# harlan® REPORT 

# e..

PMDAHYDROLYZED TOPMA: Oral (Gavage) Reproduction/Developmental Toxicity ScreeningTestin theRat (OECD 421)

StudyDirector:
TestFacility:

Sponsor:

Harlan StudyNumber: StudyCompletionDate: JS Dunster


## HarlanLaboratoriesLtd. ShardlowBusinessPark Shardlow Derbyshire DE722GD 

## UK
TheAmerican ChemistryCouncil PMDA Consortium 700 2nd StreetNE WashingtonDC 20002 UNITED STATES OF AMERICA



## 41205015
09 September 2013

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# STATEMENT OFNO DATA CONFIDENTIALITY
No claimofconfidentialityismade for anyinformationcontainedinthis study onthebasis ofits falling withinthe scope ofFIFRA §10 (d), (1), (A), (B) or (C). COMPANY TheAmericanChemistry Council PMDA Consortium

COMPANYAGENT

DATE

SIGNATURE

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# GLP COMPLIANCE STATEMENT This studymeets the requirements for 40 CFRPart 160 ofthe US EPA.

Submitter Date:

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

Sponsor Date:

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

Study Director 

## ···~····················· 

# . 0 9 SEP 2013 Date

....................................... JS Dunster

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# CONTENTS STATEMENT OFNODATACONFIDENTIALITY

...................................................................3 GLP COMPLIANCE STATEMENT

..............................................................................................5 CONTENTS

....................................................................................................................................7 STUDYDIRECTOR STATEMENT OF GLP COMPLIANCE

.................................................. 11 QUALITYASSURANCE STATEMENT

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

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

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

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

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

................................................................................................................................ 17 AdultResponses

.................................................................................................................. 1 7 Mortality

.............................................................................................................................. 17 Clinical Observations

........................................................................................................... 18 BodyWeight

........................................................................................................................ 18 Food Consumptionand FoodEfficiency

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

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

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

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

............................................................................................................................... 18 GestationLength

.................................................................................................................. 18 LitterResponses

................................................................................................................... 18 Offspring Litter Size, Sex Ratio andViability

.................................................................... 18 Offspring Growth andDevelopment

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

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

.............................................................................................................................. 19 OrganWeights

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

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

........................................................................................................................... 19 GENERAL INFORMATION

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

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

....................................................................................................................20 Multi

- Site Study Details

....................................................................................................20 Additional Responsibilities

..................................................................................................21 Deviations from StudyPlan

.................................................................................................21 Archiving

.............................................................................................................................22 1 INTRODUCTIONAND PURPOSE

...................................................................................23 1.1 Guidelines I

## Regulations

........................................................................................23 2 TEST ITEM

.........................................................................................................................24 2.1 TestItem

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

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

............................................................................................................24 3.1.1 Animals andAnimal Husbandry

.............................................................24 3.1.2 Justification

..............................................................................................25 3.2 TestItemPreparation

.............................................................................................25

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### 4 

## 3.3 Procedure

...............................................................................................................26 3.3.1 Chronological Sequence ofStudy

...........................................................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 BodyWeight

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

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

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

......................................................................27 Mating

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

.......................................................................28 LitterData

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

............................................................................28 Pathology

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

..................................................................................................29 OrganWeights

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

........................................................................................ 29 Evaluation ofData

................................................................................... 30 3.4.7.1 Treatment ofData

.................................................................................... 30 3.4.7.2 Reproductive Indices

............................................................................... 31 3.4.7.3 LitterResponses

...................................................................................... 32 3.4.7.4 StatisticalAnalysis

.................................................................................. 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 AdultReponses

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

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

.............................................................................. 34 BodyWeight

........................................................................................... 34 Food Consumption

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

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

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

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

.................................................................................................... 35 GestationLength

..................................................................................... 36 4.1.3 LitterResponses

...................................................................................... 36 OffspringLitter Size, Sex Ratio and Viability

........................................ 36 Offspring Growth andDevelopment

....................................................... 36 4.1.4 Pathology

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

.................................................................................................. 37 4.1.4.2 OrganWeights

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

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## 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 SummaryofReproductive Performance

- Groups Values

....................................46 SummaryIncidence ofDaily Clinical Observations

.............................................47 Group MeanBodyWeightValues

........................................................................49 Group MeanBodyWeight Gains

..........................................................................52 Group MeanFood Consumptions

..........................................................................55 FoodEfficiency

.....................................................................................................58 SummaryIncidence ofMatingPerformance, Fertility and Gestation Lengths

..................................................................................................................60 Group MeanLitter Size and LitterWeights

..........................................................61 Group MeanImplantationLosses and Survival Indices Values

............................62 Group Mean Sex Ratio Values

..............................................................................63 SummaryIncidence ofClinical Signs for Offspring

.............................................64 Group MeanReflexological Responses for Offspring

..........................................65 SummaryIncidence ofOffspringNecropsyFindings

...........................................66 SummaryIncidence ofNecropsyFindings

...........................................................67 Group MeanOrganWeights with Corresponding Relative (% 

## of BodyWeight) OrganWeights

...............................................................................69


# LIST OF FIGURES Figure 1 Figure 2 Figure 3 Figure 4 Group MeanBodyWeights

- Males

......................................................................74 Group MeanBodyWeights

- Females

..................................................................75 Group MeanFood Consumption

- Males

..............................................................77 Group MeanFood Consumption

- Females

..........................................................78


# LIST OF APPENDICES Appendix 1 

## Appendix 2 Appendix 3 Appendix 4 Appendix 5 Appendix 6 Appendix 7 IndividualDaily Clinical Observations

.................................................................80 Individual and Group MeanBodyWeights

.........................................................205 Individual and Group MeanBodyWeightGains

................................................217 Individual and Group MeanFood ConsumptionValues for Females FollowingMating and DuringLactation

.............................................................229 Individual Mating Performance, Fertility and GestationLengths

.......................233 Individual and Group MeanLitter Size and LitterWeights

................................237 Individual and Group MeanImplantationLosses 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 MeanReflexological Responses for Offspring

.............................................................................................................253 IndividualNecropsyFindingsfor Offspring

.......................................................257 IndividualNecropsyFindings

.............................................................................261 Individual and Group Mean OrganWeights

.......................................................269 Individual and Group MeanRelative OrganWeights

.........................................277 HistopathologyPhaseReport

..............................................................................289 Analytical Investigations

.....................................................................................404 StudyPlan

............................................................................................................410 HistologyProcessingPhaseTest Site QualityAssurance Statement.

.................430 Histology ProcessingPhaseTest Site StatementofCompliance

........................431 HistologyProcessingPhase Test Site StatementofGLP Compliance

..........................................................................................................432 Certificates ofAnalysis ofDietUsed

..................................................................433 NormalRanges for ReproductiveParametersinthe Pregnantand LactatingFemale WistarHanTM:RccHanTM:WIST StrainRat..

..........................437 NormalRanges for Offspring Parameters 

## inthe WistarHanTM: RccHanTM: WIST StrainRat

...............................................................................438 NormalRanges for Absolute andBodyWeight-Relative Organ WeightValuesintheWistarHanTM:RccHanTM:WIST StrainRat..

....................439 Certificate ofAnalysis ofthe TestItem

..............................................................441 MonitoringAuthority StatementofGLP Compliance

........................................443

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# STUDYDIRECTOR STATEMENT OF GLP COMPLIANCE HarlanLaboratories Ltd., ShardlowBusiness Park, Shardlow, Derbyshire, DE72 2GD, UK. Harlan StudyNumber: StudyTitle: 41205015 PMDA hydrolyzed to PMA: Oral (Gavage) Reproduction/ Developmental Toxicity Screening Test inthe 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 ofDirectives 2004/9/EC and 2004/10/EC. This report fully and accurately reflects the procedures used and data generated. There were no circumstances consideredto have affectedthe integrity ofthe study orthe validity ofthe data.
StudyDirector: JSDunster

·--~~---··········· Date: 

# 09SEP 2013

The signatures of the Principal Investigators are included in their respective statements of compliance which are attached inthe appendicesto this report.

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# QUALITYASSURANCE STATEMENT Harlan StudyNumber: 41205015 StudyTitle: PMDA hydrolyzed to PMA: Oral (Gavage) Reproduction/ Developmental Toxicity ScreeningTestinthe Rat (OECD 421)

The general facilities and activities are inspected at least once a year and the results are reported to the relevantresponsible person andmanagement. Study-relatedprocedures conducted atthe test facility were audited and inspected. The details of these audits and inspections are givenbelow.
Reported to the Dates and Types ofQAInspections relevant Study Directorand Test Facility Management 

## Date ofInspection Type ofInspection Phase Inspected ReportDate 15 February2013 StudyPlan NIA 

## 15 February2013 Verification 18 February 2013 Study

- based Test ItemPreparation 18 February2013 27 February2013 Parental Observations 27 February2013

04 March2013 Chemical Analysis 04 March2013 06 March2013 Pairing/Mating/Smearing 06 March2013 13 March2013 Animal Preparation 13 March2013 13 March2013 Dosing 13 March2013 02 April 2013 Litter Observations 02 April 2013 03 April 2013 PostMortem 03 April 2013 12 June 2013 ReportAudit NIA 

## 12 June 2013

This statementconfirmsthatthis reportreflects the rawdata andtheproceduresfollowed.
QualityAssurance: 

# ······~·-'

.......A

..?.-o~ Date: \ -'2. 

# I q 

# I ,**~**

The signatures ofthe Test Site Quality Assurance are included in their respective Quality Assurance Statements which are attached inthe Appendices to this Report.Harlan StudyNumber: 

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# SIGNATURE OFMANAGEMENT

TestFacilityManagement: E Wood HarlanLaboratories Ltd., ShardlowBusinessPark, Shardlow, Derbyshire, DE72 2GD, UK. Ihave conducted areviewofthis study and agree withthe scientific contentofthis report.

Date: 

# 0 9 SEP 2013

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# SUMMARY Introduction The study was performedto screenfor potential adverse effects ofthe testitem onreproduction, including offspring development, and provides an initial hazard assessment for effect on reproduction. The study is compatible with the requirements ofthe recommendations ofthe OECD Guidelines for Testing of Chemicals No. 421 "Reproduction/Developmental Toxicity ScreeningTest" (adopted27July 1995).


## Methods Thetestitemwas administeredby gavageto four groups, eachoftwelve male andtwelve 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 of50, 250 and 750 mg/kgbw/day. A control group oftwelve males and twelve females was dosed withvehicle 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 eachtreatment group on Day 15 ofthe study, with females subsequentlybeing allowedto litterandreartheiroffspringto Day 5 oflactation. Duringthe lactationphase, daily clinical observationswere performed onall surviving offspring, togetherwithlitter size and offspringweights and assessment ofsurfacerightingreflex. Adult males were sacrificed onDay 43, followed bythe sacrifice ofall females and offspring on Day 5 oflactation. 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 evaluationofreproductivetissues was performed.


## Results
AdultResponses Mortality There were no unscheduled deaths.

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## Clinical Observations No clinically observable signs oftoxicitywere detected. 

## Body Weight A slightreductioninbody weight gains was evidentfor males treatedwith 750 mg/kg bw/day. Females treated with 250 and 750 mg/kg bw/day showed a reduction in body weight gains duringthe lactationphase ofthe study; however statistical significance was not achieved.


## Food Consumption and Food Efficiency No adverse effects onfood consumptionwere detected.


## Water Consumption No adverse effectonwaterconsumptionwas detected. 

## Reproductive Performance Mating No treatment-related effects were detected inmatingperformance. 

## Fertility No treatment-related effects onfertility were detected.


## Gestation Length No treatment-related effects were detected in the length ofgestation between control and treated groups.


## LitterResponses OffspringLitter Size, Sex Ratio and Viability No differences in sex ratio or litter size were evident for offspring from treated litters when comparedto those from the controls. No significant differences inthe number ofcorpora luteaor

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## implantation sites were noted for treated females when compared to controls. The percentages of pre- andpost-implantationloss for treated females were comparableto 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 observedin offspring, orany macroscopic abnormalities detected atterminal kill. 

## Pathology Necropsy No toxicologicallyimportantmacroscopic abnormalities were detected. 

## Organ Weights No toxicologically significantorganweight changes were detected. 

## Histopathology Histopathological examinations didnotreveal any treatment-related effects.


## Conclusion The oral administration ofPMDA hydrolyzed to PMA to rats by gavage, at dose levels of750, 250 and 50 mg/kg bw/day, did not result in any toxicologically significant adverse effects at any ofthe dose levels examined. The 'No Observed Adverse Effect Level' (NOAEL) for systemic toxicitywas therefore consideredto be 750 mg/kgbw/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/kgbw/day.

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# GENERALINFORMATION Schedule Experimental StartingDate: Experimental CompletionDate: 

## Animal Welfare 18 February2013 23 August2013

The studywas designed andconductedto causethe minimum suffering ordistress to the animals consistent with the scientific objectives and in accordance with the Harlan Laboratories Ltd., Shardlow, UKpolicy on animal welfare and the requirements ofthe United Kingdom's Animals (Scientific Procedure) Act 1986. The conduct ofthe study may be reviewed, as part ofthe HarlanLaboratories Ltd, Shardlow, UKEthical ReviewProcess. 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 ofclinical signs as humane endpoints for experimental animals usedinsafetyevaluation.


## Multi- Site StudyDetails Lead QualityAssurance:

StudyPhase:

Test Site:

Principal Investigator:
Test Site QualityAssurance: J Riley HarlanLaboratories Ltd. HistologyProcessing PropathUKLimited WillowCourt NetherwoodRoad Hereford HR26JU UK
NFower
A Fox AFInternational Consultancy 4, TheMaltsters, The OldGrainBarn, George Lane, Buckden, Cambridgeshire,PE19 5XL, UK

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### 41205015



## StudyPhase:
Test Site:

Principal Investigator:
Test Site QualityAssurance:



## Additional Responsibilities Analytical Investigations:

Animal Health:



## Deviations from StudyPlan DeviationNo.1 (25 February2013) Page9 ClinicalObservations Report



## HistopathologyExamination

PeterMillarAssociates Ltd. 3 QueenCharlotteLane Edinburgh Scotland EH66AY
P Millar
J Lawrence PeterMillarAssociates Ltd.

P Watson HarlanLaboratories Ltd., Shardlow, UK P Highton HarlanLaboratories Ltd., Shardlow, UK Page 21



## On the morning of20th 

## February 2013 

## (Day 1 oftreatment), there was a fire on the site ofthe Test Facility. While the animal facility housing the study was unaffected, access to the site was restricted for much ofthe morning, resulting intechnical 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 Directorthat onthis occasionthese observations were performed earlier (approximately 4 hourspostdose) andatthe sametimethatfinal morbidity checkswereperformed.

DeviationNo.2 (12 June2013) Page4 Animal Husbandry 

## Environment:

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## On a number ofoccasions during the study, the relative humidity values were outside the ranges specifiedinthe studyplan. These deviationsto the studyplandid not affectthepurpose or integrity ofthe 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 ofthe data will be chargeableto the Sponsor. No datawill be discardedwithout contactingthe Sponsorto obtaintheirwrittenconsent.

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# 1 INTRODUCTIONAND 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, byrepeated oral administrationto the WistarHanTM:RccHanTM:WIST strainratfor up to eight weeks at dose levels of50, 250 and 750 mg/kg bw/day. A control group was dosed withvehicle alone (Carboxymethyl cellulose (1%) &Tween 80 (0.1%)). The dose levels were chosenbased onthe results ofprevious 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 ofthe test item, and the results ofthe study are believedto be ofvalue inpredictingthe likelytoxicity ofthetestitemto 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 oftreatment) and 06 April 2013 (final day ofnecropsy).


## 1.1 Guidelines I

## Regulations The study was designed to be compatible with the requirements ofthe OECD Guidelines for Testing ofChemicals, No.421: "Reproduction/Developmental Toxicity ScreeningTest" (adopted 27 July 1995).

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# 2 TESTITEM 2.1 TestItem Information as providedbythe Sponsor. Identification Description ChemicalName Purity BatchNumber Label Date Received Storage Conditions Expiry Date No correctionfor purity was made. PMDA White powder pyromellitic dianhydride 99.94% NJC1207029 PMDA (CA) BatchNoNJC1207029 Quality lkg 21 August 2012 roomtemperature inthe dark, under nitrogen 18 January 2014 Page 24



## The integrity ofsupplied data relating to the identity, purity and stability ofthe test item is the responsibility ofthe Sponsor. PMA (pyromellitic acid) is the resultanttest itemused for testing. A Certificate ofAnalysis ofTestItemis included as Appendix 25.


# 3 MATERIALSAND 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 ofeighty 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 meshlids and softwood flakes.

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### 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 ofthe study. Environmental enrichment was provided in the form ofwooden 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 gestationandlactation. The animals were housed in a single air-conditioned room within the Harlan Laboratories Ltd., Shardlow, UKBarrier Maintained Rodent Facility. The rate ofair exchange was at least fifteen air changes per hour and the low intensity fluorescent lighting was controlled to give twelve hours continuous light andtwelve hours darkness. Environmental conditions were continuously monitored by a computerised system, and print-outs ofhourly temperatures and humidities are included in the study records. The temperature and relative humidity controls were set to achieve target values of21 ± 2 °C and 55 ± 15 % respectively. Shortterm deviations from these targets were considerednotto have affectedthepurpose orintegrity ofthe 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 betweenthe treatment groups. The cage distribution withinthe holding rack was also randomised. The animals were uniquely identified within the study by an ear punching system routinelyusedinthese 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 acceptableto appropriateregulatory authorities.


## 3.2 TestItem Preparation For the purpose ofthis 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 undertakento ensure hydrolysis to produce PMA. The pH ofeachformulation was checked 1 hour after formulation. The stability and homogeneity of the test item formulations werepreviously determinedbyHarlanLaboratories Ltd., Shardlow, UK, Analytical Services (Harlan Laboratories Ltd., StudyNumber 41205014). Results from the previous study show the formulations to be stable for at least twenty-one days. Formulations were therefore preparedeverytwo weeks and stored at approximately +4 °C (range: +2 to+10°C)inthe 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 methodused for analysis offormulations andthe results obtained are giveninAppendix 16. The

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### results indicate that the prepared formulations were within acceptable ranges for the purpose of this study.


## 3.3 Procedure Animalswere allocatedtotreatment groups as follows:

DoseLevel Treatment Concentration AnimalNumbers TreatmentGroup (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 inparentheses ( ) showthe individual animal numbers allocated to eachtreatment 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 ofCarboxymethyl cellulose (1% ) & 

### Tween 80 (0.1%). The volume oftest and control item administered to each animal was based on the most recent scheduledbodyweightandwas adjusted atweekly intervals.



## 3.3.1 ChronologicalSequenceofStudy i. Groups oftwelve male and twelve female animals were treated daily at the appropriate dose level throughoutthe study (except for females during parturition where applicable). The first day ofdosingwas designated as Day 1ofthe study. 11. OnDay 15, animals were pairedon a 1male: 1female basis within eachdose group for a maximum offourteen days. 111. 

### Following evidence ofmating (designated as Day O 

## postcoitum) the males were returned to their original cages and females were transferredto individual cages. 1v. Pregnantfemales were allowedto give birth and maintaintheir offspring until Day 5

## post partum. Litter size, offspring weight and sex, surface righting and clinical signs were also recorded duringthisperiod. v. The male dose groups were killed and examinedmacroscopically onDay43. v1. At Day 5

## postpartum, all females and surviving offspring were killed and examined macroscopically.

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## 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 wererecorded.

3.4.2 BodyWeight 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 attermination. 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 ofadults until pairing. This was continued for males after the mating phase. For females showing evidence ofmating, 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 lactationperiod (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. Normalrange datafor pregnant and lactating females are presentedinAppendix 22.

3.4.4 Water Consumption Water intake was observed dailybyvisual inspection ofwaterbottles 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.

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### 3.4.5.1 

## Mating Animals were paired on a 1 

## male: 1 

## female basis within each dose group, for a period ofup 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 ofoestrus or the presence ofsperm was recorded. The presence ofsperm 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 ofgestation and lactation. 3.4.5.2 

## Pregnancy andParturition Eachpregnantfemale was observed at approximately 0830, 1230 

## and 1630 

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

## and 1230

## hours at weekends andpublic holidays. The following was recorded for each female: 1. Date ofpairing 11. Date ofmating m. Date and time ofobserved startofparturition 1v. Date andtime ofobserved completion ofparturition 3.4.5.3 

## Litter Data On completion ofparturition (Day O 

## postpartum), the number oflive and dead offspring was recorded. Offspring were individually identified within each litter by tattoo on Day 1

## post partum. For eachlitterthe following was recorded: 1. Number ofoffspringborn ii. Number ofoffspring alive recorded daily andreported onDays 1

## and 4postpartum m. Sex ofoffspring onDays 1

## and 4postpartum 1v. Clinical condition ofoffspring frombirthto Day 5postpartum v. Individual offspring weights on Days 1 

## and 4postpartum (litter weights were calculated retrospectively from this data) 3.4.5.4 

## Physical Development All live offspring were assessed for surfacerightingreflex onDay 1

## postpartum.

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## 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 5postpartum. 

## Surviving offspring were terminated via intracardiac overdose of sodium pentobarbitone. Any females which failed to achieve pregnancy orproduce alitterwere killed on or afterDay 25postcoitum. 

## For all females, the uterus was examined for signs ofimplantation and the number ofuterine 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 luteawere 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 OrganWeights 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 (postfixation) Normalranges for organweights are given inAppendix 24.

3.4.6.3 Histopathology Samples ofthe following tissues were preserved from all animals from each dose group, in buffered 10% formalin, exceptwhere stated: Coagulating gland Epididymides + Ovaries Mammary gland Prostate Seminal vesicles Testes+ Uterus/Cervix



## +Preservedin Bouin's fluid andthentransferredto Industrial Methylated Spirits (IMS) approximately

48 hours later

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## Pituitary Vagina Gross Lesions
Samples ofthe following tissues from five males and five females from each dose group were preservedinbuffered 10% formalin: Adrenals Brain (including cerebrum, cerebellum and pons) Caecum Colon Duodenum Heart Ileum Jejenum Kidneys Liver Lungs Lymphnodes (mandibular and mesenteric) Rectum Sciatic nerve Spinal cord ( cervical, mid-thoracic and lumbar) Spleen Stomach Thymus Trachea Urinarybladder 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 of5 μm and stained with Haematoxylin and Eosin for subsequent microscopic examination. In addition, sections oftestes from all control and 750 mg/kg bw/day males were also stained with Periodic Acid-Schiff(PAS) stainand examined. Microscopic examination was conducted by the Study Pathologist (P Millar at Peter Millar Associates Ltd.). A completehistopathologyphase report is presentedinAppendix 15.



## 3.4.7 Evaluation ofData 3.4.7.1 Treatment ofData Data were processed to give summary incidence or group mean values and standard deviations where appropriate. All datawere summarisedintabularform. Data shown in the appendices are frequently rounded values for presentation purposes. Group meanvalues are generally calculatedusingnon-roundedvaluestherefore is itnot always possible to calculatethe exactgroup values from the individual valuespresentedinthe appendices. For body weights and food consumptions during gestation, group mean values were calculated using data from females whichwere observedto give birthto offspring.

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### For body weights and food consumptions during lactation, group mean values were calculated using data from females withlive young atDay 5 oflactation.

3.4.7.2 Reproductive Indices Mating Performance andFertility The following parameters were calculated from the individual data during the mating period of theparental generation:

1. 

### Pre-coital Interval Calculated as the time elapsing between initial pairing and the observation ofpositive evidence ofmating.

11. 

### Fertility Indices Foreach groupthe following were calculated:
M . I d (o/) 

### Numberofanimalsmated x 100 atmg n ex ;ro = 

### Numberofanimalspaired
Numberofpregnantfemales x 100 PregnancyIndex (%) = 

### Numberofanimalsmated Gestation and ParturitionData The following parameters were calculated from individual data during the gestation and parturitionperiod ofthe parental generation:

1. 

### GestationLength Calculated as the number ofdays ofgestationincluding the day for observation ofmating andthe start ofparturition.

11. 

### ParturitionIndex The following was calculatedfor eachgroup: Numberof femalesdeliveringliveoffspring ParturitionIndex 

### (%)

## = x 100 

### Numberofpregnantfemales

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## 3.4.7.3 LitterResponses 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 meanvalues included all littersrearedto termination (Day 5 ofage).

1. 

## ImplantationLosses(%) Group mean percentile pre-implantation and post-implantation loss were calculated for eachfemale/litter as follows:

o/

. 

### 1 . 1 Numberof corporalutea

-Numberofimplantation sites 

## 100 

# ,opre-nnpantat10n oss

## = x Numberofcorporalutea



### . 1 . 1 Numberof implantation sites

- Totalnumberofoffspringborn 

### 100 %post-nnpantat1on oss- x Numberofimplantationsites

11. 

## Live Birth andViability Indices The following indices were calculatedfor eachlitter as follows: Numberof offspring aliveonDay 1 x 100 Live BirthIndex (%) = 

## Numberofoffspringborn Numberof offspring aliveonDay4 x 100 ViabilityIndex(%) = --------"'------"-----'-- 

## NumberofoffspringaliveonDay 1

111. 

## Sex Ratio(%males) Sex ratio was calculated for each litter value on Days 1 and 4postpartum, using the following formula: Number ofmale offspring x 100 Total number ofoffspring 3.4.7.4 StatisticalAnalysis 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 ofp<0.05. Statistical analysis wasperformed onthe 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

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## Body Weight Change, Offspring Surface Righting, Absolute Organ Weights, Body WeightRelative OrganWeights. Datawere analysed using the decisiontree from the Provantis

# TMTables and Statistics Module as detailed as follows: Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analysed using Bartlett's test. Intergroup variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covarities. Any transformed data were analysed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for nonparametric data. If

## no dose response was found but the data shows non-homogeneity ofmeans, 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 Studentt-test (parametric) or the MannWhitneyUtest (non-parametric). Datanot analysed bythe Provantis data capture system were assessed separatelyusing 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 ofthe 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 ofthe 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) ortheMann-WhitneyUtest (non-parametric). Due to the preponderance of non-normally distributed data, reproductive parameters (implantationlosses, offspring sex ratio and offspring surface righting) were analysed using nonparametric analyses. Probabilityvalues (p) are presented as follows: p<0.01 

# ** p<0.05 

# * p~0.05 (not significant)

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# 4 RESULTSAND DISCUSSION 4.1 Results 4.1.1 Adult Reponses 

## 4.1.1.1 Mortality There wereno unscheduled deaths duringthe study.

4.1.1.2 Clinical Observations A summary incidence of daily clinical observations is given in Table 2. Individual data is presentedinAppendix 1. No clinically observable signs oftoxicity were detected during the study. Clinical signs were confinedto the presence ofpost-dose increased salivation for tenmale andten female animals of either sex treated with 750 mg/kg bw/day. Isolated instances ofnoisy 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/kgbw/dayonDay 29 only. There were no further clinical observationsrecorded.

4.1.1.3 BodyWeight Group meanweeklybody 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 giveninAppendix 2 andAppendix 3. A slight reduction in body weight gains was evident for males treated with 750 mg/kg bw/day during the first two weeks oftreatment, 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 oftreatment, although statistical significance was only achieved during Week 1 when compared to controls. There was no difference in body weight change detected during the gestationphase for treated females in comparisonto controls, however, females treated at all

·dose levels showed a reduction in body weight gains during the lactation phase ofthe study in comparisonto the control group, although statistical significance was not achieved. There were no further differences in body weight change considered to be a result oftreatment withthetestitem.

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### Females treated with 50 mg/kg bw/day showed a statistically significant increase in cumulative body weight change from Days 

## Oto 

## 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 duringthe pre-pairing, gestationorlactationphases ofthe study.

4.1.1.5 Water Consumption Dailyvisual inspection ofwaterbottles didnotreveal 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 inTable 7. Individual dataare giveninAppendix 5. No treatment-related effects were detected in mating performance. The majority of animals matedwithinthe first four days ofpairing.

4.1.2.2 Fertility A summary ofadult performance is presented in Table 1. Group values for fertility, litter data and implantationlosses are giveninTables 7, 8 and 9. Individual dataare giveninAppendices 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 unrelatedto treatment.

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## 4.1.2.3 GestationLength 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 ofgestation between control and treated groups. Gestationlengths of22 to 23 

## Yz days were recorded for all pregnantfemales. 4.1.3 LitterResponses Intotal, elevenfemales from control, nine females from the 50 mg/kgbw/day dose group, twelve females from the 250 mg/kg bw/day, and eleven females treated with 750 mg/kg bw/day gave birthto a live litter and successfully reared young to Day 5 ofage. The following assessment of litterresponse is based onall litters rearedto termination onDay 5oflactation/age. 4.1.3.1 Offspring Litter Size, SexRatio andViability 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 dataare given inAppendices 6to 8. No differences in sex ratio or litter size were evident for offspring from treated litters when comparedto those from the controls. Statistical analysis ofthe data did notreveal any significant intergroup differences. No significant differences in the number ofcorpora lutea or implantation sites were noted for treated females whencomparedto controls. There were no toxicologically significant differences in the percentages of pre- and postimplantation loss for treated females were comparable to controls. Statistical analysis ofthe data revealed a statistically significant reduction in post-implantation loss for females treated with 50 mg/kgbw/day when comparedto controls. The significance was minimal, and would suggest increased intra-uterine survival for the low dose. In the absence ofa dose-related response, the lower implantationlosses were consideredto have arisenincidentally.

4.1.3.2 Offspring Growth andDevelopment Group mean values for total litter weights, offspring body weights and body weight changes, surface righting reflex and a summary incidence ofclinical signs are given in Tables 8, 11 and 12. Individualvalues and observations are given inAppendices 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 ofthe data did not reveal any significant intergroup differences. There were no clinically observable signs of toxicity observed in offspring.

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## No toxicologicallyimportant 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 inreproductive studies ofthis type and didnotrepresenttoxicity.



## 4.1.4 Pathology 4.1.4.1 Necropsy A summary incidence ofnecropsy findings for offspring and adults is given in Tables 13 and 14. Individual dataare given inAppendices 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 ofthis type and consideredto be unrelatedto toxicityofthe testitem. Adults There were no toxicologically significantmacroscopic 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 unrelatedto treatmentwiththetestitem. 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 inrats ofthe age and strain employed and unrelated to treatment with the testitem. A fibrous mass approximately 7mm3 

## was presented onthe median lobe ofthe lungs on one male treatedwith 50 mg/kg bw/day. Histopathological examinations confirmed this to bethepancreas withmoderate infarction. In isolation, this finding was consideredto have arisen incidentally and was unrelatedto treatmentwiththetest item. Increased pelvic space ofthe 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 consideredto be unrelatedto treatment.

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## 4.1.4.2 OrganWeights 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 dataare giveninAppendix 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 ofthe normally expectedranges. Females treated with 750 mg/kg bw/day showed an increase in absolute and relative liver weights when comparedto 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 withthe testitem. Males treated with 750 mg/kg bw/day showed a statistically significant reduction in seminal vesicle weightwhen comparedto controls (p<0.01). Althoughthere was one lowerthan 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 oftreatment (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 consideredto have arisen incidentally.

4.1.4.3 Histopathology A completehistopathologyphasereport is presentedinAppendix 15. No treatment-relatedmicroscopic changes were detected inthe tissues examined. All ofthe histopathological findings encountered were considered to have arisen spontaneously or atpostmortem.


## 4.2 Discussion The oral administration ofPMDA hydrolyzed to PMA to rats for a period ofup to eight weeks (including two weeks pre-pairing, gestation and early lactationperiod for females) at dose levels of 50, 250 and 750 mg/kg bw/day resulted in treatment-related changes at all dose levels assessed.

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## 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 ofa slightly unpalatable or irritant test item formulation. In the absence of any effects to suggest irritancy, these findings were considered notto represent systemictoxicity. A reduction in body weight gains, was evident for animals ofeither sex treated with 750 mg/kg bw/day during the first two weeks oftreatment when compared to controls. Females treated at all dose levels showed a reduction in body weight gain during the first four days ofthe lactation period, although statistical analysis did not show any significant intergroup differences when comparedto the control group. Post mortem examinations revealed an increase in thyroid/parathyroid weights for males treated with 750 mg/kg bw/day when comparedto controls, with a number ofindividual values outside ofthe 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 ofany treatment-related histopathological correlates, the toxicity ofthese findings was consideredto be minimal. In the absence of any adverse effects detected at any of the dose levels employed, the 'No ObservedAdverse Effect Level' (NOAEL) was consideredto 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/kgbw/day.

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# 5 CONCLUSION The oral administration ofPMDA hydrolyzed to PMA to rats by gavage, at dose levels of750, 250 and 50 mg/kg bw/day, did notresult in anytoxicologically significant adverse effects at any ofthe dose levels examined. The 'No Observed Adverse Effect Level' (NOAEL) for systemic toxicitywastherefore consideredto 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.

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# 6 REFERENCES SALEWSKI, E. (1964) Farbemethode zummakroskopischenNachweis vonImplantationsstellen am Uterus der Ratte. ArchExpPathPharmacol. Naunyn- Schmiedebergs, 247 p. 367.Harlan 

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# TABULAR SUMMARYREPORT OFEFFECTS OF REPRODUCTION/DEVELOPMENT

Observations Dose Level (mg/kg bw/day)

Paired animals Females showing evidence ofcopulation Pregnantfemales Conception Days 1-5 Conception Days 12-13 Gestation = 22 Days Gestation = 22 Yz Days Gestation = 23 Days Gestation = 23 YzDays Dams with live youngborn Dams with live young at Day 4postpartum Corporalutea/dam Implants/dam Live offspring/damDay 1postpartum Live offspring/dam atDay4postpartum Sexratio: %males Day 1postpartum Sex ratio: %males at Day 4postpartum Litter weight (g) atDay 1postpartum Litter weight (g) atDay4postpartum Male offspringweight (g) at Day 1postpartum Male offspringweight (g) atDay4postpartum Female offspringweight (g) at Day 1postpartum Female offspringweight (g) at Day4postpartum LOSS OFOFFSPRING/DAM Pre-implantation (corpora lutea minus implantations) 0 1 2 3 4 Pre-natal(implantations minus live births) 0 1 2 3 5 Postnatal (live births minus offspringalive on Day4

### 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 Page42

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

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### Report



# KEYTO TABLESANDAPPENDICES

M F S.D. N
1+ 

## 2+ 3+ H 

## PT PV p 

### NP 

### NIA 

# u



# .... % FoodEfficiency

StatisticalFootnotes: 

# * ** *** n 

### Male Female Standarddeviation Numberofanimals/litters Nodataavailable Occasional spermatozoapresent Continuousfew spermatozoainall fields Many spermatozoain all fields Haemorrhage Plugdetectedontrayliner Vaginalplug Pregnant Notpregnant(values excludedfrom mean and sd) Notapplicable Sexnotdetermined; priortowithinlitteridentification Priortowithinlitteridentification ( Groupmeanbodyweightgain(g/rat/period) ) xlOO

Groupmeanfoodconsumption(g/rat/day)x numberofdays

Significantlydifferentfrom control group p<0.05 Significantlydifferentfrom control groupp<0.01 Significantlydifferentfrom control groupp<0.001 Datanotappropriate for statistical analysis OrganWeightFootnotes: Epididys Epididymides Bodywt Bodyweight Page 43

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# TABLES

### Harlan Study

### Number: 41205015 Report



### Table 1 Summary ofReproductivePerformance - 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

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### Table2 Summary Incidence ofDaily 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 

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## Table2 (continued) SummaryIncidence ofDaily 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

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### Table3 Group Mean BodyWeightValues 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

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## Table 3 (continued) Group Mean Body WeightValues 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

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### Table3 (continued) Group MeanBodyWeightValues 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

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### Table4 Group Mean BodyWeight 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

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## Table4 (continued) Group Mean BodyWeightGains 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 StudyNumber: 

### 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 StudyNumber: 

### 41205015 Report



### Table5 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 StudyNumber: 

### 41205015 Report



## Table5 (continued) Group Mean Food ConsumptionsDay 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 StudyNumber: 

### 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 StudyNumber: 

### 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 StudyNumber: 

### 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 StudyNumber: 

### 41205015 Report Page 60



### Table 7 SummaryIncidence ofMatingPerformance, 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 StudyNumber: 

### 41205015 Report Page 61



### Table8 Group Mean Litter Size and LitterWeights 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 

### StudyNumber: 

### 41205015 Report Page 62



### Table9 Group MeanImplantation Losses and SurvivalIndices 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 StudyNumber: 

### 41205015 Report Page 63



### Table 10 Group Mean SexRatio 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 StudyNumber: 41205015 Report Page 64



## Table 11 Summary Incidence ofClinical 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) 1F (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 M2F (1) 1 F ( 1 ) 2F (2) Found dead 3M (3) 2F (2)



## ( ) =number of affected litters

### Harlan StudyNumber: 

### 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 StudyNumber: 

### 41205015 Report



## Table 13 SummaryIncidence ofOffspringNecropsy 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 StudyNumber: 

### 41205015



## Table 14 Summary Incidence ofNecropsy 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 StudyNumber: 

### 41205015 Report



### Table 14 (continued)SummaryIncidence ofNecropsyFindings 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 68Harlan StudyNumber: 

### 41205015 Report Page 69



### Table 15 Group Mean Organ Weightswith Corresponding Relative(% ofBodyWeight) 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 11Harlan StudyNumber: 

### 41205015 Report Page70



### Table 15 (continued)Group Mean OrganWeightswith CorrespondingRelative (% ofBodyWeight) OrganWeights 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 StudyNumber: 

### 41205015 Report Page71



### Table 15 (continued)Group Mean OrganWeightswith CorrespondingRelative (% ofBodyWeight) 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 StudyNumber: 41205015 Report Page 72



### Table 15 (continued)Group Mean Organ Weights with CorrespondingRelative (% ofBodyWeight) 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 StudyNumber: 

### 41205015 Report Page 73



# FIGURES

### Harlan StudyNumber: 41205015 Report Page74



## Figure 1 GroupMeanBodyWeights

- 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

### HarlanStudyNumber: 41205015 Report Page75



## Figure2 GroupMeanBodyWeights

- 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 DayVJ 

## El C'IS 

# ...**~** 

### Harlan StudyNumber: 41205015 Report Page 76



## Figure2 (continued) GroupMeanBodyWeights -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 StudyNumber: 41205015 Report Page 77



## Figure3 GroupMeanFood Consumption

- Males 

# IDO (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 StudyNumber: 41205015 Report Page78



## Figure4 GroupMeanFood Consumption

- Females 

# I aO (Control) l!l

### 50mg/kgbw/day • 

### 250mg/kgbw/day 

### •750mg/kgbw/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 StudyNumber: 

### 41205015 Report Page 79



# APPENDICES

### Harlan StudyNumber: 

### 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 StudyNumber: 

### 41205015 Report Page 81



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 82



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 

### StudyNumber: 

### 41205015 Report 

### Page 83



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 84



### Appendix 1 (continued) IndividualDaily 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

### StudyNumber: 

### 41205015 Report Page 85



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 86



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 87



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 88



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 89



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 90



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 91



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 92



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 93



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 94



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 95



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page96



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 97



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 98



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 99



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 100



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 101



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 102



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 103



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 104



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 105



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 106



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 107



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 108



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 109



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 110



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 111



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 112



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 41205015 Report Page 113



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 114



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 115



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 116



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 

### StudyNumber: 

### 41205015 Report Page 117



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 118



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 

### StudyNumber: 

### 41205015 Report Page 119



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 120



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 121



### Appendix 1 (continued) IndividualDaily ClinicalObservations 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 StudyNumber: 

### 41205015 Report Page 122



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 123



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 124



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 125



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 126



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 127



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 128



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 129



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 130



### Appendix 1 (continued) IndividualDaily 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

### HarlanStudyNumber: 

### 41205015 Report Page 131



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 132



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 133



### Appendix 1 (continued) IndividualDaily 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/dayHarlan StudyNumber: 

### 41205015 Report



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 135



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 136



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 137



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 138



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 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 StudyNumber: 

### 41205015 Report Page 140



### Appendix 1 (continued) IndividualDaily 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 

### StudyNumber: 

### 41205015 Report Page 141



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 142



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 143



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 144



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015 Report Page 145



### Appendix 1 (continued) IndividualDaily 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 StudyNumber: 

### 41205015



### Appendix 1 (continued) Report



### IndividualDaily 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 StudyNumber: 

### 41205015 Report



### Appendix 1 (continued) IndividualDaily 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