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

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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 

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Report Body 1 Page 3 

PAGE RESERVED FOR FLAGGING STATEMENTS 

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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

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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

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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

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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

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Organ Weights ................................................................................................................... 712

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SUMMARY 

General 

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

 on the possible health hazards likely to arise from repeated exposure over a 

relatively limited period of time. In addition it provides information on possible effects on male 

and female reproductive performance such as gonadal function, mating behavior, conception, 

development of the conceptus and parturition. 

 was administered to male rats during 48 days and to female rats for 14 days 

prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 

post partum. 

The following dose levels were applied: 

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 adjustment to the actual body 

weight was used. Control animals were dosed 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 during 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 consumption and mean body weights in males and females 

at any dose level and in any study phase. 

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Clinical Laboratory Investigations 

Hematology 

The assessment of the hematology data did not reveal any test item-related effects in males and 

females at any dose level. 

Clinical Biochemistry 

In males, the alanine aminotransferase levels were slightly and dose-dependently 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 weights were increased by approximately 20%. 

Macroscopic / Microscopic Findings 

There were no macroscopic findings related to treatment. 

There was a diffuse, midzonal/centrilobular hepatocellular hypertrophy recorded in males at 

1000 mg/kg bw/day. 

Litter Data - F1 Pups 

Findings at First Litter Check 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 noted at macroscopic examination of F1 pups. 

Macroscopic Findings 

At necropsy of pups, there were no abnormal findings. 

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Conclusion 

In conclusion, activities of alanine aminotransferase were slightly higher after administration of 

 at 1000 and 300 mg/kg body weight/day in males. Although a relationship to 

treatment 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, liver weights were 

increased, and there were minor morphological alterations in the liver of males at 1000 mg/kg 

body weight/day. These consisted of a minimal degree of hepatocellular hypertrophy. These 

findings may be considered as adaptive in nature, 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 Adverse Effect Level) for general toxicity and 

the NOEL (No Observed Effect Level) for reproduction were considered to be 1000 mg/kg body 

weight/day. 

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GENERAL INFORMATION 

Schedule 

Study Initiation Date: 30-Apr-2013 

Experimental Starting Date 

(Delivery of Animals): 02-May-2013 

First Test Item Administration: 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 from 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-accredited laboratory in accordance with the 

Animal Protection Law under license no. 252. 

Accreditation 

 is accredited as a test laboratory for analysis in the fields 

of clinical chemistry, hematology, blood coagulation and urine diagnostics in accordance with 

the Standard ISO/IEC 17025 under accreditation number STS 085 by the Accreditation 

Service. 

Multi – Site Study Details 

Lead Quality Assurance: 

 

Study Phase: Histopathology 

Study Phase Identifier: 13001 

Test Site: 

Principal Investigator: 

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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 procedure 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 examination of the liver in groups 2 

and 3. 

Amendment No. 7: The pathologist informed about a new address. 

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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 electronic raw data, specimens and 

the original final report will be sent to the Sponsor. 

The original final pathology report, all slides, dispatch list(s) and raw data provided will be sent 

to the test facility. The test facility is responsible for the transfer 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: 

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1 INTRODUCTION AND PURPOSE 

1.1 Purpose 

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

likely to arise from repeated exposure over a relatively limited period of time. In addition it 

provided information on possible effects on male and female reproductive performance such as 

gonadal function, mating behavior, conception, development of the conceptus and parturition. 

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

may provide guidance in the design of subsequent studies. 

Rationale for Choice of Species, Route of Administration and Dose Levels 

The rat is a suitable species for repeated dose and reproduction/developmental toxicity studies 

required by regulatory authorities. The oral route is one possible 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 indicated by the following 

internationally accepted guidelines and recommendations: 

• OECD guideline 422 (OECD guideline for testing of chemicals 422, “Combined 

Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity 

Screening Test in the Rat”, adopted by the Council on 22nd March 1996). 

• “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental 

Toxicity Screening Test” Health Effects Test Guideline OPPTS 870.3650 Guideline 

from the Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental 

Protection Agency, July 2000. 

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2 TEST ITEM / VEHICLE AND CONTROL ITEM 

2.1 Test Item 

Information as provided by the Sponsor (certificate 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): December 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 (Retest Date): 12-May-2014 

Storage Conditions: Room temperature (15 - 25 °C) 

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

mask) 

522

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3 MATERIALS AND METHODS 

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

report are contained in the appropriate standard operating procedures. 

3.1 Test System 

Animals: Rat, RccHanTM: WIST(SPF) 

Rationale: Recognized by international guidelines as a 

recommended test system. 

Breeder: 

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-generated 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 conditions 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 was documented in the raw data. 

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3.2 Allocation 

The group identification and animal numbers assigned to treatment are stated in the following 

table: 

Allocation and 

Dose Levels 

mg/kg 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 from 

 During 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 maintenance diet (Provimi 

Kliba SA, 4303 Kaiseraugst / Switzerland) was 

available ad libitum. Results of representative analyses 

for contaminants are included in Appendix II on 

p. 526 . 

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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 using the test item as supplied by the Sponsor. 

 was weighed into a glass beaker on a tared precision balance and 80 - 90% 

of the warmed-up (40 ± 5 °C) vehicle was added (w/v) with a syringe in small amounts under 

continuously stirring. The dose formulation was 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 sample from the control group as well as three 

samples (top, middle and bottom) of each concentration were taken prior to dosing for analysis 

of concentration and homogeneity. Due to high variation of the analytical homogeneity results, 

additional samples were taken in the first and second week from remaining formulations to 

evaluate optimized analytical conditions for sample workup and derivatization. These samples 

were analysed but results were not reported. Samples of each test item concentration were taken 

from the middle to confirm the stability (4 hours at room 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

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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 without 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

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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 with sexually mature males from the same dose 

group (1:1) until evidence of copulation was observed. The females were removed and housed 

individually if: 

- the daily vaginal smear was sperm positive, or 

- a copulation plug was observed. 

The day on which a positive mating was determined (copulation plug or sperm) was designated 

day 0 post coitum. 

If a female did not mate during the 14-day pairing period, a second pairing of this female with a 

male in the same group, which had already mated 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 histopathologically 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 delivered all her pups. 

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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 parturition, and behavioral abnormalities in nesting and nursing. 

Food Consumption: Males: Pre-pairing 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 examined for litter size, live births, 

still births and any gross anomalies. The sex ratio of 

the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 

and 4 post partum. 

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 observations 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 secretions 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 (males shortly before the scheduled sacrifice and females on day 3 

or 4 post partum) relevant parameters were performed with five P generation males and five P 

generation females randomly selected from each group. This FOB assessment was conducted 

following the daily dose administration. Animals were observed for the following: 

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Report Body 2 Page 15 

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

• Hand-held observations: muscle tone, constitution, skin, pupil size, palpebral closure 

lacrimation, salivation, reaction to handling and general abnormalities. 

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

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

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

• Reflexes: blinking, pinna reflex, extensor thrust response, paw pinch, responsiveness to 

sharp noise, righting reflex and hearing ability (Preyer’s reflex). 

• Measurements / Counts: hind limb / fore limb grip strength, rectal temperature. 

A description of all test parameters is listed under Appendix V on p. ). Any abnormal 

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

Additionally, locomotor activity was measured quantitatively for the same animals. Activity was 

measured with an Activity Monitor AMS-0151 (FMI, Germany). Activity of the animals (based 

on beam count) was recorded for 6-minute intervals over a period of 30 minutes. These data and 

the total activity over 30 minutes were reported. 

3.9 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 caused 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 thyroxine (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 microscopic examination of the thyroid glands or 

thyroid gland weights. 

3.10 Termination of the Study 

Males were sacrificed after treatment of at least 48 days, when no longer needed for the 

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

sacrificed on day 5 post partum. 

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

day 25 post coitum. 

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3.10.1 Necropsy 

All animals sacrificed were subjected to a detailed macroscopic examination. Specimens of 

abnormal tissue were fixed in neutral phosphate buffered 4% formaldehyde solution. 

At the scheduled sacrifice, all animals were weighed and sacrificed by an injection of sodium 

pentobarbital. All P generation animals were exsanguinated. 

Dead pups, except those excessively cannibalized, were examined macroscopically. 

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

the scheduled necropsy or during the study if death occurred. 

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

The number of implantation sites and corpora lutea was recorded for all dams with litters. The 

uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize 

possible hemorrhagic areas of implantation sites [see References (1)]. 

3.10.2 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 appropriate, 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 (inclusive coagulating gland) 

 

*

 In group 2, erroneously the thyroid weight of 10 males was taken. 

Report 27 of 756
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3.10.3 Tissue Preservation 

The following tissues from all parental males were preserved in neutral phosphate buffered 4% 

formaldehyde solution: 

Prostate 

Seminal vesicles with coagulating gland 

Testes (in modified Davidson Solution) 

Epididymides (in modified Davidson 

Solution) 

The following tissues from all parental females were preserved in neutral phosphate buffered 4% 

formaldehyde solution: 

Ovaries (with oviduct) Uterus (with vagina) 

In addition, from all males and females the following tissues were preserved in neutral phosphate 

buffered 4% formaldehyde solution: 

Gross lesions 

Brain 

Spinal chord (cervical, thoracic, lumbar) 

Small and large intestines1 (incl. Peyer’s 

patches) 

Stomach (forestomach and glandular stomach) 

Liver 

Kidneys 

Adrenals 

Spleen 

Lymph nodes (axillary and mesenteric) 

Aorta2

Eyes with optic nerve and harderian gland2

Lacrimal gland2

Larynx2

Nasal cavity2

Esophagus2

Heart 

Thymus 

Thyroids, and parathyroids if possible 

Trachea and lungs (preserved by inflation 

with fixative and then immersion) 

Pituitary gland2 

Urinary bladder 

Peripheral nerve (sciatic) 

Bone marrow (femur) 

Femur with knee joint2

Mammary gland (male and female)2

Pancreas2

Salivary glands – mandibular, sublingual2

Skeletal muscle2

Sternum with bone marrow2 

Pharynx2

 

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
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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 micrometers and stained with hematoxylin and eosin. 

Additionally, the testis was stained by PAS-hematoxylin. 

3.10.5 Histopathology 

Macroscopical findings, testes, epididymides, prostate, seminal vesicles, ovaries, oviduct, vagina 

and uterus from all animals of the control and high dose group were examined. The same applied 

to all occurring gross lesions and to all animals, 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, respectively, were examined histopathologically. 

Special emphasis was made on the stages of spermatogenesis and histopathology of interstitial 

cell structure. 

Since test item-related morphologic changes were detected in the liver at the high dose, these 

organs from the mid- and low-dose group were examined to establish a no-effect level. 

Histological examination of ovaries was carried out on any females that did not give birth. 

A histopathology peer review 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, organ 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 reproduction data, the following parameters were calculated: fertility 

indices, mean precoital time, post-implantation losses (absolute and percent), mean litter size, 

pup sex ratios and viability indices. 

For reproduction data, group mean values were calculated both on a litter basis and on a 

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

per litter basis. 

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

used the exact raw data values. 

565

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3.12 Statistical Analysis 

The following statistical methods were used to analyze food consumption, body and organ 

weights, grip strength, rectal temperature, clinical laboratory and reproduction data, locomotor 

activity and macroscopical findings: 

• Means and standard deviations of various data were calculated 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 variables could be assumed to follow a normal distribution 

for the comparison of the treated groups and the control groups for each sex. 

• The Steel-test [see References (3)] (many-one rank test) was applied instead of the 

Dunnett-test when the data could not be assumed to follow a normal distribution. 

• Fisher's exact-test [see References (4)] was applied if the variables could be 

dichotomized without loss of information. 

Report 30 of 756
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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 limit of ±20% with reference to the nominal content was met. 

The homogeneous distribution of in the preparations was approved because 

single results found did not deviate more than 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 formulations when kept 4 hours at room 

temperature (20 ± 5 °C) due to recoveries which met the variation limit of 10% from the timezero (homogeneity) mean value. Erroneously the 4 hours dose formulation samples were not 

stored at 37 - 40 °C (at this temperature level the 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 could 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 animals 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

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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 during the functional observational battery gave an 

indication of a test item-related effect. 

A slightly but statistically significantly lower body temperature (-1.3%) was noted in males at 

300 mg/kg bw/day. However, due to the lack of dose-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 treatment 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 consumption was slightly higher between day 8 and day 20 of the 

after pairing period (approximately 10%). Since the differences were minor, they were 

considered not to be toxicologically 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

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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 higher 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% and +10% during the pre-pairing period, +6%, 

+7%, +6% and +7% during the pairing period and +3%, +3%, +4% and +3% during the after 

pairing period (percentages refer to the 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-pairing period, +54%, +57%, 

+57% and +57% during the gestation 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 reveal any test item-related 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 and the values were within 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
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4.3.2 Clinical Biochemistry 

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

In males, the alanine aminotransferase levels were slightly, but dose-dependently increased at 

300 and 1000 mg/kg bw/day (up to 2.2-fold). These levels were in the range 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 significant differences (higher glucose 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 historical control range 

except protein at 1000 mg/kg bw/day, which was borderline to historical control data. In the 

absence of corroborating changes (especially regarding histopathology) these differences are 

therefore considered not to be toxicologically relevant. 

In females, the assessment of the clinical biochemistry data did not reveal any test item-related 

effects at any dose level. Statistically significantly higher 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

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4.4.2 Mating Performance and Fertility 

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

All females mated within the first pairing period. For one female (no. 82) in group 3, mating was 

not detected. 

The median and mean precoital times were unaffected by treatment with the test item. Mean 

precoital times were 2.9, 1.8, 2.9 and 2.6 days in groups 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-implantation loss were observed at any dose level. 

The mean number of implantations per dam was 14.7, 14.6, 14.0 and 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 ascending dose level (including female no. 96). 

153 335

157 340

157 340

157 340

Report 35 of 756
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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 only in the raw data). These 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 postnatal 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 body 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 weights or organ to brain ratios and were not 

accompanied by histopathological findings. 

No effects were observed at other dose levels or in females at any dose level. 

157 340

157 181 340

160 353

712

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4.5.2 Macroscopic Findings 

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

There were no test item-related findings noted at necropsy in males and females. 

All gross lesions recorded were 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 alterations in the liver of males. This consisted of a minimal 

degree of diffuse, midzonal/centrilobular hepatocellular 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 Litter 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% and 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

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On day 1 post partum mean pup weights were 6.3, 6.3, 6.5 and 6.2 g in order of ascending dose 

level. Also mean body weight 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 noted at macroscopic examination of F1 pups. 

188 462

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5 DISCUSSION AND CONCLUSION 

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

administration of the test item , which was administered in corn oil as vehicle 

at dosages of 100, 300, and 1000 mg/kg body weight/day, 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 pairing and gestation periods until the F1 generation reached day 4 

post partum. 

In males at 1000 mg/kg bw/day, slightly higher levels of alanine aminotransferase were observed. 

Although a relationship to treatment 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 observed and minor morphological alterations in the 

liver of males. This consisted of a minimal degree of diffuse, midzonal/centrilobular 

hepatocellular hypertrophy. This finding may be considered as adaptive in nature, within 

physiological limits and not a manifestation of frank 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 other liver alterations were recorded at this dose level. 

No test item-related effects were observed in female rats at any dose level. 

Neither clinical signs nor effects on mean food consumption, mean body weight, reproduction 

and breeding or pup development were noted at any dose level. 

Based on these results, the NOAEL (No Observed Adverse Effect Level) for general toxicity and 

the NOEL (No Observed Effect Level) for reproduction were considered to be 1000 mg/kg body 

weight/day. 

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6 REFERENCES 

1. E. Salewski: 

Arch. Exp. Path. Pharmak. 247, pp. 367-368 (1964) 

2. C.W. Dunnett: 

A Multiple Comparison Procedure for Comparing Several Treatments with a Control, 

J. Amer. Statist. Assoc. 50, pp. 1096-1121 (1955). 

3. R.G. Miller: 

Simultaneous Statistical Inference, Springer Verlag, New York (1981). 

4. R.A. Fisher: 

Statistical Methods for Research Workers, Oliver and Boyd, Edinburgh (1950). 

Report 40 of 756
7 FIGURES 

Report 41 of 756
Data of P Generation 

Report 42 of 756
14-AUG-13

 FC-GRA - 1

FOOD CONSUMPTION (G/ANIMAL/DAY) - GRAPHICS 

Data excluded from Summary Report

---

Not Reported

---

Report 43 of 756
14-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 756
14-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 756
14-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 756
14-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 756
08-AUG-13

 BW-GRA - 1

BODY WEIGHTS (G) - GRAPHICS

Data excluded from Summary Report

---

Not Reported

---

Report 48 of 756
08-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 756
08-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 756
14-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 756
14-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 756
14-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 756
08-AUG-13

 BWG-GRA - 1

BODY WEIGHT GAIN (%) - GRAPHICS

Data excluded from Summary Report

---

Not Reported

---

Report 54 of 756
08-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 756
08-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 756
14-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 756
14-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 756
14-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
20-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 756
20-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 756
20-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 756
20-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 756
20-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 756
08-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 756
08-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 756
20-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 756
20-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 756
03-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

Parameter Statistical Testing

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 756
03-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 STRENGTH BODY TEMPERATURE

 - - -

 - - *

 - - -

Report 92 of 756
14-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

Parameter Statistical Testing

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 756
14-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 756
20-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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Statistical Methods

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

Report 95 of 756
20-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 COUNT

 - - - - - -

 - - - - - -

 - - - - - -

Report 96 of 756
20-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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Statistical Methods

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

Report 97 of 756
20-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 COUNT

 - - - - - -

 - - - - - -

 - - - - - -

Report 98 of 756
14-AUG-13

 FC-SUM - 1

FOOD CONSUMPTION (G/ANIMAL/DAY) - SUMMARY 

Data excluded from Summary Report

---

Not Reported

---

Report 99 of 756
14-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 756
23-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 756
23-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 756
23-AUG-13

 FC-SUM - 1

DIFFERENCES IN FOOD CONSUMPTION (G/ANIMAL/DAY) 

Data excluded from Summary Report

---

Not Reported

---

Report 103 of 756
23-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 756
23-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 756
23-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 756
23-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 756
23-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 756
08-AUG-13

 BW-SUM - 1

BODY WEIGHTS (G) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 109 of 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
14-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 756
14-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 756
14-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 756
14-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 756
14-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 756
08-AUG-13

 BWG-SUM - 1

BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 120 of 756
08-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 756
08-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 756
08-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 756
08-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 756
08-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 756
14-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 756
14-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 756
14-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 756
14-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 756
14-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 756
08-AUG-13

 BWD-SUM - 1

DIFFERENCES IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 131 of 756
08-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 756
08-AUG-13

 BWD-SUM - 1

DIFFERENCES IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 133 of 756
08-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 756
08-AUG-13

 BWD-SUM - 1

DIFFERENCES IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 135 of 756
08-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 756
14-AUG-13

 BWD-SUM - 1

DIFFERENCES IN BODY WEIGHT GAIN (%) - SUMMARY

Data excluded from Summary Report

---

Not Reported

---

Report 137 of 756
14-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 756
14-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 756
14-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 756
14-AUG-13

 BWD-SUM - 1

DIFFERENCES IN BODY WEIGHT GAIN (%) - SUMMARY

Lactation

Full Phase Animal 96 Female Group 4

Data excluded from Summary Report

Lost Its Litter

Not Reported

---

Report 141 of 756
14-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 756
27-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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Report 143 of 756
27-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

Parameter Statistical Testing

Statistical Methods

DUNNETT

STEEL

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

significant (-)

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

Report 144 of 756
27-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 RETICULOCYTE COUNT GENERAL

DIFF.WBC COUNT (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 756
27-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 COUNT (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 756
27-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 RETICULOCYTE COUNT GENERAL

DIFF.WBC COUNT (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 756
27-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 COUNT (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 756
27-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

Parameter Statistical Testing

Data excluded from Summary Report

---

Not Reported

---

Report 149 of 756
27-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

Parameter Statistical Testing

Statistical Methods

DUNNETT

STEEL

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

significant (-)

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

Report 150 of 756
27-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 756
27-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 756
14-AUG-13

MAT-SUM - 1

MATING PERFORMANCE - SUMMARY 

Not Reported

---

Incomplete Pairing Periods

---

Report 153 of 756
14-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 756
14-AUG-13

FER-SUM - 1

FERTILITY - SUMMARY 

Not Reported

---

Report 155 of 756
14-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 756
15-AUG-13

BRE-SUM - 1

BREEDING DATA PER GROUP 

Not Reported

---

Report 157 of 756
15-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 756
15-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 756
02-DEC-13

 OW-SUM - 1

ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs

All organs reported

Not Reported

---

Report 160 of 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-DEC-13

 OW-SUM - 1

ORGAN WEIGHTS (GRAM)

Exclusions from Summary

---

Selection of Organs

All organs reported

Not Reported

---

Report 167 of 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
MAC-SUM - 1

14-AUG-13

 

MACROSCOPICAL FINDINGS - SUMMARY

ALL NECROPSIES

Not Reported

---

Report 174 of 756
MAC-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 756
MAC-SUM - 1

14-AUG-13

 

MACROSCOPICAL FINDINGS - SUMMARY

ALL NECROPSIES

Not Reported

---

Report 176 of 756
MAC-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 756
14-AUG-13

PNL-SUM - 1

DATES OF POSTNATAL AND BREEDING LOSSES OF PUPS 

Not Reported

---

Report 181 of 756
14-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
MAC-SUM - 1

15-AUG-13

 

MACROSCOPICAL FINDINGS - SUMMARY

ALL NECROPSIES

Not Reported

---

Report 188 of 756
MAC-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 756
MAC-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 756
MORT-IND - 1

14-AUG-13

 

MORTALITY DATA

ALL NECROPSIES

---

Animal(s) without death date / death status

Not Reported

---

Report 193 of 756

















































































































27-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 756
27-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 756

27-JUN-13

 HEM-IND - 4 310 of 756

27-JUN-13

 HEM-IND - 6 312 of 756
 a: See explanation on section cover page
27-JUN-13

HEM-IND - 8

 a: See explanation on section cover page

 

314 of 756
 b: See explanation on section cover page
27-JUN-13

 HEM-IND - 10 Report 316 of 756

27-JUN-13

 HEM-IND - 12 eport 318 of 756

27-JUN-13

 HEM-IND - 14 eport 320 of 756

27-JUN-13

 HEM-IND - 16 Report 322 of 756

27-JUN-13

 HEM-IND - 18 port 324 of 756
27-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 756
27-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 756

13

 4 6
-13

- 5 6
13

- 6 6
-13

- 7 56
13

 8 6


14-AUG-13

REP-IND - 1

REPRODUCTION PROCESSES 

Incomplete Pairing Period

Not Reported

---

---

Comments

---

Report 335 of 756
PL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed
PL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed
PL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed

<MM>: Mating not detected
PL: Vaginal Plug detected, SP: Sperm detected, CO: Coitus observed
15-AUG-13

BRE-IND - 1

BREEDING DATA PER LITTER 

Not Reported

---

Comments

---

Report 340 of 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-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 756
15-AUG-13

DNL-IND - 1

FEMALES NOT GIVING BIRTH 

Not Reported

---

Comments

---

Report 349 of 756
15-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 756
15-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 756
15-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 756
02-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 756












02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
02-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 756
MAC-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 756
MAC-IND - 2

14-AUG-13

 

380 of 756
MAC-IND - 3

14-AUG-13

 

381 of 756
MAC-IND - 4

14-AUG-13

 

382 of 756
MAC-IND - 5

14-AUG-13

 

383 of 756
MAC-IND - 6

14-AUG-13

 

384 of 756
MAC-IND - 7

14-AUG-13

 

385 of 756
MAC-IND - 8

14-AUG-13

 

386 of 756
MAC-IND - 9

14-AUG-13

 

387 of 756
MAC-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 756
MAC-IND - 2

14-AUG-13

 

389 of 756
MAC-IND - 3

14-AUG-13

 

390 of 756
MAC-IND - 4

14-AUG-13

 

391 of 756
MAC-IND - 5

14-AUG-13

 

392 of 756
MAC-IND - 6

14-AUG-13

 

393 of 756
MAC-IND - 7

14-AUG-13

 

394 of 756
 8

13
MAC-IND - 9

14-AUG-13

 

396 of 756
Data of F1 Pups 

Report 397 of 756
15-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 756
15-AUG-13

SYPU-IND - 2

EXTERNAL EXAMINATION AT FIRST LITTER CHECK 

Group 1 (0 mg/kg)

LACTATION

No abnormality recorded.

Report 399 of 756

15-AUG-13

SYPU-IND - 4

EXTERNAL EXAMINATION AT FIRST LITTER CHECK 

Group 3 (300 mg/kg)

LACTATION

No abnormality recorded.

Report 401 of 756
15-AUG-13

SYPU-IND - 5

EXTERNAL EXAMINATION AT FIRST LITTER CHECK 

Group 4 (1000 mg/kg)

LACTATION

No abnormality recorded.

Report 402 of 756
09-SEP-13

SYPU-IND - 1

DAILY OBSERVATION 

Incomplete Recordings

Selection of Findings

All findings reported

---

Comments

---

Not Reported

---

Report 403 of 756
09-SEP-13

SYPU-IND - 2

DAILY OBSERVATION 

Group 1 (0 mg/kg)

LACTATION

No abnormality recorded.

Report 404 of 756
09-SEP-13

SYPU-IND - 3 405 of 756
09-SEP-13

SYPU-IND - 4

DAILY OBSERVATION 

Group 3 (300 mg/kg)

LACTATION

No abnormality recorded.

Report 406 of 756
09-SEP-13

SYPU-IND - 5

DAILY OBSERVATION 

Group 4 (1000 mg/kg)

LACTATION

No abnormality recorded.

Report 407 of 756
15-AUG-13

BWPU-SUM - 1

Mean Body Weights of Pups per Litter (G)

Data excluded from Summary Report

---

Comments

---

Report 408 of 756
15-AUG-13

BWPU-SUM - 2 409 of 756
15-AUG-13

BWPU-SUM - 3 410 of 756
15-AUG-13

BWPU-SUM - 4

t 411 of 756
15-AUG-13

BWPU-SUM - 5 412 of 756
15-AUG-13

BWPU-SUM - 6

)

rt 413 of 756
15-AUG-13

BWPU-SUM - 7 414 of 756
15-AUG-13

BWPU-SUM - 8

)

rt 415 of 756
15-AUG-13

BWPU-SUM - 9 416 of 756
15-AUG-13

BWPU-IND - 1

Body Weights of Pups

Not Reported

---

Comments

---

Data excluded from Summary Report

---

Report 417 of 756





















PUP-IND - 1

02-DEC-13

INDIVIDUAL PUP DATA 

Comments

---

Not Reported

---

Report 439 of 756






















MAC-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 

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APPENDIX II 

Chemical Analysis of Feed 

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APPENDIX III 

Drinking Water Analysis 

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 1 

APPENDIX IV 

Formulation Analysis 

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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 Application Formulation Analysis ................................................7 

Table 2 Example of Calibration Curve ......................................................................................8 

LIST OF FIGURES 

Figure 1 Typical HPLC-Chromatograms of Calibration Solutions.............................................9 

Figure 2 Typical HPLC-Chromatograms of Test Samples .......................................................10 

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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 the analytical laboratories internally (at room 

temperature and backup samples: on ice) 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 was exactly weighed into a head space vial, 

1.020 mL derivatization reagent was added and incubated 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 concentration of 406.4 μg/mL. Aliquots of this stock 

standard solution were used to prepare working 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. 

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 4 

1.4.2 Work up of Samples 

The samples received were well homogenized and derivatized with derivatization 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 concentration 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 peak areas of with reference 

to the calibration curve. The latter was obtained by correlation of the peak areas of the 

calibration solutions with their corresponding concentrations [μg/mL], using the linear 

regression model following equation 1: 

y = a + b ⋅ x (1) 

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Formulation Analysis Page 5 

where 

y = Response for 

a = Intercept derived from linear regression of calibration data 

b = Slope derived from linear regression of calibration data 

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

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

dilution using equation 2: 

⋅1000

⋅⋅ = WDVx Cact (2) 

where 

Cact = 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 [%]

Cact = Actual sample concentration [mg/mL]

Cnom = Nominal sample concentration [mg/mL]

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 6 

2 RESULTS 

The linearity of the analytical system used for sample analyses was demonstrated with a good 

relationship between peak areas measured and calibration solution concentrations. All calibration 

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

linear regression analysis. The coefficients of determination (R2

) calculated were found to be 

better than 0.99. An example is presented in Table 2.

The derivative peak was assigned 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 absence of the test item 

in the vehicle control samples (corn oil) was confirmed. Examples of chromatograms are shown 

in Figure 1 and Figure 2. 

The concentrations in the dose formulations ranged from 86.1% to 112.2% 

and thus, the required content limit of ±20% with reference to the nominal content was met. 

The homogeneous distribution of in the preparations was approved because 

single results found did not deviate more than 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 formulations when kept 4 hours at room 

temperature (20 ± 5 °C) due to recoveries which 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 preparation and storage of the test item 

 in vehicle during this study. 

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 7 

TABLES 

Table 1 Detailed Results of Application Formulation Analysis 

 (Rounded results presented are based on calculations with exact data) 

Dose 

Group

Sample taken 

from/after

Date of 

Analysis

Nominal 

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) 

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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

R2

 = 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]

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 9 

FIGURES 

Figure 1 Typical HPLC-Chromatograms 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) 

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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) 

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Experimental Completion Date: 22 Jun-2013 

Formulation Analysis Page 11 

Figure 2 Cont’d 

(C) Dose group 4 (top), nominal concentration:200 mg/mL, 5065x diluted 

 Date of analysis: 13 May 2013 

(C) 

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APPENDIX V 

Functional Observational Battery 

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Scoring for the Functional Observational Battery 

Home cage 

Faeces-balls 

Scores: 0 Faeces normal 

 1 Faeces soft but round 

 2 Faeces loose 

Discoloration of Urine 

Scores: 0 Urine normal 

 1 Urine discolored 

Ventral -/lateral recumbency 

Scores: 0 Posture normal 

 1 Ventral -/lateral recumbency 

Ruffled fur 

Scores: 0 Fur normal 

 1 Slight ruffled fur over whole body or just on neck 

 2 Ruffled fur over whole body 

Observations in the hand 1 

Lifting 

Scores: 0 Can be lifted up with ease 

 1 Animal fearful, escapes or defensive 

 2 Animal aggressive, bites or grinds its teeth 

Vocalisation 

Scores: 0 No vocalisation 

 1 Spontaneous vocalisation, when held in hand 

 2 Vocalisation for > 10 sec. 

Muscle tone reduced 

Scores: 0 Animal with normal muscle tone 

 1 Animal limp (muscular hypotonus) 

 

Muscle tone increased 

Scores: 0 Animal with normal muscle tone 

 1 Animal stiff (muscular hypertonus) 

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Scoring for the Functional Observational Battery 

Open field observations (type 4-cage) 

Activity reduced 

Scores: 0 Normal activity 

 1 Animal quiet, reduced activity 

 2 Animal apathetic, hardly moves 

Activity increased 

Scores: 0 Normal activity 

 1 Increased activity 

 2 Restlessness, rapid movements 

Gait 

Scores: 0 Gait normal 

 1 Uncoordinated movements 

 2 Inability to move limbs 

Hunch back 

Scores: 0 Posture normal 

 1 Hunch back 

Straub tail 

Scores: 0 No straub tail 

 1 Straub tail present 

Spasms 

Scores: 0 No spasm 

 1 Spasms 

Convulsions 

Scores: 0 No convulsions 

 1 Bouts of muscle contractions affecting whole body, alternating tension and relaxation of muscles 

(clonic convulsions) 

 2 Bouts of longer contractions of muscles affecting whole body, body stretched out (tonic convulsions) 

 3 Alternating clonic and tonic convulsions 

Stereotypes 

Scores: 0 No stereotypes 

 1 Stereotypic movements interspersed by normal movements 

 2 Restless, violent and compulsive movements 

Ruffled fur 

Scores: 0 Fur normal 

 1 Slight ruffled fur over whole body or just on neck 

 2 Ruffled fur over whole body 

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Scoring for the Functional Observational Battery 

Open field observations (type 4-cage), cont’d 

Fur unkempt 

Scores: 0 Fur normal 

 1 Fur seems unkempt (dull, dirty or fur stuck together) 

Respiration slow 

Scores: 0 Respiration normal 

 1 Respiration slow 

Respiration accelerated 

Scores: 0 Respiration normal 

 1 Respiration accelerated 

Rales 

Scores: 0 No rales 

 1 Rales 

Rearings decreased 

The number of rearings (free-standing or against wall). Fore paws must be at least 1 cm above ground. 

Scores: 0 Rearing normal 

 1 Rearing decreased ( n < 3) 

 

Rearings increased 

The number of rearings (free-standing or against wall). Fore paws must be at least 1 cm above ground. 

Scores: 0 Rearings normal 

 1 Rearing increased (n > 8) 

Number of Faeces-balls 

Scores: 0 Number of Faeces-balls normal 

 1 Number of Faeces-balls increased (n > 3) 

Puddles of urine 

Scores: 0 No or few puddles of urine 

 1 Several puddles of urine 

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Scoring for the Functional Observational Battery 

Observations in the hand 2 

Emaciated 

Scores: 0 Animal normal 

 1 Animal emaciated 

Dehydration 

Scores: 0 Animal normal 

 1 Animal dehydrated 

Abdomen distended 

Scores: 0 Abdomen normal 

 1 Abdomen distended 

Skin cold to touch 

Scores: 0 Skin feels normal 

 1 Skin cold when touched 

Colouration of skin 

Scores: 0 Skin normal colour 

 1 Skin pale 

 2 Skin bluish 

Settings of eyes 

Scores: 0 Normal eyes 

 1 Exophthalmos 

 2 Enophthalmos 

Lacrimation 

Scores: 0 No lacrimation 

 1 Watery eyes 

 2 Obvious lacrimation, skin wet around eye 

Chromodacryorrhea 

Scores: 0 No chromodacryorrhea 

 1 Dark red, dry scab around eye (chromodacryorrhea) 

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Scoring for the Functional Observational Battery 

Observations in the hand 2, cont’d 

Palpebral closure 

Score: 0 Lid open 

 1 Lid 1⁄3 to completely closed 

Pupil size decreased 

Scores: 0 Normal size 

 1 Size decreased 

Pupil size increased 

Scores: 0 Normal size 

 1 Size increased 

Nasal mucous 

Scores: 0 No nasal mucous 

1 Slight nasal mucous running out of nose 

2 Severe nasal mucous 

Chromorhinorrhea 

Scores: 0 No chromorhinorrhea 

 1 Dark red, dried scab around nose (chromorhinorrhea) 

Salivation 

Scores: 0 No salivation 

 1 Chin wet or bedding stuck to chin 

 2 Salivation visibly dripping out of mouth 

Hair loss 

Scores: 0 No hair loss 

 1 Localised hair loss or thin fur 

 2 Gerneralised hair loss 

Mass 

Raised, defined mass under the skin 

Scores: 0 No mass detected 

1 Size smaller than 1 cm 

2 Size bigger than 1 cm 

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Scoring for the Functional Observational Battery 

Reflexes 

Blinking 

Scores: 0 Blinking 

 1 No blinking 

Pinna reflex 

Scores: 0 Auricle twitches 

 1 No visible twitch of auricle 

Pupillary reflex 

Scores: 0 Reaction of the iris 

 1 No reaction of the iris 

Extensor thrust response 

Scores: 0 Thrust of the hindlimbs 

 1 No thrust of the hindlimbs 

Pain 

Scores: 0 Retraction of foot 

 1 No retraction of foot 

Click response 

Scores: 0 Animal flinches 

 1 Animal does not flinch 

Righting reflex 

Scores: 0 Animal turns over and stands up 

 1 Animal does not turn over 

Hearing ability (Preyer’s Reflex) 

Scores: 0 Reflex reaction present 

 1 Reflex reaction absent 

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APPENDIX VI 

Clinical Laboratory Investigations 

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CLINICAL LABORATORY INVESTIGATIONS 

Blood Sampling: 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 post partum. Blood samples were drawn sublingually from all 

animals under light isoflurane anesthesia. The animals were fasted for approximately 18 hours 

before blood sampling but allowed access to water ad libitum. The samples were collected early 

in the working day to reduce biological variation caused by circadian rhythms. 

In the summary and individual tables the names of some parameters have been abbreviated. Any 

abbreviation has been defined in this section. Clinical laboratory data are expressed, with a few 

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

Key to Abbreviations of Units: 

L liter g gram m milli (10-3) 

mol mole G giga (109) μ micro (10-6) 

sec seconds T tera (1012) f femto (10-15) 

U Unit 

Hematology 

The following anticoagulants were used during blood collection: 

Complete Blood Cell Count: Tri-potassium-EDTA 

Coagulation: Sodium citrate, 3.2% (1 part anticoagulant to 9 parts 

blood) 

Complete Blood Cell Count 

Parameter Abbreviation Unit Instrumentation 

Erythrocyte count RBC T/L Advia 1201

Hemoglobin HB mmol/L Advia 120 

Hematocrit HCT rel.1 Advia 120 

Mean corpuscular volume MCV fL Advia 120 

Red cell volume distribution width RDW rel.1 Advia 120 

Mean corpuscular hemoglobin MCH fmol Advia 120 

 

1

 ADVIA 120 hematology system (Siemens) 

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Parameter Abbreviation Unit Instrumentation 

Mean corpuscular hemoglobin 

concentration 

MCHC mmol/L Advia 120 

Hemoglobin concentration 

distribution width 

HDW mmol/L Advia 120 

 

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 

Coagulation 

Parameter Abbreviation Unit Method Instrumentation 

Prothrombin time 

(=Thromboplastin time)

PT rel. 1 Clotting assay, thromboplastin 

from rabbit brain tissue, results 

as ratio of normal activity 

STA2

 

Activated partial 

thromboplastin 

time 

PTT sec Clotting assay, cephalin from 

rabbit cerebral tissue, silica 

surface activator 

STA 

 

2

 STA-compact analyzer (Roche Diagnostics) 

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 6000/5013

Urea mmol/L Urease/GLDH Cobas 6000/501 

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

Bilirubin, total* BILI-T μmol/L Reaction with 2,5-Dichlorophenyl-diazonium salt Cobas 6000/501 

Bile acids BILE AC μmol/L Colorimetric, enzymatic 

(3α-HSD, Diaphorase) 

Cobas 6000/501 

Cholesterol, total CHOLEST mmol/L Enzymatic, CHOD/PAP Cobas 6000/501 

Triglycerides TRIGLY mmol/L Glycerol-Kinase 

GPO/PAP method 

Cobas 6000/501 

Aspartate 

aminotransferase 

EC 2.6.1.14

ASAT U/L 

37 oC 

ALT/MDH Cobas 6000/501 

Alanine 

aminotransferase 

EC 2.6.1.2 

ALAT U/L 

37 oC 

ALT/LDH Cobas 6000/501 

Alkaline 

phosphatase 

EC 3.1.3.1 

ALP U/L 

37 oC 

p-Nitrophenyl-phosphate as 

substrate 

Cobas 6000/501 

Gamma-glutamyl 

transferase 

EC 2.3.2.2 

GGT U/L 

37 oC 

Substrate: L-gammaglutamyl-3-carboxy4-nitroanilide Cobas 6000/501 

Sodium mmol/L Ion selective electrode Cobas 6000/501 

Potassium mmol/L Ion selective electrode Cobas 6000/501 

Chloride mmol/L Ion selective electrode Cobas 6000/501 

Calcium mmol/L o-Cresolphthalein 

complexone method 

Cobas 6000/501 

Phosphorus mmol/L Phosphomolybdate reaction Cobas 6000/501 

Protein, total PROTEIN g/L Biuret reaction Cobas 6000/501 

Albumin g/L Bromocresol green method Cobas 6000/501 

 

3

 Cobas 6000 analyzer, Roche Diagnostics 

4

 Identification of enzymes with EC-Number (Enzyme Commission) according to Enzyme Nomenclature, 

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

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. 

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HISTORICAL DATA - HEMATOLOGY 

 

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HISTORICAL DATA - HEMATOLOGY 

 

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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 Toxicity 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 Statement ..........................................................................................................4 

Summary .........................................................................................................................................5 

Materials and Methods....................................................................................................................6 

Results .............................................................................................................................................9 

Conclusions ...................................................................................................................................10 

Table 1 Incidence All Macroscopic Findings............................................................................11 

Table 2 Incidence Selected Microscopic Finding with Grades .................................................12 

Table 3 Incidence Microscopic Findings - Reproductive Organs .............................................13 

Table 4 Incidence All Microscopic Findings.............................................................................15 

Table 5 Individual Animal Microscopic Findings.....................................................................22 

Table 6 Animal Data List ..........................................................................................................39 

Table 7 Individual Animal Data Records ..................................................................................43 

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PATHOLOGY REPORT Page 3/128 

Statement of Compliance 

The undersigned hereby declares, that the histopathology data in this report were compiled by 

him, and that they reflect accurately the primary data records. This report, consisting of 128 

pages, was created by the computer system of

This study phase was conducted in compliance with: 

Swiss Ordinance relating to Good Laboratory Practice, adopted May 18^'\5 [SR 813.112.1]. 

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

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

Principal Investigator - Toxicologic Pathologist 

Date: ^icALin S 

Report 568 of 756
PATHOLOGY REPORT Page 4/128 

Quality Assurance Statement 

The faciUties of are periodically (4x/year) inspected by the Quality Assurance 

Unit (CERTUS Quality Assurance Services GmbH). This report was inspected by the Quality 

Assurance Unit (CERTUS). 

The respective dates are given below: 

Inspection type Date(s) of inspection Date(s) of reporting 

Facility based inspection (latest): 15.11.2013 15.11.2013 

Review of relevant sections of study 

plan: 

19.09.2013 19.09.2013 

Phase report inspection: 06.11.2013 06.11.2013 

The findings were reported to the test facility ( ) management (only inspection of test 

facility (test site) , the principal investigator, the study director, the management of the 

test facility of the study director and the "lead QA". 

The methods, procedures and observations described were found to be accurately described and 

the reported results to reflect the raw data 

Date: fJo^h^ ^^-^2 

Report 569 of 756
PATHOLOGY REPORT Page 5/136 

Summary 

Pathomorphologic examination was 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 doses 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 rats of the control group 1 (0 mg/kg bw/day) 

received the vehicle, corn oil, alone. 

 

All rats were necropsied. Histopathologic examination 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 organs and tissues from five males and five 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 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). There was no morphological evidence to associate the failure to deliver 

with treatment with the test item. 

There were no macroscopic findings related to treatment. 

There were minor morphological 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 considered 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 the vehicle, corn oil, alone. 

 

Necropsy and Histopathology 

At the end of the assigned study periods, the rats were killed by exsanguination following 

anesthesia by an injection of sodium pentobarbital. Complete necropsies were performed on all 

rats. Testes and epididymides were weighed individually from all males at necropsy. From the 5 

selected animals/sex/group the terminal body weight and the weights 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 organs from all animals were preserved in 4% 

phosphate buffered neutral formaldehyde solution (10% formalin). Testes and epididymides 

were initially fixed in modified 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 nerve 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 

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Materials and Methods

mesenteric (1); male and female mammary gland area, nasal cavity, ovaries (2), 

oviducts (2), pancreas, pharynx, pituitary gland, prostate gland (1), salivary glands – 

mandibular and sublingual; sciatic nerve (2), seminal vesicles (2) with coagulation 

glands (2), skeletal muscle, small intestine - duodenum, 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 group 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 listed 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 with hematoxylin and eosin. 

Extra sections of testes stained 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 

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Materials and Methods

The sections were examined by light microscopy in September/October 2013. 

Data Compilation 

The animal data and macroscopic findings were electronically transferred 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 full descriptive terms in Table 7 - Individual Animal Data Records. Wherever possible, 

macroscopic findings were correlated with a microscopic finding. 

Microscopic findings are listed for each animal along with severity grades in Table 5 - Individual 

Animal Microscopic Findings and summarized in Table 2 - Incidence Selected Microscopic 

Finding with Grades, Table 3 - Incidence Microscopic Findings - Reproductive Organs and 

Table 4 - Incidence All Microscopic Findings. They are further given in full descriptive terms in 

Table 7 - Individual Animal Data Records. Histologic changes were described according to their 

distribution and morphologic character and were graded for severity on a scale of 1 – 5 (see key 

Table 5 - Individual Animal Microscopic Findings). 

Archiving

The original final pathology report, all slides, dispatch list(s) and raw data provided will be sent 

to the test facility. The test facility is responsible for the transfer 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. 

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Results 

Mortality 

There were no unscheduled deaths. 

Macroscopic Findings 

The few recorded macroscopic findings were considered to be spontaneous in nature and did not 

distinguish treated animals from the controls. There were four females 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 note was recorded in the liver of group 4 

(1000 mg/kg bw/day) males and consisted of a minimal degree of diffuse, midzonal/centrilobular 

hepatocellular hypertrophy recorded in 3/5 rats. 

Ovary morphology was normal in the animals which 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. 

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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 total of 28 days dosing 

for males and approximately six weeks for females, there were minor morphological 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 considered to be 1000 mg/kg bw/day. 

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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 

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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 

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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

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 

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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 

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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 

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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 

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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 

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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 

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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 

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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 

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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 

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