# STUDY NO. 09-4347

SPONSOR STUDY NO. MA-252E-93-23

PRELIMINARY EMBRYO-FETAL TOXICITY STUDY

IN RABBITS VIA WHOLE-BODY INHALATION EXPOSURE

Final Report

Submitted to:

Attn:

Date: 15 January 2010

Page 1 of 175

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LIST OF ABBREVIATIONS

Abbreviation Term

hr(s) hour(s)

min(s) minute(s)

F Female(s)

GD or GES Gestation Day

Lpm liters per minute

mg/L milligrams of test substance per liter of air

ppm parts per million

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Preliminary Embryo-Fetal Toxicity Study

in Rabbits via Whole-Body Inhalation Exposure

SUMMARY

The objective of this study was to assess any gr oss maternal and/or embryo-fetal toxicity

of in a non-rodent species, the rabbit, following whole-body inhalation

exposure of (every day fr om Gestation Day (GD) 6 to GD 28,

inclusively), covering the period of major organogenesis (which extends from

implantation to the day prior to expected delivery, approximately GD 6 to GD 28), so

that a suitable range of exposure levels coul d be selected for a definitive embryo-fetal

toxicity study.

Thirty-two time-mated female New Zealand Wh ite rabbits were distributed into 4 groups

(1 control and 3 treated groups) of 8 dams/group. These animals received whole-body

inhalation exposures every day with clean ai r (air control) or with at

exposure concentrations of 2,500, 10,000 or 15,000 ppm from GD 6 to GD 28 (GD 0 =

day of mating confirmation). The exposure dur ations were 6 hours per day for 7 days per

week.

All animals were euthanized and necropsie d on GD 29. The following parameters were

evaluated for all animals: viability, c linical observations, body weights and feed

consumption. A macroscopic postmortem evaluation was performed on GD 29, during

which corpora lutea, implantation data and ut erine weights were recorded. The fetuses

were removed, weighed (live and recently dead fetuses), sexed and examined externally

for defects. Placentas were examined and weighed.

The target and mean analytical (IR) and nominal concentrations are summarized as follows:

Group Target

Concentration

(ppm) Analytical

Concentration

(ppm) Nominal

Concentration

(ppm)

1 0 0.0 0

2 2,500 2,449 NA

3 10,000 10,103 NA

4 15,000 14,958 24,750*

*the combined nominal concentration for all 3 exposed groups

There were no effects of exposures on su rvival, clinical signs, body weights, food

consumption or maternal or pup findings at s acrifice. Therefore, the no-observed-effect

level (NOEL) for adult pregnant female rabbits for systemic and reproductive and

developmental toxicity was 15,000 ppm of

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TABLE OF CONTENTS

COVER PAGE..................................................................................................................... 1

SIGNATURE PAGE ........................................................................................................... 2

LIST OF ABBREVIATIONS.............................................................................................. 3

SUMMARY........................................................................................................................

. 4

TABLE OF CONTENTS..................................................................................................... 5

1. 

# INTRODUCTION

.................................................................................................. 8

2. 

# MATERIALS AND METHODS

2.1. Study Management ...................................................................................... 8

2.2. Study Dates .................................................................................................. 8

2.3. Experimental Outline................................................................................... 9

2.4. Justifications ................................................................................................ 9

2.5. Test Substance ........................................................................................... 10

2.6. Test Animals .............................................................................................. 12

2.7. Animal Assignment ................................................................................... 13

2.8. Animal Identification................................................................................. 13

2.9. Veterinary Care.......................................................................................... 13

2.10. Husbandry During Non-Exposure Periods ................................................ 13

2.11. Husbandry During Exposure Periods ........................................................ 15

2.12. Test Article Administration and Chamber Operation................................ 16

2.13. Experimental Evaluations .......................................................................... 19

2.14. Terminal Observations............................................................................... 20

2.15. Statistical Analysis..................................................................................... 21

2.16. Major Computer Systems .......................................................................... 22

2.17. Data Storage............................................................................................... 22

2.18. Regulatory References............................................................................... 22

2.19. Protocol Deviation ..................................................................................... 23

3. 

# RESULTS AND DISCUSSION

3.1. Chamber Monitoring.................................................................................. 24

3.2. Maternal Data ............................................................................................ 25

3.3. Fetal Data................................................................................................... 26

4. 

# CONCLUSION

.................................................................................................... 27

REFERENCES .................................................................................................................. 28

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TABLE OF CONTENTS

FIGURES

1. Diagram of Generation System and Exposure Chamber

Group 1 .......................................................................................................................

. 29

Groups 2-4 ................................................................................................................... 3 0

2. Mean Body Weights .................................................................................................... 31

3. Mean Food Consumption Values................................................................................. 32

GENERAL PREFACE ...................................................................................................... 33

TABLES

1. Summary of Survival ................................................................................................... 34

2. Summary of In-Chamber Observations ....................................................................... 35

3. Summary of Daily Viability Observations .................................................................. 37

4. Summary of Gestation Physical Examination Findings .............................................. 39

5. Mean Gestation Body Weights .................................................................................... 42

6. Mean Gestation Weight Changes ................................................................................ 45

7. Mean Gestation Food Consumption Values ................................................................ 48

8. Incidence Summary Report of Gross Necropsy Observation by Animal.................... 51

9. Summary of Pregnancy................................................................................................ 53

10. Summary of Cesarean Section Data ............................................................................ 54

11. Mean Gravid Uterine Adjusted Body Weights............................................................ 55

12. Mean Litter Weight Data ............................................................................................. 56

13. Summary of Fetal Observations................................................................................... 57

APPENDICES

A. Chamber Monito ring Results....................................................................................... 58

B. Individual Animal Term ination History ...................................................................... 66

C. Individual Gestation Daily Viability Observations ..................................................... 67

D. Individual Gestation Physi cal Examination Findings.................................................. 69

E. Individual Gestati on Body Weights............................................................................. 77

F. Individual Gestation Body Weight Changes ............................................................... 89

G. Individual Gestation Food Consumption Values....................................................... 101

H. Raw Data Listing of Gross Obse rvations with Modifiers.......................................... 113

I. Individual Cesarean Section Data.............................................................................. 116

J. Individual Gravid Uterine Adjusted Body Weights .................................................. 120

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TABLE OF CONTENTS

K. Litter Weight Data ..................................................................................................... 124

Individual Feta l Weights............................................................................................ 125

Individual Placen tal Weights ..................................................................................... 129

L. Individual Fetal Observations.................................................................................... 133

M. Equipment List........................................................................................................... 148

N. Prestudy Chamber Dist ribution Samples................................................................... 150

O. Miran Calib ration....................................................................................................... 151

P. Protocol and Protoc ol Amendments .......................................................................... 154

Q. Testing Facility Personnel ......................................................................................... 175

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1. INTRODUCTION

The purpose of this study was to assess gross maternal and/or embryo-fetal

toxicity of in a non-rodent species, the rabbit, following whole

body inhalation exposure (every day from Gestation Day (GD) 6 to GD 28,

inclusively), covering the period of ma jor organogenesis (which extends from

implantation to the day prior to expected delivery, approximately GD 6 to

GD 28).

2. MATERIALS AND METHODS

2.1. STUDY MANAGEMENT

2.1.1. SPONSOR

2.1.2. SPONSOR REPRESENTATIVE

2.1.3. TESTING FACILITY

Huntingdon Life Sciences

100 Mettlers Road

East Millstone, New Jersey 08875-2360

2.1.4. STUDY DIRECTOR

Gary M. Hoffman, BA, DABT

2.2. STUDY DATES

2.2.1. STUDY INITIATION

24 July 2009 (Date Study Director signed the Protocol)

2.2.2. ANIMAL RECEIPT DATE

20 August 2009

2.2.3. EXPOSURE INITIATION

24 and 25 August 2009

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2.2.4. EXPOSURE TERMINATION

15 and 16 September 2009

2.2.5. TERMINAL SACRIFICE

16 and 17 September 2009

2.2.6. STUDY COMPLETION

15 January 2010 (Date Final Report is signed by the Study

Director)

2.3. EXPERIMENTAL OUTLINE

Four (4) experimental groups (1 c ontrol and 3 treated groups) received

whole-body inhalation exposures every da y with clean air or with

at the exposure concentrations summarized below. The animals

were exposed every day from Gestation Day (GD) 6 to GD 28 (GD 0 =

day of mating). Each group consisted of 8 time-mated females as outlined

below:

Exposure Levels a 

# Test Animals (females)

Group Group

Designation (ppm) (mg/L) Total on

Study Necropsy

1 Air Control 0 0 8 8

2 Low 2,500 13 8 8

3 Mid 10,000 53 8 8

4 High 15,000 80 8 8

a 

# Exposures were 6 hours per day for 7 consecutive days per week. Exposure levels are

expressed as ppm and equivalent mg/L of test substance; results are reported in ppm.

The exposures were conducted via whole-body exposure.



# 2.4. JUSTIFICATIONS

2.4.1. ROUTE, DURATION AND FREQUENCY OF

ADMINISTRATION

The inhalation route is one of the potential routes of human

exposure to this test article. The duration and frequency of

exposures were as recommended in the relevant test guideline,

ensuring adequate exposure of post-implantation embryo-fetal

development.

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2.4.2. EXPOSURE LEVEL SELECTION

A pilot 4-week inhalation study was performed with male and

female CD rats exposed to target levels of 0, 2,000, 4,500, 7,500

and 10,000 ppm of Effects were limited to mild

reversible alterations in some he matology parameters at 10,000 pm

and to a lesser extent at 7,500 ppm. Based on the above

information, a high exposure level of 15,000 ppm was selected for

this study to provide slight maternal toxicity while lower levels of

10,000 and 2,500 ppm were selected to provide a range of possible

effects including a NOEL or NOAEL.

2.4.3. TEST ANIMAL SELECTION

The rabbit is accepted by Regulatory Authorities as a surrogate for

humans in the detection of effect s on embryo-fetal development. It

is the preferred non-rodent species for developmental toxicity

testing, for practical reasons and in view of the large amount of

accumulated background information in the species.

2.4.4. NUMBER OF ANIMALS

The number of animals in this study (8 time-mated females/group)

was considered the minimum necessary to allow for meaningful

interpretation of the outcome. The number of animals per group in

this study was within the range of the number of animals per group

that are routinely used in prelim inary embryo-fetal toxicity studies

by Developmental and Reproductive Toxicologists. This number

is the lowest number of pregnant animals that allows reliable

interpretation of the data (i.e., accounting for variability, such as

number of pregnant females per gr oup, maternal toxicity, number

of litters evaluated for developmental abnormalities, fetal deaths,

etc.).

2.5. TEST SUBSTANCE

or

2.5.1. TEST SUBSTANCE CATEGORY

Industrial chemical used as a po ssible refrigerant and solvent.

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2.5.2. MANUFACTURER/SUPPLIER

2.5.3. LOT NUMBERS

41024-37

41024-38

KP-4

TOX-4

TOX-5

TOX-7

2.5.4. PURITY

Approximately 100% as per Ce rtificates of Analysis

2.5.5. DESCRIPTION

Liquid in cylinder

2.5.6. DATES RECEIVED

41024-37 and 41024-38: 18 May 2009

KP-4, TOX-4, TOX-5 and TOX-7: 17 June 2009

2.5.7. EXPIRATION DATES

Not available

2.5.8. ANALYSIS

Documentation of the identity, strength, purity, composition,

stability, and method of synthesis, fabrication, and/or derivation of

the test substance and the maintenance of these records were the

responsibility of the Sponsor.

2.5.9. STORAGE

Room temperature

2.5.10. ARCHIVAL SAMPLE

Archival samples were not required for this study.

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2.5.11. DISPOSITION

The unused portion of the test substance (Lot Nos. 41024-37,

TOX-4 and TOX-5) was returned to the Sponsor on 30 September

2009. Test substance Lot Nos. 41024-38, KP-4 and TOX-7 were

retained by the Testing Facility for use on future studies.

2.6. TEST ANIMALS

2.6.1. SPECIES

Albino Rabbits

New Zealand White

2.6.2. SUPPLIER

Covance Research Products

Denver, Pennsylvania

2.6.3. NUMBER OF ANIMALS

Received:

36 time-mated females

Placed on test:

32 time-mated females

2.6.4. AGE AT RECEIPT

Approximately 6 months at receipt on GD 1 or 2, where GD 0 is

the day of mating.

2.6.5. AGE AT INITIATION OF EXPOSURE

Approximately 6 months old.

2.6.6. WEIGHT AT INITIATION OF EXPOSURE (KILOGRAMS)

Mean Range

3.3 3.0 to 3.9

2.6.7. STABILIZATION PERIOD

The stabilization period was restrict ed to approximately 4 to 5 days

prior to commencement of exposur es, as dictated by the mating

and delivery schedule for the animals.

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2.7. ANIMAL ASSIGNMENT

More animals than requir ed for the study were purchased and stabilized.

Animals considered suitable for study were randomly assigned to control

or treated groups upon arrival (4 groups of 8 animals/group).

Prior to exposures, the body weights obt ained on GD 4 were reviewed to

ensure minimization of inter-group variability based on those body

weights.

Information as to the disposition of a ll animals not utilized in the study is

maintained in the study file.

2.8. ANIMAL IDENTIFICATION

Each animal was identified with an ear-tag bearing its assigned animal

number. The assigned animal numb er plus the study number comprised

the unique animal number for each animal. In addition, each cage was

provided with a cage card which was color-coded fo r exposure level

identification and contained stu dy number and animal number

information.

2.9. VETERINARY CARE

Animals were monitored by the technical staff for any conditions requiring

possible veterinary care.

2.10. HUSBANDRY DURING NON-EXPOSURE PERIODS

2.10.1. FACILITIES MANAGEMENT/ANIMAL HUSBANDRY

Currently acceptable practices of good animal husbandry were

followed e.g., Guide for the Care and Use of Laboratory Animals ;

National Academy Press, 1996. Huntingdon Life Sciences, East

Millstone, New Jersey is fully accredited by the Association for

Assessment and Accreditation of Laboratory Animal Care

International (AAALAC).

2.10.2. HOUSING

All animals were housed individual ly in stainless steel suspended

cages with grid bottoms. A stainless steel food hopper was

attached to each cage.

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2.10.3. FEED

Global High Fiber Diet #2031C (H arlan Teklad, Madison, WI) was

available without restriction. Fresh feed was presented daily.

2.10.4. FEED ANALYSIS

Analysis of each feed lot used du ring this study was performed by

the manufacturer. Results were provided to the Testing Facility

and are maintained on file at the Testing Facility. There were no

known contaminants in the feed th at were expected to interfere

with the results of this study.

2.10.5. WATER

Water (Elizabethtown Water Company, Westfield, New Jersey)

was available without restriction via an automated watering

system.

2.10.6. WATER ANALYSIS

Water analyses are conducted by Elizabethtown Water Company,

Westfield, New Jersey (Raritan-Millstone Plant) to ensure that

water meets standards specified under the EPA Federal Safe

Drinking Water Act Regulations (40 CFR Part 141). In addition,

water samples are collected biannually from representative rooms

in the Testing Facility; chemical and microbiological water

analyses are conducted on these samples by a subcontract

laboratory. Results of all water analyses are maintained on file at

the Testing Facility. There were no known contaminants in the

water which were expected to inte rfere with the results of this

study.

2.10.7. ENVIRONMENTAL CONDITIONS

Light/Dark Cycle

A twelve-hour light/dark cycle controlled via an automatic timer

was provided.

Temperature

Temperature was monitored in accordance with Testing Facility

SOPs and maintained within the specified range to the maximum

extent possible.

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Desired Range: 16 to 22 ° C

Daily Average Range: 16 to 21 ° C

Relative Humidity

Relative humidity was monitored in accordance with Testing

Facility SOPs and maintained within the specified range to the

maximum extent possible.

Desired Range: 30 to 70%

Daily Average Range: 52 to 63%

2.10.8. ENRICHMENT

Animals were provided with enrich ment devices (toys and/or feed

treats) as per Testing Facility SOP.

2.11. HUSBANDRY DURING EXPOSURE PERIODS

Animals were individually housed in suspended, stainless steel cages.

2.11.1. FEED

None was provided during exposure.

2.11.2. WATER

None was provided during exposure.

2.11.3. ENVIRONMENTAL CONDITIONS

Chamber temperature and relative humidity were recorded every

half-hour during exposure and main tained, to the maximum extent

possible, within the ranges presented below. Excursions outside

the specified range did not affect the integrity of the study.

Temperature

Desired: 16 to 24 ° C

Actual: 14 to 20 ° C

Relative Humidity

Desired: 40 to 60%

Actual: 56 to 72%

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2.12. TEST ARTICLE ADMINISTRATION AND

CHAMBER OPERATION

2.12.1. ROUTE OF ADMINISTRATION

Inhalation as a vapor by whole-body exposure.

2.12.2. FREQUENCY AND DURATION OF ADMINISTRATION

Animals were exposed for 6 hours per day once every day at

approximately the same time each day, on GD 6 to 28 inclusive,

where GD 0 was the day of mating.

2.12.3. PRE-STUDY TRIALS

The test substance was administered as a vapor in the breathing air

of the animals. The test atmosphere was generated by an

appropriate procedure determined during pre-study trials. The

trials were performed to evaluate the optimal set of conditions and

equipment to generate a stable at mosphere at the target exposure

levels and maintain uniform conditions throughout the exposure

chambers.

2.12.4. EXPOSURE PROCEDURE

Group 1

Houseline nitrogen was delivered from a regulator with a

backpressure gauge via 1⁄4” tubing to a flowmeter regulated by a

metering valve. This nitrogen flow (~ 20 Lpm) was then directed

into the chamber turret of the 1 m 3 

# glass and stainless steel

exposure chamber where it was mixed with room air as it was

drawn into the chamber.

Groups 2, 3 and 4

Houseline nitrogen was delivered from a regulator with a

backpressure gauge through a stainle ss steel fitting to create three

flow systems: the test substanc e pressurization flow, the purge

flow and the volatilization flow.

The nitrogen for the test subs tance pressurization flow was

delivered from a regulator with a backpressure gauge via 1⁄4”

tubing through a toggle va lve attached to a backpressure gauge into

the vapor inlet valve of the test substance cylinder. The houseline

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nitrogen regulator valve was used to adjust and maintain the

pressure within the cylinder. From the pressurized cylinder, the

test substance flowed from the liquid outlet valve through another

toggle valve then through a fi lter to prevent equipment

contamination. From the filter, the test substance was directed into

a stainless steel “T” piece where on e side of the “T” was directed

towards the Group 2 exposure system, while the other side of the

“T” piece was directed towards the Groups 3 and 4 systems where

a second stainless steel “T” split the test substance flow and

directed it to the Group 3 and Group 4 exposure systems.

The exposure system set-up and deli very was the same for all test

groups. From the “T” pieces after the filter, the test substance

flowed to a liquid flowmeter with a built-in regulator via 1 

# / 8 

# ”

tubing. The outlet of the flowmeter was regulated by a metering

valve. From this metering valve, the test substance flowed via 1 

# / 8 

# ”

tubing onto the glass helix of a counter current volatilization

chamber. This glass helix was heated by a nichrome wire which

was controlled by an autotransf ormer and was inserted in the

center of the glass tube that supported the helix.

The nitrogen for the purge flow syst em was directed, via 1⁄4” tubing

to a flowmeter regulated by a mete ring valve. The purge nitrogen

was delivered via 1 

# / 8 

# ” tubing to the bottom of the tube containing

the nichrome wire. This nitr ogen flow continuously purged the

area surrounding the nichrome wire within the tube, thereby,

protecting the wire from oxidation.

The nitrogen for the volatilizatio n system was directed via 1⁄4”

tubing to a flowmeter regulated by a metering valve. From the

flowmeter, the volatilization nitr ogen (~ 20 Lpm) flowed via 1⁄4”

tubing to a ball and socket joint at the bottom of the volatilization

chamber. This nitrogen flow ed up through the volatilization

chamber passing over the coil and vol atilizing the test substance.

The pressure within the counter-c urrent volatilization chamber was

maintained slightly negative to the room and was monitored with a

magnehelic gauge.

This test substance laden nitr ogen exited the top of the

volatilization chamber via 1⁄4” tubi ng, to the turret of the 1 m 3 

# glass

and stainless steel exposure chamber. As the test substance laden

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nitrogen was drawn into each of the chambers, it was mixed with

room air.

2.12.5. CHAMBER OPERATION

The whole-body exposure chambers each had a volume of

approximately 1000 liters (1 m 3 

# ). Each chamber was operated at a

minimum flow rate of 200 liters pe r minute. The final airflow was

set to provide at least one air change (calculated by dividing the

chamber volume by the airflow rate) in 5.0 minutes (12 air

changes/hour) and a T 99 

# equilibrium time (calculated by

multiplying the air change by the expone ntial factor 4.6) of at most

23 minutes:

Grou p Airflow Rate Air Chan g e T 99



# ( L p m ) ( min ) ( min )

1 219 4.6 21

2 219 4.6 21

3 211 4.7 22

4 214 4.7 21

This chamber size and airflow rate s were considered adequate to

maintain the oxygen level at least 19% and the animal loading

factor below 5%. At the end of each exposure, all animals

generally remained in the chambe r for a minimum of 23 minutes.

During this time, each chamber was operated at approximately the

same flow rate using clean air onl y. The chambers were exhausted

through the in house filtering system , which consisted of a coarse

filter, a HEPA filter and activated charcoal.

See Figure 1 and Appendix M for equipment details.

2.12.6. NOMINAL CONCENTRATION

The nominal concentration was determined by weighing the

generation apparatus containing the test substance before and after

the exposure and calculating as follows:

Conc (ppm) = amount consumed (g) x 1000 (mg/g) x 1000 ( μ g/mg) x 22.4 ( μ L/ μ mole) x 295oK

exposure duration (min) x airflow (Lpm) x MW ( μ g/ μ mole) x 273oK

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The nominal concentration was calculated for all three test

substance-treated groups combined.

The flow of air through the chamber was monitored using

appropriate calibrated equipment. The test substance consumed

(weight difference of the cylinde r) during the exposure (kg) was

divided by the total volume of air (m 3 

# ) passing through the

chamber to calculate the nominal concentration (ppm).

During each exposure, measurements of airborne concentrations

were performed in the animals’ brea thing zone at l east 4 times using

an appropriate sampling procedure (~20 Lpm) and infrared (IR)

spectrophotometric analytical procedure.

See Appendix M for equipment details.

2.12.7. PARTICLE SIZE DISTRIBUTION ANALYSIS

During each week of exposure, particle size determinations were

performed using a TSI Aerodynamic Particle Sizer to characterize

the aerodynamic particle size distribution of any aerosol present.

The samples were drawn for 20 seconds at a flow rate of 5.0 Lpm.

The mass median aerodynamic diameter, geometric standard

deviation and total mass concentr ation were calculated based on

the amount of particles collected.

See Appendix M for equipment details.

2.13. EXPERIMENTAL EVALUATIONS

2.13.1. VIABILITY CHECKS

Animals were observed in their cages twice daily (once in the

morning and once in the afternoon) for mortality, morbidity and

signs of severe toxicity.

2.13.2. PHYSICAL OBSERVATIONS

Exposure Observations

All visible animals were observe d as a group at least once during

each exposure.

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Detailed Physical Examinations

Animals were removed from their cages and examined pretest and

weekly during the study period . Examinations included

observations of general condition, skin and fur, eyes, nose, oral

cavity, abdomen and external genita lia as well as evaluations of

respiration and palpation for tissue masses.

2.13.3. BODY WEIGHT

Body weights were recorded for all animals on presumed GD 6

through termination on GD 29.

2.13.4. FOOD CONSUMPTION

Food was available without restric tion 7 days/week. Animals were

presented with full feeders of known weight. Feeders were

reweighed on the following day and the resulting weight was

subtracted from the original f eeder weight to obtain the grams

consumed. Food consumption was measured (weighed) daily from

GD 4 through GD 29.

2.14. TERMINAL OBSERVATIONS

2.14.1. NECROPSY INFORMATION

Necropsy was performed on 8 animals/group after 28 days of

exposure.

Method of Euthanasia

Adult females: intravenous inje ction of sodium pentobarbital.

Fetuses: intraperitoneal inje ction of sodium pentobarbital.

2.14.2. TERMINAL EXAMINATIONS (SCHEDULED

TERMINATIONS)

A necropsy (macroscopic examination) comprised of an external

examination followed by an inte rnal examination (excluding the

cranial cavity) was performed. Mi nor sporadic le sions common to

this strain of animal (i.e. localized patchy hair loss) were not

sampled or recorded.

The intact uterus (ovaries at tached) was removed from the

abdominal cavity and weighed intact for visibly pregnant animals

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only. Corpora lutea were counted and the number per ovary

recorded.

The uterus was then opened and the number and location of the

following were recorded for each uterine horn:

• live fetuses

• dead fetuses (recently dead, no significant degeneration)

• late embryo-fetal deaths (recognizable dead embryo/fetus

undergoing degeneration, regardless of size)

• early embryonic deaths (evide nce of implantation, but no

recognizable embryo), or stain-positive

The placenta associated with each fetus was examined

macroscopically and weighed.

For apparently non-pregnant anim als, and for apparently empty

uterine horns, the number of uterine implantation sites were

checked after staining with ammo nium sulphide [modification of

the Salewski staining technique (Salewski, 1964)].

The uteri and ovaries of appare ntly non-pregnant rabbits were

retained in neutral buffered 10% formalin and discarded at the end

of the study when authori zed by the Study Director.

2.14.3. FETAL EXAMINATIONS

External Examinations (live fetuses)

All live GD 29 fetuses, and any recently-dead fetuses without

significant necrosis, were weighed, sexed, individually identified,

and the fetuses examined external ly for abnormalities, including

observation of the palate. All apparently normal fetuses were

discarded after euthanasia and examination.

2.15. STATISTICAL ANALYSIS

Statistical analyses for maternal and embryo-fetal data were limited to

descriptive statistics (mean, standard deviation and number). Data for nonpregnant animals were excluded from the calculations.

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2.16. MAJOR COMPUTER SYSTEMS

The following major computer/softw are systems were utilized at

Huntingdon Life Sciences, East Millstone, New Jersey.

System Version Use

Liberate Reporting

System 2.2 Generation of report tables for the clinical

observations, body weight, food

consumption and organ weight data in MS

Word formats

Microsoft Word

and/or Excel Additional formatting of report tables.

REES Scientific

Environmental

Monitoring System WIN 1.5 Monitor and record temperature, humidity

and/or light intensity re adings of applicable

rooms as well as the temperature readings

of applicable refrigerators and/freezers

TSI Aerodynamic

Particle Sizer

Spectrometer 2.9 Acquisition of particle size data

Xybion Path/Tox

System 4.2.2 Direct online capture of clinical

observations, body weights, food

consumption, organ weights and

necropsy/fetal pathology data

2.17. DATA STORAGE

All raw data, preserved specimens, and retained samples, as well as the

original study protocol and the original final report are to be maintained in

the Archives of the Testing Facili ty upon completion of the study for at

least ten years. Following this period, the Sponsor will determine the final

disposition of these materials.

2.18. REGULATORY REFERENCES

2.18.1. TEST GUIDELINES

There are no regulatory guidelines for this type of preliminary

study, although the design was based on the OECD 414 and US

EPA 870.3700 guidelines for embr yo-fetal toxicity studies.

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2.18.2. GOOD LABORATORY PRACTICES

This study was performed according to protocol, at the Testing

Facility according to Huntingd on Life Sciences’ Standard

Operating Procedures. Quality Assurance (QA) inspections and

auditing were not performed, as this was not conducted in full

compliance with GLP.

2.18.3. ANIMAL WELFARE ACT COMPLIANCE

This study complied with all appropriate parts of the Animal

Welfare Act Regulations: 9 CF R Parts 1 and 2 Final Rules,

Federal Register, Volume 54 , No. 168, August 31, 1989, pp.

36112-36163 effective October 30, 1989 and 9 CFR Part 3 Animal

Welfare Standards; Final Rule, Federal Register, Volume 56, No.

32, February 15, 1991, pp. 6426- 6505 effective March 18, 1991.

2.19. PROTOCOL DEVIATION

The following protocol deviation occu rred during the study but was not

considered to have compromised the validity or integrity of the study:

Detailed physical examinations were performed on half of the dams in the

afternoon rather than in the morning on GD 5.

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3. RESULTS AND DISCUSSION

3.1. CHAMBER MONITORING

(Appendix A)

Pre-study chamber distribution analyses showed the test substance was

evenly distributed within each chamber. The target and mean analytical

(IR) and nominal concentrations are summarized as follows:

Group Target

Concentration

(ppm) Analytical

Concentration

(ppm) Nominal

Concentration

(ppm)

1 0 0.0 0

2 2,500 2,400 NA

3 10,000 10,000 NA

4 15,000 15,000 24,750*

*the combined nominal concentration for all 3 exposed groups

The achieved mean exposure concentra tion for each group was very close to

the respective target concentration. The differences between measured

(total of 27,510 ppm) and nominal (24,750 ppm) concentrations were

considered representative of minor di fferences in calibration of the IR

spectrophotometer and/or the chamber airflows. Chamber environmental

conditions averaged 18 ◦ 

# C and 62% relative humidity.

Mean particle size distribution measurements for the exposures are

summarized as follows:

Group Test

Substance Mass Median

Aerodynamic

Diameter

( μ m) Geometric

Standard

Deviation Total

Mass

Concentration

(mg/m 3 

# )

1 Air Control 4.139 1.863 4.60 x 10 -2



# 2 4.562 1.956 4.10 x 10 -2



# 3 3.593 1.887 1.68 x 10 -2



# 4 3.109 1.762 1.34 x 10 -2

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These results indicated that the atmospheres were essentially vapor only,

as expected, since there was no substantial difference between the test

substance chambers and the air control chamber.

3.2. MATERNAL DATA

3.2.1. MORTALITY

( Appendix B )

There was no effect of exposur e on survival for females at

exposures up to 15,000 ppm. All females survived until the

termination of the study.

3.2.2. CLINICAL OBSERVATIONS

( Tables 2

, 3 and 4 ; Appendix C and D )

In-chamber observations were within normal limits on all exposure

days for all test groups.

There were no exposure-related findings in the test substance

exposed animals during the non-exposure intervals. Only

transient, minor, non-adverse findings were observed in these

exposure groups.

3.2.3. GESTATION BODY WEIGHTS

( Tables 5 and 6 ; Appendices E and F )

There were no exposure-related differences in body weights and

body weight gains in the test substance exposed animals during the

gestation period as compared with the air control group.

3.2.4. GESTATION FOOD CONSUMPTION

( Table 7 ; Appendix G )

There were no exposure-related differences in feed consumption in

the test substance exposed animals, compared to the air control

animals during the gestation period.

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3.2.5. MATERNAL MACROSCOPIC POSTMORTEM

EVALUATIONS

( Table 8 ; Appendix H )

There were no test substance related macroscopic abnormalities.

Macroscopic findings were typical of the background findings seen

in rats of this age.

3.2.6. PREGNANCY OUTCOME AND CESAREAN SECTION

DATA

( Tables 9 and 10 ; Appendix I )

One female at 15,000 ppm was not pregnant at scheduled

termination, however this was not considered to be test substancerelated. In addition, slightly increased sex ratios (% male) were

noted at ≥ 2,500 ppm, ranging from 18% to 44% as compared with

mean control values. As there was no correlation with total

number of fetuses, this was also not considered to be test

substance-related.

3.3. FETAL DATA

3.3.1. GRAVID UTERINE, PLACENTAL AND FETAL WEIGHTS

( Tables 11 and 12 ; Appendices J and K )

Decreases in body weight changes from GD 6 to 29 were noted at

≥ 2,500 ppm (-18%), but were considered non-test substancerelated as there were no signifi cant differences in body weight

between test substance-treated groups at GD 6 or GD 29. In

addition, placental weights at ≥ 2,500 ppm were increased, ranging

from 9% to 20% when compared with control values, although no

correlations were noted with fetal weights.

3.3.2. FETAL OBSERVATIONS: EXTERNAL FINDINGS

( Table13 ; Appendix L )

Exposures up to 15,000 ppm did not result in any test substancerelated external malformations.

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4. CONCLUSION

There were no effects of exposures on su rvival, clinical signs, body weights, food

consumption or maternal or pup findings atsacrifice. Therefore, the no-observedeffect level (NOEL) for adult pregna nt female rabbits for systemic and

reproductive and developmental toxicity was 15,000 ppm of

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REFERENCES

Salewski, E. 1964. Farbemethode zum makroskopischen machweis von

implantationsstellen am uterus der ratte. Archiv. Path. Exp. Pharmakol . 247: 367.

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Group 1 Chamber Generation System

and Whole-Body Exposure Chamber Figure 1

Notes:

Sampling Ports H-7 (left-bottom), H-8 (left-top), H-1 (right-bottom) and

H-2 (right-top) used for pretest distribution sampling, were located on the back wall of

the chambers.

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Groups 2, 3 and 4 Chamber Generation System

and Whole-Body Exposure Chamber Figure 1

Notes:

Sampling Ports H-7 (left-bottom), H-8 (left-top), H-1 (right-bottom) and

H-2 (right-top) used for pretest distribution sampling, were located on the back wall of

the chambers.Huntingdon Life Sciences09-4347Page 31MA-252E-93-23FinalReportMean Body Weights(grams)Figure 23100320033003400350036003700380039004 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29Gestation Day

Body Weights (grams)Group 1 - 0 ppmGroup 2 - 2,500 ppmGroup 3 - 10,000 ppmGroup 4 - 15,000 ppmHuntingdon Life Sciences09-4347Page 32MA-252E-93-23FinalReportMean Food Consumption Values(grams/animal/day)Figure 31201301401501601701801902004 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29Gestation Day

Food Consumption (g/animal/day)Group 1 - 0 ppmGroup 2 - 2,500 ppmGroup 3 - 10,000 ppmGroup 4 - 15,000 ppm

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General Preface

General Notes

Individual animal data presented in this report may be rounded. Unrounded individual

animal data were used to calculate the reported mean and standard deviation values.

Therefore, use of the reported individual values to reproduce means, standard deviations

and/or to perform any subsequent calculations may produce minor discrepancies between

the calculated values and those presented in this report.

The data collection system used for collecti ng the in-life and post-life data divides the

study into phases. The phase utilized on this study was:

Gestation Phase (GD or GES): Begins th e day of confirmation of mating (GD 0).

Corresponding exposure levels for each group were as follows:

Group 1 - 0 ppm

Group 2 - 2,500 ppm

Group 3 - 10,000 ppm

Group 4 - 15,000 ppmHuntingdon Life Sciences09-4347Page 34MA-252E-93-23FinalReportFemalesSummary of SurvivalTable 1Dose Group 1 2 3 4Exposure Level (ppm) 0 2,500 10,000 15,000n (%) n (%) n (%) n (%)Number of females entered on study8 8 8 8Removed before scheduled terminationDied0 (0) 0 (0) 0 (0) 0 (0)Moribund/elective sacrifice0 (0)0 (0) 0 (0) 0 (0)Total0 (0) 0 (0) 0 (0) 0 (0)Huntingdon Life Sciences09-4347Page 35MA-252E-93-23FinalReportSummary of In-Chamber ObservationsaTable2aObservations are based on total animals present in the chamber each day.All = 100% of animals exhibiting a given observation.Exposure Day1 2 3 4 5 6 7 8 9 10 11 12 13 14Gestation Day6 7 8 9 10 11 12 13 14 15 16 17 18 19Group 1 – 0 ppmWithin Normal Limits AllAll All All All All All All All All All All AllAllGroup 2 – 2,500 ppmWithin Normal LimitsAll All All All All All All All All All All All AllAllGroup 3 – 10,000 ppmWithin Normal LimitsAll All All All All All All All All All All All AllAllGroup 4 – 15,000 ppmWithin Normal LimitsAll All All All AllAll All All All All All All All AllHuntingdon Life Sciences09-4347Page 36MA-252E-93-23FinalReportSummary of In-Chamber ObservationsaTable2aObservations are based on total animals present in the chamber each day.All = 100% of animals exhibiting a given observation.Exposure Day15 16 17 18 19 20 21 22 23Gestation Day20 21 22 23 24 25 26 27 28Group 1 – 0 ppmWithin Normal Limits AllAll All All All AllAll All AllGroup 2 – 2,500 ppmWithin Normal LimitsAll All All All All All All All AllGroup 3 – 10,000 ppmWithin Normal LimitsAll All All All All All All All AllGroup 4 – 15,000 ppmWithin Normal LimitsAll All All All All AllAll All All

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Summary of Daily Viability Observations

Preface Table 3

Only animals with abnormal observations and intervals with findings are presented in this

table; all other animals were considered to within normal limits at all other intervals.

Corresponding exposure levels for each group were as follows:

Group 1 - 0 ppm

Group 2 - 2,500 ppm

Group 3 - 10,000 ppm

Group 4 - 15,000 ppmHuntingdon Life Sciences09-4347Page 38MA-252E-93-23FinalReportFemalesSummary of Daily Viability ObservationsTable 3Phase GESDay 1 2 14 15 16 17 18 21 23 24 26Session AM AM AM AM AM AM AM AM PM AM AMObservationsGroupDermal General, Alopecia (Limbs)1 1Dermal General, Alopecia (Head/Neck)3 1Dermal General, Alopecia (Torso)2 1Dermal General, Scab(s)4 1Gastrointestinal, No Stool2 1Daily Observations, Red Exudate (Limbs/Tail) 2 1Daily Observations, Decreased Fecal Volume 1 1 1 1 12 1 2 1 1 14 1 1Daily Observations, No Stool2 1Daily Observations, Decreased Food Consumption 1 1 1 12 1 1 2 1 14 1 1

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Summary of Gestation

Physical Examination Findings

Preface Table 4

Corresponding exposure levels for each group were as follows:

Group 1 - 0 ppm

Group 2 - 2,500 ppm

Group 3 - 10,000 ppm

Group 4 - 15,000 ppmHuntingdon Life Sciences09-4347Page 40MA-252E-93-23FinalReportFemalesSummary of Gestation Physical Examination FindingsTable 4Phase GESDay 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Session PO PO PO PO PO PO PO PO PO PO PO PO PO PO POObservationsGroupExamined1 4 8 8 8 8 8 8 8 8 8 8 8 8 8 82 4 8 8 8 8 8 8 8 8 8 8 8 8 8 83 4 8 8 8 8 8 8 8 8 8 8 8 8 8 84 4 8 8 8 8 8 8 8 8 8 8 8 8 8 8Within Normal Limits1 3 7 7 7 8 8 8 8 8 8 8 8 7 7 72 4 7 7 7 7 7 7 8 8 8 8 8 8 8 83 4 7 7 7 7 7 7 7 8 8 8 8 8 8 84 4 7 7 7 7 7 7 7 7 7 7 7 7 8 8Dermal General, Alopecia (Limbs)1 1 1 1 1Dermal General, Alopecia (Head/Neck)3 1 1 1 1 1 1 1Dermal General, Alopecia (Torso)2 1 1 1 1 1 1Dermal General, Ano-Genital Staining1 1 1 1Dermal General, Scab(s)4 1 1 1 1 1 1 1 1 1 1 1 1Huntingdon Life Sciences09-4347Page 41MA-252E-93-23FinalReportFemalesSummary of Gestation Physical Examination FindingsTable 4Phase GESDay 17 18 19 20 21 22 23 24 25 26 27 28 29Session PO PO PO PO PO PO PO PO PO PO PO PO POObservationsGroupExamined1 8 8 8 8 8 8 8 8 8 8 8 8 82 8 8 8 8 8 8 8 8 8 8 8 8 83 8 8 8 8 8 8 8 8 8 8 8 8 84 8 8 8 8 8 8 8 8 8 8 8 8 8Within Normal Limits1 6 6 6 6 6 6 6 7 7 7 7 7 72 8 8 8 8 7 7 6 7 6 6 6 6 63 8 8 8 8 7 7 7 7 7 7 7 6 64 8 8 8 8 8 7 7 7 7 7 7 7 7General Appearance, Red Exudate (Limbs/Tail) 2 1Dermal General, Alopecia (Limbs)2 1 1 1 1 13 1 1Dermal General, Alopecia (Head/Neck)1 1 1 1 1 1 1 13 1 1 1 1 1 1 1 1 14 1 1 1 1 1 1 1 1Dermal General, Alopecia (Torso)3 1Dermal General, Ano-Genital Staining1 1 1 1 1 1 1 1 1 1 1 1 1 12 1 1 1 1 1 1 1 1 1Huntingdon Life Sciences09-4347Page 42MA-252E-93-23FinalReportMean Gestation Body WeightsFemales (grams) Table5Phase GESDay 4 6 7 8 9 10 11 12 13 14 15 16Group 1 - 0 ppmMean 3207.1 3237.9 3274.1 3288.7 3310.7 3320.4 3342.1 3377.2 3405.2 3442.1 3474.0 3463.2SD 112.07 121.37 118.38 119.98 106.27 114.78 105.32 108.19 105.43 103.08 113.40 125.02N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 3363.0 3409.2 3427.9 3427.7 3442.9 3444.0 3466.0 3492.4 3489.0 3526.5 3543.3 3556.1SD 129.43 125.84 116.40 117.56 107.12 118.33 107.16 106.25 110.53 110.20 116.08 111.85N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 3341.9 3386.4 3415.0 3412.4 3416.3 3421.1 3444.0 3473.0 3496.6 3524.1 3552.6 3574.5SD 275.12 236.45 257.01 257.28 255.53 252.59 246.04 261.90 244.05 232.54 228.39 228.30N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 3237.5 3302.1 3312.6 3327.0 3332.7 3332.6 3352.2 3386.8 3400.5 3424.5 3442.0 3451.5SD 332.75 322.66 327.10 326.53 341.50 329.68 340.63 347.80 349.49 349.33 355.06 360.45N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 43MA-252E-93-23FinalReportMean Gestation Body WeightsFemales (grams) Table5Phase GESDay 17 18 19 20 21 22 23 24 25 26 27 28Group 1 - 0 ppmMean 3468.3 3479.3 3516.1 3519.4 3549.3 3564.1 3571.9 3610.9 3625.9 3654.2 3670.3 3698.8SD 131.72 136.97 132.21 131.78 134.39 138.21 129.53 131.94 137.48 156.11 150.94 163.03N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 3575.9 3599.6 3622.4 3624.4 3646.4 3666.0 3687.4 3705.1 3729.5 3732.2 3754.2 3773.8SD 94.46 91.52 87.64 94.28 93.06 96.24 104.60 92.05 106.30 110.25 116.25 114.53N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 3571.5 3586.8 3604.0 3624.4 3636.5 3660.4 3679.8 3699.7 3715.3 3734.7 3752.0 3769.4SD 228.98 217.20 220.75 229.31 231.59 231.75 220.70 222.93 219.14 208.45 210.71 201.14N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 3458.3 3474.5 3493.8 3500.2 3528.7 3552.1 3569.7 3595.8 3627.2 3643.7 3650.1 3678.5SD 354.00 357.19 347.28 350.17 347.87 356.09 368.88 365.69 376.03 386.30 386.56 394.32N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 44MA-252E-93-23FinalReportMean Gestation Body WeightsFemales (grams) Table5Phase GESDay 29Group 1 - 0 ppmMean 3721.9SD 171.73N 8Group 2 - 2,500 ppmMean 3801.7SD 113.35N 8Group 3 - 10,000 ppmMean 3788.7SD 197.07N 8Group 4 - 15,000 ppmMean 3696.6SD 394.84N 7Huntingdon Life Sciences09-4347Page 45MA-252E-93-23FinalReportMean Gestation Body Weight ChangesFemales (grams) Table6Phase GESDay 4-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17Group 1 - 0 ppmMean 30.8 36.2 14.5 22.0 9.7 21.7 35.0 28.0 36.9 31.8 -10.8 5.1SD 52.86 51.90 21.23 25.69 17.76 20.71 19.20 22.94 37.19 39.70 22.34 16.34N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 46.2 18.7 -0.2 15.2 1.1 22.0 26.4 -3.4 37.5 16.8 12.8 19.8SD 25.29 39.89 11.57 19.00 28.22 29.80 30.14 35.29 44.72 40.43 29.03 32.29N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 44.5 28.6 -2.7 4.0 4.7 23.0 28.9 23.7 27.4 28.6 21.9 -3.0SD 70.19 44.60 18.10 24.25 45.53 28.22 26.56 22.98 20.11 14.64 19.26 18.51N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 64.6 10.6 14.4 5.7 -0.2 19.6 34.6 13.6 24.0 17.5 9.5 6.8SD 108.85 61.66 45.35 25.57 18.71 30.45 41.85 20.49 37.67 28.03 9.88 24.96N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 46MA-252E-93-23FinalReportMean Gestation Body Weight ChangesFemales (grams) Table6Phase GESDay 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29Group 1 - 0 ppmMean 11.0 36.9 3.3 29.8 14.8 7.9 39.0 15.0 28.3 16.1 28.5 23.1SD 22.76 17.10 28.43 29.98 21.43 25.30 20.86 13.24 54.93 29.13 18.99 25.46N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 23.7 22.9 1.9 22.0 19.6 21.5 17.7 24.4 2.6 22.0 19.6 27.9SD 29.70 13.01 16.24 27.98 23.44 25.17 33.99 32.86 39.34 18.47 12.74 14.10N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 15.3 17.2 20.5 12.1 23.9 19.4 19.9 15.6 19.3 17.3 17.4 19.3SD 17.04 20.76 18.34 19.60 30.17 17.66 13.56 25.30 18.26 17.43 17.81 18.23N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 16.2 19.4 6.4 28.5 23.4 17.6 26.1 31.4 16.5 6.3 28.4 18.1SD 10.55 16.51 10.17 10.48 24.18 19.40 18.04 24.30 23.24 18.22 27.12 7.49N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 47MA-252E-93-23FinalReportMean Gestation Body Weight ChangesFemales (grams) Table6Phase GESDay 6-29Group 1 - 0 ppmMean 483.9SD 181.00N 8Group 2 - 2,500 ppmMean 392.6SD 130.68N 8Group 3 - 10,000 ppmMean 402.3SD 124.68N 8Group 4 - 15,000 ppmMean 394.6SD 224.90N 7Huntingdon Life Sciences09-4347Page 48MA-252E-93-23FinalReportMean Gestation Food Consumption ValuesFemales (grams/animal/day) Table7Phase GESDay 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16Group 1 - 0 ppmMean 186.9 185.1 173.2 176.8 173.3 171.4 182.5 175.1 163.9 154.7 166.1 157.5SD 22.19 13.61 18.59 22.34 17.11 27.84 18.63 18.96 30.64 42.95 45.79 64.69N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 185.7 181.9 169.0 171.0 168.7 165.1 166.9 156.2 141.4 128.4 130.4 140.3SD 8.53 19.47 19.13 22.02 20.57 23.54 26.52 37.01 38.33 69.27 74.39 59.47N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 186.5 185.3 178.5 178.1 173.2 171.5 173.4 164.0 159.9 152.6 167.3 173.1SD 13.72 17.82 23.13 28.04 33.88 28.91 28.21 36.03 26.90 31.01 27.37 23.61N 8 8 8 8 8 7 8 8 8 8 8 8Group 4 - 15,000 ppmMean 176.6 176.9 158.0 164.1 158.1 157.6 155.0 150.2 141.5 132.7 131.9 134.7SD 24.78 18.72 31.37 26.77 31.65 27.63 27.64 36.87 40.00 53.20 50.75 46.56N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 49MA-252E-93-23FinalReportMean Gestation Food Consumption ValuesFemales (grams/animal/day) Table7Phase GESDay 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28Group 1 - 0 ppm (Air Control )Mean 157.6 174.5 184.8 188.3 183.9 182.8 174.4 169.0 154.5 138.0 142.7 144.3SD 64.59 42.13 14.49 9.34 11.92 10.93 22.02 22.90 32.71 55.98 30.78 34.25N 8 8 8 8 7 8 7 7 7 8 8 8Group 2 - 2,500 ppmMean 154.5 163.9 163.4 159.9 160.9 161.7 165.4 149.1 148.9 134.5 131.8 135.7SD 42.85 36.14 36.30 37.41 34.89 30.22 28.43 43.71 33.61 35.23 35.22 34.11N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 177.2 176.3 173.7 178.5 173.5 169.0 160.8 156.3 137.8 130.3 128.1 137.6SD 20.52 22.42 22.56 23.09 26.81 37.16 37.67 36.33 37.74 37.09 29.37 24.66N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 147.5 146.9 150.1 156.2 159.5 158.0 159.5 153.2 141.9 137.3 131.9 128.6SD 38.71 35.03 33.35 30.75 32.79 26.11 31.59 30.70 41.00 43.24 40.37 42.32N 7 7 7 7 7 7 7 7 7 7 7 7Huntingdon Life Sciences09-4347Page 50MA-252E-93-23FinalReportMean Gestation Food Consumption ValuesFemales (grams/animal/day) Table7Phase GESDay 28-29 6-29Group 1 - 0 ppmMean 150.4 166.7SD 34.36 25.10N 8 8Group 2 - 2,500 ppmMean 137.6 152.4SD 31.83 33.49N 8 8Group 3 - 10,000 ppmMean 138.7 162.1SD 32.13 23.58N 8 8Group 4 - 15,000 ppmMean 139.6 147.6SD 24.91 33.96N 7 7

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Incidence Summary Report

for Gross Necropsy Observations

Preface Table 8

Corresponding dose levels for each group were as follows:

Group 1 - 0 ppm

Group 2 - 2,500 ppm

Group 3 - 10,000 ppm

Group 4 - 15,000 ppmPage 52Huntingdon Life Sciences09-4347Page 53MA-252E-93-23FinalReportFemalesSummary of PregnancyTable 9Dose Group 1 2 3 4Exposure Level (ppm) 0 2,500 10,000 15,000n (%) n (%) n (%) n (%)Number of females entered on study (mated)8 8 8 8- Non pregnant0 (0) 0 (0) 0 (0) 1 (13)- Pregnant8 (100) 8 (100) 8 (100) 7 (88)Pregnant with termination before scheduled date0 0 0 0Pregnant at scheduled termination8 8 8 7- With total implantation loss0 (0) 0 (0) 0 (0) 0 (0)- With viable fetuses8 (100) 8 (100) 8 (100) 7 (100)Huntingdon Life Sciences09-4347Page 54MA-252E-93-23FinalReportFemalesSummary of Cesarean Section DataTable 10Corpora Implant- Resorptions Dead Live Fetuses Sex Ratio Pre Impl. Post Impl.Lutea ations Early Late Total Fetuses Male Female Total (% Male) Loss (%) Loss (%)Group 1 - 0 ppmMean 10.1 9.9 0.4 0.4 0.8 0.0 3.1 6.0 9.1 34.1 1.8 6.2SD 2.36 1.96 0.74 1.06 1.16 0.00 0.99 1.07 1.13 9.36 5.05 9.27N 8 8 8 8 8 8 8 8 8 8 8 8Group 2 - 2,500 ppmMean 9.5 9.4 0.1 0.0 0.1 0.0 3.9 5.4 9.3 43.0 1.1 1.3SD 1.51 1.41 0.35 0.00 0.35 0.00 0.99 1.85 1.39 13.61 3.21 3.54N 8 8 8 8 8 8 8 8 8 8 8 8Group 3 - 10,000 ppmMean 9.6 9.3 0.3 0.0 0.3 0.0 3.6 5.4 9.0 40.3 3.7 3.0SD 1.41 1.28 0.46 0.00 0.46 0.00 1.06 1.30 1.51 10.07 5.30 5.48N 8 8 8 8 8 8 8 8 8 8 8 8Group 4 - 15,000 ppmMean 9.0 8.9 0.3 0.1 0.4 0.0 4.1 4.3 8.4 49.0 2.0 5.0SD 1.15 1.46 0.49 0.38 0.53 0.00 1.46 1.60 1.62 18.60 5.40 6.20N 7 7 7 7 7 7 7 7 7 7 7 7Impl. = ImplantationHuntingdon Life Sciences09-4347Page 55MA-252E-93-23FinalReportBwt = body weight, Adj bwt = Adjusted body weightAdjusted body weight = Body weighton Day 29 – Gravid Uterine WeightMean Gravid Uterine Adjusted Body WeightsFemales (grams) Table11Bodyweight on Bodyweighton Bwt change Gravid Uterine Adj Bwt Adj bwt changeDay 6 Day 29 Days 6-29Weight Day 29 Days 6-29Group 1 - 0 ppmMean 3237.9 3721.9 483.9 526.7 3195.2 -42.7S.D. 121.37 171.73 181.00 47.34 194.14 197.12N 8 8 8 8 8 8Group 2 - 2,500 ppmMean 3409.2 3801.7 392.6 548.2 3253.6 -155.6S.D. 125.84 113.35 130.68 59.59 114.42 123.78N 8 8 8 8 8 8Group 3 - 10,000 ppmMean 3386.4 3788.7 402.3 517.7 3271.0 -115.3S.D. 236.45 197.07 124.68 74.59 192.46 141.88N 8 8 8 8 8 8Group 4 - 15,000 ppmMean 3302.1 3696.6 394.6 513.3 3183.3 -118.8S.D. 322.66 394.84 224.90 150.54 281.30 135.93N 7 7 7 7 7 7

# Huntingdon Life Sciences 09-4347 Page 56

MA-252E-93-23 Final Report

Mean Litter Weight Data

(grams) Table 12

Total Litter Mean

Animal Litter Fetal Fetal Placental

Number Weight Weight Weight

Group 1 – 0 ppm (Air Control)

Mean 372.8 41.2 4.4

SD 31.36 3.84 0.39

N 8 8 8

Group 2 – 2,500 ppm

Mean 387.1 42.1 5.0

SD 42.56 3.18 0.58

N 8 8 8

Group 3 – 10,000 ppm

Mean 372.7 41.6 4.8

SD 58.13 3.60 0.40

N 8 8 8

Group 4 – 15,000 ppm

Mean 361.6 42.5 5.3

SD 100.3 6.93 0.67

N 7 7 7Huntingdon Life Sciences09-4347Page 57MA-252E-93-23FinalReportSummary of Fetal Observations(External) Table13Fetuses LittersGroup 1 2 3 4 1 2 3 4Observation External Examinations 73 74 72 59 8 8 8 7No abnormality detected76 72 72 60 8 8 8 7Skin/subcutisForepaw(s), subcutaneous hemorrhage 1 1Hindpaw(s), subcutaneous hemorrhage 1 1Huntingdon Life Sciences09-4347Page 58MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 1 – 0 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber Concentration DeterminationsMeanNumberMeanIndividual MMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)1 24-Aug-09 100.0 0.0 0.0 0.0 0.017592 25-Aug-09 200.0 0.0 0.0 0.0 0.019613 26-Aug-09 3 0 0.0 0.0 0.0 0.0 0.0 0.8463 1.492 2.77E-03 19 614 27-Aug-09 400.0 0.0 0.0 0.0 0.019605 28-Aug-09 500.0 0.0 0.0 0.0 0.019626 29-Aug-09 600.0 0.0 0.0 0.0 0.019627 30-Aug-09 700.0 0.0 0.0 0.0 0.019608 31-Aug-09 800.0 0.0 0.0 0.0 0.019609 1-Sep-09 900.0 0.0 0.0 0.0 0.0196210 2-Sep-09 10 0 0.0 0.0 0.0 0.0 0.0 7.056 2.396 6.76E-02 19 6011 3-Sep-09 1100.0 0.0 0.0 0.0 0.0186012 4-Sep-09 1200.0 0.0 0.0 0.0 0.0175813 5-Sep-09 1300.0 0.0 0.0 0.0 0.0185814 6-Sep-09 1400.0 0.0 0.0 0.0 0.0175715 7-Sep-09 1500.0 0.0 0.0 0.0 0.0185916 8-Sep-09 1600.0 0.0 0.0 0.0 0.0186017 9-Sep-09 17 0 0.0 0.0 0.0 0.0 0.0 4.854 1.602 8.30E-02 18 6418 10-Sep-09 1800.0 0.0 0.0 0.0 0.0175919 11-Sep-09 1900.0 0.0 0.0 0.0 0.01760Huntingdon Life Sciences09-4347Page 59MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 1 – 0 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber Concentration DeterminationsMeanNumberMeanIndividual MMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)20 12-Sep-09 2000.0 0.0 0.0 0.0 0.0176121 13-Sep-09 2100.0 0.0 0.0 0.0 0.0186122 14-Sep-09 2200.0 0.0 0.0 0.0 0.0176023 15-Sep-09 23 0 0.0 0.0 0.0 0.0 0.0 3.798 1.963 3.06E-02 18 6224 16-Sep-09 2400.0 0.0 0.0 0.0 0.01660Mean 00.0 4.139 1.863 4.60E-02 18 60S.D. 0 0.0 2.581 0.408 0.04 1 2Huntingdon Life Sciences09-4347Page 60MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 2 – 2,500 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)1 24-Aug-09 1NA 2400 2600 2200 2400 240018562 25-Aug-09 2NA 2300 2100 2300 2300 240019633 26-Aug-09 3 NA 2500 2600 2500 2400 2300 4.500 1.818 6.07E-02 19 674 27-Aug-09 4NA 2600 2800 2500 2500 260019605 28-Aug-09 5NA 2400 2300 2000 2300 280019646 29-Aug-09 6NA 2500 2600 2500 2400 250020657 30-Aug-09 7NA 2300 2700 2000 2400 210019648 31-Aug-09 8NA 2300 2100 2100 2500 230019659 1-Sep-09 9NA 2500 2700 2700 2100 2300196210 2-Sep-09 10 NA 2500 2300 2600 2500 2400 5.895 1.827 5.69E-02 19 6411 3-Sep-09 11 NA 2700 3000 2500 2500 2700196212 4-Sep-09 12 NA 2200 2100 2100 2100 2500176213 5-Sep-09 13 NA 2500 3600 2000 2100 2200176214 6-Sep-09 14 NA 2500 2400 2600 2400 2600176215 7-Sep-09 15 NA 2500 2700 2900 2200 2200176416 8-Sep-09 16 NA 2500 2200 2600 3000 2300176517 9-Sep-09 17 NA 2800 3000 2700 2800 2700 6.906 2.196 4.17E-02 18 7218 10-Sep-09 18 NA 2600 2700 2600 2400 2600166519 11-Sep-09 19 NA 2600 2600 2500 2600 25001764Huntingdon Life Sciences09-4347Page 61MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 2 – 2,500 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)20 12-Sep-09 20 NA 2400 2700 2000 2600 2300176721 13-Sep-09 21 NA 2400 2200 2300 2500 2500176522 14-Sep-09 22 NA 2400 2300 2100 2600 2400166623 15-Sep-09 23 NA 2500 2700 2100 2600 2400 0.9488 1.981 4.81E-03 17 6724 16-Sep-09 24 NA 2400 2300 2400 2400 24001664Mean NA2400 4.562 1.956 4.10E-02 18 64S.D. 265 2.603 0.177 0.03 1 3Huntingdon Life Sciences09-4347Page 62MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 3 – 10,000 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)1 24-Aug-09 1NA 11000 12000 11000 11000 1000018572 25-Aug-09 2NA 10000 9800 10000 10000 1000019633 26-Aug-09 3 NA 10000 9700 11000 10000 10000 5.538 2.241 2.50E-02 20 624 27-Aug-09 4NA 9700 8900 9000 10000 1100019615 28-Aug-09 5NA 10000 9700 10000 10000 1000019656 29-Aug-09 6NA 10000 11000 10000 10000 1000019647 30-Aug-09 7NA 9700 9200 10000 9400 1000019638 31-Aug-09 8NA 10000 9700 11000 10000 1000019649 1-Sep-09 9NA 10000 10000 9900 10000 9900195810 2-Sep-09 10 NA 9700 9600 10000 9900 9300 5.222 1.807 3.15E-02 19 5711 3-Sep-09 11 NA 10000 10000 9800 10000 10000195912 4-Sep-09 12 NA 10000 10000 10000 9800 11000166213 5-Sep-09 13 NA 10000 10000 9600 9600 11000175914 6-Sep-09 14 NA 10000 10000 10000 9900 11000166115 7-Sep-09 15 NA 9700 10000 10000 9700 9200176016 8-Sep-09 16 NA 9900 10000 10000 10000 9600166117 9-Sep-09 17 NA 10000 11000 10000 9900 9400 2.690 1.732 6.43E-03 17 6618 10-Sep-09 18 NA 10000 11000 10000 10000 10000165919 11-Sep-09 19 NA 10000 11000 9700 9700 110001463Huntingdon Life Sciences09-4347Page 63MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 3 – 10,000 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)20 12-Sep-09 20 NA 10000 10000 10000 9800 10000156521 13-Sep-09 21 NA 9900 10000 9800 9800 10000146722 14-Sep-09 22 NA 11000 11000 11000 10000 12000146623 15-Sep-09 23 NA 10000 11000 10000 10000 10000 0.9220 1.766 4.08E-03 16 6424 16-Sep-09 24 NA 10000 10000 9600 11000 100001466Mean NA10000 3.593 1.887 1.68E-02 17 62S.D. 565 2.190 0.238 0.01 2 3Huntingdon Life Sciences09-4347Page 64MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 4 – 15,000 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)1 24-Aug-09 1 24000 15000 15000 15000 15000 1500018572 25-Aug-09 2 23000 15000 14000 15000 15000 1500019613 26-Aug-09 3 24000 15000 14000 14000 15000 15000 4.951 1.923 2.85E-02 19 604 27-Aug-09 4 24000 15000 15000 15000 15000 1500019585 28-Aug-09 5 24000 15000 15000 15000 15000 1500019606 29-Aug-09 6 24000 15000 15000 15000 15000 1500019637 30-Aug-09 7 24000 14000 15000 13000 14000 1400019638 31-Aug-09 8 27000 15000 14000 15000 15000 1500019629 1-Sep-09 9 24000 15000 15000 15000 15000 15000196210 2-Sep-09 10 27000 15000 15000 15000 15000 15000 5.353 1.907 1.92E-02 19 6011 3-Sep-09 11 25000 15000 15000 16000 15000 15000186312 4-Sep-09 12 25000 16000 15000 15000 16000 16000176213 5-Sep-09 13 26000 16000 15000 16000 15000 16000176414 6-Sep-09 14 25000 15000 15000 15000 15000 14000176115 7-Sep-09 15 25000 15000 14000 16000 15000 15000176316 8-Sep-09 16 25000 15000 14000 15000 15000 15000176317 9-Sep-09 17 25000 15000 15000 15000 15000 15000 1.210 1.660 2.14E-03 18 6918 10-Sep-09 18 24000 15000 15000 15000 15000 16000166319 11-Sep-09 19 25000 15000 14000 14000 15000 150001762Huntingdon Life Sciences09-4347Page 65MA-252E-93-23FinalReportChamber Monitoring ResultsCumulative Exposure RecordAppendix AGSD = Geometric Standard Deviation, MMAD = Mass Median AerodynamicDiameter, TMC = Total Mass Concentration*Nominal concentration calculated for all 3 treated groups combined, see Group 4 for results.Group 4 – 15,000 ppmParticle Size Chamber EnvironmentDay Date Exposure Nominal* Analytical Chamber ConcentrationDeterminationsMeanNumber MeanIndividualMMAD GSD TMC Temperature Humidity(ppm) (ppm)(ppm)(μm) (mg/m3) (°C)(%)20 12-Sep-09 20 24000 15000 15000 16000 16000 14000176221 13-Sep-09 21 25000 15000 15000 15000 15000 15000176322 14-Sep-09 22 25000 15000 15000 15000 16000 15000176523 15-Sep-09 23 25000 15000 15000 15000 15000 15000 0.922 1.559 3.61E-03 17 6524 16-Sep-09 24 25000 15000 15000 15000 15000 1500015 63Mean NA15000 3.109 1.762 1.34E-02 18 62S.D. 521 2.368 0.181 0.01 1 2

# Huntingdon Life Sciences 09-4347 Page 66

MA-252E-93-23 Final Report

Females Individual Animal Termination History Appendix B

a 

# T = Terminal Sacrifice

b 

# Gestation Day 0 is defined as the day of mating confirmation Test article administration began on

Gestation Day 6 for all animals. Animal

Number Date of

Death Type of

Death a 

# Study

Day b 

# Animal

Number Date of

Death Type of

Death a 

# Study

Day b



# Group 1 – 0 ppm Group 3 – 10,000 ppm

1551 16 Sep 09 T 29 3551 16 Sep 09 T 29

1552 16 Sep 09 T 29 3552 16 Sep 09 T 29

1553 16 Sep 09 T 29 3553 16 Sep 09 T 29

1554 16 Sep 09 T 29 3554 16 Sep 09 T 29

1555 17 Sep 09 T 29 3555 17 Sep 09 T 29

1556 17 Sep 09 T 29 3556 17 Sep 09 T 29

1557 17 Sep 09 T 29 3557 17 Sep 09 T 29

1558 17 Sep 09 T 29 3558 17 Sep 09 T 29

Group 2 – 2,500 ppm Group 4 – 15,000 ppm

2551 16 Sep 09 T 29 4551 16 Sep 09 T 29

2552 16 Sep 09 T 29 4552 16 Sep 09 T 29

2553 16 Sep 09 T 29 4553 16 Sep 09 T 29

2554 16 Sep 09 T 29 4554 16 Sep 09 T 29

2555 17 Sep 09 T 29 4555 17 Sep 09 T 29

2556 17 Sep 09 T 29 4556 17 Sep 09 T 29

2557 17 Sep 09 T 29 4557 17 Sep 09 T 29

2558 17 Sep 09 T 29 4558 17 Sep 09 T 29Huntingdon Life Sciences09-4347Page 67MA-252E-93-23FinalReportFemales IndividualGestationDailyViability Observations AppendixCPhase GESAnimalDay 1 2 14 15 16 17 18 21 23 24 26Number ObservationsSession AM AM AM AM AM AM AM AM PM AM AMGroup 1 - 0 ppm1553 Daily observations, decreased fecalvolumeP P P PDaily observations, decreased food consumptionP P P1558 Dermal general, alopecia (limbs)2Group 2 - 2,500 ppm2552 Dermal general, alopecia (torso)2Gastrointestinal, no stoolPDaily observations, decreased fecal volumeP P PDaily observations, no stoolPDaily observations, decreased food consumptionP P P2557 Daily observations, red exudate (limbs/tail), hind paw(s)PDaily observations, decreased fecal volumeP P PDaily observations, decreased food consumptionP P PGroup 3 - 10,000 ppm3552 Dermal general, alopecia (head/neck)2AM = morning observation, PM = afternoon observation, P = present, 2 = moderateHuntingdon Life Sciences09-4347Page 68MA-252E-93-23FinalReportFemales IndividualGestationDailyViability Observations AppendixCPhase GESAnimalDay 1 2 14 15 16 17 18 21 23 24 26Number ObservationsSession AM AM AM AM AM AM AM AM PM AM AMGroup 4 - 15,000 ppm4552 Dermal general, scab(s), ear(s)P4553 Daily observations, decreased fecalvolumePDaily observations, decreased food consumptionP4556 Daily observations, decreased fecalvolumePDaily observations, decreased food consumptionPAM = morning observation, PM = afternoon observation, P = presentHuntingdon Life Sciences09-4347Page 69MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Group 1 - 0 ppm1551 Within normal limitsP P P P P P P P P P P P P P1552 Within normal limitsP P P P P P P P P P PDermal general, ano-genital staining1 1 11553 Within normal limitsP P P P P P P P P P P P P P1554 Within normal limitsP P P P P P P P P P P P P P1555 Within normal limitsP P P P P P P P P P P P P P P1556 Within normal limitsP P P P P P P P P P P P P P P1557 Within normal limitsP P P P P P P P P P P P P P P1558 Within normal limitsP P P P P P P P P P PDermal general, alopecia (limbs)2 2 2 2Group 2 - 2,500 ppm2551 Within normal limitsP P P P P P P P P P P P P PP = present, 1 = slight, 2 = moderateHuntingdon Life Sciences09-4347Page 70MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Group 2 - 2,500 ppm2552 Within normal limitsP P P P P P P PDermal general, alopecia (torso)2 2 2 2 2 22553 Within normal limitsP P P P P P P P P P P P P P2554 Within normal limitsP P P P P P P P P P P P P P2555 Within normal limitsP P P P P P P P P P P P P P P2556 Within normal limitsP P P P P P P P P P P P P P P2557 Within normal limitsP P P P P P P P P P P P P P P2558 Within normal limitsP P P P P P P P P P P P P P PGroup 3 - 10,000 ppm3551 Within normal limitsP P P P P P P P P P P P P P3552 Within normal limitsP P P P P P PDermal general, alopecia (head/neck)2 2 2 2 2 2 2P = present, 2 = moderateHuntingdon Life Sciences09-4347Page 71MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Group 3 - 10,000 ppm3553 Within normal limitsP P P P P P P P P P P P P P3554 Within normal limitsP P P P P P P P P P P P P P3555 Within normal limitsP P P P P P P P P P P P P P P3556 Within normal limitsP P P P P P P P P P P P P P P3557 Within normal limitsP P P P P P P P P P P P P P P3558 Within normal limitsP P P P P P P P P P P P P P PGroup 4 - 15,000 ppm4551 np Within normal limitsP P P P P P P P P P P P P P4552 Within normal limitsP PDermal general, scab(s), ear(s)P P P P P P P P P P P P4553 Within normal limitsP P P P P P P P P P P P P Pnp = not pregnant, P = presentHuntingdon Life Sciences09-4347Page 72MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Group 4 - 15,000 ppm4554 Within normal limitsP P P P P P P P P P P P P P4555 Within normal limitsP P P P P P P P P P P P P P P4556 Within normal limitsP P P P P P P P P P P P P P P4557 Within normal limitsP P P P P P P P P P P P P P P4558 Within normal limitsP P P P P P P P P P P P P P PP = presentHuntingdon Life Sciences09-4347Page 73MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 17 18 19 20 21 22 23 24 25 26 27 28 29Group 1 - 0 ppm1551 Within normal limitsP P P P P P P P P P P P P1552 Dermal general, ano-genital staining1 1 1 1 1 1 1 1 1 1 1 1 11553 Within normal limitsP P P P P P P P P P P P P1554 Within normal limitsP P P P P P P P P P P P P1555 Within normal limitsP P P P P P P P P P P P P1556 Within normal limitsP P P P P PDermal general, alopecia (head/neck)2 2 2 2 2 2 21557 Within normal limitsP P P P P P P P P P P P P1558 Within normal limitsP P P P P P P P P P P P PGroup 2 - 2,500 ppm2551 Within normal limitsP P P P P P P P P P P P PP = present, 1 = slight, 2 = moderateHuntingdon Life Sciences09-4347Page 74MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 17 18 19 20 21 22 23 24 25 26 27 28 29Group 2 - 2,500 ppm2552 Within normal limitsP P P P P P P PDermal general, alopecia (limbs)3 3 3 3 32553 Within normal limitsP P P P P P P P P P P P P2554 Within normal limitsP P P P P P P P P P P P P2555 Within normal limitsP P P P P P P P P P P P P2556 Within normal limitsP P P P P P P P P P P P P2557 Within normal limitsP P P P P P P P P P P PGeneral appearance, red exudate (limbs/tail), hindpaw(s)P2558 Within normal limitsP P P PDermal general, ano-genital staining2 2 2 2 2 2 2 2 2P = present, 2 = moderate, 3 = extremeHuntingdon Life Sciences09-4347Page 75MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 17 18 19 20 21 22 23 24 25 26 27 28 29Group 3 - 10,000 ppm3551 Within normal limitsP P P PDermal general, alopecia (head/neck)3 3 3 3Dermal general, alopecia (head/neck), head2 2 3 3 33552 Within normal limitsP P P P P P P P P P P P P3553 Within normal limitsP P P P P P P P P P P P P3554 Within normal limitsP P P P P P P P P P P P P3555 Within normal limitsP P P P P P P P P P P P P3556 Within normal limitsP P P P P P P P P P P P P3557 Within normal limitsP P P P P P P P P P P P P3558 Within normal limitsP P P P P P P P P P PDermal general, alopecia (limbs)3 3Dermal general, alopecia (torso)2P = present, 2 = moderate, 3 = extremeHuntingdon Life Sciences09-4347Page 76MA-252E-93-23FinalReportFemales IndividualGestationPhysicalExamination FindingsAppendix DAnimal Phase GESNumber ObservationsDay 17 18 19 20 21 22 23 24 25 26 27 28 29Group 4 - 15,000 ppm4551 np Within normal limitsP P P P P P P P P P P P P4552 Within normal limitsP P P P PDermal general, alopecia (head/neck)3 3 3 3 3 3 3 3Dermal general, ano-genital staining2 2 2 2 1 1 14553 Within normal limitsP P P P P P P P P P P P P4554 Within normal limitsP P P P P P P P P P P P P4555 Within normal limitsP P P P P P P P P P P P P4556 Within normal limitsP P P P P P P P P P P P P4557 Within normal limitsP P P P P P P P P P P P P4558 Within normal limitsP P P P P P P P P P P P Pnp = not pregnant, P = present, 1 = slight, 2 = moderate, 3 = extremeHuntingdon Life Sciences09-4347Page 77MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 4 6 7 8 9 10 11 12 13 14 15 16Group 1 - 0 ppm1551 3060.0 3114.8 3131.0 3139.5 3161.4 3170.3 3208.0 3238.6 3277.0 3314.1 3366.3 3361.31552 3143.9 3224.2 3205.5 3199.9 3233.8 3252.5 3282.7 3283.8 3306.4 3343.7 3391.0 3403.91553 3213.5 3236.1 3226.6 3260.6 3257.7 3267.2 3275.6 3314.0 3362.2 3344.4 3317.2 3261.11554 3198.5 3298.8 3371.4 3410.2 3408.5 3422.1 3430.3 3462.2 3508.0 3518.5 3623.0 3612.51555 3146.8 3148.0 3287.3 3285.8 3311.1 3309.8 3342.2 3408.0 3465.7 3548.0 3540.7 3531.91556 3416.1 3480.4 3481.7 3500.8 3491.3 3514.9 3538.4 3563.2 3573.3 3574.0 3603.8 3620.11557 3159.0 3115.8 3154.8 3193.1 3256.7 3230.1 3279.4 3313.7 3322.6 3401.0 3433.3 3418.81558 3319.1 3285.4 3334.8 3319.3 3365.0 3396.6 3380.4 3433.8 3426.4 3493.3 3516.3 3495.8Mean 3207.1 3237.9 3274.1 3288.7 3310.7 3320.4 3342.1 3377.2 3405.2 3442.1 3474.0 3463.2SD 112.07 121.37 118.38 119.98 106.27 114.78 105.32 108.19 105.43 103.08 113.40 125.02N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 78MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 4 6 7 8 9 10 11 12 13 14 15 16Group 2 - 2,500 ppm2551 3450.2 3533.2 3524.3 3538.1 3567.2 3590.7 3616.2 3671.7 3685.0 3731.2 3749.9 3758.02552 3443.2 3482.3 3463.8 3461.5 3468.3 3473.1 3463.4 3483.4 3398.1 3370.5 3341.5 3369.02553 3226.9 3272.9 3260.8 3274.1 3311.0 3299.3 3348.5 3368.3 3391.8 3468.2 3517.7 3536.52554 3380.4 3448.9 3430.3 3436.0 3423.7 3459.9 3459.5 3483.0 3490.9 3512.2 3571.9 3607.42555 3204.1 3235.5 3313.1 3300.3 3339.3 3289.0 3351.6 3437.8 3447.1 3548.0 3585.6 3533.62556 3285.2 3328.1 3354.6 3352.4 3372.4 3400.2 3386.7 3384.9 3378.0 3429.5 3465.9 3475.52557 3590.1 3589.6 3620.2 3622.0 3618.3 3612.1 3622.2 3621.8 3610.9 3589.5 3531.4 3574.22558 3323.9 3382.9 3456.2 3437.2 3442.9 3428.0 3480.1 3488.3 3510.4 3563.0 3582.2 3594.2Mean 3363.0 3409.2 3427.9 3427.7 3442.9 3444.0 3466.0 3492.4 3489.0 3526.5 3543.3 3556.1SD 129.43 125.84 116.40 117.56 107.12 118.33 107.16 106.25 110.53 110.20 116.08 111.85N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 79MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 4 6 7 8 9 10 11 12 13 14 15 16Group 3 - 10,000 ppm3551 3225.9 3356.0 3356.3 3361.2 3384.8 3302.6 3378.4 3420.6 3465.8 3480.6 3532.9 3540.43552 3175.5 3301.9 3256.0 3253.4 3226.2 3244.6 3280.1 3256.0 3276.5 3309.7 3337.1 3379.23553 3237.6 3338.4 3347.2 3337.1 3373.1 3351.7 3364.6 3385.1 3425.9 3444.2 3466.3 3495.63554 3478.7 3494.2 3530.8 3546.0 3528.2 3552.2 3559.6 3624.7 3653.8 3681.6 3723.0 3769.63555 3029.4 3027.8 3040.0 3042.5 3035.9 3109.6 3098.2 3112.3 3161.6 3208.4 3230.1 3251.83556 3169.8 3231.5 3325.0 3289.6 3323.8 3308.0 3352.5 3388.1 3411.4 3475.5 3512.7 3525.43557 3533.3 3504.4 3551.5 3572.6 3561.6 3586.4 3607.7 3639.5 3635.0 3639.1 3660.5 3647.83558 3885.2 3836.8 3913.3 3896.5 3897.1 3913.3 3911.1 3957.3 3942.9 3953.3 3958.3 3986.0Mean 3341.9 3386.4 3415.0 3412.4 3416.3 3421.1 3444.0 3473.0 3496.6 3524.1 3552.6 3574.5SD 275.12 236.45 257.01 257.28 255.53 252.59 246.04 261.90 244.05 232.54 228.39 228.30N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 80MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 4 6 7 8 9 10 11 12 13 14 15 16Group 4 - 15,000 ppm4551 np 3132.1x 3152.5x 3157.8x 3170.4x 3188.7x 3210.1x 3203.3x 3185.4x 3208.3x 3243.9x 3260.5x 3276.8x4552 3324.4 3347.8 3378.3 3384.5 3413.0 3411.7 3402.8 3433.0 3438.4 3500.3 3490.7 3494.24553 3279.8 3385.2 3267.2 3375.6 3352.1 3351.2 3398.4 3438.9 3452.2 3406.7 3408.5 3408.04554 3086.7 3381.2 3439.5 3442.1 3475.9 3470.0 3524.4 3613.8 3671.2 3729.7 3795.9 3806.34555 3000.3 3021.5 3086.3 3116.1 3088.4 3079.3 3092.5 3180.8 3180.7 3230.7 3253.0 3267.04556 3084.0 3067.2 3074.2 3042.6 3048.2 3086.1 3055.9 3035.9 3047.0 3062.7 3103.7 3102.54557 3927.1 3918.5 3951.5 3942.6 3971.2 3947.9 3978.1 3991.1 3986.3 3992.9 4003.2 4030.04558 2960.2 2993.0 2991.3 2985.7 2980.4 2981.7 3013.3 3014.4 3027.6 3048.4 3038.8 3052.2Mean 3237.5 3302.1 3312.6 3327.0 3332.7 3332.6 3352.2 3386.8 3400.5 3424.5 3442.0 3451.5SD 332.75 322.66 327.10 326.53 341.50 329.68 340.63 347.80 349.49 349.33 355.06 360.45N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 81MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 17 18 19 20 21 22 23 24 25 26 27 28Group 1 - 0 ppm1551 3358.7 3330.6 3373.0 3350.9 3346.4 3372.3 3397.4 3417.9 3418.9 3535.0 3539.0 3574.31552 3423.7 3433.5 3452.5 3473.6 3504.2 3536.6 3526.0 3568.9 3587.5 3593.4 3567.0 3582.61553 3257.0 3266.7 3327.1 3357.7 3387.4 3398.5 3426.6 3453.0 3469.0 3391.3 3465.2 3486.31554 3645.3 3634.5 3666.3 3691.4 3707.7 3748.6 3751.7 3781.8 3818.9 3873.4 3902.9 3953.11555 3531.4 3578.1 3592.4 3538.0 3631.3 3625.3 3659.5 3729.4 3750.6 3804.7 3830.8 3869.21556 3614.0 3626.7 3685.9 3695.7 3697.8 3732.1 3700.6 3718.2 3711.2 3749.1 3747.6 3793.51557 3403.0 3425.8 3466.5 3480.0 3521.3 3515.6 3498.7 3569.5 3585.0 3600.8 3615.0 3606.31558 3513.1 3538.3 3565.4 3568.0 3597.9 3583.5 3614.9 3648.8 3666.2 3686.1 3694.9 3724.7Mean 3468.3 3479.3 3516.1 3519.4 3549.3 3564.1 3571.9 3610.9 3625.9 3654.2 3670.3 3698.8SD 131.72 136.97 132.21 131.78 134.39 138.21 129.53 131.94 137.48 156.11 150.94 163.03N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 82MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 17 18 19 20 21 22 23 24 25 26 27 28Group 2 - 2,500 ppm2551 3762.0 3762.3 3785.3 3791.1 3793.9 3828.1 3870.2 3865.4 3930.3 3894.7 3945.6 3970.02552 3451.9 3503.1 3534.6 3503.3 3499.2 3530.1 3558.1 3580.1 3591.0 3609.9 3620.5 3633.32553 3560.1 3544.1 3587.6 3608.6 3591.7 3613.1 3663.3 3697.9 3680.2 3633.1 3673.2 3698.02554 3589.6 3622.9 3644.1 3663.7 3673.6 3682.1 3704.9 3726.4 3765.6 3799.4 3815.4 3844.62555 3523.4 3575.2 3575.1 3571.4 3625.0 3629.1 3661.0 3675.5 3669.7 3641.0 3643.8 3678.22556 3495.4 3486.0 3517.1 3519.5 3575.2 3584.4 3552.9 3605.1 3643.0 3659.5 3695.7 3723.32557 3619.7 3638.2 3653.8 3657.6 3686.5 3749.3 3755.8 3704.2 3772.5 3766.6 3766.6 3764.12558 3605.1 3664.7 3681.8 3679.7 3726.0 3711.5 3733.2 3786.4 3783.9 3853.0 3872.6 3878.9Mean 3575.9 3599.6 3622.4 3624.4 3646.4 3666.0 3687.4 3705.1 3729.5 3732.2 3754.2 3773.8SD 94.46 91.52 87.64 94.28 93.06 96.24 104.60 92.05 106.30 110.25 116.25 114.53N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 83MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 17 18 19 20 21 22 23 24 25 26 27 28Group 3 - 10,000 ppm3551 3564.1 3591.0 3616.9 3640.7 3655.2 3722.6 3729.4 3738.4 3771.9 3773.1 3757.8 3795.03552 3374.7 3395.5 3399.3 3403.3 3420.8 3406.9 3433.2 3444.4 3458.1 3490.4 3517.4 3539.03553 3472.1 3473.7 3481.3 3530.1 3512.7 3556.8 3561.1 3586.3 3627.7 3641.2 3647.8 3675.43554 3774.3 3771.0 3812.2 3829.7 3848.1 3887.9 3896.4 3897.1 3922.2 3943.0 3949.0 3962.33555 3255.5 3300.1 3327.4 3323.0 3346.3 3394.0 3443.5 3473.6 3467.9 3496.2 3513.3 3556.33556 3493.8 3505.0 3533.9 3539.3 3570.2 3578.4 3620.1 3647.5 3695.0 3709.0 3737.2 3736.33557 3661.7 3686.5 3661.8 3699.9 3680.6 3666.8 3678.2 3691.9 3673.5 3724.7 3755.3 3751.83558 3975.5 3971.6 3998.8 4029.5 4058.3 4069.8 4076.4 4118.6 4106.4 4099.7 4137.8 4139.0Mean 3571.5 3586.8 3604.0 3624.4 3636.5 3660.4 3679.8 3699.7 3715.3 3734.7 3752.0 3769.4SD 228.98 217.20 220.75 229.31 231.59 231.75 220.70 222.93 219.14 208.45 210.71 201.14N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 84MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 17 18 19 20 21 22 23 24 25 26 27 28Group 4 - 15,000 ppm4551 np 3300.8x 3306.7x 3334.2x 3357.4x 3322.7x 3388.4x 3380.2x 3372.3x 3386.0x 3426.4x 3419.4x 3432.7x4552 3490.5 3514.5 3519.2 3523.0 3556.1 3575.8 3573.2 3591.1 3603.4 3639.4 3642.2 3639.64553 3392.2 3406.0 3432.6 3457.6 3472.2 3518.1 3539.8 3556.3 3583.6 3601.6 3610.6 3658.04554 3788.1 3820.5 3840.3 3842.1 3870.1 3936.8 3973.6 4017.2 4098.8 4114.0 4090.5 4169.14555 3258.5 3277.1 3323.8 3334.1 3382.5 3383.8 3417.0 3471.6 3514.6 3563.3 3589.5 3613.04556 3122.5 3138.8 3163.9 3157.3 3183.3 3189.1 3202.1 3216.8 3238.3 3218.6 3230.7 3247.94557 4055.8 4064.2 4059.4 4070.1 4092.2 4098.9 4132.9 4136.4 4152.8 4175.5 4202.3 4210.24558 3100.5 3100.2 3117.6 3117.4 3144.8 3162.2 3149.3 3181.2 3199.0 3193.8 3184.8 3211.7Mean 3458.3 3474.5 3493.8 3500.2 3528.7 3552.1 3569.7 3595.8 3627.2 3643.7 3650.1 3678.5SD 354.00 357.19 347.28 350.17 347.87 356.09 368.88 365.69 376.03 386.30 386.56 394.32N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 85MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 29Group 1 - 0 ppm1551 3609.41552 3605.21553 3475.01554 3980.91555 3926.31556 3801.81557 3659.11558 3717.3Mean 3721.9SD 171.73N 8Huntingdon Life Sciences09-4347Page 86MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 29Group 2 - 2,500 ppm2551 3998.72552 3655.32553 3746.22554 3854.72555 3691.22556 3771.22557 3792.12558 3904.5Mean 3801.7SD 113.35N 8Huntingdon Life Sciences09-4347Page 87MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 29Group 3 - 10,000 ppm3551 3794.23552 3571.13553 3694.33554 4011.13555 3583.43556 3764.63557 3752.73558 4138.1Mean 3788.7SD 197.07N 8Huntingdon Life Sciences09-4347Page 88MA-252E-93-23FinalReportIndividual Gestation Body WeightsFemales (grams) AppendixEAnimal Phase GESNumber Day 29Group 4 - 15,000 ppm4551 np 3455.0x4552 3652.64553 3691.94554 4187.24555 3628.84556 3259.14557 4225.84558 3231.1Mean 3696.6SD 394.84N 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 89MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 4-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17Group 1 - 0 ppm1551 54.8 16.2 8.5 21.9 8.9 37.7 30.6 38.4 37.1 52.2 -5.0 -2.61552 80.3 -18.7 -5.6 33.9 18.7 30.2 1.1 22.6 37.3 47.3 12.9 19.81553 22.6 -9.5 34.0 -2.9 9.5 8.4 38.4 48.2 -17.8 -27.2 -56.1 -4.11554 100.3 72.6 38.8 -1.7 13.6 8.2 31.9 45.8 10.5 104.5 -10.5 32.81555 1.2 139.3 -1.5 25.3 -1.3 32.4 65.8 57.7 82.3 -7.3 -8.8 -0.51556 64.3 1.3 19.1 -9.5 23.6 23.5 24.8 10.1 0.7 29.8 16.3 -6.11557 -43.2 39.0 38.3 63.6 -26.6 49.3 34.3 8.9 78.4 32.3 -14.5 -15.81558 -33.7 49.4 -15.5 45.7 31.6 -16.2 53.4 -7.4 66.9 23.0 -20.5 17.3Mean 30.8 36.2 14.5 22.0 9.7 21.7 35.0 28.0 36.9 31.8 -10.8 5.1SD 52.86 51.90 21.23 25.69 17.76 20.71 19.20 22.94 37.19 39.70 22.34 16.34N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 90MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 4-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17Group 2 - 2,500 ppm2551 83.0 -8.9 13.8 29.1 23.5 25.5 55.5 13.3 46.2 18.7 8.1 4.02552 39.1 -18.5 -2.3 6.8 4.8 -9.7 20.0 -85.3 -27.6 -29.0 27.5 82.92553 46.0 -12.1 13.3 36.9 -11.7 49.2 19.8 23.5 76.4 49.5 18.8 23.62554 68.5 -18.6 5.7 -12.3 36.2 -0.4 23.5 7.9 21.3 59.7 35.5 -17.82555 31.4 77.6 -12.8 39.0 -50.3 62.6 86.2 9.3 100.9 37.6 -52.0 -10.22556 42.9 26.5 -2.2 20.0 27.8 -13.5 -1.8 -6.9 51.5 36.4 9.6 19.92557 -0.5 30.6 1.8 -3.7 -6.2 10.1 -0.4 -10.9 -21.4 -58.1 42.8 45.52558 59.0 73.3 -19.0 5.7 -14.9 52.1 8.2 22.1 52.6 19.2 12.0 10.9Mean 46.2 18.7 -0.2 15.2 1.1 22.0 26.4 -3.4 37.5 16.8 12.8 19.8SD 25.29 39.89 11.57 19.00 28.22 29.80 30.14 35.29 44.72 40.43 29.03 32.29N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 91MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 4-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17Group 3 - 10,000 ppm3551 130.1 0.3 4.9 23.6 -82.2 75.8 42.2 45.2 14.8 52.3 7.5 23.73552 126.4 -45.9 -2.6 -27.2 18.4 35.5 -24.1 20.5 33.2 27.4 42.1 -4.53553 100.8 8.8 -10.1 36.0 -21.4 12.9 20.5 40.8 18.3 22.1 29.3 -23.53554 15.5 36.6 15.2 -17.8 24.0 7.4 65.1 29.1 27.8 41.4 46.6 4.73555 -1.6 12.2 2.5 -6.6 73.7 -11.4 14.1 49.3 46.8 21.7 21.7 3.73556 61.7 93.5 -35.4 34.2 -15.8 44.5 35.6 23.3 64.1 37.2 12.7 -31.63557 -28.9 47.1 21.1 -11.0 24.8 21.3 31.8 -4.5 4.1 21.4 -12.7 13.93558 -48.4 76.5 -16.8 0.6 16.2 -2.2 46.2 -14.4 10.4 5.0 27.7 -10.5Mean 44.5 28.6 -2.7 4.0 4.7 23.0 28.9 23.7 27.4 28.6 21.9 -3.0SD 70.19 44.60 18.10 24.25 45.53 28.22 26.56 22.98 20.11 14.64 19.26 18.51N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 92MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 4-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17Group 4 - 15,000 ppm4551 np 20.4x 5.3x 12.6x 18.3x 21.4x -6.8x -17.9x 22.9x 35.6x 16.6x 16.3x 24.0x4552 23.4 30.5 6.2 28.5 -1.3 -8.9 30.2 5.4 61.9 -9.6 3.5 -3.74553 105.4 -118.0 108.4 -23.5 -0.9 47.2 40.5 13.3 -45.5 1.8 -0.5 -15.84554 294.5 58.3 2.6 33.8 -5.9 54.4 89.4 57.4 58.5 66.2 10.4 -18.24555 21.2 64.8 29.8 -27.7 -9.1 13.2 88.3 -0.1 50.022.3 14.0 -8.54556 -16.8 7.0 -31.6 5.6 37.9 -30.2 -20.0 11.1 15.7 41.0 -1.2 20.04557 -8.6 33.0 -8.9 28.6 -23.3 30.2 13.0 -4.8 6.6 10.3 26.8 25.84558 32.8 -1.7 -5.6 -5.3 1.3 31.6 1.1 13.2 20.8 -9.6 13.4 48.3Mean 64.6 10.6 14.4 5.7 -0.2 19.6 34.6 13.6 24.0 17.5 9.5 6.8SD 108.85 61.66 45.35 25.57 18.71 30.45 41.85 20.49 37.67 28.03 9.88 24.96N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 93MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29Group 1 - 0 ppm1551 -28.1 42.4 -22.1 -4.5 25.9 25.1 20.5 1.0 116.1 4.0 35.3 35.11552 9.8 19.0 21.1 30.6 32.4 -10.6 42.9 18.6 5.9 -26.4 15.6 22.61553 9.7 60.4 30.6 29.7 11.1 28.1 26.4 16.0 -77.7 73.9 21.1 -11.31554 -10.8 31.8 25.1 16.3 40.9 3.1 30.1 37.1 54.5 29.5 50.2 27.81555 46.7 14.3 -54.4 93.3 -6.0 34.2 69.9 21.2 54.1 26.1 38.4 57.11556 12.7 59.2 9.8 2.1 34.3 -31.5 17.6 -7.0 37.9 -1.5 45.9 8.31557 22.8 40.7 13.5 41.3 -5.7 -16.9 70.8 15.5 15.8 14.2 -8.7 52.81558 25.2 27.1 2.6 29.9 -14.4 31.4 33.9 17.4 19.9 8.8 29.8 -7.4Mean 11.0 36.9 3.3 29.8 14.8 7.9 39.0 15.0 28.3 16.1 28.5 23.1SD 22.76 17.10 28.43 29.98 21.43 25.30 20.86 13.24 54.93 29.13 18.99 25.46N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 94MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29Group 2 - 2,500 ppm2551 0.3 23.0 5.8 2.8 34.2 42.1 -4.8 64.9 -35.6 50.9 24.4 28.72552 51.2 31.5 -31.3 -4.1 30.9 28.0 22.0 10.9 18.9 10.6 12.8 22.02553 -16.0 43.5 21.0 -16.9 21.4 50.2 34.6 -17.7 -47.1 40.1 24.8 48.22554 33.3 21.2 19.6 9.9 8.5 22.8 21.5 39.2 33.8 16.0 29.2 10.12555 51.8 -0.1 -3.7 53.6 4.1 31.9 14.5 -5.8 -28.7 2.8 34.4 13.02556 -9.4 31.1 2.4 55.7 9.2 -31.5 52.2 37.9 16.5 36.2 27.6 47.92557 18.5 15.6 3.8 28.9 62.8 6.5 -51.6 68.3 -5.9 0.0 -2.5 28.02558 59.6 17.1 -2.1 46.3 -14.5 21.7 53.2 -2.5 69.1 19.6 6.3 25.6Mean 23.7 22.9 1.9 22.0 19.6 21.5 17.7 24.4 2.6 22.0 19.6 27.9SD 29.70 13.01 16.24 27.98 23.44 25.17 33.99 32.86 39.34 18.47 12.74 14.10N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 95MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29Group 3 - 10,000 ppm3551 26.9 25.9 23.8 14.5 67.4 6.8 9.0 33.5 1.2 -15.3 37.2 -0.83552 20.8 3.8 4.0 17.5 -13.9 26.3 11.2 13.7 32.3 27.0 21.6 32.13553 1.6 7.6 48.8 -17.4 44.1 4.3 25.2 41.4 13.5 6.6 27.6 18.93554 -3.3 41.2 17.5 18.4 39.8 8.5 0.7 25.1 20.8 6.0 13.3 48.83555 44.6 27.3 -4.4 23.3 47.7 49.5 30.1 -5.7 28.317.1 43.0 27.13556 11.2 28.9 5.4 30.9 8.2 41.7 27.4 47.5 14.0 28.2 -0.9 28.33557 24.8 -24.7 38.1 -19.3 -13.8 11.4 13.7 -18.4 51.2 30.6 -3.5 0.93558 -3.9 27.2 30.7 28.8 11.5 6.6 42.2 -12.2 -6.7 38.1 1.2 -0.9Mean 15.3 17.2 20.5 12.1 23.9 19.4 19.9 15.6 19.3 17.3 17.4 19.3SD 17.04 20.76 18.34 19.60 30.17 17.66 13.56 25.30 18.26 17.43 17.81 18.23N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 96MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29Group 4 - 15,000 ppm4551 np 5.9x 27.5x 23.2x -34.7x 65.7x -8.2x -7.9x 13.7x 40.4x -7.0x 13.3x 22.3x4552 24.0 4.7 3.8 33.1 19.7 -2.6 17.9 12.3 36.0 2.8 -2.6 13.04553 13.8 26.6 25.0 14.6 45.9 21.7 16.5 27.3 18.0 9.0 47.4 33.94554 32.4 19.8 1.8 28.0 66.7 36.8 43.6 81.6 15.2 -23.5 78.6 18.14555 18.6 46.7 10.3 48.4 1.3 33.2 54.6 43.0 48.7 26.2 23.5 15.84556 16.3 25.1 -6.6 26.0 5.8 13.0 14.7 21.5 -19.7 12.1 17.2 11.24557 8.4 -4.8 10.7 22.1 6.7 34.0 3.5 16.4 22.7 26.8 7.9 15.64558 -0.3 17.4 -0.2 27.4 17.4 -12.9 31.9 17.8-5.2 -9.0 26.9 19.4Mean 16.2 19.4 6.4 28.5 23.4 17.6 26.1 31.4 16.5 6.3 28.4 18.1SD 10.55 16.51 10.17 10.48 24.18 19.40 18.04 24.30 23.24 18.22 27.12 7.49N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 97MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 6-29Group 1 - 0 ppm1551 494.61552 381.01553 238.91554 682.11555 778.31556 321.41557 543.31558 431.9Mean 483.9SD 181.00N 8Huntingdon Life Sciences09-4347Page 98MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 6-29Group 2 - 2,500 ppm2551 465.52552 173.02553 473.32554 405.82555 455.72556 443.12557 202.52558 521.6Mean 392.6SD 130.68N 8Huntingdon Life Sciences09-4347Page 99MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 6-29Group 3 - 10,000 ppm3551 438.23552 269.23553 355.93554 516.93555 555.63556 533.13557 248.33558 301.3Mean 402.3SD 124.68N 8Huntingdon Life Sciences09-4347Page 100MA-252E-93-23FinalReportIndividual Gestation Body Weight ChangesFemales (grams) AppendixFAnimal Phase GESNumber Day 6-29Group 4 - 15,000 ppm4551 302.5x4552 304.84553 306.74554 806.04555 607.34556 191.94557 307.34558 238.1Mean 394.6SD 224.90N 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 101MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16Group 1 - 0 ppm1551 133.9 155.8 148.2 145.2 157.4 124.8 154.1 176.1 119.2 104.2 185.5 181.61552 202.3 175.5 167.4 161.3 161.5 158.2 181.7 168.2 145.7 163.8 156.1 176.81553 188.3 183.7 145.9 146.8 149.4 137.1 153.8 136.4 134.8 83.5 60.9 2.81554 195.1 191.8 192.6 195.1 191.5 193.0 196.7 186.8 197.6 171.0 194.7 196.81555 202.3 193.6 183.6 200.7 194.9 197.3 201.1 195.4 201.1 203.4 199.5 186.91556 186.7 190.1 170.9 184.0 165.1 182.5 186.9 163.7 152.8 139.2 158.2 154.21557 195.9 196.6 194.2 193.2 186.7 189.1 190.3 189.4 190.9 199.5 198.6 202.11558 190.5 193.5 182.4 188.1 179.7 189.5 195.6 184.4 168.9 172.8 175.3 158.9Mean 186.9 185.1 173.2 176.8 173.3 171.4 182.5 175.1 163.9 154.7 166.1 157.5SD 22.19 13.61 18.59 22.34 17.11 27.84 18.63 18.96 30.64 42.95 45.79 64.69N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 102MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16Group 2 - 2,500 ppm2551 187.4 194.4 165.7 172.4 186.2 164.0 175.7 178.9 161.5 150.8 156.4 163.32552 173.0 157.8 143.9 134.9 136.8 127.8 117.4 92.9 118.5 1.8 13.4 29.42553 182.2 161.1 157.3 158.0 162.2 147.3 165.5 146.2 112.0 153.4 146.2 164.72554 190.6 189.4 169.0 161.9 165.3 154.6 152.3 137.8 139.9 141.9 152.3 174.52555 195.4 201.9 193.1 197.8 194.4 182.9 191.8 205.8 187.9 197.1 200.0 183.92556 195.0 197.0 188.5 194.2 171.6 195.1 180.8 164.2 139.3 143.7 166.9 165.12557 174.5 157.5 146.9 157.7 145.3 156.4 151.2 129.9 79.9 44.6 14.2 62.12558 187.4 196.2 187.3 191.1 187.9 192.8 200.4 193.8 191.8 193.8 193.4 179.5Mean 185.7 181.9 169.0 171.0 168.7 165.1 166.9 156.2 141.4 128.4 130.4 140.3SD 8.53 19.47 19.13 22.02 20.57 23.54 26.52 37.01 38.33 69.27 74.39 59.47N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 103MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16Group 3 - 10,000 ppm3551 193.3 188.8 180.9 172.0 191.1 nw 181.6 163.0 160.7 170.8 181.2 194.43552 184.5 161.0 129.1 112.9 96.7 115.5 111.8 82.1 111.9 111.9 134.8 159.43553 154.9 153.9 166.7 181.0 177.5 156.3 161.6 163.8 164.2 151.2 154.3 157.73554 196.4 199.5 195.1 198.5 196.0 195.9 199.5 196.5 189.4 180.8 197.5 192.53555 183.0 188.1 174.1 181.9 154.9 167.6 174.1 169.1 157.3 162.8 186.6 184.83556 197.3 200.2 201.4 201.7 199.0 197.6 202.5 198.9 198.6 195.1 199.7 195.13557 190.7 193.9 184.6 185.9 180.4 178.2 177.2 172.6 155.7 138.0 131.7 128.13558 191.5 196.7 195.9 190.7 189.7 189.1 178.7 166.0 141.2 109.9 152.4 172.6Mean 186.5 185.3 178.5 178.1 173.2 171.5 173.4 164.0 159.9 152.6 167.3 173.1SD 13.72 17.82 23.13 28.04 33.88 28.91 28.21 36.03 26.90 31.01 27.37 23.61N 8 8 8 8 8 7 8 8 8 8 8 8nw = not weighedHuntingdon Life Sciences09-4347Page 104MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 15-16Group 4 - 15,000 ppm4551 np 197.2x 195.9x 197.0x 195.9x 201.0x 192.2x 195.3x 185.3x 187.8x 195.2x 200.2x 192.9x4552 192.8 188.1 181.9 180.5 181.8 169.0 156.9 165.5 161.2 145.7 137.1 147.84553 182.1 180.1 116.6 167.9 149.1 133.5 146.3 118.6 125.7 70.4 65.5 84.74554 195.9 188.9 194.4 189.7 192.7 190.3 193.7 195.8 184.8 192.9 185.9 190.84555 200.6 201.7 193.7 198.6 196.2 197.2 189.2 197.3 193.3 206.5 199.6 199.24556 154.7 157.3 138.6 134.5 123.6 136.9 117.5 104.9 86.9 79.6 78.0 95.04557 132.3 148.4 136.9 138.9 139.5 142.8 143.9 127.8 104.5 100.4 111.3 97.24558 177.7 173.6 143.9 138.4 123.7 133.4 137.5 141.8 134.2 133.2 145.7 128.1Mean 176.6 176.9 158.0 164.1 158.1 157.6 155.0 150.2 141.5 132.7 131.9 134.7SD 24.78 18.72 31.37 26.77 31.65 27.63 27.64 36.87 40.00 53.20 50.75 46.56N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 105MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28Group 1 - 0 ppm1551 130.3 200.4 192.2 187.1 nw 192.3 nw nw nw 177.9 154.8 148.71552 174.8 181.6 179.9 184.0 183.0 171.1 148.3 165.2 147.8 140.6 111.5 129.91553 7.8 72.4 160.7 170.8 173.1 165.6 156.4 155.0 105.2 25.8 143.7 119.71554 202.2 197.5 191.8 197.6 195.3 195.9 193.7 180.7 187.6 181.2 170.8 177.31555 194.7 186.9 202.4 195.2 193.9 188.9 201.4 194.3 185.6 173.9 165.0 178.41556 169.5 174.1 183.4 184.1 164.5 175.1 150.7 126.7 120.3 96.9 107.2 113.31557 195.3 194.9 198.8 199.8 195.1 189.5 187.8 187.7 181.2 188.6 182.8 189.21558 185.8 188.0 168.9 187.6 182.2 183.7 182.2 173.5 153.8 119.4 105.9 97.9Mean 157.6 174.5 184.8 188.3 183.9 182.8 174.4 169.0 154.5 138.0 142.7 144.3SD 64.59 42.13 14.49 9.34 11.92 10.93 22.02 22.90 32.71 55.98 30.78 34.25N 8 8 8 8 7 8 7 7 7 8 8 8nw = not weighedHuntingdon Life Sciences09-4347Page 106MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28Group 2 - 2,500 ppm2551 150.0 153.4 157.3 160.9 161.7 149.1 175.7 178.2 147.7 109.6 133.8 123.92552 70.1 95.3 89.4 84.0 87.8 107.6 107.2 108.8 83.2 80.5 80.8 89.52553 177.9 164.5 159.9 145.6 155.4 144.8 147.3 154.2 167.2 153.2 151.6 157.32554 177.9 181.8 178.2 160.8 159.7 148.5 162.5 163.8 144.1 139.1 142.4 144.02555 181.2 200.1 191.7 196.7 192.0 193.3 195.3 174.4 158.6 133.4 115.5 134.52556 189.3 192.9 196.8 193.1 188.3 192.0 174.8 171.0 175.5 172.2 173.7 181.42557 109.5 131.1 139.3 144.3 146.2 166.6 165.8 58.0 123.6 103.9 86.3 87.92558 180.3 191.8 194.7 193.5 195.7 191.8 194.5 184.3 191.2 183.7 170.3 166.7Mean 154.5 163.9 163.4 159.9 160.9 161.7 165.4 149.1 148.9 134.5 131.8 135.7SD 42.85 36.14 36.30 37.41 34.89 30.22 28.43 43.71 33.61 35.23 35.22 34.11N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 107MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28Group 3 - 10,000 ppm3551 186.5 198.9 186.3 191.1 190.3 194.2 194.6 172.6 160.3 146.5 124.4 127.43552 149.3 156.6 140.2 132.8 122.3 93.4 97.9 99.4 94.4 108.0 112.9 132.43553 145.6 136.1 146.0 156.0 155.3 146.1 144.8 139.0 139.8 140.2 138.1 146.23554 184.1 199.7 198.6 196.3 194.8 191.6 196.9 188.5 162.9 142.3 142.2 151.33555 203.0 187.3 189.4 199.2 196.9 195.7 191.6 183.5 153.6 148.7 152.4 160.13556 195.2 189.9 194.8 189.5 194.8 190.5 191.5 194.6 192.5 181.1 167.0 167.33557 172.0 164.1 159.5 174.5 155.5 193.6 134.4 162.6 119.0 119.7 117.1 127.43558 181.8 177.6 174.9 188.3 177.9 146.6 134.6 109.9 79.9 55.5 70.9 88.9Mean 177.2 176.3 173.7 178.5 173.5 169.0 160.8 156.3 137.8 130.3 128.1 137.6SD 20.52 22.42 22.56 23.09 26.81 37.16 37.67 36.33 37.74 37.09 29.37 24.66N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 108MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28Group 4 - 15,000 ppm4551 np 184.1x 184.5x 199.8x 187.1x 188.0x 195.1x 194.2x 191.6x 191.4x 199.4x 194.6x 181.6x4552 135.0 153.9 165.0 161.7 187.0 169.2 174.3 159.2 145.2 140.2 146.8 105.84553 91.6 99.3 101.8 117.0 126.3 131.9 126.8 125.2 107.9 105.6 104.9 102.74554 194.8 189.1 189.4 194.4 191.9 191.8 185.7 187.6 194.8 189.9 153.1 177.34555 195.9 189.6 189.7 195.1 196.9 189.6 200.6 197.3 193.4 195.2 201.4 194.44556 119.5 113.6 121.3 125.3 122.5 132.6 121.0 117.9 89.5 84.8 82.0 87.34557 134.8 129.7 137.5 142.8 131.7 135.9 134.3 131.7 115.5 101.5 99.6 95.84558 161.1 153.1 145.7 157.3 160.4 155.1 173.9 153.4 147.2 144.2 135.4 137.2Mean 147.5 146.9 150.1 156.2 159.5 158.0 159.5 153.2 141.9 137.3 131.9 128.6SD 38.71 35.03 33.35 30.75 32.79 26.11 31.59 30.70 41.00 43.24 40.37 42.32N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnant, x = excluded from calculationHuntingdon Life Sciences09-4347Page 109MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 28-29 6-29Group 1 - 0 ppm1551 151.5 159.61552 127.1 160.21553 114.2 118.31554 186.4 190.21555 190.8 192.01556 129.5 154.51557 190.8 192.01558 112.8 166.8Mean 150.4 166.7SD 34.36 25.10N 8 8Huntingdon Life Sciences09-4347Page 110MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 28-29 6-29Group 2 - 2,500 ppm2551 129.4 156.82552 90.4 90.92553 158.7 154.42554 137.0 156.12555 146.0 180.32556 186.7 178.12557 97.8 115.22558 154.5 187.2Mean 137.6 152.4SD 31.83 33.49N 8 8Huntingdon Life Sciences09-4347Page 111MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 28-29 6-29Group 3 - 10,000 ppm3551 125.5 172.53552 149.8 119.83553 151.9 153.03554 162.2 184.93555 156.2 175.33556 174.0 191.83557 114.9 154.23558 74.8 145.6Mean 138.7 162.1SD 32.13 23.58N 8 8Huntingdon Life Sciences09-4347Page 112MA-252E-93-23FinalReportIndividual Gestation Food Consumption ValuesFemales (grams/animal/day) AppendixGAnimal Phase GESNumber Day 28-29 6-29Group 4 - 15,000 ppm4551 np 190.7x 192.4x4552 142.4 157.14553 124.6 115.04554 131.7 186.24555 190.9 195.74556 121.3 110.24557 119.4 124.14558 146.8 144.8Mean 139.6 147.6SD 24.91 33.96N 7 7np = not pregnant, x = excluded from calculation

# Huntingdon Life Sciences 09-4347 Page 113

MA-252E-93-23 Final Report

Raw Data Listing of

Gross Observations with Modifiers

Preface Appendix H

Corresponding dose levels for each group were as follows:

Group 1 - 0 ppm

Group 2 - 2,500 ppm

Group 3 - 10,000 ppm

Group 4 - 15,000 ppmPage 114Page 115Huntingdon Life Sciences09-4347Page 116MA-252E-93-23FinalReportFemalesIndividual Cesarean Section DataAppendix IAnimal Corpora Implant- ResorptionsDeadLive FetusesSex Ratio Pre Impl. Post Impl.Number Lutea ations Early Late Total Fetuses Male Female Total (% Male) Loss (%) Loss (%)Group 1 - 0 ppm1551 14 12 2 0 2 0 4 6 10 40 14 171552 10 10 0 0 0 0 3 7 10 30 0 01553 9 9 0 0 0 0 4 5 9 44 0 01554 8 8 0 0 0 0 2 6 8 25 0 01555 7 7 0 0 0 0 2 5 7 29 0 01556 10 10 1 0 1 0 4 5 9 44 0 101557 13 13 0 3 3 0 2 8 10 20 0 231558 10 10 0 0 0 0 4 6 10 40 0 0Mean 10.1 9.9 0.4 0.4 0.8 0.0 3.1 6.0 9.1 34.1 1.8 6.2SD 2.36 1.96 0.74 1.06 1.16 0.00 0.99 1.07 1.13 9.36 5.05 9.27N 8 8 8 8 8 8 8 8 8 8 8 8Impl. = ImplantationHuntingdon Life Sciences09-4347Page 117MA-252E-93-23FinalReportFemalesIndividual Cesarean Section DataAppendix IAnimal Corpora Implant- ResorptionsDeadLive FetusesSex Ratio Pre Impl. Post Impl.Number Lutea ations Early Late Total Fetuses Male Female Total (% Male) Loss (%) Loss (%)Group 2 - 2,500 ppm2551 10 10 0 0 0 0 4 6 10 40 0 02552 11 11 0 0 0 0 3 8 11 27 0 02553 11 11 0 0 0 0 4 7 11 36 0 02554 9 9 0 0 0 0 6 3 9 67 0 02555 7 7 0 0 0 0 4 3 7 57 0 02556 11 10 1 0 1 0 3 6 9 33 9 102557 8 8 0 0 0 0 4 4 8 50 0 02558 9 9 0 0 0 0 3 6 9 33 0 0Mean 9.5 9.4 0.1 0.0 0.1 0.0 3.9 5.4 9.3 43.0 1.1 1.3SD 1.51 1.41 0.35 0.00 0.35 0.00 0.99 1.85 1.39 13.61 3.21 3.54N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 118MA-252E-93-23FinalReportFemalesIndividual Cesarean Section DataAppendix IAnimal Corpora Implant- ResorptionsDeadLive FetusesSex Ratio Pre Impl. Post Impl.Number Lutea ations Early Late Total Fetuses Male Female Total (% Male) Loss (%) Loss (%)Group 3 - 10,000 ppm3551 8 7 0 0 0 0 3 4 7 43 13 03552 10 10 0 0 0 0 4 6 10 40 0 03553 9 9 0 0 0 0 5 4 9 56 0 03554 8 8 1 0 1 0 2 5 7 29 0 133555 11 10 0 0 0 0 3 7 10 30 9 03556 10 10 0 0 0 0 3 7 10 30 0 03557 9 9 1 0 1 0 4 4 8 50 0 113558 12 11 0 0 0 0 5 6 11 45 8 0Mean 9.6 9.3 0.3 0.0 0.3 0.0 3.6 5.4 9.0 40.3 3.7 3.0SD 1.41 1.28 0.46 0.00 0.46 0.00 1.06 1.30 1.51 10.07 5.30 5.48N 8 8 8 8 8 8 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 119MA-252E-93-23FinalReportFemalesIndividual Cesarean Section DataAppendix IAnimal Corpora Implant- ResorptionsDeadLive FetusesSex Ratio Pre Impl. Post Impl.Number Lutea ations Early Late Total Fetuses Male Female Total (% Male) Loss (%) Loss (%)Group 4 - 15,000 ppm4551np - - - - - - - - - - - -4552 8 8 1 0 1 0 5 2 7 71 0 134553 10 10 0 0 0 0 4 6 10 40 0 04554 10 10 0 0 0 0 4 6 10 40 0 04555 10 10 0 0 0 0 5 5 10 50 0 04556 9 9 0 1 1 0 5 3 8 63 0 114557 9 9 1 0 1 0 5 3 8 63 0 114558 7 6 0 0 0 0 1 5 6 17 14 0Mean 9.0 8.9 0.3 0.1 0.4 0.0 4.1 4.3 8.4 49.0 2.0 5.0SD 1.15 1.46 0.49 0.38 0.53 0.00 1.46 1.60 1.62 18.60 5.40 6.20N 7 7 7 7 7 7 7 7 7 7 7 7np = not pregnantHuntingdon Life Sciences09-4347Page 120MA-252E-93-23FinalReportBwt = body weight, Adj bwt = Adjusted body weightAdjusted body weight = Body weighton Day 29 – Gravid Uterine WeightIndividual Gravid UterineAdjusted Body WeightsFemales (grams) AppendixJAnimal Bodyweight on Bodyweight on Bwt change Gravid Uterine Adj Bwt Adj bwt changeNumber Day 6 Day 29 Days6-29 Weight Day 29 Days 6-29Group 1 - 0 ppm1551 3114.8 3609.4 494.6 562.2 3047.2 -67.61552 3224.2 3605.2 381.0 526.0 3079.2 -145.01553 3236.1 3475.0 238.9 496.5 2978.5 -257.61554 3298.8 3980.9 682.1 507.9 3473.0 174.21555 3148.0 3926.3 778.3 456.2 3470.1 322.11556 3480.4 3801.8 321.4 496.7 3305.1 -175.31557 3115.8 3659.1 543.3 564.4 3094.7 -21.11558 3285.4 3717.3 431.9 603.3 3114.0 -171.4Mean 3237.9 3721.9 483.9 526.7 3195.2 -42.7S.D. 121.37 171.73 181.00 47.34 194.14 197.12N 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 121MA-252E-93-23FinalReportBwt = body weight, Adj bwt = Adjusted body weightAdjusted body weight = Body weighton Day 29 – Gravid Uterine WeightIndividual Gravid UterineAdjusted Body WeightsFemales (grams) AppendixJAnimal Bodyweight on Bodyweight on Bwt change Gravid Uterine Adj Bwt Adj bwt changeNumber Day 6 Day 29 Days6-29 Weight Day 29 Days 6-29Group 2 - 2,500 ppm2551 3533.2 3998.7 465.5 596.6 3402.1 -131.12552 3482.3 3655.3 173.0 579.5 3075.8 -406.52553 3272.9 3746.2 473.3 610.7 3135.5 -137.42554 3448.9 3854.7 405.8 578.8 3275.9 -173.02555 3235.5 3691.2 455.7 478.6 3212.6 -22.92556 3328.1 3771.2 443.1 554.1 3217.1 -111.02557 3589.6 3792.1 202.5 439.5 3352.6 -237.02558 3382.9 3904.5 521.6 547.4 3357.1 -25.8Mean 3409.2 3801.7 392.6 548.2 3253.6 -155.6S.D. 125.84 113.35 130.68 59.59 114.42 123.78N 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 122MA-252E-93-23FinalReportBwt = body weight, Adj bwt = Adjusted body weightAdjusted body weight = Body weighton Day 29 – Gravid Uterine WeightIndividual Gravid UterineAdjusted Body WeightsFemales (grams) AppendixJAnimal Bodyweight on Bodyweight on Bwt change Gravid Uterine Adj Bwt Adj bwt changeNumber Day 6 Day 29 Days6-29 Weight Day 29 Days 6-29Group 3 - 10,000 ppm3551 3356.0 3794.2 438.2 424 3370.2 14.23552 3301.9 3571.1 269.2 541.1 3030.0 -271.93553 3338.4 3694.3 355.9 510.3 3184.0 -154.43554 3494.2 4011.1 516.9 481.6 3529.5 35.33555 3027.8 3583.4 555.6 553.4 3030.0 2.23556 3231.5 3764.6 533.1 565.3 3199.3 -32.23557 3504.4 3752.7 248.3 422.6 3330.1 -174.33558 3836.8 4138.1 301.3 642.9 3495.2 -341.6Mean 3386.4 3788.7 402.3 517.7 3271.0 -115.3S.D. 236.45 197.07 124.68 74.59 192.46 141.88N 8 8 8 8 8 8Huntingdon Life Sciences09-4347Page 123MA-252E-93-23FinalReportBwt = body weight, Adj bwt = Adjusted body weightAdjusted body weight = Body weighton Day 29 – Gravid Uterine WeightIndividual Gravid UterineAdjusted Body WeightsFemales (grams) AppendixJAnimal Bodyweight on Bodyweight on Bwt change Gravid Uterine Adj Bwt Adj bwt changeNumber Day 6 Day 29 Days6-29 Weight Day 29 Days 6-29Group 4 - 15,000 ppm4551 np4552 3347.8 3652.6 304.8 406.2 3246.4 -101.44553 3385.2 3691.9 306.7 527.7 3164.2 -221.04554 3381.2 4187.2 806.0 722.7 3464.5 83.34555 3021.5 3628.8 607.3 622.3 3006.5 -15.04556 3067.2 3259.1 191.9 412.8 2846.3 -220.94557 3918.5 4225.8 307.3 610 3615.8 -302.74558 2993.0 3231.1 238.1 291.7 2939.4 -53.6Mean 3302.1 3696.6 394.6 513.3 3183.3 -118.8S.D. 322.66 394.84 224.90 150.54 281.30 135.93N 7 7 7 7 7 7

# Huntingdon Life Sciences 09-4347 Page 124

MA-252E-93-23 Final Report

Litter Weight Data

Preface Appendix K

Individual Fetal Weights.................................................................................................. 125

Individual Placenta l Weights ........................................................................................... 129Huntingdon Life Sciences09-4347Page 125MA-252E-93-23FinalReportIndividual Fetal WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 1 – 0 ppm1551 39.6 46.8 38.4 53.2 53.6 28.8 35.3 32.0 34.9 33.2 40.31552 37.3 34.1 27.9 30.6 34.3 39.2 44.0 35.8 36.1 43.0 48.01553 39.4 44.9 44.1 38.3 34.8 34.1 32.4 38.3 40.3 47.91554 46.2 52.8 42.5 46.8 46.5 43.6 39.6 48.1 49.71555 46.8 45.4 43.3 44.1 45.5 46.8 49.7 52.51556 40.0 44.2 41.6 44.9 37.7 38.3 38.2 31.1 38.3 45.61557 36.7 51.3 43.0 45.4 21.3 27.8 27.3 34.1 36.0 38.0 43.11558 43.4 46.0 43.0 42.2 44.6 39.1 36.6 44.7 47.7 43.4 46.6Mean 41.2SD 3.84N 8Huntingdon Life Sciences09-4347Page 126MA-252E-93-23FinalReportIndividual Fetal WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 2 – 2,500 ppm2551 41.9 46.9 42.9 45.8 40.9 40.5 43.7 40.6 34.4 41.1 42.52552 36.9 44.8 36.7 32.2 29.2 34.9 32.8 35.5 38.5 41.4 38.1 41.62553 39.4 47.9 46.4 41.9 39.0 35.8 26.9 32.7 33.6 37.2 46.6 45.42554 45.2 52.7 46.5 46.7 46.6 43.2 43.1 40.5 38.6 49.22555 46.1 49.1 44.7 46.0 41.9 42.6 48.0 50.52556 43.7 48.6 42.1 41.0 34.9 34.3 38.8 47.5 52.0 54.62557 40.0 46.2 39.9 37.2 41.4 34.3 36.0 40.3 44.62558 43.9 46.9 45.9 41.5 44.7 39.4 39.9 43.9 45.9 46.6Mean 42.1SD 3.18N 8Huntingdon Life Sciences09-4347Page 127MA-252E-93-23FinalReportIndividual Fetal WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 3 – 10,000 ppm3551 42.6 46.7 45.8 39.7 36.6 39.5 46.2 43.83552 39.0 41.4 42.2 42.7 37.5 32.0 37.9 36.5 42.0 37.3 40.63553 41.7 41.7 42.5 44.1 38.8 37.8 41.5 40.9 39.9 47.93554 49.2 52.4 48.5 42.3 51.2 46.2 49.3 54.73555 39.8 39.4 40.5 41.9 39.8 37.4 37.8 38.8 40.8 36.3 45.43556 39.8 42.9 41.0 43.6 37.1 37.3 33.2 35.0 39.8 44.2 44.03557 37.7 38.8 38.0 42.3 38.7 35.4 27.8 38.1 42.53558 43.3 47.2 45.3 40.6 46.2 40.6 39.6 35.6 39.9 44.4 48.5 48.0Mean 41.6SD 3.60N 8Huntingdon Life Sciences09-4347Page 128MA-252E-93-23FinalReportIndividual Fetal WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 4 – 15,000 ppm4552 41.3 44.7 41.8 41.5 36.8 35.5 42.5 46.34553 38.6 43.2 40.2 38.0 38.0 40.4 32.8 29.6 37.8 42.1 43.84554 48.7 58.0 57.2 47.9 50.0 38.2 39.2 35.3 46.8 54.0 60.14555 43.5 51.1 44.7 45.5 44.5 41.0 43.0 40.1 36.3 43.2 45.94556 36.5 40.1 33.7 36.8 36.6 31.3 33.6 38.5 41.24557 54.2 45.2 55.7 58.6 49.2 61.0 52.1 53.3 58.54558 34.8 16.1 43.9 36.1 37.0 34.7 41.0Mean 42.5SD 6.93N 7Huntingdon Life Sciences09-4347Page 129MA-252E-93-23FinalReportIndividual Placental WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 1 – 0 ppm1551 3.8 5.2 3.8 6.3 6.0 2.2 3.7 2.2 3.6 2.4 3.01552 4.0 3.2 3.3 3.2 3.6 4.1 4.9 4.1 3.7 4.5 5.31553 4.8 5.3 5.2 4.9 4.2 4.0 4.4 4.7 5.2 4.91554 4.8 5.9 4.4 5.0 4.4 4.1 4.1 4.5 5.71555 4.8 4.3 4.6 4.3 4.4 4.9 5.0 6.01556 4.3 4.9 4.2 4.5 4.1 4.2 4.2 3.2 4.7 4.81557 4.1 6.1 4.8 4.1 2.5 3.1 3.1 3.9 4.0 4.4 4.71558 4.6 4.9 4.7 4.4 5.4 4.0 3.9 4.7 5.0 4.5 4.9Mean 4.4SD 0.39N 8Huntingdon Life Sciences09-4347Page 130MA-252E-93-23FinalReportIndividual Placental WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 2 – 2,500 ppm2551 5.8 7.0 6.3 6.1 4.7 5.4 5.7 5.5 4.6 6.8 5.62552 4.0 4.0 4.5 3.3 3.6 3.8 3.8 3.7 4.7 4.5 4.3 4.22553 4.8 5.9 4.9 5.2 5.0 3.7 3.5 4.1 3.8 5.0 5.4 5.82554 5.5 6.5 5.7 5.3 5.6 5.4 4.8 6.0 4.9 5.62555 5.4 6.7 4.7 5.0 5.3 4.6 6.3 5.52556 4.6 4.8 4.4 5.8 3.8 4.2 3.4 3.1 5.0 6.52557 4.8 5.4 4.9 4.8 4.1 4.0 4.4 4.7 5.72558 5.1 5.0 4.9 4.5 4.8 4.8 5.1 5.4 5.9 5.3Mean 5.0SD 0.58N 8Huntingdon Life Sciences09-4347Page 131MA-252E-93-23FinalReportIndividual Placental WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 3 – 10,000 ppm3551 5.1 5.4 4.5 4.8 4.2 5.3 5.5 5.73552 4.9 4.8 4.8 5.6 5.4 3.7 4.7 5.2 5.2 5.2 4.63553 4.6 4.5 4.8 5.0 4.2 4.2 4.4 4.7 4.6 5.03554 5.4 6.0 5.5 4.8 6.1 4.4 5.6 5.53555 4.0 4.6 4.2 4.5 3.4 4.0 3.7 3.3 4.1 3.6 5.03556 4.7 4.5 4.4 5.7 4.0 4.3 4.4 4.8 4.4 5.0 5.73557 4.7 5.4 4.9 5.7 5.2 4.1 3.3 4.63558 4.6 4.6 5.4 3.9 5.6 4.6 3.7 3.5 4.6 4.3 5.2 5.7Mean 4.8SD 0.40N 8Huntingdon Life Sciences09-4347Page 132MA-252E-93-23FinalReportIndividual Placental WeightsFemales (grams) AppendixKAnimal Litter FetusNumber Mean 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Group 4 – 15,000 ppm4552 5.4 6.0 5.8 5.5 4.8 4.7 5.0 6.14553 4.6 6.2 4.7 4.1 4.7 4.6 2.4 4.2 4.4 5.2 5.34554 6.1 7.7 7.5 5.9 5.5 4.4 4.8 5.1 5.5 7.9 6.54555 5.4 6.6 5.3 5.5 5.3 5.4 5.7 4.9 4.9 5.1 5.74556 5.2 6.0 5.2 5.4 5.2 4.6 4.6 5.1 5.54557 6.0 4.7 6.4 6.8 5.7 6.8 5.1 6.4 5.94558 4.3 2.1 5.6 4.7 4.2 4.7 4.4Mean 5.3SD 0.67N 7Huntingdon Life Sciences09-4347Page 133MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 1 - 0 ppm1551 10 1 M 46.8 No abnormality detected2 F 38.4 No abnormality detected3 M 53.2 No abnormality detected4 F 53.6 No abnormality detected5 F 28.8 No abnormality detected6 F 35.3 No abnormality detected7 F 32.0 No abnormality detected8 M 34.9 No abnormality detected9 M 33.2 No abnormality detected10 F 40.3 No abnormality detected1552 10 1 F 34.1 No abnormality detected2 M 27.9 No abnormality detected3 F 30.6 No abnormality detected4 F 34.3 No abnormality detected5 M 39.2 No abnormality detected6 M 44.0 No abnormality detected7 F 35.8 No abnormality detected8 F 36.1 No abnormality detected9 F 43.0 No abnormality detected10 F 48.0 No abnormality detected1553 9 1 F 44.9 No abnormality detected2 F 44.1 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 134MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 1 - 0 ppm1553 9 3 M 38.3 No abnormality detected4 M 34.8 No abnormality detected5 M 34.1 No abnormality detected6 M 32.4 No abnormality detected7 F 38.3 No abnormality detected8 F 40.3 No abnormality detected9 F 47.9 No abnormality detected1554 8 1 F 52.8 No abnormality detected2 F 42.5 No abnormality detected3 M 46.8 No abnormality detected4 M 46.5 No abnormality detected5 F 43.6 No abnormality detected6 F 39.6 No abnormality detected7 F 48.1 No abnormality detected8 F 49.7 No abnormality detected1555 7 1 M 45.4 No abnormality detected2 F 43.3 No abnormality detected3 F 44.1 No abnormality detected4 F 45.5 No abnormality detected5 F 46.8 No abnormality detected6 F 49.7 No abnormality detected7 M 52.5 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 135MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 1 - 0 ppm1556 9 1 F 44.2 No abnormality detected2 F 41.6 No abnormality detected3 M 44.9 No abnormality detected4 M 37.7 No abnormality detected5 M 38.3 No abnormality detected6 M 38.2 No abnormality detected7 F 31.1 No abnormality detected8 F 38.3 No abnormality detected9 F 45.6 No abnormality detected1557 10 0 U 0.0 No abnormality detectedNo abnormality detectedNo abnormality detected1 M 51.3 No abnormality detected2 F 43.0 No abnormality detected3 F 45.4 No abnormality detected4 F 21.3 No abnormality detected5 F 27.8 No abnormality detected6 F 27.3 No abnormality detected7 F 34.1 No abnormality detected8 F 36.0 No abnormality detected9 M 38.0 No abnormality detected10 F 43.1 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 136MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 1 - 0 ppm1558 10 1 F 46.0 No abnormality detected2 F 43.0 No abnormality detected3 F 42.2 No abnormality detected4 M 44.6 No abnormality detected5 F 39.1 No abnormality detected6 F 36.6 No abnormality detected7 F 44.7 No abnormality detected8 M 47.7 No abnormality detected9 M 43.4 No abnormality detected10 M 46.6 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 137MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 2 - 2,500 ppm2551 10 1 F 46.9 No abnormality detected2 F 42.9 No abnormality detected3 M 45.8 No abnormality detected4 M 40.9 No abnormality detected5 M 40.5 No abnormality detected6 M 43.7 No abnormality detected7 F 40.6 No abnormality detected8 F 34.4 No abnormality detected9 F 41.1 No abnormality detected10 F 42.5 No abnormality detected2552 11 1 F 44.8 No abnormality detected2 M 36.7 No abnormality detected3 F 32.2 Skin/subcutis: forepaw(s), left, subcutaneous hemorrhage4 F 29.2 No abnormality detected5 F 34.9 No abnormality detected6 M 32.8 No abnormality detected7 F 35.5 Skin/subcutis: hindpaw(s), right, subcutaneous hemorrhage8 F 38.5 No abnormality detected9 F 41.4 No abnormality detected10 M 38.1 No abnormality detected11 F 41.6 No abnormality detected2553 11 1 M 47.9 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 138MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 2 - 2,500 ppm2553 11 2 F 46.4 No abnormality detected3 F 41.9 No abnormality detected4 F 39.0 No abnormality detected5 F 35.8 No abnormality detected6 F 26.9 No abnormality detected7 F 32.7 No abnormality detected8 F 33.6 No abnormality detected9 M 37.2 No abnormality detected10 M 46.6 No abnormality detected11 M 45.4 No abnormality detected2554 9 1 M 52.7 No abnormality detected2 M 46.5 No abnormality detected3 M 46.7 No abnormality detected4 M 46.6 No abnormality detected5 F 43.2 No abnormality detected6 F 43.1 No abnormality detected7 M 40.5 No abnormality detected8 F 38.6 No abnormality detected9 M 49.2 No abnormality detected2555 7 1 F 49.1 No abnormality detected2 M 44.7 No abnormality detected3 M 46.0 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 139MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 2 - 2,500 ppm2555 7 4 M 41.9 No abnormality detected5 F 42.6 No abnormality detected6 F 48.0 No abnormality detected7 M 50.5 No abnormality detected2556 9 1 F 48.6 No abnormality detected2 F 42.1 No abnormality detected3 F 41.0 No abnormality detected4 F 34.9 No abnormality detected5 M 34.3 No abnormality detected6 F 38.8 No abnormality detected7 F 47.5 No abnormality detected8 M 52.0 No abnormality detected9 M 54.6 No abnormality detected2557 8 1 F 46.2 No abnormality detected2 F 39.9 No abnormality detected3 M 37.2 No abnormality detected4 F 41.4 No abnormality detected5 F 34.3 No abnormality detected6 M 36.0 No abnormality detected7 M 40.3 No abnormality detected8 M 44.6 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 140MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 2 - 2,500 ppm2558 9 1 F 46.9 No abnormality detected2 F 45.9 No abnormality detected3 M 41.5 No abnormality detected4 F 44.7 No abnormality detected5 F 39.4 No abnormality detected6 F 39.9 No abnormality detected7 F 43.9 No abnormality detected8 M 45.9 No abnormality detected9 M 46.6 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 141MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 3 - 10,000 ppm3551 7 1 F 46.7 No abnormality detected2 M 45.8 No abnormality detected3 M 39.7 No abnormality detected4 F 36.6 No abnormality detected5 F 39.5 No abnormality detected6 F 46.2 No abnormality detected7 M 43.8 No abnormality detected3552 10 1 F 41.4 No abnormality detected2 M 42.2 No abnormality detected3 M 42.7 No abnormality detected4 F 37.5 No abnormality detected5 F 32.0 No abnormality detected6 F 37.9 No abnormality detected7 M 36.5 No abnormality detected8 F 42.0 No abnormality detected9 M 37.3 No abnormality detected10 F 40.6 No abnormality detected3553 9 1 M 41.7 No abnormality detected2 F 42.5 No abnormality detected3 M 44.1 No abnormality detected4 F 38.8 No abnormality detected5 M 37.8 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 142MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 3 - 10,000 ppm3553 9 6 F 41.5 No abnormality detected7 F 40.9 No abnormality detected8 M 39.9 No abnormality detected9 M 47.9 No abnormality detected3554 7 1 F 52.4 No abnormality detected2 F 48.5 No abnormality detected3 F 42.3 No abnormality detected4 M 51.2 No abnormality detected5 F 46.2 No abnormality detected6 F 49.3 No abnormality detected7 M 54.7 No abnormality detected3555 10 1 F 39.4 No abnormality detected2 F 40.5 No abnormality detected3 F 41.9 No abnormality detected4 M 39.8 No abnormality detected5 M 37.4 No abnormality detected6 F 37.8 No abnormality detected7 F 38.8 No abnormality detected8 F 40.8 No abnormality detected9 M 36.3 No abnormality detected10 F 45.4 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 143MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 3 - 10,000 ppm3556 10 1 F 42.9 No abnormality detected2 F 41.0 No abnormality detected3 F 43.6 No abnormality detected4 F 37.1 No abnormality detected5 F 37.3 No abnormality detected6 F 33.2 No abnormality detected7 M 35.0 No abnormality detected8 M 39.8 No abnormality detected9 M 44.2 No abnormality detected10 F 44.0 No abnormality detected3557 8 1 F 38.8 No abnormality detected2 M 38.0 No abnormality detected3 M 42.3 No abnormality detected4 F 38.7 No abnormality detected5 F 35.4 No abnormality detected6 F 27.8 No abnormality detected7 M 38.1 No abnormality detected8 M 42.5 No abnormality detected3558 11 1 F 47.2 No abnormality detected2 M 45.3 No abnormality detected3 F 40.6 No abnormality detected4 M 46.2 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 144MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 3 - 10,000 ppm3558 11 5 M 40.6 No abnormality detected6 F 39.6 No abnormality detected7 F 35.6 No abnormality detected8 M 39.9 No abnormality detected9 F 44.4 No abnormality detected10 M 48.5 No abnormality detected11 F 48.0 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 145MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 4 - 15,000 ppm4552 7 1 F 44.7 No abnormality detected2 M 41.8 No abnormality detected3 M 41.5 No abnormality detected4 F 36.8 No abnormality detected5 M 35.5 No abnormality detected6 M 42.5 No abnormality detected7 M 46.3 No abnormality detected4553 10 1 M 43.2 No abnormality detected2 F 40.2 No abnormality detected3 F 38.0 No abnormality detected4 M 38.0 No abnormality detected5 M 40.4 No abnormality detected6 F 32.8 No abnormality detected7 F 29.6 No abnormality detected8 F 37.8 No abnormality detected9 M 42.1 No abnormality detected10 F 43.8 No abnormality detected4554 10 1 M 58.0 No abnormality detected2 F 57.2 No abnormality detected3 M 47.9 No abnormality detected4 F 50.0 No abnormality detected5 F 38.2 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 146MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 4 - 15,000 ppm4554 10 6 F 39.2 No abnormality detected7 F 35.3 No abnormality detected8 F 46.8 No abnormality detected9 M 54.0 No abnormality detected10 M 60.1 No abnormality detected4555 10 1 M 51.1 No abnormality detected2 F 44.7 No abnormality detected3 M 45.5 No abnormality detected4 M 44.5 No abnormality detected5 F 41.0 No abnormality detected6 F 43.0 No abnormality detected7 M 40.1 No abnormality detected8 M 36.3 No abnormality detected9 F 43.2 No abnormality detected10 F 45.9 No abnormality detected4556 8 0 U 0.0 No abnormality detected1 M 40.1 No abnormality detected2 M 33.7 No abnormality detected3 F 36.8 No abnormality detected4 F 36.6 No abnormality detected5 M 31.3 No abnormality detected6 M 33.6 No abnormality detectedF = Female, M = Male, U = UnknownHuntingdon Life Sciences09-4347Page 147MA-252E-93-23FinalReportIndividual Fetal Observations(External) AppendixLAnimal Weight Abnormalities (onlyfetuses with abnormalities are listed)Number Exams Fetus Sex (g) Major in CAPITALSGroup 4 - 15,000 ppm4556 8 7 F 38.5 No abnormality detected8 M 41.2 No abnormality detected4557 8 1 F 45.2 No abnormality detected2 M 55.7 No abnormality detected3 M 58.6 No abnormality detected4 F 49.2 No abnormality detected5 M 61.0 No abnormality detected6 M 52.1 No abnormality detected7 F 53.3 No abnormality detected8 M 58.5 No abnormality detected4558 6 1 F 16.1 No abnormality detected2 M 43.9 No abnormality detected3 F 36.1 No abnormality detected4 F 37.0 No abnormality detected5 F 34.7 No abnormality detected6 F 41.0 No abnormality detectedF = Female, M = Male, U = Unknown

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Equipment List Appendix M

Exposure Chamber

1000 liter glass and stainless steel chamber (Wahmann)

Compound Generator

Counter-Current Volatilization Unit, coiled glass rod insert heated by a nichrome wire

(Crown Glass Co., Inc.)

Compound Reservoir

Sponsor Container

Variable Auto Transformer

Variable Autotransformer, Type 3PN 1010 (Staco Energy Products Company)

Flowmeters

Liquid flowmeter, size 0-65 mm, Model G603-R3, G604-R3 (Key Instruments)

Flowmeter, size 0 – 5, 0 – 10, 0 – 20, 0 - 30 or 0 - 40 Lpm (Dwyer ® 

# )

Pressure/Vacuum Gauge(s)

Union Carbide backpressure gauge, P/N SG 3800

Regulator(s)

U.S. Gauge backpressure gauge, P/N 12672-1

Norgreen, P/N R07-219-RGKA

Valves

Metering Valve, Model SS-4L Series (Nupro ® 

# Co.)

Tubing

Size 1/4”, 1/2”, 3/8” plastic (Norton or Baxter)

Teflon ® 

# /Tygon ® 

# , size 1/8”, 1/4”

1/2” stainless steel

T-Tube, stainless steel

Filters

Balston ® 

# Microfibre  Disposable Filter Units (Grade DQ)

# Huntingdon Life Sciences 09-4347 Page 149

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Equipment List Appendix M

Vacuum Pumps

Thomas Industries Inc., Model 707CM50

Balance(s)

Pelouse 4040

Air Analyzer

MIRAN ® 

# 1A Ambient Air Analyzer (Wilks) with a Cole Parmer strip chart recorder,

Model 201, and a Micronta ® 

# LCD Benchtop Digital Multimeter No. 22-195

Particle Sizer/Analyzer

TSI Aerodynamic Particle Sizer, Model 331001, with a TSI Diluter, Model 330201, and a

DELL computer, Model 486P25, equipped with an Epson LQ-570+ Dot matrix printer,

Model P630B

Environmental Monitoring

Springfield ® 

# Apollo or Sunbeam Temperature and Humidity Gauge, calibrated prestudy

with a Digital Hygrometer and Thermometer, Model 72680251 (Control Company)

Chamber Air-flow Gauge(s)

Dwyer ® 

# magnahelic gauge, calibrated prestudy with Dry Gas Meter, Model 2M (Singer)

Chamber Static Pressure

Dwyer ® 

# Magnehelic ® 

# gauge, calibrated prestudy with Dwyer  

# Mark II Manometer,

Model 25 (Dwyer  

# Instruments Inc.)

# Huntingdon Life Sciences 09-4347 Page 150

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Pre-Study Chamber Distribution Samples Appendix N

Group

(target ppm) Date Port Concentration

(ppm) Ratio to H-1

2 (2,500) 18 Aug 09 H-1 2500

H-2 2400 0.96

H-7 2400 0.96

H-1 2800

H-8 2800 1.00

3 (10,000) 19 Aug 09 H-1 10000 -

H-2 9700 0.97

H-7 9900 0.99

H-1 9300 -

H-8 9200 0.99

20 Aug 09 H-1 11000 -

H-2 11000 1.00

H-7 10000 0.91

H-1 11000 -

H-8 10000 0.91

4 (15,000) 19 Aug 09 H-1 15000 -

H-2 13000 0.87

H-7 14000 0.93

H-1 15000

H-8 15000 1.00

20 Aug 09 H-1 16000 -

H-2 15000 0.94

H-7 15000 0.94

H-1 16000 -

H-8 15000 0.94

# Huntingdon Life Sciences 09-4347 Page 151

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Miran Calibration Appendix O

Methodology for

Settings: The instrument settings for the unit are summarized below:

wavelength, microns 3.24

pathlength, dial setting 1.74

slit width, mm 1

range, absorbance 1

response, seconds 1

gain high

chart speed, cm/min 1

chart volts 1

Calibrations: The Miran ® 

# was turned on and allowed to warm up for approximately

10 minutes. The cell was flushed with room air for approximately one minute. The loop

was closed, the unit was zeroed and the calibra tion series was performed as shown below.

The resultant data were plotted to obtain a calibration curve. Each observer used a

separate syringe for calibration.

Injection Calculated Absorbance

Volume Concentration 1 

# Operator 1 Operator 2 Average

(μL) (ppm) (volts) (volts) (volts)

Liquid

60 2,506 0.2317 0.2179 0.2248

240 10,024 0.728 0.753 0.741

360 15,036 0.943 0.975 0.959

Vapor

11,000 1,950 0.1580 0.1596 0.1588

14,000 2,482 0.2030 0.2062 0.2046

56,600 10,018 0.679 0.686 0.683

84,500 14,982 0.907 0.925 0.916

100,000 17,730 0.981 0.998 0.990

1 

# Calculated Conc. (ppm)

Liquid : Injection volume ( μ L) x Density (mg/μL) x 1000 ( μ g/mg) / 5.64L / Molecular weight of

test material ( μ g/ μ mole) x (22.4 μ L/ μ mole) x (295K/273K)

Vapor : Volume injected (μL)/5.64 L

where: 5.64 L = volume of Miran closed loop

Molecular weight of test material = 130.5

# Huntingdon Life Sciences 09-4347 Page 152

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Miran Calibration Appendix O

Calibration Checks: A three-point calibration check of the Miran ® 

# was performed for

each exposure prior to sampling the chambers. The parameters are shown below:

Liquid Expected Acceptable

Injection Calculated Absorbance Absorbance

Volume Concentration Reading Range

(μL) (ppm) (volts) (volts)

60 2,506 0.2248 0.1911 – 0.2585

240 10,024 0.741 0.630 – 0.852

360 15,036 0.959 0.815 – 1.103

The absorbance was recorded after each inj ection. The absorbance was considered

satisfactory if it was within 15% of the original calibration series. If any of the

absorbance values fell outside the 15% range, the injection was rechecked as follows.

The volume for the value that was out of range was reinjected twice. The closer pair of

the three injections were averaged and the results were compared to the original curve. If

the average of the pair was within the 15% ra nge, the original was accepted. If the value

of the average was outside the 15% range, th e Study Director decided if a new graph was

to be prepared.

# Huntingdon Life Sciences 09-4347 Page 153

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Miran Calibration Appendix O

Calibration Curve for

y = -13986x 3 

# + 19899x 2 

# + 11241x

R 2 

# = 0.9065

0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000

0.050 0.150 0.250 0.350 0.450 0.550 0.650 0.750 0.850 0.950

Absorbance (Volts)

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Scientists and Supervising Personnel Appendix Q

TITLE/DEPARTMENT NAME/DEGREE

SENIOR VICE PRESIDENT,

SAFETY ASSESSMENT Sylvie J Gosselin, DVM, PhD,

Diplomate ACVP

DIRECTOR, DEVELOPMENTAL AND

REPRODUCTIVE TOXICOLOGY Robert M Parker, PhD, DABT

DIRECTOR, ANALYTICAL SERVICES Barbara A Litzenberger, BS, MT

(ASCP)

DIRECTOR, TOXICOLOGY

OPERATIONS Ian Vanterpool, FIAT

STUDY DIRECTOR Gary M Hoffman, BA, DABT

REPORT WRITER Suzanne U Mullen, AALAS LATG

VETERINARIAN Teresa S Kusznir, VMD

MANAGER/SUPERVISOR

Rodent Toxicology

Inhalation Toxicology

Pharmacy

Necropsy and Fetal Pathology Christina Savidge, BS,

AALAS RLATG

Stuart Cracknell, CBiol, MIBiol

Michael S McCarthy

Donna G Chuddley, BS,

CLA (ASCP) HT