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 

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parties require the written permission of the Sponsor(s), with the exception of regulatory 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

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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

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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

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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

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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

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PREFACE 

General Information 

Test Item: 

Study Title: Combined 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. Ceccatelli (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 

 

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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 Administration: 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 accordance with the Standard 

ISO/IEC 17025 under accreditation number STS 085 by the Swiss Accreditation Service. 

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Data Requirements / Test Guidelines 

This study was performed in accordance with the procedures indicated by the following 

internationally accepted guidelines 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 22nd 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 Toxic Substances, U.S. Environmental 

Protection Agency, July 2000. 

Animal Welfare 

This study was performed in an AAALAC-accredited laboratory in accordance with the Swiss 

Animal Protection Law under license no. 252. 

Summary of Study Plan Amendments 

First Amendment: Appointment and contact details of the principal 

investigator and peer reviewer for the histopathology 

phase were given. 

The test site QA contact 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 Director from Dr. R. Ceccatelli to K. 

Pal-Kutas. 

Third Amendment: Change of study scientist, 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. 

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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 were 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 Itingen/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 will be sent to the sponsor. 

These original documents/raw data, as well as specimens (as long as quality permits evaluation) 

will be archived for at least 10 years at the following location: 

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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 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. 

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1 SUMMARY 

The purpose of this study was to generate preliminary information concerning the effects of 

 on the possible health 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 the 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 adjustment 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 male 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 minimal erosion in glandular stomach, signs of 

moderate stress in thymus and adrenal glands as well as slight diffuse atrophy in the prostate, 

coagulating gland and seminal vesicles. The body weight and food consumption of this male was 

rapidly decreasing from the second day of treatment onwards probably 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 consumption was decreased in the second week of 

pre-pairing period), relationship to the treatment could not be excluded. 

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Test item-related clinical signs were observed 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 during the functional observational battery gave an 

indication of a test item-related effect. 

Mean body temperature in males was statistically significantly lower at the dose level of 

90 mg/kg body weight/day compared to the control group (37.3 °C compared to 38.1 in the 

control group) and it was marginally lower when compared to historical control data range (37.5 

- 39.1 °C). Additionally, slightly lower locomotor 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 weight/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 receiving 90 mg/kg body weight/day of was 

considered to be a test item-related effect. 

Food Consumption 

The mean food consumption of males receiving 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 considered to be a test item-related effect. 

Body Weights 

From day 5 of the pre-pairing period the mean 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 statistical significance. 

The mean body weight gain of males receiving 90 mg/kg body weight/day of was 

lower from day 5 of pre-pairing 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. 

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Clinical Laboratory Investigations 

The assessment of the hematology data did not reveal any test item-related 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 index and conception rate were not affected by the 

treatment with the test item. Mean number of corpora lutea and implantations per dam and the 

post-implantation loss were not affected by the treatment with the test item. The mean postnatal 

loss between days 0 and 4 post partum was higher and the mean number of living pup on day 4 

post partum were lower consequently the viability index was statistically significantly lower in 

the high dose group therefore these were considered 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 thymus weights were statistically significantly 

decreased in females of the 90 mg/kg body weight/day group. 

Macroscopical Findings and Histopathological Examinations 

Treatment-related adverse local irritative effects in the stomach were 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 increased incidences, at ≥ 10 mg/kg body 

weight/day correlated histopathologically with athropy and reduced absolute and relative thymus 

weights only at the high dose levels. Although this is considered to be most likely to be stress 

related a test item-relationship 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 with follicular cell hypertrophy in thyroid glands 

in some males and females at 90 mg/kg body weight/day. Most probably the enhanced liver cell 

metabolism resulted in an acceleration of thyroid hormone breakdown with consequent thyroid 

follicular cell hypertrophy. This finding is commonly seen in rats after being exposed to 

xenobiotics. 

No histological evidence of toxicological properties in the reproductive organs and tissues 

examined were detected at 90 mg/kg body weight/day. 

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1.2 Litter Data - F1 Pups 

Findings at First Litter Check 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 postnatal 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, three male pups in three different litters (nos. 72, 

74, 79) had no milk in stomach at first litter check 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 unaffected, 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 symptoms, decreased body weight, decreased food 

consumption, increased liver and decreased thymus weights at the dose level of 90 mg/kg body 

weight/day the NOAEL (No Observed Adverse Effect Level) for general toxicity 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 considered to be 30 mg/kg body weight/day. 

Fertility index, conception rate, mean precoital time, 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 microscopic findings detected. 

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2 PURPOSE 

The purpose of this study was to generate preliminary information on the possible health hazards 

likely to arise from repeated exposure over a relatively 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, development of the conceptus and parturition. 

This study should provide information to assess the need to conduct further investigations and 

may provide guidance in the design of subsequent studies. 

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3 MATERIALS AND METHODS 

General Remark 

Details of the materials and methods that are not specified in the subsequent sections of this 

report are contained in the appropriate standard operating procedures. 

3.1 Test System 

Animals: Rat, RccHanTM: WIST(SPF) 

Rationale: Recognized by international 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 group1

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 individual 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 conditions 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 breeder. The surplus animals were sacrificed. This was 

documented in the raw data. 

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3.2 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 

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 Makrolon 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 Harlan 

Laboratories 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 representative 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. . 

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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 Vehicle: At least seven days (based on the results in Harlan 

Laboratories study D23440, Non-GLP study / 

Sponsor Reference Number 10C0095/11X016) 

Expiry Date (Retest Date): 12-Jun-2012 

Storage Conditions: Room temperature (20 ± 5 °C) 

Safety Precautions: Routine hygienic procedures (gloves, goggles, face 

mask). 

3.4.2 Vehicle and Control Item 

Identification: Carboxymethylcellulose 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 (Retest Date): 24-Jan-2018 

Storage Conditions: In the refrigerator (2 - 8 °C) 

Safety Precautions: Routine hygienic procedures (gloves, goggles, face 

mask). 

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3.5 Dose Formulations 

The dose formulations were prepared weekly using 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 homogeneous 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 stored at room temperature (20 ± 5 °C) in glass beakers. 

Based upon the results of stability analyses performed within the Harlan Laboratories study 

D23440 Non-GLP study / Sponsor Reference Number 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 control 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 concentration 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 stability 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 was used as the analytical standard. Analyzed 

samples were not discarded without written 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 without written consent from the study director. 

The results were summarized by Dr. B. Ludwig and are included in Appendix IV on p. 421 . 

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3.5.3 Rationale for Dose Level Selections 

The dose levels were selected based on a previous dose range-finding toxicity 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 males at 90 mg/kg body weight/day. No further 

significant findings were observed. In an earlier 28-day study in rats (RCC study no. 845437), 

the test substance was dissolved in PEG 300 and 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-response relationship, accompanied by hepato- and 

nephrotoxic effects. Furthermore, the kidneys were even affected at the next lower dose of 

50 mg/kg body weight/day. 

Taking into account both the dose range-finding study and the 28-day oral toxicity study results, 

there was confidence that a longer duration of treatment and the pregnancy state induced 

sufficient toxicity in the highest dose of 90 mg/kg body weight/day to generate study results. 

3.6 Treatment 

Method: Oral, by gavage 

Rationale for Method: Administration 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 study 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 

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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 needed 

for assessment of reproductive effects 

3.8 Mating, Gestation and Lactation 

During the pairing period, females were housed with sexually mature males (1:1) until evidence 

of copulation was observed. The females were 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 all 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. 

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Food Consumption: Males: Weekly during pre-pairing and after pairing periods. 

Females: Pre-pairing period 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 recorded during the pairing period. 

Body Weights: Recorded daily from treatment start to day of necropsy. 

Duration of Gestation: It was recorded. 

Pup Data: The litters were examined 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 weight, 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 cage. Animals were observed for the following: 

changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and 

autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). 

Changes in gait, posture and response 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 (males shortly before the scheduled sacrifice and females on day 3 

post partum) relevant parameters were performed 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 posture as well as resistance to removal. 

• Hand-held observations: muscle tone, constituation, skin, pupile size, palpebral closure, 

lacrimation, salivation, reaction to handling and general abnormalities. 

• Open field observations: level of ambulatory activity including rearing (one minute 

evaluation), unusual body movements (e.g. spasms, convulsions), gait evaluation, 

behavior, hair coat, respiration, quantity of feces-balls and urine. 

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• Reflexes: blinking, palpebral closure, pinna reflex, 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 parameters is listed under Appendix V on p. ). Any abnormal 

findings were recorded and, where appropriate, graded in severity. 

Additionally, locomotor activity was measured quantitatively 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 intervals over a period of 30 minutes. 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 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 variation caused by circadian rhythms. 

The assay was performed under the responsibility of R. Draheim at Harlan Laboratories Ltd. 

(Füllinsdorf) under internal laboratory quality control 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 

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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 treatment of 28 days, as they were no longer needed for the 

assessment of reproductive effects. Pups were sacrificed on day 4 post partum. Dams were 

sacrificed on day 5 post partum. 

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

day 25 post coitum. 

3.11.1 Necropsy 

All animals sacrificed or found dead were subjected to a detailed macroscopic examination to 

establish, if possible, the cause of death. Specimens 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 cannibalized, were examined macroscopically. 

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All parent animals and pups were examined macroscopically for any structural changes, either at 

the scheduled necropsy or during the study if death occurred. 

For the parent animals, special attention was directed at the organs of the reproductive system. 

The number of implantation sites and corpora lutea was recorded for 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, seminal 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, the following organs were 

trimmed from any adherent tissue, as appropriate, 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 parental 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 parental females were preserved in neutral phosphate buffered 4% 

formaldehyde solution: 

Ovaries 

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In addition, from all males and females per group 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 investigator for histopathology 

were processed, embedded and cut at an approximate thickness of 2 - 4 micrometers and stained 

with hematoxylin and eosin. Additionally, the testis was stained by PAS-hematoxylin. Special 

stains were used at the discretion 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 the 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 histopathology of interstitial 

cell structure. 

If test item-related morphologic changes 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 reproductive 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. 

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A peer review of the histopathology results was conducted by a board-certified veterinary 

pathologist designated by the Sponsor. The details of the peer review 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: clinical signs and observations, weekly detailed 

examination, functional observational battery, food consumption, body weights, necropsy data, 

organ weights (TOX CONTROL), reproduction 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 reproduction data, the following parameters 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 were calculated both on a litter basis and on a 

percentage per group basis. Mean pup weights were calculated from the individual weights both 

on a per group and on a per litter basis. 

Computer-generated values in the tables represent the rounded-off results of calculations which 

used the exact raw data values. 

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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, locomotor 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 variables 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. 

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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 during 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 distribution 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 formulation 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 requested which was performed on 25-Aug-2011 and all values of all 

dose groups were within the acceptance criteria. 

In conclusion, the results indicate the accurate 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. 

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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 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 minimal 

erosion in glandular stomach, signs of moderate stress in thymus and adrenal glands as well as 

slight diffuse atrophy in the prostate, coagulating gland and seminal vesicles. Because the body 

weight and food consumption of this male was rapidly decreased from the second day of 

treatment and other males at 90 mg/kg body weight/day, started to show 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 incidental. 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 observed of males and females receiving 90 mg/kg body 

weight/day of . Hunched posture, ruffled fur and discoloured feces were seen. 

At the dose level of 90 mg/kg body weight/day, the male animal killed in extremies (no. 35) 

showed clinical signs such as ruffled fur from day 6 of treatment and 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 pairing 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 brown firm nodule in the 

jejunum were found. After histopathological 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 additional males were noted with ruffled fur and 

yellowish discoloured feces (no. 34 and 40) in the pre-pairing and pairing period. Male no. 37 

had scabs and reddish sore on the right shoulder appearing in the pairing period and the scabs 

were noted in the after pairing period too. 

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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 including the gestation period. Female no. 72 also 

had huched posture on the first two days of the gestation period. 

In groups 3 and 2 no clinical signs were noted in any sex during the study. 

In group 1, male no. 10 had reddish sore at the cervical region for 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, the ruffled fur noted during the detailed weekly 

clinical observations of males and females indicated a test item-related effect. 

No test item-related effect was 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 scoring 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 during the functional observational battery gave an 

indication of a test item-related effect. 

Mean values of grip strength (fore- and hind paws) and landing foot splay gave no indication of 

test item-related effects. 

Body temperature in males was statistically significantly 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 activity of this group was seen, thus a treatmentrelated effect can not be excluded. 

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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 weight/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 receiving 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 weight/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 receiving 90 mg/kg body weight/day of was 

statistically significantly lower between days 8 and 14 in the pre-pairing period and it was lower 

during the whole pre-pairing period. This was considered to be a test item-related effect. 

The mean food consumption of males was at control 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 pre-pairing period which was 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. 

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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 mean 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 statistical significance. 

The mean body weight gain of males receiving 90 mg/kg body weight/day of was 

lower from day 5 of pre-pairing 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 group 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, Gestation and Lactation Periods 

During the pre-pairing period the mean body weights 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. During the pairing, gestation and lactation periods 

mean body weights comparable to those of the control group were noted. 

Significantly lower mean body weight gain was recorded 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 weight 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

56 62 112 122 134

260 282

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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 relevance 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 and lying slightly outside the range of historical control data, 

thus, test item-realted relationship 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 weight/day no changes were noted. 

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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 (determined at necropsy) was similar in all groups and 

was unaffected by treatment. 

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4.4.4 Gestation Length 

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

The mean gestation length was 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-implantation loss were not affected by the treatment 

with the test item. 

The mean number of implantations of pregnant 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 significantly 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

586

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At 30 and 10 mg/kg body weight/day, the postnatal loss 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 hepatocellular hypertrophy associated with follicular 

hypertrophy of thyroid glands on some males and females of group 4. 

Additionally, absolute and relative mean thymus weights were statistically significantly 

decreased in females of group 4, correlated with the observation of reduced size of thymus and 

thymic atrophy noted at histopathological examination. 

No experimental relevance was attributed to increased relative mean kidney and heart weights in 

males and females of group 4 as the mean values were within the range of historical control data 

and no corroborative histopathological findings were recorded. 

4.5.2 Macroscopical Findings 

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

The relevant macroscopical change in the stomach recorded as crateriform retraction was noted 

in one female at 30 mg/kg body weight/day, correlating with ulceration and submucosal 

inflammation. 

One, three and four females receiving 10, 30 and 90 mg/kg body weight/day of had 

reduced sized thymus correlating with thymic atrophy and reduced organ weights at 90 mg/kg 

body weight/day only. This thymus finding was considered to be likely stress-related. 

Other isolated macroscopical findings were considered to be within the range of normal 

background alterations. 

158 335

592

175 361

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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 females 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 considered 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 the 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 hyperkeratosis in forestomach and minimal erosion 

in glandular stomach, signs of moderate stress in thymus and adrenal glands as well as slight 

diffuse atrophy in the prostate, coagulating gland 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 Litter 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, three male pups in three different litters (nos. 72, 

74, 79) had no milk in stomach at first litter check 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 post 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 day 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 level when included all relevant 

dams in evaluation. When excluding litters weighing more than 11 g mean body weight per 

group the mean body weight of pups were statistically 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 day 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 macroscopic examination of F1 pups. 

155 389

66 183 376

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5 DISCUSSION AND CONCLUSION 

This study is a valid investigation of the toxicological effects resulting from repeated oral-gavage 

administration of the test item 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. Administration 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, treatment with the test item resulted in a general reduction in food 

consumption, body weight and body weight gain in males 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 lower and the pup body weight development was 

decreased. An increase of the liver weights of the dams (absolute and ratios) and in males was 

observed and this correlated with diffuse hepatocellular hypertrophy which was associated with 

consequent follicular cell hypertrophy of thyroid glands in some males and females at 90 mg/kg 

body weight/day. The absolute and relative thymus weights of females were decreased and 

correlated with macroscopical and histopathological changes such as thymic atrophy. 

Degenerative stomach findings were 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 histopathology data showed correlating degenerative 

lesions in the stomach. At 10 mg/kg body weight/day, a local irritative effect was noted in one 

male. At 30 and 10 mg/kg body weight/day, no general or reproductive toxicity effects were 

noted. 

Based on the observed mortality, clinical symptoms, decreased body weight, decreased food 

consumption, increased liver and decreased thymus weights at the dose level of 90 mg/kg body 

weight/day the NOAEL (No Observed Adverse Effect Level) for general toxicity 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 considered to be 30 mg/kg body weight/day. 

Fertility index, conception rate, mean precoital time, 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 microscopic findings detected. 

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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 Comparing 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 Workers, Oliver and Boyd, Edinburgh (1950). 

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7 FIGURES 

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In-life Data - P Generation 

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IRGACURE 127 

FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS 

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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

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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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FEMALES

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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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Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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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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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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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Gestation Period

Full Phase

Full Phase

Full Phase

Full Phase

Full Phase

Full Phase

78

45

46

51

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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

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PAIRING PERIOD

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

0

40

80

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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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LACTATION PERIOD

0 7 14 21

0

40

80

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160

200

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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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Pre-Pairing Period

Full Phase Animal 35 Male Group 4

Data excluded from Summary Report

Animal Moribund

Not Reported

All Study Phases

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82

Male

Male

Group 5

Group 5

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Animal 

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Reserve Removed

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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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1 2 3 4

-4

-2

0

2

4

6

8

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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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Full Phase

Full Phase

Full Phase

Full Phase

Full Phase

Full Phase

78

45

46

51

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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 

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Reserve Removed

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PAIRING PERIOD

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

-10

0

10

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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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-10

0

10

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

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

Day

%

Harlan Laboratories Study Report 

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20-MAR-12

BWG-GRA - 3

FEMALES

ORATORIES STUDY D23451

I 127

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 

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8 SUMMARY TABLES 

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In-life Data - P Generation 

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15-MAR-12

ORATORIES STUDY D23451 SYMT-SUM - 1

127 

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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15-MAR-12

SYMT-SUM - 2

MALES

ORATORIES STUDY D23451 

IRGACURE 127 

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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15-MAR-12

SYMT-SUM - 3

MALES

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.

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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15-MAR-12

SYMT-SUM - 4

MALES

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)

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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15-MAR-12

SYMT-SUM - 5

MALES

ORATORIES STUDY D23451 

IRGACURE 127 

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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15-MAR-12

ORATORIES STUDY D23451 SYMT-SUM - 1

127 

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%

Harlan Laboratories Study Report 

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15-MAR-12

SYMT-SUM - 2

FEMALES

ORATORIES STUDY D23451 

IRGACURE 127 

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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15-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

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15-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

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15-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

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15-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)

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11-OCT-11

ORATORIES STUDY D23451 WOC-SUM - 1

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 

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11-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

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11-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

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11-OCT-11

ORATORIES STUDY D23451 WOC-SUM - 1

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 663
11-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

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11-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 

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11-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

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11-OCT-11

ORATORIES STUDY D23451 REP-SUM - 1

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 (-)

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11-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 (-)

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11-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 

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09009e5380b2cd82 Page 91 of 663
11-OCT-11

ORATORIES STUDY D23451 REP-SUM - 1

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 (-)

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11-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 

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09009e5380b2cd85 Page 93 of 663
11-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 (-)

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11-OCT-11

ORATORIES STUDY D23451 LOCA-SUM - 1

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 (-)

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11-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 663
21-NOV-11

ORATORIES STUDY D23451 LOCA-SUM - 1

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 663
21-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 663
20-MAR-12

ORATORIES STUDY D23451 FC-SUM - 1

IRGACURE 127 

FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY 

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 FC-SUM - 1

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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 FC-SUM - 1

IRGACURE 127 

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

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 FC-SUM - 1

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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BW-SUM - 1

127

BODY WEIGHTS (G) - SUMMARY

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BW-SUM - 1

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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWG-SUM - 1

127

BODY WEIGHT GAIN (%) - SUMMARY

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWG-SUM - 1

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 663
20-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 663
20-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 663
20-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 663
20-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 

09009e5380b2cd9e Page 126 of 663
20-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 

09009e5380b2cd9e Page 127 of 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

127

DIFFERENCE IN BODY WEIGHT GAIN (%) - SUMMARY

Pre-Pairing Period

Full Phase Animal 35 Male Group 4

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 

09009e5380b2cda2 Page 128 of 663
20-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 

Sponsor Reference Number 

09009e5380b2cda2 Page 129 of 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

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 

Sponsor Reference Number 

09009e5380b2cda4 Page 130 of 663
20-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 

Sponsor Reference Number 

09009e5380b2cda4 Page 131 of 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

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 

Sponsor Reference Number 

09009e5380b2cda9 Page 132 of 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

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 

09009e5380b2cdad Page 134 of 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

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

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdaf Page 136 of 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWD-SUM - 1

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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20-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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09009e5380b2cdb2 Page 139 of 663
Clinical Laboratory Investigations - P Generation 

Harlan Laboratories Study Report 

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09009e5380a814ce Page 140 of 663
03-OCT-11

ORATORIES STUDY D23451 HEM-SUM - 1

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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Harlan Laboratories Study Report 

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09009e5380a3ded1 Page 141 of 663
03-OCT-11

ORATORIES STUDY D23451 HEM-SUM - 2

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

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 

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09009e5380a3ded1 Page 142 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (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 

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09009e5380a3ded1 Page 143 of 663
03-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 COUNT (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 

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03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (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 

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03-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 COUNT (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 

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03-OCT-11

ORATORIES STUDY D23451 CHE-SUM - 1

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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Harlan Laboratories Study Report 

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09009e5380a3ded3 Page 147 of 663
03-OCT-11

ORATORIES STUDY D23451 CHE-SUM - 2

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

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 

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09009e5380a3ded3 Page 148 of 663
03-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 

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09009e5380a3ded3 Page 149 of 663
03-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 

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Reproduction and Breeding Data - P Generation 

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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. 

 

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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 

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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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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 

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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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Terminal Findings - P Generation 

Harlan Laboratories Study Report 

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09009e5380a814dd Page 157 of 663
12-OCT-11

ORATORIES STUDY D23451 OW-SUM - 1

127

ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs

All organs reported

Not Reported

---

Harlan Laboratories Study Report 

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12-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

- - -

- - -

- - -

- - -

- - -

- - **

- - -

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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

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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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

- - -

- - -

- - -

- - -

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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

- - -

- - -

- - -

- - **

- - -

- - **

- - -

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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

- - **

- - -

- - -

- - -

- - -

- - -

- - -

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12-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

- - -

- - -

- - -

- - -

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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

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09009e5380b2cdc0 Page 165 of 663
12-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

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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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

- - -

- - -

- - -

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ORATORIES STUDY D23451 OW-SUM - 1

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 663
12-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

- - -

- - -

- - -

- - -

- - -

- - **

- - *

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12-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

- - -

- - -

- - -

- - -

- - -

- - -

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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

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12-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

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12-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 

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12-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

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MAC-SUM - 1

04-OCT-11

ORATORIES STUDY D23451

127

MACROSCOPICAL FINDINGS - SUMMARY

ALL NECROPSIES

Not Reported

---

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MAC-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 

-

-

-

-

-

-

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

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MAC-SUM - 1

04-NOV-11

ORATORIES STUDY D23451

127

MACROSCOPICAL FINDINGS - SUMMARY

ALL NECROPSIES

Not Reported

---

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MAC-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 

-

-

-

-

-

-

-

-

-

-

-

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

) ) ) )

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

( ( ( (

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Data of F1 Pups 

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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 

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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 

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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 

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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 

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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) 

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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 respective time interval. 

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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 

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9 INDIVIDUAL TABLES 

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In-life Data - P Generation 

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MORT-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

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MORT-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

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MORT-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

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MORT-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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MORT-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 

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MORT-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 

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MORT-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 663
MORT-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 663
MORT-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 663
MORT-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 663
15-MAR-12

ORATORIES STUDY D23451 SYMT-IND - 1

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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-MAR-12

ORATORIES STUDY D23451 SYMT-IND - 1

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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-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 663
15-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 663
11-OCT-11

ORATORIES STUDY D23451 WOC-IND - 1

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 663
11-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 663
11-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 663
11-OCT-11

ORATORIES STUDY D23451 WOC-IND - 1

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 663
11-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 663
11-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 663
11-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 663
11-OCT-11

ORATORIES STUDY D23451 REP-IND - 1

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 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cded Page 222 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cded Page 223 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cded Page 224 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cded Page 225 of 663
11-OCT-11

ORATORIES STUDY D23451 REP-IND - 1

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 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdef Page 227 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdef Page 228 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdef Page 229 of 663
11-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 STRENGTH

GRIP STRENGTH LANDING FOOT SPLAY BODY TEMPERATURE

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdef Page 230 of 663
11-OCT-11

ORATORIES STUDY D23451 LOCA-IND - 1

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 663
11-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf1 Page 232 of 663
11-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf1 Page 233 of 663
11-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf1 Page 234 of 663
11-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf1 Page 235 of 663
21-NOV-11

ORATORIES STUDY D23451 LOCA-IND - 1

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 663
21-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf5 Page 237 of 663
21-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf5 Page 238 of 663
21-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf5 Page 239 of 663
21-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 COUNT

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf5 Page 240 of 663
20-MAR-12

ORATORIES STUDY D23451 FC-IND - 1

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 

09009e5380b2cdf7 Page 241 of 663
20-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 663
20-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 663
20-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 

09009e5380b2cdf7 Page 244 of 663
20-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 

09009e5380b2cdf7 Page 245 of 663
20-MAR-12

ORATORIES STUDY D23451 FC-IND - 1

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 

Sponsor Reference Number 

09009e5380b2cdf9 Page 246 of 663
20-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 

09009e5380b2cdf9 Page 247 of 663
20-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

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380b2cdf9 Page 248 of 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BW-IND - 1

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 

09009e5380b2cdfb Page 251 of 663
20-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

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Sponsor Reference Number 

09009e5380b2cdfb Page 252 of 663
20-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 

09009e5380b2cdfb Page 253 of 663
20-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 663
20-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 663
20-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

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Sponsor Reference Number 

09009e5380b2cdfb Page 256 of 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BW-IND - 1

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 

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20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 

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20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWG-IND - 1

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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-MAR-12

ORATORIES STUDY D23451 BWG-IND - 1

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 663
20-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 663
20-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 663
20-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 663
20-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 663
20-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 

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20-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 

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20-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 663
20-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 663
20-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 663
20-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 663
20-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 

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20-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 

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Clinical Laboratory Investigations - P Generation 

Harlan Laboratories Study Report 

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03-OCT-11

ORATORIES STUDY D23451 HEM-IND - 1

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

---

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03-OCT-11

ORATORIES STUDY D23451 HEM-IND - 2

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 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 298 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 299 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 300 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 301 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 302 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 303 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 304 of 663
03-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 COUNT (REL)

DIFF.WBC COUNT (REL) DIFF.WBC COUNT (ABS)

DIFF.WBC COUNT (ABS) GENERAL COAGULATION

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a3dea3 Page 305 of 663
03-OCT-11

ORATORIES STUDY D23451 CHE-IND - 1

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 663
03-OCT-11

ORATORIES STUDY D23451 CHE-IND - 2

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 663
03-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 663
03-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 663
03-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 663
03-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 663
03-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 663
03-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 663
03-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 663
03-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 Breeding 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 

09009e5380ab45dd 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 

09009e5380ab45dd 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 

09009e5380ab45dd 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 

Sponsor Reference Number 

09009e5380a81530 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 

Sponsor Reference Number 

09009e5380a81530 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 

Sponsor Reference Number 

09009e5380a81530 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 

Sponsor Reference Number 

09009e5380a81530 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 

Sponsor Reference Number 

09009e5380a81532 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 

Sponsor Reference Number 

09009e5380a81534 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 

09009e5380a81534 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 

Sponsor Reference Number 

09009e5380a81534 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 

Sponsor Reference Number 

09009e5380a81534 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 

09009e5380a81534 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 

09009e5380a81534 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 

Sponsor Reference Number 

09009e5380a81534 Page 333 of 663
Terminal Findings - P Generation 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a814dd Page 334 of 663
12-OCT-11

ORATORIES STUDY D23451 OW-IND - 1

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 

09009e5380b2ce18 Page 335 of 663
12-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 

Sponsor Reference Number 

09009e5380b2ce18 Page 336 of 663
12-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 

Sponsor Reference Number 

09009e5380b2ce18 Page 337 of 663
12-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 

Sponsor Reference Number 

09009e5380b2ce18 Page 338 of 663
12-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 663
12-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 

09009e5380b2ce18 Page 340 of 663
12-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 663
12-OCT-11

OW-IND - 8

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 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 663
12-OCT-11

OW-IND - 9

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 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 663
12-OCT-11

OW-IND - 10

1

2

3

4

5

6

7

8

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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 663
12-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 663
12-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 663
12-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 663
12-OCT-11

ORATORIES STUDY D23451 OW-IND - 1

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 663
12-OCT-11

OW-IND - 2

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 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 663
12-OCT-11

OW-IND - 3

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 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

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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

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09009e5380b2ce1a Page 351 of 663
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71

72

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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

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Sponsor Reference Number 

09009e5380b2ce1a Page 352 of 663
12-OCT-11

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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 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

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09009e5380b2ce1a Page 353 of 663
12-OCT-11

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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 663
12-OCT-11

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67

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69

70

61

62

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65

66

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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

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Sponsor Reference Number 

09009e5380b2ce1a Page 355 of 663
12-OCT-11

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79

80

71

72

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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 663
12-OCT-11

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50

41

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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 663
12-OCT-11

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53

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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 663
12-OCT-11

OW-IND - 12

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62

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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 663
12-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 663
MAC-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 663
MAC-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 663
MAC-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 663
MAC-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 663
MAC-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 663
MAC-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 

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MAC-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 

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MAC-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 

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MAC-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 

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MAC-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 

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MAC-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 

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MAC-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 663
MAC-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 

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MAC-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 

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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 

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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 

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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 

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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 

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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 

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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 

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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 

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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 

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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 

09009e5380a81543 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 

09009e5380b04b6f 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 

09009e5380b04b6f 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 

Sponsor Reference Number 

09009e5380b04b6f 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 

Sponsor Reference Number 

09009e5380b04b6f 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 

Sponsor Reference Number 

09009e5380b04b6f Page 410 of 663
APPENDIX I - CHEMICAL ANALYSIS OF FEED 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a81549 Page 411 of 663
Dr.-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

Unit Result Method A-08-2001

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

Order GLP Schadstoffuntersuchung

PROVIMI KLIBA AG

RINAUSTRASSE

4303 KAISERAUGST / SCHWEIZ

SCHWEIZ

Page 1 of 2

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380a815d3 Page 412 of 663
Dr.-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

Unit Result Method A-08-2001

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 without signature.

The analytical results are only valid for the delivered sample material.The testing period is the time between the receipt of the sample and the

reporting date.A plausibility check is hardly possible for samples of unknown origin.Duplication of this document or of parts of it requires 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

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APPENDIX II - DRINKING WATER ANALYSIS 

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APPENDIX III - CERTIFICATE OF ANALYSIS 

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APPENDIX IV - FORMULATION ANALYSIS 

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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 Application Formulation Analysis ................................................6 

LIST OF FIGURES 

Figure 1 Example of Calibration Curve ......................................................................................7 

Figure 2 Typical HPLC-Chromatograms of Standard Solutions ................................................8 

Figure 3 Typical HPLC-Chromatograms of Test Samples .........................................................9 

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1 MATERIALS AND METHODS 

1.1 Analytical Standard 

The test item as described in the main report was used as analytical standard. 

1.2 Study Samples and Storage 

Representative samples were dispatched to the analytical laboratories internally (on dry ice) and 

stored frozen at -20 ± 5 °C until analysis. 

1.3 Reagents and Materials 

Purified water: In-house prepared 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 water/methanol (20 + 80 v/v) were prepared for 

external standard calibration. 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 minutes 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/methanol (20 + 80 v/v) into 

the calibration range. 

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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 peak 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], using 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 calibration data 

x = Actual concentration of Irgacure 127 in sample aliquot [μg/mL] 

Sample aliquot concentrations were corrected for density of the application formulation and for 

dilution using equation 2: 

⋅1000

⋅⋅ = WDVx

cActual (2) 

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where 

cActual = 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 [%]

cActual = Actual sample concentration [mg/mL]

cNominal = Nominal sample concentration [mg/mL]

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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 working standard concentrations. All calibration 

points used met the acceptance limit of ±20% variation from the calibration curve derived by 

linear regression analysis. The regression coefficients calculated were found to be better than 

0.99. An example is presented in Figure 1. 

The peak was assigned in sample chromatograms by comparison to that of working 

standards. In blank sample chromatograms no peak appeared at the retention time of 

 and, therefore, the absence of the 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 during 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 distribution 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 formulation 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 requested which was performed on 25-Aug-2011 and all values of all 

dose groups were within the acceptance criteria. 

In conclusion, the results indicate the accurate 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.

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Table 1 Detailed Results of Application 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%

88.2% 5.3%

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) 

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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

R2

 = 0.9988

0

5000000

10000000

15000000

20000000

25000000

0.0 20 40 60 80 100 120

Concentration [μg/mL]

Peak Area [counts]

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Figure 2 Typical HPLC-Chromatograms 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) 

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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) 

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Figure 3 Cont’d 

(C) Dose group 4 (top), nominal content: 9 mg/mL, 263x diluted 

 Date of analysis: 19-Aug-2011 

(C) 

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APPENDIX V - FUNCTIONAL OBSERVATIONAL BATTERY 

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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) 

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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 

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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 wall). 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 wall). 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 

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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 chromodacryorrhea 

 1 Dark red, dry scab around eye (chromodacryorrhea) 

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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 

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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 

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APPENDIX VI - CLINICAL LABORATORY INVESTIGATIONS 

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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 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 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 variation 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. Clinical laboratory data are expressed, with a few 

exceptions, in general accordance with the International System of Units (SI). 

Key to Abbreviations of Units: 

L liter g gram m milli (10-3) 

mol mole G giga (109) μ micro (10-6) 

sec seconds T tera (1012) 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 1201

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) 

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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 

STA2

 

Activated partial 

thromboplastin 

time 

PTT sec Clotting assay, cephalin from 

rabbit cerebral tissue, silica 

surface activator 

STA 

 

2

 STA-compact analyzer (Roche Diagnostics) 

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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 6000/5013

Urea mmol/L Urease/GLDH Cobas 6000/501 

Creatinine CREAT μmol/L Enzymatic colorimetric test Cobas 6000/501 

Bilirubin, total BILI-T μmol/L Reaction with 3,5-Dichlorophenyl-diazonium salt Cobas 6000/501 

Bile acids BILE AC μmol/L Colorimetric, enzymatic 

(3α-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 2.6.1.14

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 (Enzyme Commission) according to Enzyme Nomenclature, 

Recommendations (1972) of the IUPAC and IUB, Elsevier Scient. Publ. Comp., Amsterdam, 1973 

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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) 

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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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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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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 

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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 

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HISTOPATHOLOGY PHASE REPORT 

Histopathology Phase to:

Combined Repeated Dose Toxicity Study with 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 

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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 Organ/Group/Sex: Selected Tissues 

(K0, including deaths)..........................................................................................................18 

Number of Animals with Microscopic Findings by Organ/Group/Sex 

(K0, including deaths)..........................................................................................................23 

Correlation Table: Necropsy - Microscopy..........................................................................29 

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AnaPath Phase Number10648 

Histopathology Phase Page 3 

Individual Tables 

Table of Individual Microscopic Findings (AOFT1

) ..........................................................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 

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AnaPath Phase Number10648 

Histopathology Phase Page 4 

GLP CERTIFICATE 

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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 18th 2005 [SR 813.112.1]. 

This Ordinance is based on the OECD Principles of Good Laboratory Practice, as revised in 

1997 and adopted November 26th 1997 by decision of the OECD Council [C (97) 186/Final]. 

There were no circumstances that may have affected the quality or integrity of the data. 

Principal Investigator 

Histopathology Phase: Dr. Katharina Heider 

 Veterinary Pathologist 

 Diplomate ECVP 

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AnaPath Phase Number10648 

Histopathology Phase Page 6 

QUALITY ASSURANCE STATEMENT 

AnaPath GmbH, Buchsweg 56, 4625 Oberbuchsiten / Switzerland 

The general facilities and activities are inspected periodically and the results are reported to the 

responsible person and the management. 

Study procedures were periodically inspected. The study plan and amendments (related to the 

phase) and this phase report were audited by the quality assurance. 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 histopathology phase report reflects the raw data. 

Quality Assurance: N. Häuselmann 

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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 testing of chemicals 422, “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening 

Test in the Rat”, adopted by the Council on 22nd 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 Toxic Substances, U.S. Environmental Protection Agency, July 2000. 

ARCHIVING 

Harlan Laboratories Ltd., 4452 Itingen/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 will be sent to the sponsor. 

These original documents/raw data, as well as specimens (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. 

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Histopathology Phase Page 8 

1 SUMMARY 

The purpose of this study was to generate preliminary information on the possible health 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. 

This study should provide information to assess the need to conduct further investigations and 

may provide guidance in the design 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 males 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 collected 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 terminally sacrificed males 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 histopathologically. Reproductive 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/epididymides, 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 retraction of forestomach in one group 3 female. 

• Forestomach: hyperkeratosis in some 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 submucosal 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 females 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 effect of in stomach could not be established for males and was 

established at 10 mg/kg bw/day for females. 

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Histopathology Phase Page 9 

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 Laboratories 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 were fixed in Davidson’s fluid. The histology processing was performed at Harlan Laboratories Ltd., Itingen / Switzerland. All organ and tissue 

samples to be examined by the principal investigator for histopathology were processed, embedded and cut at an approximate 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 Oberbuchsiten, Switzerland and examined by light 

microscopy. 

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 histopathology. The 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 female nos. 41-44, 47 and 71-75, 78 of groups 1 and 4 

and female nos. 45 and 46 (not pregnant) from group 1 and 51 and 59 from group 2 were examined by light microscopy: 

Ovaries 

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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 (decedent female) from groups 1 and 4 were examined by light microscopy. 

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 

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, thyroid glands, stomach, thymus, adrenal glands, and 

testes/epididymides that were detected in high dose animals, the same organs from group 2 (male 

nos. 11-15 and female nos. 51-55) and group 3 animals (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 were transferred from Harlan Laboratories Ltd. 

via electronic diskette and entered at AnaPath GmbH into the PDS PathData System. 

The microscopic findings were recorded by the undersigned pathologist using on-line input into 

the PDS PathData System V6.2d2 during histopathologic examination. 

For technical reasons, in the header of PathData, only “Harlan Laboratories” was included instead of the full name “Harlan Laboratories Study.” 

To allow the reporting of gastric findings separately in forestomach and glandular stomach, the 

organ “stomach” was divided by the study pathologist 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 possible, according to distribution, 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 both 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, grade 5 = 21 -25 corpora lutea or more. 

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All microscopic findings are listed in the “Table of Individual Microscopic Findings” (AOFT, 

animal organ finding table), along with the explanation of codes and symbols used. 

Computer-generated incidence tables derived from these data are also presented as well as the 

complete narrative of both the macroscopic and 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 glands, and testes/epididymides from group 2 and 

3 animals until December 18, 2011, and organs/tissues from additional male no. 36 on March 10, 

2012. 

Histological changes were described, wherever possible, according 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 “Table of Individual Microscopic Findings (AOFT), 

along with an explanation of the codes and symbols used. Computer-generated incidence tables 

derived from these data are given under “Number of Animals with Microscopic Findings by Organ/Group/Sex” and are also presented as the complete narrative of both the macroscopic and 

microscopic findings under “Text of Gross and Microscopic Findings.” 

2.4 Peer Review 

A histopathology peer review was 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, adrenal 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. 

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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 stress in thymus and adrenal glands. However, the 

reason for moribundity in this male could not be determined from the organs and tissues examined. Female no. 78 from group 4 died spontaneously on test day 15 and the thrombosis in the 

jejunum was considered to be the cause of death. 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 retraction, correlating with 

squamous hyperplasia and submucosal inflammation. These findings were considered to represent local irritative effects of the test item. 

One, three, and four females of groups 2, 3, and 4 showed a reduced size of thymus, correlating 

with thymic atrophy at 90 mg/kg bw/day only. This thymus finding 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 revealed 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 infiltration was noted in male no. 37. Unilateral 

single focal tubular degeneration occurred in male nos. 32, 34, and 35. 

Special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell 

structure did not reveal any differences between group 1 and group 4 males in the completeness 

of cell populations, completeness of stages, and potential 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 organ 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 considered to be the reason for missing pregnancy 

in corresponding female no. 77. 

The epididymides (except no. 37), prostate, and seminal vesicles did not reveal any relevant 

morphological changes. 

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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 females and group 4 males and a single female at 

90 mg/kg bw/day, squamous cell hyperplasia with submucosal inflammation in one group 3 female; glandular stomach: focal erosion in a single group 2 male and a single group 4 male and 

female, in the female associated with submucosal inflammation and mucosal atrophy. 

Table 1 Relevant findings 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 glandular dilation of glandular stomach 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 males and females at 90 mg/kg bw/day. This finding 

was considered to be adaptive. 

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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 hypertrophy in thyroid gland was noted in some group 4 males and females. This finding was considered to be consequent to the hepatocellular 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 thymus 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 compared 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. 

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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 incidental or stress-related. 

In organs other than reproductive, led to local irritative effects in the stomach present in all test item-treated groups in increasing incidences at the dose levels of 10, 30, and 90 

mg/kg bw/day. 

Treatment-related diffuse hepatocellular 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. Most probably, the enhanced liver cell metabolism 

resulted in an acceleration of thyroid hormone breakdown 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 level. Although this is considered 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 cortex at 30 and 90 mg/kg bw/day was considered 

to be likely consequent 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 thrombosis of jejunum. Therefore, this death was considered to be 

incidental. 

Based on the microscopic findings detected the 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. 

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5 REFERENCES 

1. Zbinden G. 1976. The role of pathology in toxicity testing. In: Progress in Toxicology. 

Special Topics. Springer Verlag, Berlin, Heidelberg, New York, Tokyo, Vol. 2, pp. 8-18. 

 

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 HARLAN LABORATORIES D23451 

————————————————————————————————————————————————————————————————————————— 

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 

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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

————————————————————————————————————————————————————————————————————————— 

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 

————————————————————————————————————————————————————————————————————————— 

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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

————————————————————————————————————————————————————————————————————————— 

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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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

————————————————————————————————————————————————————————————————————————— 

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 

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

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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

————————————————————————————————————————————————————————————————————————— 

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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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

————————————————————————————————————————————————————————————————————————— 

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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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 

————————————————————————————————————————————————————————————————————————— 

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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 — — — 

————————————————————————————————————————————————————————————————————————— 

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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 

————————————————————————————————————————————————————————————————————————— 

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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 

————————————————————————————————————————————————————————————————————————— 

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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 

————————————————————————————————————————————————————————————————————————— 

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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 

————————————————————————————————————————————————————————————————————————— 

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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. 

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

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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. 

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

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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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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. 

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

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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. 

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

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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. 

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

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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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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. 

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

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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. 

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

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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. 

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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. 

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

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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. . . 

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

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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 — — — — — ' ' ' ' ' 

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

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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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09009e5380b47383 Page 489 of 663
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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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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 — — — — ' ' — ' ' ' 

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

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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 — — — — ' ' — ' ' ' 

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

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Sponsor Reference Number 

09009e5380b47383 Page 492 of 663
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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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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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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 — — — — — ' ' ' ' ' 

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

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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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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 ' ' ' ' 

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

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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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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 

Sponsor Reference Number 

09009e5380b47383 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. . . . . . 

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

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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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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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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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09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

09009e5380b47383 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 

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09009e5380b47383 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 

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Sponsor Reference Number 

09009e5380b47383 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. 

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09009e5380b47383 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. 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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. 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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 

————————————————————————————————————————————————————————————————————————— 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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 

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

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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 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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 

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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. 

————————————————————————————————————————————————————————————————————————— 

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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 

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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. 

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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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

09009e5380b47383 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 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

09009e5380b47383 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 

Sponsor Reference Number 

09009e5380b47383 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 

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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 

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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 

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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. 

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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 

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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 

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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 study.

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 Dr. 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 

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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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Functional Observational Battery 

Grip forep. (G) 

 Mean 443.4 424.6 

 St.dev. 152.0 110.2 

 Min 180.0 314.0 

 Max 1033.3 801.7 

 N 100 19 

Grip hindp. (G) 

 Mean 282.6 275.3 

 St.dev. 81.7 57.9 

 Min 120.0 194.8 

 Max 526.7 421.3 

 N 100 19 

Land. Foot Di (CM) 

 Mean 7.5 7.5 

 St.dev. 2.7 1.5 

 Min 2.3 5.2 

 Max 13.0 10.3 

 N 100 19 

Body Temp (°C) 

 Mean 38.2 38.2 

 St.dev. 0.5 0.3 

 Min 37.1 37.5 

 Max 39.3 38.6 

 N 100 19 

Harlan Laboratories Study Report 

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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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Functional Observational Battery 

Grip forep. (G) 

 Mean --- --- --- --- 801.7 

 St.dev. 121.4 

 Min 643.3 

 Max 1033.3 

 N 10 

Grip hindp. (G) 

 Mean --- --- --- --- 421.3 

 St.dev. 51.8 

 Min 360.0 

 Max 526.7 

 N 10 

Land. Foot Di (CM) 

 Mean --- --- --- --- 7.8 

 St.dev. 2.9 

 Min 4.1 

 Max 11.6 

 N 10 

Body Temp (°C) 

 Mean --- --- --- --- 38.5 

 St.dev. 0.3 

 Min 38.1 

 Max 39.0 

 N 10 

_________________________________________________________________________________________________ 

Study 1, 2, 3 and 4: not applicable 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 3 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 523.3 387.0 496.7 533.3 543.3 

 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 

 Max 343.3 245.7 236.7 436.7 370.0 

 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 

 Max 8.1 8.7 11.5 9.9 12.6 

 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 

 Max 38.8 38.2 38.5 38.9 38.5 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 4 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 380.0 636.7 650.0 433.3 370.0 

 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 

 Max 296.7 313.3 376.7 410.0 316.7 

 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 

 Max 11.7 8.0 13.0 10.8 12.6 

 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 

 Max 38.0 39.3 39.2 38.4 38.8 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 5 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 450.0 486.7 433.3 483.3 396.7 

 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 

 Max 366.7 346.7 340.0 396.7 310.0 

 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 

 Max 9.8 11.3 10.5 11.9 8.7 

 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 

 Max 38.9 38.6 38.6 38.8 39.2 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 6 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

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HARLAN LABORATORIES LTD. HISTO - 7 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Functional Observational Battery 

Grip forep. (G) 

 Mean 406.2 384.9 

 St.dev. 171.9 120.1 

 Min 180.0 256.2 

 Max 1056.7 810.3 

 N 100 19 

Grip hindp. (G) 

 Mean 209.9 197.9 

 St.dev. 94.5 65.0 

 Min 80.0 131.8 

 Max 610.0 438.0 

 N 100 19 

Land. Foot Di (CM) 

 Mean 6.4 6.4 

 St.dev. 2.5 1.1 

 Min 1.7 4.7 

 Max 12.1 8.3 

 N 100 19 

Body Temp (°C) 

 Mean 38.6 38.6 

 St.dev. 0.3 0.2 

 Min 37.6 38.3 

 Max 39.8 39.1 

 N 100 19 

Harlan Laboratories Study Report 

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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 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Functional Observational Battery 

Grip forep. (G) 

 Mean --- --- --- --- 810.3 

 St.dev. 152.9 

 Min 600.0 

 Max 1056.7 

 N 10 

Grip hindp. (G) 

 Mean --- --- --- --- 438.0 

 St.dev. 85.2 

 Min 256.7 

 Max 610.0 

 N 10 

Land. Foot Di (CM) 

 Mean --- --- --- --- 6.0 

 St.dev. 2.3 

 Min 3.5 

 Max 9.7 

 N 10 

Body Temp (°C) 

 Mean --- --- --- --- 38.6 

 St.dev. 0.3 

 Min 38.2 

 Max 39.1 

 N 10 

_________________________________________________________________________________________________ 

Study 1, 2, 3 and 4: not applicable 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 9 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 423.3 280.0 570.0 750.0 486.7 

 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 

 Max 256.7 145.3 250.0 356.7 280.0 

 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 

 Max 11.5 9.7 8.0 11.7 12.1 

 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 

 Max 39.8 38.8 38.7 39.3 39.0 

 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 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 466.7 513.3 513.3 456.7 326.7 

 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 

 Max 240.0 250.0 273.3 260.0 273.3 

 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 

 Max 8.5 10.8 7.3 10.0 8.8 

 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 

 Max 39.1 38.6 39.4 38.7 39.2 

 N 5 5 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 11 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

 Max 513.3 413.3 420.0 423.3 373.3 

 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 

 Max 206.7 193.3 290.0 190.0 190.0 

 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 

 Max 6.4 11.5 11.1 9.7 9.6 

 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 

 Max 39.0 39.2 39.0 38.8 39.0 

 N 5 5 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 12 

CH-4452 ITINGEN, SWITZERLAND 15-MAY-08 

OECD 422 STUDIES 

HISTORICAL DATA – Functional Observational Battery 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Functional Observational Battery 

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 

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HARLAN LABORATORIES HISTO - 1 

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

____________________________________________________________________________________________________

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

Dead 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 129 104 122 101 118 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 47 / 53 44 / 56 51 / 49 51 / 49 53 / 47 

Postnatal loss until 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 129 101 121 101 118

 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 47 / 53 45 / 55 -- / -- -- / -- 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 

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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 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

____________________________________________________________________________________________________

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 12.2 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 litter 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 / 50 53 / 47 47 / 53 41 / 59 44 / 56 

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 / 59 44 / 56 

Birth Index 93.6 94.0 89.6 96.3 90.1 

Viability Index 98.1 96.2 98.9 100.0 100.0 

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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 421 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 

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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 Mean --- 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

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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 

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HARLAN LABORATORIES HISTO - 6 

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 421 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 Males Mean 10.3 St.dev. 1.3 

 N 8 

 Females

 Mean 9.7 St.dev 1.2 

 N 8 

 Males and females

 Mean 10.0 

 St.dev. 1.2 N 8 

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HARLAN LABORATORIES LTD. HISTO - 1 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ Weights 

Body Weight 

 Mean 354.4 354.4 

 St.dev. 29.4 19.5 

 Min 271.7 312.6 

 Max 461.3 410.1 

 N 230 23 

Brain 

 Mean 2.02 2.02 

 St.dev. 0.08 0.05 

 Min 1.77 1.93 

 Max 2.23 2.10 

 N 140 23 

Heart 

 Mean 1.01 1.01 

 St.dev. 0.08 0.05 

 Min 0.86 0.89 

 Max 1.28 1.10 

 N 140 23 

Liver 

 Mean 8.99 8.95 

 St.dev. 0.92 0.50 

 Min 6.86 8.27 

 Max 12.70 10.18 

 N 140 23 

Thymus 

 Mean 0.311 0.311 

 St.dev. 0.079 0.043 

 Min 0.158 0.236 

 Max 0.564 0.384 

 N 140 23 

Kidneys 

 Mean 2.19 2.17 

 St.dev. 0.20 0.12 

 Min 1.59 1.99 

 Max 2.64 2.38 

 N 140 23 

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HARLAN LABORATORIES LTD. HISTO - 2 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ Weights 

Adrenals 

 Mean 0.071 0.072 

 St.dev. 0.012 0.006 

 Min 0.038 0.061 

 Max 0.105 0.085 

 N 140 23 

Spleen 

 Mean 0.73 0.73 

 St.dev. 0.11 0.07 

 Min 0.45 0.63 

 Max 1.10 0.89 

 N 140 23 

Testes 

 Mean 3.64 3.64 

 St.dev. 0.41 0.17 

 Min 1.46 3.33 

 Max 4.67 3.92 

 N 230 23 

Prostate 

 Mean 0.94 0.94 

 St.dev. 0.17 0.16 

 Min 0.64 0.78 

 Max 1.35 1.10 

 N 30 3 

Epididymides 

 Mean 1.289 1.289 

 St.dev. 0.151 0.074 

 Min 0.641 1.182 

 Max 1.641 1.475 

 N 230 23 

Seminal Vesicles 

 Mean 1.37 1.37 

 St.dev. 0.27 0.15 

 Min 0.67 1.28 

 Max 1.93 1.54 

 N 30 3 

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HARLAN LABORATORIES LTD. HISTO - 3 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 407.12 461.29 366.46 381.5 379.7 

 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 

 Max 2.10 2.22 2.12 2.09 2.18 

 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 

 Max 1.165 1.276 1.075 1.14 1.11 

 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 

 Max 10.13 12.70 9.80 10.45 9.88 

 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 

 Max 0.45 0.33 0.43 0.490 0.402 

 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 

 Max 2.42 2.61 2.46 2.60 2.41 

 N 10 10 10 10 10 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 594 of 663
 

HARLAN LABORATORIES LTD. HISTO - 4 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 0.088 0.085 0.086 0.085 0.083 

 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 

 Max 0.759 0.899 0.913 0.87 0.93 

 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 

 Max 3.77 4.21 4.67 4.20 4.31 

 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 

 Max 0.89 1.35 1.06 

 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 

 Max 1.401 1.641 1.533 1.492 1.532 

 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 

 Max 1.763 1.778 1.93 

 N 10 10 10 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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HARLAN LABORATORIES LTD. HISTO - 5 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 406.0 369.0 384.5 456.4 342.7 

 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 

 Max 2.18 2.06 2.05 2.06 2.06 

 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 

 Max 1.05 1.02 1.09 1.09 1.01 

 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 

 Max 9.37 9.11 9.92 10.71 9.64 

 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 

 Max 0.401 0.358 0.382 0.331 0.483 

 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 

 Max 2.33 2.44 2.21 2.27 2.64 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 0.084 0.095 0.068 0.105 0.095 

 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 

 Max 0.87 0.74 0.76 0.90 0.79 

 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 

 Max 4.21 4.40 4.13 4.55 4.15 

 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 

 Max 1.412 1.467 1.439 1.456 1.390 

 N 10 10 10 10 10 

Seminal Vesicles 

 Mean --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 597 of 663
 

HARLAN LABORATORIES LTD. HISTO - 7 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 366.8 397.0 441.1 383.8 384.0 

 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 

 Max 2.01 2.06 2.12 2.16 2.10 

 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 

 Max 1.09 0.94 1.15 1.13 1.04 

 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 

 Max 9.51 9.37 10.10 9.81 10.33 

 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 

 Max 0.355 0.335 0.343 0.345 0.377 

 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 

 Max 2.27 2.36 2.56 2.30 2.44 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 598 of 663
 

HARLAN LABORATORIES LTD. HISTO - 8 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 0.075 0.096 0.094 0.084 0.078 

 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 

 Max 0.80 0.75 1.04 0.84 0.79 

 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 

 Max 4.02 4.37 4.27 4.19 4.15 

 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 

 Max 1.489 1.496 1.509 1.628 1.526 

 N 10 10 10 10 10 

Seminal Vesicles 

 Mean --- --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 599 of 663
 

HARLAN LABORATORIES LTD. HISTO - 9 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 389.6 416.1 390.0 388.6 382.1 

 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 

 Max 2.23 2.16 2.12 2.17 2.12 

 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 

 Max 1.11 1.09 1.21 1.09 1.12 

 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 

 Max 10.29 9.88 10.36 9.46 10.25 

 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 

 Max 0.564 0.498 0.346 0.520 0.360 

 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 

 Max 2.41 2.47 2.57 2.45 2.36 

 N 5 5 5 5 5 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

 Max 0.097 0.104 0.077 0.088 0.091 

 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 

 Max 0.94 0.82 1.10 0.94 0.74 

 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 

 Max 4.33 4.22 4.17 4.04 4.02 

 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 

 Max 1.513 1.562 1.538 1.417 1.471 

 N 10 10 10 10 10 

Seminal Vesicles 

 Mean --- --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 601 of 663
 

HARLAN LABORATORIES LTD. HISTO - 11 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ Weights 

Body Weight 

 Mean 355.2 334.2 341.7 

 St.dev. 18.8 21.3 20.9 

 Min 332.2 309.5 316.0 

 Max 387.0 366.8 386.6 

 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 

 Max 2.10 2.04 2.08 

 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 

 Max 1.15 1.05 1.06 

 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 

 Max 9.61 9.68 9.40 

 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 

 Max 0.521 0.267 0.396 

 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 

 Max 2.34 2.37 2.15 

 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) 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ Weights 

Adrenals 

 Mean 0.077 0.069 0.069 

 St.dev. 0.007 0.011 0.009 

 Min 0.069 0.060 0.058 

 Max 0.086 0.086 0.077 

 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 

 Max 1.05 0.74 0.83 

 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 

 Max 4.08 4.32 3.92 

 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 

 Max 1.414 1.466 1.404 

 N 10 10 10 

Seminal Vesicles 

 Mean --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

Harlan Laboratories Study Report 

Sponsor Reference Number 

09009e5380ab4596 Page 603 of 663
 

HARLAN LABORATORIES LTD. HISTO - 13 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN WEIGHTS (GRAM) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ Weights 

Body Weight 

 Mean 236.7 236.7 

 St.dev. 14.3 5.9 

 Min 193.5 226.0 

 Max 281.2 250.0 

 N 205 21 

Brain 

 Mean 1.90 1.89 

 St.dev. 0.07 0.03 

 Min 1.73 1.84 

 Max 2.09 1.94 

 N 120 21 

Heart 

 Mean 0.81 0.80 

 St.dev. 0.08 0.04 

 Min 0.63 0.74 

 Max 1.18 0.90 

 N 120 21 

Liver 

 Mean 7.93 7.90 

 St.dev. 0.91 0.41 

 Min 5.35 6.81 

 Max 12.49 8.62 

 N 119 21 

Thymus 

 Mean 0.199 0.200 

 St.dev. 0.051 0.025 

 Min 0.096 0.150 

 Max 0.371 0.258 

 N 120 21 

Kidneys 

 Mean 1.49 1.49 

 St.dev. 0.13 0.05 

 Min 1.23 1.36 

 Max 1.92 1.55 

 N 120 21 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ Weights 

Adrenals 

 Mean 0.085 0.085 

 St.dev. 0.011 0.006 

 Min 0.061 0.074 

 Max 0.110 0.096 

 N 120 21 

Spleen 

 Mean 0.70 0.69 

 St.dev. 0.16 0.05 

 Min 0.42 0.59 

 Max 1.68 0.76 

 N 120 21 

Ovaries 

 Mean 0.126 0.127 

 St.dev. 0.021 0.014 

 Min 0.087 0.119 

 Max 0.177 0.148 

 N 25 4 

Uterus 

 Mean 1.12 1.10 

 St.dev. 0.17 0.07 

 Min 0.75 1.05 

 Max 1.56 1.18 

 N 20 3 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ Weights 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ Weights 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ Weights 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

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) 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ Weights 

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 

Sponsor Reference Number 

09009e5380ab4596 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

Body Weight (gram) 

 Mean 354.4 354.4 

 St.dev. 29.4 19.5 

 Min 271.7 312.6 

 Max 461.3 410.1 

 N 230 23 

Brain 

 Mean 0.57 0.57 

 St.dev. 0.04 0.03 

 Min 0.42 0.50 

 Max 0.72 0.65 

 N 140 23 

Heart 

 Mean 0.29 0.28 

 St.dev. 0.02 0.01 

 Min 0.22 0.25 

 Max 0.34 0.32 

 N 140 23 

Liver 

 Mean 2.53 2.53 

 St.dev. 0.17 0.11 

 Min 2.09 2.40 

 Max 3.15 2.94 

 N 140 23 

Thymus 

 Mean 0.088 0.088 

 St.dev. 0.023 0.014 

 Min 0.039 0.057 

 Max 0.148 0.124 

 N 140 23 

Kidneys 

 Mean 0.62 0.62 

 St.dev. 0.05 0.03 

 Min 0.51 0.57 

 Max 0.77 0.73 

 N 140 23 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

Adrenals 

 Mean 0.020 0.020 

 St.dev. 0.004 0.002 

 Min 0.012 0.016 

 Max 0.030 0.024 

 N 140 23 

Spleen 

 Mean 0.21 0.21 

 St.dev. 0.03 0.02 

 Min 0.13 0.18 

 Max 0.31 0.24 

 N 140 23 

Testes 

 Mean 1.03 1.03 

 St.dev. 0.12 0.05 

 Min 0.46 0.92 

 Max 1.36 1.12 

 N 230 23 

Prostate 

 Mean 0.25 0.25 

 St.dev. 0.04 0.02 

 Min 0.17 0.22 

 Max 0.32 0.27 

 N 30 3 

Epididymides 

 Mean 0.365 0.365 

 St.dev. 0.042 0.015 

 Min 0.209 0.342 

 Max 0.473 0.400 

 N 230 23 

Seminal Vesicles 

 Mean 0.37 0.37 

 St.dev. 0.07 0.01 

 Min 0.20 0.36 

 Max 0.57 0.38 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 407.12 461.29 366.46 381.5 379.7 

 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 

 Max 0.61 0.54 0.63 0.64 0.61 

 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 

 Max 0.324 0.304 0.326 0.32 0.30 

 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 

 Max 2.80 2.75 2.72 2.77 2.63 

 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 

 Max 0.13 0.08 0.12 0.130 0.106 

 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 

 Max 0.73 0.66 0.68 0.69 0.65 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 0.026 0.019 0.027 0.025 0.023 

 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 

 Max 0.215 0.207 0.249 0.27 0.26 

 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 

 Max 1.08 0.99 1.32 1.24 1.16 

 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 

 Max 0.27 0.32 0.31 

 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 

 Max 0.424 0.394 0.418 0.440 0.403 

 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 

 Max 0.506 0.454 0.57 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 406.0 369.0 384.5 456.4 342.7 

 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 

 Max 0.67 0.64 0.65 0.61 0.72 

 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 

 Max 0.31 0.30 0.31 0.28 0.34 

 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 

 Max 2.87 2.62 2.76 2.82 3.15 

 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 

 Max 0.121 0.103 0.104 0.083 0.141 

 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 

 Max 0.72 0.70 0.60 0.63 0.77 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 0.027 0.027 0.022 0.030 0.030 

 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 

 Max 0.28 0.23 0.25 0.23 0.25 

 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 

 Max 1.36 1.33 1.12 1.16 1.28 

 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 

 Max 0.454 0.422 0.381 0.426 0.432 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 366.8 397.0 441.1 383.8 384.0 

 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 

 Max 0.60 0.59 0.59 0.63 0.63 

 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 

 Max 0.30 0.27 0.32 0.31 0.31 

 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 

 Max 2.59 2.49 2.84 2.56 2.79 

 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 

 Max 0.108 0.098 0.093 0.093 0.107 

 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 

 Max 0.62 0.69 0.70 0.64 0.66 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 0.021 0.028 0.026 0.022 0.023 

 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 

 Max 0.25 0.22 0.29 0.23 0.21 

 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 

 Max 1.13 1.15 1.25 1.24 1.11 

 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 

 Max 0.420 0.436 0.437 0.449 0.416 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 389.6 416.1 390.0 388.6 382.1 

 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 

 Max 0.66 0.58 0.58 0.59 0.63 

 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 

 Max 0.29 0.28 0.33 0.29 0.29 

 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 

 Max 2.66 2.60 2.85 2.46 2.68 

 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 

 Max 0.146 0.127 0.097 0.134 0.111 

 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 

 Max 0.65 0.62 0.71 0.67 0.62 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 0.026 0.027 0.021 0.023 0.024 

 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 

 Max 0.28 0.22 0.28 0.26 0.23 

 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 

 Max 1.30 1.11 1.14 1.12 1.15 

 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 

 Max 0.453 0.389 0.420 0.398 0.453 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

 Max 387.0 366.8 386.6 

 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 

 Max 0.60 0.63 0.62 

 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 

 Max 0.33 0.31 0.31 

 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 

 Max 2.73 2.73 2.63 

 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 

 Max 0.148 0.084 0.118 

 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 

 Max 0.64 0.67 0.68 

 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

Adrenals 

 Mean 0.022 0.021 0.020 

 St.dev. 0.002 0.004 0.003 

 Min 0.020 0.017 0.016 

 Max 0.025 0.027 0.023 

 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 

 Max 0.31 0.22 0.24 

 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 

 Max 1.17 1.19 1.12 

 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 

 Max 0.416 0.473 0.444 

 N 10 10 10 

Seminal Vesicles 

 Mean --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

Harlan Laboratories Study Report 

Sponsor Reference Number 

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HARLAN LABORATORIES LTD. HISTO - 13 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

Body Weight (gram) 

 Mean 236.7 236.7 

 St.dev. 14.3 5.9 

 Min 193.5 226.0 

 Max 281.2 250.0 

 N 205 21 

Brain 

 Mean 0.81 0.80 

 St.dev. 0.05 0.02 

 Min 0.69 0.77 

 Max 1.01 0.83 

 N 120 21 

Heart 

 Mean 0.34 0.34 

 St.dev. 0.03 0.02 

 Min 0.27 0.31 

 Max 0.49 0.38 

 N 120 21 

Liver 

 Mean 3.36 3.35 

 St.dev. 0.32 0.13 

 Min 2.38 2.96 

 Max 4.86 3.63 

 N 119 21 

Thymus 

 Mean 0.084 0.085 

 St.dev. 0.020 0.011 

 Min 0.045 0.067 

 Max 0.159 0.110 

 N 120 21 

Kidneys 

 Mean 0.63 0.63 

 St.dev. 0.05 0.02 

 Min 0.54 0.59 

 Max 0.75 0.66 

 N 120 21 

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HARLAN LABORATORIES LTD. HISTO - 14 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

Adrenals 

 Mean 0.036 0.036 

 St.dev. 0.005 0.003 

 Min 0.026 0.031 

 Max 0.048 0.041 

 N 120 21 

Spleen 

 Mean 0.30 0.29 

 St.dev. 0.06 0.02 

 Min 0.20 0.26 

 Max 0.65 0.32 

 N 120 21 

Ovaries 

 Mean 0.053 0.054 

 St.dev. 0.008 0.005 

 Min 0.041 0.050 

 Max 0.072 0.061 

 N 25 4 

Uterus 

 Mean 0.48 0.47 

 St.dev. 0.06 0.03 

 Min 0.31 0.44 

 Max 0.56 0.49 

 N 20 3 

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HARLAN LABORATORIES LTD. HISTO - 15 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 16 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 17 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 18 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 19 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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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 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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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09009e5380ab4579 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 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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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HARLAN LABORATORIES LTD. HISTO - 22 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 23 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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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HARLAN LABORATORIES LTD. HISTO - 24 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BODY WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Body Weight Ratios (%) 

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 

Sponsor Reference Number 

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HARLAN LABORATORIES LTD. HISTO - 1 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Brain (gram) 

 Mean 2.02 2.02 

 St.dev. 0.08 0.05 

 Min 1.77 1.93 

 Max 2.23 2.10 

 N 140 23 

Heart 

 Mean 50.11 49.75 

 St.dev. 3.69 2.10 

 Min 41.03 45.20 

 Max 60.11 53.53 

 N 140 23 

Liver 

 Mean 445.28 442.76 

 St.dev. 42.39 21.65 

 Min 348.67 407.23 

 Max 652.26 495.26 

 N 140 23 

Thymus 

 Mean 15.439 15.382 

 St.dev. 3.889 2.119 

 Min 7.568 11.448 

 Max 26.586 19.175 

 N 140 23 

Kidneys 

 Mean 108.25 107.51 

 St.dev. 9.06 4.97 

 Min 85.80 96.69 

 Max 133.97 115.81 

 N 140 23 

Harlan Laboratories Study Report 

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09009e5380ab457a 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 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Adrenals 

 Mean 3.538 3.556 

 St.dev. 0.579 0.274 

 Min 1.905 3.136 

 Max 5.416 4.150 

 N 140 23 

Spleen 

 Mean 36.26 36.28 

 St.dev. 5.12 2.99 

 Min 21.89 31.54 

 Max 55.75 43.21 

 N 140 23 

Testes 

 Mean 179.07 179.06 

 St.dev. 19.52 7.72 

 Min 71.16 155.90 

 Max 230.33 193.13 

 N 140 23 

Prostate 

 Mean 46.09 46.09 

 St.dev. 7.68 7.40 

 Min 31.79 38.70 

 Max 63.61 53.49 

 N 30 3 

Epididymides 

 Mean 63.058 62.911 

 St.dev. 7.091 3.375 

 Min 36.229 57.940 

 Max 81.739 71.679 

 N 140 23 

Seminal Vesicles 

 Mean 67.50 67.50 

 St.dev. 13.80 6.29 

 Min 33.39 63.51 

 Max 101.74 74.75 

 N 30 3 

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HARLAN LABORATORIES LTD. HISTO - 3 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 2.10 2.22 2.12 2.09 2.18 

 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 

 Max 56.817 60.110 58.129 56.00 56.80 

 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 

 Max 520.21 652.26 468.5 517.06 499.23 

 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 

 Max 21.82 15.77 21.21 23.897 19.423 

 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 

 Max 122.24 133.97 117.15 128.55 121.00 

 N 10 10 10 10 10 

Harlan Laboratories Study Report 

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HARLAN LABORATORIES LTD. HISTO - 4 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 4.195 3.834 4.577 4.273 4.271 

 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 

 Max 36.919 46.151 43.026 42.50 46.84 

 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 

 Max 193.58 193.98 230.33 202.40 202.85 

 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 

 Max 43.93 63.61 54.27 

 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 

 Max 71.091 78.524 72.247 71.882 70.393 

 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 

 Max 88.479 85.533 101.74 

 N 10 10 10 

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HARLAN LABORATORIES LTD. HISTO - 5 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 2.18 2.06 2.05 2.06 2.06 

 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 

 Max 50.69 50.19 54.71 54.00 51.60 

 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 

 Max 461.78 441.58 497.01 518.83 487.34 

 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 

 Max 21.073 17.891 19.262 16.442 23.674 

 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 

 Max 114.86 118.40 111.53 112.63 129.60 

 N 5 5 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 6 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 4.050 4.624 3.619 5.416 4.593 

 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 

 Max 42.04 37.96 38.98 44.60 38.29 

 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 

 Max 203.20 224.23 193.73 220.31 197.22 

 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 

 Max 62.604 73.228 62.981 70.494 62.473 

 N 5 5 5 5 5 

Seminal Vesicles 

 Mean --- --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

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HARLAN LABORATORIES LTD. HISTO - 7 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 2.01 2.06 2.12 2.16 2.10 

 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 

 Max 54.19 51.11 54.81 54.40 54.24 

 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 

 Max 473.43 472.95 519.92 471.70 516.91 

 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 

 Max 18.593 18.303 16.768 16.542 18.855 

 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 

 Max 113.02 121.02 125.15 111.63 122.22 

 N 5 5 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 8 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 3.756 4.710 4.695 4.050 3.834 

 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 

 Max 41.33 40.73 49.29 40.35 39.48 

 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 

 Max 187.65 206.79 194.27 189.95 190.05 

 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 

 Max 72.091 81.739 73.792 68.710 72.485 

 N 5 5 5 5 5 

Seminal Vesicles 

 Mean --- --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

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HARLAN LABORATORIES LTD. HISTO - 9 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 2.23 2.16 2.12 2.17 2.12 

 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 

 Max 54.12 51.94 57.25 51.15 52.97 

 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 

 Max 509.13 484.77 488.31 439.03 482.69 

 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 

 Max 26.586 23.657 16.696 24.132 18.998 

 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 

 Max 113.46 116.96 121.07 112.73 111.11 

 N 5 5 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 10 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

 Max 4.947 4.938 3.661 4.073 4.271 

 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 

 Max 44.49 40.39 51.85 43.40 38.91 

 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 

 Max 202.94 200.77 203.20 208.82 197.25 

 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 

 Max 72.213 72.150 74.890 71.934 77.657 

 N 5 5 5 5 5 

Seminal Vesicles 

 Mean --- --- --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

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HARLAN LABORATORIES LTD. HISTO - 11 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Brain (gram) 

 Mean 1.98 1.98 2.02 

 St.dev. 0.09 0.07 0.06 

 Min 1.88 1.87 1.96 

 Max 2.10 2.04 2.08 

 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 

 Max 58.82 52.35 53.06 

 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 

 Max 491.36 480.27 471.26 

 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 

 Max 24.802 13.574 19.022 

 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 

 Max 115.19 116.99 109.61 

 N 5 5 5 

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HARLAN LABORATORIES LTD. HISTO - 12 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Males 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Adrenals 

 Mean 3.889 3.491 3.408 

 St.dev. 0.484 0.613 0.369 

 Min 3.397 2.944 2.953 

 Max 4.592 4.441 3.755 

 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 

 Max 55.75 37.45 41.03 

 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 

 Max 208.22 196.74 196.34 

 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 

 Max 65.074 69.199 71.610 

 N 5 5 5 

Seminal Vesicles 

 Mean --- --- --- 

 St.dev. 

 Min 

 Max 

 N 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Brain (gram) 

 Mean 1.90 1.89 

 St.dev. 0.07 0.03 

 Min 1.73 1.84 

 Max 2.09 1.94 

 N 120 21 

Heart 

 Mean 42.57 42.43 

 St.dev. 3.86 1.80 

 Min 34.07 40.11 

 Max 62.45 46.35 

 N 120 21 

Liver 

 Mean 418.67 417.92 

 St.dev. 48.63 21.40 

 Min 288.88 358.40 

 Max 691.37 457.67 

 N 119 21 

Thymus 

 Mean 10.480 10.579 

 St.dev. 2.654 1.277 

 Min 4.920 8.108 

 Max 19.363 13.783 

 N 120 21 

Kidneys 

 Mean 78.67 78.73 

 St.dev. 6.33 2.56 

 Min 63.01 73.57 

 Max 101.16 82.76 

 N 120 21 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDIES 1 - 23 STUDIES 1 - 23 

PARAMETER MEAN OF INDIVIDUAL VALUES MEAN OF STUDY MEANS 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Adrenals 

 Mean 4.512 4.523 

 St.dev. 0.603 0.332 

 Min 3.082 3.980 

 Max 5.895 5.153 

 N 120 21 

Spleen 

 Mean 36.84 36.72 

 St.dev. 8.15 2.58 

 Min 21.64 30.91 

 Max 88.50 40.21 

 N 120 21 

Ovaries 

 Mean 6.636 6.741 

 St.dev. 1.132 0.706 

 Min 4.456 6.214 

 Max 9.469 7.774 

 N 25 4 

Uterus 

 Mean 59.02 58.36 

 St.dev. 8.80 2.40 

 Min 40.16 56.30 

 Max 79.39 60.99 

 N 20 3 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 1 STUDY 2 STUDY 3 STUDY 4 STUDY 5 

PARAMETER OCT-04 NOV-04 DEC-04 APR-08 MAR-06 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 6 STUDY 7 STUDY 8 STUDY 9 STUDY 10 

PARAMETER APR-07 JUN-06 MAR-07 MAR-07 APR-07 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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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HARLAN LABORATORIES LTD. HISTO - 20 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 11 STUDY 12 STUDY 13 STUDY 14 STUDY 15 

PARAMETER SEP-07 NOV-07 DEC-07 MAR-08 FEB-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 21 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 22 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 16 STUDY 17 STUDY 18 STUDY 19 STUDY 20 

PARAMETER MAY-08 JAN-08 MAR-08 FEB-08 APR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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HARLAN LABORATORIES LTD. HISTO - 23 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

Brain (gram) 

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 

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HARLAN LABORATORIES LTD. HISTO - 24 

CH-4452 ITINGEN, SWITZERLAND 19-MAY-09 

OECD 422 STUDIES 

HISTORICAL DATA – ORGAN/BRAIN WEIGHT RATIOS 

STRAIN: RAT / HanRcc:WIST 

Females 

_________________________________________________________________________________________________ 

 STUDY 21 STUDY 22 STUDY 23 

PARAMETER APR-08 APR-08 MAR-08 

_________________________________________________________________________________________________ 

Organ/Brain Weight Ratios (%) 

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 

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