### STUDY TITLE

TEST GUIDELINE(S)

AUTHOR

STUDY COMPLETION DATE

TEST FACILITY

PERFORMING LABORATORY PROJECT IDENTIFICATION

SPONSOR IDENTIFICATION NUMBER

SPONSOR

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

OECD guideline No. 422 OPPTS 870.3650

06-Dec-2013

1 of 756 

## This document is directed to USEPA pursuant the Toxic Substances Control Act (TSCA). This document is the property of the sponsor and may be used only for that purpose intended by the sponsor and as authorized under applicable law. Every other or additional use, exploitation, reproduction, publication or submission to other parties requires the written permission of the sponsor, except as otherwise required by applicable law (e.g., TSCA). The use of these studies/documents for regulatory, registration or other commercial purposes [including but not limited to Registration, Evaluation, Authorization and Restriction of Chemical Substances (REACH)], without the express written permission of the sponsor is unauthorized and strictly prohibited.

### Report Body 1 Page 1



# PAGE RESERVED FOR PROPRIETARY INFORMATION OR STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS Report 2 of 756

### Report Body 1 Page 3



# PAGE RESERVED FOR FLAGGING STATEMENTS Report 4 of 756

# CONTENTS

PAGE RESERVED FOR PROPRIETARY INFORMATION OR STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS 2

......................................................................... STUDY DIRECTOR STATEMENT OF GLP COMPLIANCE 3

................................................. PAGE RESERVED FOR FLAGGING STATEMENTS 4

............................................................. QUALITY ASSURANCE STATEMENT 5

................................................................................... CONTENTS 6

............................................................................................................................ ..... SUMMARY 11

............................................................................................................................ ... Parent Animals 11

.................................................................................................................... Litter Data - F1 Pups 12

........................................................................................................... Conclusion 13

........................................................................................................................... GENERAL INFORMATION 14

.................................................................................................... Schedule 14

............................................................................................................................ .. Animal Welfare 14

................................................................................................................... Accreditation 14

....................................................................................................................... Multi – Site Study Details 14

................................................................................................... Additional Responsibilities 15

................................................................................................. Study Plan Amendments 15

..................................................................................................... Archiving 16

............................................................................................................................ . 1 INTRODUCTION AND PURPOSE 17

....................................................................................... 1.1 Purpose 17

.......................................................................................................................... 1.2 Guidelines / Regulations 17

............................................................................................... 2 TEST ITEM / VEHICLE AND CONTROL ITEM 18

................................................................ 2.1 Test Item 18

........................................................................................................................ 2.2 Vehicle and Control Item 18

.............................................................................................. 3 MATERIALS AND METHODS 19

............................................................................................ 3.1 Test System 19

................................................................................................................... 3.2 Allocation 20

...................................................................................................................... 3.3 Husbandry 20

..................................................................................................................... 3.4 Dose Formulations 21

........................................................................................................ 3.4.1 Analysis of Dose Formulations 21

........................................................................... 3.5 Treatment 22

....................................................................................................................... 3.6 Study Schedule 23

.............................................................................................................. 3.7 Mating, Gestation and Lactation 23

................................................................................... 3.8 Observations 24

.................................................................................................................. 3.8.1 Detailed Clinical Observations 24

............................................................................ 3.8.2 Functional Observation Battery 24

.......................................................................... 3.9 Clinical Laboratory Investigations 25

................................................................................ 3.9.1 Hematology 25

......................................................................................................... 3.9.2 Clinical Biochemistry 26

.......................................................................................... 3.10 Termination of the Study 26

............................................................................................. 3.10.1 Necropsy 27

............................................................................................................ 3.10.2 Organ Weights 27

................................................................................................... Report 6 of 756

## 3.10.3 Tissue Preservation 28

........................................................................................... 3.10.4 Histotechnique 29

................................................................................................... 3.10.5 Histopathology 29

.................................................................................................. 3.11 Data Compilation and Processing 29

............................................................................... 3.12 Statistical Analysis 30

...................................................................................................... 4 RESULTS AND DISCUSSION 31

.............................................................................................. 4.1 Analysis of Dose Formulations 31

..................................................................................... 4.2 Observations (Parent Animals) 31

..................................................................................... 4.2.1 Viability / Mortality 31

............................................................................................ 4.2.2 General Cageside Observations (Daily) 31

.............................................................. 4.2.3 Detailed Clinical Observations (Weekly) 31

........................................................... 4.2.4 Functional Observational Battery 32

........................................................................ 4.2.5 Food Consumption of Males 32

............................................................................... 4.2.6 Food Consumption of Females 32

........................................................................... 4.2.7 Body Weights of Males 33

....................................................................................... 4.2.8 Body Weights of Females 33

................................................................................... 4.3 Clinical Laboratory Investigations 33

................................................................................ 4.3.1 Hematology 33

......................................................................................................... 4.3.2 Clinical Biochemistry 34

.......................................................................................... 4.4 Reproduction and Breeding Data 34

.................................................................................. 4.4.1 Summary of Performance 34

.................................................................................... 4.4.2 Mating Performance and Fertility 35

....................................................................... 4.4.3 Corpora Lutea Count 35

........................................................................................... 4.4.4 Duration of Gestation 35

.......................................................................................... 4.4.5 Implantation Rate and Post-Implantation Loss 35

................................................... 4.4.6 Litter Size at First Litter Check 36

........................................................................... 4.4.7 Postnatal Loss Days 0 - 4 Post Partum 36

................................................................ 4.5 Pathology (Parent Animals) 36

.......................................................................................... 4.5.1 Organ Weights 36

..................................................................................................... 4.5.2 Macroscopic Findings 37

......................................................................................... 4.5.3 Microscopic Findings 37

.......................................................................................... 4.6 Observations (Litter Data - F1 Pups) 37

............................................................................ 4.6.1 External Examination at First Litter Check and during Lactation 37

...................... 4.6.2 Sex Ratios 37

............................................................................................................ 4.6.3 Body Weights to Day 4 Post Partum 37

................................................................... 4.6.4 Macroscopic Findings 38

......................................................................................... 5 DISCUSSION AND CONCLUSION 39

..................................................................................... 6 REFERENCES 40

........................................................................................................................ 7 FIGURES 41

............................................................................................................................ .... Data of P Generation 42

........................................................................................................... Food Consumption of Males 43

........................................................................................ Food Consumption of Females 45

.................................................................................... Body Weights of Males 48

................................................................................................ Body Weights of Females 51

............................................................................................ Body Weight Gain of Males 54

......................................................................................... Report 7 of 756

## Body Weight Gain of Females 57

..................................................................................... Data of F1 Pups 60

................................................................................................................... Mean Body Weights of Pups per Group 61

...................................................................... 8 SUMMARY TABLES 67

............................................................................................................ Data of P Generation 68

........................................................................................................... Daily Clinical Signs of Males 69

...................................................................................... Daily Clinical Signs of Females 73

................................................................................... Detailed Weekly Clinical Observations of Males 78

........................................................ Detailed Weekly Clinical Observations of Females 82

.................................................... Functional Observational Battery (FOB) of Males 87

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

.................................................. Grip Strength and Body Temperature of Males 91

........................................................... Grip Strength and Body Temperature of Females 93

....................................................... 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 106

........................................................... Body Weights of Males 109

.............................................................................................. Body Weights of Females 115

.......................................................................................... Body Weight Gain of Males 120

....................................................................................... Body Weight Gain of Females 126

................................................................................... Differences in Body Weight Gain of Males 131

............................................................... Differences in Body Weight Gain of Females 137

........................................................... Hematology 143

................................................................................................................ Biochemistry 149

.............................................................................................................. Mating Performance 153

................................................................................................... Fertility 155

....................................................................................................................... Breeding Data per Group 157

........................................................................................... Organ Weights of Males 160

............................................................................................ Organ Weights of Females 167

......................................................................................... Macroscopical Findings of Males 174

.............................................................................. Macroscopical Findings of Females 176

........................................................................... Data of F1 Pups 178

................................................................................................................. External Examination of Pups at First Litter Check 179

.................................................. Clinical Signs or Observations of Pups 180

...................................................................... Dates of Postnatal and Breeding Losses of Pups 181

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

.................................................................... Mean Differences in Body Weights of Pups per Group 186

............................................. Macroscopical Findings of Pups 188

................................................................................ 9 INDIVIDUAL TABLES 191

....................................................................................................... Data of P Generation 192

......................................................................................................... Mortality Data of Males 193

............................................................................................. Mortality Data of Females 198

.......................................................................................... Report 8 of 756

## Daily Clinical Signs of Males 203

.................................................................................... Daily Clinical Signs of Females 207

................................................................................. Detailed Weekly Clinical Observations of Males 212

...................................................... Detailed Weekly Clinical Observations of Females 216

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

.................................................... Functional Observational Battery (FOB) of Females 223

................................................ Grip Strength and Body Temperature of Males 225

......................................................... Grip Strength and Body Temperature of Females 230

..................................................... Locomotor Activity of Males 235

..................................................................................... Locomotor Activity of Females 240

................................................................................. Food Consumption of Males 245

...................................................................................... Food Consumption of Females 250

.................................................................................. Body Weights of Males 255

.............................................................................................. Body Weights of Females 268

.......................................................................................... Body Weight Gain of Males 281

....................................................................................... Body Weight Gain of Females 294

................................................................................... Hematology 307

................................................................................................................ Biochemistry 325

.............................................................................................................. Reproduction Processes 335

.............................................................................................. Breeding Data per Litter 340

............................................................................................. Females not Giving Birth 349

........................................................................................... Organ Weights of Males 353

............................................................................................ Organ Weights of Females 366

......................................................................................... Macroscopical Findings of Males 379

.............................................................................. Macroscopical Findings of Females 388

........................................................................... Data of F1 Pups 397

................................................................................................................. External Examination of Pups at First Litter Check 398

.................................................. Daily Observation of Pups 403

......................................................................................... Mean Body Weights of Pups per Litter 408

...................................................................... Body Weights of Pups 417

................................................................................................ Individual Pup Data 439

.................................................................................................... Macroscopical Findings of Pups 462

................................................................................ APPENDIX I - CERTIFICATE OF ANALYSIS 521

.................................................................... APPENDIX II - CHEMICAL ANALYSIS OF FEED 525

............................................................. APPENDIX III - DRINKING WATER ANALYSIS 532

.............................................................. APPENDIX IV - FORMULATION ANALYSIS 538

.................................................................... APPENDIX V - FUNCTIONAL OBSERVATIONAL BATTERY 549

........................................ APPENDIX VI - CLINICAL LABORATORY INVESTIGATIONS 556

..................................... Historical Data - Hematology 561

............................................................................................ Historical Data - Clinical Biochemistry 563

............................................................................ APPENDIX VII - HISTOPATHOLOGY 565

................................................................................ Histopathology Phase Report 566

............................................................................................ APPENDIX VIII - HISTORICAL CONTROL DATA 702

........................................................... Functional Observational Battery 703

...................................................................................... Locomotor Activity 706

........................................................................................................... Report 9 of 756

## Organ Weights 712

................................................................................................................... Report 10 of 756

### Report Body 2 Page 1



# SUMMARY General The purpose of this study was to generate pre liminary 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 to male rats during 48 days and to fe male rats for 14 days prior to pairing, through the pair ing and gestation peri ods until the F1 generation reached day 4 post partum
. The following dose levels were applied: Group 1: 0 mg/kg body weight/day (control group) Group 2: 100 mg/kg body weight/day Group 3: 300 mg/kg body weight/day Group 4: 1000 mg/kg body weight/day A standard dose volume of 5 mL/kg body weight with a daily adjustme nt to the actual body weight was used. Control animals were dos ed with the vehicle alone (corn oil).


# Parent Animals Mortality / Viability No test item-related mortalities were noted in both sexes during the scheduled study period. Clinical Signs No test item-related clinical signs were noted in males and in females treated at 100, 300 and 1000 mg/kg bw/day. Functional Observational Battery None of the parameters under investigation duri ng the functional observational battery gave an indication of a test item-related effect. Food Consumption and Body Weights There were no effects on mean food consumpti on and mean body weights in males and females at any dose level and in any study phase. Report 11 of 756

### Report Body 2 Page 2



## Clinical Laboratory Investigations Hematology The assessment of the hematology data did not rev eal any test item-relate d effects in males and females at any dose level. Clinical Biochemistry In males, the alanine aminotransferase levels were slightly and dose-de pendently higher at 300 and 1000 mg/kg bw/day. Reproduction and Breeding Data No effects on reproduction and breeding were recorded at any dose level. Organ Weights In males at 1000 mg/kg bw/day, the liver we ights were increased by approximately 20%. Macroscopic / Microscopic Findings There were no macroscopic findi ngs related to treatment. There was a diffuse, midzonal/cen trilobular hepatocellular hypert rophy recorded in males at 1000 mg/kg bw/day. 

# Litter Data - F1 Pups Findings at First Litter Ch eck and during Lactation The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pup was noted at any dose level. Pup Weights to Day 4 Post Partum No test item-related findings were note d at macroscopic examination of F1 pups. Macroscopic Findings At necropsy of pups, there were no abnormal findings. Report 12 of 756

### Report Body 2 Page 3



# Conclusion In conclusion, activities of alanin e aminotransferase were slightly higher after administration of at 1000 and 300 mg/kg body wei ght/day in males. Although a relationship to treatment cannot be excluded, the va lues were well within the norma l range of the rat strain used. Therefore, these differences were not considered as adverse. Furthermore, liver weights were increased, and there were minor morphological alterati ons in the liver of males at 1000 mg/kg body weight/day. These consisted of a minimal degree of hepatocellu lar hypertrophy. These findings may be considered as adaptive in na ture, within physiological limits and not a manifestation of frank toxicity. No compound-related effects were observed in female rats at any dose level. Based on these results, the NOAEL (No Observed A dverse Effect Level) fo r general toxicity and the NOEL (No Observed Effect Level) for reproduction were consider ed to be 1000 mg/kg body weight/day. Report 13 of 756

### Report Body 2 Page 4



# GENERAL INFORMATION Schedule Study Initiation Date: 30-Apr-2013 Experimental Starting Date (Delivery of Animals): 02-May-2013 First Test Item Admi nistration: 10-May-2013 Initiation of Pairing: 23-May-2013 Blood Collection from Males: 26-Jun-2013 Necropsy of Males: 26/27-Jun-2013 First Blood Collection fro m Females: 19-Jun-2013 First Necropsy of Females: 18-Jun-2013 Experimental Completion Date: 26-Nov-2013


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


# Accreditation is accredited as a test laboratory for analysis in the fields of clinical chem istry, hematology, blood coagulati on and urine diagnostics in accordance with the Standard ISO/IEC 17025 unde r accreditation number STS 085 by the Accreditation Service. 

# Multi – Site Study Details Lead Quality Assurance: Study Phase: Histopathology Study Phase Identifier: 13001 Test Site:

Principal Investigator: Report 14 of 756

### Report Body 2 Page 5



## Test Site QA:



# Additional Responsibilities Deputy Study Director: Laboratory Coordinator: Planning Coordinator: Necropsy / Histotechnology: Clinical Laboratory Investigations: Formulation Analysis: (until 31-Jul-2013) (from 01-Aug-2013 onwards) Peer Review: 

# Study Plan Amendments Amendment No. 1: Adaptation of pro cedure for dose formulation and taking samples for analytical analysis. Amendment No. 2: Postponement of necropsy start of males. Amendment No. 3: Appointment of a pathologist who was no PI, and therefore no multi-site study anymore, as well as the responsible person for peer review histopathology. Amendment No. 4: Since left the company, took over his responsibility. Amendment No. 5: The study became a multi-site study and new PI pathologist. Amendment No. 6: Histopathological ex amination of the liver in groups 2 and 3. Amendment No. 7: The pathologist informed about a new address. Report 15 of 756

### Report Body 2 Page 6


# Archiving will retain true copies of the study plan, the final report and a sample of test item of the present study for at least ten years. The original study plan, original paper raw data, a CD with el ectronic raw data, specim ens and the original final report w ill be sent to the Sponsor. The original final pathology report, all slides, disp atch list(s) and raw data provided will be sent to the test facility. The test f acility is responsible for the tran sfer to the Sponsor`s archive. These original documents/raw data as well as the specimens (as long as quality permits evaluation) will be archived for at least 15 years at the following location:

Shipment Address: Report 16 of 756

### Report Body 2 Page 7



# 1 INTRODUCTION AND PURPOSE 1.1 Purpose The purpose of this study was to generate prelim inary information on the possible health hazards likely to arise from repeated exposure over a re latively limited period of time. In addition it provided information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, deve lopment of the conceptus and parturition. This study should provide informa tion to assess the n eed to conduct further investigations and may provide guidance in the de sign of subsequent studies. Rationale for Choice of Species, Route of Administration and Dose Levels The rat is a suitable species for repeated dose and reproduction/developm ental toxicity studies required by regulatory authorities. The oral route is one possi ble route for human exposure. Based on available toxicity data of the compound (LD50, oral, rat: >29 g/ kg bw), the dose levels of 0, 100, 300, and 1000 mg/kg bw/day were selected.


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

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

## March 1996).

• “Combined Repeated Dose Toxicity St udy with the Reproduction/Developmental Toxicity Screening Test” Health Effects Test Guideline OPPTS 870.3650 Guideline from the Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, July 2000. Report 17 of 756

### Report Body 2 Page 8



# 2 TEST ITEM / VEHICLE AND CONTROL ITEM 2.1 Test Item Information as provided by the Sponsor (certi ficate of analysis see in Appendix I on p. ).

Identification / Chemical Name: Synonym: Test Substance Number: Description: Solid, melt, white Batch Number: 0008043725 Purity: 93.8% (GC-FID) Production Date: January 2012 Expiry Date (Retest Date): Decembe r 2013, as handled at the Sponsor 31-Dec-2013, as handled at Storage Conditions: Room temperature (15 - 25 °C) Safety Precautions: Routine hygienic procedures (gloves, goggles, face mask).


# 2.2 Vehicle and Control Item Identification: Corn oil Source: Carl Roth GmbH Batch Number: 103197718 Expiry Date (Retes t Date): 12-May-2014 Storage Conditions: Room temperature (15 - 25 °C) Safety Precautions: Routine hygienic procedure (gloves, goggles, face mask) 522 Report 18 of 756

### Report Body 2 Page 9



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


# 3.1 Test System Animals: Rat, RccHan TM 

## : WIST(SPF) Rationale: Recognized by inte rnational guidelines as a recommended test system. Breeder:

Number of Animals: 48 males: 12 per group 48 females: 12 per group ∗ 

## Age (at Start of Treatment): 11 weeks Body Weight Range (at Start of Treatment): Males: 328 to 395 g Females: 217 to 255 g Identification: Cage card and individual animal number (ear tattoo). Pups: On day 1 post partum , pups were individually tattooed with Indian ink. Randomization: Performed after at least three days of acclimatization using a computer-generat ed random algorithm. Body weights (recorded on the day of allocation) were taken into consideration in order to ensure similar mean body weights in all groups. Acclimatization: Under test conditi ons after health examination. Only animals without any visible signs of illness were used for the study.

∗ 

### 50 males and 50 females were obtained from the breeder. The surplus animals were sacrificed after the commencement of treatment. This wa s documented in the raw data. Report 19 of 756

### Report Body 2 Page 10



# 3.2 Allocation The group identification and animal numbers assi gned to treatment are stated in the following table:

Allocation and Dose Levels mg/kg bw/day Group 1 Control 0 Group 2 100 Group 3 300 Group 4 1000 Group 10 Reserve Animals* Males 1 - 12 13 - 24 25 - 36 37 - 48 100, 101 Females 49 - 60 61 - 72 73 - 84 85 - 96 102, 103 * Any raw data collected during the acclimatization period on reserve animals was not reported but retained in the raw data.


# 3.3 Husbandry Room Number, 015A 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%). Ltd. There was 12- hour fluorescent light / 12-hour dark cycle with music during the light period. Accommodation: In groups of three to five in Makrolon type-4 cages with wire mesh tops during acclimatization and afterwards 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 (ISO-BLOX fromDuring the prepairing period, cages with males were interspersed amongst those holding females to promote the development of regular estrus cycles. Diet: Pelleted standard (batch nos. 43/12 and 56/12) rodent main tenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland) was available ad libitum . Results of representative analyses for contaminants are in cluded in Appendix II on p. . 526 Report 20 of 756

### Report Body 2 Page 11



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

# 3.4 Dose Formulations The dose formulations were prepared daily us ing the test item as supplied by the Sponsor. was weighed into a glass beak er on a tared precision balance and 80 - 90% of the warmed-up (40 ± 5 °C) vehicle was adde d (w/v) with a syringe in small amounts under continuously stirring. The dose formulation wa s heated on approx. 50 °C for approx. 20 minutes and then the remaining warmed-up vehicle was added. Each dose formulation was homogenized with an Ultraturrax and stirred again for approx. 20 minutes at 37 - 40 °C. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period by stirring at 37 - 40 °C temperature.
3.4.1 Analysis of Dose Formulations In the first week of dose formulation day a sa mple from the control group as well as three samples (top, middle and bottom) of each concentra tion were taken prior to dosing for analysis of concentration and homogeneity. Due to high vari ation of the analytical homogeneity results, additional samples were taken in the first and second week fr om remaining formulations to evaluate optimized analytical conditions for sample workup a nd derivatization. These samples were analysed but results were not reported. Samp les of each test item concentration were taken from the middle to confirm the st ability (4 hours at r oom temperature 15 - 25 °C). Towards the end of the study, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were delivered at ambient temperature to and analyzed. Since the dose formulation became not homogenous anymore at low temperature, samples of the exact amount of dose formulation were drawn and the entire sample was analyzed: Groups 1 and 2: 500 mg dose formulation Group 3: 250 mg dose formulation Group 4: 100 mg dose formulation 533 Report 21 of 756

### Report Body 2 Page 12



## The samples were analyzed by GC-FID. 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 The samples were not discarded wi thout written consent from the study director. The results are presented in Appendix IV on p.

. 

# 3.5 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 (within four hours after preparation) Target Dose Levels : Group 1: 0 mg/kg/day (control group) Group 2: 100 mg/kg/day Group 3: 300 mg/kg/day Group 4: 1000 mg/kg/day Rationale for Dose Level Selection: Based on the single dose toxicity results and repeated dose toxicity data of chemically similar compounds. 

## Dose Volume: 5 mL/kg body weight Dose Concentration : Group 1: 0 mg/mL Group 2: 20 mg/mL Group 3: 60 mg/mL Group 4: 200 mg/mL Duration of Acclimatization Period: Minimum 5 days Duration of Treatment Period: Males: 48 days Females: Approximately 6 weeks 539 Report 22 of 756

### Report Body 2 Page 13



# 3.6 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 48 days, when no longer needed for assessment of reproductive effects


# 3.7 Mating, Gestation and Lactation During the pairing period, females were housed w ith sexually mature males from the same dose group (1:1) until eviden ce 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

. If a female did not mate during the 14-day pairi ng period, a second pairing of this female with a male in the same group, which had already ma ted successfully, was considered. If mating was not recorded during this additional pairing period of a maximum of 14 days, the female was sacrificed and, if indicated, the reproductive organs examined hi stopathologically in order to ascertain the reason for the infertility. All dams were allowed to give birth and rear their litters (F1 pups) up to day 4 post partum
. Day 0 was designated as the day on which a female had deliver ed all her pups. Report 23 of 756

### Report Body 2 Page 14



# 3.8 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 parturit ion, and behavioral abnormalities in nesting and nursing. Food Consumption: Males: Pre-pairin g period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; after pairing period weekly. Females: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; gestation days 0 - 7, 7 - 14 and 14 - 21 and days 1 - 4 of the lactation. No food consumption was recorded during the pairing period. Body Weights: Recorded daily from treatment start to day of necropsy. Pup Data: The litters were examin ed for litter size, live births, still births and any gross anomalies. The sex ratio ofthe pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 post partum
.
3.8.1 Detailed Clinical Observations Once prior to the first administration of the test item and weekly thereafter (in the gestation period on day 0, 6, 13 and 20 post coitum ), detailed clinical observat ions were performed outside the home cage in a standard arena. Animals were observed for the following: changes in skin, fur, eyes, mucous membranes, occurrence of secretio ns and excretions, and autonomic activity (e.g. lacrimation, piloerection, pupil size , unusual respiratory pattern). Any changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies or bizarre behavior were also reported.

3.8.2 Functional Observation Battery At one time during the study (mal es shortly before the schedule d sacrifice and females on day 3 or 4 post partum ) relevant parameters were performed w ith five P generation males and five P generation females randomly selected from each group. This FOB assessment was conducted following the daily dose administration. An imals were observed for the following: Report 24 of 756

### Report Body 2 Page 15



## • Cage-side observations: faeces-balls, urine and posture as well as resistance to removal.

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

• Open field observations: level of ambulator y activity including rearing (one minute evaluation), unusual body movements (e.g. sp asms, convulsions), gait evaluation, behavior, hair coat, respiration, qua ntity of faeces-balls and urine.

• Reflexes: blinking, pinna refle x, extensor thrust response, paw pinch, responsiveness to sharp noise, righting reflex and h earing ability (Preyer’s reflex).

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


# 3.9 Clinical Laboratory Investigations Blood samples were obtained on the day before or on the day of the scheduled necropsy from 5 males randomly selected 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 cau sed by circadian rhythms. An assay was performed under the responsibility of under internal laboratory quality control conditions to assure reliable test results (see in Appendix VI on p. ).

3.9.1 Hematology The following hematology parameters were determined: Complete Blood Cell Count Erythrocyte count Hemoglobin Mean corpuscular hemoglobin concentration Hemoglobin concentration distribution width 550

557 Report 25 of 756

### Report Body 2 Page 16



## Hematocrit Mean corpuscular volume Red cell volume distribution width Mean corpuscular hemoglobin Leukocyte count, total Differential leukocyte count: Platelet count Reticulocytes Coagulation Prothrombin time (= Thromboplastin time) Activated partial Thromboplastin time

3.9.2 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

Furthermore, an additional blood sample (0.5 mL ) was collected into serum tubes for possible future measurement of thyroid releasing hormone (TSH), and the thyroid hormones triiodothyronine (T3) and thyr oxine (T4). Serum samples were stored at -80 ± 10 °C. Any samples remaining at finalization of the study report were discarded. These measurements were not necessary, since there were no changes at micr oscopic examination of the thyroid glands or thyroid gland weights.


# 3.10 Termination of the Study Males were sacrificed after tr eatment of at least 48 days, when no longer needed for the assessment of reproductiv e 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

. Report 26 of 756

### Report Body 2 Page 17



## 3.10.1 Necropsy All animals sacrificed were subjected to a detailed macroscopic examination. Specimens of abnormal tissue were fixed in neutral phos phate buffered 4% formaldehyde solution. At the scheduled sacrifice, all animals were we ighed and sacrificed by an injection of sodium pentobarbital. All P generation animals were exsanguinated. Dead pups, except those excessively canniba lized, were examined macroscopically. All parent animals and pups were examined macrosc opically for any structural changes, either at the scheduled necropsy or during the study if death occurred. For the parent animals, special attention was di rected at the organs of the reproductive system. The number of implantation sites 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 )].

3.10.2 Organ Weights At the scheduled sacrifice, the testes and epididymides of all parental males were weighed separately. In addition, from 5 males and 5 females killed at the end of the study which were selected for hematology and clinical chemistry examination from each group, the following organs were trimmed from any adherent tissue, as a ppropriate, and their wet weight taken. Adrenal glands (weighed as pairs) Brain Heart Kidneys (weighed as pairs) Uterus (including cervix) Prostate Liver Thymus Spleen Thyroid * 

## (after fixation) Ovaries (weighed as pairs) Seminal vesicles (inclusi ve coagulating gland)

* 

### In group 2, erroneously the thyroid weight of 10 males was taken. Report 27 of 756

### Report Body 2 Page 18



## 3.10.3 Tissue Preservation The following tissues from all pare ntal males were preserved in neutral phosphate buffered 4% formaldehyde solution: Prostate Seminal vesicles with coagulating gland Testes (in modified Davidson Solution) Epididymides (in modified Davidson Solution) The following tissues from all pare ntal females were preserved in neutral phosphate buffered 4% formaldehyde solution: Ovaries (with oviduct) Uterus (with vagina) In addition, from all males and females the follo wing tissues were preserved in neutral phosphate buffered 4% formaldehyde solution: Gross lesions Brain Spinal chord (cervical, thoracic, lumbar) Small and large intestines 1 

## (incl. Peyer’s patches) Stomach (forestomach and glandular stomach) Liver Kidneys Adrenals Spleen Lymph nodes (axillary and mesenteric) Aorta 2 

## Eyes with optic nerve and harderian gland 2 

## Lacrimal gland 2 

## Larynx 2 

## Nasal cavity 2 

## Esophagus 2 

## Heart Thymus Thyroids, and parathyroids if possible Trachea and lungs (preserved by inflation with fixative and then immersion) Pituitary gland 2 

## Urinary bladder Peripheral nerve (sciatic) Bone marrow (femur) Femur with knee joint 2 

## Mammary gland (male and female) 2 

## Pancreas 2 

## Salivary glands – mandibular, sublingual 2 

## Skeletal muscle 2 

## Sternum with bone marrow 2 

## Pharynx 2

1 

### Duodenum, jejunum, ileum, colon, caecum, rectum 2 

### Only examined by histopathology in case of macroscopic findings indicative of potential toxicity Report 28 of 756

### Report Body 2 Page 19



## 3.10.4 Histotechnique All organ and tissue samples to be examined by the study pathologist were processed, embedded and cut at an approximate thickness of 2 - 4 micr ometers and stained with hematoxylin and eosin. Additionally, the testis was stained by PAS-hematoxylin.

3.10.5 Histopathology Macroscopical findings, testes, epididymides, pros tate, seminal vesicles, ova ries, oviduct, vagina and uterus from all animals of the control and high dose group we re examined. The same applied to all occurring gross lesions and to all anim als, which died spontaneously or had to be terminated in extremis . The remaining organs/tissues of 5 randomly selected males and females of the control and high dose group, respect ively, were examined histopathologically. Special emphasis was made on the stages of spermatogenesis and histopat hology of interstitial cell structure. Since test item-related morphologic changes were de tected in the liver at the high dose, these organs from the mid- and low-dose group were examined to establis h a no-effect level. Histological examination of ovari es was carried out on any female s that did not give birth. A histopathology peer re view was performed. A histopathology phase report was provided by the principal investigator which is included in Appendix VII on p.

. 

# 3.11 Data Compilation and Processing The following data were recorded on-line: clinical signs and observations, food consumption, body weights, necropsy data, or gan weights, reproduction and litter data (TOX CONTROL). Microscopic data were entered into the RoeLee System. All other data were recorded on data sheets and compiled manually. From the on-line recorded reprodu ction data, the following paramete rs were calculated: fertility indices, mean precoital time, post-implantation losses (absolute and perc ent), mean litter size, pup sex ratios and viability indices. For reproduction data, group mean values we re calculated both on a litter basis and on a percentage per group basis. Mean pup weights were calculated fr om the individual weights on a per litter basis. Computer-generated values in the tables repres ent the rounded-off results of calculations which used the exact raw data values. 565 Report 29 of 756

### Report Body 2 Page 20



# 3.12 Statistical Analysis The following statistical methods were used to analyze food consumption, body and organ weights, grip strength, rectal temperature, clin ical laboratory and repr oduction data, locomotor activity and macroscopical findings:

• Means and standard deviations of various data were calc ulated and included in the report.

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

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

• Fisher's exact-test [see References ( 4 )] was applied if the variables could be dichotomized without loss of information. Report 30 of 756

### Report Body 2 Page 21



# 4 RESULTS AND DISCUSSION 4.1 Analysis of Dose Formulations (See Appendix IV on p. ) The concentrations in the dose formulations ranged from 90.5% to 112.2% and thus, the required content lim it of ±20% with refe rence to the nominal content was met. The homogeneous distribution of in the preparations was approved because single results found did not deviat e more than 14.4% from the corresponding mean and met the specified acceptance criterion of ≤ 15%. Due to a deviation close to the acceptance limit of dose group 3, prepared on 13 May 2013 (14.4%), homogeneity of this dose level was confirmed in an additional internal test. The test item was found to be stable in application formulati ons when kept 4 hours at room temperature (20 ± 5 °C) due to recoveries whic h met the variation limit of 10% from the timezero (homogeneity) mean value. Erroneously the 4 hours dose fo rmulation samples were not stored at 37 - 40 °C (at this temperature level th e animals received the dose formulation). Since the storage of the dose formulation about 4 hours at 35 °C was tested already during the implementation study D75908 (non GLP study), it coul d be concluded, that the dose formulation was stable over the course of the study.


# 4.2 Observations (Parent Animals) 4.2.1 Viability / Mortality (See Individual Tables on p. ) There were no unplanned deaths. All anim als survived until scheduled necropsy.

4.2.2 General Cageside Observations (Daily) (See Summary Tables on p. , Individual Tables on p. ) No test item-related clinical signs were noted in males and in females treated at 100, 300 and 1000 mg/kg bw/day.

4.2.3 Detailed Clinical Observations (Weekly) (See Summary Tables on p. , Individual Tables on p. ) The findings noted during the detailed weekly clinical observations of males and females did not indicate any test item-related effects. 539

193

69 203

78 212 Report 31 of 756

### Report Body 2 Page 22



## 4.2.4 Functional Observational Battery (See Summary Tables on p. , Individual Tables on p. ) The corresponding historical control data are included in Appendix VIII on p.

. None of the parameters under investigation duri ng the functional observational battery gave an indication of a test item-related effect. A slightly but statistically significantly lowe r body temperature (-1.3%) was noted in males at 300 mg/kg bw/day. However, due to the lack of do se-dependency, this finding was deemed to be incidental. Locomotor Activity (See Summary Tables on p. , Individual Tables on p. ) The corresponding historical control data are included in Appendix VIII on p.

. Locomotor activity was not affected by the treatme nt with the test item at any dose level.

4.2.5 Food Consumption of Males (See Figures on p. , Summary Tables on pp. and , Individual Tables on p. ) Pre-Pairing Period and After Pairing Period There were no test item-related effects on mean food consumption in males at any dose level and in any study phase. At 1000 mg/kg be/day, food consum ption was slightly higher be tween day 8 and day 20 of the after pairing period (approximately 10%). Since the differences were minor, they were considered not to be t oxicologically relevant.

4.2.6 Food Consumption of Females (See Figures on p. , Summary Tables on pp. and , Individual Tables on p. ) There were no effects on mean food consumption in females at any dose level and in any study phase. 87 221 703

95 235 706

43 99 103 245

45 101 106 250 Report 32 of 756

### Report Body 2 Page 23



## 4.2.7 Body Weights of Males (See Figures on pp. and , Summary Tables on pp. , and , Individual Tables on pp. and ) There were no effects on mean body weight gain and mean body weights at any dose level and in any study phase. Statistically significant differences in body weight gain occurred on several occasions in males, but were either not dose-dependent or represented slightly highe r body weight gains. Therefore, these differences were considered to be fortuitous. The overall differences in mean body weight gain at the dose levels of 0, 100, 300 and 1000 mg/kg bw/day were: +11%, +12%, +12% a nd +10% during the pre- pairing period, +6%, +7%, +6% and +7% during the pa iring period and +3%, +3%, +4% and +3% during the after pairing period (percentages refer to th e body weight gain within the period).

4.2.8 Body Weights of Females (See Figures on pp. and , Summary Tables on pp. , and , Individual Tables on pp. and ) There were no effects on mean body weight gain and mean body weights at any dose level and in any study phase. The overall differences in mean body weight gain at the dose levels of 0, 100, 300 and 1000 mg/kg bw/day were: +6%, +6%, +7% and +7 % during the pre-pairi ng period, +54%, +57%, +57% and +57% during the gest ation period and +4%, +4%, +4% and +4% during the lactation period (percentages refer to the body weight gain within the period).


# 4.3 Clinical Laboratory Investigations 4.3.1 Hematology (See Summary Tables on p. , Individual Tables on p. ) The assessment of the hematology data did not rev eal any test item-relate d effects in males and females at any dose level. The statistically significant differences from controls (higher numbers of neutrophils and reticulocytes in males at 1000 mg/kg bw/day; higher mean corpuscular hemoglobin concentration in females at 100 and 1000 mg/kg bw/day; lower MCV values in females at 100 mg/kg bw/day) occurred in one gender only an d the values were wi thin the range of historical control data or showed no dose-dependency. 48 54 109 120 131 255 281

51 57 115 126 137 268 294

143 307 Report 33 of 756

### eport Body 2 Page 24



## 4.3.2 Clinical Biochemistry (See Summary Tables on p. , Individual Tables on p. ) In males, the alanine aminotransferase levels were slightly, but dose-de pendently increased at 300 and 1000 mg/kg bw/day (up to 2.2-fold). These levels were in the ra nge of the historical control data. Nevertheless, due to the observed morphological alterations in the liver, the increase may be test item related but not adverse. Further statistically si gnificant differences (higher glucos e values at 100 and 1000 mg/kg bw/day; lower creatinine values at 1000 mg/kg bw/day; higher potassium values at 1000 mg/kg bw/day; higher protein levels at 100 and 1000 mg/kg bw /day, with higher globulin values and lower albumin/globulin ratio at 1000 mg/kg bw/day) were minor and within the hi storical control range except protein at 1000 mg/kg bw/day, which was bor derline to historical control data. In the absence of corroborating changes (especially re garding histopathology) these differences are therefore considered not to be toxicologically relevant. In females, the assessment of the clinical bioche mistry data did not reveal any test item-related effects at any dose level. Statis tically significantly hi gher chloride values occurred at 100 mg/kg bw/day, but without dose-dependency.


# 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 (100) 3 (300) 4 (1000) Female numbers 49 - 60 61 - 72 73 - 84 85 - 96 Number of females paired 12 12 12 12 Number of females mated 12 12 12 12 Number of pregnant females (A) 10 12 11 11 Number of females with implantation sites only (B) 0 0 0 1 Number of females which reared their pups until day 4 post partum 10 12 11 10 (A) Group 1 female nos. 52 and 54, group 3 female no. 84, group 4 female no. 88 were not pregnant. (B) Group 4 female no. 96 lost its litter before first litter check was recorded and therefore only implantation sites were recorded. 

## 149 325 Report 34 of 756

### Report Body 2 Page 25



## 4.4.2 Mating Performance and Fertility (See Summary Tables on p. , Individual Tables on p. ) All females mated within the first pairing peri od. For one female (no. 82) in group 3, mating was not detected. The median and mean precoital times were unaff ected by treatment with the test item. Mean precoital times were 2.9, 1.8, 2.9 and 2.6 days in gr oups 1, 2, 3 and 4, respectively. The median precoital time was 3, 2, 2 and 2 days in order of ascending dose level. Two, one and one female in the control group and at 300 and 1000 mg/kg bw/day, respectively, were not pregnant. As a result the fertility index was 83.3%, 100%, 91.7% and 91.7% in order of ascending dose level.

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 (17.7, 16.8, 15.3 and 16.7 in order of ascending dose level) and gave no indication of a test item-related effect.

4.4.4 Duration of Gestation (See Summary Tables on p. , Individual Tables on p. ) The mean duration of gestation was unaffected by exposure to the test item. Mean duration of gestation was 21.4, 21.7, 21.5 and 21.4 days, in order of ascending dose level.

4.4.5 Implantation Rate and Post-Implantation Loss (See Summary Tables on p. , Individual Tables on p. ) No effects on implantation rate or post-impla ntation loss were observed at any dose level. The mean number of implanta tions per dam was 14.7, 14.6, 14.0 a nd 15.0 in order of ascending dose levels. The mean incidence of post-implantation loss as a percentage of total implantations was 9.5%, 9.1%, 12.3% and 11.5%, in order of as cending dose level (including female no. 96). 153 335

157 340

157 340

157 340 Report 35 of 756

### Report Body 2 Page 26



## 4.4.6 Litter Size at First Litter Check (See Summary Tables on p. , Individual Tables on p. ) No effects on litter size were observed at any dose level. Mean litter size at first litter check was 13.3, 13.3, 12.3 and 13.3 pups in order of ascending dose levels. At 300 mg/kg bw/day, three pups out of 13 pups were found dead at first litter check in litter no. 75. At 1000 mg/kg bw/day, female no. 96 was observed to give birth to at least 3 dead pups, which were all missing at first litter check (recorded onl y in the raw data). Thes e isolated findings were considered to be incidental.

4.4.7 Postnatal Loss Days 0 - 4 Post Partum (See Summary Tables on pp. , Individual Tables on p. ) There was no effect on postnat al loss at any dose level. Seven pups out of 4 litters were lost post partum at 100 mg/kg bw/day. No pups were lost in the control group and at 300 and 1000 mg/kg bw/day. The findings in group 2 were considered to be incidental due to the lack of a dose-relationship.


# 4.5 Pathology (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.

. In males at 1000 mg/kg bw/day, absolute and relative liver weights were statistically significantly increased. The value relative to b ody weight was in the range of the historical control data (2.39-3.56 g). Due to the observed morphological alterations in the liver, the increase was considered to be test item related but not adverse. Higher kidney values occurred in males at 100 and 1000 mg/kg bw/day. These differences were considered to be incidental since there was no dose-dependency. Further statistically significant differences comprised only derived relative wei ghts or organ to brain ratios and were not accompanied by histopathological findings. No effects were observed at other dose le vels or in females at any dose level. 157 340

157 181 340

160 353 712 Report 36 of 756

### Report Body 2 Page 27



## 4.5.2 Macroscopic Findings (See Summary Tables on p. , Individual Tables on p. ) There were no test item-related findings not ed at necropsy in males and females. All gross lesions recorded we re considered to be within the range of normal background alterations and showed no dose dependency.

4.5.3 Microscopic Findings (See Appendix VII on p. ) There were minor morphological alte rations in the liver of males. This consisted of a minimal degree of diffuse, midzonal/centr ilobular hepatocellula r hypertrophy recorded in 3/5 rats at 1000 mg/kg bw/day. This finding may be considered as adaptive in nature, within physiological limits and not a manifestation of frank toxicity.


# 4.6 Observations (Litter Data - F1 Pups) 4.6.1 External Examination at First Li tter Check and during Lactation (See Summary Tables on p. , Individual Tables on p. ) No test item-related abnormal findings were noted at first litter check or during the first 4 days post partum at any dose level.

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 exposure to the test item. The proportion of males at first litter check was 51%, 47%, 47% a nd 53%, in order of ascending dose level.

4.6.3 Body Weights to Day 4 Post Partum (See Figures on p. , Summary Tables on p. , Individual Tables on p. ) Mean pup weights on day 0 and day 1 post partum were unaffected by treatment with the test item. 174 379

565

179 398

157 340

61 183 417 Report 37 of 756

### Report Body 2 Page 28



## On day 1 post partum mean pup weights were 6.3, 6.3, 6.5 a nd 6.2 g in order of ascending dose level. Also mean body wei ght gain was similar in all groups until day 4 post partum and no effects on mean body weights were recorded.

4.6.4 Macroscopic Findings (See Summary Table on p. , Individual Tables on p. ) No test item-related findings were note d at macroscopic examination of F1 pups. 188 462 Report 38 of 756

### Report Body 2 Page 29



# 5 DISCUSSION AND CONCLUSION This study is a valid investigation of the toxicological effects resu lting from repeated oral-gavage administration of the test item , which was administered in corn oil as vehicle at dosages of 100, 300, and 1000 mg/kg body weight/da y, and controls received the vehicle only. was administered to male rats for 48 days and to female rats for 14 days prior to pairing, through the pair ing and gestation peri ods until the F1 generation reached day 4 post partum
. In males at 1000 mg/kg bw/day, slightly higher leve ls of alanine aminotrans ferase were observed. Although a relationship to treatmen t cannot be excluded, the values were well within the normal range of the rat strain used. Therefore, these differences were not considered as adverse. Furthermore, increased liver weights were obser ved and minor morphological alterations in the liver of males. This consisted of a minima l degree of diffuse, midzonal/centrilobular hepatocellular hypertrophy. This finding may be considered as adaptive in nature, within physiological limits and not a manifestation of fr ank toxicity. None of these observations were recorded at females. In males at 300 mg/kg bw /day, the alanine aminotransferase levels were also slightly higher but no ot her liver alterations were reco rded at this dose level. No test item-related effects were observe d in female rats at any dose level. Neither clinical signs nor e ffects on mean food consump tion, mean body weight, reproduction and breeding or pup development we re noted at any dose level. Based on these results, the NOAEL (No Observed A dverse Effect Level) fo r general toxicity and the NOEL (No Observed Effect Level) for reproduction were consider ed to be 1000 mg/kg body weight/day. Report 39 of 756

### Report Body 2 Page 30



# 6 REFERENCES 1. E. Salewski: Arch. Exp. Path. Pharmak. 247, pp. 367-368 (1964) 2. C.W. Dunnett: A Multiple Comparison Procedure for Compar ing Several Treatments with a Control, J. Amer. Statist. Assoc. 50, pp. 1096-1121 (1955). 3. R.G. Miller: Simultaneous Statistical Inference, Springer Verlag, New York (1981). 4. R.A. Fisher: Statistical Methods for Research Work ers, Oliver and Boyd, Edinburgh (1950). Report 40 of 756

# 7 FIGURES Report 41 of 756

# Data of P Generation Report 42 of 75614-AUG-13 FC-GRA - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 43 of 75614-AUG-13 FC-GRA - 2



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

PRE-PAIRING

AFTER PAIRING 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 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Days G/ANIMAL/DAY

1 8 15 22 0 5 10 15 20 25 30

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Days G/ANIMAL/DAY 

### Report 44 of 75614-AUG-13 FC-GRA - 1



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

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 45 of 75614-AUG-13 FC-GRA - 2



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

PRE-PAIRING

GESTATION 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 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 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 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Days G/ANIMAL/DAY 

### Report 46 of 75614-AUG-13 FC-GRA - 3



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

LACTATION

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Days G/ANIMAL/DAY 

### Report 47 of 75608-AUG-13 BW-GRA - 1



### BODY WEIGHTS (G) - GRAPHICS

Data excluded from Summary Report

---

Not Reported

--- 

### Report 48 of 75608-AUG-13 BW-GRA - 2



### MALES BODY WEIGHTS (G) - GRAPHICS

PRE-PAIRING

PAIRING

1 2 3 4 5 6 7 8 9 10 11 12 13 14 360 380 400 420 440 460 480

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G

0 1 2 3 4 5 6 7 8 9 10 11 12 13 360 380 400 420 440 460 480

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 49 of 75608-AUG-13 BW-GRA - 3



### MALES BODY WEIGHTS (G) - GRAPHICS

AFTER PAIRING

1 8 15 22 360 380 400 420 440 460 480

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 50 of 75614-AUG-13 BW-GRA - 1



### BODY WEIGHTS (G) - GRAPHICS

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 51 of 75614-AUG-13 BW-GRA - 2



### FEMALES BODY WEIGHTS (G) - GRAPHICS

PRE-PAIRING

GESTATION

1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 100 200 300 400 500

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G

0 7 14 21 0 100 200 300 400 500

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 52 of 75614-AUG-13 BW-GRA - 3



### FEMALES BODY WEIGHTS (G) - GRAPHICS

LACTATION

1 2 3 4 5 0 100 200 300 400 500

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 53 of 75608-AUG-13 BWG-GRA - 1



### BODY WEIGHT GAIN (%) - GRAPHICS

Data excluded from Summary Report

---

Not Reported

--- 

### Report 54 of 75608-AUG-13 BWG-GRA - 2



### MALES BODY WEIGHT GAIN (%) - GRAPHICS

PRE-PAIRING

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day %

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day % 

### Report 55 of 75608-AUG-13 BWG-GRA - 3



### MALES BODY WEIGHT GAIN (%) - GRAPHICS

AFTER PAIRING

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 2 4 6 8 10 12 14

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day % 

### Report 56 of 75614-AUG-13 BWG-GRA - 1



### BODY WEIGHT GAIN (%) - GRAPHICS

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 57 of 75614-AUG-13 BWG-GRA - 2



### FEMALES BODY WEIGHT GAIN (%) - GRAPHICS

PRE-PAIRING

GESTATION

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day %

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day % 

### Report 58 of 75614-AUG-13 BWG-GRA - 3



### FEMALES BODY WEIGHT GAIN (%) - GRAPHICS

LACTATION

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

Group 1 (0 mg/kg) Group 2 (100 mg/kg)

Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day % 

### Report 59 of 756

# Data of F1 Pups Report 60 of 75615-AUG-13 BWPU-GRA - 1



### Mean Body Weights of Pups per Group On a Litter Basis (G) - MALES + FEMALES

Data excluded from Summary Report

---

Not Reported

--- 

### Report 61 of 75615-AUG-13 BWPU-GRA - 2



### MALES + FEMALES Mean Body Weights of Pups per Group On a Litter Basis (G) - MALES + FEMALES

LACTATION

0 1 2 3 4 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0

Group 1 (0 mg/kg) Group 2 (100 mg/kg) Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 62 of 75615-AUG-13 BWPU-GRA - 1



### Mean Body Weights of Pups per Group On a Litter Basis (G) - MALES

Data excluded from Summary Report

---

Not Reported

--- 

### Report 63 of 75615-AUG-13 BWPU-GRA - 2



### MALES Mean Body Weights of Pups per Group On a Litter Basis (G) - MALES

LACTATION

0 1 2 3 4 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0

Group 1 (0 mg/kg) Group 2 (100 mg/kg) Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 64 of 75615-AUG-13 BWPU-GRA - 1



### Mean Body Weights of Pups per Group On a Litter Basis (G) - FEMALES

Data excluded from Summary Report

---

Not Reported

--- 

### Report 65 of 75615-AUG-13 BWPU-GRA - 2



### FEMALES Mean Body Weights of Pups per Group On a Litter Basis (G) - FEMALES

LACTATION

0 1 2 3 4 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0

Group 1 (0 mg/kg) Group 2 (100 mg/kg) Group 3 (300 mg/kg) Group 4 (1000 mg/kg) Day G 

### Report 66 of 756

# 8 SUMMARY TABLES Report 67 of 756

# Data of P Generation Report 68 of 75608-AUG-13 SYMT-SUM - 1



### DAILY 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% 

### Report 69 of 75608-AUG-13 SYMT-SUM - 2



### MALES DAILY CLINICAL SIGNS - SUMMARY

PRE-PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

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

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

### Report 70 of 75608-AUG-13 SYMT-SUM - 3



### MALES DAILY CLINICAL SIGNS - SUMMARY

PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

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

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

### Report 71 of 75608-AUG-13 SYMT-SUM - 4



### MALES DAILY CLINICAL SIGNS - SUMMARY

AFTER PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

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

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

### Report 72 of 75608-AUG-13 SYMT-SUM - 1



### DAILY 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% 

### Report 73 of 75608-AUG-13 SYMT-SUM - 2



### FEMALES DAILY CLINICAL SIGNS - SUMMARY

PRE-PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. HAIR LOSS (3) NECK (CERVICAL) 1 2 3 4 5 6 7 1 2 3 4 5 6 7

1 1 1 2 2 2 2 2 2 2 2 1 1 1 Weeks / Days

- 1 2

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

### Report 74 of 75608-AUG-13 SYMT-SUM - 3



### FEMALES DAILY CLINICAL SIGNS - SUMMARY

PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. HAIR LOSS (3)
WOUND (3) NECK (CERVICAL)

ABDOMEN 1 2 3 4 5 6 7 1 2 3 4 5 6

1 1 1

2 2 2 Weeks / Days

-

- 1 2

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

< < 1 G

G %

% 

### Report 75 of 75608-AUG-13 SYMT-SUM - 4



### FEMALES DAILY CLINICAL SIGNS - SUMMARY

GESTATION

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. HAIR LOSS (3)
SCABS (3)
WOUND (3) NECK (CERVICAL)

ABDOMEN

ABDOMEN 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4

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

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

2 1 . . . . . . . . . . . . . . . . . . . . Weeks / Days

-

-

- 1 2 3 4

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

. < < < . . . . . . . . . . . . . . . . . .

< < . . . . . . . . . . . . . . . . . . . . G

G

G %

%

% 

### Report 76 of 75608-AUG-13 SYMT-SUM - 5



### FEMALES DAILY CLINICAL SIGNS - SUMMARY

LACTATION

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. 1 2 3 4 5 Weeks / Days 1

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

### Report 77 of 75608-AUG-13 WOC-SUM - 1



### DETAILED WEEKLY CLINICAL OBSERVATION - 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% 

### Report 78 of 75608-AUG-13 WOC-SUM - 2



### MALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

PRE-PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - - - 6 - - - - - - 6 - Weeks / Days 1 2

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

### Report 79 of 75608-AUG-13 WOC-SUM - 3



### MALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - - - 6 - - - - - - 6 - Weeks / Days 1 2

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

### Report 80 of 75608-AUG-13 WOC-SUM - 4



### MALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

AFTER PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - - - 6 - - - - - - 6 - - - - - - 6 - - Weeks / Days 1 2 3 4

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

### Report 81 of 75620-AUG-13 WOC-SUM - 1



### DETAILED WEEKLY CLINICAL OBSERVATION - 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% 

### Report 82 of 75620-AUG-13 WOC-SUM - 2



### FEMALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

ACCLIMATIZATION

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg)

Group 10 (Reserve) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - - - - 7

- Days

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

### Report 83 of 75620-AUG-13 WOC-SUM - 3



### FEMALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

PRE-PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - - - 6

- - - - - - 3

- Days 1

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

### Report 84 of 75620-AUG-13 WOC-SUM - 4



### FEMALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

PAIRING

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded. - - - - - - 6

- - - - - - 3

- - - - - - - - - - - - - - - Days 1

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

### Report 85 of 75620-AUG-13 WOC-SUM - 5



### FEMALES DETAILED WEEKLY CLINICAL OBSERVATION - SUMMARY

GESTATION

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) APPEARANCE

No further abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. HAIR LOSS (3)
WOUND (3) NECK (CERVICAL)

ABDOMEN 0

- - - - - 6

- - - - - - 3

- - - - - - 0

- - - - -

1
. . .
2
. . . Days

-

- 1 2

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

< . . . G

G %

% 

### Report 86 of 75608-AUG-13 FOBM-SUM - 1



### FUNCTIONAL OBSERVATION BATTERY - 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% 

### Report 87 of 75608-AUG-13 FOBM-SUM - 2



### MALES FUNCTIONAL OBSERVATION BATTERY - SUMMARY

.
AFTER PAIRING

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

Open field observation (type 4-cage)

No further abnormality recorded.

No abnormality recorded.

Open field observation (type 4-cage)

No further abnormality recorded. Rearings decreased (1)

Rearings decreased (1) - - - - - - - - - - - - - - - - - - 5 - - - - - - - - -

2

2 Weeks / Days

1

1 -

- 1 2 3 4

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

% G

G 

### Report 88 of 75620-AUG-13 FOBF-SUM - 1



### FUNCTIONAL OBSERVATION BATTERY - 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% 

### Report 89 of 75620-AUG-13 FOBF-SUM - 2



### FEMALES FUNCTIONAL OBSERVATION BATTERY - SUMMARY

LACTATION

Group 1 (0 mg/kg)

Group 2 (100 mg/kg)

Group 3 (300 mg/kg)

Group 4 (1000 mg/kg) No abnormality recorded.

No abnormality recorded.

No abnormality recorded.

No abnormality recorded. - - - 3

- - Days

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

### Report 90 of 75603-DEC-13 REP-SUM - 1



### Functional Observational Battery - SUMMARY

AFTER PAIRING PERIOD MALES Reported Parameter

Grip Fore Grip Hind DEGREES GRIP FORELIMB

GRIP HINDLIMB BODY TEMPERATURE DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN Statistical Testing Parameter Data excluded from Summary Report

--- Not Reported

---

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

### Report 91 of 75603-DEC-13 REP-SUM - 2



### Functional Observational Battery - SUMMARY MALES

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) AFTER PAIRING PERIOD MALES Group 1

Group 2

Group 3

Group 4 MEAN/MEDIAN

ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N Grip Fore Grip Hind DEGREES

KILOGRAM KILOGRAM C

0.34 0.36 38.3 0.13 0.08 0.3 5 5 5
0.45 0.40 38.1 0.16 0.11 0.2 5 5 5
0.37 0.34 37.8 0.07 0.08 0.2 5 5 5
0.52 0.35 38.2 0.11 0.06 0.4 5 5 5 GRIP STRENG TH BODY TEMPER ATURE

- - -

- - *

- - - 

### Report 92 of 75614-AUG-13 REP-SUM - 1



### Functional Observational Battery - SUMMARY Lactation Period

LACTATION PERIOD Reported Parameter

Grip Fore Grip Hind DEGREES GRIP FORELIMB

GRIP HINDLIMB BODY TEMPERATURE DUNNETT, MEAN DUNNETT, MEAN DUNNETT, MEAN Statistical Testing Parameter Data excluded from Summary Report

--- Not Reported

---

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

### Report 93 of 75614-AUG-13 REP-SUM - 2



### Functional Observational Battery - SUMMARY Lactation Period FEMALES

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

Group 2

Group 3

Group 4 MEAN/MEDIAN

ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N Grip Fore Grip Hind DEGREES

KILOGRAM KILOGRAM C

0.31 0.20 38.9 0.14 0.09 0.3 5 5 5
0.21 0.11 38.8 0.05 0.04 0.3 5 5 5
0.27 0.18 39.0 0.13 0.06 0.3 5 5 5
0.24 0.14 38.9 0.07 0.02 0.4 5 5 5 GRIP STRENGTH BODY TEMPERATURE

- - -

- - -

- - - 

### Report 94 of 75620-AUG-13 LOCA-SUM - 1



### LOCOMOTOR ACTIVITY - SUMMARY

AFTERPAIRING PERIOD MALES 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 STEEL, MEDIAN Statistical Testing Parameter Data excluded from Summary Report

--- Not Reported

---

Statistical Methods STEEL STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Report 95 of 75620-AUG-13 LOCA-SUM - 2



### LOCOMOTOR ACTIVITY - SUMMARY MALES

*/**/- : Significant at 5% (*), 1% (**) or not significant (-) AFTERPAIRING PERIOD MALES Group 1

Group 2

Group 3

Group 4 MEAN/MEDIAN

ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N 6 12 18 24 30 total

min min min min min

392 302 242 170 126 1284 97 157 105 63 92 385 5 5 5 5 5 5
240 187 189 182 108 914 7 25 41 56 51 133 5 5 5 5 5 5
390 317 261 199 254 1250 161 82 115 142 126 523 5 5 5 5 5 5
396 228 224 145 145 1045 69 45 34 52 101 203 5 5 5 5 5 5 LOW BEAMS C OUNT

- - - - - -

- - - - - -

- - - - - - 

### Report 96 of 75620-AUG-13 LOCA-SUM - 1



### LOCOMOTOR ACTIVITY - SUMMARY

LACTATION PERIOD 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 STEEL, MEDIAN Statistical Testing Parameter Data excluded from Summary Report

--- Not Reported

---

Statistical Methods STEEL STEEL-Test sig. at 5% (*), 1% (**) or not significant (-) 

### Report 97 of 75620-AUG-13 LOCA-SUM - 2



### LOCOMOTOR ACTIVITY - SUMMARY FEMALES

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

Group 2

Group 3

Group 4 MEAN/MEDIAN

ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N
MEAN/MEDIAN ST.DEV. N 6 12 18 24 30 total

min min min min min

263 191 163 136 133 852 46 70 46 35 65 201 5 5 5 5 5 5
292 212 200 148 157 957 107 40 63 20 39 225 5 5 5 5 5 5
301 157 158 102 174 972 32 47 24 38 86 142 5 5 5 5 5 5
292 129 96 132 137 779 67 47 65 43 81 236 5 5 5 5 5 5 LOW BEAMS C OUNT

- - - - - -

- - - - - -

- - - - - - 

### Report 98 of 75614-AUG-13 FC-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 99 of 75614-AUG-13 FC-SUM - 2



### MALES

PRE-PAIRING

AFTER PAIRING Days 1-4

Days 4-8

Days 8-11

Days 11-14

MEAN OF MEANS Over PRE-PAIRING
Days 1-8

Days 8-15

Days 15-20

MEAN OF MEANS Over AFTER PAIRING

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 100 mg/kg 300 mg/kg 1000 mg/kg

25.5 25.2 24.8 23.7 2.5 1.4 2.2 2.3 12 12 12 12 22.4 22.1 22.2 21.8 2.1 1.9 2.0 1.8 12 12 12 12 17.7 18.8 19.2 15.8 3.4 3.0 3.6 2.3 12 12 12 12 26.5 25.3 26.1 27.2 2.3 2.8 3.0 1.9 12 12 12 12 23.0 22.9 23.1 22.1

20.4 21.0 21.0 21.9 1.1 1.5 2.0 2.5 12 12 12 12 18.7 18.8 19.8 20.5 1.8 1.8 1.8 2.0 12 12 12 12 19.8 20.4 20.6 22.0 1.3 1.9 1.7 2.3 12 12 12 12 19.6 20.1 20.4 21.5 

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

- - -

- - -

- - -

- - -

- - -

- - *

- - *

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

### Report 100 of 75623-AUG-13 FC-SUM - 1



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

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 101 of 75623-AUG-13 FC-SUM - 2



### FEMALES

PRE-PAIRING

GESTATION

LACTATION Days 1-4

Days 4-8

Days 8-11

Days 11-14

MEAN OF MEANS Over PRE-PAIRING
Days 0-7

Days 7-14

Days 14-21

MEAN OF MEANS Over GESTATION (Days 0-21)
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 MEAN ST.DEV. N

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

0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

18.5 17.8 17.8 17.9 1.6 2.0 2.1 1.3 12 12 12 12 15.5 15.0 14.8 15.5 1.1 1.9 1.6 1.4 12 12 12 12 15.1 15.0 14.4 15.3 1.5 1.9 1.0 1.1 12 12 12 12 15.5 15.9 15.3 17.1 2.0 2.1 1.4 1.3 12 12 12 12 16.2 15.9 15.6 16.5

18.4 19.6 18.5 19.4 1.6 2.7 1.2 1.9 10 12 10 11 20.1 21.1 20.1 21.7 1.9 2.4 2.1 1.7 10 12 10 11 22.9 23.9 23.0 25.0 2.2 2.4 2.3 2.1 10 12 10 11 20.4 21.5 20.5 22.0

29.5 28.3 25.6 32.4 2.5 6.4 6.6 3.1 10 12 11 10 

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

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 102 of 75623-AUG-13 FC-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 103 of 75623-AUG-13 FC-SUM - 2



### MALES

PRE-PAIRING

AFTER PAIRING Days 1-4

Days 4-8

Days 8-11

Days 11-14

MEAN OF MEANS Over PRE-PAIRING DIFF (%)* Over PRE-PAIRING
Days 1-8

Days 8-15

Days 15-20 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 (%)* MEAN ST.DEV. N DIFF (%)* MEAN ST.DEV. N DIFF (%)* Group 1 Group 2 Group 3 Group 4

0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

25.5 25.2 24.8 23.7 2.5 1.4 2.2 2.3 12 12 12 12

-1.2 -2.7 -7.1 22.4 22.1 22.2 21.8 2.1 1.9 2.0 1.8 12 12 12 12

-1.3 -0.9 -2.7 17.7 18.8 19.2 15.8 3.4 3.0 3.6 2.3 12 12 12 12

+6.2 +8.5 -10.7 26.5 25.3 26.1 27.2 2.3 2.8 3.0 1.9 12 12 12 12

-4.5 -1.5 +2.6 23.0 22.9 23.1 22.1
-0.4 +0.4 -3.9

20.4 21.0 21.0 21.9 1.1 1.5 2.0 2.5 12 12 12 12

+2.9 +2.9 +7.4 18.7 18.8 19.8 20.5 1.8 1.8 1.8 2.0 12 12 12 12

+0.5 +5.9 +9.6 19.8 20.4 20.6 22.0 1.3 1.9 1.7 2.3 12 12 12 12

+3.0 +4.0 +11.1 

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

*: Percentage relative to the control group ---

---

---

---

---

---

---

--- 

### Report 104 of 75623-AUG-13 FC-SUM - 3



### MALES

AFTER PAIRING MEAN OF MEANS Over AFTER PAIRING DIFF (%)* Over AFTER PAIRING Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

19.6 20.1 20.4 21.5
+2.6 +4.1 +9.7 

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

*: Percentage relative to the control group --- 

### Report 105 of 75623-AUG-13 FC-SUM - 1



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

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 106 of 75623-AUG-13 FC-SUM - 2



### FEMALES

PRE-PAIRING

GESTATION Days 1-4

Days 4-8

Days 8-11

Days 11-14

MEAN OF MEANS Over PRE-PAIRING DIFF (%)* Over PRE-PAIRING
Days 0-7

Days 7-14

Days 14-21 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 (%)* MEAN ST.DEV. N DIFF (%)* MEAN ST.DEV. N DIFF (%)* Group 1 Group 2 Group 3 Group 4

0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

18.5 17.8 17.8 17.9 1.6 2.0 2.1 1.3 12 12 12 12

-3.8 -3.8 -3.2 15.5 15.0 14.8 15.5 1.1 1.9 1.6 1.4 12 12 12 12

-3.2 -4.5 ±0.0 15.1 15.0 14.4 15.3 1.5 1.9 1.0 1.1 12 12 12 12

-0.7 -4.6 +1.3 15.5 15.9 15.3 17.1 2.0 2.1 1.4 1.3 12 12 12 12

+2.6 -1.3 +10.3 16.2 15.9 15.6 16.5
-1.9 -3.7 +1.9

18.4 19.6 18.5 19.4 1.6 2.7 1.2 1.9 10 12 10 11

+6.5 +0.5 +5.4 20.1 21.1 20.1 21.7 1.9 2.4 2.1 1.7 10 12 10 11

+5.0 ±0.0 +8.0 22.9 23.9 23.0 25.0 2.2 2.4 2.3 2.1 10 12 10 11

+4.4 +0.4 +9.2 

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

*: Percentage relative to the control group ---

---

---

---

---

---

---

--- 

### Report 107 of 75623-AUG-13 FC-SUM - 3



### FEMALES

GESTATION

LACTATION MEAN OF MEANS Over GESTATION (Days 0-21) DIFF (%)* Over GESTATION (Days 0-21)
Days 1-4 MEAN

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

0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

20.4 21.5 20.5 22.0
+5.4 +0.5 +7.8

29.5 28.3 25.6 32.4 2.5 6.4 6.6 3.1 10 12 11 10

-4.1 -13.2 +9.8 

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

*: Percentage relative to the control group ---

--- 

### Report 108 of 75608-AUG-13 BW-SUM - 1



### BODY WEIGHTS (G) - SUMMARY

Data excluded from Summary Report

---

Not Reported

--- 

### Report 109 of 75608-AUG-13 BW-SUM - 2



### MALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

367 370 370 370 17 9 14 13 12 12 12 12 369 372 372 372 17 10 14 14 12 12 12 12 374 380 379 375 17 11 14 14 12 12 12 12 377 382 381 379 18 10 15 15 12 12 12 12 381 385 385 382 18 11 14 16 12 12 12 12 385 390 390 388 18 11 16 17 12 12 12 12 386 392 391 388 18 11 17 18 12 12 12 12 391 397 396 393 19 11 17 18 12 12 12 12 394 400 399 396 19 11 17 18 12 12 12 12 398 404 404 399 19 12 18 20 12 12 12 12 400 408 407 401 21 12 19 20 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 110 of 75608-AUG-13 BW-SUM - 3



### MALES

PRE-PAIRING

PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

403 410 410 404 22 11 18 20 12 12 12 12 404 412 411 404 22 12 19 20 12 12 12 12 407 415 414 406 22 13 19 21 12 12 12 12

407 412 414 406 24 13 21 23 12 12 12 12 409 414 417 409 23 13 22 24 12 12 12 12 408 418 420 412 23 14 23 22 12 12 12 12 412 422 423 413 23 14 22 22 12 12 12 12 414 424 426 415 22 14 23 21 12 12 12 12 416 425 427 417 23 14 22 22 12 12 12 12 417 428 428 419 23 15 22 22 12 12 12 12 420 430 431 422 24 16 24 22 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 111 of 75608-AUG-13 BW-SUM - 4



### MALES

PAIRING

AFTER PAIRING 9

10

11

12

13

1

2

3

4

5

6 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 100 mg/kg 300 mg/kg 1000 mg/kg

421 432 432 425 23 16 23 23 12 12 12 12 424 435 435 428 24 17 23 23 12 12 12 12 427 438 438 430 25 17 23 23 12 12 12 12 429 439 439 432 24 17 24 22 12 12 12 12 431 440 440 432 24 16 25 22 12 12 12 12

434 445 444 436 25 16 26 23 12 12 12 12 436 445 446 436 26 16 25 24 12 12 12 12 437 448 448 439 25 16 25 23 12 12 12 12 439 449 449 441 26 15 25 24 12 12 12 12 442 451 450 442 25 15 25 24 12 12 12 12 444 453 453 445 25 16 25 25 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 112 of 75608-AUG-13 BW-SUM - 5



### MALES

AFTER PAIRING 7

8

9

10

11

12

13

14

15

16

17 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 100 mg/kg 300 mg/kg 1000 mg/kg

446 455 454 447 26 17 26 26 12 12 12 12 447 458 457 449 26 16 26 25 12 12 12 12 449 460 459 452 25 17 26 26 12 12 12 12 450 459 459 450 26 16 27 26 12 12 12 12 450 457 461 451 27 16 28 26 12 12 12 12 451 459 462 453 27 16 29 27 12 12 12 12 449 458 463 454 28 15 28 27 12 12 12 12 451 460 466 454 28 15 28 27 12 12 12 12 453 463 468 457 28 15 29 26 12 12 12 12 455 464 470 458 28 15 28 28 12 12 12 12 456 466 472 459 28 16 28 27 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 113 of 75608-AUG-13 BW-SUM - 6



### MALES

AFTER PAIRING 18

19

20

21

22 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 100 mg/kg 300 mg/kg 1000 mg/kg

458 468 473 461 27 15 28 27 12 12 12 12 460 470 475 463 27 17 28 26 12 12 12 12 462 472 476 465 27 18 28 26 12 12 12 12 458 466 470 458 24 18 31 28 12 12 12 12 439 459 468 454 30 16 31 29 7 7 7 7 Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

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

### Report 114 of 75614-AUG-13 BW-SUM - 1



### BODY WEIGHTS (G) - SUMMARY

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 115 of 75614-AUG-13 BW-SUM - 2



### FEMALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

237 235 234 236 8 9 9 10 12 12 12 12 238 235 236 238 9 8 9 10 12 12 12 12 241 237 238 239 9 9 9 11 12 12 12 12 241 236 238 240 9 10 10 11 12 12 12 12 240 239 238 242 8 10 10 10 12 12 12 12 246 242 244 246 9 9 10 9 12 12 12 12 247 241 244 246 9 10 10 11 12 12 12 12 248 242 244 248 10 10 11 10 12 12 12 12 246 243 243 249 9 11 10 10 12 12 12 12 251 247 248 250 10 10 9 10 12 12 12 12 253 247 251 251 10 10 10 10 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 116 of 75614-AUG-13 BW-SUM - 3



### FEMALES

PRE-PAIRING

GESTATION 12

13

14

0

1

2

3

4

5

6

7 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 100 mg/kg 300 mg/kg 1000 mg/kg

250 245 249 251 11 11 11 11 12 12 12 12 248 248 248 253 10 12 10 11 12 12 12 12 252 249 250 253 10 10 10 10 12 12 12 12

255 254 253 256 11 11 9 13 10 12 10 11 259 258 257 260 10 11 9 12 10 12 10 11 264 263 262 264 11 13 8 13 10 12 10 11 266 267 266 268 11 14 9 12 10 12 10 11 268 269 269 271 11 14 11 12 10 12 10 11 272 271 274 275 12 13 10 14 10 12 10 11 275 275 277 279 12 15 11 14 10 12 10 11 278 280 279 281 13 16 11 12 10 12 10 11 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 117 of 75614-AUG-13 BW-SUM - 4



### FEMALES

GESTATION 8

9

10

11

12

13

14

15

16

17

18 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 100 mg/kg 300 mg/kg 1000 mg/kg

280 282 282 284 12 16 12 14 10 12 10 11 285 285 286 287 13 16 11 13 10 12 10 11 289 290 291 292 13 16 12 14 10 12 10 11 295 297 295 298 13 16 13 13 10 12 10 11 299 302 300 302 12 18 13 13 10 12 10 11 302 306 304 307 13 16 14 13 10 12 10 11 311 313 310 315 14 18 15 15 10 12 10 11 316 322 317 321 14 19 13 14 10 12 10 11 325 331 327 332 15 19 15 15 10 12 10 11 339 344 341 346 14 20 16 15 10 12 10 11 356 359 358 362 15 23 17 15 10 12 10 11 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 118 of 75614-AUG-13 BW-SUM - 5



### FEMALES

GESTATION

LACTATION 19

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 MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

370 374 371 377 14 24 18 17 10 12 10 11 386 388 387 393 16 26 18 19 10 12 10 11 394 398 396 401 18 28 15 18 10 12 10 11

293 297 295 296 12 18 15 16 10 12 11 10 295 300 298 300 13 19 13 15 10 12 11 10 298 304 301 305 11 19 13 13 10 12 11 10 303 309 306 308 13 18 11 14 10 12 11 10 286 289 290 296 11 16 15 14 10 12 11 10 Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHTS (G) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 119 of 75608-AUG-13 BWG-SUM - 1



### BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

--- 

### Report 120 of 75608-AUG-13 BWG-SUM - 2



### MALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

0 0 0 0 0 0 0 0 12 12 12 12 1 1 0 0 1 1 1 1 12 12 12 12 2 3 2 1 1 1 1 1 12 12 12 12 3 3 3 2 1 0 1 1 12 12 12 12 4 4 4 3 1 1 1 1 12 12 12 12 5 6 5 5 1 1 1 1 12 12 12 12 5 6 6 5 1 1 1 1 12 12 12 12 6 7 7 6 1 1 1 2 12 12 12 12 7 8 8 7 2 1 1 2 12 12 12 12 8 9 9 8 2 2 2 2 12 12 12 12 9 10 10 8 2 2 2 2 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

* *

-

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 121 of 75608-AUG-13 BWG-SUM - 3



### MALES

PRE-PAIRING

PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

10 11 11 9 2 1 2 2 12 12 12 12 10 11 11 9 2 2 2 2 12 12 12 12 11 12 12 10 2 2 2 2 12 12 12 12

0 0 0 0 0 0 0 0 12 12 12 12 1 0 1 1 1 1 1 1 12 12 12 12 0 1 1 2 1 1 2 1 12 12 12 12 1 2 2 2 1 1 1 1 12 12 12 12 2 3 3 2 1 1 1 1 12 12 12 12 2 3 3 3 2 2 1 1 12 12 12 12 2 4 3 3 1 2 2 1 12 12 12 12 3 4 4 4 1 2 2 1 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - *

- - -

- - -

- - -

- - -

- - -

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

### Report 122 of 75608-AUG-13 BWG-SUM - 4



### MALES

PAIRING

AFTER PAIRING 9

10

11

12

13

1

2

3

4

5

6 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 100 mg/kg 300 mg/kg 1000 mg/kg

3 5 4 5 1 2 2 1 12 12 12 12 4 5 5 5 2 2 2 1 12 12 12 12 5 6 6 6 1 2 2 2 12 12 12 12 5 6 6 6 2 2 2 2 12 12 12 12 6 7 6 7 2 2 2 1 12 12 12 12

0 0 0 0 0 0 0 0 12 12 12 12 0 0 0 0 1 1 1 0 12 12 12 12 1 1 1 1 1 1 1 0 12 12 12 12 1 1 1 1 1 1 1 1 12 12 12 12 2 1 1 1 1 1 1 1 12 12 12 12 2 2 2 2 1 1 1 1 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 123 of 75608-AUG-13 BWG-SUM - 5



### MALES

AFTER PAIRING 7

8

9

10

11

12

13

14

15

16

17 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 100 mg/kg 300 mg/kg 1000 mg/kg

3 2 2 3 1 1 1 1 12 12 12 12 3 3 3 3 1 1 1 1 12 12 12 12 3 3 3 4 1 1 1 1 12 12 12 12 4 3 3 3 1 1 1 1 12 12 12 12 4 3 4 4 2 1 1 1 12 12 12 12 4 3 4 4 2 1 1 1 12 12 12 12 3 3 4 4 2 1 1 1 12 12 12 12 4 3 5 4 2 1 1 1 12 12 12 12 4 4 5 5 2 1 1 1 12 12 12 12 5 4 6 5 2 1 1 1 12 12 12 12 5 5 6 5 2 1 2 1 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 124 of 75608-AUG-13 BWG-SUM - 6



### MALES

AFTER PAIRING 18

19

20

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 100 mg/kg 300 mg/kg 1000 mg/kg

6 5 6 6 2 1 2 1 12 12 12 12 6 6 7 6 2 1 2 1 12 12 12 12 6 6 7 7 2 2 2 1 12 12 12 12 5 5 6 5 2 2 2 2 12 12 12 12 Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

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

### Report 125 of 75614-AUG-13 BWG-SUM - 1



### BODY WEIGHT GAIN (%) - SUMMARY

Gestation

Lactation Full Phase Full Phase Full Phase Full Phase Full Phase

Full Phase 52 54 82 84 88

96 Female Female Female Female Female

Female Group 1

Group 1 Group 3 Group 3 Group 4

Group 4 Animal Animal Animal Animal Animal

Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Lost Its Litter

Not Reported

--- 

### Report 126 of 75614-AUG-13 BWG-SUM - 2



### FEMALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

0 0 0 0 0 0 0 0 12 12 12 12 0 0 1 1 1 1 1 1 12 12 12 12 2 1 2 1 1 2 1 2 12 12 12 12 2 0 2 2 2 1 2 2 12 12 12 12 1 2 2 2 1 1 1 1 12 12 12 12 4 3 4 4 2 1 2 2 12 12 12 12 4 2 5 4 2 2 2 2 12 12 12 12 4 3 4 5 2 1 2 2 12 12 12 12 4 3 4 5 1 2 1 2 12 12 12 12 6 5 6 6 2 2 2 2 12 12 12 12 7 5 8 6 2 2 2 2 12 12 12 12 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - *

- - -

- - -

- - -

- - *

- - -

- - -

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

### Report 127 of 75614-AUG-13 BWG-SUM - 3



### FEMALES

PRE-PAIRING

GESTATION 12

13

14

0

1

2

3

4

5

6

7 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 100 mg/kg 300 mg/kg 1000 mg/kg

5 4 6 6 3 2 3 3 12 12 12 12 5 5 6 7 2 3 2 2 12 12 12 12 6 6 7 7 2 2 3 2 12 12 12 12

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

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - *

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 128 of 75614-AUG-13 BWG-SUM - 4



### FEMALES

GESTATION 8

9

10

11

12

13

14

15

16

17

18 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 100 mg/kg 300 mg/kg 1000 mg/kg

10 11 11 11 2 3 2 1 10 12 10 11 11 12 13 12 2 3 2 2 10 12 10 11 13 14 15 14 2 3 2 2 10 12 10 11 15 17 17 16 2 3 3 2 10 12 10 11 17 19 19 18 2 4 3 3 10 12 10 11 18 20 20 20 2 3 3 2 10 12 10 11 22 23 23 23 2 4 3 2 10 12 10 11 24 27 25 26 2 6 3 3 10 12 10 11 27 30 30 30 2 5 3 3 10 12 10 11 33 35 35 35 3 5 4 4 10 12 10 11 39 41 42 42 4 6 4 4 10 12 10 11 Day

Day

Day

Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 129 of 75614-AUG-13 BWG-SUM - 5



### FEMALES

GESTATION

LACTATION 19

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 MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

45 47 47 47 5 7 5 5 10 12 10 11 51 52 53 54 5 8 4 6 10 12 10 11 54 57 57 57 6 9 4 5 10 12 10 11

0 0 0 0 0 0 0 0 10 12 11 10 1 1 1 2 1 1 2 2 10 12 11 10 2 2 2 3 1 2 2 3 10 12 11 10 4 4 4 4 2 3 2 3 10 12 11 10 -2 -3 -2 0 1 2 4 4 10 12 11 10 Day

Day

Day

Day

Day

Day

Day

Day 

### BODY WEIGHT GAIN (%) - SUMMARY

- - -

- - -

- - -

- - -

- - -

- - -

- - -

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

### Report 130 of 75608-AUG-13 BWD-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 131 of 75608-AUG-13 BWD-SUM - 2



### MALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

6 7 7 6 1 1 1 2 12 12 12 12 4 4 4 3 1 1 1 1 12 12 12 12 11 12 12 10 2 2 2 2 12 12 12 12 Day

Day

Day 

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

- - -

- - -

- - -

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

### Report 132 of 75608-AUG-13 BWD-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 133 of 75608-AUG-13 BWD-SUM - 2



### MALES

PAIRING 1- 7

7-13

1-13 MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

2 4 3 3 1 2 2 1 12 12 12 12 3 3 3 3 1 1 1 1 12 12 12 12 6 7 6 7 2 2 2 1 12 12 12 12 Day

Day

Day 

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

- - -

- - -

- - -

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

### Report 134 of 75608-AUG-13 BWD-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 135 of 75608-AUG-13 BWD-SUM - 2



### MALES

AFTER PAIRING 1- 8

8-15

15-22

1-22 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 100 mg/kg 300 mg/kg 1000 mg/kg

3 3 3 3 1 1 1 1 12 12 12 12 1 1 2 2 2 1 1 1 12 12 12 12 -1 -1 -1 -1 1 1 0 1 7 7 7 7 3 3 4 3 1 1 1 1 7 7 7 7 Day

Day

Day

Day 

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

- - -

- - -

- - -

- *

-

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

### Report 136 of 75614-AUG-13 BWD-SUM - 1



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

Data excluded from Summary Report

---

Not Reported

--- 

### Report 137 of 75614-AUG-13 BWD-SUM - 2



### FEMALES

PRE-PAIRING 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 100 mg/kg 300 mg/kg 1000 mg/kg

4 3 4 5 2 1 2 2 12 12 12 12 2 3 3 2 1 2 2 2 12 12 12 12 6 6 7 7 2 2 3 2 12 12 12 12 Day

Day

Day 

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

- - -

- - -

- - -

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

### Report 138 of 75614-AUG-13 BWD-SUM - 1



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

Gestation Full Phase Full Phase Full Phase Full Phase Full Phase 52 54 82 84 88 Female Female Female Female Female Group 1

Group 1 Group 3 Group 3 Group 4 Animal Animal Animal Animal Animal Data excluded from Summary Report

Not Pregnant Not Pregnant Mating Not Detected Not Pregnant Not Pregnant

Not Reported

--- 

### Report 139 of 75614-AUG-13 BWD-SUM - 2



### FEMALES

GESTATION 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 100 mg/kg 300 mg/kg 1000 mg/kg

9 10 10 10 2 3 2 1 10 12 10 11 12 12 11 12 2 3 2 1 10 12 10 11 27 27 28 28 4 4 2 3 10 12 10 11 54 57 57 57 6 9 4 5 10 12 10 11 Day

Day

Day

Day 

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

- - -

- - -

- - -

- - -

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

### Report 140 of 75614-AUG-13 BWD-SUM - 1



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

Lactation Full Phase 96 Female Group 4

Animal Data excluded from Summary Report

Lost Its Litter

Not Reported

--- 

### Report 141 of 75614-AUG-13 BWD-SUM - 2



### FEMALES

LACTATION 1- 4 MEAN ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

4 4 4 4 2 3 2 3 10 12 11 10 Day 

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

- - -

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

### Report 142 of 75627-JUN-13 HEM-SUM - 1



### Hematology - SUMMARY

On day 5 post partum Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW RETI RETI L RETI M RETI H RETI 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 RETICULOCYTE (REL) RETICULOCYTE (ABS) MATURITY INDEX (L-RETI) MATURITY INDEX (M-RETI) MATURITY INDEX (H-RETI) 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 STEEL DUNNETT STEEL STEEL STEEL DUNNETT STEEL STEEL STEEL STEEL STEEL STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL Statistical Testing Parameter Data excluded from Summary Report

--- Not Reported

--- 

### Report 143 of 75627-JUN-13 HEM-SUM - 2



### Hematology - SUMMARY

On the day of the scheduled necropsy Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW RETI RETI L RETI M RETI H RETI 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 RETICULOCYTE (REL) RETICULOCYTE (ABS) MATURITY INDEX (L-RETI) MATURITY INDEX (M-RETI) MATURITY INDEX (H-RETI) 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 STEEL DUNNETT STEEL STEEL STEEL DUNNETT STEEL STEEL STEEL STEEL STEEL STEEL DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT DUNNETT STEEL STEEL Statistical Testing Parameter

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

### Report 144 of 75627-JUN-13 HEM-SUM - 3

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

### Hematology - SUMMARY MALES

On the day of the scheduled necropsy

On the day of the scheduled necropsy

On the day of the scheduled 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 RETI RETI L RETI M RETI H RETI WBC

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

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

rel. 1 rel. 1 rel. 1 rel. 1 rel. 1 rel. 1 GENERAL

GENERAL RETICULOCYT E COUNT GENERAL

DIFF.WBC CO UNT (REL) 8.88 9.9 0.47 52.8 0.125 1.12 21.22 8.72 10.1 0.47 54.2 0.157 1.16 21.42 9.05 10.1 0.48 52.8 0.122 1.11 21.06 8.38 9.5 0.44 53.0 0.128 1.14 21.45

1.63 0.017 163 0.718 0.259 0.025 7.69 1.77 0.020 178 0.692 0.281 0.031 8.84 1.64 0.021 193 0.673 0.275 0.034 7.90 1.67 0.021 213 0.689 0.270 0.042 8.17

0.139 0.012 0.004 0.816 0.018 0.008 0.144 0.010 0.004 0.817 0.022 0.007 0.148 0.010 0.003 0.806 0.021 0.008 0.234 0.009 0.003 0.713 0.019 0.010 - - - - - - -
- - - - - - -
- - - - - - -

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

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

### Report 145 of 75627-JUN-13 HEM-SUM - 4

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

### Hematology - SUMMARY MALES

On the day of the scheduled necropsy

On the day of the scheduled necropsy Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 NEUT EOS BASO LYMPH MONO LUC PLATELETS

PT PTT G/l G/l G/l G/l G/l G/l G/l

rel. 1 sec DIFF.WBC CO UNT (ABS) GENERAL

COAGULATION 0.99 0.09 0.03 6.38 0.14 0.06 900 1.24 0.10 0.03 7.21 0.19 0.07 987 1.08 0.09 0.03 6.48 0.17 0.07 913 1.81 0.06 0.02 6.01 0.18 0.08 943

0.78 23.1 0.75 23.5 0.75 23.9 0.84 21.6 - - - - - - -
- - - - - - - ** - - - - - -

- -
- -
- - 

### Report 146 of 75627-JUN-13 HEM-SUM - 5

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

### Hematology - SUMMARY FEMALES

On day 5 post partum

On day 5 post partum

On 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 RETI RETI L RETI M RETI H RETI WBC

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

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

rel. 1 rel. 1 rel. 1 rel. 1 rel. 1 rel. 1 GENERAL

GENERAL RETICULOCYT E COUNT GENERAL

DIFF.WBC CO UNT (REL) 7.15 8.5 0.41 57.0 0.139 1.18 20.76 7.47 8.6 0.40 53.1 0.130 1.15 21.66 6.77 8.1 0.39 58.3 0.141 1.20 20.54 7.12 8.3 0.39 54.2 0.133 1.17 21.59

1.42 0.068 468 0.458 0.398 0.141 7.80 1.39 0.049 372 0.611 0.335 0.033 6.74 1.46 0.070 453 0.500 0.401 0.101 5.80 1.42 0.051 368 0.511 0.414 0.076 7.61

0.323 0.002 0.004 0.655 0.018 0.008 0.280 0.005 0.004 0.675 0.025 0.006 0.256 0.003 0.005 0.712 0.020 0.006 0.340 0.005 0.004 0.614 0.021 0.011 - - - * - - **

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

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

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

### Report 147 of 75627-JUN-13 HEM-SUM - 6

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

### Hematology - SUMMARY FEMALES

On day 5 post partum

On day 5 post partum Group 1 Group 2 Group 3 Group 4

Group 1 Group 2 Group 3 Group 4 NEUT EOS BASO LYMPH MONO LUC PLATELETS

PT PTT G/l G/l G/l G/l G/l G/l G/l

rel. 1 sec DIFF.WBC CO UNT (ABS) GENERAL

COAGULATION 2.50 0.02 0.03 5.06 0.12 0.06 1378 1.90 0.03 0.03 4.55 0.16 0.06 1370 1.53 0.01 0.03 4.05 0.14 0.05 1490 2.54 0.04 0.03 4.77 0.17 0.07 1285

0.96 23.2 0.90 24.1 0.89 24.4 0.88 23.2 - - - - - - -
- - - - - - -
- - - - - - -

- -
- -
- - 

### Report 148 of 75627-JUN-13 CHE-SUM - 1



### Biochemistry - SUMMARY

On day 5 post partum Reported Parameter

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

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

--- Not Reported

--- 

### Report 149 of 75627-JUN-13 CHE-SUM - 2



### Biochemistry - SUMMARY

On the day of the scheduled necropsy Reported Parameter

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

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

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 (-) 

### Report 150 of 75627-JUN-13 CHE-SUM - 3

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

### Biochemistry - SUMMARY MALES

On the day of the scheduled necropsy

On the day of the scheduled necropsy

On the day of the scheduled 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 8.08 4.89 27.5 1.09 25.66 2.18 0.87 10.04 4.54 23.8 1.54 31.95 2.27 0.80 9.58 5.65 28.1 0.41 31.24 2.22 0.96 10.32 6.41 22.5 0.71 41.86 2.44 1.59

58.9 20.4 73.7 0.0 143.8 4.18 101.0 60.1 24.3 69.9 0.0 144.6 4.21 100.3 58.8 32.7 62.0 0.0 145.0 4.43 102.1 68.6 44.1 64.0 0.0 145.4 4.60 101.7

2.79 1.77 67.39 43.81 23.58 1.80 2.83 1.64 69.94 45.27 24.67 1.82 2.91 1.65 71.39 45.97 25.42 1.76 2.86 1.75 72.25 44.63 27.62 1.61 * - - - - - -
- - - - - - - ** - * - - - -

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

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

### Report 151 of 75627-JUN-13 CHE-SUM - 4

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

### Biochemistry - SUMMARY FEMALES

On day 5 post partum

On day 5 post partum

On 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 6.42 5.31 27.8 0.87 20.77 2.05 0.54 5.48 5.17 26.6 0.46 18.65 1.77 0.45 7.37 5.09 30.1 1.60 54.70 2.17 1.05 6.78 5.09 27.8 0.77 56.82 2.12 0.81

68.4 38.6 39.6 0.0 141.2 3.89 99.6 78.4 32.5 39.3 0.0 143.0 3.96 101.6 83.4 46.3 41.4 0.0 142.6 3.79 99.8 66.2 42.0 43.1 0.0 143.4 3.85 99.9

2.89 2.14 66.22 41.57 24.65 1.73 2.74 2.07 61.45 40.62 20.83 2.06 2.91 2.33 64.76 42.22 22.54 1.79 2.83 2.58 62.40 39.88 22.52 1.75 - - - - - - -
- - - - - - -
- - - - - - -

- - - - - - *

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

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

### Report 152 of 75614-AUG-13 MAT-SUM - 1



### MATING PERFORMANCE - SUMMARY

Not Reported

--- Incomplete Pairing Periods

--- 

### Report 153 of 75614-AUG-13 MAT-SUM - 2



### MATING PERFORMANCE - SUMMARY
Number of females mated during the first pairing period

Median precoital time Mean precoital time N Mating not detected Not mated 1 2 3 4 5 7 Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

5 4 3 5 6 4 8 1 3

1 1 3 1 1 1
3 2 2 2 2.9 1.8 2.9 2.6 12 12 11 12

1 Day of the pairing

*

- - - -

-
-
- - -
- -

- - -

- - - - period

*/**/- : Steel Test, significant at 5% (*), 1% (**) or not significant (-) x 

### Report 154 of 75614-AUG-13 FER-SUM - 1



### FERTILITY - SUMMARY

Not Reported

--- 

### Report 155 of 75614-AUG-13 FER-SUM - 2



### FERTILITY - SUMMARY
Percentages of fertility figures

Percentage mating (%) Fertility index (%) Conception rate (%) Gestation index (%)

Percentage mating (%) Fertility index (%) Conception rate (%) Gestation index (%) Group 1 Group 2 Group 3 Group 4

Group 10 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

Reserve 100.0 100.0 100.0 100.0

83.3 100.0 91.7 91.7
83.3 100.0 91.7 91.7
100.0 100.0 100.0 90.9 ---

---

---

---

-

-

-

-

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 / Females pregnant) * 100 #/##/- : Fisher's Exact Test, significant at 5% (#), 1% (##) or not significant (-) 

### Report 156 of 75615-AUG-13 BRE-SUM - 1



### BREEDING DATA PER GROUP

Not Reported

--- 

### Report 157 of 75615-AUG-13 BRE-SUM - 2



### BREEDING DATA PER GROUP

LITTERS TOTAL EXCLUDED EVALUATED
DURATION OF GESTATION MEAN (+) ST.DEV. N
CORPORA LUTEA TOTAL MEAN (+) ST.DEV. N
IMPLANTATIONS TOTAL MEAN (+) ST.DEV. N
POST IMPLANTATION LOSS % OF IMPLANTATIONS LITTERS AFFECTED (#) TOTAL (#) MEAN (+) ST.DEV. N
DEAD PUPS AT FIRST LITTER CHECK LITTERS AFFECTED (#) TOTAL MEAN (+) ST.DEV. N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

10 12 11 11
10 12 11 11

21.4 21.7 21.5 21.4 0.5 0.5 0.5 0.7 10 12 10 11

177 202 168 184 17.7 16.8 15.3 16.7 4.1 3.6 3.5 2.5 10 12 11 11

147 175 154 165 14.7 14.6 14.0 15.0 1.6 2.2 2.7 2.9 10 12 11 11

9.5 9.1 12.3 11.5 5 8 9 7 14 16 19 19 1.4 1.3 1.7 1.7 1.9 1.2 1.6 2.2 10 12 11 11

1 0 0 3 0 0.0 0.0 0.3 0.0 0.0 0.0 0.9 0.0 10 12 11 11 - - -

- - -

- - -

- - -

- - -

- - -

- - -

- - - - - - -

- - -

#/##/- : Fisher's Exact Test, significant at 5% (#), 1% (##) or not significant (-) +/++/- : Steel Test, significant at 5% (+), 1% (++) or not significant (-) Kuckuck 

### Report 158 of 75615-AUG-13 BRE-SUM - 3



### BREEDING DATA PER GROUP

LIVING PUPS AT FIRST LITTER CHECK % OF MALES / FEMALES (#) TOTAL MEAN (+) ST.DEV. N POSTNATAL LOSS DAYS 0 - 4 P.P. % OF LIVING PUPS LITTERS AFFECTED (#) TOTAL (#) MEAN (+) ST.DEV. N

LIVING PUPS ON DAY 4 P.P. TOTAL MEAN (+) ST.DEV. N BIRTH INDEX (#) VIABILITY INDEX (#) Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

133 159 135 146 13.3 13.3 12.3 13.3 1.7 2.5 2.8 4.6 10 12 11 11

0.0 4.4 0.0 0.0 0 4 0 0 0 7 0 0 0.0 0.6 0.0 0.0 0.0 1.0 0.0 0.0 10 12 11 11

133 152 135 146 13.3 12.7 12.3 13.3 1.7 2.9 2.8 4.6 10 12 11 11
90.5 90.9 87.7 88.5
100.0 95.6 100.0 100.0 - - -

- - -

- - - #

- -

- - -

- - -

- - - #

- - 51 / 49 47 / 53 47 / 53 53 / 47

Birth index = (pups born alive / number of implantations) * 100 Viability index = (pups alive before culling on day 4 p.p. / pups born alive) * 100 #/##/- : Fisher's Exact Test, significant at 5% (#), 1% (##) or not significant (-) +/++/- : Steel Test, significant at 5% (+), 1% (++) or not significant (-) 

### Report 159 of 75602-DEC-13 OW-SUM - 1



### ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs All organs reported Not Reported

--- 

### Report 160 of 75602-DEC-13 OW-SUM - 2

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

BRAIN

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 100 mg/kg 300 mg/kg 1000 mg/kg 442.0 452.2 454.2 442.4 27.8 16.3 27.6 25.5 387.9 426.4 412.6 406.5 482.3 476.2 492.5 495.7 12 12 12 12
2.15 2.23 2.11 2.19 0.10 0.07 0.05 0.10 2.00 2.15 2.07 2.06 2.26 2.30 2.19 2.30 5 5 5 5
1.09 1.19 1.10 1.09 0.02 0.12 0.06 0.04 1.06 1.03 1.02 1.05 1.11 1.36 1.17 1.15 5 5 5 5
0.027 0.027 0.029 0.027 0.004 0.006 0.008 0.005 0.024 0.015 0.023 0.021 0.034 0.033 0.043 0.034 5 10 5 5
11.33 11.57 11.30 13.56 0.63 0.86 0.47 0.63 10.63 10.85 10.82 12.67 12.08 12.94 11.86 14.22 5 5 5 5
0.397 0.423 0.352 0.303 0.040 0.067 0.068 0.052 0.342 0.353 0.254 0.234 0.440 0.501 0.413 0.358 5 5 5 5
2.40 2.64 2.36 2.63 0.12 0.20 0.11 0.08 2.21 2.36 2.25 2.51 2.49 2.81 2.53 2.70 5 5 5 5 

### Males after pairing ORGAN WEIGHTS (GRAM) - SUMMARY
MALES

- - -

- - -

- - -

- - -

- - **

- - -

*

- * 

### Report 161 of 75602-DEC-13 OW-SUM - 3

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

SPLEEN

TESTES

PROSTATE

EPIDIDYMID

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

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg 0.079 0.075 0.072 0.085 0.015 0.007 0.013 0.003 0.066 0.068 0.058 0.081 0.103 0.086 0.093 0.089 5 5 5 5
0.83 0.88 0.78 0.77 0.07 0.10 0.09 0.08 0.71 0.77 0.68 0.69 0.88 0.98 0.88 0.87 5 5 5 5
4.40 4.38 4.28 4.27 0.39 0.34 0.29 0.27 3.70 3.67 3.62 3.87 4.93 4.88 4.73 4.82 12 12 12 12
0.88 1.03 0.75 1.02 0.10 0.37 0.13 0.18 0.80 0.61 0.63 0.86 1.05 1.56 0.94 1.27 5 5 5 5
1.602 1.593 1.595 1.594 0.129 0.147 0.113 0.121 1.442 1.278 1.407 1.409 1.863 1.799 1.838 1.801 12 12 12 12
1.66 1.55 1.61 1.56 0.30 0.28 0.16 0.39 1.29 1.24 1.42 1.14 2.01 1.95 1.85 2.09 5 5 5 5 

### Males after pairing ORGAN WEIGHTS (GRAM) - SUMMARY
MALES

- - -

- - -

- - -

- - -

- - -

- - - 

### Report 162 of 75602-DEC-13 OW-SUM - 4

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

BRAIN

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 100 mg/kg 300 mg/kg 1000 mg/kg 442.0 452.2 454.2 442.4 27.8 16.3 27.6 25.5 387.9 426.4 412.6 406.5 482.3 476.2 492.5 495.7 12 12 12 12
0.47 0.50 0.48 0.50 0.02 0.03 0.03 0.04 0.45 0.46 0.44 0.45 0.50 0.53 0.51 0.53 5 5 5 5
0.24 0.26 0.24 0.25 0.01 0.02 0.02 0.01 0.23 0.23 0.22 0.24 0.24 0.29 0.27 0.27 5 5 5 5
0.006 0.006 0.006 0.006 0.001 0.001 0.002 0.001 0.005 0.003 0.005 0.005 0.008 0.008 0.010 0.008 5 10 5 5
2.48 2.57 2.54 3.12 0.12 0.11 0.08 0.14 2.37 2.48 2.43 2.95 2.67 2.76 2.64 3.28 5 5 5 5
0.087 0.094 0.079 0.070 0.010 0.017 0.016 0.010 0.075 0.075 0.057 0.058 0.097 0.115 0.094 0.080 5 5 5 5
0.52 0.59 0.53 0.60 0.03 0.04 0.04 0.02 0.48 0.54 0.48 0.58 0.55 0.64 0.57 0.62 5 5 5 5 

### Males after pairing ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY
MALES

- - -

- - -

*

- -

- - -

- - **

- - -

*

- ** 

### Report 163 of 75602-DEC-13 OW-SUM - 5

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

SPLEEN

TESTES

PROSTATE

EPIDIDYMID

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

MEAN ST.DEV. MINIMUM MAXIMUM N

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg 0.018 0.017 0.016 0.019 0.003 0.002 0.003 0.002 0.015 0.014 0.013 0.018 0.023 0.020 0.019 0.022 5 5 5 5
0.18 0.20 0.18 0.18 0.02 0.03 0.02 0.02 0.16 0.16 0.15 0.16 0.20 0.23 0.20 0.20 5 5 5 5
1.00 0.97 0.95 0.97 0.13 0.08 0.09 0.09 0.81 0.82 0.80 0.85 1.22 1.12 1.07 1.11 12 12 12 12
0.19 0.23 0.17 0.23 0.02 0.07 0.03 0.04 0.17 0.14 0.14 0.19 0.23 0.33 0.22 0.28 5 5 5 5
0.364 0.353 0.352 0.362 0.040 0.033 0.031 0.036 0.325 0.286 0.293 0.307 0.460 0.395 0.413 0.429 12 12 12 12
0.36 0.34 0.37 0.36 0.06 0.07 0.05 0.09 0.28 0.26 0.30 0.26 0.44 0.45 0.43 0.47 5 5 5 5 

### Males after pairing ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY
MALES

- - -

- - -

- - -

- - -

- - -

- - - 

### Report 164 of 75602-DEC-13 OW-SUM - 6

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

HEART

THYROIDS

LIVER

THYMUS

KIDNEYS

ADRENALS 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 100 mg/kg 300 mg/kg 1000 mg/kg 2.15 2.23 2.11 2.19 0.10 0.07 0.05 0.10 2.00 2.15 2.07 2.06 2.26 2.30 2.19 2.30 5 5 5 5
50.64 53.43 52.00 49.75 2.41 4.60 2.64 3.60 46.90 46.82 47.89 46.93 53.50 59.13 54.81 55.83 5 5 5 5
1.235 1.226 1.358 1.208 0.159 0.242 0.407 0.185 1.096 0.837 1.050 1.019 1.504 1.500 2.067 1.478 5 5 5 5
527.70 519.20 535.66 620.04 19.71 38.07 32.30 47.78 493.18 471.74 495.89 555.70 542.47 562.61 570.19 690.29 5 5 5 5
18.532 18.944 16.638 13.843 2.226 2.791 3.046 2.304 15.545 16.182 12.271 10.833 21.550 22.773 19.761 16.574 5 5 5 5
111.97 118.47 111.89 119.97 9.74 8.49 5.86 5.86 100.45 107.27 106.39 116.20 123.00 129.30 121.63 130.10 5 5 5 5
3.700 3.342 3.401 3.866 0.674 0.255 0.640 0.233 2.920 3.136 2.802 3.553 4.682 3.739 4.450 4.120 5 5 5 5 

### Males after pairing ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY
MALES

- - -

- - -

- - -

- - **

- - *

- - -

- - - 

### Report 165 of 75602-DEC-13 OW-SUM - 7

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

TESTES

PROSTATE

EPIDIDYMID

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

MEAN ST.DEV. MINIMUM MAXIMUM N Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg 38.94 39.45 37.12 35.35 4.24 3.94 4.11 3.71 32.27 35.81 31.92 30.70 43.00 44.55 40.87 38.43 5 5 5 5
189.07 204.61 200.57 191.71 14.49 7.79 7.00 11.28 168.18 196.09 191.78 179.57 204.50 212.17 207.73 207.87 5 5 5 5
41.06 46.30 35.65 46.56 5.19 16.49 5.44 8.00 37.90 26.52 29.58 37.72 50.24 67.83 42.92 58.80 5 5 5 5
72.196 74.218 71.696 70.984 3.265 0.764 4.195 3.356 68.584 73.435 67.321 67.500 75.890 75.364 77.295 76.389 5 5 5 5
77.08 69.44 76.25 71.94 12.50 12.25 5.93 19.98 58.64 57.67 67.94 49.57 88.94 88.64 84.47 96.76 5 5 5 5 

### Males after pairing ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY
MALES

- - -

- - -

- - -

- - -

- - - 

### Report 166 of 75602-DEC-13 OW-SUM - 1



### ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs All organs reported Not Reported

--- 

### Report 167 of 75602-DEC-13 OW-SUM - 2

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

BRAIN

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 100 mg/kg 300 mg/kg 1000 mg/kg 279.6 280.8 278.1 283.3 14.4 15.9 15.1 12.0 261.9 255.2 264.6 268.1 308.3 308.8 307.6 304.1 10 12 11 11
2.02 1.98 1.95 1.95 0.06 0.09 0.06 0.09 1.94 1.87 1.85 1.87 2.10 2.10 1.98 2.07 5 5 5 5
0.90 0.97 0.98 0.99 0.10 0.06 0.12 0.07 0.78 0.92 0.78 0.89 1.01 1.06 1.09 1.07 5 5 5 5
0.021 0.026 0.026 0.026 0.003 0.007 0.005 0.003 0.018 0.020 0.018 0.023 0.026 0.039 0.032 0.032 5 5 5 5
9.16 9.27 9.68 10.71 0.62 1.60 1.29 0.76 8.79 6.77 8.80 9.73 10.25 11.01 11.90 11.65 5 5 5 5
0.246 0.298 0.220 0.247 0.038 0.084 0.094 0.039 0.207 0.201 0.148 0.199 0.301 0.408 0.382 0.305 5 5 5 5
1.75 1.83 1.75 1.78 0.11 0.21 0.20 0.06 1.61 1.55 1.59 1.70 1.89 2.12 2.08 1.84 5 5 5 5 

### Females giving birth ORGAN WEIGHTS (GRAM) - SUMMARY
FEMALES

- - -

- - -

- - -

- - -

- - -

- - -

- - - 

### Report 168 of 75602-DEC-13 OW-SUM - 3

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

SPLEEN

OVARIES

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 Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg 0.085 0.102 0.090 0.096 0.016 0.021 0.017 0.013 0.068 0.081 0.073 0.085 0.104 0.131 0.113 0.116 5 5 5 5
0.73 0.66 0.86 0.86 0.04 0.08 0.11 0.11 0.69 0.54 0.70 0.77 0.80 0.74 0.99 0.99 5 5 5 5
0.164 0.162 0.162 0.159 0.019 0.034 0.020 0.041 0.132 0.114 0.127 0.115 0.181 0.188 0.178 0.214 5 5 5 5
0.91 0.99 0.99 1.11 0.09 0.16 0.15 0.23 0.81 0.83 0.81 0.83 1.02 1.23 1.17 1.35 5 5 5 5 

### Females giving birth ORGAN WEIGHTS (GRAM) - SUMMARY
FEMALES

- - -

- - -

- - -

- - - 

### Report 169 of 75602-DEC-13 OW-SUM - 4

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

BRAIN

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 100 mg/kg 300 mg/kg 1000 mg/kg 279.6 280.8 278.1 283.3 14.4 15.9 15.1 12.0 261.9 255.2 264.6 268.1 308.3 308.8 307.6 304.1 10 12 11 11
0.74 0.70 0.70 0.70 0.04 0.03 0.05 0.05 0.69 0.67 0.61 0.61 0.79 0.74 0.74 0.75 5 5 5 5
0.33 0.34 0.35 0.35 0.04 0.01 0.03 0.03 0.28 0.33 0.29 0.32 0.38 0.36 0.38 0.39 5 5 5 5
0.008 0.009 0.009 0.009 0.002 0.002 0.002 0.002 0.006 0.007 0.006 0.008 0.010 0.013 0.012 0.012 5 5 5 5
3.34 3.29 3.43 3.83 0.13 0.56 0.30 0.25 3.24 2.44 3.17 3.55 3.55 3.81 3.93 4.16 5 5 5 5
0.090 0.106 0.079 0.088 0.016 0.029 0.034 0.015 0.076 0.067 0.049 0.073 0.113 0.141 0.137 0.108 5 5 5 5
0.64 0.65 0.62 0.64 0.05 0.08 0.04 0.03 0.57 0.56 0.57 0.59 0.68 0.73 0.69 0.68 5 5 5 5 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY
FEMALES

- - -

- - -

- - -

- - -

- - -

- - -

- - - 

### Report 170 of 75602-DEC-13 OW-SUM - 5

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

SPLEEN

OVARIES

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 Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg 0.031 0.037 0.032 0.034 0.006 0.009 0.005 0.005 0.024 0.029 0.025 0.030 0.039 0.047 0.037 0.043 5 5 5 5
0.27 0.23 0.30 0.31 0.02 0.03 0.04 0.04 0.25 0.19 0.26 0.28 0.30 0.26 0.36 0.37 5 5 5 5
0.060 0.057 0.058 0.057 0.007 0.010 0.005 0.017 0.048 0.043 0.048 0.041 0.068 0.065 0.061 0.080 5 5 5 5
0.33 0.35 0.35 0.39 0.02 0.05 0.07 0.07 0.30 0.30 0.28 0.30 0.35 0.43 0.43 0.48 5 5 5 5 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%) - SUMMARY
FEMALES

- - -

- - -

- - -

- - - 

### Report 171 of 75602-DEC-13 OW-SUM - 6

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

HEART

THYROIDS

LIVER

THYMUS

KIDNEYS

ADRENALS 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 100 mg/kg 300 mg/kg 1000 mg/kg 2.02 1.98 1.95 1.95 0.06 0.09 0.06 0.09 1.94 1.87 1.85 1.87 2.10 2.10 1.98 2.07 5 5 5 5
44.43 49.07 50.23 50.52 3.64 1.73 6.91 2.68 40.21 46.46 39.59 46.11 48.10 50.75 57.30 52.94 5 5 5 5
1.040 1.317 1.336 1.346 0.168 0.332 0.275 0.206 0.874 1.010 0.909 1.230 1.294 1.857 1.624 1.711 5 5 5 5
453.40 469.13 498.05 550.85 30.51 85.81 82.90 61.61 418.57 341.92 446.70 470.05 497.57 547.76 643.24 622.99 5 5 5 5
12.130 15.110 11.235 12.657 1.658 4.309 4.637 2.019 10.299 9.571 8.000 9.614 14.333 20.299 19.293 15.099 5 5 5 5
86.51 92.50 90.03 91.26 3.94 10.65 13.20 5.51 82.99 78.28 80.30 82.13 91.75 105.47 112.43 96.26 5 5 5 5
4.170 5.196 4.645 4.945 0.652 1.264 0.988 0.780 3.505 4.091 3.687 4.208 4.952 7.005 6.108 6.010 5 5 5 5 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY
FEMALES

- - -

- - -

- - -

- - -

- - -

- - -

- - - 

### Report 172 of 75602-DEC-13 OW-SUM - 7

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

OVARIES

UTERUS 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 100 mg/kg 300 mg/kg 1000 mg/kg 36.21 33.31 43.99 44.46 1.83 3.72 5.48 7.10 34.47 27.27 35.53 37.20 38.14 36.82 50.25 52.94 5 5 5 5
8.101 8.157 8.323 8.107 0.922 1.671 1.171 1.969 6.567 5.876 6.447 6.150 8.969 9.733 9.622 11.088 5 5 5 5
44.97 50.12 50.94 57.38 5.20 7.09 7.20 13.88 38.57 41.92 40.91 40.10 50.52 61.19 59.39 72.19 5 5 5 5 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%) - SUMMARY
FEMALES

- - *

- - -

- - - 

### Report 173 of 756MAC-SUM - 1 14-AUG-13



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

Not Reported

--- 

### Report 174 of 756MAC-SUM - 2 14-AUG-13

KIDNEYS

THYMUS

AXILLARY L.NODES PELVIC DILATION

ORGAN MISSING

ORGAN MISSING 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg Group 1 Group 2 Group 3 Group 4

0 1 1 0

1 0 0 0

1 0 0 0 ANIMALS COMPLETED ANIMALS EXAMINED 12 12 12 12 12 12 12 12 ANIMALS WITHOUT FINDINGS 11 11 11 12 

### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES MALES

ANIMALS AFFECTED

-

-

- 

### Report 175 of 756MAC-SUM - 1 14-AUG-13



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

Not Reported

--- 

### Report 176 of 756MAC-SUM - 2 14-AUG-13

STOMACH

LIVER

OVARIES DISCOLORATION

DIAPHRAGMATIC HERNIA

CYST(S) 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg Group 1 Group 2 Group 3 Group 4

0 0 0 1

0 0 1 0

0 0 0 1 ANIMALS COMPLETED ANIMALS EXAMINED 12 12 12 12 12 12 12 12 ANIMALS WITHOUT FINDINGS 12 12 11 11 

### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES FEMALES

ANIMALS AFFECTED

-

-

- 

### Report 177 of 756

# Data of F1 Pups Report 178 of 756

### Page 1


# 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.
1 (0) 133/0 No abnormal findings 2 (100) 159/0 Wound on the nose No milk in the stomach 67 67 1,6,7,8 7,8 3 (300) 135/3 No abnormal findings 4 (1000) 146/0 No abnormal findings Report 179 of 756

### Page 1


# Clinical Signs or Observations of Pups

Group (mg/kg) Type of abnormal finding Litter No. Pup No. 1 (0) No abnormal findings 2 (100) Wound on the nose on day 2-4 post partum 67 6 3 (300) No abnormal findings 4 (1000) No abnormal findings Report 180 of 75614-AUG-13 PNL-SUM - 1



### DATES OF POSTNATAL AND BREEDING LOSSES OF PUPS

Not Reported

--- 

### Report 181 of 75614-AUG-13 PNL-SUM - 2



### DATES OF POSTNATAL AND BREEDING LOSSES OF PUPS

2 M F U
4 M F U

2 M F U
4 M F U Group 1 Group 2 Group 3 Group 4

Group 10 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg

Reserve 1 4

1 1 Ascertained on

Ascertained on - - -

- - -

----

- - -

- - -

----

-

-

-

-

-

- day post partum

day post partum 

### Report 182 of 75615-AUG-13 BWPU-SUM - 1

Excl 

### Mean Body Weights of Pups per Group On a Litter Basis (G)

Data excluded from Summary Report

---

Not Reported

--- 

### Report 183 of 75615-AUG-13 BWPU-SUM - 2



### Mean Body Weights of Pups per Group On a Litter Basis (G)

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 0

1 M

F

M+F

M

F

M+F MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N 6.1 5.8 6.4

0.0 0.0 0.0 1 1 1 6.0 5.7 6.1 0.0 0.0 0.0 1 1 1 6.0 5.8 6.3 0.0 0.0 0.0 1 1 1 6.5 6.5 6.7 6.3 0.4 0.5 0.6 0.6 10 12 11 10 6.2 6.0 6.3 6.0 0.5 0.7 0.5 0.5 10 12 11 10 6.3 6.3 6.5 6.2 0.4 0.5 0.6 0.5 10 12 11 10 

### LACTATION Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg DAY SEX

- - -

- - -

- - -



### Report 184 of 75615-AUG-13 BWPU-SUM - 3



### Mean Body Weights of Pups per Group On a Litter Basis (G)

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 4 M

F

M+F MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N 9.5 9.6 9.6 9.0

0.7 1.0 1.3 1.1 10 12 11 10 8.9 8.9 9.2 8.6 0.7 1.3 1.2 0.9 10 12 11 10 9.2 9.4 9.4 8.8 0.7 0.8 1.3 1.0 10 12 11 10 

### LACTATION Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg DAY SEX

- - -

- - -

- - -



### Report 185 of 75615-AUG-13 BWPUD-SUM - 1

Excl 

### Mean Differences in Body Weights of Pups per Group On a Litter Basis (%)

Data excluded from Summary Report

---

Not Reported

--- 

### Report 186 of 75615-AUG-13 BWPUD-SUM - 2



### Mean Differences in Body Weights of Pups per Group On a Litter Basis (%)

*/**/- : DUNNETT-Test based on pooled variance sig. at 5% (*), 1% (**) or not sig. (-) 1- 4 M

F

M+F MEAN ST.DEV. N MEAN ST.DEV. N MEAN ST.DEV. N 45.9 48.2 44.0 42.6

4.6 7.2 8.2 6.3 10 12 11 10 45.2 44.7 45.4 42.8 4.2 6.5 8.6 5.8 10 12 11 10 45.5 47.2 44.6 42.7 3.7 5.5 7.8 5.8 10 12 11 10 

### LACTATION Group 1 Group 2 Group 3 Group 4 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg DAY SEX

- - -

- - -

- - -



### Report 187 of 756MAC-SUM - 1 15-AUG-13



### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES

Not Reported

--- 

### Report 188 of 756MAC-SUM - 2 15-AUG-13

SKIN SORE(S) THICKENED HEMORRHAGIC 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg Group 1 Group 2 Group 3 Group 4

0 1 0 0 0 0 0 1 0 0 0 1 ANIMALS COMPLETED ANIMALS EXAMINED 68 73 67 68 68 73 67 68 ANIMALS WITHOUT FINDINGS 68 72 67 66 

### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES MALES

ANIMALS AFFECTED

*/**/- : Fisher's Exact Test significant at 5% (*), 1% (**) or not significant (-) - - -

- - -

- - - -

-

- 

### Report 189 of 756MAC-SUM - 3 15-AUG-13

GENERAL OBSERVATIONS

SKIN REDUCED IN SIZE

SORE(S) 0 mg/kg 100 mg/kg 300 mg/kg 1000 mg/kg Group 1 Group 2 Group 3 Group 4

0 1 0 0

0 1 0 0 ANIMALS COMPLETED ANIMALS EXAMINED 65 79 71 60 65 79 71 60 ANIMALS WITHOUT FINDINGS 65 78 71 60 

### MACROSCOPICAL FINDINGS - SUMMARY ALL NECROPSIES FEMALES

ANIMALS AFFECTED

*/**/- : Fisher's Exact Test significant at 5% (*), 1% (**) or not significant (-) - - -

- - - -

- 

### Report 190 of 756

# 9 INDIVIDUAL TABLES Report 191 of 756

# Data of P Generation Report 192 of 756MORT-IND - 1 14-AUG-13



### MORTALITY DATA ALL NECROPSIES

--- Animal(s) without death date / death status

Not Reported

--- 

### Report 193 of 75627-JUN-13 HEM-IND - 1



### Hematology

On day 5 post partum Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW RETI RETI L RETI M RETI H RETI 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 RETICULOCYTE (REL) RETICULOCYTE (ABS) MATURITY INDEX (L-RETI) MATURITY INDEX (M-RETI) MATURITY INDEX (H-RETI) 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) a b coagulated sample not enough sample Comments

Data excluded from Summary Report

---
Not Reported

--- 

### Report 307 of 75627-JUN-13 HEM-IND - 2



### Hematology

On the day of the scheduled necropsy Reported Parameter

RBC HB HCT MCV RDW MCH MCHC HDW RETI RETI L RETI M RETI H RETI 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 RETICULOCYTE (REL) RETICULOCYTE (ABS) MATURITY INDEX (L-RETI) MATURITY INDEX (M-RETI) MATURITY INDEX (H-RETI) 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) 

### Report 308 of 75627-JUN-13 HEM-IND - 4



### 310 of 75627-JUN-13 HEM-IND - 6



### 312 of 756a: See explanation on section cover page27-JUN-13 HEM-IND - 8

a: See explanation on section cover page 

### 314 of 756b: See explanation on section cover page27-JUN-13 HEM-IND - 10 

### Report 316 of 75627-JUN-13 HEM-IND - 12 

### eport 318 of 75627-JUN-13 HEM-IND - 14 

### eport 320 of 75627-JUN-13 HEM-IND - 16 

### Report 322 of 75627-JUN-13 HEM-IND - 18 

### port 324 of 75627-JUN-13 CHE-IND - 1



### Biochemistry

On 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 Comments

---
Data excluded from Summary Report

---
Not Reported

--- 

### Report 325 of 75627-JUN-13 CHE-IND - 2



### Biochemistry

On the day of the scheduled 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 

### Report 326 of 75613 4 

### 6-13 - 5 

### 613 - 6 

### 6-13 - 7 

### 5613 8 

### 614-AUG-13 REP-IND - 1



### REPRODUCTION PROCESSES

Incomplete Pairing Period Not Reported

---

--- Comments

--- 

### Report 335 of 756PL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observedPL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observedPL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed

<MM>: Mating not detectedPL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed15-AUG-13 BRE-IND - 1



### BREEDING DATA PER LITTER

Not Reported

--- Comments

--- 

### Report 340 of 75615-AUG-13 BRE-IND - 2



### BREEDING DATA PER LITTER

Group 1

LITTER DURATION CORPORA IMPLANTATION OF LUTEA SITES GESTATION L R L R

TOTAL 87 90 68 79 N 10 10 10 10 10 MEAN 21.4 8.7 9.0 6.8 7.9 ST.DEV. 0.5 1.6 3.0 1.5 2.4 

### Report 341 of 75615-AUG-13 BRE-IND - 3



### BREEDING DATA PER LITTER

Group 1

LITTER FIRST LITTER CHECK P. NATAL LOSS LIVING PUPS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0-4 BEFORE DAY 4 ON DAY 4 P.P M F U M F U M+F M F U M F U M F M+F

TOTAL 0 0 0 68 65 0 133 0 0 0 68 65 0 68 65 133 N 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 MEAN 0.0 0.0 0.0 6.8 6.5 0.0 13.3 0.0 0.0 0.0 6.8 6.5 0.0 6.8 6.5 13.3 ST.DEV. 0.0 0.0 0.0 2.0 1.7 0.0 1.7 0.0 0.0 0.0 2.0 1.7 0.0 2.0 1.7 1.7 

### Report 342 of 75615-AUG-13 BRE-IND - 4



### BREEDING DATA PER LITTER

Group 2

LITTER DURATION CORPORA IMPLANTATION OF LUTEA SITES GESTATION L R L R

TOTAL 106 96 92 83 N 12 12 12 12 12 MEAN 21.7 8.8 8.0 7.7 6.9 ST.DEV. 0.5 1.7 2.7 1.4 1.7 

### Report 343 of 75615-AUG-13 BRE-IND - 5



### BREEDING DATA PER LITTER

Group 2

LITTER FIRST LITTER CHECK P. NATAL LOSS LIVING PUPS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0-4 BEFORE DAY 4 ON DAY 4 P.P M F U M F U M+F M F U M F U M F M+F

TOTAL 0 0 0 75 84 0 159 2 5 0 73 79 0 73 79 152 N 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 MEAN 0.0 0.0 0.0 6.3 7.0 0.0 13.3 0.2 0.4 0.0 6.1 6.6 0.0 6.1 6.6 12.7 ST.DEV. 0.0 0.0 0.0 2.0 2.0 0.0 2.5 0.4 0.8 0.0 1.9 2.4 0.0 1.9 2.4 2.9 

### Report 344 of 75615-AUG-13 BRE-IND - 6



### BREEDING DATA PER LITTER

Group 3

LITTER DURATION CORPORA IMPLANTATION OF LUTEA SITES GESTATION L R L R

TOTAL 86 82 82 72 N 10 11 10 11 11 MEAN 21.5 7.8 8.2 7.5 6.5 ST.DEV. 0.5 2.3 2.3 1.7 2.7 

### Report 345 of 75615-AUG-13 BRE-IND - 7



### BREEDING DATA PER LITTER

Group 3

LITTER FIRST LITTER CHECK P. NATAL LOSS LIVING PUPS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0-4 BEFORE DAY 4 ON DAY 4 P.P M F U M F U M+F M F U M F U M F M+F

TOTAL 3 0 0 64 71 0 135 0 0 0 64 71 0 64 71 135 N 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 MEAN 0.3 0.0 0.0 5.8 6.5 0.0 12.3 0.0 0.0 0.0 5.8 6.5 0.0 5.8 6.5 12.3 ST.DEV. 0.9 0.0 0.0 2.0 3.1 0.0 2.8 0.0 0.0 0.0 2.0 3.1 0.0 2.0 3.1 2.8 

### Report 346 of 75615-AUG-13 BRE-IND - 8



### BREEDING DATA PER LITTER

Group 4

LITTER DURATION CORPORA IMPLANTATION OF LUTEA SITES GESTATION L R L R

TOTAL 90 94 84 81 N 11 11 11 11 11 MEAN 21.4 8.2 8.5 7.6 7.4 ST.DEV. 0.7 1.7 2.1 1.5 2.4 

### Report 347 of 75615-AUG-13 BRE-IND - 9



### BREEDING DATA PER LITTER

Group 4

LITTER FIRST LITTER CHECK P. NATAL LOSS LIVING PUPS LIVING PUPS DEAD PUPS LIVING PUPS DAYS 0-4 BEFORE DAY 4 ON DAY 4 P.P M F U M F U M+F M F U M F U M F M+F

TOTAL 0 0 0 77 69 0 146 0 0 0 77 69 0 77 69 146 N 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 MEAN 0.0 0.0 0.0 7.0 6.3 0.0 13.3 0.0 0.0 0.0 7.0 6.3 0.0 7.0 6.3 13.3 ST.DEV. 0.0 0.0 0.0 2.6 2.5 0.0 4.6 0.0 0.0 0.0 2.6 2.5 0.0 2.6 2.5 4.6 

### Report 348 of 75615-AUG-13 DNL-IND - 1



### FEMALES NOT GIVING BIRTH

Not Reported

--- Comments

--- 

### Report 349 of 75615-AUG-13 DNL-IND - 2



### FEMALES NOT GIVING BIRTH
Group 1

LITTER CORPORA IMPLANTATION LUTEA SITES L R L R

TOTAL 0 0 0 0 N 0 0 2 2 MEAN 0.0 0.0 STD.DEV. - - - - 

### Report 350 of 75615-AUG-13 DNL-IND - 3



### FEMALES NOT GIVING BIRTH
Group 3

LITTER CORPORA IMPLANTATION LUTEA SITES L R L R

TOTAL 0 0 0 0 N 0 0 1 1 MEAN 0.0 0.0 STD.DEV. - - - - 

### Report 351 of 75615-AUG-13 DNL-IND - 4



### FEMALES NOT GIVING BIRTH
Group 4

LITTER CORPORA IMPLANTATION LUTEA SITES L R L R

TOTAL 0 0 0 0 N 0 0 1 1 MEAN 0.0 0.0 STD.DEV. - - - - 

### Report 352 of 75602-DEC-13 OW-IND - 1

Comments

Exclusions 

### ORGAN WEIGHTS (GRAM)

---

---

Selection of Organs All organs reported

--- Animals without scheduled necropsy Not Reported

--- 

### Report 353 of 75602-DEC-13 OW-IND - 1

Comments

Exclusions 

### ORGAN WEIGHTS (GRAM)

---

---

Selection of Organs All organs reported

--- Animals without scheduled necropsy Not Reported

--- 

### Report 366 of 75602-DEC-13 OW-IND - 2

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN WEIGHTS (GRAM)

Group 1 (0 mg/kg) FEMALES Report 367 of 75602-DEC-13 OW-IND - 3

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN WEIGHTS (GRAM)

Group 2 (100 mg/kg) FEMALES Report 368 of 75602-DEC-13 OW-IND - 4

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN WEIGHTS (GRAM)

Group 3 (300 mg/kg) FEMALES Report 369 of 75602-DEC-13 OW-IND - 5

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN WEIGHTS (GRAM)

Group 4 (1000 mg/kg) FEMALES Report 370 of 75602-DEC-13 OW-IND - 6

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%)

Group 1 (0 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 371 of 75602-DEC-13 OW-IND - 7

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%)

Group 2 (100 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 372 of 75602-DEC-13 OW-IND - 8

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%)

Group 3 (300 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 373 of 75602-DEC-13 OW-IND - 9

Animal

Animal BODY W. BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BODY WEIGHT RATIOS (%)

Group 4 (1000 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 374 of 75602-DEC-13 OW-IND - 10

Animal

Animal BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%)

Group 1 (0 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 375 of 75602-DEC-13 OW-IND - 11

Animal

Animal BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%)

Group 2 (100 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 376 of 75602-DEC-13 OW-IND - 12

Animal

Animal BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%)

Group 3 (300 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 377 of 75602-DEC-13 OW-IND - 13

Animal

Animal BRAIN HEART THYROIDS LIVER THYMUS KIDNEYS

ADRENALS SPLEEN OVARIES UTERUS 

### Females giving birth ORGAN/BRAIN WEIGHT RATIOS (%)

Group 4 (1000 mg/kg) FEMALES

(GRAM) (%) (%) (%) (%) (%)

(%) (%) (%) (%) 

### Report 378 of 756MAC-IND - 1 14-AUG-13



### MACROSCOPICAL FINDINGS ALL NECROPSIES

Animals without necropsy

--- Animals not recorded

--- Animals not completed

--- Animals with not translated finding

---

Not Reported

--- 

### Report 379 of 756MAC-IND - 2 14-AUG-13 

### 380 of 756MAC-IND - 3 14-AUG-13 

### 381 of 756MAC-IND - 4 14-AUG-13 

### 382 of 756MAC-IND - 5 14-AUG-13 

### 383 of 756MAC-IND - 6 14-AUG-13 

### 384 of 756MAC-IND - 7 14-AUG-13 

### 385 of 756MAC-IND - 8 14-AUG-13 

### 386 of 756MAC-IND - 9 14-AUG-13 

### 387 of 756MAC-IND - 1 14-AUG-13



### MACROSCOPICAL FINDINGS ALL NECROPSIES

Animals without necropsy

--- Animals not recorded

--- Animals not completed

--- Animals with not translated finding

---

Not Reported

--- 

### Report 388 of 756MAC-IND - 2 14-AUG-13 

### 389 of 756MAC-IND - 3 14-AUG-13 

### 390 of 756MAC-IND - 4 14-AUG-13 

### 391 of 756MAC-IND - 5 14-AUG-13 

### 392 of 756MAC-IND - 6 14-AUG-13 

### 393 of 756MAC-IND - 7 14-AUG-13 

### 394 of 7568 13MAC-IND - 9 14-AUG-13 

### 396 of 756

# Data of F1 Pups Report 397 of 75615-AUG-13 SYPU-IND - 1



### EXTERNAL EXAMINATION AT FIRST LITTER CHECK

Incomplete Recordings

Selection of Findings All findings reported --- Comments

---

Not Reported

--- 

### Report 398 of 75615-AUG-13 SYPU-IND - 2



### EXTERNAL EXAMINATION AT FIRST LITTER CHECK

Group 1 (0 mg/kg) LACTATION
No abnormality recorded. 

### Report 399 of 75615-AUG-13 SYPU-IND - 4



### EXTERNAL EXAMINATION AT FIRST LITTER CHECK

Group 3 (300 mg/kg) LACTATION
No abnormality recorded. 

### Report 401 of 75615-AUG-13 SYPU-IND - 5



### EXTERNAL EXAMINATION AT FIRST LITTER CHECK

Group 4 (1000 mg/kg) LACTATION
No abnormality recorded. 

### Report 402 of 75609-SEP-13 SYPU-IND - 1



### DAILY OBSERVATION

Incomplete Recordings

Selection of Findings All findings reported --- Comments

---

Not Reported

--- 

### Report 403 of 75609-SEP-13 SYPU-IND - 2



### DAILY OBSERVATION

Group 1 (0 mg/kg) LACTATION
No abnormality recorded. 

### Report 404 of 75609-SEP-13 SYPU-IND - 3 

### 405 of 75609-SEP-13 SYPU-IND - 4



### DAILY OBSERVATION

Group 3 (300 mg/kg) LACTATION
No abnormality recorded. 

### Report 406 of 75609-SEP-13 SYPU-IND - 5



### DAILY OBSERVATION

Group 4 (1000 mg/kg) LACTATION
No abnormality recorded. 

### Report 407 of 75615-AUG-13 BWPU-SUM - 1



### Mean Body Weights of Pups per Litter (G)

Data excluded from Summary Report

--- Comments

--- 

### Report 408 of 75615-AUG-13 BWPU-SUM - 2 

### 409 of 75615-AUG-13 BWPU-SUM - 3 

### 410 of 75615-AUG-13 BWPU-SUM - 4 

### t 411 of 75615-AUG-13 BWPU-SUM - 5 

### 412 of 75615-AUG-13 BWPU-SUM - 6



### ) rt 413 of 75615-AUG-13 BWPU-SUM - 7 

### 414 of 75615-AUG-13 BWPU-SUM - 8



### ) rt 415 of 75615-AUG-13 BWPU-SUM - 9 

### 416 of 75615-AUG-13 BWPU-IND - 1



### Body Weights of Pups

Not Reported

--- Comments

---
Data excluded from Summary Report

--- 

### Report 417 of 756PUP-IND - 1 02-DEC-13



### INDIVIDUAL PUP DATA

Comments

---

Not Reported

--- 

### Report 439 of 756MAC-IND - 1 15-AUG-13



### MACROSCOPICAL FINDINGS ALL NECROPSIES

Animals without necropsy

--- Animals not recorded

--- Animals not completed

--- Animals with not translated finding

---

Not Reported

--- 

### Report 462 of 756

# APPENDIX I Certificate of Analysis Report 521 of 756

### Report 522 of 756

### Report 523 of 756

### Report 524 of 756

# APPENDIX II Chemical Analysis of Feed Report 525 of 756

### of 756

### f 756

### f 756

### f 756

### 756

### 531 of 756

# APPENDIX III Drinking Water Analysis Report 532 of 756

### f 756

### of 756

### of 756

### 536 of 756

### 537 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 1



# APPENDIX IV Formulation Analysis Report 538 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 2 

# CONTENTS 1 MATERIALS AND METHODS...........................................................................................3 1.1 Reference Item.........................................................................................................3 1.2 Study Samples and Storage .....................................................................................3 1.3 Reagents and Materials............................................................................................3 1.4 Analytical Procedure ...............................................................................................3 1.4.1 Preparation of Calibration Solutions .........................................................3 1.4.2 Work up of Samples ..................................................................................4 1.4.3 Gas Chromatographic Conditions .............................................................4 1.4.4 Evaluation of Results.................................................................................4 2 RESULTS ...................................................................................................................... ........6 TABLES..........................................................................................................................................7 FIGURES ........................................................................................................................ ................9 

# LIST OF TABLES Table 1 Detailed Results of App lication Formulation Analysis ................................................7 Table 2 Example of Calibration Curve ......................................................................................8 

# LIST OF FIGURES Figure 1 Typical HPLC-Chromatogr ams of Calibration Solutions.............................................9 Figure 2 Typical HPLC-Chromat ograms of Test Samples .......................................................10 Report 539 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 3 

# 1 MATERIALS AND METHODS 1.1 Reference Item The test item as described in the main report was used as reference item.


# 1.2 Study Samples and Storage Representative samples were dispatched to th e analytical laboratories internally (at room temperature and backup samples: on i ce) and either directly analyzed or stored in the refrigerator (5 ± 3 °C) until analysis.


# 1.3 Reagents and Materials Chloroform: Baker no. 7386 N-Methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA): Sigma-Aldrich no. M7891 N,O-Bis(trimethylsilyl) trifluoroacetamide (BSTFA): Fluka no. 15222 Derivatization reagent MSTFA/BSTFA (1:5)


# 1.4 Analytical Procedure 1.4.1 Preparation of Calibration Solutions Stock solutions of derivatized test item were prepared for external standard calibration by reaction with derivatization reagent (see Section 1.3 ). The derivatization ratio was: 20 mg test item : 1 mL MSTFA/BSTFA (1:5). For example, 20.32 mg of wa s exactly weighed into a head space vial, 1.020 mL derivatization reagent was added and incuba ted for 1 h at 90 °C in a water bath. After cooling down the solution was transferred to a 50 mL volumetric flask and brought to volume with chloroform to yield a solution with a conc entration of 406.4 μg/mL. Aliquots of this stock standard solution were used to prepare worki ng standard solutions in chloroform with a concentration range of 5.283 to 79.65 μg/mL. On each occasion calibration solutions derived from two stock standard solutions were used for calibration. Report 540 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 4 

## 1.4.2 Work up of Samples The samples received were well homogenized a nd derivatized with deri vatization reagent (see Section 1.3 ). The derivatization ratio was: 20 mg of /mL formulation: 1 mL MSTFA/BSTFA (1:5). For example, to 0.5 mL formulation with a conc entration of 20 mg/mL, 0.5 mL of derivatization reagent was added and incubated for 1 h at 90 °C in a water bath for derivatization. After cooling down the solution, 10 mL chloroform was added to the tube sample. Sample solutions were further diluted with chloroform into the calibration range.

1.4.3 Gas Chromatographic Conditions Computerized System: EZ Chrom Elite; Agilent Technologies Column: ZB-5HT; 30 m x 0.25 mm; 0.25 μm Carrier Gas: Helium Temperature gradient: Rate [°C/min] Temp. [°C] Time [min] 40 2 30 360 5 Running time: 17.67 min Injector temperature: 250 °C Injection mode: Split 1:5 Flow: 1.5 mL/min (constant flow) Detector: FID; 370 °C (H2: 30; Air: 400; N2: 30 mL/min) Injection Volume: 1 μL Retention Time: Ca. 13 min

1.4.4 Evaluation of Results Injected samples were quantified by comparing pe ak areas of with reference to the calibration curve. The latter was obtai ned by correlation of th e peak areas of the calibration solutions with thei r corresponding concentrations [μg/mL], using the linear regression model following equation 1: y = a + b ⋅ x (1) Report 541 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 5 

## where y = Response for a = Intercept derived from linear regression of calibration data b = Slope derived from linear re gression of calibration data x = Actual concentration of in sample aliquot [μg/mL] Sample aliquot concentrations were corrected fo r density of the applicat ion formulation and for dilution using equation 2:


## 1000 ⋅ ⋅⋅ = W DVx C act 

## (2) where C act 

## = 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 [ 0.92 g/mL, density of vehicle as provided by the supplier ] W = Sample weight [g] The sample recovery was determined as follows: 100 C C ⋅=
nom act 

## R 

## (3)
where R = Sample recovery [ % ] C act 

## = Actual sample concentration [ mg/mL ] C nom 

## = Nominal sample concentration [ mg/mL ] Report 542 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 6 

# 2 RESULTS The linearity of the analytical system used fo r sample analyses was demonstrated with a good relationship between peak areas measured and ca libration solution concentrations. All calibration points used met the acceptance limit of ±20% va riation from the calibration curve derived by linear regression analysis. The coefficients of determination (R 2 

## ) calculated were found to be better than 0.99. An example is presented in Table 2

. The derivative peak was a ssigned in sample chromatograms by comparison to that of calibration solutions. In blank sample chromatograms no significant peak appeared at the retention time of derivatized and, therefore, the ab sence of the test item in the vehicle control samples (corn oil) was co nfirmed. Examples of chromatograms are shown in Figure 1 and Figure 2

. The concentrations in the do se formulations ranged from 86.1% to 112.2% and thus, the required content lim it 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 deviat e more than 14.4% from the corresponding mean and met the specified acceptance criterion of ≤ 15%. Due to a deviation close to the acceptance limit of dose group 3, prepared on 13 May 2013 (14.4%), homogeneity of this dose level was confirmed in an additional internal test. The test item was found to be stable in application formulati ons when kept 4 hours at room temperature (20 ± 5 °C) due to recoveries whic h met the variation limit of 10% from the timezero (homogeneity) mean value. Detailed results are shown in Table 1. In conclusion, the results indicate the accurate pr eparation and storage of the test item in vehicle during this study. Report 543 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 7 

# TABLES Table 1 Detailed Results of A pplication Formulation Analysis (Rounded results presented are based on calculations with exact data)

Dose Group Sample taken from/after Date of Analysis Nominal Conc. [mg/mL] Actual Conc. [mg/mL] Recovery Mean Recovery Coeff. of Variation Variation from Mean Recovery
1 vehicle 13-May-13 0.0 nd --- --- --- --- top 13-May-13 20.0 18.50 92.5% middle 13-May-13 20.0 19.53 97.7% bottom 13-May-13 20.0 20.09 100.4% 4 hours/20 ± 5°C 13-May-13 20.0 20.52 102.6% --- --- 5.9% top 13-May-13 60.0 54.59 91.0% middle 13-May-13 60.0 51.66 86.1% bottom 13-May-13 60.0 67.32 112.2% 4 hours/20 ± 5°C 13-May-13 60.0 59.23 98.7% --- --- 2.4% top 13-May-13 200.0 206.8 103.4% middle 13-May-13 200.0 186.4 93.2% --- bottom 13-May-13 200.0 188.8 94.4% 4 hours/20 ± 5°C 13-May-13 200.0 209.2 104.6% --- --- 7.9% 1 vehicle 18-Jun-13 0.0 --- --- --- --- --- 2 middle 21-Jun-13 20.0 18.15 90.7% --- --- --- 3 middle 18-Jun-13 60.0 54.29 90.5% --- --- --- 4 middle 18-Jun-13 200.0 220.8 110.4% --- --- --- --- 2

4 97.0% 5.8% 3 96.4% 14.4% 96.9% 4.1% Date of Preparation: 13-May-2013

---

Date of Preparation: 14-Jun-2013 1 2


### nd: No signal detected 1 

### Signal detected was below the lowest calibration point 2 

### Result of backup sample (n = 2) Report 544 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 8 

## Table 2 Example of Calibration Curve Date of analysis: 13 May 2013 Standard Concentration [ μg /mL] Peak Area [counts] Variation of Peak Area 5.283 211457 8.9% 10.16 338373 0.1% 20.32 611530 -4.1% 40.23 1206209 -1.5% 60.15 1807984 -0.2% 79.65 2333691 -2.2% 10.21 343927 1.3% 20.00 645013 2.7% 40.01 1198718 -1.5% 60.01 1828521 1.2% 79.59 2441523 2.4%

Calibration Curve by Linear Regression y = 29470x + 38552 R 2 = 0.9987

0 500'000 1'000'000 1'500'000 2'000'000 2'500'000 3'000'000

0.0 10 20 30 40 50 60 70 80 90 Concentration [μg/mL]Peak Area [counts] 

### Report 545 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 9 

# FIGURES Figure 1 Typical HPLC-Chromatogr ams of Calibration Solutions (A) Calibration solution: 5.283 μg/mL (B) Calibration solution: 79.65 μg/mL Date of analysis: 13 May 2013 (A)

(B) Report 546 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 10 

## Figure 2 Typical HPLC-Chromatograms of Test Samples (A) Dose group 1, control sample, 569x diluted (B) Dose group 2 (top), nominal concentration: 20 mg/mL, 577x diluted Date of analysis: 13 May 2013 (A)

(B) Report 547 of 756

### HEGE / SDV Experimental Completion Date: 22 Jun-2013
Formulation Analysis Page 11 

## Figure 2 Cont’d 

## (C) Dose group 4 (top), nominal concen tration:200 mg/mL, 5065x diluted Date of analysis: 13 May 2013 (C) Report 548 of 756

# APPENDIX V Functional Observational Battery Report 549 of 756

# 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) Report 550 of 756

# 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 Report 551 of 756

# Scoring for the Functional Observational Battery Open field observations (type 4-cage), cont’d Fur unkempt Scores: 0 Fur normal 1 Fur seems unkempt (dull, dirty or fur stuck together) Respiration slow Scores: 0 Respiration normal 1 Respiration slow Respiration accelerated Scores: 0 Respiration normal 1 Respiration accelerated Rales Scores: 0 No rales 1 Rales Rearings decreased The number of rearings (free-standing or against wa ll). Fore paws must be at least 1 cm above ground. Scores: 0 Rearing normal 1 Rearing decreased ( n < 3) Rearings increased The number of rearings (free-standing or against wa ll). Fore paws must be at least 1 cm above ground. Scores: 0 Rearings normal 1 Rearing increased (n > 8) Number of Faeces-balls Scores: 0 Number of Faeces-balls normal 1 Number of Faeces-balls increased (n > 3) Puddles of urine Scores: 0 No or few puddles of urine 1 Several puddles of urine Report 552 of 756

# Scoring for the Functional Observational Battery Observations in the hand 2 Emaciated Scores: 0 Animal normal 1 Animal emaciated Dehydration Scores: 0 Animal normal 1 Animal dehydrated Abdomen distended Scores: 0 Abdomen normal 1 Abdomen distended Skin cold to touch Scores: 0 Skin feels normal 1 Skin cold when touched Colouration of skin Scores: 0 Skin normal colour 1 Skin pale 2 Skin bluish Settings of eyes Scores: 0 Normal eyes 1 Exophthalmos 2 Enophthalmos Lacrimation Scores: 0 No lacrimation 1 Watery eyes 2 Obvious lacrimation, skin wet around eye Chromodacryorrhea Scores: 0 No ch romodacryorrhea 1 Dark red, dry scab around eye (chromodacryorrhea) Report 553 of 756

# 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 Report 554 of 756

# 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 Report 555 of 756

# APPENDIX VI Clinical Laboratory Investigations Report 556 of 756

# CLINICAL LABORATORY INVESTIGATIONS Blood Sampling: On the day of the scheduled necropsy: 26-Jun-2013 (males) On day 5 post partum: 19 to 21-Jun-2013 (females) Blood samples were obtained on the day before or on the day of the scheduled necropsy from 5 males randomly selected from each group. Blood samples from 5 lactating females from each group were obtained on day 5 pos t 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 cause d by circadian rhythms. In the summary and individual tables the names of some parameters have been abbreviated. Any abbreviation has been defined in this section. Clin ical laboratory data ar e expressed, with a few exceptions, in general accordance with th e International System of Units (SI). Key to Abbreviations of Units: L liter g gram m milli (10 -3 

## ) mol mole G giga (10 9 

## ) μ micro (10 -6 

## ) sec seconds T tera (10 12 

## ) f femto (10 -15 

## ) U Unit 

# Hematology The following anticoagulants were used during blood collection: Complete Blood Cell Count : Tri-potassium-EDTA Coagulation: Sodium citrate, 3.2% (1 part anticoagulant to 9 parts blood) Complete Blood Cell Count Parameter Abbreviation Unit Instrumentation Erythrocyte count RBC T/L Advia 120 1 

## Hemoglobin HB mmol/L Advia 120 Hematocrit HCT rel.1 Advia 120 Mean corpuscular volume MCV fL Advia 120 Red cell volume distribution width RDW rel.1 Advia 120 Mean corpuscular hemoglobin MCH fmol Advia 120

1 

### ADVIA 120 hematology system (Siemens) Report 557 of 756

## Parameter Abbreviation Unit Instrumentation Mean corpuscular hemoglobin concentration MCHC mmol/L Advia 120 Hemoglobin concentration distribution width HDW mmol/L Advia 120

Reticulocyte count RETI relative 

## rel.1 absolute 

## G/L Advia 120 Reticulocyte maturity index (low, medium, high fluorescence) L RETI M RETI H RETI rel.1 rel.1 rel.1 Advia 120

Leukocyte count, total WBC G/L 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 CoagulationParameter Abbreviation Unit Method Instrumentation Prothrombin time (=Thromboplastin time) 

## PT rel. 1 Clotting assay, thromboplastin from rabbit brain tissue, results as ratio of normal activity STA 2



## Activated partial thromboplastin time PTT sec Clotting assay, cephalin from rabbit cerebral tissue, silica surface activator STA

2 

### STA-compact analyzer (Roche Diagnostics) Report 558 of 756

# Clinical Biochemistry Lithium heparin was used as anticoagulant during blood collection.Parameter Abbreviation Unit Method Instrumentation Glucose mmol/L Hexokinase/G6P-DH Cobas 6000/501 3 

## Urea mmol/L Urease/GLDH Cobas 6000/501 Creatinine CREAT μmol/L Enzymatic colorimetric test Cobas 6000/501Bilirubin, total* BILI-T μmol/L Reaction with 2,5-Dichlorophenyl-diazonium salt Cobas 6000/501 Bile acids BILE AC μmol/L Colorimetric, enzymatic (3 α -HSD, Diaphorase) Cobas 6000/501 Cholesterol, total CHOLEST mmol/L Enzymatic, CHOD/PAP Cobas 6000/501 Triglycerides TRIGLY mmol/L Glycerol-Kinase GPO/PAP method Cobas 6000/501 Aspartate aminotransferase EC 2.6.1.1 4 

## ASAT U/L 37 oC ALT/MDH Cobas 6000/501

Alanine aminotransferase EC 2.6.1.2 ALAT U/L 37 oC ALT/LDH Cobas 6000/501

Alkaline phosphatase EC 3.1.3.1 ALP U/L 37 oC p-Nitrophenyl-phosphate as substrate Cobas 6000/501
Gamma-glutamyl transferase EC 2.3.2.2 GGT U/L 37 oC Substrate: L-gammaglutamyl-3-carboxy4-nitroanilide Cobas 6000/501

Sodium mmol/L Ion selective electrode Cobas 6000/501 Potassium mmol/L Ion selective electrode Cobas 6000/501 Chloride mmol/L Ion selective electrode Cobas 6000/501 Calcium mmol/L o-Cresolphthalein complexone method Cobas 6000/501 Phosphorus mmol/L Phosphomolybdate reaction Cobas 6000/501 Protein, total PROTEIN g/L Biuret reaction Cobas 6000/501 Albumin g/L Bromocresol green method Cobas 6000/501

3 

### Cobas 6000 analyzer, Roche Diagnostics 4 

### Identification of enzymes with EC-Number (Enz yme Commission) according to Enzyme Nomenclature, Recommendations (1972) of the IUPAC and IUB, Elsevier Scient. Publ. Comp., Amsterdam, 1973 Report 559 of 756

## Parameter Abbreviation Unit Method Instrumentation Globulin g/L Calculated value (total protein minus albumin) Albumin / Globulin Ratio A/G RATIO Calculated value (albumin / globulin)

* Remark: Individual values under the lower limit of quantification (LLOQ, 1.7 μmol/L) were reported as 0.00 μmol/L. Report 560 of 756

## HISTORICAL DATA - HEMATOLOGY Report 561 of 756

## HISTORICAL DATA - HEMATOLOGY Report 562 of 756

## HISTORICAL DATA - CLINICAL BIOCHEMISTRY Report 563 of 756

### Report 564 of 756

# APPENDIX VII Histopathology Report 565 of 756

# Pathology Report

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

This report contains 136 pages Report 566 of 756

### PATHOLOGY REPORT Page 2/136



## Table of Contents Statement of Compliance ........................................................................................................ ........3 Quality Assurance Statem ent ..........................................................................................................4 Summary .........................................................................................................................................5 Materials and Methods.......................................................................................................... ..........6 Results ........................................................................................................................

..................... 9 Conclusions .................................................................................................................... ...............10 Table 1 Incidence All Macroscopic Findings ............................................................................11 Table 2 Incidence S elected Microscopic Finding with Grades .................................................12 Table 3 Incidence Microscopic F indings - Reproductive Organs ............................................. 13 Table 4 Incidence All Microscopic Findings .............................................................................15 Table 5 Individual A nimal Microscopic Findings.....................................................................22 Table 6 Ani mal Data List ..........................................................................................................39 Table 7 Individual A nimal Data Records .................................................................................. 43 Report 567 of 756PATHOLOG Y REPOR T Pag e 3/12 8



### Statemen t o f

Complianc e Th e undersigne d hereb y declares , tha t th e histopatholog y dat a i n thi s repor t wer e compile d b y him , an d tha t

the y reflec t

accuratel y th e primar y dat a records

. Thi s report , consistin g o f 12 8 pages , wa s create d b y th e compute r syste m o f This stud y phas e wa s conducte d i n complianc e with : Swis s Ordinanc e relatin g t o Goo d Laborator y Practice , adopte d Ma y 18^' \5 [S R 813.112.1]

. Thi s Ordinanc e i s base d o n th e OEC D Principle s o f Goo d Laboratory Practice , a s revise d i n 199 7 an d adopte d Novembe r 26' ^ 199 7 b y decisio n o f th e OEC D Counci l [C(97)186/Final]

.

Principa l Investigato r

- Toxicologi c Pathologis t

Date : 

# ^icALin S Report 568 of 756PATHOLOG Y REPOR T Pag e 4/12 8



### Qualit y Assuranc e Statemen t
Th e faciUtie s o f ar e periodicall y (4x/year ) inspecte d b y th e Qualit y Assuranc e Uni t (CERTU S Qualit y Assuranc e Service s GmbH)

. Thi s repor t wa s inspecte d b y th e Qualit y Assuranc e Uni t

(CERTUS)

. Th e respectiv e date s ar

e give n below : Inspectio n typ e Date(s ) o f inspectio n Date(s ) o f reportin g Facilit y base d inspectio n (latest) : 15.11.201 3 15.11.201 3 Revie w o f

relevan t section s o f

stud y plan : 19.09.201 3 19.09.201 3
Phas e repor

t inspection : 06.11.201 3 06.11.201 3

Th e findings wer e reporte d t o th e tes t facilit y ( ) managemen t (onl y inspectio n o f

tes t facilit y (tes t

site ) , th e principa l investigator , th e stud y director , th e managemen t o f th e tes t facilit y o f

th e stud y directo r

an d th e "lea d QA"

. Th e methods , procedure s an d observation s describe d wer e foun d t o b e accuratel y describe d an d th e reporte d result s t o reflec t th e ra w dat a

Date : 

# fJo^h^

^^-^2 Report 569 of 756

### PATHOLOGY REPORT Page 5/136



## Summary Pathomorphologic examination wa s performed on 96 Han Wistar rats (48 males, 48 females) which had been subjected to a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, with the test item . The In-Life part of this study was conducted at during May/June 2013. The rats were assigned to four dose groups each containing twelve animals of both sexes. The test item was administered by gavage at dos es of 100, 300 and 1000 mg/kg bw/day (dose groups 2, 3 and 4 respectively) from one day prior to mating, during mating, during gestation and up to the day prior to necropsy on day four post-partum – at least a total of 28 days dosing for males and approximately six weeks for females. The ra ts of the control group 1 (0 mg/kg bw/day) received the vehicle, corn oil, alone. All rats were necropsied. Histopathologic examin ation was performed all reproductive organs of group 1 (0 mg/kg bw/day) and group 4 (1000 mg/kg bw/day) males and females as well as an extensive list of or gans and tissues from five males and fi ve females of groups 1 and 4. Ovaries of females which failed to give birth as well as all tissues with macroscopic findings were also examined along with the liver from 5 males of groups 2 (100 mg/kg bw/day) and 3 (300 mg/kg bw/day). PAS stained sections of testes from all group 1 and 4 males were also subjectively assessed for spermatogenesis stages.

There were no unscheduled deaths. There were four females which fa iled to give birth - nos. 52 and 54 group 1 (0 mg/kg bw/day, control), 84 group 3 (300 mg/kg bw/day) and 88 group 4 (1000 mg/kg bw/day). There was no morphological evidence to associate th e failure to deliver with treatment with the test item. There were no macroscopic findi ngs related to treatment. There were minor morphologi cal alterations in the liver of males. This consisted of a minimal degree of diffuse, midzonal/centrilobular hepatocellular hypertrophy recorded in 3/5 rats of group 4 (1000 mg/kg bw/day) animals. This finding may be considered as adaptive in nature, within physiological limits and not a manifestation of frank toxicity. Based on the above, the NOAEL was cons idered to be 1000 mg/kg bw/day. Report 570 of 756

### PATHOLOGY REPORT Page 6/136



## Materials and Methods Study Design
Dose group Dose mg/kg bw/day Number of rats Animal numbers males females males females 1 0 12 12 1 – 12 49 – 60 2 100 12 12 13 – 24 61 – 72 3 300 12 12 25 – 36 73 – 84 4 1000 12 12 37 – 48 85 – 96 

## Administration of the Test Item The test item was administered once daily by gavage from one day prior to mating, during mating, during gestation and up to the day prior to necropsy on day four post-partum – at least a total of 28 days dosing for males and approximately six weeks for females. Rats of the control group 1 (0 mg/kg bw/day) received th e vehicle, corn oil, alone. Necropsy and Histopathology At the end of the assigned st udy periods, the rats were kille d by exsanguination following anesthesia by an injection of sodium pentobarbital. Complete n ecropsies were performed on all rats. Testes and epididymides were weighed indi vidually from all males at necropsy. From the 5 selected animals/sex/group the terminal body weight and the we ights of the adrenal glands (weighed as pairs), brain, heart, kidneys (weighed as pairs), liver, ovaries (weighed as pairs), prostate, seminal vesicles including coagulating glands, spleen, thymus and uterus (including cervix) were recorded at necropsy. Weights of thyroids were recorded after fixation. Body and organ weights are reported in the main toxicology report. Representative tissue samples of the following or gans from all animals were preserved in 4% phosphate buffered neutral formaldehyde solution (10% formalin). Testes and epididymides were initially fixed in m odified Davidson’s solution. Adrenal glands (2), aorta, bone – sternum and femur including joint; bone marrow – femoral (1) and sternal; brain - medulla oblongata, cerebellum and pons, midbrain and cerebrum (4); eyes with optic ne rve and Harderian glands; epididymides (2), esophagus, heart (1), kidneys (2), lacrimal glands, large intestine - cecum, colon and rectum (3); larynx, liver (2), lungs (2), lymph nodes – axillary (2) and Report 571 of 756

### PATHOLOGY REPORT Page 7/136



## Materials and Methods mesenteric (1); male and female mammary gland area, nasal cavity, ovaries (2), oviducts (2), pancreas, phar ynx, pituitary gland, prostate gland (1), salivary glands – mandibular and sublingual; sciatic nerve (2), seminal vesicles (2) with coagulation glands (2), skeletal muscle, small intestine - duode num, jejunum and ileum (3) with Peyer’s patches (2); spinal cord - cervical, thoracic and lumbar (3); spleen (1), stomach - forestomach and glandular (2); testes (4), thymus (1), thyroid glands (2) with parathyroid glands (2), trachea (1), urinary bladder (1), uterus with uterine cervix (3), vagina (1) and all organs or tissues with macroscopic abnormalities

. Organs listed in bold italics were examined from all group 1 (0 mg/kg/day, control) and group 4 (1000 mg/kg/day) animals. Organs listed in bold were examined from the 5 males and 5 females of group 1 (0 mg/kg/day, control) and gro up 4 (1000 mg/kg/day) animals selected for histopathology evaluation. Animals selected for histopathology evaluation: males females Group 1 (0 mg/kg bw/day) 1, 2, 3, 4, 5 50, 51, 55, 56, 60 Group 4 (1000 mg/kg bw/day) 37, 38, 39, 40, 41 86, 87, 90, 91, 94 Following fixation, organs from the above li sted animals were trimmed, processed and embedded in paraffin wax. Sections (numbers given in parentheses) were cut at a thickness of 2- 4 micrometers and stained w ith hematoxylin and eosin. Extra sections of testes stai ned by the PAS method from males of groups 1 and 4 were also prepared. In addition the ovaries of animal number 84 - failed to give birth (group 3, 300 mg/kg/day) were prepared and examined. Following examination of the above tissues, sections of liver were prepared and examined from the below listed selected males from groups 2 and 3: males Group 2 (100 mg/kg bw/day) 13, 14, 15, 16, 17 Group 3 (300 mg/kg bw/day) 25, 26, 27, 28, 29 Report 572 of 756

### PATHOLOGY REPORT Page 8/136



## Materials and Methods The sections were examined by light microscopy in September/October 2013. Data Compilation The animal data and macroscopic findings were el ectronically transferre d from the necropsy raw data files of into the computer system of where the microscopic findings were recorded by the undersigned pathologist using on-line input. Macroscopic findings are presented in summary in Table 1 - Incidence All Macroscopic Findings and in fu ll descriptive terms in Table 7 - Individual Animal Data Records. Wherever possible, macroscopic findings were correlat ed with a m icroscopic finding. Microscopic findings are listed for each animal along with severity grades in Table 5 - Individual Anim al Microscopic Findi ngs and summarized in Table 2 - Incidence Selected Microscopic Finding with Grades, Table 3 - Incidence Microscopic Findings - Re productive Organs and Table 4 - Incidence All Microscopic Findi ngs. They are further given in full descriptive term s in Table 7 - Individual Animal Data Records. Histologic changes were described according to their distribution and mo rphologic charac ter and were graded for severi ty on a scale of 1 – 5 (see key Table 5 - Individual Animal Microscopic Findings). Archiving The original final pathology report, all slides, d ispatch list(s) and raw data provided will be sent to the test facility. The test f acility is responsible for the tran sfer to the sponsor`s archive. Peer Review A peer review was conducted at the Test Facility by: , Global Head of Pathology, . Any diagnostic discrepancies were resolved by discussion, and the diagnoses presented in this report represent the consensus opinion. Report 573 of 756

### PATHOLOGY REPORT Page 9/136



## Results Mortality There were no unscheduled deaths. Macroscopic Findings The few recorded macroscopic findings were consid ered to be spontaneous in nature and did not distinguish treated animals from the controls. There were four fe males which failed to give birth - nos. 52 and 54 group 1 (0 mg /kg bw/day, control), 84 group 3 (300 mg/kg bw/day) and 88 group 4 (1000 mg/kg bw/day). Microscopic Findings The only treatment related microscopic finding of not e was recorded in the liver of group 4 (1000 mg/kg bw/day) males and consisted of a mi nimal degree of diffuse, midzonal/centrilobular hepatocellular hypertrophy recorded in 3/5 rats. Ovary morphology was normal in the animals whic h failed to deliver and testes morphology did not reveal any disturbances of spermatogenic staging. The remainder of the recorded microscopic findings were within the range of background pathology encountered in Han Wistar rats of this age in this type of study and occurred at similar incidences and severity in both control and treated rats. Report 574 of 756

### PATHOLOGY REPORT Page 10/136



## Conclusions Following the administration of by once daily gavage to Han Wistar rats at doses up to 1000 mg/kg bw/day from one day prior to mating, during mating, during gestation and up to the day prior to necropsy on day four post-partum – at least a tota l of 28 days dosing for males and approximately six weeks for female s, there were minor morphological alterations in the liver of males. This consiste d of a minimal degree of diffuse, midzonal/centrilobular hepatocellular hypertrophy recorded in 3/5 rats of group 4 (1000 mg/kg bw/day) animals. This finding may be considered as adaptive in nature, within physiological limits and not a manifestation of frank toxicity. Based on the above, the NOAEL was cons idered to be 1000 mg/kg bw/day. Report 575 of 756

### PATHOLOGY REPORT Page 11/136



## Table 1 Incidence All Macroscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Stomach Forestomach/glandular mucosa 0 0 0 0 0 0 0 1 junction: discoloration Liver Diaphragmatic hernia left median lobe 0 0 0 0 0 0 1 0 Kidneys Pelvic dilation 0 1 1 0 0 0 0 0 Ovaries Cyst(s) 0 0 0 1 Thymus Organ missing 1 0 0 0 0 0 0 0 Axillary lymph nodes Organ missing 1 0 0 0 0 0 0 0 

### Report 576 of 756

### PATHOLOGY REPORT Page 12/136



## Table 2 Incidence Selected Microscopic Finding with Grades
SEX: MALE DOSE GROUP: 1 2 3 4 number of animals **12 12 12 12** Liver number examined 5 5 5 5 Midzonal/centrilobular hypertrophy, diffuse (minimal) 0 0 0 3 

### Report 577 of 756

### PATHOLOGY REPORT Page 13/136



## Table 3 Incidence Microscopic Findi ngs - Reproductive Organs
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12**
Testes number examined 12 12 Seminiferous cell debris, 5 5 intratubular Seminiferous tubular 1 1 atrophy, focal/multifocal Testes - PAS stain number examined 12 12 Seminiferous cell debris, 4 4 intratubular Seminiferous tubular 1 1 atrophy, focal/multifocal Epididymides number examined 12 12 Inflammatory infiltrate, 3 1 lymphoid Prostate Gland number examined 12 12 Inflammatory infiltrate, 0 1 lymphoid Inflammatory infiltrate, 0 2 granulolymphocytic Seminal Vesicles number examined 12 12 Coagulating Glands number examined 12 11 

### Report 578 of 756

### PATHOLOGY REPORT Page 14/136



## Table 3 Incidence Microscopic Findings - Reproductive Organs
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12** Ovaries number examined 12 1 12 Pigment, yellow-brown 1 0 1 Oviducts number examined 12 11
Uterus number examined 12 12 Implantation site(s) 10 11 Proestrus epithelium 1 1 Estrus epithelium 1 0 Vagina number examined 12 12 Epithelial mucification 10 9 Mucosanguinal epithelial 9 8 debris in lumen Proestrus epithelium 1 1 Estrus epithelium 1 0 

### Report 579 of 756

### PATHOLOGY REPORT Page 15/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Brain - cerebrum number examined 5 5 5 5 Brain - midbrain number examined 5 5 5 5 Brain - pons,cerebellum number examined 5 5 5 5 Brain - medulla oblongata number examined 5 5 5 5 Spinal Cord - cervical number examined 5 5 5 5 Spinal Cord - midthoracic number examined 5 5 5 5 Spinal Cord - lumbar number examined 5 5 5 5 Sciatic Nerve number examined 5 5 4 5
Heart number examined 5 5 5 5 Myofiber necrosis 2 1 0 0 Cardiomyopathy 3 2 0 2 

### Report 580 of 756

### PATHOLOGY REPORT Page 16/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Trachea number examined 5 5 5 5 Inflammatory infiltrate, 2 2 1 0 granulolymphocytic Lungs number examined 5 5 5 5 Vascular mineralisation, 1 3 1 1 focal Alveolar macrophage foci 1 0 0 0 Alveolar inflammation, 1 2 1 2 lymphocytic Intraalveolar fibrosis, 1 0 0 0 focal Osseous metaplasia 0 0 1 0 Stomach - glandular number examined 5 5 5 5 Microcyst, squamous 0 0 1 0 Stomach - forestomach number examined 5 5 5 5 Squamous hyperplasia, 0 1 0 0 diffuse Duodenum number examined 5 5 5 5 Jejunum number examined 5 5 5 5 

### Report 581 of 756

### PATHOLOGY REPORT Page 17/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Ileum number examined 5 5 5 5 Peyer's Patches (GALT) number examined 5 4 5 5 Mineralization, focal 1 0 0 0 Cecum number examined 5 5 5 5 Colon number examined 5 5 5 5
Rectum number examined 5 5 5 5 Liver number examined 5 5 5 5 5 1 5 Hepatodiaphragmatic nodule 0 0 0 0 0 1 0 Hepatocellular vacuolation 4 3 1 3 0 0 0 Hematopoietic cell foci 0 0 0 1 1 0 2 Inflammatory infiltrate, 5 4 5 3 4 1 3 lymphoid Hepatocellular pigment, 0 0 0 0 1 0 0 yellow-brown Midzonal/centrilobular 0 0 0 3 0 0 0 hypertrophy, diffuse 

### Report 582 of 756

### PATHOLOGY REPORT Page 18/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Kidneys number examined 5 1 1 5 5 5 Pelvic dilation 0 1 1 0 1 0 Cystic tubules 0 0 0 1 0 0 Inflammatory infiltrate, 1 0 0 0 1 0 lymphoid Tubular mineralisation 1 0 0 0 0 0 Urinary Bladder number examined 5 5 5 4
Testes number examined 12 12 Seminiferous cell debris, 5 5 intratubular Seminiferous tubular 1 1 atrophy, focal/multifocal Testes - PAS stain number examined 12 12 Seminiferous cell debris, 4 4 intratubular Seminiferous tubular 1 1 atrophy, focal/multifocal Epididymides number examined 12 12 Inflammatory infiltrate, 3 1 lymphoid 

### Report 583 of 756

### PATHOLOGY REPORT Page 19/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Prostate Gland number examined 12 12 Inflammatory infiltrate, 0 1 lymphoid Inflammatory infiltrate, 0 2 granulolymphocytic Seminal Vesicles number examined 12 12 Coagulating Glands number examined 12 11 Ovaries number examined 12 1 12 Pigment, yellow-brown 1 0 1 Oviducts number examined 12 11
Uterus number examined 12 12 Implantation site(s) 10 11 Proestrus epithelium 1 1 Estrus epithelium 1 0 

### Report 584 of 756

### PATHOLOGY REPORT Page 20/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Vagina number examined 12 12 Epithelial mucification 10 9 Mucosanguinal epithelial 9 8 debris in lumen Proestrus epithelium 1 1 Estrus epithelium 1 0 Thyroid Glands number examined 5 5 5 5 Follicular hypertrophy/ 0 0 0 1 hyperplasia, diffuse Parathyroid Glands number examined 2 4 4 4 Adrenal Glands number examined 5 5 5 5 Inflammatory infiltrate, 0 0 3 3 lymphoid Spleen number examined 5 5 5 5 Hemopoietic foci, primarily 5 4 5 5 erythroid Hemosiderin pigment 5 5 5 5 

### Report 585 of 756

### PATHOLOGY REPORT Page 21/136



## Table 4 Incidence All Microscopic Findings
SEX: MALE FEMALE DOSE GROUP: 1 2 3 4 1 2 3 4 number of animals **12 12 12 12 12 12 12 12** Bone Marrow - femoral number examined 5 5 5 5 Adipocytes 4 5 1 0 Pigment, yellow-brown 1 0 0 0 Thymus number examined 5 5 5 5 Lymphoid atrophy - 0 0 3 1 involution Axillary Lymph Nodes number examined 5 4 5 5 Pigment, yellow-brown 0 2 0 1 Mesenteric Lymph Node number examined 5 5 5 5 Macrophage foci, pigmented 0 0 1 0 Lymphoid hyperplasia 0 0 1 0 

### Report 586 of 756