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STUDY TITLE

 ( 14-DAY PALATABILITY AND DOSE RANGEFINDING STUDY IN FEMALE F344/DuCrl RATS

Test Guidelines

Not Applicable 

Author(s)

Study Completion Date

03 August 2012

Sponsor

The Dow Chemical Company

Midland, Michigan 48674 

Performing Laboratory 

Toxicology & Environmental Research and Consulting 

The Dow Chemical Company

Midland, Michigan 48674 

Laboratory Project Study ID 

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COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS 

Compound: 

Title: ( 14-DAY PALATABILITY AND 

DOSE RANGE-FINDING STUDY IN FEMALE F344fDuCrl RATS 

This report does not meet the definition of a GLP study as it appears in: 

United States Environmental Protection Agency 

Title 40 Code of Federal Regulations Part 160 

Federal Register, 17 August 1989 

Organization for Economic Cooperation and Development 

ENVILMC/CHEM(98) 17, Paris - January 26, 1998 

NON-GlP STUDY 

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SIGNATURE PAGE 

Compound: 

THE DOW CHEMICAL COMPANY 

STUDY 10: 

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Title: ( 14-DAY PALATABILITY AND 

DOSE RANGE-FINDING STUDY IN FEMALE F344IDuCrl RATS 

Diplomate, American College of Veterinary Pathologists 

Lead Scientist 

Study Director 

Study Pathologist 

Co-Author 

Reviewed by: 

USEPA TSCA 8(e)/FIFRA 6(a)(2) ASSESSMENT ~ - \ \ 

This test material has been reviewed for possible TSCA 8(e)/FIFRA 6(a)(2) submission _.... :J+-I2-_~\. O~ l)"?> \" 

InitialsIDate 

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TABLE OF CONTENTS

Page

STUDY TITLE ............................................................................................................... 1

COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS ............. 2

SIGNATURE PAGE ...................................................................................................... 3

SUMMARY .................................................................................................................... 7

INTRODUCTION .......................................................................................................... 8

Purpose ....................................................................................................................... 8

Test Guidelines........................................................................................................... 8

Archiving ................................................................................................................... 8

Safety.......................................................................................................................... 8

TEST MATERIAL INFORMATION ............................................................................ 8

Test Material Name .................................................................................................... 8

Chemical Name .......................................................................................................... 8

Synonyms ................................................................................................................... 8

Supplier, City, State (Lot, Reference Number) .......................................................... 8

Purity/Characterization (Method of Analysis and Reference) ................................... 9

Characteristics ............................................................................................................ 9

Molecular Formula .................................................................................................. 9

Molecular Weight .................................................................................................... 9

Chemical Structure .................................................................................................. 9

CAS Number ........................................................................................................... 9

Vehicle ....................................................................................................................... 9

Previous Toxicity Information ................................................................................... 9

STUDY DESIGN.......................................................................................................... 10

Experimental Design and Critical Dates .................................................................. 10

Route and Justification, Method of Administration, Frequency and Duration ........ 10

Dose Levels and Justification................................................................................... 10

Text Table 1. Dose Levels .................................................................................... 10

Dose Preparation ...................................................................................................... 10

Analysis .................................................................................................................... 11

Dose Confirmation, Homogeneity, and Stability .................................................. 11

Retainer Samples ................................................................................................... 11

TEST SYSTEM ............................................................................................................ 11

Species and Sex ........................................................................................................ 11

Strain and Justification ............................................................................................. 11

Supplier and Location .............................................................................................. 11

Age at Study Start .................................................................................................... 11

Physical and Acclimation ......................................................................................... 11

Housing .................................................................................................................... 12

Enrichment ............................................................................................................... 12

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TABLE OF CONTENTS

Page

Randomization and Identification ............................................................................ 12

Text Table 2. Animal Identification Numbers ..................................................... 12

Feed and Water ........................................................................................................ 13

Animal Welfare ........................................................................................................ 13

STUDY SPECIFIC PARAMETERS ............................................................................ 13

Daily Observations ................................................................................................... 13

Body Weights/Body Weight Gains .......................................................................... 14

Feed Consumption ................................................................................................... 14

Test Material Intake ................................................................................................. 14

Clinical Pathology .................................................................................................... 14

Clinical Chemistry ................................................................................................. 14

Anatomic Pathology ................................................................................................. 15

STATISTICS AND CALCULATIONS ....................................................................... 15

RESULTS ..................................................................................................................... 16

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

Cage-Side Observations ........................................................................................... 16

Feed Consumption ................................................................................................... 16

Body Weights/Body Weight Gain ........................................................................... 16

Test Material Intake ................................................................................................. 16

Clinical Pathology .................................................................................................... 16

Clinical Chemistry ................................................................................................. 16

Anatomic Pathology ................................................................................................. 17

Organ Weight ........................................................................................................ 17

Gross Pathology..................................................................................................... 17

CONCLUSIONS........................................................................................................... 17

ACKNOWLEDGEMENTS .......................................................................................... 17

REFERENCES ............................................................................................................. 18

FIGURES ...................................................................................................................... 19

FIGURE 1. Body Weights .................................................................................... 19

FIGURE 2. Cumulative Body Weight Gains ....................................................... 20

TABLES ....................................................................................................................... 21

TABLE 1. Study Design....................................................................................... 21

TABLE 2. Feed Consumption (g/day) Summary ................................................. 22

TABLE 3. Body Weight/Body Weight Gains Summary (g) ................................ 24

TABLE 4. Test Material Intake Summary ........................................................... 27

TABLE 5. Clinical Chemistry Summary ............................................................. 28

TABLE 6. Organ and Organ/Body Weights Summary ........................................ 29

TABLE 7. Gross Pathological Observations ........................................................ 30

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TABLE OF CONTENTS

Page

APPENDICES .............................................................................................................. 35

APPENDIX TABLE 1. Individual Feed Consumption (g/day) ........................... 35

APPENDIX TABLE 2. Individual Body Weight/Body Weight Gains (g) .......... 37

APPENDIX TABLE 3. Individual Clinical Chemistry ........................................ 40

APPENDIX TABLE 4. Individual Organ and Organ/Body Weights .................. 41

APPENDIX TABLE 5. Individual Animal Pathology Report ............................. 42

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SUMMARY 

Three female F344/DuCrl rats per group were given test diets formulated to supply 0, 250, 

500, or 1000 milligrams ( kilogram body weight/day (mg/kg/day, 

mkd) for 15 days to evaluate dietary tolerance and palatability. These dietary levels 

corresponded to time-weighted average doses of 0, 258, 522, or 1022 mg/kg/day. 

Parameters evaluated were daily cage-side observations, body weights, body weight gains, 

feed consumption, clinical chemistry, liver and kidney weights, and gross pathology. 

There were no treatment-related effects in cage-side observations, body weights, body 

weight gains, feed consumption, clinical chemistry parameters, and liver or kidney weights. 

There were no treatment-related gross observations at necropsy. 

Based on these observations, rodent diets containing targeted doses of up to and 

including 1000 mg/kg/day were considered palatable to F344/DuCrl rats to be used for the 

subsequent 28-day dietary toxicity study. 

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INTRODUCTION

Purpose

The purpose of this study was to evaluate dietary tolerance and palatability of 

( following dietary administration for 15 consecutive days in order to set 

appropriate dose-levels for a subsequent 28-day dietary toxicity guideline study (OECD 

407). 

Test Guidelines

This report outlines a palatability/dietary tolerance study for which no test guidelines 

exist. 

Archiving

The data, protocol, protocol changes/revisions, if applicable, and final report were 

archived by the Toxicology & Environmental Research and Consulting archivist and 

stored at The Dow Chemical Company, Midland, Michigan. 

Safety

All personnel involved in the study were advised of the safety precautions to follow when 

handling the test material and treated animals prior to study initiation. Chemical safety 

information was made available.

TEST MATERIAL INFORMATION

Test Material Name 

Chemical Name

Synonyms 

Supplier, City, State (Lot, Reference Number) 

The Dow Chemical Company, Midland, Michigan (Lot# Batch 

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Purity/Characterization (Method of Analysis and Reference)

The purity of the test material was determined to be ± by gas 

chromatography with identification by Fourier transform infrared spectroscopy and gas 

chromatography mass spectrometry

Characteristics

Molecular Formula

Molecular Weight

CAS Number

Vehicle

LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) 

Previous Toxicity Information 

In an acute oral (Up-and-Down Procedure) five female Wistar Han rats were 

administered suspended in corn oil as a single oral dose and observed for 14 days 

post treatment All animals were subjected to necropsy at sacrifice and 

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there were no abnormalities detected in any of the rats. The estimated acute oral LD50

was greater than 2000 mg/kg body weight. 

STUDY DESIGN

Experimental Design and Critical Dates

Three female F344/DuCrl rats per group were fed diets supplying 0, 250, 500, or 1000 

mg kg/day for 15 days to evaluate dietary tolerance and palatability. Parameters 

evaluated consisted of daily cage-side observations, body weights, feed consumption, 

clinical chemistry, liver and kidney weights and gross pathological observations at 

necropsy (Table 1). Test material administration for all animals began on May 15, 2012. 

Rats were necropsied on May 30, 2012. 

Route and Justification, Method of Administration, Frequency and Duration 

The oral route was selected because it represented a possible route of human exposure. 

Thus, oral administration of the test material to rats via the diet represented an 

appropriate route of exposure. Animals were fed treated diets seven days/week for 15 

days.

Dose Levels and Justification 

The dose levels selected are shown in Text Table 1. The high-dose of 1000 mg/kg/day 

represented the OECD test limit. The remaining dose levels were expected to provide 

dose-response data for any treatment-related effects observed in the high-dose group. 

Text Table 1. Dose Levels

Dose Levels

(mg/kg/day)* No. of Female Rats/Dose

0 3 

250 3 

500 3 

1000 3 

TOTAL 12 

 * Dose levels were not corrected for purity

Dose Preparation

Diets were prepared by serially diluting a concentrated test material-feed mixture 

(premix) with ground feed. The appropriate concentrations of the test material mixed in 

the diet were calculated based on pre-study (test day -4 to -1) body weight and feed 

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consumption data. The concentrations of the test material in the diets were not adjusted 

for purity.

Analysis 

Dose Confirmation, Homogeneity, and Stability

Dose confirmation and homogeneity analyses were not conducted due to the probe 

nature of this study. Stability analyses were conducted concurrently in a separate 

analytical study. ( was reported to be stable for 36 days 

in the feed at concentrations ranging from 0.005 to 10% 

Retainer Samples

Due to the short duration of this study, retainer samples were not taken. 

TEST SYSTEM

Species and Sex

Rats (female) (nulliparous and non-pregnant) 

Strain and Justification 

F344/DuCrl rats were selected because of their general acceptance and suitability for 

toxicity testing, availability of historical background data and the reliability of the 

commercial supplier. Female rats were selected because they are generally the more 

sensitive of the sexes to palatability issues.

Supplier and Location

Charles River (CR) (Kingston, New York) 

Age at Study Start 

Approximately 7 weeks 

Physical and Acclimation 

During the acclimation period each animal was evaluated by a laboratory veterinarian, or 

a trained animal/toxicology technician under the direct supervision of a laboratory 

veterinarian, to determine the general health status and acceptability for study purposes. 

The animals were housed two-three per cage in stainless steel cages, in rooms designed to 

maintain adequate conditions (temperature, humidity, and photocycle), prior to 

randomization. Animals were acclimated to the laboratory (fully accredited by the 

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Association for Assessment and Accreditation of Laboratory Animal Care International -

AAALAC International) for approximately one week prior to the start of the study. 

Housing

After assignment to the study, animals were housed one per cage in stainless steel, solid 

bottom cages. Ground corn cob and shredded aspen bedding was used in the cages

(Harlan Laboratories, Inc., Indianapolis, Indiana). Cages contained a feed crock and a 

pressure activated lixit valve-type watering system. The following environmental 

conditions were maintained in the animal room.

Temperature: 22°C with a tolerance of ± 1°C (and a maximum 

permissible excursion of ± 3°C) 

Humidity: 40-70% 

Air Changes: 12-15 times/hour (average) 

Photoperiod: 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.) 

Enrichment

Enrichment for rats included the use of ground corn cob and shredded aspen bedding and 

open areas on the cage sides for visualization of other rats. 

Randomization and Identification 

Before administration of the test material began, animals were stratified by body weight 

and then randomly assigned to treatment groups (test day -5) using a computer program 

designed to increase the probability of uniform group mean weights and standard 

deviations at the start of the study. Animals placed on study were uniquely identified via 

subcutaneously implanted transponders (BioMedic Data Systems, Seaford, Delaware) 

that were correlated to unique alphanumeric identification numbers as shown in Text 

Table 2. 

Text Table 2. Animal Identification Numbers

Dose Level

mg/kg/day Females

0 12A2852-12A2854 

250 12A2855-12A2857 

500 12A2858-12A2860 

1000 12A2861-12A2863 

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Feed and Water 

Animals were provided LabDiet Certified Rodent Diet #5002 (PMI Nutrition 

International, St. Louis, Missouri) in meal form. Feed and municipal water were

provided ad libitum. Analyses of the feed were performed by PMI Nutrition International 

to confirm the diet provided adequate nutrition and to quantify the levels of selected

contaminants. Drinking water obtained from the municipal water source was periodically 

analyzed for chemical parameters and biological contaminants by the municipal water 

department. In addition, specific analyses for chemical contaminants were conducted at 

periodic intervals by an independent testing facility. Copies of these analyses are 

maintained in the study file. There were no contaminants at levels that would have 

interfered with the study results or interpretation.

Animal Welfare 

In accordance with the U.S. Department of Agriculture animal welfare regulations, 9 

CFR, Subchapter A, Parts 1-4, the animal care and use activities required for conduct of 

this study were reviewed and approved by the Institutional Animal Care and Use 

Committee (IACUC). The IACUC determined that the proposed Activities were in full 

accordance with these Final Rules. The IACUC-approved Animal Care and Use 

Activities used for this study were Subchronic/Chronic Tox 01, Humane Endpoints 01, 

and Animal ID 01. 

STUDY SPECIFIC PARAMETERS

Daily Observations 

A cage-side examination was conducted at least once a day, approximately at the same 

time each day (usually in the morning). This examination was typically performed with 

the animals in their cages and was designed to detect significant clinical abnormalities 

that were clearly visible upon a limited examination, and to monitor the general health of 

the animals. The animals were not hand-held for these observations unless deemed 

necessary. Significant abnormalities that could have been observed included, but were 

not limited to: decreased/increased activity, repetitive behavior, vocalization, 

incoordination/limping, injury, neuromuscular function (convulsion, fasciculation, 

tremor, and twitches), altered respiration, blue/pale skin and mucous membranes, severe 

eye injury (rupture), alterations in fecal consistency, and fecal/urinary quantity. In 

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addition, all animals were observed for morbidity, mortality, and the availability of feed 

and water at least twice daily.

Body Weights/Body Weight Gains 

All animals were weighed pre-exposure, (test days -4, -3, -2, and -1), daily throughout the 

study, and prior to necropsy on test day 16 (terminal). Body weight gains were 

calculated relative to day 1. 

Feed Consumption

The amount of feed consumed was determined prior to treatment (test days -4 to -3, -3 to 

-2, and -2 to -1) and daily throughout the treatment period for all animals by weighing 

feed containers at the start and end of a measurement cycle. Feed consumption was 

calculated using the following equation: 

Feed consumption (g/day) = (initial weight of feed container - final weight of feed container)

(# of days in measurement cycle) 

Test Material Intake

The test material intake (TMI, expressed as mkd) was calculated using feed

concentrations, body weights and feed consumption data in the following equation: 

Clinical Pathology 

Animals were fasted overnight prior to blood collection. Blood samples were obtained 

from the orbital sinus following anesthesia with CO2/O2 at the scheduled necropsy. 

Clinical Chemistry

Sample Preparation 

Blood samples were collected and serum was separated from cells as soon as 

possible. Serum parameters were measured using a cobas c311 Clinical 

Chemistry Analyzer (Roche Diagnostics, Indianapolis, Indiana). 

 1000 g/kg

2

Current [g]BW Previous [g]BW 

100

(% of test material in feed) (1000 ) mg/g) dayg (feed consumptio n 





 



 +

∗ ∗ 















TMI =

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Enzyme Activities of:

Alkaline phosphatase (ALP) 

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Gamma-glutamyl transpeptidase (GGT) 

Concentrations of: 

Albumin (ALB) 

Albumin/Globulin Ratio (A/G) - calculated

Cholesterol (CHOL) 

Creatinine (CREA)

Electrolytes (NA, K, PHOS, CL and CA)

Globulin (GLOB) - calculated

Glucose (GLUC)

Total bilirubin (TBIL)

Total protein (TP) 

Triglycerides (TRIG)

Urea nitrogen (UN)

Anatomic Pathology

Fasted rats, submitted alive for necropsy were anesthetized by the inhalation of CO2/O2 and 

blood samples obtained from the orbital sinus. Their tracheas were exposed and clamped, 

and the animals were euthanized by decapitation. A complete gross necropsy was

conducted on all animals by a veterinary pathologist assisted by a team of trained 

individuals. The necropsy included an examination of the external tissues and all orifices. 

The head was removed, the cranial cavity opened, and the brain, pituitary and adjacent 

cervical tissues examined. The eyes were examined in situ by application of a moistened 

microscope slide to each cornea. The skin was reflected from the carcass, the thoracic and 

abdominal cavities were opened and the viscera examined. All visceral tissues were 

dissected from the carcass, re-examined and selected tissue were incised. The liver and 

kidneys were trimmed, weighed and preserved in neutral, phosphate-buffered 10% 

formalin. The ratios of liver or kidney weights to terminal body weight were calculated. 

Microscopic examination of tissues was not conducted. 

STATISTICS AND CALCULATIONS

Descriptive statistics only (means and standard deviations) were reported for body 

weight, body weight gains, feed consumption, clinical chemistry, and organ weight data.

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RESULTS

Mortality

All rodents survived the 15-day test period. 

Cage-Side Observations

There were no cage-side observations in any treatment group noted during the study 

period (data maintained in the study file).

Feed Consumption

Mean feed consumption data are summarized in Table 2 and individual data are reported 

in Appendix Table 1. There were no treatment related differences in the feed 

consumption in any of the treatment groups when compared to the controls. 

Body Weights/Body Weight Gain 

Mean body weight and body weight gain data are presented in Figures 1 & 2, 

summarized in Table 3 and individual data are reported in Appendix Table 2. There were 

no treatment-related differences in the body weights in any treatment group throughout 

the study when compared to controls. At study termination, body weight gains relative to 

test day 1 were similar to the controls in all of the treatment groups.

Test Material Intake

Test material intake data are summarized in Table 4. Rats were given diets formulated to 

provide 0, 250, 500, or 1000 mg/kg/day, which corresponded to time-weighted average 

doses of 0, 258, 522, or 1022 mg/kg/day, respectively, at the end of the study. 

Clinical Pathology 

Clinical Chemistry

Clinical chemistry data are summarized in Table 5 and individual data are reported 

in Appendix Table 3. There were no treatment-related alterations in any of the 

clinical chemistry parameters.

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Anatomic Pathology

Organ Weight

Terminal body and organ weight data are summarized in Table 6; individual data 

are reported in Appendix Table 4. There were no treatment-related alterations in 

the liver or kidney weights.

Gross Pathology

There were no gross pathologic observations (Table 7 and Appendix Table 5). 

CONCLUSIONS

There were no treatment-related effects in cage-side observations, body weights, body 

weight gains, feed consumption, clinical chemistry parameters, and liver or kidney 

weights. There were no treatment-related gross observations at necropsy. 

Based on these observations, rodent diets containing targeted doses of up to and 

including 1000 mg/kg/day were considered palatable to F344-DuCrl rats to be used for 

the subsequent 28-day dietary toxicity study. 

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the contributions of the following individuals to the 

conduct of the study and report preparation: 

Clinical Pathology

Document Management 

Laboratory Veterinarian 

Mammalian Toxicology Technologist 

Animal Technician

Necropsy Crew and Animal Care Staff

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REFERENCES

Organisation for Economic Co-operation and Development, OECD Guidelines for 

Testing of Chemicals. Guideline Number 407 (Repeated Dose 28-day Oral 

Toxicity Study in Rodents), 03 October 2008. 

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

FIGURE 1. Body Weights 

130

135

140

145

150

155

160

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

BODY WEIGHT (G)

TEST DAYS

0 MKD

250 MKD

500 MKD

1000 MKD

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

FIGURE 2. Cumulative Body Weight Gains 

0

4

8

12

16

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

BODY WEIGHT GAINS (G)

TEST DAYS

0 MKD

250 MKD

500 MKD

1000 MKD

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING 

STUDY IN FEMALE F344/DuCrl RATS

TABLE 1. Study Design

Study Parameters No. of Animals/Dose 

Body Weights 3 

Feed Consumption 3 

Cage-Side Clinical Observations 3 

Clinical Chemistry 3 

Necropsy 3 

Organ Weights 3 

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 2. Feed Consumption (g/day) Summary

 DAYS ON TEST

 DOSE --------------------------------------------------------

MKD 1-2 2-3 3-4 4-5 5-6 6-7 7-8 

 =========================================================================

0 MEAN 10.3 9.9 9.9 10.2 11.1 10.8 10.2

 S.D. 0.6 0.3 0.7 0.5 0.6 1.4 1.1

N= 3 3 3 3 3 3 3

 250 MEAN 10.2 9.6 10.2 9.6 11.0 10.2 9.9

 S.D. 0.6 1.3 0.5 0.9 0.5 1.4 1.0

N= 3 3 3 3 3 3 3

 500 MEAN 10.0 9.8 10.4 10.1 11.2 10.6 9.2

 S.D. 0.7 1.8 1.3 0.8 0.3 0.9 0.5

N= 3 3 3 3 3 3 3

 1000 MEAN 9.9 9.2 9.7 10.4 10.6 11.1 10.0

 S.D. 0.1 0.8 0.7 1.6 1.1 1.1 0.7

N= 3 3 3 3 3 3 3

 =========================================================================

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 2. Feed Consumption (g/day) Summary (continued)

 DAYS ON TEST

 DOSE --------------------------------------------------------

MKD 8-9 9-10 10-11 11-12 12-13 13-14 14-15

 =========================================================================

0 MEAN 10.8 11.0 11.4 11.4 11.7 10.7 10.1

 S.D. 0.8 1.3 0.7 0.5 0.2 0.6 0.9

N= 3 3 3 3 3 3 3

 250 MEAN 10.6 10.2 9.7 11.3 10.6 10.3 10.2

 S.D. 0.6 0.9 0.8 0.4 0.5 0.6 0.3

N= 3 3 3 3 3 3 3

 500 MEAN 10.7 10.7 10.9 11.2 10.9 10.4 10.0

 S.D. 1.6 0.7 1.3 0.8 0.9 0.8 0.7

N= 3 3 3 3 3 3 3

 1000 MEAN 10.2 10.6 11.2 11.0 10.8 10.0 10.4

 S.D. 1.6 1.3 1.2 1.6 0.8 0.4 1.7

N= 3 3 3 3 3 3 3

 =========================================================================

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 3. Body Weight/Body Weight Gains Summary (g)

 DAYS ON TEST

 DOSE --------------------------------------------------------------------------------------------------------

 MKD 1 2 GAIN 3 GAIN 4 GAIN 5 GAIN 6 GAIN 7 GAIN

 =========================================================================================================================

 0 MEAN 133.8 134.9 1.0& 135.0 1.1& 135.0 1.1& 137.0 3.2& 139.7 5.9& 141.4 7.5&

 S.D. 2.9 1.2 1.7 1.5 1.6 3.0 0.2 3.2 0.5 3.9 1.3 4.6 2.1

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 250 MEAN 132.6 134.7 2.1& 134.1 1.5& 135.5 2.9& 135.8 3.2& 138.4 5.8& 139.8 7.2&

 S.D. 1.7 2.0 0.7 2.8 1.6 1.9 0.2 2.3 0.6 2.6 0.9 3.9 2.1

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 500 MEAN 132.7 133.9 1.2& 134.1 1.4& 135.2 2.6& 137.3 4.7& 139.6 6.9& 141.5 8.8&

 S.D. 1.8 2.1 0.5 4.4 2.6 2.7 2.0 1.3 0.8 1.7 0.9 2.7 1.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 1000 MEAN 133.6 135.5 2.0& 135.7 2.1& 136.1 2.6& 138.7 5.1& 140.1 6.5& 141.8 8.2&

 S.D. 6.0 5.4 1.0 5.9 1.7 4.7 1.6 4.9 1.8 5.9 1.8 5.4 2.3

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 =========================================================================================================================

 & INDICATES NO STATISTICAL COMPARISON OF MEANS.

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 3. Body Weight/Body Weight Gains Summary (g) (continued)

 DAYS ON TEST

 DOSE --------------------------------------------------------------------------------------------------------

 MKD 1 8 GAIN 9 GAIN 10 GAIN 11 GAIN 12 GAIN 13 GAIN

 =========================================================================================================================

 0 MEAN 133.8 142.3 8.5& 143.4 9.6& 146.7 12.9& 148.1 14.3& 148.6 14.8& 149.9 16.1&

 S.D. 2.9 3.8 1.0 5.3 2.5 5.6 2.8 5.0 2.2 4.6 1.8 2.5 0.6

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 250 MEAN 132.6 140.6 8.0& 141.9 9.3& 144.5 11.9& 144.8 12.2& 146.1 13.5& 147.1 14.5&

 S.D. 1.7 3.2 1.6 4.1 2.4 2.2 0.6 3.7 2.0 2.5 0.8 3.6 1.9

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 500 MEAN 132.7 140.6 8.0& 142.7 10.1& 144.5 11.8& 147.3 14.7& 147.9 15.3& 148.0 15.4&

 S.D. 1.8 3.1 1.7 2.8 1.5 2.0 1.9 2.8 1.0 3.9 2.2 4.2 3.3

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 1000 MEAN 133.6 143.4 9.9& 143.5 9.9& 145.2 11.7& 147.8 14.3& 149.3 15.8& 149.5 15.9&

 S.D. 6.0 5.3 1.4 5.2 1.3 5.0 3.3 5.6 3.9 6.1 3.7 4.9 3.5

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 =========================================================================================================================

 & INDICATES NO STATISTICAL COMPARISON OF MEANS.

 THERE WERE NO STATISTICAL DIFFERENCES FROM CONTROL AT ALPHA=0.05.

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STUDY ID: 

PAGE 26

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 3. Body Weight/Body Weight Gains Summary (g) (continued)

 DAYS ON TEST

 DOSE ----------------------------------------

MKD 1 14 GAIN 15 GAIN

=========================================================

0 MEAN 133.8 150.8 16.9& 151.0 17.1&

 S.D. 2.9 5.2 2.3 4.8 2.0

N= 3 3 3 3 3

 250 MEAN 132.6 147.9 15.3& 148.3 15.7&

 S.D. 1.7 2.7 1.3 3.0 1.4

N= 3 3 3 3 3

 500 MEAN 132.7 149.2 16.5& 149.5 16.8&

 S.D. 1.8 2.0 1.5 2.2 0.8

N= 3 3 3 3 3

 1000 MEAN 133.6 149.7 16.2& 151.1 17.5&

 S.D. 6.0 4.6 3.2 6.1 5.2

N= 3 3 3 3 3

 =========================================================

& INDICATES NO STATISTICAL COMPARISON OF MEANS.

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STUDY ID: 

PAGE 27

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 4. Test Material Intake Summary

DOSE 0 MKD 250 MKD 500 MKD 1000 MKD

Feed 

Period

(in Days)

Day(s) PPMa MKDb % Test 

Materia

l in 

Diet

PPMa MKDb % Test 

Material 

in Diet

PPMa MKDb % Test 

Material 

in Diet

PPMa MKDb

1-2 1 0 0 0.352 3521 269 0.704 7041 528 1.41 14082 1036

2-3 1 0 0 0.352 3521 251 0.704 7041 515 1.41 14082 955

3-4 1 0 0 0.352 3521 266 0.704 7041 544 1.41 14082 1005

4-5 1 0 0 0.352 3521 249 0.704 7041 522 1.41 14082 1066

5-6 1 0 0 0.352 3521 282 0.704 7041 570 1.41 14082 1071

6-7 1 0 0 0.352 3521 258 0.704 7041 531 1.41 14082 1109

7-8 1 0 0 0.352 3521 249 0.704 7041 459 1.41 14082 988

8-9 1 0 0 0.355 3550 266 0.712 7120 538 1.41 14051 999

9-10 1 0 0 0.355 3550 253 0.712 7120 531 1.41 14051 1032

10-11 1 0 0 0.355 3550 238 0.712 7120 532 1.41 14051 1074

11-12 1 0 0 0.355 3550 276 0.712 7120 540 1.41 14051 1040

12-13 1 0 0 0.355 3550 257 0.712 7120 525 1.41 14051 1016

13-14 1 0 0 0.355 3550 248 0.712 7120 498 1.41 14051 939

14-15 1 0 0 0.355 3550 244 0.712 7120 477 1.41 14051 972

Time Weighted Avg.c 0 0 3535 258 7081 522 14067 1022

±SDd 15.1 12.7 41.0 28.0 16.1 48.9

14 Sum of Days

a

PPM = % Test Material in 

diet * 10000

b

MKD = (PPM * Food consumption (mg/day) for that period) / (Average 

body weight (kg) for that period) c

TWA = Time Weighted Average = Sum (PPM or MKD period * number of 

days for that period) / sum of all days d

SD = Standard 

Deviation

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STUDY ID: 

PAGE 28

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 5. Clinical Chemistry Summary

 UN ALT ALP AST TP ALB GLOB A/G CHOL TRIG TBIL CREA GGT

 DOSE MG/DL U/L U/L U/L G/DL G/DL G/DL RATIO MG/DL MG/DL MG/DL MG/DL U/L

 MKD

 =========================================================================================================================

 0 MEAN 17 38 140 88 6.6 4.5 2.0 2.2 74 27 0.05 0.3 1.5

 S.D. 1 4 11 14 0.3 0.2 0.2 0.1 3 2 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 250 MEAN 19 45 138 93 6.6 4.6 2.0 2.2 75 28 0.05 0.3 1.5

 S.D. 3 6 27 15 0.4 0.2 0.2 0.2 4 4 0.00 0.1 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 500 MEAN 17 38 128 84 6.7 4.6 2.1 2.2 82 26 0.05 0.3 1.5

 S.D. 1 2 2 3 0.3 0.1 0.3 0.2 9 3 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 1000 MEAN 17 40 124 83 6.5 4.5 2.0 2.3 77 30 0.05 0.3 1.5

 S.D. 1 5 13 8 0.1 0.0 0.1 0.2 2 6 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 =========================================================================================================================

 TBIL LOWEST DETECTION LIMIT IS 0.10. INDIVIDUAL VALUES <0.10 WERE REPORTED AS 0.05 (ONE-HALF THE DETECTION LIMIT) FOR

 STATISTICAL ANALYSIS. 

 GGT LOWEST DETECTION LIMIT IS 3.0. INDIVIDUAL VALUES <3.0 WERE REPORTED AS 1.5 (ONE-HALF THE DETECTION LIMIT) FOR 

 STATISTICAL ANALYSIS. 

 UN=UREA NITROGEN, ALT=ALANINE AMINOTRANSFERASE, ALP=ALKALINE PHOSPHATASE, AST=ASPARTATE AMINOTRANSFERASE, 

 TP=TOTAL PROTEIN, ALB=ALBUMIN, GLOB=GLOBULIN, A/G=RATIO OF ALBUMIN/GLOBULIN, CHOL=CHOLESTEROL, TRIG=TRIGLYCERIDES, 

 TBIL=TOTAL BILIRUBIN, CREA=CREATININE, GGT=GAMMA GLUTAMYL TRANSPEPTIDASE

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PAGE 29

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 6. Organ and Organ/Body Weights Summary

 FINAL KIDNEYS LIVER

 DOSE BODY --------------------------------

MKD WT. (G) (G) (G/100) (G) (G/100)

=========================================================

0 MEAN 136.8 1.009 0.738 3.924 2.867

 S.D. 6.1 0.038 0.050 0.246 0.068

N= 3 3 3 3 3

 250 MEAN 134.6 0.965 0.717 3.952 2.937

 S.D. 1.2 0.071 0.046 0.232 0.155

N= 3 3 3 3 3

 500 MEAN 136.0 0.985 0.725 3.868 2.845

 S.D. 0.9 0.016 0.016 0.165 0.117

N= 3 3 3 3 3

 1000 MEAN 137.5 0.982 0.714 3.925 2.853

 S.D. 4.0 0.070 0.032 0.284 0.136

 N= 3 3 3 3 3

 =========================================================

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STUDY ID: 

PAGE 30

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 7. Gross Pathological Observations

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

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

Removal Reasons: All of those SELECTED -----------------------------------

 0 250 500 1000 

MKD MKD MKD MKD 

 Number of Animals on Study : 3 3 3 3

Number of Animals Completed: (3) (3) (3) (3)

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

ADRENAL GLANDS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

AORTA;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

AUDITORY SEBACEOUS GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

BONE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

BONE - JOINT;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

BONE MARROW;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

BRAIN;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

CECUM;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

CERVIX;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

COLON;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

CRANIAL NERVE - OPTIC;

 Submitted........................................................................................ (3) (3) (3) (3)

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STUDY ID: 

PAGE 31

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 7. Gross Pathological Observations (continued)

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

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

Removal Reasons: All of those SELECTED -----------------------------------

 0 250 500 1000 

MKD MKD MKD MKD 

 Number of Animals on Study : 3 3 3 3

Number of Animals Completed: (3) (3) (3) (3)

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

CRANIAL NERVE - OPTIC; (continued)

 No Visible Lesions............................................................................... 3 3 3 3

DUODENUM;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

ESOPHAGUS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

EYE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

HEART;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

ILEUM;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

JEJUNUM;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

KIDNEYS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

LACRIMAL/HARDERIAN GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

LARYNX;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

LIVER;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

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STUDY ID: 

PAGE 32

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 7. Gross Pathological Observations (continued)

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

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

Removal Reasons: All of those SELECTED -----------------------------------

 0 250 500 1000 

MKD MKD MKD MKD 

 Number of Animals on Study : 3 3 3 3

Number of Animals Completed: (3) (3) (3) (3)

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

LUNG;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

LYMPH NODE; 

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

MAMMARY GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

MEDIASTINAL TISSUE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

MESENTERIC TISSUE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

NASAL TISSUE - PHARYNX;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

ORAL TISSUE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

OVARIES;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

OVIDUCT;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

PANCREAS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

PARATHYROID GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

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STUDY ID: 

PAGE 33

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 7. Gross Pathological Observations (continued)

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

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

Removal Reasons: All of those SELECTED -----------------------------------

 0 250 500 1000 

MKD MKD MKD MKD 

 Number of Animals on Study : 3 3 3 3

 Number of Animals Completed: (3) (3) (3) (3)

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

PARATHYROID GLAND; (continued)

 No Visible Lesions............................................................................... 3 3 3 3 

PERIPHERAL NERVE - TIBIAL;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

PITUITARY GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

RECTUM;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

SALIVARY GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

SKELETAL MUSCLE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3

SKIN AND SUBCUTIS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

SPINAL CORD;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

SPLEEN;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

STOMACH;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

THYMUS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

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STUDY ID: 

PAGE 34

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

TABLE 7. Gross Pathological Observations (continued)

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

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

Removal Reasons: All of those SELECTED -----------------------------------

 0 250 500 1000 

MKD MKD MKD MKD 

 Number of Animals on Study : 3 3 3 3

Number of Animals Completed: (3) (3) (3) (3)

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

THYROID GLAND;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

TONGUE;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

TRACHEA;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

URINARY BLADDER;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

UTERUS;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

VAGINA;

 Submitted........................................................................................ (3) (3) (3) (3)

 No Visible Lesions............................................................................... 3 3 3 3 

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STUDY ID: 

PAGE 35

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 1. Individual Feed Consumption (g/day)

 DAYS ON TEST

 DOSE ANIMAL --------------------------------------------------------

MKD NUMBER 1-2 2-3 3-4 4-5 5-6 6-7 7-8 

 ===========================================================================

0 2852 10.9 9.7 9.6 9.7 11.7 10.3 9.1

 2853 10.2 9.7 9.4 10.3 10.6 9.8 11.2

2854 9.8 10.3 10.7 10.6 11.1 12.4 10.3

MEAN 10.3 9.9 9.9 10.2 11.1 10.8 10.2

S.D. 0.6 0.3 0.7 0.5 0.6 1.4 1.1

N= 3 3 3 3 3 3 3

 ===========================================================================

250 2855 10.8 10.9 10.3 10.2 11.6 11.3 8.9

 2856 10.2 9.6 9.6 8.6 10.7 8.7 9.8

2857 9.6 8.4 10.6 9.9 10.8 10.7 10.9

 MEAN 10.2 9.6 10.2 9.6 11.0 10.2 9.9

S.D. 0.6 1.3 0.5 0.9 0.5 1.4 1.0

N= 3 3 3 3 3 3 3

 ===========================================================================

500 2858 10.0 8.0 10.1 10.9 11.0 10.3 9.5

 2859 9.3 10.0 9.2 9.4 11.2 9.9 9.5

2860 10.6 11.5 11.8 9.9 11.5 11.6 8.7

MEAN 10.0 9.8 10.4 10.1 11.2 10.6 9.2

S.D. 0.7 1.8 1.3 0.8 0.3 0.9 0.5

N= 3 3 3 3 3 3 3

 ===========================================================================

1000 2861 9.9 9.5 10.4 12.1 11.9 12.1 10.7

 2862 10.0 9.8 9.5 10.3 10.0 10.0 9.8

2863 9.8 8.3 9.1 8.9 9.9 11.2 9.4

MEAN 9.9 9.2 9.7 10.4 10.6 11.1 10.0

 S.D. 0.1 0.8 0.7 1.6 1.1 1.1 0.7

N= 3 3 3 3 3 3 3

 ===========================================================================

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STUDY ID: 

PAGE 36

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 1. Individual Feed Consumption (g/day) (continued)

 DAYS ON TEST

 DOSE ANIMAL --------------------------------------------------------

MKD NUMBER 8-9 9-10 10-11 11-12 12-13 13-14 14-15

 ===========================================================================

0 2852 10.1 10.1 11.9 11.3 11.6 10.0 9.7

 2853 10.7 10.4 10.6 11.0 11.5 11.2 9.4

2854 11.7 12.5 11.8 12.0 11.9 11.0 11.1

MEAN 10.8 11.0 11.4 11.4 11.7 10.7 10.1

S.D. 0.8 1.3 0.7 0.5 0.2 0.6 0.9

N= 3 3 3 3 3 3 3

 ===========================================================================

250 2855 11.1 11.0 9.2 11.2 11.0 11.0 10.3

 2856 10.8 9.3 9.4 11.7 10.1 9.9 9.8

2857 10.0 10.2 10.6 10.9 10.7 10.0 10.4

 MEAN 10.6 10.2 9.7 11.3 10.6 10.3 10.2

S.D. 0.6 0.9 0.8 0.4 0.5 0.6 0.3

N= 3 3 3 3 3 3 3

 ===========================================================================

500 2858 8.9 11.5 9.6 10.7 11.0 10.9 9.8

 2859 11.5 10.2 12.1 10.7 10.0 10.7 10.8

2860 11.8 10.3 11.0 12.1 11.8 9.5 9.5

MEAN 10.7 10.7 10.9 11.2 10.9 10.4 10.0

S.D. 1.6 0.7 1.3 0.8 0.9 0.8 0.7

N= 3 3 3 3 3 3 3

 ===========================================================================

1000 2861 12.0 12.0 12.5 12.8 11.3 10.5 12.2

 2862 9.6 10.3 10.2 9.8 9.8 9.8 8.8

2863 9.0 9.4 11.0 10.3 11.2 9.8 10.1

MEAN 10.2 10.6 11.2 11.0 10.8 10.0 10.4

S.D. 1.6 1.3 1.2 1.6 0.8 0.4 1.7

N= 3 3 3 3 3 3 3

 ===========================================================================

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STUDY ID: 

PAGE 37

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 2. Individual Body Weight/Body Weight Gains (g)

 DAYS ON TEST

 DOSE ANIMAL --------------------------------------------------------------------------------------------------------

 MKD NUMBER 1 2 GAIN 3 GAIN 4 GAIN 5 GAIN 6 GAIN 7 GAIN

 ===========================================================================================================================

 0 2852 131.0 133.7 2.7 133.2 2.2 132.0 1.0 133.7 2.7 136.4 5.4 137.9 6.9

 2853 133.8 134.8 1.0 135.7 1.9 134.9 1.1 137.4 3.6 138.7 4.9 139.6 5.8

 2854 136.7 136.1 -0.6 136.0 -0.7 138.0 1.3 140.0 3.3 144.0 7.3 146.6 9.9

 MEAN 133.8 134.9 1.0 135.0 1.1 135.0 1.1 137.0 3.2 139.7 5.9 141.4 7.5

 S.D. 2.9 1.2 1.7 1.5 1.6 3.0 0.2 3.2 0.5 3.9 1.3 4.6 2.1

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 250 2855 133.4 136.3 2.9 136.7 3.3 136.4 3.0 136.4 3.0 139.6 6.2 141.9 8.5

 2856 130.6 132.4 1.8 131.1 0.5 133.3 2.7 133.3 2.7 135.4 4.8 135.3 4.7

 2857 133.8 135.4 1.6 134.4 0.6 136.7 2.9 137.7 3.9 140.2 6.4 142.1 8.3

 MEAN 132.6 134.7 2.1 134.1 1.5 135.5 2.9 135.8 3.2 138.4 5.8 139.8 7.2

 S.D. 1.7 2.0 0.7 2.8 1.6 1.9 0.2 2.3 0.6 2.6 0.9 3.9 2.1

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 500 2858 130.6 131.5 0.9 129.0 -1.6 132.7 2.1 135.8 5.2 137.7 7.1 138.3 7.7

 2859 134.1 135.0 0.9 136.9 2.8 134.9 0.8 137.9 3.8 140.0 5.9 143.2 9.1

 2860 133.3 135.1 1.8 136.4 3.1 138.1 4.8 138.3 5.0 141.0 7.7 142.9 9.6

 MEAN 132.7 133.9 1.2 134.1 1.4 135.2 2.6 137.3 4.7 139.6 6.9 141.5 8.8

 S.D. 1.8 2.1 0.5 4.4 2.6 2.7 2.0 1.3 0.8 1.7 0.9 2.7 1.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 1000 2861 135.9 136.8 0.9 136.1 0.2 137.1 1.2 141.8 5.9 144.1 8.2 145.9 10.0

 2862 138.1 140.2 2.1 141.3 3.2 140.3 2.2 141.2 3.1 142.8 4.7 143.8 5.7

 2863 126.7 129.6 2.9 129.6 2.9 131.0 4.3 133.1 6.4 133.3 6.6 135.7 9.0

 MEAN 133.6 135.5 2.0 135.7 2.1 136.1 2.6 138.7 5.1 140.1 6.5 141.8 8.2

 S.D. 6.0 5.4 1.0 5.9 1.7 4.7 1.6 4.9 1.8 5.9 1.8 5.4 2.3

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

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STUDY ID: 

PAGE 38

( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 2. Individual Body Weight/Body Weight Gains (g) (continued)

 DAYS ON TEST

 DOSE ANIMAL --------------------------------------------------------------------------------------------------------

 MKD NUMBER 1 8 GAIN 9 GAIN 10 GAIN 11 GAIN 12 GAIN 13 GAIN

 ===========================================================================================================================

 0 2852 131.0 138.3 7.3 137.8 6.8 141.2 10.2 143.2 12.2 144.4 13.4 147.2 16.2

 2853 133.8 142.8 9.0 144.1 10.3 146.5 12.7 147.9 14.1 147.9 14.1 150.4 16.6

 2854 136.7 145.8 9.1 148.4 11.7 152.4 15.7 153.2 16.5 153.5 16.8 152.2 15.5

 MEAN 133.8 142.3 8.5 143.4 9.6 146.7 12.9 148.1 14.3 148.6 14.8 149.9 16.1

 S.D. 2.9 3.8 1.0 5.3 2.5 5.6 2.8 5.0 2.2 4.6 1.8 2.5 0.6

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 250 2855 133.4 141.1 7.7 144.4 11.0 145.9 12.5 146.8 13.4 147.2 13.8 149.4 16.0

 2856 130.6 137.1 6.5 137.2 6.6 142.0 11.4 140.5 9.9 143.2 12.6 143.0 12.4

 2857 133.8 143.5 9.7 144.1 10.3 145.7 11.9 147.1 13.3 147.9 14.1 148.9 15.1

 MEAN 132.6 140.6 8.0 141.9 9.3 144.5 11.9 144.8 12.2 146.1 13.5 147.1 14.5

 S.D. 1.7 3.2 1.6 4.1 2.4 2.2 0.6 3.7 2.0 2.5 0.8 3.6 1.9

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 500 2858 130.6 137.2 6.6 139.6 9.0 143.8 13.2 144.1 13.5 143.4 12.8 144.1 13.5

 2859 134.1 141.5 7.4 143.5 9.4 146.7 12.6 149.4 15.3 150.0 15.9 147.5 13.4

 2860 133.3 143.2 9.9 145.1 11.8 142.9 9.6 148.5 15.2 150.4 17.1 152.5 19.2

 MEAN 132.7 140.6 8.0 142.7 10.1 144.5 11.8 147.3 14.7 147.9 15.3 148.0 15.4

 S.D. 1.8 3.1 1.7 2.8 1.5 2.0 1.9 2.8 1.0 3.9 2.2 4.2 3.3

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 1000 2861 135.9 146.6 10.7 146.5 10.6 149.8 13.9 153.3 17.4 155.1 19.2 154.1 18.2

 2862 138.1 146.4 8.3 146.5 8.4 146.0 7.9 148.0 9.9 149.9 11.8 150.0 11.9

 2863 126.7 137.3 10.6 137.5 10.8 139.9 13.2 142.2 15.5 143.0 16.3 144.4 17.7

 MEAN 133.6 143.4 9.9 143.5 9.9 145.2 11.7 147.8 14.3 149.3 15.8 149.5 15.9

 S.D. 6.0 5.3 1.4 5.2 1.3 5.0 3.3 5.6 3.9 6.1 3.7 4.9 3.5

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 2. Individual Body Weight/Body Weight Gains (g) (continued)

 DAYS ON TEST

 DOSE ----------------------------------------

MKD 1 14 GAIN 15 GAIN

=========================================================

0 MEAN 133.8 150.8 16.9& 151.0 17.1&

 S.D. 2.9 5.2 2.3 4.8 2.0

N= 3 3 3 3 3

 250 MEAN 132.6 147.9 15.3& 148.3 15.7&

 S.D. 1.7 2.7 1.3 3.0 1.4

N= 3 3 3 3 3

 500 MEAN 132.7 149.2 16.5& 149.5 16.8&

 S.D. 1.8 2.0 1.5 2.2 0.8

N= 3 3 3 3 3

 1000 MEAN 133.6 149.7 16.2& 151.1 17.5&

 S.D. 6.0 4.6 3.2 6.1 5.2

N= 3 3 3 3 3

 =========================================================

& INDICATES NO STATISTICAL COMPARISON OF MEANS.

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APPENDIX TABLE 3. Individual Clinical Chemistry

 UN ALT ALP AST TP ALB GLOB A/G CHOL TRIG TBIL CREA GGT

 DOSE ANIMAL MG/DL U/L U/L U/L G/DL G/DL G/DL RATIO MG/DL MG/DL MG/DL MG/DL U/L

 MKD NUMBER

 ===========================================================================================================================

 0 2852 17 42 152 104 6.9 4.7 2.2 2.1 77 28 0.05 0.3 1.5

 2853 18 37 137 82 6.5 4.5 2.0 2.3 74 27 0.05 0.3 1.5

 2854 16 35 131 79 6.3 4.4 1.9 2.3 71 25 0.05 0.3 1.5

 MEAN 17 38 140 88 6.6 4.5 2.0 2.2 74 27 0.05 0.3 1.5

 S.D. 1 4 11 14 0.3 0.2 0.2 0.1 3 2 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 250 2855 21 52 169 109 6.9 4.7 2.2 2.1 79 31 0.05 0.3 1.5

 2856 16 40 122 79 6.1 4.3 1.8 2.4 71 29 0.05 0.2 1.5

 2857 19 42 122 92 6.8 4.7 2.1 2.2 74 23 0.05 0.3 1.5

 MEAN 19 45 138 93 6.6 4.6 2.0 2.2 75 28 0.05 0.3 1.5

 S.D. 3 6 27 15 0.4 0.2 0.2 0.2 4 4 0.00 0.1 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 500 2858 17 40 128 83 6.5 4.6 1.9 2.4 90 28 0.05 0.3 1.5

 2859 17 39 126 82 6.6 4.6 2.0 2.3 73 23 0.05 0.3 1.5

 2860 16 36 130 87 7.1 4.7 2.4 2.0 84 28 0.05 0.3 1.5

 MEAN 17 38 128 84 6.7 4.6 2.1 2.2 82 26 0.05 0.3 1.5

 S.D. 1 2 2 3 0.3 0.1 0.3 0.2 9 3 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 1000 2861 17 45 139 87 6.6 4.5 2.1 2.1 77 33 0.05 0.3 1.5

 2862 17 40 114 88 6.4 4.5 1.9 2.4 75 24 0.05 0.3 1.5

 2863 18 36 119 73 6.5 4.5 2.0 2.3 78 34 0.05 0.3 1.5

 MEAN 17 40 124 83 6.5 4.5 2.0 2.3 77 30 0.05 0.3 1.5

 S.D. 1 5 13 8 0.1 0.0 0.1 0.2 2 6 0.00 0.0 0.0

 N= 3 3 3 3 3 3 3 3 3 3 3 3 3

 ===========================================================================================================================

 TBIL LOWEST DETECTION LIMIT IS 0.10. VALUES <0.10 ARE REPORTED AS 0.05 (ONE-HALF THE DETECTION LIMIT) FOR STATISTICAL ANALYSIS.

 GGT LOWEST DETECTION LIMIT IS 3.0. VALUES <3.0 ARE REPORTED AS 1.5 (ONE-HALF THE DETECTION LIMIT) FOR STATISTICAL ANALYSIS.

 UN=UREA NITROGEN, ALT=ALANINE AMINOTRANSFERASE, ALP=ALKALINE PHOSPHATASE, AST=ASPARTATE AMINOTRANSFERASE, 

 TP=TOTAL PROTEIN, ALB=ALBUMIN, GLOB=GLOBULIN, A/G=RATIO OF ALBUMIN/GLOBULIN, CHOL=CHOLESTEROL, TRIG=TRIGLYCERIDES, 

 TBIL=TOTAL BILIRUBIN, CREA=CREATININE, GGT=GAMMA GLUTAMYL TRANSPEPTIDASE

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 4. Individual Organ and Organ/Body Weights

 FINAL KIDNEYS LIVER

 DOSE ANIMAL BODY --------------------------------

MKD NUMBER WT. (G) (G) (G/100) (G) (G/100)

===========================================================

0 2852 131.1 1.044 0.796 3.755 2.864

 2853 136.1 0.968 0.711 3.811 2.800

2854 143.3 1.014 0.708 4.207 2.936

MEAN 136.8 1.009 0.738 3.924 2.867

S.D. 6.1 0.038 0.050 0.246 0.068

N= 3 3 3 3 3

 ===========================================================

250 2855 136.0 1.046 0.769 4.147 3.049

 2856 133.9 0.930 0.695 3.695 2.760

2857 133.8 0.918 0.686 4.015 3.001 

MEAN 134.6 0.965 0.717 3.952 2.937

S.D. 1.2 0.071 0.046 0.232 0.155

N= 3 3 3 3 3

 ===========================================================

500 2858 135.0 0.996 0.738 3.764 2.788

 2859 136.7 0.967 0.707 3.781 2.766

 2860 136.2 0.992 0.728 4.058 2.979

MEAN 136.0 0.985 0.725 3.868 2.845

S.D. 0.9 0.016 0.016 0.165 0.117

N= 3 3 3 3 3

 ===========================================================

1000 2861 141.5 1.062 0.751 4.253 3.006

 2862 137.4 0.954 0.694 3.774 2.747

2863 133.6 0.931 0.697 3.749 2.806

MEAN 137.5 0.982 0.714 3.925 2.853

S.D. 4.0 0.070 0.032 0.284 0.136

N= 3 3 3 3 3

 ===========================================================

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report

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

Animal Ref.: 2852 Group: 1 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 0 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 131.1g

Organ Weights:

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

KIDNEYS : 1.044g LIVER : 3.755g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2853 Group: 1 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 0 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 136.1g

Organ Weights:

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

KIDNEYS : 0.968g< LIVER : 3.811g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2854 Group: 1 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 0 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 143.3g

Organ Weights:

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

KIDNEYS : 1.014g LIVER : 4.207g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2855 Group: 2 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 250 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 136g

Organ Weights:

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

KIDNEYS : 1.046g LIVER : 4.147g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2856 Group: 2 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 250 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 133.9g

Organ Weights:

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

KIDNEYS : 0.930g< LIVER : 3.695g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2857 Group: 2 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 250 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 133.8g

Organ Weights:

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

KIDNEYS : 0.918g< LIVER : 4.015g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2858 Group: 3 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 500 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 135g

Organ Weights:

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

KIDNEYS : 0.996g< LIVER : 3.764g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2859 Group: 3 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 500 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 136.7g

Organ Weights:

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

KIDNEYS : 0.967g< LIVER : 3.781g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2860 Group: 3 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 500 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 136.2g

Organ Weights:

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

KIDNEYS : 0.992g< LIVER : 4.058g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2861 Group: 4 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 1000 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 141.5g

Organ Weights:

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

KIDNEYS : 1.062g LIVER : 4.253g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2862 Group: 4 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 1000 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 137.4g

Organ Weights:

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

KIDNEYS : 0.954g< LIVER : 3.774g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

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( 14-DAY PALATABILITY AND DOSE RANGE-FINDING STUDY IN FEMALE F344/DuCrl RATS

APPENDIX TABLE 5. Individual Animal Pathology Report (continued)

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

Animal Ref.: 2863 Group: 4 Sex: Female Species: Rat Strain: F344/DuCrl

Test Material: l Dose: 1000 MKD Route: Dietary Study Type: Repeated Dose Toxicity

Date of Death : 05/30/2012 Study Day No. (Week): 16 (3) Mode of Death: SCHEDULED NECROPSY

Date of Necropsy: 05/30/2012 Gross Examiner: Renee Hukkanen ** NECROPSY COMPLETE **

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

Terminal Body Weight: 133.6g

Organ Weights:

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

KIDNEYS : 0.931g< LIVER : 3.749g 

Gross Pathology Observations: None

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

Any remaining protocol required tissues, which have been examined, have no visible lesions

-