Page 1 of 640 

REPORT 

BENZOFLEX 1046: 

Oral (Gavage) Combined Repeat Dose Toxicity Study with 

Reproduction/Developmental Toxicity Screening Test in the 

Rat (OECD 422 with Recovery Groups) 

Study Director: J Dunster 

Test Facility: Harlan Laboratories Ltd. 

Shardlow Business Park 

Shardlow 

Derbyshire 

DE72 2GD 

UK 

Sponsor: Eastman Chemical Company 

100 North Eastman Road 

P.O. Box 511 

Kingsport 

TN 37662-5054 

USA 

 

Harlan Study Number: 41204605 

Study Completion Date: 13 November 2013 
Harlan Study Number: 41204605 Report Page 2 

This page has intentionally been left blank 
Harlan Study Number: 41204605 Report Page 3 

CONTENTS 

CONTENTS .................................................................................................................................... 3

STUDY DIRECTOR STATEMENT OF GLP COMPLIANCE .................................................... 9

QUALITY ASSURANCE STATEMENT.................................................................................... 11

SIGNATURE OF MANAGEMENT ............................................................................................ 13

SUMMARY .................................................................................................................................. 15

Introduction .......................................................................................................................... 15

Methods....... ...................................................................................................................... 15

Results....... ......................................................................................................................... 16

Adult Responses .................................................................................................................. 16

Mortality .............................................................................................................................. 16

Clinical Observations ........................................................................................................... 16

Behavioural Assessment ...................................................................................................... 16

Functional Performance Tests ............................................................................................. 16

Sensory Reactivity Assessments .......................................................................................... 16

Body Weight ........................................................................................................................ 16

Food Consumption ............................................................................................................... 17

Water Consumption ............................................................................................................. 17

Reproductive Performance .................................................................................................. 17

Mating ............................................................................................................................... 17

Fertility ............................................................................................................................... 17

Gestation Lengths ................................................................................................................ 17

Litter Responses ................................................................................................................... 17

Offspring Litter Size, Sex Ratio and Viability .................................................................... 17

Offspring Growth and Development ................................................................................... 18

Laboratory Investigations .................................................................................................... 18

Haematology ........................................................................................................................ 18

Blood Chemistry .................................................................................................................. 18

Urinalysis ............................................................................................................................. 18

Pathology ............................................................................................................................. 18

Necropsy .............................................................................................................................. 18

Organ Weights ..................................................................................................................... 18

Histopathology ..................................................................................................................... 19

Conclusion ........................................................................................................................... 19

GENERAL INFORMATION ....................................................................................................... 20

Schedule ............................................................................................................................... 20

Animal Welfare .................................................................................................................... 20

Multi – Site Study Details .................................................................................................... 20

Additional Responsibilities .................................................................................................. 21

Deviations from Study Plan ................................................................................................. 21

Archiving ............................................................................................................................. 22

1 INTRODUCTION AND PURPOSE ................................................................................... 23

1.1 Guidelines / Regulations ........................................................................................ 23

2 TEST ITEM ......................................................................................................................... 24

2.1 Test Item ................................................................................................................ 24
Harlan Study Number: 41204605 Report Page 4 

3 MATERIALS AND METHODS ........................................................................................ 24

3.1 Test System ........................................................................................................... 24

3.1.1 Animals and Animal Husbandry ............................................................. 24

3.1.2 Justification ............................................................................................. 25

3.2 Test Item Preparation ............................................................................................ 25

3.3 Procedure ............................................................................................................... 26

3.3.1 Chronological Sequence of Study ........................................................... 26

3.3.1.1 Non-Recovery Dose Groups ................................................................... 26

3.3.1.2 Recovery Dose Groups ........................................................................... 27

3.4 Observations .......................................................................................................... 27

3.4.1 Clinical Observations .............................................................................. 27

3.4.2 Functional Observations .......................................................................... 27

3.4.2.1 Behavioural Assessments ........................................................................ 27

3.4.2.2 Functional Performance Tests ................................................................. 28

3.4.2.3 Sensory Reactivity .................................................................................. 28

3.4.3 Body Weight ........................................................................................... 29

3.4.4 Food Consumption .................................................................................. 29

3.4.5 Water Consumption ................................................................................ 29

3.4.6 Reproductive Performance ...................................................................... 29

3.4.6.1 Mating ..................................................................................................... 30

3.4.6.2 Pregnancy and Parturition ....................................................................... 30

3.4.6.3 Litter Data ............................................................................................... 30

3.4.6.4 Physical Development ............................................................................. 30

3.4.7 Laboratory Investigations ........................................................................ 31

3.4.7.1 Haematology ........................................................................................... 31

3.4.7.2 Blood Chemistry ..................................................................................... 32

3.4.7.3 Urinalysis ................................................................................................ 32

3.4.8 Pathology ................................................................................................. 32

3.4.8.1 Necropsy ................................................................................................. 32

3.4.8.2 Organ Weights ........................................................................................ 33

3.4.8.3 Histopathology ........................................................................................ 33

3.4.9 Evaluation of Data ................................................................................... 35

3.4.9.1 Treatment of Data ................................................................................... 35

3.4.9.2 Reproductive Indices ............................................................................... 35

3.4.9.3 Litter Responses ...................................................................................... 36

3.4.9.4 Statistical Analysis .................................................................................. 37

4 RESULTS AND DISCUSSION .......................................................................................... 39

4.1 Results ................................................................................................................... 39

4.1.1 Adult Reponses ....................................................................................... 39

4.1.1.1 Mortality .................................................................................................. 39

4.1.1.2 Clinical Observations .............................................................................. 39

4.1.1.3 Functional Observations .......................................................................... 39

4.1.1.4 Body Weight ........................................................................................... 40

4.1.1.5 Food Consumption .................................................................................. 41

4.1.1.6 Water Consumption ................................................................................ 41

4.1.2 Reproductive Performance ...................................................................... 41
Harlan Study Number: 41204605 Report Page 5 

4.1.2.1 Mating ..................................................................................................... 41

4.1.2.2 Fertility .................................................................................................... 41

4.1.2.3 Gestation Length ..................................................................................... 42

4.1.3 Litter Responses ...................................................................................... 42

4.1.3.1 Offspring Litter Size, Sex Ratio and Viability ........................................ 42

4.1.3.2 Offspring Growth and Development ....................................................... 42

4.1.4 Laboratory Investigations ........................................................................ 43

4.1.4.1 Haematology............................................................................................ 43

4.1.4.2 Blood Chemistry ...................................................................................... 43

4.1.4.3 Urinalysis ................................................................................................. 44

4.1.5 Pathology ................................................................................................. 44

4.1.5.1 Necropsy .................................................................................................. 44

4.1.5.2 Organ Weights ......................................................................................... 45

4.1.5.3 Histopathology ........................................................................................ 45

4.2 Discussion .............................................................................................................. 46

5 CONCLUSION .................................................................................................................... 47

6 REFERENCES .................................................................................................................... 48

TABULAR SUMMARY REPORT OF EFFECTS OF 

REPRODUCTION/DEVELOPMENT ................................................................................ 49

KEY TO TABLES AND APPENDICES ..................................................................................... 50

KEY TO SCORING SYSTEM AND EXPLANATION FOR BEHAVIOURAL 

ASSESSMENTS AND SENSORY REACTIVITY TESTS ............................................... 51

TABLES ........................................................................................................................................ 57

FIGURES .................................................................................................................................... 153

APPENDICES ............................................................................................................................. 163

LIST OF TABLES 

Table 1 Summary of Reproductive Performance - Groups Values .................................... 58

Table 2 Summary Incidence of Daily Clinical Observations ............................................. 59

Table 3 Summary Incidence of Behavioural Assessments (Observations) ........................ 61

Table 4 Summary Incidence of Behavioural Assessments (Scores) .................................. 65

Table 5 Group Mean Functional Test Values and Standard Deviations ............................ 79

Table 6 Summary Incidence of Sensory Reactivity Assessments (Scores) ........................ 81

Table 7 Group Mean Body Weight Values ........................................................................ 83

Table 8 Group Mean Body Weight Gains .......................................................................... 88

Table 9 Group Mean Food Consumptions .......................................................................... 93

Table 10 Food Efficiency ..................................................................................................... 98

Table 11 Group Mean Daily Water Consumptions ............................................................ 102

Table 12 Summary Incidence of Mating Performance, Fertility and Gestation 

Lengths ................................................................................................................ 117

Table 13 Group Mean Litter Size and Litter Weights ........................................................ 118

Table 14 Group Mean Implantation Losses and Survival Indices Values .......................... 119

Table 15 Group Mean Sex Ratio Values ............................................................................ 120

Table 16 Summary Incidence of Clinical Signs for Offspring ........................................... 121
Harlan Study Number: 41204605 Report Page 6 

Table 17 Group Mean Reflexological Responses for Offspring ........................................ 122

Table 18 Group Mean Haematological Values .................................................................. 123

Table 19 Group Mean Blood Chemical Values ................................................................. 127

Table 20 Summary Incidence of Urinalytical Findings ..................................................... 135

Table 21 Summary Incidence of Offspring Necropsy Findings ......................................... 137

Table 22 Summary Incidence of Necropsy Findings ......................................................... 138

Table 23 Group Mean Organ Weights with Corresponding Relative (% of 

Body Weight) Organ Weights ............................................................................. 140

LIST OF FIGURES 

Figure 1 Group Mean Body Weights - Males .................................................................... 154

Figure 2 Group Mean Body Weights - Females ................................................................ 156

Figure 3 Group Mean Food Consumption - Males ............................................................ 159

Figure 4 Group Mean Food Consumption – Females ........................................................ 160

LIST OF APPENDICES 

Appendix 1 Individual Daily Clinical Observations ............................................................... 164

Appendix 2 Individual Behavioural Assessments (Observations) .......................................... 196

Appendix 3 Individual Behavioural Assessments (Scores) .................................................... 204

Appendix 4 Individual and Group Mean Functional Test Values (Grip Strength) ................. 260

Appendix 5 Individual and Group Mean Functional Test Values (Motor 

Activity) ............................................................................................................... 268

Appendix 6 Individual Sensory Reactivity Assessments ........................................................ 276

Appendix 7 Individual and Group Mean Body Weights ........................................................ 284

Appendix 8 Individual and Group Mean Body Weight Gains ................................................ 300

Appendix 9 Individual and Group Mean Food Consumption Values for Females 

Following Mating and During Lactation ............................................................. 316

Appendix 10 Individual and Group Mean Water Consumption Values for 

Females Following Mating and Lactation ........................................................... 320

Appendix 11 Individual Mating Performance, Fertility and Gestation Lengths ....................... 324

Appendix 12 Individual and Group Mean Litter Size and Litter Weights ................................ 328

Appendix 13 Individual and Group Mean Implantation Losses and Survival 

Indices ................................................................................................................. 332

Appendix 14 Individual and Group Mean Sex Ratio Values for Offspring ............................. 336

Appendix 15 Individual Clinical Signs for Offspring ............................................................... 340

Appendix 16 Individual and Group Mean Reflexological Responses for 

Offspring ............................................................................................................. 344

Appendix 17 Individual Haematological Values ...................................................................... 348

Appendix 18 Individual Coagulation Values ............................................................................ 360

Appendix 19 Individual Blood Chemical Values ..................................................................... 372

Appendix 20 Individual Bile Acid Values ................................................................................ 384
Harlan Study Number: 41204605 Report Page 7 

Appendix 21 Individual and Group Mean Urinalytical Findings .............................................. 396

Appendix 22 Individual Necropsy Findings for Offspring ....................................................... 402

Appendix 23 Individual Necropsy Findings ............................................................................. 406

Appendix 24 Individual Organ Weights ................................................................................... 414

Appendix 25 Individual Relative Organ Weights ..................................................................... 426

Appendix 26 Histopathology Phase Report .............................................................................. 444

Appendix 27 Analytical Investigations ..................................................................................... 583

Appendix 28 Study Plan ............................................................................................................ 594

Appendix 29 Histology Processing Phase Test Site Quality Assurance Statement .................. 623

Appendix 30 Histology Processing Phase Test Site Statement of Compliance ........................ 624

Appendix 31 Histology Processing Phase Test Site Statement of GLP 

Compliance .......................................................................................................... 625

Appendix 32 Certificates of Analysis of Diet Used .................................................................. 626

Appendix 33 Laboratory Methods ............................................................................................ 630

Appendix 34 Normal Ranges for Reproductive Parameters in the Pregnant and 

Lactating Female Wistar HanTM:RccHanTM:WIST Strain Rat ............................ 633

Appendix 35 Normal Ranges for Offspring Parameters in the Wistar HanTM: 

RccHanTM:WIST Strain Rat ................................................................................ 634

Appendix 36 Normal Ranges for Haematological and Blood Chemical Values in 

the Wistar HanTM:RccHanTM:WIST Strain Rat ................................................... 635

Appendix 37 Normal Ranges for Absolute and Body Weight-Relative Organ 

Weight Values in the Wistar HanTM:RccHanTM:WIST Strain Rat ...................... 637

Appendix 38 Certificate of Analysis of the Test Item ............................................................... 639

Appendix 39 Monitoring Authority Statement of GLP Compliance ........................................ 640
Harlan Study Number: 41204605 Report Page 8 

This page has intentionally been left blank 
   
Harlan Study Number: 41204605 Report Page 10 

This page has intentionally been left blank 
   
Harlan Study Number: 41204605 Report Page 12 

This page has intentionally been left blank 

Harlan Study Number: 41204605 Report Page 14 

This page has intentionally been left blank 
Harlan Study Number: 41204605 Report Page 15 

SUMMARY 

Introduction 

The study was designed to investigate the systemic toxicity and potential adverse effects of the 

test item on reproduction (including offspring development) and is designed to be compatible 

with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined 

Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” 

(adopted 22 March 1996). 

Methods.......

The test item was administered by gavage to three groups, each of twelve male and twelve 

female Wistar HanTM:RccHanTM:WIST strain rats, for up to eight weeks (including a two week 

pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 30, 60 and 

120 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle 

alone (Arachis oil BP). Two recovery groups, each of five males and five females, were treated 

with the high dose (120 mg/kg bw/day) or the vehicle alone for forty-two consecutive days and 

then maintained without treatment for a further fourteen days. 

Clinical signs, behavioural assessments, body weight change and food and water consumption 

were monitored during the study. 

Pairing of non-recovery animals within each dose group was undertaken on a one male: one 

female basis within each treatment group on Day 15 of the study, with females subsequently 

being allowed to litter and rear their offspring to Day 5 of lactation. 

During the lactation phase, daily clinical observations were performed on all surviving offspring, 

together with litter size and offspring weights and assessment of surface righting reflex. 

Extensive functional observations were performed on five selected non-recovery males from 

each dose group after the completion of the pairing phase, and for five selected parental females 

from each dose group on Day 4 post partum. Urinalysis was performed on five non-recovery 

males per dose group during the final week of treatment and five non-recovery males and 

females from each dose group were selected for haematology and blood chemistry assessments 

prior to termination. 

Adult non-recovery males were terminated on Day 43, followed by the termination of all females 

and offspring on Day 5 post partum. Any female which did not produce a pregnancy was 

terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy 

examination and histopathological evaluation of selected tissues was performed. 

Following forty-two days of treatment, recovery group animals were maintained without 

treatment for a further fourteen days. Urinalysis was performed on all recovery group males 

during the final week of the treatment period. In addition, haematological and blood chemical 
Harlan Study Number: 41204605 Report Page 16 

assessments were performed on all recovery group animals at the end of the treatment-free 

period. These animals were then subjected to a gross necropsy. 

Results.......

Adult Responses 

Mortality 

There were no unscheduled deaths. 

Clinical Observations 

There were no clinically observable signs of toxicity detected during the study. 

Behavioural Assessment 

No treatment-related effects were detected. 

Functional Performance Tests 

No treatment-related effects were detected. 

Sensory Reactivity Assessments 

There were no treatment-related changes in sensory reactivity. 

Body Weight 

Actual body weight losses and reduced body weight gains were evident for some animals of 

either sex treated with 120 mg/kg bw/day when compared to controls. Reduced body weight 

gains were also evident during the first two weeks of treatment for animals of either sex treated 

with 60 mg/kg bw/day. 

Reduced body weight gains were evident for females treated with 120 and 60 mg/kg bw/day 

throughout the gestation phase, when compared to controls. 
Harlan Study Number: 41204605 Report Page 17 

Actual body weights were lower for treated females during the study when compared to controls. 

For recovery animals, high dose males showed a reduction in body weight gains and actual body 

weight losses when compared to controls during the first three weeks of treatment, with recovery 

thereafter. 

Food Consumption 

Reduced dietary intake was evident for males treated with 120 and 60 mg/kg bw/day. Females at 

all dose levels showed a reduction in dietary intake during the pre-pairing phase when compared 

to controls. Reductions in dietary intake at all dose levels were also evident during gestation 

when compared to controls. 

Water Consumption 

Daily measurements of water bottles did not reveal any significant intergroup differences. 

Reproductive Performance 

Mating 

No treatment-related effects were detected in mating performance. 

Fertility 

There were no treatment-related changes detected in fertility. 

Gestation Lengths 

No treatment-related effects were detected in the length of gestation between control and treated 

groups. 

Litter Responses 

Offspring Litter Size, Sex Ratio and Viability 

One female treated with 120 mg/kg bw/day showed both corpora lutea and implantation sites, 

but did not produce a litter. Furthermore, there were two total litter losses observed at 120 mg/kg 

bw/day. 
Harlan Study Number: 41204605 Report Page 18 

No differences in sex ratio or litter size were evident for offspring from treated litters when 

compared to those from the controls. No significant differences in the number or corpora lutea 

or implantation sites were noted for treated females when compared to controls. The percentages 

of pre- and post-implantation loss for treated females were comparable to controls. 

Offspring Growth and Development 

No significant differences in litter weights or offspring weights were evident in the treated 

groups when compared to controls. There were no clinically observable signs of toxicity 

observed in offspring, or any macroscopic abnormalities detected at terminal kill. 

Laboratory Investigations 

Haematology 

There were no toxicologically significant changes detected in the haematology parameters 

investigated. 

Blood Chemistry 

There were no toxicologically significant changes detected in the blood chemical parameter 

investigated. 

Urinalysis 

There were no treatment-related changes detected. 

Pathology 

Necropsy 

There were no treatment-related macroscopic abnormalities detected. 

Organ Weights 

There were no toxicologically significant organ weight changes detected. 
Harlan Study Number: 41204605 Report Page 19 

Histopathology 

Histopathological examinations did not reveal any treatment-related changes. 

Conclusion 

The oral administration of Benzoflex 1046 to rats by gavage, at dose levels of 120, 60 and 

30 mg/kg bw/day, resulted in treatment-related changes at all dose levels. The effects detected at 

60 and 30 mg/kg bw/day were considered not to represent an adverse effect. Therefore a ‘No 

Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was considered to be 60 mg/kg 

bw/day. 

The presence of two females which showed a total litter loss and one female which was pregnant 

but did not produce a litter at the high dose level cannot be completely discounted as a treatment 

effect upon reproduction even though other parameters such as fertility and histopathology of 

reproductive organs showed no treatment effects. This effect upon reproduction can only be 

classified as equivocal on the basis of only limited toxicological findings on reproduction and 

that these findings were only observed at dose levels where other evidence of general toxicity 

could be observed in the adult female (reduced body weight gain and food consumption). 

Therefore, it must be concluded that the ‘No Observed Effect Level’ (NOEL) for reproductive 

toxicity was considered to be 60 mg/kg bw/day. 
Harlan Study Number: 41204605 Report Page 20 

GENERAL INFORMATION 

Schedule 

Experimental Starting Date: 02 January 2013 

Experimental Completion Date: 11 November 2013 

Animal Welfare 

The study was designed and conducted to cause the minimum suffering or distress to the animals 

consistent with the scientific objectives and in accordance with the Harlan Laboratories Ltd, 

Shardlow, UK policy on animal welfare and the requirements of the United Kingdom’s Animals 

(Scientific Procedure) Act 1986. The conduct of the study may be reviewed, as part of the 

Harlan Laboratories Ltd, Shardlow, UK Ethical Review Process. 

The study was conducted in accordance with the UK Home Office Guidance document on 

Regulatory Toxicology and Safety Evaluation Studies and the OECD guidance document on 

recognition, assessment and use of clinical signs as humane endpoints for experimental animals 

used in safety evaluation. 

Multi – Site Study Details 

Lead Quality Assurance: J Riley 

Harlan Laboratories Ltd. 

 

Study Phase: Histology Processing 

 

Test Site: TUPI Manufacturing 

PO Box 305 

Diss 

Norfolk 

IP22 4XL 

UK 

Principal Investigator: R Trindall 

 

Test Site Quality Assurance: S Needham 

TUPI Manufacturing 
Harlan Study Number: 41204605 Report Page 21 

Study Phase: Histopathology Examination 

Test Site: Peter Millar Associates Ltd. 

3 Queen Charlotte Street 

Edinburgh 

SCOTLAND 

EH6 6AY 

Principal Investigator: P Millar 

Test Site Quality Assurance: J Lawrence 

Peter Millar Associate Ltd. 

Additional Responsibilities 

Analytical Investigations: P Watson 

Harlan Laboratories Ltd., Shardlow, UK 

Animal Health: P Highton 

Harlan Laboratories Ltd., Shardlow, UK 

 

Clinical Pathology: J Kemp 

Harlan Laboratories Ltd., Shardlow, UK 

Deviations from Study Plan 

Deviation No. 1 (22 August 2013) 

Urinalysis

During the collection of urine for the recovery male urinalytical investigations, the recovery 

females were also housed in metabolism cages overnight and urine samples were collected. 

These samples were also examined and data was recorded. This was not required by the Study 

Plan and no data was collected for non-recovery females therefore this data will be kept in the 

Study file but will not be reported. 

Organ weights

The ovaries and uterus for female No. 89 were not recorded due to a technician error. 

These deviations were considered not to affect the purpose or integrity of the study. 
Harlan Study Number: 41204605 Report Page 22 

Archiving 

Unless instructed otherwise by the Sponsor, the study plan, all raw data (paper and electronic) 

generated at the test facility, all original data including tissue blocks and tissue slides generated 

at the histology processing Test Site, the final report and the histopathology examination phase 

report and any raw data will be retained in the Harlan Laboratories Ltd, Shardlow, UK archives 

for five years after which instructions will be sought as to further retention or disposal. 

Unprocessed wet tissue samples will be retained for two years prior to disposal. Further 

retention or return of the data will be chargeable to the Sponsor. 

No data will be discarded without contacting the Sponsor to obtain their written consent. 
Harlan Study Number: 41204605 Report Page 23 

1 INTRODUCTION AND PURPOSE 

The study was performed according to the study plan presented in Appendix 28 and was 

designed to screen for potential adverse effects on reproduction, including offspring 

development, by repeated oral administration to the Wistar HanTM:RccHanTM:WIST strain rat for 

up to eight weeks at dose levels of 30, 60 and 120 mg/kg bw/day. A control group was dosed 

with vehicle alone (Arachis oil BP). Two recovery groups were treated with the high dose level 

of 120 mg/kg bw/day or the vehicle alone (Arachis oil BP) for forty-two days and then 

maintained without treatment for a further fourteen days. 

The dose levels were chosen based on the results of previous toxicity work (Harlan Laboratories 

Ltd., Study Numbers 41204604 and 41300243). The oral route was selected as the most 

appropriate route of exposure, based on the physical properties of the test item, and the results of 

the study are believed to be of value in predicting the likely toxicity of the test item to man. 

The study was performed between 02 January 2013 and 11 November 2013 (date of final 

histopathology report). The in-life phase of the study was conducted between 27 March 2013 

(first day of treatment) and 22 May 2013 (final day of necropsy). 

1.1 Guidelines / Regulations 

The study was designed to be compatible with the requirements of OECD Guidelines for Testing 

of Chemicals, No.422: “Combined Repeated Dose Toxicity Study with the Reproduction/ 

Developmental Toxicity Screening Test” (adopted 22 March 1996). 
Harlan Study Number: 41204605 Report Page 24 

2 TEST ITEM 

2.1 Test Item 

Information as provided by the Sponsor. 

Identification : Benzoflex 1046 

Description : Clear colourless liquid 

Purity : not supplied 

Batch Number : V046212201 

Label : Benzoflex (TM) 1046 Plasticiser Batch V046212201 

Date Received : 21 May 2012 

Storage Conditions : room temperature in the dark 

Expiry Date : 30 April 2014 

No correction for purity was made. 

The integrity of supplied data relating to the identity, purity and stability of the test item is the 

responsibility of the Sponsor. 

A Certificate of Analysis of Test Item is included as Appendix 38. 

3 MATERIALS AND METHODS 

3.1 Test System 

3.1.1 Animals and Animal Husbandry 

A sufficient number of male and female Wistar HanTM:RccHanTM:WIST strain rats were 

obtained from Harlan Laboratories U.K. Ltd., Blackthorn, Bicester, Oxon, UK. On receipt the 

animals were examined for signs of ill-health or injury. The animals were acclimatised for six 

days during which time their health status was assessed. A total of one hundred and sixteen 

animals (fifty eight males and fifty eight females) were accepted into the study. At the start of 

treatment the males weighed 295 to 346g, the females weighed 182 to 212g, and were 

approximately twelve weeks old. 

Initially, all animals were housed in groups of four or five in solid floor polypropylene cages 

with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). 

During the pairing phase, the non-recovery animals were transferred to polypropylene grid floor 

cages suspended over trays lined with absorbent paper on a one male: one female basis within 

each dose group. Following evidence of successful mating, the males were returned to their 

original cages. Mated females were housed individually during gestation and lactation in solid 

floor polypropylene cages with stainless steel mesh lids and softwood flakes. Recovery group 

animals were housed in groups of five in solid floor polypropylene cages with stainless steel 

mesh lids and furnished with softwood flake bedding. 
Harlan Study Number: 41204605 Report Page 25 

The animals were allowed free access to food and water. A pelleted diet (Rodent 2018C Teklad 

Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK.) was used. Certificates of 

analysis of the batches of diet used are given in Appendix 32. Mains drinking water was 

supplied from polycarbonate bottles attached to the cage. The diet and drinking water were 

considered not to contain any contaminant at a level that might have affected the purpose or 

integrity of the study. Environmental enrichment was provided in the form of wooden chew 

blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK) except for paired animals and 

mated females during gestation and lactation. Mated females were also given softwood flakes, 

as bedding, throughout gestation and lactation. 

The animals were housed in a single air-conditioned room within the Harlan Laboratories Ltd., 

Shardlow, UK Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen 

air changes per hour and the low intensity fluorescent lighting was controlled to give twelve 

hours continuous light and twelve hours darkness. Environmental conditions were continuously 

monitored by a computerised system, and print-outs of hourly temperatures and humidities are 

included in the study records. The temperature and relative humidity controls were set to 

achieve target values of 21 ± 2 °C and 55 ± 15% respectively. Short term deviations from these 

targets were considered not to have affected the purpose or integrity of the study. 

The animals were randomly allocated to treatment groups using a stratified body weight 

randomisation procedure and the group mean body weights were then determined to ensure 

similarity between the treatment groups. The cage distribution within the holding rack was also 

randomised. The animals were uniquely identified within the study by an ear punching system 

routinely used in these laboratories. 

3.1.2 Justification 

The rat was selected for this study as it is a readily available rodent species historically used in 

safety evaluation studies and is acceptable to appropriate regulatory authorities. 

3.2 Test Item Preparation 

For the purpose of this study the test item was prepared at the appropriate concentrations as a 

solution in Arachis oil BP. The stability and homogeneity of the test item formulations were 

determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. Results show the 

formulations to be stable for at least sixteen days. Formulations were therefore prepared twice 

monthly and stored at approximately +4 °C in the dark. 

Samples of the test item formulation were taken and analysed for concentration of Benzoflex 

1046 at Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The method used for 

analysis of formulations and the results obtained are given in Appendix 27. The results indicate 

that the prepared formulations were within ± 4% of the nominal concentration. 
Harlan Study Number: 41204605 Report Page 26 

3.3 Procedure 

Animals were allocated to treatment groups as follows: 

Treatment Group Dose Level 

(mg/kg bw/day) 

Treatment 

Volume (mL/kg) 

Concentration 

(mg/mL) 

Animal Numbers 

Male Female 

Control 0 4 0 12 (1-12) 12 (13-24) 

Recovery Control 0 4 0 5 (97-101) 5 (102-106) 

Low 30 4 7.5 12 (25-36) 12 (37-48) 

Intermediate 60 4 15 12 (49-60) 12 (61-72) 

High 120 4 30 12 (73-84) 12 (85-96) 

Recovery High 120 4 30 5 (107-111) 5 (112-116) 

The numbers in parentheses ( ) show the individual animal numbers allocated to each treatment 

group. 

The test item was administered daily by gavage using a stainless steel cannula attached to a 

disposable plastic syringe. Control animals were treated in an identical manner with 4 ml/kg of 

Arachis oil BP. 

The volume of test and control item administered to each animal was based on the most recent 

scheduled body weight and was adjusted at weekly intervals. 

3.3.1 Chronological Sequence of Study 

3.3.1.1 Non-Recovery Dose Groups 

i. Groups of twelve male and twelve female animals were treated daily at the appropriate 

dose level throughout the study (except for females during parturition where applicable). 

The first day of dosing was designated as Day 1 of the study. 

ii. Prior to the start of treatment and once weekly thereafter, all animals were observed for 

signs of functional/behavioural toxicity. 

iii. On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a 

maximum of fourteen days. 

iv. Following evidence of mating (designated as Day 0 post coitum) the males were returned 

to their original cages and females were transferred to individual cages. 

v. On completion of the pairing phase (during Week 6), five selected males per dose group 

were evaluated for functional/sensory responses to various stimuli. 

vi. Pregnant females were allowed to give birth and maintain their offspring until Day 5 post 

partum. Litter size, offspring weight and sex, surface righting and clinical signs were 

also recorded during this period. 

vii. At Day 4 post partum, five selected females per dose group were evaluated for 

functional/sensory responses to various stimuli. 
Harlan Study Number: 41204605 Report Page 27 

viii. Blood samples were taken from five males from each dose group for hematological and 

blood chemical assessments on Day 42. The male dose groups were killed and examined 

macroscopically on Day 43. 

ix. Blood samples were taken from five randomly selected females from each dose group for 

haematological and blood chemical assessment on Day 4 post partum. At Day 5 post 

partum, all females and surviving offspring were killed and examined macroscopically. 

Any female which did not produce a pregnancy was also killed and examined 

macroscopically. 

3.3.1.2 Recovery Dose Groups 

i. Groups of five male and five female rats were dosed according to dose group 

continuously up to the point of sacrifice of non-recovery males at which time treatment 

was discontinued. 

ii. The males and females were maintained without treatment for a further fourteen days. 

iii. Urinalysis was performed for all males during the final week of recovery. 

iv. Blood samples were taken for haematological and blood chemical assessment on Day 56. 

v. After fourteen days of recovery, males and females were killed and examined 

macroscopically. 

3.4 Observations 

3.4.1 Clinical Observations 

All animals were examined for overt signs of toxicity, ill-health and behavioural change 

immediately before dosing, up to thirty minutes after dosing, and one and five hours after dosing, 

during the working week. Animals were observed immediately before dosing, soon after dosing, 

and one hour after dosing at weekends and public holidays (except for females during parturition 

where applicable). During the treatment-free period, recovery animals were observed daily. All 

observations were recorded. 

3.4.2 Functional Observations 

Prior to the start of treatment and at weekly intervals thereafter, all non-recovery animals were 

observed for signs of functional/behavioural toxicity. Functional performance tests were also 

performed on five selected males and females from each non-recovery dose level, prior to 

termination, together with an assessment of sensory reactivity to various stimuli. 

3.4.2.1 Behavioural Assessments 

Detailed individual clinical observations were performed for each animal using a purpose built 

arena. The following parameters were observed: 
Harlan Study Number: 41204605 Report Page 28 

Gait Hyper/Hypothermia 

Tremors Skin colour 

Twitches Respiration 

Convulsions Palpebral closure 

Bizarre/Abnormal/Stereotypic behavior Urination 

Salivation Defecation 

Pilo-erection Transfer arousal 

Exophthalmia Tail elevation 

Lachrymation 

This test was developed from the methods used by Irwin (1968) and Moser et al (1988). The 

scoring system used is outlined in The Key to Scoring System and Explanation for Behavioral 

Assessments and Sensory Reactivity Tests. 

3.4.2.2 Functional Performance Tests 

Motor Activity. Purpose-built 44 infra-red beam automated activity monitors were used to assess 

motor activity. Animals were randomly allocated to the activity monitors. The tests were 

performed at approximately the same time on each occasion (at least two hours after dosing), 

under similar laboratory conditions. The evaluation period was thirty minutes for each animal. 

The percentage of time each animal was active and mobile was recorded for the overall thirty 

minute period and also during the final 20% of the period (considered to be the asymptotic 

period, Reiter and Macphail, 1979). 

Forelimb/Hindlimb Grip Strength. An automated meter was used. Each animal was allowed to 

grip the proximal metal bar of the meter with its forepaws. The animal was pulled by the base of 

the tail until its grip was broken. The animal was drawn along the trough of the meter by the tail 

until its hind paws gripped the distal metal bar. The animal was pulled by the base of the tail 

until its grip was broken. A record of the force required to break the grip for each animal was 

made. Three consecutive trials were performed for each animal. The assessment was developed 

from the method employed by Meyer et al (1979). 

3.4.2.3 Sensory Reactivity 

Each animal was individually assessed for sensory reactivity to auditory, visual and 

proprioceptive stimuli. This assessment was developed from the methods employed by Irwin 

(1968) and Moser et al (1988). 

The following parameters were observed: 

Grasp response Touch escape 

Vocalisation Pupil reflex 
Harlan Study Number: 41204605 Report Page 29 

Toe pinch Blink reflex 

Tail pinch Startle reflex 

Finger approach 

3.4.3 Body Weight 

Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males 

until termination and weekly for females until mating was evident. Body weights were then 

recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum. 

Recovery animals were weighed on Day 1 (prior to dosing) and then weekly until termination. 

Normal range data for body weight changes in pregnant and lactating females are shown in 

Appendix 34. 

3.4.4 Food Consumption 

During the pre-pairing period, weekly food consumption was recorded for each cage of adults. 

This was continued for males after the mating phase. For females showing evidence of mating, 

food consumption was recorded for the periods covering post coitum Days 0-7, 7-14 and 14-20. 

For females with live litters, food consumption was recorded on Days 1 and 4 post partum. 

Weekly food consumptions were performed for each cage of recovery group animals throughout 

the study period. 

Food efficiency (the ratio of body weight change/dietary intake) was calculated retrospectively 

for non-recovery males (except during the mating phase) and recovery group animals throughout 

the study period and for non-recovery females during the pre-pairing phase. Due to offspring 

growth and milk production, food efficiency could not be accurately calculated for females, 

during gestation and lactation.

Normal range data for pregnant and lactating females are presented in Appendix 34. 

3.4.5 Water Consumption 

Water intake was measured daily throughout the study (with the exception of the pairing phase). 

3.4.6 Reproductive Performance 

Normal range data for reproductive parameters and offspring are presented in Appendix 34 and 

Appendix 35. 
Harlan Study Number: 41204605 Report Page 30 

3.4.6.1 Mating 

Non-recovery animals were paired on a 1 male: 1 female basis within each dose group, for a 

period of up to fourteen days. Cage tray-liners were checked each morning for the presence of 

ejected copulation plugs and each female was examined for the presence of a copulation plug in 

the vagina. A vaginal smear was prepared for each female and the stage of oestrus or the 

presence of sperm was recorded. The presence of sperm within the vaginal smear and/or vaginal 

plug in situ was taken as positive evidence of mating (Day 0 of gestation) and the males were 

subsequently returned to their original holding cages (unless required for additional pairing). 

Mated females were housed individually during the period of gestation and lactation. 

3.4.6.2 Pregnancy and Parturition 

Each pregnant female was observed at approximately 0830, 1230 and 1630 hours and around the 

period of expected parturition. Observations were carried out at approximately 0830 and 

1230 hours at weekends and public holidays. The following was recorded for each female: 

i. Date of pairing 

ii. Date of mating 

iii. Date and time of observed start of parturition 

iv. Date and time of observed completion of parturition 

3.4.6.3 Litter Data 

On completion of parturition (Day 0 post partum), the number of live and dead offspring was 

recorded. Offspring were individually identified within each litter by tattoo on Day 1 post 

partum. 

For each litter the following was recorded: 

i. Number of offspring born 

ii. Number of offspring alive recorded daily and reported on Days 1 and 4 post partum

iii. Sex of offspring on Days 1 and 4 post partum

iv. Clinical condition of offspring from birth to Day 5 post partum

v. Individual offspring weights on Days 1 and 4 post partum (litter weights were calculated 

retrospectively from this data) 

3.4.6.4 Physical Development 

All live offspring were assessed for surface righting reflex on Day 1 post partum.
Harlan Study Number: 41204605 Report Page 31 

3.4.7 Laboratory Investigations 

Haematological and blood chemical investigations were performed on five males and five 

females selected from each non-recovery test and control group prior to termination (Day 42 for 

males and Day 4 post partum for females). In addition haematological and blood chemical 

investigations were performed on all recovery group animals after the fourteen day treatmentfree period at termination (Day 56). Blood samples were obtained from the lateral tail vein. 

Where necessary repeat samples were taken by cardiac puncture at termination. Animals were 

not fasted prior to sampling. 

Urinalytical investigations were performed on five non-recovery males from the control and each 

test group during the final week of treatment and on all recovery males during the final week of 

the recovery period. Urine samples were collected overnight by housing the rats in metabolism 

cages. Animals were maintained under conditions of normal hydration during collection but 

without access to food. 

The methods used for haematological, blood chemical and urinalytical investigations are 

presented in Appendix 33. 

3.4.7.1 Haematology 

The following parameters were measured on blood collected into tubes containing potassium 

EDTA anti-coagulant: 

Haemoglobin (Hb) 

Erythrocyte count (RBC) 

Haematocrit (Hct) 

Erythrocyte indices - mean corpuscular haemoglobin (MCH) 

 - mean corpuscular volume (MCV) 

 - mean corpuscular haemoglobin concentration (MCHC) 

Total leucocyte count (WBC) 

Differential leucocyte count - neutrophils (Neut) 

 - lymphocytes (Lymph) 

 - monocytes (Mono) 

 - eosinophils (Eos) 

 - basophils (Bas) 

Platelet count (PLT) 

Reticulocyte count (Retic) - Methylene blue stained slides were prepared but reticulocytes 

were not assessed 
Harlan Study Number: 41204605 Report Page 32 

Prothrombin time (CT) was assessed by ‘Innovin’ and Activated partial thromboplastin time 

(APTT) was assessed by ‘Actin FS’ using samples collected into sodium citrate solution 

(0.11 mol/l). 

3.4.7.2 Blood Chemistry 

The following parameters were measured on plasma from blood collected into tubes containing 

lithium heparin anti-coagulant: 

Urea Calcium (Ca++) 

Glucose Inorganic phosphorus (P) 

Total protein (Tot.Prot.) Aspartate aminotransferase (ASAT) 

Albumin Alanine aminotransferase (ALAT) 

Albumin/Globulin (A/G) ratio (by calculation) Alkaline phosphatase (AP) 

Sodium (Na+) Creatinine (Creat) 

Potassium (K+) Total cholesterol (Chol) 

Chloride (Cl-) Total bilirubin (Bili) 

 Bile acids 

3.4.7.3 Urinalysis 

The following parameters were measured on collected urine: 

Volume Ketones 

Specific Gravity Bilirubin 

pH Urobilinogen 

Protein Blood 

Glucose Appearance 

3.4.8 Pathology 

3.4.8.1 Necropsy 

Adult non-recovery males were killed by intravenous overdose of a suitable barbiturate agent 

followed by exsanguination on Day 43. Adult non-recovery females were killed by intravenous 

overdose of a suitable barbiturate agent followed by exsanguination on Day 5 post partum. 

Surviving offspring were terminated via intracardiac overdose of sodium pentobarbitone. Any 

females which failed to achieve pregnancy or produce a litter were killed on or after Day 25 post 

coitum. 
Harlan Study Number: 41204605 Report Page 33 

For all non-recovery females, the uterus was examined for signs of implantation and the number 

of uterine implantations in each horn was recorded. This procedure was enhanced; as necessary, 

by staining the uteri with a 0.5% ammonium polysulphide solution (Salewski 1964). The 

corpora lutea were also counted. 

Recovery group animals were killed by intravenous overdose of a suitable barbiturate agent 

followed by exsanguination on Day 57. 

All adult animals and offspring, including those dying during the study, were subjected to a full 

external and internal examination, and any macroscopic abnormalities were recorded. 

3.4.8.2 Organ Weights 

The following organs were dissected free from fat and weighed before fixation from five 

selected males and five selected females from each non-recovery dose group and from all 

recovery group animals. Tissues shown in bold were weighed from all remaining animals: 

Adrenals Prostate 

Brain Seminal vesicles 

Epididymides Spleen 

Heart Testes 

Kidneys Thymus 

Liver Thyroid (weighed post-fixation with Parathyroid) 

Ovaries Uterus (weighed with Cervix) 

Pituitary (post fixation) 

Normal ranges for organ weights are given in Appendix 37. 

3.4.8.3 Histopathology 

Samples of the following tissues were removed from five selected males and five selected 

females from each dose group and preserved in buffered 10% formalin, except where stated. 

Tissues shown in bold were preserved from all remaining animals: 

Adrenals Ovaries 

Aorta (thoracic) Pancreas 

Bone & bone marrow (femur including stifle joint) Pituitary 

Bone & bone marrow (sternum) Prostate 

Brain (including cerebrum, cerebellum and pons) Oesophagus 

Caecum Rectum 

Coagulating gland Salivary glands (submaxillary) 

Colon Sciatic nerve 
Harlan Study Number: 41204605 Report Page 34 

Duodenum Seminal vesicles 

Epididymides Skin (hind limb) 

Eyes*

 Spinal cord (cervical, mid-thoracic and 

Gross lesions lumbar) 

Heart Spleen 

Ileum (including peyer’s patches) Stomach 

Jejunum Thyroid/parathyroid 

Kidneys Trachea

Liver Testes

Lungs (with bronchi) #

 Thymus 

Lymph nodes (mandibular and mesenteric) Urinary bladder

Mammary gland Uterus/Cervix

Muscle (skeletal) Vagina 

Tissues were despatched to the Test Site (TUPI Manufacturing) for processing (Principal 

Investigator: R Trindall). The tissues from five selected non-recovery control and 1000 mg/kg 

bw/day dose group animals, any animals dying during the study, and any animals which failed to 

mate or did not achieve a pregnancy were prepared as paraffin blocks, sectioned at a nominal 

thickness of 5 μm and stained with haematoxylin and eosin for subsequent microscopic 

examination. The tissues shown in bold from the remaining control and 120 mg/kg bw/day 

animals and animals which did not achieve a pregnancy were also processed. In addition, 

sections of testes and epididymides from all control and 120 mg/kg bw/day males were also 

stained with Periodic Acid-Schiff (PAS) stain and examined. 

Detailed qualitative examination of the testes was undertaken, taking into account the tubular 

stages of the spermatogenic cycle. The examination was conducted in order to identify 

treatment-related effects such as missing germ cell layers or types, retained spermatids, 

multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen. 

Any cell-or stage-specificity of testicular findings was noted. 

Microscopic examination was conducted by the Study Pathologist (Peter Millar at Peter Millar 

Associates Ltd). A complete histopathology phase report is presented in Appendix 26. 

 

*

 = eyes fixed in Davidson’s fluid 

 = preserved in Bouin’s fluid then transferred to 70% Industrial Methylated Spirits (IMS) approximately 

forty-eight hours later #

 = lungs were inflated to approximately normal inspiratory volume with buffered 10% formalin before 

 immersion in fixative 
Harlan Study Number: 41204605 Report Page 35 

3.4.9 Evaluation of Data 

3.4.9.1 Treatment of Data 

Data were processed to give summary incidence or group mean values and standard deviations 

where appropriate. All data were summarised in tabular form. 

Data shown in the appendices are frequently rounded values for presentation purposes. Group 

mean values are generally calculated using non-rounded values therefore is it not always possible 

to calculate the exact group values from the individual values presented in the appendices. 

For body weights and food consumptions during gestation, group mean values were calculated 

using data from females which were observed to give birth to offspring. 

For body weights and food consumptions during lactation, group mean values were calculated 

using data from females with live young at Day 5 of lactation. 

3.4.9.2 Reproductive Indices 

Mating Performance and Fertility 

The following parameters were calculated from the individual data during the mating period of 

the parental generation: 

i. Pre-coital Interval 

Calculated as the time elapsing between initial pairing and the observation of positive 

evidence of mating. 

ii. Fertility Indices 

For each group the following were calculated: 

Mating Index (%) = Number of animals paired

Number of animals mated x 100 

 

Pregnancy Index (%) = Number of animals mated

Number of pregnant females x 100 

 

Gestation and Parturition Data 

The following parameters were calculated from individual data during the gestation and 

parturition period of the parental generation: 

i. Gestation Length 
Harlan Study Number: 41204605 Report Page 36 

Calculated as the number of days of gestation including the day for observation of mating 

and the start of parturition. 

ii. Parturition Index 

The following was calculated for each group: 

Parturition Index (%) = Number of pregnant females

Number of females delivering live offspring x 100 

3.4.9.3 Litter Responses 

The standard unit of assessment was considered to be the litter, therefore values were first 

calculated for each litter and the group mean was calculated using their individual litter values. 

Group mean values included all litters reared to termination (Day 5 of age). 

i. Implantation Losses (%) 

Group mean percentile pre-implantation and post-implantation loss were calculated for 

each female/litter as follows: 

% pre–implantation loss = Number of corpora lutea

Number of corpora lutea - Number of implantation sites x100 

% post–implantation loss = Number of implantation sites

Number of implantation sites- Total number of offspring born x 100 

ii. Live Birth and Viability Indices 

The following indices were calculated for each litter as follows: 

Live Birth Index (%) = Number of offspring born

Number of offspring alive on Day 1 x 100 

Viability Index (%) = Number of offspring alive on Day 1

Number of offspring alive on Day 4 x 100 

iii. Sex Ratio (% males) 

Sex ratio was calculated for each litter value on Days 1 and 4 post partum, using the 

following formula: 
Harlan Study Number: 41204605 Report Page 37 

Total number of offspring

Number of male offspring x 100 

3.4.9.4 Statistical Analysis 

Where considered appropriate, quantitative data was subjected to statistical analysis to detect the 

significance of intergroup differences from control; statistical significance was achieved at a 

level of p<0.05. Statistical analysis was performed on the following parameters: 

Grip Strength, Motor Activity, Body Weight, Body Weight Change, Food Consumption during 

gestation and lactation, Water Consumption during gestation and lactation, Pre-Coital Interval, 

Gestation Length, Litter Size, Litter Weight, Sex Ratio, Corpora Lutea, Implantation Sites, 

Implantation Losses, Viability Indices, Offspring Body Weight, Offspring Body Weight Change, 

Offspring Surface Righting, Haematology, Blood Chemistry, Absolute Organ Weights, Body 

Weight-Relative Organ Weights. 

Data were analysed using the decision tree from the ProvantisTM Tables and Statistics Module as 

detailed as follows: 

Where appropriate, data transformations were performed using the most suitable method. The 

homogeneity of variance from mean values was analysed using Bartlett’s test. Intergroup 

variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate 

covarities. Any transformed data were analysed to find the lowest treatment level that showed a 

significant effect using the Williams Test for parametric data or the Shirley Test for nonparametric data. If no dose response was found but the data shows non-homogeneity of means, 

the data were analysed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to 

determine significant difference from the control group. Where the data were unsuitable for 

these analyses, pair-wise tests was performed using the Student t-test (parametric) or the MannWhitney U test (non-parametric). 

Data not analysed by the Provantis data capture system were assessed separately using the SPSS 

statistical package. Initially, the homogeneity of the data was assessed using Levene’s test. 

Where Levene’s test was shown to be non-significant (p≥0.05), parametric analysis of the data 

was applied, incorporating analysis of variance (ANOVA). If this data was shown to be 

significant, this analysis was followed by pair-wise comparisons using Dunnett’s test. Where 

Levene’s test was significant, non-parametric analysis of the data was analysed incorporating the 

Kruskal-Wallis test which if significant, was followed by the Mann-Whitney U test. Dose 

response relationship was also be investigated by linear regression. Where the data was 

unsuitable for these analyses, then pair-wise tests were performed using the Student t-test 

(parametric) or the Mann-Whitney U test (non-parametric). 

Due to the preponderance of non-normally distributed data, reproductive parameters 

(implantation losses, offspring sex ratio and offspring surface righting) were analysed using nonparametric analyses. 
Harlan Study Number: 41204605 Report Page 38 

Probability values (p) are presented as follows: 

p<0.01 ** 

p<0.05 * 

p>0.05 (not significant) 
Harlan Study Number: 41204605 Report Page 39 

4 RESULTS AND DISCUSSION 

4.1 Results 

4.1.1 Adult Reponses 

4.1.1.1 Mortality 

There were no unscheduled deaths detected during the study. 

4.1.1.2 Clinical Observations 

A summary incidence of daily clinical observations is given in Table 2. Individual data is 

presented in Appendix 1. 

There were no clinically observable signs of toxicity detected during the study. 

Clinical signs were confined to the presence of post-dose increased salivation for animals of 

either sex treated with 120 mg/kg bw/day. Isolated instances of increased salivation following 

dosing were also evident at 60 mg/kg bw/day. Increased salivation is often recorded following 

the oral administration of an unpleasant tasting and/or locally irritant test item formulation and, 

in isolation, is considered not to be indicative of systemic toxicity. 

4.1.1.3 Functional Observations 

Summary incidence of behavioural assessment observations are given in Table 3 and group mean 

behavioural assessment scores are given in Table 4. Group mean functional performance test 

values and standard deviations are given in Table 5 (statistically significant differences are 

indicated). Individual values are given in Appendices 2 to 5. Group mean sensory reactivity 

assessment scores are given in Table 6. Individual responses are given in Appendix 6. 

Behavioural Assessments 

No treatment-related effects were detected in the behavioural assessment parameters 

investigated. 

All inter and intra group differences in urination and defecation scores were considered to be a 

result of normal variation for rats of the strain and age used and were of no toxicological 

importance. 

Functional Performance Tests 

No treatment-related effects were detected in the functional performance parameters 

investigated. 
Harlan Study Number: 41204605 Report Page 40 

Females from all treatment groups showed a statistically significant increase in forelimb grip 

strength when compared to controls. The significance achieved was minimal (p<0.05) and only 

occurred during one out of three tests. In the absence of a dose-related response, these increases 

were considered to be unrelated to treatment. 

Females treated with 120 mg/kg bw/day showed an increase in hind limb grip strength when 

compared to controls. This was only observed in one out of three tests performed, and as such, 

was considered not to represent a true effect of treatment. 

Sensory Reactivity Assessments 

There were no treatment-related changes in sensory reactivity. 

All inter and intra group differences in sensory reactivity scores were considered to be a result of 

normal variation for rats of the strain and age used and were of no toxicological importance. 

4.1.1.4 Body Weight 

Group mean weekly body weights and standard deviations are given in Table 7 and are presented 

graphically in Figure 1 and Figure 2. Group mean weekly body weight gains and standard 

deviations are given in Table 8 (statistically significant differences are indicated). Individual 

data are given in Appendix 7 and Appendix 8. 

Actual body weight losses and reduced body weight gains were evident for some animals of 

either sex treated with 120 mg/kg bw/day when compared to controls, with statistically 

significant reductions evident for females from Day 1 to Day 15 (p<0.01). 

Reduced body weight gains were also evident during the first two weeks of treatment for animals 

of either sex treated with 60 mg/kg bw/day, with statistically significant reductions observed for 

females (p<0.01) when compared to controls. Recovery was evident in males thereafter. 

Reduced body weight gains were evident for females treated with 120 and 60 mg/kg bw/day 

throughout the gestation phase, when compared to control females (p<0.05 – p<0.01). 

Furthermore, actual body weights were lower for treated females during the study when 

compared to controls, with statistical significance achieved for females during gestation and 

lactation for all treated females when compared to controls. 

For recovery animals, high dose males showed a reduction in body weight gains and actual body 

weight losses when compared to controls during the first three weeks of treatment, with recovery 

thereafter. 
Harlan Study Number: 41204605 Report Page 41 

4.1.1.5 Food Consumption 

Group mean food consumptions are given in Table 9 (statistically significant differences are 

indicated) and are presented graphically in Figure 3 and Figure 4. Individual values for females 

during gestation and lactation are presented in Appendix 9. Food efficiency for males and for 

females during the pre-mating phase is given in Table 10. 

Reduced dietary intake was evident for males treated with 120 mg/kg bw/day during the first two 

weeks of treatment. Females treated with 120 mg/kg bw/day showed a reduction in dietary 

intake during the pre-pairing phase when compared to controls. Statistically significant 

reductions in dietary intake at all dose levels were evident during gestation when compared to 

controls. No such effects were detected during lactation. 

4.1.1.6 Water Consumption 

Group mean daily water consumptions are given in Table 11. Individual and group mean daily 

water consumptions for females following mating and lactation are presented in Appendix 10. 

Daily measurements of water bottles did not reveal any significant intergroup differences for 

males or for females during the pre-pairing, gestation and lactation phases of the study. 

Females treated with 30 mg/kg bw/day showed a statistically significant reduction in water 

consumption during the final week of gestation. In the absence of a true dose related response 

the intergroup difference was considered not to be of toxicological importance. 

4.1.2 Reproductive Performance 

4.1.2.1 Mating 

A summary of adult performance is presented in Table 1. A summary incidence for mating 

performance is presented in Table 12. Individual data are given in Appendix 11. 

No treatment-related effects were detected in mating performance. All animals mated within 

five days of pairing. 

4.1.2.2 Fertility 

A summary of adult performance is presented in Table 1. Group values for fertility, litter data 

and implantation losses are given in Tables 12, 13 and 14. Individual data are given in 

Appendices 11 to 13. 

There were no treatment-related changes detected in fertility. 
Harlan Study Number: 41204605 Report Page 42 

There were two non-pregnant females at the high dose. One non-pregnant female was present in 

the intermediate dose level and two non-pregnant females were present in the low dose. Nonpregnancies are low incidence findings in reproductive studies of this type and considered not to 

represent an effect of treatment. 

4.1.2.3 Gestation Length 

A summary of gestation lengths is presented in Table 12. Individual lengths are given in 

Appendix 11. 

No treatment-related effects were detected in the length of gestation between control and treated 

groups. Gestation lengths were spread over 21 to 24 1⁄2 days. 

4.1.3 Litter Responses 

In total, twelve females from the control group, nine females treated with 30 mg/kg bw/day, 

eleven females treated with 60 mg/kg bw/day and seven females treated with 120 mg/kg bw/day 

gave birth to a live litter and successfully reared young to Day 5 of age. The following 

assessment of litter response is based on all litters reared to termination on Day 5 of 

lactation/age. 

4.1.3.1 Offspring Litter Size, Sex Ratio and Viability 

Group mean corpora lutea and implantation counts, litter size, implantation losses, survival 

indices and sex ratio are given in Tables 13 to 15. Individual data are given in Appendices 12 to 

14. 

One female treated with 120 mg/kg bw/day showed both corpora lutea and implantation sites, 

but did not produce a litter. Furthermore, there were two total litter losses observed at 120 mg/kg 

bw/day and one total litter loss observed at 30 mg/kg bw/day. 

No differences in sex ratio or litter size were evident for offspring from treated litters when 

compared to those from the controls. No significant differences in the number of corpora lutea 

or implantation sites were noted for treated females when compared to controls. The percentages 

of pre- and post-implantation losses for treated females were comparable to controls. Statistical 

analysis of the data did not reveal any significant intergroup differences. 

4.1.3.2 Offspring Growth and Development 

Group mean values for total litter weights, offspring body weights and body weight changes, 

surface righting reflex and a summary incidence of clinical signs are given in Tables 13, 16 and 

17. Individual values and observations are given in Appendices 12, 15 and 16. 
Harlan Study Number: 41204605 Report Page 43 

No significant differences in litter weights or offspring weights were evident in the treated 

groups when compared to controls. Statistical analysis of the data did not reveal any significant 

intergroup differences. 

There were no clinically observable signs of toxicity observed in offspring. 

4.1.4 Laboratory Investigations 

4.1.4.1 Haematology 

Group mean values and standard deviations for test and control group animals are given in Table 

18 (statistically significant differences are indicated). Individual data are given in Appendix 17 

and Appendix 18. 

There were no toxicologically significant changes detected in the haematology parameters 

investigated. 

Non-recovery and recovery females treated with 120 mg/kg bw/day showed a statistically 

significant increase in platelet counts when compared to the concurrent controls. In the absence 

of any associated histopathology correlates the intergroup differences were considered to have 

arisen incidentally and were considered of no toxicological significance. 

4.1.4.2 Blood Chemistry 

Group mean values and standard deviations for test and control group animals are given in Table 

19 (statistically significant differences are indicated). Individual data are given in Appendices 

19 and 20. 

There were no toxicologically significant changes detected in the blood chemical parameters 

investigated. 

Non-recovery females treated with 120 mg/kg bw/day showed a statistically significant increase 

in bilirubin and a statistically significant reduction in bile acids. In the absence of any associated 

histopathological correlates the intergroup differences were considered not to be of toxicological 

importance. 

Non-recovery males treated with 120 mg/kg bw/day showed a slight but statistically significant 

reduction in albumin/globulin ratio and urea when compared to controls. The significance 

achieved was minimal (p<0.05) and the majority of individual values were within the normally 

expected ranges. As such, these reductions were considered to have arisen incidentally. 

Non-recovery males treated with 30 mg/kg bw/day showed a statistically significant increase in 

alkaline phosphatase values when compared to controls, with one value outside of the normally 

expected ranges. In the absence of a dose-related response, this increase was considered to have 

arisen incidentally and was of no toxicological importance. Recovery males treated with 
Harlan Study Number: 41204605 Report Page 44 

120 mg/kg bw/day showed a statistically significant increase in alkaline phosphatase levels when 

compared to the recovery controls. All individual values were within the normally expected 

ranges, and as such, this increase was considered not to represent systemic toxicity. 

Recovery females treated with 120 mg/kg bw/day showed a statistically significant reduction in 

albumin/globulin ratio and alkaline phosphatase. In the absence of similar findings detected 

following the treatment period, the intergroup differences were considered to have arisen 

incidentally and were considered unrelated to test item toxicity. 

Finally, aspartate aminotransferase levels were lower for recovery males when compared to 

recovery controls. This reduction was attributable to four higher than expected control values 

and was considered not to represent an effect of treatment. 

4.1.4.3 Urinalysis 

A summary of urinalytical findings is given in Table 20. Individual data are given in 

Appendix 21. 

There were no treatment-related changes detected in the urinalytical parameters investigated. 

Statistical analysis of the quantitative data did not reveal any significant intergroup differences. 

4.1.5 Pathology 

4.1.5.1 Necropsy 

A summary incidence of necropsy findings for offspring and adults is given in Tables 21 and 22. 

Individual data are given in Appendices 22 and 23. 

Offspring

No treatment-related macroscopic abnormalities were detected in interim death or terminal kill 

offspring. The incidental findings observed were those occasionally observed in reproductive 

studies of this type and were considered to be unrelated to toxicity of the test item. 

Adults

There were no treatment-related macroscopic abnormalities detected. 

One male treated with 30 mg/kg bw/day displayed a fibrous mass on the mammary gland. One 

female treated with 30 mg/kg bw/day displayed a distended left horn of the uterus and a cream 

coloured fluid was present in the vagina. One male treated with 120 mg/kg bw/day displayed 

small seminal vesicles. Another male treated with 120 mg/kg bw/day showed a yellow fluidfilled mass attached to the left cauda of the epididymis. One female treated with 120 mg/kg 
Harlan Study Number: 41204605 Report Page 45 

bw/day showed reddened eyes. These macroscopic changes were considered to be low incidence 

findings in rats of the age and strain employed, and considered not to represent systemic toxicity. 

4.1.5.2 Organ Weights 

Group mean absolute and body weight-relative organ weights and standard deviations for test 

and control group animals are presented in Table 23 (statistically significant differences are 

indicated). Individual data are given in Appendix 24 and Appendix 25. 

There were no toxicologically significant organ weight changes detected for treated animals 

when compared to controls. 

Non-recovery males treated at all dose levels showed a statistically significant increase in kidney 

weights, both absolute and relative to terminal body weights, when compared to controls. In the 

absence of a dose-related response and no histopathological correlates, these increases were 

considered to be of minimal toxicological importance. 

Non-recovery males treated with 120 mg/kg bw/day showed a statistically significant increase in 

liver weights when compared to controls. All individual values were within the normally 

expected ranges, and in the absence of any treatment-related histopathological changes in the 

liver, this increase was considered to represent an adaptive response to treatment with a 

xenobiotic and considered not to represent systemic toxicity. 

Non-recovery males treated with 120 mg/kg bw/day also showed a reduction in prostate weights 

when compared to controls. The significance achieved was minimal and although there were 

two lower than expected values in the treated groups, there were also two higher than expected 

values in the control group. Furthermore, there were no histopathological correlates; therefore 

this reduction was without toxicological importance. 

Finally, non-recovery females treated with 120 and 60 mg/kg bw/day showed a reduction in 

thymus weights and females treated with 120 mg/kg bw/day showed a reduction in pituitary 

weight when compared to controls. There were no histopathological correlates, therefore the 

toxicological significance of these reductions were considered to be of minimal importance. 

No organ weight changes were noted in the recovery group animals after the fourteen day 

treatment-free period. 

4.1.5.3 Histopathology 

A complete histopathology phase report is presented in Appendix 26. 

Histopathological examinations did not reveal any treatment-related changes in the tissues 

examined. 

All of the histopathological findings encountered were considered to have occurred 

spontaneously or at post mortem. 
Harlan Study Number: 41204605 Report Page 46 

4.2 Discussion 

The oral administration of Benzoflex 1046 to rats for a period of up to eight weeks (including 

two weeks pre-pairing, gestation and early lactation period for females) at dose levels of 120, 60 

and 30 mg/kg bw/day resulted in treatment-related changes at all dose levels employed. 

There were no clinical signs considered to be related to systemic toxicity. Actual body weight 

losses and reduced body weight gains were evident at 120 mg/kg bw/day. Reduced body weight 

gains were also evident during the first two weeks of treatment for animals of either sex treated 

with 60 mg/kg bw/day. Recovery was evident in males thereafter. Reduced body weight gains 

were evident for females treated with 120 mg/kg bw/day throughout the gestation phase, when 

compared to control females. Reduced body weight gain was also evident at 60 mg/kg bw/day 

during gestation albeit to a much lesser extent. Reduced dietary intake was evident for males 

treated with 120 mg/kg bw/day. Females treated with 120 mg/kg bw/day showed a reduction in 

dietary intake during the pre-pairing phase when compared to controls. Reductions in dietary 

intake at all dose levels were evident during gestation when compared to controls. The effects at 

60 and 30 mg/kg bw/day were at a lesser extent than at 120 mg/kg bw/day. 

There were no toxicologically important haematology, blood chemical or organ weight changes 

detected. 

No treatment-related macroscopic or microscopic were detected. 

Due to the changes detected in this study, a ‘No Observed Adverse Effect Level’ (NOAEL) was 

considered to be 60 mg/kg bw/day for systemic toxicity. 

There were two total litter losses at 120 mg/kg bw/day and one total litter loss at 30 mg/kg 

bw/day. These females all had a small number of offspring born (1 or 2 pups). The female 

treated with 30 mg/kg bw/day had a greater number of corpora lutea and implantation sites 

therefore resulting in a high post implantation loss. The females treated with 120 mg/kg bw/day 

had a much lower number of corpora lutea and implantation sites and consequently a lower post 

implantation loss. A true treatment related effect on embryo lethality has therefore not been 

established and the total litter losses between the two groups are considered not to be related. It 

is not unusual for dams with low litter size not to maintain the litter during lactation especially if 

their health is compromised and as there was no effect on post natal survival in the remaining 

litters a true treatment related effect on offspring development can not be confirmed. The female 

that did not produce a litter in the high dose group may represent an atypical finding because no 

other treatment related effects on embryo survival were evident. Although these results may 

represent normal biological variation the findings are equivocal therefore the ‘No Observed 

Effect level’ (NOEL) for reproductive toxicity was considered to be 60 mg/kg bw/day. 
Harlan Study Number: 41204605 Report Page 47 

5 CONCLUSION 

The oral administration of Benzoflex 1046 to rats by gavage, at dose levels of 120, 60 and 

30 mg/kg bw/day, resulted in treatment-related changes at all dose levels. The effects detected at 

60 and 30 mg/kg bw/day were considered not to represent an adverse effect. Therefore a ‘No 

Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was considered to be 60 mg/kg 

bw/day. 

The presence of two females which showed a total litter loss and one female which was pregnant 

but did not produce a litter at the high dose level cannot be completely discounted as a treatment 

effect upon reproduction even though other parameters such as fertility and histopathology of 

reproductive organs showed no treatment effects. This effect upon reproduction can only be 

classified as equivocal on the basis of only limited toxicological findings on reproduction and 

that these findings were only observed at dose levels where other evidence of general toxicity 

could be observed in the adult female (reduced body weight gain and food consumption). 

Therefore, it must be concluded that the ‘No Observed Effect Level’ (NOEL) for reproductive 

toxicity was considered to be 60 mg/kg bw/day. 
Harlan Study Number: 41204605 Report Page 48 

6 REFERENCES 

Irwin, S. (1968). Comprehensive Observational Assessment: la. A Systematic, Quantitative 

Procedure for Assessing the Behavioral and Physiologic State of the Mouse. 

Psychopharmacologia 13, 222-257. 

Meyer, O.A., et al (1979). A Method for the Routine Assessment of Fore- and Hindlimb Grip 

Strength of Rats and Mice. Neurobehavioral Toxicology 1, 233-236. 

Moser, V.C., et al (1988). Comparison of Chlordimeform and Carbaryl using a Functional 

Observational Battery. Fundamental and Applied Toxicology 11, 189-206. 

Reiter, L.W., and MacPhail, R.C. (1979). Motor Activity: A Survey of Methods with Potential 

Use in Toxicology Testing. Neurobehavioral Toxicology 1 (1), 53-66. 

Salewski, E. (1964). Färbemethode zum makroskopischen Nachweis von Implantationsstellen 

am Uterus der Ratte. Naunyn - Schmiedebergs Arch Exp Path Pharmakol. 247, 367. 
Harlan Study Number: 41204605 Report Page 49 

TABULAR SUMMARY REPORT OF EFFECTS OF 

REPRODUCTION/DEVELOPMENT 

Observations Dose Level (mg/kg bw/day) 

0 (Control) 30 60 120 

Paired animals n 12 12 12 12

Females showing evidence of copulation n 12 12 12 12

Pregnant females n 12 10 11 9

Conception Days 1-5 n 12 12 12 12

Gestation = 21 Days n 1 0 0 1

Gestation = 22 Days n 1 3 3 0

Gestation = 22 1⁄2 Days n 5 5 3 1

Gestation = 23 Days n 3 1 2 3

Gestation = 23 1⁄2 Days n 2 0 2 4

Gestation = 24 Days n 0 0 1 0

Gestation = 24 1⁄2 Days n 0 1 0 0

Dams with live young born n 12 10 11 9

Dams with live young at Day 4 post partum n 12 9 11 7

Corpora lutea/dam 13.3 13.2 11.5 11.3

Implants/dam 12.3 12.2 10.8 10.3

Live offspring/dam at Day 1 post partum 11.4 11.7 9.1 8.7

Live offspring/dam at Day 4 post partum 11.3 11.7 9.1 8.7

Sex ratio: % males at Day 1 post partum 43.0 38.9 50.6 54.9

Sex ratio: % males at Day 4 post partum 43.2 38.9 50.6 54.9

Litter weight (g) at Day 1 post partum 69.37 68.03 56.51 55.76

Litter weight (g) at Day 4 post partum 97.43 96.48 80.46 79.90

Male offspring weight (g) at Day 1 post partum 6.40 6.06 6.63 6.50

Male offspring weight (g) at Day 4 post partum 8.99 8.57 9.56 9.19

Female offspring weight (g) at Day 1 post partum 6.07 5.85 6.21 6.19

Female offspring weight (g) at Day 4 post partum 8.77 8.37 9.13 9.02

LOSS OF OFFSPRING/DAM 

Pre-implantation (corpora lutea minus implantations)

0 n 4 4 7 4

1 n 6 4 2 2

2 n 1 1 1 3

3 n 0 0 1 1

4 n 0 1 0 0

5 n 1 0 0 0

Pre-natal (implantations minus live births)

0 n 5 3 5 1

1 n 5 5 2 0

2 n 1 1 1 4

3 n 1 0 1 2

4 n 0 0 1 1

5 n 0 0 0 1

8 n 0 1 1 0

10 n 0 0 0 1

Post natal (live births minus offspring alive on Day 4 post partum)

0 n 11 9 11 7

1 n 1 0 0 0

 

n = Number 

x = Mean 

x

x

x

x

x

x

x

x

x

x

x

x
Harlan Study Number: 41204605 Report Page 50 

KEY TO TABLES AND APPENDICES 

M Male 

F Female 

S.D. Standard deviation 

N Number of animals/litters 

. No data available 

1+ Occasional spermatozoa present 

2+ Continuous few spermatozoa in all fields

3+ Many spermatozoa in all fields

H Haemorrhage 

PT Plug detected on tray liner 

PV Vaginal plug 

P Pregnant 

NP Not pregnant (values excluded from mean and sd) 

NL Evidence of pregnancy but no litter detected (values excluded from mean 

and sd, where applicable) 

TLL Total litter loss (values excluded from mean and sd, where applicable) 

N/A Not applicable 

U Sex not determined; prior to within litter identification 

% Food Efficiency x100

Group mean food consumption (g/rat/day) x number of days

Group mean bodyweight gain (g/rat/period)

















Statistical Footnotes: 

* Significantly different from control group p<0.05 

** Significantly different from control group p<0.01 

*** Significantly different from control group p<0.001 

n Data not appropriate for statistical analysis 

 

Organ Weight Footnotes: 

Epididys Epididymides 

Bodywt Body weight 

Thyroid Thyroid/Parathyroid 

Uterus Uterus with Cervix 

Sem Ves Seminal vesicles 
Harlan Study Number: 41204605 Report Page 51 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS 

1. NEUROLOGIC 

These parameters are the first to be evaluated when the animal is placed in the arena: 

1.1 Transfer Arousal (Time to Movement) and Locomotion 

-2 = animal stays in one place 

-1 = slow, deliberate movement 

0 = moderate, undisturbed investigation of environment 

1 = active progression around arena 

2 = darting movements 

1.2 Tail Elevation 

0 = flattened 

1 = rigidly horizontally extended 

2 = rigidly diagonally elevated 

3 = rigidly vertical 

4 = diagonally retrograde (past vertical) 

2. GAIT AND CO-ORDINATION 

Tiptoe Hindlimbs raised on tiptoe during movement 

High stepping Forelimbs lifted high during movement 

Spastic Shuffling of limbs 

Waddling Lateral movements 

Dysmetric Unco-ordinated movement with tremors 

Splayed Thighs splayed outwards, animal appears crouched 

Scissor Forelimbs cross over when extended 

Ataxic Lack of co-ordinated movement of trunk, pelvis and limbs. 

Observation graded: Slight 

 Moderate (does not fall) 

 Extreme (falls repeatedly) 
Harlan Study Number: 41204605 Report Page 52 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS (CONTINUED) 

3. CNS EXCITATION 

3.1 Tremors 

These are general involuntary movements of the muscles 

Exertion only occurs during movement 

Rest only occurs when animal is resting 

Whole body 

Head only 

Body only 

Tail only 

When present, any observation is also graded: 

Slight 

Moderate 

Extreme 

3.2 Twitches 

Identified as brief, coarse jerks of body or limbs - observation graded: 

Slight 

Moderate 

Extreme 

3.3 Convulsions 

Clonic Convulsions with alternate contraction and relaxation of muscles 

Running excitement Often accompanied by clonic convulsions 

Champing Clonus of the paws only 

Hopping Animal repeatedly “hops” into the air 

Asphyxeal Terminal convulsion, results in death from respiratory failure 

Tonic Seizure in which the head, body and limbs are arched backwards 

Emprosthotonus Seizure where the head, body and limbs are arched forwards 

 

3.4 Bizarre Behaviour 

Any bizarre behavior is recorded using a unique code. 
Harlan Study Number: 41204605 Report Page 53 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS (CONTINUED) 

4. AUTONOMIC 

Salivation* Excessive visible wetness around the mouth 

Pilo-erection* Fur stands up - marked cases are described as “puff ball” 

appearance 

Exophthalmia Bulging eyes 

Lachrymation Tear staining (clear fluid) 

Chromodacryorrhea (red/pink fluid) 

Hyperthermia 

Hypothermia 

Skin colour** Blue (cyanotic) 

Redness of extremities 

Skin pallor 

Respiration Decreased respiratory rate 

 Gasping 

 Increased rate 

 Laboured 

 Noisy 

Palpebral closure Degree of eyelid closure e.g. ptosis - observation is graded: 

Slight 

Moderate 

Severe 

Urination and defecation During the study this can only be observed as urogenital 

wetness and/or diarrhoea. In the open arena, the number of 

occasions that the animal defecates/urinates is recorded 

 

*

 When present, observation is graded slight or extreme. 

** When present, observation is graded slight, moderate, or extreme. 
Harlan Study Number: 41204605 Report Page 54 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS (CONTINUED) 

5. MANIPULATIVE TESTS 

Performed in the open arena: 

5.1 Grasp Response 

The animal is grasped around the body and its reaction is scored: 

0 = no response 

1 = animal struggles slightly but becomes passive 

2 = animal repeatedly struggles with/without vocalisation 

3 = animal struggles violently with/without vocalisation 

4 = animal attempts to bite operator 

5.2 Vocalisation 

The number of vocalisations exhibited by the animal during handling. 

5.3 Toe Pinch 

On handling one toe of a hindfoot is lightly pressed with a pair of forceps: 

-3 = no response 

-2 = animal shows awareness of actions 

-1 = withdrawal 

0 = rapid withdrawal with single vocalisation 

1 = rapid withdrawal with multiple vocalisations 

5.4 Tail Pinch 

Whilst animal is in the arena, the end of the tail is lightly pressed with forceps: 

-2 = no response 

-1 = animal freezes/shows awareness of grasping 

0 = animal attempts to escape/struggles with none or single vocalisation 

1 = animal struggles violently with multiple vocalisations 
Harlan Study Number: 41204605 Report Page 55 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS (CONTINUED) 

5.5 Finger Approach 

Whilst animal is in the arena the operator moves one finger towards the animal: 

-1 = animal is oblivious to approach 

0 = animal is aware of finger but is unmoved 

1 = head sways from side to side 

2 = moves towards finger 

3 = investigates finger by moving onto it 

5.6 Touch Escape 

Whilst animal is in the arena the operator runs his finger down the body of the animal: 

-2 = no response 

-1 = animal twitches ears, investigates finger 

0 = animal crouches 

1 = animal moves away but is unhurried 

2 = animal moves away as if startled 

5.7 Pupil Reflex 

The animal is placed in a darkened area to allow the pupils to dilate. A light beam is shone into 

each eye separately and the pupil is observed for immediate constriction. 

The response recorded: 

-2 = no response 

-1 = sluggish 

0 = normal 
Harlan Study Number: 41204605 Report Page 56 

KEY TO SCORING SYSTEM AND EXPLANATION FOR 

BEHAVIOURAL ASSESSMENTS AND SENSORY REACTIVITY 

TESTS (CONTINUED) 

5.8 Blink Reflex (Palpebral Closure) 

The operator attempts to touch the eye of the rat, the response is recorded: 

-2 = no response 

-1 = sluggish 

0 = normal blink reflex 

1 = rapid or repeated eye blink 

5.9 Startle Reflex 

A sharp sudden noise is produced by a noise generator or finger snap or similar. Each animal is 

held lightly but firmly facing the origin of the noise. The response is recorded: 

-1 = no response 

0 = normal 

1 = hyper-responsive 
Harlan Study Number: 41204605 Report Page 57 

TABLES 
Harlan Study Number: 41204605 Report 

Table 1 Summary of Reproductive Performance - Groups Values 

Dose Group (mg/kg bw/da

 0 (Control) 30 60 

Males 

Initial group size 12 12 12 Paired 12 12 12 Failed to induce pregnancy in female partner 0 2 1 Induced pregnancy in female partner 12 10 11 Surviving to terminal necropsy 12 12 12 

Females 

Initial group size 12 12 12 Paired 12 12 12 Non-pregnant 0 2 1 Pregnant 12 10 11 No litter observed 0 0 0 Total litter loss 0 1 0 Rearing young to Day 5 of age 12 9 11 
Harlan Study Number: 41204605 Report 

Table 2 Summary Incidence of Daily Clinical Observations  Day Numbers Relative to Start Date Sex: Male  Group 1 Group 2 Group 3 Group 4  0 (Control) 30 60 120  mg/kg bw/day Scheduled kill  Number of Observations 17 12 12 17  Number of Animals 17 12 12 17  Days from ƒ to 43 57 43 43 43 43 43 57 Increased salivation  Number of Observations 1 . 8 108  Number of Animals 1 . 5 17  Days from ƒ to 3 3 . 36 42 3 42 
Harlan Study Number: 41204605 Report 

Table 2 (continued) Summary Incidence of Daily Clinical Observations  Day Numbers Relative to Start Date Sex: Female  Group 1 Group 2 Group 3 Group 4  0 (Control) 30 60 120  mg/kg bw/day Littering  Number of Observations 2 . 2 1  Number of Animals 2 . 2 1  Days from ƒ to 38 38 . 38 38 40 40 Not Observed Due to Littering  Number of Observations . . 2 .  Number of Animals . . 2 .  Days from ƒ to . . 38 38 . Scheduled kill  Number of Observations 17 12 12 17  Number of Animals 17 12 12 17  Days from ƒ to 42 57 42 46 42 46 42 57 Increased salivation  Number of Observations . . 2 88  Number of Animals . . 2 17  Days from ƒ to . . 41 41 3 43 
Harlan Study Number: 41204605 Report 

Table 3 Summary Incidence of Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group (Sex) Clinical Sign ƒ1 7 14 21 28 35 38/4 post partum  1(M) ANIMALS ALIVE 17 17 17 17 17 17 17  ANIMALS NORMAL 12 12 12 12 12 12 12  1(F) ANIMALS ALIVE 17 17 17 17 17 17 17  ANIMALS NORMAL 12 12 12 12 12 12 12 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 3 (continued) Summary Incidence of Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group (Sex) Clinical Sign ƒ1 7 14 21 28 35 38/4 post partum #

 2(M) ANIMALS ALIVE 12 12 12 12 12 12 12  ANIMALS NORMAL 12 12 12 12 12 12 12  2(F) ANIMALS ALIVE 12 12 12 12 12 12 12  ANIMALS NORMAL 12 12 12 12 12 12 12 # = Day 25 post coitum for female Numbers 43 and 48 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 3 (continued) Summary Incidence of Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group (Sex) Clinical Sign ƒ1 7 14 21 28 35 38/4 post partum #

 3(M) ANIMALS ALIVE 12 12 12 12 12 12 12  ANIMALS NORMAL 12 12 12 12 12 12 12  3(F) ANIMALS ALIVE 12 12 12 12 12 12 12  ANIMALS NORMAL 12 12 12 12 12 12 12 # = Day 25 post coitum for female Number 62 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 3 (continued) Summary Incidence of Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group (Sex) Clinical Sign ƒ1 7 14 21 28 35 38/4 post partum #

 4(M) ANIMALS ALIVE 17 17 17 17 17 17 17  ANIMALS NORMAL 12 12 12 12 12 12 12  4(F) ANIMALS ALIVE 17 17 17 17 17 17 17  ANIMALS NORMAL 12 12 12 12 12 12 12 # = Day 25 post coitum for female Numbers 85, 87 and 88 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 Summary Incidence of Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.5 0.1 0.0  S.D. 0.0 1.0 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.6 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.8 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.6 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.6 0.2 0.0  S.D. 0.0 0.5 0.4 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 38 Relative to Start Date  Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(M) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 4 (continued) Summary Incidence of Behavioural Assessments (Scores)  Day: 4 post partum # 

 Transfer Urinƒ Defƒ Tail elƒ  Group arousal ation ecation evation  (Sex)  1(F) Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.0 0.3 0.2 0.0  S.D. 0.0 0.5 0.4 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ # = Day 25 post coitum for female Numbers 43, 48, 62, 85, 87 and 88 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 5 Group Mean Functional Test Values and Standard Deviations  Test 1 Test 1 Test 2 Test 2 Test 3 Test 3 Overall Overall Las Group Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb activity mobile act (Sex) g g g g g g  1(M) Mean 1065.0 408.0 1168.0 333.4 961.4 422.8 431.6 0.6  S.D. 147.1 170.5 226.6 154.1 530.9 205.2 82.7 0.9  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 2(M) Mean 1001.4 318.2 904.6 306.0 1014.8 337.2 253.4 0.8  S.D. 260.1 125.4 335.0 131.3 311.3 145.3 121.0 1.8  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 3(M) Mean 902.2 363.6 983.6 383.6 915.8 334.4 434.0 0.8  S.D. 418.2 87.9 450.0 112.8 373.4 79.7 109.8 1.3  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 4(M) Mean 953.8 320.6 1215.2 535.0 1132.0 450.8 328.2 1.0  S.D. 296.4 101.8 478.8 278.0 308.5 108.2 179.6 1.4  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒGeneral Footnote: Unit = Time (seconds) for Motor Activity Assessments Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 5 (continued) Group Mean Functional Test Values and Standard Deviations  Test 1 Test 1 Test 2 Test 2 Test 3 Test 3 Overall Overall Las Group Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb activity mobile act (Sex) g g g g g g  1(F) Mean 553.8 238.8 951.2 194.2 851.2 190.8 556.6 4.8  S.D. 145.4 104.4 230.5 73.3 280.4 55.1 122.8 4.5  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 2(F) Mean 983.0* 274.0 730.0 240.4 758.6 254.0 573.2 1.2  S.D. 88.7 30.9 296.3 88.2 226.3 19.6 130.2 1.3  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 3(F) Mean 876.0* 274.4 939.8 241.2 957.0 192.2 571.2 1.8  S.D. 226.2 110.2 137.9 41.9 241.9 45.6 221.6 0.8  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒ 4(F) Mean 773.0* 273.0 845.6 374.4 797.6 341.6** 555.4 0.6  S.D. 233.2 90.2 114.3 265.5 139.6 108.0 241.5 0.9  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒGeneral Footnote: Unit = Time (seconds) for Motor Activity Assessments Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 6 Summary Incidence of Sensory Reactivity Assessments (Scores)  Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Star Group response isation pinch pinch approach escape reflex reflex refl (Sex)  1(M) Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 2(M) Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 3(M) Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 4(M) Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 6 (continued) Summary Incidence of Sensory Reactivity Assessments (Scores)  Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Star Group response isation pinch pinch approach escape reflex reflex refl (Sex)  1(F) Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 2(F) Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 3(F) Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 4(F) Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 7 Group Mean Body Weight Values  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group  (Sex) 1 8 15 22 29 36 43  1(M) Mean 316.4 329.5 343.0 347.8 359.3 369.3 368.8  S.D. 9.2 11.0 12.5 14.2 17.6 20.0 19.3  N 12 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  2(M) Mean 324.9 335.2 351.3 360.2 371.3 381.7 386.5  S.D. 16.5 20.1 25.7 26.7 29.1 29.7 35.1  N 12 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  3(M) Mean 318.4 324.5 333.1 342.5 350.0 359.6 364.7  S.D. 11.2 15.3 20.8 17.8 20.5 22.1 21.3  N 12 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(M) Mean 319.3 321.2 328.1 338.0 343.0 350.2 359.9  S.D. 12.9 17.2 24.7 22.6 25.4 26.2 23.4  N 12 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 7 (continued) Group Mean Body Weight Values Pre-Pairing  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group  (Sex) 1 8 15  1(F) Mean 204.8 211.3 223.5  S.D. 5.0 8.0 8.8  N 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  2(F) Mean 197.6 200.6 205.3  S.D. 7.0 11.2 9.9  N 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  3(F) Mean 199.7 197.8 205.1  S.D. 6.2 10.2 11.1  N 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(F) Mean 200.3 198.8 201.9  S.D. 5.8 7.3 7.9  N 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 7 (continued) Group Mean Body Weight Values 

Group(Sex) 

Body Weight (g)

Day Numbers 

Gestation Lactation

0 7 14 20 1 4

1(F) Mean 224.1 251.8 283.5 348.3 258.9 269.9 

S.D. 8.9 8.9 10.1 15.6 15.7 13.1 N 12 12 12 12 12 12

2(F) Mean 205.4** 228.8*** 257.1*** 314.2** 235.2** 244.6** 

S.D. 13.1 9.9 14.2 28.3 10.2 10.4 N 10 10 10 10 9 9

3(F) Mean 206.2*** 226.8*** 251.3*** 300.4*** 226.5*** 239.0***

S.D. 8.9 10.5 17.1 24.0 14.8 14.8 N 11 11 11 11 11 11 

4(F) Mean 205.9*** 223.3*** 240.3*** 287.6*** 227.0*** 237.3**

S.D. 6.4 9.5 11.9 22.9 8.5 10.4 N 9 9 9 9 7 7 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 7 (continued) Group Mean Body Weight Values Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group  (Sex) 1 8 15 22 29 36 43 50 57  1(M) Mean 322.0 335.0 350.0 359.6 372.4 381.6 384.2 394.6 397.8  S.D. 9.9 13.7 15.0 17.9 20.9 23.6 24.4 25.6 25.9  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(M) Mean 317.6 318.8 328.2 326.2 342.8 348.6 356.4 371.0 369.8  S.D. 12.5 16.1 18.8 14.9 25.9 26.8 26.6 28.9 29.3  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 7 (continued) Group Mean Body Weight Values Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group  (Sex) 1 8 15 22 29 36 43 50 57  1(F) Mean 189.4 194.2 200.6 206.0 206.6 209.8 212.2 220.8 218.4  S.D. 6.5 7.7 7.8 10.0 10.6 12.1 13.1 12.1 11.5  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(F) Mean 198.2 195.8 200.0 205.2 208.6 210.6 215.4 221.8 220.8  S.D. 5.2 5.4 7.0 9.7 9.4 8.4 10.6 13.2 10.1  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 8 Group Mean Body Weight Gains  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Abs %  Gain Gain  Group From: 1 8 15 22 29 36 1 1  (Sex) To: 8 15 22 29 36 43 43 43  1(M) Mean 13.1 13.5 4.8 11.6 10.0 ƒ0.5 52.4 16.5  S.D. 4.1 5.8 5.6 4.8 4.2 4.5 14.8 4.6  N 12 12 12 12 12 12 12 12  2(M) Mean 10.3 16.1 8.9 11.1 10.4 4.8 61.6 18.8  S.D. 6.3 6.6 3.1 4.1 3.0 7.8 21.3 5.9  N 12 12 12 12 12 12 12 12  3(M) Mean 6.1 8.6 9.4 7.5 9.6 5.1 46.3 14.5  S.D. 8.0 9.6 8.1 7.3 4.2 7.1 18.6 5.9  N 12 12 12 12 12 12 12 12  4(M) Mean 1.9 6.9 9.9 5.0 7.2 9.8 40.7 12.7  S.D. 7.4 10.6 6.6 7.8 6.4 9.7 15.5 4.8  N 12 12 12 12 12 12 12 12 Dose Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw
Harlan Study Number: 41204605 Report 

Table 8 (continued) Group Mean Body Weight Gains Pre-Pairing  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Abs %  Gain Gain  Group From: 1 8 1 1  (Sex) To: 8 15 15 15  1(F) Mean 6.5 12.3 18.8 9.2  S.D. 7.2 3.7 8.8 4.4  N 12 12 12 12  2(F) Mean 3.0 4.8** 7.8 3.9  S.D. 5.7 5.4 7.0 3.5  N 12 12 12 12  3(F) Mean ƒ1.8** 7.3** 5.4 2.7  S.D. 8.6 6.7 8.7 4.4  N 12 12 12 12  4(F) Mean ƒ1.4** 3.1** 1.7 0.9  S.D. 5.6 4.8 8.0 4.0  N 12 12 12 12 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 8 (continued) Group Mean Body Weight Gains 

Increase in Body Weight (g) 

Days

 Cumulative Body Weight Change (g

Days 

 Gestation Lactation GestationGroup (sex) 

From: 0 7 14 1 0 0

To: 7 14 20 4 14 20

1(F) Mean 27.8 31.7 64.8 11.0 59.4 124.2 

 S.D. 6.1 4.3 10.7 8.5 5.8 13.3 

 N 12 12 12 12 12 12 

2(F) Mean 23.4 28.3 57.1 9.3 51.7 108.8 

 S.D. 8.2 7.1 15.2 9.0 11.6 22.1  N 10 10 10 9 10 10

3(F) Mean 20.6** 24.5* 49.1** 12.5 45.1** 94.2** 

 S.D. 5.1 8.3 12.8 6.2 12.4 20.1 

 N 11 11 11 11 11 11 

4(F) Mean 17.4** 17.0** 47.2* 10.3 34.4*** 81.7*** 

 S.D. 8.8 9.2 19.4 8.3 14.2 25.4 

 N 9 9 9 7 9 9

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Table 8 (continued) Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Abs  Gain G Group From: 1 8 15 22 29 36 43 50 1  (Sex) To: 8 15 22 29 36 43 50 57 57  1(M) Mean 13.0 15.0 9.6 12.8 9.2 2.6 10.4 3.2 75.8  S.D. 4.0 3.0 3.2 3.4 3.5 1.7 4.0 0.4 17.3  N 5 5 5 5 5 5 5 5 5  4(M) Mean 1.2** 9.4* ƒ2.0 16.6 5.8 7.8** 14.6 ƒ1.2** 52.2  S.D. 6.7 3.8 21.1 26.3 2.9 1.5 3.0 2.0 19.4  N 5 5 5 5 5 5 5 5 5 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 8 (continued) Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Abs %  Gain Gain  Group From: 1 8 15 22 29 36 43 50 1 1  (Sex) To: 8 15 22 29 36 43 50 57 57 57  1(F) Mean 4.8 6.4 5.4 0.6 3.2 2.4 8.6 ƒ2.4 29.0 15 S.D. 4.0 4.7 7.2 4.2 7.9 6.8 4.4 4.2 8.5 4 N 5 5 5 5 5 5 5 5 5 5  4(F) Mean ƒ2.4* 4.2 5.2 3.4 2.0 4.8 6.4 ƒ1.0 22.6 11 S.D. 5.3 4.3 7.0 2.9 2.4 5.7 4.9 4.6 8.2 4 N 5 5 5 5 5 5 5 5 5 5 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

 Table 9 Group Mean Food Consumptions  Day Numbers Relative to Start Date  Group From: 1 8 22 29 36  (Sex) To: 8 15 29 36 43  1(M) Mean 18.3 18.3 18.6 19.5 20.0  N 12 12 12 12 12  2(M) Mean 18.7 18.7 20.0 21.1 21.8  N 12 12 12 12 12  3(M) Mean 16.2 16.5 17.8 19.4 21.2  N 12 12 12 12 12  4(M) Mean 15.2 15.1 17.7 18.4 20.7  N 12 12 12 12 12 Food Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 9 (continued) Group Mean Food Consumptions Pre-Pairing  Day Numbers Relative to Start Date  Group From: 1 8  (Sex) To: 8 15  1(F) Mean 15.0 14.6  N 12 12  2(F) Mean 13.4 13.3  N 12 12  3(F) Mean 11.1 13.2  N 12 12  4(F) Mean 11.0 11.5  N 12 12 Food Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 9 (continued) Group Mean Food Consumptions 

 Day Numbers  Gestation Lactation 

Group (Sex) 

From: 0 7 14 1 To: 7 14 20 4 

1(F) Mean 19.1 22.6 26.3 26.8 

S.D. 1.4 1.8 2.0 4.8 N 11 11 12 12 

2(F) Mean 16.8* 19.9* 23.1* 23.6 

S.D. 1.9 2.7 3.0 5.4 N 10 10 10 9 

3(F) Mean 15.3*** 18.3** 22.0** 24.4 

S.D. 1.6 3.0 2.9 4.7 N 11 11 11 9 

4(F) Mean 14.5*** 17.0** 21.4** 22.9 

S.D. 2.5 3.2 3.4 8.5 N 9 9 9 6 

Food Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 9 (continued) Group Mean Food Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 1 8 15 22 29 36 43 50  (Sex) To: 8 15 22 29 36 43 50 57  1(M) Mean 17.7 18.1 19.7 19.2 19.8 20.1 22.5 20.1  N 5 5 5 5 5 5 5 5  4(M) Mean 15.2 15.8 19.1 16.5 17.7 20.5 22.1 19.8  N 5 5 5 5 5 5 5 5 Food Consumption = g/animal/day. Dose Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw
Harlan Study Number: 41204605 Report 

Table 9 (continued) Group Mean Food Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 1 8 15 22 29 36 43 50  (Sex) To: 8 15 22 29 36 43 50 57  1(F) Mean 12.8 12.9 15.0 13.7 14.3 14.9 17.3 14.9  N 5 5 5 5 5 5 5 5  4(F) Mean 11.2 11.6 16.0 12.9 13.8 15.3 17.4 15.7  N 5 5 5 5 5 5 5 5 Food Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 10 Food Efficiency  Day Numbers Relative to Start Date  Group From: 1 8 22 29 36  (Sex) To: 8 15 29 36 43  1(M) Mean 10.2 10.5 8.8 7.3 ƒ0.4  N 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  2(M) Mean 7.8 12.3 7.9 7.1 2.8  N 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  3(M) Mean 5.4 7.6 6.1 7.1 3.3  N 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  4(M) Mean 1.8 6.4 4.0 5.5 6.3  N 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 10 (continued) Food Efficiency Pre-Pairing  Day Numbers Relative to Start Date  Group From: 1 8  (Sex) To: 8 15  1(F) Mean 6.2 12.1  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ  2(F) Mean 3.2 5.2  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ  3(F) Mean ƒ2.5 7.6  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ  4(F) Mean ƒ1.9 3.7  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 10 (continued) Food Efficiency Recovery Groups  Day Numbers Relative to Start Date  Group From: 1 8 15 22 29 36 43 50  (Sex) To: 8 15 22 29 36 43 50 57  1(M) Mean 10.5 11.9 7.0 9.5 6.6 1.8 6.6 2.2  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  4(M) Mean 1.1 8.5 ƒ1.5 14.3 4.7 5.5 9.4 ƒ0.9  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 10 (continued) Food Efficiency Recovery Groups  Day Numbers Relative to Start Date  Group From: 1 8 15 22 29 36 43 50  (Sex) To: 8 15 22 29 36 43 50 57  1(F) Mean 5.3 7.0 5.2 0.6 3.2 2.3 7.1 ƒ2.3  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  4(F) Mean ƒ3.1 5.2 4.6 3.7 2.1 4.5 5.3 ƒ0.9  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 Group Mean Daily Water Consumptions  Day Numbers Relative to Start Date  Group From: 3 4 5 6 7 8 9 10 11 12 13  (Sex) To: 4 5 6 7 8 9 10 11 12 13 14  1(M) Mean 26 26.3 26.3 29 24 30 29.7 26.3 25.7 30.3 28.7  N 12 12 12 12 12 12 12 12 12 12 12  2(M) Mean 30.3 26.7 28.7 32 27 30.3 31.3 26.3 29.7 31 28  N 12 12 12 12 12 12 12 12 12 12 12  3(M) Mean 28.7 29.7 29 33.3 25 29.3 34 27.7 28.7 31 30  N 12 12 12 12 12 12 12 12 12 12 12  4(M) Mean 30.3 31 29 35 27 26.3 36 31.3 30.3 28.3 32.3  N 12 12 12 12 12 12 12 12 12 12 12 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions  Day Numbers Relative to Start Date  Group From: 14 22 23 24 25 26 27 28 29 30 31  (Sex) To: 15 23 24 25 26 27 28 29 30 31 32  1(M) Mean 29.7 27 31 27.7 26 27.7 29.3 33.7 29.7 32 29.7  N 12 12 12 12 12 12 12 12 12 12 12  2(M) Mean 30.3 25 30.7 28.7 25.7 29.3 31.7 33.3 33 35 33.3  N 12 12 12 12 12 12 12 12 12 12 12  3(M) Mean 29.3 26 32.3 30.3 30.3 34.7 33.7 36 31 34.7 35.3  N 12 12 12 12 12 12 12 12 12 12 12  4(M) Mean 31 27.7 32.7 35.3 32.7 36 32 36 35 34.7 31.7  N 12 12 12 12 12 12 12 12 12 12 12 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions  Day Numbers Relative to Start Date  Group From: 32 33 34 35 36 37 38 39 40 41 42  (Sex) To: 33 34 35 36 37 38 39 40 41 42 43  1(M) Mean 29.3 32.3 32.7 32.3 28.7 29.7 30 27.7 18.7 31 24.7  N 12 12 12 12 12 12 12 12 12 12 12  2(M) Mean 33.7 33 33.7 30.7 30 31.3 30.3 30.7 20 33 28  N 12 12 12 12 12 12 12 12 12 12 12  3(M) Mean 36.7 34.3 37 34 30.7 33 30.3 28.7 21.7 34 26.3  N 12 12 12 12 12 12 12 12 12 12 12  4(M) Mean 35.3 33 38 33 32 33.7 29.7 28.3 18 32.7 26.7  N 12 12 12 12 12 12 12 12 12 12 12 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Pre-Pairing  Day Numbers Relative to Start Date  Group From: 3 4 5 6 7 8 9 10 11 12 13 1 (Sex) To: 4 5 6 7 8 9 10 11 12 13 14 1 1(F) Mean 25.7 24.7 24 27.3 21 22.3 26 22.3 23.3 27.7 25 2 N 12 12 12 12 12 12 12 12 12 12 12 1 2(F) Mean 25.7 22.7 21.3 26.3 21.3 22 25.7 21.3 27 26.7 25.7 2 N 12 12 12 12 12 12 12 12 12 12 12 1 3(F) Mean 28.3 24.7 24 31 26 21.7 31.3 27.7 29 28.7 31.3 2 N 12 12 12 12 12 12 12 12 12 12 12 1 4(F) Mean 28 23.7 24 30.3 28.7 24.7 28 25.3 29.7 27.3 27.7 2 N 12 12 12 12 12 12 12 12 12 12 12 1Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Water Consumptions 

 Day Numbers  Gestation Lactation 

Group (Sex) 

From: 0 7 14 1 To: 7 14 20 4 

1(F) Mean 31.8 35.6 42.8 41.0 

S.D. 8.2 10.3 10.2 10.1 N 12 12 12 12 

2(F) Mean 29.4 35.7 38.1* 37.1 

S.D. 9.2 14.6 10.9 11.5 N 10 10 10 9 

3(F) Mean 32.9 36.5 38.5 38.0 

S.D. 13.7 16.5 13.4 15.0 N 11 11 11 11 

4(F) Mean 34.1 35.4 41.6 38.8 

S.D. 12.5 12.3 11.3 12.2 N 9 9 9 7 

Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day     
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 3 4 5 6 7 8 9 10 11 12 13  (Sex) To: 4 5 6 7 8 9 10 11 12 13 14  1(M) Mean 35 31 18 48 32 32 33 30 33 34 31  N 5 5 5 5 5 5 5 5 5 5 5  4(M) Mean 41 37 32 35 30 32 35 31 39 36 33  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 14 15 16 17 18 19 20 21 22 23 24  (Sex) To: 15 16 17 18 19 20 21 22 23 24 25  1(M) Mean 31 31 33 26 30 30 36 30 28 31 28  N 5 5 5 5 5 5 5 5 5 5 5  4(M) Mean 32 37 37 39 35 34 55 39 30 40 36  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 25 26 27 28 29 30 31 32 33 34 35  (Sex) To: 26 27 28 29 30 31 32 33 34 35 36  1(M) Mean 29 34 29 31 34 35 30 28 34 36 32  N 5 5 5 5 5 5 5 5 5 5 5  4(M) Mean 33 43 42 46 35 38 39 36 41 46 49  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 36 37 38 39 40 41 42 43 44 45 46  (Sex) To: 37 38 39 40 41 42 43 44 45 46 47  1(M) Mean 29 31 33 28 18 32 29 31 33 32 26  N 5 5 5 5 5 5 5 5 5 5 5  4(M) Mean 42 50 39 40 36 48 32 31 33 34 36  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 47 48 49 50 51 52 53 54 55 56  (Sex) To: 48 49 50 51 52 53 54 55 56 57  1(M) Mean 30 34 33 31 3 33 25 25 28 24  N 5 5 5 5 5 5 5 5 5 5  4(M) Mean 32 34 33 38 4 39 28 30 32 26  N 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 3 4 5 6 7 8 9 10 11 12 13  (Sex) To: 4 5 6 7 8 9 10 11 12 13 14  1(F) Mean 19 17 32 4 18 20 26 18 22 21 24  N 5 5 5 5 5 5 5 5 5 5 5  4(F) Mean 28 30 25 28 20 21 22 22 24 23 25  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 14 15 16 17 18 19 20 21 22 23 24  (Sex) To: 15 16 17 18 19 20 21 22 23 24 25  1(F) Mean 18 22 21 30 21 22 26 24 18 22 19  N 5 5 5 5 5 5 5 5 5 5 5  4(F) Mean 23 27 26 28 20 19 34 24 24 26 26  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 25 26 27 28 29 30 31 32 33 34 35  (Sex) To: 26 27 28 29 30 31 32 33 34 35 36  1(F) Mean 21 22 23 19 26 21 19 19 20 17 22  N 5 5 5 5 5 5 5 5 5 5 5  4(F) Mean 25 28 26 27 25 30 26 28 26 33 27  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 36 37 38 39 40 41 42 43 44 45 46  (Sex) To: 37 38 39 40 41 42 43 44 45 46 47  1(F) Mean 18 25 22 22 26 27 20 24 25 26 22  N 5 5 5 5 5 5 5 5 5 5 5  4(F) Mean 25 34 29 24 28 33 29 33 30 25 28  N 5 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 11 (continued) Group Mean Daily Water Consumptions Recovery Groups  Day Numbers Relative to Start Date  Group From: 47 48 49 50 51 52 53 54 55 56  (Sex) To: 48 49 50 51 52 53 54 55 56 57  1(F) Mean 25 25 26 19 7 27 24 21 24 19  N 5 5 5 5 5 5 5 5 5 5  4(F) Mean 29 30 26 25 4 29 26 27 25 18  N 5 5 5 5 5 5 5 5 5 5 Water Consumption = g/animal/day. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Table 12 Summary Incidence of Mating Performance, Fertility and Gestation Lengths 

Group

Number 

of Males 

Paired 

Number of Females Pre-Coital Interval (Days) Mating 

Index 

(%) 

Pregnancy

Index 

(%) 

Gestation Length (Days) 

Paired Mated Pregnant 1 2 3 4 5 21 22 221⁄2 23 231⁄2 24 2

1 12 12 12 12 4 1 5 2 0 100 100 1 1 5 3 2 0 2 12 12 12 10 3 4 3 1 1 100 83 0 3 5 1 0 0 3 12 12 12 11 4 5 2 1 0 100 92 0 3 3 2 2 1 4 12 12 12 10 1 2 5 2 2 100 83 1 0 1 3 4 0 
Harlan Study Number: 41204605 Report 

Table 13 Group Mean Litter Size and Litter Weights 

Group 

Number 

of 

Corpora 

Lutea 

Number of 

Implantation

Sites 

Total 

Number of Offspring 

Born 

Number of Live 

Offspring 

Litter Weight 

(g) 

Offspring Weight (g) 

Day 1 Day 4 

Day 1 Day 4 Day 1 Day 4 Males Females Males Female

1 Mean 13.3 12.3 11.6 11.4 11.3 69.37 97.43 6.40 6.07 8.99 8.77 

S.D. 1.7 2.6 2.5 2.4 2.5 12.03 16.10 0.64 0.81 1.33 1.63 N 12 12 12 12 12 12 12 12 12 12 12 

2 Mean 13.2 12.2 11.7 11.7 11.7 68.03 96.48 6.06 5.85 8.57 8.37 

S.D. 2.1 2.7 2.9 2.9 2.9 14.78 20.20 0.63 0.47 1.06 0.85 

N 10 10 9 9 9 9 9 9 9 9 9 

3 Mean 11.5 10.8 9.1 9.1 9.1 56.51 80.46 6.63 6.21 9.56 9.13 

S.D. 2.8 2.9 3.5 3.5 3.5 19.63 23.88 0.66 0.69 1.39 1.49 N 11 11 11 11 11 11 11 11 11 11 11 

4 Mean 11.3 10.3 8.1 8.7 8.7 55.76 79.90 6.50 6.19 9.19 9.02 

S.D. 3.0 2.9 3.2 2.1 2.1 17.12 24.79 0.73 0.42 1.08 0.78 N 9 9 7 7 7 7 7 7 7 7 7 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 14 Group Mean Implantation Losses and Survival Indices Values 

Group 

PreImplantation 

Loss (%)

Post -

Implantation 

Loss (%) 

Live 

Birth Index 

(%) 

Viability Index (%) 

1 Mean 8.9 5.2 98.7 99.2 

S.D. 13.6 6.5 3.0 2.6 N 12 12 12 12 

2 Mean 8.3 14.2 100.0 100.0 

S.D. 12.0 23.8 0.0 0.0 N 10 10 10 9 

3 Mean 6.4 15.6 100.0 100.0 

S.D. 12.8 22.3 0.0 0.0 N 11 11 11 11 

4 Mean 8.3 28.1 95.8 100.0 

S.D. 9.1 22.4 12.5 0.0 N 9 9 9 7 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 15 Group Mean Sex Ratio Values 

Group 

Sex Ratio (% Males) Post Partum Day: 

At birth 1 4 

1 Mean 43.9 43.0 43.2 

S.D. 17.1 17.8 17.6 N 12 12 12 

2 Mean 38.9 38.9 38.9 

S.D. 10.3 10.3 10.3 N 9 9 9 

3 Mean 50.6 50.6 50.6 

S.D. 16.1 16.1 16.1 N 11 11 11 

4 Mean 54.9 54.9 54.9 

S.D. 24.9 24.9 24.9 N 7 7 7 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Table 16 Summary Incidence of Clinical Signs for Offspring 

Dose Level (mg/kg bw/day) 

0 (Control) 30 60 

Number of litters 12 10 11 Small . . . Cold . . . Weak . 2M (1) . Pale 1F (1) . . No milk in stomach 1F (1) 2M (1) . Bruised head 1F (1) . . Scab on dorsal region 1F (1) . . Swollen left hind limb 1F (1) . . Open wound on right hind limb . . 1F (1) Missing 2F (2) 2M (1) . Found dead 2M (2) . . () = Number of litters 
Harlan Study Number: 41204605 Report 

Table 17 Group Mean Reflexological Responses for Offspring 

Group Surface Righting (% passed) 

1 Mean 96.0 

S.D. 8.0 

N 12 

2 Mean 95.1 

S.D. 9.8 N 9 

3 Mean 81.5 

S.D. 18.6 N 11 

4 Mean 83.7 

S.D. 17.0 N 7 

 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Table 18 Group Mean Haematological Values  Group Hb RBC Hct MCH MCV MCHC WBC Neut Lymph Mono Eos Bas  (Sex) g/dl 10^12/l % pg fl g/dl 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l  1(M) Mean 16.24 9.140 50.32 17.78 55.10 32.24 6.50 0.940 5.536 0.000n 0.028 0.000n  S.D. 0.68 0.321 1.57 0.85 1.99 0.55 0.35 0.383 0.437 0.000 0.038 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  2(M) Mean 16.62 9.424 51.08 17.66 54.20 32.52 7.20 1.412 5.738 0.000n 0.058 0.000n  S.D. 0.35 0.344 1.61 0.47 1.26 0.41 1.21 0.366 1.179 0.000 0.066 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  3(M) Mean 16.12 9.140 49.78 17.64 54.44 32.40 7.46 1.130 6.256 0.000n 0.078 0.000n  S.D. 0.75 0.276 2.04 0.83 1.68 0.68 0.57 0.379 0.435 0.000 0.078 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(M) Mean 16.04 8.828 48.82 18.20 55.38 32.86 6.26 0.866 5.348 0.000n 0.048 0.000n  S.D. 0.90 0.633 2.33 0.44 2.02 0.81 0.55 0.529 0.804 0.000 0.054 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 18 (continued) Group Mean Haematological Values  Group Hb RBC Hct MCH MCV MCHC WBC Neut Lymph Mono Eos Bas CT  (Sex) g/dl 10^12/l % pg fl g/dl 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l Seco 1(F) Mean 13.74 7.298 42.38 18.90 58.26 32.46 5.40 1.778 3.600 0.014n 0.010n 0.000n 9 S.D. 0.53 0.581 1.81 0.89 2.48 0.30 0.94 0.676 0.654 0.031 0.022 0.000 0 N 5 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 2(F) Mean 13.48 7.394 42.12 18.26 57.06 31.98 4.76 1.456 3.304 0.000n 0.000n 0.000n 9 S.D. 1.19 0.767 3.86 0.65 1.38 0.30 1.03 0.475 1.193 0.000 0.000 0.000 0 N 5 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 3(F) Mean 13.04 7.102 40.98 18.36 57.74 31.80 5.30 2.138 3.162 0.000n 0.000n 0.000n 8 S.D. 0.62 0.448 2.37 0.76 2.45 0.58 1.37 0.913 1.071 0.000 0.000 0.000 0 N 5 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ 4(F) Mean 13.54 7.096 42.48 19.06 59.86 31.88 4.92 1.594 3.302 0.000n 0.026n 0.000n 9 S.D. 0.45 0.184 1.86 0.61 1.77 0.75 1.47 0.740 0.983 0.000 0.036 0.000 0 N 5 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Table 18 (continued) Group Mean Haematological Values Recovery Groups  Group Hb RBC Hct MCH MCV MCHC WBC Neut Lymph Mono Eos Bas  (Sex) g/dl 10^12/l % pg fl g/dl 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l  1(M) Mean 16.02 8.800 49.10 18.30 56.00 32.66 8.40 1.184 7.110 0.000n 0.106 0.000n  S.D. 0.59 0.760 2.25 1.47 3.43 0.88 1.90 0.300 2.068 0.000 0.070 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(M) Mean 15.52 9.050 48.24 17.14 53.32 32.14 6.56 1.434 5.088 0.000n 0.038 0.000n  S.D. 0.23 0.089 0.67 0.40 1.09 0.11 0.71 0.182 0.735 0.000 0.058 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 18 (continued) Group Mean Haematological Values Recovery Groups  Group Hb RBC Hct MCH MCV MCHC WBC Neut Lymph Mono Eos Bas  (Sex) g/dl 10^12/l % pg fl g/dl 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l 10^9/l  1(F) Mean 14.28 7.774 43.32 18.38 55.74 32.96 3.22 0.588 2.592 0.000n 0.040 0.000n  S.D. 1.96 1.123 5.96 0.34 0.87 0.35 2.04 0.433 1.622 0.000 0.032 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(F) Mean 15.18 8.392 46.12 18.10 54.98 32.94 3.52 0.614 2.890 0.000n 0.016 0.000n  S.D. 0.42 0.342 1.20 0.46 1.24 0.27 0.43 0.047 0.397 0.000 0.022 0.000  N 5 5 5 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 Group Mean Blood Chemical Values  Tot.  Group Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++  (Sex) mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/ 1(M) Mean 43.2 142.8 6.974 3.94 1.294 147.0 4.492 103.0 2.75 S.D. 4.4 16.1 0.284 0.15 0.035 2.2 0.428 3.2 0.08 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ 2(M) Mean 43.0 149.2 6.954 3.86 1.268 146.8 4.584 103.2 2.75 S.D. 3.2 25.1 0.464 0.22 0.171 2.5 0.980 1.6 0.09 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ 3(M) Mean 41.4 148.0 7.168 3.88 1.182 146.6 4.778 103.8 2.75 S.D. 2.9 13.5 0.437 0.19 0.066 4.2 0.372 2.5 0.17 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ 4(M) Mean 38.2* 145.4 7.296 3.92 1.142* 146.2 4.940 102.8 2.77 S.D. 3.3 10.5 0.562 0.25 0.067 2.2 0.779 2.2 0.19 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values  Group P ASAT ALAT AP Creat Chol Bili Bile Acid  (Sex) mmol/l IU/l IU/l IU/l mg/dl mg/dl mg/dl μmol/l 

 1(M) Mean 1.76 108.0 62.0 173.6 0.720 82.6 0.094 7.96  S.D. 0.40 30.8 8.4 34.0 0.030 9.6 0.021 4.82  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(M) Mean 1.74 93.2 64.8 243.2* 0.730 80.0 0.086 6.44  S.D. 0.64 16.3 7.3 45.0 0.046 17.5 0.065 4.13  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(M) Mean 1.72 90.8 65.0 181.8 0.720 78.0 0.124 7.30  S.D. 0.33 11.9 8.0 38.4 0.058 15.5 0.041 4.04  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 2.14 91.4 54.0 170.8 0.712 72.6 0.124 7.44  S.D. 0.53 16.9 7.8 28.7 0.059 7.9 0.038 3.07  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values  Tot.  Group Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++  (Sex) mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l  1(F) Mean 48.6 135.2 6.420 3.62 1.308 145.2 4.328 102.6 2.624  S.D. 11.3 13.7 0.486 0.23 0.098 2.2 0.329 2.6 0.128  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  2(F) Mean 51.0 122.2 6.454 3.70 1.350 147.8 4.710 104.6 2.750  S.D. 4.7 12.1 0.386 0.12 0.089 2.2 0.604 3.2 0.164  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  3(F) Mean 55.0 131.0 6.472 3.72 1.344 145.0 4.280 104.2 2.590  S.D. 10.1 16.6 0.248 0.13 0.076 2.5 0.519 1.3 0.078  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  4(F) Mean 57.4 125.4 6.764 3.82 1.296 147.2 5.046 102.8 2.728  S.D. 6.0 10.6 0.257 0.13 0.096 1.8 0.718 2.4 0.080  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values  Group P ASAT ALAT AP Creat Chol Bili Bile Acid  (Sex) mmol/l IU/l IU/l IU/l mg/dl mg/dl mg/dl μmol/l 

 1(F) Mean 1.00 88.0 82.0 128.6 0.848 82.2 0.084 10.84  S.D. 0.19 23.8 8.2 36.8 0.319 13.1 0.015 4.65  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2(F) Mean 0.96 99.2 75.8 147.2 0.758 69.8 0.076 6.06  S.D. 0.55 23.8 18.8 24.7 0.053 15.9 0.005 1.41  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3(F) Mean 0.86 83.0 72.0 138.0 0.710 64.4 0.086 7.34  S.D. 0.68 16.2 14.9 31.4 0.046 8.7 0.011 4.90  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 1.00 79.6 62.6 169.2 0.848 71.0 0.112* 4.68*  S.D. 0.29 14.9 17.4 73.3 0.235 32.1 0.028 1.13  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values Recovery Groups  Tot.  Group Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++  (Sex) mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/ 1(M) Mean 52.0 197.6 6.322 3.48 1.228 147.2 4.516 102.0 2.58 S.D. 6.6 39.5 0.654 0.31 0.096 2.5 0.667 2.0 0.13 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ 4(M) Mean 50.6 170.0 6.688 3.66 1.216 145.6 4.566 103.2 2.63 S.D. 3.8 19.3 0.161 0.17 0.055 1.5 0.234 0.8 0.05 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values Recovery Groups  Group P ASAT ALAT AP Creat Chol Bili Bile Acid  (Sex) mmol/l IU/l IU/l IU/l mg/dl mg/dl mg/dl μmol/l 

 1(M) Mean 1.50 123.6 83.6 116.6 0.628 89.6 0.080 9.64  S.D. 0.52 39.4 45.5 9.9 0.049 24.0 0.036 12.80  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(M) Mean 1.62 68.0** 56.0 157.4* 0.668 92.2 0.106 8.30  S.D. 0.19 6.8 9.4 39.0 0.045 9.4 0.015 3.00  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values Recovery Groups  Tot.  Group Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++  (Sex) mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/ 1(F) Mean 53.2 150.4 7.364 4.44 1.520 149.4 4.942 104.2 2.78 S.D. 5.4 41.3 0.732 0.44 0.053 3.6 0.711 3.3 0.12 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ 4(F) Mean 51.0 152.0 7.406 4.14 1.276** 147.4 4.682 104.0 2.76 S.D. 4.9 8.5 0.237 0.11 0.107 1.3 0.276 1.0 0.05 N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒDose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 19 (continued) Group Mean Blood Chemical Values Recovery Groups  Group P ASAT ALAT AP Creat Chol Bili Bile Acid  (Sex) mmol/l IU/l IU/l IU/l mg/dl mg/dl mg/dl μmol/l 

 1(F) Mean 1.42 115.2 58.0 103.0 0.704 83.0 0.078 4.86  S.D. 0.35 88.3 6.0 23.6 0.046 12.1 0.013 0.51  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4(F) Mean 1.50 77.8 63.8 75.6* 0.682 83.0 0.072 7.20  S.D. 0.20 17.4 11.0 8.2 0.022 17.7 0.019 6.46  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Table 20 Summary Incidence of Urinalytical Findings 

MALES 

 DOSE LEVEL: 0 30 60 120  (Control) (mg/kg bw/day) (mg/kg bw/day) (mg/kg bw/day)  GROUP: 1 2 3 4 Volume Mean (ml) 23.75 17.40 22.40 22.80  S.D. 6.24 5.94 7.44 9.04  N 4 5 5 5 Specific Gravity Mean 1.0128 1.0138 1.0122 1.0124  S.D. 0.0043 0.0040 0.0032 0.0049  N 4 5 5 5 pH Examined 5 5 5 5 (Incidence) 5 0 0 0 0  6 2 2 4 4  7 3 3 1 1 Protein Examined 5 5 5 5 (Incidence) 1+ 5 5 5 5 Glucose Examined 5 5 5 5 (Incidence) Normal 5 5 5 5 Ketones Examined 5 5 5 5 (Incidence) Neg. 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 20 (continued) Summary Incidence of Urinalytical Findings 

MALES 

 DOSE LEVEL: 0 30 60 120  (Control) (mg/kg bw/day) (mg/kg bw/day) (mg/kg bw/day)  GROUP: 1 2 3 4 Urobilinogen Examined 5 5 5 5 

(Incidence) Normal 5 5 5 5 Bilirubin Examined 5 5 5 5 

(Incidence) Neg. 5 5 5 5 

Blood - Erythrocytes Examined 5 5 5 5 (Incidence) Neg. 5 5 5 5 Blood - Haemoglobin Examined 5 5 5 5 (Incidence) Neg. 5 5 5 5 Appearance Examined 5 5 5 5 

 Clear 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 21 Summary Incidence of Offspring Necropsy Findings 

Interim Deaths Terminal Kill (Day 

Group Post-Partum Day of Termination Number of affected Litters Number of offspring Macroscopic Findings Number of Litters Number of Offspring 

1 Pre Day 1 1 1M Autolytic changes detected 1 1F 

 1 1M No abnormalities detected 1 1F  10 . 

2 9 . 3 1 1F 

 10 . 

4 Pre Day 1 1 1M 1F Autolytic changes detected 1 1M 

 5 1 1M No abnormalities detected 6 . 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/da
Harlan Study Number: 41204605 Report 

Table 22 Summary Incidence of Necropsy Findings  ------------ MALES Removal Reason: SCHEDULED KILL ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 0 30 6 (Control) mg/kg  Number of Animals Examined : 17 12 1 Group : (1) (2)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒEpididymides;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 12 1 Mass; left ...................................................................................... 0 0 Mammary Gland;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 11 1 Mass ............................................................................................ 0 1 Seminal Vesicles;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 12 1 Small ........................................................................................... 0 0 
Harlan Study Number: 41204605 Report 

Table 22 (continued) Summary Incidence of Necropsy Findings  ----------- FEMALES Removal Reason: SCHEDULED KILL ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 0 30 6 (Control) mg/kg  Number of Animals Examined : 17 12 1 Group : (1) (2)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒEyes;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 12 1 Reddened; right ................................................................................. 0 0 Uterus & Cervix;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 11 1 Distended; left horn ............................................................................ 0 1 Vagina;  Submitted........................................................................................ (17) (12) (1 No Visible Lesions............................................................................... 17 11 1 Fluid Filled .................................................................................... 0 1 
Harlan Study Number: 41204605 Report 

Table 23 Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ MALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ Terminal Bodyweight ........... Mean (g) 368.8 386.5 364.7 359.9  S.D. 19.3 35.1 21.3 23.4  N 12 12 12 12 Adrenals ...................... Mean (g) 0.07054 0.06724 0.06116 0.06958  S.D. 0.00993 0.01276 0.00784 0.00459  N 5 5 5 5  Mean (%) 0.018 0.018 0.017 0.019  S.D. 0.003 0.004 0.002 0.002  N 5 5 5 5 Brain (Including Cerebrum, Cerebellum And Pons) .......... Mean (g) 2.05486 2.11214 2.05006 2.02022  S.D. 0.08179 0.04234 0.11192 0.05576  N 5 5 5 5  Mean (%) 0.538 0.571 0.566 0.562  S.D. 0.030 0.055 0.034 0.049  N 5 5 5 5 Epididymides .................. Mean (g) 1.46903 1.46486 1.39471 1.42588  S.D. 0.16359 0.20559 0.09263 0.16008  N 12 12 12 12  Mean (%) 0.398 0.380 0.384 0.396  S.D. 0.039 0.050 0.033 0.031  N 12 12 12 12 Heart ......................... Mean (g) 1.09622 1.12728 1.04006 1.04942  S.D. 0.08287 0.12438 0.15560 0.24704  N 5 5 5 5  Mean (%) 0.287 0.305 0.285 0.288  S.D. 0.023 0.050 0.026 0.053  N 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ MALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ Kidneys ....................... Mean (g) 2.09492 2.34530* 2.28052* 2.50644**  S.D. 0.26027 0.20846 0.11630 0.49391  N 5 5 5 5  Mean (%) 0.548 0.631* 0.629* 0.689**  S.D. 0.057 0.037 0.023 0.092  N 5 5 5 5 Liver ......................... Mean (g) 11.4692 11.4094 11.1958 12.1312**  S.D. 0.72540 1.41625 1.14413 1.89008  N 5 5 5 5  Mean (%) 3.004 3.056 3.082 3.343**  S.D. 0.191 0.085 0.180 0.310  N 5 5 5 5 Pituitary ..................... Mean (g) 0.01188 0.01317 0.01328 0.01343  S.D. 0.00210 0.00318 0.00403 0.00390  N 12 12 12 12  Mean (%) 0.003 0.003 0.004 0.004  S.D. 0.001 0.001 0.001 0.001  N 12 12 12 12 Prostate ...................... Mean (g) 0.58791 0.56530 0.54142 0.49996*  S.D. 0.12897 0.07772 0.07102 0.10906  N 12 12 12 12  Mean (%) 0.160 0.147 0.149 0.139*  S.D. 0.036 0.025 0.019 0.028  N 12 12 12 12 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ MALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ Seminal Vesicles .............. Mean (g) 1.98853 2.09621 1.85843 1.65654  S.D. 0.35281 0.32206 0.24142 0.56221  N 12 12 12 12  Mean (%) 0.540 0.542 0.511 0.456  S.D. 0.103 0.070 0.071 0.144  N 12 12 12 12 Spleen ........................ Mean (g) 0.67532 0.68622 0.70070 0.68724  S.D. 0.07424 0.11915 0.09007 0.06466  N 5 5 5 5  Mean (%) 0.176 0.183 0.193 0.191  S.D. 0.014 0.021 0.024 0.022  N 5 5 5 5 Testes ........................ Mean (g) 3.54083 3.67949 3.57387 3.44931  S.D. 0.27102 0.22075 0.26153 0.44585  N 12 12 12 12  Mean (%) 0.962 0.957 0.982 0.959  S.D. 0.080 0.081 0.081 0.111  N 12 12 12 12 Thymus ........................ Mean (g) 0.44996 0.37970 0.39078 0.36374  S.D. 0.06312 0.06863 0.10430 0.05655  N 5 5 5 5  Mean (%) 0.119 0.102 0.107 0.101  S.D. 0.022 0.015 0.026 0.016  N 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ MALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒ Thyroid/Parathyroid ........... Mean (g) 0.02086 0.02310 0.02042 0.02392  S.D. 0.00499 0.00269 0.00407 0.00534  N 5 5 5 5  Mean (%) 0.005 0.006 0.006 0.007  S.D. 0.001 0.001 0.001 0.001  N 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ FEMALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ Terminal Bodyweight ........... Mean (g) 274.0 240.2 236.4 233.2  S.D. 13.1 33.3 18.1 18.5  N 12 12 12 12 Adrenals ...................... Mean (g) 0.09412 0.09080 0.08688 0.08354  S.D. 0.01057 0.01118 0.01306 0.01381  N 5 5 5 5  Mean (%) 0.034 0.042 0.037 0.036  S.D. 0.004 0.007 0.007 0.004  N 5 5 5 5 Brain (Including Cerebrum, Cerebellum And Pons) .......... Mean (g) 1.82766 1.80580 1.81458 1.79434  S.D. 0.05221 0.04933 0.04234 0.08993  N 5 5 5 5  Mean (%) 0.663 0.853 0.771 0.769  S.D. 0.042 0.234 0.059 0.058  N 5 5 5 5 Heart ......................... Mean (g) 0.96620 0.83188 0.79450 0.76636  S.D. 0.16500 0.12342 0.06622 0.14537  N 5 5 5 5  Mean (%) 0.349 0.390 0.337 0.328  S.D. 0.050 0.104 0.036 0.064  N 5 5 5 5 Kidneys ....................... Mean (g) 1.59194 1.48776 1.51298 1.41826  S.D. 0.09496 0.07908 0.17224 0.10175  N 5 5 5 5  Mean (%) 0.577 0.704 0.640 0.606  S.D. 0.046 0.208 0.050 0.032  N 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ FEMALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ Liver ......................... Mean (g) 11.5588 9.80792 10.3356 10.2245  S.D. 1.15216 0.96526 1.07891 1.08438  N 5 5 5 5  Mean (%) 4.188 4.617 4.370 4.370  S.D. 0.427 1.259 0.234 0.411  N 5 5 5 5 Ovaries ....................... Mean (g) 0.10820 0.11041 0.10215 0.09284  S.D. 0.01302 0.01068 0.01532 0.01224  N 12 9 11 7  Mean (%) 0.040 0.048 0.043 0.039  S.D. 0.005 0.010 0.007 0.006  N 12 9 11 7 Pituitary ..................... Mean (g) 0.01720 0.01874 0.01733 0.01409*  S.D. 0.00219 0.00470 0.00209 0.00202  N 12 8 10 7  Mean (%) 0.006 0.008 0.007 0.006*  S.D. 0.001 0.002 0.001 0.001  N 12 8 10 7 Spleen ........................ Mean (g) 0.61280 0.53334 0.52158 0.54270  S.D. 0.07238 0.05712 0.09310 0.02346  N 5 5 5 5  Mean (%) 0.222 0.251 0.222 0.232  S.D. 0.031 0.066 0.043 0.015  N 5 5 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ FEMALES ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 30 60 120 

 Control mg/kg bw/day  ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒ Thymus ........................ Mean (g) 0.26878 0.23310 0.22170* 0.18640*  S.D. 0.04921 0.04087 0.05661 0.03448  N 5 5 5 5  Mean (%) 0.097 0.113 0.095* 0.080*  S.D. 0.014 0.047 0.028 0.016  N 5 5 5 5 Thyroid/Parathyroid ........... Mean (g) 0.01898 0.02260 0.02160 0.02118  S.D. 0.00299 0.00499 0.00367 0.00201  N 5 5 5 5  Mean (%) 0.007 0.011 0.009 0.009  S.D. 0.001 0.004 0.002 0.001  N 5 5 5 5 Uterus & Cervix ............... Mean (g) 0.68538 0.65874 0.62923 0.61047  S.D. 0.13143 0.09946 0.13848 0.05708  N 12 9 11 7  Mean (%) 0.252 0.289 0.264 0.257  S.D. 0.058 0.092 0.057 0.035  N 12 9 11 7  
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒƒ MALES ƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Kidneys ....................... Mean (g) 2.11860 2.30742  S.D. 0.06606 0.47074  N 5 5  Mean (%) 0.534 0.620  S.D. 0.034 0.089  N 5 5 Liver ......................... Mean (g) 12.0344 11.3880  S.D. 1.30935 0.91637  N 5 5  Mean (%) 3.019 3.085  S.D. 0.162 0.214  N 5 5 Pituitary ..................... Mean (g) 0.01082 0.01100  S.D. 0.00101 0.00210  N 5 5  Mean (%) 0.003 0.003  S.D. 0.000 0.001  N 5 5 Prostate ...................... Mean (g) 0.60260 0.48336  S.D. 0.10012 0.09687  N 5 5  Mean (%) 0.151 0.131  S.D. 0.016 0.028  N 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒƒ MALES ƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Seminal Vesicles .............. Mean (g) 2.11602 2.07198  S.D. 0.23668 0.35038  N 5 5  Mean (%) 0.534 0.558  S.D. 0.077 0.062  N 5 5 Spleen ........................ Mean (g) 0.64076 0.60758  S.D. 0.04745 0.10857  N 5 5  Mean (%) 0.162 0.164  S.D. 0.021 0.027  N 5 5 Testes ........................ Mean (g) 3.57770 3.40932  S.D. 0.23303 0.25097  N 5 5  Mean (%) 0.903 0.925  S.D. 0.095 0.076  N 5 5 Thymus ........................ Mean (g) 0.42268 0.32344  S.D. 0.06598 0.05761  N 5 5  Mean (%) 0.106 0.088  S.D. 0.011 0.019  N 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒƒ MALES ƒƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Thyroid/Parathyroid ........... Mean (g) 0.02258 0.02162  S.D. 0.00117 0.00274  N 5 5  Mean (%) 0.006 0.006  S.D. 0.000 0.001  N 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒ FEMALES ƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Terminal Bodyweight ........... Mean (g) 218.4 220.8  S.D. 11.5 10.1  N 5 5 Adrenals ...................... Mean (g) 0.07984 0.08284  S.D. 0.01130 0.01186  N 5 5  Mean (%) 0.036 0.038  S.D. 0.004 0.006  N 5 5 Brain (Including Cerebrum, Cerebellum And Pons) .......... Mean (g) 1.78686 1.84922  S.D. 0.09015 0.13123  N 5 5  Mean (%) 0.819 0.839  S.D. 0.049 0.075  N 5 5 Heart ......................... Mean (g) 0.76796 0.70458  S.D. 0.10617 0.02719  N 5 5  Mean (%) 0.351 0.320  S.D. 0.039 0.020  N 5 5 Kidneys ....................... Mean (g) 1.36402 1.36676  S.D. 0.13965 0.08392  N 5 5  Mean (%) 0.626 0.621  S.D. 0.067 0.056  N 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒ FEMALES ƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Liver ......................... Mean (g) 7.27868 7.73596  S.D. 0.90210 0.39415  N 5 5  Mean (%) 3.324 3.505  S.D. 0.247 0.143  N 5 5 Ovaries ....................... Mean (g) 0.10370 0.09744  S.D. 0.02236 0.01659  N 5 5  Mean (%) 0.047 0.044  S.D. 0.010 0.009  N 5 5 Pituitary ..................... Mean (g) 0.01666 0.01988  S.D. 0.00235 0.00392  N 5 5  Mean (%) 0.008 0.009  S.D. 0.001 0.002  N 5 5 Spleen ........................ Mean (g) 0.51454 0.45104  S.D. 0.10796 0.03879  N 5 5  Mean (%) 0.235 0.205  S.D. 0.043 0.024  N 5 5 
Harlan Study Number: 41204605 Report 

Table 23 (continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Recovery Groups  ƒƒƒƒ FEMALES ƒƒƒƒ  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  0 120  Control mg/kg bw/day  ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Thymus ........................ Mean (g) 0.28620 0.29462  S.D. 0.03899 0.04860  N 5 5  Mean (%) 0.131 0.134  S.D. 0.014 0.023  N 5 5 Thyroid/Parathyroid ........... Mean (g) 0.01988 0.01704  S.D. 0.00421 0.00470  N 5 5  Mean (%) 0.009 0.008  S.D. 0.002 0.002  N 5 5 Uterus & Cervix ............... Mean (g) 0.62746 0.77958  S.D. 0.13815 0.27845  N 5 5  Mean (%) 0.287 0.357  S.D. 0.058 0.144  N 5 5  
Harlan Study Number: 41204605 Report Page 153 

FIGURES 
Harlan Study Number: 41204605 Report 

Figure 1 Group Mean Body Weights - Males Non-Recovery Groups 
Harlan Study Number: 41204605 Report 

Figure 1 (continued) Group Mean Body Weights - Males Recovery Groups 
Harlan Study Number: 41204605 Report 

Figure 2 Group Mean Body Weights - Females Pre-Pairing 
Harlan Study Number: 41204605 Report 

Figure 2 (continued) Group Mean Body Weights - Females Gestation 
Harlan Study Number: 41204605 Report 

Figure 2 (continued) Group Mean Body Weights - Females Recovery Groups 
Harlan Study Number: 41204605 Report 

Figure 3 Group Mean Food Consumption - Males 
Harlan Study Number: 41204605 Report 

Figure 4 Group Mean Food Consumption – Females Non-Recovery Groups 
Harlan Study Number: 41204605 Report 

Figure 4 (continued) Group Mean Food Consumption – Females Recovery Groups 
Harlan Study Number: 41204605 Report Page 162 

This page has intentionally been left blank 
Harlan Study Number: 41204605 Report Page 163 

APPENDICES 
Harlan Study Number: 41204605 Report 

Appendix 1 Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  1(M) 1 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  2 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  3 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  4 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  5 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  6 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  7 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  8 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  9 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  10 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  11 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  12 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  1(M) 1 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  2 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  3 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  4 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  5 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  6 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  7 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  8 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  9 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  10 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  11 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  12 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  2(M) 25 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  26 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  27 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  28 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  29 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  30 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  31 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  32 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  33 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  34 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  35 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  36 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  2(M) 25 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  26 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  27 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  28 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  29 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  30 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  31 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  32 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  33 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  34 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  35 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  36 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  3(M) 49 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  50 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  51 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  52 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  53 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  54 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  55 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  56 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  57 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  58 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  59 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  3(M) 49 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  50 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  51 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  52 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X .  53 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . X X . . . X X  54 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  55 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  56 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . X . . . . .  57 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  58 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . X  59 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  3(M) 60 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  3(M) 60 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  4(M) 73 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . .  74 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  75 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  76 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  77 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . .  78 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . . . .  79 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X .  80 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . .  81 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  4(M) 73 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . . X .  74 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation X . . . . . . . . . . X . . . . X . X .  75 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . X . . . . . . . . . . . . . . . . . .  76 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation X X X X . . . X . X . . X . X . . X X X  77 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . X X . X  78 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . X X X . X . . X . . . X . X X . . X .  79 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation X . . X . . . X . X . X X . . . . . . .  80 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X X . X . . X . . . . . . . . X . .  81 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . X . . . X . . X . . . . . . . . . X . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20  4(M) 82 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  83 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . .  84 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42  4(M) 82 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X X . . . X X X . . X . . X X . . .  83 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation X . . X . . . . . . . . . . . X . X X X  84 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . X . . . . . . . X . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  1(F) 13 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  14 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  15 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  16 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Littering . . . . . . . . . . . . . . . . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  17 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  18 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  19 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Littering . . . . . . . . . . . . . . . . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  20 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  21 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  22 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  23 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  24 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  1(F) 13 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  14 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  15 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  16 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Littering . . . . . . . . . . . . . X . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  17 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  18 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . X .  19 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Littering . . . . . . . . . . . . . X . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  20 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  21 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  22 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  23 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  24 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  2(F) 37 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  38 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  39 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  40 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  41 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  42 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  43 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  44 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  45 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  46 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  47 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  48 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  2(F) 37 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  38 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  39 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  40 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  41 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  42 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  43 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . X .  44 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  45 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  46 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  47 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  48 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  3(F) 61 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  62 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . .  63 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . .  64 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  65 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  66 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  67 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Littering . . . . . . . . . . . . . . . . . . . . . . . .  Not Observed Due to Littering . . . . . . . . . . . . . . . . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  68 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Littering . . . . . . . . . . . . . . . . . . . . . . . .  Not Observed Due to Littering . . . . . . . . . . . . . . . . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  69 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  70 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  71 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  3(F) 61 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  62 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  Increased salivation . . . . . . . . . . . . . . . . X . . . . . .  63 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  Increased salivation . . . . . . . . . . . . . . . . X . . . . . .  64 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  65 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  66 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  67 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Littering . . . . . . . . . . . . . X . . . . . . . . .  Not Observed Due to Littering . . . . . . . . . . . . . X . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  68 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Littering . . . . . . . . . . . . . X . . . . . . . . .  Not Observed Due to Littering . . . . . . . . . . . . . X . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  69 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . X .  70 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  71 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  3(F) 72 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  3(F) 72 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  4(F) 85 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . .  86 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . .  87 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . . . . X  88 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X . . . . .  89 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . . . . .  90 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X . . . . X  91 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Littering . . . . . . . . . . . . . . . . . . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . . . . .  92 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . . . . . . . .  93 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  4(F) 85 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  Increased salivation . . . . . . . . . . . . . . . . X . . . . . .  86 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  Increased salivation X X . . . X . . . . . . . . . . . . . . . . .  87 No Abnormalities Detected X X X X X X X X X X X X X X X X X X . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . X . . . . .  Increased salivation X . . . . . X X . . . . . . X X . . . . . . .  88 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  Increased salivation . X . . . . X . . . . . . . . . . . . . . . .  89 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X X . X . X . . . . . . . . . . X . . . . . .  90 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  Increased salivation . X . X . . . X . . . . . . X X . . . . . . .  91 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Littering . . . . . . . . . . . . . . . X . . . . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  Increased salivation . . . . . X X . . . . . . . . . X . . . . . .  92 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X . . . .  Scheduled kill . . . . . . . . . . . . . . . . . . X . . . .  Increased salivation . X . X . . . . . . . . . . . . . . . . . . .  93 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . .  Scheduled kill . . . . . . . . . . . . . . . . . . . . X . .  Increased salivation X . . . . X X X . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  4(F) 94 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . . . X .  95 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . X  96 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47  4(F) 94 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . X .  Increased salivation . . . . . . . . . . . . . . . X . . X . . . .  95 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X . . .  Scheduled kill . . . . . . . . . . . . . . . . . . . X . . .  Increased salivation X X . . . . . . . . . . . . . . . . . . . . .  96 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X .  Scheduled kill . . . . . . . . . . . . . . . . . . . . . X .  Increased salivation . . . . . . X X . . . . . . . . X . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28  1(M) 97 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  98 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  99 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . . . . . . . . . . .  100 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  101 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57  1(M) 97 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  98 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  99 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . . . . .  100 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  101 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28  4(M) 107 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . X . . . . . . X X .  108 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . X . . . X X  109 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X . . . X X . . X X  110 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . . . . . . X . X . X  111 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . X . . X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57  4(M) 107 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . . . . . . . X . . . X X . . . . . . . . . . . . . .  108 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . X . . . X . X . . . . X . . . . . . . . . . . . . .  109 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X . X . . . . . X X X X . . . . . . . . . . . . . . .  110 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X X X . . . . . . . X . . . . . . . . . . . . . . . .  111 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . X . . . . . . . X . X X . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28  1(F) 102 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  103 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  104 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  105 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  106 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57  1(F) 102 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  103 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  104 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  105 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  106 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28  4(F) 112 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . X . . . . . X . .  113 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . X . . X .  114 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . X . . . . . . . . . . . . . . X . . . . X X X . X X  115 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . X . . . X  116 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . .  Increased salivation . . . . . . . . . . . . . . . . . . . . . . . X . . X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 1 (continued) Individual Daily Clinical Observations  Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57  4(F) 112 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X . . . . . . . . . . X . . . . . . . . . . . . . . .  113 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . X . . . X X . . . . X X . . . . . . . . . . . . . .  114 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X X X . . . X X . . X . . . . . . . . . . . . . . . .  115 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation . X X . . . . . . X . X X . . . . . . . . . . . . . .  116 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X  Scheduled kill . . . . . . . . . . . . . . . . . . . . . . . . . . . X  Increased salivation X X X . . . . . . . . X X . . . . . . . . . . . . . . X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 38  1(M) 1 No Abnormalities Detected X X X X X X X  2 No Abnormalities Detected X X X X X X X  3 No Abnormalities Detected X X X X X X X  4 No Abnormalities Detected X X X X X X X  5 No Abnormalities Detected X X X X X X X  6 No Abnormalities Detected X X X X X X X  7 No Abnormalities Detected X X X X X X X  8 No Abnormalities Detected X X X X X X X  9 No Abnormalities Detected X X X X X X X  10 No Abnormalities Detected X X X X X X X  11 No Abnormalities Detected X X X X X X X  12 No Abnormalities Detected X X X X X X X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 Day 4 post partum

 1(F) 13 No Abnormalities Detected X X X X X X X  14 No Abnormalities Detected X X X X X X X  15 No Abnormalities Detected X X X X X X X  16 No Abnormalities Detected X X X X X X X  17 No Abnormalities Detected X X X X X X X  18 No Abnormalities Detected X X X X X X X  19 No Abnormalities Detected X X X X X X X  20 No Abnormalities Detected X X X X X X X  21 No Abnormalities Detected X X X X X X X  22 No Abnormalities Detected X X X X X X X  23 No Abnormalities Detected X X X X X X X  24 No Abnormalities Detected X X X X X X X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 38  2(M) 25 No Abnormalities Detected X X X X X X X  26 No Abnormalities Detected X X X X X X X  27 No Abnormalities Detected X X X X X X X  28 No Abnormalities Detected X X X X X X X  29 No Abnormalities Detected X X X X X X X  30 No Abnormalities Detected X X X X X X X  31 No Abnormalities Detected X X X X X X X  32 No Abnormalities Detected X X X X X X X  33 No Abnormalities Detected X X X X X X X  34 No Abnormalities Detected X X X X X X X  35 No Abnormalities Detected X X X X X X X  36 No Abnormalities Detected X X X X X X X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 Day 4 post partum #

 2(F) 37 No Abnormalities Detected X X X X X X X  38 No Abnormalities Detected X X X X X X X  39 No Abnormalities Detected X X X X X X X  40 No Abnormalities Detected X X X X X X X  41 No Abnormalities Detected X X X X X X X  42 No Abnormalities Detected X X X X X X X  43 No Abnormalities Detected X X X X X X X  44 No Abnormalities Detected X X X X X X X  45 No Abnormalities Detected X X X X X X X  46 No Abnormalities Detected X X X X X X X  47 No Abnormalities Detected X X X X X X X  48 No Abnormalities Detected X X X X X X X # = Day 25 post coitum for female Numbers 43 and 48 

X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 38  3(M) 49 No Abnormalities Detected X X X X X X X  50 No Abnormalities Detected X X X X X X X  51 No Abnormalities Detected X X X X X X X  52 No Abnormalities Detected X X X X X X X  53 No Abnormalities Detected X X X X X X X  54 No Abnormalities Detected X X X X X X X  55 No Abnormalities Detected X X X X X X X  56 No Abnormalities Detected X X X X X X X  57 No Abnormalities Detected X X X X X X X  58 No Abnormalities Detected X X X X X X X  59 No Abnormalities Detected X X X X X X X  60 No Abnormalities Detected X X X X X X X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 Day 4 post partum #

 3(F) 61 No Abnormalities Detected X X X X X X X  62 No Abnormalities Detected X X X X X X X  63 No Abnormalities Detected X X X X X X X  64 No Abnormalities Detected X X X X X X X  65 No Abnormalities Detected X X X X X X X  66 No Abnormalities Detected X X X X X X X  67 No Abnormalities Detected X X X X X X X  68 No Abnormalities Detected X X X X X X X  69 No Abnormalities Detected X X X X X X X  70 No Abnormalities Detected X X X X X X X  71 No Abnormalities Detected X X X X X X X  72 No Abnormalities Detected X X X X X X X # = Day 25 post coitum for female Number 62 

X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 38  4(M) 73 No Abnormalities Detected X X X X X X X  74 No Abnormalities Detected X X X X X X X  75 No Abnormalities Detected X X X X X X X  76 No Abnormalities Detected X X X X X X X  77 No Abnormalities Detected X X X X X X X  78 No Abnormalities Detected X X X X X X X  79 No Abnormalities Detected X X X X X X X  80 No Abnormalities Detected X X X X X X X  81 No Abnormalities Detected X X X X X X X  82 No Abnormalities Detected X X X X X X X  83 No Abnormalities Detected X X X X X X X  84 No Abnormalities Detected X X X X X X X X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 2 (continued) Individual Behavioural Assessments (Observations)  Day Numbers Relative to Start Date Group Animal (Sex) Number Clinical Sign ƒ1 7 14 21 28 35 Day 4 post partum #

 4(F) 85 No Abnormalities Detected X X X X X X X  86 No Abnormalities Detected X X X X X X X  87 No Abnormalities Detected X X X X X X X  88 No Abnormalities Detected X X X X X X X  89 No Abnormalities Detected X X X X X X X  90 No Abnormalities Detected X X X X X X X  91 No Abnormalities Detected X X X X X X X  92 No Abnormalities Detected X X X X X X X  93 No Abnormalities Detected X X X X X X X  94 No Abnormalities Detected X X X X X X X  95 No Abnormalities Detected X X X X X X X  96 No Abnormalities Detected X X X X X X X # = Day 25 post coitum for female Numbers 85, 87 and 88 

X = Present Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 1 0 0  3 0 1 0 0  4 0 0 0 0  5 0 0 0 0  6 0 0 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 0 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 0 0 0  14 0 1 0 0  15 0 0 0 0  16 0 1 0 0  17 0 0 0 0  18 0 0 0 0  19 0 0 0 0  20 0 0 0 0  21 0 0 0 0  22 0 0 0 0  23 0 0 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 0 0 0  26 0 0 0 0  27 0 0 0 0  28 0 0 0 0  29 0 1 1 0  30 0 3 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 2 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.5 0.1 0.0  S.D. 0.0 1.0 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 2 0 0  38 0 0 0 0  39 0 0 0 0  40 0 2 0 0  41 0 0 0 0  42 0 0 0 0  43 0 1 0 0  44 0 0 0 0  45 0 0 0 0  46 0 0 0 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.8 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 0 0 0  51 0 0 0 0  52 0 1 0 0  53 0 0 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 0 0 0  58 0 2 0 0  59 0 0 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.6 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 0 0 0  63 0 1 0 0  64 0 0 0 0  65 0 0 0 0  66 0 0 0 0  67 0 0 0 0  68 0 0 0 0  69 0 0 0 0  70 0 0 0 0  71 0 0 0 0  72 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 1 0 0  75 0 0 0 0  76 0 0 0 0  77 0 0 0 0  78 0 0 0 0  79 0 1 0 0  80 0 0 0 0  81 0 0 0 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: ƒ1 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 0 0 0  90 0 0 0 0  91 0 1 0 0  92 0 0 0 0  93 0 0 0 0  94 0 0 0 0  95 0 0 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 0 0 0  4 0 0 0 0  5 0 0 0 0  6 0 0 0 0  7 0 1 1 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 0 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 0 0 0  14 0 0 0 0  15 0 0 0 0  16 0 0 0 0  17 0 0 0 0  18 0 0 0 0  19 0 0 0 0  20 0 0 0 0  21 0 0 0 0  22 0 0 0 0  23 0 0 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 0 0 0  26 0 0 0 0  27 0 0 0 0  28 0 1 0 0  29 0 0 0 0  30 0 0 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 0 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 1 0 0  38 0 0 0 0  39 0 0 0 0  40 0 0 0 0  41 0 0 0 0  42 0 0 0 0  43 0 0 0 0  44 0 0 1 0  45 0 0 0 0  46 0 0 0 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 0 0 0  51 0 0 0 0  52 0 0 0 0  53 0 0 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 0 0 0  58 0 0 0 0  59 0 1 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 0 0 0  63 0 0 0 0  64 0 0 0 0  65 0 0 0 0  66 0 0 0 0  67 0 0 0 0  68 0 0 0 0  69 0 0 0 0  70 0 1 1 0  71 0 0 0 0  72 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.1 0.0  S.D. 0.0 0.3 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 0 0 0  75 0 0 0 0  76 0 0 0 0  77 0 0 0 0  78 0 1 0 0  79 0 0 0 0  80 0 0 0 0  81 0 0 0 0  82 0 1 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 7 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 0 0 0  90 0 0 0 0  91 0 0 0 0  92 0 0 0 0  93 0 0 0 0  94 0 0 0 0  95 0 0 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 1 0 0  4 0 0 0 0  5 0 0 0 0  6 0 1 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 0 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 0 0 0  14 0 0 0 0  15 0 0 0 0  16 0 0 0 0  17 0 0 0 0  18 0 0 0 0  19 0 0 0 0  20 0 0 0 0  21 0 1 0 0  22 0 0 0 0  23 0 0 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 0 0 0  26 0 0 0 0  27 0 1 0 0  28 0 0 0 0  29 0 0 0 0  30 0 0 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 0 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 1 1 0  38 0 1 0 0  39 0 0 0 0  40 0 0 0 0  41 0 0 0 0  42 0 0 0 0  43 0 0 0 0  44 0 0 0 0  45 0 0 0 0  46 0 1 0 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 1 0 0  51 0 0 0 0  52 0 0 0 0  53 0 1 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 1 0 0  58 0 0 0 0  59 0 0 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 0 0 0  63 0 0 0 0  64 0 0 0 0  65 0 1 0 0  66 0 0 0 0  67 0 0 0 0  68 0 1 0 0  69 0 0 0 0  70 0 0 0 0  71 0 0 0 0  72 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 0 0 0  75 0 0 0 0  76 0 0 0 0  77 0 0 0 0  78 0 0 0 0  79 0 0 0 0  80 0 1 0 0  81 0 1 1 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 14 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 1 0 0  90 0 0 0 0  91 0 1 0 0  92 0 0 0 0  93 0 1 0 0  94 0 0 0 0  95 0 1 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 1 0 0  4 0 0 0 0  5 0 0 0 0  6 0 0 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 1 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 1 0 0  14 0 0 0 0  15 0 1 0 0  16 0 0 0 0  17 0 0 0 0  18 0 0 0 0  19 0 0 0 0  20 0 0 0 0  21 0 0 0 0  22 0 0 0 0  23 0 0 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 0 0 0  26 0 1 0 0  27 0 1 0 0  28 0 1 0 0  29 0 0 0 0  30 0 1 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 1 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 0 0 0  38 0 0 0 0  39 0 0 0 0  40 0 0 0 0  41 0 0 0 0  42 0 0 0 0  43 0 1 0 0  44 0 0 0 0  45 0 0 0 0  46 0 1 0 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 0 0 0  51 0 1 0 0  52 0 0 0 0  53 0 1 1 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 0 0 0  58 0 0 0 0  59 0 1 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 0 0 0  63 0 0 0 0  64 0 0 0 0  65 0 1 0 0  66 0 1 0 0  67 0 0 0 0  68 0 0 0 0  69 0 0 0 0  70 0 0 0 0  71 0 0 0 0  72 0 1 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 1 0 0  74 0 0 0 0  75 0 0 0 0  76 0 0 0 0  77 0 0 0 0  78 0 0 0 0  79 0 0 0 0  80 0 0 0 0  81 0 1 0 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 21 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 1 0 0  89 0 0 0 0  90 0 1 0 0  91 0 0 0 0  92 0 0 0 0  93 0 0 0 0  94 0 0 0 0  95 0 0 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 0 0 0  4 0 0 0 0  5 0 0 0 0  6 0 0 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 0 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 0 0 0  14 0 0 0 0  15 0 0 0 0  16 0 0 0 0  17 0 0 0 0  18 0 1 0 0  19 0 0 0 0  20 0 0 0 0  21 0 0 0 0  22 0 0 0 0  23 0 0 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 0 0 0  26 0 0 0 0  27 0 1 0 0  28 0 1 0 0  29 0 0 0 0  30 0 1 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 1 0 0  35 0 0 0 0  36 0 1 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.4 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 0 0 0  38 0 0 0 0  39 0 0 0 0  40 0 0 0 0  41 0 0 0 0  42 0 0 0 0  43 0 0 0 0  44 0 0 0 0  45 0 1 0 0  46 0 0 0 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 1 0 0  51 0 0 0 0  52 0 0 0 0  53 0 0 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 1 0 0  58 0 1 0 0  59 0 0 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 1 0 0  63 0 0 0 0  64 0 0 0 0  65 0 0 0 0  66 0 0 0 0  67 0 0 0 0  68 0 1 0 0  69 0 0 0 0  70 0 1 1 0  71 0 0 0 0  72 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 0 0 0  75 0 1 0 0  76 0 0 0 0  77 0 0 1 0  78 0 0 0 0  79 0 0 0 0  80 0 1 0 0  81 0 1 0 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.1 0.0  S.D. 0.0 0.5 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 28 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 0 0 0  90 0 0 0 0  91 0 0 0 0  92 0 1 0 0  93 0 0 0 0  94 0 1 0 0  95 0 0 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 0 0 0  4 0 0 0 0  5 0 1 0 0  6 0 0 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 1 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 1 0 0  14 0 0 0 0  15 0 1 0 0  16 0 1 0 0  17 0 1 0 0  18 0 0 0 0  19 0 1 0 0  20 0 1 0 0  21 0 0 0 0  22 0 0 0 0  23 0 0 0 0  24 0 1 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.6 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 1 0 0  26 0 0 0 0  27 0 0 0 0  28 0 0 0 0  29 0 0 0 0  30 0 0 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 0 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 0 0 0  38 0 0 0 0  39 0 0 0 0  40 0 0 0 0  41 0 0 0 0  42 0 0 0 0  43 0 1 0 0  44 0 1 0 0  45 0 0 0 0  46 0 0 0 0  47 0 1 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 1 0 0  50 0 0 0 0  51 0 0 0 0  52 0 0 0 0  53 0 0 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 0 0 0  58 0 0 0 0  59 0 0 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.1 0.0 0.0  S.D. 0.0 0.3 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 1 0 0  62 0 0 0 0  63 0 1 1 0  64 0 0 0 0  65 0 1 0 0  66 0 0 0 0  67 0 1 0 0  68 0 1 0 0  69 0 1 1 0  70 0 0 0 0  71 0 0 0 0  72 0 1 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.6 0.2 0.0  S.D. 0.0 0.5 0.4 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 0 0 0  75 0 0 0 0  76 0 0 0 0  77 0 0 0 0  78 0 0 0 0  79 0 0 0 0  80 0 0 0 0  81 0 0 0 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 35 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 1 0 0  90 0 0 0 0  91 0 1 0 0  92 0 1 0 0  93 0 0 0 0  94 0 0 0 0  95 0 1 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 38 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(M) 1 0 0 0 0  2 0 0 0 0  3 0 0 0 0  4 0 0 0 0  5 0 0 0 0  6 0 0 0 0  7 0 0 0 0  8 0 0 0 0  9 0 0 0 0  10 0 0 0 0  11 0 0 0 0  12 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 4 post partum  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  1(F) 13 0 0 0 0  14 0 0 0 0  15 0 0 0 0  16 0 0 0 0  17 0 0 0 0  18 0 0 0 0  19 0 1 0 0  20 0 0 0 0  21 0 1 0 0  22 0 1 0 0  23 0 1 0 0  24 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.0 0.0  S.D. 0.0 0.5 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 38 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(M) 25 0 1 0 0  26 0 0 0 0  27 0 0 0 0  28 0 1 1 0  29 0 0 0 0  30 0 0 0 0  31 0 0 0 0  32 0 0 0 0  33 0 0 0 0  34 0 0 0 0  35 0 0 0 0  36 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 4 post partum #

 Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  2(F) 37 0 1 0 0  38 0 0 0 0  39 0 1 0 0  40 0 0 0 0  41 0 1 1 0  42 0 0 0 0  43 0 0 0 0  44 0 0 0 0  45 0 0 0 0  46 0 0 1 0  47 0 0 0 0  48 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.3 0.2 0.0  S.D. 0.0 0.5 0.4 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ # = Day 25 post coitum for female Numbers 43 and 48 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 38 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(M) 49 0 0 0 0  50 0 0 0 0  51 0 0 0 0  52 0 0 0 0  53 0 0 0 0  54 0 0 0 0  55 0 0 0 0  56 0 0 0 0  57 0 0 0 0  58 0 0 0 0  59 0 0 0 0  60 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 4 post partum #

 Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  3(F) 61 0 0 0 0  62 0 0 0 0  63 0 0 0 0  64 0 1 0 0  65 0 0 0 0  66 0 0 0 0  67 0 0 0 0  68 0 1 1 0  69 0 0 0 0  70 0 0 0 0  71 0 0 0 0  72 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.1 0.0  S.D. 0.0 0.4 0.3 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ # = Day 25 post coitum for female Number 62 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 38 Relative to Start Date  Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(M) 73 0 0 0 0  74 0 0 0 0  75 0 0 0 0  76 0 1 0 0  77 0 0 0 0  78 0 0 0 0  79 0 0 0 0  80 0 0 0 0  81 0 1 0 0  82 0 0 0 0  83 0 0 0 0  84 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0  S.D. 0.0 0.4 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 3 (continued) Individual Behavioural Assessments (Scores)  Day: 4 post partum #

 Group Animal Transfer Urinƒ Defƒ Tail elƒ  (Sex) Number arousal ation ecation evation  4(F) 85 0 0 0 0  86 0 0 0 0  87 0 0 0 0  88 0 0 0 0  89 0 0 0 0  90 0 0 0 0  91 0 0 0 0  92 0 0 0 0  93 0 0 0 0  94 0 0 0 0  95 0 0 0 0  96 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0  N 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ # = Day 25 post coitum for female Numbers 85, 87 and 88 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 Individual and Group Mean Functional Test Values (Grip Strength)  Day: 38 Relative to Start Date  Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  1(M) 1 879 267 1458 279 845 301  2 1125 556 1146 499 1877 667  3 942 272 1245 222 899 625  4 1156 318 829 495 579 246  5 1223 627 1162 172 607 275  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 1065.0 408.0 1168.0 333.4 961.4 422.8  S.D. 147.1 170.5 226.6 154.1 530.9 205.2  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 4 post partum

 Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  1(F) 13 707 181 680 145 985 224  16 544 282 948 136 1173 238  19 344 175 1129 146 529 169  20 501 153 773 297 584 104  22 673 403 1226 247 985 219  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 553.8 238.8 951.2 194.2 851.2 190.8  S.D. 145.4 104.4 230.5 73.3 280.4 55.1  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 38 Relative to Start Date  Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  2(M) 25 811 238 836 267 651 335  26 688 540 797 537 866 585  27 1352 265 537 221 1362 218  28 1050 257 903 229 875 294  29 1106 291 1450 276 1320 254  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 1001.4 318.2 904.6 306.0 1014.8 337.2  S.D. 260.1 125.4 335.0 131.3 311.3 145.3  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 4 post partum

 Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  2(F) 37 1002 221 1081 310 954 239  39 916 282 416 236 499 253  42 1105 300 1010 171 531 231  45 1013 290 590 346 855 277  46 879 277 553 139 954 270  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 983.0 274.0 730.0 240.4 758.6 254.0  S.D. 88.7 30.9 296.3 88.2 226.3 19.6  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 38 Relative to Start Date  Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  3(M) 49 1523 359 1602 546 602 314  50 610 335 554 249 475 311  51 683 262 1312 376 954 289  52 1143 504 753 429 1333 475  53 552 358 697 318 1215 283  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 902.2 363.6 983.6 383.6 915.8 334.4  S.D. 418.2 87.9 450.0 112.8 373.4 79.7  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 4 post partum

 Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  3(F) 66 1045 229 887 198 1011 137  67 1067 152 941 240 566 160  68 504 352 761 245 1227 241  71 857 423 969 308 951 188  72 907 216 1141 215 1030 235  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 876.0 274.4 939.8 241.2 957.0 192.2  S.D. 226.2 110.2 137.9 41.9 241.9 45.6  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 38 Relative to Start Date  Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  4(M) 73 1327 440 1775 392 1382 568  74 635 260 637 340 1263 424  75 775 273 1062 926 1291 470  76 828 212 1641 289 607 282  77 1204 418 961 728 1117 510  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 953.8 320.6 1215.2 535.0 1132.0 450.8  S.D. 296.4 101.8 478.8 278.0 308.5 108.2  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 4 (continued) Individual and Group Mean Functional Test Values (Grip Strength)  Day: 4 post partum

 Group Animal Test 1 Test 1 Test 2 Test 2 Test 3 Test 3  (Sex) Number Forelimb Hindlimb Forelimb Hindlimb Forelimb Hindlimb  g g g g g g  4(F) 86 991 269 1004 831 779 427  90 605 412 771 321 932 441  91 474 297 708 311 584 378  92 794 196 848 138 779 274  95 1001 191 897 271 914 188  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 773.0 273.0 845.6 374.4 797.6 341.6  S.D. 233.2 90.2 114.3 265.5 139.6 108.0  N 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 Individual and Group Mean Functional Test Values (Motor Activity)  Day: 38 Relative to Start Date  Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  1(M) 1 520 0 13 0  2 325 0 0 0  3 442 2 18 0  4 499 1 1 0  5 372 0 8 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 431.6 0.6 8.0 0.0  S.D. 82.7 0.9 7.7 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 4 post partum

 Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  1(F) 13 720 3 121 0  16 392 0 77 0  19 528 8 15 0  20 520 2 9 0  22 623 11 17 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 556.6 4.8 47.8 0.0  S.D. 122.8 4.5 49.3 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 38 Relative to Start Date  Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  2(M) 25 284 0 0 0  26 433 4 4 0  27 265 0 9 0  28 125 0 21 0  29 160 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 253.4 0.8 6.8 0.0  S.D. 121.0 1.8 8.8 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 4 post partum

 Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  2(F) 37 546 3 32 0  39 771 0 135 0  42 527 0 107 0  45 606 1 114 0  46 416 2 2 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 573.2 1.2 78.0 0.0  S.D. 130.2 1.3 57.6 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 38 Relative to Start Date  Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  3(M) 49 301 0 5 0  50 550 3 50 0  51 512 1 6 0  52 336 0 4 0  53 471 0 3 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 434.0 0.8 13.6 0.0  S.D. 109.8 1.3 20.4 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 4 post partum

 Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  3(F) 66 650 2 56 0  67 750 2 62 1  68 302 1 19 0  71 370 1 18 0  72 784 3 198 1  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 571.2 1.8 70.6 0.4  S.D. 221.6 0.8 74.1 0.5  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 38 Relative to Start Date  Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  4(M) 73 43 0 0 0  74 343 0 1 0  75 328 3 0 0  76 537 2 3 0  77 390 0 4 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 328.2 1.0 1.6 0.0  S.D. 179.6 1.4 1.8 0.0  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 5 (continued) Individual and Group Mean Functional Test Values (Motor Activity)  Day: 4 post partum

 Group Animal Overall Overall Last 20% Last 20%  (Sex) Number activity mobile activity mobile  4(F) 86 756 2 92 2  90 644 1 107 0  91 739 0 102 0  92 178 0 0 0  95 460 0 8 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  Mean 555.4 0.6 61.8 0.4  S.D. 241.5 0.9 53.1 0.9  N 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ Unit = Time (seconds) Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 Individual Sensory Reactivity Assessments  Day: 38 Relative to Start Date  Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  1(M) 1 0 0 0 0 0 0 0 0 0  2 0 0 0 0 0 0 0 0 0  3 0 0 0 0 0 0 0 0 0  4 0 0 0 0 0 0 0 0 0  5 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 4 post partum

 Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  1(F) 13 0 0 0 0 0 0 0 0 0  16 0 0 0 0 0 0 0 0 0  19 0 0 0 0 0 0 0 0 0  20 0 0 0 0 0 0 0 0 0  22 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 38 Relative to Start Date  Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  2(M) 25 0 0 0 0 0 0 0 0 0  26 0 0 0 0 0 0 0 0 0  27 0 0 0 0 0 0 0 0 0  28 0 1 0 0 0 0 0 0 0  29 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 4 post partum

 Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  2(F) 37 0 0 0 0 0 0 0 0 0  39 0 1 0 0 0 0 0 0 0  42 0 0 0 0 0 0 0 0 0  45 0 0 0 0 0 0 0 0 0  46 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 38 Relative to Start Date  Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  3(M) 49 0 0 0 0 0 0 0 0 0  50 0 0 0 0 0 0 0 0 0  51 0 0 0 0 0 0 0 0 0  52 0 1 0 0 0 0 0 0 0  53 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 4 post partum

 Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  3(F) 66 0 0 0 0 0 0 0 0 0  67 0 0 0 0 0 0 0 0 0  68 0 0 0 0 0 0 0 0 0  71 0 0 0 0 0 0 0 0 0  72 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 38 Relative to Start Date  Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  4(M) 73 0 0 0 0 0 0 0 0 0  74 0 0 0 0 0 0 0 0 0  75 0 0 0 0 0 0 0 0 0  76 0 0 0 0 0 0 0 0 0  77 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 6 (continued) Individual Sensory Reactivity Assessments  Day: 4 post partum

 Group Animal Grasp Vocalƒ Toe Tail Finger Touch Pupil Blink Startle  (Sex) Number response isation pinch pinch approach escape reflex reflex reflex  4(F) 86 0 0 0 0 0 0 0 0 0  90 0 0 0 0 0 0 0 0 0  91 0 0 0 0 0 0 0 0 0  92 0 0 0 0 0 0 0 0 0  95 0 0 0 0 0 0 0 0 0  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  Mean 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 Individual and Group Mean Body Weights  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43  1(M) 1 325 344 360 361 376 388 387  2 330 345 362 373 392 412 408  3 310 325 348 359 377 389 386  4 310 322 344 355 365 375 373  5 317 324 335 341 358 365 357  6 309 322 340 334 343 357 357  7 318 328 338 343 349 354 350  8 307 314 318 325 336 345 343  9 331 345 355 363 376 382 385  10 320 339 347 344 349 358 367  11 302 318 331 337 343 349 352  12 318 328 338 338 348 358 361  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 316.4 329.5 343.0 347.8 359.3 369.3 368.8  S.D. 9.2 11.0 12.5 14.2 17.6 20.0 19.3  N 12 12 12 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43  2(M) 25 303 306 321 330 337 344 338  26 335 353 373 385 399 410 412  27 327 332 352 358 372 384 379  28 302 305 312 322 330 339 332  29 338 352 367 379 384 397 402  30 302 311 316 322 330 341 349  31 336 359 383 393 409 418 434  32 346 359 385 396 413 422 438  33 325 337 355 365 380 398 405  34 329 335 345 358 369 377 381  35 311 323 335 339 350 360 367  36 345 350 371 375 382 390 401  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 324.9 335.2 351.3 360.2 371.3 381.7 386.5  S.D. 16.5 20.1 25.7 26.7 29.1 29.7 35.1  N 12 12 12 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43  3(M) 49 325 341 363 372 382 394 387  50 339 349 358 364 372 382 386  51 316 319 317 317 321 324 328  52 307 307 317 337 355 361 358  53 303 310 322 332 347 357 356  54 322 331 339 354 368 378 393  55 334 339 341 348 344 350 367  56 325 333 337 351 349 355 362  57 318 330 344 342 348 360 368  58 311 326 354 353 369 385 388  59 316 302 298 322 322 339 350  60 305 307 307 318 323 330 333  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 318.4 324.5 333.1 342.5 350.0 359.6 364.7  S.D. 11.2 15.3 20.8 17.8 20.5 22.1 21.3  N 12 12 12 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43  4(M) 73 318 327 341 352 355 364 354  74 306 307 322 330 335 345 340  75 334 343 349 361 364 369 375  76 338 345 359 372 389 393 401  77 312 302 290 309 317 328 337  78 330 330 347 358 356 365 376  79 321 328 343 352 360 361 374  80 331 328 345 338 332 354 363  81 295 284 279 293 290 290 311  82 307 319 331 334 351 361 375  83 324 326 321 332 329 327 351  84 315 315 310 325 338 345 362  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 319.3 321.2 328.1 338.0 343.0 350.2 359.9  S.D. 12.9 17.2 24.7 22.6 25.4 26.2 23.4  N 12 12 12 12 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Pre-Pairing  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15  1(F) 13 209 215 230  14 196 198 208  15 210 217 225  16 200 200 217  17 204 208 221  18 203 209 215  19 205 206 220  20 202 219 232  21 201 211 229  22 203 225 239  23 212 208 216  24 212 219 230  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 204.8 211.3 223.5  S.D. 5.0 8.0 8.8  N 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Pre-Pairing  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15  2(F) 37 195 196 203  38 194 189 196  39 185 185 198  40 211 215 212  41 198 205 202  42 194 202 210  43 199 202 205  44 195 192 201  45 197 201 212  46 192 188 186  47 206 212 217  48 205 220 222  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 197.6 200.6 205.3  S.D. 7.0 11.2 9.9  N 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Pre-Pairing  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15  3(F) 61 192 193 199  62 199 180 178  63 201 209 208  64 207 206 217  65 204 207 212  66 193 193 196  67 197 180 201  68 206 205 216  69 206 208 212  70 204 196 212  71 199 202 211  72 188 195 199  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 199.7 197.8 205.1  S.D. 6.2 10.2 11.1  N 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Pre-Pairing  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15  4(F) 85 211 203 197  86 203 211 210  87 207 204 215  88 196 188 189  89 205 204 205  90 197 191 195  91 199 193 192  92 192 198 206  93 197 201 206  94 192 190 196  95 201 196 204  96 203 207 208  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 200.3 198.8 201.9  S.D. 5.8 7.3 7.9  N 12 12 12  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights 

Group (Sex) 

Animal Number 

 Body Weights (g) Day

After Mating Lactation 

0 7 14 20 1 4 

1(F) 13 229 251 279 336 254 260 

 14 208 234 265 338 239 250  15 231 262 290 354 258 279  16 216 253 283 359 237 261

 17 223 249 283 347 253 268  18 222 261 289 331 280 286  19 216 242 269 320 238 261 20 235 251 291 365 276 291  21 226 252 285 352 262 263  22 239 267 304 375 282 289 23 217 247 283 360 263 266  24 227 253 281 342 265 265  Mean 224.1 251.8 283.5 348.3 258.9 269.9  S.D. 8.9 8.9 10.1 15.6 15.7 13.1 N 12 12 12 12 12 12 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights 

Group (Sex) 

Animal Number 

 Body Weights (g) Day

After Mating Lactation 

0 7 14 20 1 4 

2(F) 37 208 236 263 323 235 242 

 38 197 231 262 329 240 251  39 199 235 272 340 243 244  40 225 241 280 350 243 266

 41 202 220 238 267 240 237  42 210 231 258 316 237 245  43 215 225 234 236  44 200 225 242 299 215 238  45 210 231 257 321 227 239  46 180 206 237 267 229 228 47 223 232 262 330 248 248  48 210 248 254 246  Mean 205.4 228.8 257.1 314.2 235.2 244.6  S.D. 13.1 9.9 14.2 28.3 10.2 10.4 N 10 10 10 10 9 9 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights 

Group (Sex) 

Animal Number 

 Body Weights (g) Day

After Mating Lactation 

0 7 14 20 1 4 

3(F) 61 199 217 241 272 218 229 

 62 183 186 188 204  63 212 220 227 268 219 228  64 213 235 269 321 235 259

 65 211 232 256 315 223 237  66 195 217 236 276 222 237  67 193 214 231 279 208 220 68 216 245 273 344 230 252  69 218 239 275 304 262 264  70 207 226 248 305 215 224 71 208 233 264 317 239 249  72 196 217 244 303 220 230  Mean 206.2 226.8 251.3 300.4 226.5 239.0  S.D. 8.9 10.5 17.1 24.0 14.8 14.8 N 11 11 11 11 11 11 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights 

Group (Sex) 

Animal Number 

 Body Weights (g) Day

After Mating Lactation 

0 7 14 20 1 4 

4(F) 85 196 205 215 219 

 86 210 222 245 292 232 232  87 208 232 246 275  88 190 193 196 201 

 89 214 232 230 254 215 231  90 202 209 228 288 233 235  91 198 215 237 294 219 231 92 203 228 258 324 235 252  93 207 234 248 256 229 231  94 196 221 241 285 233 241 95 212 214 223 282 213 222  96 211 235 253 313 224 248  Mean 205.9 223.3 240.3 287.6 227.0 237.3  S.D. 6.4 9.5 11.9 22.9 8.5 10.4 N 9 9 9 9 7 7 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43 50 57  1(M) 97 327 341 361 371 385 392 396 406 409  98 315 325 340 350 364 373 377 394 397  99 321 336 350 359 370 381 384 393 396  100 336 354 368 382 399 413 415 425 429  101 311 319 331 336 344 349 349 355 358  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 322.0 335.0 350.0 359.6 372.4 381.6 384.2 394.6 397.8  S.D. 9.9 13.7 15.0 17.9 20.9 23.6 24.4 25.6 25.9  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43 50 57  4(M) 107 308 317 329 332 335 345 352 367 368  108 323 323 336 350 359 366 376 392 393  109 308 305 309 316 315 317 325 339 336  110 312 305 312 317 326 331 339 349 347  111 337 344 355 316 379 384 390 408 405  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 317.6 318.8 328.2 326.2 342.8 348.6 356.4 371.0 369.8  S.D. 12.5 16.1 18.8 14.9 25.9 26.8 26.6 28.9 29.3  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43 50 57  1(F) 102 196 196 199 211 215 211 207 217 218  103 189 196 197 211 213 218 213 228 228  104 196 205 213 216 215 221 232 235 231  105 182 189 202 201 195 209 213 221 212  106 184 185 192 191 195 190 196 203 203  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 189.4 194.2 200.6 206.0 206.6 209.8 212.2 220.8 218.4  S.D. 6.5 7.7 7.8 10.0 10.6 12.1 13.1 12.1 11.5  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 7 (continued) Individual and Group Mean Body Weights Recovery Groups  Body Weights (g)  ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  Day Numbers Relative to Start Date  Group Animal  (Sex) Number 1 8 15 22 29 36 43 50 57  4(F) 112 197 192 203 209 210 210 219 227 221  113 202 205 211 214 221 220 229 233 233  114 193 195 196 210 211 216 212 223 222  115 194 192 194 189 195 198 200 199 205  116 205 195 196 204 206 209 217 227 223  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ  Mean 198.2 195.8 200.0 205.2 208.6 210.6 215.4 221.8 220.8  S.D. 5.2 5.4 7.0 9.7 9.4 8.4 10.6 13.2 10.1  N 5 5 5 5 5 5 5 5 5  ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 Individual and Group Mean Body Weight Gains  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36  (Sex) Number To: 8 15 22 29 36 43  1(M) 1 19 16 1 15 12 ƒ1  2 15 17 11 19 20 ƒ4  3 15 23 11 18 12 ƒ3  4 12 22 11 10 10 ƒ2  5 7 11 6 17 7 ƒ8  6 13 18 ƒ6 9 14 0  7 10 10 5 6 5 ƒ4  8 7 4 7 11 9 ƒ2  9 14 10 8 13 6 3  10 19 8 ƒ3 5 9 9  11 16 13 6 6 6 3  12 10 10 0 10 10 3  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 13.1 13.5 4.8 11.6 10.0 ƒ0.5  S.D. 4.1 5.8 5.6 4.8 4.2 4.5  N 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36  (Sex) Number To: 8 15 22 29 36 43  2(M) 25 3 15 9 7 7 ƒ6  26 18 20 12 14 11 2  27 5 20 6 14 12 ƒ5  28 3 7 10 8 9 ƒ7  29 14 15 12 5 13 5  30 9 5 6 8 11 8  31 23 24 10 16 9 16  32 13 26 11 17 9 16  33 12 18 10 15 18 7  34 6 10 13 11 8 4  35 12 12 4 11 10 7  36 5 21 4 7 8 11  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 10.3 16.1 8.9 11.1 10.4 4.8  S.D. 6.3 6.6 3.1 4.1 3.0 7.8  N 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36  (Sex) Number To: 8 15 22 29 36 43  3(M) 49 16 22 9 10 12 ƒ7  50 10 9 6 8 10 4  51 3 ƒ2 0 4 3 4  52 0 10 20 18 6 ƒ3  53 7 12 10 15 10 ƒ1  54 9 8 15 14 10 15  55 5 2 7 ƒ4 6 17  56 8 4 14 ƒ2 6 7  57 12 14 ƒ2 6 12 8  58 15 28 ƒ1 16 16 3  59 ƒ14 ƒ4 24 0 17 11  60 2 0 11 5 7 3  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 6.1 8.6 9.4 7.5 9.6 5.1  S.D. 8.0 9.6 8.1 7.3 4.2 7.1  N 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36  (Sex) Number To: 8 15 22 29 36 43  4(M) 73 9 14 11 3 9 ƒ10  74 1 15 8 5 10 ƒ5  75 9 6 12 3 5 6  76 7 14 13 17 4 8  77 ƒ10 ƒ12 19 8 11 9  78 0 17 11 ƒ2 9 11  79 7 15 9 8 1 13  80 ƒ3 17 ƒ7 ƒ6 22 9  81 ƒ11 ƒ5 14 ƒ3 0 21  82 12 12 3 17 10 14  83 2 ƒ5 11 ƒ3 ƒ2 24  84 0 ƒ5 15 13 7 17  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 1.9 6.9 9.9 5.0 7.2 9.8  S.D. 7.4 10.6 6.6 7.8 6.4 9.7  N 12 12 12 12 12 12  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Pre-Pairing  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8  (Sex) Number To: 8 15  1(F) 13 6 15  14 2 10  15 7 8  16 0 17  17 4 13  18 6 6  19 1 14  20 17 13  21 10 18  22 22 14  23 ƒ4 8  24 7 11  ƒƒƒƒƒ ƒƒƒƒƒ  Mean 6.5 12.3  S.D. 7.2 3.7  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Pre-Pairing  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8  (Sex) Number To: 8 15  2(F) 37 1 7  38 ƒ5 7  39 0 13  40 4 ƒ3  41 7 ƒ3  42 8 8  43 3 3  44 ƒ3 9  45 4 11  46 ƒ4 ƒ2  47 6 5  48 15 2  ƒƒƒƒƒ ƒƒƒƒƒ  Mean 3.0 4.8  S.D. 5.7 5.4  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Pre-Pairing  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8  (Sex) Number To: 8 15  3(F) 61 1 6  62 ƒ19 ƒ2  63 8 ƒ1  64 ƒ1 11  65 3 5  66 0 3  67 ƒ17 21  68 ƒ1 11  69 2 4  70 ƒ8 16  71 3 9  72 7 4  ƒƒƒƒƒ ƒƒƒƒƒ  Mean ƒ1.8 7.3  S.D. 8.6 6.7  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Pre-Pairing  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8  (Sex) Number To: 8 15  4(F) 85 ƒ8 ƒ6  86 8 ƒ1  87 ƒ3 11  88 ƒ8 1  89 ƒ1 1  90 ƒ6 4  91 ƒ6 ƒ1  92 6 8  93 4 5  94 ƒ2 6  95 ƒ5 8  96 4 1  ƒƒƒƒƒ ƒƒƒƒƒ  Mean ƒ1.4 3.1  S.D. 5.6 4.8  N 12 12  ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains 

Increase in Body Weight (g) 

Days 

 Cumulative Body Weight Chang

Days 

After Mating Lactation After Mating

Group (sex) 

Animal Number 

From: 0 7 14 1 0 0 To: 7 14 20 4 14 20 

1(F) 13 22 28 57 6 50 107 

14 26 31 73 11 57 130 

15 31 28 64 21 59 123 

16 37 30 76 24 67 143 

17 26 34 64 15 60 124 

18 39 28 42 6 67 109 

19 26 27 51 23 53 104 

20 16 40 74 15 56 130 

21 26 33 67 1 59 126 

22 28 37 71 7 65 136 

23 30 36 77 3 66 143 

24 26 28 61 0 54 115 

Mean 27.8 31.7 64.8 11.0 59 124 S.D. 6.1 4.3 10.7 8.5 6 13 N 12 12 12 12 12 12 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains 

Increase in Body Weight (g) 

Days 

 Cumulative Body Weight Chang

Days 

After Mating Lactation After Mating

Group (sex) 

Animal Number 

From: 0 7 14 1 0 0 To: 7 14 20 4 14 20 

2(F) 37 28 27 60 7 55 115 

38 34 31 67 11 65 132 39 36 37 68 1 73 141 40 16 39 70 23 55 125 41 TLL 18 18 29 -3 36 65 42 21 27 58 8 48 106 43 NP 10 9 2 19 21 44 25 17 57 23 42 99 45 21 26 64 12 47 111 46 26 31 30 -1 57 87 47 9 30 68 0 39 107 

48 NP 38 6 -8 44 36 

Mean 23.4 28.3 57.1 9.3 52 109 S.D. 8.2 7.1 15.2 9.0 12 22 N 10 10 10 9 10 10 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains 

Increase in Body Weight (g) 

Days 

 Cumulative Body Weight Chang

Days 

After Mating Lactation After Mating

Group (sex) 

Animal Number 

From: 0 7 14 1 0 0 To: 7 14 20 4 14 20 

3(F) 61 18 24 31 11 42 73 

62 NP 3 2 16 5 21 

63 8 7 41 9 15 56 

64 22 34 52 24 56 108 

65 21 24 59 14 45 104 

66 22 19 40 15 41 81 

67 21 17 48 12 38 86 

68 29 28 71 22 57 128 

69 21 36 29 2 57 86 

70 19 22 57 9 41 98 

71 25 31 53 10 56 109 

72 21 27 59 10 48 107 

Mean 20.6 24.5 49.1 12.5 45 94 S.D. 5.1 8.3 12.8 6.2 12 20 N 11 11 11 11 11 11 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains 

Increase in Body Weight (g) 

Days 

 Cumulative Body Weight Chang

Days 

After Mating Lactation After Mating

Group (sex) 

Animal Number 

From: 0 7 14 1 0 0 To: 7 14 20 4 14 20 

4(F) 85 NP 9 10 4 19 23 

 86 12 23 47 0 35 82  87 NL 24 14 29 38 67  88 NP 3 3 5 6 11  89 TLL 18 -2 24 16 16 40  90 7 19 60 2 26 86  91 17 22 57 12 39 96  92 25 30 66 17 55 121  93 TLL 27 14 8 2 41 49  94 25 20 44 8 45 89  95 2 9 59 9 11 70  96 24 18 60 24 42 102 

Mean 17.4 17.0 47.2 10.3 34 82 S.D. 8.8 9.2 19.4 8.3 14 25 N 9 9 9 7 9 9 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36 43 50  (Sex) Number To: 8 15 22 29 36 43 50 57  1(M) 97 14 20 10 14 7 4 10 3  98 10 15 10 14 9 4 17 3  99 15 14 9 11 11 3 9 3  100 18 14 14 17 14 2 10 4  101 8 12 5 8 5 0 6 3  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 13.0 15.0 9.6 12.8 9.2 2.6 10.4 3.2  S.D. 4.0 3.0 3.2 3.4 3.5 1.7 4.0 0.4  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36 43 50  (Sex) Number To: 8 15 22 29 36 43 50 57  4(M) 107 9 12 3 3 10 7 15 1  108 0 13 14 9 7 10 16 1  109 ƒ3 4 7 ƒ1 2 8 14 ƒ3  110 ƒ7 7 5 9 5 8 10 ƒ2  111 7 11 ƒ39 63 5 6 18 ƒ3  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 1.2 9.4 ƒ2.0 16.6 5.8 7.8 14.6 ƒ1.2  S.D. 6.7 3.8 21.1 26.3 2.9 1.5 3.0 2.0  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36 43 50  (Sex) Number To: 8 15 22 29 36 43 50 57  1(F) 102 0 3 12 4 ƒ4 ƒ4 10 1  103 7 1 14 2 5 ƒ5 15 0  104 9 8 3 ƒ1 6 11 3 ƒ4  105 7 13 ƒ1 ƒ6 14 4 8 ƒ9  106 1 7 ƒ1 4 ƒ5 6 7 0  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean 4.8 6.4 5.4 0.6 3.2 2.4 8.6 ƒ2.4  S.D. 4.0 4.7 7.2 4.2 7.9 6.8 4.4 4.2  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 8 (continued) Individual and Group Mean Body Weight Gains Recovery Groups  Increase in Body Weight (g)  Day Numbers Relative to Start Date  Group Animal From: 1 8 15 22 29 36 43 50  (Sex) Number To: 8 15 22 29 36 43 50 57  4(F) 112 ƒ5 11 6 1 0 9 8 ƒ6  113 3 6 3 7 ƒ1 9 4 0  114 2 1 14 1 5 ƒ4 11 ƒ1  115 ƒ2 2 ƒ5 6 3 2 ƒ1 6  116 ƒ10 1 8 2 3 8 10 ƒ4  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  Mean ƒ2.4 4.2 5.2 3.4 2.0 4.8 6.4 ƒ1.0  S.D. 5.3 4.3 7.0 2.9 2.4 5.7 4.9 4.6  N 5 5 5 5 5 5 5 5  ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 9 Individual and Group Mean Food Consumption Values for Females Following Mating and D

Mean Food Consumption (g/rat/day)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

1(F) 13 20 22 25 32

14 18 20 25 29 15 20 23 25 29 16 19 24 28 3317 18 22 25 21 18 * * 29 22 19 17 20 23 29 20 20 25 29 28 21 20 23 26 2522 21 25 29 30 23 20 24 27 17 24 17 20 26 26

Mean 19.1 22.6 26.3 26.8 S.D. 1.4 1.8 2.0 4.8 N 11 11 12 12 

* = data unavailable Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 9 (continued) Individual and Group Mean Food Consumption Values for Females Following 

Lactation 

Mean Food Consumption (g/rat/day)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

2(F) 37 18 22 26 22 

38 19 23 28 2839 20 23 26 20 40 18 23 26 35 41 TLL 14 16 22 1542 15 18 21 23 43 NP 16 19 19 44 17 16 19 26 45 17 21 25 19 46 15 18 20 18 47 15 18 21 21 48 NP 19 20 18 

Mean 16.8 19.9 23.1 23.6 S.D. 1.9 2.7 3.0 5.4 N 10 10 10 9 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Appendix 9 (continued) Individual and Group Mean Food Consumption Values for Females Following 

Lactation 

Mean Food Consumption (g/rat/day)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

3(F) 61 13 17 21 * 

62 NP 8 10 13 63 15 13 23 32 64 14 17 19 31 65 17 18 23 88■66 14 16 19 23 67 13 15 19 20 68 17 23 25 25 69 15 21 27 20 70 17 19 26 20 71 16 20 19 26 72 16 22 22 23 

Mean 15.3 18.3 22.0 24.4 S.D. 1.6 3.0 2.9 4.7 N 11 11 11 9 

* = data unavailable ■ = food scattered in cage, value excluded from mean and S.D. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 9 (continued) Individual and Group Mean Food Consumption Values for Females Following 

Lactation 

Mean Food Consumption (g/rat/day)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

4(F) 85 NP 11 13 13 

86 13 15 24 11

87 NL 16 17 23 88 NP 10 11 13 89 TLL 16 18 19 49

90 13 17 25 26 91 15 17 20 33 92 15 18 22 25 

93 TLL 17 21 19 17 

94 13 17 24 29 95 10 10 15 15 96 18 20 26 97■

Mean 14.5 17.0 21.4 22.9 S.D. 2.5 3.2 3.4 8.5 N 9 9 9 6 

■ = food scattered in cage, value excluded from mean and S.D. Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 10 Individual and Group Mean Water Consumption Values for Females Following Mating and 

Water Consumption (g)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

1(F) 13 26 31 37 37

14 28 29 36 42 15 30 34 43 49 16 29 32 41 4617 26 30 38 33 18 49 58 60 43 19 31 31 41 43 20 46 53 64 49 21 30 31 40 3922 31 35 40 43 23 28 35 39 29 24 26 28 36 39

Mean 31.8 35.6 42.8 41.0 S.D. 8.2 10.3 10.2 10.1 N 12 12 12 12 

Water consumption = g/animal/day Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 10 (continued) Individual and Group Mean Water Consumption Values for Females Followin

Lactation 

Water Consumption (g)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

2(F) 37 43 64 49 40 

38 28 32 35 3939 35 43 47 41 40 27 31 34 48 41 TLL 26 26 34 2542 23 25 30 37 43 NP 32 30 34 44 26 28 31 41 45 25 31 37 28 46 24 25 29 25 47 37 57 58 37 48 NP 42 35 35 

Mean 29.4 35.7 38.1 37.1 S.D. 9.2 14.6 10.9 11.5 N 10 10 10 9 

Water consumption = g/animal/day Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 10 (continued) Individual and Group Mean Water Consumption Values for Females Followin

Lactation 

Water Consumption (g)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

3(F) 61 28 38 45 28 

62 NP 23 27 24 

63 39 41 40 31 64 30 29 30 41 65 31 35 36 3666 21 26 29 30 67 32 31 39 52 68 24 32 36 44 69 26 30 38 33 70 35 38 39 31 71 67 58 68 50 72 38 37 45 44 

Mean 32.9 36.5 38.5 38.0 S.D. 13.7 16.5 13.4 15.0 N 11 11 11 11 

Water consumption = g/animal/day Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 10 (continued) Individual and Group Mean Water Consumption Values for Females Followin

Lactation 

Water Consumption (g)

After Mating Lactation

Group (Sex)

AnimalNumber

From: 0 7 14 1

To: 7 14 20 4

4(F) 85 NP 37 45 36 

86 26 26 47 30

87 NL 33 30 37 88 NP 28 26 32 89 TLL 48 57 60 37

90 30 30 40 39 91 25 31 36 41 92 25 31 34 36 

93 TLL 50 43 37 32 

94 43 41 43 45 95 27 23 37 28 96 32 36 41 52 

Mean 34.1 35.4 41.6 38.8 S.D. 12.5 12.3 11.3 12.2 N 9 9 9 7 

Water consumption = g/animal/day Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 11 Individual Mating Performance, Fertility and Gestation Lengths Group: 1 Dose Level: 0 (Control) 

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status 

13 F 1 M 2 3 PT 2+ P 

14 F 2 M 3 5 PT H 3+ P 

15 F 3 M 4 8 PT H 3+ P 

16 F 4 M 1 5 PT H 1+ P 17 F 5 M 1 3 PT H 1+ P 18 F 6 M 4 3 PT PV 3+ P 

19 F 7 M 1 5 PT 2+ P 

20 F 8 M 3 PV 3+ P 

21 F 9 M 1 4 PT 2+ P 22 F 10 M 3 3 PT 3+ P 23 F 11 M 3 4 PT 3+ P 24 F 12 M 3 4 PT H 3+ P 
Harlan Study Number: 41204605 Report 

Appendix 11 (continued) Individual Mating Performance, Fertility and Gestation Lengths Group: 2 Dose Level: 30 mg/kg bw/day 

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status 

37 F 25 M 3 4 PT H 2+ P 

38 F 26 M 3 2 PT H 2+ P 

39 F 27 M 2 5 PT H 2+ P 40 F 28 M 4 6 PT 3+ P 

41 F 29 M 2 2 PT H 3+ P 

42 F 30 M 2 3 PT 1+ P 43 F 31 M 5 5 PT H 3+ NP 

44 F 32 M 1 5 PT 2+ P 

45 F 33 M 2 7 PT H 3+ P 

46 F 34 M 1 4 PT H 1+ P 47 F 35 M 3 3 PT H 3+ P 

48 F 36 M 1 2 PT H 2+ NP 
Harlan Study Number: 41204605 Report 

Appendix 11 (continued) Individual Mating Performance, Fertility and Gestation Lengths Group: 3 Dose Level: 60 mg/kg bw/day 

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status 

61 F 49 M 2 2 PT 2+ P 

62 F 50 M 3 4 PT H 3+ NP 

63 F 51 M 2 4 PT 2+ P 

64 F 52 M 1 5 PT H 3+ P 65 F 53 M 3 4 PT 3+ P 66 F 54 M 2 4 PT 3+ P 

67 F 55 M 1 4 PT 3+ P 

68 F 56 M 1 4 PT 3+ P 

69 F 57 M 4 3 PT H 2+ P 

70 F 58 M 1 3 PT 2+ P 71 F 59 M 2 3 PT H 3+ P 72 F 60 M 2 5 PT 3+ P 
Harlan Study Number: 41204605 Report 

Appendix 11 (continued) Individual Mating Performance, Fertility and Gestation Lengths Group: 4 Dose Level: 120 mg/kg bw/day 

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status 

85 F 73 M 3 4 PT H 3+ NP 86 F 74 M 3 3 PT 3+ P 

87 F 75 M 1 4 PT H 3+ NL 

88 F 76 M 3 2 PT H 2+ NP 89 F 77 M 5 5 PT 3+ P 

90 F 78 M 3 4 PT H 3+ P 91 F 79 M 3 4 PT 3+ P 

92 F 80 M 2 1 PT 3+ P 

93 F 81 M 5 6 PT 3+ P 

94 F 82 M 4 6 PT H 3+ P 

95 F 83 M 2 3 PT H 3+ P 

96 F 84 M 4 3 PT H 3+ P 
Harlan Study Number: 41204605 Report 

Appendix 12 Individual and Group Mean Litter Size and Litter Weights Group: 1 Dose Level: 0(Control)

Animal/Litter

Number 

Number 

of 

Corpora 

Lutea 

Number of 

Implantation 

Sites 

Total 

Number of Offspring 

Born 

Number of Live 

Offspring 

Litter Weight 

(g) 

Mean Offspring Weight 

(g) 

Day 1 Day 4 Day 1 Day 4 

Day 1 Day 4 

Males Females Males Fem

13 12 12 11 11 10 75.2 99.2 7.2 6.7 10.1 914 15 14 11 11 11 63.7 98.6 6.0 5.6 9.2 815 14 13 12 12 12 69.5 103.9 5.9 5.7 8.7 816 14 14 14 14 14 88.3 120.1 6.6 6.1 8.8 817 14 14 13 12 12 65.3 86.5 5.9 5.2 7.7 718 10 5 5 5 5 39.4 60.6 7.8 8.1 11.9 119 12 11 10 10 10 68.3 104.3 6.9 6.8 10.6 120 12 12 11 11 11 68.1 93.5 6.6 6.1 9.0 821 16 14 14 14 14 75.9 103.4 5.6 5.2 7.6 722 15 14 14 14 14 82.8 121.3 6.0 5.8 8.8 823 14 13 13 12 12 71.3 88.2 6.2 5.8 7.5 724 12 11 11 11 11 64.6 89.6 6.0 5.8 7.9 8

Mean 13.3 12.3 11.6 11.4 11.3 69.37 97.43 6.40 6.07 8.99 8

S.D. 1.7 2.6 2.5 2.4 2.5 12.03 16.10 0.64 0.81 1.33 1N 12 12 12 12 12 12 12 12 12 12 
Harlan Study Number: 41204605 Report 

Appendix 12 (continued) Individual and Group Mean Litter Size and Litter Weights Group: 2 Dose Level: 30 mg/kg bw/day

Animal/Litter

Number 

Number 

of 

Corpora 

Lutea 

Number of 

Implantation 

Sites 

Total 

Number of Offspring 

Born 

Number of Live 

Offspring 

Litter Weight 

(g) 

Mean Offspring Weight 

(g) 

Day 1 Day 4 Day 1 Day 4 

Day 1 Day 4 

Males Females Males Fem

37 13 13 12 12 12 69.6 96.5 5.9 5.8 8.3 738 16 14 12 12 12 71.9 105.7 6.0 6.0 8.8 839 13 13 13 13 13 77.6 110.4 6.2 5.8 8.7 840 17 16 16 16 16 87.9 127.3 5.5 5.5 8.2 7

41 TLL 11 10 2 2 11.2 5.6 

42 13 12 11 11 11 64.6 96.1 5.8 5.9 8.6 8

43 NP 

44 13 12 12 12 12 62.1 90.4 5.2 5.2 7.5 745 12 12 11 11 11 63.7 87.1 6.2 5.6 8.4 746 10 6 5 5 5 35.6 53.1 7.5 6.9 11.2 147 14 14 13 13 13 79.3 101.7 6.2 6.1 7.7 8

48 NP 

Mean 13.2 12.2 11.7 11.7 11.7 68.03 96.48 6.06 5.85 8.57 8

S.D. 2.1 2.7 2.9 2.9 2.9 14.78 20.20 0.63 0.47 1.06 0N 10 10 9 9 9 9 9 9 9 9 
Harlan Study Number: 41204605 Report 

Appendix 12 (continued) Individual and Group Mean Litter Size and Litter Weights Group: 3 Dose Level: 60 mg/kg bw/day

Animal/Litter

Number 

Number 

of 

Corpora 

Lutea 

Number of 

Implantation 

Sites 

Total 

Number of Offspring 

Born 

Number of Live 

Offspring 

Litter Weight 

(g) 

Mean Offspring Weight 

(g) 

Day 1 Day 4 Day 1 Day 4 

Day 1 Day 4 

Males Females Males Fem

61 9 9 5 5 5 35.7 53.3 7.3 7.0 10.9 1

62 NP 

63 7 4 4 4 4 27.8 45.6 7.3 6.7 11.6 164 12 12 12 12 12 69.5 94.5 5.8 5.7 7.9 765 13 13 12 12 12 69.6 96.7 6.1 5.6 8.4 766 10 10 7 7 7 45.4 69.7 6.8 6.4 10.1 967 10 10 9 9 9 58.1 81.8 6.5 6.3 9.1 968 18 16 14 14 14 91.8 119.4 6.8 6.3 8.8 869 12 12 4 4 4 30.9 47.3 7.8 7.5 11.9 170 11 11 11 11 11 58.7 82.7 5.6 5.0 7.9 771 12 11 11 11 11 66.7 96.6 6.7 5.9 9.7 872 12 11 11 11 11 67.4 97.5 6.3 6.0 9.0 8

Mean 11.5 10.8 9.1 9.1 9.1 56.51 80.46 6.63 6.21 9.56 9

S.D. 2.8 2.9 3.5 3.5 3.5 19.63 23.88 0.66 0.69 1.39 1N 11 11 11 11 11 11 11 11 11 11 
Harlan Study Number: 41204605 Report 

Appendix 12 (continued) Individual and Group Mean Litter Size and Litter Weights Group: 4 Dose Level: 120 mg/kg bw/day

Animal/Litter

Number 

Number 

of 

Corpora 

Lutea 

Number of 

Implantation 

Sites 

Total 

Number of Offspring 

Born 

Number of Live 

Offspring 

Litter Weight 

(g) 

Mean Offspring Weight 

(g) 

Day 1 Day 4 Day 1 Day 4 

Day 1 Day 4 

Males Females Males Fem

85 NP 

86 11 10 8 5 5 27.7 40.5 5.4 6.1 7.9 9

87 NL 12 10 88 NP 89 TLL 6 4 2 2 11.4 5.8 5.6 

90 10 8 8 8 8 54.0 78.4 6.9 6.3 9.9 991 13 13 11 11 11 71.0 103.7 6.8 6.1 9.9 992 12 12 10 10 10 63.0 87.3 6.6 6.2 9.0 8

93 TLL 4 4 1 1 5.2 5.2 

94 13 12 8 8 8 51.3 74.9 6.9 6.3 9.7 995 14 11 8 8 8 44.4 61.0 5.6 5.5 7.7 796 13 13 11 11 11 78.9 113.5 7.3 6.9 10.5 1

Mean 11.3 10.3 8.1 8.7 8.7 55.76 79.90 6.50 6.19 9.19 9

S.D. 3.0 2.9 3.2 2.1 2.1 17.12 24.79 0.73 0.42 1.08 0N 9 9 7 7 7 7 7 7 7 7 
Harlan Study Number: 41204605 Report 

Appendix 13 Individual and Group Mean Implantation Losses and Survival Indices 

Group (Sex) 

Litter 

Number 

PreImplantation 

Loss (%)

Post -

Implantation 

Loss (%) 

Live 

Birth Index 

(%) 

Viability Index (%) 

1(F) 13 0 8 100 91 

14 7 21 100 100 15 7 8 100 100 16 0 0 100 100 17 0 7 92 100 18 50 0 100 100 19 8 9 100 100 20 0 8 100 100 21 13 0 100 100 22 7 0 100 100 23 7 0 92 100 24 8 0 100 100 

Mean 8.9 5.2 98.7 99.2 S.D. 13.6 6.5 3.0 2.6 N 12 12 12 12 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 13 (continued) Individual and Group Mean Implantation Losses and Survival Indices 

Group (Sex) 

Litter Number 

PreImplantation 

Loss (%)

Post -

Implantation 

Loss (%) 

Live 

Birth Index 

(%) 

Viability Index (%) 

2(F) 37 0 8 100 100 

 38 13 14 100 100  39 0 0 100 100  40 6 0 100 100  41 TLL 9 80 100 0  42 8 8 100 100  43 NP  44 8 0 100 100  45 0 8 100 100  46 40 17 100 100  47 0 7 100 100  48 NP 

Mean 8.3 14.2 100.0 100.0 S.D. 12.0 23.8 0.0 0.0 N 10 10 10 9 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 13 (continued) Individual and Group Mean Implantation Losses and Survival Indices 

Group (Sex) 

Litter Number 

PreImplantation 

Loss (%)

Post -

Implantation 

Loss (%) 

Live 

Birth Index 

(%) 

Viability Index (%) 

3(F) 61 0 44 100 100 

62 NP 63 43 0 100 100 64 0 0 100 100 65 0 8 100 100 66 0 30 100 100 67 0 10 100 100 68 11 13 100 100 69 0 67 100 100 70 0 0 100 100 71 8 0 100 100 72 8 0 100 100 

Mean 6.4 15.6 100.0 100.0 S.D. 12.8 22.3 0.0 0.0 N 11 11 11 11 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 13 (continued) Individual and Group Mean Implantation Losses and Survival Indices 

Group (Sex) 

Litter Number 

PreImplantation 

Loss (%)

Post -

Implantation 

Loss (%) 

Live 

Birth Index 

(%) 

Viability Index (%) 

4(F) 85 NP 

86 9 20 63 100 

87 NL 17 100 

88 NP 89 TLL 33 50 100 0 

90 20 0 100 100 

91 0 15 100 100 

92 0 17 100 100 

93 TLL 0 75 100 0 

94 8 33 100 100 

95 21 27 100 100 

96 0 15 100 100 

Mean 10.2 28.1 95.8 100.0 S.D. 12.1 22.4 12.5 0.0 N 9 9 9 7 

Dose Levels: Group 1 ƒ 0(Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 14 Individual and Group Mean Sex Ratio Values for Offspring Group: 1 Dose Level: 0 (Control) 

Litter Number 

Sex Ratio (Post Partum) Day: 

At birth 1 4

Male Female % Male Male Female % Male Male Female % Male 

13 3 8 27 3 8 27 3 7 30 14 5 6 45 5 6 45 5 6 45 15 4 8 33 4 8 33 4 8 33

16 6 8 43 6 8 43 6 8 43 17 5 8 38 4 8 33 4 8 33 18 4 1 80 4 1 80 4 1 8019 6 4 60 6 4 60 6 4 60 20 2 9 18 2 9 18 2 9 18 21 8 6 57 8 6 57 8 6 57 22 8 6 57 8 6 57 8 6 57 23 4 9 31 3 9 25 3 9 25 24 4 7 36 4 7 36 4 7 36 

Mean 43.9 43.0 43.2S.D. 17.1 17.8 17.6 N 12 12 12 
Harlan Study Number: 41204605 Report 

Appendix 14 (continued) Individual and Group Mean Sex Ratio Values for Offspring Group: 2 Dose Level: 30 mg/kg bw/day 

Litter Number 

Sex Ratio (Post Partum) Day: 

At birth 1 4

Male Female % Male Male Female % Male Male Female % Male 

37 4 8 33 4 8 33 4 8 33 38 7 5 58 7 5 58 7 5 58 39 6 7 46 6 7 46 6 7 46

40 6 10 38 6 10 38 6 10 38 41 TLL 2 0 100 2 0 100 42 4 7 36 4 7 36 4 7 3643 NP 44 3 9 25 3 9 25 3 9 25 45 3 8 27 3 8 27 3 8 2746 2 3 40 2 3 40 2 3 40 47 6 7 46 6 7 46 6 7 46 48 NP 

Mean 38.9 38.9 38.9S.D. 10.3 10.3 10.3 N 9 9 9 
Harlan Study Number: 41204605 Report 

Appendix 14 (continued) Individual and Group Mean Sex Ratio Values for Offspring Group: 3 Dose Level: 60 mg/kg bw/day 

Litter Number 

Sex Ratio (Post Partum) Day: 

At birth 1 4

Male Female % Male Male Female % Male Male Female % Male 

61 3 2 60 3 2 60 3 2 60 

62 NP 

63 2 2 50 2 2 50 2 2 50

64 7 5 58 7 5 58 7 5 58 65 6 6 50 6 6 50 6 6 50 66 2 5 29 2 5 29 2 5 2967 6 3 67 6 3 67 6 3 67 68 7 7 50 7 7 50 7 7 50 69 3 1 75 3 1 75 3 1 7570 6 5 55 6 5 55 6 5 55 71 2 9 18 2 9 18 2 9 18 72 5 6 45 5 6 45 5 6 45 

Mean 50.6 50.6 50.6S.D. 16.1 16.1 16.1 N 50.6 11 11 
Harlan Study Number: 41204605 Report 

Appendix 14 (continued) Individual and Group Mean Sex Ratio Values for Offspring Group: 4 Dose Level: 120 mg/kg bw/day 

Litter Number 

Sex Ratio (Post Partum) Day: 

At birth 1 4

Male Female % Male Male Female % Male Male Female % Male 

85 NP 

86 4 1 80 4 1 80 4 1 80 

87 NL 

88 NP 89 TLL 1 1 50 1 1 50 

90 6 2 75 6 2 75 6 2 75 91 5 6 45 5 6 45 5 6 45 92 2 8 20 2 8 20 2 8 20 

93 TLL 0 1 0 0 1 0

94 2 6 25 2 6 25 2 6 25 95 6 2 75 6 2 75 6 2 75 96 7 4 64 7 4 64 7 4 64 

Mean 54.9 54.9 54.9S.D. 24.9 24.9 24.9 N 7 7 7 
Harlan Study Number: 41204605 Report 

Appendix 15 Individual Clinical Signs for Offspring Group: 1 Dose Level: 0 (Control) 

Litter Number Affected Offspring Sex and Identity Clinical Observation 

13 F5 Missing 

14 No Abnormalities Detected 15 No Abnormalities Detected 16 No Abnormalities Detected 17 1M Found dead 

 F12 Scab on dorsal region 

18 No Abnormalities Detected 19 No Abnormalities Detected 20 No Abnormalities Detected 21 No Abnormalities Detected 22 F13 Swollen left hind limb 23 1M Found dead 

 F9 Bruised head 

24 F4 No milk in stomach, Pale 

 Missing 
Harlan Study Number: 41204605 Report 

Appendix 15 (continued) Individual Clinical Signs for Offspring Group: 2 Dose Level: 30 mg/kg bw/day 

Litter Number Affected Offspring Sex and Identity Clinical Observation 

37 No Abnormalities Detected 

38 No Abnormalities Detected 39 No Abnormalities Detected 40 No Abnormalities Detected 

41 TLL M1 M2 No milk in stomach, Weak 

 Missing 

42 No Abnormalities Detected 

43 NP . 

44 No Abnormalities Detected 45 No Abnormalities Detected 46 No Abnormalities Detected 47 No Abnormalities Detected 

48 NP . 
Harlan Study Number: 41204605 Report 

Appendix 15 (continued) Individual Clinical Signs for Offspring Group: 3 Dose Level: 60 mg/kg bw/day 

Litter Number Affected Offspring Sex and Identity Clinical Observation 

61 No Abnormalities Detected 

62 NP . 

63 No Abnormalities Detected 64 No Abnormalities Detected 65 No Abnormalities Detected 66 No Abnormalities Detected 67 No Abnormalities Detected 68 No Abnormalities Detected 69 No Abnormalities Detected 70 No Abnormalities Detected 71 F5 Open wound on right hind limb 72 No Abnormalities Detected 
Harlan Study Number: 41204605 Report 

Appendix 15 (continued) Individual Clinical Signs for Offspring Group: 4 Dose Level: 120 mg/kg bw/day 

Litter Number Affected Offspring Sex and Identity Clinical Observation 

85 NP . 

86 1F Cold, Weak, No milk in stomach 

1M, 1F Found dead 

1U Missing M4 Small M1 Found dead 

87 NL . 88 NP . 89 TLL M1, F2 (Whole litter) Small, Cold, No milk in stomach 

 Missing 

90 No Abnormalities Detected 91 No Abnormalities Detected 92 No Abnormalities Detected 

93 TLL F1 No milk in stomach 

 Cold, Pale, Weak  Missing 

94 No Abnormalities Detected 95 M4 Small 96 No Abnormalities Detected 
Harlan Study Number: 41204605 Report 

Appendix 16 Individual and Group Mean Reflexological Responses for Offspring Group: 1 Dose Level: 0 (Control) 

Litter Number 

Surface righting 

(Day 1 Post Partum) 

Number of offspring 

% passed 

examined passed 

13 11 11 100.0 14 11 11 100.0 15 12 11 91.7 16 14 14 100.0 17 12 9 75.0 18 5 5 100.0 19 10 10 100.0 20 11 11 100.0 21 14 12 85.7 22 14 14 100.0 23 12 12 100.0 24 11 11 100.0 

 Mean 96.0  S.D. 8.0  N 12 
Harlan Study Number: 41204605 Report 

Appendix 16 (continued) Individual and Group Mean Reflexological Responses for Offspring Group: 2 Dose Level: 30 mg/kg bw/day 

Litter Number 

Surface righting 

(Day 1 Post Partum) 

Number of offspring 

% passed 

examined passed 

37 12 12 100.0 38 12 12 100.0 39 13 13 100.0 40 16 13 81.3 

41 TLL 2 0 0.0 

42 11 11 100.0 

43 NP 

44 12 9 75.0 45 11 11 100.0 46 5 5 100.0 47 13 13 100.0 

48 NP 

 Mean 95.1  S.D. 9.8  N 9 
Harlan Study Number: 41204605 Report 

Appendix 16 (continued) Individual and Group Mean Reflexological Responses for Offspring Group: 3 Dose Level: 60 mg/kg bw/day 

Litter Number 

Surface righting 

(Day 1 Post Partum) 

Number of offspring 

% passed 

examined passed 

61 5 5 100.0 

62 NP 

63 4 4 100.0 64 12 10 83.3 65 12 12 100.0 66 7 6 85.7 67 9 7 77.8 68 14 14 100.0 69 4 2 50.0 70 11 7 63.6 71 11 6 54.5 72 11 9 81.8 

 Mean 81.5  S.D. 18.6  N 11 
Harlan Study Number: 41204605 Report 

Appendix 16 (continued) Individual and Group Mean Reflexological Responses for Offspring Group: 4 Dose Level: 120 mg/kg bw/day 

Litter Number 

Surface righting 

(Day 1 Post Partum) 

Number of offspring 

% passed 

examined passed 

85 NP 

86 5 3 60.0 

87 NL 88 NP 89 TLL 2 2 100.0 

90 8 8 100.0 91 11 11 100.0 92 10 6 60.0 

93 TLL 1 0 0.0 

94 8 7 87.5 95 8 7 87.5 96 11 10 90.9 

 Mean 83.7  S.D. 17.0  N 7 
Harlan Study Number: 41204605 Report 

Appendix 17 Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 1(M) 1 42 17.1 8.89 51.6 19.2 58.1 33.1 6.7 16 1.07 84 5.63 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 2 42 15.9 8.88 49.7 17.9 55.9 32.0 6.5 19 1.24 80 5.20 0 0.00 1 0.07 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 3 42 16.8 9.66 51.9 17.4 53.8 32.3 5.9 10 0.59 90 5.31 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 4 42 15.9 9.21 50.4 17.3 54.7 31.6 6.6 20 1.32 80 5.28 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 5 42 15.5 9.06 48.0 17.1 53.0 32.2 6.8 7 0.48 92 6.26 0 0.00 1 0.07 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 2(M) 25 42 17.2 9.82 53.8 17.5 54.8 31.9 7.0 18 1.26 82 5.74 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 26 42 16.3 9.38 49.8 17.4 53.1 32.7 8.9 15 1.34 85 7.57 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 27 42 16.4 9.05 50.1 18.1 55.3 32.6 7.8 26 2.03 72 5.62 0 0.00 2 0.16 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 28 42 16.6 9.73 51.2 17.1 52.6 32.4 5.7 24 1.37 75 4.28 0 0.00 1 0.06 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 29 42 16.6 9.14 50.5 18.2 55.2 33.0 6.6 16 1.06 83 5.48 0 0.00 1 0.07 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 3(M) 49 42 17.0 8.92 51.1 19.0 57.2 33.3 7.3 12 0.88 88 6.42 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 50 42 16.3 9.15 49.6 17.8 54.2 32.9 6.6 14 0.92 86 5.68 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 51 42 15.4 8.98 47.8 17.2 53.2 32.2 8.1 16 1.30 83 6.72 0 0.00 1 0.08 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 52 42 15.3 9.04 47.9 16.9 53.0 31.9 7.8 22 1.72 76 5.93 0 0.00 2 0.16 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 53 42 16.6 9.61 52.5 17.3 54.6 31.7 7.5 11 0.83 87 6.53 0 0.00 2 0.15 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 4(M) 73 42 17.4 9.65 51.1 18.1 52.9 34.2 6.3 7 0.44 92 5.80 0 0.00 1 0.06 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 74 42 15.9 9.03 48.7 17.6 53.9 32.7 6.6 5 0.33 95 6.27 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 75 42 16.4 9.08 51.2 18.1 56.4 32.1 6.5 13 0.85 85 5.53 0 0.00 2 0.13 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 76 42 15.2 8.25 46.0 18.4 55.7 32.9 6.6 25 1.65 75 4.95 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 77 42 15.3 8.13 47.1 18.8 58.0 32.4 5.3 20 1.06 79 4.19 0 0.00 1 0.05 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 1(F) 13 43 14.4 7.64 44.2 18.9 57.9 32.6 4.7 26 1.22 73 3.43 0 0.00 1 0.05 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 16 42 13.0 6.46 39.9 20.1 61.8 32.6 6.2 29 1.80 71 4.40 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 19 42 13.5 6.99 41.1 19.3 58.9 32.8 6.5 36 2.34 63 4.10 1 0.07 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 20 42 14.0 7.94 43.6 17.7 54.9 32.2 4.3 23 0.99 77 3.31 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 22 43 13.8 7.46 43.1 18.5 57.8 32.1 5.3 48 2.54 52 2.76 0 0.00 0 0.00 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 2(F) 37 43 14.0 7.53 43.2 18.6 57.5 32.3 6.2 30 1.86 70 4.34 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 39 42 12.5 6.93 39.3 18.1 56.7 31.9 4.1 40 1.64 60 2.46 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 42 42 12.5 6.51 38.5 19.2 59.2 32.3 4.0 35 1.40 65 2.60 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 45 42 13.1 7.45 41.4 17.6 55.6 31.7 4.0 43 1.72 57 2.28 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 46 42 15.3 8.55 48.2 17.8 56.3 31.7 5.5 12 0.66 88 4.84 0 0.00 0 0.00 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 3(F) 66 42 13.0 6.58 40.4 19.7 61.4 32.2 5.6 60 3.36 40 2.24 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 67 42 13.0 7.27 40.6 17.9 55.8 32.0 3.7 39 1.44 61 2.26 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 68 42 12.1 6.71 37.5 18.0 55.8 32.2 5.5 24 1.32 76 4.18 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 71 42 13.3 7.29 43.1 18.2 59.1 30.8 4.4 39 1.72 61 2.68 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 72 42 13.8 7.66 43.3 18.0 56.6 31.8 7.3 39 2.85 61 4.45 0 0.00 0 0.00 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 4(F) 86 44 14.3 7.26 45.5 19.7 62.7 31.4 2.9 20 0.58 78 2.26 0 0.00 2 0.06 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 90 44 13.2 7.18 42.8 18.4 59.6 30.9 5.8 33 1.91 67 3.89 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 91 44 13.5 7.23 42.1 18.6 58.2 32.0 5.3 22 1.17 78 4.13 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 92 42 13.5 6.83 41.1 19.7 60.2 32.8 6.6 38 2.51 61 4.03 0 0.00 1 0.07 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 95 43 13.2 6.98 40.9 18.9 58.6 32.3 4.0 45 1.80 55 2.20 0 0.00 0 0.00 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Recovery Groups Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 1(M) 97 56 15.8 7.56 46.7 20.8 61.8 33.8 7.5 15 1.13 84 6.30 0 0.00 1 0.08 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 98 56 16.0 9.23 51.1 17.4 55.3 31.4 11.5 6 0.69 92 10.58 0 0.00 2 0.23 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 99 56 16.3 9.49 50.3 17.2 53.0 32.4 8.4 17 1.43 82 6.89 0 0.00 1 0.08 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 100 56 16.8 9.09 50.8 18.4 55.9 33.0 8.2 17 1.39 82 6.72 0 0.00 1 0.08 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 101 56 15.2 8.63 46.6 17.7 54.0 32.7 6.4 20 1.28 79 5.06 0 0.00 1 0.06 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Recovery Groups Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 4(M) 107 56 15.2 9.12 47.3 16.6 51.9 32.0 5.9 22 1.30 78 4.60 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 108 56 15.4 9.04 47.8 17.0 52.9 32.2 6.4 27 1.73 71 4.54 0 0.00 2 0.13 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 109 56 15.8 8.90 48.9 17.7 54.9 32.3 6.7 22 1.47 78 5.23 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 110 56 15.6 9.09 48.5 17.2 53.4 32.1 7.7 18 1.39 82 6.31 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 111 56 15.6 9.10 48.7 17.2 53.5 32.1 6.1 21 1.28 78 4.76 0 0.00 1 0.06 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Recovery Groups Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 1(F) 102 56 10.8 5.81 32.8 18.6 56.4 32.9 0.6 6 0.04 92 0.55 0 0.00 2 0.01 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 103 56 15.4 8.42 46.3 18.3 55.0 33.2 4.0 23 0.92 77 3.08 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 104 56 14.8 7.86 44.4 18.8 56.4 33.4 5.9 19 1.12 80 4.72 0 0.00 1 0.06 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 105 56 15.3 8.36 47.1 18.3 56.3 32.5 3.7 13 0.48 85 3.15 0 0.00 2 0.07 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 106 56 15.1 8.42 46.0 17.9 54.6 32.8 1.9 20 0.38 77 1.46 0 0.00 3 0.06 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 17 (continued) Individual Haematological Values Recovery Groups Group Animal (Sex) Number Day Hb RBC Hct MCH MCV MCHC WBC Neu% Neut Lym% Lymph Mon% Mono Eos% Eos Bas% Ba Number g/dl 10^12/l % pg fl g/dl 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^9/l % 10^ 4(F) 112 56 14.9 8.25 45.1 18.1 54.7 33.1 3.5 18 0.63 82 2.87 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 113 56 15.2 8.74 46.8 17.4 53.6 32.5 3.5 16 0.56 84 2.94 0 0.00 0 0.00 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 114 56 15.0 8.30 45.5 18.1 54.8 33.0 4.1 15 0.62 84 3.44 0 0.00 1 0.04 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 115 56 15.9 8.73 47.9 18.2 54.8 33.2 3.6 19 0.68 80 2.88 0 0.00 1 0.04 0 0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒ 116 56 14.9 7.94 45.3 18.7 57.0 32.9 2.9 20 0.58 80 2.32 0 0.00 0 0.00 0 0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  1(M) 1 42 9.8 15.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  2 42 8.8 14.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  3 42 9.3 15.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  4 42 9.3 14.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  5 42 9.3 14.9 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  2(M) 25 42 10.1 15.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  26 42 9.9 17.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  27 42 9.1 15.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  28 42 9.6 14.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  29 42 9.2 16.0 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  3(M) 49 42 9.6 18.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  50 42 10.1 18.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  51 42 9.0 14.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  52 42 8.9 15.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  53 42 9.8 18.1 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  4(M) 73 42 10.6 17.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  74 42 9.2 14.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  75 42 9.6 17.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  76 42 8.9 14.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  77 42 8.9 14.3 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  1(F) 13 43 9.2 18.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  16 42 9.3 13.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  19 42 8.4 15.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  20 42 8.7 15.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  22 43 9.4 18.0 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  2(F) 37 43 8.6 15.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  39 42 9.1 18.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  42 42 8.7 18.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  45 42 8.8 17.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  46 42 10.2 16.6 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  3(F) 66 42 8.9 14.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  67 42 8.5 15.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  68 42 8.5 17.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  71 42 9.2 17.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  72 42 8.4 17.7 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  4(F) 86 44 9.5 15.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  90 44 9.1 13.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  91 44 8.5 16.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  92 42 8.9 18.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  95 43 9.0 16.7 Dose Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values Recovery Groups  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  1(M) 97 56 9.1 15.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  98 56 9.8 14.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  99 56 9.4 15.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  100 56 10.6 16.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  101 56 9.0 16.6 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values Recovery Groups  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  4(M) 107 56 9.6 16.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  108 56 9.3 16.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  109 56 9.1 13.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  110 56 10.7 16.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  111 56 9.7 15.1 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values Recovery Groups  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  1(F) 102 56 9.1 12.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  103 56 8.6 15.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  104 56 9.6 15.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  105 56 9.4 17.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  106 56 9.5 16.1 Dose Levels: Group 1 ƒ 0 (Control) Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 18 (continued) Individual Coagulation Values Recovery Groups  Group Animal  (Sex) Number Day CT APTT  Number Seconds Seconds  4(F) 112 56 9.5 17.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  113 56 8.7 15.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  114 56 9.1 15.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  115 56 8.9 16.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ  116 56 8.7 15.9 Dose Levels: Group 1 ƒ 0 (Control) Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  1(M) 1 42 41 124 7.20 4.1 1.31 146 5.16 99 2.69 1.9 100 73 178 0.69 88  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  2 42 39 154 6.93 3.9 1.27 147 4.26 105 2.82 1.8 83 51 181 0.75 83  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  3 42 41 139 7.30 4.1 1.30 148 4.44 101 2.86 2.3 156 67 224 0.75 90  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  4 42 50 133 6.85 3.8 1.25 150 4.58 107 2.69 1.6 82 58 149 0.72 66  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  5 42 45 164 6.59 3.8 1.34 144 4.02 103 2.70 1.2 119 61 136 0.69 86 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  2(M) 25 42 44 117 7.60 4.2 1.24 151 6.10 101 2.90 2.8 120 72 209 0.80 97  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  26 42 38 140 6.88 3.6 1.13 145 4.74 104 2.73 1.8 80 60 265 0.67 68  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  27 42 42 155 6.69 3.8 1.31 145 3.69 104 2.69 1.2 84 66 265 0.72 82  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  28 42 46 186 6.40 3.9 1.54 146 3.74 105 2.66 1.3 97 71 293 0.73 57  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  29 42 45 148 7.20 3.8 1.12 147 4.65 102 2.77 1.6 85 55 184 0.73 96 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  3(M) 49 42 45 141 7.41 3.9 1.11 153 4.78 108 2.87 1.6 100 59 198 0.74 99  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  50 42 42 160 7.17 3.8 1.15 144 4.57 102 2.50 1.7 83 62 140 0.67 57  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  51 42 38 138 7.11 4.0 1.27 146 5.00 103 2.92 2.2 84 74 155 0.67 74  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  52 42 39 165 6.49 3.6 1.23 142 4.29 104 2.63 1.3 80 57 178 0.71 75  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  53 42 43 136 7.66 4.1 1.15 148 5.25 102 2.83 1.8 107 73 238 0.81 85 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  4(M) 73 42 41 146 7.81 4.0 1.05 146 5.60 102 2.51 2.8 97 53 128 0.69 78  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  74 42 38 159 6.85 3.7 1.14 145 4.39 100 2.77 1.9 114 47 163 0.75 69  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  75 42 38 130 8.00 4.3 1.14 150 5.95 102 3.03 2.4 95 62 201 0.73 70  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  76 42 33 149 6.86 3.7 1.14 145 4.24 105 2.68 2.2 69 46 193 0.62 83  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  77 42 41 143 6.96 3.9 1.24 145 4.52 105 2.86 1.4 82 62 169 0.77 63 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  1(F) 13 43 66 116 6.34 3.5 1.27 147 4.51 102 2.72 1.2 77 72 139 1.41 89  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  16 42 43 139 5.82 3.4 1.40 144 4.47 104 2.40 1.0 79 77 95 0.76 68  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  19 42 37 131 6.20 3.6 1.42 142 3.99 102 2.67 1.1 82 93 124 0.62 68  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  20 42 53 154 6.62 3.6 1.19 147 3.97 106 2.65 1.0 130 87 99 0.75 94  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  22 43 44 136 7.12 4.0 1.26 146 4.70 99 2.68 0.7 72 81 186 0.70 92 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  2(F) 37 43 49 141 6.21 3.7 1.43 147 5.12 99 2.96 1.4 128 96 167 0.80 74  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  39 42 51 113 6.57 3.6 1.25 150 4.51 106 2.75 0.6 94 94 159 0.76 85  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  42 42 45 120 6.42 3.7 1.34 145 4.46 105 2.52 0.5 71 67 120 0.67 76  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  45 42 52 126 6.03 3.6 1.45 147 3.96 106 2.69 0.6 119 70 121 0.76 71  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  46 42 58 111 7.04 3.9 1.28 150 5.50 107 2.83 1.7 84 52 169 0.80 43 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  3(F) 66 42 46 129 6.33 3.6 1.28 142 4.16 105 2.51 0.5 108 60 155 0.72 68  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  67 42 65 114 6.29 3.7 1.47 145 4.12 103 2.64 1.0 71 71 142 0.68 59  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  68 42 67 147 6.58 3.8 1.34 149 5.17 106 2.70 2.0 91 88 175 0.77 78  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  71 42 49 116 6.86 3.9 1.34 145 4.15 103 2.56 0.4 73 86 126 0.65 60  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  72 42 48 149 6.30 3.6 1.29 144 3.80 104 2.54 0.4 72 55 92 0.73 57 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  4(F) 86 44 66 128 6.66 3.9 1.37 149 6.18 103 2.86 1.2 99 35 111 1.20 34  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  90 44 54 134 7.00 3.8 1.16 145 4.90 101 2.74 1.4 68 68 155 0.69 113  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  91 44 61 107 7.03 3.9 1.24 146 5.25 104 2.70 0.7 88 78 114 0.63 90  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  92 42 55 128 6.72 3.9 1.39 149 4.48 106 2.69 0.8 81 75 291 0.97 72  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  95 43 51 130 6.41 3.6 1.32 147 4.42 100 2.65 0.9 62 57 175 0.75 46 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values Recovery Groups  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/d 1(M) 97 56 57 153 6.56 3.5 1.18 149 4.55 105 2.63 2.0 185 163 115 0.57 101  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 98 56 43 220 5.84 3.2 1.18 143 4.12 101 2.47 1.2 123 78 112 0.64 55  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 99 56 58 160 7.32 4.0 1.19 147 5.66 100 2.79 2.1 75 67 122 0.70 120  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 100 56 55 244 6.21 3.4 1.19 148 4.18 101 2.56 1.3 117 60 104 0.63 89  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 101 56 47 211 5.68 3.3 1.40 149 4.07 103 2.46 0.9 118 50 130 0.60 83 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values Recovery Groups  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/d 4(M) 107 56 49 173 6.76 3.8 1.26 145 4.37 103 2.66 1.8 72 67 135 0.66 98  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 108 56 48 141 6.62 3.7 1.24 146 4.55 104 2.62 1.6 72 55 218 0.61 77  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 109 56 48 195 6.65 3.6 1.22 144 4.31 102 2.57 1.3 56 43 122 0.69 99  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 110 56 57 173 6.49 3.4 1.12 145 4.75 104 2.60 1.7 69 63 138 0.73 89  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ 111 56 51 168 6.92 3.8 1.24 148 4.85 103 2.72 1.7 71 52 174 0.65 98 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values Recovery Groups  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  1(F) 102 56 53 185 6.35 3.8 1.52 147 4.61 103 2.62 1.0 272 65 86 0.64 69  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  103 56 54 104 7.47 4.6 1.59 148 5.28 103 2.82 1.9 73 56 91 0.68 73  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  104 56 46 202 6.99 4.2 1.53 146 3.93 102 2.70 1.4 64 50 144 0.76 83  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  105 56 52 133 8.27 4.9 1.44 151 5.08 103 2.92 1.6 73 63 92 0.72 96  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  106 56 61 128 7.74 4.7 1.52 155 5.81 110 2.87 1.2 94 56 102 0.72 94 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 19 (continued) Individual Blood Chemical Values Recovery Groups  Group Animal Tot.  (Sex) Number Day Urea Glucose Prot. Albumin A/G Na+ K+ Clƒ Ca++ P ASAT ALAT AP Creat Chol  Number mg/dl mg/dl g/dl g/dl Ratio mmol/l mmol/l mmol/l mmol/l mmol/l IU/l IU/l IU/l mg/dl mg/dl  4(F) 112 56 58 138 7.66 4.0 1.09 146 5.14 104 2.83 1.7 60 49 70 0.69 101  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  113 56 52 160 7.13 4.1 1.35 149 4.67 105 2.69 1.2 72 63 81 0.71 64  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  114 56 45 152 7.62 4.3 1.32 148 4.67 103 2.78 1.6 106 73 80 0.68 69  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  115 56 48 153 7.41 4.2 1.28 148 4.45 103 2.78 1.6 81 76 83 0.65 79  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ ƒƒƒƒƒ  116 56 52 157 7.21 4.1 1.34 146 4.48 105 2.75 1.4 70 58 64 0.68 102 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 1(M) 1 42 5.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  2 42 6.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  3 42 16.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  4 42 7.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  5 42 4.6 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 2(M) 25 42 3.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  26 42 3.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  27 42 3.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  28 42 10.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  29 42 11.2 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 3(M) 49 42 6.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  50 42 3.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  51 42 13.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  52 42 8.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  53 42 4.4 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 4(M) 73 42 2.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  74 42 9.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  75 42 7.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  76 42 10.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  77 42 6.2 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 1(F) 13 43 11.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  16 42 14.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  19 42 3.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  20 42 15.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  22 43 9.2 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 2(F) 37 43 7.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  39 42 6.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  42 42 4.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  45 42 5.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  46 42 6.8 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 3(F) 66 42 3.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  67 42 4.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  68 42 8.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  71 42 15.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  72 42 4.2 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 4(F) 86 44 4.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  90 44 6.3  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  91 44 4.0  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  92 42 3.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  95 43 5.4 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values Recovery Groups  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 1(M) 97 56 5.2  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  98 56 3.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  99 56 32.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  100 56 3.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  101 56 3.6 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values Recovery Groups  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 4(M) 107 56 4.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  108 56 6.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  109 56 10.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  110 56 11.8  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  111 56 8.1 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values Recovery Groups  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 1(F) 102 56 4.9  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  103 56 4.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  104 56 5.7  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  105 56 4.4  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  106 56 4.8 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 20 (continued) Individual Bile Acid Values Recovery Groups  Group Animal  (Sex) Number Day Bile Acid  Number μmol/l 

 4(F) 112 56 3.5  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  113 56 4.6  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  114 56 4.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  115 56 5.1  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ  116 56 18.7 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 21 Individual and Group Mean Urinalytical Findings 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

1(M) 1 17.0 1.019 6 1+ Normal Negative Normal Negative Negative Negativ

 2 24.0 1.010 6 1+ Normal Negative Normal Negative Negative Negativ 3 22.0 1.012 7 1+ Normal Negative Normal Negative Negative Negativ 4 . . 7 1+ Normal Negative Normal Negative Negative Negativ 5 32.0 1.010 7 1+ Normal Negative Normal Negative Negative Negativ

Mean 23.8 1.013 S.D. 6.2 0.004 

N 4 4 

. = data unavailable; water bottle leaked Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 21 (continued) Individual and Group Mean Urinalytical Findings 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

2(M) 25 15.0 1.016 7 1+ Normal Negative Normal Negative Negative Negativ

 26 27.0 1.009 7 1+ Normal Negative Normal Negative Negative Negativ

 27 19.0 1.010 6 1+ Normal Negative Normal Negative Negative Negativ 28 12.0 1.016 7 1+ Normal Negative Normal Negative Negative Negativ 29 14.0 1.018 6 1+ Normal Negative Normal Negative Negative Negativ

Mean 17.4 1.014 S.D. 5.9 0.004 

N 5 5 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 21 (continued) Individual and Group Mean Urinalytical Findings 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

3(M) 49 15.0 1.016 6 1+ Normal Negative Normal Negative Negative Negativ

 50 28.0 1.010 6 1+ Normal Negative Normal Negative Negative Negativ

 51 16.0 1.014 6 1+ Normal Negative Normal Negative Negative Negativ 52 32.0 1.008 6 1+ Normal Negative Normal Negative Negative Negativ 53 21.0 1.013 7 1+ Normal Negative Normal Negative Negative Negativ

Mean 22.4 1.012 S.D. 7.4 0.003 

N 5 5 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 21 (continued) Individual and Group Mean Urinalytical Findings 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

4(M) 73 8.0 1.021 6 1+ Normal Negative Normal Negative Negative Negativ

 74 24.0 1.010 6 1+ Normal Negative Normal Negative Negative Negativ

 75 31.0 1.009 7 1+ Normal Negative Normal Negative Negative Negativ 76 22.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ 77 29.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ

Mean 22.8 1.012 S.D. 9.0 0.005 

N 5 5 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 21 (continued) Individual and Group Mean Urinalytical Findings Recovery Groups 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

1(M) 97 28.0 1.010 6 1+ Normal Negative Normal Negative Negative Negativ

 98 27.0 1.009 6 1+ Normal Negative Normal Negative Negative Negativ 99 20.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ

 100 22.0 1.012 5 1+ Normal Negative Normal Negative Negative Negativ 101 11.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ

Mean 21.6 1.011 S.D. 6.8 0.001 

N 5 5 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 21 (continued) Individual and Group Mean Urinalytical Findings Recovery Groups 

Group 

Animal Number 

Volume 

(ml) 

Specific 

Gravity pH Protein Glucose Ketones Urobilinogen Bilirubin 

Blood - 

Erythrocytes 

Blood - 

Haemoglob

(Sex) 

4(M) 107 18.0 1.016 5 1+ Normal Negative Normal Negative Negative Negativ

 108 22.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ 109 21.0 1.013 6 1+ Normal Negative Normal Negative Negative Negativ

 110 20.0 1.016 6 1+ Normal Negative Normal Negative Negative Negativ 111 23.0 1.011 6 1+ Normal Negative Normal Negative Negative Negativ

Mean 20.8 1.013 S.D. 1.9 0.003 

N 5 5 

Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day
Harlan Study Number: 41204605 Report 

Appendix 22 Individual Necropsy Findings for Offspring Group: 1 Dose Level: 0 (Control) 

Litter Number

Interim Deaths Term

Necropsy Day (Post 

Partum) 

Offspring Sex & 

Number Macroscopic Observation Total Number of Offspring Mac

13 3M 7F No a14 5M 6F No a15 4M 8F No a16 6M 8F No a17 Pre Day 1 1M Autolytic changes detected F12 Sc

 4M 7F No a

18 4M 1F No a19 6M 4F No a20 2M 9F No a21 8M 6F No a22 F13 Sw

 8M 5F No a

23 Pre Day 1 1M No abnormalities detected 3M 9F No a24 3M 7F No a
Harlan Study Number: 41204605 Report 

Appendix 22 (continued) Individual Necropsy Findings for Offspring Group: 2 Dose Level: 30 mg/kg bw/day 

Litter Number

Interim Deaths Terminal 

Necropsy Day (Post 

Partum) 

Offspring Sex & 

Number Macroscopic Observation Total Number of Offspring Macros

37 4M 8F No abno38 7M 5F No abno39 6M 7F No abno40 6M 10F No abno

41 TLL . 

42 4M 7F No abno

43 NP . 

44 3M 9F No abno45 3M 8F No abno46 2M 3F No abno47 6M 7F No abno

48 NP . 
Harlan Study Number: 41204605 Report 

Appendix 22 (continued) Individual Necropsy Findings for Offspring Group: 3 Dose Level: 60 mg/kg bw/day 

Litter Number

Interim Deaths Terminal 

Necropsy Day (Post 

Partum) 

Offspring Sex & 

Number Macroscopic Observation Total Number of Offspring Macros

61 3M 2F No abno

62 NP . 

63 2M 2F No abno64 7M 5F No abno65 6M 6F No abno66 2M 5F No abno

67 6M 3F No abno68 7M 7F No abno69 3M 1F No abno70 6M 5F No abno71 F5 Open woun

 2M 8F No abno

72 5M 6F No abno
Harlan Study Number: 41204605 Report 

Appendix 22 (continued) Individual Necropsy Findings for Offspring Group: 4 Dose Level: 120 mg/kg bw/day 

Litter Number

Interim Deaths Terminal 

Necropsy Day (Post 

Partum) 

Offspring Sex & 

Number Macroscopic Observation Total Number of Offspring Macros

85 NP . 86 Pre Day 1 1M 1F Autolytic changes detected M4 

 5 1M No abnormalities detected 1M 2F No abno

87 NL . 88 NP . 89 TLL . 90 6M 2F No abno

91 5M 6F No abno92 2M 8F No abno93 TLL . 94 2M 8F No abno95 6M 2F No abno96 7M 4F No abno
Harlan Study Number: 41204605 Report 

Appendix 23 Individual Necropsy Findings Group: 1 Dose Level: 0 (Control) Sex: Male 

 Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  1 SCHEDULED KILL 43 (7) No abnormalities detected  2 SCHEDULED KILL 43 (7) No abnormalities detected  3 SCHEDULED KILL 43 (7) No abnormalities detected  4 SCHEDULED KILL 43 (7) No abnormalities detected  5 SCHEDULED KILL 43 (7) No abnormalities detected  6 SCHEDULED KILL 43 (7) No abnormalities detected  7 SCHEDULED KILL 43 (7) No abnormalities detected  8 SCHEDULED KILL 43 (7) No abnormalities detected  9 SCHEDULED KILL 43 (7) No abnormalities detected  10 SCHEDULED KILL 43 (7) No abnormalities detected  11 SCHEDULED KILL 43 (7) No abnormalities detected  12 SCHEDULED KILL 43 (7) No abnormalities detected  97 SCHEDULED KILL 57 (9) No abnormalities detected  98 SCHEDULED KILL 57 (9) No abnormalities detected  99 SCHEDULED KILL 57 (9) No abnormalities detected  100 SCHEDULED KILL 57 (9) No abnormalities detected  101 SCHEDULED KILL 57 (9) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 1 Dose Level: 0 (Control) Sex: Female 

 Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  13 SCHEDULED KILL 44 (7) No abnormalities detected  14 SCHEDULED KILL 45 (7) No abnormalities detected  15 SCHEDULED KILL 45 (7) No abnormalities detected  16 SCHEDULED KILL 43 (7) No abnormalities detected  17 SCHEDULED KILL 42 (6) No abnormalities detected  18 SCHEDULED KILL 46 (7) No abnormalities detected  19 SCHEDULED KILL 43 (7) No abnormalities detected  20 SCHEDULED KILL 43 (7) No abnormalities detected  21 SCHEDULED KILL 42 (6) No abnormalities detected  22 SCHEDULED KILL 44 (7) No abnormalities detected  23 SCHEDULED KILL 44 (7) No abnormalities detected  24 SCHEDULED KILL 44 (7) No abnormalities detected  102 SCHEDULED KILL 57 (9) No abnormalities detected  103 SCHEDULED KILL 57 (9) No abnormalities detected  104 SCHEDULED KILL 57 (9) No abnormalities detected  105 SCHEDULED KILL 57 (9) No abnormalities detected  106 SCHEDULED KILL 57 (9) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 2 Dose Level: 30 mg/kg bw/day Sex: Male  Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  25 SCHEDULED KILL 43 (7) No abnormalities detected  26 SCHEDULED KILL 43 (7) No abnormalities detected  27 SCHEDULED KILL 43 (7) Mammary Gland; Mass: Soft fibrous mass approximately 40mm x 32mm x  All remaining tissues had no abnormalities detected  28 SCHEDULED KILL 43 (7) No abnormalities detected  29 SCHEDULED KILL 43 (7) No abnormalities detected  30 SCHEDULED KILL 43 (7) No abnormalities detected  31 SCHEDULED KILL 43 (7) No abnormalities detected  32 SCHEDULED KILL 43 (7) No abnormalities detected  33 SCHEDULED KILL 43 (7) No abnormalities detected  34 SCHEDULED KILL 43 (7) No abnormalities detected  35 SCHEDULED KILL 43 (7) No abnormalities detected  36 SCHEDULED KILL 43 (7) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 2 Dose Level: 30 mg/kg bw/day Sex: Female 

 Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  37 SCHEDULED KILL 44 (7) No abnormalities detected  38 SCHEDULED KILL 44 (7) No abnormalities detected  39 SCHEDULED KILL 43 (7) No abnormalities detected  40 SCHEDULED KILL 45 (7) No abnormalities detected  41 SCHEDULED KILL 45 (7) No abnormalities detected  42 SCHEDULED KILL 43 (7) No abnormalities detected  43 SCHEDULED KILL 46 (7) No abnormalities detected  44 SCHEDULED KILL 42 (6) No abnormalities detected  45 SCHEDULED KILL 43 (7) No abnormalities detected  46 SCHEDULED KILL 43 (7) No abnormalities detected  47 SCHEDULED KILL 44 (7) No abnormalities detected  48 SCHEDULED KILL 42 (6) Uterus & Cervix; left horn; Distended  Vagina; Fluid Filled: vagina filled with a viscous cream coloured f All remaining tissues had no abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 3 Dose Level: 60 mg/kg bw/day Sex: Male  Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  49 SCHEDULED KILL 43 (7) No abnormalities detected  50 SCHEDULED KILL 43 (7) No abnormalities detected  51 SCHEDULED KILL 43 (7) No abnormalities detected  52 SCHEDULED KILL 43 (7) No abnormalities detected  53 SCHEDULED KILL 43 (7) No abnormalities detected  54 SCHEDULED KILL 43 (7) No abnormalities detected  55 SCHEDULED KILL 43 (7) No abnormalities detected  56 SCHEDULED KILL 43 (7) No abnormalities detected  57 SCHEDULED KILL 43 (7) No abnormalities detected  58 SCHEDULED KILL 43 (7) No abnormalities detected  59 SCHEDULED KILL 43 (7) No abnormalities detected  60 SCHEDULED KILL 43 (7) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 3 Dose Level: 60 mg/kg bw/day Sex: Female  Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  61 SCHEDULED KILL 44 (7) No abnormalities detected  62 SCHEDULED KILL 44 (7) No abnormalities detected  63 SCHEDULED KILL 45 (7) No abnormalities detected  64 SCHEDULED KILL 42 (6) No abnormalities detected  65 SCHEDULED KILL 44 (7) No abnormalities detected  66 SCHEDULED KILL 43 (7) No abnormalities detected  67 SCHEDULED KILL 43 (7) No abnormalities detected  68 SCHEDULED KILL 43 (7) No abnormalities detected  69 SCHEDULED KILL 46 (7) No abnormalities detected  70 SCHEDULED KILL 42 (6) No abnormalities detected  71 SCHEDULED KILL 43 (7) No abnormalities detected  72 SCHEDULED KILL 43 (7) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 4 Dose Level: 120 mg/kg bw/day Sex: Male  Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ 73 SCHEDULED KILL 43 (7) No abnormalities detected  74 SCHEDULED KILL 43 (7) No abnormalities detected  75 SCHEDULED KILL 43 (7) No abnormalities detected  76 SCHEDULED KILL 43 (7) No abnormalities detected  77 SCHEDULED KILL 43 (7) No abnormalities detected  78 SCHEDULED KILL 43 (7) No abnormalities detected  79 SCHEDULED KILL 43 (7) No abnormalities detected  80 SCHEDULED KILL 43 (7) No abnormalities detected  81 SCHEDULED KILL 43 (7) Seminal Vesicles; Small  All remaining tissues had no abnormalities detected  82 SCHEDULED KILL 43 (7) No abnormalities detected  83 SCHEDULED KILL 43 (7) Epididymides; left; Mass: Yellow fluid filled mass attached to left cauda appr All remaining tissues had no abnormalities detected  84 SCHEDULED KILL 43 (7) No abnormalities detected  107 SCHEDULED KILL 57 (9) No abnormalities detected  108 SCHEDULED KILL 57 (9) No abnormalities detected  109 SCHEDULED KILL 57 (9) No abnormalities detected  110 SCHEDULED KILL 57 (9) No abnormalities detected  111 SCHEDULED KILL 57 (9) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 23 (continued) Individual Necropsy Findings Group: 4 Dose Level: 120 mg/kg bw/day Sex: Female  Animal Death  No. Mode Of Death Day (Week) Observation(s) ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ  85 SCHEDULED KILL 44 (7) No abnormalities detected  86 SCHEDULED KILL 45 (7) No abnormalities detected  87 SCHEDULED KILL 42 (6) No abnormalities detected  88 SCHEDULED KILL 44 (7) No abnormalities detected  89 SCHEDULED KILL 47 (7) No abnormalities detected  90 SCHEDULED KILL 45 (7) No abnormalities detected  91 SCHEDULED KILL 45 (7) No abnormalities detected  92 SCHEDULED KILL 43 (7) Eyes; right; Reddened  All remaining tissues had no abnormalities detected  93 SCHEDULED KILL 45 (7) No abnormalities detected  94 SCHEDULED KILL 46 (7) No abnormalities detected  95 SCHEDULED KILL 44 (7) No abnormalities detected  96 SCHEDULED KILL 46 (7) No abnormalities detected  112 SCHEDULED KILL 57 (9) No abnormalities detected  113 SCHEDULED KILL 57 (9) No abnormalities detected  114 SCHEDULED KILL 57 (9) No abnormalities detected  115 SCHEDULED KILL 57 (9) No abnormalities detected  116 SCHEDULED KILL 57 (9) No abnormalities detected 
Harlan Study Number: 41204605 Report 

Appendix 24 Individual Organ Weights  Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus  Number g g g g g g g g g g g g  1(M) 1 43 0.0581 2.0822 1.5987 0.9971 2.4687 11.5575 0.0099 0.4667 1.9006 0.7467 3.7905 0.4097  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 2 43 0.0702 2.0747 1.7685 1.1389 2.0907 11.2223 0.0116 0.6168 2.1267 0.7086 3.5050 0.3666  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 3 43 0.0800 1.9760 1.4845 1.1247 2.1392 12.1917 0.0147 0.7261 2.1056 0.7302 3.4192 0.4711  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 4 43 0.0807 2.1679 1.4767 1.1957 2.0357 12.0105 0.0097 0.7637 2.1446 0.6028 4.1733 0.4723  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 5 43 0.0637 1.9735 1.4990 1.0247 1.7403 10.3642 0.0129 0.5305 1.5048 0.5883 3.8388 0.5301  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 6 43 1.4727 0.0085 0.5505 2.5415 3.5059  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 7 43 1.5903 0.0138 0.6420 2.6145 3.4840  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 8 43 1.2074 0.0133 0.7711 1.7422 3.3825  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 9 43 1.2312 0.0145 0.6204 1.7531 3.3719  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 10 43 1.3602 0.0104 0.5350 1.9416 3.5372  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 11 43 1.3371 0.0101 0.4977 2.0028 3.2770  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 12 43 1.6021 0.0131 0.3344 1.4843 3.2046 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights  Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus  Number g g g g g g g g g g g g  2(M) 25 43 0.0770 2.1372 1.5198 1.1696 2.1160 10.1829 0.0093 0.6037 1.8288 0.5382 3.8787 0.4073  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 26 43 0.0567 2.0927 1.5777 1.1603 2.6201 12.9691 0.0114 0.5351 2.3914 0.7391 3.7004 0.4313  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 27 43 0.0766 2.1649 1.4901 0.9074 2.2130 11.5656 0.0100 0.4496 2.0913 0.8204 3.5200 0.4029  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 28 43 0.0503 2.0540 1.2894 1.2097 2.2781 9.7607 0.0105 0.5503 1.6608 0.5851 3.5151 0.2591  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 29 43 0.0756 2.1119 1.5380 1.1894 2.4993 12.5685 0.0145 0.4790 2.2428 0.7483 3.5709 0.3979  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 30 43 1.1684 0.0127 0.4837 1.4604 3.4274  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 31 43 1.3905 0.0202 0.5578 2.2572 3.7541  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 32 43 1.4268 0.0118 0.5769 1.9099 3.9447  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 33 43 2.0040 0.0168 0.6039 2.3568 3.9830  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 34 43 1.3297 0.0160 0.6901 2.0812 3.5668  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 35 43 1.3723 0.0127 0.7027 2.4918 3.3421  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 36 43 1.4716 0.0121 0.5508 2.3821 3.9507 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus  Number g g g g g g g g g g g g  3(M) 49 43 0.0650 2.1442 1.5270 1.1145 2.2945 11.7335 0.0118 0.5468 1.8117 0.8223 3.3389 0.3730  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 50 43 0.0634 2.1021 1.4456 1.2587 2.4639 12.9700 0.0117 0.5096 1.8957 0.7253 3.8168 0.5490  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 51 43 0.0483 1.9788 1.4209 0.8485 2.1485 10.3283 0.0093 0.4782 1.6541 0.7303 3.8069 0.3860  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 52 43 0.0602 1.8888 1.3618 1.0180 2.2668 10.4300 0.0095 0.6354 1.6759 0.5937 3.4527 0.2561  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 53 43 0.0689 2.1364 1.2331 0.9606 2.2289 10.5174 0.0251 0.3992 1.6450 0.6319 3.1444 0.3898  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 54 43 1.3350 0.0121 0.5411 1.4608 4.1205  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 55 43 1.4606 0.0120 0.5393 1.7287 3.3939  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 56 43 1.2274 0.0135 0.4708 2.1486 3.5594  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 57 43 1.3815 0.0134 0.6128 1.9654 3.6626  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 58 43 1.4531 0.0134 0.6437 2.3075 3.6690  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 59 43 1.4152 0.0133 0.5514 1.9694 3.3873  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 60 43 1.4753 0.0142 0.5687 2.0383 3.5340 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus  Number g g g g g g g g g g g g  4(M) 73 43 0.0706 2.0865 1.5167 1.2403 2.5906 11.0026 0.0110 0.6003 2.2712 0.5761 3.8236 0.4114  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 74 43 0.0686 2.0673 1.3831 0.8235 2.3176 10.9380 0.0111 0.4942 1.7587 0.7363 3.3153 0.3554  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 75 43 0.0622 2.0115 1.5424 1.0267 2.4837 14.2434 0.0192 0.4779 2.1295 0.6908 4.5289 0.4317  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 76 43 0.0739 1.9561 1.5100 1.3562 3.2500 14.1214 0.0117 0.4704 2.3240 0.7274 3.2993 0.3163  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 77 43 0.0726 1.9797 1.1414 0.8004 1.8903 10.3508 0.0090 0.4956 1.1099 0.7056 3.0299 0.3039  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 78 43 1.6729 0.0174 0.7242 1.2244 3.4350  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 79 43 1.4283 0.0107 0.5826 1.9512 3.5184  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 80 43 1.4141 0.0110 0.3381 0.8787 3.4750  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 81 43 1.1353 0.0213 0.3264 0.6662 2.7805  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 82 43 1.5408 0.0150 0.4939 1.8223 3.0862  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 83 43 1.4871 0.0129 0.4437 1.6051 3.7225  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 84 43 1.3384 0.0109 0.5522 2.1373 3.3771 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual and Group Mean Organ Weights  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus Th Number g g g g g g g g g g  1(F) 13 44 0.0780 1.7754 0.7426 1.5757 10.4316 0.1039 0.0173 0.5223 0.2388 0.6201  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 14 45 0.1117 0.0149 0.9791  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 15 45 0.0970 0.0185 0.4851  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 16 43 0.0990 1.7971 1.0950 1.7195 12.9887 0.1001 0.0177 0.7082 0.2205 0.8279  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 17 42 0.0960 0.0143 0.6275  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 18 46 0.1048 0.0142 0.6166  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 19 43 0.1021 1.8869 0.8399 1.4535 10.4310 0.1220 0.0179 0.6167 0.2636 0.7567  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 20 43 0.1026 1.8810 1.0458 1.6062 12.4086 0.1170 0.0173 0.6509 0.3489 0.6045  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 21 42 0.1394 0.0164 0.7806  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 22 44 0.0889 1.7979 1.1077 1.6048 11.5342 0.1112 0.0167 0.5659 0.2721 0.6212  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 23 44 0.0999 0.0193 0.6079  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 24 44 0.0954 0.0219 0.6974 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual and Group Mean Organ Weights  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus Th Number g g g g g g g g g g  2(F) 37 44 0.0873 1.7358 0.8392 1.5533 11.1502 0.0990 0.0177 0.5225 0.1934 0.7999  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 38 44 0.1198 0.0248 0.5871  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 39 43 0.0916 1.8015 1.0030 1.5194 10.2572 0.1231 0.0156 0.5322 0.1949 0.6283  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 40 45 0.1182 0.6445  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 41 45 0.1175 0.0134 0.6505  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 42 43 0.0766 1.8347 0.8018 1.5593 9.8442 0.1034 0.0170 0.5259 0.2780 0.7484  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 43 46 0.1213 0.0173 0.5024  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 44 42 0.1043 0.0275 0.5827  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 45 43 0.1077 1.7901 0.6585 1.3899 8.7335 0.0938 0.0153 0.6227 0.2263 0.6787  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 46 43 0.0908 1.8669 0.8569 1.4169 9.0545 0.1112 0.0163 0.4634 0.2729 0.4935  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 47 44 0.1209 0.0157 0.7656  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 48 42 0.0614 0.0161 1.1611 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual and Group Mean Organ Weights  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus Th Number g g g g g g g g g g  3(F) 61 44 0.0999 0.0185 0.5030  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 62 44 0.0729 0.0131 0.9181  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 63 45 0.0809 0.0204 0.6160  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 64 42 0.1030 0.0174 0.5227  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 65 44 0.0995 0.7605  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 66 43 0.1056 1.7515 0.7917 1.3373 9.4765 0.0895 0.0205 0.6843 0.2788 0.8072  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 67 43 0.0856 1.8602 0.7191 1.5060 9.6079 0.1008 0.0166 0.4756 0.2149 0.5571  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 68 43 0.0690 1.8356 0.8064 1.7576 12.1130 0.1305 0.0181 0.5086 0.1436 0.7466  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 69 46 0.0836 0.0160 0.4464  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 70 42 0.1077 0.0149 0.5092  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 71 43 0.0848 1.7946 0.7587 1.5960 10.5654 0.1029 0.0166 0.4535 0.1967 0.8483  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 72 43 0.0894 1.8310 0.8966 1.3680 9.9153 0.1254 0.0143 0.4859 0.2745 0.6045 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual and Group Mean Organ Weights  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus Th Number g g g g g g g g g g  4(F) 85 44 0.1017 0.0103 1.5485  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 86 45 0.0888 1.7854 1.0071 1.3644 9.0150 0.0832 0.0145 0.5141 0.1413 0.6532  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 87 42 0.0882 0.0092 0.8556  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 88 44 0.0662 0.0127 1.4173  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 89 47 0.0185  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 90 45 0.0741 1.8717 0.6783 1.5150 11.5112 0.0837 0.0134 0.5356 0.1717 0.5285  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 91 45 0.0870 1.6482 0.7977 1.5231 11.1669 0.0798 0.0126 0.5316 0.1768 0.5656  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 92 43 0.1017 1.8641 0.6956 1.4046 10.0126 0.1040 0.0140 0.5737 0.2228 0.6354  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 93 45 0.1054 0.0174 0.7370  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 94 46 0.1018 0.0175 0.5832  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 95 44 0.0661 1.8023 0.6531 1.2842 9.4170 0.1105 0.0112 0.5585 0.2194 0.6978  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 96 46 0.0869 0.0154 0.6096 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Recovery Groups  Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymu Number g g g g g g g g g g g g  1(M) 97 57 0.0608 1.9700 1.5098 1.0489 2.0859 12.3281 0.0117 0.5926 1.7827 0.6225 3.2232 0.4801  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 98 57 0.0554 1.9682 1.5134 1.0201 2.1867 11.4149 0.0113 0.6099 2.0251 0.6932 3.7925 0.4361  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 99 57 0.0834 2.1806 1.5696 0.9110 2.0341 12.6113 0.0105 0.5531 2.0866 0.6420 3.4634 0.3878  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 100 57 0.0711 2.1512 1.4384 1.0801 2.1844 13.6442 0.0114 0.7631 2.3645 0.5716 3.6981 0.4824  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 101 57 0.0681 2.0919 1.5864 0.9064 2.1019 10.1734 0.0092 0.4943 2.3212 0.6745 3.7113 0.3270 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Recovery Groups Group Animal Epididyƒ Seminal  (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymu Number g g g g g g g g g g g g  4(M) 107 57 0.0658 1.9515 1.5934 1.2918 2.3302 12.2472 0.0115 0.5029 2.2599 0.7708 3.1249 0.2525  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 108 57 0.0896 2.1700 1.5912 0.9008 2.4416 10.8199 0.0122 0.5496 2.4607 0.6149 3.7864 0.3428  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 109 57 0.0457 1.8899 1.2985 0.8557 1.5978 10.3209 0.0099 0.3494 1.7025 0.4703 3.2571 0.3189  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 110 57 0.0692 1.8959 1.5481 1.0223 2.2585 11.1208 0.0134 0.5901 1.6976 0.5680 3.4834 0.4075  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒ 111 57 0.0613 1.9703 1.5401 1.0616 2.9090 12.4310 0.0080 0.4248 2.2392 0.6139 3.3948 0.2955 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Recovery Groups  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus T Number g g g g g g g g g g  1(F) 102 57 0.0835 1.6439 0.7834 1.1600 7.0625 0.0697 0.0153 0.3876 0.2690 0.4636  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 103 57 0.0808 1.8065 0.7103 1.3251 7.6694 0.1189 0.0170 0.5741 0.3042 0.5652  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 104 57 0.0903 1.8855 0.9450 1.5139 8.6135 0.1237 0.0198 0.6573 0.3159 0.8382  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 105 57 0.0840 1.8279 0.6772 1.4741 6.7837 0.0928 0.0176 0.4336 0.3163 0.6584  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 106 57 0.0606 1.7705 0.7239 1.3470 6.2643 0.1134 0.0136 0.5201 0.2256 0.6119 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 24 (continued) Individual Organ Weights Recovery Groups  Group Animal  (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Uterus T Number g g g g g g g g g g  4(F) 112 57 0.0766 1.7284 0.7293 1.2428 7.8026 0.0847 0.0208 0.4092 0.3352 0.8694  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 113 57 0.0936 1.7160 0.6661 1.3160 7.8622 0.0748 0.0199 0.4098 0.2320 0.7530  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 114 57 0.0838 1.9468 0.7260 1.4308 7.4768 0.1068 0.0163 0.4896 0.2873 0.5201  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 115 57 0.0941 1.8415 0.6870 1.4223 7.2535 0.1104 0.0165 0.4800 0.2681 1.2054  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 116 57 0.0661 2.0134 0.7145 1.4219 8.2847 0.1105 0.0259 0.4666 0.3505 0.5500 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 Individual Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  1(M) 1 43 387 0.0150 0.5380 0.4131 0.2576 0.6379 2.9864 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 2 43 408 0.0172 0.5085 0.4335 0.2791 0.5124 2.7506 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 3 43 386 0.0207 0.5119 0.3846 0.2914 0.5542 3.1585 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 4 43 373 0.0216 0.5812 0.3959 0.3206 0.5458 3.2200 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 5 43 357 0.0178 0.5528 0.4199 0.2870 0.4875 2.9031 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 6 43 357 0.4125 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 7 43 350 0.4544 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 8 43 343 0.3520 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 9 43 385 0.3198 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 10 43 367 0.3706 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 11 43 352 0.3799 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 12 43 361 0.4438 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  1(M) 1 43 0.1206 0.4911 0.1929 0.9795 0.1059 0.0057  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  2 43 0.1512 0.5213 0.1737 0.8591 0.0899 0.0055  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  3 43 0.1881 0.5455 0.1892 0.8858 0.1220 0.0031  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  4 43 0.2047 0.5750 0.1616 1.1188 0.1266 0.0066  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  5 43 0.1486 0.4215 0.1648 1.0753 0.1485 0.0065  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  6 43 0.1542 0.7119 0.9820  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  7 43 0.1834 0.7470 0.9954  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  8 43 0.2248 0.5079 0.9862  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  9 43 0.1611 0.4554 0.8758  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  10 43 0.1458 0.5290 0.9638  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  11 43 0.1414 0.5690 0.9310  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  12 43 0.0926 0.4112 0.8877 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  2(M) 25 43 338 0.0228 0.6323 0.4496 0.3460 0.6260 3.0127 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 26 43 412 0.0138 0.5079 0.3829 0.2816 0.6359 3.1478 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 27 43 379 0.0202 0.5712 0.3932 0.2394 0.5839 3.0516 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 28 43 332 0.0152 0.6187 0.3884 0.3644 0.6862 2.9400 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 29 43 402 0.0188 0.5253 0.3826 0.2959 0.6217 3.1265 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 30 43 349 0.3348 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 31 43 434 0.3204 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 32 43 438 0.3258 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 33 43 405 0.4948 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 34 43 381 0.3490 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 35 43 367 0.3739 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 36 43 401 0.3670 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  2(M) 25 43 0.1786 0.5411 0.1592 1.1475 0.1205 0.0064  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  26 43 0.1299 0.5804 0.1794 0.8982 0.1047 0.0060  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  27 43 0.1186 0.5518 0.2165 0.9288 0.1063 0.0051  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  28 43 0.1658 0.5002 0.1762 1.0588 0.0780 0.0073  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  29 43 0.1192 0.5579 0.1861 0.8883 0.0990 0.0064  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  30 43 0.1386 0.4185 0.9821  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  31 43 0.1285 0.5201 0.8650  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  32 43 0.1317 0.4361 0.9006  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  33 43 0.1491 0.5819 0.9835  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  34 43 0.1811 0.5462 0.9362  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  35 43 0.1915 0.6790 0.9107  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  36 43 0.1374 0.5940 0.9852 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  3(M) 49 43 387 0.0168 0.5541 0.3946 0.2880 0.5929 3.0319 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 50 43 386 0.0164 0.5446 0.3745 0.3261 0.6383 3.3601 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 51 43 328 0.0147 0.6033 0.4332 0.2587 0.6550 3.1489 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 52 43 358 0.0168 0.5276 0.3804 0.2844 0.6332 2.9134 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 53 43 356 0.0194 0.6001 0.3464 0.2698 0.6261 2.9543 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 54 43 393 0.3397 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 55 43 367 0.3980 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 56 43 362 0.3391 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 57 43 368 0.3754 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 58 43 388 0.3745 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 59 43 350 0.4043 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 60 43 333 0.4430 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  3(M) 49 43 0.1413 0.4681 0.2125 0.8628 0.0964 0.0062  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  50 43 0.1320 0.4911 0.1879 0.9888 0.1422 0.0055  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  51 43 0.1458 0.5043 0.2227 1.1606 0.1177 0.0066  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  52 43 0.1775 0.4681 0.1658 0.9644 0.0715 0.0060  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  53 43 0.1121 0.4621 0.1775 0.8833 0.1095 0.0038  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  54 43 0.1377 0.3717 1.0485  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  55 43 0.1469 0.4710 0.9248  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  56 43 0.1301 0.5935 0.9833  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  57 43 0.1665 0.5341 0.9953  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  58 43 0.1659 0.5947 0.9456  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  59 43 0.1575 0.5627 0.9678  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  60 43 0.1708 0.6121 1.0613 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  4(M) 73 43 354 0.0199 0.5894 0.4284 0.3504 0.7318 3.1081 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 74 43 340 0.0202 0.6080 0.4068 0.2422 0.6816 3.2171 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 75 43 375 0.0166 0.5364 0.4113 0.2738 0.6623 3.7982 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 76 43 401 0.0184 0.4878 0.3766 0.3382 0.8105 3.5215 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 77 43 337 0.0215 0.5874 0.3387 0.2375 0.5609 3.0715 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 78 43 376 0.4449 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 79 43 374 0.3819 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 80 43 363 0.3896 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 81 43 311 0.3650 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 82 43 375 0.4109 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 83 43 351 0.4237 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 84 43 362 0.3697 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  4(M) 73 43 0.1696 0.6416 0.1627 1.0801 0.1162 0.0076  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  74 43 0.1454 0.5173 0.2166 0.9751 0.1045 0.0054  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  75 43 0.1274 0.5679 0.1842 1.2077 0.1151 0.0062  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  76 43 0.1173 0.5796 0.1814 0.8228 0.0789 0.0078  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  77 43 0.1471 0.3293 0.2094 0.8991 0.0902 0.0059  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  78 43 0.1926 0.3256 0.9136  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  79 43 0.1558 0.5217 0.9407  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  80 43 0.0931 0.2421 0.9573  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  81 43 0.1050 0.2142 0.8941  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  82 43 0.1317 0.4859 0.8230  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  83 43 0.1264 0.4573 1.0605  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  84 43 0.1525 0.5904 0.9329 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual and Group Mean Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  1(F) 13 44 263 0.0297 0.6751 0.2824 0.5991 3.9664 0.0395 0.0066 0.1986 0.0908 0.0061  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 14 45 255 0.0438 0.0058  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 15 45 281 0.0345 0.0066  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 16 43 265 0.0374 0.6782 0.4132 0.6489 4.9014 0.0378 0.0067 0.2672 0.0832 0.0071  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 17 42 268 0.0358 0.0053  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 18 46 286 0.0366 0.0050  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 19 43 264 0.0387 0.7147 0.3181 0.5506 3.9511 0.0462 0.0068 0.2336 0.0998 0.0071  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 20 43 291 0.0353 0.6464 0.3594 0.5520 4.2641 0.0402 0.0059 0.2237 0.1199 0.0082  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 21 42 269 0.0518 0.0061  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 22 44 299 0.0297 0.6013 0.3705 0.5367 3.8576 0.0372 0.0056 0.1893 0.0910 0.0058  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 23 44 268 0.0373 0.0072  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 24 44 279 0.0342 0.0078 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual and Group Mean Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  2(F) 37 44 246 0.0355 0.7056 0.3411 0.6314 4.5326 0.0402 0.0072 0.2124 0.0786 0.0111  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 38 44 256 0.0468 0.0097  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 39 43 244 0.0375 0.7383 0.4111 0.6227 4.2038 0.0505 0.0064 0.2181 0.0799 0.0076  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 40 45 274 0.0431  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 41 45 234 0.0502 0.0057  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 42 43 145 0.0528 1.2653 0.5530 1.0754 6.7891 0.0713 0.0117 0.3627 0.1917 0.0161  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 43 46 241 0.0503 0.0072  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 44 42 241 0.0433 0.0114  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 45 43 241 0.0447 0.7428 0.2732 0.5767 3.6239 0.0389 0.0063 0.2584 0.0939 0.0068  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 46 43 230 0.0395 0.8117 0.3726 0.6160 3.9367 0.0483 0.0071 0.2015 0.1187 0.0119  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 47 44 252 0.0480 0.0062  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 48 42 278 0.0221 0.0058 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual and Group Mean Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  3(F) 61 44 224 0.0446 0.0083  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 62 44 209 0.0349 0.0063  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 63 45 222 0.0364 0.0092  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 64 42 261 0.0395 0.0067  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 65 44 244 0.0408  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 66 43 233 0.0453 0.7517 0.3398 0.5739 4.0672 0.0384 0.0088 0.2937 0.1197 0.0081  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 67 43 218 0.0393 0.8533 0.3299 0.6908 4.4073 0.0462 0.0076 0.2182 0.0986 0.0106  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 68 43 257 0.0268 0.7142 0.3138 0.6839 4.7132 0.0508 0.0070 0.1979 0.0559 0.0082  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 69 46 265 0.0315 0.0060  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 70 42 231 0.0466 0.0065  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 71 43 247 0.0343 0.7266 0.3072 0.6462 4.2775 0.0417 0.0067 0.1836 0.0796 0.0072  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 72 43 226 0.0396 0.8102 0.3967 0.6053 4.3873 0.0555 0.0063 0.2150 0.1215 0.0120 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual and Group Mean Relative Organ Weights  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  4(F) 85 44 216 0.0471 0.0048  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 86 45 230 0.0386 0.7763 0.4379 0.5932 3.9196 0.0362 0.0063 0.2235 0.0614 0.0088  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 87 42 258 0.0342 0.0036  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 88 44 194 0.0341 0.0065  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 89 47 232 0.0080  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 90 45 234 0.0317 0.7999 0.2899 0.6474 4.9193 0.0358 0.0057 0.2289 0.0734 0.0089  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 91 45 242 0.0360 0.6811 0.3296 0.6294 4.6144 0.0330 0.0052 0.2197 0.0731 0.0083  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 92 43 248 0.0410 0.7517 0.2805 0.5664 4.0373 0.0419 0.0056 0.2313 0.0898 0.0080  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 93 45 229 0.0460 0.0076  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 94 46 241 0.0422 0.0073  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 95 44 216 0.0306 0.8344 0.3024 0.5945 4.3597 0.0512 0.0052 0.2586 0.1016 0.0114  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 96 46 258 0.0337 0.0060 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day  
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  1(M) 97 57 409 0.0149 0.4817 0.3691 0.2565 0.5100 3.0142 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 98 57 397 0.0140 0.4958 0.3812 0.2570 0.5508 2.8753 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 99 57 396 0.0211 0.5507 0.3964 0.2301 0.5137 3.1847 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 100 57 429 0.0166 0.5014 0.3353 0.2518 0.5092 3.1805 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 101 57 358 0.0190 0.5843 0.4431 0.2532 0.5871 2.8417 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  1(M) 97 57 0.1449 0.4359 0.1522 0.7881 0.1174 0.0059  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  98 57 0.1536 0.5101 0.1746 0.9553 0.1098 0.0059  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  99 57 0.1397 0.5269 0.1621 0.8746 0.0979 0.0054  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  100 57 0.1779 0.5512 0.1332 0.8620 0.1124 0.0053  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  101 57 0.1381 0.6484 0.1884 1.0367 0.0913 0.0060 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  Group Animal Relative Relative Relative Relative Relative Relative Rela (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pitu Number g % % % % % % %  4(M) 107 57 368 0.0179 0.5303 0.4330 0.3510 0.6332 3.3280 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 108 57 393 0.0228 0.5522 0.4049 0.2292 0.6213 2.7532 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 109 57 336 0.0136 0.5625 0.3865 0.2547 0.4755 3.0717 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 110 57 347 0.0199 0.5464 0.4461 0.2946 0.6509 3.2048 0.0 ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒ 111 57 405 0.0151 0.4865 0.3803 0.2621 0.7183 3.0694 0.0Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  (continued)  Group Animal Relative Relative Relative Relative Relative Relative  (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid  Number % % % % % %  4(M) 107 57 0.1367 0.6141 0.2095 0.8492 0.0686 0.0065  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  108 57 0.1398 0.6261 0.1565 0.9635 0.0872 0.0061  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  109 57 0.1040 0.5067 0.1400 0.9694 0.0949 0.0066  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  110 57 0.1701 0.4892 0.1637 1.0039 0.1174 0.0050  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ  111 57 0.1049 0.5529 0.1516 0.8382 0.0730 0.0051 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  1(F) 102 57 218 0.0383 0.7541 0.3594 0.5321 3.2397 0.0320 0.0070 0.1778 0.1234 0.0078  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 103 57 228 0.0354 0.7923 0.3115 0.5812 3.3638 0.0521 0.0075 0.2518 0.1334 0.0114  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 104 57 231 0.0391 0.8162 0.4091 0.6554 3.7288 0.0535 0.0086 0.2845 0.1368 0.0097  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 105 57 212 0.0396 0.8622 0.3194 0.6953 3.1999 0.0438 0.0083 0.2045 0.1492 0.0087  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 106 57 203 0.0299 0.8722 0.3566 0.6635 3.0859 0.0559 0.0067 0.2562 0.1111 0.0077 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report 

Appendix 25 (continued) Individual Relative Organ Weights Recovery Groups  Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative R (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid  Number g % % % % % % % % % %  4(F) 112 57 221 0.0347 0.7821 0.3300 0.5624 3.5306 0.0383 0.0094 0.1852 0.1517 0.0085  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 113 57 233 0.0402 0.7365 0.2859 0.5648 3.3743 0.0321 0.0085 0.1759 0.0996 0.0065  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 114 57 222 0.0377 0.8769 0.3270 0.6445 3.3679 0.0481 0.0073 0.2205 0.1294 0.0095  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 115 57 205 0.0459 0.8983 0.3351 0.6938 3.5383 0.0539 0.0080 0.2341 0.1308 0.0100  ƒƒƒƒƒƒ ƒƒƒƒ ƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒƒƒƒƒƒƒƒ ƒ 116 57 223 0.0296 0.9029 0.3204 0.6376 3.7151 0.0496 0.0116 0.2092 0.1572 0.0043 Dose Levels: Group 1 ƒ 0 (Control) Group 2 ƒ 30 mg/kg bw/day Group 3 ƒ 60 mg/kg bw/day Group 4 ƒ 120 mg/kg bw/day 
Harlan Study Number: 41204605 Report Page 444 

Appendix 26 Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 445 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 446 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 447 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 448 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 449 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 450 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 451 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 452 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 453 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 454 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 455 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 456 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 457 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 458 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 459 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 460 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 461 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 462 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 463 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 464 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 465 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 466 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 467 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 468 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 469 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 470 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 471 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 472 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 473 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 474 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 475 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 476 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 477 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 478 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 479 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 480 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 481 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 482 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 483 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 484 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 485 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 486 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 487 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 488 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 489 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 490 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 491 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 492 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 493 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 494 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 495 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 496 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 497 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 498 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 499 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 500 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 501 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 502 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 503 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 504 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 505 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 506 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 507 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 508 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 509 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 510 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 511 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 512 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 513 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 514 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 515 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 516 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 517 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 518 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 519 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 520 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 521 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 522 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 523 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 524 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 525 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 526 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 527 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 528 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 529 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 530 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 531 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 532 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 533 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 534 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 535 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 536 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 537 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 538 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 539 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 540 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 541 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 542 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 543 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 544 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 545 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 546 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 547 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 548 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 549 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 550 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 551 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 552 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 553 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 554 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 555 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 556 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 557 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 558 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 559 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 560 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 561 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 562 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 563 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 564 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 565 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 566 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 567 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 568 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 569 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 570 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 571 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 572 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 573 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 574 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 575 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 576 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 577 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 578 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 579 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 580 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 581 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 582 

Appendix 26 (continued) Histopathology Phase Report 
Harlan Study Number: 41204605 Report Page 583 

Appendix 27 Analytical Investigations 

1 MATERIALS AND METHODS 

1.1 Introduction 

The test item concentration in the test samples was determined by high performance liquid 

chromatography with UV detection (HPLC/UV) using an external standard technique. The test 

item gave a chromatographic profile consisting of a single peak. 

1.2 Test Item 

The test item described in the main part of this study was also used as the analytical standard. 

1.3 Analytical Procedure 

1.3.1 Preparation of Standard Solutions 

Stock solutions of test item in acetonitrile were prepared for external standard calibration. An 

aliquot, 100 mg (nominal) of test item was accurately weighed into a 100 mL volumetric flask 

and brought to volume with acetonitrile to yield a solution with a concentration of 1 mg/mL. 

Aliquots of this stock standard solution were used to prepare working standard solutions in 

acetonitrile with a concentration of 0.1 mg/mL. 

On each occasion standard solutions derived from two stock standard solutions were used for 

calculation. 

1.3.2 Analysis of Samples 

The formulations received were extracted with acetonitrile. An aliquot of test item formulation 

was accurately weighed into a volumetric flask and brought to volume with acetonitrile, this was 

then ultra-sonicated for 15 minutes and centrifuged at 4500 rpm for 10 minutes. Where 

necessary, sample solutions were further diluted with acetonitrile to achieve the working 

concentration. 

1.3.3 Preparation of Accuracy Samples 

Samples of Arachis Oil BP were accurately fortified with known amounts of test item equivalent 

to the lowest and highest anticipated dose concentrations. These samples were then prepared for 

analysis as the test samples in section 1.3.2. 
Harlan Study Number: 41204605 Report Page 584 

Appendix 27 (continued) Analytical Investigations 

1.3.4 Preparation of Linearity Standards 

A range of standard solutions were prepared in acetonitrile from a stock solution of 1 mg/mL by 

serial dilution covering the concentration range 0 to 0.1511 mg/mL. 

1.3.5 Instrumental Setup 

HPLC : Agilent Technologies 1200, incorporating autosampler 

 and workstation 

Column : Luna 5μ C8 (250 x 4.6 mm id) at 40 oC 

Flow-rate : 1 mL/min 

UV detector wavelength : 231 nm 

Injection volume : 10 L 

Retention time : ~ 12 mins 

1.4 Study Samples and Storage 

Representative samples were dispatched to the analytical laboratories internally (under ambient 

conditions) and stored at room temperature until analysis.
Harlan Study Number: 41204605 Report Page 585 

Appendix 27 (continued) Analytical Investigations 

2 RESULTS 

2.1 Validation of Analytical Method 

2.1.1 Specificity 

The control dose samples and a solvent blank did not significantly affect the chromatogram at 

the retention time of the test item whose area changed accordingly with known concentration. 

2.1.2 Linearity 

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

relationship between peak areas measured and working standard concentrations. The regression 

coefficient calculated was found to be 1.000. The linearity is presented in Figure 5. 

2.1.3 Accuracy 

The fortified samples of Arachis Oil BP were found to have a recovery value of ± 10% of the 

fortification. The results are presented in Table 24. 

2.1.4 Test Item Formulations 

The formulations investigated during the study were found to comprise test item in the range of 

98% to 104% and, thus, the required content limit of ±10% with reference to the nominal content 

was met. 

In addition, the test item was found to be stable in the formulations when kept for 16 days in a 

refrigerator (4 C) due to results which met the variation limit of 10% from the time-zero mean. 

In conclusion, the results indicate the accurate use of the test item and Arachis Oil BP as vehicle 

during this study. The formulations were found to be homogeneously prepared and sufficient 

formulation stability under storage conditions was approved. Results are presented in Table 25 

to Table 26. 

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

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

and, therefore, the absence of the test item in the vehicle control samples was confirmed. 

Examples of chromatograms are shown in Figure 6 to Figure 9.
Harlan Study Number: 41204605 Report Page 586 

Appendix 27 (continued) Analytical Investigations 

3 DISCUSSION 

The detection system was found to have acceptable linearity. The analytical procedure had 

acceptable recoveries of test item in the vehicle. The method of analysis was validated and 

proven to be suitable for use.
Harlan Study Number: 41204605 Report Page 587 

Appendix 27 (continued) Analytical Investigations 

TABLES 

Table 24 Results of Accuracy Analysis 

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

Fortification 

(mg/g) 

Concentration 

Found (mg/g) 

Recovered 

(%) 

Mean Recovery 

(%) 

3.51 3.50 100 99 

3.78 3.75 99 

249 256 103 103 

247 257 104 

Table 25 Results of Formulation Analysis 

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

Week Number Nominal Concentration 

(mg/mL) 

Concentration Found 

(mg/mL) (expressed as % of 

nominal) 

1 0 ND - 

7.5 7.51 100 

15 15.3 102 

30 30.8 103 

2 0 ND - 

7.5 7.63 102 

15 15.6 104 

30 31.3 104 

3 0 ND - 

7.5 7.34 98 

15 15.0 100 

30 30.2 101 

4 0 ND - 

7.5 7.37 98 

15 14.9 99 

30 30.3 101 

 

ND = none detected 

- = not applicable 
Harlan Study Number: 41204605 Report Page 588 

Appendix 27 (continued) Analytical Investigations 

Table 25 (continued) Results of Formulation Analysis 

5 0 ND - 

7.5 7.53 100 

15 15.1 101 

30 30.6 102 

6 0 ND - 

7.5 7.51 100 

15 15.2 101 

30 30.6 102 

7 0 ND - 

7.5 7.41 99 

15 15.2 101 

30 30.5 102 

Table 26 Results of Formulation Stability Analysis 

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

Nominal 

Concentration 

(mg/mL) 

Concentration Found 

Initially (mg/mL) 

Concentration Found After Storage for 16 

Days 

(mg/mL) (expressed as % of 

initial) 

3.75 3.88 3.86 99 

250 258 258 100 

Results of Formulation Homogeneity Analysis 

The test item formulations were deemed homogeneous by visual inspection.

 

ND = none detected 

- = not applicable 
Harlan Study Number: 41204605 Report Page 589 

Appendix 27 (continued) Analytical Investigations 

FIGURES 

Figure 5 Linearity 
Harlan Study Number: 41204605 Report Page 590 

Appendix 27 (continued) Analytical Investigations 

Figure 6 Chromatogram of Calibration Solution 

Minutes

0 2 4 6 8 10 12 14

mAU

0

50

100

150

200

250

300

mAU

0

50

100

150

200

250

300

11.725

VWD: Signal A, 231 nm

Standard B

Retention Time
Harlan Study Number: 41204605 Report Page 591 

Appendix 27 (continued) Analytical Investigations 

Figure 7 Chromatogram of Control Sample 

Minutes

0 2 4 6 8 10 12 14

mAU

0

50

100

150

200

250

300

mAU

0

50

100

150

200

250

300

VWD: Signal A, 231 nm

Control

Retention Time
Harlan Study Number: 41204605 Report Page 592 

Minutes

0 2 4 6 8 10 12 14

mAU

0

50

100

150

200

250

300

mAU

0

50

100

150

200

250

300

11.803

VWD: Signal A, 231 nm

7.5mg_ml

Retention Time

Appendix 27 (continued) Analytical Investigations 

Figure 8 Chromatogram of Test Sample (low level) 
Harlan Study Number: 41204605 Report Page 593 

Appendix 27 (continued) Analytical Investigations 

Figure 9 Chromatogram of Test Sample (high level) 

Minutes

0 2 4 6 8 10 12 14

mAU

0

50

100

150

200

250

300

mAU

0

50

100

150

200

250

300

11.730

VWD: Signal A, 231 nm

30mg_ml

Retention Time
Harlan Study Number: 41204605 Report Page 594 

Appendix 28 Study Plan 
Harlan Study Number: 41204605 Report Page 595 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 596 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 597 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 598 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 599 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 600 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 601 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 602 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 603 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 604 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 605 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 606 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 607 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 608 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 609 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 610 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 611 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 612 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 613 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 614 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 615 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 616 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 617 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 618 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 619 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 620 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 621 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 622 

Appendix 28 (continued) Study Plan 
Harlan Study Number: 41204605 Report Page 623 

Appendix 29 Histology Processing Phase Test Site Quality Assurance Statement 
Harlan Study Number: 41204605 Report Page 624 

Appendix 30 Histology Processing Phase Test Site Statement of Compliance 
Harlan Study Number: 41204605 Report Page 625 

Appendix 31 Histology Processing Phase Test Site Statement of GLP Compliance 
Harlan Study Number: 41204605 Report Page 626 

Appendix 32 Certificates of Analysis of Diet Used 
Harlan Study Number: 41204605 Report Page 627 

Appendix 32 (continued) Certificates of Analysis of Diet Used 
Harlan Study Number: 41204605 Report Page 628 

Appendix 32 (continued) Certificates of Analysis of Diet Used 
Harlan Study Number: 41204605 Report Page 629 

Appendix 32 (continued) Certificates of Analysis of Diet Used 
Harlan Study Number: 41204605 Report Page 630 

Appendix 33 Laboratory Methods 

UNITS 

HAEMATOLOGY 

Parameters measured on potassium EDTA - treated blood: 

Haemoglobin (Hb) - estimated by measurement of cyanmethaemoglobin using the 

Ac

.T5 Diff analyser 

g/dl 

Total erythrocyte count (RBC) - estimated by the Ac

.T5 Diff analyser 1012/l 

Haematocrit (Hct) - derived from MCV and RBC by the Ac

.T5 Diff analyser % 

Mean Corpuscular Haemoglobin (MCH) - derived from the Hb concentration and RBC by the 

Ac

.T5 Diff analyser 

pg 

Mean Corpuscular Volume (MCV) - estimated by the Ac

.T5 Diff analyser fl 

Mean Corpuscular Haemoglobin Concentration (MCHC) - derived from Hb concentration, RBC 

and MCV by the Ac

.T5 Diff analyser 

g/dl 

Total leucocyte count (WBC) - estimated by the Ac

.T5 Diff analyser 109/l 

Differential leucocyte count - determined by visual assessment of May-Grünwald-Giemsa 

stained blood film: 

109

/l 

 Neutrophils (Neut) 

 Lymphocytes (Lymph) 

 Monocytes (Mono) 

 Eosinophils (Eos) 

 Basophils (Bas) 

Platelet count (PLT) - estimated by the Ac

.T5 Diff analyser 109/l 

Reticulocyte count (Retics) - Methylene Blue stained blood film prepared but count not performed % 

Parameters measured on citrate-treated blood: 

Prothrombin time (CT) - estimated by ‘Innovin’ Dade Siemens reagent kit No. B4212-50 and Bio 

Mérieux Option 4 coagulometer 

secs 

Activated partial thromboplastin time (APTT) - estimated by ‘Actin FS’ Dade Siemens reagent kit 

No. B4218-20 and Bio Mérieux Option 4 coagulometer 

secs 
Harlan Study Number: 41204605 Report Page 631 

Appendix 33 (continued) Laboratory Methods 

UNITS 

BLOOD CHEMISTRY 

Parameters measured on lithium heparin treated blood: 

Urea - estimated by ILab reagent kit No. 00182554400 and 

ILab 600 auto-analyser 

mg/dl 

Glucose - estimated by ILab reagent kit No. 0018250840 and 

ILab 600 auto-analyser 

mg/dl 

Total protein (Tot.Prot.) - estimated by ILab reagent kit No. 0018251440 

and ILab 600 auto-analyser 

g/dl 

Albumin - estimated by ILab reagent kit No. 0018250040 and ILab 600 auto-analyser g/dl 

Albumin/Globulin (A/G) ratio = 

total protein albumin

albumin



Sodium (Na+) - estimated by ISE electrode No. 0018262400 and ILab 600 auto-analyser mmol/l 

Potassium (K+) - estimated by ISE electrode No. 0018263500 and ILab 600 auto-analyser mmol/l 

Chloride (Cl-) - estimated by ISE electrode No. 0018263600 and ILab 600 auto-analyser mmol/l 

Calcium (Ca++) - estimated by ILab reagent kit No. 0018250340 

and ILab 600 auto-analyser 

mmol/l 

Inorganic phosphorus (P) - estimated by ILab reagent kit No. 0018251240 

and ILab 600 auto-analyser 

mmol/l 

Aspartate aminotransferase (ASAT) - estimated by ILab reagent kit No. 0018257540 and ILab 

600 auto-analyser 

IU/l 

Alanine aminotransferase (ALAT) - estimated by ILab reagent kit No. 0018257440 

and ILab 600 auto-analyser 

IU/l 

Alkaline phosphatase (AP) - estimated by ILab reagent kit No. 0018259640 

and ILab 600 auto-analyser 

IU/l 

Creatinine (Creat) - estimated by ILab reagent kit No. 0018255540 

and ILab 600 auto-analyser 

mg/dl 

Total cholesterol (Chol) - estimated by ILab reagent kit No. 0018250540 

and ILab 600 auto-analyser 

mg/dl 

Total bilirubin (Bili) - estimated by ILab reagent kit No. 0018258340 

and ILab 600 auto-analyser 

mg/dl 

Bile acids (Bile) - estimated by Randox Kit No. B13863 and ILab 600 auto-analyser μmol/l 
Harlan Study Number: 41204605 Report Page 632 

Appendix 33 (continued) Laboratory Methods 

URINALYSIS 

Specific gravity – measured directly by Refractometer (Atago Co., Tokyo, Japan) 

pH, protein, glucose, ketones, urobilinogen, bilirubin and blood – estimated by Cobas, Roche Combur9 Test 

Strips 
Harlan Study Number: 41204605 Report Page 633 

Appendix 34 Normal Ranges for Reproductive Parameters in the Pregnant and Lactating 

Female Wistar HanTM:RccHanTM:WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. APPROXIMATE AGE: Fourteen to Nineteen weeks 

UPDATED: November 2011 

Range * No. of Animals 

MATING & GESTATION 

Pre-Coital Interval (Days) 1 - 5 209 

(2) (1)

Gestation Lengths (Days) 21.8 - 23.5 213 

(22.7) (0.4)

FOOD CONSUMPTIONS (g/rat/day) 

Gestation Days 0 - 7 15 - 23 208 

(19) (2)

Gestation Days 7 - 14 17 - 25 208 

(21) (2)

Gestation Days 14 - 20 19 - 27 206 

(23) (2)

Lactation Days 1 - 4 18 - 36 196 

(27) (4)

BODY WEIGHT CHANGE (g) 

Gestation Days 0 - 7 13 - 35 208 

(24) (5)

Gestation Days 7 - 14 16 - 36 180 

(26) (5)

Gestation Days 14 - 20 44 - 81 179 

(63) (9)

Lactation Days 1 - 4 -3 - 24 209 

(10) (7)

CORPORA LUTEA & 

IMPLANTATIONS 

Corpora Lutea (Number) 10 - 19 208 

(15) (2)

Implantations (Number) 9 - 18 208 

(13) (2)

Pre-Implantation loss (%) 0 - 27 200 

(8) (10)

Post-Implantation loss (%) 0 - 24 207 

 (7) (8) 

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively)
Harlan Study Number: 41204605 Report Page 634 

Appendix 35 Normal Ranges for Offspring Parameters in the Wistar HanTM: 

RccHanTM:WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. AGE: 0 – 4 Days 

UPDATED: November 2011 

OFFSPRING DATA Range * No. of Animals 

SURVIVAL INDICES (%) 

Live Birth Indices 97 - 100 214 

 (100) (1) 

Viability on Day 4 92 - 100 214 

 (99) (4) 

LITTER SIZE 

Litter size at birth 7 - 17 213 

 (12) (3) 

Litter size at Day 1 8 - 17 210 

 (12) (2) 

Litter size at Day 4 7 - 17 209 

 (12) (2) 

LITTER WEIGHT (g) 

Litter weight at Day 1 48.2 - 93.1 209 

 (70.6) (11.2) 

Litter weight at Day 4 71.0 - 131.7 208 

 (101.3) (15.2) 

SEX RATIOS 

% Males at Day 1 24 - 76 203 

 (50) (13) 

% Males at Day 4 24 - 76 203 

 (50) (13) 

OFFSPRING BODY WEIGHTS (g) 

Male body Weights at Day 1 4.8 - 7.0 208 

 (5.9) (0.5) 

Male body Weights at Day 4 6.6 - 10.8 209 

 (8.7) (1.0) 

Female body Weights at Day 1 4.6 - 6.7 206 

 (5.7) (0.5) 

Female body Weight at Day 4 6.5 - 10.1 200 

 (8.3) (0.9) 

DEVELOPMENTAL & REFLEX 

MARKERS 

Surface Righting (%) 61.9 - 100.0 213 

 (87.5) (12.8) 

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively)
Harlan Study Number: 41204605 Report Page 635 

Appendix 36 Normal Ranges for Haematological and Blood Chemical Values in the Wistar 

HanTM:RccHanTM:WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. 

UPDATED: November 2011 

APPROXIMATE AGE: Eighteen weeks 

PHASE: Prior to Termination 

HAEMATOLOGY 

Male Female 

Range* No. of 

Animals Range* No. of Animals 

Hb (g/dl) 15.4 - 17.2 70 11.7 - 14.7 71 

 (16.3) (0.4) (13.2) (0.8) 

RBC (1012/l) 8.52 - 9.54 62 6.25 - 7.70 67 

 (9.03) (0.25) (6.98) (0.36) 

Hct (%) 44.9 - 50.4 69 35.2 - 43.3 71 

 (47.6) (1.4) (39.2) (2.0) 

MCH (pg) 17.0 - 19.3 67 17.7 - 20.1 69 

 (18.1) (0.6) (18.9) (0.6) 

MCV (fl) 50.5 - 55.5 66 53.1 - 59.2 66 

 (53.0) (1.2) (56.1) (1.5) 

MCHC (g/dl) 32.2 - 35.9 70 32.1 - 35.0 69 

 (34.0) (0.9) (33.6) (0.7) 

WBC (109/l) 4.8 - 9.8 72 2.3 - 8.7 70 

 (7.3) (1.2) (5.5) (1.6) 

Neut (109/l) 0.29 - 1.26 62 0.45 - 2.84 67 

 (0.78) (0.24) (1.64) (0.60) 

Lymph (109/l) 3.97 - 8.70 73 1.49 - 6.28 71 

 (6.33) (1.18) (3.88) (1.20) 

Mono (109/l) 0.00 - 0.00 75 0.00 - 0.00 70 

 (0.00) (0.00) (0.00) (0.00) 

Eos (109/l) 0.00 - 0.13 65 0.00 - 0.02 66 

 (0.05) (0.04) (0.00) (0.01) 

Bas (109/l) 0.00 75 0.00 75 

 

CT (secs) 8.7 - 10.8 60 8.0 - 10.1 68 

 (9.8) (0.5) (9.1) (0.5) 

APTT (secs) 12.8 - 18.6 70 10.9 - 19.7 69 

 (15.7) (1.4) (15.3) (2.2) 

PLT (109/l) 464 - 660 68 570 - 1043 73 

 (562) (49) (807) (118) 

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41204605 Report Page 636 

Appendix 36 (continued) Normal Ranges for Haematological and Blood Chemical 

 Values in the Wistar HanTM:RccHanTM:WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. APPROXIMATE AGE: Eighteen weeks 

UPDATED: November 2011 PHASE: Prior to Termination 

BLOOD CHEMISTRY 

Male Female 

Range* No. of 

Animals Range* No. of Animals 

Urea (mg/dl) 35 - 58 71 37 - 63 67

(46) (6) (50) (7)

Glucose (mg/dl) 118 - 169 64 97 - 149 66

(143) (13) (123) (13)

Tot.Prot. (g/dl) 6.38 - 7.54 65 5.65 - 6.90 67

(6.96) (0.29) (6.27) (0.31)

Albumin (g/dl) 3.4 - 4.2 73 3.2 - 4.0 71

(3.8) (0.2) (3.6) (0.2)

A/G Ratio 1.04 - 1.35 66 1.11 - 1.65 72

(1.20) (0.08) (1.38) (0.14)

Na+ (mmol/l) 145 - 155 68 144 - 152 68

(150) (2) (148) (2)

K+ (mmol/l) 3.90 - 4.92 59 3.70 - 4.90 70

(4.41) (0.25) (4.30) (0.30)

Cl- (mmol/l) 98 - 107 72 100 - 108 74

(102) (2) (104) (2)

Ca++ (mmol/l) 2.32 - 3.00 70 2.34 - 2.85 67

(2.66) (0.17) (2.60) (0.13)

P (mmol/l) 1.2 - 2.7 70 0.2 - 1.7 75

(1.9) (0.4) (0.9) (0.4)

ASAT (IU/l) 56 - 91 65 55 - 92 64

(73) (9) (73) (9)

ALAT (IU/l) 36 - 67 61 31 - 87 66

(52) (8) (59) (14)

AP (IU/l) 80 - 289 68 84 - 240 42

(184) (52) (162) (39)

Creat (mg/dl) 0.56 - 0.87 71 0.59 - 0.81 65

(0.71) (0.08) (0.70) (0.06)

Chol (mg/dl) 56 - 102 68 51 - 78 58

(79) (12) (64) (7)

Bili (mg/dl) 0.00 - 0.16 65 0.00 - 0.11 75

(0.08) (0.04) (0.06) (0.03)

Bile Acids (μmol/l) 0.0 - 13.9 33 4.6 - 21.0 31

(6.9) (3.5) (12.8) (4.1)

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41204605 Report Page 637 

Appendix 37 Normal Ranges for Absolute and Body Weight-Relative Organ Weight 

Values in the Wistar HanTM:RccHanTM:WIST Strain Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. APPROXIMATE AGE: Eighteen to Twenty Weeks 

UPDATED: November 2011 

MALE ORGAN WEIGHTS 

ABSOLUTE WEIGHT (g) RELATIVE TO TERMINAL BODY 

WEIGHT (%) 

Range (g)* No. of 

Animals Range (%)* No. of Animals 

Adrenals 0.0420 - 0.0809 140 0.0104 - 0.0210 150 

 (0.0614) (0.0097) (0.0157) (0.0027) 

Brain 1.8435 - 2.1774 150 0.4340 - 0.5724 151 

 (2.0105) (0.0835) (0.5032) (0.0346) 

Epididymides 1.1566 - 1.6432 222 0.2896 - 0.4105 210 

 (1.3999) (0.1216) (0.3501) (0.0302) 

Heart 1.0013 - 1.4852 139 0.2562 - 0.3723 143 

 (1.2433) (0.1210) (0.3142) (0.0290) 

Kidneys 1.8425 - 2.7070 162 0.4519 - 0.6867 174 

 (2.2747) (0.2161) (0.5693) (0.0587) 

Liver 10.0646 - 15.2853 163 2.7634 - 3.5536 163 

 (12.6750) (1.3052) (3.1585) (0.1975) 

Pituitary 0.0074 - 0.0120 78 0.0020 - 0.0029 73

(0.0097) (0.0012) (0.0025) (0.0002) 

Prostate 0.3731 - 0.7418 85 0.0925 - 0.1918 89 

(0.5575) (0.0922) (0.1421) (0.0248) 

Seminal vesicles 1.5821 - 2.7187 87 0.3940 - 0.6642 84 

(2.1504) (0.2841) (0.5291) (0.0676) 

Spleen 0.5302 - 0.8397 150 0.1361 - 0.2054 151 

 (0.6850) (0.0774) (0.1708) (0.0173) 

Testes 3.0354 - 4.2231 224 0.7534 - 1.0558 213 

 (3.6292) (0.2969) (0.9046) (0.0756) 

Thymus 0.2866 - 0.6494 149 0.0749 - 0.1634 151 

 (0.4680) (0.0907) (0.1191) (0.0221) 

Thyroid/Parathyroid 0.0107 - 0.0286 159 0.0029 - 0.0070 157 

 (0.0196) (0.0045) (0.0049) (0.0010) 

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41204605 Report Page 638 

Appendix 37 (continued) Normal Ranges for Absolute and Body Weight-Relative Organ 

 Weight Values in the Wistar HanTM:RccHanTM: WIST Strain 

 Rat 

SUPPLIER: Harlan Laboratories U.K. Ltd. APPROXIMATE AGE: Eighteen Weeks 

UPDATED: November 2011 

LACTATING FEMALE ORGAN 

WEIGHTS 

ABSOLUTE WEIGHT (g) RELATIVE TO TERMINAL 

BODY WEIGHT (%) 

Range (g)* No. of 

Animals Range (%)* No. of 

Animals 

Adrenals 0.0654 - 0.1085 132 0.0259 - 0.0407 133 

 (0.0870) (0.0108) (0.0333) (0.0037) 

Brain 1.7469 - 1.9906 130 0.6378 - 0.7871 137 

 (1.8687) (0.0609) (0.7125) (0.0373) 

Heart 0.7786 - 1.1823 128 0.3065 - 0.4480 127 

 (0.9805) (0.1009) (0.3772) (0.0354) 

Kidneys 1.2887 - 1.7435 139 0.4980 - 0.6713 150 

 (1.5161) (0.1137) (0.5846) (0.0433) 

Liver 8.5995 - 12.9085 147 3.5429 - 4.6890 145 

 (10.7540) (1.0772) (4.1159) (0.2865) 

Ovaries 0.0822 - 0.1410 134 0.0336 - 0.0519 131 

 (0.1116) (0.0147) (0.0427) (0.0046) 

Pituitary 0.0109 - 0.0171 69 0.0042 - 0.0066 71 

 (0.0140) (0.0015) (0.0054) (0.0006) 

Spleen 0.4475 - 0.7611 124 0.1797 - 0.2755 121 

 (0.6043) (0.0784) (0.2276) (0.0240) 

Thymus 0.1497 - 0.3320 134 0.0607 - 0.1201 128 

 (0.2409) (0.0456) (0.0904) (0.0148) 

Thyroid/Parathyroid 0.0095 - 0.0226 136 0.0037 - 0.0085 134 

 (0.0160) (0.0033) (0.0061) (0.0012) 

Uterus 0.4968 - 0.8480 126 0.2005 - 0.3144 114 

 (0.6724) (0.0878) (0.2575) (0.0285) 

 

* Range = mean ± 2 standard deviations 

(values in brackets indicate group mean and standard deviation respectively) 
Harlan Study Number: 41204605 Report Page 639 

Appendix 38 Certificate of Analysis of the Test Item 
Harlan Study Number: 41204605 Report Page 640 

Appendix 39 Monitoring Authority Statement of GLP Compliance