harlan® 

REPORT e.. 

PMDA HYDROLYZED TO PMA: 

Oral (Gavage) Reproduction/Developmental Toxicity 

Screening Test in the Rat (OECD 421) 

Study Director: 

Test Facility: 

Sponsor: 

Harlan Study Number: 

Study Completion Date: 

JS Dunster 

Harlan Laboratories Ltd. 

Shardlow Business Park 

Shardlow 

Derbyshire 

DE722GD 

UK 

The American Chemistry Council 

PMDA Consortium 

700 2nd Street NE 

Washington DC 

20002 

UNITED STATES OF AMERICA 

41205015 

09 September 2013 

Page 1 of 443 
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STATEMENT OF NO DATA CONFIDENTIALITY 

No claim of confidentiality is made for any information contained in this study on the basis of its 

falling within the scope ofFIFRA §10 (d), (1), (A), (B) or (C). 

COMPANY The American Chemistry Council PMDA Consortium 

COMPANY AGENT 

DATE 

SIGNATURE 
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GLP COMPLIANCE STATEMENT 

This study meets the requirements for 40 CFR Part 160 of the US EPA. 

Submitter Date: ..................................... . 

Sponsor Date: ..................................... . 

Study Director ···~····················· Date . 0 9 SEP 2013 ...................................... . 

JS Dunster 
Harlan Study Number: 41205015 Report Page 6 

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CONTENTS 

STATEMENT OFNO DATA CONFIDENTIALITY ................................................................... 3 

GLP COMPLIANCE STATEMENT .............................................................................................. 5 

CONTENTS .................................................................................................................................... 7 

STUDY DIRECTOR STATEMENT OF GLP COMPLIANCE .................................................. 11 

QUALITY ASSURANCE STATEMENT .................................................................................... 13 

SIGNATURE OF MANAGEMENT ............................................................................................ 15 

SUMMARY .................................................................................................................................. 17 

Introduction .......................................................................................................................... 17 

Methods ............................................................................................................................. 17 

Results ................................................................................................................................ 17 

Adult Responses .................................................................................................................. 1 7 

Mortality .............................................................................................................................. 17 

Clinical Observations ........................................................................................................... 18 

Body Weight ........................................................................................................................ 18 

Food Consumption and Food Efficiency ............................................................................. 18 

Water Consumption ............................................................................................................. 18 

Reproductive Performance .................................................................................................. 18 

Mating ............................................................................................................................... 18 

Fertility ............................................................................................................................... 18 

Gestation Length .................................................................................................................. 18 

Litter Responses ................................................................................................................... 18 

Offspring Litter Size, Sex Ratio and Viability .................................................................... 18 

Offspring Growth and Development ................................................................................... 19 

Pathology ............................................................................................................................. 19 

Necropsy .............................................................................................................................. 19 

Organ Weights ..................................................................................................................... 19 

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 I Regulations ........................................................................................ 23 

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

2.1 Test Item ................................................................................................................ 24 

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 
Harlan Study Number: 41205015 Report Page 8 

4 

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

3 .3 .1 Chronological Sequence of Study ........................................................... 26 

3 .4 Observations .......................................................................................................... 27 

3.4.5.1 

3.4.5.2 

3.4.5.3 

3.4.5.4 

3.4.6.1 

3.4.6.2 

3.4.6.3 

3.4.1 

3.4.2 

3.4.3 

3.4.4 

3.4.5 

3.4.6 

3.4.7 

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

Body Weight ........................................................................................... 27 

Food Consumption .................................................................................. 27 

Water Consumption ................................................................................. 27 

Reproductive Performance ...................................................................... 27 

Mating ..................................................................................................... 28 

Pregnancy and Parturition ....................................................................... 28 

Litter Data ............................................................................................... 28 

Physical Development. ............................................................................ 28 

Pathology ................................................................................................. 29 

Necropsy .................................................................................................. 29 

Organ Weights ......................................................................................... 29 

Histopathology ........................................................................................ 29 

Evaluation of Data ................................................................................... 30 

3.4.7.1 Treatment of Data .................................................................................... 30 

3.4.7.2 Reproductive Indices ............................................................................... 31 

3.4.7.3 Litter Responses ...................................................................................... 32 

3.4.7.4 Statistical Analysis .................................................................................. 32 

RESULTS AND DISCUSSION .......................................................................................... 34 

4.1 Results ................................................................................................................... 34 

4.1.1.1 

4.1.1.2 

4.1.1.3 

4.1.1.4 

4.1.1.5 

4.1.2.1 

4.1.2.2 

4.1.2.3 

4.1.3.1 

4.1.3.2 

4.1.1 Adult Reponses ....................................................................................... 34 

Mortality .................................................................................................. 34 

Clinical Observations .............................................................................. 34 

Body Weight ........................................................................................... 34 

Food Consumption .................................................................................. 35 

Water Consumption ................................................................................. 35 

4.1.2 Reproductive Performance ...................................................................... 35 

Mating ..................................................................................................... 35 

Fertility .................................................................................................... 35 

Gestation Length ..................................................................................... 36 

4.1.3 Litter Responses ...................................................................................... 36 

Offspring Litter Size, Sex Ratio and Viability ........................................ 36 

Offspring Growth and Development ....................................................... 36 

4.1.4 Pathology ................................................................................................. 37 

4.1.4.1 Necropsy .................................................................................................. 37 

4.1.4.2 Organ Weights ......................................................................................... 38 

4.1.4.3 Histopathology ........................................................................................ 38 

4.2 Discussion ............................................................................................................. 38 

5 CONCLUSION ................................................................................................................... 40 

6 REFERENCES .................................................................................................................... 41 

TABULAR SUMMARY REPORT OF EFFECTS OF 

REPRODUCTION/DEVELOPMENT ......................................................................................... 42 

KEY TO TABLES AND APPENDICES ..................................................................................... 43 
Harlan Study Number: 41205015 Report Page 9 

TABLES ........................................................................................................................................ 45 

FIGURES ...................................................................................................................................... 73 

APPENDICES ............................................................................................................................... 79 

LIST OF TABLES 

Table 1 

Table 2 

Table 3 

Table 4 

Table 5 

Table 6 

Table 7 

Table 8 

Table 9 

Table 10 

Table 11 

Table 12 

Table 13 

Table 14 

Table 15 

Summary of Reproductive Performance - Groups Values ................................... .46 

Summary Incidence of Daily Clinical Observations ............................................ .4 7 

Group Mean Body Weight Values ....................................................................... .49 

Group Mean Body Weight Gains .......................................................................... 52 

Group Mean Food Consumptions .......................................................................... 55 

Food Efficiency ..................................................................................................... 58 

Summary Incidence of Mating Performance, Fertility and Gestation 

Lengths .................................................................................................................. 60 

Group Mean Litter Size and Litter Weights .......................................................... 61 

Group Mean Implantation Losses and Survival Indices Values ............................ 62 

Group Mean Sex Ratio Values .............................................................................. 63 

Summary Incidence of Clinical Signs for Offspring ............................................. 64 

Group Mean Reflexological Responses for Offspring .......................................... 65 

Summary Incidence of Offspring Necropsy Findings ........................................... 66 

Summary Incidence ofNecropsy Findings ........................................................... 67 

Group Mean Organ Weights with Corresponding Relative (% of 

Body Weight) Organ Weights ............................................................................... 69 

LIST OF FIGURES 

Figure 1 

Figure 2 

Figure 3 

Figure 4 

Group Mean Body Weights - Males ...................................................................... 74 

Group Mean Body Weights - Females .................................................................. 75 

Group Mean Food Consumption - Males .............................................................. 77 

Group Mean Food Consumption - Females .......................................................... 78 

LIST OF APPENDICES 

Appendix 1 

Appendix 2 

Appendix 3 

Appendix 4 

Appendix 5 

Appendix 6 

Appendix 7 

Individual Daily Clinical Observations ................................................................. 80 

Individual and Group Mean Body Weights ......................................................... 205 

Individual and Group Mean Body Weight Gains ................................................ 217 

Individual and Group Mean Food Consumption Values for Females 

Following Mating and During Lactation ............................................................. 229 

Individual Mating Performance, Fertility and Gestation Lengths ....................... 233 

Individual and Group Mean Litter Size and Litter Weights ................................ 23 7 

Individual and Group Mean Implantation Losses and Survival 

Indices .................................................................................................................. 241 
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Appendix 8 

Appendix 9 

Appendix 10 

Appendix 11 

Appendix 12 

Appendix 13 

Appendix 14 

Appendix 15 

Appendix 16 

Appendix 17 

Appendix 18 

Appendix 19 

Appendix 20 

Appendix21 

Appendix22 

Appendix 23 

Appendix24 

Appendix25 

Appendix 26 

Individual and Group Mean Sex Ratio Values for Offspring ............................. 245 

Individual Clinical Signs for Offspring ............................................................... 249 

Individual and Group Mean Reflexological Responses for 

Offspring ............................................................................................................. 253 

Individual Necropsy Findings for Offspring ....................................................... 257 

Individual Necropsy Findings ............................................................................. 261 

Individual and Group Mean Organ Weights ....................................................... 269 

Individual and Group Mean Relative Organ Weights ......................................... 277 

Histopathology Phase Report .............................................................................. 289 

Analytical Investigations ..................................................................................... 404 

Study Plan ............................................................................................................ 410 

Histology Processing Phase Test Site Quality Assurance Statement. ................. 430 

Histology Processing Phase Test Site Statement of Compliance ........................ 4 31 

Histology Processing Phase Test Site Statement of GLP 

Compliance .......................................................................................................... 432 

Certificates of Analysis of Diet Used .................................................................. 433 

Normal Ranges for Reproductive Parameters in the Pregnant and 

Lactating Female Wistar HanTM:RccHanTM:WIST Strain Rat.. .......................... 437 

Normal Ranges for Offspring Parameters in the Wistar HanTM: 

RccHanTM: WIST Strain Rat ............................................................................... 438 

Normal Ranges for Absolute and Body Weight-Relative Organ 

Weight Values in the Wistar HanTM:RccHanTM:WIST Strain Rat.. .................... 439 

Certificate of Analysis of the Test Item .............................................................. 441 

Monitoring Authority Statement of GLP Compliance ........................................ 443 
Harlan Study Number: 41205015 Report Page 11 

STUDY DIRECTOR STATEMENT OF GLP COMPLIANCE 

Harlan Laboratories Ltd., Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD, UK. 

Harlan Study Number: 

Study Title: 

41205015 

PMDA hydrolyzed to PMA: Oral (Gavage) Reproduction/ 

Developmental Toxicity Screening Test in the Rat (OECD 421) 

This study was performed in compliance with UK GLP standards (Schedule 1, Good Laboratory 

Practice Regulations (SI 1999/3106 as amended by SI 2004/0994)). These Regulations are in 

accordance with GLP standards published as OECD Principles on Good Laboratory Practice 

(revised 1997, ENV /MC/CHEM(98) 17); and are in accordance with, and implement, the 

requirements of Directives 2004/9/EC and 2004/10/EC. 

This report fully and accurately reflects the procedures used and data generated. There were no 

circumstances considered to have affected the integrity of the study or the validity of the data. 

Study Director: JS Dunster 

·--~~---··········· 

Date: 0 9 SEP 2013 

The signatures of the Principal Investigators are included in their respective statements of 

compliance which are attached in the appendices to this report. 
Harlan Study Number: 41205015 Report Page 12 

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QUALITY ASSURANCE STATEMENT 

Harlan Study Number: 41205015 

Study Title: PMDA hydrolyzed to PMA: Oral (Gavage) Reproduction/ 

Developmental Toxicity Screening Test in the Rat (OECD 421) 

The general facilities and activities are inspected at least once a year and the results are reported 

to the relevant responsible person and management. 

Study-related procedures conducted at the test facility were audited and inspected. The details of 

these audits and inspections are given below. 

Reported to the 

Dates and Types of QA Inspections relevant Study 

Director and Test 

Facility Management 

Date of Inspection Type of Inspection Phase Inspected Report Date 

15 February 2013 Study Plan NIA 15 February 2013 Verification 

18 February 2013 Study - based Test Item Preparation 18 February 2013 

27 February 2013 Parental Observations 27 February 2013 

04 March 2013 Chemical Analysis 04 March 2013 

06 March 2013 Pairing/Mating/Smearing 06 March 2013 

13 March 2013 Animal Preparation 13 March 2013 

13 March 2013 Dosing 13 March 2013 

02 April 2013 Litter Observations 02 April 2013 

03 April 2013 Post Mortem 03 April 2013 

12 June 2013 Report Audit NIA 12 June 2013 

This statement confirms that this report reflects the raw data and the procedures followed. 

Quality Assurance: 

······~·-' ....... A .. ?.-o~ 

Date: \ -'2. I q I , ~ 

The signatures of the Test Site Quality Assurance are included in their respective Quality Assurance Statements 

which are attached in the Appendices to this Report. 
Harlan Study Number: 41205015 Report Page 14 

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SIGNATURE OF MANAGEMENT 

Test Facility Management: E Wood 

Harlan Laboratories Ltd., Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD, UK. 

I have conducted a review of this study and agree with the scientific content of this report. 

Date: 0 9 SEP 2013 
Harlan Study Number: 41205015 Report Page 16 

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Harlan Study Number: 41205015 Report Page 17 

SUMMARY 

Introduction 

The study was performed to screen for potential adverse effects of the test item on reproduction, 

including offspring development, and provides an initial hazard assessment for effect on 

reproduction. The study is compatible with the requirements of the recommendations of the 

OECD Guidelines for Testing of Chemicals No. 421 "Reproduction/Developmental Toxicity 

Screening Test" (adopted 27 July 1995). 

Methods 

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

Wistar HanTM:RccHanTM:WIST strain rats, for up to eight weeks (including a two week prepairing phase, pairing, gestation and early lactation for females), at dose levels of 50, 250 and 

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

alone (Carboxymethyl cellulose (1%) & Tween 80 (0.1%)). 

Clinical signs, body weight change, food and water consumption were monitored during the 

study. 

Pairing of 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. 

Adult males were sacrificed on Day 43, followed by the sacrifice of all females and offspring on 

Day 5 of lactation. 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 reproductive tissues was performed. 

Results 

Adult Responses 

Mortality 

There were no unscheduled deaths. 
Harlan Study Number: 41205015 Report Page 18 

Clinical Observations 

No clinically observable signs of toxicity were detected. 

Body Weight 

A slight reduction in body weight gains was evident for males treated with 750 mg/kg bw/day. 

Females treated with 250 and 750 mg/kg bw/day showed a reduction in body weight gains 

during the lactation phase of the study; however statistical significance was not achieved. 

Food Consumption and Food Efficiency 

No adverse effects on food consumption were detected. 

Water Consumption 

No adverse effect on water consumption was detected. 

Reproductive Performance 

Mating 

No treatment-related effects were detected in mating performance. 

Fertility 

No treatment-related effects on fertility were detected. 

Gestation Length 

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 

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 
Harlan Study Number: 41205015 Report Page 19 

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. 

Pathology 

Necropsy 

No toxicologically important macroscopic abnormalities were detected. 

Organ Weights 

No toxicologically significant organ weight changes were detected. 

Histopathology 

Histopathological examinations did not reveal any treatment-related effects. 

Conclusion 

The oral administration of PMDA hydrolyzed to PMA to rats by gavage, at dose levels of 750, 

250 and 50 mg/kg bw/day, did not result in any toxicologically significant adverse effects at any 

of the dose levels examined. The 'No Observed Adverse Effect Level' (NOAEL) for systemic 

toxicity was therefore considered to be 750 mg/kg bw/day. 

There were no treatment-related effects on reproductive performance or offspring development. 

The 'No Observed Effect Level' (NOEL) for reproductive toxicity was therefore considered to 

be 750 mg/kg bw/day. 
Harlan Study Number: 41205015 Report Page20 

GENERAL INFORMATION 

Schedule 

Experimental Starting Date: 

Experimental Completion Date: 

Animal Welfare 

18 February 2013 

23 August 2013 

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: 

Study Phase: 

Test Site: 

Principal Investigator: 

Test Site Quality Assurance: 

J Riley 

Harlan Laboratories Ltd. 

Histology Processing 

Propath UK Limited 

Willow Court 

Netherwood Road 

Hereford 

HR26JU 

UK 

NFower 

A Fox 

AF International Consultancy 

4, The Maltsters, The Old Grain Barn, George Lane, 

Buckden, Cambridgeshire, PE 19 5XL, UK 
Harlan Study Number: 41205015 

Study Phase: 

Test Site: 

Principal Investigator: 

Test Site Quality Assurance: 

Additional Responsibilities 

Analytical Investigations: 

Animal Health: 

Deviations from Study Plan 

Deviation No.1 (25 February 2013) 

Page 9 Clinical Observations 

Report 

Histopathology Examination 

Peter Millar Associates Ltd. 

3 Queen Charlotte Lane 

Edinburgh 

Scotland 

EH66AY 

P Millar 

J Lawrence 

Peter Millar Associates Ltd. 

P Watson 

Harlan Laboratories Ltd., Shardlow, UK 

P Highton 

Harlan Laboratories Ltd., Shardlow, UK 

Page 21 

On the morning of 20th February 2013 (Day 1 of treatment), there was a fire on the site of the 

Test Facility. While the animal facility housing the study was unaffected, access to the site was 

restricted for much of the morning, resulting in technical procedures being performed later than 

normal. The delay in dosing for this study was such, that the scheduled 5 hour and post dose 

observations could not be performed within the normal working day. It was agreed with the 

Study Director that on this occasion these observations were performed earlier (approximately 4 

hours post dose) and at the same time that final morbidity checks were performed. 

Deviation No.2 (12 June 2013) 

Page 4 Animal Husbandry 

Environment: 
Harlan Study Number: 41205015 Report Page 22 

On a number of occasions during the study, the relative humidity values were outside the ranges 

specified in the study plan. 

These deviations to the study plan did not affect the purpose or integrity of the study. 

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 will be retained in the Harlan Laboratories Ltd, Shardlow, UK archives for ten 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: 41205015 Report Page23 

1 INTRODUCTION AND PURPOSE 

The study was performed according to the study plan presented in Appendix 17 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 50, 250 and 750 mg/kg bw/day. A control group was dosed 

with vehicle alone (Carboxymethyl cellulose (1%) & Tween 80 (0.1%)). 

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

Ltd., Project Number 41205014). 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 humans. 

The study was performed between 18 February 2013 and 23 August 2013. The in-life phase of 

the study was conducted between 20 February 2013 (first day of treatment) and 06 April 2013 

(final day of necropsy). 

1.1 Guidelines I Regulations 

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

Testing of Chemicals, No.421: "Reproduction/Developmental Toxicity Screening Test" (adopted 

27 July 1995). 
Harlan Study Number: 41205015 Report 

2 TEST ITEM 

2.1 Test Item 

Information as provided by the Sponsor. 

Identification 

Description 

Chemical Name 

Purity 

Batch Number 

Label 

Date Received 

Storage Conditions 

Expiry Date 

No correction for purity was made. 

PMDA 

White powder 

pyromellitic dianhydride 

99.94% 

NJC1207029 

PMDA (CA) Batch No NJC1207029 Quality lkg 

21 August 2012 

room temperature in the dark, under nitrogen 

18 January 2014 

Page 24 

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

responsibility of the Sponsor. PMA (pyromellitic acid) is the resultant test item used for testing. 

A Certificate of Analysis of Test Item is included as Appendix 25. 

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 

seven days during which time their health status was assessed. A total of eighty animals (forty 

males and forty females) were accepted into the study. At the start of treatment the males 

weighed 298 to 350g, the females weighed 198 to 222g, and were approximately twelve weeks 

old. 

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

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

pairing phase, the animals were transferred to polypropylene grid floor cages suspended over 

trays lined with absorbent paper on a one male: one female basis. 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. 
Harlan Study Number: 41205015 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 21. 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 least one day prior to dosing at the 

appropriate concentrations as a suspension in Carboxymethyl cellulose (1 %) & Tween 80 

(0.1 % ). This was undertaken to ensure hydrolysis to produce PMA. The pH of each formulation 

was checked 1 hour after formulation. The stability and homogeneity of the test item 

formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical 

Services (Harlan Laboratories Ltd., Study Number 41205014). Results from the previous study 

show the formulations to be stable for at least twenty-one days. Formulations were therefore 

prepared every two weeks and stored at approximately +4 °C (range: +2 to+ 10°C) in the dark. 

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

hydrolyzed to PMA at Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The 

method used for analysis of formulations and the results obtained are given in Appendix 16. The 
Harlan Study Number: 41205015 Report Page 26 

results indicate that the prepared formulations were within acceptable ranges for the purpose of 

this study. 

3.3 Procedure 

Animals were allocated to treatment groups as follows: 

Dose Level Treatment Concentration Animal Numbers 

Treatment Group (mg/kg bw/day) Volume (mL/kg) (mg/mL) Male Female 

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

Low 50 IO 5 12 (25-36) 12 (37-48) 

Intermediate 250 IO 25 12 (49-60) 12 (61-72) 

High 750 10 75 12 (73-84) 12 (85-96) 

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 10 mL/kg 

of Carboxymethyl cellulose (1 % ) & Tween 80 (0.1 % ). 

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 

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. 

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

maximum of fourteen days. 

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

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

1v. 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. 

v. The male dose groups were killed and examined macroscopically on Day 43. 

v1. At Day 5 post partum, all females and surviving offspring were killed and examined 

macroscopically. 
Harlan Study Number: 41205015 Report Page 27 

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, soon after dosing, and one hour 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). All observations were recorded. 

3.4.2 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 postpartum. 

Animals were also weighed at termination. 

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

Appendix 22. 

3.4.3 Food Consumption 

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

until pairing. 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 during the 

lactation period (Days 1-4). 

Weekly food efficiency (body weight gain/food intake) was calculated retrospectively for males 

and for females during the pre-pairing phase. Due to offspring growth and milk production for 

lactation, food efficiency for females could not be accurately calculated for females during 

gestation and lactation. 

Normal range data for pregnant and lactating females are presented in Appendix 22. 

3.4.4 Water Consumption 

Water intake was observed daily by visual inspection of water bottles for any overt changes. 

3.4.5 Reproductive Performance 

Normal range data for reproductive parameters and offspring are presented in Appendix 22 and 

Appendix 23. 
Harlan Study Number: 41205015 Report Page 28 

3.4.5.1 Mating 

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 O of gestation) and the males were 

subsequently returned to their original holding cages. Mated females were housed individually 

during the period of gestation and lactation. 

3.4.5.2 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: 

1. Date of pairing 

11. Date of mating 

m. Date and time of observed start of parturition 

1v. Date and time of observed completion of parturition 

3.4.5.3 Litter Data 

On completion of parturition (Day O postpartum), 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: 

1. Number of offspring born 

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

m. Sex of offspring on Days 1 and 4 postpartum 

1v. Clinical condition of offspring from birth to Day 5 postpartum 

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

retrospectively from this data) 

3.4.5.4 Physical Development 

All live offspring were assessed for surface righting reflex on Day 1 postpartum. 
Harlan Study Number: 41205015 Report Page 29 

3.4.6 Pathology 

3.4.6.1 Necropsy 

Adult males were killed by intravenous overdose of sodium pentobarbitone followed by 

exsanguination on Day 43. Adult females were killed by intravenous overdose of sodium 

pentobarbitone 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. 

For all 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. 

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. 

3.4.6.2 Organ Weights 

The following organs were removed from terminal kill adult animals, dissected free from fat and 

weighed: 

Adrenals 

Brain 

Epididymides 

Heart 

Kidneys 

Liver 

Ovaries 

Pituitary (post-fixation) 

Prostate 

Seminal vesicles 

Spleen 

Testes 

Thymus 

Thyroid/parathyroid (post fixation) 

Normal ranges for organ weights are given in Appendix 24. 

3.4.6.3 Histopathology 

Samples of the following tissues were preserved from all animals from each dose group, in 

buffered 10% formalin, except where stated: 

Coagulating gland 

Epididymides + 

Ovaries 

Mammary gland 

Prostate 

Seminal vesicles 

Testes+ 

Uterus/Cervix 

+ Preserved in Bouin's fluid and then transferred to Industrial Methylated Spirits (IMS) approximately 

48 hours later 
Harlan Study Number: 41205015 Report Page 30 

Pituitary Vagina 

Gross Lesions 

Samples of the following tissues from five males and five females from each dose group were 

preserved in buffered 10% formalin: 

Adrenals 

Brain (including cerebrum, cerebellum and pons) 

Caecum 

Colon 

Duodenum 

Heart 

Ileum 

Jejenum 

Kidneys 

Liver 

Lungs 

Lymph nodes (mandibular and 

mesenteric) 

Rectum 

Sciatic nerve 

Spinal cord ( cervical, mid-thoracic and 

lumbar) 

Spleen 

Stomach 

Thymus 

Trachea 

Urinary bladder 

Rectum 

All tissues were despatched to the histology processing Test Site (Propath UK Ltd) for 

processing (Principal Investigator: N Fower). The tissues from control and 750 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. In 

addition, sections of testes from all control and 750 mg/kg bw/day males were also stained with 

Periodic Acid-Schiff (PAS) stain and examined. 

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

Associates Ltd.). A complete histopathology phase report is presented in Appendix 15. 

3.4. 7 Evaluation of Data 

3.4.7.1 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. 
Harlan Study Number: 41205015 Report Page 31 

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. 

3.4.7.2 Reproductive Indices 

Mating Performance and Fertility 

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

the parental generation: 

1. Pre-coital Interval 

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

evidence of mating. 

11. Fertility Indices 

For each group the following were calculated: 

M . I d (o/) Number of animals mated x atmg n ex 100 ;ro = 

Number of animals paired 

Number of pregnant females x 100 Pregnancy Index (%) = 

Number of animals mated 

Gestation and Parturition Data 

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

parturition period of the parental generation: 

1. Gestation Length 

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

and the start of parturition. 

11. Parturition Index 

The following was calculated for each group: 

Number of females delivering live offspring Parturition Index (%) = x 100 

Number of pregnant females 
Harlan Study Number: 41205015 Report Page 32 

3.4.7.3 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). 

1. Implantation Losses(%) 

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

each female/litter as follows: 

o/ . 1 . 1 Number of corpora lutea - Number of implantation sites 100 ,o pre-nnp antat10n oss = x 

Number of corpora lutea 

. 1 . 1 Number of implantation sites - Total number of offspring born % 100 post-nnp antat1on oss - x 

Number of implantation sites 

11. Live Birth and Viability Indices 

The following indices were calculated for each litter as follows: 

Number of offspring alive on Day 1 x Live Birth 100 Index (%) = 

Number of offspring born 

Number of offspring alive on Day 4 x Viability 100 Index(%) = --------"'------"-----'--

Number of offspring alive on Day 1 

111. Sex Ratio(% males) 

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

following formula: 

Number of male offspring x 100 

Total number of offspring 

3.4.7.4 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: 

Body Weight, Body Weight Change, Food Consumption during gestation and lactation, PreCoital Interval, Gestation Length, Litter Size, Litter Weight, Sex Ratio, Corpora Lutea, 

Implantation Sites, Implantation Losses, Viability Indices, Offspring Body Weight, Offspring 
Harlan Study Number: 41205015 Report Page 33 

Body Weight Change, Offspring Surface Righting, Absolute Organ Weights, Body WeightRelative Organ Weights. 

Data were analysed using the decision tree from the Provantis TM 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 ANOV A, or if required, ANCOV A 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 (p2'.: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. 

Probability values (p) are presented as follows: 

p<0.01 ** 

p<0.05 * 

p~0.05 (not significant) 
Harlan Study Number: 41205015 Report Page 34 

4 RESULTS AND DISCUSSION 

4.1 Results 

4.1.1 Adult Reponses 

4.1.1.1 Mortality 

There were no unscheduled deaths 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. 

No clinically observable signs of toxicity were detected during the study. Clinical signs were 

confined to the presence of post-dose increased salivation for ten male and ten female animals of 

either sex treated with 750 mg/kg bw/day. Isolated instances of noisy respiration were noted for 

one male treated with 750 mg/kg bw/day on Days 38 and 39, and for one male treated with 

250 mg/kg bw/day on Day 29 only. There were no further clinical observations recorded. 

4.1.1.3 Body Weight 

Group mean weekly body weights and standard deviations are given in Table 3 and are presented 

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

deviations are given in Table 4 (statistically significant differences are indicated). Individual 

data are given in Appendix 2 and Appendix 3. 

A slight reduction in body weight gains was evident for males treated with 750 mg/kg bw/day 

during the first two weeks of treatment, with statistically significant differences detected during 

the first week in comparison to control values (p<0.05). This resulted in a lower overall body 

weight gain for the study period at 750 mg/kg bw/day in comparison to the concurrent control 

group. 

Reduced body weight gains were also noted for females treated with 750 mg/kg bw/day during 

the first two weeks of treatment, although statistical significance was only achieved during Week 

1 when compared to controls. There was no difference in body weight change detected during 

the gestation phase for treated females in comparison to controls, however, females treated at all 

· dose levels showed a reduction in body weight gains during the lactation phase of the study in 

comparison to the control group, although statistical significance was not achieved. 

There were no further differences in body weight change considered to be a result of treatment 

with the test item. 
Harlan Study Number: 41205015 Report Page 35 

Females treated with 50 mg/kg bw/day showed a statistically significant increase in cumulative 

body weight change from Days O to 20 when compared to controls. The significance achieved 

was minimal and in the absence of a dose-related response, was considered to have arisen 

incidentally. 

4.1.1.4 Food Consumption 

Group mean food consumptions are given in Table 5 and are presented graphically in Figure 3 

and Figure 4. Individual values for females during gestation and lactation are presented in 

Appendix 3. Food efficiency for males and for females during the pre-mating phase is given in 

Table 6. 

No adverse effects on dietary intake were detected for males during the treatment period or for 

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

4.1.1.5 Water Consumption 

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

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 7. Individual data are given in Appendix 5. 

No treatment-related effects were detected in mating performance. The majority of animals 

mated within the first four 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 7, 8 and 9. Individual data are given in Appendices 5 

to 7. 

No treatment-related effects on fertility were detected for treated animals when compared to 

controls. 

There were five non-pregnant females in this study ( one control female, three females treated 

with 50 mg/kg bw/day and one female treated with 750 mg/kg bw/day). These failures to 

reproduce were not observed in a dose-dependent manner and were therefore considered to be 

unrelated to treatment. 
Harlan Study Number: 41205015 Report Page 36 

4.1.2.3 Gestation Length 

A summary of gestation lengths is presented in Table 7. Individual lengths are given m 

Appendix 5. 

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

groups. Gestation lengths of 22 to 23 Yz days were recorded for all pregnant females. 

4.1.3 Litter Responses 

In total, eleven females from control, nine females from the 50 mg/kg bw/day dose group, twelve 

females from the 250 mg/kg bw/day, and eleven females treated with 750 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 8 to 10 (statistically significant differences are 

indicated). Individual data are given in Appendices 6 to 8. 

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

compared to those from the controls. Statistical analysis of the data did not reveal any significant 

intergroup differences. 

No significant differences in the number of corpora lutea or implantation sites were noted for 

treated females when compared to controls. 

There were no toxicologically significant differences in the percentages of pre- and postimplantation loss for treated females were comparable to controls. Statistical analysis of the data 

revealed a statistically significant reduction in post-implantation loss for females treated with 

50 mg/kg bw/day when compared to controls. The significance was minimal, and would suggest 

increased intra-uterine survival for the low dose. In the absence of a dose-related response, the 

lower implantation losses were considered to have arisen incidentally. 

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 8, 11 and 

12. Individual values and observations are given in Appendices 6, 9 and 10. 

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. 
Harlan Study Number: 41205015 Report Page 37 

No toxicologically important differences in surface righting were detected for litters from treated 

groups when compared to control litters. Statistical analysis did not reveal any significant 

intergroup differences. 

No treatment-related clinical signs were observed. The clinical signs observed were those 

occasionally observed in reproductive studies of this type and did not represent toxicity. 

4.1.4 Pathology 

4.1.4.1 Necropsy 

A summary incidence of necropsy findings for offspring and adults is given in Tables 13 and 14. 

Individual data are given in Appendices 11 and 12. 

Offspring 

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

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

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

Adults 

There were no toxicologically significant macroscopic abnormalities detected. 

One control male and one low dose male showed small epididymides and small and flaccid 

testes. These animals failed to produce a pregnancy in their female partners. Such findings are 

occasionally observed in reproductive toxicity studies of this type and are considered to be 

unrelated to treatment with the test item. 

One control male showed reddened lungs. Reddened lungs were also apparent in one female 

treated with 750 mg/kg bw/day. These findings were considered to be a low incidence finding 

occasionally observed in rats of the age and strain employed and unrelated to treatment with the 

test item. 

A fibrous mass approximately 7mm3 was presented on the median lobe of the lungs on one male 

treated with 50 mg/kg bw/day. Histopathological examinations confirmed this to be the pancreas 

with moderate infarction. In isolation, this finding was considered to have arisen incidentally and 

was unrelated to treatment with the test item. 

Increased pelvic space of the kidneys was evident for one female treated with 50 mg/kg bw/day. 

One male treated with 250 mg/kg bw/day also showed increased pelvic space and a fluid filled 

left kidney. Such findings are occasionally observed in the strain of rats employed and 

considered to be unrelated to treatment. 
Harlan Study Number: 41205015 Report Page 38 

4.1.4.2 Organ Weights 

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

and control group animals are presented in Table 15 (statistically significant differences are 

indicated). Individual data are given in Appendix 13 and Appendix 14. 

Males treated with 750 mg/kg bw/day showed an increase in thyroid/parathyroid weights when 

compared to controls, with a number of absolute and relative values outside of the normally 

expected ranges. 

Females treated with 750 mg/kg bw/day showed an increase in absolute and relative liver 

weights when compared to controls (p<0.05) with one higher than expected absolute and relative 

value. 

There were no further organ weight changes which were considered to be related to treatment 

with the test item. 

Males treated with 750 mg/kg bw/day showed a statistically significant reduction in seminal 

vesicle weight when compared to controls (p<0.01). Although there was one lower than expected 

absolute seminal vesicle weight detected in the high dose, there were three control values which 

were higher than the normally expected ranges. The reduction in seminal vesicle weights was 

therefore considered to be attributable to the higher control weights observed, and did not 

represent an effect of treatment (absolute weight ranges l.5821-2.7187g; relative weight ranges 

0.3940 - 0.6642%). 

Males treated with 750 and 250 mg/kg bw/day showed an increase in kidney weights, both 

absolute and relative to terminal body weights compared to controls. All individual values were 

within the normally expected ranges, and as such, the minimal increase in each case was 

considered to have arisen incidentally. 

4.1.4.3 Histopathology 

A complete histopathology phase report is presented in Appendix 15. 

No treatment-related microscopic changes were detected in the tissues examined. 

All of the histopathological findings encountered were considered to have arisen spontaneously 

or at post mortem. 

4.2 Discussion 

The oral administration of PMDA hydrolyzed to PMA 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 50, 250 and 750 mg/kg bw/day resulted in treatment-related changes at all dose levels 

assessed. 
Harlan Study Number: 41205015 Report Page 39 

Increased salivation was observed following dosing for animals of either sex treated with 

750 mg/kg bw/day. Isolated instances of noisy respiration were also evident at 750 mg/kg 

bw/day and for one male treated with 250 mg/kg bw/day on Day 29. These findings are 

occasionally observed following the oral administration of a slightly unpalatable or irritant test 

item formulation. In the absence of any effects to suggest irritancy, these findings were 

considered not to represent systemic toxicity. 

A reduction in body weight gains, was evident for animals of either sex treated with 750 mg/kg 

bw/day during the first two weeks of treatment when compared to controls. Females treated at 

all dose levels showed a reduction in body weight gain during the first four days of the lactation 

period, although statistical analysis did not show any significant intergroup differences when 

compared to the control group. 

Post mortem examinations revealed an increase in thyroid/parathyroid weights for males treated 

with 750 mg/kg bw/day when compared to controls, with a number of individual values outside 

of the normally expected ranges. Lactating females treated with 750 mg/kg bw/day showed an 

increase in liver weights when compared to controls, with one high value detected for both the 

absolute and relative values. In the absence of any treatment-related histopathological correlates, 

the toxicity of these findings was considered to be minimal. 

In the absence of any adverse effects detected at any of the dose levels employed, the 'No 

Observed Adverse Effect Level' (NOAEL) was considered to be 750 mg/kg bw/day. 

No treatment-related effects on reproductive performance or offspring development were 

detected. The 'No Observed Effect Level' (NOEL) for reproductive toxicity was therefore 

established at 750 mg/kg bw/day. 
Harlan Study Number: 41205015 Report Page 40 

5 CONCLUSION 

The oral administration of PMDA hydrolyzed to PMA to rats by gavage, at dose levels of 750, 

250 and 50 mg/kg bw/day, did not result in any toxicologically significant adverse effects at any 

of the dose levels examined. The 'No Observed Adverse Effect Level' (NOAEL) for systemic 

toxicity was therefore considered to be 750 mg/kg bw/day. 

There were no treatment-related effects on reproductive performance or offspring development. 

The 'No Observed Effect Level' (NOEL) for reproductive toxicity was therefore considered to 

be 750 mg/kg bw/day. 
Harlan Study Number: 41205015 Report Page 41 

6 REFERENCES 

SALEWSKI, E. (1964) Farbemethode zum makroskopischen Nachweis von Implantationsstellen 

am Uterus der Ratte. Arch Exp Path Pharmacol. Naunyn- Schmiedebergs, 247 p. 367. 
Harlan Study Number: 41205015 Report 

TABULAR SUMMARY REPORT OF EFFECTS OF 

REPRODUCTION/DEVELOPMENT 

Observations 

Dose Level (mg/kg bw/day) 

Paired animals 

Females showing evidence of copulation 

Pregnant females 

Conception Days 1-5 

Conception Days 12-13 

Gestation = 22 Days 

Gestation = 22 Yz Days 

Gestation = 23 Days 

Gestation = 23 Yz Days 

Dams with live young born 

Dams with live young at Day 4 postpartum 

Corpora lutea/dam 

Implants/dam 

Live offspring/dam Day 1 postpartum 

Live offspring/dam at Day 4 postpartum 

Sex ratio: % males Day 1 postpartum 

Sex ratio: % males at Day 4 postpartum 

Litter weight (g) at Day 1 postpartum 

Litter weight (g) at Day 4 postpartum 

Male offspring weight (g) at Day 1 postpartum 

Male offspring weight (g) at Day 4 postpartum 

Female offspring weight (g) at Day 1 postpartum 

Female offspring weight (g) at Day 4 postpartum 

LOSS OF OFFSPRING/DAM 

Pre-implantation (corpora lutea minus implantations) 

0 

1 

2 

3 

4 

Pre-natal (implantations minus live births) 

0 

1 

2 

3 

5 

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

0 

1 

2 

3 

n =Number 

x =Mean 

0 (Control) 

n 12 

n 12 

n 11 

n 11 

n 0 

n 0 

n 6 

n 2 

n 3 

n 11 

n 11 

x 14.0 

x 13.1 

x 11.7 

x 11.5 

x 50.8 

x 52.1 

x 66.82 

x 93.14 

x 5.90 

x 8.30 

x 5.59 

x 8.14 

n 6 

n 3 

n 0 

n 1 

n 1 

n 2 

n 5 

n 3 

n 1 

n 0 

n 7 

n 4 

n 0 

n 0 

50 250 

12 12 

12 12 

9 12 

9 12 

0 0 

0 1 

7 8 

0 1 

2 2 

9 12 

9 12 

13.6 14.0 

13.0 13.1 

12.7 11.1 

12.2 11.0 

49.6 48.2 

50.2 48.7 

72.54 66.44 

98.14 93.68 

5.87 6.18 

8.14 8.83 

5.60 5.84 

7.77 8.40 

5 4 

3 6 

1 1 

0 1 

0 0 

6 3 

3 1 

0 5 

0 1 

0 2 

7 11 

1 1 

0 0 

1 0 

Page 42 

750 

12 

12 

11 

9 

2 

0 

9 

0 

2 

11 

11 

14.1 

13.5 

12.9 

12.7 

46.3 

47.1 

71.34 

96.67 

5.69 

7.73 

5.41 

7.53 

6 

3 

2 

0 

0 

7 

3 

0 

1 

0 

9 

2 

0 

0 
Harlan Study Number: 41205015 Report 

KEY TO TABLES AND APPENDICES 

M 

F 

S.D. 

N 

1+ 

2+ 

3+ 

H 

PT 

PV 

p 

NP 

NIA 

u 

.... 

% Food Efficiency 

Statistical Footnotes: 

* 

** 

*** 

n 

Male 

Female 

Standard deviation 

Number of animals/litters 

No data available 

Occasional spermatozoa present 

Continuous few spermatozoa in all fields 

Many spermatozoa in all fields 

Haemorrhage 

Plug detected on tray liner 

Vaginal plug 

Pregnant 

Not pregnant (values excluded from mean and sd) 

Not applicable 

Sex not determined; prior to within litter identification 

Prior to within litter identification 

( Group mean bodyweight gain (g/rat/period) ) xlOO 

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

Significantly different from control group p<0.05 

Significantly different from control group p<0.01 

Significantly different from control group p<0.001 

Data not appropriate for statistical analysis 

Organ Weight Footnotes: 

Epididys Epididymides 

Bodywt Body weight 

Page 43 
Harlan Study Number: 41205015 Report Page 44 
Harlan Study Number: 41205015 Report Page 45 

TABLES 
Harlan Study Number: 41205015 Report 

Table 1 Summary of Reproductive Performance - Groups Values 

Males 

Initial group size 

Paired 

Failed to induce pregnancy in female partner 

Induced pregnancy in female partner 

Surviving to terminal necropsy 

Females 

Initial group size 

Paired 

Non-pregnant 

Rearing young to Day 5 of age 

o (Control) 

12 

12 

11 

12 

12 

12 

1 

11 

Dose Group (mg/kg bw/day) 

50 

12 

12 

3 

9 

12 

12 

12 

3 

9 

250 

12 

12 

0 

12 

12 

12 

12 

0 

12 

Page46 

750 

12 

12 

11 

12 

12 

12 

11 
Harlan Study Number: 41205015 Report 

Table 2 Summary Incidence of Daily Clinical Observations 

Sex: Male 

scab 

Number of Animals 

Days from - to 

Scheduled kill 

Number of Animals 

Days from - to 

Increased salivation 

Number of Animals 

Days from - to 

Noisy respiration Number of Animals 

Days from - to 

Day Numbers Relative to Start Date 

Group 1 o (Control) 

1 

22 31 

12 

43 43 

Group 2 Group 3 Group 4 

50 mg/kg bw/day 250 mg/kg bw/day 750 mg/kg bw/day 

1 

22 31 

12 

43 43 

12 

43 43 

1 

29 29 

1 

28 43 

12 

43 43 

10 

16 38 

1 

38 39 

Page 47 
Harlan Study Number: 41205015 Report 

Table 2 ( continued) Summary Incidence of Daily Clinical Observations 

Sex: Female 

Scheduled kill 

Number of Animals 

Days from - to 

Increased salivation 

Number of Animals 

Days from - to 

Day Numbers Relative to Start Date 

Group 1 

O (Control) 

12 

42 45 

Group 2 Group 3 Group 4 

50 mg/kg bw/day 250 mg/kg bw/day 750 mg/kg bw/day 

12 

42 45 

12 

42 46 

12 

42 54 

10 

21 28 

Page 48 
Harlan Study Number: 41205015 Report Page 49 

Table 3 Group Mean Body Weight Values 

Body Weights (g) 

Day Numbers Relative to Start Date 

Group 

(Sex) 1 8 15 22 29 36 43 

1 (M) Mean 317 .1 333.2 348.1 357 .1 370.8 381 .8 391.7 

S.D. 7.6 11 . 5 12.6 12.5 16.3 17.0 19.7 

N 12 12 12 12 12 12 12 --- --- --- --- --- 2(M) Mean 316 .1 333.4 344.4 350.9 364.7 375.3 387 .1 

S.D. 11.3 15 .1 17.9 20.5 17.2 18.3 21.2 

N 12 12 12 12 12 12 12 --- --- --- --- --- --- -- 3(M) Mean 319.9 335.8 348.3 359.5 373.8 380.2 389.7 

S.D. 11.3 13.3 17.0 18.0 21 .5 24.8 25.4 

N 12 12 12 12 12 12 12 -- --- --- --- --- --- --- --- --- 4(M) Mean 316.8 326.8 335.9 346.3 356.9 365.0 377.3 

S.D. 10.0 13.4 17.2 14.8 12.0 15.0 15.9 

N 12 12 12 12 12 12 12 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 50 

Table 3 (continued) Group Mean Body Weight Values 

Body Weights (g) 

Day Numbers Relative to Start Date 

Group 

(Sex) 1 B 15 

1 ( F) Mean 210.0 214.2 220.3 

S.D. 6.5 6.6 6.7 

N 12 12 12 -- --- --- --- -- 2(F) Mean 209.7 214.5 220.4 

S.D. 5.3 7.6 9.2 

N 12 12 12 -- --- --- --- --- 3(F) Mean 207.5 209.3 214.8 

S.D. 4 .1 6.3 5.8 

N 12 12 12 -- --- --- --- --- 4(F) Mean 211 . 1 211.2 215.8 

S.D. 7.3 8.8 11.3 

N 12 12 12 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 51 

Table 3 ( continued) Group Mean Body Weight Values 

Body Weight (g) 

Group Day Numbers 

(Sex) 

Gestation Lactation 

0 7 14 20 1 4 

1 ( F) Mean 223.0 249.6 273.7 336.1 240.8 259.0 

S.D. 8.5 9.6 10.6 15.6 15.4 13.7 

N 11 11 11 11 11 11 -- --- --- --- --- --- --- --

2(F) Mean 222.0 255.2 280.7 349.6 254.8 264 .1 

S.D. 9.0 12.3 17.2 19.9 23.2 22.9 

N 9 9 9 9 9 9 -- --- --- --- --- --- ---

3(F) Mean 216.6 245.7 269.3 330.3 250.5 257.8 

S.D. 9.0 10.4 11 . 6 15.6 16.9 13.9 

N 12 12 12 12 12 12 -- --- --- --- --- --- ---

4(F) Mean 223.5 251.9 279.6 345.1 257.2 262.0 

S.D. 16.8 13.8 16.4 18.8 14. 1 14.4 

N 11 11 11 11 11 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 52 

Table 4 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 16 .1 14.9 9.0 13.7 11 . 0 9.9 74.6 23.5 

S.D. 4.3 3.2 7.9 5.4 5.7 4 .1 14.7 4.5 

N 12 12 12 12 12 12 12 12 

2(M) Mean 17.3 11 . 0 6.5 13.8 10.7 11.8 71.0 22.4 

S.D. 6.2 5.0 9.0 7.3 6.2 6.5 13.5 4.0 

N 12 12 12 12 12 12 12 12 

3(M) Mean 15.9 12.4 11.3 14.3 6.4 9.5 69.8 21.8 

S.D. 4.0 5.5 2.9 6.7 6.2 3.6 18.8 5.6 

N 12 12 12 12 12 12 12 12 

4(M) Mean 10.0* 9.2 10.3 10.7 8 .1 12.3 60.5 19 .1 

S.D. 6.9 9.4 6.6 6.8 6.3 3.6 11.2 3.5 

N 12 12 12 12 12 12 12 12 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 53 

Table 4 (continued) Group Mean Body Weight Gains 

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 4.2 6 .1 10.3 4.9 

S.D. 4.0 3.6 4.7 2.3 

N 12 12 12 12 

2(F) Mean 4.8 5.9 10.8 5.1 

S.D. 4.0 4.5 6.8 3.3 

N 12 12 12 12 

3(F) Mean 1.8 5.5 7.3 3.5 

S.D. 4.2 2.6 3.3 1.6 

N 12 12 12 12 

4(F) Mean 0.1* 4.7 4.8 2.2 

S.D. 3.5 4.7 6.7 3.1 

N 12 12 12 12 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 54 

Table 4 ( continued) Group Mean Body Weight Gains 

Increase in Body Weight (g) Cumulative Body Weight Change (g) 

Days Days 

Gestation Lactation Gestation 

Group From: 0 7 14 1 0 0 

(sex) To: 7 14 20 4 14 20 

1 ( F) Mean 26.6 24 .1 62.4 18.2 50.7 113. 1 

S.D. 5.4 2.8 8.0 6.9 7.0 12.2 

N 11 11 11 11 11 11 

2(F) Mean 33.2 25.4 68.9 9.3 58.7 127.6* 

S.D. 6.3 7.4 8.5 12.3 11 . 4 13.9 

N 9 9 9 9 9 9 

3(F) Mean 29.1 23.7 60.9 7.3 52.8 113. 7 

S.D. 4.9 4.5 7.7 18. 1 4.5 9.2 

N 12 12 12 12 12 12 

4(F) Mean 28.5 27.7 65.5 4.8 56.2 121 . 6 

S.D. 7.9 5.7 5.6 8.7 10 .1 11 . 3 

N 11 11 11 11 11 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report 

Table 5 Group Mean Food Consumptions 

Day Numbers Relative to Start Date 

Food Consumption= g/animal/day. 

Dose Levels: Group 1 - o (Control) 

Group From: 

(Sex) To: 

1 (M) Mean 

N 

2(M) Mean 

N 

3(M) Mean 

N 

4(M) Mean 

N 

Group 2 - 50 mg/kg bw/day 

1 8 29 36 

8 15 36 43 

19 .1 19.6 21.8 21.8 

12 12 12 12 

19.7 19.7 21. 7 22.5 

12 12 12 12 

20.0 20.0 21.5 22 .1 

12 12 12 12 

18.8 18.8 20.5 22.0 

12 12 12 12 

Group 3 - 250 mg/kg bw/day 

Page 55 

Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report 

Table 5 ( continued) Group Mean Food Consumptions 

Day Numbers Relative to Start Date 

Food Consumption= g/animal/day. 

Dose Levels: Group 1 - O (Control) 

Group 

(Sex) 

1 (F) 

2(F) 

3(F) 

4(F) 

Group 2 - 50 mg/kg bw/day 

From: 1 8 

To: 8 15 

Mean 13.6 14.0 

N 12 12 

Mean 14.0 14.6 

N 12 12 

Mean 13.0 14.4 

N 12 12 

Mean 12.4 13.3 

N 12 12 

Group 3 - 250 mg/kg bw/day 

Page 56 

Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 

Table 5 ( continued) Group Mean Food Consumptions 

Food Consumption= g/animal/day. 

Dose Levels: Group 1 - O(Control) 

Group From: 0 

(Sex) To: 7 

1 ( F) Mean 18.0 

S.D. 0.8 

N 11 

2(F) Mean 19.6 

S.D. 1. 7 

N 9 

3(F) Mean 18.0 

S.D. 1.9 

N 12 

4(F) Mean 18.5 

S.D. 2.8 

N 11 

Group 2 - 50 mg/kg bw/day 

Report Page 57 

Day Numbers 

Gestation Lactation 

7 14 

14 20 4 

20.6 22.6 26.3 

1.6 1.9 4.5 

11 11 11 

22.9 24.5 25.0 

2.5 2.0 8.3 

9 9 9 

21.3 23.2 25 .1 

1 .8 1.8 5.0 

12 12 12 

21.9 23.7 24.6 

3.6 5.1 6.0 

11 11 11 

Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 58 

Table 6 Food Efficiency 

Day Numbers Relative to Start Date 

Group From: 1 8 29 36 

(Sex) To: 8 15 36 43 

1 ( M) Mean 12 .1 10.9 7 .1 6.5 

N 12 12 12 12 -- -- --

2(M) Mean 12.6 8.0 7.0 7.5 

N 12 12 12 12 -- -- -- --

3(M) Mean 11.4 8.9 4.2 6 .1 

N 12 12 12 12 -- -- -- --

4(M) Mean 7.6 6.9 5.6 8.0 

N 12 12 12 12 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 59 

Table 6 ( continued) Food Efficiency 

Day Numbers Relative to Start Date 

Group From: 1 8 

(Sex) To: 8 15 

1 ( F) Mean 4.4 6.2 

N 12 12 -- -

2(F) Mean 4.9 5.8 

N 12 12 

-- -

3(F) Mean 1.9 5.5 

N 12 12 -- -

4(F) Mean 0.0 5.0 

N 12 12 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 60 

Table 7 Summary Incidence of Mating Performance, Fertility and Gestation Lengths 

Number Number of Females Pre-Coital Interval (Days) Mating Pregnancy Gestation Length (Days) Females of Parturition Group Index Index with live Males Paired Mated Pregnant 1 2 3 4 12 13 (%) (%) 22 22':; 23 23':, Offspring Index (%) 

Paired 

---

12 12 12 11 2 6 3 1 0 0 100 92 0 6 2 3 11 100 

2 12 12 12 9 2 4 5 1 0 0 100 75 0 7 0 2 9 100 

3 12 12 12 12 3 1 5 3 0 0 100 100 1 8 1 2 12 100 

4 12 12 12 11 5 2 3 0 1 1 100 92 0 9 0 2 11 100 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 61 

Table 8 Group Mean Litter Size and Litter Weights 

Offspring 

Number Number of Total Number of Live Litter Weight Offspring Weight (g) Body Weight Change 

Group of . Number of Offspring (g) (g) Implantation Off . Corpora Sites spring Day 1 Day 4 Days 1-4 

Lutea Born 

Day 1 Day 4 Day 1 Day 4 Males Females Males Females Males Females 

Mean 14.0 13.1 12.0 11. 7 11.5 66.82 93.14 5.90 5.59 8.30 8.14 2.40 2.54 

S.D. 2.0 1.8 1. 7 1.8 1.8 8.89 10.32 0.57 0.52 0.77 0.89 0.42 0.50 

N 11 11 11 11 11 11 11 11 11 11 11 11 11 

2 Mean 13.6 13.0 12.8 12. 7 12.2 72.54 98.14 5.87 5.60 8.14 7.77 2.27 2 .17 

S.D. 1.3 1. 7 1.6 1. 7 1.5 9.67 21.29 0.46 0.50 1.00 0.97 0.67 0.65 

N 9 9 9 9 9 9 9 9 9 9 9 9 9 

3 Mean 14.0 13.1 11.1 11.1 11.0 66.44 93.68 6.18 5.84 8.83 8.40 2.65 2.56 

S.D. 1.2 1.1 1.6 1.6 1. 7 10.28 12.44 0.62 0.53 1.12 0.97 0.69 0.56 

N 12 12 12 12 12 12 12 12 12 12 12 12 12 

4 Mean 14 .1 13.5 12.9 12.9 12.7 71.34 96.67 5.69 5.41 7.73 7.53 2.04 2.12 

S.D. 1. 7 1.8 2.1 2 .1 2.1 8.89 14.66 0.39 0.33 1.04 0.87 0.79 0.72 

N 11 11 11 11 11 11 11 11 11 11 11 11 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 62 

Table9 Group Mean Implantation Losses and Survival Indices Values 

Pre- Post Live 

Group Implantation Implantation Birth Viability 

Loss (%) Loss (%) Index Index (%) 

(%) 

Mean 6 .1 8.2 97.6 97.7 

S.D. 8.4 5.9 4.1 3.9 

N 11 11 11 11 

2 Mean 4.2 1 .6* 99 .1 96.9 

S.D. 5.4 3.2 2.8 7.2 

N 9 9 9 9 

3 Mean 6.3 15.0 100.0 99.2 

S.D. 6.0 12.6 0.0 2.6 

N 12 12 12 12 

4 Mean 4.4 4.2 100.0 98.6 

S.D. 5.5 7.2 0.0 3.1 

N 11 11 11 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 63 

Table 10 Group Mean Sex Ratio Values 

Sex Ratio (% Males) Post Partum Day: 

Group 

At birth 1 4 

Mean 52.2 50.8 52 .1 

S.D. 11.1 12.9 13.6 

N 11 11 11 

2 Mean 49.0 49.6 50.2 

S.D. 10.3 11.0 10.8 

N 9 9 9 

3 Mean 48.2 48.2 48.7 

S.D. 19.4 19.4 19.6 

N 12 12 12 

4 Mean 46.3 46.3 47 .1 

S.D. 15.8 15.8 16.0 

N 11 11 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 64 

Table 11 Summary Incidence of Clinical Signs for Offspring 

Dose Level (mg/kg bw/day) 

o (Control) 50 250 750 

Number of litters 11 9 12 11 

Small 1 M ( 1) 2F ( 1) 1 F ( 1) SM 6F (1) 

Cold 1F ( 1) 1F 

Weak 1F ( 1) 

No milk in stomach 1F ( 1) 

Physical injury to tail 1 F ( 1 ) 

Bruised snout 1F ( 1) 

Missing 3F (3) 1 M 2F ( 1) 1 F ( 1 ) 2F (2) 

Found dead 3M (3) 2F (2) 

( ) = number of affected litters 
Harlan Study Number: 41205015 Report Page 65 

Table 12 Group Mean Reflexological Responses for Offspring 

Group Surface Righting (% 

passed) 

Mean 98.2 

S.D. 4.1 

N 11 

2 Mean 96.6 

S.D. 5.8 

N 9 

3 Mean 99.2 

S.D. 2.9 

N 12 

4 Mean 94.4 

S.D. 6.8 

N 11 

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report 

Table 13 Summary Incidence of Offspring Necropsy Findings 

Group 

2 

3 

4 

Interim Deaths 

Post-Partum Day 

of Termination 

Pre Day 1 

Pre Day 

3 

Number of 

affected 

Litters 

2 

Dose Levels: Group 1 - O(Control) 

Number of 

offspring 

2M 

1F 

1F 

Macroscopic Findings 

Autolytic changes detected 

Autolytic changes detected 

Autolytic changes detected 

Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 

Page 66 

Terminal Kill (Day 5 Post Partum) 

Number 

of 

Litters 

11 

8 

11 

10 

Number of 

Offspring 

1F 

1F 

BM 5F 

Macroscopic Findings 

No abnormalities detected 

Physical injury to tail 

No abnormalities detected 

Small 

No abnormalities detected 

Small 

No abnormalities detected 

Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 

Table 14 Summary Incidence of Necropsy Findings 

Removal Reason: SCHEDULED KILL 

Epididymides; 

Report 

Number of Animals Examined 

Group 

Submitted ....................................................................................... . No Visible Lesions .............................................................................. . Small .......................................................................................... . 

Kidneys; 

Submitted ....................................................................................... . No Visible Lesions .............................................................................. . Increased Pelvic Space; left ................................................................... . Fluid Filled; left ............................................................................. . 

Lungs (With Bronchi); 

Submitted ....................................................................................... . No Visible Lesions .............................................................................. . Reddened ....................................................................................... . Mass; median lobe .............................................................................. . 

Testes; 

Submitted ....................................................................................... . No Visible Lesions .............................................................................. . small .......................................................................................... . Flaccid ........................................................................................ . 

- - - - - - - - - - - - MALES - - - - - - - - - - - -

0 

(Control) 

12 

( 1 ) 

( 12) 

11 

1 

( 12) 

12 

0 

0 

( 12) 

11 

1 

0 

( 12) 

11 

1 

1 

50 250 750 

mg/kg bw/day 

12 12 12 

(2) (3) (4) 

( 12) ( 12) ( 12) 

11 12 12 

1 0 0 

( 12) ( 12) ( 12) 

12 11 12 

0 1 0 

0 1 0 

( 12) ( 12) ( 12) 

11 12 12 

0 0 0 

1 0 0 

( 12) ( 12) ( 12) 

11 12 12 

1 0 0 

1 0 0 

Page 67 
Harlan Study Number: 41205015 Report 

Table 14 (continued) Summary Incidence of Necropsy Findings 

Removal Reason: SCHEDULED KILL 

Kidneys; 

Number of Animals Examined 

Group 

Submitted ....................................................................................... . No Visible Lesions .............................................................................. . Increased Pelvic Space ......................................................................... . 

Lungs (With Bronchi); Submitted ....................................................................................... . No Visible Lesions .............................................................................. . Reddened ....................................................................................... . 

----------- FEMALES-----------

0 

(Control) 

12 

( 1) 

( 12) 

12 

0 

(12) 

12 

0 

50 250 750 

mg/kg bw/day 

12 12 12 

(2) (3) (4) 

( 12) 

11 

1 

(12) 

12 

0 

( 12) 

12 

0 

(12) 

12 

0 

(12) 

12 

0 

( 12) 

11 

1 

Page 68 
Harlan Study Number: 41205015 Report Page 69 

Table 15 Group Mean Organ Weights with Corresponding Relative(% of Body Weight) Organ Weights 

MALES FEMALES 

0 50 250 750 0 50 250 750 

Control mg/kg bw/day Control mg/kg bw/day -- Terminal Bodyweight ........... Mean (g) 391.7 387 .1 389.7 377.3 260.0 264.6 262.7 264.5 

S.D. 19.7 21.2 25.4 15.9 14.2 22.3 13.8 18.7 

N 12 12 12 12 12 12 12 12 

Adrenals ...................... Mean (g) 0.07733 0.07727 0.07648 0.07786 0.09064 0.09596 0.08623 0.09124 

S.D. 0.01722 0.01133 0.00906 0.01186 0. 01061 0.01426 0.01698 0.01095 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.020 0.020 0.020 0.021 0.035 0.035 0.033 0.034 

S.D. 0.005 0.003 0.002 0.003 0.005 0.004 0.007 0.004 

N 12 12 12 12 11 9 12 11 

Brain (Including Cerebrum, 

Cerebellum And Pons) .......... Mean (g) 2.03886 2.05351 2.00657 2.04878 1.90139 1 . 91826 1.89318 1 .82885 

S.D. 0.07409 0 .14066 0.07741 0.08893 0.09438 0.06991 0.10176 0.08184 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.522 0.531 0.517 0.544 0.728 0.713 0.722 0.685 

S.D. 0.036 0.032 0.043 0.034 0.056 0.062 0.044 0.053 

N 12 12 12 12 11 9 12 11 

Epididymides .................. Mean (g) 1 .50798 1 .45067 1 .53983 1.55011 

S.D. 0 .16327 0.25404 0.14747 0 .13382 

N 12 12 12 12 

Mean (%) 0.386 0.375 0.395 0.412 

S.D. 0.043 0.064 0.025 0.039 

N 12 12 12 12 

Heart ......................... Mean (g) 1.08130 1.09015 1. 08160 1.07313 0.79873 0.83593 0.83788 0.87860 

S.D. 0.14933 0 .14402 0. 12861 0.08857 0.08955 0.06553 0.09604 0 .13396 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.276 0.282 0.278 0.285 0.305 0.311 0.320 0.327 

S.D. 0.035 0.034 0.030 0.029 0.035 0.032 0.042 0.041 

N 12 12 12 12 11 9 12 11 
Harlan Study Number: 41205015 Report Page 70 

Table 15 ( continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights 

MALES FEMALES 

0 50 250 750 0 50 250 750 

Control mg/kg bw/day Control mg/kg bw/day 

Kidneys ....................... Mean (g) 2.23022 2.28936 2.34418* 2.28579* 1. 55611 1.62707 1.59563 1 .59636 

S.D. 0.16673 0.17052 0.12382 0.13199 0.08910 0.10647 0.12440 0.12193 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.570 0.592 0.603* 0.606* 0.595 0.602 0.607 0.596 

S.D. 0.036 0.034 0.032 0.035 0.038 0.017 0.032 0.036 

N 12 12 12 12 11 9 12 11 

Liver ......................... Mean (g) 11.6926 12.0888 11.5928 12.0924 10.2252 10.8431 10.9219 11.6024* 

S.D. 1.29760 0.75438 0.89692 0.51977 0.77985 1.12681 1.01349 1 .11696 

N 12 12 12 12 11 9 12 11 

Mean (%) 2.981 3.125 2.983 3.207 3.906 4.003 4.158 4.326* 

S.D. 0.234 0.138 0.262 0 .111 0.287 0.120 0.316 0.253 

N 12 12 12 12 11 9 12 11 

Ovaries ....................... Mean (g) 0 .11722 0.12553 0.12268 0.12010 

S.D. 0.00918 0.01563 0.02622 0.01751 

N 11 9 12 11 

Mean (%) 0.045 0.046 0.047 0.045 

S.D. 0.004 0.005 0.010 0.005 

N 11 9 12 11 

Pituitary ..................... Mean (g) 0.01168 0.01294 0.01178 0.01130 0.01583 0.01782 0.01633 0.01458 

S.D. 0.00133 0.00200 0.00121 0.00167 0.00268 0.00338 0.00170 0.00137 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.003 0.003 0.003 0.003 0.006 0.007 0.006 0.005 

S.D. 0.000 0.000 0.000 0.000 0.001 0.001 0.001 0.001 

N 12 12 12 12 11 9 12 11 
Harlan Study Number: 41205015 Report Page 71 

Table 15 ( continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights 

MALES FEMALES 

0 50 250 750 0 50 250 750 

Control mg/kg bw/day Control mg/kg bw/day 

Prostate ...................... Mean (g) 0.62029 0.60661 0.57636 0.57441 

S.D. 0 .11523 0. 11916 0.10369 0.06976 

N 12 12 12 12 

Mean (%) 0.159 0.157 0.148 0.152 

S.D. 0.032 0.030 0.026 0.019 

N 12 12 12 12 

Seminal Vesicles .............. Mean (g) 2.38888 2.32278 2.31123 1.97182** 

S.D. 0.32354 0.51436 0.30956 0.21594 

N 12 12 12 12 

Mean (%) 0.612 0.600 0.595 0.523** 

S.D. 0.098 0.129 0.089 0.052 

N 12 12 12 12 

Spleen ........................ Mean (g) 0.70733 0.74522 0.73263 0.83303 0.66129 0.68476 0.60335 0.65806 

S.D. 0.07769 0.11126 0.03997 0.48636 0.07042 0.11645 0.10455 0.07280 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.180 0.192 0.189 0.219 0.253 0.253 0.230 0.245 

S.D. 0.015 0.022 0.015 0.118 0.027 0.035 0.039 0.017 

N 12 12 12 12 11 9 12 11 

Testes ........................ Mean (g) 3.47304 3.46771 3.67058 3.78636 

S.D. 0.69737 0.70571 0.37595 0.32022 

N 12 12 12 12 

Mean (%) 0.889 0.899 0.943 1.005 

S.D. 0.188 0.181 0.092 0.092 

N 12 12 12 12 
Harlan Study Number: 41205015 Report Page 72 

Table 15 ( continued) Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights 

MALES FEMALES 

0 50 250 750 0 50 250 750 

Control mg/kg bw/day Control mg/kg bw/day 

Thymus ........................ Mean (g) 0.38762 0.36622 0.42591 0.39864 0.23420 0.21809 0.22130 0.23275 

S.D. 0.07266 0.11113 0.09767 0.08768 0.06495 0.05236 0.06007 0.06652 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.098 0.094 0.110 0.106 0.089 0.080 0.084 0.087 

S.D. 0.015 0.027 0.025 0.023 0.024 0.016 0.020 0.024 

N 12 12 12 12 11 9 12 11 

Thyroid/Parathyroid ........... Mean (g) 0.02288 0.02905 0.02392 0.02843* 0.02325 0.02798 0.02151 0.02535 

S.D. 0.00448 0.00571 0.00302 0.00796 0.00321 0.00548 0.00384 0.00765 

N 12 12 12 12 11 9 12 11 

Mean (%) 0.006 0.008 0.006 0.008* 0.009 0.010 0.008 0.010 

S.D. 0.001 0.002 0.001 0.002 0.001 0.002 0.001 0.003 

N 12 12 12 12 11 9 12 11 
Harlan Study Number: 41205015 Report Page 73 

FIGURES 
Harlan Study Number: 41205015 Report Page 74 

Figure 1 Group Mean Body Weights - Males 

j-+-O(Control) -somg/kgbw/day --.-2somg/kgbw/day ~750mg/kgbw/dayl 

400 

390 

380 

370 

360 

<ll 

e 350 ... = 

~ 

340 

330 

320 

310 

300 

1 8 15 22 29 36 43 

Day 
Harlan Study Number: 41205015 Report Page 75 

Figure 2 Group Mean Body Weights - Females 

Pre-Pairing ....._O(Control) -50mglkgbw/day .........,250mglkgbw/day ~750mglk.gbw/day 

222 

220 

218 

216 

214 

...,; 212 a 

as 

.... 

1)11 210 

208 

206 

204 

202 

200 

1 8 15 

Day 
VJ 

El 

C'IS 

... 

~ 

Harlan Study Number: 41205015 Report Page 76 

Figure 2 (continued) Group Mean Body Weights -Females 

Gestation 

--.-o(Control) -50mg/kgbw/day .........-250mg/kgbw/day """'*"""750mg/kgbw/day 

375 -.-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

350 

325 

300 

275 

250 

225-

200 -t-~~~~~~~~~~---,.~~~~...-~~~~~~~~~~~~~~~---~~~~~~~~~~~~~~----1 

0 7 14 20 

Day 
Harlan Study Number: 41205015 Report Page 77 

Figure 3 Group Mean Food Consumption - Males 

I DO (Control) 1111150mg/kgbw/clay •250mglkgbw/clay •750mglkgbw/dayl 

23 -.-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-

22 

21 

! 20 

;;. 

OS 

t 

19 

18 

17 

16 +-----'-----

1-8 8-15 29-36 36-43 

Days 
Harlan Study Number: 41205015 Report Page 78 

Figure 4 Group Mean Food Consumption - Females 

I a O (Control) l!l 50 mg/kg bw/day • 250 mg/kg bw/day •750 mg/kg bw/dayl 

30 -.-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~----. 

25 

20 

~ 

~ 15 

i 

10 

5 

0 

1-8 8-15 0-7 

Pre-Pairing 

7-14 

Gestation 

Days 

14-20 1-4 

Lactation 
Harlan Study Number: 41205015 Report Page 79 

APPENDICES 
Harlan Study Number: 41205015 Report Page 80 

Appendix 1 Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

8 No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 81 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued} 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex} Number Clinical Sign Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (M} 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

a No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control} Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 82 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre Post 1h Pre 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

a No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 83 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

a No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 84 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

8 No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 85 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x 

Scab 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 

Scheduled kill 

5 No Abnormalities Detected 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 

Scheduled kill 

7 No Abnormalities Detected 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 

Scheduled kill 

9 No Abnormalities Detected 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 

Scheduled kill 

11 No Abnormalities Detected 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 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 86 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected 

Scab 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 

Scheduled kill 

5 No Abnormalities Detected 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 

Scheduled kill 

7 No Abnormalities Dete.cted 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 

Scheduled kill 

9 No Abnormalities Detected 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 

Scheduled kill 

11 No Abnormalities Detected 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 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 87 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre 

1(M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x 

Scab 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 

Scheduled kill 

5 No Abnormalities Detected 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 

Scheduled kill 

7 No Abnormalities Detected 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 

Scheduled kill 

9 No Abnormalities Detected 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 

Scheduled kill 

11 No Abnormalities Detected 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 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 88 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled kill 

6 No Abnormalities Detected 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 

Scheduled kill 

8 No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 89 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h 

1 (M) 1 No Abnormalities Detected 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 

Scheduled kill 

3 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

4 No Abnormalities Detected 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 

Scheduled .kill 

6 No Abnormalities Detected 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 

Scheduled kill 

8 No Abnormalities Detected 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 

Scheduled kill 

10 No Abnormalities Detected 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 

Scheduled kill 

12 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 90 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 42 42 42 42 43 

(Sex) Number Clinical Sign Pre Post 1h Sh A.M. 

1 (M) 1 No Abnormalities Detected x x x x x 

Scheduled kill x 

2 No Abnormalities Detected x x x x x 

Scheduled kill x 

3 No Abnormalities Detected x x x x x 

Scab 

Scheduled kill x 

4 No Abnormalities Detected x x x x x 

Scheduled kill x 

5 No Abnormalities Detected x x x x x 

Scheduled kill x 

6 No Abnormalities Detected x x x x x 

Scheduled kill x 

7 No Abnormalities Detected x x x x x 

Scheduled kill x 

a No Abnormalities Detected x x x x x 

Scheduled kill x 

9 No Abnormalities Detected x x x x x 

Scheduled kill x 

10 No Abnormalities Detected x x x x x 

Scheduled kill x 

11 No Abnormalities Detected x x x x x 

Scheduled kill x 

12 No Abnormalities Detected x x x x x 

Scheduled kill x 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 91 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 92 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1 h Sh Pre Post 1h 5h Pre Post 1h 5h 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 93 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre Post 1h Pre 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 94 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 95 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 96 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

36 No Abnormalities Detected x x x 

Scab x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 97 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

36 No Abnormalities Detected 

Scab x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 98 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 99 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 100 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h 

2(M) 25 No Abnormalities Detected 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 

Scheduled kill 

27 No Abnormalities Detected 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 

Scheduled kill 

29 No Abnormalities Detected 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 

Scheduled kill 

31 No Abnormalities Detected 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 

Scheduled kill 

33 No Abnormalities Detected 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 

Scheduled kill 

35 No Abnormalities Detected 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 

Scab 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 101 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 42 42 42 42 43 

(Sex) Number Clinical Sign Pre Post 1h 5h A.M. 

2(M) 25 No Abnormalities Detected x x x x x 

Scheduled kill x 

26 No Abnormalities Detected x x x x x 

Scheduled kill x 

27 No Abnormalities Detected x x x x x 

Scheduled kill x 

28 No Abnormalities Detected x x x x x 

Scheduled kill x 

29 No Abnormalities Detected x x x x x 

Scheduled kill x 

30 No Abnormalities Detected x x x x x 

Scheduled kill x 

31 No Abnormalities Detected x x x x x 

Scheduled kill x 

32 No Abnormalities Detected x x x x x 

Scheduled kill x 

33 No Abnormalities Detected x x x x x 

Scheduled kill x 

34 No Abnormalities Detected x x x x x 

Scheduled kill x 

35 No Abnormalities Detected x x x x x 

Scheduled kill x 

36 No Abnormalities Detected x x x x x 

Scab 

Scheduled kill x 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 102 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 103 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 104 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre Post 1h Pre 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - so mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 105 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 106 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 107 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 108 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration x 

50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 109 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration x x x 

50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 110 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 111 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h 

3(M) 49 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Noisy respiration 50 No Abnormalities Detected 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 

Scheduled kill 

52 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

53 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

54 No Abnormalities Detected 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 

Scheduled kill 

56 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

57 No Abnormalities Detected 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 

Scheduled kill 

59 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

60 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 112 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 42 42 42 42 43 

(Sex) Number Clinical Sign Pre Post 1h 5h A.M. 

3(M) 49 No Abnormalities Detected x x x x x 

Scheduled kill x 

Noisy respiration 50 No Abnormalities Detected x x x x x 

Scheduled kill x 

51 No Abnormalities Detected x x x x x 

Scheduled kill x 

52 No Abnormalities Detected x x x x x 

Scheduled kill x 

53 No Abnormalities Detected x x x x x 

Scheduled kill x 

54 No Abnormalities Detected x x x x x 

Scheduled kill x 

55 No Abnormalities Detected x x x x x 

Scheduled kill x 

56 No Abnormalities Detected x x x x x 

Scheduled kill x 

57 No Abnormalities Detected x x x x x 

Scheduled kill x 

58 No Abnormalities Detected x x x x x 

Scheduled kill x 

59 No Abnormalities Detected x x x x x 

Scheduled kill x 

60 No Abnormalities Detected x x x x x 

Scheduled kill x 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 113 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 114 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

so No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 115 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 116 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 '-- 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 117 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 118 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

4(M) 73 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

75 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation x 

77 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation x x 

81 No Abnormalities Detected x x x x x x x x x x x x x x 

Scab 

Scheduled kill 

Increased salivation x 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 119 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre 

4(M) 73 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation x 

75 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

77 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation x x 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected x x x x x x x x x x 

Scab x x x x x 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 120 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected 

Scab 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 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 121 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected 

Scab 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 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 122 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h 

4(M) 73 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

74 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

76 No Abnormalities Detected 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 

Scheduled kill 

78 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

79 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

80 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

81 No Abnormalities Detected 

Scab 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 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 123 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 42 42 42 42 43 

(Sex) Number Clinical Sign Pre Post 1h 5h A.M. 

4(M) 73 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

74 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

75 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

76 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

77 No Abnormalities Detected x x x x x 

Scheduled kill x 

78 No Abnormalities Detected x x x x x 

Scheduled kill x 

79 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

80 No Abnormalities Detected x x x x x 

Scheduled kill x 

Increased salivation 

81 No Abnormalities Detected 

Scab x x x x x 

Scheduled kill x 

Increased salivation 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 124 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 125 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 126 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 127 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation x 

84 No Abnormalities Detected 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 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 128 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

x = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 129 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation x 

84 No Abnormalities Detected 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 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 130 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation x 

Noisy respiration 83 No Abnormalities Detected x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation x x 

84 No Abnormalities Detected 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 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 131 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 132 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre 

4(M) 82 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

Increased salivation 

Noisy respiration 83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 133 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h Sh Pre Post 1 h Pre Post 1h Pre Post 1h Pre Post 1h 

4(M) 82 No Abnormalities Detected x x x x x x x x x x 

Scheduled kill 

Increased salivation x 

Noisy respiration x x x x x 

83 No Abnormalities Detected 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 

Scheduled kill 

Increased salivation 

x = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 

(Sex) Number Clinical Sign 

4(M) 82 No Abnormalities Detected 

Scheduled kill 

Increased salivation 

Noisy respiration 

83 No Abnormalities Detected 

Scheduled kill 

Increased salivation 

84 No Abnormalities Detected 

Scheduled kill 

Increased salivation 

X = Present 

Dose Levels: Group 1 - o (Control) 

42 42 42 42 43 

Pre Post 1h 5h A.M. 

x x x x x 

x 

x x x x x 

x 

x x x x x 

x 

Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 

Page 134 

Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 135 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 136 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 137 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 

(Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre Post 1h Pre 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 138 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 139 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 

(Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre 

1 ( F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

x = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 140 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 141 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 

(Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 142 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 

(Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre 

1 ( F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 143 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 

(Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 144 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 

(Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h 

1 (F) 13 No Abnormalities Detected 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 

Scheduled kill 

15 No Abnormalities Detected 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 

Scheduled kill 

17 No Abnormalities Detected 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 

Scheduled kill 

19 No Abnormalities Detected x x x x x x x x x x x x x x x 

Scheduled kill 

20 No Abnormalities Detected 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 

Scheduled kill 

22 No Abnormalities Detected 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 

Scheduled kill 

24 No Abnormalities Detected x x x x x x x x x x x x 

Littering x 

Not Observed Due to Littering x x 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 Report Page 145 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 42 42 42 42 42 43 43 43 43 43 44 44 44 44 44 

(Sex) Number Clinical Sign A.M. Pre Post 1 h 5h A.M. Pre Post 1h 5h A.M. Pre Post 1h 5h 

1 ( F) 13 No Abnormalities Detected x x x x x 

Scheduled kill x 

14 No Abnormalities Detected x x x x x 

Scheduled kill x 

15 No Abnormalities Detected x x x x x 

Scheduled kill x 

16 No Abnormalities Detected x x x x x x x x x x x x 

Scheduled kill 

17 No Abnormalities Detected x 

Scheduled kill x 

18 No Abnormalities Detected 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 

Scheduled kill 

20 No Abnormalities Detected x 

Scheduled kill x 

21 No Abnormalities Detected x x x x x 

Scheduled kill x 

22 No Abnormalities Detected 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 

Scheduled kill x 

24 No Abnormalities Detected x x x x x x x x x x x x 

Littering 

Not Observed Due to Littering 

Scheduled kill 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 
Harlan Study Number: 41205015 

Appendix 1 ( continued) 

Report 

Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 45 45 45 45 45 46 46 46 46 47 47 47 48 48 48 

(Sex) Number Clinical Sign 

1 ( F) 13 No Abnormalities Detected 

Scheduled kill 

14 No Abnormalities Detected 

Scheduled kill 

15 No Abnormalities Detected 

Scheduled kill 

16 No Abnormalities Detected 

Scheduled kill 

17 No Abnormalities Detected 

Scheduled kill 

18 No Abnormalities Detected 

Scheduled kill 

19 No Abnormalities Detected 

Scheduled kill 

20 No Abnormalities Detected 

Scheduled kill 

21 No Abnormalities Detected 

Scheduled kill 

22 No Abnormalities Detected 

Scheduled kill 

23 No Abnormalities Detected 

Scheduled kill 

24 No Abnormalities Detected 

Littering 

A.M. Pre Post 1h 5h A.M. Pre Post 1h Pre Post 1h Pre Post 1h 

x 

x 

x 

x 

x 

x 

x 

Not Observed Due to Littering Scheduled kill x 

X = Present 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

Page 146 
Harlan Study Number: 41205015 Report 

Appendix 1 ( continued) Individual Daily Clinical Observations 

Day Numbers Relative to Start Date 

(continued) 

Group Animal 

(Sex) Number Clinical Sign 

1 (F) 13 No Abnormalities Detected 

Scheduled kill 

14 No Abnormalities Detected 

Scheduled kill 

15 No Abnormalities Detected 

Scheduled kill 

16 No Abnormalities Detected 

Scheduled kill 

17 No Abnormalities Detected 

Scheduled kill 

18 No Abnormalities Detected 

Scheduled kill 

19 No Abnormalities Detected 

Scheduled kill 

20 No Abnormalities Detected 

Scheduled kill 

21 No Abnormalities Detected 

Scheduled kill 

22 No Abnormalities Detected 

Scheduled kill 

23 No Abnormalities Detected 

Scheduled kill 

24 No Abnormalities Detected 

Littering 

X = Present 

Not Observed Due to Littering 

Scheduled kill 

48 49 49 49 49 50 50 50 50 51 51 51 51 

Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh 

52 52 

Pre Post 

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

Page 147