated-doseoral toxicity study in rats -Summaryofdetailed 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 0Table 2-15 Twenty-eight-day repeated-dose oral toxicity study in rats Summary ofdetailed 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 week3 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 1week2 300 5 5 0 0 0 0

### Table 2-16Twenty-eight-dayrepeated-dose oral toxicity study in rats Summaryofdetailed 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 inrats

Summaryofdetailed 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 fromvehicle control at P<0 .05. ** Significantly different from vehicle control at P<0

.01 .

### p. 59

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

Summaryofdetailed 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~m in)') 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 vehiclecontrol at P<0

.05. ** Significantly different from vehicle control at P<0

.01 .Table 2-19Twenty-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 2-20Twenty-eight-day repeated-dose oral toxicity study in rats Summaryofdetailed clinical observations Period Exp.group Observations in arena Number of Stereotypicbehavior (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 week3 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-doseoral toxicity study in rats

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

Summaryofdetailed clinical observations Observations in arena Sex Period Exp. group Number of A bnorm al 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-doseoral toxicity study in rats

Summaryofreflex (scoring scale for reflex) SENSORIMOTORFUNCTION

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 rightingreflex

+ Normal - Abnormal reactionTable 3-1 Twenty-eigbt-day repeated-dose oraltoxicity study in rats Summary ofreflex 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

Summaryofreflex Sensorimotor function Sex Period Exp . group Number of Pain response (tail pinch) Pupillary refl ex 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 370f27 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 fromvehicle control at P<0 .05. ** Significantly different from vehiclecontrol at P<0

.01 .Table 5 Twenty-eight-day repeated-dose oral toxicity study in rats Summary ofx

moor_~Cdvlty Sex Period Exp . group Numberof 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 differentfrom vehicle control at P<0

.05. ** Significantly different from vehicle control at P<0

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### Addendum

2-1 Twenty-eight-day repeated-dose oral toxicity study in rats

. --Detailed-elieieal observations ofindividualanimals (Predosing) -- Sex Exp,group AnimalNo Removal fromcage

. (mglkg/day) Ease ofremoval 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-doseoral toxicity study in rats

__ -- --Detailed clinical observations-ef individual-animals (Predosing) Sex Exp.group Animal No . Removal from cage

. (mg/kg/day) Ease ofremoval 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 0Addendum 2-3 Twenty-eight-day repeated-dose oral toxicity study in rats --Detailed-ctimcal observations ofindividual animals (week 1) 

### Sex Animal No.

Exp.group Rmnoval fromcage (mg/kg/day) Ease ofremoval 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 0Addendum 2-4 Twenty-eight-day repeated-dose oral toxicity study in rats

-~- -I3~ etailed clinical observaYions ofindividual ani m

als (week 1) Sex Exp'gr°up Animal No . Removal fromcage. (mg/kg/day) Ease ofremoval 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 ofindividu-la animals (week 2) Sex ExP~grouP Animal No . Removal from cage (mg/kg/day) Ease ofremoval 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

### Addendum2-6 Twenty-eight-dayrepeated-doseoral toxicity study in rats

_ _ _ _ Detailed clinical observations-of individualanirnals (week 2) Sex Exp.group Animal No. Rem oval f romcage (mB4Wday) Ease ofremoval 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-elfnkMObservati ons ofindividua 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 0Addendum 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 ofremoval 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

### Addendum2-9 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 ofremoval 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 0Addendum 2-10 Twenty-eight-day repeated-dose oral toxicity study in rats



### __ _ -___-DcWledclinical observations-of individual-animals (week 4) Sex Animal No . Exp .group Removal fromcage (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 0Addendum 2-11 Twenty-eight-day repcated-dose oral toxicity study in rats -Detaiied-cliaicai observations ofindividualanimals (Recovery week 1) Sex Animal No . 

### Exp.gronp Removal fromcage (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

### Addendum2-12 Twenty-eight-day repeated-dose oral toxicity study in rats

_ _ --------Detail ed clinical observations-of individual animals (Recovery week 1) Sex Exp.group Animal No . Removal from cage - (mg/kg/day) Ease ofremoval 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-doseoral 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 ofremoval 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

### Addendum2-14 Twenty-eight-day repeated-dose oral toxicity study in rats -- - -----D

etailed clinical observations-Dfindividual-animals (Recoveryweek 2 )

Female 

### (mglk¬

Jday) Exp.group Animal No

. Removal from cage Ease ofremoval 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

Addendum2-15 Twenty-eight-day repeated-dose oral toxicity study in rats

-- --Detailed-clinical-observations ofindividual 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 0Addendum 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 0Addendum 2-17 Twenty-eight-day repeated-dose oral toxicity study in rats - Detailed-clin1W

-observations ofindividual 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

Addendum2-18 Twenty-eight-day repeated-dose oral toxicity study in rats

__ -cisiled clinical observations-ofindividual 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 observati ons ofindividual 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 ofindividual 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

Addendum2-21 Twenty-eight-day repeated-dose oral toxicity study in rats

Detailed clinical obs

ervations 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 - - ~ - - -

### Addendum2-22 Twenty-eight-day repeated-dose oral toxicity study in rats Detailed clinical observations ofindividual 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

Addendum2-23 Twenty-eight-day repeated-dose oral toxicity study in rats

-Detailed clinical obs

ervations 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-ofindividual -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 . --Detaiiedolinical observations of individualanimals (Recove ryweek 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 0Addendum 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 ofindividual 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

Addendum2-28 Twenty-eight-day repeated-dose oral toxicity study in rats - -- -----Heteikd clinical observation"findividual-animals (Recoveryweek 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

### Addendum2-29 Twenty-eight-day repeated-doseoral toxicity study in rats --Detaited-cllttirff observations ofindividuVanimals (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 ofindividual 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

### Addendum2-32 Twenty-eight-day repeated-dose oral toxicity study in rats - _ __- Detailed clinical observations-ofindividual 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

### Addendum2-33 Twenty-eight-day repeated-dose oral toxicity study in rats

__Detailed rlinicalobservations ofindividual 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 ofindividual 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 --- ---Det ailed 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 0Addendum2-37 Twenty-eight-day repeated-dose oral toxicity study in rats -Detailed-eli :ricxl observations ofindividual 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-0findividual animals (week 4) H andl ing observati ons 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

### -

Addendum2-39 Twenty-eight-day repeated-dose oral toxicity study in rats

--Detai7-edcl`uriddobservati ons ofindividnff animals (Recoveryweek 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 inrats

_.____-Djetailed clinical observations-ofindividualanimals (Recovery week 1) 

### Handlingobservations 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 ofindividual animals (Recovery week2) 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 70 - - - 0

### Addendum2-43 Twenty-eight-day repeated-dose oral toxicity study in rats -Detailsd-Winical observations ofi 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-doseoral toxicity study in rats - -- ---------i ~~aed clinical observations-ofindividual 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 0Addendum 2-45 Twenty-eight-day repeated-dose oral toxicity study in rats --Detaiied-clinMobservations o findividual 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

### Addendum2-46 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 0Addendum2-47 Twenty-eight-day repeated-dose oral toxicity study in rats -Hetail~ealobservations ofindividual-animals (week 2) 

### ' Observations in arena Sex Exp. group Animal No . Posture Motor Respiration Lid Gait (mgf1cg/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 0Addendum 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

### Addendum2-49 Twenty-eight-day repeated-dose oral toxicity study in rats ° --Detailed clini

cai observations ofindividuia 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

### Addendum2-50 Twenty-eight-day repeated-doseoral 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

__Detailedcli`m

- c--la observations ofindividiuaI 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 0Addendum 2-52 Twenty-eight-day repeated-dose oral toxicity study in rats 

### --- -- --Detailed clinical observations-ofindividual animals (weak4) 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 ofindividual 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 ofindividual 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-doseoral toxicity study in rats - - ----Hetailed clinical observations-ofindividual 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

### Addendum2-57 Twenty-eight-day repeated-dose oral toxicity study in rats - -Detall®d-slinie

.$1 observations o

f 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 Addendum2-58 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

### Addendum2-59 Twenty-eight-day repeated-dose oral toxicity study in rats -- -Detailed-cli-ric`alobservations ofindividual 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-dayrepeated-doseoral toxicity study in rats

_ _ - D etailed clinical observations-ofindividual-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 0Addendum 2-61 Twenty-eight-day repeated-dose oral toxicity study in rats -Detailed-elirrieal observations ofindividual animals (week2) 

### 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 0Addendum 2-62 Twenty-eight-day repeated-dose oral toxicity study in rats .___- .Detailed clinical observations ofindividual 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 0Addendum 2-63 Twenty-eight-day repeated-dose oral toxicity study in rats Detailed clinical observations ofindividual 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 ofindividual_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-doseoral 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 ofindividual_animals (week4) 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 0Addendum 2-67 Twenty-eight-day repeated-dose oral toxicity study in rats

- .Detailod-slisisal observations ofindividual 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-ofindividual-animals (Recoveryweek 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

### Addendum2-69 Twenty-eight-day repeated-dose oral toxicity study in rat

__Detailedr.linical-observations ofindividual animals (Recoveryweek 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 0Addendum 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 0Addendum 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

Addendum3-2 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

### Addendum4-2 Twenty-eight-day repeated-dose oral toxicity study in rats _-_- Grip strengrth ofindividual-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 388Addendum 5-1 Twenty-eight-day repeated-dose oral toxicity study in rats

__MotQ r-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 11 217 40 31 43 53 0 384 F 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 ' Addendum5-2 Twenty-eight-day repeated-dose oral toxicity study in rats

Motoractivity ofindividual 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 895N q A b O q A

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### p. 206

Addendum 13-1 Twenty-eight-day repeated-dose oraltoxicity study in rats

Pathological findings of individual animals Sex Ezp-group -No aFate -Macroscopic findings
Male Vehicle control Histopathological findings') 1 ta Noabnormalities detected No abnormalities detected - 2 s d 

### - ------ ~W 'Ro no

. ----------------~Wo ;!~o- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E 3 n s er Microgranuloma + ta 11 i~ . . . . . . . . . . . . ---------------6ei ;~j ;~ ;-------------------------------- Dilatation ofventricle + ----------------------------------------------------------------------------=----------------------- 

### 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 mammarygland

. ta, terminal autopsy- +, slight

### ' p. 207

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

Pathological findings ofindividual 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 Noabnormalities detected

------ . . .---------------------------------------------------------------------- . . . . .--- . . .---------- 9 ta No abnormalities detected Noabnormalities detected . . . . .- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ----------- .----------------- 10 ta No abnormalities detected Noabnormalities 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 oraltoxicity study in rats

Pathological findi n~s ofindividual anim als sex E~'~°~---~m~ Fate -Macroscopic findings

(ing/lcg/day) No

. Histopathological findings) 11 ta Noabnormalities detected No abnormalities detected

---------------------------------------------------------------------------------------------------- . . 12 ta Noabnormalities detected No abnormalities detected ---------- ------------------------- . . .-------------- . . .-------------- . . . . . . . .------------------------- Male 10 13 ta No abnormalities detected Noabnormalities 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 andspleen. 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 Noabnormalities dete " ---------------------------------------------------------- ------------------------ ------------- 17 ta No abnormalities detected No abnormalities detect~d
------- . ._. . . .---------------------------------- . . . . .-------------------------------- .___. Male 30 18 ta Noabnormalities detected _ No abnormalities detecte~d -----------

-- ---------------------------------------------------------- -------------------------------------- . . 19 ta Noabnormalities detected No abnormalities detected ------------ ---------------- ; ;----------------------------------------------------------- ._. . .--- . . 20 ta ---No abnormaht<es detected No abnormalities detected a) Organs/tissues e

xamined 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 Noabnormalities detected . .-----------------------------------------------------------------------=-------------------------- 22 ta No abnormalities detected Noabnormalities 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 Noabnormalities detected 25 ta Noabnormalities detec ted Noabnormalities detected

### p. 211

Addendum 13-6 Twenty-eight-day repeated-dose oral toxicity study in rats

Pathological find

i ngs ofindividual animals -- ---- Sex -----Exp-group

(mg/k ¬ ~day) ~~ Fate Macroscopic findings . Histopathological fin.dings`)

ta Spleen Spleen Blackish change Hemosiderin depositiori + Increased cxumedullary

4-4- h to

Male 300 

### 26 iesxs
. .------------------- " ---- " - " ------------= ----- . ._- ema po -___.___. . -- .- . . .------ " ------==------------- " 27 ta Spleen Liver

Blackish change Increased extramedullary hematopoiesis + Spleen Congestion + Hemosiderindeposition + Increasedextramedullary .-_---------- " ---- ------------------- . . .--------------- hematopoiesis ~!------------ . . .-------- " 28 ta Spleen Liver

Enlargement Focal necrosis ofhepatocytes + Bone marrow Increasedhematopoiesis 4 - Spleen Congestion + Hemosiderin deposition + Increasedextramedullary - 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, eyeball, skeletal muscle, bone and mammarygland

. 

### 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 ofindividual animals ° Sex Exp.group Animal Fate Macroscopic findings Histopathological findinge

(m g/kg1day) No.

31 ta Noabnormalities 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 Noabnormalities detected Spleen ` Hemosiderin deposition +
. .--- . . .--------------------------------------------------------------------------------------------- 35 ta No abnonnalities detected Spleen Hemosiderin deposition + a) Organs/tissues examined as follows: liver, bone marrow andspleen. ta, terminal autopsy- +, slight.

### p. 213

Addendum 13-8 Twenty-eight-day repeated-dose oral toxicity study in rats

Pathological findings ofindividual 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 -------------- Noabnormalities ~~!#------------ --- 38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .------- ------------- 38 ta No abnormalities detected Noabnormalities 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 andcervix), 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 repeateddose oral toxicity study in rats

_ Pathological find9ngofindividual animals Sex E-xp.groiip-----A nimal No. Fate --Macroscopic findings Histopatbologicalfindings 41 ta No abnormalities detected No abnormalities detected

--------------------- . . . . . . . . .---------------------------------------------------------------------- . . Vehicle control ----42----- ta ---No -abnormalities
.detected

. . . . . . . . . . . . . . . No abnormalities -detected

. . . . . . . . . . . . . . . ---------- ; :---- ------- Female (R=very) ._. 43
. . . . . ta Noabnormalities detected Noabnormalities detected

------------------- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ---- 44 ta No abnormalities detected Noabnormalities detected

-------------------------------------------- . . .------------------------------------ . . .-------------- 45 ta No abnormalities detected No abnormalities detected a) Organs/tissues examined as follows: liver, bone marrow andspleen. ta, terminal autopsy

.

### p. 215

Addendum 13-10 Twenty-eightday repeated-dose oral toxicity study in rats

Pathological findings ofindividual animals set- --J--Exp4oW ~~ Fate Macroscopic findings Histopathological ~ndings°~ _46 ta No abnormalities detected Noabnormalities detee

abnormalities * . .-_47-----ta- .-No detected

_.-- . .------- .Noabnormalities detec Female 10 48 ta No abnormalities detected Noabnormalities 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 inrats

Pathological findings ofindividual animals " Sex Exp'group---Anima1 Fate Macroscopic findings Histopathological findings")

mgkgd ay) No.

------------ -------------------------------------------------------------------- ---------- Female 30 53 ta No abaormalities detected No abnormalities detected ------------------------------------------------------------------- ----------- 52, ta Noabnormahhes detected No abnormaliti d tected 51 ta Noabnormalities detected No abnormalities detected

-----;;-- . . .---.---------------------------------------------- . . . .----------- 54 ta No abnormalities detected Noabnormalities detected

- __ es e

------------------------------- ; ;------------------------------------------------------------- . . . . . . . . 55 ta No abnormalities detected Noabnormalities 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 ofindividual animals Sex- -"-~m~

y ) N~ pate lVtacroscopicfindings Histopathological findings" 56 ta No abnormalities detected . Spleen Hemosiderin depositio + ----------------------------------------------p-------------------- .~ . . . . . . . . . . . . . . . . 57 ta- No abnormalittes detected S leen Hemosiderindeposition+
. .--------- . ._. .---------------------------------------------------------------------- . . .----------- . . 58 ta Noabnormalities detected Spleen Female 100 Hemosiderin deposition + Increasedextremedullary

,

------ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . hematap~fiesis + - ------------ " ------- r. . . . . . . . . . . . . . . . 59 ta Noabnormalities 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 + Increasedextramedullary . hematopoiesis + Spleen Congestion + Hemosiderin deposition ++ Increasedextramedullary ---- hematopoiesis + ~ --S-~~" -- " .- ._ .-_------------------------ --__---------------------------- Female 300 p Spleen Blackish change Hemosiderin deposition ++ Increased extramedullary

----- " -_.- hemiesis + ----------------- ------------------------ ---------atopo----------------------------_--

P Bone marrow Blackish change Increased hematopoiesis f Spleen Hemosiderindeposition ++ Increased extramedullary hematopoiesis + ------------------------------- " ----------------------_- ._.- . .-------------- " ---- . . .----------- 65 ta No abnormalities detected Bone marrow Increased hematopoiesis t Spleen Hemosiderin deposition ++ Increasedextramedullary 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 andcervix), 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 mammarygland . 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 ofindividual 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 +~-

---- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . " - . . . .-------------------------- .70 ta No abnormalities detected Spleen Hemosiderin deposition ++ a) Organs/tissues examined as follows : liver, bone marrow

andspleen. ta, terminal autopsy

. i-+, moderate.

### APPENDIX



## PHOTOS HISTOPATHOLOGICAL EXAMIIdATIONS

(Study code: 4~)

### Photo. 1 Spleen ofa male rat fromvehicle control group. Normal . No. 1 animal . HE. x 187

.5.

Photo . 2 Spleen ofa male rat from300mg/kg/day group . Congestion and increased extramedullary hematopoiesis. No. 28 animal . HE. x 187 .5.

### Photo. 3 Spleen ofa male rat from vehiclecontrol group

. Normal . No. 1 animal . Berlin blue. x187.5. i



### Photo . 4 Spleen of a male rat from300 mg/kg/day group . Hemosiderin deposition. No . 28 animal . Berlin blue. x187.5.

### _ APPENI?IXZ

# FINAL REPORT STABILITYANALYSIS OF(IM, HOMOGENEITY, STABILITYAND CONCENTRATION

ANALYSES OF THE TEST SUBSTANCE FORMULATION

(Study code:jlmb)

# CER~ I Receipt No . STUDY CODE: 4~



# FINAL REPORT

STABILITYANALYSIS OI~, HOMOGENEITY, STABILITYAND 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) .

. 

# Y 1MI~ '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 ofthe 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" onJapanese GLP [Notification No. 1121003 ofthe 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 werevalid. 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 ofthe 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 Itemof Inspections/Audits Dates of Dates of Report of Inspections/Audits Inspections/Audits Protocol April 22, 2009 April 22, 2009 Confirmation ofthe answer fromstudy April 23, 2009 April 23, 2009 director (protocol) IR spectrum

oftest 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 fromstudy 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 oftest substance May 27, 2009 2009 May 27 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 Fi nal report September 25, 2009 September 25, 200 9 I, the undersigned, hereby declare that this report provides an accurate description ofthe 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 DIRECTORAND PERSONS CONCERNEDWITHTHE STUDYANDTHE OPERATION .. .. .. .. . .. .. .. .. . .. .. . .. .. . .. .. . .. .. . .. .. .. .. . .. .. . ... . .. .. . .. .. . .. .. . .. .. . .. .. .. .. .. . ... . .. .. .. .. . .. .. .. . .. .. .. . .. APPRIOVAL BYAUTHOR . .. .. . .. .. . .. . .. .. .. .. . .. .. . .. .. .. .. .. . .. .. . .. . .. .. .. . .. .. .. .. .. . .. .. .. .. .. . .. .. .. . .. .. .. .. . .. SUMMARY .. . .. .. . .. .. .. .. .. . .. .. .. . .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. .. . .. .. .. .. . .. .. .. MATERIALS . .. .. .. . .. .. . ... . .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . ... . .. .. .. . .. .. .. . . 1 . TEST SUBSTANCE .. . .. .. .. . .. .. . .. .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. .. . . 6 METHODS .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. . ... . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . ... 7 1 . SUBJECT STUDY .. .. . .. .. .. . .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. . .. .. .. .. . .. .. .. .. .. . .. .. . .. .. .. .. . .. .. .. . .. . 7 2. STABILITY ANALYSIS OF THE TEST SUBSTANCE . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. .. . . 7 3. HOMOGENEITY, STABILITY ANDCONCENTRATION ANALYSES OF THE TEST SUBSTANCE FORMULATION . .. .. .. . .. .. .. . .. .. .. . .. . ... . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. .. . .. .. .. . . g THE ENVIRONMENTAL FACTORS THAT MIGHT HAVE AFFECTEDTHE RELIABILITY OF THE STUDY RESULTS . .. .. . .. .. .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. .. .. . .. .. . .. .. .. 12 RESULTS AND DISCUSSION . .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. .. .. .. . .. .. .. . .. 12 1 . RESULTS .. .. . .. .. .. .. .. . .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. .. .. . .. .. .. .. . .. .. .. . .. .. 12 2. DISCUSSION . .. .. .. .. . .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. . .. .. .. . .. .. .. . .. .. .. .. .. . .. .. .. .. . .. .. .. . ... . 13

## TABLES -- - -- --- - -1 I~omogeneity and stability analyses ofthe test substance formulation .. . .. .. .. .. .. .. .. .. .. 14 , , 2 Concentration analysis ofthe dose formulation .. .. . .. .. .. .. .. .. .. .. .. . .. .. .. .. . .. .. . .. .. .. .. .. .. .. .. .. 14 I 

# I FIGURES 1 IR spectrummeasured prior to the administration period . ... .. .. . .. .. .. . .. .. .. . .. .. .. .. .. . .. .. .. . 15 2 IR spectrummeasured.after the end of the administration period . .. .. .. .. . .. .. .. .. . .. .. .. . .. 15 REFERENCE 1 IR spectrumprovided 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 ofExamination (Termination ofAnalysis) : 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 ofJIM paper data. After termination ofthe retention period, any measures taken will be done so with the approval ofthe 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 ofthe test substance formulation) APPROVAL BYAUTHOR 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 roomtemperature 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 roomtemperature in the test substance storage roomunder a light shielding condition (actual temperature: 19.5-22.2°C, tolerance temperature: 10-30°C) after obtaining storage information at roomtemperature. . Storage place and period: Cabinet No . 5, from March 19, 2009 to March 31, 2009 Cabinet No. 1, from

March 31, 2009 toJuly 10, 2009 1 .9 Handling Precaution `Gloves, mask, cap, protective glasses and lab coat wereworn. The test substance was warmed up at about 40°C when precipitation ofthe test substance was observed. METHODS 1 . SUBJECT STUDY Twenty-Eight-Day Repeated-Dose Oral Toxicity Study of 410in Rats (Study Code: loom 2. STABILITY ANALYSIS OF THE TEST SUBSTANCE The infrared (IR) spectrumwas 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 : 4000cm"' - 500 cm"' ,3) Pre-Treatment Potassiumbromide neat 2 .2 i Criteria for Judgment 

### IR spectrumofthe 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'