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## STUDY TITLE

( 14

- DAY PALATABILITY AND DOSE RANGE

FINDING 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

## SIGNATURE PAGE

Compound: THE DOW CHEMICAL COMPANY

STUDY 10:

PAGE 3



## 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 Chemi stry ................................................................................................. 14

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

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

RESU LTS ..................................................................................................................... 16

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

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

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

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

Te st 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 gros s pathology.

There were no treatment

- related effects in cage -side observations, body weights, body

weight gains, feed consumption, clinical chemistry param eters, 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

C hemical Name

Synonyms

Supplier, City, State (Lot, Refer ence 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

C haracteristics

Molecular Formula

Molecular Weight

CAS Number

Veh icle

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 ani mals were subjected to necropsy at sacrifice and

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## there were no abnormalities detected in any of the rats. T he estimated acute oral LD 50



## was greater than 2000 mg/kg body weight.

STUDY DESIGN

Experimental Design and Critical Dates

Th ree female F344/DuCrl ra ts 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 d aily 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 Admini stration, 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 represent ed 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 we re expected to provide

dose-response da ta for any treatment

- related effects observed i n the high-dose group.

Text Table 1. Dose Levels

Dose Levels

(mg/kg/day )* No. of Female R ats /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) wit h ground feed. The appropriate c oncentrations 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 fee d at concentrations ranging from 0.005 to 10%

Retainer Samples

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

.

TEST S YSTEM

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 Accred itation 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 syst em. 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 admin istration 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

.

Tex t 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 w ere

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

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 conducte d at

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

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 Anim al 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 coul d 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/pa le 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 d ays -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 d ays -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 CO 2 

## /O 2 

## at th e 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). g/kg 1000 2 [g]BW

Previous [g]BW Current 100 feed) in material test of (% mg/g) (1000 ) day

g

n consumptio (feed

** **  ** **  ** **  **+ ∗**  **∗ **  ****

** ** 

** ** 

** ** 

**=** 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 CO 2 

## /O 2 

## 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, a nd the brain, pituitary and adjacent

cervical tissues examined. T he 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 weight s 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 bod y

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 fi le).

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 group s 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 . R ats 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 th e

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 a lterations in

the liver or kidney weights.

Gross Pathology

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

CONCLUSIONS

There were no treatment

- related effects in cage -side observations, body weights, body

weight gains, feed consumption, clinical chemistry param eters, 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

O rganisation 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

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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 15BODY WEIGHT (G)

TEST DAYS 0 MKD

250 MKD

500 MKD

1000 MKD

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- DAY PALATABILITY AND DOSE RANGE

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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 15BODY WEIGHT GAINS (G)

TEST DAYS 0 MKD

250 MKD

500 MKD

1000 MKD

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( 14

- DAY PALATABILITY AND DOSE RANGE -F INDING

STUDY IN FEMALE F344/DuCrl RATS

TABLE 1. St ud y 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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TABLE 2. Fe e d 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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TABLE 2. F eed 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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TABLE 3. Body W eight/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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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.

### THE DOW CHEMICAL COMPANY

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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.

### THE DOW CHEMICAL COMPANY

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TABLE 4. Tes t Material I ntake Summary

DOSE 0 MKD 250 MKD 500 MKD 1000 MKD

Feed

Period

(in Days) Day(s) PPM a MKD b % Test

Materia

l in

Diet PPM a MKD b % Test

Material

in Diet PPM a MKD b % Test

Material

in Diet PPM a MKD b

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

±SD d 15.1 12.7 41.0 28.0 16.1 48.9

14 Sum of Days

a PPM = % Test Material in

d iet * 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

### THE DOW CHEMICAL COMPANY

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TABLE 5. Cli n ical 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. IND IVID UAL 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 (O NE

- 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=TOT AL BILIRUBIN, CREA=CREATININE, GGT=GAMMA GLUTAMYL TRANSPEPTIDASE

### THE DOW CHEMICAL COMPANY

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TABLE 6. Or ga n 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

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

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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TABLE 7. Gr o ss 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)

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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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;

Submi tted........................................................................................ (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

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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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)

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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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

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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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

### THE DOW CHEMICAL COMPANY

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- DAY PALATABILITY AND DOSE RANGE

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APPENDIX T A BLE 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

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

### THE DOW CHEMICAL COMPANY

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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

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

### THE DOW CHEMICAL COMPANY

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APPENDIX T A BLE 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

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

### THE DOW CHEMICAL COMPANY

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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

286 0 133.3 143.2 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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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 T A BLE 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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APPENDIX T A BLE 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 3.00 1

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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APPENDIX T A BLE 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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APPENDIX TABLE 5 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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 Weigh ts:

-------------- 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 . I ndividual 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 NEC ROPSY

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 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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 W eights:

-------------- 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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APPENDIX TABLE 5 . I ndividual 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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APPENDIX TABLE 5 . I ndividual 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: No ne

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

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

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APPENDIX TABLE 5 . I ndividual 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