### STUDY TITLE

TEST GUIDELINE(S)

AUTHOR

STUDY COMPLETION DATE

TEST FACILITY

PERFORMING LABORATORY PROJECT IDENTIFICATION Harlan Laboratories Study:


## SPONSOR IDENTIFICATION NUMBER

SPONSOR

PAGE

This document contains manufacturing and trade secrets of the Sponsor(s). It is the property of the Sponsor(s) and may be used only for that purpose for which it was intended by the Spons or(s). Every other or additional use, e xploitation, reproducti on, publication or submission to other parties require the written permission of th e Sponsor(s), with the exception of regulat ory agencies acting within the limits of their administrative authority. 

### Final

Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat

OECD Guideline No. 422 OPPTS 870.3650

K. Pal-Kutas (Study Director)

15-May-2012

Harlan Laboratories Ltd. Wölferstrasse 4 4414 Füllinsdorf / Switzerland

Sponsor Reference Number

Page 1 of 663

# CONTENTS

CONTENTS 2

.......................................................................................................................... STATEMENT OF COMPLIANCE 7

...................................................................................... QUALITY ASSURANCE STATEMENT 8

............................................................................ SIGNATURE(S) OF ADDITIONAL SCIENTIST(S) 9

.......................................................... PREFACE 10

........................................................................................................................... General Information 10

..................................................................................................... Responsibilities 10

............................................................................................................ Schedule 11

....................................................................................................................... Accreditation 11

................................................................................................................ Data Requirements / Test Guidelines 12

........................................................................... Animal Welfare 12

............................................................................................................ Summary of Study Plan Amendments 12

......................................................................... Deviations from Study Plan 13

......................................................................................... Archiving 13

...................................................................................................................... 1 SUMMARY 15

..................................................................................................................... 1.1 Parent Animals 15

....................................................................................................... 1.2 Litter Data - F1 Pups 18

.............................................................................................. 1.3 Conclusion 18

.............................................................................................................. 2 PURPOSE 19

........................................................................................................................ 3 MATERIALS AND METHODS 20

..................................................................................... 3.1 Test System 20

............................................................................................................ 3.2 Allocation 21

............................................................................................................... 3.3 Husbandry 21

.............................................................................................................. 3.4 Test Item / Vehicle 22

................................................................................................. 3.4.1 Test Item 22

....................................................................................................... 3.4.2 Vehicle and Control Item 22

............................................................................. 3.5 Dose Formulations 23

................................................................................................. 3.5.1 Storage of Dose Formulations 23

...................................................................... 3.5.2 Analysis of Dose Formulations 23

.................................................................... 3.5.3 Rationale for Dose Level Selections 24

............................................................ 3.6 Treatment 24

............................................................................................................... 3.7 Study Schedule 25

....................................................................................................... 3.8 Mating, Gestation and Lactation 25

............................................................................ 3.9 Observations 25

........................................................................................................... 3.9.1 Detailed Clinical Observations 26

.................................................................... 3.9.2 Functional Observation Battery 26

................................................................... 3.10 Clinical Laboratory Investigations 27

....................................................................... 3.10.1 Hematology 27

................................................................................................ 3.10.2 Clinical Biochemistry 28

................................................................................. 3.11 Termination of the Study 28

...................................................................................... 3.11.1 Necropsy 28

.................................................................................................... Harlan Laboratories Study Report
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09009e5380b4b37c 

## Page 2 of 663

## 3.11.2 Organ Weights 29

........................................................................................... 3.11.3 Tissue Preservation 29

.................................................................................... 3.11.4 Histotechnique 30

............................................................................................ 3.11.5 Histopathology 30

........................................................................................... 3.12 Data Compilation and Processing 31

........................................................................ 3.13 Statistical Analysis 32

............................................................................................... 4 RESULTS 33

......................................................................................................................... 4.1 Analysis of Dose Formulations 33

.............................................................................. 4.2 Parent Animals 34

....................................................................................................... 4.2.1 Viability / Mortality 34

..................................................................................... 4.2.2 Clinical Observations (Daily) 34

...................................................................... 4.2.3 Detailed Clinical Observations (Weekly) 35

.................................................... 4.2.4 Functional Observational Battery 35

................................................................ 4.2.5 Locomotor Activity 36

...................................................................................... 4.2.6 Food Consumption of Males 36

........................................................................ 4.2.7 Food Consumption of Females 36

.................................................................... 4.2.8 Body Weights of Males 37

................................................................................ 4.2.9 Body Weights of Females 37

............................................................................ 4.3 Clinical Laboratory Investigations 38

......................................................................... 4.3.1 Hematology 38

.................................................................................................. 4.3.2 Clinical Biochemistry 38

................................................................................... 4.4 Reproduction and Breeding Data 39

........................................................................... 4.4.1 Summary of Performance 39

............................................................................ 4.4.2 Mating Performance and Fertility 39

................................................................ 4.4.3 Corpora Lutea Count 39

.................................................................................... 4.4.4 Gestation Length 40

.......................................................................................... 4.4.5 Implantation Rate and Post-implantation Loss 40

............................................ 4.4.6 Litter Size at First Litter Check 40

.................................................................... 4.4.7 Postnatal Loss Days 0 - 4 Post Partum 40

......................................................... 4.5 Terminal Findings - Parent Animals 41

...................................................................... 4.5.1 Organ Weights 41

............................................................................................. 4.5.2 Macroscopical Findings 41

............................................................................... 4.5.3 Histopathology Findings 42

.............................................................................. 4.6 Litter Data - F1 Pups 42

.............................................................................................. 4.6.1 External Examination at First Litter Check and during Lactation 42

............... 4.6.2 Sex Ratios 43

..................................................................................................... 4.6.3 Body Weights on Day 4 Post Partum 43

........................................................... 4.6.4 Macroscopical Findings 43

............................................................................... 5 DISCUSSION AND CONCLUSION 44

.............................................................................. 6 REFERENCES 45

................................................................................................................. 7 FIGURES 46

......................................................................................................................... In-life Data - P Generation 47

........................................................................................... Food Consumption of Males 48

................................................................................. Food Consumption of Females 50

............................................................................. Body Weights of Males 53

......................................................................................... Harlan Laboratories Study Report
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## Body Weights of Females 56

..................................................................................... Body Weight Gain of Males 59

................................................................................. Body Weight Gain of Females 62

.............................................................................. Data of F1 Pups 65

............................................................................................................ Body Weights of Pups 66

........................................................................................... 8 SUMMARY TABLES 69

..................................................................................................... In-life Data - P Generation 70

........................................................................................... Daily Clinical Signs or Observations of Males 71

..................................................... Daily Clinical Signs or Observations of Females 76

................................................. Findings at Detailed Weekly Clinical Observations of Males 82

.............................. Findings at Detailed Weekly Clinical Observations of Females 85

.......................... Functional Observational Battery (FOB) of Males 89

............................................... Functional Observational Battery (FOB) of Females 92

........................................... Locomotor Activity of Males 95

................................................................................ Locomotor Activity of Females 97

............................................................................ Food Consumption of Males 99

................................................................................. Food Consumption of Females 101

........................................................................... Differences in Food Consumption of Males 103

....................................................... Differences in Food Consumption of Females 105

.................................................... Body Weights of Males 108

....................................................................................... Body Weights of Females 112

................................................................................... Body Weight Gain of Males 118

............................................................................... Body Weight Gain of Females 122

............................................................................ Differences in Body Weight Gain of Males 128

........................................................ Differences in Body Weight Gain of Females 134

.................................................... Clinical Laboratory Investigations - P Generation 140

..................................................... Hematology 141

......................................................................................................... Biochemistry 147

....................................................................................................... Reproduction and Breeding Data - P Generation 151

....................................................... Mating Performance 152

............................................................................................ Fertility 153

................................................................................................................ Corpora Lutea Count 154

........................................................................................... Breeding Data per Group 155

.................................................................................... Terminal Findings - P Generation 157

.............................................................................. Organ Weights and Ratios of Males 158

................................................................... Organ Weights and Ratios of Females 168

................................................................ Macroscopical Findings of Males 175

....................................................................... Macroscopical Findings of Females 177

.................................................................... Data of F1 Pups 179

.......................................................................................................... External Examination at First Litter Check 180

........................................................ Clinical Signs or Observations 181

............................................................................ Dates of Postnatal Pup Loss 182

................................................................................ Mean Body Weights of Pups per Group 183

............................................................. Mean Body Weights of Pups per Group with Exclusions 184

................................... Harlan Laboratories Study Report
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09009e5380b4b37c 

## Page 4 of 663

## Differences in Mean Body Weight Gain of Pups during the Lactation Period 185

.................................................................................................................. Macroscopical Findings 186

...................................................................................... 9 INDIVIDUAL TABLES 187

................................................................................................ In-life Data - P Generation 188

......................................................................................... Mortality Data of Males 189

...................................................................................... Mortality Data of Females 194

.................................................................................. Daily Clinical Signs or Observations of Males 199

................................................... Daily Clinical Signs or Observations of Females 206

............................................... Findings at Detailed Weekly Clinical Observations of Males 214

............................ Findings at Detailed Weekly Clinical Observations of Females 217

........................ Functional Observational Battery (FOB) of Males 221

............................................. Functional Observational Battery (FOB) of Females 226

......................................... Locomotor Activity of Males 231

.............................................................................. Locomotor Activity of Females 236

.......................................................................... Food Consumption of Males 241

............................................................................... Food Consumption of Females 246

........................................................................... Body Weights of Males 251

....................................................................................... Body Weights of Females 260

................................................................................... Body Weight Gain of Males 273

............................................................................... Body Weight Gain of Females 282

............................................................................ Clinical Laboratory Investigations - P Generation 295

..................................................... Hematology 296

......................................................................................................... Biochemistry 306

....................................................................................................... Reproduction and Breeding Data - P Generation 316

....................................................... Reproduction Processes 317

...................................................................................... Corpora Lutea Count 321

........................................................................................... Implantations 325

....................................................................................................... Breeding Data per Litter 326

...................................................................................... Terminal Findings - P Generation 334

.............................................................................. Organ Weights and Ratios of Males 335

................................................................... Organ Weights and Ratios of Females 348

................................................................ Macroscopical Findings of Males 361

....................................................................... Macroscopical Findings of Females 367

.................................................................... Data of F1 Pups 375

.......................................................................................................... Mean Body Weights of Pups per Litter 376

............................................................... Body Weights of Pups 380

......................................................................................... Individual Pup Data 389

............................................................................................. APPENDIX I - CHEMICAL ANALYSIS OF FEED 411

....................................................... Feed Batch No. 28/11 of 18-Apr-2011 412

....................................................................... APPENDIX II - DRINKING WATER ANALYSIS 414

........................................................ Drinking Water Sampled on 25-Jul-2011 415

.................................................................. APPENDIX III - CERTIFICATE OF ANALYSIS 418

.......................................................... Batch No. 0004234484 419

............................................................................................... APPENDIX IV - FORMULATION ANALYSIS 420

............................................................. Harlan Laboratories Study Report
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09009e5380b4b37c 

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## Determination of Content, Homogeneity and Stability of in

Application Formulations 421

........................................................................................... APPENDIX V - FUNCTIONAL OBSERVATIONAL BATTERY 431

................................ Scoring for FOB 432

......................................................................................................... APPENDIX VI - CLINICAL LABORATORY INVESTIGATIONS 438

.............................. Methods 439

...................................................................................................................... Historical Data - Hematology 443

.................................................................................... Historical Data - Clinical Biochemistry 445

..................................................................... APPENDIX VII - HISTOPATHOLOGY 447

......................................................................... Text 448

............................................................................................................................ . Tables 464

......................................................................................................................... Peer Review 572

................................................................................................................ APPENDIX VIII - HISTORICAL CONTROL DATA 573

.................................................... Historical Data - Functional Observational Battery 574

................................................... Historical Data - Breeding 586

.......................................................................................... Historical Data - Organ Weights 592

................................................................................ Harlan Laboratories Study Report
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# PREFACE
General Information

Test Item: Study Title: Combin ed Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat Sponsor:
Study Monitor: Dr. K. Hempel Test Facility: Harlan Laboratories Ltd. Wölferstrasse 4 4414 Füllinsdorf / Switzerland Lead QA: Harlan Laboratories Ltd. Quality Assurance GLP Zelgliweg 1 4452 Itingen / Switzerland Test Site: AnaPath GmbH Buchsweg 56 4625 Oberbuchsiten / Switzerland Test Site QA: AnaPath GmbH Quality Assurance Buchsweg 56 4625 Oberbuchsiten / Switzerland ana.path-qa@bluewin.ch Contact person: N. Häuselmann



# Responsibilities
Test Facility: Study Director: Dr. R. Ceccat elli (until 18-Dec-2011) K. Pal-Kutas (from 19-Dec-2011 onwards) Deputy Study Director: Dr. S. Whitlow Laboratory / Technical Coordinator: D. Frei Necropsy / Histotechnology: Dr. K. Weber (until 20-Mar-2012) S. Gähler (from 21-Mar-2012 onwards) Clinical Laboratory Investigations: R. Draheim Formulation Analysis: Dr. B. Ludwig Harlan Laboratories Study Report
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## Quality Assurance: Head of Lead QA: J. Riley

Test Site(s): Principal Investigator(s): Study Phase Histopathology: Dr. K. Heider AnaPath GmbH Buchsweg 56 4625 Oberbuchsiten / Switzerland k.heider@intergga.ch Phase Number: 10648 Test Site: AnaPath GmbH Histopathology Peer Review (PR): Dr. H.J. Chevalier AnaPath GmbH Buchsweg 56 4625 Oberbuchsiten / Switzerland j.chevalier@eblcom.ch Test Site QA: AnaPath GmbH Quality Assurance Buchsweg 56 4625 Oberbuchsiten ana.path-qa@bluewin.ch Contact person: N. Häuselmann



# Schedule
Experimental Starting Date (Delivery of Animals): 04-Aug-2011 First Test Item Admi nistration: 11-Aug-2011 Initiation of Pairing: 24-Aug-2011 First Possible Day 0 p.c.: 25-Aug-2011 Termination (Last Necropsies): 01-Oct-2011 Experimental Completion Date: 05-Mar-2012



# Accreditation

“Harlan Laboratories Ltd.” is accredited as a test laboratory for analysis in the fields of clinical chemistry, hematology, blood-coagulation and urine diagnostics in accordan ce with the Standard ISO/IEC 17025 under accreditation number STS 085 by the Swiss Accreditation Service. Harlan Laboratories Study Report
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09009e5380b4b3fe 

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# Data Requirements / Test Guidelines This study was performed in accordance with the procedures indica ted by the following internationally accepted guide lines and recommendations:

• OECD guideline 422 (OECD guideline for testing of chemicals 422, “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rat”, adopted by the Council on 22 nd 

## March 1996).

• “Combined Repeated Dose Toxicity St udy with the Reproduction/Developmental Toxicity Screening Test” Health Effects Test Guideline OPPTS 870.3650 Guideline from the Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, July 2000.



# Animal Welfare This study was performed in an AAALAC-accred ited laboratory in accord ance with the Swiss Animal Protection Law under license no. 252.



# Summary of Study Plan Amendments

First Amendment: Appointment and c ontact details of the principal investigator and peer revi ewer for the histopathology phase were given. The test site QA cont act details were given. Details of archiving at AnaPath GmbH were given. Correction of the purity of the test item based on the outcome of the final report 11L00060 (“Characterization of “ before start of toxicological studies). Typing error in reporting a study number. Extention of examination of reproductive organs to all the animals.

Second Amendment: Change of Study Direct or from Dr. R. Ceccatelli to K. Pal-Kutas.

Third Amendment: Change of study scie ntist, responsible for necropsy and histotechnique, from Dr. K. Weber to Susan Gaehler. Change of archiving text on Sponsor’s request. Correction of data compilation and processing. Correction of the description of the statistical method. Fourth Amendment: Change of archiving text on Sponsor’s request. Harlan Laboratories Study Report
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# Deviations from Study Plan The body weight of some males exceeded the range given in the study plan. It was 291 to 371 g instead of 275 to 325 g. A second sampling of about 2 g of each concentration was taken from the middle only to confirm 7 day stability because 

## the values of the first stability we re outside the acceptance criteria and therefore the analysis had to be repeated. The relative humidity exceeded the given range in the study plan. The highest value was 79.4% instead of 70%. The seminal vesicles including coagulating glands were weighed together instead of separately as given in the Study plan. The name of the vehicle was not precisely given in the Study Plan. According to certificate of analysis data sheet of vehicle the vehicle name was Carboxymethylcellulose Sodium Salt. These deviations had no impact on the study.



# Archiving Harlan Laboratories Ltd., 4452 Itin gen/Switzerland will retain true copies of the study plan, the final report and a sample of test item of the present study for at least ten years. The original study plan, original paper raw data, a CD with el ectronic raw data, specimens and the original final report w ill be sent to the sponsor. These original documents/raw data, as well as sp ecimens (as long as quality permits evaluation) will be archived for at least 10 years at the following location: Harlan Laboratories Study Report
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## AnaPath GmbH (4625 Oberbuchsiten / Switzerland) will retain a copy of the raw data generated at the test site AnaPath GmbH, and an electro nic version of the pathology phase report for at least 10 years. Duplicate signature pages will be retained at AnaPath GmbH for at least ten years or until transfer to the Study Director if requested. Harlan Laboratories Study Report
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09009e5380b4b3fe 

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# 1 SUMMARY
The purpose of this study was to generate pre liminary information concerning the effects of on the possible heal th hazards likely to arise from repeated exposure over a relatively limited period of time. In addition it provides information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition. was administered orally by gavage to male rats for 28 days and to female rats for 14 days prior to pairing, through th e pairing and gestation periods until the F1 generation reached day 4 post partum. The following dose levels were applied:

Allocation and Dose Levels mg/kg body weight/day Group 1 control 0 Group 2

10 Group 3

30 Group 4

90 Males 1 - 10 11 - 20 21 - 30 31 - 40 Females 41 - 50 51 - 60 61 - 70 71 - 80
A standard dose volume of 10 mL/kg body weight with a daily adjustme nt to the actual body weight was used. Control animals were dosed with the vehicle alone (Carboxymethylcellulose sodium salt 0.5%). The following results were obtained:



# 1.1 Parent Animals Mortality and General Tolerability At 90 mg/kg body weight/day, one ma le was killed for ethical reason on day 9 of treatment in the pre-pairing period and one female died spontaneously on day 2 of pairing period (on day 16 of treatment). After histopathological examination it was concluded that the cause of death of the female was likely the thrombosis in jejunum and, therefore, this death was considered to be incidental and not test item related. Histopathological examination of the male showed slight diffuse hyperkeratosis in forestomach and mini mal erosion in glandular stomach, signs of moderate stress in thymus and ad renal glands as well as slight diffuse atrophy in the prostate, coagulating gland and seminal ve sicles. The body weight and food consumption of this male was rapidly decreasing from the second day of tr eatment onwards probab ly due to individual sensitivity. Since other males at 90 mg/kg body weight/day, started to show body weight and food consumption reduction later in the treatment period (the body weight started to decrease from the pairing period onwards and the food cons umption was decreased in the second week of pre-pairing period), relationship to the treatment could not be excluded. Harlan Laboratories Study Report
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## Test item-related clinical signs were observe d of males and females receiving 90 mg/kg body weight/day of Hunched posture, ruffled fur and discoloured feces were seen in the pre-pairing and pairing period in males and in the pre-pairing, through pairing and gestation period in females. Functional Observational Battery None of the parameters under investigation duri ng the functional observational battery gave an indication of a test item-related effect. Mean body temperature in males was statistical ly significantly lower at the dose level of 90 mg/kg body weight/day compared to the c ontrol group (37.3 °C compared to 38.1 in the control group) and it was margina lly lower when compared to hist orical control data range (37.5 - 39.1 °C). Additionally, slightly lower locomo tor activity of this group was seen, thus a treatment-related effect can not be excluded. Locomotor Activity For females at the dose level of 90 mg/kg body wei ght/day, total level of locomotor activity was statistically significantly reduced. In males the total level of activity was lower when compared to controls or other test item-treated groups but it did not reach statistical significance. The reduced locomotor activity in animals receiv ing 90 mg/kg body weight/day of was considered to be a test item-related effect. Food Consumption The mean food consumption of males receivin g 90 mg/kg body weight/day of was statistically significantly lower on the second week of pre-pairing period, and for females during the whole pre-pairing period. This was consid ered to be a test item-related effect. Body Weights From day 5 of the pre-pairing period the m ean body weight of males receiving 90 mg/kg body weight/day of was minimally decreased throughout the study when compared to the control group, although not reaching a level of statistic al significance. The mean body weight gain of males receiving 90 mg/kg body weight/day of was lower from day 5 of pre-pairi ng period when compared to controls and it was statistically significantly reduced between days 8 and 14. In correlation with the low food consumption this was considered to be a test item-related effect. Harlan Laboratories Study Report
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## Clinical Laboratory Investigations The assessment of the hematology data did not re veal any test item-rela ted effect in any dose group in any sex. Minimally increased total cholesterol level of females at the dose level of 90 mg/kg body weight/day was observed. Reproduction and Breeding Data All pairs mated. Mean precoital time, fertility in dex and conception rate we re not affected by the treatment with the test item. Mean number of corpora lutea and implan tations per dam and the post-implantation loss were not affected by the treat ment with the test item. The mean postnatal loss between days 0 and 4 post partum was highe r and the mean number of living pup on day 4 post partum were lower consequently the viabilit y index was statistically significantly lower in the high dose group therefore these were consid ered to be test item-related effects. Organ Weights

Absolute and relative mean liver weights (both relative to body weight and relative to brain weight) were statistically increased in males and females of group 4 (90 mg/kg body weight/day). Additionally, absolute and relative mean thym us weights were statistically significantly decreased in females of the 90 mg/kg body weight/day group. Macroscopical Findings and His topathological Examinations

Treatment-related adverse local ir ritative effects in the stomach we re observed in all test itemtreated groups at incidences of 1, 2 and 2 animals at the dose levels 10, 30 and 90 mg/kg body weight/day, respectively. The reduced size in thymus in females, occurring in increa sed incidences, at ≥ 10 mg/kg body weight/day correlated histopathologically with at hropy and reduced absolute and relative thymus weights only at the high dose leve ls. Although this is considered to be most likely to be stress related a test item-rela tionship cannot be excluded at the 90 mg/kg body weight/day dose level. Treatment-related diffuse liver cell hypertrophy at 90 mg/kg body weight/day was considered to be adaptive. This hypertrophy was associated wi th follicular ce ll hypertrophy in thyroid glands in some males and females at 90 mg/kg body wei ght/day. Most probably th e enhanced liver cell metabolism resulted in an acceleration of thyr oid hormone breakdown with consequent thyroid follicular cell hypertrophy. This finding is comm only seen in rats after being exposed to xenobiotics. No histological evidence of toxicological properti es in the reproductive organs and tissues examined were detected at 90 mg/kg body weight/day. Harlan Laboratories Study Report
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# 1.2 Litter Data - F1 Pups Findings at First Litter Ch eck and during Lactation The mean litter size of dams receiving 90 mg/kg body weight/day of was slightly lower when compaired to controls. Mean postnat al loss between days 0 and 4 post partum was higher and the mean number of living pup on day 4 post partum was lower in the group receiving 90 mg/kg body weight/day. The sex ratio was not affected. No abnormal pup was noted at any dose level. At the dose level of 90 mg/kg body weight/day, thr ee male pups in three different litters (nos. 72, 74, 79) had no milk in stomach at first litter ch eck and they were missing afterwards on days 4, 2, 2 post partum, respectively. Pup Weights Up to and Including Day 4 Post Partum Mean pup weights on day 1 post partum were una ffected, whereas, the mean body weight of pups on day 4 post partum (dose level of 90 mg/kg body weight/day) was significantly lower and therefore considered to be a test item-related effect. Macroscopical Findings At necropsy of pups, there were no abnormal findings noted.



# 1.3 Conclusion Based on the observed mortality, clinical sy mptoms, decreased body weight, decreased food consumption, increased liver and decreased thym us weights at the dose level of 90 mg/kg body weight/day the NOAEL (No Observed Adverse Effect Level) for general t oxicity in parental males and females was considered to be 30 mg/kg body weight/day. Based on the significantly lower body weight of pups and the decreased viability index on day 4 post partum at the high dose level of 90 mg/ kg body weight/day, the NOAEL for reproduction/ developmental toxicity was consider ed to be 30 mg/kg body weight/day. Fertility index, conception rate, mean precoital ti me, number of implantations were not affected by the treatment in any test item-treated group. No developmental effects were seen at dose levels of 30 and 10 mg/kg body weight/day. A NOAEL (No Observed Adverse Effect Level) for the local irritative effect of in stomach could not be established for males and was established at 10 mg/kg bw/day for females based on the microscopi c findings detected. Harlan Laboratories Study Report
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# 2 PURPOSE
The purpose of this study was to generate prelim inary information on the possible health hazards likely to arise from repeated exposure over a re latively limited period of time. In addition it provided information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, deve lopment of the conceptus and parturition. This study should provide informa tion to assess the n eed to conduct further investigations and may provide guidance in the de sign of subsequent studies. Harlan Laboratories Study Report
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# 3 MATERIALS AND METHODS

General Remark

Details of the materials and met hods that are not specified in th e subsequent sections of this report are contained in th e appropriate standard operating procedures.



# 3.1 Test System
Animals: Rat, RccHan TM 

## : WIST(SPF) Rationale: Recognized by inte rnational guidelines as a recommended test system. Breeder: Harlan Laboratories, B.V. Kreuzelweg 53 5961 NM Horst / Netherlands Number of Animals: 40 males: 10 per group 40 females: 10 per group 1 

## Age (at Start of Treatment): 11 weeks Body Weight Range (at Start of Treatment): Males: 291 to 371 g Females: 182 to 213 g Identification: Cage card and indivi dual animal number (ear tattoo). Pups: On day 1 post partum , pups were individually tattooed with Indian ink. Randomization: Computer-generated random algorithm. In addition body weights (recorded on the day of allocation) were taken into consideration in order to ensure similar mean body weights in all groups. Acclimatization: Under test conditi ons after health examination. Only animals without any visible signs of illness were used for the study.

1 

### 42 males and 42 females were obtained from the br eeder. The surplus animals were sacrificed. This was documented in the raw data. Harlan Laboratories Study Report
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# 3.2 Allocation The group identification and animal numbers assi gned to treatment are stated in the following table:

Allocation and Dose Levels mg/kg body weight/day Group 1 control 0 Group 2

10 Group 3

30 Group 4

90 Males 1 - 10 11 - 20 21 - 30 31 - 40 Females 41 - 50 51 - 60 61 - 70 71 - 80



# 3.3 Husbandry
Room Number, Füllinsdorf: 011A Conditions: Standard laboratory conditions. Air-conditioned with 10 - 15 air changes per hour, continuously monitored environmental conditions (temp. range: 22 ± 3 °C; relative humidity range: 30 - 70%). There was 12-hour fluorescent light / 12-hour dark cycle with music during the light period. Accommodation: Individually in Ma krolon type-3 cages with wire mesh tops and sterilized standard softwood bedding (‘Lignocel’ J.Rettenmaier & Söhne GmbH & CoKG, 73494 Rosenberg / Germany, imported by Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) with paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK and ISO-BLOX from HarlanLaboratories B.V., Netherlands). During the prepairing period, cages with males were interspersed amongst those holding females to promote the development of regular estrus cycles. Diet: Pelleted standard Harlan Teklad 2018C (batch no. 28/11) rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) was available ad libitum . Results of representa tive analyses for contaminants are included in Appendix I on p.

. Water: Community tap-water from Füllinsdorf was available ad libitum in water bottles. Results of bacteriological assay, chemical and contaminant analyses of representative samples are included in Appendix II on p.

. 412

415 Harlan Laboratories Study Report
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# 3.4 Test Item / Vehicle Test item and data as provided by the Sponsor (certificate of analysis see in Appendix III on p. ).

3.4.1 Test Item

Identification: Test Substance Number: 11/0095-1 Test Item Name for Report: Description: Powder, white to slightly yellow Batch Number: 0004234484 CAS Number: 474510-57-1 Purity: 94.8 g/100 g (see final report 11L00060) Correction Factor: Was not applied Stability of Test Item in Ve hicle: At least seven days (based on the results in Harlan Laboratories study D23440, Non-GLP study / Sponsor Reference Number 10C0095/11X016) Expiry Date (Retes t Date): 12-Jun-2012 Storage Conditions: Room temperature (20 ± 5 °C) Safety Precautions: Routine hygieni c procedures (gloves, goggles, face mask).

3.4.2 Vehicle and Control Item Identification: Carboxymethylcellu lose sodium salt 0.5% (Medium Viscosity) Vehicle Name for Report: CMC 0.5% Justification for selection: As used in previous dose range-finding study (Harlan Laboratories study D23440, Non-GLP study / Sponsor Reference Number 10C0095/11X016 ) Source: Fluka Chemie GmbH, 9471 Buchs / Switzerland Description: White to faintly beige powder Batch Number: 1367388 34707017 Expiry Date (Retes t Date): 24-Jan-2018 Storage Conditions: In the refrigerator (2 - 8 °C) Safety Precautions: Routine hygieni c procedures (gloves, goggles, face mask). 419 Harlan Laboratories Study Report
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# 3.5 Dose Formulations The dose formulations were prepared weekly us ing the test item as supplied by the Sponsor. was weighed into a glass beaker on a tared precision balance and approximately 80% of the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous suspension was prepared. Having obtained a hom ogeneous mixture, the remaining vehicle was added. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

3.5.1 Storage of Dose Formulations
Dose formulations were stor ed at room temperature (20 ± 5 °C) in glass beakers. Based upon the results of stability analyses performed with in the Harlan Laboratories study D23440 Non-GLP study / Sponsor Reference Nu mber 10C0095/11X016 dose formulations were stable for at least one week.

3.5.2 Analysis of Dose Formulations On the first treatment day samples from the c ontrol group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 2 g of each concentrati on were taken from the middle only to confirm stability (2 hrs and 7 days). Due to technical mistake of the first 7 day stability test, another 7 day stab ility analysis was performed and confirmed. During the last week of the treatment, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to Dr. B. Ludwig (Harlan Laboratories Ltd., Itingen / Switzerland) and stored there at -20 ± 5 °C until analysis. The samples were analyzed following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item wa s used as the analytical standard. Analyzed samples were not discarded without wr itten consent from the study director. Duplicates were taken of all samples and were stored at Harlan Laboratories Ltd., Füllinsdorf / Switzerland. The samples were not discarded wi thout written consent from the study director. The results were summarized by Dr. B. Ludw ig and are included in Appendix IV on p.

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## 3.5.3 Rationale for Dose Level Selections The dose levels were selected based on a previ ous dose range-finding t oxicity study in Han Wistar rats, Harlan Laboratories study D23440, Non-GLP study / Sponsor Reference Number 10C0095/11X016, using dose levels of 10, 30, and 90 mg/kg body weight/day where the substance was administered in aqueous CMC (0.5%). The treatment resulted in a lower food consumption and body weight predominantly in ma les at 90 mg/kg body weight/day. No further significant findings were observed. In an ear lier 28-day study in rats (RCC study no. 845437), the test substance was dissolved in PEG 300 a nd administered at dose level of 5, 50, 100 and 160 mg/kg body weight/day. Mortality and clinical signs were observed at 100 and 160 mg/kg body weight/day, indicating a steep dose-respons e relationship, accompanied by hepato- and nephrotoxic effects. Furthermore, the kidneys were even affect ed at the next lower dose of 50 mg/kg body weight/day. Taking into account both the dose ra nge-finding study and the 28-day oral toxicity study results, there was confidence that a l onger duration of treatment and the pregnancy state induced sufficient toxicity in the highe st dose of 90 mg/kg body weight/day to generate study results.



# 3.6 Treatment

Method: Oral, by gavage Rationale for Method: Administrati on by gavage is a common and accepted route of exposure for this type of studies. Frequency of Administration: Once daily, 7 days / week (from day 1 of pre-pairing period until one day before the necropsy). Target Dose Levels: Group 1: 0 mg/kg body weight/day (control group) Group 2: 10 mg/kg body weight/day Group 3: 30 mg/kg body weight/day Group 4: 90 mg/kg body weight/day Rationale for Dose Level Selection: The dose levels were selected based on a previous dose range-finding toxicity study in Han Wistar rats, Harlan Laboratories st udy D23440, Non-GLP study / Sponsor Reference Number 10C0095/11X016, using dose levels of 10, 30 and 90 mg/kg body weight/day, resulting in a lower food consumption and body weight in males at 90 mg/kg body weight/day. Dose Volume: 10 mL/kg body weight Duration of Acclimatization Period: 7 days Duration of Treatment Period: Males: 4 weeks Females: Approximately 7 weeks Harlan Laboratories Study Report
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# 3.7 Study Schedule
Study Sequence Females Males Acclimatization 5 days minimum 5 days minimum First Test Item Administration Day 1 of pre-pairing Day 1 of pre-pairing Pre-Pairing 14 days 14 days Pairing 14 days maximum 14 days maximum Gestation Approximately 21 days Treatment Ends On day 4 post partum On day before sacrifice Necropsy On day 5 post partum (pups on day 4 post partum) After treatment of at least 28 days, when no longer neededfor assessment of reproductive effects



# 3.8 Mating, Gestation and Lactation During the pairing period, females were housed w ith sexually mature males (1:1) until evidence of copulation was observed. The females we re removed and housed individually if:

- the daily vaginal smear was sperm positive, or

- a copulation plug was observed. The day on which a positive mating was determined (copulation plug or sperm) was designated day 0 post coitum. All dams were allowed to give birth and rear their litters (F1 pups) up to day 4 post partum. Day 0 post partum was designated as the day on which a female had delivered a ll her pups.



# 3.9 Observations The following observations were recorded:
Viability / Mortality: Twice daily Clinical Signs: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy). Additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing. Harlan Laboratories Study Report
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## Food Consumption: Males: Weekly during pre-pair ing and after pairing periods. Females: Pre-pairing peri od days 1 - 8 and 8 - 14; gestation days 0 - 7, 7 - 14 and 14 - 21 post coitum, and days 1 - 4 post partum. No food consumption was r ecorded during the pairing period. Body Weights: Recorded daily fromtreatment start to day of necropsy. Duration of Gestation: It was recorded. Pup Data: The litters were examin ed for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 post partum. Litter we ight, number of runts, mortality, survival rate and any abnormal behavior were recorded.

3.9.1 Detailed Clinical Observations Once prior to the first administration of the test item and weekly thereafter, detailed clinical observations were performed outside the home ca ge. Animals were observed for the following: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lacrim ation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and res ponse to handling as well as the presence of clonic or tonic movements, stereotypes or bizarre behavior were also reported.

3.9.2 Functional Observation Battery At one time during the study (mal es shortly before the schedule d sacrifice and females on day 3 post partum) relevant parameters were perfor med with five P generation males and five P generation females from each group. This FOB assessment was conducted following the daily dose administration. Animals were observed for the following:

• Cage-side observations: feces-balls, urine and po sture as well as resistance to removal.

• Hand-held observations: muscle tone, constitu ation, skin, pupile size, palpebral closure, lacrimation, salivation, reaction to handling and general abnormalities.

• Open field observations: level of ambulator y activity including rearing (one minute evaluation), unusual body movements (e.g. sp asms, convulsions), gait evaluation, behavior, hair coat, respiration, qua ntity of feces-balls and urine. Harlan Laboratories Study Report
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## • Reflexes: blinking, palpebral closure, pinna re flex, extensor thrust response, paw pinch, responsiveness to sharp noise, righting reflex and hearing ability (Preyer’s reflex).

• Measurements / Counts: hind limb / fore limb grip strength, landing foot splay, rectal temperature. A description of all test paramete rs is listed under Appendix V on p. ). Any abnormal findings were recorded and, where a ppropriate, graded in severity. Additionally, locomotor activity was measured quan titatively for the same animals. Activity was measured with an Activity Monitor AMS-0151 (FMI , Germany). Activity of the animals (based on beam count) was recorded for 6-minute interval s over a period of 30 mi nutes. These data and the total activity over 30 minutes were reported.



# 3.10 Clinical Laboratory Investigations Blood samples were obtained on the day of the scheduled necropsy from 5 males from each group. Blood samples from 5 lactating females from each group were obtained on day 5 post partum. Blood samples were drawn sublingually from all animals under light isoflurane anesthesia. The animals were fasted for appr oximately 18 hours before blood sampling but allowed access to water ad libitum . The samples were collected early in the working day to reduce biological variation cau sed by circadian rhythms. The assay was performed under the responsibility of R. Draheim at Harlan Laboratories Ltd. (Füllinsdorf) under internal laboratory quality contro l conditions to assure reliable test results (see in Appendix VI on p. ).

3.10.1 Hematology The following hematology parameters were determined: Complete Blood Cell Count
Erythrocyte count Hemoglobin Hematocrit Mean corpuscular volume Red cell volume distribution width Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration Hemoglobin concentration distribution width Leukocyte count, total Differential leukocyte count Platelet count 432

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## Coagulation
Prothrombin time (= Thromboplastin time) Activated partial Thromboplastin time

3.10.2 Clinical Biochemistry The following clinical biochemistry parameters were determined:

Glucose Urea Creatinine Bilirubin, total Cholesterol, total Triglycerides Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Gamma-glutamyl-transferase Bile acids Sodium Potassium Chloride Calcium Phosphorus Protein, total Albumin Globulin Albumin/Globulin ratio



# 3.11 Termination of the Study

Males were sacrificed after tr eatment of 28 days, as they were no longer needed for the assessment of reproductive effects. Pups were sacrificed on da y 4 post partum. Dams were sacrificed on day 5 post partum.

If birth did not occur on the expected date (day 21 post coitu m), the dam was sacrificed on day 25 post coitum.

3.11.1 Necropsy All animals sacrificed or found dead were subject ed to a detailed macroscopic examination to establish, if possible, the cause of death. Speci mens of abnormal tissue were fixed in neutral phosphate buffered 4% formaldehyde solution. At the scheduled sacrifice, all animals were sacrificed by an injection of sodium pentobarbital. All P generation animals were exsanguinated. Dead pups, except those excessively canniba lized, were examined macroscopically. Harlan Laboratories Study Report
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## All parent animals and pups were examined macrosc opically for any structural changes, either at the scheduled necropsy or during the study if death occurred. For the parent animals, special attention was di rected at the organs of the reproductive system. The number of implantation sites an d corpora lutea was recorded fo r all dams with litters. The uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites [see References ( 1 )].

3.11.2 Organ Weights At the scheduled sacrifice, the testes, se minal vesicles including coagulating glands, epididymides and cauda epididymis of all parental males and ovaries from all parental females were weighed separately.
In addition, from all males and females killed at the end of the study, th e following organs were trimmed from any adherent tissue, as a ppropriate, and their wet weight taken.
Adrenal glands (weighed as pairs) Brain Heart Kidneys (weighed as pairs) Pituitary gland Liver Thymus Spleen Thyroid glands (with parathyroid glands) Prostate Uterus

3.11.3 Tissue Preservation The following tissues from all pare ntal males were preserved in neutral phosphate buffered 4% formaldehyde solution:

Prostate Seminal vesicles with coagulating gland Testes (in Bouin’s fixative) Epididymides (in Bouin’s fixative)
The following tissues from all pare ntal females were preserved in neutral phosphate buffered 4% formaldehyde solution:

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## In addition, from all males and females per grou p and from all animals found dead or killed in extremis, the following tissues were preserved in neutral phosphate buffered 4% formaldehyde solution:

Gross lesions Brain (cerebrum, cerebellum, pons) Spinal chord Small and large intestines (incl. Peyer’s patches) Stomach Liver Kidneys Adrenals Spleen Heart Thymus Thyroids, and parathyroids if possible Trachea and lungs (preserved by inflation with fixative and then immersion) Uterus (with vagina) Urinary bladder Lymph nodes (mesenterial, mandibular) Peripheral nerve (sciatic) Bone marrow

3.11.4 Histotechnique All organ and tissue samples to be examined by the principal i nvestigator for histopathology were processed, embedded and cut at an approximate thickness of 2 - 4 micrometers and stained with hematoxylin and eosin. Additionally, the te stis was stained by PAS-hematoxylin. Special stains were used at the disc retion of the study pathologist.

3.11.5 Histopathology Slides of all organs and tissues listed collected at terminal sacrifice from five males and females and reproductive organs from all animals of the control and high-dose groups were examined by the principal investigator for th e histopathology. The same applied to all occurring gross lesions and to all animals, which died spontaneously or had to be terminated in extremis. Special emphasis was made on the stages of spermatogenesis and histopat hology of interstitial cell structure. If test item-related morphologic ch anges were detected in organs of any high-dose animal, those same organs from the mid- and low-dose group were examined to establish a no-effect level, if possible. Histological examination of ovaries was carried out on any females that did not give birth. In addition, microscopic examination of the reproductiv e organs of all infertile males was made, if necessary. A histopathology peer review was performed and the name of the peer reviewing pathologist was listed in the raw data and the report. Harlan Laboratories Study Report
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## A peer review of the histopa thology results was conducted by a board-ce rtified veterinary pathologist designated by the Spons or. The details of the peer re view were added by study plan amendment. A histopathology phase report was provided by the principal investigator which is included in Appendix VII on p.

. A histopathology peer review was performed by Dr. J. Chevalier from AnaPath and the results are included in Appendix VII on p.

.



# 3.12 Data Compilation and Processing The following data were recorded on-line: clin ical signs and observations, weekly detailed examination, functional observational battery, f ood consumption, body wei ghts, necropsy data, organ weights (TOX CONTROL), reproducti on and litter data (RCC-TOX LIMS). Locomotor activity was recorded on-line and the results were printed and transcribed into the computer system for compilation and analysis. Microscopic data were entered into the PathData System. All other data were recorded on data sheets and compiled manually. From the on-line recorded reprodu ction data, the following paramete rs were calculated: fertility indices, mean precoital time, post-implantation losses, mean litter size, pup sex ratios and viability indices. The number of corpora lutea was recorded on data sheets. For reproduction data, group mean values we re calculated both on a litter basis and on a percentage per group basis. Mean pup weights we re calculated from the individual weights both on a per group and on a per litter basis. Computer-generated values in the tables repres ent the rounded-off results of calculations which used the exact raw data values. 448

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# 3.13 Statistical Analysis The following statistical methods were used to analyze food consumption, body weights, reproduction data, parental organ weights, grip strength, locomo tor activity, body temperature and clinical laboratory investigation:

• Means and standard deviations of various data were calculated.

• The Dunnett-test [see References ( 2 )] (many to one t-test) based on a pooled variance estimate was applied if the va riables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.

• The Steel-test [see References ( 3 )] (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.

• Fisher's exact-test [see References ( 4 )] was applied if the variables could be dichotomized without loss of information. Harlan Laboratories Study Report
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# 4 RESULTS
The following dose levels were applied: Group 1: 0 mg/kg body weight/day (control group) Group 2: 10 mg/kg body weight/day Group 3: 30 mg/kg body weight/day Group 4: 90 mg/kg body weight/day



# 4.1 Analysis of Dose Formulations (See Appendix IV on p. ) The application formulations investigated durin g the study were found to comprise in the range of 84.4% to 96.1% and, thus, the requi red content limit of ±20% with reference to the nominal content was met. The homogeneous di stribution of in the preparations was approved because single results found did not deviate more than 6.2% (<15%) from the corresponding mean.

The test item was found to be stable in application formulations when kept two hours at room temperature due to recoveries which met the variation limit of 10% from the time-zero (homogeneity) mean. The first result of 7-day stability formulati on analysis prepared on 11-Aug-2011 exceeded the acceptance criteria in all dose groups, the values deviated more than 10 % of nominal; which might be caused by erroneous sample collection. Respective samples were re-analysed to confirm the correct conduct of analytical work and also analysis of the duplicate samples exceeded the acceptance criteria. Due to these results additional 7-day stability at room temperature analysis was request ed which was performed on 25-A ug-2011 and all values of all dose groups were within the acceptance criteria.
In conclusion, the results indicate the accura te use of the test item and Carboxymethylcellulose 0.5% (Medium Viscosity) as vehicle during this study. Application formulations were found to be homogeneously prepared and sufficient formulation stability under storage conditions was approved. 421 Harlan Laboratories Study Report
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# 4.2 Parent Animals

4.2.1 Viability / Mortality (See Individual Tables on p. ) At the dose level of 90 mg/kg body weight/day, one male (no. 35) was killed for ethical reason on day 9 of treatment in the pre-pairing period and one female (no. 78) died spontaneously on day 2 of pairing period (on da y 16 of treatment). After histopathological examination it was concluded that the cause of d eath of the female was likely the thrombosis in jejunum and, therefore, this death was considered to be incide ntal and not test item related. Histopathological examination of the male showed slight diffu se hyperkeratosis in forestomach and minimal erosion in glandular stom ach, signs of moderate stress in thym us and adrenal glands as well as slight diffuse atrophy in the pr ostate, coagulating gl and and seminal vesicles. Because the body weight and food consumption of this male wa s rapidly decreased from the second day of treatment and other males at 90 mg/kg body wei ght/day, started to s how body weight and food consumption reduction later in the treatment period, this moribundity was considered to be either an individual sensitivity of this animal or inci dental. However, a test item-related effect could not be excluded. All the other animals survived until the scheduled necropsy.

4.2.2 Clinical Observations (Daily) (See Summary Tables on p. , Individual Tables on p. ) Test item-related clinical signs were observe d of males and females receiving 90 mg/kg body weight/day of . Hunched posture, ru ffled fur and discoloured feces were seen.

At the dose level of 90 mg/kg body weight/day, the male an imal killed in extremies (no. 35) showed clinical signs such as ruffled fur from day 6 of treatment a nd hunched posture, ruffled fur and yellowish discoloured feces from day 8 of treatment. At necropsy no macroscopical finding was noted for this animal. Female no. 78, treated at the dose level of 90 mg/kg body weight/day and found dead on day 2 of the pa iring period, had ruffled fur from day 6 of treatment and yellowish discoloured feces from day 9 of treatment. At necropsy examination, dark red discoloration of the thymus, enlarged stomach and redish br own firm nodule in the jejunum were found. After histopa thological examination it was concluded that the cause of death was likely the thrombosis of jejunum therefore this death was considered to be incidental. At the dose level of 90 mg/kg body weight/day addi tional males were noted with ruffled fur and yellowish discoloured feces (no. 34 and 40) in the pre-pairing and pa iring period. Male no. 37 had scabs and reddish sore on the right shoulder appearing in the pair ing period and the scabs were noted in the after pairing period too. 189

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## Three additional females in this group (nos. 72, 73, 74) had ruffled fur starting in the pretreatment period through pairing period. Female no. 73 had yellowish discoloured feces from the second week of pre-pairing period up to and in cluding the gestation period. Female no. 72 also had huched posture on the first tw o days of the gestation period. In groups 3 and 2 no clini cal signs were noted in any sex during the study. In group 1, male no. 10 had reddis h sore at the cervical region fo r a short period in the pairing period.

4.2.3 Detailed Clinical Observations (Weekly) (See Summary Tables on p. , Individual Tables on p. ) At the dose level of 90 mg/kg body weight/day, th e ruffled fur noted during the detailed weekly clinical observations of males and fema les indicated a test item-related effect.

No test item-related effect wa s found in the other dose groups.

4.2.4 Functional Observational Battery (See Summary Tables on p. , Individual Tables on p. ) A description of the test parameters and sc oring used is included in Appendix V on p.

. The corresponding historical control data are included in Appendix VIII on p.

. None of the parameters under investigation duri ng the functional observational battery gave an indication of a test item-related effect. Mean values of grip strength (f ore- and hind paws) and landing f oot splay gave no indication of test item-related effects. Body temperature in males was st atistically significan tly lower at the dose level of 90 mg/kg body weight/day compared to the control group (37.3 °C compared to 38.1 °C in the control group). Additionally, slightly lower locomotor activ ity of this group was seen, thus a treatmentrelated effect can not be excluded. 82 214

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## 4.2.5 Locomotor Activity (See Summary Tables on p. , Individual Tables on p. ) Locomotor activity was assessed quantitatively in terms of low beam counts in activity monitor. For females at the dose level of 90 mg/kg body wei ght/day, total level of locomotor activity was statistically significantly reduced. In males the total level of activity was lower when compared to controls or other test item-treated groups but it did not reach statistical significance. The reduced locomotor activity in animals receiv ing 90 mg/kg body weight/day of was considered to be a test item-related effect. In females at the dose level of 30 mg/kg body wei ght/day the low beam count at 30 minutes was lower when compared to control but the total level of activity was not affected in this dose group.

4.2.6 Food Consumption of Males (See Figures on p. , Summary Tables on pp. and , Individual Tables on p. ) The mean food consumption of males receivin g 90 mg/kg body weight/day of was statistically significantly lower between days 8 a nd 14 in the pre-pairing period and it was lower during the whole pre-pairing peri od. This was considered to be a test item-related effect. The mean food consumption of males was at cont rol level for each test item-treated groups after the pairing period. In groups 30 and 10 mg/kg body weight/day, food consumption of males was not affected by the treatment of the test item.

4.2.7 Food Consumption of Females (See Figures on p. , Summary Tables on pp. and , Individual Tables on p. ) Pre-pairing, Gestation and Lactation Periods The mean food consumption of females receiving 90 mg/kg body weight/day of was statistically significantly lower during the pr e-pairing period which wa s considered to be a test item-related effect.

There was no effect of treatment with on the food consumption of females in the gestation or lactation periods. 95 231

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## In groups 30 and 10 mg/kg body weight/day, the mean food consumption of females was not affected by the treatment of the test item.

4.2.8 Body Weights of Males (See Figures on pp. and , Summary Tables on pp. , and , Individual Tables on pp. and ) Pre-pairing and Pairing Periods From day 5 of the pre-pairing period the m ean body weight of males receiving 90 mg/kg body weight/day of was minimally decreased throughout the study when compared to the control group, although not reaching a level of statistic al significance. The mean body weight gain of males receiving 90 mg/kg body weight/day of was lower from day 5 of pre-pairi ng period when compared to controls and it was statistically significantly reduced between days 8 and 14. In correlation with the low food consumption this was considered to be a test item-related effect. Thereafter mean values similar to the control group were achieved during the pairing and after pairing periods. In groups 30 and 10 mg/kg body weight/day, mean body weights and mean body weight gains of the males were similar to that of the control grou p during the study.

4.2.9 Body Weights of Females (See Figures on pp. and , Summary Tables on pp. , and , Individual Tables on pp. and ) Pre-pairing, Pairing, Gestat ion and Lactation Periods During the pre-pairing period the mean body wei ghts of females at the dose level of 90 mg/kg body weight/day were minimally below of the control level achiving levels of occasional statistical significance from day 9 onwards. Duri ng the pairing, gestation and lactation periods mean body weights comparable to thos e of the control group were noted. Significantly lower mean body weight gain was reco rded from day 4 of the pre-pairing period was considered to be a test item-related effects. During the gestation period, minimally increased mean body weight gain values were found while there was no difference in mean body wei ght gain noted during the lactation period. In groups 30 and 10 mg/kg body weight/day, mean body weights and mean body weight gains of the females were similar to that of the control group during the study. 53 59 108 118 128 251 273

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# 4.3 Clinical Laboratory Investigations

4.3.1 Hematology (See Summary Tables on p. , Individual Tables on p. )

Males No changes to be of toxicological releva nce were noted in males in any dose group.

Females No changes were noted in females in any dose group.

4.3.2 Clinical Biochemistry (See Summary Tables on p. , Individual Tables on p. ) The assessment of the biochemistry data did not reveal any test item-related effect in any dose group in any sex.

Males No changes were noted in males in any dose group.

Females The total cholesterol level was statistically significantly higher in females treated at the dose level of 90 mg/kg body weight/day a nd lying slightly outside the range of historical control data, thus, test item-realted rela tionship cannot be excluded. The creatinine level was statistically significantly higher in females treated at the dose level of 10 mg/kg body weight/day however the value was within the historical background range. In absence of dose relationship no experimental relevance was attributed to this finding. At the dose level of 30 mg/kg body we ight/day no changes were noted. 141 296

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# 4.4 Reproduction and Breeding Data

4.4.1 Summary of Performance P Animals Breeding for F1 Litters

Group (mg/kg/day) 1 (0) 2 (10) 3 (30) 4 (90) Female numbers 41-50 51-60 61-70 71-80 Number of females paired 10 10 10 10 Number of females mated (A) 10 10 10 9 Number of non-pregnant females (B) 2 1 0 1 Number of females, which died before the scheduled necropsy (C) 0 0 0 1 Number of females, which did not deliver any pups (D) 0 1 0 0 Number of females which reared their pups until day 4 post partum 8 8 10 8 (A) Female no. 78 died spontaneously on day 2 in the pairing period (B) Female nos. 45, 46, 51 and 77 were not pregnant (C) Female no. 78 died spontaneously on day 2 in the pairing period (D) Female no. 59 had 3 late embryonic losses only



## 4.4.2 Mating Performance and Fertility (See Summary Tables on p. , Individual Tables on p. ) Mating performance and fertility were unaffected by treatment. All females mated within the first pairing period. The pre-coital interval was unaffected by treatment with the test item.

4.4.3 Corpora Lutea Count (See Summary Tables on p. , Individual Tables on p. ) Mean number of corpora lutea per dam (determine d at necropsy) was similar in all groups and was unaffected by treatment. 152 317

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## 4.4.4 Gestation Length (See Summary Tables on p. , Individual Tables on p. ) The mean gestation length wa s unaffected by treatment.

4.4.5 Implantation Rate and Post-implantation Loss (See Summary Tables on p. , Individual Tables on p. ) The number of implantation and the post-implan tation loss were not affected by the treatment with the test item. The mean number of implantations of pre gnant females was similar in all groups. The mean incidence of post-implantation loss as a percentage of total implantations was 7.8, 7.9, 7.3 and 9.0 %, in order of ascending dose level.

4.4.6 Litter Size at First Litter Check (See Summary Tables on p. , Individual Tables on p. ) The corresponding historical control data are included in Appendix VIII on p.

. The litter size was unaffected by treatment in any dose group. The mean litter size of dams receiving 90 mg/kg body weight/day of was slightly lower when compared to controls (11.4 compared to 11.9) but was within the historical control data range (10.3 - 13.2).

4.4.7 Postnatal Loss Days 0 - 4 Post Partum (See Summary Tables on pp. and , Individual Tables on p. ) The corresponding historical control data are included in Appendix VIII on p.

. Mean postnatal loss between days 0 and 4 post partum was higher (7.7 compared to 0.0 in control or to the range of historical control data 0.0 - 3.8) and the mean number of living pup on day 4 post partum was lower (10.5 compared to 11.9 in control, however it was within the range of historical control data 10.3 - 13.2) in the group receiving 90 mg/kg body weight/day. Also the viability index was statistically significantl y lower in the high dose group (92.3 compared to 100.0 in the control or the range of the historical control data 96.2 - 100.0) therefore these were considered to be test item-related effects. 155 326

155 325

155 327

586

155 182 327

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## At 30 and 10 mg/kg body weight/day, the postnatal lo ss and viability index were not affected by the treatment of the test item.



# 4.5 Terminal Findings - Parent Animals

4.5.1 Organ Weights (See Summary Tables on p. , Individual Tables on p. ) The corresponding historical control data are included in Appendix VIII on p.

. Absolute and relative mean liver weights (both relative to body weight and relative to brain weight) were statistically increased in males and females of group 4 (90 mg/kg body weight/day). This finding correlated to diffuse hepatocel lular hypertrophy associated with follicular hypertrophy of thyroid glands on so me males and females of group 4. Additionally, absolute and relative mean thym us weights were statistically significantly decreased in females of group 4, correlated with the observation of reduced size of thymus and thymic atrophy noted at hi stopathological examination. No experimental relevance was at tributed to increased relative mean kidney and heart weights in males and females of group 4 as the mean values we re within the range of historical control data and no corroborative histopatholog ical findings were recorded.

4.5.2 Macroscopical Findings (See Summary Tables on p. , Individual Tables on p. ) The relevant macroscopical change in the stomac h recorded as crateriform retraction was noted in one female at 30 mg/kg body weight/day, correlating with ulcera tion and submucosal inflammation. One, three and four females receiving 10, 30 an d 90 mg/kg body weight/day of had reduced sized thymus correlating with thym ic atrophy and reduced organ weights at 90 mg/kg body weight/day only. This thymus finding was considered to be lik ely stress-related. Other isolated macroscopical fi ndings were considered to be within the range of normal background alterations. 158 335

592

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## 4.5.3 Histopathology Findings (See Appendix VII on p. ) Under the conditions of this experiment, induced the following treatment-related local irritative effects:

• Forestomach: hyperkeratosis in some female s receiving 30 mg/kg body weight/day and all males receiving 90 mg/kg body weight/day and a single female at 90 mg/kg body weight/day, squamous cell hyperplasia with submucosal inflammation in a female at 30 mg/kg body weight/day; glandular stomach: focal erosion in one male at 10 mg/kg body weight/day and one male and female each at 90 mg/kg body weight/day, in the female associated with submucosal inflammation, mucosal atrophy. Under the conditions of this experiment, induced the following treatment-related adaptive findings that are commonly seen in rats exposed with xenobiotics:

• Minimal to slight diffuse hepatocellular hypertrophy, caracterized by an increase in endoplasmic reticulum, was recorded in liver in all males and females at 90 mg/kg body weight/day. This finding was considered to be adaptive. Diffuse follicular cell hypertrophy in thyroid gland was noted in some males and females at 90 mg/kg body weight/day. This finding was consider ed to be consequent to the hepatocellular hypertrophy. Histopathological examination of female no. 78 which died spontaneously receiving 90 mg/kg body weight/day revealed that th e cause of death was likely the thrombosis of jejunum and, therefore, this death was considered to be incidental and not test item related. Histopathological examination of the male no. 35 in the 90 mg/kg body weight/day group, which was killed in extremis, showed slight diffuse hy perkeratosis in forestomach and minimal erosion in glandular stomach, signs of mo derate stress in thymus and ad renal glands as well as slight diffuse atrophy in the prostate, coagulating gla nd and seminal vesicles. The cause of moribundity could not be determind from the organs and tissues determined.



# 4.6 Litter Data - F1 Pups

4.6.1 External Examination at First Li tter Check and during Lactation (See Summary Tables on p. , Individual Tables on p. ) No milk in stomach was found in one female pup in litter no. 67 (parent animals treated with the dose level of 30 mg/kg body weight/day) on day 4 post partum. 448

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## At the dose level of 90 mg/kg body weight/day, thr ee male pups in three different litters (nos. 72, 74, 79) had no milk in stomach at first litter chec k and they were missing afterwards on day 4, 2, 2 post partum, respectively.

4.6.2 Sex Ratios (See Summary Tables on p. , Individual Tables on p. ) Sex ratios at first litter check and on day 4 pos t partum were unaffected by treatment with the test item. The proportion of males on day 4 post partum was 48, 46, 53 and 49%, in order of ascending dose level.

4.6.3 Body Weights on Day 4 Post Partum (See Figures on p. , Summary Tables on p. , Individual Tables on p. ) Mean pup weights on day 1 post partum were unaffected by treatment with the test item. On day 1 post partum mean pup weights were 6.3, 5.7, 5.9 and 5.8 g in order of ascending dose level. During the lactation period (on da y 4 post partum), mean pup weight development resulted to be generally lower at the dose level of 90 mg/ kg body weight/day (except for litter 71 resulting 12.7 g mean pup weight which was the highest in this study). Mean pup weights on day 4 post partum were 9.6, 8.4, 8.5 and 8.1 g in order of ascending dose leve l when included all relevant dams in evaluation. When excluding litters we ighing more than 11 g mean body weight per group the mean body weight of pups were statistica lly significantly lower at the dose level of 90 mg/kg body weight/day. The mean values were as follows: 9.3, 8.4, 8.3 and 7.4 g in order of ascending dose level. Therefore, the mean body weight of pups on da y 4 post partum at the dose level of 90 mg/kg body weight/day was considered to be adverse test item related effect.

4.6.4 Macroscopical Findings (See Summary Table on p. , Individual Tables on p. ) No findings were noted at macros copic examination of F1 pups. 155 389

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# 5 DISCUSSION AND CONCLUSION
This study is a valid investigation of the toxicological effects resu lting from repeated oral-gavage administration of the test ite m to rats over at least 28 days. was administered in 0.5% carboxymethylcellulose as vehicle at dosages of 10, 30, and 90 mg/kg body weight/day, and controls received the vehicle only. was administered to male rats for 28 days and to female rats for 14 days prior to pairing. Administ ration of the test item continued through the pairing and gestation periods until the F1 generation reached day 4 post partum. At 90 mg/kg body weight/day, treatm ent with the test item resulted in a general re duction in food consumption, body weight and body weight gain in ma les and females. Test item-related clinical signs were observed in males and females such as hunched posture, ruffled fur and discoloured feces. The locomotor activity was reduced in both sexes. The postnatal loss was increased therefore the viability index was decreased. The mean number of live fetuses on day 4 post partum was lo wer and the pup body weight development was decreased. An increase of the liver weights of the dams (absolut e and ratios) and in males was observed and this correlated with diffuse hepa tocellular hypertrophy which was associated with consequent follicular cell hypertrophy of thyroi d glands in some males and females at 90 mg/kg body weight/day. The absolute and relative thym us weights of females were decreased and correlated with macroscopical and histopath ological changes such as thymic atrophy. Degenerative stomach findings we re present in some males and females at histopathological examination. At 30 mg/kg body weight/day, the mucosa in the stomach showed at necropsy to be thickened with irregular surface in one female. The hist opathology data showed correlating degenerative lesions in the stomach. At 10 mg /kg body weight/day, a local irrita tive effect was noted in one male. At 30 and 10 mg/kg body weight/day, no ge neral or reproductive t oxicity effects were noted. Based on the observed mortality, clinical sy mptoms, decreased body weight, decreased food consumption, increased liver and decreased thym us weights at the dose level of 90 mg/kg body weight/day the NOAEL (No Observed Adverse Effect Level) for general t oxicity in parental males and females was considered to be 30 mg/kg body weight/day. Based on the significantly lower body weight of pups and the decreased viability index on day 4 post partum at the high dose level of 90 mg/ kg body weight/day, the NOAEL for reproduction/ developmental toxicity was consider ed to be 30 mg/kg body weight/day. Fertility index, conception rate, mean precoital ti me, number of implantations were not affected by the treatment in any test item-treated group. No developmental effects were seen at dose levels of 30 and 10 mg/kg body weight/day. A NOAEL (No Observed Adverse Effect Level) for the local irritative effect of in stomach could not be established for males and was established at 10 mg/kg bw/day for females based on the microscopi c findings detected. Harlan Laboratories Study Report
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# 6 REFERENCES

1. E. Salewski: Arch. Exp. Path. Pharmak. 247, pp. 367-368 (1964).

2. C.W. Dunnett: A Multiple Comparison Procedure for Comparin g Several Treatments with a Control, J. Amer. Statist. Assoc. 50, pp. 1096-1121 (1955).

3. R.G. Miller: Simultaneous Statistical Inference, Springer Verlag, New York (1981).

4. R.A. Fisher: Statistical Methods for Research Work ers, Oliver and Boyd, Edinburgh (1950). Harlan Laboratories Study Report
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# 7 FIGURES Harlan Laboratories Study Report
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# In-life Data - P Generation Harlan Laboratories Study Report
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### FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

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### FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 5 10 15 20 25 30

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Days G/ANIMAL/DAY

1 2 3 4 0 5 10 15 20 25 30

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Days G/ANIMAL/DAY 

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### FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS

Gestation Period
Full Phase Full Phase Full Phase Full Phase Full Phase 45 46 51 59 77 Female Female Female Female Female Group 1

Group 1 Group 2 Group 2 Group 4 Animal Animal Animal Animal Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

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### FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS

PRE-PAIRING PERIOD

GESTATION PERIOD 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 5 10 15 20 25 30 35

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Days G/ANIMAL/DAY

0 7 14 21 0 5 10 15 20 25 30 35

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Days G/ANIMAL/DAY 

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### FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS

LACTATION PERIOD

1 2 3 4 5 0 5 10 15 20 25 30 35

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Days G/ANIMAL/DAY 

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### BODY WEIGHTS (G) - GRAPHICS

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

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### BODY WEIGHTS (G) - GRAPHICS

PRE-PAIRING PERIOD

PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 40 80 120 160 200 240 280 320 360 400

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G

1 2 3 4 5 6 7 8 9 10 11 12 0 40 80 120 160 200 240 280 320 360 400

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G 

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### BODY WEIGHTS (G) - GRAPHICS

AFTER PAIRING PERIOD

1 2 3 4 0 40 80 120 160 200 240 280 320 360 400

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G 

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### BODY WEIGHTS (G) - GRAPHICS

Pairing Period

Gestation Period Full Phase

Full Phase Full Phase Full Phase Full Phase Full Phase 78

45 46 51 59 77 Female

Female Female Female Female Female Group 4

Group 1 Group 1 Group 2 Group 2 Group 4 Animal

Animal Animal Animal Animal Animal Data excluded from Summary Report

Animal Found Dead

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

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### FEMALES ORATORIES STUDY D23451 I 127



### BODY WEIGHTS (G) - GRAPHICS

PRE-PAIRING PERIOD

PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 40 80 120 160 200 240 280 320 360

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G

1 2 3 4 5 6 7 8 9 10 11 12 0 40 80 120 160 200 240 280 320 360

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G 

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### BODY WEIGHTS (G) - GRAPHICS

GESTATION PERIOD

LACTATION PERIOD

0 7 14 21 0 40 80 120 160 200 240 280 320 360

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G

1 2 3 4 5 0 40 80 120 160 200 240 280 320 360

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day G 

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### BODY WEIGHT GAIN (%) - GRAPHICS

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

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### MALES ORATORIES STUDY D23451 I 127



### BODY WEIGHT GAIN (%) - GRAPHICS

PRE-PAIRING PERIOD

PAIRING PERIOD 1 2 3 4 5 6 7 8 9 10 11 12 13 14 -4 -2 0 2 4 6 8 10 12 14 16

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day %

1 2 3 4 5 6 7 8 9 10 11 12 -4 -2 0 2 4 6 8 10 12 14 16

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day % 

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### BODY WEIGHT GAIN (%) - GRAPHICS

AFTER PAIRING PERIOD

1 2 3 4 -4 -2 0 2 4 6 8 10 12 14 16

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day % 

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### BODY WEIGHT GAIN (%) - GRAPHICS

Pairing Period

Gestation Period Full Phase

Full Phase Full Phase Full Phase Full Phase Full Phase 78

45 46 51 59 77 Female

Female Female Female Female Female Group 4

Group 1 Group 1 Group 2 Group 2 Group 4 Animal

Animal Animal Animal Animal Animal Data excluded from Summary Report

Animal Found Dead

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

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### BODY WEIGHT GAIN (%) - GRAPHICS

PRE-PAIRING PERIOD

PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 -10 0 10 20 30 40 50 60 70

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day %

1 2 3 4 5 6 7 8 9 10 11 12 -10 0 10 20 30 40 50 60 70

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day % 

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### BODY WEIGHT GAIN (%) - GRAPHICS

GESTATION PERIOD

LACTATION PERIOD

0 7 14 21 -10 0 10 20 30 40 50 60 70

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day %

1 2 3 4 5 -10 0 10 20 30 40 50 60 70

Group 1 (0 mg/kg) Group 2 (10 mg/kg)

Group 3 (30 mg/kg) Group 4 (90 mg/kg) Day % 

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# Data of F1 Pups Harlan Laboratories Study Report
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# 8 SUMMARY TABLES Harlan Laboratories Study Report
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# In-life Data - P Generation Harlan Laboratories Study Report
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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

Incomplete Recordings

--- Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed

Selection of Findings All findings reported Data excluded from Summary Report

--- Affected animals as percentage to observed animals
0 0% < between 1% and 9% 1 between 10% and 19% 2 between 20% and 29%

... ... 9 between 90% and 99% A 100% 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

ACCLIMATIZATION

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 1 2 3 4 5 6 7 Days

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

COLORS

No further abnormality recorded. HUNCHED POSTURE (1)
RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . . . 1 1

. . . . . 1 1 1 2 1 1 1 1 2

. . . . . . . 2 2

. . 2 2 2 Days

. . . . . . . 1 1

. . . . . 2 2 2 2 1 1 1 1 1 -

-

- 1 1 1 1 1

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) . . . . . . . 1 1

. . 1 1 2 %

%

G % G

G 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

COLORS

No further abnormality recorded. REDDISH SORE (3)

RUFFLED FUR (3)
SCABS (3)

REDDISH SORE (3)

STAINED/DISCOLORED YELLO (3) NECK (CERVICAL)

SHOULDER RIGHT

SHOULDER RIGHT

FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . 1 1 1 1 1

. .

2 2 2 2 2 2 2 2

. . . .

. . . . . . . . . . 1 1

. . . . . . 1 1 1 1

. .

2 2 2 2 2 1 1 1

. . . . Days

2 2 2 2 1 1 1 1

. . . . -

-

-

-

- 1 1 1 1 1

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) . . . . . 1 1 1 1 1

. .

. . . . . . . . . . 1 1

. . . . . . 1 1 1 1

. .

2 2 2 2 2 1 1 1

. . . . G

%

G

G

G %

%

%

% G 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

AFTER PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

No further abnormality recorded. SCABS (3) SHOULDER RIGHT 1 2 3 4

1

. . . Days

-

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 1

. . . G % 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

Incomplete Recordings

--- Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed

Selection of Findings All findings reported Data excluded from Summary Report

--- Affected animals as percentage to observed animals
0 0% < between 1% and 9% 1 between 10% and 19% 2 between 20% and 29%

... ... 9 between 90% and 99% A 100% 

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### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

ACCLIMATIZATION

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 1 2 3 4 5 6 7 Days

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7a 

## Page 77 of 66315-MAR-12 SYMT-SUM - 3



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

COLORS

No further abnormality recorded. RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . 3 3 3 3 3 3 4 4 4

. . . . . . . . 1 1 1 1 1 1 Days

. . . . . 1 1 1 2 2 2 1 1 1

-

- 1 1 1 1 1

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) . . . . . . . . 1 1 1 2 2 2 %

G % G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7a 

## Page 78 of 66315-MAR-12 SYMT-SUM - 4



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

COLORS

No further abnormality recorded. RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

4 2 1

1 1 1 Days

1 1 1

-

- 1 1 1 1 1

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 2 1 1 %

G % G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7a 

## Page 79 of 66315-MAR-12 SYMT-SUM - 5



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

GESTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

COLORS

No further abnormality recorded. HUNCHED POSTURE (1)
RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3) FECES 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5

1 1

. . . . . . . . . . . . . . . . . . . . . .
3 3 2 2 2 2 1 1

. . . . . . . . . . . . . . . .

1 1 1 1 1 1 1 1 1 1 1

. . . . . . . . . . . . . Days

1 1

. . . . . . . . . . . . . . . . . . . . . .
1 2 2 2 1 1 1 1

. . . . . . . . . . . . . . . . -

-

- 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 1 1 1 1 1 1 1 1 1 1 1

. . . . . . . . . . . . . %

%

G % G

G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7a 

## Page 80 of 66315-MAR-12 SYMT-SUM - 6



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS - SUMMARY

LACTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 1 2 3 4 5 Days

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7a 

## Page 81 of 66311-OCT-11 WOC-SUM - 1 ORATORIES STUDY D23451 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

Incomplete Recordings

--- Not Reported

---

Selection of Findings All findings reported Data excluded from Summary Report

--- Affected animals as percentage to observed animals
0 0% < between 1% and 9% 1 between 10% and 19% 2 between 20% and 29%

... ... 9 between 90% and 99% A 100% 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7c 

## Page 82 of 66311-OCT-11 WOC-SUM - 2



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

No further abnormality recorded. RUFFLED FUR (3) 1 2

1 1 Weeks

2 1

- 0

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) % G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7c 

## Page 83 of 66311-OCT-11 WOC-SUM - 3



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

No further abnormality recorded. REDDISH SORE (3)

RUFFLED FUR (3) NECK (CERVICAL) 1 2

1

2 Weeks

1 -

- 0

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 1 G

% %

G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7c 

## Page 84 of 66311-OCT-11 WOC-SUM - 1 ORATORIES STUDY D23451 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

Incomplete Recordings

--- Not Reported

---

Selection of Findings All findings reported Data excluded from Summary Report

--- Affected animals as percentage to observed animals
0 0% < between 1% and 9% 1 between 10% and 19% 2 between 20% and 29%

... ... 9 between 90% and 99% A 100% 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7f 

## Page 85 of 66311-OCT-11 WOC-SUM - 2



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

No further abnormality recorded. RUFFLED FUR (3) 1 2

3 4 Weeks

1 1

- 0

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) % G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7f 

## Page 86 of 66311-OCT-11 WOC-SUM - 3



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

PAIRING PERIOD

Group 3 (30 mg/kg)
No abnormality recorded. 1 2 Weeks 0

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7f 

## Page 87 of 66311-OCT-11 WOC-SUM - 4



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS - SUMMARY

GESTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

APPEARANCE

No further abnormality recorded. RUFFLED FUR (3) 1 2 3

-

2

. . Weeks

2

. . - 0

G : Rounded group means of grades of affected animals % : Affected animals as percentage to observed animals (See explanation on cover page) % G 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd7f 

## Page 88 of 66311-OCT-11 REP-SUM - 1 ORATORIES STUDY D23451 127



### Functional Observational Battery - SUMMARY

AFTER PAIRING PERIOD Reported Parameter

GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore Grip Hind Distance DEGREES GRIP STRENGTH 1

GRIP STRENGTH 2 GRIP STRENGTH 3 GRIP STRENGTH 4 GRIP STRENGTH 5 GRIP STRENGTH 6 GRIP FORELIMB GRIP HINDLIMB Landing Foot Splay BODY TEMPERATURE DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN Not Reported

--- Data excluded from Summary Report

---

Parameter Statistical Testing

Statistical Methods DUNNETT DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd82 

## Page 89 of 66311-OCT-11 REP-SUM - 2

GRIP STRENGTH

GRIP_1

GRIP_2

GRIP_3

GRIP_4

GRIP_5

GRIP_6

Grip Fore

Grip Hind

LANDING FOOT SPLAY

Distance MEAN

ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.24 0.28 0.29 0.29 0.08 0.05 0.05 0.05 5 5 5 5

0.33 0.31 0.33 0.33 0.07 0.06 0.07 0.07 5 5 5 5

0.34 0.32 0.26 0.30 0.05 0.10 0.05 0.08 5 5 5 5

0.15 0.13 0.19 0.19 0.05 0.03 0.01 0.04 5 5 5 5

0.15 0.17 0.14 0.18 0.06 0.03 0.04 0.01 5 5 5 5

0.18 0.17 0.16 0.18 0.10 0.08 0.03 0.05 5 5 5 5

0.30 0.30 0.29 0.31 0.05 0.06 0.03 0.03 5 5 5 5

0.16 0.16 0.16 0.18 0.06 0.03 0.01 0.02 5 5 5 5

7.2 4.4 6.8 6.3 2.2 0.8 4.1 2.5 5 5 5 5 

### AFTER PAIRING PERIOD Functional Observational Battery - SUMMARY

MALES

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - - ORATORIES STUDY D23451 127

---------------------

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

---------------------

cm

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd82 

## Page 90 of 66311-OCT-11 REP-SUM - 3

BODY TEMPERATURE

DEGREES MEAN

ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

38.1 37.9 38.0 37.3 0.4 0.3 0.1 0.4 5 5 5 5 

### AFTER PAIRING PERIOD Functional Observational Battery - SUMMARY

MALES

- - **

ORATORIES STUDY D23451 127

---------------------

C

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd82 

## Page 91 of 66311-OCT-11 REP-SUM - 1 ORATORIES STUDY D23451 127



### Functional Observational Battery - SUMMARY

LACTATION PERIOD Reported Parameter

GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore Grip Hind Distance DEGREES GRIP STRENGTH 1

GRIP STRENGTH 2 GRIP STRENGTH 3 GRIP STRENGTH 4 GRIP STRENGTH 5 GRIP STRENGTH 6 GRIP FORELIMB GRIP HINDLIMB Landing Foot Splay BODY TEMPERATURE DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN Not Reported

--- Data excluded from Summary Report

---

Parameter Statistical Testing

Statistical Methods DUNNETT DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd85 

## Page 92 of 66311-OCT-11 REP-SUM - 2

GRIP STRENGTH

GRIP_1

GRIP_2

GRIP_3

GRIP_4

GRIP_5

GRIP_6

Grip Fore

Grip Hind

LANDING FOOT SPLAY

Distance MEAN

ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.38 0.30 0.39 0.32 0.11 0.07 0.07 0.05 5 5 5 5

0.38 0.36 0.42 0.34 0.16 0.05 0.10 0.10 5 5 5 5

0.31 0.38 0.35 0.36 0.09 0.07 0.10 0.06 5 5 5 5

0.24 0.21 0.25 0.20 0.11 0.08 0.06 0.03 5 5 5 5

0.22 0.21 0.23 0.22 0.13 0.07 0.04 0.05 5 5 5 5

0.22 0.17 0.25 0.22 0.10 0.02 0.04 0.07 5 5 5 5

0.36 0.35 0.39 0.34 0.08 0.05 0.04 0.06 5 5 5 5

0.23 0.20 0.24 0.21 0.11 0.05 0.05 0.04 5 5 5 5

7.9 5.3 7.3 7.3 2.4 2.2 1.6 1.2 5 5 5 5 

### LACTATION PERIOD Functional Observational Battery - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - - ORATORIES STUDY D23451 127

---------------------

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

KILOGRAM

---------------------

cm

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd85 

## Page 93 of 66311-OCT-11 REP-SUM - 3

BODY TEMPERATURE

DEGREES MEAN

ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

38.7 38.5 38.6 38.3 0.3 0.3 0.2 0.4 5 5 5 5 

### LACTATION PERIOD Functional Observational Battery - SUMMARY

FEMALES

- - -

ORATORIES STUDY D23451 127

---------------------

C

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd85 

## Page 94 of 66311-OCT-11 LOCA-SUM - 1 ORATORIES STUDY D23451 127



### LOCOMOTOR ACTIVITY - SUMMARY

LOCOMOTOR ACTIVITY Reported Parameter

6 12 18 24 30 total 6 min

12 min 18 min 24 min 30 min total STEEL, MEDIAN

STEEL, MEDIAN STEEL, MEDIAN STEEL, MEDIAN STEEL, MEDIAN DUNNETT, MEAN Not Reported

--- Data excluded from Summary Report

---

Parameter Statistical Testing

Statistical Methods DUNNETT

STEEL DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd87 

## Page 95 of 66311-OCT-11 LOCA-SUM - 2

LOW BEAMS COUNT

6

12

18

24

30

total MEDIAN

ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

441.00 474.00 474.00 420.00 59.48 131.59 67.10 78.58 5 5 5 5

309.00 338.00 328.00 251.00 86.81 98.39 83.22 97.00 5 5 5 5

215.00 253.00 122.00 194.00 87.79 87.40 101.78 71.80 5 5 5 5

172.00 199.00 169.00 117.00 94.51 100.12 139.52 55.68 5 5 5 5

170.00 172.00 211.00 70.00 80.32 74.88 117.74 102.01 5 5 5 5

1348 1420 1307 1171 244 373 403 292 5 5 5 5 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY - SUMMARY

MALES

- - -

- - -

- - -

- - -

- - -

- - - ORATORIES STUDY D23451 127

---------------------

min

min

min

min

min

min

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd87 

## Page 96 of 66321-NOV-11 LOCA-SUM - 1 ORATORIES STUDY D23451 127



### LOCOMOTOR ACTIVITY - SUMMARY

LOCOMOTOR ACTIVITY Reported Parameter

6 12 18 24 30 total 6 min

12 min 18 min 24 min 30 min total STEEL, MEDIAN

STEEL, MEDIAN STEEL, MEDIAN STEEL, MEDIAN STEEL, MEDIAN DUNNETT, MEAN Not Reported

--- Data excluded from Summary Report

---

Parameter Statistical Testing

Statistical Methods DUNNETT

STEEL DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd89 

## Page 97 of 66321-NOV-11 LOCA-SUM - 2

LOW BEAMS COUNT

6

12

18

24

30

total MEDIAN

ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEDIAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

309.00 306.00 251.00 222.00 62.00 36.57 47.49 22.11 5 5 5 5

208.00 155.00 198.00 149.00 56.23 31.70 36.26 43.49 5 5 5 5

186.00 163.00 189.00 117.00 56.44 29.84 53.30 67.59 5 5 5 5

184.00 118.00 170.00 76.00 51.42 29.08 48.56 60.26 5 5 5 5

131.00 104.00 63.00 9.00 93.07 32.56 66.49 44.01 5 5 5 5

976 865 878 567 257 116 103 160 5 5 5 5 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - -

- - ** ORATORIES STUDY D23451 127

---------------------

min

min

min

min

min

min

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd89 

## Page 98 of 66320-MAR-12 FC-SUM - 1 ORATORIES STUDY D23451 IRGACURE 127



### FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd8b 

## Page 99 of 66320-MAR-12 FC-SUM - 2



### MALES

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD Days 1-8

Days 8-14

MEAN OF MEANS Over PRE-PAIRING PERIOD

Days 1-3 MEAN

ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

22.6 22.8 23.2 21.5 1.4 2.2 1.7 2.5 10 10 10 9
23.5 23.3 23.3 20.5 1.0 2.4 1.5 4.0 10 10 10 9
23.0 23.1 23.2 21.0

25.0 25.1 25.1 25.3 2.0 1.4 1.7 2.1 10 10 10 9 ORATORIES STUDY D23451 IRGACURE 127



### FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY

- - -

- - *

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd8b 

## Page 100 of 66320-MAR-12 FC-SUM - 1 ORATORIES STUDY D23451 IRGACURE 127



### FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY

Gestation Period
Full Phase Full Phase Full Phase Full Phase Full Phase 45 46 51 59 77 Female Female Female Female Female Group 1

Group 1 Group 2 Group 2 Group 4 Animal Animal Animal Animal Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd8e 

## Page 101 of 66320-MAR-12 FC-SUM - 2



### FEMALES

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD Days 1-8

Days 8-14

MEAN OF MEANS Over PRE-PAIRING PERIOD

Days 0-7

Days 7-14

Days 14-21

MEAN OF MEANS Over GESTATION PERIOD

Days 1-4 MEAN

ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

14.6 14.6 14.5 10.6 0.8 1.2 0.9 3.2 10 10 10 10
15.5 15.2 15.2 13.6 0.9 1.4 1.0 1.3 10 10 10 10
15.1 14.9 14.9 12.1

18.6 18.2 18.4 18.9 1.3 1.2 1.5 2.2 8 8 10 8
20.8 20.1 20.3 21.3 1.7 1.5 1.9 2.6 8 8 10 8
23.1 21.8 22.0 22.8 1.9 1.6 1.8 2.9 8 8 10 8
20.8 20.0 20.3 21.0

27.1 26.5 28.2 32.8 3.3 1.8 7.7 26.8 8 8 10 8 ORATORIES STUDY D23451 IRGACURE 127



### FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY

- - **

- - **

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd8e 

## Page 102 of 66320-MAR-12 FC-SUM - 1 ORATORIES STUDY D23451 IRGACURE 127



### DIFFERENCES IN MEAN FOOD CONSUMPTION (G/ANIMAL/DAY)

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd90 

## Page 103 of 66320-MAR-12 FC-SUM - 2



### MALES

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD Days 1-8

Days 8-14

MEAN OF MEANS Over PRE-PAIRING PERIOD DIFF (%)* Over PRE-PAIRING PERIOD

Days 1-3 MEAN

ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)* Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

22.6 22.8 23.2 21.5 1.4 2.2 1.7 2.5 10 10 10 9

+0.9 +2.7 -4.9
23.5 23.3 23.3 20.5 1.0 2.4 1.5 4.0 10 10 10 9

-0.9 -0.9 -12.8
23.0 23.1 23.2 21.0

+0.4 +0.9 -8.7

25.0 25.1 25.1 25.3 2.0 1.4 1.7 2.1 10 10 10 9

+0.4 +0.4 +1.2 ORATORIES STUDY D23451 IRGACURE 127



### DIFFERENCES IN MEAN FOOD CONSUMPTION (G/ANIMAL/DAY)

*: Percentage relative to the control group ---

---

---

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd90 

## Page 104 of 66320-MAR-12 FC-SUM - 1 ORATORIES STUDY D23451 IRGACURE 127



### DIFFERENCES IN MEAN FOOD CONSUMPTION (G/ANIMAL/DAY)

Gestation Period
Full Phase Full Phase Full Phase Full Phase Full Phase 45 46 51 59 77 Female Female Female Female Female Group 1

Group 1 Group 2 Group 2 Group 4 Animal Animal Animal Animal Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd93 

## Page 105 of 66320-MAR-12 FC-SUM - 2



### FEMALES

PRE-PAIRING PERIOD

GESTATION PERIOD Days 1-8

Days 8-14

MEAN OF MEANS Over PRE-PAIRING PERIOD DIFF (%)* Over PRE-PAIRING PERIOD

Days 0-7

Days 7-14

Days 14-21

MEAN OF MEANS Over GESTATION PERIOD DIFF (%)* Over GESTATION PERIOD

MEAN ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)*

MEAN ST.DEV. N DIFF (%)* Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

14.6 14.6 14.5 10.6 0.8 1.2 0.9 3.2 10 10 10 10

±0.0 -0.7 -27.4
15.5 15.2 15.2 13.6 0.9 1.4 1.0 1.3 10 10 10 10

-1.9 -1.9 -12.3
15.1 14.9 14.9 12.1

-1.3 -1.3 -19.9

18.6 18.2 18.4 18.9 1.3 1.2 1.5 2.2 8 8 10 8

-2.2 -1.1 +1.6
20.8 20.1 20.3 21.3 1.7 1.5 1.9 2.6 8 8 10 8

-3.4 -2.4 +2.4
23.1 21.8 22.0 22.8 1.9 1.6 1.8 2.9 8 8 10 8

-5.6 -4.8 -1.3
20.8 20.0 20.3 21.0

-3.8 -2.4 +1.0 ORATORIES STUDY D23451 IRGACURE 127



### DIFFERENCES IN MEAN FOOD CONSUMPTION (G/ANIMAL/DAY)

*: Percentage relative to the control group ---

---

---

---

---

---

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd93 

## Page 106 of 66320-MAR-12 FC-SUM - 3



### FEMALES

LACTATION PERIOD Days 1-4 MEAN

ST.DEV. N DIFF (%)* Group 1 Group 2 Group 3 Group 4

0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

27.1 26.5 28.2 32.8 3.3 1.8 7.7 26.8 8 8 10 8

-2.2 +4.1 +21.0 ORATORIES STUDY D23451 IRGACURE 127



### DIFFERENCES IN MEAN FOOD CONSUMPTION (G/ANIMAL/DAY)

*: Percentage relative to the control group --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd93 

## Page 107 of 66320-MAR-12 BW-SUM - 1 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G) - SUMMARY

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd96 

## Page 108 of 66320-MAR-12 BW-SUM - 2



### MALES

PRE-PAIRING PERIOD 1

2

3

4

5

6

7

8

9

10

11 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

313 311 315 312 13 12 11 12 10 10 10 9
318 316 319 316 13 11 12 12 10 10 10 9
320 317 321 318 13 12 12 14 10 10 10 9
323 321 324 321 14 13 13 15 10 10 10 9
327 324 329 322 14 15 13 15 10 10 10 9
332 329 335 327 15 15 14 16 10 10 10 9
333 331 336 327 15 15 15 17 10 10 10 9
338 333 340 330 17 18 15 18 10 10 10 9
341 337 342 329 17 17 16 21 10 10 10 9
345 339 344 329 17 18 16 24 10 10 10 9
347 342 346 334 17 18 16 24 10 10 10 9 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd96 

## Page 109 of 66320-MAR-12 BW-SUM - 3



### MALES

PRE-PAIRING PERIOD

PAIRING PERIOD 12

13

14

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

351 347 350 337 17 19 16 24 10 10 10 9
352 346 351 336 18 19 17 26 10 10 10 9
357 351 355 341 18 21 18 24 10 10 10 9

354 347 352 335 20 19 18 25 10 10 10 9
358 352 355 336 20 19 18 27 10 10 10 9
358 351 357 338 20 20 17 26 10 10 10 9
360 351 360 339 19 22 17 28 10 10 10 9
363 355 361 340 20 20 18 31 10 10 10 9
365 359 363 343 19 20 18 29 10 10 10 9
366 359 364 346 19 21 19 28 10 10 10 9
367 362 365 346 19 22 19 28 10 10 10 9 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd96 

## Page 110 of 66320-MAR-12 BW-SUM - 4



### MALES

PAIRING PERIOD

AFTER PAIRING PERIOD 9

10

11

1

2

3

4 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

371 366 369 351 20 21 18 31 10 10 10 9
371 366 369 350 21 21 20 32 10 10 10 9
374 369 371 356 20 21 21 29 10 10 10 9

376 371 373 355 21 22 20 30 10 10 10 9
377 374 374 358 22 23 20 29 10 10 10 9
379 374 377 360 21 22 21 30 10 10 10 9
364 359 361 345 21 22 20 29 10 10 10 9 Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd96 

## Page 111 of 66320-MAR-12 BW-SUM - 1 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G) - SUMMARY

Pairing Period

Gestation Period Full Phase

Full Phase Full Phase Full Phase Full Phase Full Phase 78

45 46 51 59 77 Female

Female Female Female Female Female Group 4

Group 1 Group 1 Group 2 Group 2 Group 4 Animal

Animal Animal Animal Animal Animal Data excluded from Summary Report

Animal Found Dead

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 112 of 66320-MAR-12 BW-SUM - 2



### FEMALES

PRE-PAIRING PERIOD 1

2

3

4

5

6

7

8

9

10

11 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

198 196 195 199 9 9 8 10 10 10 10 10
199 197 196 201 8 8 7 8 10 10 10 10
202 201 198 200 7 8 6 11 10 10 10 10
202 201 200 198 6 9 6 12 10 10 10 10
203 200 201 195 9 10 9 12 10 10 10 10
206 203 202 196 8 8 8 12 10 10 10 10
208 205 204 197 8 8 6 18 10 10 10 10
211 208 207 199 8 9 7 19 10 10 10 10
208 205 205 195 9 10 9 13 10 10 10 10
211 208 206 201 8 8 8 12 10 10 10 10
214 211 208 202 8 9 6 12 10 10 10 10 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - *

- - -

- - *

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 113 of 66320-MAR-12 BW-SUM - 3



### FEMALES

PRE-PAIRING PERIOD

PAIRING PERIOD 12

13

14

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

214 211 211 203 7 10 8 11 10 10 10 10
213 209 209 201 9 9 9 12 10 10 10 10
215 210 209 205 9 8 8 11 10 10 10 10

222 213 213 208 10 7 7 17 9 8 7 7
222 217 215 213 10 6 7 12 7 7 7 6
229 223 221 219 13 7 8 16 3 3 4 3
226 204 12 0 0 0 2 1
238 0 0 0 1 0
239 0 0 0 1 0
241 0 0 0 1 0
242 0 0 0 1 0 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - *

- - *

- - -

- - *

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) --- ---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 114 of 66320-MAR-12 BW-SUM - 4



### FEMALES

PAIRING PERIOD

GESTATION PERIOD 9

10

0

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

246 0 0 0 1 0
240 0 0 0 1 0

218 211 216 205 11 6 10 19 8 8 10 8
223 217 221 211 12 5 9 15 8 8 10 8
228 221 224 217 11 5 9 14 8 8 10 8
232 224 228 220 12 5 9 14 8 8 10 8
234 227 231 224 11 5 7 14 8 8 10 8
237 230 233 227 11 7 8 14 8 8 10 8
240 233 235 230 11 6 9 14 8 8 10 8
242 235 237 233 10 5 10 15 8 8 10 8
245 237 241 237 11 7 9 15 8 8 10 8 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) --- --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 115 of 66320-MAR-12 BW-SUM - 5



### FEMALES

GESTATION PERIOD 9

10

11

12

13

14

15

16

17

18

19 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

249 242 244 241 11 6 10 14 8 8 10 8
252 246 247 245 12 7 11 15 8 8 10 8
258 252 252 248 12 7 11 15 8 8 10 8
263 254 256 252 11 7 11 15 8 8 10 8
265 258 259 256 11 6 12 16 8 8 10 8
271 263 264 263 12 7 12 18 8 8 10 8
278 268 269 268 12 7 13 18 8 8 10 8
287 278 278 278 13 8 13 19 8 8 10 8
298 288 287 287 13 7 14 22 8 8 10 8
311 301 301 300 13 8 16 23 8 8 10 8
323 316 314 310 14 10 17 27 8 8 10 8 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 116 of 66320-MAR-12 BW-SUM - 6



### FEMALES

GESTATION PERIOD

LACTATION PERIOD 20

21

1

2

3

4

5 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

337 330 326 322 13 10 18 32 8 8 10 8
347 336 330 329 15 11 21 28 8 8 10 8

250 238 236 239 14 9 16 18 8 8 10 8
252 242 241 241 11 7 18 23 8 8 10 8
259 248 248 246 10 4 18 26 8 8 10 8
263 252 252 251 11 7 15 21 8 8 10 8
241 231 231 234 10 5 12 19 8 8 10 8 Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd99 

## Page 117 of 66320-MAR-12 BWG-SUM - 1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%) - SUMMARY

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9c 

## Page 118 of 66320-MAR-12 BWG-SUM - 2



### MALES

PRE-PAIRING PERIOD 1

2

3

4

5

6

7

8

9

10

11 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0 0 0 0 0 0 0 0 10 10 10 9
2 2 1 2 1 1 1 1 10 10 10 9
2 2 2 2 1 1 1 1 10 10 10 9
3 3 3 3 1 1 1 2 10 10 10 9
5 4 4 3 1 1 1 2 10 10 10 9
6 6 6 5 1 1 1 2 10 10 10 9
6 6 7 5 1 1 2 2 10 10 10 9
8 7 8 6 2 2 1 2 10 10 10 9
9 8 9 5 2 2 2 4 10 10 10 9
10 9 9 6 2 2 2 5 10 10 10 9
11 10 10 7 2 2 2 5 10 10 10 9 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - *

- - **

- - **

- - *

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9c 

## Page 119 of 66320-MAR-12 BWG-SUM - 3



### MALES

PRE-PAIRING PERIOD

PAIRING PERIOD 12

13

14

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

12 11 11 8 2 2 2 5 10 10 10 9
12 11 11 8 2 3 2 5 10 10 10 9
14 13 13 9 2 3 2 4 10 10 10 9

0 0 0 0 0 0 0 0 10 10 10 9
1 1 1 0 1 1 1 1 10 10 10 9
1 1 1 1 1 1 1 1 10 10 10 9
2 1 2 1 1 2 1 2 10 10 10 9
2 2 3 1 1 2 1 4 10 10 10 9
3 3 3 3 1 2 2 3 10 10 10 9
3 4 3 3 1 2 1 2 10 10 10 9
4 4 4 3 1 2 1 3 10 10 10 9 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - **

- - **

- - **

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9c 

## Page 120 of 66320-MAR-12 BWG-SUM - 4



### MALES

PAIRING PERIOD

AFTER PAIRING PERIOD 9

10

11

1

2

3

4 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

5 6 5 5 1 2 2 3 10 10 10 9
5 6 5 4 1 2 2 4 10 10 10 9
6 6 5 6 2 2 1 3 10 10 10 9

0 0 0 0 0 0 0 0 10 10 10 9
0 1 0 1 1 1 0 1 10 10 10 9
1 1 1 1 1 1 0 1 10 10 10 9
-3 -3 -3 -3 1 0 1 1 10 10 10 9 Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9c 

## Page 121 of 66320-MAR-12 BWG-SUM - 1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%) - SUMMARY

Pairing Period

Gestation Period Full Phase

Full Phase Full Phase Full Phase Full Phase Full Phase 78

45 46 51 59 77 Female

Female Female Female Female Female Group 4

Group 1 Group 1 Group 2 Group 2 Group 4 Animal

Animal Animal Animal Animal Animal Data excluded from Summary Report

Animal Found Dead

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9e 

## Page 122 of 66320-MAR-12 BWG-SUM - 2



### FEMALES

PRE-PAIRING PERIOD 1

2

3

4

5

6

7

8

9

10

11 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0 0 0 0 0 0 0 0 10 10 10 10
1 1 1 1 3 3 2 2 10 10 10 10
2 3 2 1 2 2 2 3 10 10 10 10
2 3 3 -1 2 2 1 4 10 10 10 10
3 2 3 -2 1 1 1 5 10 10 10 10
4 4 4 -2 3 3 2 5 10 10 10 10
5 5 5 -1 2 2 1 8 10 10 10 10
7 6 7 0 2 2 1 8 10 10 10 10
5 5 6 -2 2 1 1 5 10 10 10 10
7 7 6 1 3 3 2 5 10 10 10 10
8 8 7 1 3 3 1 6 10 10 10 10 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - *

- - **

- - **

- - **

- - **

- - **

- - **

- - **

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9e 

## Page 123 of 66320-MAR-12 BWG-SUM - 3



### FEMALES

PRE-PAIRING PERIOD

PAIRING PERIOD 12

13

14

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

8 8 8 2 3 3 1 5 10 10 10 10
7 7 7 1 2 2 1 5 10 10 10 10
8 8 8 3 3 3 2 5 10 10 10 10

0 0 0 0 0 0 0 0 9 8 7 7
1 1 1 0 1 1 1 2 7 7 7 6
3 3 2 2 1 1 1 2 3 3 4 3
4 4 1 0 0 0 2 1
6 0 0 0 1 0
7 0 0 0 1 0
8 0 0 0 1 0
8 0 0 0 1 0 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - **

- - **

- - **

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) --- ---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9e 

## Page 124 of 66320-MAR-12 BWG-SUM - 4



### FEMALES

PAIRING PERIOD

GESTATION PERIOD 9

10

0

1

2

3

4

5

6

7

8 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

10 0 0 0 1 0
7 0 0 0 1 0

0 0 0 0 0 0 0 0 8 8 10 8
2 3 2 3 2 2 1 3 8 8 10 8
4 5 4 6 2 2 2 4 8 8 10 8
6 6 5 8 2 2 2 4 8 8 10 8
7 8 7 10 2 2 2 4 8 8 10 8
9 9 8 11 2 2 3 5 8 8 10 8
10 11 9 12 2 2 3 5 8 8 10 8
11 11 10 14 2 2 3 6 8 8 10 8
12 13 11 16 2 2 3 5 8 8 10 8 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) --- --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cd9e 

## Page 125 of 66320-MAR-12 BWG-SUM - 5



### FEMALES

GESTATION PERIOD 9

10

11

12

13

14

15

16

17

18

19 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

14 15 13 18 3 2 3 6 8 8 10 8
15 17 14 20 2 2 4 6 8 8 10 8
18 19 16 22 3 3 4 7 8 8 10 8
20 20 19 24 3 3 4 8 8 8 10 8
22 23 20 26 3 3 4 7 8 8 10 8
24 25 22 29 3 3 4 6 8 8 10 8
28 27 25 31 3 2 4 7 8 8 10 8
32 32 29 36 3 3 4 7 8 8 10 8
36 37 33 41 3 3 5 6 8 8 10 8
42 43 39 47 4 2 6 5 8 8 10 8
48 50 45 52 4 3 6 6 8 8 10 8 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 126 of 66320-MAR-12 BWG-SUM - 6



### FEMALES

GESTATION PERIOD

LACTATION PERIOD 20

21

1

2

3

4

5 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

54 56 51 57 4 4 7 6 8 8 10 8
59 59 53 61 4 5 8 5 8 8 10 8

0 0 0 0 0 0 0 0 8 8 10 8
1 2 2 0 2 1 3 3 8 8 10 8
4 5 5 3 3 3 5 6 8 8 10 8
5 6 7 5 3 3 4 4 8 8 10 8
-3 -3 -2 -2 3 3 4 4 8 8 10 8 Day

Day

Day

Day

Day

Day

Day ORATORIES STUDY D23451

127



### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 127 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Pre-Pairing Period
Full Phase 35 Male Group 4

Animal Data excluded from Summary Report

Animal Moribund

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
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## Page 128 of 66320-MAR-12 BWD-SUM - 2



### MALES

PRE-PAIRING PERIOD 1- 8

8-14

1-14 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

8 7 8 6 2 2 1 2 10 10 10 9
5 5 4 3 1 1 1 2 10 10 10 9
14 13 13 9 2 3 2 4 10 10 10 9 Day

Day

Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - *

- - **

- - **

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
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09009e5380b2cda2 

## Page 129 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
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## Page 130 of 66320-MAR-12 BWD-SUM - 2



### MALES

PAIRING PERIOD 1- 8

8-11

1-11 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

4 4 4 3 1 2 1 3 10 10 10 9
2 2 1 3 1 1 1 1 10 10 10 9
6 6 5 6 2 2 1 3 10 10 10 9 Day

Day

Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
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## Page 131 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

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## Page 132 of 66320-MAR-12 BWD-SUM - 2



### MALES

AFTER PAIRING PERIOD 1- 4 MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

-3 -3 -3 -3 1 0 1 1 10 10 10 9 Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cda9 

## Page 133 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
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09009e5380b2cdad 

## Page 134 of 66320-MAR-12 BWD-SUM - 2



### FEMALES

PRE-PAIRING PERIOD 1- 8

8-14

1-14 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

7 6 7 0 2 2 1 8 10 10 10 10
2 1 1 3 3 2 2 6 10 10 10 10
8 8 8 3 3 3 2 5 10 10 10 10 Day

Day

Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - **

- - -

- - **

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdad 

## Page 135 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Gestation Period
Full Phase Full Phase Full Phase Full Phase Full Phase 45 46 51 59 77 Female Female Female Female Female Group 1

Group 1 Group 2 Group 2 Group 4 Animal Animal Animal Animal Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Not Pregnant Implantat. Only Not Pregnant

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

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## Page 136 of 66320-MAR-12 BWD-SUM - 2



### FEMALES

GESTATION PERIOD 0- 7

7-14

14-21

0-21 MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N

MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

11 11 10 14 2 2 3 6 8 8 10 8
12 12 11 13 2 2 1 1 8 8 10 8
28 27 25 25 3 2 4 5 8 8 10 8
59 59 53 61 4 5 8 5 8 8 10 8 Day

Day

Day

Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdaf 

## Page 137 of 66320-MAR-12 BWD-SUM - 1 ORATORIES STUDY D23451 127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdb2 

## Page 138 of 66320-MAR-12 BWD-SUM - 2



### FEMALES

LACTATION PERIOD 1- 5 MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

-3 -3 -2 -2 3 3 4 4 8 8 10 8 Day ORATORIES STUDY D23451

127



### DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

- - -

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 

### Harlan Laboratories Study Report
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## Page 139 of 663

# Clinical Laboratory Investigations - P Generation Harlan Laboratories Study Report
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## Page 140 of 66303-OCT-11 HEM-SUM - 1 ORATORIES STUDY D23451 127



### Hematology - SUMMARY

Before necropsy Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW WBC NEUT EOS BASO LYMPH MONO LUC NEUT EOS BASO LYMPH MONO LUC PLATELETS PT PTT ERYTHROCYTES (RBC)

HEMOGLOBIN (HB) HEMATOCRIT (HCT) MEAN CORPUSCULAR VOLUME (MCV) RED CELL VOL. DISTR. WIDTH (RDW) MEAN CORPUSCULAR HEMOGLOBIN (MCH) MEAN CORPUSCULAR HEMOGLOBIN CONC. (MCHC) HEMOGLOBIN CONC. DISTR. WIDTH LEUKOCYTES, TOTAL (WBC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) THROMBOCYTES (PLATELETS) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME (PTT) DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL STEEL STEEL STEEL STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL Statistical Testing Parameter Data excluded from Summary Report

---
Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded1 

## Page 141 of 66303-OCT-11 HEM-SUM - 2 ORATORIES STUDY D23451 127



### Hematology - SUMMARY

Day 5 post partum Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW WBC NEUT EOS BASO LYMPH MONO LUC NEUT EOS BASO LYMPH MONO LUC PLATELETS PT PTT ERYTHROCYTES (RBC)

HEMOGLOBIN (HB) HEMATOCRIT (HCT) MEAN CORPUSCULAR VOLUME (MCV) RED CELL VOL. DISTR. WIDTH (RDW) MEAN CORPUSCULAR HEMOGLOBIN (MCH) MEAN CORPUSCULAR HEMOGLOBIN CONC. (MCHC) HEMOGLOBIN CONC. DISTR. WIDTH LEUKOCYTES, TOTAL (WBC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) THROMBOCYTES (PLATELETS) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME (PTT) DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL STEEL STEEL STEEL STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL Statistical Testing Parameter

Statistical Methods DUNNETT

STEEL DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
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09009e5380a3ded1 

## Page 142 of 66303-OCT-11 HEM-SUM - 3

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Hematology - SUMMARY MALES ORATORIES STUDY D23451

127

Before necropsy

Before necropsy

Before necropsy Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS) 9.02 10.3 0.46 51.4 0.125 1.15 22.29 9.17 10.2 0.47 51.2 0.124 1.11 21.63 8.90 10.0 0.46 51.3 0.126 1.12 21.95 8.80 9.9 0.45 51.6 0.135 1.12 21.71

1.58 9.57 0.153 0.008 0.022 0.786 0.019 1.53 8.00 0.160 0.008 0.011 0.797 0.017 1.58 8.89 0.165 0.008 0.018 0.786 0.019 1.78 7.60 0.132 0.007 0.015 0.815 0.021

0.008 1.35 0.08 0.20 7.68 0.17 0.011 1.26 0.06 0.10 6.35 0.13 0.011 1.64 0.07 0.17 6.72 0.17 0.008 1.02 0.07 0.11 6.16 0.17 - - - - - - -

- - - - - - -

- - - - * - -

- - - - - - -

- - - - - - - * - - - - - -

- - - * - -

- - - - - -

- - - * - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded1 

## Page 143 of 66303-OCT-11 HEM-SUM - 4

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Hematology - SUMMARY MALES ORATORIES STUDY D23451

127

Before necropsy Group 1 Group 2 Group 3 Group 4 LUC PLATELETS PT PTT

G/l G/l rel. 1 sec DIFF.WBC CO UNT (ABS) GENERAL COAGULATION

0.10 1098 0.78 22.3 0.10 1014 0.76 25.3 0.11 1057 0.77 23.8 0.07 1118 0.75 21.9 - - - -

- - - -

- - - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded1 

## Page 144 of 66303-OCT-11 HEM-SUM - 5

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Hematology - SUMMARY FEMALES ORATORIES STUDY D23451

127

Day 5 post partum

Day 5 post partum

Day 5 post partum Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS) 7.50 8.9 0.42 56.8 0.159 1.19 20.94 7.60 8.7 0.42 54.7 0.139 1.14 20.90 7.40 8.5 0.41 55.4 0.145 1.16 20.86 6.94 8.4 0.40 58.1 0.147 1.21 20.78

1.54 7.03 0.272 0.002 0.009 0.675 0.026 1.46 6.98 0.314 0.005 0.006 0.643 0.026 1.46 8.33 0.306 0.005 0.008 0.647 0.028 1.46 8.85 0.271 0.008 0.007 0.668 0.038

0.009 2.01 0.02 0.07 4.67 0.19 0.006 2.24 0.04 0.06 4.42 0.18 0.010 2.58 0.05 0.07 5.32 0.24 0.008 2.74 0.05 0.08 5.55 0.35 - - - - - - -

- - - - - - - * - - - - - -

- - - - - - -

- - - - - - -

- - - - - - -

- - - - - -

- - - - - -

- - - - - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded1 

## Page 145 of 66303-OCT-11 HEM-SUM - 6

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Hematology - SUMMARY FEMALES ORATORIES STUDY D23451

127

Day 5 post partum Group 1 Group 2 Group 3 Group 4 LUC PLATELETS PT PTT

G/l G/l rel. 1 sec DIFF.WBC CO UNT (ABS) GENERAL COAGULATION

0.06 1372 0.87 26.4 0.05 1350 0.82 26.4 0.08 1489 0.82 27.1 0.07 1387 0.84 26.4 - - - -

- - - -

- - - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded1 

## Page 146 of 66303-OCT-11 CHE-SUM - 1 ORATORIES STUDY D23451 127



### Biochemistry - SUMMARY

Before necropsy Reported Parameter

GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO GLUCOSE

UREA CREATININE BILIRUBIN, TOTAL BILE ACIDS CHOLESTEROL, TOTAL TRIGLYCERIDES ASPARTATE AMINOTRANSFERASE (ASAT) ALANINE AMINOTRANSFERASE (ALAT) ALKALINE PHOSPHATASE (ALP) GAMMA-GLUTAMYLTRANSFERASE (GGT) SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN, TOTAL ALBUMIN GLOBULIN A/G RATIO DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL Statistical Testing Parameter Data excluded from Summary Report

---
Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded3 

## Page 147 of 66303-OCT-11 CHE-SUM - 2 ORATORIES STUDY D23451 127



### Biochemistry - SUMMARY

Day 5 post partum Reported Parameter

GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO GLUCOSE

UREA CREATININE BILIRUBIN, TOTAL BILE ACIDS CHOLESTEROL, TOTAL TRIGLYCERIDES ASPARTATE AMINOTRANSFERASE (ASAT) ALANINE AMINOTRANSFERASE (ALAT) ALKALINE PHOSPHATASE (ALP) GAMMA-GLUTAMYLTRANSFERASE (GGT) SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN, TOTAL ALBUMIN GLOBULIN A/G RATIO DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL Statistical Testing Parameter

Statistical Methods DUNNETT

STEEL DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not significant (-) STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded3 

## Page 148 of 66303-OCT-11 CHE-SUM - 3

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Biochemistry - SUMMARY MALES ORATORIES STUDY D23451

127

Before necropsy

Before necropsy

Before necropsy Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l GENERAL

GENERAL

GENERAL 8.23 7.78 25.1 2.22 23.64 1.88 0.46 7.62 7.09 25.3 1.63 21.26 2.01 0.61 7.30 6.88 24.2 1.49 17.34 2.16 0.72 8.10 8.88 25.7 2.09 34.24 2.43 0.52

74.7 40.7 83.5 0.0 142.2 3.84 100.5 79.2 45.0 85.2 0.0 144.0 3.89 102.4 68.5 41.9 75.5 0.0 142.4 4.00 101.1 64.7 46.9 75.3 0.0 143.2 4.05 101.2

2.68 1.66 67.93 43.60 24.32 1.79 2.67 1.61 66.63 43.08 23.55 1.85 2.74 1.75 67.61 43.30 24.31 1.70 2.79 1.93 65.20 43.23 21.97 1.98 - - - - - - -

- - - - - - -

- - - - - - -

- - - - - - -

- - - - - - -

- - - - - - -

- - - - - -

- - - - - - * - - - - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded3 

## Page 149 of 66303-OCT-11 CHE-SUM - 4

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) 

### Biochemistry - SUMMARY FEMALES ORATORIES STUDY D23451

127

Day 5 post partum

Day 5 post partum

Day 5 post partum Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l GENERAL

GENERAL

GENERAL 7.40 6.61 28.4 1.82 45.33 1.81 0.75 6.52 7.42 34.4 1.79 14.36 1.51 0.57 7.38 7.35 30.0 1.17 14.89 2.11 0.89 7.32 7.41 30.5 1.80 49.42 2.45 1.00

73.5 44.8 35.7 0.0 141.2 3.98 101.0 86.6 37.0 24.3 0.0 140.4 4.15 102.8 80.4 39.0 25.4 0.0 139.8 4.26 101.7 75.3 59.8 32.0 0.0 140.6 4.41 100.4

2.80 2.31 65.19 43.81 21.38 2.01 2.69 2.15 64.22 42.74 21.48 2.03 2.74 2.09 63.45 41.93 21.52 1.94 2.89 2.27 61.80 42.58 19.22 2.17 - - * - - - -

- - - - - - -

- - - - - * -

- - - - - - -

- - - - - - -

- - - - - - -

- - - - - -

- - - - - -

- - - - - - 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3ded3 

## Page 150 of 663

# Reproduction and Breedin g Data - P Generation Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a814d2 

## Page 151 of 663

### H ORATORIES REP3 - 1 IRGACURE 127 17-NOV-11



## MATING PERFORMANCE

NUMBER OF FEMALES MATED DURING THE FIRST PAIRING PERIOD

____________________________________________________________________________________________________ Day of the GROUP 1 GROUP 2 GROUP 3 GROUP 4 pairing period 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ 1 1 2 3 2 2 2 1 - 1 3 4 4 3 3 4 3 3 2 3 5 - - 1 - 11 - - 1 -

____________________________________________________________________________________________________ Median precoital time 3 3 3 3 Mean precoital time 2.9 2.8 3.6 2.8 N 10 10 10 9

____________________________________________________________________________________________________ +: Steel-test significant at 5% level.



### Harlan Laboratories Study Report
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## Page 152 of 663

### H ORATORIES REP4 - 1 IRGACURE 127 17-NOV-11



## FERTILITY

FEMALES SCHEDULED FOR BREEDING

____________________________________________________________________________________________________ GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ Percentage mating 100.0 100.0 100.0 100.0 Fertility index (%) 80.0 90.0 100.0 88.9 Conception rate (%) 80.0 90.0 100.0 88.9
Gestation index (%) (Breeding) 100.0 88.9 100.0 100.0

____________________________________________________________________________________________________ Percentage mating = (Females mated / Females paired) * 100 Fertility index = (Females achieving a pregnancy / Females paired) * 100 Conception rate = (Females achieving a pregnancy / Females mated) * 100 Gestation index = (Number of females with living pups / Number of females pregnant) * 100 # / ## : Fisher's Exact Test significant at 5% (#) or 1% (##) level



### Harlan Laboratories Study Report
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09009e5380a814d6 

## Page 153 of 663

### H ORATORIES PAR-SUM - 1 IRGACURE 127 12-OCT-11



## CORPORA LUTEA COUNT SUMMARY P GENERATION FEMALES

____________________________________________________________________________________________________ GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________
Corpora Lutea

-------------
MEAN 14.0 14.2 13.9 13.9 ST.DEV. 1.4 1.4 1.6 3.4 N 8 9 10 8

+: Steel-test sig. at 5% level.



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## Page 154 of 663

### H ORATORIES PUP-SUM - 1 IRGACURE 127 11-OCT-11



## BREEDING DATA PER GROUP

____________________________________________________________________________________________________ GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ LITTERS TOTAL 8 8 10 8

DURATION OF GESTATION MEAN (+) 21.6 21.4 21.7 21.9 ST.DEV 0.52 0.52 0.48 0.64 N 8 8 10 8

IMPLANTATIONS TOTAL 103 114 137 100 MEAN (+) 12.9 14.3 13.7 12.5 ST.DEV 1.13 1.04 1.49 3.07 N 8 8 10 8

POST IMPLANTATION LOSS % OF IMPLANTATIONS 7.8 7.9 7.3 9.0 LITTERS AFFECTED (#) 5 5 7 3 TOTAL (#) 8 9 10 9 MEAN (+) 1.0 1.1 1.0 1.1 ST.DEV 1.31 1.13 0.82 1.81 N 8 8 10 8

DEAD PUPS AT FIRST LITTER CHECK LITTERS AFFECTED (#) 0 0 1 1 TOTAL 0 0 1 1 MEAN (+) 0.0 0.0 0.1 0.1 ST.DEV 0.00 0.00 0.32 0.35 N 8 8 10 8

LIVING PUPS AT FIRST LITTER CHECK % OF MALES / FEMALES (#) 48 / 52 46 / 54 53 / 47 49 / 51 TOTAL 95 105 127 91 MEAN (+) 11.9 13.1 12.7 11.4 ST.DEV 1.73 1.55 2.00 3.25 N 8 8 10 8

POSTNATAL LOSS DAYS 0 - 4 P.P. % OF LIVING PUPS 0.0 1.0 0.0 7.7 LITTERS AFFECTED (#) 0 1 0 4 # TOTAL (#) 0 1 0 7 ## MEAN (+) 0.0 0.1 0.0 0.9 ST.DEV 0.00 0.35 0.00 1.13 N 8 8 10 8

LIVING PUPS DAY 4 P.P. % OF MALES / FEMALES (#) 48 / 52 46 / 54 53 / 47 49 / 51 TOTAL 95 104 127 84 MEAN (+) 11.9 13.0 12.7 10.5 ST.DEV 1.73 1.41 2.00 3.96 N 8 8 10 8

____________________________________________________________________________________________________ + : Steel-test significant at 5% level # / ## : Fisher's Exact Test significant at 5% (#) or 1% (##) level



### Harlan Laboratories Study Report
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## Page 155 of 663

### H ORATORIES PUP-SUM - 2 IRGACURE 127 11-OCT-11



## BREEDING DATA PER GROUP

____________________________________________________________________________________________________ GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ BIRTH INDEX (#) 92.2 92.1 92.7 91.0
VIABILITY INDEX (#) 100.0 99.0 100.0 92.3 ##

____________________________________________________________________________________________________ # / ## : Fisher's Exact Test significant at 5% (#) or 1% (##) level Birth index = (number of pups born alive / number of implantations) * 100 Viability index = (number of alive pups on day 4 p.p. / number of pups born alive) * 100



### Harlan Laboratories Study Report
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## Page 156 of 663

# Terminal Findings - P Generation Harlan Laboratories Study Report
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## Page 157 of 66312-OCT-11 OW-SUM - 1 ORATORIES STUDY D23451 127



### ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs All organs reported Not Reported

--- 

### Harlan Laboratories Study Report
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## Page 158 of 66312-OCT-11 OW-SUM - 2

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BODY W.

BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

351.3 348.2 349.4 334.5 22.2 22.3 18.7 28.8 326.5 323.1 307.1 294.2 390.0 402.6 371.8 381.0 10 10 10 9

2.00 1.98 1.98 1.98 0.08 0.07 0.05 0.05 1.83 1.86 1.88 1.87 2.12 2.08 2.03 2.03 10 10 10 9

0.010 0.010 0.010 0.010 0.001 0.002 0.001 0.001 0.009 0.006 0.009 0.009 0.013 0.012 0.012 0.013 10 9 10 9

0.92 0.97 0.96 0.99 0.05 0.05 0.06 0.09 0.83 0.88 0.84 0.84 1.01 1.05 1.05 1.16 10 10 10 9

0.025 0.024 0.028 0.027 0.006 0.004 0.005 0.004 0.017 0.016 0.019 0.023 0.033 0.029 0.035 0.034 10 10 10 9

8.96 8.82 9.09 9.94 0.66 0.65 0.47 0.90 8.10 7.94 8.26 8.80 9.99 10.29 9.99 11.23 10 10 10 9

0.338 0.341 0.370 0.338 0.056 0.092 0.088 0.105 0.270 0.220 0.275 0.258 0.429 0.498 0.573 0.592 10 10 10 9 

### . ORGAN WEIGHTS (GRAM) - SUMMARY

MALES

- - -

- - -

- - -

- - -

- - -

- - **

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 159 of 66312-OCT-11 OW-SUM - 3

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) KIDNEYS

ADRENALS

SPLEEN

TESTIS(L)

TESTIS(R)

PROSTATE

EPIDIDI(R) MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

2.05 2.05 1.95 2.18 0.12 0.17 0.13 0.20 1.88 1.85 1.77 1.89 2.22 2.47 2.17 2.42 10 10 10 9

0.084 0.085 0.077 0.080 0.011 0.012 0.008 0.015 0.071 0.070 0.062 0.061 0.104 0.111 0.092 0.113 10 10 10 9

0.75 0.76 0.73 0.68 0.10 0.09 0.10 0.12 0.60 0.63 0.60 0.54 0.90 0.91 0.89 0.95 10 10 10 9

1.91 1.87 1.87 1.72 0.11 0.09 0.13 0.36 1.74 1.73 1.61 0.93 2.06 2.01 2.03 2.31 10 10 10 9

1.92 1.84 1.85 1.73 0.10 0.11 0.14 0.36 1.76 1.60 1.69 0.96 2.05 1.95 2.03 2.30 10 10 10 9

1.00 1.05 0.98 0.93 0.11 0.20 0.10 0.16 0.77 0.80 0.89 0.72 1.19 1.38 1.13 1.18 10 10 10 9

0.664 0.628 0.641 0.596 0.075 0.067 0.070 0.086 0.575 0.519 0.495 0.425 0.826 0.715 0.744 0.743 10 10 10 9 

### . ORGAN WEIGHTS (GRAM) - SUMMARY

MALES

- - -

- - -

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 160 of 66312-OCT-11 OW-SUM - 4

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) EPIDIDI(L)

EPIDCAUD(L

EPIDCAUD(R

SEMINAL VE MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.662 0.652 0.641 0.597 0.081 0.070 0.093 0.088 0.564 0.549 0.524 0.462 0.826 0.718 0.810 0.750 10 10 10 9

0.271 0.282 0.272 0.256 0.027 0.017 0.034 0.057 0.242 0.253 0.217 0.137 0.338 0.307 0.324 0.357 10 10 10 9

0.281 0.281 0.275 0.259 0.028 0.018 0.027 0.056 0.250 0.245 0.208 0.135 0.349 0.304 0.316 0.346 10 10 10 9

1.19 1.19 1.17 1.24 0.22 0.16 0.16 0.17 0.91 0.88 0.95 1.02 1.55 1.45 1.48 1.48 10 10 10 9 

### . ORGAN WEIGHTS (GRAM) - SUMMARY

MALES

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 161 of 66312-OCT-11 OW-SUM - 5

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BODY W.

BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

351.3 348.2 349.4 334.5 22.2 22.3 18.7 28.8 326.5 323.1 307.1 294.2 390.0 402.6 371.8 381.0 10 10 10 9

0.57 0.57 0.57 0.59 0.04 0.04 0.04 0.05 0.50 0.48 0.52 0.53 0.62 0.62 0.66 0.69 10 10 10 9

0.003 0.003 0.003 0.003 0.000 0.001 0.000 0.000 0.003 0.002 0.002 0.003 0.004 0.004 0.003 0.004 10 9 10 9

0.26 0.28 0.27 0.30 0.02 0.02 0.02 0.03 0.23 0.25 0.24 0.25 0.29 0.30 0.30 0.34 10 10 10 9

0.007 0.007 0.008 0.008 0.002 0.001 0.002 0.001 0.005 0.005 0.006 0.007 0.010 0.008 0.010 0.010 10 10 10 9

2.55 2.53 2.60 2.97 0.09 0.06 0.09 0.14 2.44 2.44 2.45 2.77 2.73 2.63 2.69 3.21 10 10 10 9

0.097 0.099 0.107 0.100 0.017 0.029 0.026 0.023 0.071 0.064 0.078 0.083 0.122 0.145 0.160 0.155 10 10 10 9 

### . ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY

MALES

- - -

- - -

- - -

- - **

- - -

- - **

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 162 of 66312-OCT-11 OW-SUM - 6

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) KIDNEYS

ADRENALS

SPLEEN

TESTIS(L)

TESTIS(R)

PROSTATE

EPIDIDI(R) MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.58 0.59 0.56 0.65 0.02 0.02 0.05 0.06 0.56 0.56 0.50 0.59 0.61 0.61 0.65 0.77 10 10 10 9

0.024 0.024 0.022 0.024 0.003 0.003 0.003 0.004 0.020 0.020 0.018 0.018 0.030 0.031 0.030 0.032 10 10 10 9

0.22 0.22 0.21 0.20 0.02 0.03 0.03 0.03 0.18 0.19 0.18 0.16 0.25 0.26 0.26 0.25 10 10 10 9

0.55 0.54 0.54 0.52 0.03 0.04 0.03 0.12 0.51 0.45 0.49 0.24 0.61 0.59 0.59 0.65 10 10 10 9

0.55 0.53 0.53 0.53 0.04 0.04 0.04 0.12 0.50 0.45 0.47 0.25 0.62 0.57 0.59 0.67 10 10 10 9

0.29 0.30 0.28 0.28 0.04 0.06 0.04 0.04 0.22 0.24 0.24 0.21 0.35 0.43 0.36 0.34 10 10 10 9

0.190 0.180 0.184 0.180 0.026 0.017 0.020 0.032 0.157 0.160 0.138 0.112 0.235 0.207 0.206 0.213 10 10 10 9 

### . ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY

MALES

- - **

- - -

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 163 of 66312-OCT-11 OW-SUM - 7

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) EPIDIDI(L)

EPIDCAUD(L

EPIDCAUD(R

SEMINAL VE MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.190 0.187 0.183 0.180 0.028 0.017 0.025 0.030 0.153 0.169 0.146 0.121 0.235 0.209 0.218 0.207 10 10 10 9

0.077 0.081 0.078 0.077 0.008 0.003 0.008 0.017 0.067 0.076 0.061 0.036 0.096 0.087 0.087 0.099 10 10 10 9

0.080 0.081 0.079 0.078 0.009 0.005 0.008 0.019 0.066 0.073 0.058 0.035 0.099 0.087 0.091 0.101 10 10 10 9

0.34 0.34 0.34 0.37 0.06 0.04 0.05 0.05 0.26 0.27 0.27 0.30 0.44 0.38 0.42 0.44 10 10 10 9 

### . ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY

MALES

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc0 

## Page 164 of 66312-OCT-11 OW-SUM - 8

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS

KIDNEYS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

2.00 1.98 1.98 1.98 0.08 0.07 0.05 0.05 1.83 1.86 1.88 1.87 2.12 2.08 2.03 2.03 10 10 10 9

0.513 0.507 0.506 0.501 0.059 0.097 0.058 0.068 0.446 0.306 0.452 0.443 0.613 0.625 0.638 0.647 10 9 10 9

45.79 48.80 48.29 49.85 2.68 3.34 3.29 3.79 41.50 42.31 41.38 44.92 51.37 53.61 52.13 57.71 10 10 10 9

1.249 1.194 1.438 1.344 0.250 0.196 0.289 0.182 0.833 0.816 0.936 1.144 1.571 1.436 1.809 1.692 10 10 10 9

447.65 444.67 459.71 503.66 34.36 33.60 29.99 47.69 405.00 403.98 406.90 433.50 508.16 530.41 517.62 561.50 10 10 10 9

16.862 17.134 18.682 17.090 2.540 4.435 4.268 5.110 13.366 11.458 13.614 12.956 21.566 25.025 28.794 29.453 10 10 10 9

102.41 103.53 98.63 110.14 6.45 8.96 7.57 9.97 94.55 95.02 89.45 96.02 112.24 127.32 115.43 123.59 10 10 10 9 

### . ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY

MALES

- - -

- - -

- - *

- - -

- - **

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc0 

## Page 165 of 66312-OCT-11 OW-SUM - 9

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) ADRENALS

SPLEEN

TESTIS(L)

TESTIS(R)

PROSTATE

EPIDIDI(R)

EPIDIDI(L) MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

4.191 4.253 3.881 4.038 0.480 0.548 0.395 0.743 3.604 3.571 3.100 3.128 5.049 5.337 4.532 5.650 10 10 10 9

37.58 38.47 36.82 34.59 4.37 4.53 4.90 6.16 30.46 32.67 29.56 27.69 44.12 46.43 44.50 47.26 10 10 10 9

95.43 94.49 94.37 86.93 5.27 4.09 7.33 18.42 88.32 89.90 79.31 46.27 104.08 101.52 105.18 114.93 10 10 10 9

95.77 92.74 93.36 87.86 4.97 4.58 7.35 18.06 89.34 85.07 83.25 47.76 103.57 98.48 104.15 114.43 10 10 10 9

49.73 52.73 49.57 46.96 4.71 10.08 4.93 7.63 42.08 42.21 44.28 38.50 56.67 69.79 57.65 59.00 10 10 10 9

33.131 31.615 32.407 30.154 3.353 3.082 3.606 4.175 28.186 27.861 24.874 21.144 38.962 35.556 37.015 36.965 10 10 10 9

32.977 32.807 32.377 30.191 3.086 2.972 4.646 4.236 28.480 28.209 26.332 22.985 38.962 36.080 40.299 37.313 10 10 10 9 

### . ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY

MALES

- - -

- - -

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc0 

## Page 166 of 66312-OCT-11 OW-SUM - 10

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) EPIDCAUD(L

EPIDCAUD(R

SEMINAL VE MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

13.503 14.219 13.751 12.983 1.173 0.812 1.784 2.833 12.222 13.234 10.905 6.816 15.943 15.825 16.788 17.761 10 10 10 9

14.005 14.159 13.888 13.107 1.275 0.891 1.537 2.795 12.626 12.981 10.452 6.716 16.462 15.260 16.373 17.214 10 10 10 9

59.45 60.11 59.15 62.97 9.61 7.99 9.33 8.13 45.96 47.31 47.74 50.75 73.11 74.74 78.72 73.63 10 10 10 9 

### . ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY

MALES

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc0 

## Page 167 of 66312-OCT-11 OW-SUM - 1 ORATORIES STUDY D23451 127



### ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs All organs reported Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 168 of 66312-OCT-11 OW-SUM - 2

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BODY W.

BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

232.0 223.2 223.9 225.2 10.3 3.6 11.7 18.7 215.2 218.1 200.0 190.8 248.2 229.2 245.9 247.4 8 8 10 8

1.85 1.83 1.81 1.85 0.06 0.08 0.08 0.08 1.76 1.66 1.71 1.75 1.93 1.92 1.99 2.00 8 8 10 8

0.014 0.014 0.014 0.014 0.002 0.002 0.002 0.002 0.011 0.011 0.011 0.011 0.017 0.016 0.016 0.016 8 8 10 8

0.76 0.78 0.75 0.82 0.05 0.04 0.06 0.08 0.70 0.72 0.64 0.68 0.83 0.87 0.86 0.93 8 8 10 8

0.021 0.020 0.021 0.020 0.004 0.003 0.005 0.004 0.015 0.017 0.016 0.015 0.028 0.024 0.031 0.025 8 8 10 8

7.49 7.28 7.84 9.82 0.33 0.39 0.75 2.12 6.83 6.72 6.57 7.69 7.84 7.78 9.43 13.97 8 8 10 8

0.189 0.178 0.173 0.129 0.030 0.039 0.041 0.056 0.155 0.100 0.102 0.070 0.241 0.232 0.237 0.241 8 8 10 8 

### . ORGAN WEIGHTS (GRAM) - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - -

- - **

- - * BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 169 of 66312-OCT-11 OW-SUM - 3

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) KIDNEYS

ADRENALS

SPLEEN

OVARIES(L)

OVARIES(R)

UTERUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

1.41 1.34 1.41 1.49 0.05 0.10 0.13 0.14 1.35 1.22 1.27 1.27 1.47 1.49 1.67 1.66 8 8 10 8

0.082 0.080 0.079 0.077 0.008 0.010 0.009 0.010 0.068 0.066 0.063 0.059 0.095 0.093 0.089 0.086 8 8 10 8

0.71 0.64 0.63 0.67 0.07 0.08 0.07 0.10 0.60 0.56 0.49 0.55 0.79 0.77 0.74 0.83 8 8 10 8

0.056 0.060 0.060 0.062 0.008 0.007 0.009 0.010 0.049 0.046 0.050 0.052 0.070 0.068 0.076 0.079 8 8 10 8

0.062 0.063 0.058 0.063 0.007 0.011 0.011 0.009 0.050 0.039 0.045 0.051 0.070 0.073 0.075 0.076 8 8 10 8

1.08 1.11 1.04 1.05 0.09 0.10 0.09 0.18 0.99 1.01 0.93 0.79 1.26 1.24 1.21 1.24 8 8 10 8 

### . ORGAN WEIGHTS (GRAM) - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 170 of 66312-OCT-11 OW-SUM - 4

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BODY W.

BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

232.0 223.2 223.9 225.2 10.3 3.6 11.7 18.7 215.2 218.1 200.0 190.8 248.2 229.2 245.9 247.4 8 8 10 8

0.80 0.82 0.81 0.83 0.05 0.03 0.05 0.08 0.72 0.76 0.74 0.71 0.87 0.85 0.88 0.93 8 8 10 8

0.006 0.006 0.006 0.006 0.001 0.001 0.001 0.001 0.005 0.005 0.005 0.005 0.008 0.007 0.007 0.007 8 8 10 8

0.33 0.35 0.34 0.36 0.02 0.02 0.02 0.03 0.30 0.32 0.32 0.32 0.35 0.39 0.36 0.41 8 8 10 8

0.009 0.009 0.009 0.009 0.002 0.001 0.002 0.002 0.006 0.008 0.008 0.006 0.013 0.011 0.014 0.012 8 8 10 8

3.23 3.27 3.50 4.38 0.15 0.15 0.27 0.92 3.00 3.03 3.09 3.24 3.39 3.46 4.08 6.11 8 8 10 8

0.082 0.080 0.077 0.057 0.016 0.017 0.018 0.022 0.065 0.045 0.051 0.031 0.112 0.104 0.108 0.102 8 8 10 8 

### . ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY

FEMALES

- - -

- - -

- - -

- - *

- - -

- - **

- - * BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 171 of 66312-OCT-11 OW-SUM - 5

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) KIDNEYS

ADRENALS

SPLEEN

OVARIES(L)

OVARIES(R)

UTERUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

0.61 0.60 0.63 0.66 0.03 0.04 0.04 0.05 0.56 0.55 0.58 0.58 0.66 0.67 0.71 0.73 8 8 10 8

0.036 0.036 0.036 0.034 0.004 0.004 0.003 0.004 0.030 0.030 0.031 0.028 0.040 0.041 0.041 0.039 8 8 10 8

0.31 0.29 0.28 0.30 0.04 0.04 0.03 0.04 0.24 0.25 0.25 0.25 0.37 0.35 0.33 0.35 8 8 10 8

0.024 0.027 0.027 0.028 0.003 0.003 0.005 0.004 0.021 0.021 0.020 0.022 0.031 0.030 0.033 0.035 8 8 10 8

0.027 0.028 0.026 0.028 0.004 0.005 0.004 0.003 0.021 0.017 0.020 0.022 0.030 0.032 0.032 0.031 8 8 10 8

0.47 0.50 0.46 0.47 0.05 0.04 0.04 0.07 0.41 0.45 0.38 0.35 0.56 0.56 0.52 0.57 8 8 10 8 

### . ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY

FEMALES

- - *

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 172 of 66312-OCT-11 OW-SUM - 6

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) BRAIN

PITUITARY

HEART

THYROIDS

LIVER

THYMUS

KIDNEYS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

1.85 1.83 1.81 1.85 0.06 0.08 0.08 0.08 1.76 1.66 1.71 1.75 1.93 1.92 1.99 2.00 8 8 10 8

0.751 0.756 0.752 0.745 0.111 0.080 0.115 0.094 0.585 0.663 0.591 0.621 0.899 0.856 0.899 0.860 8 8 10 8

41.27 42.43 41.63 44.51 3.11 3.13 2.82 5.02 37.97 37.50 37.43 35.98 47.16 47.03 47.51 51.43 8 8 10 8

1.127 1.105 1.144 1.106 0.189 0.138 0.209 0.211 0.852 0.919 0.936 0.806 1.481 1.283 1.558 1.337 8 8 10 8

405.13 398.25 433.25 532.14 22.81 19.18 39.05 113.81 365.24 359.36 384.21 411.11 439.20 420.54 526.82 767.58 8 8 10 8

10.226 9.741 9.538 7.011 1.694 2.215 2.075 3.074 8.516 5.405 5.965 3.846 12.819 12.410 12.742 12.957 8 8 10 8

76.35 73.11 78.06 80.74 3.66 4.85 7.30 7.27 72.19 66.67 67.84 71.75 83.52 80.54 92.27 91.21 8 8 10 8 

### . ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - **

- - *

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 173 of 66312-OCT-11 OW-SUM - 7

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) ADRENALS

SPLEEN

OVARIES(L)

OVARIES(R)

UTERUS MEAN

ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg

4.454 4.340 4.371 4.196 0.412 0.379 0.387 0.535 3.598 3.886 3.684 3.122 4.922 4.844 4.917 4.914 8 8 10 8

38.52 34.97 34.92 36.33 3.70 4.59 2.76 5.90 33.69 29.17 28.65 30.00 44.32 42.29 38.17 45.86 8 8 10 8

3.045 3.292 3.328 3.379 0.436 0.362 0.542 0.624 2.591 2.629 2.762 2.751 3.704 3.676 4.246 4.341 8 8 10 8

3.360 3.468 3.186 3.421 0.381 0.579 0.528 0.606 2.674 2.108 2.601 2.550 3.750 3.904 4.144 4.343 8 8 10 8

58.59 60.61 57.34 57.00 4.44 5.96 5.94 10.64 51.30 54.59 47.74 40.50 66.67 70.86 67.60 68.13 8 8 10 8 

### . ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY

FEMALES

- - -

- - -

- - -

- - -

- - - BORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc2 

## Page 174 of 663MAC-SUM - 1 04-OCT-11 ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc5 

## Page 175 of 663MAC-SUM - 2 04-OCT-11

STOMACH

ILEUM

THYMUS

MANDIBULAR L.NODE CONTENTS BLACK-BROWN CONTENTS:

DISCOLORATION

FOCUS/FOCI

FOCUS/FOCI DISCOLORATION 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg Group 1 Group 2 Group 3 Group 4

0 0 0 1 1 0 0 0

0 0 2 0

4 4 3 1

1 0 0 0 1 0 0 0 0 0 0 10 10 0 0 0

0 0 20 0

40 40 30 10

10 0 0 0 10 0 0 0 ANIMALS COMPLETED ANIMALS EXAMINED 10 10 10 10 10 10 10 10 ANIMALS WITHOUT FINDINGS 4 6 5 8

ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

% % % % % % % %

% % % %

% % % %

% % % % % % % % 

### MALES

ANIMALS AFFECTED

-

-

-

-

-

- ) ) ) ) ) ) ) )

) ) ) )

) ) ) )

) ) ) ) ) ) ) ) ( ( ( ( ( ( ( (

( ( ( (

( ( ( (

( ( ( ( ( ( ( ( 

### Harlan Laboratories Study Report
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## Page 176 of 663MAC-SUM - 1 04-NOV-11 ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdc7 

## Page 177 of 663MAC-SUM - 2 04-NOV-11

GENERAL OBSERVATIONS

STOMACH

JEJUNUM

OVARIES

UTERUS

THYMUS BEGINNING AUTOLYSIS

CRATERIFORM RETRACTION ENLARGED DISCOLORATION

NODULE(S)

DISCOLORATION

CONTAINS FLUID DILATION DISCOLORATION

REDUCED IN SIZE DISCOLORATION 0 mg/kg 10 mg/kg 30 mg/kg 90 mg/kg Group 1 Group 2 Group 3 Group 4

0 0 0 1

0 0 1 0

0 0 0 1 1 1 1 0

0 0 0 1

0 0 0 1

0 1 0 0 0 1 0 0 0 0 1 0

0 1 3 4 0 0 0 1 0 0 0 10

0 0 10 0

0 0 0 10 10 10 10 0

0 0 0 10

0 0 0 10

0 10 0 0 0 10 0 0 0 0 10 0

0 10 30 40 0 0 0 10 ANIMALS COMPLETED ANIMALS EXAMINED 10 10 10 10 10 10 10 10 ANIMALS WITHOUT FINDINGS 9 7 5 4

ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

% % % %

% % % %

% % % % % % % %

% % % %

% % % %

% % % % % % % % % % % %

% % % % % % % % 

### FEMALES

ANIMALS AFFECTED

-

-

-

-

-

-

-

-

-

-

- ) ) ) )

) ) ) )
) ) ) ) ) ) ) )

) ) ) )

) ) ) )

) ) ) ) ) ) ) ) ) ) ) )

) ) ) ) ) ) ) ) ( ( ( (

( ( ( (
( ( ( ( ( ( ( (

( ( ( (

( ( ( (

( ( ( ( ( ( ( ( ( ( ( (

( ( ( ( ( ( ( ( 

### Harlan Laboratories Study Report
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## Page 178 of 663

# Data of F1 Pups Harlan Laboratories Study Report
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## Page 179 of 663

### ratories Study Report Page 1 Sp onsor Reference Number


# External Examination of Pups at First Litter Check after Parturition
Group (mg/kg) No. of live/dead pups examined Type of abnormal finding Litter No. Pup No. / Sex

1 (0) 95/0 No findings were observed

2 (10) 105/0 No findings were observed

3 (30) 127/1 No findings were observed

4 (90) 91/1 No milk in the stomach 72 74 79 3/M 8/M 6/M M Male pup Harlan Laboratories Study Report
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## Page 180 of 663

### ratories Study Report Page 1 Sp onsor Reference Number


# Clinical Signs or Observations - Pups
Group (mg/kg) Type of abnormal finding Litter No. Pup No. / Sex

1 (0) No abnormal findings

2 (10) No abnormal findings

3 (30) No milk in the stomach on day 4 post partum 67 11/F

4 (90) No abnormal findings

F Female pup Harlan Laboratories Study Report
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## Page 181 of 663

### ratories Study Report Page 1 Sp onsor Reference Number


# Dates of Postnatal Pup Loss during Lactation
Group Ascertained on day post partum (mg/kg) 1 (FLC) 2 3 4 1 (0) 2 (10) 1F

3 (30) 1M

4 (90) 1F 2M/1F 2M/2F

FLC First litter check F Female pup M Male pup Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 182 of 663

### H ORATORIES BW-SUM - 1 IRGACURE 127 06-OCT-11



## MEAN BODY WEIGHTS OF PUPS PER GROUP (GRAM)

____________________________________________________________________________________________________ DAY SEX GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ 1 M MEAN 6.4 5.9 6.1 6.0 ST.DEV. 0.59 0.52 0.84 0.94 T STAT -- -1.23 -0.91 -0.98 MINIMUM 5.8 5.3 5.0 5.1 MAXIMUM 7.2 6.9 7.7 8.2 N 8 8 10 8

F MEAN 6.2 5.5 5.7 5.7 ST.DEV. 0.65 0.50 0.73 0.84 T STAT -- -1.99 -1.64 -1.44 MINIMUM 5.5 5.1 4.6 4.8 MAXIMUM 7.1 6.4 6.6 7.6 N 8 8 10 8

M+F MEAN 6.3 5.7 5.9 5.8 ST.DEV. 0.63 0.51 0.75 0.82 T STAT -- -1.72 -1.31 -1.33 MINIMUM 5.6 5.2 4.8 5.0 MAXIMUM 7.1 6.6 7.1 7.7 N 8 8 10 8

4 M MEAN 9.6 8.7 8.7 8.2 ST.DEV. 1.10 0.98 1.88 1.98 T STAT -- -1.20 -1.22 -1.80 MINIMUM 8.3 7.5 5.1 6.3 MAXIMUM 11.4 10.5 11.6 12.5 N 8 8 10 8

F MEAN 9.5 8.2 8.3 8.0 ST.DEV. 1.26 0.95 1.75 2.08 T STAT -- -1.72 -1.57 -1.96 MINIMUM 8.1 7.0 4.7 6.0 MAXIMUM 11.6 9.9 10.7 12.7 N 8 8 10 8

M+F MEAN 9.6 8.4 8.5 8.1 ST.DEV. 1.18 0.94 1.81 2.03 T STAT -- -1.49 -1.39 -1.87 MINIMUM 8.2 7.3 4.9 6.2 MAXIMUM 11.5 10.2 11.0 12.7 N 8 8 10 8

____________________________________________________________________________________________________ * / ** : Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a814f5 

## Page 183 of 663

### H ORATORIES BW-SUM - 1 IRGACURE 127 23-JAN-12



## MEAN BODY WEIGHTS OF PUPS PER GROUP (GRAM) F1 PUPS

____________________________________________________________________________________________________ DAY SEX GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG

____________________________________________________________________________________________________ 0 M MEAN -- -- -- -- ST.DEV. -- -- -- -- N -- -- -- --

F MEAN -- -- -- -- ST.DEV. -- -- -- -- N -- -- -- --

M+F MEAN -- -- -- -- ST.DEV. -- -- -- -- N -- -- -- --

1 M MEAN 6.3 5.9 5.9 5.7 ST.DEV. 0.57 0.52 0.64 0.37 N 7 8 9 7

F MEAN 6.1 5.5 5.6 5.5 ST.DEV. 0.60 0.50 0.69 0.38 N 7 8 9 7

M+F MEAN 6.2 5.7 5.7 5.6 ST.DEV. 0.59 0.51 0.66 0.37 N 7 8 9 7

4 M MEAN 9.4 8.7 8.4 7.6 * ST.DEV. 0.91 0.98 1.69 1.00 N 7 8 9 7

F MEAN 9.2 8.2 8.1 7.3 * ST.DEV. 1.02 0.95 1.64 0.90 N 7 8 9 7

M+F MEAN 9.3 8.4 8.3 7.4 * ST.DEV. 0.97 0.94 1.68 0.92 N 7 8 9 7

____________________________________________________________________________________________________ * / ** : Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level Note: Litters excluded from evaluation: No 44 (Group 1), No 65 (Group 3), No 71 (Group 4)



### Harlan Laboratories Study Report
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09009e5380b05c95 

## Page 184 of 663

### ratories Study Report Page 1 Sp onsor Reference Number


# Differences in Mean Body Weight Gain (G) of Pups During the Lactation Period
Group Body weight gain from 1 - 4 (mg/kg) g %* 1 (0) 3.3 +52.4

2 (10) 2.7 +47.4

3 (30) 2.6 +44.1

4 (90) 2.3 +39.7

* Increase within the re spective time interval. Harlan Laboratories Study Report
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09009e5380a814f7 

## Page 185 of 663

### ratories Study Report Page 1 Sp onsor Reference Number


# Macroscopical Findings - Pups
Group (mg/kg) Macroscopical finding(s)

1 (0) No findings

2 (10) No findings

3 (30) No findings

4 (90) No findings Harlan Laboratories Study Report
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## Page 186 of 663

# 9 INDIVIDUAL TABLES Harlan Laboratories Study Report
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## Page 187 of 663

# In-life Data - P Generation Harlan Laboratories Study Report
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## Page 188 of 663MORT-IND - 1 20-MAR-12 ORATORIES STUDY D23451 127



### MORTALITY DATA ALL NECROPSIES

--- Animal(s) without death date / death status

Not Reported

81 82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
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## Page 189 of 663MORT-IND - 2 20-MAR-12



### Group 1 (0 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

AFTER PAIRING PERIOD ( Days 1 to 4 )

10 0 0 0 1 2 3 4 5 6 7 8 9 10 08-SEP-11

08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 4

4 4 4 4 4 4 4 4 4

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded 

### MALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL DEATH DATE DAY P K S O COMMENT 

### Harlan Laboratories Study Report
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## Page 190 of 663MORT-IND - 3 20-MAR-12



### Group 2 (10 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

AFTER PAIRING PERIOD ( Days 1 to 4 )

10 0 0 0 11 12 13 14 15 16 17 18 19 20 08-SEP-11

08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 4

4 4 4 4 4 4 4 4 4

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded 

### MALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL DEATH DATE DAY P K S O COMMENT 

### Harlan Laboratories Study Report
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## Page 191 of 663MORT-IND - 4 20-MAR-12



### Group 3 (30 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

AFTER PAIRING PERIOD ( Days 1 to 4 )

10 0 0 0 21 22 23 24 25 26 27 28 29 30 08-SEP-11

08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 4

4 4 4 4 4 4 4 4 4

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded 

### MALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL DEATH DATE DAY P K S O COMMENT 

### Harlan Laboratories Study Report
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## Page 192 of 663MORT-IND - 5 20-MAR-12



### Group 4 (90 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

AFTER PAIRING PERIOD ( Days 1 to 4 ) 0

9 1

0 0

0 0

0 35

31 32 33 34 36 37 38 39 40 19-AUG-11

08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 08-SEP-11 9

4 4 4 4 4 4 4 4 4 Total:

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded 

### MALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL

ANIMAL DEATH DATE

DEATH DATE DAY

DAY P

P K

K S

S O

O COMMENT

COMMENT 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cddc 

## Page 193 of 663MORT-IND - 1 20-MAR-12 ORATORIES STUDY D23451 127



### MORTALITY DATA ALL NECROPSIES

--- Animal(s) without death date / death status

Not Reported

83 84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde0 

## Page 194 of 663MORT-IND - 2 20-MAR-12



### Group 1 (0 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

GESTATION PERIOD ( Days 0 to 25 )

LACTATION PERIOD ( Days 1 to 5 ) 2

8 0

0 0

0 0

0 45 46

41 42 43 44 47 48 49 50 19-SEP-11

22-SEP-11

23-SEP-11 23-SEP-11 23-SEP-11 24-SEP-11 21-SEP-11 23-SEP-11 21-SEP-11 23-SEP-11 25

25

5 5 5 5 5 5 5 5 Total:

Total: X

X

X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded 

### FEMALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL

ANIMAL DEATH DATE

DEATH DATE DAY

DAY P

P K

K S

S O

O COMMENT

COMMENT 

### Harlan Laboratories Study Report
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09009e5380b2cde0 

## Page 195 of 663MORT-IND - 3 20-MAR-12



### Group 2 (10 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

GESTATION PERIOD ( Days 0 to 25 )

LACTATION PERIOD ( Days 1 to 5 ) 2

8 0

0 0

0 0

0 51 59

52 53 54 55 56 57 58 60 22-SEP-11

19-SEP-11

23-SEP-11 23-SEP-11 20-SEP-11 21-SEP-11 23-SEP-11 23-SEP-11 23-SEP-11 22-SEP-11 25

25

5 5 5 5 5 5 5 5 Total:

Total: X

X

X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded 

### FEMALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL

ANIMAL DEATH DATE

DEATH DATE DAY

DAY P

P K

K S

S O

O COMMENT

COMMENT 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde0 

## Page 196 of 663MORT-IND - 4 20-MAR-12



### Group 3 (30 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

GESTATION PERIOD ( Days 0 to 25 )

LACTATION PERIOD ( Days 1 to 5 )

10 0 0 0 61 62 63 64 65 66 67 68 69 70 23-SEP-11

23-SEP-11 24-SEP-11 25-SEP-11 21-SEP-11 22-SEP-11 23-SEP-11 20-SEP-11 21-SEP-11 01-OCT-11 5

5 5 5 5 5 5 5 5 5

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded

No mortality data recorded

No mortality data recorded 

### FEMALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL DEATH DATE DAY P K S O COMMENT 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde0 

## Page 197 of 663MORT-IND - 5 20-MAR-12



### Group 4 (90 mg/kg)

ACCLIMATIZATION ( Days 1 to 7 )

PRE-PAIRING PERIOD ( Days 1 to 14 )

PAIRING PERIOD ( Days 1 to 14 )

GESTATION PERIOD ( Days 0 to 25 )

LACTATION PERIOD ( Days 1 to 5 ) 0

1

8 0

0

0 1

0

0 0

0

0 78

77

71 72 73 74 75 76 79 80 26-AUG-11

21-SEP-11

22-SEP-11 22-SEP-11 23-SEP-11 21-SEP-11 25-SEP-11 23-SEP-11 23-SEP-11 23-SEP-11 2

25

5 5 5 5 5 5 5 5 Total:

Total:

Total: X

X X X X X X X X X

P = PLANNED NECROPSY , K = KILLED IN EXTR. , S = SPONTAN. DEATH , O = OTHER No mortality data recorded

No mortality data recorded 

### FEMALES ORATORIES STUDY D23451

127



### MORTALITY DATA ALL NECROPSIES

ANIMAL

ANIMAL

ANIMAL DEATH DATE

DEATH DATE

DEATH DATE DAY

DAY

DAY P

P

P K

K

K S

S

S O

O

O COMMENT

COMMENT

COMMENT 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde0 

## Page 198 of 66315-MAR-12 SYMT-IND - 1 ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

Incomplete Recordings

--- Comments

---

Data excluded from Summary Report

---

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed

Selection of Findings All findings reported 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 199 of 66315-MAR-12 SYMT-IND - 2



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

ACCLIMATIZATION

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) 1 2 3 4 5 6 7 Days

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 200 of 66315-MAR-12 SYMT-IND - 3



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 34

Animal 35

Animal 40 APPEARANCE

COLORS

APPEARANCE

COLORS

APPEARANCE RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

HUNCHED POSTURE (1) RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

RUFFLED FUR (3) FECES

FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . . . . . . . . . 1

. . . . . . . 2 2 Days

. . . . . . . . . . . . . 1

. . . . . . . 1 1

. . . . . 2 2 2 2

. . . . . . . . 1 1 1 1 1 1 -

-

-

-

-

- 1 1 1 1 1

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 201 of 66315-MAR-12 SYMT-IND - 4



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PRE-PAIRING PERIOD

Group 4 (90 mg/kg)

Animal 40
COLORS STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . . . . . . . 2 2 2 Days

- 1 1 1 1 1

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 202 of 66315-MAR-12 SYMT-IND - 5



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) Animal 10

Animal 34

Animal 37 APPEARANCE

APPEARANCE

COLORS

APPEARANCE REDDISH SORE (3)

RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

SCABS (3)

REDDISH SORE (3) NECK (CERVICAL)

FECES

SHOULDER RIGHT

SHOULDER RIGHT 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . 1 1 1 1 1

. .

1 1 1 1 1

. . . . . . .

. . . . . . . . . . 1 1

. . . . . . 1 1 1 1

. . Days

1 1 1 1 1 1 1 1

. . . . -

-

-

-

- 1 1 1 1 1

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 203 of 66315-MAR-12 SYMT-IND - 6



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PAIRING PERIOD

Group 4 (90 mg/kg)

Animal 40
APPEARANCE

COLORS RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

2 2 2 2 2 1 1 1

. . . . Days

2 2 2 2 1 1 1 1

. . . . -

- 1 1 1 1 1

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 204 of 66315-MAR-12 SYMT-IND - 7



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

AFTER PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 37
APPEARANCE SCABS (3) SHOULDER RIGHT 1 2 3 4

1

. . . Days

- No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde2 

## Page 205 of 66315-MAR-12 SYMT-IND - 1 ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

Incomplete Recordings

--- Comments

---

Data excluded from Summary Report

---

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed

Selection of Findings All findings reported 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 206 of 66315-MAR-12 SYMT-IND - 2



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

ACCLIMATIZATION

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) 1 2 3 4 5 6 7 Days

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 207 of 66315-MAR-12 SYMT-IND - 3



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 72

Animal 73

Animal 74

Animal 78 APPEARANCE

APPEARANCE

COLORS

APPEARANCE

APPEARANCE RUFFLED FUR (3)

RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

RUFFLED FUR (3)

RUFFLED FUR (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . . . . . . . 1 1 1 Days

. . . . . 2 2 2 2 2 2 1 1 1

. . . . . . . . . . . 1 2 2

. . . . . 1 1 1 1 1 1 1 1 1

. . . . . 1 1 1 2 2 2 1 1 1 -

-

-

-

- 1 1 1 1 1

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 208 of 66315-MAR-12 SYMT-IND - 4



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PRE-PAIRING PERIOD

Group 4 (90 mg/kg)

Animal 78
COLORS STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

. . . . . . . . 1 1 1 1 1 1 Days

- 1 1 1 1 1

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 209 of 66315-MAR-12 SYMT-IND - 5



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 72

Animal 73

Animal 74

Animal 78 APPEARANCE

APPEARANCE

COLORS

APPEARANCE

APPEARANCE RUFFLED FUR (3)

RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

RUFFLED FUR (3)

RUFFLED FUR (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

1 1 1 Days

1 1

2 1 1

1

1

. -

-

-

-

- 1 1 1 1 1

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 210 of 66315-MAR-12 SYMT-IND - 6



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

PAIRING PERIOD

Group 4 (90 mg/kg)

Animal 78
COLORS STAINED/DISCOLORED YELLO (3) FECES 1 2 3 4 5 6 7 8 9 0 1 2 3 4

1

. Days

- 1 1 1 1 1

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 211 of 66315-MAR-12 SYMT-IND - 7



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

GESTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 72

Animal 73

Animal 74 APPEARANCE

APPEARANCE

COLORS

APPEARANCE HUNCHED POSTURE (1) RUFFLED FUR (3)

RUFFLED FUR (3)

STAINED/DISCOLORED YELLO (3)

RUFFLED FUR (3) FECES 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5

1 1 1 1 1 1 1 1 1 1 1

. . . . . . . . . . . . . Days

1 1

. . . . . . . . . . . . . . . . . . . . . . 2 2

. . . . . . . . . . . . . . . . . . . . . .

1 1 1 1 1 1

. . . . . . . . . . . . . . . . . .

1 2 2 2 1 1 1 1

. . . . . . . . . . . . . . . . -

-

-

-

- 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 212 of 66315-MAR-12 SYMT-IND - 8



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DAILY CLINICAL SIGNS OR OBSERVATIONS

LACTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) 1 2 3 4 5 Days

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde4 

## Page 213 of 66311-OCT-11 WOC-IND - 1 ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

Incomplete Recordings

--- Comments

---

Data excluded from Summary Report

---

Not Reported

---

Selection of Findings All findings reported 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde7 

## Page 214 of 66311-OCT-11 WOC-IND - 2



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 35

Animal 40 APPEARANCE

APPEARANCE RUFFLED FUR (3)

RUFFLED FUR (3) 1 2 Weeks

2

. 1 -

- 0

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde7 

## Page 215 of 66311-OCT-11 WOC-IND - 3



### MALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg) Animal 10

Animal 34

Animal 40 APPEARANCE

APPEARANCE

APPEARANCE REDDISH SORE (3)

RUFFLED FUR (3)

RUFFLED FUR (3) NECK (CERVICAL) 1 2

1 Weeks

1

1 -

-

- 0

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cde7 

## Page 216 of 66311-OCT-11 WOC-IND - 1 ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

Incomplete Recordings

--- Comments

---

Data excluded from Summary Report

---

Not Reported

---

Selection of Findings All findings reported 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdea 

## Page 217 of 66311-OCT-11 WOC-IND - 2



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

PRE-PAIRING PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 72

Animal 73

Animal 74

Animal 78 APPEARANCE

APPEARANCE

APPEARANCE

APPEARANCE RUFFLED FUR (3)

RUFFLED FUR (3)

RUFFLED FUR (3)

RUFFLED FUR (3) 1 2 Weeks

2 1

. 1

1 1

1 1 -

-

-

- 0

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdea 

## Page 218 of 66311-OCT-11 WOC-IND - 3



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

PAIRING PERIOD

Group 3 (30 mg/kg) 1 2 Weeks 0

No abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdea 

## Page 219 of 66311-OCT-11 WOC-IND - 4



### FEMALES ORATORIES STUDY D23451 IRGACURE 127



### DETAILED WEEKLY CLINICAL SIGNS

GESTATION PERIOD

Group 1 (0 mg/kg)

Group 2 (10 mg/kg)

Group 3 (30 mg/kg)

Group 4 (90 mg/kg)

Animal 72

Animal 74 APPEARANCE

APPEARANCE RUFFLED FUR (3)

RUFFLED FUR (3) 1 2 3

- Weeks

2

. .

1

. . -

- 0

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No further abnormality recorded. 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdea 

## Page 220 of 66311-OCT-11 REP-IND - 1 ORATORIES STUDY D23451 127



### Functional Observational Battery

AFTER PAIRING PERIOD Reported Parameter

GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore Grip Hind Distance DEGREES GRIP STRENGTH 1

GRIP STRENGTH 2 GRIP STRENGTH 3 GRIP STRENGTH 4 GRIP STRENGTH 5 GRIP STRENGTH 6 GRIP FORELIMB GRIP HINDLIMB Landing Foot Splay BODY TEMPERATURE Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cded 

## Page 221 of 66311-OCT-11 REP-IND - 2

1 2 3 4 5

1 2 3 4 5 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.20 0.28 0.36 0.11 0.12 0.19 0.28 0.17 0.27 0.26 0.16 0.10 0.16 0.23 0.18 0.38 0.34 0.14 0.14 0.10 0.30 0.32 0.30 0.40 0.11 0.15 0.12 0.34 0.34 0.42 0.34 0.23 0.26 0.34 0.37

0.14 10.4 37.8 0.14 4.4 37.6 0.13 6.5 38.0 0.13 7.3 38.2 0.28 7.6 38.7 

### AFTER PAIRING PERIOD Functional Observational Battery

Group 1 (0 mg/kg) MALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cded 

## Page 222 of 66311-OCT-11 REP-IND - 3

11 12 13 14 15

11 12 13 14 15 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.35 0.27 0.31 0.19 0.21 0.11 0.31 0.24 0.35 0.39 0.11 0.17 0.19 0.33 0.32 0.37 0.42 0.12 0.14 0.12 0.37 0.24 0.23 0.15 0.11 0.20 0.31 0.21 0.24 0.32 0.32 0.12 0.15 0.15 0.29

0.17 3.2 37.5 0.16 4.0 38.3 0.13 4.5 38.0 0.21 5.0 37.9 0.14 5.3 38.0 

### AFTER PAIRING PERIOD Functional Observational Battery

Group 2 (10 mg/kg) MALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cded 

## Page 223 of 66311-OCT-11 REP-IND - 4

21 22 23 24 25

21 22 23 24 25 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.24 0.32 0.35 0.17 0.10 0.19 0.30 0.28 0.29 0.26 0.18 0.20 0.17 0.28 0.37 0.46 0.21 0.19 0.13 0.16 0.34 0.28 0.28 0.27 0.20 0.14 0.12 0.28 0.30 0.29 0.23 0.19 0.16 0.15 0.27

0.16 5.4 38.1 0.19 7.2 38.0 0.16 3.2 38.1 0.15 13.6 37.8 0.17 4.4 38.1 

### AFTER PAIRING PERIOD Functional Observational Battery

Group 3 (30 mg/kg) MALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cded 

## Page 224 of 66311-OCT-11 REP-IND - 5

31 32 33 34 36

31 32 33 34 36 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.35 0.29 0.42 0.17 0.18 0.16 0.35 0.24 0.46 0.23 0.16 0.16 0.26 0.31 0.31 0.29 0.23 0.26 0.18 0.20 0.28 0.24 0.31 0.32 0.21 0.18 0.16 0.29 0.30 0.28 0.32 0.17 0.18 0.12 0.30

0.17 6.9 37.6 0.19 4.0 37.0 0.21 3.6 37.8 0.18 9.6 37.1 0.15 7.6 37.1 

### AFTER PAIRING PERIOD Functional Observational Battery

Group 4 (90 mg/kg) MALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cded 

## Page 225 of 66311-OCT-11 REP-IND - 1 ORATORIES STUDY D23451 127



### Functional Observational Battery

LACTATION PERIOD Reported Parameter

GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore Grip Hind Distance DEGREES GRIP STRENGTH 1

GRIP STRENGTH 2 GRIP STRENGTH 3 GRIP STRENGTH 4 GRIP STRENGTH 5 GRIP STRENGTH 6 GRIP FORELIMB GRIP HINDLIMB Landing Foot Splay BODY TEMPERATURE Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdef 

## Page 226 of 66311-OCT-11 REP-IND - 2

41 42 43 44 47

41 42 43 44 47 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.40 0.21 0.42 0.22 0.17 0.16 0.35 0.27 0.34 0.21 0.14 0.10 0.12 0.27 0.52 0.51 0.21 0.15 0.11 0.17 0.41 0.40 0.60 0.36 0.41 0.38 0.37 0.45 0.27 0.26 0.34 0.29 0.33 0.28 0.29

0.18 7.8 38.7 0.12 4.5 38.7 0.14 7.0 39.0 0.39 10.6 39.0 0.30 9.6 38.2 

### LACTATION PERIOD Functional Observational Battery

Group 1 (0 mg/kg) FEMALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdef 

## Page 227 of 66311-OCT-11 REP-IND - 3

52 53 54 55 56

52 53 54 55 56 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.38 0.28 0.35 0.17 0.17 0.19 0.34 0.30 0.40 0.45 0.25 0.19 0.16 0.38 0.18 0.33 0.27 0.12 0.21 0.15 0.26 0.33 0.41 0.42 0.33 0.32 0.19 0.39 0.34 0.38 0.41 0.18 0.16 0.18 0.37

0.17 8.2 38.5 0.20 4.9 38.3 0.16 5.6 38.9 0.28 6.0 38.8 0.17 2.0 38.2 

### LACTATION PERIOD Functional Observational Battery

Group 2 (10 mg/kg) FEMALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdef 

## Page 228 of 66311-OCT-11 REP-IND - 4

61 62 63 64 65

61 62 63 64 65 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.51 0.34 0.30 0.17 0.21 0.20 0.38 0.36 0.42 0.51 0.20 0.19 0.23 0.43 0.38 0.44 0.39 0.32 0.30 0.31 0.40 0.33 0.58 0.27 0.26 0.26 0.27 0.40 0.35 0.32 0.31 0.30 0.21 0.23 0.33

0.19 6.1 38.4 0.21 5.6 38.4 0.31 9.5 38.8 0.26 7.6 38.7 0.25 7.9 38.7 

### LACTATION PERIOD Functional Observational Battery

Group 3 (30 mg/kg) FEMALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdef 

## Page 229 of 66311-OCT-11 REP-IND - 5

71 72 73 74 75

71 72 73 74 75 GRIP_1 GRIP_2 GRIP_3 GRIP_4 GRIP_5 GRIP_6 Grip Fore

Grip Hind Distance DEGREES 0.28 0.28 0.39 0.25 0.25 0.23 0.32 0.30 0.46 0.44 0.19 0.20 0.29 0.40 0.40 0.41 0.37 0.16 0.19 0.17 0.39 0.32 0.32 0.28 0.21 0.29 0.27 0.31 0.30 0.20 0.32 0.22 0.16 0.13 0.27

0.24 6.2 38.7 0.22 7.0 37.8 0.17 8.9 38.5 0.25 8.3 38.1 0.17 6.3 38.5 

### LACTATION PERIOD Functional Observational Battery

Group 4 (90 mg/kg) FEMALES

KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM KILOGRAM

KILOGRAM cm C BORATORIES STUDY D23451 127

GRIP STRENG TH

GRIP STRENG TH LANDING FOO T SPLAY BODY TEMPER ATURE 

### Harlan Laboratories Study Report
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## Page 230 of 66311-OCT-11 LOCA-IND - 1 ORATORIES STUDY D23451 127



### LOCOMOTOR ACTIVITY

LOCOMOTOR ACTIVITY Reported Parameter

6 12 18 24 30 total 6 min

12 min 18 min 24 min 30 min total Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf1 

## Page 231 of 66311-OCT-11 LOCA-IND - 2

1 2 3 4 5 6 12 18 24 30 total

492.00 460.00 299.00 379.00 57.00 1687 359.00 242.00 175.00 205.00 170.00 1151 441.00 277.00 279.00 172.00 283.00 1452 453.00 378.00 215.00 166.00 159.00 1371 359.00 309.00 80.00 148.00 182.00 1078 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 1 (0 mg/kg) MALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

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Sponsor Reference Number

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## Page 232 of 66311-OCT-11 LOCA-IND - 3

11 12 13 14 15 6 12 18 24 30 total

410.00 303.00 233.00 164.00 172.00 1282 474.00 389.00 253.00 374.00 296.00 1786 548.00 338.00 287.00 277.00 120.00 1570 587.00 350.00 293.00 121.00 274.00 1625 253.00 136.00 79.00 199.00 172.00 839 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 2 (10 mg/kg) MALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 233 of 66311-OCT-11 LOCA-IND - 4

21 22 23 24 25 6 12 18 24 30 total

503.00 252.00 122.00 222.00 263.00 1362 469.00 367.00 313.00 418.00 198.00 1765 474.00 340.00 245.00 169.00 211.00 1439 490.00 328.00 118.00 68.00 307.00 1311 337.00 162.00 68.00 92.00 0.00 659 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 3 (30 mg/kg) MALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 234 of 66311-OCT-11 LOCA-IND - 5

31 32 33 34 36 6 12 18 24 30 total

488.00 251.00 194.00 115.00 220.00 1268 318.00 147.00 133.00 82.00 70.00 750 420.00 337.00 324.00 219.00 225.00 1525 522.00 401.00 171.00 181.00 0.00 1275 414.00 244.00 206.00 117.00 58.00 1039 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 4 (90 mg/kg) MALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 235 of 66321-NOV-11 LOCA-IND - 1 ORATORIES STUDY D23451 127



### LOCOMOTOR ACTIVITY

LOCOMOTOR ACTIVITY Reported Parameter

6 12 18 24 30 total 6 min

12 min 18 min 24 min 30 min total Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf5 

## Page 236 of 66321-NOV-11 LOCA-IND - 2

41 42 43 44 47 6 12 18 24 30 total

309.00 174.00 230.00 189.00 95.00 997 220.00 131.00 106.00 87.00 5.00 549 326.00 229.00 233.00 183.00 255.00 1226 358.00 208.00 186.00 225.00 131.00 1108 225.00 280.00 136.00 184.00 177.00 1002 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 1 (0 mg/kg) FEMALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 237 of 66321-NOV-11 LOCA-IND - 3

52 53 54 55 56 6 12 18 24 30 total

377.00 212.00 163.00 162.00 136.00 1050 312.00 171.00 188.00 90.00 58.00 819 306.00 149.00 107.00 118.00 104.00 784 304.00 155.00 164.00 147.00 135.00 905 279.00 127.00 161.00 109.00 92.00 768 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 2 (10 mg/kg) FEMALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 238 of 66321-NOV-11 LOCA-IND - 4

61 62 63 64 65 6 12 18 24 30 total

251.00 171.00 182.00 170.00 21.00 795 207.00 155.00 102.00 235.00 63.00 762 214.00 250.00 200.00 193.00 12.00 869 267.00 198.00 250.00 109.00 171.00 995 325.00 202.00 189.00 139.00 113.00 968 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 3 (30 mg/kg) FEMALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 239 of 66321-NOV-11 LOCA-IND - 5

71 72 73 74 75 6 12 18 24 30 total

242.00 149.00 82.00 101.00 70.00 644 218.00 175.00 185.00 76.00 9.00 663 255.00 151.00 117.00 32.00 95.00 650 222.00 62.00 0.00 0.00 0.00 284 198.00 119.00 121.00 155.00 3.00 596 

### LOCOMOTOR ACTIVITY LOCOMOTOR ACTIVITY

Group 4 (90 mg/kg) FEMALES

min min min min min min

BORATORIES STUDY D23451 127

LOW BEAMS C OUNT 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 240 of 66320-MAR-12 FC-IND - 1 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Comments

Data excluded from Summary Report ---

A ANIMAL MORIBUND

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 241 of 66320-MAR-12 FC-IND - 2



### MALES

Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

1-8 8-14

1-3

1-8 8-14

1-3 1 2 3 4 5 6 7

1 2 3 4 5 6 7

8 9 10

8 9 10 21.4 23.3 22.7 25.2 21.1 20.5 23.3 21.9 24.5 23.2 25.3 22.2 22.6 23.4

26.0 25.1 22.3 23.8 23.0 24.1 28.3

21.9 23.3 23.3 23.5 24.0 23.9

25.8 27.9 24.1 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf7 

## Page 242 of 66320-MAR-12 FC-IND - 3



### MALES

Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

1-8 8-14

1-3

1-8 8-14

1-3 11 12 13 14 15 16 17

11 12 13 14 15 16 17

18 19 20

18 19 20 21.6 27.4 24.2 21.6 22.2 21.0 21.1 21.5 27.8 24.6 23.1 23.5 21.7 22.0

24.4 28.1 24.7 23.6 26.4 25.6 24.9

24.6 24.2 20.4 25.5 24.1 19.2

24.1 25.7 23.8 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf7 

## Page 243 of 66320-MAR-12 FC-IND - 4



### MALES

Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

1-8 8-14

1-3

1-8 8-14

1-3 21 22 23 24 25 26 27

21 22 23 24 25 26 27

28 29 30

28 29 30 22.8 22.9 27.0 22.3 20.4 24.7 22.7 22.4 23.8 26.2 22.1 20.8 24.3 22.7

26.2 24.9 24.0 24.3 22.1 26.9 25.4

22.6 24.1 22.8 22.7 24.4 23.3

23.7 26.5 27.6 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 244 of 66320-MAR-12 FC-IND - 5



### MALES

Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

AFTER PAIRING PERIOD

1-8 8-14

1-3

1-8 8-14

1-3 31 32 33 34 35 36 37

31 32 33 34 35 36 37

38 39 40

38 39 40 24.6 18.8 22.0 20.6 9.0 23.6 25.3 23.8 18.4 23.7 13.9 22.9 26.4

24.2 23.0 25.1 25.2 25.6 30.0

18.5 21.0 19.2 18.3 20.4 16.7

23.2 24.8 26.6 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days Animal

Animal

Animal

Animal ---

A: See explanation on section cover page A 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 245 of 66320-MAR-12 FC-IND - 1 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Comments

Data excluded from Summary Report ---

A B NOT PREGNANT IMPLANTAT. ONLY

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed 

### Harlan Laboratories Study Report
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## Page 246 of 66320-MAR-12 FC-IND - 2



### FEMALES

Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD 1-8 8-14

0-7 7-14 14-21

1-4

1-8 8-14

0-7 7-14 14-21

1-4 41 42 43 44 45 46 47

41 42 43 44 45 46 47

41 42 43 44 45 46 47

48 49 50

48 49 50

48 49 50 13.4 14.6 15.3 14.7 15.6 15.4 13.3 13.7 15.4 16.5 15.1 16.3 16.2 15.2

17.6 17.2 18.7 18.9 19.7 20.7 18.2 19.5 18.8 21.2 22.5 17.8 18.0 18.7 22.3 21.8 24.5 24.1 18.7 15.8 19.3

25.7 22.5 30.5 31.4 29.3

14.5 15.6 14.2 15.2 16.5 15.1

20.3 20.7 17.2 22.1 22.9 20.6 24.8 24.8 22.9

27.0 27.9 22.8 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days

Days

Days Animal

Animal

Animal

Animal

Animal

Animal

A: See explanation on section cover page A A 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 247 of 66320-MAR-12 FC-IND - 3



### FEMALES

Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD 1-8 8-14

0-7 7-14 14-21

1-4

1-8 8-14

0-7 7-14 14-21

1-4 51 52 53 54 55 56 57

51 52 53 54 55 56 57

51 52 53 54 55 56 57

58 59 60

58 59 60

58 59 60 14.0 16.2 13.4 15.1 13.4 14.2 14.9 15.2 17.1 14.3 17.2 15.0 14.3 15.3

18.4 20.5 17.6 18.7 18.7 18.2 18.2 17.4 23.0 19.3 21.0 20.3 19.5 20.4 14.3 24.6 21.1 21.2 22.8 20.5 23.2

30.2 24.9 25.0 26.1 25.8 25.4

13.7 16.7 14.0 13.1 16.7 14.1

17.0 22.5 16.7 18.3 21.6 18.6 20.8 22.7 19.9

27.3 27.6 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days

Days

Days Animal

Animal

Animal

Animal

Animal

Animal

A, B: See explanation on section cover page A

B 

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## Page 248 of 66320-MAR-12 FC-IND - 4



### FEMALES

Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD 1-8 8-14

0-7 7-14 14-21

1-4

1-8 8-14

0-7 7-14 14-21

1-4 61 62 63 64 65 66 67

61 62 63 64 65 66 67

61 62 63 64 65 66 67

68 69 70

68 69 70

68 69 70 14.9 13.7 14.4 15.6 13.6 15.1 13.4 15.1 13.4 14.7 15.9 14.6 14.8 14.8

17.7 17.3 18.3 20.2 17.8 18.4 16.7 20.1 17.8 21.3 24.8 19.0 20.4 18.8 23.1 20.2 21.3 24.7 21.9 22.4 18.5

32.5 34.6 32.9 32.4 30.4 31.5 8.4

14.5 13.8 15.8 16.5 16.2 16.5

21.0 19.8 16.6 21.5 19.6 20.0 23.8 22.5 22.0

25.6 30.1 23.9 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days

Days

Days Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf9 

## Page 249 of 66320-MAR-12 FC-IND - 5



### FEMALES

Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

GESTATION PERIOD

LACTATION PERIOD 1-8 8-14

0-7 7-14 14-21

1-4

1-8 8-14

0-7 7-14 14-21

1-4 71 72 73 74 75 76 77

71 72 73 74 75 76 77

71 72 73 74 75 76 77

78 79 80

78 79 80

78 79 80 12.7 4.3 11.1 11.1 12.0 12.1 11.9 13.4 12.8 13.5 16.2 13.9 13.0 13.4

20.6 16.6 16.9 21.3 16.3 17.7 17.1 25.0 18.0 18.9 21.6 19.0 21.8 16.2 26.3 17.3 24.0 23.1 22.0 24.1 14.3

28.9 7.6 23.1 23.9 23.2 33.2

5.3 10.8 14.5 11.1 13.7 14.8

20.5 21.1 21.7 24.5 20.4 25.4

96.6 25.8 ORATORIES STUDY D23451 127



### FOOD CONSUMPTION (G/ANIMAL/DAY)

Days

Days

Days

Days

Days

Days Animal

Animal

Animal

Animal

Animal

Animal

A: See explanation on section cover page A 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdf9 

## Page 250 of 66320-MAR-12 BW-IND - 1 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed Comments

---

Data excluded from Summary Report
A ANIMAL MORIBUND 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 251 of 66320-MAR-12 BW-IND - 2



### MALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7

1 2 3 4 5 6 7

1 2 3 4 5 6 7

8 9 10 295 323 313 328 298 298 326 301 328 315 334 305 306 333 304 329 316 333 307 305 335 306 334 321 336 309 308 337 311 344 324 338 313 311 343 315 346 329 345 317 316 347 318 349 328 348 320 313 345 321 355 330 353 323 317 354 321 361 334 355 327 321 356 327 364 340 358 327 325 358 329 368 342 362 332 323 362 337 372 344 366 334 327 366 334 373 344 366 336 328 365 341 381 348 369 340 337 370

336 379 349 368 336 330 369 342 384 353 377 342 335 370 336 385 348 379 341 334 370 339 388 350 372 344 338 373 345 390 352 376 349 336 379 349 393 356 379 350 340 380 350 391 356 379 349 342 380 353 393 354 379 350 339 381 359 402 358 381 356 343 387 356 402 356 381 354 347 390 367 407 360 380 358 348 392

364 409 360 388 359 348 392 367 410 359 384 359 351 398 366 409 360 389 361 352 398 350 396 343 370 344 341 384

309 308 330 314 312 337 313 315 341 320 318 344 323 320 347 329 325 354 325 324 356 336 331 363 335 331 367 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 252 of 66320-MAR-12 BW-IND - 3



### MALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 8 9 10

8 9 10

8 9 10 342 335 371 345 338 373 347 340 375 347 342 381 354 343 383

353 338 383 354 339 387 359 347 385 358 348 387 359 351 391 361 352 393 362 351 395 368 356 396 369 357 402 366 357 403 367 361 402

369 364 406 371 364 407 375 369 408 362 352 395 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 253 of 66320-MAR-12 BW-IND - 4



### MALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17

11 12 13 14 15 16 17

11 12 13 14 15 16 17

18 19 20 302 337 312 301 312 307 307 309 341 315 305 315 314 315 309 345 319 308 313 314 313 311 352 323 310 317 320 316 313 360 325 314 321 323 319 316 366 330 319 326 329 323 319 368 333 321 330 329 322 320 378 334 323 332 332 328 325 380 336 324 335 338 329 326 386 339 329 336 341 333 330 388 344 329 341 344 334 334 395 349 335 341 347 339 332 395 348 335 343 348 337 334 403 356 341 345 354 344

330 393 354 341 336 346 343 339 400 356 341 344 355 344 335 398 354 342 350 356 349 320 403 355 345 354 351 347 330 405 357 345 358 357 351 336 410 361 347 358 364 352 336 412 361 349 357 365 356 342 417 364 350 361 365 356 346 419 368 354 367 371 360 348 419 367 354 368 373 362 349 422 371 358 373 376 360

351 427 374 357 374 379 363 351 432 373 361 381 378 369 351 430 375 359 380 380 371 338 413 361 343 364 365 352

324 311 297 329 316 304 330 318 304 334 320 307 336 323 308 340 328 313 343 330 316 343 329 316 349 333 322 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 254 of 66320-MAR-12 BW-IND - 5



### MALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 18 19 20

18 19 20

18 19 20 350 333 320 352 337 324 358 341 326 356 340 324 362 346 329

361 339 325 364 343 334 361 342 325 360 348 331 365 348 336 367 355 340 366 354 338 367 356 338 370 359 345 368 358 346 372 361 348

374 363 349 375 364 353 379 366 351 363 351 337 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 255 of 66320-MAR-12 BW-IND - 6



### MALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 21 22 23 24 25 26 27

21 22 23 24 25 26 27

21 22 23 24 25 26 27

28 29 30 320 324 334 306 295 325 314 324 329 339 310 301 334 314 324 330 338 312 299 334 321 327 335 343 315 301 339 320 329 341 349 314 305 343 328 336 344 359 322 311 349 332 337 349 362 321 310 350 334 341 354 363 325 314 355 341 344 356 368 323 314 358 338 344 357 369 328 315 360 346 346 360 369 329 316 362 345 349 364 373 335 319 370 349 347 365 375 335 318 370 349 354 373 380 336 322 376 352

353 372 378 337 318 370 356 355 375 380 342 319 375 355 355 375 381 346 323 375 360 359 374 383 346 325 378 361 359 377 384 346 325 380 358 363 377 384 349 323 386 362 364 381 385 347 321 385 363 367 382 390 348 324 384 364 371 382 386 353 328 393 364 374 384 394 350 327 394 367 374 387 395 354 326 396 371

377 390 394 357 330 399 372 379 393 396 357 330 399 373 382 395 397 357 330 403 378 362 381 379 345 317 386 359

311 307 310 317 311 313 320 316 315 320 323 317 328 327 324 331 334 329 331 336 330 334 339 335 337 344 337 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 256 of 66320-MAR-12 BW-IND - 7



### MALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 28 29 30

28 29 30

28 29 30 339 345 338 342 346 344 344 350 347 346 353 349 348 354 351

344 348 346 347 355 352 348 357 353 351 363 359 355 366 359 355 366 365 357 368 364 358 370 366 365 376 369 360 374 366 363 369 371

367 376 374 367 375 376 369 379 379 355 365 362 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 257 of 66320-MAR-12 BW-IND - 8



### MALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 31 32 33 34 35 36 37

31 32 33 34 35 36 37

31 32 33 34 35 36 37

38 39 40 317 310 323 303 308 327 316 318 316 327 304 308 334 326 318 315 329 305 299 339 329 322 315 333 306 289 344 334 324 317 336 307 282 344 335 328 326 343 312 266 350 344 331 327 341 308 258 350 345 333 327 343 314 245 353 352 334 324 347 312 237 358 352 335 328 350 314 362 356 339 331 354 315 366 366 342 335 359 305 368 365 342 339 360 297 365 366 347 340 360 311 368 373

342 326 359 309 361 368 342 328 361 310 367 371 342 332 360 304 372 371 346 338 363 296 363 380 345 343 367 285 369 382 348 348 368 296 371 382 350 347 368 305 373 386 346 349 370 305 374 384 352 353 377 302 383 393 353 356 376 294 381 394 355 360 380 313 386 399

355 362 380 310 385 396 358 365 383 317 385 401 357 366 385 318 388 407 344 349 367 303 371 390

317 288 303 320 294 307 320 294 311 325 300 310 324 299 313 323 302 312 325 300 314 330 302 315 325 302 303 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

---

---

---

---

---

---

---

---

---

---

---

---

---

---

---

A: See explanation on section cover page A 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 258 of 66320-MAR-12 BW-IND - 9



### MALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 38 39 40

38 39 40

38 39 40 326 304 291 327 309 302 336 309 310 336 309 311 341 311 316

335 309 303 337 310 296 340 308 311 339 309 314 341 310 315 346 312 319 348 313 323 345 314 323 352 317 329 349 317 326 353 320 335

357 319 336 360 321 336 359 322 340 347 308 328 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdfb 

## Page 259 of 66320-MAR-12 BW-IND - 1 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed Comments

---

Data excluded from Summary Report
A B C ANIMAL FOUND DEAD NOT PREGNANT IMPLANTAT. ONLY 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 260 of 66320-MAR-12 BW-IND - 2



### FEMALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 41 42 43 44 45 46 47

41 42 43 44 45 46 47

41 42 43 44 45 46 47 186 187 201 195 201 197 197 191 195 204 190 192 195 202 193 196 207 192 201 203 203 194 196 206 193 202 206 199 189 196 207 197 204 207 202 198 201 212 195 200 203 208 196 202 215 198 206 210 207 200 204 219 204 212 214 207 192 200 213 201 211 211 210 202 206 219 198 210 211 213 203 209 223 202 213 217 213 204 211 222 203 213 220 211 197 205 218 206 214 217 212 205 212 224 200 209 215 217

209 214 230 207 227 221 210 219 229 210 228 214 232

203 216 228 210 214 232 213 208 220 230 210 220 234 224 214 224 238 218 222 240 227 219 225 239 219 228 243 232 220 226 240 223 228 243 235 223 226 248 229 234 249 235 228 233 249 229 236 249 236 230 233 247 233 238 254 244 235 237 252 234 240 256 241 236 235 259 242 247 260 248 241 240 261 242 244 258 247 248 246 269 246 242 256 253 253 249 273 252 243 249 259 257 253 275 255 235 247 260 263 255 280 263 241 252 267 269 264 290 267 242 250 274 278 277 296 273 244 248 282 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal ---

--- ---

--- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 261 of 66320-MAR-12 BW-IND - 3



### FEMALES
Group 1 (0 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 41 42 43 44 45 46 47

41 42 43 44 45 46 47

48 49 50

48 49 50 287 286 309 283 247 246 294 303 301 320 293 254 249 310 315 308 337 309 253 255 324 330 329 351 319 258 252 327 338 339 365 329 255 244 335 340 336 357 333 263 256 251 258 249 257 246 244

244 236 256 253 238 245 246 257 256 239 247 251 262 260 257 255 246 266 258 260 237 225 246 239 231

210 212 195 206 213 201 212 213 203 211 209 201 215 216 200 211 223 205 217 220 204 224 218 210 221 220 203 219 226 210 223 227 212 225 219 211 227 224 209 221 231 214

233 233 222 238 221 240 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

--- --- --- --- ---

--- --- --- --- ---

--- --- --- --- ---

---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- B: See explanation on section cover page B B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 262 of 66320-MAR-12 BW-IND - 4



### FEMALES
Group 1 (0 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 48 49 50

48 49 50 236 225 215 242 234 216 245 239 220 250 244 225 252 246 231 253 249 235 257 251 238 260 251 239 264 257 244 265 262 248 270 263 250 276 271 258 278 274 263 283 276 263 291 283 269 296 292 276 305 304 285 316 313 292 332 323 305 344 336 314 356 349 332 362 364 340 337

274 264 234 269 262 243 274 272 249 280 275 261 255 251 245 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day Animal

Animal --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 263 of 66320-MAR-12 BW-IND - 5



### FEMALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 51 52 53 54 55 56 57

51 52 53 54 55 56 57

51 52 53 54 55 56 57 209 188 194 205 183 198 193 205 196 198 205 188 193 187 212 195 202 203 190 202 194 211 198 202 205 183 203 197 213 193 196 211 187 205 200 208 203 202 211 194 200 196 214 204 205 206 190 206 201 216 208 208 218 189 209 208 219 198 200 217 192 208 204 213 213 208 219 197 204 201 219 213 207 216 195 211 208 223 214 208 220 191 211 209 221 208 203 222 197 210 209 217 214 210 224 198 205 204

224 216 214 202 213 214 230 217 218 216 217 231 220 218

228 213 213 216 198 216 215 233 222 217 221 212 222 220 240 226 222 224 215 225 222 241 227 222 229 218 229 226 242 231 228 233 222 230 227 248 235 232 236 224 237 232 252 238 237 238 226 236 234 253 237 238 240 228 240 237 257 240 239 245 232 243 242 257 247 246 249 234 247 242 258 252 248 252 239 249 249 256 256 253 260 247 258 250 248 262 257 261 250 257 252 246 261 258 266 256 259 261 249 271 268 271 257 264 266 251 275 270 275 263 273 271 248 284 279 284 275 282 281 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal ---

--- ---

--- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 264 of 66320-MAR-12 BW-IND - 6



### FEMALES
Group 2 (10 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 51 52 53 54 55 56 57

51 52 53 54 55 56 57

58 59 60

58 59 60 243 292 288 292 283 294 292 247 304 304 304 293 307 305 253 316 317 323 308 323 325 252 331 331 337 325 333 338 244 340 344 339 334 334 349 249 338 341 255 251 236

252 236 245 241 233 242

254 239 246 248 236 244 253 244 247 251 253 252 262 245 258 245 257 252 235 227 227 235 235 234

195 206 185 200 209 191 202 213 193 202 213 193 200 209 187 204 219 194 206 218 198 206 220 198 202 214 191 207 223 199 210 226 203 209 224 202 203 218 196 209 215 205

214 205 215 208 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

---

---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 265 of 66320-MAR-12 BW-IND - 7



### FEMALES
Group 2 (10 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 58 59 60

58 59 60 212 213 204 216 223 209 220 228 213 222 237 214 227 238 218 227 240 218 232 245 222 234 247 227 235 251 225 240 252 232 245 256 232 251 259 238 252 261 242 258 260 247 263 261 249 269 266 253 279 271 261 291 275 273 305 277 284 321 279 295 334 280 308 336 283 311 327 285

281 277 272

228 224 235 233 244 243 250 245 234 222 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day Animal

Animal ---

--- ---

--- ---

--- ---

C: See explanation on section cover page C 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 266 of 66320-MAR-12 BW-IND - 8



### FEMALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 61 62 63 64 65 66 67

61 62 63 64 65 66 67

61 62 63 64 65 66 67 187 194 202 191 203 182 186 192 199 201 187 204 189 187 196 200 208 194 207 191 190 194 201 208 196 208 194 191 191 200 209 199 210 187 192 195 205 205 193 211 195 191 197 203 210 198 212 196 197 201 206 214 206 216 196 200 192 201 213 202 217 192 198 201 205 210 197 216 196 196 203 209 214 203 215 200 201 204 209 217 207 219 199 201 197 205 214 204 218 195 203 204 209 210 200 218 199 199

209 212 221 210 208 209 210 216 224 213 206 211 226 219 211

218

211 215 226 209 214 205 211 210 220 228 213 222 209 216 216 222 230 220 223 214 219 220 225 237 225 229 217 219 224 226 238 230 230 221 223 228 229 241 235 235 220 224 228 230 244 238 237 226 224 232 232 247 244 236 225 226 233 234 251 245 239 230 228 237 236 254 249 240 234 232 241 238 258 254 243 237 231 245 244 265 257 250 239 236 250 249 268 262 255 244 240 250 252 272 264 255 246 247 258 259 279 273 262 250 251 266 262 286 275 266 255 255 274 270 296 282 271 263 265 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal ---

---

--- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 267 of 66320-MAR-12 BW-IND - 9



### FEMALES
Group 3 (30 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 61 62 63 64 65 66 67

61 62 63 64 65 66 67

68 69 70

68 69 70 284 280 303 291 281 273 272 297 295 323 308 293 288 278 311 308 339 323 302 300 295 326 322 348 332 310 314 304 333 327 348 339 322 311 293 328 321 337 339 326

223 233 227 235 254 228 214 237 241 231 248 255 235 205 242 257 249 252 254 245 204 254 259 247 247 262 250 217 235 235 230 230 239 221 205

202 198 200 203 205 196 200 199 201 206 204 203 208 208 207 212 209 203 207 205 210 212 208 213 214 212 213 216 213 212 214 210 214 218 216 218 219 214 218 221 218 215

224 226 229 234 238 239 241 242 246 240 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 268 of 66320-MAR-12 BW-IND - 10



### FEMALES
Group 3 (30 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 68 69 70

68 69 70 219 214 238 226 222 239 234 226 242 237 227 242 238 231 244 245 229 245 248 232 248 250 233 250 254 239 251 257 239 258 263 244 261 267 247 265 273 253 269 279 252 272 282 254 278 287 257 282 298 267 293 311 277 301 325 289 315 338 294 328 358 308 340 367 314 343

321 338

267 246 236 272 254 235 275 251 246 279 256 253 252 230 233 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day Animal

Animal ---

--- --- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 269 of 66320-MAR-12 BW-IND - 11



### FEMALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 71 72 73 74 75 76 77

71 72 73 74 75 76 77

71 72 73 74 75 76 77 196 198 206 209 186 213 189 197 196 212 210 188 209 192 191 188 215 204 184 215 196 186 183 206 199 189 219 192 187 178 201 195 193 214 189 187 174 215 199 191 207 195 185 164 221 196 187 216 198 188 165 218 207 194 219 196 184 177 203 203 193 210 193 186 186 223 201 197 209 199 186 188 219 195 195 210 202 186 192 213 201 199 213 200 189 190 212 202 199 213 197 187 192 219 218 199 210 203

179 219 196 221 205

215 202 220 204 203 221 204

186 173 214 216 201 215 207 193 189 222 216 209 212 209 204 196 227 224 211 220 214 207 199 217 225 214 228 217 213 202 225 228 219 229 216 219 204 230 228 219 236 219 219 210 228 232 220 237 227 224 213 233 229 225 241 228 233 210 239 237 231 244 231 236 221 245 241 231 247 234 239 224 245 246 233 251 235 246 229 243 249 235 257 234 250 233 244 255 240 260 229 255 234 252 258 246 266 228 255 237 263 261 249 273 229 256 244 273 261 254 283 230 274 250 277 274 265 288 227 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day Animal

Animal

Animal --- ---

--- --- ---

--- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 270 of 66320-MAR-12 BW-IND - 12



### FEMALES
Group 4 (90 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 71 72 73 74 75 76 77

71 72 73 74 75 76 77

78 79 80

78 79 80 277 252 292 285 275 301 226 292 257 309 297 291 316 229 301 261 323 303 301 333 229 311 260 338 321 315 347 232 319 273 341 332 320 352 230 322 270 339 333 320 230 260 230 230 219

261 215 230 241 222 250 259 203 223 245 226 263 261 193 242 248 235 276 257 214 246 261 236 276 243 197 227 240 218 250

196 190 210 203 194 204 202 194 215 193 192 216 184 193 214 188 198 208 186 200 220 179 200 223 176 195 215 192 203 214 194 204 222 196 207 224 182 204 222 197 208 216

193 208 228

205 232

234 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

--- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- A, B: See explanation on section cover page B

A 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 271 of 66320-MAR-12 BW-IND - 13



### FEMALES
Group 4 (90 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 78 79 80

78 79 80

201 232 212 235 217 241 224 247 225 250 228 252 232 258 237 262 238 263 239 269 248 276 251 278 253 282 253 287 266 297 273 301 281 315 289 327 300 335 307 353 316 368 326 365 332

229 266 235 271 239 273 241 278 239 256 ORATORIES STUDY D23451 127



### BODY WEIGHTS (G)

Day

Day Animal

Animal ---

--- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2cdff 

## Page 272 of 66320-MAR-12 BWG-IND - 1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Not Reported All Study Phases
81

82 Male Male Group 5 Group 5 Animal Animal Reserve Removed Reserve Removed Comments

---

Data excluded from Summary Report
A ANIMAL MORIBUND 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 273 of 66320-MAR-12 BWG-IND - 2



### MALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7

1 2 3 4 5 6 7

1 2 3 4 5 6 7

8 9 10 0 0 0 0 0 0 0 2 2 1 2 3 2 2 3 2 1 2 3 2 3 4 3 3 2 4 3 3 5 7 4 3 5 4 5 7 7 5 5 7 6 6 8 8 5 6 7 5 6 9 10 6 8 8 6 9 9 12 7 8 10 8 9 11 13 9 9 10 9 10 11 14 9 10 11 8 11 14 15 10 12 12 10 12 13 16 10 12 13 10 12 15 18 11 13 14 13 13

0 0 0 0 0 0 0 2 1 1 2 2 1 0 0 2 0 3 2 1 0 1 2 0 1 2 2 1 3 3 1 2 4 2 3 4 4 2 3 4 3 3 4 3 2 3 4 4 3 5 4 1 3 4 3 3 7 6 3 3 6 4 5 6 6 2 3 5 5 6 9 7 3 3 7 5 6

0 0 0 0 0 0 0 1 0 0 -1 0 1 2 0 0 0 0 1 1 2 -4 -3 -5 -5 -4 -2 -2

0 0 0 1 1 2 1 2 3 4 3 4 4 4 5 6 5 8 5 5 8 9 8 10 8 7 11 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 274 of 66320-MAR-12 BWG-IND - 3



### MALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 8 9 10

8 9 10

8 9 10 11 9 13 11 10 13 12 11 14 12 11 16 14 11 16

0 0 0 0 0 1 2 3 1 1 3 1 2 4 2 2 4 3 3 4 3 4 5 3 4 6 5 4 6 5 4 7 5

0 0 0 1 0 0 1 1 0 -2 -3 -3 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 275 of 66320-MAR-12 BWG-IND - 4



### MALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17

11 12 13 14 15 16 17

11 12 13 14 15 16 17

18 19 20 0 0 0 0 0 0 0 2 1 1 1 1 2 2 2 3 2 2 0 2 2 3 5 4 3 1 4 3 4 7 4 4 3 5 4 5 9 6 6 4 7 5 6 9 7 7 6 7 5 6 12 7 7 6 8 7 7 13 8 8 7 10 7 8 15 9 9 7 11 8 9 15 10 10 9 12 9 10 17 12 11 9 13 10 10 17 11 11 10 13 10 10 20 14 13 10 15 12

0 0 0 0 0 0 0 3 2 1 0 3 2 0 1 1 0 0 4 3 2 -3 3 0 1 6 1 1 0 3 1 1 7 3 2 2 4 2 2 7 5 3 2 5 2 2 6 5 4 4 6 3 3 8 5 4 5 7 4 4 10 7 5 5 7 4 4 10 8 6 6 7 5 5 11 9 5

0 0 0 0 0 0 0 0 1 0 1 2 0 2 0 1 0 1 1 0 2 -4 -3 -3 -4 -3 -4 -3

0 0 0 2 2 2 2 2 2 3 3 3 4 4 4 5 6 5 6 6 6 6 6 6 8 7 8 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 276 of 66320-MAR-12 BWG-IND - 5



### MALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 18 19 20

18 19 20

18 19 20 8 7 8 9 8 9 11 10 10 10 9 9 12 11 11

0 0 0 1 1 2 0 1 0 0 3 2 1 3 3 2 5 4 1 4 4 2 5 4 2 6 6 2 5 6 3 7 7

0 0 0 0 0 1 1 1 0 -3 -3 -4 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 277 of 66320-MAR-12 BWG-IND - 6



### MALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 21 22 23 24 25 26 27

21 22 23 24 25 26 27

21 22 23 24 25 26 27

28 29 30 0 0 0 0 0 0 0 1 2 1 1 2 3 0 1 2 1 2 1 3 2 2 3 3 3 2 4 2 3 5 4 3 3 6 4 5 6 7 5 5 7 6 5 8 8 5 5 8 6 7 9 9 6 6 9 8 8 10 10 6 6 10 8 8 10 11 7 7 11 10 8 11 10 7 7 11 10 9 13 12 10 8 14 11 9 13 12 9 8 14 11 11 15 14 10 9 16 12

0 0 0 0 0 0 0 1 1 1 2 0 1 0 0 1 1 3 1 1 1 2 1 1 3 2 2 1 2 1 2 3 2 3 1 3 1 2 4 1 4 2 3 2 2 3 1 4 2 4 3 3 3 2 4 2 5 3 2 5 3 6 2 6 3 4 4 3 6 3 6 4 4 5 3 7 4

0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 1 1 0 0 1 1 -4 -2 -4 -3 -4 -3 -4

0 0 0 2 2 1 3 3 2 3 5 2 5 7 4 7 9 6 6 10 6 7 11 8 8 12 9 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 278 of 66320-MAR-12 BWG-IND - 7



### MALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 28 29 30

28 29 30

28 29 30 9 13 9 10 13 11 11 14 12 11 15 12 12 16 13

0 0 0 1 2 2 1 3 2 2 4 4 3 5 4 3 5 6 4 6 5 4 6 6 6 8 7 5 8 6 6 6 7

0 0 0 0 0 0 1 1 1 -3 -3 -3 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 279 of 66320-MAR-12 BWG-IND - 8



### MALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

PRE-PAIRING PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4

1 2 3 4 5 6 7 8 9 31 32 33 34 35 36 37

31 32 33 34 35 36 37

31 32 33 34 35 36 37

38 39 40 0 0 0 0 0 0 0 0 2 1 0 0 2 3 0 2 2 1 -3 4 4 1 1 3 1 -6 5 6 2 2 4 1 -9 5 6 3 5 6 3 -14 7 9 4 5 6 2 -16 7 9 5 5 6 4 -21 8 11 5 4 8 3 -23 9 11 6 6 8 4 11 13 7 7 10 4 12 16 8 8 11 1 12 15 8 9 11 -2 11 16 9 10 11 3 12 18

0 0 0 0 0 0 0 0 1 0 2 1 0 2 0 -2 3 1 1 4 1 -4 1 3 1 5 2 -8 2 4 2 7 3 -4 3 4 2 6 3 -1 3 5 1 7 3 -1 4 4 3 8 5 -2 6 7 3 9 5 -5 6 7 4 10 6 1 7 8

0 0 0 0 0 0 1 1 1 2 0 1 1 1 1 3 1 3 -3 -3 -3 -2 -4 -1

0 0 0 1 2 1 1 2 3 3 4 2 2 4 3 2 5 3 2 4 4 4 5 4 2 5 0 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

---

---

---

---

---

---

---

---

---

---

---

---

---

---

---

A: See explanation on section cover page A 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 280 of 66320-MAR-12 BWG-IND - 9



### MALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

AFTER PAIRING PERIOD

10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 11

1 2 3 4 38 39 40

38 39 40

38 39 40 3 6 -4 3 7 0 6 8 2 6 8 3 8 8 4

0 0 0 1 0 -2 1 0 2 1 0 4 2 0 4 3 1 5 4 1 6 3 2 7 5 3 8 4 3 8 5 4 11

0 0 0 1 1 0 1 1 1 -3 -3 -2 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce01 

## Page 281 of 66320-MAR-12 BWG-IND - 1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Not Reported All Study Phases
83

84 Female Female Group 5

Group 5 Animal Animal Reserve Removed Reserve Removed Comments

---

Data excluded from Summary Report
A B C ANIMAL FOUND DEAD NOT PREGNANT IMPLANTAT. ONLY 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 282 of 66320-MAR-12 BWG-IND - 2



### FEMALES
Group 1 (0 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 41 42 43 44 45 46 47

41 42 43 44 45 46 47

41 42 43 44 45 46 47 0 0 0 0 0 0 0 3 4 2 -3 -5 -1 3 4 5 3 -1 0 3 3 4 5 2 -1 1 5 1 2 5 3 1 1 5 3 6 7 6 0 0 3 6 6 8 7 2 2 7 5 8 9 9 5 5 9 5 3 7 6 3 5 7 6 9 10 9 2 4 7 8 9 12 11 4 6 10 8 10 13 11 4 6 12 7 6 10 9 6 6 10 8 11 13 12 3 4 9 10

0 0 0 0 0 0 0 2 0 2 0 4 2

0 0 0 0 0 0 0 3 2 1 0 3 1 5 6 4 4 4 3 4 7 8 4 5 4 7 5 9 9 4 5 6 7 5 10 10 4 9 9 9 7 10 12 8 9 9 10 8 11 14 8 8 11 11 10 14 16 10 10 11 12 11 13 17 9 14 15 15 12 16 19 11 15 15 14 12 16 22 14 18 17 13 10 18 25 15 20 20 13 7 22 27 17 21 21 10 7 22 30 18 23 25 13 9 25 33 22 27 27 13 8 28 37 28 30 30 14 7 32 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal ---

--- ---

--- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 283 of 66320-MAR-12 BWG-IND - 3



### FEMALES
Group 1 (0 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 41 42 43 44 45 46 47

41 42 43 44 45 46 47

48 49 50

48 49 50 42 32 35 35 15 6 38 50 39 40 39 18 8 45 55 43 48 47 18 10 52 63 52 54 52 20 9 53 67 57 60 57 19 5 57 68 56 56 59 23 11 17 11 16 11 15 5

0 0 0 0 0 0 5 1 1 0 1 6 3 3 8 4 5 4 2 9 -3 -5 -4 -5 -3

0 0 0 -2 1 3 1 0 4 1 -1 3 2 2 2 0 5 5 3 4 5 7 3 7 5 4 4 4 7 7 6 7 9 7 3 8 8 6 7 5 9 9

0 0 0 2 0 3 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

--- --- --- --- ---

--- --- --- --- ---

--- --- --- --- ---

---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- B: See explanation on section cover page B B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 284 of 66320-MAR-12 BWG-IND - 4



### FEMALES
Group 1 (0 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 48 49 50

48 49 50 0 0 0 2 4 1 4 6 2 6 9 5 7 9 7 7 11 9 9 11 11 10 12 11 12 14 14 12 16 16 14 17 16 17 20 20 18 22 23 20 23 22 23 26 25 25 30 28 29 35 33 34 39 36 40 43 42 46 49 46 51 55 55 53 62 58 57

0 0 0 -2 -1 4 0 3 7 2 4 12 -7 -5 5 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day Animal

Animal --- ---

--- --- ---

--- --- ---

--- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 285 of 66320-MAR-12 BWG-IND - 5



### FEMALES
Group 2 (10 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 51 52 53 54 55 56 57

51 52 53 54 55 56 57

51 52 53 54 55 56 57 0 0 0 0 0 0 0 -2 4 2 0 2 -3 -3 1 4 4 -1 4 2 0 1 5 5 0 0 3 2 2 3 1 3 2 4 3 0 8 4 3 6 1 1 2 8 6 0 4 4 4 4 11 7 6 3 6 7 5 5 3 6 5 5 5 2 13 7 6 8 3 4 5 13 7 5 7 7 7 7 14 8 7 4 7 8 6 10 5 8 8 6 8 4 14 9 9 8 3 6

0 0 0 0 0 0 2 1 2 2 1 3 3 2

0 0 0 0 0 0 0 2 4 2 2 7 3 2 5 6 4 4 8 4 3 6 6 4 6 10 6 5 6 8 7 8 12 6 6 9 10 9 9 13 9 8 10 11 11 11 14 9 9 11 11 12 11 15 11 10 13 12 12 14 17 12 12 13 16 15 15 18 14 13 13 18 16 17 21 15 16 12 20 19 20 25 19 16 9 23 21 21 26 19 17 8 22 21 23 29 20 22 9 27 26 26 30 22 24 10 29 27 27 32 26 26 9 33 31 32 39 30 31 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal ---

--- ---

--- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 286 of 66320-MAR-12 BWG-IND - 6



### FEMALES
Group 2 (10 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 51 52 53 54 55 56 57

51 52 53 54 55 56 57

58 59 60

58 59 60 7 37 35 36 43 36 36 9 43 43 41 48 42 42 11 48 49 50 55 49 51 11 55 56 56 64 54 57 7 59 62 57 68 54 62 9 59 60 12 10 4

0 0 0 0 0 0

1 1 0 3 1 1 0 3 1 4 8 4 4 4 6 1 10 4 -7 -4 -7 -3 1 -3

0 0 0 3 2 3 4 3 5 4 4 4 3 2 1 5 6 5 6 6 7 6 7 7 4 4 3 7 8 8 8 10 10 7 9 10 4 6 6 7 5 11

0 0 0 1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

---

---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 287 of 66320-MAR-12 BWG-IND - 7



### FEMALES
Group 2 (10 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 58 59 60

58 59 60 0 0 0 2 5 3 4 7 4 5 11 5 7 12 7 7 13 7 10 15 9 10 16 11 11 18 10 13 19 14 15 20 14 18 22 17 19 23 19 22 22 21 24 23 22 27 25 24 32 28 28 37 29 34 44 30 39 51 31 45 57 32 51 59 33 53 54 34

32 30 28

0 0 3 4 7 8 10 10 2 -1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day Animal

Animal ---

--- ---

--- ---

--- ---

C: See explanation on section cover page C 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 288 of 66320-MAR-12 BWG-IND - 8



### FEMALES
Group 3 (30 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 61 62 63 64 65 66 67

61 62 63 64 65 66 67

61 62 63 64 65 66 67 0 0 0 0 0 0 0 3 2 -1 -2 0 4 0 5 3 3 1 2 5 2 4 4 3 3 2 7 3 2 3 3 4 4 3 3 4 6 1 1 4 7 3 5 5 4 4 5 8 6 7 6 6 8 7 8 8 3 3 5 6 7 6 6 7 5 4 3 7 8 5 8 7 6 6 6 10 8 9 8 7 8 8 9 8 5 6 6 7 7 7 9 9 8 4 5 7 10 7

0 0 0 0 0 0 0 2 1 2 -1 1 2 4 1

4

0 0 0 0 0 0 0 -1 2 1 2 4 2 2 3 3 1 6 4 4 4 4 4 5 8 7 6 4 6 5 5 10 8 8 6 8 6 6 13 10 7 7 8 7 8 14 11 10 6 10 8 9 17 11 10 7 11 9 11 17 12 12 8 12 10 12 19 13 14 10 14 11 14 22 14 15 10 16 13 17 23 17 17 12 18 16 18 25 19 19 14 19 17 20 26 19 20 17 22 20 23 31 23 22 19 26 22 27 32 25 25 21 30 26 31 35 27 28 26 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal ---

---

--- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 289 of 66320-MAR-12 BWG-IND - 9



### FEMALES
Group 3 (30 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 61 62 63 64 65 66 67

61 62 63 64 65 66 67

68 69 70

68 69 70 35 30 34 40 32 33 29 41 37 43 48 37 40 32 47 43 50 55 41 46 40 54 49 54 59 45 53 44 58 52 54 63 51 51 39 55 49 49 63 53

0 0 0 0 0 0 0 7 4 2 6 0 3 -4 9 10 10 7 0 7 -5 14 11 9 5 3 9 1 6 1 2 -2 -6 -3 -4

0 0 0 0 3 -2 -1 0 1 2 3 1 3 5 4 5 6 2 2 3 5 5 5 7 6 7 6 7 7 6 6 6 7 8 9 9 8 8 9 9 10 8

0 1 2 5 6 7 8 8 10 7 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 290 of 66320-MAR-12 BWG-IND - 10



### FEMALES
Group 3 (30 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 68 69 70

68 69 70 0 0 0 3 3 0 6 5 2 8 6 2 8 8 3 12 7 3 13 8 4 14 9 5 16 11 6 17 12 9 20 14 10 22 15 11 24 18 13 27 18 14 28 18 17 31 20 19 36 25 23 42 29 27 48 35 33 54 37 38 63 43 43 67 47 44

50 42

0 0 0 2 3 0 3 2 4 4 4 7 -6 -7 -1 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day Animal

Animal ---

--- --- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 291 of 66320-MAR-12 BWG-IND - 11



### FEMALES
Group 4 (90 mg/kg)

PRE-PAIRING PERIOD

PAIRING PERIOD

GESTATION PERIOD

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 71 72 73 74 75 76 77

71 72 73 74 75 76 77

71 72 73 74 75 76 77 0 0 0 0 0 0 0 0 -1 3 1 1 -2 2 -3 -5 4 -2 -1 1 4 -5 -7 0 -5 2 3 2 -5 -10 -3 -7 4 0 0 -5 -12 4 -5 3 -3 4 -6 -17 7 -6 1 1 5 -4 -17 5 -1 4 3 4 -6 -11 -1 -3 4 -2 2 -5 -6 8 -4 6 -2 6 -5 -5 6 -6 5 -1 7 -5 -3 3 -4 7 0 6 -4 -4 2 -3 7 0 5 -5 -3 6 4 7 -1 8

0 0 0 0 0

-2 3 -1 -1 3 0 4

0 0 0 0 0 0 0 4 10 3 0 4 -2 1 9 14 6 3 5 2 4 11 15 1 4 7 6 5 14 17 5 5 9 6 5 18 18 7 6 9 10 6 18 22 6 7 10 10 10 20 24 9 6 12 12 10 25 22 12 9 15 13 12 26 28 14 12 15 15 13 28 30 14 14 16 17 14 32 33 13 15 17 19 13 34 35 14 18 20 21 11 37 35 17 19 23 24 10 37 37 23 21 24 27 11 37 42 27 21 26 32 11 47 45 29 27 32 34 10 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day Animal

Animal

Animal --- ---

--- --- ---

--- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

--- --- --- --- --- --- ---

B: See explanation on section cover page B 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 292 of 66320-MAR-12 BWG-IND - 12



### FEMALES
Group 4 (90 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

PRE-PAIRING PERIOD

PAIRING PERIOD

17 18 19 20 21 22 23 24 25

1 2 3 4 5

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 2 3 4 5 6 7 8 9 10 71 72 73 74 75 76 77

71 72 73 74 75 76 77

78 79 80

78 79 80 49 46 36 32 37 40 10 56 49 44 37 45 47 11 61 51 51 40 50 55 11 67 51 58 48 57 61 12 71 58 59 54 60 64 11 73 56 58 54 59 11 39 11 11 6

0 0 0 0 0 0 -1 -6 -3 1 2 5 0 -10 5 3 6 10 -2 0 7 8 7 10 -7 -8 -2 0 -2 0

0 0 0 3 2 -3 3 2 2 -1 1 3 -6 2 2 -4 4 -1 -5 6 5 -9 6 6 -10 3 2 -2 7 2 -1 7 6 0 9 7 -7 7 6 0 10 3

0 0 0

-1 2

2 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day

Day

Day Animal

Animal

Animal

Animal ---

--- --- --- --- ---

--- --- --- --- --- ---

--- --- --- --- --- ---

---

--- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- ---

--- --- --- A, B: See explanation on section cover page B

A 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 293 of 66320-MAR-12 BWG-IND - 13



### FEMALES
Group 4 (90 mg/kg)

GESTATION PERIOD

LACTATION PERIOD

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1 2 3 4 5 78 79 80

78 79 80

0 0 5 2 8 4 11 7 12 8 13 9 15 11 18 13 18 14 19 16 23 19 25 20 26 22 26 24 32 28 35 30 40 36 43 41 49 44 53 53 57 59 62 58 65

0 0 3 2 4 3 5 5 5 -4 ORATORIES STUDY D23451 127



### BODY WEIGHT GAIN (%)

Day

Day Animal

Animal ---

--- ---

--- ---

--- --- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce0d 

## Page 294 of 663

# Clinical Laboratory Investigations - P Generation Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a814ce 

## Page 295 of 66303-OCT-11 HEM-IND - 1 ORATORIES STUDY D23451 127



### Hematology

Before necropsy Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW WBC NEUT EOS BASO LYMPH MONO LUC NEUT EOS BASO LYMPH MONO LUC PLATELETS PT PTT ERYTHROCYTES (RBC)

HEMOGLOBIN (HB) HEMATOCRIT (HCT) MEAN CORPUSCULAR VOLUME (MCV) RED CELL VOL. DISTR. WIDTH (RDW) MEAN CORPUSCULAR HEMOGLOBIN (MCH) MEAN CORPUSCULAR HEMOGLOBIN CONC. (MCHC) HEMOGLOBIN CONC. DISTR. WIDTH LEUKOCYTES, TOTAL (WBC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) THROMBOCYTES (PLATELETS) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME (PTT) Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 296 of 66303-OCT-11 HEM-IND - 2 ORATORIES STUDY D23451 127



### Hematology

Day 5 post partum Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW WBC NEUT EOS BASO LYMPH MONO LUC NEUT EOS BASO LYMPH MONO LUC PLATELETS PT PTT ERYTHROCYTES (RBC)

HEMOGLOBIN (HB) HEMATOCRIT (HCT) MEAN CORPUSCULAR VOLUME (MCV) RED CELL VOL. DISTR. WIDTH (RDW) MEAN CORPUSCULAR HEMOGLOBIN (MCH) MEAN CORPUSCULAR HEMOGLOBIN CONC. (MCHC) HEMOGLOBIN CONC. DISTR. WIDTH LEUKOCYTES, TOTAL (WBC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) NEUTROPHILS (NEUT) EOSINOPHILS (EOS) BASOPHILS (BASO) LYMPHOCYTES (LYMPH) MONOCYTES (MONO) LARGE UNSTAINED CELLS (LUC) THROMBOCYTES (PLATELETS) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME (PTT) 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 297 of 66303-OCT-11 HEM-IND - 3

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 8.92 10.6 0.46 50.9 0.135 1.19 23.30 8.68 10.4 0.47 54.4 0.122 1.20 22.11 9.39 10.6 0.48 50.9 0.121 1.13 22.12 8.87 9.6 0.44 49.4 0.127 1.09 21.99 9.26 10.5 0.48 51.4 0.118 1.13 21.96

1.71 9.05 0.194 0.008 0.022 0.751 0.019 1.58 12.49 0.100 0.012 0.017 0.846 0.014 1.45 8.14 0.154 0.009 0.026 0.770 0.026 1.61 8.14 0.153 0.007 0.024 0.786 0.023 1.53 10.01 0.123 0.005 0.019 0.837 0.009

0.008 1.75 0.08 0.20 6.79 0.17 0.012 1.25 0.15 0.21 10.56 0.17 0.016 1.25 0.08 0.21 6.26 0.21 0.007 1.25 0.06 0.19 6.39 0.19 0.007 1.23 0.05 0.19 8.38 0.09

0.07 1019 0.74 22.3 0.15 1289 0.82 21.8 0.13 1057 0.75 25.5 0.06 1152 0.78 23.7 0.07 971 0.80 22.0 

### Before necropsy Hematology

Group 1 (0 mg/kg) MALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 298 of 66303-OCT-11 HEM-IND - 4

11 12 13 14 15

11 12 13 14 15

11 12 13 14 15

11 12 13 14 15 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 9.66 10.6 0.50 51.2 0.114 1.10 21.37 8.77 9.8 0.46 52.4 0.132 1.12 21.38 9.09 10.0 0.45 50.1 0.133 1.10 21.91 9.07 10.3 0.46 50.7 0.117 1.13 22.36 9.27 10.1 0.48 51.7 0.126 1.09 21.14

1.44 5.96 0.170 0.005 0.009 0.797 0.009 1.59 9.71 0.169 0.009 0.014 0.779 0.018 1.59 7.96 0.160 0.008 0.005 0.798 0.014 1.45 9.68 0.141 0.008 0.021 0.797 0.018 1.56 6.68 0.154 0.005 0.011 0.802 0.017

0.011 1.01 0.03 0.05 4.75 0.05 0.010 1.64 0.09 0.14 7.57 0.18 0.016 1.27 0.06 0.04 6.35 0.11 0.014 1.36 0.08 0.20 7.72 0.18 0.010 1.03 0.04 0.07 5.36 0.12

0.06 894 0.72 25.4 0.10 948 0.75 23.0 0.13 1135 0.77 25.3 0.14 1003 0.76 20.8 0.07 1088 0.78 25.3 

### Before necropsy Hematology

Group 2 (10 mg/kg) MALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 299 of 66303-OCT-11 HEM-IND - 5

21 22 23 24 25

21 22 23 24 25

21 22 23 24 25

21 22 23 24 25 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 8.82 9.9 0.45 51.1 0.124 1.12 21.97 8.52 9.9 0.45 53.1 0.125 1.16 21.92 9.49 10.7 0.49 51.2 0.124 1.12 21.94 8.72 9.7 0.44 50.2 0.127 1.11 22.14 8.96 10.0 0.46 51.1 0.130 1.11 21.77

1.54 6.22 0.120 0.014 0.017 0.815 0.026 1.54 10.17 0.152 0.006 0.018 0.786 0.021 1.64 9.31 0.199 0.008 0.023 0.740 0.019 1.72 8.76 0.165 0.011 0.013 0.788 0.014 1.46 9.99 0.262 0.005 0.024 0.674 0.019

0.008 0.75 0.09 0.10 5.07 0.16 0.017 1.55 0.06 0.18 7.99 0.21 0.011 1.85 0.07 0.21 6.89 0.18 0.008 1.45 0.10 0.12 6.90 0.12 0.015 2.62 0.05 0.24 6.74 0.19

0.05 946 0.77 24.7 0.18 1093 0.80 23.5 0.10 1095 0.80 21.4 0.07 1144 0.75 25.5 0.15 1009 0.76 23.8 

### Before necropsy Hematology

Group 3 (30 mg/kg) MALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 300 of 66303-OCT-11 HEM-IND - 6

31 32 33 34 36

31 32 33 34 36

31 32 33 34 36

31 32 33 34 36 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 8.33 9.8 0.44 53.0 0.129 1.17 22.09 8.89 9.8 0.46 51.4 0.138 1.10 21.38 8.55 9.8 0.47 54.4 0.134 1.14 21.01 8.97 10.0 0.45 50.5 0.141 1.11 22.06 9.28 10.0 0.45 48.9 0.134 1.08 22.02

1.87 7.38 0.166 0.007 0.016 0.770 0.034 1.76 7.41 0.160 0.006 0.009 0.798 0.018 1.58 7.76 0.132 0.008 0.015 0.815 0.022 1.95 9.23 0.106 0.007 0.019 0.836 0.021 1.76 6.23 0.108 0.019 0.013 0.831 0.017

0.007 1.23 0.05 0.12 5.68 0.25 0.008 1.19 0.05 0.07 5.91 0.14 0.008 1.03 0.06 0.12 6.32 0.17 0.011 0.97 0.06 0.17 7.72 0.20 0.012 0.67 0.12 0.08 5.18 0.11

0.05 1151 0.75 24.9 0.06 1189 0.79 21.9 0.06 1237 0.82 21.0 0.11 951 0.71 21.7 0.07 1060 0.75 24.4 

### Before necropsy Hematology

Group 4 (90 mg/kg) MALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 301 of 66303-OCT-11 HEM-IND - 7

41 42 43 44 47

41 42 43 44 47

41 42 43 44 47

41 42 43 44 47 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 7.15 8.7 0.41 57.1 0.167 1.21 21.20 7.06 8.6 0.43 61.0 0.176 1.21 19.90 7.86 9.2 0.44 56.6 0.121 1.17 20.74 7.92 9.3 0.45 57.3 0.141 1.18 20.57 7.51 8.7 0.39 52.1 0.189 1.16 22.28

1.46 6.88 0.313 0.001 0.009 0.647 0.020 1.63 5.23 0.255 0.001 0.007 0.706 0.026 1.40 7.29 0.269 0.002 0.013 0.675 0.030 1.45 6.32 0.324 0.007 0.014 0.611 0.038 1.76 9.43 0.272 0.005 0.009 0.683 0.023

0.010 2.15 0.00 0.06 4.45 0.14 0.005 1.33 0.01 0.04 3.69 0.14 0.013 1.96 0.01 0.09 4.92 0.22 0.007 2.05 0.04 0.09 3.86 0.24 0.009 2.57 0.04 0.08 6.44 0.21

0.07 1157 0.94 26.5 0.03 1543 0.84 28.4 0.09 1318 0.79 26.4 0.04 1427 0.88 24.5 0.09 1413 0.87 26.3 

### Day 5 post partum Hematology

Group 1 (0 mg/kg) FEMALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 302 of 66303-OCT-11 HEM-IND - 8

52 53 54 55 56

52 53 54 55 56

52 53 54 55 56

52 53 54 55 56 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 7.86 8.2 0.41 51.6 0.145 1.05 20.33 7.49 8.6 0.43 57.0 0.154 1.15 20.17 7.98 9.1 0.44 54.6 0.127 1.14 20.94 7.36 9.0 0.41 56.1 0.128 1.22 21.78 7.33 8.4 0.40 54.0 0.143 1.15 21.28

1.44 5.33 0.314 0.003 0.006 0.643 0.028 1.50 7.96 0.247 0.008 0.006 0.690 0.037 1.49 4.93 0.308 0.004 0.006 0.654 0.023 1.32 8.71 0.339 0.006 0.015 0.610 0.026 1.56 7.95 0.387 0.005 0.005 0.582 0.014

0.006 1.67 0.01 0.03 3.42 0.15 0.011 1.97 0.06 0.05 5.50 0.30 0.005 1.52 0.02 0.03 3.22 0.11 0.004 2.95 0.05 0.13 5.32 0.23 0.007 3.08 0.04 0.04 4.63 0.11

0.03 1424 0.86 24.5 0.09 1684 0.81 26.2 0.02 1170 0.77 28.5 0.04 1312 0.82 27.7 0.05 1161 0.85 26.4 

### Day 5 post partum Hematology

Group 2 (10 mg/kg) FEMALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 303 of 66303-OCT-11 HEM-IND - 9

61 62 63 64 65

61 62 63 64 65

61 62 63 64 65

61 62 63 64 65 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 7.09 8.2 0.39 55.5 0.143 1.15 20.81 7.30 8.4 0.40 55.3 0.158 1.15 20.83 7.29 8.2 0.40 55.3 0.169 1.13 20.41 7.59 8.7 0.42 55.4 0.134 1.15 20.71 7.73 9.2 0.43 55.5 0.123 1.20 21.56

1.48 8.31 0.271 0.005 0.006 0.680 0.023 1.47 6.67 0.306 0.005 0.008 0.647 0.030 1.66 9.84 0.340 0.003 0.007 0.612 0.028 1.43 9.44 0.241 0.009 0.010 0.690 0.038 1.28 7.40 0.402 0.005 0.008 0.556 0.024

0.014 2.25 0.04 0.05 5.65 0.20 0.004 2.04 0.03 0.05 4.31 0.20 0.010 3.35 0.03 0.07 6.03 0.27 0.012 2.28 0.09 0.10 6.51 0.36 0.005 2.97 0.04 0.06 4.11 0.18

0.12 1515 0.82 27.1 0.03 1244 0.82 30.7 0.10 1809 0.82 25.8 0.11 1452 0.87 39.8 0.03 1427 0.86 26.2 

### Day 5 post partum Hematology

Group 3 (30 mg/kg) FEMALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 304 of 66303-OCT-11 HEM-IND - 10

71 72 73 74 75

71 72 73 74 75

71 72 73 74 75

71 72 73 74 75 RBC HB HCT MCV RDW MCH MCHC

HDW WBC NEUT EOS BASO LYMPH MONO

LUC NEUT EOS BASO LYMPH MONO

LUC PLATELETS PT PTT 6.81 8.5 0.40 58.5 0.137 1.25 21.35 6.90 8.1 0.39 56.0 0.142 1.18 21.04 7.17 8.4 0.41 57.4 0.153 1.18 20.51 6.37 7.7 0.37 58.4 0.150 1.21 20.77 7.43 9.1 0.45 60.3 0.155 1.22 20.21

1.28 6.42 0.271 0.011 0.019 0.669 0.023 1.46 8.08 0.174 0.008 0.007 0.767 0.038 1.59 12.27 0.380 0.002 0.006 0.562 0.045 1.47 8.97 0.249 0.003 0.006 0.668 0.063 1.52 8.52 0.430 0.011 0.011 0.514 0.024

0.008 1.74 0.07 0.12 4.30 0.15 0.006 1.40 0.06 0.06 6.20 0.31 0.006 4.66 0.02 0.08 6.89 0.55 0.011 2.24 0.03 0.05 5.99 0.56 0.010 3.66 0.09 0.10 4.38 0.20

0.05 870 0.87 21.2 0.05 1574 0.91 26.7 0.07 1536 0.80 29.7 0.09 1551 0.83 25.8 0.09 1405 0.84 26.4 

### Day 5 post partum Hematology

Group 4 (90 mg/kg) FEMALES

T/l mmol/l rel. 1 fl rel. 1 fmol mmol/l

mmol/l G/l rel. 1 rel. 1 rel. 1 rel. 1 rel. 1

rel. 1 G/l G/l G/l G/l G/l

G/l G/l rel. 1 sec BORATORIES STUDY D23451 127

GENERAL

GENERAL DIFF.WBC CO UNT (REL)

DIFF.WBC CO UNT (REL) DIFF.WBC CO UNT (ABS)

DIFF.WBC CO UNT (ABS) GENERAL COAGULATION 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3dea3 

## Page 305 of 66303-OCT-11 CHE-IND - 1 ORATORIES STUDY D23451 127



### Biochemistry

Before necropsy Reported Parameter

GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO GLUCOSE

UREA CREATININE BILIRUBIN, TOTAL BILE ACIDS CHOLESTEROL, TOTAL TRIGLYCERIDES ASPARTATE AMINOTRANSFERASE (ASAT) ALANINE AMINOTRANSFERASE (ALAT) ALKALINE PHOSPHATASE (ALP) GAMMA-GLUTAMYLTRANSFERASE (GGT) SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN, TOTAL ALBUMIN GLOBULIN A/G RATIO Comments

---

Data excluded from Summary Report

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 306 of 66303-OCT-11 CHE-IND - 2 ORATORIES STUDY D23451 127



### Biochemistry

Day 5 post partum Reported Parameter

GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO GLUCOSE

UREA CREATININE BILIRUBIN, TOTAL BILE ACIDS CHOLESTEROL, TOTAL TRIGLYCERIDES ASPARTATE AMINOTRANSFERASE (ASAT) ALANINE AMINOTRANSFERASE (ALAT) ALKALINE PHOSPHATASE (ALP) GAMMA-GLUTAMYLTRANSFERASE (GGT) SODIUM POTASSIUM CHLORIDE CALCIUM PHOSPHORUS PROTEIN, TOTAL ALBUMIN GLOBULIN A/G RATIO 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 307 of 66303-OCT-11 CHE-IND - 3

1 2 3 4 5

1 2 3 4 5

1 2 3 4 5 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 6.50 8.08 26.0 2.39 23.30 1.57 0.30 10.55 7.41 22.8 2.39 25.00 1.75 0.71 8.40 7.13 24.4 1.77 27.10 1.91 0.44 7.70 6.69 26.5 2.51 15.80 2.61 0.30 8.00 9.60 25.7 2.03 27.00 1.57 0.54

88.2 50.5 83.5 0.0 142.0 3.93 101.9 59.7 33.3 92.2 0.0 142.0 3.84 98.2 72.5 31.3 52.9 0.0 143.0 3.79 101.2 74.5 43.1 79.7 0.0 141.0 3.74 100.5 78.5 45.4 109.4 0.0 143.0 3.92 100.6

2.72 1.91 66.97 42.93 24.04 1.79 2.70 1.65 67.89 43.62 24.27 1.80 2.59 1.51 66.59 43.19 23.40 1.85 2.62 1.55 67.63 43.26 24.37 1.78 2.77 1.68 70.55 45.02 25.53 1.76 

### Before necropsy Biochemistry

Group 1 (0 mg/kg) MALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 308 of 66303-OCT-11 CHE-IND - 4

11 12 13 14 15

11 12 13 14 15

11 12 13 14 15 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 8.60 8.35 25.5 2.25 28.50 1.56 0.43 6.80 5.94 25.7 2.05 31.30 2.35 0.50 7.90 6.52 24.4 1.09 12.50 2.29 0.68 6.80 7.24 25.7 1.43 18.10 1.75 0.55 8.00 7.39 25.2 1.35 15.90 2.08 0.88

81.0 53.4 98.7 0.0 144.0 3.51 101.9 68.8 42.6 63.1 0.0 141.0 4.43 99.5 91.4 47.4 100.7 0.0 143.0 3.72 102.0 68.2 42.2 74.2 0.0 143.0 3.77 101.8 86.6 39.3 89.3 0.0 149.0 4.00 106.6

2.63 1.36 66.96 45.45 21.51 2.11 2.74 1.63 68.13 44.26 23.87 1.85 2.61 1.60 66.90 43.85 23.05 1.90 2.73 1.86 65.85 40.50 25.35 1.60 2.65 1.61 65.30 41.34 23.96 1.73 

### Before necropsy Biochemistry

Group 2 (10 mg/kg) MALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 309 of 66303-OCT-11 CHE-IND - 5

21 22 23 24 25

21 22 23 24 25

21 22 23 24 25 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 6.30 5.73 25.7 1.91 17.80 1.82 0.57 8.60 8.26 25.2 1.24 21.60 2.34 0.82 6.90 6.77 24.4 1.60 19.90 2.73 0.88 7.70 7.53 21.2 1.01 12.30 2.32 0.96 7.00 6.11 24.7 1.69 15.10 1.59 0.38

74.5 51.3 77.2 0.0 142.0 3.98 100.6 69.0 46.4 76.1 0.0 142.0 4.19 101.1 70.5 30.5 73.4 0.0 143.0 4.17 99.4 56.7 44.3 95.8 0.0 143.0 3.86 101.9 71.9 37.0 55.2 0.0 142.0 3.82 102.5

2.71 1.90 66.59 44.35 22.24 1.99 2.78 1.81 65.87 39.60 26.27 1.51 2.81 1.56 73.82 46.18 27.64 1.67 2.71 1.93 64.89 40.90 23.99 1.70 2.69 1.56 66.89 45.48 21.41 2.12 

### Before necropsy Biochemistry

Group 3 (30 mg/kg) MALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 310 of 66303-OCT-11 CHE-IND - 6

31 32 33 34 36

31 32 33 34 36

31 32 33 34 36 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 7.40 9.23 29.7 2.42 31.70 2.29 0.54 8.70 8.76 28.4 2.59 18.60 2.36 0.41 9.30 8.20 22.0 1.29 35.30 2.79 0.72 6.60 11.80 28.1 2.51 73.80 2.86 0.44 8.50 6.40 20.4 1.63 11.80 1.86 0.51

70.9 47.5 67.5 0.0 144.0 3.68 100.9 51.5 45.5 70.7 0.0 144.0 4.03 101.2 63.5 39.5 62.7 0.0 143.0 3.96 99.7 66.1 67.2 113.1 0.0 142.0 4.19 100.8 71.6 34.8 62.3 0.0 143.0 4.41 103.2

2.81 1.97 64.40 43.52 20.88 2.08 2.76 2.21 63.31 41.83 21.48 1.95 2.87 1.76 66.60 41.93 24.67 1.70 2.80 2.06 65.35 44.74 20.61 2.17 2.71 1.65 66.35 44.12 22.23 1.98 

### Before necropsy Biochemistry

Group 4 (90 mg/kg) MALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 311 of 66303-OCT-11 CHE-IND - 7

41 42 43 44 47

41 42 43 44 47

41 42 43 44 47 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 6.80 6.95 31.9 2.13 61.50 1.36 0.73 9.90 5.20 25.7 0.99 9.90 1.95 1.02 8.10 6.46 28.5 2.19 42.90 2.21 0.69 5.60 6.85 28.8 1.24 12.48 1.34 0.53 6.60 7.60 27.0 2.54 99.85 2.19 0.77

64.6 50.3 46.3 0.0 142.0 3.96 102.6 70.4 48.9 30.0 0.0 141.0 3.96 102.8 59.1 24.8 19.8 0.0 143.0 3.91 100.5 82.1 35.8 21.8 0.0 140.0 3.94 99.9 91.1 64.1 60.7 0.0 140.0 4.12 99.3

2.77 2.40 60.96 40.69 20.27 2.01 2.68 2.20 66.42 45.76 20.66 2.21 2.86 2.53 67.47 44.96 22.51 2.00 2.78 1.89 64.37 44.28 20.09 2.20 2.92 2.53 66.75 43.37 23.38 1.86 

### Day 5 post partum Biochemistry

Group 1 (0 mg/kg) FEMALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 312 of 66303-OCT-11 CHE-IND - 8

52 53 54 55 56

52 53 54 55 56

52 53 54 55 56 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 7.40 7.54 34.1 2.07 13.70 1.65 0.46 5.80 8.44 35.2 1.74 16.30 1.66 0.81 6.50 5.56 36.3 2.07 9.20 1.05 0.25 6.80 7.75 30.1 1.35 7.70 1.42 0.85 6.10 7.80 36.1 1.74 24.90 1.75 0.49

62.3 21.3 22.7 0.0 141.0 4.10 104.3 66.9 38.8 21.1 0.0 141.0 4.23 102.2 72.9 37.2 26.5 0.0 138.0 3.86 100.9 73.9 50.7 29.1 0.0 141.0 4.31 102.9 156.9 36.8 22.3 0.0 141.0 4.27 103.9

2.63 1.79 62.65 43.32 19.33 2.24 2.73 2.41 62.19 42.76 19.43 2.20 2.62 1.75 66.57 43.34 23.23 1.87 2.80 2.73 64.90 40.86 24.04 1.70 2.67 2.06 64.80 43.43 21.37 2.03 

### Day 5 post partum Biochemistry

Group 2 (10 mg/kg) FEMALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 313 of 66303-OCT-11 CHE-IND - 9

61 62 63 64 65

61 62 63 64 65

61 62 63 64 65 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 8.00 9.12 34.1 1.35 15.10 2.62 1.82 6.70 7.13 32.7 1.29 9.20 1.93 0.58 8.00 5.89 27.1 1.02 23.08 2.15 0.59 7.00 7.68 30.2 0.75 17.99 1.63 0.52 7.20 6.92 25.9 1.44 9.10 2.24 0.93

66.0 54.2 27.0 0.0 138.0 4.55 100.1 63.9 39.5 18.9 0.0 140.0 4.07 103.2 133.2 52.0 27.6 0.0 141.0 3.98 102.0 79.2 28.4 19.7 0.0 139.0 4.51 100.5 59.5 20.9 33.9 0.0 141.0 4.19 102.9

2.78 2.15 63.01 40.47 22.54 1.80 2.72 2.04 63.78 45.21 18.57 2.43 2.79 2.15 63.34 41.83 21.51 1.94 2.73 2.22 61.19 40.60 20.59 1.97 2.70 1.89 65.92 41.52 24.40 1.70 

### Day 5 post partum Biochemistry

Group 3 (30 mg/kg) FEMALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 314 of 66303-OCT-11 CHE-IND - 10

71 72 73 74 75

71 72 73 74 75

71 72 73 74 75 GLUCOSE UREA CREAT BILI-T BILE AC CHOLEST TRIGLY

ASAT ALAT ALP GGT SODIUM POTASSIUM CHLORIDE

CALCIUM PHOSPHORUS PROTEIN ALBUMIN GLOBULIN A/G RATIO 5.50 4.91 31.9 1.75 21.90 2.76 0.29 8.00 8.13 32.2 2.02 53.80 2.40 1.23 8.90 8.26 30.7 2.80 118.28 2.02 1.12 6.20 9.81 32.0 1.52 38.80 2.50 1.27 8.00 5.94 25.5 0.91 14.34 2.57 1.09

79.5 45.6 26.7 0.0 142.0 3.92 105.2 53.0 70.5 22.3 0.0 141.0 3.81 99.3 98.3 55.6 39.1 0.0 140.0 4.74 98.6 71.7 89.2 46.0 0.0 140.0 4.93 99.9 74.0 38.2 25.7 0.0 140.0 4.67 99.1

2.60 1.79 63.76 40.37 23.39 1.73 3.05 2.17 63.73 48.11 15.62 3.08 2.99 2.52 58.80 42.22 16.58 2.55 2.96 2.62 58.08 39.77 18.31 2.17 2.85 2.23 64.65 42.44 22.21 1.91 

### Day 5 post partum Biochemistry

Group 4 (90 mg/kg) FEMALES

mmol/l mmol/l μmol/l μmol/l μmol/l mmol/l mmol/l

U/l U/l U/l U/l mmol/l mmol/l mmol/l

mmol/l mmol/l g/l g/l g/l BORATORIES STUDY D23451 127

GENERAL

GENERAL

GENERAL 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a3de08 

## Page 315 of 663

# Reproduction and Breedin g Data - P Generation Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a814d2 

## Page 316 of 663

### H ORATORIES REP1 - 1 IRGACURE 127 17-NOV-11



## REPRODUCTION PROCESSES
GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ Female Male Mating Pregnant Schedule Delivery Necropsy Number Number Date recorded

____________________________________________________________________________________________________ 41 1 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 42 2 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 43 3 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 44 4 28-AUG-11 Yes Breeding 19-SEP-11 24-SEP-11 45 5 25-AUG-11 No Breeding 19-SEP-11 46 6 28-AUG-11 No Breeding 22-SEP-11 47 7 26-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 48 8 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 49 9 26-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 50 10 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab45dd 

## Page 317 of 663

### H ORATORIES REP1 - 2 IRGACURE 127 17-NOV-11



## REPRODUCTION PROCESSES
GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ Female Male Mating Pregnant Schedule Delivery Necropsy Number Number Date recorded

____________________________________________________________________________________________________ 51 11 28-AUG-11 No Breeding 52 12 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 53 13 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 54 14 25-AUG-11 Yes Breeding 15-SEP-11 20-SEP-11 55 15 26-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 56 16 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 57 17 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 58 18 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 59 19 25-AUG-11 Yes Breeding 19-SEP-11 60 20 27-AUG-11 Yes Breeding 17-SEP-11 22-SEP-11

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 318 of 663

### H ORATORIES REP1 - 3 IRGACURE 127 17-NOV-11



## REPRODUCTION PROCESSES
GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ Female Male Mating Pregnant Schedule Delivery Necropsy Number Number Date recorded

____________________________________________________________________________________________________ 61 21 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 62 22 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 63 23 28-AUG-11 Yes Breeding 19-SEP-11 24-SEP-11 64 24 29-AUG-11 Yes Breeding 20-SEP-11 25-SEP-11 65 25 25-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 66 26 27-AUG-11 Yes Breeding 17-SEP-11 22-SEP-11 67 27 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 68 28 25-AUG-11 Yes Breeding 15-SEP-11 20-SEP-11 69 29 25-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 70 30 04-SEP-11 Yes Breeding 26-SEP-11 01-OCT-11

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 319 of 663

### H ORATORIES REP1 - 4 IRGACURE 127 17-NOV-11



## REPRODUCTION PROCESSES
GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ Female Male Mating Pregnant Schedule Delivery Necropsy Number Number Date recorded

____________________________________________________________________________________________________ 71 31 25-AUG-11 Yes Breeding 17-SEP-11 22-SEP-11 72 32 26-AUG-11 Yes Breeding 17-SEP-11 22-SEP-11 73 33 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 74 34 25-AUG-11 Yes Breeding 16-SEP-11 21-SEP-11 75 34 29-AUG-11 Yes Breeding 20-SEP-11 25-SEP-11 76 36 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 77 37 27-AUG-11 No Breeding 21-SEP-11 78 38 --- - --- 26-AUG-11 79 39 27-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11 80 40 28-AUG-11 Yes Breeding 18-SEP-11 23-SEP-11

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 320 of 663

### H ORATORIES PAR-IND - 1 IRGACURE 127 12-OCT-11



## CORPORA LUTEA COUNT P GENERATION FEMALES GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ Corpora Lutea

--------------------- ANIMAL NUMBER

____________________________________________________________________________________________________ 41 13 42 14 43 13 44 17 45 (A) -- 46 (A) -- 47 14 48 13 49 13 50 15 (A) = Not pregnant



### Harlan Laboratories Study Report
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## Page 321 of 663

### H ORATORIES PAR-IND - 2 IRGACURE 127 12-OCT-11



## CORPORA LUTEA COUNT P GENERATION FEMALES GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ Corpora Lutea

--------------------- ANIMAL NUMBER

____________________________________________________________________________________________________ 51 (A) -- 52 13 53 15 54 14 55 13 56 16 57 16 58 15 59 12 60 14 (A) = Not pregnant



### Harlan Laboratories Study Report
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## Page 322 of 663

### H ORATORIES PAR-IND - 3 IRGACURE 127 12-OCT-11



## CORPORA LUTEA COUNT P GENERATION FEMALES GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ Corpora Lutea

--------------------- ANIMAL NUMBER

____________________________________________________________________________________________________ 61 14 62 14 63 17 64 15 65 12 66 14 67 12 68 14 69 12 70 15



### Harlan Laboratories Study Report
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## Page 323 of 663

### H ORATORIES PAR-IND - 4 IRGACURE 127 12-OCT-11



## CORPORA LUTEA COUNT P GENERATION FEMALES GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ Corpora Lutea

--------------------- ANIMAL NUMBER

____________________________________________________________________________________________________ 71 7 72 13 73 16 74 13 75 19 76 14 77 (A) -- 78 (B) -- 79 14 80 15 (A) = Not pregnant (B) = Spontaneous death



### Harlan Laboratories Study Report
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## Page 324 of 663

### H ORATORIES REP2 - 1 IRGACURE 127 17-NOV-11



## IMPLANTATIONS

FEMALES SCHEDULED FOR BREEDING

____________________________________________________________________________________________________ GROUP 1 GROUP 2 GROUP 3 GROUP 4 0 MG/KG 10 MG/KG 30 MG/KG 90 MG/KG Female Implant. Female Implant. Female Implant. Female Implant. Number sites Number sites Number sites Number sites

____________________________________________________________________________________________________ 41 12 <S> 51 0 <S> 61 14 <S> 71 7 <S> 42 13 <S> 52 13 <S> 62 14 <S> 72 9 <S> 43 13 <S> 53 13 <S> 63 17 <S> 73 16 <S> 44 11 <S> 54 14 <S> 64 14 <S> 74 12 <S> 45 0 <S> 55 15 <S> 65 12 <S> 75 14 <S> 46 0 <S> 56 16 <S> 66 14 <S> 76 13 <S> 47 14 <S> 57 15 <S> 67 12 <S> 77 0 <S> 48 12 <S> 58 14 <S> 68 14 <S> 79 14 <S> 49 14 <S> 59 3 <S> 69 12 <S> 80 15 <S> 50 14 <S> 60 14 <S> 70 14 <S>

____________________________________________________________________________________________________ Mean 12.9 13.0 13.7 12.5 St.dev. 1.1 3.9 1.5 3.1 N 8 9 10 8

____________________________________________________________________________________________________ Non pregnant females were not used for calculation of Mean, St.dev. and N +: Steel-test significant at 5% level. <S>: After staining



### Harlan Laboratories Study Report
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## Page 325 of 663

### H ORATORIES PUP-LIT - 1 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER DURATION OF IMPLANTATION GESTATION SITES

____________________________________________________________________________________________________ 41 22 12 42 22 13 43 22 13 44 22 11 47 21 14 48 21 12 49 21 14 50 22 14

____________________________________________________________________________________________________ Total 103 N 8 8

Mean 21.6 12.9 St.dev. 0.5 1.1

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 326 of 663

### H ORATORIES PUP-LIT - 2 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER FIRST LITTER CHECK P.NATAL LOSS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0 - 4 DAY 4 P.P. M F M F TOT. M F M F TOT.

____________________________________________________________________________________________________ 41 0 0 8 3 11 0 0 8 3 11 42 0 0 5 4 9 0 0 5 4 9 43 0 0 7 6 13 0 0 7 6 13 44 0 0 6 4 10 0 0 6 4 10 47 0 0 7 6 13 0 0 7 6 13 48 0 0 3 9 12 0 0 3 9 12 49 0 0 6 8 14 0 0 6 8 14 50 0 0 4 9 13 0 0 4 9 13

____________________________________________________________________________________________________ Total 0 0 46 49 95 0 0 46 49 95 N 8 8 8 8 8 8 8 8 8 8

Mean 0.0 0.0 5.8 6.1 11.9 0.0 0.0 5.8 6.1 11.9 St.dev. 0.0 0.0 1.7 2.4 1.7 0.0 0.0 1.7 2.4 1.7

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 327 of 663

### H ORATORIES PUP-LIT - 3 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER DURATION OF IMPLANTATION GESTATION SITES

____________________________________________________________________________________________________ 52 22 13 53 22 13 54 21 14 55 21 15 56 21 16 57 21 15 58 22 14 60 21 14

____________________________________________________________________________________________________ Total 114 N 8 8

Mean 21.4 14.3 St.dev. 0.5 1.0

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 328 of 663

### H ORATORIES PUP-LIT - 4 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER FIRST LITTER CHECK P.NATAL LOSS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0 - 4 DAY 4 P.P. . M F M F TOT. M F M F TOT.

____________________________________________________________________________________________________ 52 0 0 5 6 11 0 0 5 6 11 53 0 0 6 6 12 0 0 6 6 12 54 0 0 4 10 14 0 0 4 10 14 55 0 0 7 5 12 0 0 7 5 12 56 0 0 6 9 15 0 1 6 8 14 57 0 0 10 5 15 0 0 10 5 15 58 0 0 7 7 14 0 0 7 7 14 60 0 0 3 9 12 0 0 3 9 12

____________________________________________________________________________________________________ Total 0 0 48 57 105 0 1 48 56 104 N 8 8 8 8 8 8 8 8 8 8

Mean 0.0 0.0 6.0 7.1 13.1 0.0 0.1 6.0 7.0 13.0 St.dev. 0.0 0.0 2.1 2.0 1.6 0.0 0.4 2.1 1.9 1.4

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 329 of 663

### H ORATORIES PUP-LIT - 5 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER DURATION OF IMPLANTATION GESTATION SITES

____________________________________________________________________________________________________ 61 22 14 62 22 14 63 22 17 64 22 14 65 22 12 66 21 14 67 21 12 68 21 14 69 22 12 70 22 14

____________________________________________________________________________________________________ Total 137 N 10 10

Mean 21.7 13.7 St.dev. 0.5 1.5

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 330 of 663

### H ORATORIES PUP-LIT - 6 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER FIRST LITTER CHECK P.NATAL LOSS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0 - 4 DAY 4 P.P. M F M F TOT. M F M F TOT.

____________________________________________________________________________________________________ 61 0 0 6 8 14 0 0 6 8 14 62 0 0 7 6 13 0 0 7 6 13 63 0 0 9 8 17 0 0 9 8 17 64 0 0 8 5 13 0 0 8 5 13 65 0 0 4 6 10 0 0 4 6 10 66 0 0 9 4 13 0 0 9 4 13 67 0 0 5 7 12 0 0 5 7 12 68 0 0 8 4 12 0 0 8 4 12 69 0 0 6 4 10 0 0 6 4 10 70 1 0 5 8 13 0 0 5 8 13

____________________________________________________________________________________________________ Total 1 0 67 60 127 0 0 67 60 127 N 10 10 10 10 10 10 10 10 10 10

Mean 0.1 0.0 6.7 6.0 12.7 0.0 0.0 6.7 6.0 12.7 St.dev. 0.3 0.0 1.8 1.7 2.0 0.0 0.0 1.8 1.7 2.0

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 331 of 663

### H ORATORIES PUP-LIT - 7 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER DURATION OF IMPLANTATION GESTATION SITES

____________________________________________________________________________________________________ 71 23 7 72 22 9 73 22 16 74 22 12 75 22 14 76 21 13 79 22 14 80 21 15

____________________________________________________________________________________________________ Total 100 N 8 8

Mean 21.9 12.5 St.dev. 0.6 3.1

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81534 

## Page 332 of 663

### H ORATORIES PUP-LIT - 8 IRGACURE 127 11-OCT-11



## BREEDING DATA PER LITTER GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER FIRST LITTER CHECK P.NATAL LOSS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0 - 4 DAY 4 P.P. M F M F TOT. M F M F TOT.

____________________________________________________________________________________________________ 71 0 0 1 6 7 0 0 1 6 7 72 0 1 3 4 7 1 2 2 2 4 73 0 0 5 9 14 0 0 5 9 14 74 0 0 8 4 12 1 0 7 4 11 75 0 0 8 6 14 0 0 8 6 14 76 0 0 5 8 13 0 0 5 8 13 79 0 0 6 3 9 2 0 4 3 7 80 0 0 9 6 15 0 1 9 5 14

____________________________________________________________________________________________________ Total 0 1 45 46 91 4 3 41 43 84 N 8 8 8 8 8 8 8 8 8 8

Mean 0.0 0.1 5.6 5.8 11.4 0.5 0.4 5.1 5.4 10.5 St.dev. 0.0 0.4 2.7 2.1 3.2 0.8 0.7 2.8 2.4 4.0

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 333 of 663

# Terminal Findings - P Generation Harlan Laboratories Study Report
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## Page 334 of 66312-OCT-11 OW-IND - 1 ORATORIES STUDY D23451 127

Comments

Exclusions 

### ORGAN WEIGHTS (GRAM)

---

---

Selection of Organs All organs reported

--- Animals without scheduled necropsy Not Reported

--- 

### Harlan Laboratories Study Report
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## Page 335 of 66312-OCT-11 OW-IND - 2

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 341.9 2.10 0.011 0.98 0.033 8.76 0.311 390.0 1.96 0.011 0.89 0.021 9.96 0.324 326.5 2.02 0.009 0.90 0.020 8.30 0.335 352.4 1.98 0.010 0.93 0.024 9.09 0.427 331.0 2.00 0.009 0.83 0.030 8.10 0.369 327.2 1.97 0.009 0.87 0.024 8.65 0.303 365.6 2.04 0.010 0.94 0.017 9.99 0.339 351.5 2.12 0.013 1.01 0.030 9.01 0.429 344.4 1.83 0.009 0.94 0.021 8.40 0.276 382.6 2.02 0.012 0.88 0.031 9.36 0.270

2.05 0.104 0.77 1.91 1.96 1.19 0.712 2.20 0.079 0.86 2.04 2.03 1.09 0.616 1.91 0.076 0.69 2.00 2.03 1.03 0.617 1.99 0.085 0.68 1.89 1.82 0.94 0.577 2.00 0.081 0.76 1.80 1.80 1.02 0.699 1.88 0.071 0.60 1.74 1.76 0.92 0.674 2.22 0.103 0.90 1.85 1.93 0.96 0.575 2.08 0.081 0.85 2.06 2.05 0.97 0.826 2.01 0.074 0.64 1.85 1.87 0.77 0.670 2.16 0.087 0.79 1.97 1.93 1.09 0.674

0.736 0.273 0.268 1.47 0.597 0.261 0.259 1.27 0.670 0.256 0.271 0.94 0.596 0.242 0.250 0.91 0.701 0.271 0.267 1.17 0.674 0.251 0.271 1.06 0.581 0.258 0.285 1.09 0.826 0.338 0.349 1.55 0.564 0.275 0.289 1.09 0.676 0.281 0.297 1.39 

### . ORGAN WEIGHTS (GRAM)

Group 1 (0 mg/kg) MALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
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## Page 336 of 66312-OCT-11 OW-IND - 3

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 325.1 1.86 0.009 0.94 0.019 7.94 0.246 402.6 1.94 0.012 1.04 0.023 10.29 0.256 354.1 2.08 0.98 0.023 8.99 0.284 335.4 1.92 0.012 0.89 0.026 8.81 0.220 354.4 2.08 0.010 0.88 0.026 9.15 0.374 353.5 1.96 0.006 1.05 0.016 8.71 0.348 343.6 1.99 0.009 0.97 0.027 8.91 0.498 350.3 2.02 0.011 0.97 0.029 8.84 0.326 339.4 1.98 0.011 0.97 0.027 8.41 0.417 323.1 2.01 0.010 0.98 0.021 8.12 0.439

1.85 0.071 0.63 1.78 1.60 0.80 0.519 2.47 0.093 0.79 1.83 1.83 1.12 0.688 2.11 0.111 0.77 1.87 1.93 1.06 0.715 2.01 0.082 0.70 1.73 1.85 1.34 0.610 2.10 0.080 0.75 1.90 1.87 1.02 0.628 1.97 0.070 0.91 1.87 1.83 0.96 0.586 2.06 0.090 0.80 1.99 1.95 0.84 0.682 2.13 0.092 0.66 1.94 1.88 1.10 0.583 1.92 0.079 0.89 2.01 1.95 0.84 0.704 1.91 0.077 0.73 1.82 1.71 1.38 0.560

0.549 0.253 0.245 0.88 0.699 0.307 0.293 1.45 0.714 0.283 0.304 1.35 0.570 0.279 0.293 1.26 0.702 0.285 0.270 1.26 0.601 0.279 0.297 1.26 0.718 0.292 0.289 1.20 0.700 0.305 0.283 1.03 0.696 0.271 0.270 1.16 0.567 0.266 0.264 1.08 

### . ORGAN WEIGHTS (GRAM)

Group 2 (10 mg/kg) MALES

---

ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
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## Page 337 of 66312-OCT-11 OW-IND - 4

21 22 23 24 25 26 27 28 29 30

21 22 23 24 25 26 27 28 29 30

21 22 23 24 25 26 27 28 29 30 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 354.4 2.02 0.010 1.05 0.027 9.16 0.275 371.8 2.01 0.010 0.91 0.027 9.51 0.401 371.0 1.93 0.009 0.94 0.021 9.99 0.296 338.1 2.00 0.011 0.95 0.034 9.10 0.397 307.1 2.03 0.010 0.84 0.019 8.26 0.410 356.7 1.96 0.009 0.97 0.035 8.75 0.307 350.5 1.88 0.012 0.98 0.034 9.28 0.291 340.7 1.97 0.009 0.94 0.027 8.72 0.371 358.1 1.99 0.009 1.02 0.028 8.96 0.573 345.4 2.00 0.011 0.95 0.032 9.16 0.382

2.09 0.078 0.87 1.91 1.88 1.00 0.602 1.90 0.078 0.72 1.91 2.03 0.89 0.744 1.89 0.081 0.67 2.03 2.01 0.90 0.644 1.94 0.081 0.89 1.98 1.99 0.91 0.695 2.00 0.092 0.60 1.61 1.69 1.10 0.590 2.03 0.067 0.69 1.75 1.70 1.13 0.673 2.17 0.076 0.67 1.89 1.78 0.91 0.638 1.77 0.076 0.62 1.78 1.72 1.12 0.624 1.78 0.077 0.72 1.81 1.70 0.95 0.495 1.93 0.062 0.84 1.99 1.97 0.90 0.705

0.533 0.243 0.276 1.15 0.810 0.323 0.283 1.08 0.617 0.324 0.316 1.26 0.697 0.270 0.270 1.20 0.552 0.257 0.278 1.26 0.671 0.294 0.287 1.28 0.593 0.253 0.289 1.48 0.677 0.266 0.266 0.95 0.524 0.217 0.208 0.95 0.732 0.272 0.272 1.07 

### . ORGAN WEIGHTS (GRAM)

Group 3 (30 mg/kg) MALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
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09009e5380b2ce18 

## Page 338 of 66312-OCT-11 OW-IND - 5

31 32 33 34 36 37 38 39 40

31 32 33 34 36 37 38 39 40

31 32 33 34 36 37 38 39 40 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 329.3 1.95 0.009 0.89 0.028 9.12 0.288 342.6 1.95 0.010 1.03 0.023 10.21 0.304 350.3 2.00 0.009 0.98 0.025 11.23 0.406 294.2 1.95 0.009 0.98 0.030 9.01 0.258 361.8 2.01 0.013 1.00 0.024 10.04 0.317 381.0 2.01 0.011 1.16 0.034 11.16 0.592 337.2 1.87 0.010 0.84 0.025 10.42 0.281 295.8 2.03 0.009 1.01 0.027 8.80 0.263 318.6 2.01 0.009 0.98 0.023 9.50 0.336

1.97 0.080 0.54 1.73 1.70 0.95 0.589 2.41 0.078 0.58 1.88 1.88 1.01 0.606 2.28 0.113 0.73 1.69 1.81 1.18 0.612 1.89 0.061 0.70 1.92 1.97 0.78 0.626 2.42 0.080 0.73 2.31 2.30 1.15 0.743 2.23 0.070 0.95 0.93 0.96 0.85 0.425 2.16 0.080 0.72 1.65 1.62 0.72 0.518 2.29 0.089 0.61 1.65 1.69 0.82 0.619 1.93 0.067 0.59 1.68 1.68 0.90 0.625

0.668 0.270 0.259 1.39 0.574 0.260 0.263 1.28 0.624 0.283 0.282 1.05 0.593 0.258 0.251 1.22 0.750 0.357 0.346 1.48 0.462 0.137 0.135 1.39 0.490 0.246 0.252 1.06 0.571 0.251 0.298 1.31 0.639 0.245 0.244 1.02 

### . ORGAN WEIGHTS (GRAM)

Group 4 (90 mg/kg) MALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 339 of 66312-OCT-11 OW-IND - 6

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 341.9 0.61 0.003 0.29 0.010 2.56 0.091 390.0 0.50 0.003 0.23 0.005 2.55 0.083 326.5 0.62 0.003 0.28 0.006 2.54 0.103 352.4 0.56 0.003 0.26 0.007 2.58 0.121 331.0 0.60 0.003 0.25 0.009 2.45 0.111 327.2 0.60 0.003 0.27 0.007 2.64 0.093 365.6 0.56 0.003 0.26 0.005 2.73 0.093 351.5 0.60 0.004 0.29 0.009 2.56 0.122 344.4 0.53 0.003 0.27 0.006 2.44 0.080 382.6 0.53 0.003 0.23 0.008 2.45 0.071

0.60 0.030 0.23 0.56 0.57 0.35 0.208 0.56 0.020 0.22 0.52 0.52 0.28 0.158 0.58 0.023 0.21 0.61 0.62 0.32 0.189 0.56 0.024 0.19 0.54 0.52 0.27 0.164 0.60 0.024 0.23 0.54 0.54 0.31 0.211 0.57 0.022 0.18 0.53 0.54 0.28 0.206 0.61 0.028 0.25 0.51 0.53 0.26 0.157 0.59 0.023 0.24 0.59 0.58 0.28 0.235 0.58 0.021 0.19 0.54 0.54 0.22 0.195 0.56 0.023 0.21 0.51 0.50 0.28 0.176

0.215 0.080 0.078 0.43 0.153 0.067 0.066 0.33 0.205 0.078 0.083 0.29 0.169 0.069 0.071 0.26 0.212 0.082 0.081 0.35 0.206 0.077 0.083 0.32 0.159 0.071 0.078 0.30 0.235 0.096 0.099 0.44 0.164 0.080 0.084 0.32 0.177 0.073 0.078 0.36 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 1 (0 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 340 of 66312-OCT-11 OW-IND - 7

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 325.1 0.57 0.003 0.29 0.006 2.44 0.076 402.6 0.48 0.003 0.26 0.006 2.56 0.064 354.1 0.59 0.28 0.006 2.54 0.080 335.4 0.57 0.004 0.27 0.008 2.63 0.066 354.4 0.59 0.003 0.25 0.007 2.58 0.106 353.5 0.55 0.002 0.30 0.005 2.46 0.098 343.6 0.58 0.003 0.28 0.008 2.59 0.145 350.3 0.58 0.003 0.28 0.008 2.52 0.093 339.4 0.58 0.003 0.29 0.008 2.48 0.123 323.1 0.62 0.003 0.30 0.006 2.51 0.136

0.57 0.022 0.19 0.55 0.49 0.25 0.160 0.61 0.023 0.20 0.45 0.45 0.28 0.171 0.60 0.031 0.22 0.53 0.55 0.30 0.202 0.60 0.024 0.21 0.52 0.55 0.40 0.182 0.59 0.023 0.21 0.54 0.53 0.29 0.177 0.56 0.020 0.26 0.53 0.52 0.27 0.166 0.60 0.026 0.23 0.58 0.57 0.24 0.198 0.61 0.026 0.19 0.55 0.54 0.31 0.166 0.57 0.023 0.26 0.59 0.57 0.25 0.207 0.59 0.024 0.23 0.56 0.53 0.43 0.173

0.169 0.078 0.075 0.27 0.174 0.076 0.073 0.36 0.202 0.080 0.086 0.38 0.170 0.083 0.087 0.38 0.198 0.080 0.076 0.36 0.170 0.079 0.084 0.36 0.209 0.085 0.084 0.35 0.200 0.087 0.081 0.29 0.205 0.080 0.080 0.34 0.175 0.082 0.082 0.33 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 2 (10 mg/kg) MALES

---

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 341 of 66312-OCT-11 OW-IND - 8

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21 22 23 24 25 26 27 28 29 30

21 22 23 24 25 26 27 28 29 30 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 354.4 0.57 0.003 0.30 0.008 2.58 0.078 371.8 0.54 0.003 0.24 0.007 2.56 0.108 371.0 0.52 0.002 0.25 0.006 2.69 0.080 338.1 0.59 0.003 0.28 0.010 2.69 0.117 307.1 0.66 0.003 0.27 0.006 2.69 0.134 356.7 0.55 0.003 0.27 0.010 2.45 0.086 350.5 0.54 0.003 0.28 0.010 2.65 0.083 340.7 0.58 0.003 0.28 0.008 2.56 0.109 358.1 0.56 0.003 0.28 0.008 2.50 0.160 345.4 0.58 0.003 0.28 0.009 2.65 0.111

0.59 0.022 0.25 0.54 0.53 0.28 0.170 0.51 0.021 0.19 0.51 0.55 0.24 0.200 0.51 0.022 0.18 0.55 0.54 0.24 0.174 0.57 0.024 0.26 0.59 0.59 0.27 0.206 0.65 0.030 0.20 0.52 0.55 0.36 0.192 0.57 0.019 0.19 0.49 0.48 0.32 0.189 0.62 0.022 0.19 0.54 0.51 0.26 0.182 0.52 0.022 0.18 0.52 0.50 0.33 0.183 0.50 0.022 0.20 0.51 0.47 0.27 0.138 0.56 0.018 0.24 0.58 0.57 0.26 0.204

0.150 0.069 0.078 0.32 0.218 0.087 0.076 0.29 0.166 0.087 0.085 0.34 0.206 0.080 0.080 0.35 0.180 0.084 0.091 0.41 0.188 0.082 0.080 0.36 0.169 0.072 0.082 0.42 0.199 0.078 0.078 0.28 0.146 0.061 0.058 0.27 0.212 0.079 0.079 0.31 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 3 (30 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 342 of 66312-OCT-11 OW-IND - 9

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31 32 33 34 36 37 38 39 40 Animal

Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 329.3 0.59 0.003 0.27 0.009 2.77 0.087 342.6 0.57 0.003 0.30 0.007 2.98 0.089 350.3 0.57 0.003 0.28 0.007 3.21 0.116 294.2 0.66 0.003 0.33 0.010 3.06 0.088 361.8 0.56 0.004 0.28 0.007 2.78 0.088 381.0 0.53 0.003 0.30 0.009 2.93 0.155 337.2 0.55 0.003 0.25 0.007 3.09 0.083 295.8 0.69 0.003 0.34 0.009 2.97 0.089 318.6 0.63 0.003 0.31 0.007 2.98 0.105

0.60 0.024 0.16 0.53 0.52 0.29 0.179 0.70 0.023 0.17 0.55 0.55 0.29 0.177 0.65 0.032 0.21 0.48 0.52 0.34 0.175 0.64 0.021 0.24 0.65 0.67 0.27 0.213 0.67 0.022 0.20 0.64 0.64 0.32 0.205 0.59 0.018 0.25 0.24 0.25 0.22 0.112 0.64 0.024 0.21 0.49 0.48 0.21 0.154 0.77 0.030 0.21 0.56 0.57 0.28 0.209 0.61 0.021 0.19 0.53 0.53 0.28 0.196

0.203 0.082 0.079 0.42 0.168 0.076 0.077 0.37 0.178 0.081 0.081 0.30 0.202 0.088 0.085 0.41 0.207 0.099 0.096 0.41 0.121 0.036 0.035 0.36 0.145 0.073 0.075 0.31 0.193 0.085 0.101 0.44 0.201 0.077 0.077 0.32 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 4 (90 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 343 of 66312-OCT-11 OW-IND - 10

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10 Animal

Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 2.10 0.524 46.67 1.571 417.14 14.810 1.96 0.561 45.41 1.071 508.16 16.531 2.02 0.446 44.55 0.990 410.89 16.584 1.98 0.505 46.97 1.212 459.09 21.566 2.00 0.450 41.50 1.500 405.00 18.450 1.97 0.457 44.16 1.218 439.09 15.381 2.04 0.490 46.08 0.833 489.71 16.618 2.12 0.613 47.64 1.415 425.00 20.236 1.83 0.492 51.37 1.148 459.02 15.082 2.02 0.594 43.56 1.535 463.37 13.366

97.62 4.952 36.67 90.95 93.33 56.67 33.905 112.24 4.031 43.88 104.08 103.57 55.61 31.429 94.55 3.762 34.16 99.01 100.50 50.99 30.545 100.51 4.293 34.34 95.45 91.92 47.47 29.141 100.00 4.050 38.00 90.00 90.00 51.00 34.950 95.43 3.604 30.46 88.32 89.34 46.70 34.213 108.82 5.049 44.12 90.69 94.61 47.06 28.186 98.11 3.821 40.09 97.17 96.70 45.75 38.962 109.84 4.044 34.97 101.09 102.19 42.08 36.612 106.93 4.307 39.11 97.52 95.54 53.96 33.366

35.048 13.000 12.762 70.00 30.459 13.316 13.214 64.80 33.168 12.673 13.416 46.53 30.101 12.222 12.626 45.96 35.050 13.550 13.350 58.50 34.213 12.741 13.756 53.81 28.480 12.647 13.971 53.43 38.962 15.943 16.462 73.11 30.820 15.027 15.792 59.56 33.465 13.911 14.703 68.81 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 1 (0 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 344 of 66312-OCT-11 OW-IND - 11

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20

11 12 13 14 15 16 17 18 19 20 Animal

Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 1.86 0.484 50.54 1.022 426.88 13.226 1.94 0.619 53.61 1.186 530.41 13.196 2.08 47.12 1.106 432.21 13.654 1.92 0.625 46.35 1.354 458.85 11.458 2.08 0.481 42.31 1.250 439.90 17.981 1.96 0.306 53.57 0.816 444.39 17.755 1.99 0.452 48.74 1.357 447.74 25.025 2.02 0.545 48.02 1.436 437.62 16.139 1.98 0.556 48.99 1.364 424.75 21.061 2.01 0.498 48.76 1.045 403.98 21.841

99.46 3.817 33.87 95.70 86.02 43.01 27.903 127.32 4.794 40.72 94.33 94.33 57.73 35.464 101.44 5.337 37.02 89.90 92.79 50.96 34.375 104.69 4.271 36.46 90.10 96.35 69.79 31.771 100.96 3.846 36.06 91.35 89.90 49.04 30.192 100.51 3.571 46.43 95.41 93.37 48.98 29.898 103.52 4.523 40.20 100.00 97.99 42.21 34.271 105.45 4.554 32.67 96.04 93.07 54.46 28.861 96.97 3.990 44.95 101.52 98.48 42.42 35.556 95.02 3.831 36.32 90.55 85.07 68.66 27.861

29.516 13.602 13.172 47.31 36.031 15.825 15.103 74.74 34.327 13.606 14.615 64.90 29.688 14.531 15.260 65.63 33.750 13.702 12.981 60.58 30.663 14.235 15.153 64.29 36.080 14.673 14.523 60.30 34.653 15.099 14.010 50.99 35.152 13.687 13.636 58.59 28.209 13.234 13.134 53.73 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 2 (10 mg/kg) MALES

---

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 345 of 66312-OCT-11 OW-IND - 12

21 22 23 24 25 26 27 28 29 30

21 22 23 24 25 26 27 28 29 30

21 22 23 24 25 26 27 28 29 30 Animal

Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 2.02 0.495 51.98 1.337 453.47 13.614 2.01 0.498 45.27 1.343 473.13 19.950 1.93 0.466 48.70 1.088 517.62 15.337 2.00 0.550 47.50 1.700 455.00 19.850 2.03 0.493 41.38 0.936 406.90 20.197 1.96 0.459 49.49 1.786 446.43 15.663 1.88 0.638 52.13 1.809 493.62 15.479 1.97 0.457 47.72 1.371 442.64 18.832 1.99 0.452 51.26 1.407 450.25 28.794 2.00 0.550 47.50 1.600 458.00 19.100

103.47 3.861 43.07 94.55 93.07 49.50 29.802 94.53 3.881 35.82 95.02 101.00 44.28 37.015 97.93 4.197 34.72 105.18 104.15 46.63 33.368 97.00 4.050 44.50 99.00 99.50 45.50 34.750 98.52 4.532 29.56 79.31 83.25 54.19 29.064 103.57 3.418 35.20 89.29 86.73 57.65 34.337 115.43 4.043 35.64 100.53 94.68 48.40 33.936 89.85 3.858 31.47 90.36 87.31 56.85 31.675 89.45 3.869 36.18 90.95 85.43 47.74 24.874 96.50 3.100 42.00 99.50 98.50 45.00 35.250

26.386 12.030 13.663 56.93 40.299 16.070 14.080 53.73 31.969 16.788 16.373 65.28 34.850 13.500 13.500 60.00 27.192 12.660 13.695 62.07 34.235 15.000 14.643 65.31 31.543 13.457 15.372 78.72 34.365 13.503 13.503 48.22 26.332 10.905 10.452 47.74 36.600 13.600 13.600 53.50 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 3 (30 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 346 of 66312-OCT-11 OW-IND - 13

31 32 33 34 36 37 38 39 40

31 32 33 34 36 37 38 39 40

31 32 33 34 36 37 38 39 40 Animal

Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN TESTIS(L) TESTIS(R) PROSTATE EPIDIDI(R)

EPIDIDI(L) EPIDCAUD(L EPIDCAUD(R SEMINAL VE 1.95 0.462 45.64 1.436 467.69 14.769 1.95 0.513 52.82 1.179 523.59 15.590 2.00 0.450 49.00 1.250 561.50 20.300 1.95 0.462 50.26 1.538 462.05 13.231 2.01 0.647 49.75 1.194 499.50 15.771 2.01 0.547 57.71 1.692 555.22 29.453 1.87 0.535 44.92 1.337 557.22 15.027 2.03 0.443 49.75 1.330 433.50 12.956 2.01 0.448 48.76 1.144 472.64 16.716

101.03 4.103 27.69 88.72 87.18 48.72 30.205 123.59 4.000 29.74 96.41 96.41 51.79 31.077 114.00 5.650 36.50 84.50 90.50 59.00 30.600 96.92 3.128 35.90 98.46 101.03 40.00 32.103 120.40 3.980 36.32 114.93 114.43 57.21 36.965 110.95 3.483 47.26 46.27 47.76 42.29 21.144 115.51 4.278 38.50 88.24 86.63 38.50 27.701 112.81 4.384 30.05 81.28 83.25 40.39 30.493 96.02 3.333 29.35 83.58 83.58 44.78 31.095

34.256 13.846 13.282 71.28 29.436 13.333 13.487 65.64 31.200 14.150 14.100 52.50 30.410 13.231 12.872 62.56 37.313 17.761 17.214 73.63 22.985 6.816 6.716 69.15 26.203 13.155 13.476 56.68 28.128 12.365 14.680 64.53 31.791 12.189 12.139 50.75 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 4 (90 mg/kg) MALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce18 

## Page 347 of 66312-OCT-11 OW-IND - 1 ORATORIES STUDY D23451 127

Comments

Exclusions 

### ORGAN WEIGHTS (GRAM)

---

---

Selection of Organs All organs reported

--- Animals without scheduled necropsy Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 348 of 66312-OCT-11 OW-IND - 2

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41 42 43 44 47 48 49 50 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 227.9 1.87 0.014 0.71 0.020 6.83 0.192 215.2 1.88 0.011 0.76 0.022 7.29 0.241 233.7 1.87 0.015 0.81 0.022 7.84 0.171 235.5 1.93 0.012 0.78 0.018 7.76 0.174 223.1 1.89 0.017 0.74 0.028 7.54 0.192 248.2 1.78 0.013 0.77 0.021 7.54 0.162 241.1 1.76 0.013 0.83 0.015 7.73 0.225 230.9 1.82 0.016 0.70 0.021 7.37 0.155

1.35 0.080 0.73 0.056 0.050 1.07 1.38 0.083 0.79 0.049 0.064 1.12 1.46 0.089 0.63 0.050 0.070 1.14 1.43 0.095 0.77 0.050 0.062 0.99 1.47 0.068 0.71 0.070 0.067 1.26 1.38 0.078 0.60 0.063 0.053 1.03 1.47 0.084 0.78 0.051 0.066 1.05 1.35 0.082 0.69 0.061 0.065 1.01 

### . ORGAN WEIGHTS (GRAM)

Group 1 (0 mg/kg) FEMALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 349 of 66312-OCT-11 OW-IND - 3

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52 53 54 55 56 57 58 60 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 225.0 1.85 0.013 0.87 0.023 7.78 0.181 220.1 1.75 0.012 0.79 0.017 7.18 0.165 221.9 1.87 0.014 0.75 0.021 6.72 0.173 223.1 1.87 0.016 0.78 0.024 7.49 0.232 226.6 1.92 0.016 0.72 0.019 7.40 0.198 229.2 1.87 0.016 0.78 0.023 7.35 0.167 221.4 1.85 0.013 0.76 0.017 7.61 0.100 218.1 1.66 0.011 0.75 0.018 6.73 0.206

1.46 0.079 0.66 0.068 0.039 1.01 1.22 0.068 0.74 0.046 0.064 1.24 1.28 0.089 0.77 0.054 0.072 1.04 1.37 0.083 0.63 0.064 0.067 1.21 1.28 0.093 0.56 0.065 0.065 1.07 1.38 0.086 0.60 0.065 0.073 1.23 1.49 0.073 0.59 0.060 0.064 1.05 1.22 0.066 0.56 0.060 0.063 1.01 

### . ORGAN WEIGHTS (GRAM)

Group 2 (10 mg/kg) FEMALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 350 of 66312-OCT-11 OW-IND - 4

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61 62 63 64 65 66 67 68 69 70 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 223.0 1.73 0.011 0.71 0.017 7.78 0.170 225.6 1.99 0.015 0.78 0.031 8.41 0.179 222.8 1.78 0.016 0.80 0.022 7.97 0.141 223.6 1.78 0.012 0.72 0.018 7.66 0.196 230.4 1.79 0.016 0.75 0.018 7.13 0.159 216.8 1.85 0.014 0.77 0.021 7.75 0.224 200.0 1.71 0.011 0.64 0.016 6.57 0.102 245.9 1.81 0.014 0.86 0.019 8.00 0.184 219.6 1.86 0.011 0.77 0.020 7.66 0.237 231.1 1.79 0.016 0.73 0.026 9.43 0.139

1.30 0.071 0.61 0.071 0.045 1.03 1.35 0.088 0.74 0.056 0.069 0.95 1.31 0.075 0.64 0.053 0.063 1.08 1.37 0.078 0.62 0.054 0.048 1.15 1.37 0.085 0.57 0.055 0.057 0.98 1.36 0.088 0.66 0.064 0.069 1.02 1.27 0.063 0.49 0.065 0.045 0.95 1.67 0.089 0.66 0.050 0.075 0.93 1.56 0.084 0.71 0.056 0.051 1.05 1.55 0.071 0.63 0.076 0.056 1.21 

### . ORGAN WEIGHTS (GRAM)

Group 3 (30 mg/kg) FEMALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 351 of 66312-OCT-11 OW-IND - 5

71 72 73 74 75 76 79 80

71 72 73 74 75 76 79 80 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 237.3 1.86 0.016 0.81 0.015 7.69 0.241 190.8 1.77 0.011 0.79 0.023 8.33 0.111 215.3 1.87 0.016 0.77 0.025 10.48 0.090 228.7 2.00 0.013 0.88 0.018 11.31 0.083 210.7 1.89 0.013 0.68 0.023 7.77 0.128 242.4 1.81 0.015 0.80 0.016 10.03 0.139 228.6 1.82 0.013 0.93 0.023 13.97 0.070 247.4 1.75 0.013 0.90 0.020 9.00 0.168

1.37 0.076 0.60 0.053 0.069 0.94 1.27 0.069 0.55 0.054 0.053 0.79 1.53 0.084 0.75 0.063 0.056 1.07 1.61 0.086 0.60 0.056 0.051 0.81 1.40 0.059 0.59 0.052 0.060 1.21 1.62 0.076 0.83 0.068 0.074 1.15 1.66 0.083 0.73 0.079 0.064 1.24 1.46 0.086 0.70 0.072 0.076 1.18 

### . ORGAN WEIGHTS (GRAM)

Group 4 (90 mg/kg) FEMALES ORATORIES STUDY D23451

127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 352 of 66312-OCT-11 OW-IND - 6

41 42 43 44 47 48 49 50

41 42 43 44 47 48 49 50 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 227.9 0.82 0.006 0.31 0.009 3.00 0.084 215.2 0.87 0.005 0.35 0.010 3.39 0.112 233.7 0.80 0.006 0.35 0.009 3.35 0.073 235.5 0.82 0.005 0.33 0.008 3.30 0.074 223.1 0.85 0.008 0.33 0.013 3.38 0.086 248.2 0.72 0.005 0.31 0.008 3.04 0.065 241.1 0.73 0.005 0.34 0.006 3.21 0.093 230.9 0.79 0.007 0.30 0.009 3.19 0.067

0.59 0.035 0.32 0.025 0.022 0.47 0.64 0.039 0.37 0.023 0.030 0.52 0.62 0.038 0.27 0.021 0.030 0.49 0.61 0.040 0.33 0.021 0.026 0.42 0.66 0.030 0.32 0.031 0.030 0.56 0.56 0.031 0.24 0.025 0.021 0.41 0.61 0.035 0.32 0.021 0.027 0.44 0.58 0.036 0.30 0.026 0.028 0.44 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 1 (0 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 353 of 66312-OCT-11 OW-IND - 7

52 53 54 55 56 57 58 60

52 53 54 55 56 57 58 60 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 225.0 0.82 0.006 0.39 0.010 3.46 0.080 220.1 0.80 0.005 0.36 0.008 3.26 0.075 221.9 0.84 0.006 0.34 0.009 3.03 0.078 223.1 0.84 0.007 0.35 0.011 3.36 0.104 226.6 0.85 0.007 0.32 0.008 3.27 0.087 229.2 0.82 0.007 0.34 0.010 3.21 0.073 221.4 0.84 0.006 0.34 0.008 3.44 0.045 218.1 0.76 0.005 0.34 0.008 3.09 0.094

0.65 0.035 0.29 0.030 0.017 0.45 0.55 0.031 0.34 0.021 0.029 0.56 0.58 0.040 0.35 0.024 0.032 0.47 0.61 0.037 0.28 0.029 0.030 0.54 0.56 0.041 0.25 0.029 0.029 0.47 0.60 0.038 0.26 0.028 0.032 0.54 0.67 0.033 0.27 0.027 0.029 0.47 0.56 0.030 0.26 0.028 0.029 0.46 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 2 (10 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 354 of 66312-OCT-11 OW-IND - 8

61 62 63 64 65 66 67 68 69 70

61 62 63 64 65 66 67 68 69 70 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 223.0 0.78 0.005 0.32 0.008 3.49 0.076 225.6 0.88 0.007 0.35 0.014 3.73 0.079 222.8 0.80 0.007 0.36 0.010 3.58 0.063 223.6 0.80 0.005 0.32 0.008 3.43 0.088 230.4 0.78 0.007 0.33 0.008 3.09 0.069 216.8 0.85 0.006 0.36 0.010 3.57 0.103 200.0 0.86 0.006 0.32 0.008 3.29 0.051 245.9 0.74 0.006 0.35 0.008 3.25 0.075 219.6 0.85 0.005 0.35 0.009 3.49 0.108 231.1 0.77 0.007 0.32 0.011 4.08 0.060

0.58 0.032 0.27 0.032 0.020 0.46 0.60 0.039 0.33 0.025 0.031 0.42 0.59 0.034 0.29 0.024 0.028 0.48 0.61 0.035 0.28 0.024 0.021 0.51 0.59 0.037 0.25 0.024 0.025 0.43 0.63 0.041 0.30 0.030 0.032 0.47 0.64 0.032 0.25 0.033 0.023 0.48 0.68 0.036 0.27 0.020 0.031 0.38 0.71 0.038 0.32 0.026 0.023 0.48 0.67 0.031 0.27 0.033 0.024 0.52 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 3 (30 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 355 of 66312-OCT-11 OW-IND - 9

71 72 73 74 75 76 79 80

71 72 73 74 75 76 79 80 Animal

Animal BODY W. BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 237.3 0.78 0.007 0.34 0.006 3.24 0.102 190.8 0.93 0.006 0.41 0.012 4.37 0.058 215.3 0.87 0.007 0.36 0.012 4.87 0.042 228.7 0.87 0.006 0.38 0.008 4.95 0.036 210.7 0.90 0.006 0.32 0.011 3.69 0.061 242.4 0.75 0.006 0.33 0.007 4.14 0.057 228.6 0.80 0.006 0.41 0.010 6.11 0.031 247.4 0.71 0.005 0.36 0.008 3.64 0.068

0.58 0.032 0.25 0.022 0.029 0.40 0.67 0.036 0.29 0.028 0.028 0.41 0.71 0.039 0.35 0.029 0.026 0.50 0.70 0.038 0.26 0.024 0.022 0.35 0.66 0.028 0.28 0.025 0.028 0.57 0.67 0.031 0.34 0.028 0.031 0.47 0.73 0.036 0.32 0.035 0.028 0.54 0.59 0.035 0.28 0.029 0.031 0.48 

### . ORGAN/BODY WEIGHT RATIOS (%)

Group 4 (90 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 356 of 66312-OCT-11 OW-IND - 10

41 42 43 44 47 48 49 50

41 42 43 44 47 48 49 50 Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 1.87 0.749 37.97 1.070 365.24 10.267 1.88 0.585 40.43 1.170 387.77 12.819 1.87 0.802 43.32 1.176 419.25 9.144 1.93 0.622 40.41 0.933 402.07 9.016 1.89 0.899 39.15 1.481 398.94 10.159 1.78 0.730 43.26 1.180 423.60 9.101 1.76 0.739 47.16 0.852 439.20 12.784 1.82 0.879 38.46 1.154 404.95 8.516

72.19 4.278 39.04 2.995 2.674 57.22 73.40 4.415 42.02 2.606 3.404 59.57 78.07 4.759 33.69 2.674 3.743 60.96 74.09 4.922 39.90 2.591 3.212 51.30 77.78 3.598 37.57 3.704 3.545 66.67 77.53 4.382 33.71 3.539 2.978 57.87 83.52 4.773 44.32 2.898 3.750 59.66 74.18 4.505 37.91 3.352 3.571 55.49 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 1 (0 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 357 of 66312-OCT-11 OW-IND - 11

52 53 54 55 56 57 58 60

52 53 54 55 56 57 58 60 Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 1.85 0.703 47.03 1.243 420.54 9.784 1.75 0.686 45.14 0.971 410.29 9.429 1.87 0.749 40.11 1.123 359.36 9.251 1.87 0.856 41.71 1.283 400.53 12.406 1.92 0.833 37.50 0.990 385.42 10.313 1.87 0.856 41.71 1.230 393.05 8.930 1.85 0.703 41.08 0.919 411.35 5.405 1.66 0.663 45.18 1.084 405.42 12.410

78.92 4.270 35.68 3.676 2.108 54.59 69.71 3.886 42.29 2.629 3.657 70.86 68.45 4.759 41.18 2.888 3.850 55.61 73.26 4.439 33.69 3.422 3.583 64.71 66.67 4.844 29.17 3.385 3.385 55.73 73.80 4.599 32.09 3.476 3.904 65.78 80.54 3.946 31.89 3.243 3.459 56.76 73.49 3.976 33.73 3.614 3.795 60.84 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 2 (10 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 358 of 66312-OCT-11 OW-IND - 12

61 62 63 64 65 66 67 68 69 70

61 62 63 64 65 66 67 68 69 70 Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 1.73 0.636 41.04 0.983 449.71 9.827 1.99 0.754 39.20 1.558 422.61 8.995 1.78 0.899 44.94 1.236 447.75 7.921 1.78 0.674 40.45 1.011 430.34 11.011 1.79 0.894 41.90 1.006 398.32 8.883 1.85 0.757 41.62 1.135 418.92 12.108 1.71 0.643 37.43 0.936 384.21 5.965 1.81 0.773 47.51 1.050 441.99 10.166 1.86 0.591 41.40 1.075 411.83 12.742 1.79 0.894 40.78 1.453 526.82 7.765

75.14 4.104 35.26 4.104 2.601 59.54 67.84 4.422 37.19 2.814 3.467 47.74 73.60 4.213 35.96 2.978 3.539 60.67 76.97 4.382 34.83 3.034 2.697 64.61 76.54 4.749 31.84 3.073 3.184 54.75 73.51 4.757 35.68 3.459 3.730 55.14 74.27 3.684 28.65 3.801 2.632 55.56 92.27 4.917 36.46 2.762 4.144 51.38 83.87 4.516 38.17 3.011 2.742 56.45 86.59 3.966 35.20 4.246 3.128 67.60 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 3 (30 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 359 of 66312-OCT-11 OW-IND - 13

71 72 73 74 75 76 79 80

71 72 73 74 75 76 79 80 Animal

Animal BRAIN PITUITARY HEART THYROIDS LIVER THYMUS

KIDNEYS ADRENALS SPLEEN OVARIES(L) OVARIES(R) UTERUS 1.86 0.860 43.55 0.806 413.44 12.957 1.77 0.621 44.63 1.299 470.62 6.271 1.87 0.856 41.18 1.337 560.43 4.813 2.00 0.650 44.00 0.900 565.50 4.150 1.89 0.688 35.98 1.217 411.11 6.772 1.81 0.829 44.20 0.884 554.14 7.680 1.82 0.714 51.10 1.264 767.58 3.846 1.75 0.743 51.43 1.143 514.29 9.600

73.66 4.086 32.26 2.849 3.710 50.54 71.75 3.898 31.07 3.051 2.994 44.63 81.82 4.492 40.11 3.369 2.995 57.22 80.50 4.300 30.00 2.800 2.550 40.50 74.07 3.122 31.22 2.751 3.175 64.02 89.50 4.199 45.86 3.757 4.088 63.54 91.21 4.560 40.11 4.341 3.516 68.13 83.43 4.914 40.00 4.114 4.343 67.43 

### . ORGAN/BRAIN WEIGHT RATIOS (%)

Group 4 (90 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) (%) (%) ORATORIES STUDY D23451 127 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1a 

## Page 360 of 663MAC-IND - 1 04-OCT-11 ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

Animals without necropsy

---

Animals not recorded

---

Animals not completed

---

Animals with not translated finding

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 361 of 663MAC-IND - 2 04-OCT-11



### Group 1 (0 mg/kg)

1

2

3

4

5

6

7

8

9 CONTENTS:, BLACK.

FOCUS/FOCI, ISOLATED, D=1 MM, REDDISH.

FOCUS/FOCI, ISOLATED, D=1 MM, DARK RED. DISCOLORATION, DARK RED.

FOCUS/FOCI, ISOLATED, D=1 MM, DARK RED.

FOCUS/FOCI, SEVERAL, D=1 MM, DARK RED. 

### MALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011 STOMACH

NO FINDINGS NOTED

MANDIBULAR L.NODE

NO FINDINGS NOTED

THYMUS
MANDIBULAR L.NODE

THYMUS

NO FINDINGS NOTED

THYMUS

NO FINDINGS NOTED Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 362 of 663MAC-IND - 3 04-OCT-11



### Group 1 (0 mg/kg)

10

FOCUS/FOCI, SEVERAL, D=1 MM, DARK RED. 

### MALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

THYMUS Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 363 of 663MAC-IND - 4 04-OCT-11



### Group 2 (10 mg/kg)

11

12

13

14

15

16

17

18

19

20 FOCUS/FOCI, D=1 MM, MANY, DARK RED.

FOCUS/FOCI, MANY, D=1 MM, DARK RED.

FOCUS/FOCI, MANY, D=1 MM, DARK RED.

FOCUS/FOCI, MANY, D=1 MM, DARK RED. 

### MALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011 NO FINDINGS NOTED

NO FINDINGS NOTED

THYMUS

NO FINDINGS NOTED

NO FINDINGS NOTED

THYMUS

THYMUS

THYMUS

NO FINDINGS NOTED

NO FINDINGS NOTED Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 364 of 663MAC-IND - 5 04-OCT-11



### Group 3 (30 mg/kg)

21

22

23

24

25

26

27

28

29

30 FOCUS/FOCI, MANY, D=1 MM, DARK RED.

FOCUS/FOCI, MANY, D=1 MM, DARK RED.

MUCOSA: DISCOLORATION, DARK RED.

FOCUS/FOCI, MANY, D=1 MM, DARK RED.

MUCOSA: DISCOLORATION, REDDISH. 

### MALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011 NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

THYMUS

THYMUS

NO FINDINGS NOTED

NO FINDINGS NOTED

ILEUM

THYMUS

ILEUM Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 365 of 663MAC-IND - 6 04-OCT-11



### Group 4 (90 mg/kg)

31

32

33

34

35

36

37

38

39

40 FOCUS/FOCI, ISOLATED, D=1 MM, DARK RED.

CONTENTS BLACK-BROWN. 

### MALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

KILLED IN EXTR. , 19-AUG-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011

PLANNED NECROPSY (AFTER TREATMENT) , 08-SEP-2011 THYMUS

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

STOMACH

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1c 

## Page 366 of 663MAC-IND - 1 04-NOV-11 ORATORIES STUDY D23451 127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

Animals without necropsy

---

Animals not recorded

---

Animals not completed

---

Animals with not translated finding

---

Not Reported

--- 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 367 of 663MAC-IND - 2 04-NOV-11



### Group 1 (0 mg/kg)

41

42

43

44

45

46

47

48

49

50 PYLORUS, MUCOSA: DISCOLORATION, YELLOWISH. 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 24-SEP-2011

PLANNED NECROPSY (.) , 19-SEP-2011

PLANNED NECROPSY (.) , 22-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011 NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

STOMACH

NO FINDINGS NOTED

NO FINDINGS NOTED Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 368 of 663MAC-IND - 3 04-NOV-11



### Group 2 (10 mg/kg)

51

52

53

54

55

56

57

58

59 PYLORUS, MUCOSA: DISCOLORATION, YELLOWISH.

REDUCED IN SIZE.

RIGHT HORN: DILATION, D=6 MM. RIGHT HORN: CONTAINS FLUID, BLUISH. CERVIX: CONTAINS FLUID, BLUISH. LEFT HORN: CONTAINS FETUS. 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 22-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 20-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 19-SEP-2011 NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

NO FINDINGS NOTED

STOMACH

NO FINDINGS NOTED

NO FINDINGS NOTED

THYMUS

UTERUS Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 369 of 663MAC-IND - 4 04-NOV-11



### Group 2 (10 mg/kg)

60 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 22-SEP-2011

NO FINDINGS NOTED Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 370 of 663MAC-IND - 5 04-NOV-11



### Group 3 (30 mg/kg)

61

62

63

64

65

66

67

68

69 MUCOSA: DISCOLORATION, GRAY WHITE.

MUCOSA, FORESTOMACH: CRATERIFORM RETRACTION, D=2 MM.
REDUCED IN SIZE.

REDUCED IN SIZE.

REDUCED IN SIZE.

BOTH HORNS: DISCOLORATION, DARK RED. 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 24-SEP-2011

PLANNED NECROPSY (.) , 25-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

PLANNED NECROPSY (.) , 22-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 20-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011 NO FINDINGS NOTED

STOMACH

STOMACH
THYMUS

NO FINDINGS NOTED

THYMUS

NO FINDINGS NOTED

THYMUS

NO FINDINGS NOTED

UTERUS Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 371 of 663MAC-IND - 6 04-NOV-11



### Group 3 (30 mg/kg)

70 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 01-OCT-2011

NO FINDINGS NOTED Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 372 of 663MAC-IND - 7 04-NOV-11



### Group 4 (90 mg/kg)

71

72

73

74

75

76

77

78

79 REDUCED IN SIZE.

REDUCED IN SIZE.

REDUCED IN SIZE.

BOTH SIDES: DISCOLORATION, REDDISH.

BEGINNING AUTOLYSIS.
ENLARGED. NODULE(S), D=10X5 MM, RED BROWN, FIRM. DISCOLORATION, DARK RED.

REDUCED IN SIZE. 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 22-SEP-2011

PLANNED NECROPSY (.) , 22-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

PLANNED NECROPSY (.) , 25-SEP-2011

PLANNED NECROPSY (.) , 23-SEP-2011

PLANNED NECROPSY (.) , 21-SEP-2011

SPONTAN. DEATH , 26-AUG-2011

PLANNED NECROPSY (.) , 23-SEP-2011 NO FINDINGS NOTED

THYMUS

THYMUS

THYMUS

NO FINDINGS NOTED

NO FINDINGS NOTED

OVARIES

GENERAL OBSERVATIONS
STOMACH
JEJUNUM
THYMUS

THYMUS Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 373 of 663MAC-IND - 8 04-NOV-11



### Group 4 (90 mg/kg)

80 

### FEMALES ORATORIES STUDY D23451

127



### MACROSCOPICAL FINDINGS ALL NECROPSIES

PLANNED NECROPSY (.) , 23-SEP-2011

NO FINDINGS NOTED Animal 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2ce1e 

## Page 374 of 663

# Data of F1 Pups Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a8148e 

## Page 375 of 663

### H ORATORIES BW-LIT - 1 IRGACURE 127 06-OCT-11



## MEAN BODY WEIGHTS OF PUPS PER LITTER (GRAM)
GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 41 M -- 6.9 10.6 F -- 6.4 10.2 M+F -- 6.8 10.5

42 M -- 6.3 9.8 F -- 6.8 10.4 M+F -- 6.5 10.1

43 M -- 7.2 10.3 F -- 6.9 10.1 M+F -- 7.1 10.2

44 M -- 7.1 11.4 F -- 7.1 11.6 M+F -- 7.1 11.5

47 M -- 5.8 8.5 F -- 5.5 8.2 M+F -- 5.7 8.4

48 M -- 6.0 9.4 F -- 5.9 9.2 M+F -- 5.9 9.2

49 M -- 5.8 8.3 F -- 5.5 8.1 M+F -- 5.6 8.2

50 M -- 6.0 8.6 F -- 5.7 8.5 M+F -- 5.8 8.5

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81540 

## Page 376 of 663

### H ORATORIES BW-LIT - 2 IRGACURE 127 06-OCT-11



## MEAN BODY WEIGHTS OF PUPS PER LITTER (GRAM)
GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 52 M -- 6.9 10.5 F -- 6.4 9.9 M+F -- 6.6 10.2

53 M -- 6.5 9.5 F -- 6.2 9.1 M+F -- 6.3 9.3

54 M -- 5.6 8.1 F -- 5.4 8.1 M+F -- 5.5 8.1

55 M -- 6.0 8.8 F -- 5.5 8.2 M+F -- 5.8 8.5

56 M -- 5.3 7.8 F -- 5.1 7.4 M+F -- 5.2 7.5

57 M -- 5.6 7.5 F -- 5.2 7.0 M+F -- 5.5 7.3

58 M -- 5.7 8.3 F -- 5.3 7.8 M+F -- 5.5 8.0

60 M -- 5.9 9.0 F -- 5.2 7.8 M+F -- 5.4 8.1

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 377 of 663

### H ORATORIES BW-LIT - 3 IRGACURE 127 06-OCT-11



## MEAN BODY WEIGHTS OF PUPS PER LITTER (GRAM)
GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 61 M -- 5.8 8.7 F -- 5.5 8.6 M+F -- 5.6 8.6

62 M -- 6.2 9.5 F -- 5.8 9.2 M+F -- 6.0 9.4

63 M -- 5.0 6.3 F -- 4.9 6.4 M+F -- 4.9 6.4

64 M -- 6.6 9.7 F -- 6.5 9.5 M+F -- 6.6 9.7

65 M -- 7.7 11.6 F -- 6.6 10.7 M+F -- 7.1 11.0

66 M -- 5.4 7.9 F -- 5.0 7.6 M+F -- 5.2 7.8

67 M -- 5.0 5.1 F -- 4.6 4.7 M+F -- 4.8 4.9

68 M -- 6.2 9.6 F -- 5.5 8.5 M+F -- 5.9 9.2

69 M -- 6.6 9.9 F -- 6.6 9.9 M+F -- 6.6 9.9

70 M -- 6.2 8.8 F -- 5.8 8.3 M+F -- 5.9 8.5

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81540 

## Page 378 of 663

### H ORATORIES BW-LIT - 4 IRGACURE 127 06-OCT-11



## MEAN BODY WEIGHTS OF PUPS PER LITTER (GRAM)
GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 71 M 7.4 8.2 12.5 F 7.2 7.6 12.7 M+F 7.2 7.7 12.7

72 M -- 5.2 6.3 F -- 4.8 6.0 M+F -- 5.0 6.2

73 M -- 6.0 7.8 F -- 5.7 7.5 M+F -- 5.8 7.6

74 M -- 6.1 7.5 F -- 5.8 7.1 M+F -- 6.0 7.4

75 M -- 5.9 8.3 F -- 5.9 8.4 M+F -- 5.9 8.3

76 M -- 5.9 9.1 F -- 5.6 8.5 M+F -- 5.7 8.7

79 M -- 5.1 6.3 F -- 5.2 6.6 M+F -- 5.2 6.4

80 M -- 5.8 7.8 F -- 5.3 7.0 M+F -- 5.6 7.5

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81540 

## Page 379 of 663

### H ORATORIES BW-IND - 1 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 41 1 M -- 7.0 11.1 2 M -- 6.7 10.3 3 M -- 6.9 10.7 4 M -- 6.9 10.2 5 M -- 6.6 10.3 6 M -- 7.3 10.7 7 M -- 6.8 10.7 8 M -- 7.1 10.7 9 F -- 6.4 9.9 10 F -- 6.6 10.8 11 F -- 6.3 9.9

42 1 M -- 7.0 10.6 2 M -- 7.7 11.6 3 M -- 5.1 8.3 4 M -- 5.2 8.3 5 M -- 6.6 10.5 6 F -- 7.0 9.9 7 F -- 6.3 11.3 8 F -- 6.9 9.8 9 F -- 6.8 10.7

43 1 M -- 6.9 10.1 2 M -- 6.9 10.5 3 M -- 7.6 10.5 4 M -- 7.6 10.6 5 M -- 7.0 9.8 6 M -- 7.4 10.5 7 M -- 7.1 10.4 8 F -- 7.0 10.4 9 F -- 7.4 10.5 10 F -- 6.8 10.0 11 F -- 6.7 10.0 12 F -- 6.9 9.6 13 F -- 6.9 10.1

44 1 M -- 7.6 11.6 2 M -- 7.3 11.7 3 M -- 7.0 11.4 4 M -- 7.0 11.4 5 M -- 7.0 11.3 6 M -- 6.7 11.0 7 F -- 7.0 11.2 8 F -- 6.9 11.6 9 F -- 7.5 11.9 10 F -- 6.9 11.6

47 1 M -- 6.2 9.2 2 M -- 5.9 8.3 3 M -- 5.5 8.0 4 M -- 5.7 8.6 5 M -- 5.9 8.7 6 M -- 5.9 8.7 7 M -- 5.7 8.2 8 F -- 5.9 8.8 9 F -- 5.4 7.8 10 F -- 5.7 8.5 11 F -- 5.4 7.9 12 F -- 5.4 8.0 13 F -- 5.2 8.0

48 1 M -- 5.8 9.0 2 M -- 6.3 9.5 3 M -- 6.0 9.5 4 F -- 5.2 8.3 5 F -- 6.0 9.3

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 380 of 663

### H ORATORIES BW-IND - 2 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 48 6 F -- 5.8 9.0 7 F -- 6.0 9.4 8 F -- 6.4 9.9 9 F -- 5.9 8.9 10 F -- 6.0 9.4 11 F -- 6.1 9.3 12 F -- 5.6 9.1

49 1 M -- 5.9 8.7 2 M -- 5.5 8.2 3 M -- 5.8 8.5 4 M -- 6.1 8.4 5 M -- 5.8 8.0 6 M -- 5.6 8.2 7 F -- 5.7 8.5 8 F -- 5.8 8.8 9 F -- 5.5 7.9 10 F -- 5.4 8.0 11 F -- 5.4 8.0 12 F -- 4.9 7.3 13 F -- 5.8 8.2 14 F -- 5.3 7.9

50 1 M -- 6.0 8.8 2 M -- 6.0 8.5 3 M -- 5.7 8.5 4 M -- 6.2 8.8 5 F -- 5.7 8.4 6 F -- 5.7 8.3 7 F -- 6.0 8.5 8 F -- 5.8 8.3 9 F -- 5.6 8.6 10 F -- 5.9 8.6 11 F -- 6.0 9.0 12 F -- 5.8 8.6 13 F -- 5.2 7.8

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 381 of 663

### H ORATORIES BW-IND - 3 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 52 1 M -- 6.6 10.5 2 M -- 7.3 11.3 3 M -- 6.1 9.4 4 M -- 7.1 10.7 5 M -- 7.2 10.5 6 F -- 6.1 9.4 7 F -- 6.3 9.8 8 F -- 6.8 10.4 9 F -- 6.5 10.0 10 F -- 6.2 9.5 11 F -- 6.8 10.5

53 1 M -- 6.7 9.7 2 M -- 6.6 9.4 3 M -- 6.4 9.5 4 M -- 6.5 9.6 5 M -- 6.7 9.6 6 M -- 6.2 9.2 7 F -- 6.4 9.5 8 F -- 5.9 8.6 9 F -- 6.1 8.7 10 F -- 6.2 9.3 11 F -- 6.6 9.6 12 F -- 6.0 8.7

54 1 M -- 6.0 8.9 2 M -- 5.7 8.3 3 M -- 4.6 6.4 4 M -- 6.1 9.0 5 F -- 5.7 8.6 6 F -- 5.2 7.6 7 F -- 5.5 8.4 8 F -- 6.0 8.6 9 F -- 5.2 7.4 10 F -- 5.5 8.0 11 F -- 5.1 7.6 12 F -- 5.8 8.8 13 F -- 5.3 8.1 14 F -- 5.2 8.2

55 1 M -- 6.2 9.0 2 M -- 5.9 8.7 3 M -- 5.7 8.5 4 M -- 5.7 8.3 5 M -- 6.0 8.8 6 M -- 6.0 9.1 7 M -- 6.1 8.9 8 F -- 5.4 8.1 9 F -- 5.4 7.8 10 F -- 5.7 8.7 11 F -- 5.7 8.5 12 F -- 5.3 8.1

56 1 M -- 4.4 6.9 2 M -- 5.7 8.3 3 M -- 5.2 7.7 4 M -- 5.9 8.3 5 M -- 5.9 8.1 6 M -- 5.0 7.3 7 F -- 5.0 7.4 8 F -- 5.3 7.5 9 F -- 5.2 7.5 10 F -- 5.1 7.6 11 F -- 5.0 7.7 12 F -- 5.4 7.7 13 F -- 5.2 --

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 382 of 663

### H ORATORIES BW-IND - 4 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 56 14 F -- 4.9 7.2 15 F -- 4.5 6.4

57 1 M -- 5.7 7.7 2 M -- 5.3 7.1 3 M -- 5.8 7.9 4 M -- 5.7 7.8 5 M -- 5.4 7.4 6 M -- 5.8 7.5 7 M -- 5.5 7.5 8 M -- 5.8 7.8 9 M -- 5.3 7.0 10 M -- 5.5 7.4 11 F -- 5.4 7.6 12 F -- 5.2 7.0 13 F -- 5.6 7.6 14 F -- 4.9 6.1 15 F -- 5.0 6.6

58 1 M -- 5.8 8.5 2 M -- 5.8 8.4 3 M -- 6.0 8.4 4 M -- 5.8 8.5 5 M -- 5.5 7.8 6 M -- 5.7 8.1 7 M -- 5.7 8.3 8 F -- 5.5 8.4 9 F -- 5.0 7.7 10 F -- 5.6 8.0 11 F -- 5.3 7.7 12 F -- 4.7 6.9 13 F -- 5.5 8.1 14 F -- 5.1 7.6

60 1 M -- 5.7 9.1 2 M -- 6.0 8.5 3 M -- 6.0 9.4 4 F -- 5.2 8.1 5 F -- 4.7 6.6 6 F -- 5.2 7.8 7 F -- 5.4 8.5 8 F -- 5.7 8.4 9 F -- 5.4 8.1 10 F -- 5.4 8.2 11 F -- 5.4 7.8 12 F -- 4.8 6.8

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 383 of 663

### H ORATORIES BW-IND - 5 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 61 1 M -- 6.2 9.2 2 M -- 5.7 8.5 3 M -- 6.2 9.0 4 M -- 5.5 8.5 5 M -- 5.5 9.0 6 M -- 5.6 7.9 7 F -- 5.3 8.2 8 F -- 5.0 7.6 9 F -- 5.4 8.7 10 F -- 5.6 8.7 11 F -- 5.6 8.7 12 F -- 6.2 9.4 13 F -- 5.6 8.3 14 F -- 5.6 8.8

62 1 M -- 6.1 9.5 2 M -- 6.3 9.7 3 M -- 5.8 8.7 4 M -- 6.3 9.7 5 M -- 6.6 9.7 6 M -- 6.3 10.1 7 M -- 6.2 9.6 8 F -- 5.7 9.0 9 F -- 5.6 9.1 10 F -- 6.0 9.0 11 F -- 6.0 9.4 12 F -- 6.2 9.6 13 F -- 5.5 8.8

63 1 M -- 5.2 6.6 2 M -- 5.0 6.6 3 M -- 5.1 5.7 4 M -- 5.6 7.3 5 M -- 4.3 4.3 6 M -- 4.9 6.7 7 M -- 5.2 7.1 8 M -- 5.2 6.9 9 M -- 4.5 5.8 10 F -- 5.0 6.1 11 F -- 5.2 7.1 12 F -- 4.3 5.6 13 F -- 5.0 6.3 14 F -- 5.2 7.2 15 F -- 5.0 6.4 16 F -- 4.8 6.1 17 F -- 4.6 6.5

64 1 M -- 6.5 9.7 2 M -- 6.7 9.7 3 M -- 6.8 9.7 4 M -- 6.7 9.8 5 M -- 6.8 10.3 6 M -- 6.7 9.7 7 M -- 6.5 9.4 8 M -- 6.5 9.6 9 F -- 6.5 9.6 10 F -- 6.8 9.3 11 F -- 6.7 10.0 12 F -- 6.3 9.3 13 F -- 6.3 9.6

65 1 M -- 8.2 12.2 2 M -- 7.8 11.8 3 M -- 7.3 11.2 4 M -- 7.6 10.9 5 F -- 6.7 10.5

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 384 of 663

### H ORATORIES BW-IND - 6 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 65 6 F -- 6.7 10.8 7 F -- 6.8 10.9 8 F -- 7.0 11.1 9 F -- 6.6 10.3 10 F -- 6.2 10.3

66 1 M -- 5.3 7.8 2 M -- 5.6 8.4 3 M -- 5.6 8.3 4 M -- 5.7 7.8 5 M -- 4.9 7.2 6 M -- 5.5 8.1 7 M -- 4.9 7.5 8 M -- 5.0 7.6 9 M -- 5.8 8.2 10 F -- 5.2 7.8 11 F -- 5.1 7.8 12 F -- 5.1 7.8 13 F -- 4.6 7.1

67 1 M -- 4.9 5.1 2 M -- 5.1 5.1 3 M -- 5.1 5.2 4 M -- 4.9 5.0 5 M -- 5.0 4.8 6 F -- 4.5 4.6 7 F -- 4.5 4.5 8 F -- 4.5 5.0 9 F -- 4.5 4.4 10 F -- 4.7 4.9 11 F -- 4.8 4.1 12 F -- 4.7 5.6

68 1 M -- 5.9 9.7 2 M -- 6.4 9.9 3 M -- 5.0 8.1 4 M -- 6.1 9.6 5 M -- 6.8 10.3 6 M -- 6.2 9.3 7 M -- 6.4 10.0 8 M -- 6.4 9.9 9 F -- 5.9 9.3 10 F -- 5.7 8.8 11 F -- 5.9 9.3 12 F -- 4.6 6.6

69 1 M -- 6.4 9.3 2 M -- 6.0 9.4 3 M -- 7.4 11.5 4 M -- 5.8 8.8 5 M -- 7.7 11.1 6 M -- 6.5 9.6 7 F -- 6.5 10.1 8 F -- 6.5 9.8 9 F -- 6.6 10.0 10 F -- 6.8 9.9

70 1 M -- 6.3 8.7 2 M -- 6.4 8.9 3 M -- 6.1 8.5 4 M -- 6.6 9.5 5 M -- 5.8 8.6 6 M -- -- -- 7 F -- 5.7 8.2 8 F -- 5.8 8.2 9 F -- 5.7 8.3

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 385 of 663

### H ORATORIES BW-IND - 7 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 70 10 F -- 6.2 8.6 11 F -- 5.6 8.0 12 F -- 5.9 8.6 13 F -- 5.7 8.3 14 F -- 5.5 8.0

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 386 of 663

### H ORATORIES BW-IND - 8 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 71 1 M 7.4 8.2 12.5 2 F 7.0 8.4 14.0 3 F 6.9 7.5 11.9 4 F 7.4 6.9 11.5 5 F 7.1 7.4 12.9 6 F 7.7 8.1 13.7 7 F 7.0 7.4 12.2

72 1 M -- 5.6 6.3 2 M -- 5.5 6.4 3 M -- 4.6 -- 4 F -- 5.2 6.3 5 F -- 4.8 5.6 6 F -- 4.5 -- 7 F -- 4.7 -- 8 F -- -- --

73 1 M -- 6.1 8.1 2 M -- 5.3 6.8 3 M -- 6.2 8.3 4 M -- 6.0 8.2 5 M -- 6.3 7.4 6 F -- 5.6 7.1 7 F -- 6.0 7.8 8 F -- 5.2 7.1 9 F -- 5.4 7.3 10 F -- 5.3 7.0 11 F -- 5.9 7.9 12 F -- 5.8 7.9 13 F -- 5.8 7.5 14 F -- 6.0 7.7

74 1 M -- 6.0 7.3 2 M -- 6.1 7.7 3 M -- 6.5 7.9 4 M -- 6.7 8.1 5 M -- 6.3 8.1 6 M -- 5.8 6.7 7 M -- 6.0 7.0 8 M -- 5.3 -- 9 F -- 5.8 7.1 10 F -- 6.1 6.5 11 F -- 5.7 7.5 12 F -- 5.6 7.3

75 1 M -- 5.5 7.1 2 M -- 6.2 8.9 3 M -- 5.4 8.2 4 M -- 6.2 9.0 5 M -- 5.8 8.3 6 M -- 6.5 8.5 7 M -- 5.4 8.1 8 M -- 6.1 8.5 9 F -- 5.6 8.5 10 F -- 6.2 8.5 11 F -- 6.1 8.3 12 F -- 5.0 8.1 13 F -- 5.7 8.7 14 F -- 6.5 8.1

76 1 M -- 5.8 8.7 2 M -- 5.6 8.7 3 M -- 6.0 9.1 4 M -- 6.2 9.6 5 M -- 5.9 9.2 6 F -- 5.2 7.9

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81543 

## Page 387 of 663

### H ORATORIES BW-IND - 9 IRGACURE 127 06-OCT-11



## BODY WEIGHTS OF PUPS (GRAM)
GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP SEX DAY 0 DAY 1 DAY 4

____________________________________________________________________________________________________ 76 7 F -- 6.0 8.9 8 F -- 5.6 8.3 9 F -- 5.8 8.1 10 F -- 5.7 8.8 11 F -- 5.6 8.9 12 F -- 5.9 9.0 13 F -- 4.9 7.9

79 1 M -- 5.4 6.2 2 M -- 4.6 6.1 3 M -- 5.2 6.3 4 M -- 5.3 -- 5 M -- 5.3 6.7 6 M -- 5.0 -- 7 F -- 4.8 7.1 8 F -- 5.1 6.4 9 F -- 5.7 6.3

80 1 M -- 5.6 7.6 2 M -- 6.1 8.3 3 M -- 6.2 8.6 4 M -- 5.7 7.5 5 M -- 5.7 7.4 6 M -- 5.7 7.2 7 M -- 6.5 8.8 8 M -- 5.6 7.7 9 M -- 5.3 7.0 10 F -- 5.5 7.2 11 F -- 5.4 -- 12 F -- 5.5 7.4 13 F -- 5.4 7.0 14 F -- 4.7 6.7 15 F -- 5.4 7.0

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 388 of 663

### H ORATORIES PUP-IND - 1 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 41 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 42 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 43 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 389 of 663

### H ORATORIES PUP-IND - 2 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 43 2 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 44 1 M DAY 5 Planned necropsy FLC No Findings 19-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 390 of 663

### H ORATORIES PUP-IND - 3 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 44 10 F DAY 5 Planned necropsy FLC No Findings 19-SEP-11 LLC No Findings MACRO No Findings LITTER 47 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 48 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 391 of 663

### H ORATORIES PUP-IND - 4 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 48 8 F DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 49 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 50 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 392 of 663

### H ORATORIES PUP-IND - 5 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 1 (0 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 50 3 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 393 of 663

### H ORATORIES PUP-IND - 6 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 52 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 53 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 394 of 663

### H ORATORIES PUP-IND - 7 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 53 11 F DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 54 1 M DAY 5 Planned necropsy FLC No Findings 15-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 55 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 395 of 663

### H ORATORIES PUP-IND - 8 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 55 6 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 56 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 2 Missing FLC No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 15 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 396 of 663

### H ORATORIES PUP-IND - 9 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 57 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 15 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 58 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 397 of 663

### H ORATORIES PUP-IND - 10 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 2 (10 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 58 7 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 60 1 M DAY 5 Planned necropsy FLC No Findings 17-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 398 of 663

### H ORATORIES PUP-IND - 11 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 61 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 62 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 399 of 663

### H ORATORIES PUP-IND - 12 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 62 8 F DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 63 1 M DAY 5 Planned necropsy FLC No Findings 19-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 15 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 400 of 663

### H ORATORIES PUP-IND - 13 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 63 16 F DAY 5 Planned necropsy FLC No Findings 19-SEP-11 LLC No Findings MACRO No Findings 17 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 64 1 M DAY 5 Planned necropsy FLC No Findings 20-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 65 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 401 of 663

### H ORATORIES PUP-IND - 14 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 65 7 F DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 66 1 M DAY 5 Planned necropsy FLC No Findings 17-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 67 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 402 of 663

### H ORATORIES PUP-IND - 15 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 67 5 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings DAY 4 No Milk in the Stomach LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 68 1 M DAY 5 Planned necropsy FLC No Findings 15-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 403 of 663

### H ORATORIES PUP-IND - 16 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 69 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 70 1 M DAY 5 Planned necropsy FLC No Findings 26-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 1 Dead at FLC FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 404 of 663

### H ORATORIES PUP-IND - 17 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 3 (30 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 70 12 F DAY 5 Planned necropsy FLC No Findings 26-SEP-11 LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 405 of 663

### H ORATORIES PUP-IND - 18 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 71 1 M DAY 5 Planned necropsy FLC No Findings 17-SEP-11 LLC No Findings MACRO No Findings 2 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 72 1 M DAY 5 Planned necropsy FLC No Findings 17-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 4 Missing FLC No Milk in the Stomach 4 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 2 Missing FLC No Findings 7 F DAY 4 Missing FLC No Findings 8 F DAY 1 Dead at FLC FLC No Findings LLC No Findings MACRO No Findings LITTER 73 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 406 of 663

### H ORATORIES PUP-IND - 19 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 73 9 F DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 74 1 M DAY 5 Planned necropsy FLC No Findings 16-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 2 Missing FLC No Milk in the Stomach 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 75 1 M DAY 5 Planned necropsy FLC No Findings 20-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b04b6f 

## Page 407 of 663

### H ORATORIES PUP-IND - 20 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 75 4 M DAY 5 Planned necropsy FLC No Findings 20-SEP-11 LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 11 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 76 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 408 of 663

### H ORATORIES PUP-IND - 21 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 76 11 F DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 79 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 4 Missing FLC No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 2 Missing FLC No Milk in the Stomach 7 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings LITTER 80 1 M DAY 5 Planned necropsy FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 2 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 3 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 4 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 5 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 6 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 7 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 8 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 9 M DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 10 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 409 of 663

### H ORATORIES PUP-IND - 22 IRGACURE 127 15-MAR-12



## INDIVIDUAL PUP DATA F1 PUPS GROUP 4 (90 MG/KG)

____________________________________________________________________________________________________ LITTER PUP END OF P.P. PHASE FIRST LITTER CHECK (FLC), CLINICAL SIGNS (DAY P.P.), DELIVERY LAST LITTER CHECK (LLC), MACROSCOPIC FINDINGS (MACRO)

____________________________________________________________________________________________________ LITTER 80 11 F DAY 4 Spontaneous death FLC No Findings 18-SEP-11 LLC No Findings MACRO No Findings 12 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 13 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 14 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings 15 F DAY 5 Planned necropsy FLC No Findings LLC No Findings MACRO No Findings

____________________________________________________________________________________________________



### Harlan Laboratories Study Report
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## Page 410 of 663

# APPENDIX I - CHEMICAL ANALYSIS OF FEED Harlan Laboratories Study Report
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09009e5380a81549 

## Page 411 of 663Dr.-Hell-Str. 6, 24107 Kiel, Germany Fax: +49(0431)1228-498 eMail: zentrale@lufa-itl.de 

### LUFA-ITL GmbH

D-PL-14082-01-00 26.04.2011 20.04.2011 TEKLAD GLOBAL RODENT 2018C - PEL. 10 MM ECKIG Alleinfuttermittel für Mäuse und Ratten Rezeptur 3263 - GLP-Batch: 28/11 Fabr.-Code: 1104013 - Hergestellt: 18.04.11 - MHD: 18.01.12 10.05.2011

1209835

copper Selenium cadmium lead mercury Arsenic

Aflatoxine B1 Aflatoxine B2 Aflatoxine G1 Aflatoxine G2 Sum Aflatoxines

PCB 28 PCB 52 PCB 101 PCB 118 PCB 138 PCB 153 PCB 180 sum PCB

Dieldrin HCH-gamma (Lindan) Heptachlor mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

μg/kg μg/kg μg/kg μg/kg μg/kg

mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg
mg/kg mg/kg mg/kg Substance Sample code Date of sampling Sample acceptance Sample no. 

## TEST REPORT Customer no.

limits acc. GV-SOLAS A-08-2001 Unit Result Method Date

VDLUFA VII 2.2.2.6 VDLUFA VII 2.2.2.5; ICPMS VDLUFA VII 2.2.2.5; ICPMS VDLUFA VII 2.2.2.5; ICPMS §64 LFGB L00.00-19 VDLUFA VII 2.2.2.5; ICPMS

HPLC-VDLUFA Bd. III, 16.1.4 HPLC-VDLUFA Bd. III, 16.1.4 HPLC-VDLUFA Bd. III, 16.1.4 HPLC-VDLUFA Bd. III, 16.1.4 Calculated

§64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 Calculated
§64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 Trace-Elements/Heavy-Metals

Mycotoxins

PCB

Organochlorous-Pesticides GC-Multiresidueanalysis 11,8 <0,10 0,06 <0,10 <0,02 <0,10

<1,00 <1,00 <1,00 <1,00 <1,0

<0,0020 <0,0020 <0,0020 <0,0020 <0,0020 <0,0020 <0,0020 <0,002

<0,002 <0,002 <0,00200 Packaging plastic bag LUFA - ITL Dr.-Hell-Str. 6, 24107 Kiel

0,4 1,5 0,1 1

10 5 5 5

0,05

0,1 a) a) a) 549848

OM OM OM OM OM OM

OM OM OM OM OM

OM OM OM OM OM OM OM OM

OM OM OM 

### Order nr. 832581

GLP Schadstoffuntersuchung Order PROVIMI KLIBA AG RINAUSTRASSE 4303 KAISERAUGST / SCHWEIZ SCHWEIZ

Page 1 of 2 

### Harlan Laboratories Study Report
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09009e5380a815d3 

## Page 412 of 663Dr.-Hell-Str. 6, 24107 Kiel, Germany Fax: +49(0431)1228-498 eMail: zentrale@lufa-itl.de 

### LUFA-ITL GmbH

D-PL-14082-01-00 (HH) Zentrale Analytik - Organische Henkel KGaA, Henkelstrasse 67 ¿ Gebäude Z43, 40589 Düsseldorf

(TG) TIERGESUNDHEITSDIENST, SENATOR-GERAUER STR 23, 85586 POING, Accreditation acc.: ISO/IEC 17025:2005, Accreditation-No.: DAP-PL-2963.00 10.05.2011 1209835

Heptachlorepoxide-cis Heptachlorepoxide-trans o,p-DDD o,p-DDE o,p-DDT p,p-DDD p,p-DDE p,p-DDT Sum DDTs Sum Heptachlor

Malathion

N-Nitrosodiethylamin N-Nitrosodimethylamin Sum Nitrosamines

dienestrol diethyl stilbestrol hexestrol Sum Estrogenes mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg
mg/kg

μg/kg μg/kg μg/kg
μg/kg μg/kg μg/kg μg/kg Substance Customer no. Page 2 of 2

limits acc. GV-SOLAS A-08-2001 Unit Result Method

External laboratory

Methods

Methods Date

§64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 §64 LFGB L00.00-34 Calculated Calculated

§64 LFGB L00.00-34
GC-Inhousemethod(HH) GC-Inhousemethod(HH) Calculated(HH)

no object(TG) no object(TG) no object(TG) Calculated(TG) Organo-Phosphorous Pesticides GC-Multiresidueanalysis

nitrosamines

Estrogenes <0,00200 <0,00200 <0,00200 <0,00200

<0,002 <0,00200 <0,00200 <0,00200 <0,005 <0,005

<0,010

<5,00 <5,00

n.d.

<10,0 <1,00 <2,00

n.d.

PROVIMI KLIBA AG Copies Explanation: OM = on original matter; DM = on dry matter base a) See note 0,05 0,01

1

10 10

This electronically transmitted report was checked and released. It is in accordance with the requirements of DIN EN ISO/IEC 17025:2005 for simplified reports and valid wit hout signature.

The analytical results are only valid for the delivered sample material.The testing period is the time between the receipt of t he sample and the reporting date.A plausib ility check is hardly possible for samples of unknown origin.Duplication of this document or of parts of it r equires the authorization from laboratory. v) Remitted to an accredited laboratory v) v) v) v)

LUFA - ITL Dr. Wehage, Tel. 0431/1228-220 a) a) a) a) a) a) a) a) OM OM OM OM OM OM OM OM OM OM

OM

OM OM OM

OM OM OM OM Order nr. 832581 Sample no. 549848

Calculated

Calculated v) Explanation: "<", n.d.: not detected, below limit of detection 

### Harlan Laboratories Study Report
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## Page 413 of 663

# APPENDIX II - DRINKING WATER ANALYSIS Harlan Laboratories Study Report
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## Page 414 of 663

### Harlan Laboratories Study Report
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## Page 415 of 663

### Harlan Laboratories Study Report
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## Page 416 of 663

### Harlan Laboratories Study Report
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## Page 417 of 663

# APPENDIX III - CERTIFICATE OF ANALYSIS Harlan Laboratories Study Report
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## Page 418 of 663

### Harlan Laboratories Study Report
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## Page 419 of 663

# APPENDIX IV - FORMULATION ANALYSIS Harlan Laboratories Study Report
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## Page 420 of 663

### ratories Study D23451 BESC / SDV Experi mental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 1


# Determination of Content, Homogeneity and Stability of in Application Formulations

CONTENTS

1 MATERIALS AND METHODS...........................................................................................2 1.1 Analytical Standard .................................................................................................2 1.2 Study Samples and Storage .....................................................................................2 1.3 Reagents and Materials............................................................................................2 1.4 Analytical Procedure ...............................................................................................2 1.4.1 Preparation of Standard Solutions.............................................................2 1.4.2 Analysis of Samples ..................................................................................2 1.4.3 High Performance Liquid Chromatographic Determination.....................3 1.4.4 Evaluation of Results.................................................................................3 2 RESULTS AND CONCLUSION..........................................................................................5



# LIST OF TABLES
Table 1 Detailed Results of App lication Formulation Analysis ................................................6



# LIST OF FIGURES
Figure 1 Example of Calibration Curve ......................................................................................7 Figure 2 Typical HPLC-Chromatogr ams of Standard Solutions ................................................8 Figure 3 Typical HPLC-Chromat ograms of Test Samples .........................................................9 Harlan Laboratories Study Report
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### ratories Study D23451 BESC / SDV Experi mental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 2 

# 1 MATERIALS AND METHODS
1.1 Analytical Standard

The test item as described in the main report was used as an alytical standard.



# 1.2 Study Samples and Storage Representative samples were dispatched to the anal ytical laboratories internally (on dry ice) and stored frozen at -20 ± 5 °C until analysis.



# 1.3 Reagents and Materials

Purified water: In-house pr epared by a Milli-Q water purification system (Millipore) Methanol: Baker no. 8402



# 1.4 Analytical Procedure

1.4.1 Preparation of Standard Solutions
Stock solutions of in purified wate r/methanol (20 + 80 v/v) were prepared for external standard calib ration. For example, 20.09 mg of was exactly weighed into a 50 mL volumetric flask and approximately 40 mL of purified water/methanol (20 + 80 v/v) was added. Then, the mixture was sonicated for 5 mi nutes and the flask was brought to volume with purified water/methanol (20 + 80 v/v) to yield a solution with a concentration of 401.8 μg/mL. Aliquots of this stock standard solution were used to prepare working standard solutions in purified water/methanol (20 + 80 v/v) with a concentration range of 10.05 to 100.5 μg/mL. On each occasion standard solutions derived from two stock standard solutions were used for calibration.

1.4.2 Analysis of Samples The samples received were dissolved in purified water/methanol (20 + 80 v/v) by sonication for 5 minutes and then diluted to volume with purified water/methanol (20 + 80 v/v). Where necessary, sample solutions were further diluted with purified water/metha nol (20 + 80 v/v) into the calibration range. Harlan Laboratories Study Report
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### ratories Study D23451 BESC / SDV Ex perimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 3


## 1.4.3 High Performance Liquid Chromatographic Determination Typical Apparatus: Pump: Merck-Hitachi L-7100 Sampling Unit: Merck-Hitachi L-7200 Column Oven: Merck-Hitachi L-7300 UV Detector: Merck-Hitachi L-7400 Interface: Merck-Hitachi D-7000 Column: Inertsil ODS-3 C18; 50 x 4.6 mm, 3 μm Pre-Column: Phenomenex C18; 4 x 3 mm Column Temperature: Ambient Eluent: Purified water/ methanol (35 + 65 v/v) Run Time: 5 min, isocratic Flow: 1.0mL/min Wave Length: 260 nm Injection Volume: 10 μL

1.4.4 Evaluation of Results Injected samples were quantified by comparing p eak areas of with reference to the calibration curve. The latter was obtained by correlation of the peak areas of the working standards with their corresponding concentrations [μg/mL], usi ng the linear regression model following equation 1:

y = a + b

⋅ x (1)
where y = Response of Irgacure 127 a = Intercept derived from linear regression of calibration data b = Slope derived from linear regression of ca libration data
x = Actual concentration of Irgacure 127 in sa mple aliquot [μg/mL] Sample aliquot concentrations were corrected fo r density of the applicat ion formulation and for dilution using equation 2:



## 1000

⋅ ⋅⋅ = W DVx c Actual 

## (2) Harlan Laboratories Study Report
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### ratories Study D23451 BESC / SDV Ex perimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 4


## where

c Actual 

## = Actual sample concentration [ mg/mL ]

x = Actual concentration of in sample aliquot according to equation 1 [ μg/mL ] V = Dilution volume [mL] D = Density of application formulation [ 1.0133 g/mL; density of vehicle as determined at Harlan Laboratories ] W = Sample weight [g] The sample recovery was determined as follows:

100 c c
⋅= Nominal Actual 

## R (3)

where R = Sample recovery [ % ]
c Actual 

## = Actual sample concentration [ mg/mL ]
c Nominal 

## = Nominal sample concentration [ mg/mL ] Harlan Laboratories Study Report
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## Page 424 of 663

### ratories Study D23451 BESC / SDV Experim ental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 5 

# 2 RESULTS AND CONCLUSION
The linearity of the analytical systems used for sample analyses was demonstrated with a good relationship between peak areas measured and wo rking standard concentrations. All calibration points used met the acceptance limit of ±20% va riation from the calibration curve derived by linear regression analysis. The regression coeffici ents calculated were found to be better than 0.99. An example is presented in Figure 1.

The peak was assigned in sample ch romatograms by comparison to that of working standards. In blank sample chromatograms no peak appeared at the retention time of and, therefore, the absence of th e test item in the vehicle control samples [Carboxymethylcellulose 0.5% (Medium Viscosity)] was confirmed. Examples of chromatograms are shown in Figure 2 and Figure 3

. The application formulations investigated durin g the study were found to comprise in the range of 84.4% to 96.1% and, thus, the required content limit of ± 20% with reference to the nominal content was met. The homogeneous di stribution of Irgacure 127 in the preparations was approved because single results found did not deviate more than 6.2% (<15%) from the corresponding mean.

The test item was found to be stable in application formulations when kept two hours at room temperature due to recoveries which met the variation limit of 10% from the time-zero (homogeneity) mean. The first result of 7-day stability formulati on analysis prepared on 11-Aug-2011 exceeded the acceptance criteria in all dose groups, the values deviated more than 10 % of nominal; which might be caused by erroneous sample collection. Respective samples were re-analysed to confirm the correct conduct of analytical work and also analysis of the duplicate samples exceeded the acceptance criteria. Due to these results additional 7-day stability at room temperature analysis was request ed which was performed on 25-A ug-2011 and all values of all dose groups were within the acceptance criteria.
In conclusion, the results indicate the accu rate use of the test item and Carboxymethylcellulose 0.5% (Medium Viscosity) as vehicle during this study. Application formulations were found to be homogeneously prepared and sufficient formulation stability under storage conditions was approved. Detailed results are shown in Table 1

. Harlan Laboratories Study Report
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### ratories Study D23451 BESC / SDV Experimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 6


## Table 1 Detailed Results of A pplication Formulation Analysis (Rounded results presented are based on calculations with exact data)

Dose Group Sample taken from/after Date of Analysis Nominal Concentration [mg/mL] Actual Concentration [mg/mL] Recovery Mean Recovery Coeff. of Variation Variation from Mean Recovery

1 vehicle 19-Aug-11 0.0 0.000 --- --- --- --- top 19-Aug-11 1.0 0.940 94.0% middle 19-Aug-11 1.0 0.961 96.1% bottom 19-Aug-11 1.0 0.853 85.3% 2 hours/RT 19-Aug-11 1.0 0.867 86.7% --- --- 5.5% 19/22-Aug-11 1.0 0.124 12.4% --- --- 86.5%

31-Aug-11 1.0 0.233 23.3% --- --- 74.6% top 19-Aug-11 3.0 2.695 89.8% middle 19-Aug-11 3.0 2.844 94.8% bottom 19-Aug-11 3.0 2.804 93.5% 2 hours/RT 19-Aug-11 3.0 2.913 97.1% --- --- 4.7% 19/22-Aug-11 3.0 1.107 36.9% --- --- 60.2%

31-Aug-11 3.0 1.604 53.5% --- --- 42.3% top 19-Aug-11 9.0 7.810 86.8% middle 19-Aug-11 9.0 7.595 84.4% --- bottom 10-Nov-11 9.0 8.410 93.4% 2 hours/RT 19/22-Aug-11 9.0 7.310 81.2% --- --- 7.9% 19/22-Aug-11 9.0 2.385 26.5% --- --- 70.0%

31-Aug-11 9.0 4.644 51.6% --- --- 41.5% 4
7 days/RT 6.2%

7 days/RT

7 days/RT 3 2.8%

5.3% 88.2% Date of Preparation: 11-Aug-2011

91.8%

92.7% 2 ---

--- 1

1 1 2 1 2

2

2

2 7 days/RT 05-Sep-11 1.0 0.966 96.6% --- --- --- 3 7 days/RT 05-Sep-11 3.0 3.005 100.2% --- --- --- 4 7 days/RT 05-Sep-11 9.0 8.500 94.4% --- --- --- Date of Preparation: 25-Aug-2011

1 vehicle 16-Sep-11 0.0 0.000 --- --- --- --- 2 middle 16-Sep-11 1.0 0.946 94.6% --- --- --- 3 middle 16-Sep-11 3.0 2.858 95.3% --- --- --- 4 middle 16-Sep-11 9.0 8.463 94.0% --- --- --- Date of Preparation: 15-Sep-2011

1 

### overall mean of first and repeated analysis of original sample (n=3) 2 

### mean of backup sample (n=2) Harlan Laboratories Study Report
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## Page 426 of 663

### ratories Study D23451 BESC / SDV Experimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 7 

## Figure 1 Example of Calibration Curve Date of analysis: 19-Aug-2011

Standard Concentration [ μg /mL] Peak Area
[counts] Variation of Peak Area 10.05 2109644 -1.4% 20.09 4128861 -1.0% 40.18 8323097 1.1% 60.27 12444845 1.2% 80.36 16610757 1.5% 100.5 20770805 1.7%

10.34 2105070 -4.2% 20.67 4221214 -1.5% 41.34 8505553 0.5% 62.01 12618522 -0.2% 82.68 16839427 0.1% 103.4 20394996 -3.0%

Calibration Curve by Linear Regression
y = 202227x + 107275 R 2 = 0.9988

0 5000000 10000000 15000000 20000000 25000000

0.0 20 40 60 80 100 120 Concentration [μg/mL]Peak Area [counts] 

### Harlan Laboratories Study Report
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### ratories Study D23451 BESC / SDV Experimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 8 

## Figure 2 Typical HPLC-Chromatogr ams of Standard Solutions (A) Standard solution: 10.05 μg/mL (B) Standard solution: 100.5 μg/mL Date of analysis: 19-Aug-2011 (A)

(B) Harlan Laboratories Study Report
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## Page 428 of 663

### ratories Study D23451 BESC / SDV Experimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 9 

## Figure 3 Typical HPLC-Chromatograms of Test Samples (A) Dose group 1, control sample, 53x diluted (B) Dose group 2 (top), nominal content: 1 mg/mL, 50x diluted Date of analysis: 19-Aug-2011 (A)

(B) Harlan Laboratories Study Report
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## Page 429 of 663

### ratories Study D23451 BESC / SDV Experimental Completion Date: 10-Nov-2011 Sponsor Reference Number
Formulation Analysis Page 10 

## Figure 3 Cont’d (C) Dose group 4 (top), nominal co ntent: 9 mg/mL, 263x diluted Date of analysis: 19-Aug-2011 (C) Harlan Laboratories Study Report
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## Page 430 of 663

# APPENDIX V - FUNCTIONAL OBSERVATIONAL BATTERY Harlan Laboratories Study Report
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## Page 431 of 663

### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery Home cage

Faeces-balls Scores: 0 Faeces normal 1 Faeces soft but round 2 Faeces loose

Discoloration of Urine Scores: 0 Urine normal 1 Urine discolored Ventral -/lateral recumbency Scores: 0 Posture normal 1 Ventral -/lateral recumbency

Ruffled fur Scores: 0 Fur normal 1 Slight ruffled fur over whole body or just on neck 2 Ruffled fur over whole body



## Observations in the hand 1
Lifting Scores: 0 Can be lifted up with ease 1 Animal fearful, escapes or defensive 2 Animal aggressive, bites or grinds its teeth

Vocalisation Scores: 0 No vocalisation 1 Spontaneous vocalisation, when held in hand 2 Vocalisation for > 10 sec.

Muscle tone reduced Scores: 0 Animal with normal muscle tone 1 Animal limp (muscular hypotonus)

Muscle tone increased Scores: 0 Animal with normal muscle tone 1 Animal stiff (muscular hypertonus) Harlan Laboratories Study Report
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### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery Open field observations (type 4-cage)
Activity reduced Scores: 0 Normal activity 1 Animal quiet, reduced activity 2 Animal apathetic, hardly moves Activity increased Scores: 0 Normal activity 1 Increased activity 2 Restlessness, rapid movements

Gait Scores: 0 Gait normal 1 Uncoordinated movements 2 Inability to move limbs

Hunch back Scores: 0 Posture normal 1 Hunch back

Straub tail Scores: 0 No straub tail 1 Straub tail present Spasms Scores: 0 No spasm 1 Spasms

Convulsions Scores: 0 No convulsions 1 Bouts of muscle contractions affecting whole body, alternating tension and relaxation of muscles (clonic convulsions) 2 Bouts of longer contractions of muscles affecting whole body, body stretched out (tonic convulsions) 3 Alternating clonic and tonic convulsions Stereotypes Scores: 0 No stereotypes 1 Stereotypic movements interspersed by normal movements 2 Restless, violent and compulsive movements

Ruffled fur Scores: 0 Fur normal 1 Slight ruffled fur over whole body or just on neck 2 Ruffled fur over whole body Harlan Laboratories Study Report
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### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery Open field observations (type 4-cage), cont’d
Fur unkempt Scores: 0 Fur normal 1 Fur seems unkempt (dull, dirty or fur stuck together) Respiration slow Scores: 0 Respiration normal 1 Respiration slow Respiration accelerated Scores: 0 Respiration normal 1 Respiration accelerated

Rales Scores: 0 No rales 1 Rales Rearings decreased The number of rearings (free-standing or against wa ll). Fore paws must be at least 1 cm above ground. Scores: 0 Rearing normal 1 Rearing decreased ( n < 3) Rearings increased The number of rearings (free-standing or against wa ll). Fore paws must be at least 1 cm above ground. Scores: 0 Rearings normal 1 Rearing increased (n > 8)

Number of Faeces-balls Scores: 0 Number of Faeces-balls normal 1 Number of Faeces-balls increased (n > 3)

Puddles of urine Scores: 0 No or few puddles of urine 1 Several puddles of urine Harlan Laboratories Study Report
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### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery

Observations in the hand 2

Emaciated Scores: 0 Animal normal 1 Animal emaciated Dehydration Scores: 0 Animal normal 1 Animal dehydrated

Abdomen distended Scores: 0 Abdomen normal 1 Abdomen distended

Skin cold to touch Scores: 0 Skin feels normal 1 Skin cold when touched

Colouration of skin Scores: 0 Skin normal colour 1 Skin pale 2 Skin bluish Settings of eyes Scores: 0 Normal eyes 1 Exophthalmos 2 Enophthalmos

Lacrimation Scores: 0 No lacrimation 1 Watery eyes 2 Obvious lacrimation, skin wet around eye Chromodacryorrhea Scores: 0 No ch romodacryorrhea 1 Dark red, dry scab around eye (chromodacryorrhea) Harlan Laboratories Study Report
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### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery
Observations in the hand 2, cont’d
Palpebral closure Score: 0 Lid open 1 Lid 1⁄3 to completely closed Pupil size decreased Scores: 0 Normal size 1 Size decreased Pupil size increased Scores: 0 Normal size 1 Size increased

Nasal mucous Scores: 0 No nasal mucous 1 Slight nasal mucous running out of nose 2 Severe nasal mucous

Chromorhinorrhea Scores: 0 No chromorhinorrhea 1 Dark red, dried scab around nose (chromorhinorrhea)

Salivation Scores: 0 No salivation 1 Chin wet or bedding stuck to chin 2 Salivation visibly dripping out of mouth

Hair loss Scores: 0 No hair loss 1 Localised hair loss or thin fur 2 Gerneralised hair loss

Mass Raised, defined mass under the skin Scores: 0 No mass detected 1 Size smaller than 1 cm 2 Size bigger than 1 cm Harlan Laboratories Study Report
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### FOB Scoring - ToxControl



# Scoring for the Functional Observational Battery

Reflexes
Blinking Scores: 0 Blinking 1 No blinking

Pinna reflex Scores: 0 Auricle twitches 1 No visible twitch of auricle Pupillary reflex Scores: 0 Reaction of the iris 1 No reaction of the iris
Extensor thrust response Scores: 0 Thrust of the hindlimbs 1 No thrust of the hindlimbs

Pain Scores: 0 Retraction of foot 1 No retraction of foot Click response Scores: 0 Animal flinches 1 Animal does not flinch Righting reflex Scores: 0 Animal turns over and stands up 1 Animal does not turn over Hearing ability (Preyer’s Reflex) Scores: 0 Reflex reaction present 1 Reflex reaction absent Harlan Laboratories Study Report
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# APPENDIX VI - CLINICAL LABORATORY INVESTIGATIONS Harlan Laboratories Study Report
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# CLINICAL LABORATORY INVESTIGATIONS
Blood Sampling: Before necropsy: 08-Sep-2011 (males) Day 5 post partum: 20 to 25-Sep-2011 (females) Blood samples were obtained on the day before or on the day of the scheduled necropsy from 5 males from each group. Blood samples from 5 lact ating females from each group were obtained on day 5 post partum. Blood samples were draw n sublingually from all animals under light isoflurane anesthesia. The animals were fa sted for approximately 18 hours before blood sampling but allowed access to water ad libitum . The samples were collected early in the working day to reduce biological varia tion caused by circadian rhythms. In the summary and individual tables the names of some parameters have been abbreviated. Any abbreviation has been defined in this section. Clin ical laboratory data ar e expressed, with a few exceptions, in general accordance with th e International System of Units (SI). Key to Abbreviations of Units: L liter g gram m milli (10 -3 

## ) mol mole G giga (10 9 

## ) μ micro (10 -6 

## ) sec seconds T tera (10 12 

## ) f femto (10 -15 

## ) U Unit


# Hematology
The following anticoagulants were used during blood collection: Complete Blood Cell Count : Tri-potassium-EDTA Coagulation: Sodium citrate, 3.2% (1 part anticoagulant to 9 parts blood) Complete Blood Cell Count

Parameter Abbreviation Unit Instrumentation Erythrocyte count RBC T/L Advia 120 1 

## Hemoglobin HB mmol/L Advia 120 Hematocrit HCT rel.1 Advia 120 Mean corpuscular volume MCV fL Advia 120 Red cell volume distribution width RDW rel.1 Advia 120 Mean corpuscular hemoglobin MCH fmol Advia 120

1 

### ADVIA 120 hematology system (Siemens) Harlan Laboratories Study Report
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## Parameter Abbreviation Unit Instrumentation Mean corpuscular hemoglobin concentration MCHC mmol/L Advia 120
Hemoglobin concentration distribution width HDW mmol/L Advia 120

Leukocyte count, total WBC G/L Advia 120
Differential leukocyte count relative absolute 

## Advia 120 Neutrophils NEUT rel.1 G/L Advia 120 Eosinophils EOS rel.1 G/L Advia 120 Basophils BASO rel.1 G/L Advia 120 Lymphocytes LYMPH rel.1 G/L Advia 120 Monocytes MONO rel.1 G/L Advia 120 Large unstained cells LUC rel.1 G/L Advia 120

Platelet count PLATELETS G/L Advia 120

Coagulation

Parameter Abbreviation Unit Method Instrumentation

Prothrombin time (=Thromboplastin time) 

## PT rel. 1 Clotting assay, thromboplastin from rabbit brain tissue, results as ratio of normal activity STA 2



## Activated partial thromboplastin time PTT sec Clotting assay, cephalin from rabbit cerebral tissue, silica surface activator STA

2 

### STA-compact analyzer (Roche Diagnostics) Harlan Laboratories Study Report
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# Clinical Biochemistry
Lithium heparin was used as anticoagulant during blood collection.

Parameter Abbreviation Unit Method Instrumentation

Glucose mmol/L Hexokinase/G6P-DH Cobas 6000/501 3 

## Urea mmol/L Urease/GLDH Cobas 6000/501 Creatinine CREAT μmol/L Enzymatic colorimetric test Cobas 6000/501Bilirubin, total BILI-T μmol/L Reaction with 3,5-Dichlorophenyl-diazonium salt Cobas 6000/501
Bile acids BILE AC μmol/L Colorimetric, enzymatic (3 α -HSD, Diaphorase) Cobas 6000/501
Cholesterol, total CHOLEST mmol/L Enzymatic, CHOD/PAP Cobas 6000/501 Triglycerides TRIGLY mmol/L Glycerol-Kinase GPO/PAP method Cobas 6000/501
Aspartate aminotransferase EC 2.6.1.1 4 

## ASAT U/L 37 oC ALT/MDH Cobas 6000/501

Alanine aminotransferase EC 2.6.1.2 ALAT U/L 37 oC ALT/LDH Cobas 6000/501

Alkaline phosphatase EC 3.1.3.1 ALP U/L 37 oC p-Nitrophenyl-phosphate as substrate Cobas 6000/501

Gamma-glutamyl transferase EC 2.3.2.2 GGT U/L 37 oC Substrate: L-gammaglutamyl-3-carboxy4-nitroanilide Cobas 6000/501

Sodium mmol/L Ion selective electrode Cobas 6000/501 Potassium mmol/L Ion selective electrode Cobas 6000/501 Chloride mmol/L Ion selective electrode Cobas 6000/501 Calcium mmol/L o-Cresolphthalein complexone method Cobas 6000/501
Phosphorus mmol/L Phosphomolybdate reaction Cobas 6000/501 Protein, total PROTEIN g/L Biuret reaction Cobas 6000/501 Albumin g/L Bromocresol green method Cobas 6000/501

3 

### Cobas 6000 analyzer, Roche Diagnostics 4 

### Identification of enzymes with EC-Number (Enz yme Commission) according to Enzyme Nomenclature, Recommendations (1972) of the IUPAC and IUB, Elsevier Scient. Publ. Comp., Amsterdam, 1973 Harlan Laboratories Study Report
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## Parameter Abbreviation Unit Method Instrumentation
Globulin g/L Calculated value (total protein minus albumin) Albumin / Globulin Ratio A/G RATIO Calculated value (albumin / globulin) Harlan Laboratories Study Report
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## HISTORICAL DATA - HEMATOLOGY
STRAIN: RAT / HanRcc:WIST (MALES) AGE: FROM 13 TO 19 WEEKS DATA COLLECTION PERIOD: 18-OCT-04 TO 13-JUN-08

PARAMETER UNIT N MEAN STAND.DEV 95% TOLERANCE LIMITS

-------------------------------------------------------------------------------------------------- ERYTHROCYTES (RBC) T/l 160 8.88 0.49 7.97 9.96 HEMOGLOBIN (HB) mmol/l 160 10.3 0.4 9.6 11.0 HEMATOCRIT (HCT) rel. 1 160 0.45 0.02 0.42 0.50 MEAN CORPUSCULAR VOLUME (MCV) fl 160 51.1 2.5 46.7 56.0 RED CELL VOL. DISTR. WIDTH (RDW) rel. 1 160 0.143 0.033 0.115 0.234 MEAN CORPUSCULAR HEMOGLOBIN (MCH) fmol 160 1.16 0.06 1.06 1.28 MEAN CORPUSCULAR HEMOGLOBIN CONC. mmol/l 160 22.77 0.89 21.27 24.45 HEMOGLOBIN CONC. DISTR. WIDTH mmol/l 160 1.84 0.17 1.55 2.14

RETICULOCYTE COUNT................................................................................ RETICULOCYTE (REL) rel. 1 50 0.021 0.004 --- --- RETICULOCYTE (ABS) G/l 50 191 37 --- --- MATURITY INDEX (L-RETI) rel. 1 50 0.566 0.077 --- --- MATURITY INDEX (M-RETI) rel. 1 50 0.341 0.040 --- --- MATURITY INDEX (H-RETI) rel. 1 50 0.092 0.043 --- --- LEUKOCYTES, TOTAL (WBC) G/l 160 8.82 1.84 5.33 12.32
DIFF.WBC COUNT (REL).............................................................................. NEUTROPHILS (NEUT) rel. 1 130 0.147 0.039 0.092 0.221 EOSINOPHILS (EOS) rel. 1 160 0.012 0.005 0.005 0.023 BASOPHILS (BASO) rel. 1 160 0.010 0.006 0.003 0.022 LYMPHOCYTES (LYMPH) rel. 1 160 0.802 0.044 0.717 0.870 MONOCYTES (MONO) rel. 1 160 0.018 0.007 0.009 0.036 LARGE UNSTAINED CELLS (LUC) rel. 1 160 0.009 0.005 0.002 0.021
DIFF.WBC COUNT (ABS).............................................................................. NEUTROPHILS (NEUT) G/l 130 1.30 0.33 0.72 2.00 EOSINOPHILS (EOS) G/l 160 0.10 0.04 0.04 0.19 BASOPHILS (BASO) G/l 160 0.09 0.06 0.02 0.22 LYMPHOCYTES (LYMPH) G/l 160 7.10 1.64 4.32 10.46 MONOCYTES (MONO) G/l 160 0.16 0.07 0.07 0.34 LARGE UNSTAINED CELLS (LUC) G/l 160 0.08 0.05 0.02 0.21 THROMBOCYTES (PLATELETS) G/l 160 1002 130 805 1260

COAGULATION....................................................................................... PROTHROMBIN TIME (PT) rel. 1 158 0.77 0.06 0.68 0.96 PARTIAL THROMBOPLASTIN TIME (PTT) sec 158 22.7 3.8 12.5 28.1



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## Page 443 of 663

## HISTORICAL DATA - HEMATOLOGY
STRAIN: RAT / HanRcc:WIST (FEMALES) AGE: FROM 13 TO 19 WEEKS DATA COLLECTION PERIOD: 18-OCT-04 TO 13-JUN-08

PARAMETER UNIT N MEAN STAND.DEV 95% TOLERANCE LIMITS

-------------------------------------------------------------------------------------------------- ERYTHROCYTES (RBC) T/l 159 7.50 0.64 6.38 8.88 HEMOGLOBIN (HB) mmol/l 159 9.1 0.6 8.0 10.3 HEMATOCRIT (HCT) rel. 1 159 0.40 0.03 0.36 0.46 MEAN CORPUSCULAR VOLUME (MCV) fl 159 53.9 3.2 47.6 61.5 RED CELL VOL. DISTR. WIDTH (RDW) rel. 1 159 0.157 0.033 0.121 0.263 MEAN CORPUSCULAR HEMOGLOBIN (MCH) fmol 159 1.21 0.06 1.09 1.34 MEAN CORPUSCULAR HEMOGLOBIN CONC. mmol/l 159 22.51 0.98 20.76 24.48 HEMOGLOBIN CONC. DISTR. WIDTH mmol/l 159 1.62 0.14 1.44 1.92

RETICULOCYTE COUNT................................................................................ RETICULOCYTE (REL) rel. 1 50 0.042 0.017 --- --- RETICULOCYTE (ABS) G/l 50 321 111 --- --- MATURITY INDEX (L-RETI) rel. 1 50 0.513 0.116 --- --- MATURITY INDEX (M-RETI) rel. 1 50 0.358 0.046 --- --- MATURITY INDEX (H-RETI) rel. 1 50 0.129 0.103 --- --- LEUKOCYTES, TOTAL (WBC) G/l 159 7.94 1.86 4.80 12.03
DIFF.WBC COUNT (REL).............................................................................. NEUTROPHILS (NEUT) rel. 1 130 0.287 0.092 0.090 0.434 EOSINOPHILS (EOS) rel. 1 159 0.008 0.004 0.002 0.017 BASOPHILS (BASO) rel. 1 159 0.007 0.003 0.002 0.015 LYMPHOCYTES (LYMPH) rel. 1 159 0.672 0.102 0.488 0.883 MONOCYTES (MONO) rel. 1 159 0.025 0.009 0.013 0.045 LARGE UNSTAINED CELLS (LUC) rel. 1 159 0.009 0.006 0.002 0.024
DIFF.WBC COUNT (ABS).............................................................................. NEUTROPHILS (NEUT) G/l 130 2.39 1.04 0.76 4.70 EOSINOPHILS (EOS) G/l 159 0.06 0.03 0.02 0.13 BASOPHILS (BASO) G/l 159 0.05 0.03 0.02 0.12 LYMPHOCYTES (LYMPH) G/l 159 5.27 1.22 3.28 7.91 MONOCYTES (MONO) G/l 159 0.20 0.08 0.07 0.38 LARGE UNSTAINED CELLS (LUC) G/l 159 0.07 0.06 0.01 0.24 THROMBOCYTES (PLATELETS) G/l 149 1255 198 924 1695

COAGULATION....................................................................................... PROTHROMBIN TIME (PT) rel. 1 158 0.77 0.06 0.66 0.91 PARTIAL THROMBOPLASTIN TIME (PTT) sec 158 23.9 3.9 14.7 32.4



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## Page 444 of 663

## HISTORICAL DATA - CLINICAL BIOCHEMISTRY
STRAIN: RAT / HanRcc:WIST (MALES) AGE: FROM 13 TO 19 WEEKS DATA COLLECTION PERIOD: 18-OCT-04 TO 13-JUN-08

PARAMETER UNIT N MEAN STAND.DEV 95% TOLERANCE LIMITS

-------------------------------------------------------------------------------------------------- GLUCOSE mmol/l 160 7.30 1.21 4.80 10.18 UREA mmol/l 160 6.95 1.26 4.84 9.17 CREATININE μmol/l 159 25.2 3.7 19.0 35.5 BILIRUBIN, TOTAL μmol/l 159 2.04 0.46 1.19 3.24 BILE ACIDS μmol/l 120 47.55 37.64 2.61 114.66 CHOLESTEROL, TOTAL mmol/l 159 1.73 0.29 1.26 2.41 TRIGLYCERIDES mmol/l 65 0.55 0.22 --- --- ASPARTATE AMINOTRANSFERASE (ASAT) U/l 159 73.7 12.1 55.9 106.9 ALANINE AMINOTRANSFERASE (ALAT) U/l 159 53.2 12.2 33.3 77.3 ALKALINE PHOSPHATASE (ALP) U/l 160 94.7 24.1 59.8 151.6 GAMMA-GLUTAMYLTRANSFERASE (GGT) U/l 159 0.2 0.8 0.0 2.8 SODIUM mmol/l 160 142.4 2.1 136.6 145.5 POTASSIUM mmol/l 159 4.20 0.62 3.33 6.30 CHLORIDE mmol/l 160 103.2 2.0 99.4 107.6 CALCIUM mmol/l 160 2.69 0.16 2.51 2.91 PHOSPHORUS mmol/l 160 1.96 0.24 1.53 2.43 PROTEIN, TOTAL g/l 160 66.52 2.77 61.16 71.25 ALBUMIN g/l 159 41.51 1.64 37.65 44.47 GLOBULIN g/l 159 24.93 2.10 21.34 28.48 A/G RATIO - 159 1.68 0.20 1.42 2.00



### Harlan Laboratories Study Report
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## HISTORICAL DATA - CLINICAL BIOCHEMISTRY
STRAIN: RAT / HanRcc:WIST (FEMALES) AGE: FROM 13 TO 19 WEEKS DATA COLLECTION PERIOD: 18-OCT-04 TO 13-JUN-08

PARAMETER UNIT N MEAN STAND.DEV 95% TOLERANCE LIMITS

-------------------------------------------------------------------------------------------------- GLUCOSE mmol/l 159 5.84 0.80 4.41 7.42 UREA mmol/l 156 7.37 1.21 5.15 9.87 CREATININE μmol/l 148 28.1 4.0 21.8 36.0 BILIRUBIN, TOTAL μmol/l 149 2.01 0.74 0.81 3.61 BILE ACIDS μmol/l 128 44.36 25.90 4.05 97.86 CHOLESTEROL, TOTAL mmol/l 159 1.39 0.31 0.90 2.09 TRIGLYCERIDES mmol/l 65 0.75 0.48 --- --- ASPARTATE AMINOTRANSFERASE (ASAT) U/l 159 93.8 32.7 60.5 194.7 ALANINE AMINOTRANSFERASE (ALAT) U/l 159 52.5 12.8 31.8 85.5 ALKALINE PHOSPHATASE (ALP) U/l 159 38.2 12.0 20.8 75.7 GAMMA-GLUTAMYLTRANSFERASE (GGT) U/l 158 0.2 0.6 0.0 2.6 SODIUM mmol/l 158 140.0 2.9 133.2 145.3 POTASSIUM mmol/l 158 3.74 0.53 2.86 4.60 CHLORIDE mmol/l 158 101.9 3.0 95.8 106.9 CALCIUM mmol/l 159 2.76 0.17 2.54 3.01 PHOSPHORUS mmol/l 159 2.32 0.49 1.41 3.48 PROTEIN, TOTAL g/l 159 65.47 3.51 58.82 72.84 ALBUMIN g/l 158 42.16 3.22 37.10 51.96 GLOBULIN g/l 158 23.34 2.08 19.31 27.96 A/G RATIO - 158 1.82 0.24 1.43 2.29



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# APPENDIX VII - HISTOPATHOLOGY Harlan Laboratories Study Report
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## Page 447 of 663

# HISTOPATHOLOGY PHASE REPORT

Histopathology Phase to: Combined Repeated Dose Toxicity Study w ith the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat.

Subtitle: Histopathology Examinations

Study Director: K Pal-Kutas Test Facility: Harlan Laboratories Ltd. Wölferstrasse 4 4414 Füllinsdorf / Switzerland
Principal Investigator: K Heider Test Site: AnaPath GmbH Buchsweg 56 4625 Oberbuchsiten / Switzerland
Sponsor:

Study Identification: Harlan Laboratories Study Number D23451 Sponsor Reference Number 85R0095/11X015

AnaPath Phase Number 10648

Version: Final Phase Report Completion Date: May 10, 2012
Page 1 of 124 Harlan Laboratories Study Report
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## Page 448 of 663

### ratories Study D23451 Histopathology Phase Report Page 2 / 124

AnaPath Phase Number10648 Histopathology Phase Page 2 

# CONTENTS

CONTENTS....................................................................................................................................2 GLP CERTIFICATE................................................................................................................ .......4 STATEMENT OF COMPLIANCE ................................................................................................5 QUALITY ASSURANCE STATEMENT......................................................................................6 DATA REQUIREMENTS / TEST GUIDELINE...........................................................................7 ARCHIVING ..................................................................................................................................7 1 SUMMARY...................................................................................................................... .....8 2 MATERIALS AND METHODS...........................................................................................9 2.1 Allocation ................................................................................................................9 2.2 Necropsy and Histopathology .................................................................................9 2.3 Data Compilation...................................................................................................10 2.4 Peer Review...........................................................................................................11 3 RESULTS ...................................................................................................................... ......12 3.1 Mortality ................................................................................................................12 3.2 Macroscopic Findings............................................................................................12 3.3 Microscopic Findings ............................................................................................12 3.3.1 Reproductive Organs...............................................................................12 3.3.2 Stomach ...................................................................................................13 3.3.3 Liver ........................................................................................................13 3.3.4 Thyroid gland ..........................................................................................14 3.3.5 Thymus....................................................................................................14 3.3.6 Adrenal glands.........................................................................................14 3.3.7 Other Findings.........................................................................................14 4 DISCUSSION AND CONCLUSION .................................................................................15 5 REFERENCES ................................................................................................................... .16 

# LIST OF TABLES
Table 1 Relevant findings in stomach......................................................................................13 Table 2 Relevant finding in liver .............................................................................................14 Table 3 Relevant findings in thyroid gland..............................................................................14 Summary Tables Explanation of Codes and Symbols .....................................................................................17 Summary Incidence of Gradings by Or gan/Group/Sex: Selected Tissues (K0, including deaths)..........................................................................................................18 Number of Animals with Micros copic Findings by Organ/Group/Sex (K0, including deaths)..........................................................................................................23 Correlation Table: Necr opsy - Microscopy..........................................................................29 Harlan Laboratories Study Report
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### ratories Study D23451 Histopathology Phase Report Page 3 / 124

AnaPath Phase Number10648 Histopathology Phase Page 3



## Individual Tables Table of Individual Micr oscopic Findings (AOFT 1 

## ) ..........................................................40 Animal Heading Data: Dose Group 01 ................................................................................56 Text of Gross and Microscopic Findings: Dose Group 01 ..................................................57 Animal Heading Data: Dose Group 02 ................................................................................75 Text of Gross and Microscopic Findings: Dose Group 02 ..................................................76 Animal Heading Data: Dose Group 03 ................................................................................89 Text of Gross and Microscopic Findings: Dose Group 03 ..................................................90 Animal Heading Data: Dose Group 04 ..............................................................................104 Text of Gross and Microscopic Findings: Dose Group 04 ................................................105 Last Page ...........................................................................................................................124

1 

### Animal Organ Finding Table Harlan Laboratories Study Report
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### ratories Study D23451 Histopathology Phase Report Page 4 / 124

AnaPath Phase Number10648 Histopathology Phase Page 4 

# GLP CERTIFICATE Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 451 of 663

### ratories Study D23451 Histopathology Phase Report Page 5 / 124

AnaPath Phase Number10648 Histopathology Phase Page 5


## GOOD LABORATORY PRACTICE 

# STATEMENT OF COMPLIANCE

This histopathology phase has been performed in compliance with the: Swiss Ordinance relating to Good Laboratory Practice, adopted May 18 th 

## 2005 [SR 813.112.1]. This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26 th 

## 1997 by decision of the OECD Council [C (97) 186/Final]. There were no circumstances that may have aff ected the quality or integrity of the data.

Principal Investigator Histopathology Phase: Dr. Katharina Heider Veterinary Pathologist Diplomate ECVP Harlan Laboratories Study Report
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### ratories Study D23451 Histopathology Phase Report Page 6 / 124

AnaPath Phase Number10648 Histopathology Phase Page 6 

# QUALITY ASSURANCE STATEMENT
AnaPath GmbH, Buchsweg 56, 4625 Oberbuchsiten / Switzerland The general facilities and activitie s are inspected periodically and the results are reported to the responsible person and the management. Study procedures were periodical ly inspected. The study plan a nd amendments (related to the phase) and this phase report were audited by the quality assuranc e. The dates are given below:

Dates of Report to Dates and Types of QA Inspections the Principal Investigator and to the Test Site Management the Study Director, Lead QA and to the Test Facility Management 14.09.2011 - Study plan --- 14.09.2011 06.12.2011 - Process based (histopathology) 06.12.2011 ---

25./26.01.2012 - Phase report 26.01.2012 26.01.2012



## This statement also confirms that this hi stopathology phase report reflects the raw data.

Quality Assurance: N. Häuselmann Harlan Laboratories Study Report
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## Page 453 of 663

### ratories Study D23451 Histopathology Phase Report Page 7 / 124

AnaPath Phase Number10648 Histopathology Phase Page 7 

# DATA REQUIREMENTS / TEST GUIDELINE
This study was performed in accordance with the procedures indicated by the following internationally accepted guidelines and recommendations:

• OECD guideline 422 (OECD guideline for te sting of chemicals 422, “Combined Repeated Dose Toxicity Study with the Repr oduction/Developmental Toxicity Screening Test in the Rat”, adopted by the Council on 22 nd 

## March 1996).

• “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test” Health Effects Test Guideline OPPTS 870.3650 Guideline from the Office of Prevention, Pesticides and T oxic Substances, U.S. Environmental Protection Agency, July 2000. 

# ARCHIVING
Harlan Laboratories Ltd., 4452 Itin gen/Switzerland will retain true copies of the study plan, the final report and a sample of test item of the present study for at least ten years. The original study plan, original paper raw data , a CD with electronic raw data, specimens and the original final report w ill be sent to the sponsor. These original documents/raw data, as well as sp ecimens (as long as quality permits evaluation) will be archived for at least 10 years at the following location:

10

AnaPath GmbH (4625 Oberbuchsiten / Switzerland) will retain a copy of the raw data generated at the test site AnaPath GmbH, and an electronic version of the pathology phase report for at least 10 years. Duplicate signature pages will be retained at AnaPath GmbH for at least ten years or until transfer to the Study Director if requested. Harlan Laboratories Study Report
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A naPath Phase Number10648 Histopathology Phase Page 8 

# 1 SUMMARY
The purpose of this study was to generate prelim inary information on the possible health hazardslikely to arise from repeated exposure over a relatively limited period of time. In addition it provides information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition. This study should provide informa tion to assess the need to c onduct further investigations and may provide guidance in the de sign of subsequent studies. Eighty rats were assigned to 4 groups each containing 10 males and 10 females. The control, low, intermediate, and high dose group animals were treated with 0, 10, 30 or 90 mg/kg bw/day, respectively. At the end of the study period, all ma les were sacrificed on study day 29 and all surviving females on day 5 post partum (study days 40 to 53) and offspring on day 4 post partum. All surviving animals were necropsied and examined post mortem . Also the moribund sacrificed male no. 35 and the decedent female no.78 were examined post mortem . Histological examinations were performed on all organs and tissues colle cted at terminal sacrifice from five males and females, including the decedent high-dose female no. 78 and the moribund killed high-dose male no. 35. To gather the histopathology result from 5 te rminally sacrificed ma les of high dose, also the slides of male no. 36 were examined. In sddition, the reproductive organs from all animals of the control and high-dose groups were evaluated histop athologically. Reproduc tive organs were also examined from male nos. 11 and 19, and on ovaries from female nos. 45, 46, 51, and 77. In addition, the liver, stomach, thymus, testes/epidi dymides, thyroid glands, and adrenal glands were examined histopathologically in groups 2 and 3 (male nos.11-15 and 21-25; female nos. 51- 55 and 61-65). Under the conditions of this experiment, induced the following treatment-related local irritative effects:

• Macroscopically detected crateriform retrac tion of forestomach in one group 3 female.

• Forestomach: hyperkeratosis insome group 3 females and some males and a single female of group 4, squamous cell hyperplasia with submucosal inflammation in a single group 3 female; glandular stomach: mucosal glandular dilation in some group 3 and 4 males, focal erosion in a single male of group 2 and each a single male and female of group 4, in the female associated with s ubmucosal inflammation, mucosal atrophy in a single group 4 female. Under the conditions of this experiment, induced the following treatment-related adaptive findings:

• Liver cell hypertrophy in all males and female s of group 4, associated with follicular cell hypertrophy of thyroid glands in some males and females of group 4. Based on the microscopic findings detected the NOAEL (No Observed Adverse Effect Level) for the local irritative eff ect of in stomach could no t be established for males and was established at 10 mg/kg bw/day for females. Harlan Laboratories Study Report
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# 2 

# MATERIALS AND METHODS
2.1 Allocation The group identification and animal numbers assigned to treatment are stated in the following table:

Allocation and Dose Levels mg/kg body weight/day Group 1 control 0 Group 2

10 Group 3

30 Group 4

90 Males 1 - 10 11 – 20 21 - 30 31 – 40 Females 41 - 50 51 – 60 61 - 70 71 – 80



# 2.2 Necropsy and Histopathology All necropsies were performed at Harlan Labora tories Ltd., Itingen / Switzerland. The tissues from all animals were preserved in buffered 10% formalin, except testes/epididymides which were preserved in Bouin’s fluid and the eyes we re fixed in Davidson’s fluid. The histology processing was performed at Harlan Laboratories Lt d., Itingen / Switzerland. All organ and tissue samples to be examined by the principal inves tigator for histopathology were processed, embedded and cut at an approx imate thickness of 2 - 4 micrometers and stained with hematoxylin and eosin. Additionally, the testis was stained by PAS- hematoxylin in group 1 and 4 males. Prepared slides were sent to AnaPath GmbH, 4625 Ober buchsiten, Switzerland and examined by light microscopy. Slides of all organs and tissues listed collected at terminal sacr ifice from five males and females and reproductive organs from all animals of th e control and high-dose groups were examined by the principal investigator for histopathology. Th e same applied to all occurring gross lesions. Sections from the following organs and tissues from male nos. 1-10 and 31-40 from groups 1 and 4 as well as male nos. 11 (partner to female no. 51) and 19 (partner to female no. 59) from group 2 were examined by light microscopy:

Prostate Seminal vesicles with coagulating gland Testes (in Bouin’s fixative) Epididymides (in Bouin’s fixative)
Sections from the following organ from fema le nos. 41-44, 47 and 71-75, 78 of groups 1 and 4 and female nos. 45 and 46 (not pregnant) fromgroup 1 and 51 and 59 from group 2 were examined by light microscopy:

Ovaries Harlan Laboratories Study Report
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## Sections from the following organs and tissues from male nos. 1-5 and 31-35 from groups 1 and 4 and female nos. 41-44, 47 and 71-75, 78 (deced ent female) from groups 1 and 4 were examined by light microscopy.

Gross lesions Brain (cerebrum, cerebellum, pons) Spinal chordSmall and large intestines (incl. Peyer’s patches) Stomach Liver Kidneys Adrenals Spleen Heart Thymus Thyroids and parathyroids Trachea and lungs (preserved by inflation with fixative and then immersion) Uterus (with vagina) Urinary bladder Lymph nodes (mesenterial, mandibular) Peripheral nerve (sciatic) Bone marrow
Gross lesions were examined microscopically in all groups 01 to 04. Due to morphologic changes in the liver, thyroi d glands, stomach, thymus, adrenal glands, and testes/epididymides that were detected in high do se animals, the same organs from group 2 (male nos. 11-15 and female nos. 51-55) and group 3 an imals (male nos. 21-25 and female nos. 61-65) were examined to establish a no-effect level.


# 2.3 Data Compilation The animal heading data and necropsy findings we re transferred from Harlan Laboratories Ltd. via electronic diskette and entered at AnaP ath GmbH into the PDS PathData System. The microscopic findings were recorded by the u ndersigned pathologist us ing on-line input into the PDS PathData System V6.2d2 du ring histopathologic examination. For technical reasons, in the header of PathDa ta, only “Harlan Laboratories” was included instead of the full name “Har lan Laboratories Study.” To allow the reporting of gastric findings separa tely in forestomach and glandular stomach, the organ “stomach” was divided by the study pathologi st into “forestomach” and “glandular stomach”. Only, when gross lesions were noted at necropsy, the organ “stomach” appears in the AOFT with a “G” for gross lesion. Histologic changes were described, wherever possi ble, according to dist ribution, severity and morphologic character. Severity scores were assigned as given under “Explanation of Codes and Symbols”. The grading used for the microscopic examination of corpora lutea in bot h ovaries combined was as follows: Grade 1 = 1 - 5 corpora lutea, grade 2 = 6 -10 corpora lutea, grade 3 = 11 -15 corpora lutea, grade 4 = 16 -20 corpora lutea, grad e 5 = 21 -25 corpora lutea or more. Harlan Laboratories Study Report
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## All microscopic findings are listed in the “Table of Individual Microsc opic Findings” (AOFT, animal organ finding table), along with the explanation of codes and symbols used. Computer-generated incidence tabl es derived from these data are also presented as well as the complete narrative of both the macroscopic a nd microscopic findings given for each animal under “Text of Gross and Microscopic Findings”. The originally requested slides were evaluated from October 24 to November 11, 2011, and the liver, stomach, thymus, thyroid glands, adrenal gl ands, and testes/epididymides from group 2 and 3 animals until December 18, 2011, and organs/tissu es from additional male no. 36 on March 10, 2012. Histological changes were describe d, wherever possible, accordi ng to distribution, severity and morphologic character. Severity scores were assigned as given under “Explanation of Codes and Symbols”. All microscopic findings are listed in the “Tab le of Individual Microscopic Findings (AOFT), along with an explanation of the codes and symb ols used. Computer-generated incidence tables derived from these data are given under “Numbe r of Animals with Microscopic Findings by Organ/Group/Sex” and are also presented as the co mplete narrative of both the macroscopic and microscopic findings under “Text of Gross and Microscopic Findings.”



# 2.4 Peer Review A histopathology peer review wa s performed by Dr. Hans-Jörg Chevalier, AnaPath GmbH, 4625 Oberbuchsiten, Switzerland. This review included the following evaluations:

• All protocol-designated tissues from: Group 1: male no. 1; female no. 41; Group 4: male no. 31; female no. 71;

• Liver, stomach, thyroid gland, thymus, adrena l glands, and testes/epididymides from all animals in study. The summary incidence tables and individual animal data sheets contained in the final report reflect the mutually agreed -upon diagnoses and gradings. Harlan Laboratories Study Report
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# 3 RESULTS
3.1 Mortality Male no. 35 from group 4 was killed in extremis on test day 9. This male showed minimal to slight stomach findings and signs of moderate st ress in thymus and adrenal glands. However, the reason for moribundity in this male could not be determined fromthe organs and tissues examined. Female no. 78 from group 4 died spontaneous ly on test day 15 and the thrombosis in the jejunum was considered to be the cause of deat h. Therefore, this death was considered to be likely incidental. All other animals survived the scheduled study period.


# 3.2 Macroscopic Findings In group 3 female no. 63, the forestomach showed a crateriform retrac tion, correlating with squamous hyperplasia and submucosal inflamma tion. These findings were considered to represent local irritative effects of the test item. One, three, and four females of groups 2, 3, a nd 4 showed a reduced si ze of thymus, correlating with thymic atrophy at 90 mg/kg bw/day only. This thymus findi ng was considered to be likely stress-related. All other gross lesions recorded were considered to be within the range of normal background alterations.


# 3.3 Microscopic Findings

3.3.1 Reproductive Organs The histopathological evaluation of the reproductive organs re vealed some changes in testes/epididymides of high-dose males: Marked diffuse tubular atrophy of testes associated with edema and aspermia in epididymides and incidental unilateral focal lymphoid cell in filtration was noted in male no. 37. Unilateral single focal tubular degeneration oc curred in male nos. 32, 34, and 35. Special emphasis on stages of spermatogenesis a nd histopathology of inters titial testic ular cell structure did not reveal any di fferences between group 1 and group 4 males in the completeness of cell populations, completeness of stages, and pot ential degenerative changes, except male no. 37. The stages of spermatogenesis could not be established in degenerative tubules. Group 1 male nos. 5 and 6 and group 2 male nos. 11 and 19 did not reveal relevant findings in reproductive organs and the corresponding females did also not show orga n findings explaining missing pregnancy (nos. 45, 46, 51) or missing delivery (no. 59). In group 4 male no. 37, the marked diffuse tubular atrophy in testes was cons idered to be the reason for missing pregnancy in corresponding female no. 77. The epididymides (except no. 37), prostate, and se minal vesicles did not reveal any relevant morphological changes. Harlan Laboratories Study Report
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## 3.3.2 Stomach The following treatment-related local irritative effects were present in the stomach: Forestomach: hyperkeratosis in some group 3 fema les and group 4 males and a single female at90 mg/kg bw/day, squamous cell hyperplasia with submucosal inflammation in one group 3 female; glandular stomach: focal erosion in a sing le group 2 male and a single group 4 male and female, in the female associated with s ubmucosal inflammation and mucosal atrophy.

Table 1 Relevant fi ndings in stomach

Groups 1 2 3 4 FORESTOMACH Tissues examined 5 M 6 F 5 M 5 F 5 M 5 F 6 M 6 F Hyperkeratosis Mean severity 0 0 0 0 0 0 0 0 0 0 2 1.0 3 1.3 1 1.0 Total Affected 0 0 0 0 0 2 3 1 Squamous cell hyperplasia (+submucosal inflammation) Mean severity 0 0 0 0 0 0 0 0 0 0 1 3.0 0 0 0 0 Total Affected 0 0 0 0 0 1 0 0 GLANDULAR STOMACH Tissues examined 5 M 6 F 5 M 5 F 5 M 5 F 6 M 6 F Erosion Mean severity 0 0 0 0 1 1.0 0 0 0 0 0 0 1 1.0 1 3.0 Total Affected 0 0 1 0 0 0 1 1 Submucosal inflammation Mean severity 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2.0 Total Affected 0 0 1 0 0 0 1 1 Mucosal atrophy Mean severity 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1.0 Total Affected 0 0 0 0 0 0 0 1


## The presence of mucosal glandu lar dilation of glandular stom ach in group 3 and 4 males was considered to be likely incidental. In addition, the focal peritoneal inflammation in glandular stomach of decedent female no. 78 was considered to be likely associated with the thrombosis in jejunum.
3.3.3 Liver Minimal to slight diffuse hepatocellular hypertrophy, characterized by an increase in endoplasmatic reticulum, was recorded in liver in all ma les and females at 90 mg/kg bw/day. This finding was considered to be adaptive. Harlan Laboratories Study Report
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## Table 2 Relevant finding in liver

Groups 1 2 3 4 Tissues examined 5 M 5 F 5 M 5 F 5 M 5 F 5 M 6 F Hepatocellular hypertrophy Mean severity 0 0 0 0 0 0 0 0 0 0 0 0 5 1.4 6 1.3 Total Affected 0 0 0 0 0 0 5 6



## 3.3.4 Thyroid gland Diffuse follicular cell hypertr ophy in thyroid gland was noted in some group 4 males and females. This finding was considered to be c onsequent to the hepa tocellular hypertrophy. Table 3 Relevant findings in thyroid gland

Groups 1 2 3 4 Tissues examined 5 M 5 F 5 M 5F 5 M 5 F 5 M 6 F Follicular cell hypertrophy: Mean severity 0 0 0 0 0 0 0 0 0 0 0 0 2 1.0 2 1.0 Total Affected 0 0 0 0 0 0 2 2



## 3.3.5 Thymus Increased incidence and/or mean severity of t hymus atrophy was recorded in group 3 and 4 animals when compared with group 2 or the control group.

3.3.6 Adrenal glands Increased incidence and mean severity of diffuse fatty change in adrenal cortex was diagnosed in group 3 and 4 males and group 4 females when co mpared with the corresponding control groups.

3.3.7 Other Findings The remaining microscopical findings recorded in this study were within the range of normal background lesions which may be recorded in animals of this strain and age. Harlan Laboratories Study Report
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# 4 DISCUSSION AND CONCLUSION
Under the conditions of this experiment, did not induce any test item-related findings in reproductive organs since the testicular tubular findings occurring in some males of group 4 were considered to be in cidental or stress-related. In organs other than reproductive, led to local irritative effects in the stomach present in all test item-treated gr oups in increasing incidences at the dose levels of 10, 30, and 90 mg/kg bw/day. Treatment-related diffuse hepato cellular hypertrophy at 90 mg/kg bw /day was considered to be adaptive. This hypertrophy was associated with follicular cell hypertrophy in thyroid glands in some males and females at 90 mg/kg bw/day. Mo st probably, the enhanced liver cell metabolism resulted in an acceleration of thyroid hormone br eakdown with consequent thyroid follicular cell hypertrophy. This finding is often seen in rats after being exposed to xenobiotics. The reduced size in thymus occurring in increased incidences in females at ≥ 10 mg/kg bw/day correlated histopathologically with diffuse cortical atrophy and reduced absolute and relative weights only at the high dose leve l. Although this is cons idered to be most likely stress-related, a test item-relationship cannot be excluded at 90 mg/kg bw/day. The increased diffuse fatty change in adrenal co rtex at 30 and 90 mg/kg bw/day was considered to be likely cons equent to stress. Group 4 male no. 35 was killed in extremis but the cause of moribundity could not be determined from the organs and tissues examined. Group 4 female no. 78 died spontaneously and the cause of death was likely the thro mbosis of jejunum. Therefore, th is death was considered to be incidental.

Based on the microscopic findings detected the NOAEL (No Observed Adverse Effect Level) for the local irritative eff ect of in stomach could no t be established for males and was established at 10 mg/kg bw/day for females. Harlan Laboratories Study Report
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# 5 REFERENCES

1. Zbinden G. 1976. The role of pa thology in toxicity testing. In : Progress in Toxicology. Special Topics. Springer Verlag, Berlin, He idelberg, New York, Tokyo, Vol. 2, pp. 8-18. Harlan Laboratories Study Report
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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— EXPLANATION OF CODES AND SYMBOLS

—————————————————————————————————————————————————————————————————————————

CODES AND SYMBOLS USED AT ANIMAL LEVEL:

———————————————————————————————————————— M = Male animal F = Female animal K0 = Terminal sacrifice group + = Intercurrent death/sacrificed moribund +1 = Found dead +2 = Sacrificed moribund

CODES AND SYMBOLS USED AT ORGAN LEVEL:

——————————————————————————————————————— G = Gross observation checked off histologically * = Comment in text of individual animal data 0 = Tissue not present for histologic examination ' = Histologic examination not required + = Organ examined, findings present — = Organ examined, no pathologic findings noted (AOFT only) ( = Only one of paired organs examined/present

CODES AND SYMBOLS USED AT FINDING LEVEL:

————————————————————————————————————————— GRADE 1 = Minimal / very few / very small GRADE 2 = Slight / few / small GRADE 3 = Moderate / moderate number / moderate size GRADE 4 = Marked / many / large GRADE 5 = Massive / extensive number / extensive size P = Finding present, severity not scored ( = Finding unilateral in paired organs * = Comment in text of individual animal data Harlan Laboratories Study Report
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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS SELECTED TISSUES

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— LIVER : 5 5 5 6 — Diffuse Hypertrophy GRADE 1 : — — — 4 GRADE 2 : — — — 2

TOTAL AFFECTED : — — — 6 MEAN GRADE/TISS.AFF.: — — — 1.3

————————————————————————————————————————————————————————————————————————— FORESTOMACH : 5 5 5 6 — Hyperkeratosis GRADE 1 : — — — 2 GRADE 2 : — — — 1

TOTAL AFFECTED : — — — 3 MEAN GRADE/TISS.AFF.: — — — 1.3

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH : 5 5 5 6 — Erosion GRADE 1 : — 1 — 1

TOTAL AFFECTED : — 1 — 1 MEAN GRADE/TISS.AFF.: — 1.0 — 1.0

————————————————————————————————————————————————————————————————————————— THYMUS : 8 8 6 6 — Atrophy GRADE 1 : — 1 2 2 GRADE 3 : — — — 1

TOTAL AFFECTED : — 1 2 3 MEAN GRADE/TISS.AFF.: — 1.0 1.0 1.7

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS SELECTED TISSUES

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— TESTES : 10 6 5 10 — Tubular Atrophy GRADE 4 : — — — 1

TOTAL AFFECTED : — — — 1 MEAN GRADE/TISS.AFF.: — — — 4.0

......................................................................... — Focal Tubular Degen. GRADE 1 : — — — 3

TOTAL AFFECTED : — — — 3 MEAN GRADE/TISS.AFF.: — — — 1.0

......................................................................... — Edema GRADE 2 : — — — 1

TOTAL AFFECTED : — — — 1 MEAN GRADE/TISS.AFF.: — — — 2.0

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 5 5 6 — Follic.C.Hypertrophy GRADE 1 : — — — 3

TOTAL AFFECTED : — — — 3 MEAN GRADE/TISS.AFF.: — — — 1.0

————————————————————————————————————————————————————————————————————————— ADRENAL CORTICES : 5 5 5 6 — Diffuse Fatty Change GRADE 1 : 2 2 2 4 GRADE 2 : — — 1 1 GRADE 3 : — — — 1

TOTAL AFFECTED : 2 2 3 6 MEAN GRADE/TISS.AFF.: 1.0 1.0 1.3 1.5

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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS SELECTED TISSUES

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— LIVER : 5 5 5 6 — Diffuse Hypertrophy GRADE 1 : — — — 4 GRADE 2 : — — — 2

TOTAL AFFECTED : — — — 6 MEAN GRADE/TISS.AFF.: — — — 1.3

————————————————————————————————————————————————————————————————————————— FORESTOMACH : 6 5 5 6 — Squamous Hyperplasia GRADE 3 : — — 1 —

TOTAL AFFECTED : — — 1 — MEAN GRADE/TISS.AFF.: — — 3.0 —

......................................................................... — Submucosal Inflamm. GRADE 3 : — — 1 —

TOTAL AFFECTED : — — 1 — MEAN GRADE/TISS.AFF.: — — 3.0 —

......................................................................... — Hyperkeratosis GRADE 1 : — — 2 1

TOTAL AFFECTED : — — 2 1 MEAN GRADE/TISS.AFF.: — — 1.0 1.0

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH : 6 5 5 6 — Mucosal Atrophy GRADE 1 : — — — 1

TOTAL AFFECTED : — — — 1 MEAN GRADE/TISS.AFF.: — — — 1.0

......................................................................... Harlan Laboratories Study Report
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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS SELECTED TISSUES

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH : 6 5 5 6 — Erosion GRADE 3 : — — — 1

TOTAL AFFECTED : — — — 1 MEAN GRADE/TISS.AFF.: — — — 3.0

......................................................................... — Submucosal Inflamm. GRADE 2 : — — — 1

TOTAL AFFECTED : — — — 1 MEAN GRADE/TISS.AFF.: — — — 2.0

————————————————————————————————————————————————————————————————————————— THYMUS : 5 6 6 7 — Atrophy GRADE 1 : 3 3 2 1 GRADE 2 : 1 1 2 1 GRADE 3 : — — 1 5

TOTAL AFFECTED : 4 4 5 7 MEAN GRADE/TISS.AFF.: 1.3 1.3 1.8 2.6

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 5 5 6 — Follic.C.Hypertrophy GRADE 1 : — — — 2

TOTAL AFFECTED : — — — 2 MEAN GRADE/TISS.AFF.: — — — 1.0

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————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS SELECTED TISSUES

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— ADRENAL CORTICES : 5 5 5 6 — Diffuse Fatty Change GRADE 1 : 1 3 3 3 GRADE 2 : — — — 1

TOTAL AFFECTED : 1 3 3 4 MEAN GRADE/TISS.AFF.: 1.0 1.0 1.0 1.3

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### PATHOLOGY REPORT PAGE : 23/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— HEART : 5 — — 6 — Prog.Cardiomyopathy : 1 — — —

————————————————————————————————————————————————————————————————————————— TRACHEA : 5 — — 6 — Glandular Ectasia : 1 — — 2

————————————————————————————————————————————————————————————————————————— LIVER : 5 5 5 6 — Inflammatory Foci : 5 5 5 5 — Diffuse Hypertrophy : — — — 6 — Fatty Change:Perip. : 3 1 1 2

————————————————————————————————————————————————————————————————————————— SPLEEN : 5 — — 6 — Hematopoiesis : 5 — — 6 — Congestion : 3 — — 3

————————————————————————————————————————————————————————————————————————— MESENT. LYMPH NODE : 5 — — 6 — Lymphoid Hyperplasia: 1 — — —

————————————————————————————————————————————————————————————————————————— KIDNEYS : 5 — — 6 — Tubular Basophilia : 3 — — 3 — Hyaline Droplets : — — — 1 — Pelvic Dilation : — — — 1

————————————————————————————————————————————————————————————————————————— FORESTOMACH : 5 5 5 6 — Hyperkeratosis : — — — 3

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH : 5 5 5 6 — Glandular Dilation : — — 2 2 — Erosion : — 1 — 1

————————————————————————————————————————————————————————————————————————— ILEUM : 5 — 2 5 — Congestion : — — 2 —

————————————————————————————————————————————————————————————————————————— PEYER'S PATCHES : 5 — — 6 — Mineralization : — — — 1

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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### PATHOLOGY REPORT PAGE : 24/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— CECUM : 5 — — 6 — Congestion : 1 — — —

————————————————————————————————————————————————————————————————————————— RECTUM : 5 — — 6 — Mixed Cell Infiltr. : — — — 1 — Dilation : 1 — — 1

————————————————————————————————————————————————————————————————————————— LUNG : 5 — — 6 — Congestion : — — — 1 — Alveol.Histiocytosis: 1 — — 1 — Osseous Metaplasia : 1 — — —

————————————————————————————————————————————————————————————————————————— THYMUS : 8 8 6 6 — Macrophage Increase : 5 2 3 5 — Epithelial Cyst : 3 5 2 2 — Hemorrhage : 2 2 3 — — Congestion : 2 2 — 1 — Atrophy : — 1 2 3

————————————————————————————————————————————————————————————————————————— TESTES : 10 6 5 10 — Tubular Atrophy : — — — 1 — Focal Tubular Degen.: — — — 3 — Edema : — — — 1

————————————————————————————————————————————————————————————————————————— EPIDIDYMIDES : 10 6 5 10 — Incr.Cellular Debris: — 1 — — — Aspermia : — — — 1 — Lymphoid C.Infiltr. : — — — 1

————————————————————————————————————————————————————————————————————————— MANDIB.LYMPH NODES : 5 — — 6 — Lymphoid Hyperplasia: 3 — — 3 — Plasmocytosis : — — — 1 — Congestion : 3 — — —

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 471 of 663

### PATHOLOGY REPORT PAGE : 25/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 5 5 6 — Follic.C.Hypertrophy: — — — 3 — Ultimobranchial Cyst: — 1 — — — Thymic Ectopia : — — 1 —

————————————————————————————————————————————————————————————————————————— ADRENAL CORTICES : 5 5 5 6 — Congestion : — — — 1 — Diffuse Fatty Change: 2 2 3 6 — Access.Cort.Tissue : 1 — — —

————————————————————————————————————————————————————————————————————————— PROSTATE GLAND : 10 2 — 10 — Inflammation : — — — 1 — Atrophy : 2 — — 1

————————————————————————————————————————————————————————————————————————— COAGULATING GLANDS : 10 2 — 10 — Atrophy : — — — 1

————————————————————————————————————————————————————————————————————————— SEMINAL VESICLES : 10 2 — 10 — Atrophy : 2 — — 1

————————————————————————————————————————————————————————————————————————— BONE MARROW, FEMUR : 5 — — 6 — Fat Cells in Marrow : 2 — — 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 472 of 663

### PATHOLOGY REPORT PAGE : 26/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— GENERAL OBSERVATIONS : — — — 1 — Beginning Autolysis : — — — 1

————————————————————————————————————————————————————————————————————————— HEART : 5 — — 6 — Prog.Cardiomyopathy : 1 — — 1

————————————————————————————————————————————————————————————————————————— TRACHEA : 5 — — 6 — Glandular Ectasia : 2 — — 3

————————————————————————————————————————————————————————————————————————— LIVER : 5 5 5 6 — Inflammatory Foci : 5 5 5 5 — Diffuse Hypertrophy : — — — 6 — Fatty Change:Perip. : 1 1 1 1

————————————————————————————————————————————————————————————————————————— SPLEEN : 5 — — 6 — Hematopoiesis : 5 — — 5 — Hemosiderin Deposits: — — — 1 — Congestion : 5 — — 4 — Lymphoid Depletion : — — — 1 — Red Pulp Atrophy : — — — 1

————————————————————————————————————————————————————————————————————————— MESENT. LYMPH NODE : 5 — — 6 — Lymphoid Hyperplasia: 2 — — 1

————————————————————————————————————————————————————————————————————————— KIDNEYS : 5 — — 6 — Corticomed.Mineral. : 2 — — 1 — Tubular Basophilia : 2 — — 2

————————————————————————————————————————————————————————————————————————— FORESTOMACH : 6 5 5 6 — Dilation : — — — 1 — Squamous Hyperplasia: — — 1 — — Submucosal Inflamm. : — — 1 — — Hyperkeratosis : — — 2 1

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 473 of 663

### PATHOLOGY REPORT PAGE : 27/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH : 6 5 5 6 — Dilation : — — — 1 — Glandular Dilation : 3 2 3 2 — Mucosal Atrophy : — — — 1 — Periton.Inflammation: — — — 1 — Erosion : — — — 1 — Submucosal Inflamm. : — — — 1

————————————————————————————————————————————————————————————————————————— JEJUNUM : 5 — — 6 — Thrombosis : — — — 1

————————————————————————————————————————————————————————————————————————— CECUM : 5 — — 6 — Mixed Cell Infiltr. : — — — 1 — Congestion : 1 — — —

————————————————————————————————————————————————————————————————————————— RECTUM : 5 — — 6 — Dilation : — — — 1

————————————————————————————————————————————————————————————————————————— LUNG : 5 — — 6 — Congestion : — — — 1 — Hemorrhage : 1 — — — — Alveol.Histiocytosis: 2 — — 3 — Perivascular Cuffing: 1 — — —

————————————————————————————————————————————————————————————————————————— THYMUS : 5 6 6 7 — Macrophage Increase : 1 — 1 2 — Epithelial Cyst : 3 3 3 1 — Congestion : — — — 1 — Atrophy : 4 4 5 7

————————————————————————————————————————————————————————————————————————— OVARIES : 10 2 — 10 — Corpora Lutea : 10 2 — 10 — Congestion : — — — 1

————————————————————————————————————————————————————————————————————————— MANDIB.LYMPH NODES : 5 — — 6 — Lymphoid Hyperplasia: 4 — — 4 — Plasmocytosis : 5 — — 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 474 of 663

### PATHOLOGY REPORT PAGE : 28/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 5 5 6 — Follic.C.Hypertrophy: — — — 2

————————————————————————————————————————————————————————————————————————— ADRENAL CORTICES : 5 5 5 6 — Diffuse Fatty Change: 1 3 3 4 — Foc.Hypertrophy/Z.F.: — — 1 — — Hypertrophy/Z.Glom. : — — — 1 — Mixed Cell Infiltr. : 1 — 1 1 — Hematopoiesis : 1 — — —

————————————————————————————————————————————————————————————————————————— UTERUS : 5 1 1 6 — Implantation Sites : 5 — — 5 — Dilation : — 1 — — — Fibrosis : — — — 1 — Congestion : — — 1 —

————————————————————————————————————————————————————————————————————————— CERVIX : — 1 — — — Dilation : — 1 — —

————————————————————————————————————————————————————————————————————————— VAGINA : 5 1 — 6 — Mucification Epith. : 5 — — 5

————————————————————————————————————————————————————————————————————————— BONE MARROW, FEMUR : 5 — — 6 — Fat Cells in Marrow : 2 — — 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 475 of 663

### PATHOLOGY REPORT PAGE : 29/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 01, MALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 1

................... STOMACH — 01: Contents:, black. — No corresponding finding.

.........................................................................
ANIMAL NO: 3

................... MANDIBULAR LYMPH NODES — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, bilateral, reddish. grade 1.

.........................................................................
ANIMAL NO: 5

................... THYMUS — 01: Focus/foci, isolated, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. MANDIBULAR LYMPH NODES — 01: Discoloration, dark red. — Congestion, multifocal, bilateral, grade 2.

.........................................................................
ANIMAL NO: 6

................... THYMUS — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, grade 1. dark red.

.........................................................................
ANIMAL NO: 8

................... THYMUS — 01: Focus/foci, several, d=1 mm, — Congestion, diffuse, grade 1. dark red.

......................................................................... Harlan Laboratories Study Report
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## Page 476 of 663

### PATHOLOGY REPORT PAGE : 30/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 01, MALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 10

................... THYMUS — 01: Focus/foci, several, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red.

......................................................................... Harlan Laboratories Study Report
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## Page 477 of 663

### PATHOLOGY REPORT PAGE : 31/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 01, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 48

................... STOMACH — 01: Pylorus, mucosa: — No corresponding finding. discoloration, yellowish.

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## Page 478 of 663

### PATHOLOGY REPORT PAGE : 32/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 02, MALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 13

................... THYMUS — 01: Focus/foci, d=1 mm, many, — Congestion, diffuse, grade 1. dark red.

.........................................................................
ANIMAL NO: 16

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red.

.........................................................................
ANIMAL NO: 17

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red.

.........................................................................
ANIMAL NO: 18

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Congestion, diffuse, grade 1. dark red.

......................................................................... Harlan Laboratories Study Report
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## Page 479 of 663

### PATHOLOGY REPORT PAGE : 33/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 02, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 55

................... STOMACH — 01: Pylorus, mucosa: — SEE UNDER: GLANDULAR STOMACH. discoloration, yellowish. GLANDULAR STOMACH Finding 01 in STOMACH — Mucosal glandular dilation, diffuse, grade 1.

.........................................................................
ANIMAL NO: 58

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 2.

.........................................................................
ANIMAL NO: 59

................... UTERUS — 01: Right horn: dilation, d=6 mm. — Dilation, bilateral, grade 3. — 02: Right horn: contains fluid, — Dilation, bilateral, grade 3. bluish. — 03: Cervix: contains fluid, — SEE UNDER: CERVIX. bluish. — 04: Left horn: contains fetus. — Dilation, bilateral, grade 3. CERVIX Finding 03 in UTERUS — Dilation, grade 2.

......................................................................... Harlan Laboratories Study Report
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## Page 480 of 663

### PATHOLOGY REPORT PAGE : 34/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 03, MALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 24

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 1. dark red.

.........................................................................
ANIMAL NO: 25

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red.

.........................................................................
ANIMAL NO: 28

................... ILEUM — 01: Mucosa: discoloration, dark — Congestion, diffuse, grade 2. red.

.........................................................................
ANIMAL NO: 29

................... THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 1. dark red.

.........................................................................
ANIMAL NO: 30

................... ILEUM — 01: Mucosa: discoloration, — Congestion, diffuse, grade 2. reddish.

......................................................................... Harlan Laboratories Study Report
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## Page 481 of 663

### PATHOLOGY REPORT PAGE : 35/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 03, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 62

................... STOMACH — 01: Mucosa: discoloration, gray — No corresponding finding. white.

.........................................................................
ANIMAL NO: 63

................... STOMACH — 01: Mucosa, forestomach: — SEE UNDER: FORESTOMACH. crateriform retraction, d=2
mm. FORESTOMACH Finding 01 in STOMACH — Squamous cell hyperplasia, focal, grade 3. Finding 01 in STOMACH — Submucosal inflammation, chronic, purulent, grade 3. THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 1.

.........................................................................
ANIMAL NO: 65

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 2.

.........................................................................
ANIMAL NO: 67

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3.

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## Page 482 of 663

### PATHOLOGY REPORT PAGE : 36/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 03, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 69

................... UTERUS — 01: Both horns: discoloration, — Congestion, diffuse, grade 2. dark red.

......................................................................... Harlan Laboratories Study Report
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## Page 483 of 663

### PATHOLOGY REPORT PAGE : 37/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 04, MALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 31

................... THYMUS — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, grade 1. dark red.

.........................................................................
ANIMAL NO: 36

................... STOMACH — 01: Contents black—brown. — No corresponding finding.

......................................................................... Harlan Laboratories Study Report
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## Page 484 of 663

### PATHOLOGY REPORT PAGE : 38/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 04, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ANIMAL NO: 72

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3.

.........................................................................
ANIMAL NO: 73

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3.

.........................................................................
ANIMAL NO: 74

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3.

.........................................................................
ANIMAL NO: 77

................... OVARIES — 01: Both sides: discoloration, — Congestion, diffuse, bilateral, reddish. grade 1.

.........................................................................
ANIMAL NO: 78

................... GENERAL OBSERVATIONS — 01: Beginning autolysis. — Beginning autolysis, grade 2. STOMACH — 01: Enlarged. — SEE UNDER: FORESTOMACH. SEE UNDER: GLANDULAR STOMACH. Harlan Laboratories Study Report
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### PATHOLOGY REPORT PAGE : 39/ 124 SUMMARY TABLES HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— CORRELATION TABLE: NECROPSY — MICROSCOPY DOSE GROUP 04, FEMALE

—————————————————————————————————————————————————————————————————————————

NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

FORESTOMACH Finding 01 in STOMACH — Dilation, grade 2. GLANDULAR STOMACH Finding 01 in STOMACH — Dilation, grade 2. JEJUNUM — 01: Nodule(s), d=10x5 mm, red — Thrombosis, focal, grade 3. brown, firm. THYMUS — 01: Discoloration, dark red. — Congestion, diffuse, grade 2.

.........................................................................
ANIMAL NO: 79

................... THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3.

......................................................................... Harlan Laboratories Study Report
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## Page 486 of 663

### PATHOLOGY REPORT PAGE : 40/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— HEART — — — + — ' ' ' ' ' — Prog.Cardiomyopathy . . . 1. .

......................................................................... TRACHEA — — — + — ' ' ' ' ' — Glandular Ectasia . . . 1. .

......................................................................... LIVER + + + + + ' ' ' ' ' — Inflammatory Foci 2. 1. 2. 1. 2. — Fatty Change:Perip. 1. 2. . 1. .

......................................................................... SPLEEN + + + + + ' ' ' ' ' — Hematopoiesis 1. 1. 1. 1. 1. — Congestion . . 1. 1. 2.

......................................................................... MESENT. LYMPH NODE — — — + — ' ' ' ' ' — Lymphoid Hyperplasia . . . 1. .

......................................................................... KIDNEYS — + — + + ' ' ' ' ' — Tubular Basophilia . ( 1. . ( 1. 1.

......................................................................... URINARY BLADDER — — — — — ' ' ' ' '

......................................................................... STOMACH —G ' ' ' ' ' ' ' ' '

......................................................................... FORESTOMACH — — — — — ' ' ' ' '

......................................................................... GLANDULAR STOMACH — — — — — ' ' ' ' '

......................................................................... DUODENUM — — — — — ' ' ' ' '

......................................................................... JEJUNUM — — — — — ' ' ' ' '

......................................................................... ILEUM — — — — — ' ' ' ' '

......................................................................... PEYER'S PATCHES — — — — — ' ' ' ' '

......................................................................... CECUM — — + — — ' ' ' ' ' — Congestion . . 1. . .

......................................................................... Harlan Laboratories Study Report
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## Page 487 of 663

### PATHOLOGY REPORT PAGE : 41/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— COLON — — — — — ' ' ' ' '

......................................................................... RECTUM — + — — — ' ' ' ' ' — Dilation . 1. . . .

......................................................................... LUNG — — — + + ' ' ' ' ' — Alveol.Histiocytosis . . . 1. . — Osseous Metaplasia . . . . 1.

......................................................................... THYMUS + + + + +G +G ' +G ' +G — Macrophage Increase 1. 1. 1. 1. . . . 1. — Epithelial Cyst 2. . 1. . . 1. . . — Hemorrhage . . . . 2. . . 2. — Congestion . . . . . 1. 1. .

......................................................................... TESTES — — —* — — —* — — — —

......................................................................... EPIDIDYMIDES — — — — — — — — — —

......................................................................... MANDIB.LYMPH NODES — + +G + +G ' ' ' ' ' — Lymphoid Hyperplasia . 1. 2. 2. . — Congestion . . 1. 2. 2.

......................................................................... THYROID GLAND — — — — — ' ' ' ' '

......................................................................... PARATHYROID GLANDS ( — ( — ( — — ( — ' ' ' ' '

......................................................................... ADRENAL CORTICES — + — + + ' ' ' ' ' — Diffuse Fatty Change . . . 1. 1. — Access.Cort.Tissue . ( 1. . . .

......................................................................... ADRENAL MEDULLAS — — — — — ' ' ' ' '

......................................................................... SCIATIC NERVES — — — — — ' ' ' ' '

......................................................................... CEREBRUM — — — — — ' ' ' ' '

......................................................................... CEREBELLUM — — — — — ' ' ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 488 of 663

### PATHOLOGY REPORT PAGE : 42/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— PONS — — — — — ' ' ' ' '

......................................................................... PROSTATE GLAND — — + — + — — — — — — Atrophy . . 1. . 1. . . . . .

......................................................................... COAGULATING GLANDS — — ( — — — — — — — —

......................................................................... SEMINAL VESICLES — — + — + — — — — — — Atrophy . . 1. . ( 1. . . . . .

......................................................................... BONE MARROW, FEMUR — — + — + ' ' ' ' ' — Fat Cells in Marrow . . 1. . 1.

......................................................................... SPINAL CORD,CERVICAL — — — — — ' ' ' ' '

......................................................................... SPINAL CORD,MIDTHOR. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD,LUMBAR — — — — — ' ' ' ' '

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## Page 489 of 663

### PATHOLOGY REPORT PAGE : 43/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— HEART — + — — ' ' — ' ' ' — Prog.Cardiomyopathy . 1. . . .

......................................................................... TRACHEA — — + + ' ' — ' ' ' — Glandular Ectasia . . 1. 1. .

......................................................................... LIVER + + + + ' ' + ' ' ' — Inflammatory Foci 1. 1. 2. 1. 1. — Fatty Change:Perip. . . . 1. .

......................................................................... SPLEEN + + + + ' ' + ' ' ' — Hematopoiesis 1. 3. 2. 2. 1. — Congestion 1. 1. 2. 1. 1.

......................................................................... MESENT. LYMPH NODE — — — + ' ' + ' ' ' — Lymphoid Hyperplasia . . . 1. 1.

......................................................................... KIDNEYS + + + — ' ' — ' ' ' — Corticomed.Mineral. 1. . 1. . . — Tubular Basophilia ( 1. ( 1. . . .

......................................................................... URINARY BLADDER — — — — ' ' — ' ' '

......................................................................... STOMACH ' ' ' ' ' ' ' 'G ' '

......................................................................... FORESTOMACH — — — — ' ' — — ' '

......................................................................... GLANDULAR STOMACH — + — — ' ' + + ' ' — Glandular Dilation . 1. . . 1. 2.

......................................................................... DUODENUM — — — — ' ' — ' ' '

......................................................................... JEJUNUM — — — — ' ' — ' ' '

......................................................................... ILEUM — — — — ' ' — ' ' '

......................................................................... PEYER'S PATCHES — — — — ' ' — ' ' '

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## Page 490 of 663

### PATHOLOGY REPORT PAGE : 44/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— CECUM + — — — ' ' — ' ' ' — Congestion 1. . . . .

......................................................................... COLON — — — — ' ' — ' ' '

......................................................................... RECTUM — — — — ' ' — ' ' '

......................................................................... LUNG — — + + ' ' — ' ' ' — Hemorrhage . . . 1. . — Alveol.Histiocytosis . . 1. 2. . — Perivascular Cuffing . . . 1. .

......................................................................... THYMUS + + + + ' ' + ' ' ' — Macrophage Increase . 1. . . . — Epithelial Cyst 1. . . 1. 1. — Atrophy 1. . 2. 1. 1.

......................................................................... OVARIES + + + + + + + + + + — Corpora Lutea 4. 3. 3. 4. 3. 5. 4. 5. 5. 3.

......................................................................... MANDIB.LYMPH NODES + + + + ' ' + ' ' ' — Lymphoid Hyperplasia . 2. 1. 2. 1. — Plasmocytosis 2. 2. 1. 1. 1.

......................................................................... THYROID GLAND ( — — — — ' ' — ' ' '

......................................................................... PARATHYROID GLANDS ( — — — ( — ' ' 0 ' ' '

......................................................................... ADRENAL CORTICES — — + + ' ' + ' ' ' — Diffuse Fatty Change . . . . 1. — Mixed Cell Infiltr. . . ( 1. . . — Hematopoiesis . . . ( 1. .

......................................................................... ADRENAL MEDULLAS — — — — ' ' — ' ' '

......................................................................... SCIATIC NERVES — — — — ' ' — ' ' '

......................................................................... CEREBRUM — — — — ' ' — ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 491 of 663

### PATHOLOGY REPORT PAGE : 45/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, 0 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— CEREBELLUM — — — — ' ' — ' ' '

......................................................................... PONS — — — — ' ' — ' ' '

......................................................................... UTERUS + + + + ' ' + ' ' ' — Implantation Sites 3. 2. 2. 2. 4.

......................................................................... VAGINA + + + + ' ' + ' ' ' — Mucification Epith. 2. 2. 3. 1. 4.

......................................................................... BONE MARROW, FEMUR + — — — ' ' + ' ' ' — Fat Cells in Marrow 2. . . . 2.

......................................................................... SPINAL CORD,CERVICAL — — — — ' ' — ' ' '

......................................................................... SPINAL CORD,MIDTHOR. — — — — ' ' — ' ' '

......................................................................... SPINAL CORD,LUMBAR — — — — ' ' — ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 492 of 663

### PATHOLOGY REPORT PAGE : 46/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, 10 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 11 12 13 14 15 16 17 18 19 20 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— LIVER + + + + + ' ' ' ' ' — Inflammatory Foci 2. 2. 1. 1. 1. — Fatty Change:Perip. . 1. . . .

......................................................................... FORESTOMACH — — — — — ' ' ' ' '

......................................................................... GLANDULAR STOMACH — — — — + ' ' ' ' ' — Erosion . . . . 1.

......................................................................... THYMUS — + +G + + +G +G +G ' ' — Macrophage Increase . . 1. . 1. . . . — Epithelial Cyst . 1. . 1. 1. 1. . 1. — Hemorrhage . . . . . 2. 2. . — Congestion . . 1. . . . . 1. — Atrophy . 1. . . . . . .

......................................................................... TESTES — — — —* —* ' ' ' — '

......................................................................... EPIDIDYMIDES — — — — — ' ' ' + ' — Incr.Cellular Debris . . . . . 1.

......................................................................... THYROID GLAND — — — — + ' ' ' ' ' — Ultimobranchial Cyst . . . . ( 1.

......................................................................... ADRENAL CORTICES — — + + — ' ' ' ' ' — Diffuse Fatty Change . . 1. 1. .

......................................................................... ADRENAL MEDULLAS ( — 0 ( — — — ' ' ' ' '

......................................................................... PROSTATE GLAND — ' ' ' ' ' ' ' — '

......................................................................... COAGULATING GLANDS — ' ' ' ' ' ' ' — '

......................................................................... SEMINAL VESICLES — ' ' ' ' ' ' ' — '

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## Page 493 of 663

### PATHOLOGY REPORT PAGE : 47/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, 10 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 51 52 53 54 55 56 57 58 59 60 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— LIVER + + + + + ' ' ' ' ' — Inflammatory Foci 1. 1. 1. 1. 2. — Fatty Change:Perip. . . . 1. .

......................................................................... STOMACH ' ' ' ' 'G ' ' ' ' '

......................................................................... FORESTOMACH — — — — — ' ' ' ' '

......................................................................... GLANDULAR STOMACH — — — + + ' ' ' ' ' — Glandular Dilation . . . 1. 1.

......................................................................... THYMUS + + + + — ' ' +G ' ' — Epithelial Cyst 2. 1. . 1. . . — Atrophy . 1. 1. 1. . 2.

......................................................................... OVARIES + ' ' ' ' ' ' ' + ' — Corpora Lutea 5. 4.

......................................................................... THYROID GLAND — — — — — ' ' ' ' '

......................................................................... ADRENAL CORTICES — + + — + ' ' ' ' ' — Diffuse Fatty Change . 1. 1. . 1.

......................................................................... ADRENAL MEDULLAS — — — ( — — ' ' ' ' '

......................................................................... UTERUS ' ' ' ' ' ' ' ' +G ' — Dilation 3.

......................................................................... CERVIX ' ' ' ' ' ' ' ' + ' — Dilation 2.

......................................................................... VAGINA ' ' ' ' ' ' ' ' — '

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## Page 494 of 663

### PATHOLOGY REPORT PAGE : 48/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, 30 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 21 22 23 24 25 26 27 28 29 30 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— LIVER + + + + + ' ' ' ' ' — Inflammatory Foci 2. 1. 1. 2. 1. — Fatty Change:Perip. 1. . . . .

......................................................................... FORESTOMACH — — — — — ' ' ' ' '

......................................................................... GLANDULAR STOMACH — + — + — ' ' ' ' ' — Glandular Dilation . 1. . 1. .

......................................................................... ILEUM ' ' ' ' ' ' ' +G ' +G — Congestion 2. 2.

......................................................................... THYMUS + — + +G +G ' ' ' +G ' — Macrophage Increase 1. . . 1. . 1. — Epithelial Cyst . . 1. . 1. . — Hemorrhage . . . 1. 2. 1. — Atrophy 1. . 1. . . .

......................................................................... TESTES — — — — — ' ' ' ' '

......................................................................... EPIDIDYMIDES — — — — — ' ' ' ' '

......................................................................... THYROID GLAND — + — — — ' ' ' ' ' — Thymic Ectopia . ( 2. . . .

......................................................................... ADRENAL CORTICES + — — + + ' ' ' ' ' — Diffuse Fatty Change 2. . . 1. 1.

......................................................................... ADRENAL MEDULLAS — — — — — ' ' ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 495 of 663

### PATHOLOGY REPORT PAGE : 49/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, 30 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 61 62 63 64 65 66 67 68 69 70 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— LIVER + + + + + ' ' ' ' ' — Inflammatory Foci 1. 1. 1. 1. 1. — Fatty Change:Perip. . . . 1. .

......................................................................... STOMACH ' —G 'G ' ' ' ' ' ' '

......................................................................... FORESTOMACH — + + — + ' ' ' ' ' — Squamous Hyperplasia . . 3. . . — Submucosal Inflamm. . . 3* . . — Hyperkeratosis . 1. . . 1.

......................................................................... GLANDULAR STOMACH + — + + — ' ' ' ' ' — Glandular Dilation 1. . 1. 1. .

......................................................................... THYMUS — + +G + +G ' +G ' ' ' — Macrophage Increase . . . 1. . . — Epithelial Cyst . 1. . 1. 1. . — Atrophy . 2. 1. 1. 2. 3.

......................................................................... THYROID GLAND — — — — — ' ' ' ' '

......................................................................... ADRENAL CORTICES + — — + + ' ' ' ' ' — Diffuse Fatty Change 1. . . 1. 1. — Foc.Hypertrophy/Z.F. . . . ( 1. . — Mixed Cell Infiltr. . . . 2. .

......................................................................... ADRENAL MEDULLAS — — — — — ' ' ' ' '

......................................................................... UTERUS ' ' ' ' ' ' ' ' +G ' — Congestion 2.

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## Page 496 of 663

### PATHOLOGY REPORT PAGE : 50/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 MK0 MK0 MK0 MK0 MK0+ MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— HEART — — — — — — ' ' ' '

......................................................................... TRACHEA — — + — + — ' ' ' ' — Glandular Ectasia . . 1. . 1. .

......................................................................... LIVER + + + + + + ' ' ' ' — Inflammatory Foci 2. 1. 1. 1. . 1. — Diffuse Hypertrophy 1. 2. 1. 2. 1. 1. — Fatty Change:Perip. . 1. . . 2. .

......................................................................... SPLEEN + + + + + + ' ' ' ' — Hematopoiesis 1. 1. 2. 1. 1. 1. — Congestion . 1. . 1. 1. .

......................................................................... MESENT. LYMPH NODE — — — — — — ' ' ' '

......................................................................... KIDNEYS + + + — — + ' ' ' ' — Tubular Basophilia ( 1. ( 1. ( 1. . . . — Hyaline Droplets . . 1. . . . — Pelvic Dilation . . . . . ( 1.

......................................................................... URINARY BLADDER — — — — — — ' ' ' '

......................................................................... STOMACH ' ' ' ' ' —G ' ' ' '

......................................................................... FORESTOMACH — + — — + + ' ' ' ' — Hyperkeratosis . 1. . . 2. 1.

......................................................................... GLANDULAR STOMACH — — — + + — ' ' ' ' — Glandular Dilation . . . 1. 1. . — Erosion . . . . 1. .

......................................................................... DUODENUM — — — — — — ' ' ' '

......................................................................... JEJUNUM — — — — — — ' ' ' '

......................................................................... ILEUM — — — — — 0 ' ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 497 of 663

### PATHOLOGY REPORT PAGE : 51/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 MK0 MK0 MK0 MK0 MK0+ MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— PEYER'S PATCHES — — — — — + ' ' ' ' — Mineralization . . . . . 1.

......................................................................... CECUM — — — — — — ' ' ' '

......................................................................... COLON — — — — — — ' ' ' '

......................................................................... RECTUM + + — — — — ' ' ' ' — Mixed Cell Infiltr. . 2. . . . . — Dilation 1. . . . . .

......................................................................... LUNG + — — — + — ' ' ' ' — Congestion . . . . 1. . — Alveol.Histiocytosis 1. . . . . .

......................................................................... THYMUS +G + + + +* + ' ' ' ' — Macrophage Increase 1. 1. 1. 1. . 1. — Epithelial Cyst . 1. . . . 1. — Congestion 1. . . . . . — Atrophy 1. 1. . . 3. .

......................................................................... TESTES — + — + + — + — —* —* — Tubular Atrophy . . . . . . 4. . . . — Focal Tubular Degen. . ( 1. . ( 1. ( 1. . . . . . — Edema . . . . . . 2. . . .

......................................................................... EPIDIDYMIDES — — — — — — + — — — — Aspermia . . . . . . P. . . . — Lymphoid C.Infiltr. . . . . . . ( 1. . . .

......................................................................... MANDIB.LYMPH NODES — — + + + — ' ' ' ' — Lymphoid Hyperplasia . . 1. 2. 1. . — Plasmocytosis . . . 1. . .

......................................................................... THYROID GLAND + + — — — + ' ' ' ' — Follic.C.Hypertrophy 1. 1. . . . 1.

......................................................................... PARATHYROID GLANDS ( — — ( — ( — — — ' ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 498 of 663

### PATHOLOGY REPORT PAGE : 52/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 MK0 MK0 MK0 MK0 MK0+ MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— ADRENAL CORTICES + + + + + + ' ' ' ' — Congestion . . 1. . . . — Diffuse Fatty Change 1. 1. 2. 1. 3. 1.

......................................................................... ADRENAL MEDULLAS — — — ( — — ( — ' ' ' '

......................................................................... SCIATIC NERVES — — — — — — ' ' ' '

......................................................................... CEREBRUM — — — — — — ' ' ' '

......................................................................... CEREBELLUM — — — — — — ' ' ' '

......................................................................... PONS — — — — — — ' ' ' '

......................................................................... PROSTATE GLAND — — — + + — — — — — — Inflammation . . . 2. . . . . . . — Atrophy . . . . 2. . . . . .

......................................................................... COAGULATING GLANDS — — — ( — + — — — — — — Atrophy . . . . 2. . . . . .

......................................................................... SEMINAL VESICLES — — — — + — — — — — — Atrophy . . . . 2. . . . . .

......................................................................... BONE MARROW, FEMUR — — + — + + ' ' ' ' — Fat Cells in Marrow . . 1. . 1. 1.

......................................................................... SPINAL CORD,CERVICAL — — — — — — ' ' ' '

......................................................................... SPINAL CORD,MIDTHOR. — — — — — — ' ' ' '

......................................................................... SPINAL CORD,LUMBAR — — — — — — ' ' ' '

......................................................................... Harlan Laboratories Study Report
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## Page 499 of 663

### PATHOLOGY REPORT PAGE : 53/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0+ FK0 FK0

————————————————————————————————————————————————————————————————————————— GENERAL OBSERVATIONS ' ' ' ' ' ' ' +G ' ' — Beginning Autolysis 2.

......................................................................... HEART — — — + — ' ' — ' ' — Prog.Cardiomyopathy . . . 1. . .

......................................................................... TRACHEA — + — + + ' ' — ' ' — Glandular Ectasia . 1. . 1. 1. .

......................................................................... LIVER + + + + + ' ' + ' ' — Inflammatory Foci 1. 1. 1. 1. 1. . — Diffuse Hypertrophy 1. 2. 1. 2. 1. 1. — Fatty Change:Perip. 2. . . . . .

......................................................................... SPLEEN + + + + + ' ' + ' ' — Hematopoiesis 1. 2. 2. 2. 2. . — Hemosiderin Deposits . . . . . 2. — Congestion 1. 1. 2. . 2. . — Lymphoid Depletion . . . . . 2. — Red Pulp Atrophy . . . . . 1.

......................................................................... MESENT. LYMPH NODE + — — — — ' ' — ' ' — Lymphoid Hyperplasia 1. . . . . .

......................................................................... KIDNEYS — — + — — ' ' + ' ' — Corticomed.Mineral. . . 1. . . . — Tubular Basophilia . . ( 1. . . ( 1.

......................................................................... URINARY BLADDER — — — — — ' ' — ' '

......................................................................... STOMACH ' ' ' ' ' ' ' 'G ' '

......................................................................... FORESTOMACH + — — — — ' ' + ' ' — Dilation . . . . . 2. — Hyperkeratosis 1. . . . . .

......................................................................... Harlan Laboratories Study Report
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## Page 500 of 663

### PATHOLOGY REPORT PAGE : 54/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0+ FK0 FK0

————————————————————————————————————————————————————————————————————————— GLANDULAR STOMACH + — — + + ' ' + ' ' — Dilation . . . . . 2. — Glandular Dilation 1. . . . 1. . — Mucosal Atrophy 1. . . . . . — Periton.Inflammation . . . . . 2. — Erosion . . . 3. . . — Submucosal Inflamm. . . . 2. . .

......................................................................... DUODENUM — — — — — ' ' — ' '

......................................................................... JEJUNUM — — — — — ' ' +G ' ' — Thrombosis . . . . . 3.

......................................................................... ILEUM — — — — — ' ' — ' '

......................................................................... PEYER'S PATCHES — — — — — ' ' — ' '

......................................................................... CECUM — — — — + ' ' — ' ' — Mixed Cell Infiltr. . . . . 1. .

......................................................................... COLON — — — — — ' ' — ' '

......................................................................... RECTUM — — — + — ' ' — ' ' — Dilation . . . 1. . .

......................................................................... LUNG + — — + + ' ' + ' ' — Congestion . . . . . 1. — Alveol.Histiocytosis 2. . . 1. 1. .

......................................................................... THYMUS + +G +G +G + ' ' +G +G ' — Macrophage Increase 1. . . . 1. . . — Epithelial Cyst . 1. . . . . . — Congestion . . . . . 2. . — Atrophy 1. 3. 3. 3. 3. 2. 3.

......................................................................... OVARIES + + + + + + +G + + + — Corpora Lutea 3. 3. 4. 3. 4. 3. 5. 5. 4. 3. — Congestion . . . . . . 1. . . .

......................................................................... Harlan Laboratories Study Report
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## Page 501 of 663

### PATHOLOGY REPORT PAGE : 55/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 90 MG/KG BW/DAY

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0+ FK0 FK0

————————————————————————————————————————————————————————————————————————— MANDIB.LYMPH NODES + + + + + ' ' — ' ' — Lymphoid Hyperplasia 1. 1. . 2. 2. . — Plasmocytosis . . 1. 1. 2. .

......................................................................... THYROID GLAND + — — + — ' ' — ' ' — Follic.C.Hypertrophy 1. . . 1. . .

......................................................................... PARATHYROID GLANDS ( — — — 0 — ' ' ( — ' '

......................................................................... ADRENAL CORTICES + + + + + ' ' — ' ' — Diffuse Fatty Change . 1. 1. 2. 1. . — Hypertrophy/Z.Glom. . . . . 1. . — Mixed Cell Infiltr. ( 1. . . . . .

......................................................................... ADRENAL MEDULLAS — — — — — ' ' — ' '

......................................................................... SCIATIC NERVES — — — — — ' ' — ' '

......................................................................... CEREBRUM — — — — — ' ' — ' '

......................................................................... CEREBELLUM — — — — — ' ' — ' '

......................................................................... PONS — — — — — ' ' — ' '

......................................................................... UTERUS + + + + + ' ' — ' ' — Implantation Sites 3. 3. 2. 2. 3. . — Fibrosis . . . . 2. .

......................................................................... VAGINA + + + + + ' ' — ' ' — Mucification Epith. 1. 2. 1. 3. 3. .

......................................................................... BONE MARROW, FEMUR — + — — + ' ' + ' ' — Fat Cells in Marrow . 1. . . 1. 2.

......................................................................... SPINAL CORD,CERVICAL — — — — — ' ' — ' '

......................................................................... SPINAL CORD,MIDTHOR. — — — — — ' ' — ' '

......................................................................... SPINAL CORD,LUMBAR — — — — — ' ' — ' '

......................................................................... Harlan Laboratories Study Report
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## Page 502 of 663

### PATHOLOGY REPORT PAGE : 56/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 01, 0 MG/KG BW/DAY

—————————————————————————————————————————————————————————————————————————

ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 1 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 2 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 3 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 4 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 5 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 6 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 7 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 8 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 9 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 10 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11

......................................................................... 41 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 42 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 43 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 44 F K0 K0 44 11—AUG—11 23—SEP—11 24—SEP—11 45 F K0 K0 39 11—AUG—11 18—SEP—11 19—SEP—11 46 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11 47 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 48 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 49 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 50 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11

......................................................................... Harlan Laboratories Study Report
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## Page 503 of 663

### PATHOLOGY REPORT PAGE : 57/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 1

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Contents:, black. — No corresponding finding. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 —Periportal fatty change, fine droplet, grade 1 SPLEEN: —Hematopoiesis, grade 1 STOMACH: No microscopic finding corresponding to necropsy observation no. 01. THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, multiple, grade 2 PARATHYROID GLANDS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 504 of 663

### PATHOLOGY REPORT PAGE : 58/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 2

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Periportal fatty change, fine droplet, grade 2 SPLEEN: —Hematopoiesis, grade 1 KIDNEYS: —Tubular basophilia, focal, unilateral, grade 1 RECTUM: —Dilation, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Accessory cortical tissue, single, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 505 of 663

### PATHOLOGY REPORT PAGE : 59/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 3

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

MANDIBULAR LYMPH NODES — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, bilateral, reddish. grade 1. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 CECUM: —Congestion, diffuse, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, multiple, grade 1 TESTES: Rete testis transitional tubules MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Congestion, diffuse, bilateral, grade 1 This finding corresponds to necropsy observation no: 01. PARATHYROID GLANDS: Only one of paired organs examined/present PROSTATE GLAND: —Atrophy, diffuse, grade 1 COAGULATING GLANDS (ANTERIOR PROSTATE): Only one of paired organs examined/present SEMINAL VESICLES: —Atrophy, diffuse, bilateral, grade 1 Harlan Laboratories Study Report
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## Page 506 of 663

### PATHOLOGY REPORT PAGE : 60/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 3

......................................................................... BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 4

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

HEART: —Progressive cardiomyopathy, focal, grade 1 TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Periportal fatty change, fine droplet, grade 1 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 MESENTERIC LYMPH NODE: —Lymphoid hyperplasia, diffuse, germinal centers, grade 1 KIDNEYS: —Tubular basophilia, focal, unilateral, grade 1 LUNG: —Alveolar histiocytosis, multifocal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 Harlan Laboratories Study Report
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## Page 507 of 663

### PATHOLOGY REPORT PAGE : 61/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 4

.........................................................................
MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Congestion, focal, bilateral, grade 2 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 5

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, isolated, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. MANDIBULAR LYMPH NODES — 01: Discoloration, dark red. — Congestion, multifocal, bilateral, grade 2. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 2 KIDNEYS: —Tubular basophilia, focal, bilateral, grade 1 LUNG: —Osseous metaplasia, focal, grade 1 Harlan Laboratories Study Report
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## Page 508 of 663

### PATHOLOGY REPORT PAGE : 62/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 5

.........................................................................
THYMUS: —Hemorrhage, multifocal, grade 2 This finding corresponds to necropsy observation no: 01. MANDIBULAR LYMPH NODES: —Congestion, multifocal, bilateral, grade 2 This finding corresponds to necropsy observation no: 01. PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 PROSTATE GLAND: —Atrophy, diffuse, grade 1 SEMINAL VESICLES: —Atrophy, diffuse, unilateral, grade 1 BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 6

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
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## Page 509 of 663

### PATHOLOGY REPORT PAGE : 63/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 6

.........................................................................
* MICROSCOPIC FINDINGS

THYMUS: —Epithelial Cyst, single, grade 1 —Congestion, diffuse, grade 1 This finding corresponds to necropsy observation no: 01. TESTES: Rete testis transitional tubules ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 7

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

NO MICROSCOPIC FINDINGS NOTED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 510 of 663

### PATHOLOGY REPORT PAGE : 64/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 8

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, several, d=1 mm, — Congestion, diffuse, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Congestion, diffuse, grade 1 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 9

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

NO MICROSCOPIC FINDINGS NOTED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 511 of 663

### PATHOLOGY REPORT PAGE : 65/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 10

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, several, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Increased number of macrophages, cortex, grade 1 —Hemorrhage, multifocal, grade 2 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 512 of 663

### PATHOLOGY REPORT PAGE : 66/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 41

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 KIDNEYS: —Corticomedullary mineralization, multifocal, bilateral, grade 1 —Tubular basophilia, focal, unilateral, grade 1 CECUM: —Congestion, diffuse, grade 1 THYMUS: —Epithelial Cyst, multiple, grade 1 —Atrophy, diffuse, cortex, grade 1 OVARIES: —Corpora lutea, bilateral, grade 4 MANDIBULAR LYMPH NODES: —Plasmocytosis, bilateral, grade 2 THYROID GLAND (BOTH LOBES): Only one of paired organs examined/present PARATHYROID GLANDS: Only one of paired organs examined/present UTERUS: —Implantation sites, multiple, grade 3 VAGINA: —Epithelial mucification, diffuse, grade 2 BONE MARROW (FEMUR): —Fat cells in marrow, grade 2 Harlan Laboratories Study Report
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## Page 513 of 663

### PATHOLOGY REPORT PAGE : 67/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 41

.........................................................................
ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 42

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

HEART: —Progressive cardiomyopathy, focal, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 SPLEEN: —Hematopoiesis, grade 3 —Congestion, diffuse, grade 1 KIDNEYS: —Tubular basophilia, multifocal, unilateral, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, focal, with mixed cells in it, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 OVARIES: —Corpora lutea, bilateral, grade 3 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Plasmocytosis, bilateral, grade 2 Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 514 of 663

### PATHOLOGY REPORT PAGE : 68/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 42

.........................................................................
UTERUS: —Implantation sites, multiple, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 43

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 2 SPLEEN: —Hematopoiesis, grade 2 —Congestion, diffuse, grade 2 KIDNEYS: —Corticomedullary mineralization, multifocal, bilateral, grade 1 LUNG: —Alveolar histiocytosis, focal, grade 1 THYMUS: —Atrophy, diffuse, cortex, grade 2 OVARIES: —Corpora lutea, bilateral, grade 3 Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 515 of 663

### PATHOLOGY REPORT PAGE : 69/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 43

.........................................................................
MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 —Plasmocytosis, bilateral, grade 1 ADRENAL CORTICES: —Mixed cell infiltration, focal, unilateral, grade 1 UTERUS: —Implantation sites, single, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 44

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Periportal fatty change, fine droplet, grade 1 SPLEEN: —Hematopoiesis, grade 2 —Congestion, diffuse, grade 1 MESENTERIC LYMPH NODE: —Lymphoid hyperplasia, diffuse, germinal centers, grade 1 Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 516 of 663

### PATHOLOGY REPORT PAGE : 70/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 44

.........................................................................
LUNG: —Hemorrhage, focal, grade 1 —Alveolar histiocytosis, focal, grade 2 —Perivascular cuffing, focal, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 OVARIES: —Corpora lutea, bilateral, grade 4 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Plasmocytosis, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Hematopoiesis, focal, unilateral, grade 1 UTERUS: —Implantation sites, single, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 39 * ANIMAL NO. : 45

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED. Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 517 of 663

### PATHOLOGY REPORT PAGE : 71/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 45

.........................................................................
* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 3

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 46

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 5

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 47

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED. Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 518 of 663

### PATHOLOGY REPORT PAGE : 72/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 47

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 MESENTERIC LYMPH NODE: —Lymphoid hyperplasia, diffuse, germinal centers, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 OVARIES: —Corpora lutea, bilateral, grade 4 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 —Plasmocytosis, bilateral, grade 1 PARATHYROID GLANDS: Tissue not present for histologic examination ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 UTERUS: —Implantation sites, multiple, grade 4 VAGINA: —Epithelial mucification, diffuse, grade 4 BONE MARROW (FEMUR): —Fat cells in marrow, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 519 of 663

### PATHOLOGY REPORT PAGE : 73/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 48

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Pylorus, mucosa: — No corresponding finding. discoloration, yellowish. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

STOMACH: No microscopic finding corresponding to necropsy observation no. 01. FORESTOMACH: Organ examined, no pathologic findings noted GLANDULAR STOMACH: —Mucosal glandular dilation, diffuse, grade 2 OVARIES: —Corpora lutea, bilateral, grade 5

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 49

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED. Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 520 of 663

### PATHOLOGY REPORT PAGE : 74/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, 0 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 49

.........................................................................
* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 5

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 50

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 521 of 663

### PATHOLOGY REPORT PAGE : 75/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 02, 10 MG/KG BW/DAY

—————————————————————————————————————————————————————————————————————————

ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 11 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 12 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 13 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 14 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 15 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 16 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 17 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 18 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 19 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 20 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11

......................................................................... 51 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11 52 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 53 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 54 F K0 K0 40 11—AUG—11 19—SEP—11 20—SEP—11 55 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 56 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 57 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 58 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 59 F K0 K0 39 11—AUG—11 18—SEP—11 19—SEP—11 60 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11

......................................................................... Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 522 of 663

### PATHOLOGY REPORT PAGE : 76/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 11

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 ADRENAL MEDULLAS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 12

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 —Periportal fatty change, fine droplet, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 ADRENAL MEDULLAS: Tissue not present for histologic examination ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 523 of 663

### PATHOLOGY REPORT PAGE : 77/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 13

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, d=1 mm, many, — Congestion, diffuse, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Congestion, diffuse, grade 1 This finding corresponds to necropsy observation no: 01. ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ADRENAL MEDULLAS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 14

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED. Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 524 of 663

### PATHOLOGY REPORT PAGE : 78/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 14

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 TESTES: Rete testis transitional tubules ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 15

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 GLANDULAR STOMACH: —Erosion, single, acute, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, single, grade 1 TESTES: Rete testis transitional tubules Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 525 of 663

### PATHOLOGY REPORT PAGE : 79/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 15

......................................................................... THYROID GLAND (BOTH LOBES): —Ultimobranchial cyst, single, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 16

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Epithelial Cyst, single, grade 1 —Hemorrhage, multifocal, grade 2 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 526 of 663

### PATHOLOGY REPORT PAGE : 80/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 17

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Hemorrhage, multifocal, grade 2 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 18

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Congestion, diffuse, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Epithelial Cyst, multiple, grade 1 —Congestion, diffuse, grade 1 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 527 of 663

### PATHOLOGY REPORT PAGE : 81/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 19

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

EPIDIDYMIDES: —Increased intratubular cellular debris, caput, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 20

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 528 of 663

### PATHOLOGY REPORT PAGE : 82/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 51

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Epithelial Cyst, multiple, grade 2 OVARIES: —Corpora lutea, bilateral, grade 5 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 52

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Epithelial Cyst, multiple, grade 1 —Atrophy, diffuse, cortex, grade 1 Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 529 of 663

### PATHOLOGY REPORT PAGE : 83/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 52

.........................................................................
ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 53

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, focal, grade 1 THYMUS: —Atrophy, diffuse, cortex, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 530 of 663

### PATHOLOGY REPORT PAGE : 84/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 40 * ANIMAL NO. : 54

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Periportal fatty change, fine droplet, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, focal, with mixed cells in it, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 ADRENAL MEDULLAS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 55

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Pylorus, mucosa: — SEE UNDER: GLANDULAR STOMACH. discoloration, yellowish. GLANDULAR STOMACH Finding 01 in STOMACH — Mucosal glandular dilation, diffuse, grade 1. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 531 of 663

### PATHOLOGY REPORT PAGE : 85/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 55

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 STOMACH: For diagnosis of necropsy observation no. 01 see under: GLANDULAR STOMACH. GLANDULAR STOMACH: —Mucosal glandular dilation, diffuse, grade 1 This finding corresponds to necropsy observation no.: 01 in the STOMACH. ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 56

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 532 of 663

### PATHOLOGY REPORT PAGE : 86/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 57

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 58

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 2. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Atrophy, diffuse, cortex, grade 2 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 533 of 663

### PATHOLOGY REPORT PAGE : 87/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 39 * ANIMAL NO. : 59

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

UTERUS — 01: Right horn: dilation, d=6 mm. — Dilation, bilateral, grade 3. — 02: Right horn: contains fluid, — Dilation, bilateral, grade 3. bluish. — 03: Cervix: contains fluid, — SEE UNDER: CERVIX. bluish. — 04: Left horn: contains fetus. — Dilation, bilateral, grade 3. CERVIX Finding 03 in UTERUS — Dilation, grade 2. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 4 UTERUS: For diagnosis of necropsy observation no. 03 see under: CERVIX. —Dilation, bilateral, grade 3 This finding corresponds to necropsy observations nos: 01,02,04. CERVIX: —Dilation, grade 2 This finding corresponds to necropsy observation no.: 03 in the UTERUS. VAGINA: Organ examined, no pathologic findings noted

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 534 of 663

### PATHOLOGY REPORT PAGE : 88/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 10 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 60

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 535 of 663

### PATHOLOGY REPORT PAGE : 89/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 03, 30 MG/KG BW/DAY

—————————————————————————————————————————————————————————————————————————

ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 21 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 22 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 23 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 24 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 25 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 26 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 27 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 28 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 29 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 30 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11

......................................................................... 61 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 62 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 63 F K0 K0 44 11—AUG—11 23—SEP—11 24—SEP—11 64 F K0 K0 45 11—AUG—11 24—SEP—11 25—SEP—11 65 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 66 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11 67 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 68 F K0 K0 40 11—AUG—11 19—SEP—11 20—SEP—11 69 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 70 F K0 K0 52 11—AUG—11 01—OCT—11 01—OCT—11

......................................................................... Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 536 of 663

### PATHOLOGY REPORT PAGE : 90/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 21

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 —Periportal fatty change, fine droplet, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Atrophy, diffuse, cortex, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 22

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, focal, grade 1 Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 537 of 663

### PATHOLOGY REPORT PAGE : 91/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 22

......................................................................... THYROID GLAND (BOTH LOBES): —Thymic ectopia, focal, unilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 23

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 538 of 663

### PATHOLOGY REPORT PAGE : 92/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 24

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Hemorrhage, multifocal, grade 1 This finding corresponds to necropsy observation no: 01. ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 25

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 2. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 539 of 663

### PATHOLOGY REPORT PAGE : 93/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 25

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Hemorrhage, multifocal, grade 2 This finding corresponds to necropsy observation no: 01. ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 26

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 540 of 663

### PATHOLOGY REPORT PAGE : 94/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 27

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 28

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ILEUM — 01: Mucosa: discoloration, dark — Congestion, diffuse, grade 2. red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

ILEUM: —Congestion, diffuse, grade 2 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 541 of 663

### PATHOLOGY REPORT PAGE : 95/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 29

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, many, d=1 mm, — Hemorrhage, multifocal, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Increased number of macrophages, cortex, grade 1 —Hemorrhage, multifocal, grade 1 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 30

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

ILEUM — 01: Mucosa: discoloration, — Congestion, diffuse, grade 2. reddish. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 542 of 663

### PATHOLOGY REPORT PAGE : 96/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 30

.........................................................................
* MICROSCOPIC FINDINGS

ILEUM: —Congestion, diffuse, grade 2 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 543 of 663

### PATHOLOGY REPORT PAGE : 97/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 61

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, focal, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 62

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Mucosa: discoloration, gray — No corresponding finding. white. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 544 of 663

### PATHOLOGY REPORT PAGE : 98/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 62

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 STOMACH: No microscopic finding corresponding to necropsy observation no. 01. FORESTOMACH: —Hyperkeratosis, diffuse, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 63

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Mucosa, forestomach: — SEE UNDER: FORESTOMACH. crateriform retraction, d=2
mm. FORESTOMACH Finding 01 in STOMACH — Squamous cell hyperplasia, focal, grade 3. Finding 01 in STOMACH — Submucosal inflammation, chronic, purulent, grade 3. THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 1. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 545 of 663

### PATHOLOGY REPORT PAGE : 99/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 63

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, focal, grade 1 STOMACH: For diagnosis of necropsy observation no. 01 see under: FORESTOMACH. FORESTOMACH: —Squamous cell hyperplasia, focal, grade 3 This finding corresponds to necropsy observation no.: 01 in the STOMACH. —Submucosal inflammation, chronic, purulent, grade 3 Likely ulceration of nonglandular stomach although not in section. This finding corresponds to necropsy observation no.: 01 in the STOMACH. GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 THYMUS: —Atrophy, diffuse, cortex, grade 1 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 45 * ANIMAL NO. : 64

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED. Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 546 of 663

### PATHOLOGY REPORT PAGE : 100/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 64

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Periportal fatty change, fine droplet, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, focal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 —Focal hypertrophy of z.fasciculata, single, unilateral, grade 1 —Mixed cell infiltration, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 65

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 2. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 547 of 663

### PATHOLOGY REPORT PAGE : 101/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 65

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 FORESTOMACH: —Hyperkeratosis, diffuse, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 2 This finding corresponds to necropsy observation no: 01. ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 66

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 548 of 663

### PATHOLOGY REPORT PAGE : 102/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 67

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

THYMUS: —Atrophy, diffuse, cortex, grade 3 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 40 * ANIMAL NO. : 68

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 549 of 663

### PATHOLOGY REPORT PAGE : 103/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 30 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 69

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

UTERUS — 01: Both horns: discoloration, — Congestion, diffuse, grade 2. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

UTERUS: —Congestion, diffuse, grade 2 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 52 * ANIMAL NO. : 70

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS
NO EXAMINATION REQUIRED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 550 of 663

### PATHOLOGY REPORT PAGE : 104/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 04, 90 MG/KG BW/DAY

—————————————————————————————————————————————————————————————————————————

ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 31 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 32 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 33 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 34 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 35 M K0 +2 9 11—AUG—11 19—AUG—11 19—AUG—11 36 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 37 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 38 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 39 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11 40 M K0 K0 28 11—AUG—11 07—SEP—11 08—SEP—11

......................................................................... 71 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11 72 F K0 K0 42 11—AUG—11 21—SEP—11 22—SEP—11 73 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 74 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 75 F K0 K0 45 11—AUG—11 24—SEP—11 25—SEP—11 76 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 77 F K0 K0 41 11—AUG—11 20—SEP—11 21—SEP—11 78 F K0 +1 15 11—AUG—11 25—AUG—11 26—AUG—11 79 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11 80 F K0 K0 43 11—AUG—11 22—SEP—11 23—SEP—11

......................................................................... Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 551 of 663

### PATHOLOGY REPORT PAGE : 105/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 31

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Focus/foci, isolated, d=1 mm, — Congestion, diffuse, grade 1. dark red. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 2 —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hematopoiesis, grade 1 KIDNEYS: —Tubular basophilia, focal, unilateral, grade 1 RECTUM: —Dilation, grade 1 LUNG: —Alveolar histiocytosis, focal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Congestion, diffuse, grade 1 This finding corresponds to necropsy observation no: 01. —Atrophy, diffuse, cortex, grade 1 THYROID GLAND (BOTH LOBES): —Follicular cell hypertrophy, diffuse, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 552 of 663

### PATHOLOGY REPORT PAGE : 106/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 32

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 2 —Periportal fatty change, fine droplet, grade 1 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 KIDNEYS: —Tubular basophilia, focal, unilateral, grade 1 FORESTOMACH: —Hyperkeratosis, diffuse, grade 1 RECTUM: —Mixed cell infiltration, focal, grade 2 THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 1 TESTES: —Focal tubular degeneration, single, with atrophy, unilateral, grade 1 THYROID GLAND (BOTH LOBES): —Follicular cell hypertrophy, diffuse, bilateral, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 553 of 663

### PATHOLOGY REPORT PAGE : 107/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 33

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hematopoiesis, grade 2 KIDNEYS: —Tubular basophilia, focal, unilateral, grade 1 —Hyaline droplets, convoluted portion of proximal tubules, bilateral, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Congestion, diffuse, bilateral, grade 1 —Diffuse fatty change, zona fasciculata, bilateral, grade 2 BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 554 of 663

### PATHOLOGY REPORT PAGE : 108/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 34

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 2 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, focal, with mixed cells in it, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 TESTES: —Focal tubular degeneration, single, with atrophy, unilateral, grade 1 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Plasmocytosis, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ADRENAL MEDULLAS: Only one of paired organs examined/present PROSTATE GLAND: —Inflammation, focal, chronic, active, grade 2 COAGULATING GLANDS (ANTERIOR PROSTATE): Only one of paired organs examined/present Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 555 of 663

### PATHOLOGY REPORT PAGE : 109/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 34

.........................................................................
ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0/+2 DAYS ON TEST : 9 * ANIMAL NO. : 35

......................................................................... * CAUSE OF DEATH / MORBIDITY

SYSTEMIC: —Not Evident

* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Diffuse hepatocellular hypertrophy, grade 1 —Periportal fatty change, medium droplet, grade 2 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 FORESTOMACH: —Hyperkeratosis, diffuse, grade 2 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 —Erosion, single, acute, grade 1 Harlan Laboratories Study Report
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## Page 556 of 663

### PATHOLOGY REPORT PAGE : 110/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 35

.........................................................................
LUNG: —Congestion, diffuse, grade 1 THYMUS: On block no.4 —Atrophy, diffuse, cortex, grade 3 TESTES: —Focal tubular degeneration, single, with atrophy, unilateral, grade 1 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 3 PROSTATE GLAND: —Atrophy, diffuse, grade 2 COAGULATING GLANDS (ANTERIOR PROSTATE): —Atrophy, diffuse, bilateral, grade 2 SEMINAL VESICLES: —Atrophy, diffuse, bilateral, grade 2 BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 36

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

STOMACH — 01: Contents black—brown. — No corresponding finding. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
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## Page 557 of 663

### PATHOLOGY REPORT PAGE : 111/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 36

.........................................................................
* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hematopoiesis, grade 1 KIDNEYS: —Pelvic dilation, unilateral, grade 1 STOMACH: No microscopic finding corresponding to necropsy observation no. 01. FORESTOMACH: —Hyperkeratosis, diffuse, grade 1 ILEUM: Tissue not present for histologic examination PEYER'S PATCHES: —Mineralization, focal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Epithelial Cyst, single, grade 1 THYROID GLAND (BOTH LOBES): —Follicular cell hypertrophy, diffuse, bilateral, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 ADRENAL MEDULLAS: Only one of paired organs examined/present BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 558 of 663

### PATHOLOGY REPORT PAGE : 112/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 37

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TESTES: —Tubular atrophy, diffuse, bilateral, grade 4 —Edema, diffuse, bilateral, grade 2 EPIDIDYMIDES: —Aspermia, bilateral —Lymphoid cell infiltration, focal, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 38

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

NO MICROSCOPIC FINDINGS NOTED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 559 of 663

### PATHOLOGY REPORT PAGE : 113/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY MALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 39

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TESTES: Rete testis transitional tubules NO MICROSCOPIC FINDINGS NOTED.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 28 * ANIMAL NO. : 40

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TESTES: Rete testis transitional tubules NO MICROSCOPIC FINDINGS NOTED.

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
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## Page 560 of 663

### PATHOLOGY REPORT PAGE : 114/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 71

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 1 —Periportal fatty change, medium droplet, grade 2 SPLEEN: —Hematopoiesis, grade 1 —Congestion, diffuse, grade 1 MESENTERIC LYMPH NODE: —Lymphoid hyperplasia, diffuse, germinal centers, grade 1 FORESTOMACH: —Hyperkeratosis, diffuse, grade 1 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 —Mucosal atrophy, focal, grade 1 LUNG: —Alveolar histiocytosis, focal, grade 2 THYMUS: —Increased number of macrophages, cortex, grade 1 —Atrophy, diffuse, cortex, grade 1 OVARIES: —Corpora lutea, bilateral, grade 3 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 THYROID GLAND (BOTH LOBES): —Follicular cell hypertrophy, diffuse, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present Harlan Laboratories Study Report
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## Page 561 of 663

### PATHOLOGY REPORT PAGE : 115/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 71

.........................................................................
ADRENAL CORTICES: —Mixed cell infiltration, focal, unilateral, grade 1 UTERUS: —Implantation sites, single, grade 3 VAGINA: —Epithelial mucification, diffuse, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 72

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 2 SPLEEN: —Hematopoiesis, grade 2 —Congestion, diffuse, grade 1 THYMUS: —Epithelial Cyst, single, grade 1 —Atrophy, diffuse, cortex, grade 3 This finding corresponds to necropsy observation no: 01. Harlan Laboratories Study Report
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## Page 562 of 663

### PATHOLOGY REPORT PAGE : 116/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 72

.........................................................................
OVARIES: —Corpora lutea, bilateral, grade 3 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 UTERUS: —Implantation sites, multiple, grade 3 VAGINA: —Epithelial mucification, diffuse, grade 2 BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 73

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

LIVER: —Inflammatory foci, focal, grade 1 —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hematopoiesis, grade 2 —Congestion, diffuse, grade 2 Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 563 of 663

### PATHOLOGY REPORT PAGE : 117/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 73

.........................................................................
KIDNEYS: —Corticomedullary mineralization, multifocal, bilateral, grade 1 —Tubular basophilia, focal, unilateral, grade 1 THYMUS: —Atrophy, diffuse, cortex, grade 3 This finding corresponds to necropsy observation no: 01. OVARIES: —Corpora lutea, bilateral, grade 4 MANDIBULAR LYMPH NODES: —Plasmocytosis, bilateral, grade 1 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 UTERUS: —Implantation sites, multiple, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 74

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
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## Page 564 of 663

### PATHOLOGY REPORT PAGE : 118/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 74

.........................................................................
* MICROSCOPIC FINDINGS

HEART: —Progressive cardiomyopathy, focal, grade 1 TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 2 SPLEEN: —Hematopoiesis, grade 2 GLANDULAR STOMACH: —Erosion, single, grade 3 —Submucosal inflammation, focal, grade 2 RECTUM: —Dilation, grade 1 LUNG: —Alveolar histiocytosis, focal, grade 1 THYMUS: —Atrophy, diffuse, cortex, grade 3 This finding corresponds to necropsy observation no: 01. OVARIES: —Corpora lutea, bilateral, grade 3 MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Plasmocytosis, bilateral, grade 1 THYROID GLAND (BOTH LOBES): —Follicular cell hypertrophy, diffuse, bilateral, grade 1 PARATHYROID GLANDS: Tissue not present for histologic examination ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 2 UTERUS: —Implantation sites, multiple, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 3 Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 565 of 663

### PATHOLOGY REPORT PAGE : 119/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 74

.........................................................................
ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 45 * ANIMAL NO. : 75

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

TRACHEA: —Glandular ectasia, grade 1 LIVER: —Inflammatory foci, multifocal, grade 1 —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hematopoiesis, grade 2 —Congestion, diffuse, grade 2 GLANDULAR STOMACH: —Mucosal glandular dilation, multifocal, grade 1 CECUM: —Mixed cell infiltration, multifocal, grade 1 LUNG: —Alveolar histiocytosis, multifocal, grade 1 THYMUS: —Increased number of macrophages, cortex, grade 1 —Atrophy, diffuse, cortex, grade 3 OVARIES: —Corpora lutea, bilateral, grade 4 Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 566 of 663

### PATHOLOGY REPORT PAGE : 120/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 75

.........................................................................
MANDIBULAR LYMPH NODES: —Lymphoid hyperplasia, diffuse, follicles, bilateral, grade 2 —Plasmocytosis, bilateral, grade 2 ADRENAL CORTICES: —Diffuse fatty change, zona fasciculata, bilateral, grade 1 —Hypertrophy (z.glomerulosa), diffuse, bilateral, grade 1 UTERUS: —Implantation sites, single, grade 3 —Fibrosis, focal, peritoneum, grade 2 VAGINA: —Epithelial mucification, diffuse, grade 3 BONE MARROW (FEMUR): —Fat cells in marrow, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 76

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 567 of 663

### PATHOLOGY REPORT PAGE : 121/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 41 * ANIMAL NO. : 77

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

OVARIES — 01: Both sides: discoloration, — Congestion, diffuse, bilateral, reddish. grade 1. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 5 —Congestion, diffuse, bilateral, grade 1 This finding corresponds to necropsy observation no: 01.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0/+1 DAYS ON TEST : 15 * ANIMAL NO. : 78

......................................................................... * CAUSE OF DEATH / MORBIDITY

JEJUNUM: —Thrombosis, grade 3

* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

GENERAL OBSERVATIONS — 01: Beginning autolysis. — Beginning autolysis, grade 2. Harlan Laboratories Study Report
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## Page 568 of 663

### PATHOLOGY REPORT PAGE : 122/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 78

.........................................................................
STOMACH — 01: Enlarged. — SEE UNDER: FORESTOMACH. SEE UNDER: GLANDULAR STOMACH. FORESTOMACH Finding 01 in STOMACH — Dilation, grade 2. GLANDULAR STOMACH Finding 01 in STOMACH — Dilation, grade 2. JEJUNUM — 01: Nodule(s), d=10x5 mm, red — Thrombosis, focal, grade 3. brown, firm. THYMUS — 01: Discoloration, dark red. — Congestion, diffuse, grade 2. NO OTHER NECROPSY OBSERVATIONS NOTED

* MICROSCOPIC FINDINGS

GENERAL OBSERVATIONS: —Beginning autolysis, grade 2 This finding corresponds to necropsy observation no: 01. LIVER: —Diffuse hepatocellular hypertrophy, grade 1 SPLEEN: —Hemosiderin deposits, multifocal, within parenchyma, grade 2 —Lymphoid depletion, grade 2 —Atrophy of red pulp, grade 1 KIDNEYS: —Tubular basophilia, multifocal, unilateral, grade 1 STOMACH: For diagnosis of necropsy observation no. 01 see under: FORESTOMACH,GLANDULAR STOMACH. FORESTOMACH: —Dilation, grade 2 This finding corresponds to necropsy observation no.: 01 in the STOMACH. Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 569 of 663

### PATHOLOGY REPORT PAGE : 123/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 78

.........................................................................
GLANDULAR STOMACH: —Dilation, grade 2 This finding corresponds to necropsy observation no.: 01 in the STOMACH. —Peritoneal inflammation, focal, grade 2 JEJUNUM: —Thrombosis, focal, grade 3 This finding corresponds to necropsy observation no: 01. LUNG: —Congestion, diffuse, grade 1 THYMUS: —Congestion, diffuse, grade 2 This finding corresponds to necropsy observation no: 01. —Atrophy, diffuse, cortex, grade 2 OVARIES: —Corpora lutea, bilateral, grade 5 PARATHYROID GLANDS: Only one of paired organs examined/present BONE MARROW (FEMUR): —Fat cells in marrow, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 79

.........................................................................
* NECROPSY OBSERVATION CORRESPONDING MICROSCOPIC FINDING

THYMUS — 01: Reduced in size. — Atrophy, diffuse, cortex, grade 3. NO OTHER NECROPSY OBSERVATIONS NOTED Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 570 of 663

### PATHOLOGY REPORT PAGE : 124/ 124 INDIVIDUAL ANIMAL DATA HARLAN LABORATORIES D23451

————————————————————————————————————————————————————————————————————————— TEST ITEM : PATHOL. NO.: 10648 KHE TEST SYSTEM : RAT, REPRODUCTION, ORAL (GAVAGE) DATE : 10—MAY—12 SPONSOR : PathData©System V6.2d2

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 90 MG/KG BW/DAY FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 79

.........................................................................
* MICROSCOPIC FINDINGS

THYMUS: —Atrophy, diffuse, cortex, grade 3 This finding corresponds to necropsy observation no: 01. OVARIES: —Corpora lutea, bilateral, grade 4

—————————————————————————————————————————————————————————————————————————

* STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 80

.........................................................................
* NECROPSY FINDINGS

NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

OVARIES: —Corpora lutea, bilateral, grade 3

————————————————————————————————————————————————————————————————————————— Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b47383 

## Page 571 of 663

# ANAPATH GmbH

Buchsweg 56, 4625 Oberbuchsiten / Switzerland


## Peer Review AnaPath 10648 HJC Harlan Laboratories Study D23451 (AnaPath Number 10648 KHE)

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test in the Han Wistar Rat

General This review inc1uded the following evaluations:
o All protocol-designated tissues from: Group 1: male 1; female 41; Group 4: male 31 ; female 7l; oLiver , stomaeh, thymus, thyroid gland, adrenal glands , testes , epididymides from all animals in the stud y
.

Results and Summary There were no discrepancies in diagnoses , terminology or grading noted between the study and reviewing pathologists.
The final report reflects the mutually agreed-upon diagnoses.

Peer Review Pathologist D r . Hans-Jörg Chevalier

AnaPath GmbH

Date: 12.05.2012 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b4b366 

## Page 572 of 663

# APPENDIX VIII - HISTORICAL CONTROL DATA Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380a81560 

## Page 573 of 663

### HARLAN LABORATORIES LTD. HISTO - 1 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 443.4 424.6**  **St.dev. 152.0 110.2 Min 180.0 314.0**  **7 Max 1033.3 801.** 

**N 100 19**

**Grip hindp. (G) Mean 282.6 275.3**  **St.dev. 81.7 57.9 Min 120.0 194.8**  **3 Max 526.7 421.** 

**N 100 19**

**Land. Foot Di (CM) Mean 7.5 7.5**  **St.dev. 2.7 1.5 Min 2.3 5.2**  **3 Max 13.0 10.** 

**N 100 19**

**Body Temp (°C) Mean 38.2 38.2**  **St.dev. 0.5 0.3 Min 37.1 37.5**  **6 Max 39.3 38.** 

**N 100 19** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 574 of 663

### HARLAN LABORATORIES LTD. HISTO - 2 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean --- --- --- --- 801.7**  **St.dev. 121.4 Min 643.3**  **3 Max 1033.** 

**N 10**

**Grip hindp. (G) Mean --- --- --- --- 421.3**  **St.dev. 51.8 Min 360.0**  **7 Max 526.** 

**N 10**

**Land. Foot Di (CM) Mean --- --- --- --- 7.8**  **St.dev. 2.9 Min 4.1**  **6 Max 11.** 

**N 10**

**Body Temp (°C) Mean --- --- --- --- 38.5**  **St.dev. 0.3 Min 38.1**  **0 Max 39.** 

**N 10**

**________________________________________________________________________________________________ _**  **Study 1, 2, 3 and 4: not applicable** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 575 of 663

### HARLAN LABORATORIES LTD. HISTO - 3 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 458.0 323.5 423.3 482.7 492.0**  **St.dev. 76.7 50.7 74.3 34.4 52.2 Min 353.3 262.0 343.3 436.7 416.7**  **3 Max 523.3 387.0 496.7 533.3 543.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 290.0 194.8 199.3 390.0 278.0**  **St.dev. 54.5 41.9 30.5 34.1 79.5 Min 206.7 139.3 163.3 353.3 186.7**  **0 Max 343.3 245.7 236.7 436.7 370.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 6.1 7.3 8.8 6.6 7.5**  **St.dev. 1.7 1.2 2.6 2.1 3.0 Min 4.2 5.8 5.4 4.1 5.6**  **6 Max 8.1 8.7 11.5 9.9 12.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 38.1 38.0 38.1 38.0 37.9**  **St.dev. 0.6 0.2 0.4 0.6 0.4 Min 37.6 37.7 37.6 37.2 37.6**  **5 Max 38.8 38.2 38.5 38.9 38.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 576 of 663

### HARLAN LABORATORIES LTD. HISTO - 4 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 329.3 538.0 436.0 366.0 335.3**  **St.dev. 45.5 86.6 156.1 106.9 44.3 Min 283.3 436.7 290.0 180.0 263.3**  **0 Max 380.0 636.7 650.0 433.3 370.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 247.3 236.0 291.3 272.7 276.7**  **St.dev. 52.0 66.1 55.9 104.8 34.4 Min 173.3 150.0 236.7 160.0 240.0**  **7 Max 296.7 313.3 376.7 410.0 316.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 8.6 6.2 10.3 7.7 6.5**  **St.dev. 3.1 2.4 2.1 2.8 3.8 Min 4.3 2.3 7.4 3.4 2.7**  **6 Max 11.7 8.0 13.0 10.8 12.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 37.7 38.6 38.6 38.1 38.3**  **St.dev. 0.2 0.5 0.5 0.3 0.4 Min 37.4 38.0 38.0 37.6 37.7**  **8 Max 38.0 39.3 39.2 38.4 38.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 577 of 663

### HARLAN LABORATORIES LTD. HISTO - 5 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 408.0 418.7 314.0 424.7 353.3**  **St.dev. 75.8 39.5 80.9 44.5 67.6 Min 273.3 386.7 223.3 380.0 233.3**  **7 Max 450.0 486.7 433.3 483.3 396.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 296.0 311.3 258.7 317.3 218.7**  **St.dev. 69.2 33.1 46.0 64.0 68.8 Min 200.0 260.0 230.0 226.7 120.0**  **0 Max 366.7 346.7 340.0 396.7 310.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 7.0 10.1 6.9 8.8 5.4**  **St.dev. 2.5 2.2 3.0 2.1 1.9 Min 4.0 6.1 2.3 7.0 4.1**  **7 Max 9.8 11.3 10.5 11.9 8.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 38.6 38.4 38.3 38.6 38.3**  **St.dev. 0.2 0.2 0.2 0.3 0.7 Min 38.4 38.1 38.0 38.1 37.4**  **2 Max 38.9 38.6 38.6 38.8 39.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 578 of 663

### HARLAN LABORATORIES LTD. HISTO - 6 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 422.0 358.7 382.0**  **St.dev. 62.4 29.6 80.1 Min 326.7 316.7 276.7**  **Max 486.7 390.0 483.3**

**N 5 5 5**

**Grip hindp. (G) Mean 249.3 220.0 262.7**  **St.dev. 47.7 43.2 41.8 Min 196.7 163.3 223.3**  **Max 300.0 283.3 323.3**

**N 5 5 5**

**Land. Foot Di (CM) Mean 5.2 6.5 9.5**  **St.dev. 1.9 2.8 2.0 Min 3.2 3.0 7.3**  **Max 8.0 9.2 11.6**

**N 5 5 5**

**Body Temp (°C) Mean 38.0 38.2 37.5**  **St.dev. 0.2 0.4 0.4 Min 37.7 37.6 37.1**  **Max 38.2 38.7 38.1**

**N 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 579 of 663

### HARLAN LABORATORIES LTD. HISTO - 7 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 406.2 384.9**  **St.dev. 171.9 120.1 Min 180.0 256.2**  **3 Max 1056.7 810.** 

**N 100 19**

**Grip hindp. (G) Mean 209.9 197.9**  **St.dev. 94.5 65.0 Min 80.0 131.8**  **0 Max 610.0 438.** 

**N 100 19**

**Land. Foot Di (CM) Mean 6.4 6.4**  **St.dev. 2.5 1.1 Min 1.7 4.7**  **3 Max 12.1 8.** 

**N 100 19**

**Body Temp (°C) Mean 38.6 38.6**  **St.dev. 0.3 0.2 Min 37.6 38.3**  **1 Max 39.8 39.** 

**N 100 19** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 580 of 663

### HARLAN LABORATORIES LTD. HISTO - 8 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean --- --- --- --- 810.3**  **St.dev. 152.9 Min 600.0**  **7 Max 1056.** 

**N 10**

**Grip hindp. (G) Mean --- --- --- --- 438.0**  **St.dev. 85.2 Min 256.7**  **0 Max 610.** 

**N 10**

**Land. Foot Di (CM) Mean --- --- --- --- 6.0**  **St.dev. 2.3 Min 3.5**  **7 Max 9.** 

**N 10**

**Body Temp (°C) Mean --- --- --- --- 38.6**  **St.dev. 0.3 Min 38.2**  **1 Max 39.** 

**N 10**

**________________________________________________________________________________________________ _**  **Study 1, 2, 3 and 4: not applicable** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 581 of 663

### HARLAN LABORATORIES LTD. HISTO - 9 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 361.9 256.2 459.3 490.7 420.0**  **St.dev. 53.0 26.2 129.3 163.4 74.1 Min 299.3 226.0 240.0 350.0 306.7**  **7 Max 423.3 280.0 570.0 750.0 486.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 176.9 131.8 204.0 270.7 204.7**  **St.dev. 55.6 8.0 56.2 59.5 51.8 Min 123.3 124.7 106.7 200.0 150.0**  **0 Max 256.7 145.3 250.0 356.7 280.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 7.7 5.6 5.5 7.7 8.3**  **St.dev. 2.4 2.4 2.7 2.6 2.3 Min 5.3 3.9 1.7 5.6 6.2**  **1 Max 11.5 9.7 8.0 11.7 12.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 39.1 38.5 38.3 38.7 38.8**  **St.dev. 0.5 0.3 0.3 0.4 0.1 Min 38.8 38.1 38.1 38.3 38.7**  **0 Max 39.8 38.8 38.7 39.3 39.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 582 of 663

### HARLAN LABORATORIES LTD. HISTO - 10 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 364.7 430.0 382.0 342.7 265.3**  **St.dev. 63.2 102.5 93.3 107.1 47.9 Min 313.3 310.0 253.3 180.0 200.0**  **7 Max 466.7 513.3 513.3 456.7 326.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 192.0 192.7 192.7 200.7 198.0**  **St.dev. 34.3 62.7 56.7 36.4 61.4 Min 143.3 90.0 133.3 173.3 133.3**  **3 Max 240.0 250.0 273.3 260.0 273.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 6.4 6.0 5.4 7.8 6.0**  **St.dev. 2.2 3.2 1.3 2.7 3.6 Min 3.7 3.2 4.1 3.8 2.0**  **8 Max 8.5 10.8 7.3 10.0 8.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 38.7 38.4 38.8 38.4 38.7**  **St.dev. 0.3 0.4 0.4 0.5 0.3 Min 38.4 37.7 38.4 37.6 38.3**  **2 Max 39.1 38.6 39.4 38.7 39.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 583 of 663

### HARLAN LABORATORIES LTD. HISTO - 11 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 390.7 334.0 339.4 278.7 299.3**  **St.dev. 101.4 68.8 56.1 87.4 60.3 Min 296.7 253.3 270.0 206.7 233.3**  **3 Max 513.3 413.3 420.0 423.3 373.** 

**N 5 5 5 5 5**

**Grip hindp. (G) Mean 179.3 149.3 199.3 163.3 161.3**  **St.dev. 27.5 42.3 56.6 32.6 32.3 Min 150.0 80.0 140.0 120.0 113.3**  **0 Max 206.7 193.3 290.0 190.0 190.** 

**N 5 5 5 5 5**

**Land. Foot Di (CM) Mean 4.7 7.1 7.8 6.8 5.6**  **St.dev. 1.7 3.2 2.4 2.6 2.4 Min 1.9 3.4 5.4 4.0 3.5**  **6 Max 6.4 11.5 11.1 9.7 9.** 

**N 5 5 5 5 5**

**Body Temp (°C) Mean 38.7 38.7 38.7 38.5 38.7**  **St.dev. 0.3 0.4 0.2 0.2 0.3 Min 38.3 38.2 38.4 38.2 38.4**  **0 Max 39.0 39.2 39.0 38.8 39.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 584 of 663

### HARLAN LABORATORIES LTD. HISTO - 12 **CH -4452 ITINGEN, SWITZERLAND 15-MAY-08** 



## OECD 422 STUDIES **HISTORICAL DATA – Functional Observational Battery**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**unctional Observational Battery F** 

**Grip forep. (G) Mean 367.3 351.5 370.0**  **St.dev. 105.2 58.8 79.1 Min 266.7 286.7 276.7**  **Max 480.0 416.7 446.7**

**N 5 5 5**

**Grip hindp. (G) Mean 180.0 160.9 164.7**  **St.dev. 57.4 30.0 55.6 Min 130.0 123.3 110.0**  **Max 246.7 200.0 236.7**

**N 5 5 5**

**Land. Foot Di (CM) Mean 5.7 4.9 6.8**  **St.dev. 3.1 1.8 2.7 Min 3.0 3.2 3.2**  **Max 9.8 7.6 10.7**

**N 5 5 5**

**Body Temp (°C) Mean 38.6 38.7 38.6**  **St.dev. 0.1 0.4 0.3 Min 38.4 38.3 38.1**  **Max 38.7 39.3 39.0**

**N 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b08ce1 

## Page 585 of 663

### HARLAN LABORATORIES **HISTO - 1**  **CH -**  **4452 ITINGEN, SWITZERLAND 13-**  **MAR -**  **12**


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WIST(SPF) -**  **Breede r: Harlan NL** 

**____________________________________________________________________________________________________ STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**  **OECD 421 OECD**  **421 OECD 422 OECD 422 OECD 421**  **PARAMETER MAY**  **-09 DEC**  **-09 FEB**  **- 10**  **FEB -**  **10 MAR**  **- 10** 

**____________________________________________________________________________________________________ Number of**  **females 10 9**  **10 8**  **10 Duration of gestation**  **Mean per female 21. 2**  **21. 4**  **21. 5**  **21.3 21. 5**  **St.dev. 0.4**  **0.5 0.7**  **0.5 0.5 N**  **10 9 10 8**  **10 Implantations**  **Mean per female 13. 6**  **13.2 13.5**  **13.4 12**  **.9 St.dev.**  **1.3 4.2**  **1. 2**  **1.1 2**  **.5 N**  **10 9 10 8**  **10 Post Implantation loss**  **% of Implantations 5.1**  **12 .6**  **9.6 5.6**  **8.5 Number of females affected**  **6 7**  **7 3**  **6 Total**  **7 15**  **13 6**  **11 Mean per female**  **0.7 1.7**  **1.3 0.8**  **1.1 St.dev.**  **0.7 1.6**  **1.8 1.2**  **1.1 Number of females**  **10 9**  **10 8**  **10**

**Dea d pups at first litter check**  **Number of females affected 0 1 1**  **0 0 Total**  **0 2 6**  **0 0 Mean per female**  **0.0 0. 2**  **0.6 0.0 0.0**  **St.dev. 0.0 0.7**  **1.9 0.0**  **0.0 Number of females**  **10 9 10**  **8 10**  **Living pups at first litter check Total 12**  **9 104**  **122 101**  **118 Mean per female 12.**  **9 11**  **.6 12**  **.2 12**  **.6 11 .8**  **St.dev. 1.4**  **4.5 2.0**  **1 .1 2**  **.9 Number of females**  **10 9 10 8**  **10 % of male / female pups 4**  **7 / 5**  **3 44**  **/ 5 6**  **51 / 4**  **9 51**  **/ 4 9**  **53 / 4**  **7**
**Postnatal loss unt il**  **day 4 p.p. Percent of living pups 0.**  **0 2.9**  **0. 8**  **0.0 0.0**  **Females affected 0**  **2 1 0**  **0 Total**  **0 3**  **1 0**  **0 Mean per female 0.**  **0 0.3**  **0.1 0. 0**  **0. 0**  **St.dev. 0. 0**  **0.7 0.3 0.0**  **0 .0**  **Number of females 10 9**  **10 8 10**  **Living pups day 4 p.p. Total 12**  **9 101**  **121 10**  **1 118**  **Mean per female 12. 9**  **11 .2**  **12 .1**  **12 .6**  **11.8 St.dev. 1.**  **4 4.9**  **2.1 1.1**  **2 .9**  **Number of females 10 9**  **10 8 10**  **% of male / female pups 4 7**  **/ 5 3**  **45 / 5**  **5 --**  **/**
**-- --**  **/ -- 53**  **/ 47**

**Birth Index 94**  **.9 87**  **.4 90**  **.4 94.4**  **91 .5**  **Viability Index 100**  **.0 97.1**  **99.2 100 .0**  **100 .0**  

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2506a 

## Page 586 of 663

### HARLAN LABORATORIES **HISTO - 2**  **CH -**  **4452 ITINGEN, SWITZERLAND 13** 
**- MAR**  **- 12** 


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WIST(SPF) -**  **Breeder: Harlan N L** 

**____________________________________________________________________________________________________ STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**  **OECD 422 OECD 421 OECD 421 OECD 422 OECD 421**  **PARAMETER MAR -**  **10 MAR**
**- 10 APR** 
**- 10 AUG** 
**- 10 SEP** 
**- 10** 

**____________________________________________________________________________________________________ Number of females**  **9 7**  **8 6 8**  **Duration of gestation Mean per female 21.**  **2 21.**  **6 21.**  **4 21.2**  **21. 4**  **St.dev. 0.4 0.5 0.5**  **0.4 0.5**  **N 9 7**  **8 6 7**  **Implantations Mean per female 1**  **2.2 11.9**  **13. 3**  **13.7 11.4**  **St.dev. 1.5**  **2.9 2.0**  **1.2 4.5**  **N 9 7**  **8 6**  **8 Post Implantation loss**  **% of Implantations 6.4**  **6.0 10**  **.4 3.7**  **9.9 Number of females affected**  **6 5**  **4 3 4**  **Total 7**  **5 11 3 9**  **Mean per female 0.8**  **0. 7 1**  **.4 0.5**  **1. 1**  **St.dev. 0**  **.7 0.**  **5 1 .9**  **0.6 1.5 Number of females**  **9 7 8**  **6 8 Dead pups at first litter check**  **Number of females affected 1**  **0 2 0 0**  **Total 1**  **0 2 0 0**  **Mean per female 0. 1**  **0. 0**  **0. 3**  **0.0 0.0 St.dev.**  **0.3 0.0**  **0.5 0.0 0.0**  **Number of females 9**  **7 8 6 8**  **Living pups at first li tter check**  **Total 103**  **78 95 79 82**  **Mean per female 11 .4**  **11 .**  **1 11 .9**  **13. 2 10**  **.3 St.dev.**  **1.1 3.**  **1 2.5 1.2**  **4.5 Number of**  **females 9 7 8**  **6 8 % of male / female pups**  **50 / 5**  **0 53**  **/ 4 7**  **47 / 5**  **3 41**  **/ 5 9**  **44 / 5**  **6 Postnatal loss until day 4 p**  **.p. Percent of living pups**  **1.9 3.8**  **1. 1**  **0.0 0.0**  **Females affected 2 2 1**  **0 0 Total**  **2 3**  **1 0 0**  **Mean per female 0. 2**  **0. 4**  **0. 1**  **0. 0**  **0. 0**  **St.dev. 0.4**  **0.8 0.4 0.0 0.0**  **Number of females**  **9 7 8**  **6 8 Living pups day 4 p.p.**  **Total 101**  **75 94 79 82**  **Mean per female 11 .2**  **10 .**  **7 11 .8**  **13 .**  **2 10**  **.3 St.dev.**  **1.2 3.**  **2 2 .4**  **1. 2 4**  **.5 Number of**  **females 9 7 8**  **6 8 % of male / female pups** 
**-- / --**  **53 / 47 48**  **/ 52 41**  **/ 5 9**  **44 / 5**  **6**

**Birth Index 93.6**  **94 .0**  **89 .6**  **96.3 90.1**  **Viability Index 98.1**  **96 .**  **2 98.9 100**  **. 0 100**  **.0** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2506a 

## Page 587 of 663

### HARLAN LABORATORIES **HISTO - 3**  **CH -**  **4452 ITINGEN, SWITZERLAND 13** 
**- MAR**  **- 12** 


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WIST(SPF) -**  **Breeder: Harlan NL**

**____________________________________________________________________________________________________ STUDY 11**  **OECD 42 1**  **PARAMETER SEP**  **- 10** 

**____________________________________________________________________________________________________ Number of females**  **8 Duration of gestation**  **Mean per female 21. 8**  **St.dev. 0.5**  **N 8**  **Implantations Mean per female**  **12.6 St.dev.**  **2.5 N**  **8**

**Post Implantation loss**  **% of Implantations 10**  **.9 Number of females affected**  **6 Total**  **11 Mean per female**  **1. 4**  **St.dev. 1.1**  **Number of females 8**  **Dead pups at first litter check Number of females affected 0**  **Total 0 Mean per female**  **0.0 St.dev. 0.0**  **Number of females 8**  **Living pups at first litter check Total**  **90 Mean per female**  **11. 3**  **St.dev. 3.0**  **Number of females 8**  **% of male / female pups 41**  **/ 59 Postnatal loss until day 4 p.p.**  **Percent of living pups 0.0**  **Females affected 0 Total**  **0 Mean per female 0.**  **0 St.dev.**  **0.0 Number of**  **females 8**  **Living pups day 4 p.p. Total**  **90 Mean per female**  **11.3 St.dev.**  **3.0 Number of**  **females 8 % of male / female pups** 
**-- / --** 

**Birth Index 89**  **.1 Viability**  **Index 100 .0**  

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380b2506a 

## Page 588 of 663

### HARLAN LABORATORIES **HISTO - 4**  **CH -**  **4452 ITINGEN, SWITZERLAND 13** 
**- MAR**  **- 12** 


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WIST(SPF) -**  **Breeder: Harlan NL**

**____________________________________________________________________________________________________ STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**  **OECD 421 OECD 421 OECD 422 OECD 422 OECD 421 PARAMETER**  **MAY -**  **09 DEC**
**- 09 FEB** 
**- 10 FEB** 
**- 10 MAR** 
**- 10** 

**____________________________________________________________________________________________________ Mean body weights of pups** 

**Day 0 Males Mean**  **--- 6.2**  **5.7 ---**  **6.6 St.dev.** 
**--- 0.1**  **0.2**
**--- 0.4**  **N ---**  **2 2** 
**--- 2** 
**Females M**  **ean ---**  **5.8 5.3** 
**--- 6.3**  **St.dev.**
**--- 0.1**  **0.2**
**--- 0.3**  **N ---**  **2 2** 
**--- 2** 
**Males and females Mean**  **--- 6.0**  **5.5 ---**  **6.4 St.dev.** 
**--- 0.1 0.2** 
**--- 0.4**  **N ---**  **2 2**
**--- 2** 

**Day 1 Males Mean 6.**  **1 6.0**  **5.8 6.2**  **6.5 St.dev 0.**  **4 0.4 0.6**  **0.5 0.8**  **N 10 9 10 8**  **10**
**Females Mean**  **5.7 5.7 5.6**  **5.9 6.2**  **St.dev. 0.4**  **0.5 0.6 0.5**  **0.8 N 10**  **9 10 8 10** 
**Males and females Mean**  **5.9 5.9**  **5.7 6.1**  **6.4 St.dev**  **0.4 0.5**  **0.5 0.5 0.8**  **N 10 9 10 8**  **10**

**Day 4 Males Mean**  **8.7 8.7 8.7**  **9 .4**  **9.6 St.dev.**  **0.8 0.9**  **0.9 0.7**  **1.6 N**  **10 8 10 8**  **10**
**Females Mean**  **8.4 8.4 8.4**  **9.0 9.3**  **St.dev 0.7**  **0.9 0.9 0**  **.7 1.6**  **N 10**  **8 10 8**  **10**
**Males and females Mean**  **8.6 8.5 8.5**  **9.2 9.5**  **St.dev. 0.8**  **1.0 0.9**  **0.7 1.5**  **N 10 8**  **10 8 10**  

### Harlan Laboratories Study Report
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## Page 589 of 663

### HARLAN LABORATORIES **HISTO - 5**  **CH -**  **4452 ITINGEN, SWITZERLAND 13** 
**- MAR**  **-12**


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WIST(SPF) -**  **Breeder: Harlan NL**

**____________________________________________________________________________________________________ STUDY**  **6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 OECD 422 OECD 421 OECD 421 OECD 422 OECD 421**  **PARAMETER MAR -**  **10 MAR**
**- 10 APR** 
**- 10 AUG** 
**- 10 SEP** 
**- 10** 

**____________________________________________________________________________________________________ Mean body weights of pups** 

**Day 0 Males Mean**  **--- 5.9** 
**--- ---**  **--- St.dev.** 
**--- 0.1** 
**--- ---**  **--- N**  **--- 2** 
**--- ---**  **--- Females**  **Mean ---**  **5.5 ---**  **--- ---**  **St.dev.**
**--- 0.1** 
**--- ---**  **--- N**  **--- 2** 
**--- ---**  **--- Males and females**  **Mean ---**  **5.7 ---**  **--- ---**  **St.dev.**
**--- 0.1** 
**--- ---**  **--- N**  **--- 2** 
**--- ---**  **---**

**Day 1 Males**  **Mean 6.1**  **6.5 6.3 6.0 6.1**  **St.dev 0.3 0.4**  **0.5 0.2**  **0.7 N**  **9 7 8**  **6 7**
**Females Mean**  **5.9 6.0 6.0**  **5. 8 5.9**  **St.dev. 0.2 0.5**  **0.5 0.1 0.9**  **N 9 7**  **8 6**  **8**
**Males and females Mean**  **6.0 6.3 6.1**  **5.9 6.1**  **St.dev 0.2 0.**  **4 0.5**  **0.1 0.9**  **N 9 7**  **8 6**  **8**

**Day 4 Males Mean**  **9 .2**  **9.9 9.7 8.9**  **9.1 St.dev.**  **0. 5**  **1. 0 0**  **.8 0.4**  **1.4 N**  **9 7 8**  **6 7** 
**Females Mean**  **9 .0 9.5**  **9.5 8.6**  **9.3 St.dev 0.**  **4 1.1 0**  **.8 0.3**  **1.9 N**  **9 7 8**  **6 8** 
**Males and females Mean**  **9 .1 9.**  **7 9.**  **6 8.7**  **9.4 St.dev. 0.**  **4 1.**  **0 0 .8**  **0.4 1.8**  **N 9**  **7 8 6**  **8** 

### Harlan Laboratories Study Report
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## Page 590 of 663

### HARLAN LABORATORIES **HISTO - 6**  **CH -**  **4452 ITINGEN, SWITZERLAND 13** 
**- MAR**  **- 12** 


## OECD 421 / 422 STUDIES **HISTORICAL DATA -**  **BREEDING**
**STRAIN: RAT / RccHanTM: WI ST(SPF)**  **- Breeder: Harlan NL** 

**____________________________________________________________________________________________________ STUDY 11**  **OECD 42 1**  **PARAMETER SEP**  **- 10** 

**____________________________________________________________________________________________________ Mean body weights of pups** 

**Day 0 Males Mean**  **--- St.dev.** 
**--- N**  **--- Females**  **Mean ---**  **St.dev.**
**--- N**  **--- Males and females**  **Mean ---**  **St.dev.**
**--- N**  **---**

**Day 1 Males Mean**  **6. 5**  **St.dev 0.5**  **N 8** 
**Females Mean**  **6.2 St.dev. 0.6**  **N 8** 
**Males and females Mean**  **6.3 St.dev**  **0.6 N**  **8**

**Day 4 M ales**  **Mean 10.3**  **St.dev. 1.3**  **N 8** 
**Females Mean**  **9.7 St.de**  **v 1.2**  **N 8** 
**Males and females Mean**  **10 .0**  **St.dev. 1.2**  **N 8**  

### Harlan Laboratories Study Report
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## Page 591 of 663

### HARLAN LABORATORIES LTD. HISTO - 1 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 354.4 354.4**  **St.dev. 29.4 19.5 Min 271.7 312.6**  **1 Max 461.3 410.** 

**N 230 23**

**Brain Mean 2.02 2.02**  **St.dev. 0.08 0.05 Min 1.77 1.93**  **10 Max 2.23 2.** 

**N 140 23**

**Heart Mean 1.01 1.01**  **St.dev. 0.08 0.05 Min 0.86 0.89**  **10 Max 1.28 1.** 

**N 140 23**

**Liver Mean 8.99 8.95**  **St.dev. 0.92 0.50 Min 6.86 8.27**  **18 Max 12.70 10.** 

**N 140 23**

**Thymus Mean 0.311 0.311**  **St.dev. 0.079 0.043 Min 0.158 0.236**  **384 Max 0.564 0.** 

**N 140 23**

**Kidneys Mean 2.19 2.17**  **St.dev. 0.20 0.12 Min 1.59 1.99**  **38 Max 2.64 2.** 

**N 140 23** 

### Harlan Laboratories Study Report
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## Page 592 of 663

### HARLAN LABORATORIES LTD. HISTO - 2 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.071 0.072**  **St.dev. 0.012 0.006 Min 0.038 0.061**  **085 Max 0.105 0.** 

**N 140 23**

**Spleen Mean 0.73 0.73**  **St.dev. 0.11 0.07 Min 0.45 0.63**  **89 Max 1.10 0.** 

**N 140 23**

**Testes Mean 3.64 3.64**  **St.dev. 0.41 0.17 Min 1.46 3.33**  **92 Max 4.67 3.** 

**N 230 23**

**Prostate Mean 0.94 0.94**  **St.dev. 0.17 0.16 Min 0.64 0.78**  **10 Max 1.35 1.** 

**N 30 3**

**Epididymides Mean 1.289 1.289**  **St.dev. 0.151 0.074 Min 0.641 1.182**  **475 Max 1.641 1.** 

**N 230 23**

**Seminal Vesicles Mean 1.37 1.37**  **St.dev. 0.27 0.15 Min 0.67 1.28**  **54 Max 1.93 1.** 

**N 30 3** 

### Harlan Laboratories Study Report
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## Page 593 of 663

### HARLAN LABORATORIES LTD. HISTO - 3 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 353.84 410.06 332.31 355.2 360.9**  **St.dev. 21.95 24.79 19.23 20.1 13.0 Min 330.44 377.64 308.15 325.3 335.5**  **7 Max 407.12 461.29 366.46 381.5 379.** 

**N 10 10 10 10 10**

**Brain Mean 2.03 2.06 1.93 2.00 2.04**  **St.dev. 0.05 0.09 0.11 0.07 0.09 Min 1.95 1.94 1.77 1.90 1.92**  **18 Max 2.10 2.22 2.12 2.09 2.** 

**N 10 10 10 10 10**

**Heart Mean 1.056 1.102 0.994 1.03 1.02**  **St.dev. 0.063 0.083 0.059 0.06 0.08 Min 0.972 0.985 0.903 0.96 0.88**  **11 Max 1.165 1.276 1.075 1.14 1.** 

**N 10 10 10 10 10**

**Liver Mean 9.40 10.18 8.33 8.95 9.07**  **St.dev. 0.52 1.09 0.78 0.72 0.68 Min 8.55 8.94 7.20 7.81 8.00**  **88 Max 10.13 12.70 9.80 10.45 9.** 

**N 10 10 10 10 10**

**Thymus Mean 0.37 0.24 0.30 0.351 0.313**  **St.dev. 0.05 0.06 0.07 0.086 0.070 Min 0.30 0.16 0.19 0.258 0.217**  **402 Max 0.45 0.33 0.43 0.490 0.** 

**N 10 10 10 10 10**

**Kidneys Mean 2.25 2.38 2.05 2.27 2.27**  **St.dev. 0.12 0.16 0.23 0.22 0.09 Min 2.03 2.18 1.59 1.96 2.18**  **41 Max 2.42 2.61 2.46 2.60 2.** 

**N 10 10 10 10 10** 

### Harlan Laboratories Study Report
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## Page 594 of 663

### HARLAN LABORATORIES LTD. HISTO - 4 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.070 0.066 0.067 0.074 0.071**  **St.dev. 0.009 0.010 0.012 0.007 0.009 Min 0.055 0.053 0.042 0.063 0.054**  **083 Max 0.088 0.085 0.086 0.085 0.** 

**N 10 10 10 10 10**

**Spleen Mean 0.673 0.775 0.683 0.72 0.78**  **St.dev. 0.076 0.100 0.103 0.09 0.08 Min 0.525 0.577 0.541 0.60 0.65**  **93 Max 0.759 0.899 0.913 0.87 0.** 

**N 10 10 10 10 10**

**Testes Mean 3.46 3.76 3.39 3.59 3.81**  **St.dev. 0.24 0.27 0.52 0.32 0.24 Min 3.11 3.46 2.80 3.07 3.53**  **31 Max 3.77 4.21 4.67 4.20 4.** 

**N 10 10 10 10 10**

**Prostate**

**--- Mean 0.78 1.10 --- 0.92**  **St.dev. 0.09 0.13 0.08 Min 0.64 0.94 0.81**  **06 Max 0.89 1.35 1.** 

**N 10 10 10**

**Epididymides Mean 1.206 1.475 1.204 1.242 1.289**  **St.dev. 0.101 0.099 0.169 0.136 0.107 Min 1.049 1.322 1.012 1.099 1.178**  **532 Max 1.401 1.641 1.533 1.492 1.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**--- Mean 1.282 1.537 --- 1.28**  **St.dev. 0.306 0.143 0.28 Min 0.673 1.264 0.98**  **93 Max 1.763 1.778 1.** 

**N 10 10 10** 

### Harlan Laboratories Study Report
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## Page 595 of 663

### HARLAN LABORATORIES LTD. HISTO - 5 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 340.7 342.3 346.8 365.8 312.6**  **St.dev. 33.6 17.8 27.7 45.3 22.3 Min 310.2 312.5 303.4 320.8 271.7**  **7 Max 406.0 369.0 384.5 456.4 342.** 

**N 10 10 10 10 10**

**Brain Mean 2.03 2.02 1.96 1.99 1.99**  **St.dev. 0.10 0.04 0.06 0.06 0.05 Min 1.91 1.96 1.89 1.92 1.94**  **06 Max 2.18 2.06 2.05 2.06 2.** 

**N 5 5 5 5 5**

**Heart Mean 0.97 0.95 0.97 0.99 0.97**  **St.dev. 0.07 0.05 0.08 0.08 0.03 Min 0.87 0.87 0.88 0.90 0.94**  **01 Max 1.05 1.02 1.09 1.09 1.** 

**N 5 5 5 5 5**

**Liver Mean 8.27 8.30 8.62 9.64 9.02**  **St.dev. 0.98 0.52 1.30 1.01 0.91 Min 6.96 7.75 6.86 8.00 7.42**  **64 Max 9.37 9.11 9.92 10.71 9.** 

**N 5 5 5 5 5**

**Thymus Mean 0.338 0.306 0.283 0.270 0.383**  **St.dev. 0.070 0.043 0.057 0.052 0.070 Min 0.230 0.261 0.242 0.191 0.308**  **483 Max 0.401 0.358 0.382 0.331 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 2.03 2.26 1.99 2.09 2.24**  **St.dev. 0.27 0.13 0.20 0.12 0.29 Min 1.75 2.12 1.75 1.98 1.89**  **64 Max 2.33 2.44 2.21 2.27 2.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 596 of 663

### HARLAN LABORATORIES LTD. HISTO - 6 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.068 0.074 0.061 0.068 0.073**  **St.dev. 0.011 0.016 0.005 0.026 0.017 Min 0.057 0.055 0.057 0.038 0.057**  **095 Max 0.084 0.095 0.068 0.105 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.77 0.69 0.66 0.68 0.66**  **St.dev. 0.10 0.03 0.10 0.16 0.13 Min 0.64 0.65 0.52 0.51 0.45**  **79 Max 0.87 0.74 0.76 0.90 0.** 

**N 5 5 5 5 5**

**Testes Mean 3.56 3.63 3.55 3.80 3.47**  **St.dev. 0.37 0.84 0.30 0.40 0.34 Min 3.14 1.46 3.18 3.35 2.92**  **15 Max 4.21 4.40 4.13 4.55 4.** 

**N 10 10 10 10 10**

**Prostate**

**-- --- --- --- Mean --- -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 1.236 1.225 1.227 1.311 1.182**  **St.dev. 0.105 0.202 0.091 0.093 0.098 Min 1.091 0.745 1.133 1.138 1.056**  **390 Max 1.412 1.467 1.439 1.456 1.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**--- --- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 597 of 663

### HARLAN LABORATORIES LTD. HISTO - 7 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 342.8 370.8 373.1 351.6 364.0**  **St.dev. 16.8 22.1 26.5 18.1 14.1 Min 319.4 343.1 342.2 330.5 334.7**  **0 Max 366.8 397.0 441.1 383.8 384.** 

**N 10 10 10 10 10**

**Brain Mean 1.96 1.98 2.06 2.10 1.99**  **St.dev. 0.04 0.09 0.07 0.06 0.07 Min 1.91 1.83 1.94 2.02 1.91**  **10 Max 2.01 2.06 2.12 2.16 2.** 

**N 5 5 5 5 5**

**Heart Mean 0.94 0.89 1.06 1.07 1.01**  **St.dev. 0.09 0.02 0.06 0.07 0.02 Min 0.86 0.87 0.99 0.99 0.99**  **04 Max 1.09 0.94 1.15 1.13 1.** 

**N 5 5 5 5 5**

**Liver Mean 8.27 8.61 9.35 8.95 8.83**  **St.dev. 0.83 0.45 0.67 0.65 0.85 Min 7.37 8.16 8.39 8.14 8.33**  **33 Max 9.51 9.37 10.10 9.81 10.** 

**N 5 5 5 5 5**

**Thymus Mean 0.303 0.278 0.272 0.292 0.291**  **St.dev. 0.032 0.043 0.052 0.049 0.071 Min 0.276 0.231 0.228 0.220 0.228**  **377 Max 0.355 0.335 0.343 0.345 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 1.99 2.19 2.33 2.21 2.15**  **St.dev. 0.17 0.11 0.14 0.07 0.18 Min 1.79 2.10 2.20 2.13 1.97**  **44 Max 2.27 2.36 2.56 2.30 2.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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## Page 598 of 663

### HARLAN LABORATORIES LTD. HISTO - 8 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.062 0.077 0.085 0.074 0.065**  **St.dev. 0.008 0.017 0.007 0.006 0.012 Min 0.054 0.052 0.075 0.068 0.051**  **078 Max 0.075 0.096 0.094 0.084 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.68 0.67 0.82 0.77 0.63**  **St.dev. 0.07 0.06 0.13 0.05 0.10 Min 0.61 0.61 0.71 0.71 0.54**  **79 Max 0.80 0.75 1.04 0.84 0.** 

**N 5 5 5 5 5**

**Testes Mean 3.55 3.69 3.85 3.82 3.67**  **St.dev. 0.22 0.30 0.30 0.23 0.35 Min 3.33 3.32 3.19 3.52 3.06**  **15 Max 4.02 4.37 4.27 4.19 4.** 

**N 10 10 10 10 10**

**Prostate**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 1.314 1.328 1.394 1.378 1.309**  **St.dev. 0.119 0.104 0.133 0.124 0.140 Min 1.064 1.185 1.090 1.250 1.005**  **526 Max 1.489 1.496 1.509 1.628 1.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 599 of 663

### HARLAN LABORATORIES LTD. HISTO - 9 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 357.3 381.5 356.1 362.3 339.7**  **St.dev. 28.9 19.5 26.6 10.4 24.8 Min 316.4 355.2 309.9 353.0 306.4**  **1 Max 389.6 416.1 390.0 388.6 382.** 

**N 10 10 10 10 10**

**Brain Mean 2.08 2.10 2.07 2.08 2.05**  **St.dev. 0.10 0.05 0.07 0.09 0.09 Min 1.95 2.04 1.96 1.94 1.89**  **12 Max 2.23 2.16 2.12 2.17 2.** 

**N 5 5 5 5 5**

**Heart Mean 1.04 1.01 1.06 1.03 0.96**  **St.dev. 0.10 0.06 0.09 0.04 0.10 Min 0.88 0.95 0.99 0.99 0.87**  **12 Max 1.11 1.09 1.21 1.09 1.** 

**N 5 5 5 5 5**

**Liver Mean 9.52 9.37 9.30 8.85 8.84**  **St.dev. 1.05 0.58 1.05 0.44 1.07 Min 7.70 8.41 7.70 8.34 7.57**  **25 Max 10.29 9.88 10.36 9.46 10.** 

**N 5 5 5 5 5**

**Thymus Mean 0.352 0.384 0.279 0.322 0.275**  **St.dev. 0.141 0.091 0.071 0.119 0.068 Min 0.178 0.252 0.172 0.234 0.178**  **360 Max 0.564 0.498 0.346 0.520 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 2.27 2.29 2.26 2.24 1.99**  **St.dev. 0.13 0.17 0.18 0.18 0.23 Min 2.07 2.08 2.13 2.02 1.74**  **36 Max 2.41 2.47 2.57 2.45 2.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 600 of 663

### HARLAN LABORATORIES LTD. HISTO - 10 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.083 0.082 0.069 0.074 0.077**  **St.dev. 0.014 0.016 0.008 0.012 0.010 Min 0.061 0.062 0.058 0.056 0.068**  **091 Max 0.097 0.104 0.077 0.088 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.81 0.79 0.89 0.78 0.69**  **St.dev. 0.11 0.03 0.13 0.11 0.06 Min 0.68 0.75 0.77 0.68 0.60**  **74 Max 0.94 0.82 1.10 0.94 0.** 

**N 5 5 5 5 5**

**Testes Mean 3.89 3.92 3.60 3.61 3.33**  **St.dev. 0.29 0.26 0.34 0.42 0.71 Min 3.43 3.55 3.09 2.72 1.48**  **02 Max 4.33 4.22 4.17 4.04 4.** 

**N 10 10 10 10 10**

**Prostate**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 1.364 1.312 1.350 1.261 1.198**  **St.dev. 0.087 0.196 0.148 0.178 0.238 Min 1.215 0.881 1.140 0.866 0.641**  **471 Max 1.513 1.562 1.538 1.417 1.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 601 of 663

### HARLAN LABORATORIES LTD. HISTO - 11 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 355.2 334.2 341.7**  **St.dev. 18.8 21.3 20.9 Min 332.2 309.5 316.0**  **6 Max 387.0 366.8 386.** 

**N 10 10 10**

**Brain Mean 1.98 1.98 2.02**  **St.dev. 0.09 0.07 0.06 Min 1.88 1.87 1.96**  **08 Max 2.10 2.04 2.** 

**N 5 5 5**

**Heart Mean 1.04 0.94 1.01**  **St.dev. 0.07 0.08 0.05 Min 0.98 0.86 0.96**  **06 Max 1.15 1.05 1.** 

**N 5 5 5**

**Liver Mean 9.12 8.64 8.41**  **St.dev. 0.54 1.00 0.70 Min 8.44 7.48 7.52**  **40 Max 9.61 9.68 9.** 

**N 5 5 5**

**Thymus Mean 0.376 0.242 0.327**  **St.dev. 0.102 0.022 0.074 Min 0.263 0.216 0.239**  **396 Max 0.521 0.267 0.** 

**N 5 5 5**

**Kidneys Mean 2.11 2.13 2.01**  **St.dev. 0.23 0.18 0.13 Min 1.78 1.93 1.81**  **15 Max 2.34 2.37 2.** 

**N 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4596 

## Page 602 of 663

### HARLAN LABORATORIES LTD. HISTO - 12 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.077 0.069 0.069**  **St.dev. 0.007 0.011 0.009 Min 0.069 0.060 0.058**  **077 Max 0.086 0.086 0.** 

**N 5 5 5**

**Spleen Mean 0.84 0.68 0.73**  **St.dev. 0.16 0.06 0.12 Min 0.61 0.60 0.55**  **83 Max 1.05 0.74 0.** 

**N 5 5 5**

**Testes Mean 3.74 3.73 3.35**  **St.dev. 0.26 0.26 0.59 Min 3.39 3.36 1.82**  **92 Max 4.08 4.32 3.** 

**N 10 10 10**

**Prostate**

**--- --- Mean ---**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 1.285 1.334 1.222**  **St.dev. 0.102 0.104 0.190 Min 1.132 1.169 0.823**  **404 Max 1.414 1.466 1.** 

**N 10 10 10**

**Seminal Vesicles**

**--- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 603 of 663

### HARLAN LABORATORIES LTD. HISTO - 13 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 236.7 236.7**  **St.dev. 14.3 5.9 Min 193.5 226.0**  **0 Max 281.2 250.** 

**N 205 21**

**Brain Mean 1.90 1.89**  **St.dev. 0.07 0.03 Min 1.73 1.84**  **94 Max 2.09 1.** 

**N 120 21**

**Heart Mean 0.81 0.80**  **St.dev. 0.08 0.04 Min 0.63 0.74**  **90 Max 1.18 0.** 

**N 120 21**

**Liver Mean 7.93 7.90**  **St.dev. 0.91 0.41 Min 5.35 6.81**  **62 Max 12.49 8.** 

**N 119 21**

**Thymus Mean 0.199 0.200**  **St.dev. 0.051 0.025 Min 0.096 0.150**  **258 Max 0.371 0.** 

**N 120 21**

**Kidneys Mean 1.49 1.49**  **St.dev. 0.13 0.05 Min 1.23 1.36**  **55 Max 1.92 1.** 

**N 120 21** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 604 of 663

### HARLAN LABORATORIES LTD. HISTO - 14 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.085 0.085**  **St.dev. 0.011 0.006 Min 0.061 0.074**  **096 Max 0.110 0.** 

**N 120 21**

**Spleen Mean 0.70 0.69**  **St.dev. 0.16 0.05 Min 0.42 0.59**  **76 Max 1.68 0.** 

**N 120 21**

**Ovaries Mean 0.126 0.127**  **St.dev. 0.021 0.014 Min 0.087 0.119**  **148 Max 0.177 0.** 

**N 25 4**

**Uterus Mean 1.12 1.10**  **St.dev. 0.17 0.07 Min 0.75 1.05**  **18 Max 1.56 1.** 

**N 20 3** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 605 of 663

### HARLAN LABORATORIES LTD. HISTO - 15 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean --- 238.84 235.06 --- 236.5**  **St.dev. 26.48 14.36 18.9 Min 193.48 205.48 213.7**  **Max 281.18 256.93 267.9**

**N 10 10 10**

**Brain Mean --- 1.94 1.94 --- 1.89**  **St.dev. 0.07 0.08 0.07 Min 1.84 1.82 1.77**  **Max 2.06 2.09 1.97**

**N 10 10 10**

**Heart Mean --- 0.825 0.898 --- 0.79**  **St.dev. 0.073 0.113 0.09 Min 0.688 0.806 0.68**  **Max 0.954 1.184 1.00**

**N 10 10 10**

**Liver Mean --- 7.76 8.02 --- 8.62**  **St.dev. 0.66 0.81 1.95 Min 6.70 6.98 6.69**  **Max 8.66 9.62 12.49**

**N 10 10 10**

**Thymus Mean --- 0.18 0.21 --- 0.175**  **St.dev. 0.07 0.07 0.045 Min 0.10 0.13 0.109**  **Max 0.33 0.37 0.229**

**N 10 10 10**

**Kidneys Mean --- 1.49 1.55 --- 1.47**  **St.dev. 0.14 0.10 0.12 Min 1.23 1.39 1.29**  **Max 1.70 1.66 1.67**

**N 10 10 10** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4596 

## Page 606 of 663

### HARLAN LABORATORIES LTD. HISTO - 16 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean --- 0.079 0.089 --- 0.087**  **St.dev. 0.012 0.010 0.010 Min 0.061 0.069 0.069**  **Max 0.100 0.101 0.101**

**N 10 10 10**

**Spleen Mean --- 0.695 0.720 --- 0.76**  **St.dev. 0.317 0.135 0.33 Min 0.423 0.527 0.56**  **Max 1.544 0.990 1.68**

**N 10 10 10**

**Ovaries Mean --- 0.120 --- --- ---**  **St.dev. 0.015 Min 0.087**  **Max 0.142**

**N 10**

**Uterus Mean --- 1.182 --- --- ---**  **St.dev. 0.168 Min 0.995**  **Max 1.563**

**N 10** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 607 of 663

### HARLAN LABORATORIES LTD. HISTO - 17 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 238.8 238.8 246.7 236.5 226.0**  **St.dev. 4.9 11.5 10.2 12.9 13.7 Min 229.7 221.4 230.1 215.7 203.3**  **Max 245.4 251.9 263.8 254.2 250.7**

**N 10 5 10 10 10**

**Brain Mean 1.89 1.88 1.94 1.85 1.84**  **St.dev. 0.04 0.07 0.08 0.08 0.03 Min 1.84 1.79 1.88 1.73 1.82**  **Max 1.96 1.97 2.07 1.92 1.89**

**N 5 5 5 5 5**

**Heart Mean 0.82 0.79 0.86 0.74 0.84**  **St.dev. 0.05 0.06 0.09 0.06 0.08 Min 0.77 0.73 0.75 0.66 0.74**  **Max 0.90 0.86 0.99 0.81 0.89**

**N 5 5 5 5 5**

**Liver Mean 8.07 8.05 8.46 7.62 7.58**  **St.dev. 0.66 0.65 0.36 0.66 0.77 Min 7.43 7.14 7.84 6.75 6.91**  **Max 9.17 8.81 8.71 8.38 8.88**

**N 5 5 5 5 5**

**Thymus Mean 0.211 0.208 0.207 0.172 0.150**  **St.dev. 0.040 0.014 0.031 0.025 0.036 Min 0.172 0.194 0.177 0.133 0.107**  **Max 0.259 0.225 0.258 0.199 0.202**

**N 5 5 5 5 5**

**Kidneys Mean 1.55 1.47 1.51 1.38 1.36**  **St.dev. 0.11 0.10 0.08 0.04 0.09 Min 1.39 1.39 1.38 1.32 1.26**  **Max 1.69 1.61 1.57 1.42 1.51**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 608 of 663

### HARLAN LABORATORIES LTD. HISTO - 18 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.083 0.088 0.084 0.074 0.082**  **St.dev. 0.009 0.009 0.010 0.009 0.010 Min 0.068 0.075 0.076 0.063 0.075**  **Max 0.091 0.098 0.098 0.084 0.099**

**N 5 5 5 5 5**

**Spleen Mean 0.66 0.68 0.70 0.63 0.67**  **St.dev. 0.12 0.08 0.04 0.10 0.10 Min 0.57 0.60 0.64 0.52 0.51**  **Max 0.87 0.79 0.74 0.79 0.75**

**N 5 5 5 5 5**

**Ovaries Mean --- --- --- --- 0.122**  **St.dev. 0.021 Min 0.095**  **Max 0.143**

**N 5**

**Uterus Mean --- --- --- --- 1.07**  **St.dev. 0.13 Min 0.85**  **Max 1.18**

**N 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4596 

## Page 609 of 663

### HARLAN LABORATORIES LTD. HISTO - 19 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 237.3 243.3 231.5 241.3 238.3**  **St.dev. 13.5 4.4 9.3 15.2 16.2 Min 225.4 236.5 220.7 218.3 217.8**  **Max 259.9 247.5 240.7 269.6 254.0**

**N 5 5 5 10 5**

**Brain Mean 1.87 1.90 1.93 1.88 1.89**  **St.dev. 0.05 0.07 0.07 0.07 0.07 Min 1.79 1.83 1.84 1.81 1.79**  **Max 1.92 2.00 2.03 1.96 1.96**

**N 5 5 5 5 5**

**Heart Mean 0.75 0.82 0.85 0.84 0.81**  **St.dev. 0.02 0.05 0.07 0.06 0.07 Min 0.73 0.76 0.78 0.80 0.74**  **Max 0.77 0.87 0.97 0.95 0.90**

**N 5 5 5 5 5**

**Liver Mean 7.98 8.02 7.80 7.76 8.38**  **St.dev. 0.41 0.90 0.52 0.47 1.15 Min 7.46 6.68 7.19 7.19 6.93**  **Max 8.50 8.89 8.37 8.32 9.99**

**N 5 5 5 5 5**

**Thymus Mean 0.181 0.215 0.200 0.258 0.231**  **St.dev. 0.015 0.028 0.050 0.050 0.061 Min 0.166 0.177 0.142 0.220 0.178**  **Max 0.202 0.250 0.267 0.344 0.306**

**N 5 5 5 5 5**

**Kidneys Mean 1.48 1.55 1.52 1.54 1.54**  **St.dev. 0.07 0.19 0.17 0.08 0.24 Min 1.37 1.28 1.32 1.44 1.26**  **Max 1.54 1.72 1.72 1.67 1.92**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4596 

## Page 610 of 663

### HARLAN LABORATORIES LTD. HISTO - 20 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.074 0.093 0.087 0.088 0.096**  **St.dev. 0.006 0.011 0.007 0.014 0.006 Min 0.065 0.082 0.079 0.070 0.090**  **Max 0.078 0.108 0.094 0.106 0.102**

**N 5 5 5 5 5**

**Spleen Mean 0.74 0.69 0.65 0.73 0.74**  **St.dev. 0.06 0.12 0.04 0.13 0.05 Min 0.67 0.56 0.62 0.59 0.68**  **Max 0.81 0.82 0.71 0.90 0.80**

**N 5 5 5 5 5**

**Ovaries Mean 0.119 0.148 --- --- ---**  **St.dev. 0.010 0.028 Min 0.103 0.109**  **Max 0.129 0.177**

**N 5 5**

**Uterus Mean 1.05 --- --- --- ---**  **St.dev. 0.19 Min 0.75**  **Max 1.21**

**N 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 611 of 663

### HARLAN LABORATORIES LTD. HISTO - 21 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 228.2 232.6 233.3 237.5 240.5**  **St.dev. 12.2 15.8 10.6 2.9 15.0 Min 206.9 214.3 216.6 234.5 223.0**  **Max 243.1 254.9 249.0 241.9 271.9**

**N 10 9 10 5 10**

**Brain Mean 1.90 1.91 1.87 1.85 1.90**  **St.dev. 0.07 0.04 0.06 0.09 0.05 Min 1.82 1.88 1.82 1.75 1.85**  **Max 2.02 1.97 1.96 1.96 1.96**

**N 5 4 5 5 5**

**Heart Mean 0.76 0.76 0.80 0.78 0.76**  **St.dev. 0.06 0.05 0.05 0.05 0.08 Min 0.70 0.68 0.73 0.72 0.63**  **Max 0.84 0.80 0.87 0.86 0.86**

**N 5 4 5 5 5**

**Liver Mean 7.34 7.18 7.68 8.08 8.28**  **St.dev. 0.73 0.74 0.51 0.83 0.98 Min 6.42 6.34 7.00 7.09 7.23**  **Max 8.16 8.06 8.43 8.78 9.65**

**N 5 4 5 5 5**

**Thymus Mean 0.180 0.205 0.197 0.185 0.190**  **St.dev. 0.017 0.019 0.022 0.047 0.016 Min 0.166 0.177 0.170 0.112 0.168**  **Max 0.208 0.219 0.223 0.232 0.207**

**N 5 4 5 5 5**

**Kidneys Mean 1.46 1.42 1.46 1.53 1.52**  **St.dev. 0.18 0.10 0.13 0.14 0.09 Min 1.23 1.31 1.29 1.31 1.43**  **Max 1.63 1.55 1.62 1.69 1.62**

**N 5 4 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 612 of 663

### HARLAN LABORATORIES LTD. HISTO - 22 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.079 0.086 0.096 0.092 0.084**  **St.dev. 0.015 0.009 0.008 0.016 0.008 Min 0.065 0.075 0.086 0.074 0.072**  **Max 0.097 0.095 0.107 0.110 0.091**

**N 5 4 5 5 5**

**Spleen Mean 0.61 0.62 0.74 0.68 0.70**  **St.dev. 0.07 0.09 0.06 0.10 0.12 Min 0.54 0.52 0.65 0.60 0.60**  **Max 0.69 0.70 0.81 0.84 0.89**

**N 5 4 5 5 5**

**Ovaries Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4596 

## Page 613 of 663

### HARLAN LABORATORIES LTD. HISTO - 23 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Body Weight Mean 232.4 234.1 227.3**  **St.dev. 8.0 8.8 11.5 Min 218.1 221.9 208.5**  **Max 241.4 253.3 247.2**

**N 10 10 10**

**Brain Mean 1.89 1.91 1.87**  **St.dev. 0.06 0.07 0.07 Min 1.84 1.82 1.78**  **Max 1.99 2.00 1.97**

**N 5 5 5**

**Heart Mean 0.77 0.80 0.78**  **St.dev. 0.05 0.05 0.07 Min 0.72 0.76 0.69**  **Max 0.85 0.86 0.84**

**N 5 5 5**

**Liver Mean 8.13 7.92 7.51**  **St.dev. 0.28 0.13 0.43 Min 7.77 7.76 7.02**  **Max 8.50 8.05 8.01**

**N 5 4 5**

**Thymus Mean 0.191 0.212 0.213**  **St.dev. 0.039 0.052 0.084 Min 0.149 0.167 0.137**  **Max 0.239 0.295 0.349**

**N 5 5 5**

**Kidneys Mean 1.53 1.47 1.47**  **St.dev. 0.14 0.11 0.05 Min 1.39 1.39 1.40**  **Max 1.76 1.65 1.53**

**N 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4596 

## Page 614 of 663

### HARLAN LABORATORIES LTD. HISTO - 24 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN WEIGHTS (GRAM)**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan Weights O** 

**Adrenals Mean 0.079 0.092 0.082**  **St.dev. 0.008 0.010 0.016 Min 0.067 0.078 0.063**  **Max 0.088 0.105 0.102**

**N 5 5 5**

**Spleen Mean 0.73 0.76 0.72**  **St.dev. 0.08 0.09 0.13 Min 0.62 0.70 0.56**  **Max 0.81 0.91 0.92**

**N 5 5 5**

**Ovaries Mean --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 615 of 663

### HARLAN LABORATORIES LTD. HISTO - 1 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 354.4 354.4**  **St.dev. 29.4 19.5 Min 271.7 312.6**  **1 Max 461.3 410.** 

**N 230 23**

**Brain Mean 0.57 0.57**  **St.dev. 0.04 0.03 Min 0.42 0.50**  **65 Max 0.72 0.** 

**N 140 23**

**Heart Mean 0.29 0.28**  **St.dev. 0.02 0.01 Min 0.22 0.25**  **32 Max 0.34 0.** 

**N 140 23**

**Liver Mean 2.53 2.53**  **St.dev. 0.17 0.11 Min 2.09 2.40**  **94 Max 3.15 2.** 

**N 140 23**

**Thymus Mean 0.088 0.088**  **St.dev. 0.023 0.014 Min 0.039 0.057**  **124 Max 0.148 0.** 

**N 140 23**

**Kidneys Mean 0.62 0.62**  **St.dev. 0.05 0.03 Min 0.51 0.57**  **73 Max 0.77 0.** 

**N 140 23** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 616 of 663

### HARLAN LABORATORIES LTD. HISTO - 2 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.020 0.020**  **St.dev. 0.004 0.002 Min 0.012 0.016**  **024 Max 0.030 0.** 

**N 140 23**

**Spleen Mean 0.21 0.21**  **St.dev. 0.03 0.02 Min 0.13 0.18**  **24 Max 0.31 0.** 

**N 140 23**

**Testes Mean 1.03 1.03**  **St.dev. 0.12 0.05 Min 0.46 0.92**  **12 Max 1.36 1.** 

**N 230 23**

**Prostate Mean 0.25 0.25**  **St.dev. 0.04 0.02 Min 0.17 0.22**  **27 Max 0.32 0.** 

**N 30 3**

**Epididymides Mean 0.365 0.365**  **St.dev. 0.042 0.015 Min 0.209 0.342**  **400 Max 0.473 0.** 

**N 230 23**

**Seminal Vesicles Mean 0.37 0.37**  **St.dev. 0.07 0.01 Min 0.20 0.36**  **38 Max 0.57 0.** 

**N 30 3** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 617 of 663

### HARLAN LABORATORIES LTD. HISTO - 3 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 353.84 410.06 332.31 355.2 360.9**  **St.dev. 21.95 24.79 19.23 20.1 13.0 Min 330.44 377.64 308.15 325.3 335.5**  **7 Max 407.12 461.29 366.46 381.5 379.** 

**N 10 10 10 10 10**

**Brain Mean 0.57 0.50 0.58 0.56 0.56**  **St.dev. 0.04 0.03 0.02 0.04 0.03 Min 0.48 0.42 0.54 0.51 0.53**  **61 Max 0.61 0.54 0.63 0.64 0.** 

**N 10 10 10 10 10**

**Heart Mean 0.299 0.269 0.299 0.29 0.28**  **St.dev. 0.015 0.020 0.016 0.02 0.02 Min 0.272 0.240 0.279 0.27 0.25**  **30 Max 0.324 0.304 0.326 0.32 0.** 

**N 10 10 10 10 10**

**Liver Mean 2.66 2.48 2.50 2.52 2.51**  **St.dev. 0.12 0.13 0.12 0.14 0.11 Min 2.48 2.30 2.34 2.36 2.32**  **63 Max 2.80 2.75 2.72 2.77 2.** 

**N 10 10 10 10 10**

**Thymus Mean 0.10 0.06 0.09 0.099 0.087**  **St.dev. 0.01 0.01 0.02 0.023 0.018 Min 0.09 0.04 0.06 0.069 0.063**  **106 Max 0.13 0.08 0.12 0.130 0.** 

**N 10 10 10 10 10**

**Kidneys Mean 0.64 0.58 0.62 0.64 0.63**  **St.dev. 0.05 0.04 0.06 0.04 0.02 Min 0.56 0.53 0.52 0.59 0.60**  **65 Max 0.73 0.66 0.68 0.69 0.** 

**N 10 10 10 10 10** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 618 of 663

### HARLAN LABORATORIES LTD. HISTO - 4 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.020 0.016 0.020 0.021 0.020**  **St.dev. 0.003 0.002 0.003 0.002 0.003 Min 0.015 0.013 0.014 0.018 0.015**  **023 Max 0.026 0.019 0.027 0.025 0.** 

**N 10 10 10 10 10**

**Spleen Mean 0.190 0.189 0.205 0.20 0.22**  **St.dev. 0.021 0.019 0.022 0.03 0.02 Min 0.155 0.144 0.165 0.17 0.17**  **26 Max 0.215 0.207 0.249 0.27 0.** 

**N 10 10 10 10 10**

**Testes Mean 0.98 0.92 1.02 1.02 1.06**  **St.dev. 0.06 0.06 0.12 0.13 0.07 Min 0.91 0.80 0.89 0.81 0.96**  **16 Max 1.08 0.99 1.32 1.24 1.** 

**N 10 10 10 10 10**

**Prostate**

**--- Mean 0.22 0.27 --- 0.26**  **St.dev. 0.03 0.03 0.03 Min 0.17 0.23 0.22**  **31 Max 0.27 0.32 0.** 

**N 10 10 10**

**Epididymides Mean 0.342 0.360 0.361 0.352 0.357**  **St.dev. 0.039 0.024 0.037 0.051 0.028 Min 0.288 0.316 0.315 0.288 0.324**  **403 Max 0.424 0.394 0.418 0.440 0.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**--- Mean 0.361 0.377 --- 0.36**  **St.dev. 0.078 0.047 0.09 Min 0.203 0.308 0.26**  **57 Max 0.506 0.454 0.** 

**N 10 10 10** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 619 of 663

### HARLAN LABORATORIES LTD. HISTO - 5 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 340.7 342.3 346.8 365.8 312.6**  **St.dev. 33.6 17.8 27.7 45.3 22.3 Min 310.2 312.5 303.4 320.8 271.7**  **7 Max 406.0 369.0 384.5 456.4 342.** 

**N 10 10 10 10 10**

**Brain Mean 0.61 0.60 0.58 0.54 0.65**  **St.dev. 0.04 0.02 0.04 0.05 0.05 Min 0.57 0.58 0.54 0.49 0.60**  **72 Max 0.67 0.64 0.65 0.61 0.** 

**N 5 5 5 5 5**

**Heart Mean 0.29 0.28 0.29 0.27 0.32**  **St.dev. 0.02 0.01 0.02 0.01 0.02 Min 0.27 0.27 0.27 0.26 0.28**  **34 Max 0.31 0.30 0.31 0.28 0.** 

**N 5 5 5 5 5**

**Liver Mean 2.48 2.46 2.55 2.60 2.94**  **St.dev. 0.31 0.11 0.20 0.15 0.18 Min 2.09 2.33 2.26 2.47 2.73**  **15 Max 2.87 2.62 2.76 2.82 3.** 

**N 5 5 5 5 5**

**Thymus Mean 0.101 0.091 0.084 0.072 0.124**  **St.dev. 0.019 0.011 0.015 0.011 0.014 Min 0.071 0.079 0.067 0.059 0.103**  **141 Max 0.121 0.103 0.104 0.083 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 0.61 0.67 0.59 0.57 0.73**  **St.dev. 0.08 0.03 0.01 0.04 0.04 Min 0.52 0.62 0.58 0.51 0.68**  **77 Max 0.72 0.70 0.60 0.63 0.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 620 of 663

### HARLAN LABORATORIES LTD. HISTO - 6 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.021 0.022 0.018 0.018 0.024**  **St.dev. 0.004 0.005 0.002 0.007 0.005 Min 0.016 0.016 0.017 0.012 0.018**  **030 Max 0.027 0.027 0.022 0.030 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.23 0.21 0.20 0.18 0.22**  **St.dev. 0.03 0.01 0.04 0.03 0.05 Min 0.20 0.19 0.16 0.16 0.13**  **25 Max 0.28 0.23 0.25 0.23 0.** 

**N 5 5 5 5 5**

**Testes Mean 1.05 1.06 1.03 1.04 1.11**  **St.dev. 0.14 0.24 0.07 0.08 0.11 Min 0.93 0.46 0.86 0.95 0.99**  **28 Max 1.36 1.33 1.12 1.16 1.** 

**N 10 10 10 10 10**

**Prostate**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 0.366 0.358 0.354 0.362 0.380**  **St.dev. 0.051 0.056 0.020 0.042 0.038 Min 0.313 0.232 0.330 0.292 0.317**  **432 Max 0.454 0.422 0.381 0.426 0.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 621 of 663

### HARLAN LABORATORIES LTD. HISTO - 7 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 342.8 370.8 373.1 351.6 364.0**  **St.dev. 16.8 22.1 26.5 18.1 14.1 Min 319.4 343.1 342.2 330.5 334.7**  **0 Max 366.8 397.0 441.1 383.8 384.** 

**N 10 10 10 10 10**

**Brain Mean 0.57 0.56 0.57 0.58 0.56**  **St.dev. 0.02 0.04 0.02 0.04 0.04 Min 0.55 0.51 0.55 0.54 0.53**  **63 Max 0.60 0.59 0.59 0.63 0.** 

**N 5 5 5 5 5**

**Heart Mean 0.27 0.25 0.29 0.30 0.29**  **St.dev. 0.02 0.02 0.02 0.01 0.01 Min 0.26 0.22 0.27 0.28 0.27**  **31 Max 0.30 0.27 0.32 0.31 0.** 

**N 5 5 5 5 5**

**Liver Mean 2.40 2.42 2.57 2.49 2.49**  **St.dev. 0.16 0.05 0.20 0.08 0.18 Min 2.25 2.38 2.30 2.36 2.33**  **79 Max 2.59 2.49 2.84 2.56 2.** 

**N 5 5 5 5 5**

**Thymus Mean 0.088 0.078 0.075 0.081 0.082**  **St.dev. 0.012 0.014 0.014 0.013 0.021 Min 0.077 0.066 0.063 0.064 0.064**  **107 Max 0.108 0.098 0.093 0.093 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 0.58 0.62 0.64 0.62 0.61**  **St.dev. 0.04 0.06 0.03 0.02 0.05 Min 0.53 0.54 0.61 0.58 0.54**  **66 Max 0.62 0.69 0.70 0.64 0.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 622 of 663

### HARLAN LABORATORIES LTD. HISTO - 8 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.018 0.022 0.023 0.020 0.018**  **St.dev. 0.002 0.005 0.002 0.001 0.004 Min 0.016 0.015 0.020 0.019 0.015**  **023 Max 0.021 0.028 0.026 0.022 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.20 0.19 0.22 0.21 0.18**  **St.dev. 0.03 0.02 0.03 0.02 0.02 Min 0.18 0.16 0.20 0.19 0.15**  **21 Max 0.25 0.22 0.29 0.23 0.** 

**N 5 5 5 5 5**

**Testes Mean 1.04 1.00 1.03 1.09 1.01**  **St.dev. 0.06 0.11 0.10 0.08 0.08 Min 0.98 0.85 0.89 0.95 0.85**  **11 Max 1.13 1.15 1.25 1.24 1.** 

**N 10 10 10 10 5**

**Prostate**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 0.384 0.360 0.375 0.392 0.359**  **St.dev. 0.034 0.038 0.040 0.386 0.035 Min 0.316 0.312 0.306 0.341 0.286**  **416 Max 0.420 0.436 0.437 0.449 0.** 

**N 10 10 5 10 10**

**Seminal Vesicles**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 623 of 663

### HARLAN LABORATORIES LTD. HISTO - 9 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 357.3 381.5 356.1 362.3 339.7**  **St.dev. 28.9 19.5 26.6 10.4 24.8 Min 316.4 355.2 309.9 353.0 306.4**  **1 Max 389.6 416.1 390.0 388.6 382.** 

**N 10 10 10 10 10**

**Brain Mean 0.57 0.55 0.57 0.57 0.59**  **St.dev. 0.05 0.02 0.02 0.02 0.03 Min 0.52 0.53 0.54 0.54 0.56**  **63 Max 0.66 0.58 0.58 0.59 0.** 

**N 5 5 5 5 5**

**Heart Mean 0.28 0.27 0.29 0.28 0.27**  **St.dev. 0.01 0.01 0.03 0.01 0.01 Min 0.27 0.26 0.27 0.27 0.26**  **29 Max 0.29 0.28 0.33 0.29 0.** 

**N 5 5 5 5 5**

**Liver Mean 2.57 2.47 2.54 2.41 2.52**  **St.dev. 0.10 0.11 0.21 0.06 0.15 Min 2.44 2.33 2.29 2.31 2.33**  **68 Max 2.66 2.60 2.85 2.46 2.** 

**N 5 5 5 5 5**

**Thymus Mean 0.094 0.102 0.077 0.087 0.079**  **St.dev. 0.033 0.026 0.021 0.028 0.022 Min 0.056 0.063 0.047 0.065 0.054**  **111 Max 0.146 0.127 0.097 0.134 0.** 

**N 5 5 5 5 5**

**Kidneys Mean 0.61 0.60 0.62 0.61 0.57**  **St.dev. 0.02 0.02 0.06 0.05 0.04 Min 0.59 0.58 0.56 0.56 0.52**  **62 Max 0.65 0.62 0.71 0.67 0.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 624 of 663

### HARLAN LABORATORIES LTD. HISTO - 10 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.022 0.022 0.019 0.020 0.022**  **St.dev. 0.002 0.004 0.002 0.003 0.002 Min 0.019 0.017 0.016 0.016 0.018**  **024 Max 0.026 0.027 0.021 0.023 0.** 

**N 5 5 5 5 5**

**Spleen Mean 0.22 0.21 0.24 0.21 0.20**  **St.dev. 0.04 0.02 0.03 0.03 0.02 Min 0.18 0.19 0.21 0.19 0.17**  **23 Max 0.28 0.22 0.28 0.26 0.** 

**N 5 5 5 5 5**

**Testes Mean 1.10 1.03 1.01 1.00 0.98**  **St.dev. 0.12 0.06 0.06 0.12 0.19 Min 0.88 0.93 0.93 0.77 0.48**  **15 Max 1.30 1.11 1.14 1.12 1.** 

**N 10 10 10 10 10**

**Prostate**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 0.384 0.344 0.379 0.348 0.352**  **St.dev. 0.037 0.047 0.031 0.049 0.065 Min 0.334 0.229 0.316 0.239 0.209**  **453 Max 0.453 0.389 0.420 0.398 0.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**-- --- --- --- --- Mean -**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 625 of 663

### HARLAN LABORATORIES LTD. HISTO - 11 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 355.2 334.2 341.7**  **St.dev. 18.8 21.3 20.9 Min 332.2 309.5 316.0**  **6 Max 387.0 366.8 386.** 

**N 10 10 10**

**Brain Mean 0.56 0.59 0.59**  **St.dev. 0.03 0.03 0.04 Min 0.52 0.55 0.52**  **62 Max 0.60 0.63 0.** 

**N 5 5 5**

**Heart Mean 0.30 0.28 0.29**  **St.dev. 0.02 0.02 0.01 Min 0.27 0.25 0.27**  **31 Max 0.33 0.31 0.** 

**N 5 5 5**

**Liver Mean 2.59 2.56 2.45**  **St.dev. 0.14 0.19 0.15 Min 2.41 2.31 2.30**  **63 Max 2.73 2.73 2.** 

**N 5 5 5**

**Thymus Mean 0.107 0.072 0.095**  **St.dev. 0.030 0.008 0.021 Min 0.075 0.061 0.073**  **118 Max 0.148 0.084 0.** 

**N 5 5 5**

**Kidneys Mean 0.60 0.63 0.59**  **St.dev. 0.05 0.03 0.06 Min 0.52 0.61 0.54**  **68 Max 0.64 0.67 0.** 

**N 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 626 of 663

### HARLAN LABORATORIES LTD. HISTO - 12 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.022 0.021 0.020**  **St.dev. 0.002 0.004 0.003 Min 0.020 0.017 0.016**  **023 Max 0.025 0.027 0.** 

**N 5 5 5**

**Spleen Mean 0.24 0.20 0.21**  **St.dev. 0.06 0.01 0.02 Min 0.16 0.19 0.17**  **24 Max 0.31 0.22 0.** 

**N 5 5 5**

**Testes Mean 1.05 1.12 0.98**  **St.dev. 0.08 0.06 0.17 Min 0.95 0.99 0.56**  **12 Max 1.17 1.19 1.** 

**N 10 10 10**

**Prostate**

**-- --- --- Mean -**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 0.363 0.400 0.358**  **St.dev. 0.033 0.039 0.058 Min 0.305 0.347 0.252**  **444 Max 0.416 0.473 0.** 

**N 10 10 10**

**Seminal Vesicles**

**-- --- --- Mean -**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 627 of 663

### HARLAN LABORATORIES LTD. HISTO - 13 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 236.7 236.7**  **St.dev. 14.3 5.9 Min 193.5 226.0**  **0 Max 281.2 250.** 

**N 205 21**

**Brain Mean 0.81 0.80**  **St.dev. 0.05 0.02 Min 0.69 0.77**  **83 Max 1.01 0.** 

**N 120 21**

**Heart Mean 0.34 0.34**  **St.dev. 0.03 0.02 Min 0.27 0.31**  **38 Max 0.49 0.** 

**N 120 21**

**Liver Mean 3.36 3.35**  **St.dev. 0.32 0.13 Min 2.38 2.96**  **63 Max 4.86 3.** 

**N 119 21**

**Thymus Mean 0.084 0.085**  **St.dev. 0.020 0.011 Min 0.045 0.067**  **110 Max 0.159 0.** 

**N 120 21**

**Kidneys Mean 0.63 0.63**  **St.dev. 0.05 0.02 Min 0.54 0.59**  **66 Max 0.75 0.** 

**N 120 21** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 628 of 663

### HARLAN LABORATORIES LTD. HISTO - 14 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.036 0.036**  **St.dev. 0.005 0.003 Min 0.026 0.031**  **041 Max 0.048 0.** 

**N 120 21**

**Spleen Mean 0.30 0.29**  **St.dev. 0.06 0.02 Min 0.20 0.26**  **32 Max 0.65 0.** 

**N 120 21**

**Ovaries Mean 0.053 0.054**  **St.dev. 0.008 0.005 Min 0.041 0.050**  **061 Max 0.072 0.** 

**N 25 4**

**Uterus Mean 0.48 0.47**  **St.dev. 0.06 0.03 Min 0.31 0.44**  **49 Max 0.56 0.** 

**N 20 3** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 629 of 663

### HARLAN LABORATORIES LTD. HISTO - 15 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean --- 238.84 235.06 --- 236.5**  **St.dev. 26.48 14.36 18.9 Min 193.48 205.48 213.7**  **Max 281.18 256.93 267.9**

**N 10 10 10**

**Brain Mean --- 0.82 0.83 --- 0.80**  **St.dev. 0.09 0.04 0.06 Min 0.70 0.76 0.70**  **Max 1.01 0.91 0.87**

**N 10 10 10**

**Heart Mean --- 0.347 0.383 --- 0.33**  **St.dev. 0.022 0.051 0.02 Min 0.309 0.335 0.31**  **Max 0.394 0.487 0.37**

**N 10 10 10**

**Liver Mean --- 3.27 3.41 --- 3.63**  **St.dev. 0.34 0.29 0.65 Min 2.61 2.90 3.13**  **Max 3.74 3.96 4.86**

**N 10 10 10**

**Thymus Mean --- 0.07 0.09 --- 0.074**  **St.dev. 0.02 0.03 0.019 Min 0.05 0.06 0.045**  **Max 0.13 0.15 0.107**

**N 10 10 10**

**Kidneys Mean --- 0.63 0.66 --- 0.62**  **St.dev. 0.03 0.05 0.03 Min 0.57 0.58 0.56**  **Max 0.67 0.75 0.67**

**N 10 10 10** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 630 of 663

### HARLAN LABORATORIES LTD. HISTO - 16 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean --- 0.033 0.038 --- 0.037**  **St.dev. 0.005 0.005 0.006 Min 0.026 0.029 0.027**  **Max 0.043 0.045 0.046**

**N 10 10 10**

**Spleen Mean --- 0.285 0.307 --- 0.32**  **St.dev. 0.100 0.056 0.12 Min 0.218 0.219 0.23**  **Max 0.549 0.407 0.65**

**N 10 10 10**

**Ovaries Mean --- 0.051 --- --- ---**  **St.dev. 0.005 Min 0.043**  **Max 0.057**

**N 10**

**Uterus Mean --- 0.495 --- --- ---**  **St.dev. 0.041 Min 0.436**  **Max 0.556**

**N 10** 

### Harlan Laboratories Study Report
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## Page 631 of 663

### HARLAN LABORATORIES LTD. HISTO - 17 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 238.8 238.8 246.7 236.5 226.0**  **St.dev. 4.9 11.5 10.2 12.9 13.7 Min 229.7 221.4 230.1 215.7 203.3**  **Max 245.4 251.9 263.8 254.2 250.7**

**N 10 5 10 10 10**

**Brain Mean 0.79 0.79 0.77 0.78 0.82**  **St.dev. 0.02 0.06 0.03 0.03 0.04 Min 0.76 0.71 0.74 0.75 0.79**  **Max 0.82 0.86 0.80 0.81 0.90**

**N 5 5 5 5 5**

**Heart Mean 0.34 0.33 0.34 0.31 0.37**  **St.dev. 0.02 0.04 0.04 0.01 0.03 Min 0.33 0.30 0.30 0.30 0.32**  **Max 0.38 0.39 0.41 0.33 0.40**

**N 5 5 5 5 5**

**Liver Mean 3.39 3.38 3.38 3.22 3.37**  **St.dev. 0.25 0.27 0.13 0.16 0.27 Min 3.11 3.00 3.25 3.01 3.15**  **Max 3.79 3.60 3.57 3.43 3.83**

**N 5 5 5 5 5**

**Thymus Mean 0.089 0.087 0.083 0.073 0.067**  **St.dev. 0.017 0.007 0.009 0.009 0.016 Min 0.072 0.079 0.075 0.058 0.046**  **Max 0.111 0.095 0.098 0.080 0.088**

**N 5 5 5 5 5**

**Kidneys Mean 0.65 0.62 0.61 0.59 0.61**  **St.dev. 0.04 0.05 0.04 0.03 0.05 Min 0.58 0.56 0.55 0.56 0.55**  **Max 0.70 0.68 0.64 0.63 0.67**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 632 of 663

### HARLAN LABORATORIES LTD. HISTO - 18 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.035 0.037 0.034 0.032 0.036**  **St.dev. 0.004 0.003 0.003 0.005 0.004 Min 0.028 0.034 0.030 0.027 0.033**  **Max 0.039 0.040 0.037 0.039 0.042**

**N 5 5 5 5 5**

**Spleen Mean 0.28 0.28 0.28 0.27 0.30**  **St.dev. 0.05 0.02 0.01 0.05 0.03 Min 0.24 0.26 0.27 0.22 0.25**  **Max 0.36 0.32 0.30 0.35 0.33**

**N 5 5 5 5 5**

**Ovaries Mean --- --- --- --- 0.054**  **St.dev. 0.011 Min 0.041**  **Max 0.070**

**N 5**

**Uterus Mean --- --- --- --- 0.48**  **St.dev. 0.06 Min 0.37**  **Max 0.52**

**N 5** 

### Harlan Laboratories Study Report
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## Page 633 of 663

### HARLAN LABORATORIES LTD. HISTO - 19 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 237.3 243.3 231.5 241.3 238.3**  **St.dev. 13.5 4.4 9.3 15.2 16.2 Min 225.4 236.5 220.7 218.3 217.8**  **Max 259.9 247.5 240.7 269.6 254.0**

**N 5 5 5 10 5**

**Brain Mean 0.79 0.78 0.83 0.81 0.80**  **St.dev. 0.06 0.04 0.03 0.04 0.07 Min 0.69 0.76 0.78 0.76 0.72**  **Max 0.85 0.85 0.86 0.87 0.88**

**N 5 5 5 5 5**

**Heart Mean 0.32 0.34 0.37 0.36 0.34**  **St.dev. 0.01 0.02 0.03 0.02 0.05 Min 0.30 0.32 0.32 0.34 0.30**  **Max 0.33 0.36 0.41 0.39 0.42**

**N 5 5 5 5 5**

**Liver Mean 3.37 3.29 3.37 3.32 3.51**  **St.dev. 0.14 0.32 0.20 0.11 0.33 Min 3.25 2.83 3.05 3.17 3.17**  **Max 3.53 3.64 3.56 3.45 3.93**

**N 5 5 5 5 5**

**Thymus Mean 0.077 0.088 0.086 0.110 0.096**  **St.dev. 0.010 0.012 0.021 0.020 0.021 Min 0.065 0.072 0.065 0.095 0.072**  **Max 0.088 0.106 0.112 0.144 0.124**

**N 5 5 5 5 5**

**Kidneys Mean 0.63 0.64 0.66 0.66 0.65**  **St.dev. 0.04 0.07 0.07 0.02 0.08 Min 0.58 0.54 0.58 0.64 0.58**  **Max 0.66 0.69 0.73 0.69 0.75**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 634 of 663

### HARLAN LABORATORIES LTD. HISTO - 20 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.031 0.038 0.037 0.038 0.040**  **St.dev. 0.003 0.004 0.004 0.008 0.002 Min 0.028 0.034 0.033 0.029 0.037**  **Max 0.035 0.044 0.043 0.048 0.042**

**N 5 5 5 5 5**

**Spleen Mean 0.31 0.28 0.28 0.31 0.31**  **St.dev. 0.03 0.05 0.02 0.06 0.01 Min 0.28 0.23 0.26 0.26 0.29**  **Max 0.35 0.34 0.30 0.37 0.32**

**N 5 5 5 5 5**

**Ovaries Mean 0.050 0.061 --- --- ---**  **St.dev. 0.004 0.011 Min 0.044 0.045**  **Max 0.055 0.072**

**N 5 5**

**Uterus Mean 0.44 --- --- --- ---**  **St.dev. 0.08 Min 0.31**  **Max 0.52**

**N 5** 

### Harlan Laboratories Study Report
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## Page 635 of 663

### HARLAN LABORATORIES LTD. HISTO - 21 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 228.2 232.6 233.3 237.5 240.5**  **St.dev. 12.2 15.8 10.6 2.9 15.0 Min 206.9 214.3 216.6 234.5 223.0**  **Max 243.1 254.9 249.0 241.9 271.9**

**N 5 9 10 5 10**

**Brain Mean 0.83 0.83 0.80 0.78 0.79**  **St.dev. 0.03 0.04 0.05 0.03 0.06 Min 0.79 0.78 0.73 0.74 0.69**  **Max 0.85 0.88 0.84 0.82 0.85**

**N 5 4 5 5 5**

**Heart Mean 0.33 0.33 0.34 0.33 0.32**  **St.dev. 0.01 0.02 0.01 0.02 0.04 Min 0.32 0.31 0.33 0.31 0.27**  **Max 0.35 0.35 0.36 0.37 0.35**

**N 5 4 5 5 5**

**Liver Mean 3.18 3.11 3.28 3.40 3.44**  **St.dev. 0.21 0.13 0.17 0.32 0.17 Min 2.88 2.96 3.04 3.00 3.24**  **Max 3.39 3.25 3.47 3.67 3.66**

**N 5 4 5 5 5**

**Thymus Mean 0.078 0.089 0.084 0.078 0.079**  **St.dev. 0.007 0.008 0.007 0.020 0.008 Min 0.069 0.081 0.076 0.048 0.073**  **Max 0.087 0.098 0.092 0.097 0.092**

**N 5 4 5 5 5**

**Kidneys Mean 0.63 0.62 0.62 0.64 0.63**  **St.dev. 0.06 0.02 0.05 0.05 0.02 Min 0.56 0.59 0.56 0.55 0.59**  **Max 0.71 0.64 0.67 0.70 0.66**

**N 5 4 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab4579 

## Page 636 of 663

### HARLAN LABORATORIES LTD. HISTO - 22 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.034 0.037 0.041 0.039 0.035**  **St.dev. 0.005 0.004 0.003 0.006 0.003 Min 0.029 0.033 0.038 0.031 0.032**  **Max 0.040 0.041 0.045 0.045 0.040**

**N 5 4 5 5 5**

**Spleen Mean 0.27 0.27 0.32 0.28 0.29**  **St.dev. 0.02 0.03 0.03 0.04 0.02 Min 0.24 0.24 0.28 0.25 0.27**  **Max 0.28 0.30 0.34 0.35 0.33**

**N 5 4 5 5 5**

**Ovaries Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab4579 

## Page 637 of 663

### HARLAN LABORATORIES LTD. HISTO - 23 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Body Weight (gram) Mean 232.4 234.1 227.3**  **St.dev. 8.0 8.8 11.5 Min 218.1 221.9 208.5**  **Max 241.4 253.3 247.2**

**N 10 10 10**

**Brain Mean 0.81 0.81 0.82**  **St.dev. 0.02 0.02 0.06 Min 0.78 0.79 0.75**  **Max 0.83 0.83 0.89**

**N 5 5 5**

**Heart Mean 0.33 0.34 0.34**  **St.dev. 0.02 0.03 0.04 Min 0.30 0.32 0.31**  **Max 0.35 0.37 0.40**

**N 5 5 5**

**Liver Mean 3.48 3.38 3.32**  **St.dev. 0.07 0.12 0.41 Min 3.41 3.23 2.89**  **Max 3.60 3.50 3.84**

**N 5 4 5**

**Thymus Mean 0.082 0.090 0.093**  **St.dev. 0.017 0.021 0.035 Min 0.062 0.071 0.062**  **Max 0.101 0.123 0.146**

**N 5 5 5**

**Kidneys Mean 0.65 0.62 0.65**  **St.dev. 0.05 0.04 0.02 Min 0.61 0.59 0.62**  **Max 0.73 0.69 0.67**

**N 5 5 5** 

### Harlan Laboratories Study Report
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## Page 638 of 663

### HARLAN LABORATORIES LTD. HISTO - 24 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Body Weight Ratios (%) O** 

**Adrenals Mean 0.034 0.039 0.037**  **St.dev. 0.004 0.004 0.008 Min 0.028 0.033 0.026**  **Max 0.039 0.044 0.046**

**N 5 5 5**

**Spleen Mean 0.31 0.32 0.32**  **St.dev. 0.04 0.03 0.08 Min 0.26 0.30 0.23**  **Max 0.35 0.38 0.44**

**N 5 5 5**

**Ovaries Mean --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 639 of 663

### HARLAN LABORATORIES LTD. HISTO - 1 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 2.02 2.02**  **St.dev. 0.08 0.05 Min 1.77 1.93**  **10 Max 2.23 2.** 

**N 140 23**

**Heart Mean 50.11 49.75**  **St.dev. 3.69 2.10 Min 41.03 45.20**  **53 Max 60.11 53.** 

**N 140 23**

**Liver Mean 445.28 442.76**  **St.dev. 42.39 21.65 Min 348.67 407.23**  **26 Max 652.26 495.** 

**N 140 23**

**Thymus Mean 15.439 15.382**  **St.dev. 3.889 2.119 Min 7.568 11.448**  **175 Max 26.586 19.** 

**N 140 23**

**Kidneys Mean 108.25 107.51**  **St.dev. 9.06 4.97 Min 85.80 96.69**  **81 Max 133.97 115.** 

**N 140 23** 

### Harlan Laboratories Study Report
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## Page 640 of 663

### HARLAN LABORATORIES LTD. HISTO - 2 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Males**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.538 3.556**  **St.dev. 0.579 0.274 Min 1.905 3.136**  **150 Max 5.416 4.** 

**N 140 23**

**Spleen Mean 36.26 36.28**  **St.dev. 5.12 2.99 Min 21.89 31.54**  **21 Max 55.75 43.** 

**N 140 23**

**Testes Mean 179.07 179.06**  **St.dev. 19.52 7.72 Min 71.16 155.90**  **13 Max 230.33 193.** 

**N 140 23**

**Prostate Mean 46.09 46.09**  **St.dev. 7.68 7.40 Min 31.79 38.70**  **49 Max 63.61 53.** 

**N 30 3**

**Epididymides Mean 63.058 62.911**  **St.dev. 7.091 3.375 Min 36.229 57.940**  **679 Max 81.739 71.** 

**N 140 23**

**Seminal Vesicles Mean 67.50 67.50**  **St.dev. 13.80 6.29 Min 33.39 63.51**  **75 Max 101.74 74.** 

**N 30 3** 

### Harlan Laboratories Study Report
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## Page 641 of 663

### HARLAN LABORATORIES LTD. HISTO - 3 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 2.03 2.06 1.93 2.00 2.04**  **St.dev. 0.05 0.09 0.11 0.07 0.09 Min 1.95 1.94 1.77 1.90 1.92**  **18 Max 2.10 2.22 2.12 2.09 2.** 

**N 10 10 10 10 10**

**Heart Mean 52.129 53.526 51.438 51.69 49.96**  **St.dev. 2.966 3.200 3.042 2.99 4.39 Min 48.206 49.986 47.989 45.69 41.03**  **80 Max 56.817 60.110 58.129 56.00 56.** 

**N 10 10 10 10 10**

**Liver Mean 464.83 495.26 430.55 447.89 445.88**  **St.dev. 31.38 59.70 28.84 36.62 34.63 Min 406.54 444.42 389.03 373.85 386.98**  **23 Max 520.21 652.26 468.5 517.06 499.** 

**N 10 10 10 10 10**

**Thymus Mean 18.22 11.45 15.80 17.572 15.455**  **St.dev. 2.57 2.81 3.89 4.229 3.649 Min 14.90 7.57 10.25 12.919 10.453**  **423 Max 21.82 15.77 21.21 23.897 19.** 

**N 10 10 10 10 10**

**Kidneys Mean 111.37 115.81 105.81 113.87 111.45**  **St.dev. 7.22 9.11 10.38 11.33 4.50 Min 100.81 104.19 85.80 93.89 105.20**  **00 Max 122.24 133.97 117.15 128.55 121.** 

**N 10 10 10 10 10** 

### Harlan Laboratories Study Report
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## Page 642 of 663

### HARLAN LABORATORIES LTD. HISTO - 4 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.460 3.218 3.447 3.683 3.474**  **St.dev. 0.418 0.387 0.612 0.336 0.450 Min 2.705 2.586 2.269 3.287 2.744**  **271 Max 4.195 3.834 4.577 4.273 4.** 

**N 10 10 10 10 10**

**Spleen Mean 33.168 37.640 35.227 36.18 38.57**  **St.dev. 3.212 4.620 4.301 4.03 4.30 Min 26.184 28.258 28.439 29.55 30.98**  **84 Max 36.919 46.151 43.026 42.50 46.** 

**N 10 10 10 10 10**

**Testes Mean 170.91 182.52 175.02 179.70 187.36**  **St.dev. 13.09 8.17 21.83 12.38 13.53 Min 154.16 170.10 158.13 159.10 170.89**  **85 Max 193.58 193.98 230.33 202.40 202.** 

**N 10 10 10 10 10**

**Prostate**

**--- Mean 38.70 53.49 --- 46.10**  **St.dev. 4.21 5.91 3.97 Min 31.79 44.95 41.35**  **27 Max 43.93 63.61 54.** 

**N 10 10 10**

**Epididymides Mean 59.603 71.679 62.054 62.075 63.250**  **St.dev. 5.511 4.165 6.253 5.404 3.272 Min 52.057 67.653 56.508 56.498 59.308**  **393 Max 71.091 78.524 72.247 71.882 70.** 

**N 10 10 10 10 10**

**Seminal Vesicles**

**--- Mean 63.507 74.752 --- 64.25**  **St.dev. 16.006 7.200 14.76 Min 33.386 60.537 50.74**  **74 Max 88.479 85.533 101.** 

**N 10 10 10** 

### Harlan Laboratories Study Report
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## Page 643 of 663

### HARLAN LABORATORIES LTD. HISTO - 5 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 2.03 2.02 1.96 1.99 1.99**  **St.dev. 0.10 0.04 0.06 0.06 0.05 Min 1.91 1.96 1.89 1.92 1.94**  **06 Max 2.18 2.06 2.05 2.06 2.** 

**N 5 5 5 5 5**

**Heart Mean 47.87 46.90 49.67 49.88 48.61**  **St.dev. 2.64 3.06 3.51 3.31 1.78 Min 44.31 42.49 46.52 45.49 47.41**  **60 Max 50.69 50.19 54.71 54.00 51.** 

**N 5 5 5 5 5**

**Liver Mean 407.23 410.54 439.59 485.15 452.28**  **St.dev. 38.23 23.52 58.77 47.99 44.53 Min 365.53 376.78 348.67 402.12 376.66**  **34 Max 461.78 441.58 497.01 518.83 487.** 

**N 5 5 5 5 5**

**Thymus Mean 16.678 15.153 14.444 13.572 19.175**  **St.dev. 3.516 2.015 2.830 2.621 3.162 Min 11.734 13.286 11.835 9.587 15.885**  **674 Max 21.073 17.891 19.262 16.442 23.** 

**N 5 5 5 5 5**

**Kidneys Mean 99.86 111.89 101.83 105.06 112.01**  **St.dev. 10.99 6.53 9.19 4.47 12.94 Min 89.91 103.04 88.99 101.66 95.92**  **60 Max 114.86 118.40 111.53 112.63 129.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 644 of 663

### HARLAN LABORATORIES LTD. HISTO - 6 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.361 3.653 3.136 3.435 3.637**  **St.dev. 0.504 0.742 0.303 1.327 0.836 Min 2.793 2.754 2.880 1.905 2.885**  **593 Max 4.050 4.624 3.619 5.416 4.** 

**N 5 5 5 5 5**

**Spleen Mean 37.97 34.29 33.89 34.11 32.94**  **St.dev. 3.68 2.13 5.00 7.48 6.51 Min 32.75 32.60 27.70 25.77 21.89**  **29 Max 42.04 37.96 38.98 44.60 38.** 

**N 5 5 5 5 5**

**Testes Mean 174.19 178.89 177.44 193.13 172.51**  **St.dev. 18.15 62.66 9.85 16.22 15.56 Min 159.69 71.16 168.29 177.04 155.91**  **22 Max 203.20 224.23 193.73 220.31 197.** 

**N 5 5 5 5 5**

**Prostate**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 58.350 60.515 60.004 65.247 57.940**  **St.dev. 3.331 14.655 2.130 4.372 2.997 Min 53.770 36.229 57.608 58.467 54.089**  **473 Max 62.604 73.228 62.981 70.494 62.** 

**N 5 5 5 5 5**

**Seminal Vesicles**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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09009e5380ab457a 

## Page 645 of 663

### HARLAN LABORATORIES LTD. HISTO - 7 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.96 1.98 2.06 2.10 1.99**  **St.dev. 0.04 0.09 0.07 0.06 0.07 Min 1.91 1.83 1.94 2.02 1.91**  **10 Max 2.01 2.06 2.12 2.16 2.** 

**N 5 5 5 5 5**

**Heart Mean 47.99 45.20 51.62 50.86 50.84**  **St.dev. 3.58 3.32 3.74 3.53 2.09 Min 45.07 43.23 47.47 45.88 49.00**  **24 Max 54.19 51.11 54.81 54.40 54.** 

**N 5 5 5 5 5**

**Liver Mean 421.39 434.59 454.58 427.31 443.25**  **St.dev. 34.10 24.64 47.39 37.13 45.44 Min 386.12 415.28 397.74 376.40 397.68**  **91 Max 473.43 472.95 519.92 471.70 516.** 

**N 5 5 5 5 5**

**Thymus Mean 15.493 14.079 13.201 13.951 14.547**  **St.dev. 1.828 2.750 2.472 2.608 3.246 Min 14.060 11.398 11.183 10.170 11.361**  **855 Max 18.593 18.303 16.768 16.542 18.** 

**N 5 5 5 5 5**

**Kidneys Mean 101.70 110.42 112.95 105.67 107.91**  **St.dev. 7.73 7.72 7.55 5.90 8.37 Min 91.77 103.74 104.59 98.44 101.33**  **22 Max 113.02 121.02 125.15 111.63 122.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab457a 

## Page 646 of 663

### HARLAN LABORATORIES LTD. HISTO - 8 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.183 3.873 4.150 3.507 3.264**  **St.dev. 0.389 0.831 0.434 0.329 0.520 Min 2.834 2.546 3.557 3.161 2.560**  **834 Max 3.756 4.710 4.695 4.050 3.** 

**N 5 5 5 5 5**

**Spleen Mean 34.91 34.12 39.55 36.52 31.54**  **St.dev. 3.70 4.11 5.45 2.31 4.95 Min 32.17 31.04 36.81 34.26 27.10**  **48 Max 41.33 40.73 49.29 40.35 39.** 

**N 5 5 5 5 5**

**Testes Mean 180.56 185.11 181.47 176.83 176.86**  **St.dev. 7.34 14.48 12.92 11.84 13.68 Min 170.51 167.87 164.03 166.70 156.99**  **05 Max 187.65 206.79 194.27 189.95 190.** 

**N 5 5 5 5 5**

**Prostate**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 67.452 66.071 66.699 63.865 61.971**  **St.dev. 3.895 9.666 7.107 3.594 7.742 Min 61.996 58.575 56.119 60.319 51.498**  **485 Max 72.091 81.739 73.792 68.710 72.** 

**N 5 5 5 5 5**

**Seminal Vesicles**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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09009e5380ab457a 

## Page 647 of 663

### HARLAN LABORATORIES LTD. HISTO - 9 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 2.08 2.10 2.07 2.08 2.05**  **St.dev. 0.10 0.05 0.07 0.09 0.09 Min 1.95 2.04 1.96 1.94 1.89**  **12 Max 2.23 2.16 2.12 2.17 2.** 

**N 5 5 5 5 5**

**Heart Mean 50.21 48.13 51.24 49.54 46.80**  **St.dev. 4.70 2.49 3.90 1.46 3.54 Min 42.47 45.88 47.28 47.34 43.98**  **97 Max 54.12 51.94 57.25 51.15 52.** 

**N 5 5 5 5 5**

**Liver Mean 457.64 447.23 448.96 424.84 430.73**  **St.dev. 52.33 30.74 37.91 12.51 41.02 Min 371.52 398.98 393.70 407.31 395.55**  **69 Max 509.13 484.77 488.31 439.03 482.** 

**N 5 5 5 5 5**

**Thymus Mean 16.870 18.334 13.518 15.357 13.532**  **St.dev. 6.544 4.428 3.503 5.179 3.878 Min 8.567 11.635 8.377 11.366 8.612**  **998 Max 26.586 23.657 16.696 24.132 18.** 

**N 5 5 5 5 5**

**Kidneys Mean 108.85 109.07 109.32 107.57 96.69**  **St.dev. 5.64 7.77 7.25 4.70 8.46 Min 99.61 98.54 103.07 101.51 89.94**  **11 Max 113.46 116.96 121.07 112.73 111.** 

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab457a 

## Page 648 of 663

### HARLAN LABORATORIES LTD. HISTO - 10 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 4.004 3.935 3.313 3.525 3.736**  **St.dev. 0.736 0.753 0.335 0.490 0.395 Min 2.930 2.948 2.833 2.906 3.303**  **271 Max 4.947 4.938 3.661 4.073 4.** 

**N 5 5 5 5 5**

**Spleen Mean 38.74 37.78 43.21 37.28 33.62**  **St.dev. 4.76 2.14 5.54 4.06 4.02 Min 34.13 34.58 37.53 33.36 29.01**  **91 Max 44.49 40.39 51.85 43.40 38.** 

**N 5 5 5 5 5**

**Testes Mean 179.22 179.81 177.44 185.17 171.74**  **St.dev. 17.40 12.87 15.81 14.80 19.11 Min 161.50 168.64 159.73 171.39 144.10**  **25 Max 202.94 200.77 203.20 208.82 197.** 

**N 5 5 5 5 5**

**Prostate**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 63.214 59.585 66.784 64.005 61.260**  **St.dev. 5.703 12.132 5.775 5.509 9.962 Min 58.473 43.215 60.411 58.116 50.990**  **657 Max 72.213 72.150 74.890 71.934 77.** 

**N 5 5 5 5 5**

**Seminal Vesicles**

**--- --- --- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 649 of 663

### HARLAN LABORATORIES LTD. HISTO - 11 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.98 1.98 2.02**  **St.dev. 0.09 0.07 0.06 Min 1.88 1.87 1.96**  **08 Max 2.10 2.04 2.** 

**N 5 5 5**

**Heart Mean 52.75 47.53 49.87**  **St.dev. 3.48 4.62 2.54 Min 50.29 41.83 46.28**  **06 Max 58.82 52.35 53.** 

**N 5 5 5**

**Liver Mean 460.42 436.98 416.42**  **St.dev. 18.49 43.53 35.55 Min 443.92 385.03 380.26**  **26 Max 491.36 480.27 471.** 

**N 5 5 5**

**Thymus Mean 18.940 12.269 16.185**  **St.dev. 4.761 1.273 3.605 Min 13.523 10.670 12.182**  **022 Max 24.802 13.574 19.** 

**N 5 5 5**

**Kidneys Mean 106.55 107.49 99.48**  **St.dev. 8.54 7.03 7.41 Min 94.77 99.45 91.81**  **61 Max 115.19 116.99 109.** 

**N 5 5 5** 

### Harlan Laboratories Study Report
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09009e5380ab457a 

## Page 650 of 663

### HARLAN LABORATORIES LTD. HISTO - 12 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**ales M** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.889 3.491 3.408**  **St.dev. 0.484 0.613 0.369 Min 3.397 2.944 2.953**  **755 Max 4.592 4.441 3.** 

**N 5 5 5**

**Spleen Mean 42.81 34.30 36.09**  **St.dev. 9.44 3.51 5.15 Min 30.23 29.93 27.97**  **03 Max 55.75 37.45 41.** 

**N 5 5 5**

**Testes Mean 191.78 184.89 155.90**  **St.dev. 19.05 13.23 39.62 Min 166.35 164.30 92.20**  **34 Max 208.22 196.74 196.** 

**N 5 5 5**

**Prostate**

**--- --- Mean ---**  **St.dev. Min**  **Max**

**N**

**Epididymides Mean 62.738 63.947 58.651**  **St.dev. 4.190 5.009 12.733 Min 55.273 58.251 41.638**  **610 Max 65.074 69.199 71.** 

**N 5 5 5**

**Seminal Vesicles**

**--- --- Mean ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
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## Page 651 of 663

### HARLAN LABORATORIES LTD. HISTO - 13 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.90 1.89**  **St.dev. 0.07 0.03 Min 1.73 1.84**  **94 Max 2.09 1.** 

**N 120 21**

**Heart Mean 42.57 42.43**  **St.dev. 3.86 1.80 Min 34.07 40.11**  **35 Max 62.45 46.** 

**N 120 21**

**Liver Mean 418.67 417.92**  **St.dev. 48.63 21.40 Min 288.88 358.40**  **67 Max 691.37 457.** 

**N 119 21**

**Thymus Mean 10.480 10.579**  **St.dev. 2.654 1.277 Min 4.920 8.108**  **783 Max 19.363 13.** 

**N 120 21**

**Kidneys Mean 78.67 78.73**  **St.dev. 6.33 2.56 Min 63.01 73.57**  **76 Max 101.16 82.** 

**N 120 21** 

### Harlan Laboratories Study Report
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## Page 652 of 663

### HARLAN LABORATORIES LTD. HISTO - 14 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**Females**

**________________________________________________________________________________________________ _**  **STUDIES 1 - 23 STUDIES 1 - 23**

**PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 4.512 4.523**  **St.dev. 0.603 0.332 Min 3.082 3.980**  **153 Max 5.895 5.** 

**N 120 21**

**Spleen Mean 36.84 36.72**  **St.dev. 8.15 2.58 Min 21.64 30.91**  **21 Max 88.50 40.** 

**N 120 21**

**Ovaries Mean 6.636 6.741**  **St.dev. 1.132 0.706 Min 4.456 6.214**  **774 Max 9.469 7.** 

**N 25 4**

**Uterus Mean 59.02 58.36**  **St.dev. 8.80 2.40 Min 40.16 56.30**  **99 Max 79.39 60.** 

**N 20 3** 

### Harlan Laboratories Study Report
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## Page 653 of 663

### HARLAN LABORATORIES LTD. HISTO - 15 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean --- 1.94 1.94 --- 1.89**  **St.dev. 0.07 0.08 0.07 Min 1.84 1.82 1.77**  **Max 2.06 2.09 1.97**

**N 10 10 10**

**Heart Mean --- 42.571 46.348 --- 41.86**  **St.dev. 3.885 6.176 3.96 Min 35.145 41.619 38.30**  **Max 48.275 62.446 51.37**

**N 10 10 10**

**Liver Mean --- 399.91 413.60 --- 457.67**  **St.dev. 30.82 42.26 106.86 Min 342.62 361.00 369.13**  **Max 438.10 507.57 691.37**

**N 10 10 10**

**Thymus Mean --- 9.17 10.92 --- 9.277**  **St.dev. 3.74 3.39 2.323 Min 4.92 6.68 6.147**  **Max 17.75 19.19 12.493**

**N 10 10 10**

**Kidneys Mean --- 76.85 80.04 --- 77.72**  **St.dev. 6.74 5.87 6.39 Min 63.01 72.28 70.24**  **Max 84.22 90.82 88.84**

**N 10 10 10** 

### Harlan Laboratories Study Report
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## Page 654 of 663

### HARLAN LABORATORIES LTD. HISTO - 16 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5**
**PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean --- 4.086 4.599 --- 4.628**  **St.dev. 0.655 0.533 0.596 Min 3.082 3.562 3.631**  **Max 5.071 5.200 5.566**

**N 10 10 10**

**Spleen Mean --- 35.709 37.118 --- 40.21**  **St.dev. 15.906 6.812 17.32 Min 21.643 27.287 30.40**  **Max 78.416 52.241 88.50**

**N 10 10 10**

**Ovaries Mean --- 6.214 --- --- ---**  **St.dev. 0.822 Min 4.456**  **Max 7.675**

**N 10**

**Uterus Mean --- 60.988 --- --- ---**  **St.dev. 9.160 Min 50.514**  **Max 79.393**

**N 10** 

### Harlan Laboratories Study Report
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## Page 655 of 663

### HARLAN LABORATORIES LTD. HISTO - 17 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.89 1.88 1.94 1.85 1.84**  **St.dev. 0.04 0.07 0.08 0.08 0.03 Min 1.84 1.79 1.88 1.73 1.82**  **Max 1.96 1.97 2.07 1.92 1.89**

**N 5 5 5 5 5**

**Heart Mean 43.16 42.24 44.31 40.12 45.30**  **St.dev. 3.09 2.72 4.78 1.68 3.88 Min 40.06 38.38 39.77 37.98 40.27**  **Max 47.90 45.24 51.53 42.49 49.16**

**N 5 5 5 5 5**

**Liver Mean 426.94 428.59 437.37 412.80 410.70**  **St.dev. 41.04 29.24 23.02 30.61 35.22 Min 390.63 390.05 409.13 373.03 377.96**  **Max 497.79 462.48 460.94 445.68 470.21**

**N 5 5 5 5 5**

**Thymus Mean 11.174 11.091 10.672 9.289 8.108**  **St.dev. 2.284 1.138 1.198 1.155 1.961 Min 9.054 9.833 9.350 7.386 5.736**  **Max 13.776 12.609 12.433 10.405 11.054**

**N 5 5 5 5 5**

**Kidneys Mean 81.80 78.44 78.21 75.03 73.57**  **St.dev. 6.55 3.09 3.27 3.91 4.08 Min 73.13 74.72 73.72 68.80 69.01**  **Max 91.51 81.61 81.45 78.43 79.88**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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## Page 656 of 663

### HARLAN LABORATORIES LTD. HISTO - 18 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10**
**PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 4.359 4.663 4.342 4.046 4.440**  **St.dev. 0.476 0.519 0.445 0.625 0.496 Min 3.580 3.963 3.989 3.292 4.121**  **Max 4.819 5.209 4.914 4.846 5.312**

**N 5 5 5 5 5**

**Spleen Mean 34.54 36.11 36.08 34.03 36.47**  **St.dev. 5.66 5.14 1.56 6.13 5.16 Min 29.95 31.57 33.54 27.26 27.93**  **Max 44.21 44.46 37.42 43.99 40.89**

**N 5 5 5 5 5**

**Ovaries Mean --- --- --- --- 6.595**  **St.dev. 1.116 Min 5.185**  **Max 7.832**

**N 5**

**Uterus Mean --- --- --- --- 57.79**  **St.dev. 6.59 Min 46.49**  **Max 62.72**

**N 5** 

### Harlan Laboratories Study Report
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## Page 657 of 663

### HARLAN LABORATORIES LTD. HISTO - 19 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.87 1.90 1.93 1.88 1.89**  **St.dev. 0.05 0.07 0.07 0.07 0.07 Min 1.79 1.83 1.84 1.81 1.79**  **Max 1.92 2.00 2.03 1.96 1.96**

**N 5 5 5 5 5**

**Heart Mean 40.29 43.47 43.89 44.59 42.74**  **St.dev. 1.78 3.39 2.96 2.87 3.74 Min 38.39 37.92 39.68 41.50 39.67**  **Max 42.96 47.05 47.69 49.22 48.78**

**N 5 5 5 5 5**

**Liver Mean 427.75 423.23 404.39 412.34 443.19**  **St.dev. 28.19 55.36 15.95 19.65 65.06 Min 401.66 334.01 386.93 387.22 373.62**  **Max 474.27 480.39 425.15 431.85 527.02**

**N 5 5 5 5 5**

**Thymus Mean 9.714 11.278 10.303 13.783 12.155**  **St.dev. 0.719 1.200 2.294 3.037 2.954 Min 8.920 9.570 7.507 11.519 9.721**  **Max 10.858 12.496 13.138 19.063 15.624**

**N 5 5 5 5 5**

**Kidneys Mean 79.36 81.65 78.52 82.10 81.42**  **St.dev. 4.41 11.57 6.82 4.09 12.79 Min 73.86 63.91 69.42 75.66 67.77**  **Max 86.00 91.70 85.85 85.33 101.16**

**N 5 5 5 5 5** 

### Harlan Laboratories Study Report
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## Page 658 of 663

### HARLAN LABORATORIES LTD. HISTO - 20 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15**
**PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 3.980 4.878 4.499 4.699 5.064**  **St.dev. 0.360 0.588 0.466 0.752 0.250 Min 3.387 4.088 4.014 3.876 4.785**  **Max 4.320 5.504 5.025 5.544 5.355**

**N 5 5 5 5 5**

**Spleen Mean 39.49 36.51 33.73 38.49 39.00**  **St.dev. 3.31 6.78 1.16 5.88 3.74 Min 36.24 28.13 31.94 32.63 34.59**  **Max 43.47 44.35 34.92 46.00 44.76**

**N 5 5 5 5 5**

**Ovaries Mean 6.380 7.774 --- --- ---**  **St.dev. 0.630 1.544 Min 5.562 5.952**  **Max 7.190 9.469**

**N 5 5**

**Uterus Mean 56.30 --- --- --- ---**  **St.dev. 10.69 Min 40.16**  **Max 67.22**

**N 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

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## Page 659 of 663

### HARLAN LABORATORIES LTD. HISTO - 21 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Brain (gram) Mean 1.90 1.91 1.87 1.85 1.90**  **St.dev. 0.07 0.04 0.06 0.09 0.05 Min 1.82 1.88 1.82 1.75 1.85**  **Max 2.02 1.97 1.96 1.96 1.96**

**N 5 4 5 5 5**

**Heart Mean 40.17 39.69 42.98 41.99 40.28**  **St.dev. 2.90 2.66 2.88 2.96 4.02 Min 37.59 35.84 39.49 38.26 34.07**  **Max 44.56 41.98 47.50 45.66 44.37**

**N 5 4 5 5 5**

**Liver Mean 386.31 375.78 411.98 436.11 436.11**  **St.dev. 36.75 32.81 33.84 29.24 50.39 Min 338.85 334.74 369.93 405.40 388.67**  **Max 430.52 408.67 462.06 471.24 512.71**

**N 5 4 5 5 5**

**Thymus Mean 9.489 10.717 10.582 10.056 10.044**  **St.dev. 0.997 1.037 1.168 2.581 1.048 Min 8.243 9.356 9.257 5.936 8.595**  **Max 10.987 11.650 12.250 12.119 11.077**

**N 5 4 5 5 5**

**Kidneys Mean 76.84 74.37 78.40 82.76 80.01**  **St.dev. 9.78 3.97 7.49 5.81 4.23 Min 66.01 69.79 68.24 74.85 75.60**  **Max 87.58 78.79 89.06 90.62 85.83**

**N 5 4 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 660 of 663

### HARLAN LABORATORIES LTD. HISTO - 22 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20**
**PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 4.131 4.510 5.153 4.945 4.449**  **St.dev. 0.695 0.483 0.453 0.711 0.336 Min 3.427 3.964 4.698 4.215 3.883**  **Max 5.115 5.032 5.895 5.895 4.747**

**N 5 4 5 5 5**

**Spleen Mean 32.25 32.59 39.79 36.48 36.72**  **St.dev. 2.93 4.42 3.08 4.75 6.36 Min 28.40 27.56 35.79 33.93 31.84**  **Max 35.22 37.06 44.19 44.94 47.49**

**N 5 4 5 5 5**

**Ovaries Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 661 of 663

### HARLAN LABORATORIES LTD. HISTO - 23 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O**  **(gram) Brain**  **Brain Mean 1.89 1.91 1.87**  **St.dev. 0.06 0.07 0.07 Min 1.84 1.82 1.78**  **Max 1.99 2.00 1.97**

**N 5 5 5**

**Heart Mean 40.75 42.07 41.73**  **St.dev. 1.77 3.99 4.26 Min 38.99 38.40 34.97**  **Max 42.97 46.98 45.91**

**N 5 5 5**

**Liver Mean 430.29 415.11 403.48**  **St.dev. 19.98 23.86 32.86 Min 414.07 388.36 370.91**  **Max 462.88 441.12 441.61**

**N 5 4 5**

**Thymus Mean 10.141 11.046 11.424**  **St.dev. 2.282 2.413 4.446 Min 7.518 8.538 6.977**  **Max 12.719 14.775 18.465**

**N 5 5 5**

**Kidneys Mean 80.69 76.85 78.69**  **St.dev. 5.04 4.87 3.18 Min 75.20 70.85 75.17**  **Max 88.40 82.64 82.87**

**N 5 5 5** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 662 of 663

### HARLAN LABORATORIES LTD. HISTO - 24 **CH -4452 ITINGEN, SWITZERLAND 19-MAY-09** 



## OECD 422 STUDIES **HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS**

**TRAIN: RAT / HanRcc:WIST S** 
**emales F** 

**________________________________________________________________________________________________ _**  **STUDY 21 STUDY 22 STUDY 23**
**PARAMETER APR-08 APR-08 MAR-08**

**________________________________________________________________________________________________ _** 
**rgan/Brain Weight Ratios (%) O** 

**Adrenals Mean 4.191 4.799 4.426**  **St.dev. 0.404 0.477 0.907 Min 3.639 4.161 3.315**  **Max 4.626 5.300 5.730**

**N 5 5 5**

**Spleen Mean 38.89 39.87 38.76**  **St.dev. 5.07 4.35 7.50 Min 31.33 35.96 29.37**  **Max 44.09 47.28 50.31**

**N 5 5 5**

**Ovaries Mean --- --- ---**  **St.dev. Min**  **Max**

**N**

**Uterus Mean --- --- ---**  **St.dev. Min**  **Max**

**N** 

### Harlan Laboratories Study Report
Sponsor Reference Number

09009e5380ab457a 

## Page 663 of 663