## FINAL REPORT

Volume 1 of 2 (Text, Figures 1-2, Tables 1-27 and Appendix A - Tables A1-A31)

STUDY TITLE

A 5-DAY REPEATED-DOSE I NHALATION TOXICITY STUDY OF IN SPRAGUE-DAWLEY RATS

STUDY NUMBER

STUDY DIRECTOR

STUDY INITIATION DATE

9 January 2008

STUDY COMPLETION DATE

14 May 2008

PERFORMING LABORATORY

SPONSOR

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# S TATEMENT 

# O F 

# N O 

# D ATA 

# C ONFIDENTIALITY 

# C LAIMS



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

basis of its falling within the scope of FIFRA 10 (d) 1(A), (B) or (C).

Sponsor:

Sponsor's Agent: _____

____________________ ______ _____________ Signature Date

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## 53401 1



# COMPLIANCE STATEMENT

This study, designated was conducted in compliance with the United States Environmental Protection Agency (EPA) Good Laboratory Practice Standards
(40 CFR Part 792), 18 September 1989; the Organisation for Economic Cooperation and Development (OECD) Principles of Good Laboratory Practice [ 

## C (97) 1 86/Final], 26 November 1997; the Japanese Ministry of 

## Agriculture, Forestry and Fisheries (MAFF)

Good Laboratory Practice for Agricultural Chemicals 

# (1 1 Nousan No. 6283),

1 October 1999; the standard operating procedures of

and the protocol as approved by the sponsor. A Certificate 

# of Analysis was provided by the sponsor (presented 

# in Appendix 

# B); the characterization analyses were conducted according to unknown standards.

Director, Inhalath Toxicology Study Director

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# T ABLE 

# O F 

# C ONTENTS



## VOLUME 1 Page

Statement Of No Data Confidentiality Claims........................................2 Compliance Statement...............................................................................3

Table Of Contents......................................................................................4 Index Of Figures ........................................................................................7

Index Of Tables..........................................................................................8 Index Of Appendices ...............................................................................10 1. Summary...................................................................................................13 1.1. Objective....................................................................................................13 1.2. Study Design..............................................................................................13
1.3. Results........................................................................................................14
1.4. Conclusions................................................................................................14

2. Introduction..............................................................................................15 2.1. General Study Information ........................................................................15 2.2. Key Study Dates ........................................................................................15

3. Study Design.............................................................................................16 4. Experimental Procedures - Materials And Methods............................17
4.1. Test Substance Identification.....................................................................17 4.2. Exposure Methods .....................................................................................17 4.3. Test Atmosphere Generation And Monitoring ..........................................18 4.4. Methods For Characterization Of Exposure Atmospheres ........................18 4.4.1. Nominal Exposure Concentrations ............................................................18 4.4.2. Analyzed Exposure Concentrations...........................................................19

4.5. Test System................................................................................................19 4.6. Organization Of Test Groups, Exposure Levels And Treatment Regimen .....................................................................................................20 4.7. Animal Receipt And Acclimation/Pretest Period ......................................21 4.8. Animal Housing.........................................................................................21 4.9. Diet, Drinking Water And Maintenance....................................................21

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## V OLUME 1 (continued) Page

4.10. Environmental Conditions .........................................................................22 4.11. Assignment Of Animals To Treatment Groups.........................................22

5. Parameters Evaluated .............................................................................24
5.1. Clinical Observations And Survival ..........................................................24 5.2. Body Weights.............................................................................................24 5.3. Food Consumption.....................................................................................25 5.4. Clinical Pathology......................................................................................25 5.4.1. Hematology And Coagulation ...................................................................26 5.4.2. Serum Chemistry .......................................................................................26

5.5. Anatomic Pathology...................................................................................27 5.5.1. Macroscopic Examination .........................................................................27 5.5.2. Organ Weights ...........................................................................................29

5.6. Statistical Methods.....................................................................................29
5.7. Data Retention ...........................................................................................30

6. Results And Discussion............................................................................31
6.1. Clinical Observations And Survival ..........................................................31 6.2. Body Weights.............................................................................................31 6.3. Food Consumption.....................................................................................32 6.4. Clinical Pathology......................................................................................32 6.4.1. Hematology And Coagulation ...................................................................32 6.4.2. Serum Chemistry .......................................................................................33

6.5. Anatomic Pathology...................................................................................33 6.5.1. Macroscopic Examination .........................................................................33 6.5.2. Organ Weights ...........................................................................................33

7. Conclusions...............................................................................................35 8. Key Study Personnel And Report Submission......................................36 9. Quality Assurance Unit Statement.........................................................37 9.1. Phases Inspected ........................................................................................37 9.2. Approval ....................................................................................................39

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## V OLUME 1 (continued) Page

10. References.................................................................................................40

11. Deviations From The Protocol................................................................41

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# I NDEX 

# O F 

# F IGURES



## VOLUME 1 (continued) Page

1. Summary Of Body Weights [G] (Males)...................................................................43

2. Summary Of Body Weights [G] (Females) ...............................................................44

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# I NDEX 

# O F 

# T ABLES



## VOLUME 1 Page

1. Summary Of Survival And Disposition (Groups 1-4)...............................................46

2. Summary Of Survival And Disposition (Group 5)....................................................48

3. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (Detailed Physical Examinations/Dispositions - Groups 1-4) ...................................50

4. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (Detailed Physical Examinations/Dispositions - Group 5) ........................................52

5. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (At Time Of Exposure - Groups 1-4).........................................................................54

6. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (At Time Of Exposure - Group 5)..............................................................................56

7. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (Approximately 15-30 Minutes Into Exposure - Groups 1-4)...................................58

8. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (Approximately 15-30 Minutes Into Exposure - Group 5)........................................60

9. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (End Of Exposure - Groups 1-4)................................................................................62

10. Summary Of Clinical Findings: Total Occurrence/No. Of Animals (End Of Exposure - Group 5).....................................................................................66

11. Summary Of Body Weights [G] (Groups 1-4) ..........................................................68

12. Summary Of Body Weights [G] (Group 5) ...............................................................72

13. Summary Of Body Weight Changes [G] (Groups 1-4).............................................74

14. Summary Of Body Weight Changes [G] (Group 5)..................................................76

15. Summary Of Cumulative Body Weight Changes [G] (Groups 1-4) .........................78

16. Summary Of Cumulative Body Weight Changes [G] (Group 5)..............................80

17. Summary Of Food Consumption [G/Animal/Day] (Groups 1-4) .............................82

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## V OLUME 1 (continued) Page

18. Summary Of Food Consumption [G/Animal/Day] (Group 5) ..................................84

19. Summary Of Hematology Values (Groups 1-4)........................................................86

20. Summary Of Hematology Values (Group 5).............................................................98

21. Summary Of Serum Chemistry Values (Groups 1-4)..............................................110

22. Summary Of Serum Chemistry Values (Group 5)...................................................120

23. Summary Of Macroscopic Findings (Unscheduled Death).....................................130

24. Summary Of Macroscopic Findings (Groups 1-4) ..................................................131

25. Summary Of Macroscopic Findings (Group 5) .......................................................133

26. Summary Of Organ Weights And Relative Organ Weights (Groups 1-4)..............135

27. Summary Of Organ Weights And Relative Organ Weights (Group 5)...................141

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# I NDEX 

# O F 

# A PPENDICES



## VOLUME 1 (continued) Page

A. Individual Animal Data............................................................................................147

A1. Individual Survival And Disposition (Groups 1-4) ...........................................148

A2. Individual Survival And Disposition (Group 5) ................................................150

A3. Individual Clinical Observations (Detailed Physical Examinations/Dispositions - Groups 1-4)...........................152

A4. Individual Clinical Observations (Detailed Physical Examinations/Dispositions - Group 5)................................157

A5. Individual Clinical Observations (At Time Of Exposure - Groups 1-4)...........159

A6. Individual Clinical Observations (At Time Of Exposure - Group 5)................161

A7. Individual Clinical Observations (Approximately 15-30 Minutes Into Exposure - Groups 1-4)...........................162

A8. Individual Clinical Observations (Approximately 15-30 Minutes Into Exposure - Group 5)................................163

A9. Individual Clinical Observations (End Of Exposure - Groups 1-4)..................164

A10. Individual Clinical Observations (End Of Exposure - Group 5).......................168

A11. Individual Body Weights [G] (Groups 1-4).......................................................169

A12. Individual Body Weights [G] (Group 5)............................................................177

A13. Individual Body Weight Changes [G] (Groups 1-4) .........................................179

A14. Individual Body Weight Changes [G] (Group 5) ..............................................187

A15. Individual Cumulative Body Weight Changes [G] (Groups 1-4) .....................189

A16. Individual Cumulative Body Weight Changes [G] (Group 5) ..........................197

A17. Individual Food Consumption [G/Animal/Day] (Groups 1-4)..........................199

A18. Individual Food Consumption [G/Animal/Day] (Group 5)...............................207

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## V OLUME 1 (continued) Page

A19. Individual Hematology Values (Groups 1-4) ....................................................209

A20. Individual Hematology Values (Group 5) .........................................................233

A21. Individual Serum Chemistry Values (Groups 1-4)............................................239

A22. Individual Serum Chemistry Values (Group 5).................................................255

A23. Individual Macroscopic Findings (Unscheduled Death)...................................259

A24. Individual Macroscopic Findings (Groups 1-4).................................................260

A25. Individual Macroscopic Findings (Group 5) .....................................................299

A26. Individual Organ Weights And Final Body Weights [G] (Groups 1-4)............309

A27. Individual Organ Weights And Final Body Weights [G] (Group 5).................317

A28. Individual Organ Weights Relative To Final Body Weights [G/100 G] (Groups 1-4) .......................................................................................................319

A29. Individual Organ Weights Relative To Final Body Weights [G/100 G] (Group 5) ............................................................................................................327

A30. Individual Organ Weights Relative To Brain Weights [G/100 G] (Groups 1-4) .......................................................................................................329

A31. Individual Organ Weights Relative To Brain Weights [G/100 G] (Group 5) ............................................................................................................337

VOLUME 2

B. Certificate Of Analysis (Sponsor Provided Data)....................................................340

C. Exposure Atmosphere Generation Report ( .........................................................................342

D. Pretest Clinical Observations ...................................................................................369

E. Animal Room Environmental Conditions ...............................................................372

F. Unscheduled Clinical Observations .........................................................................377

G. Clinical Pathology Methods, Procedures And References ......................................382

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## V OLUME 2 (continued) Page

H. Historical Control Data ( ..................................387

I. Study Protocol ..........................................................................................................412

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# 1. S UMMARY


# 1.1. O BJECTIVE 

## The objective of this dose range-finding study was to evaluate potential toxic effects of the test substance when administered via whole-body inhalation to rats for 5 consecutive days. Standard hematology and serum chemistry evaluations were performed at the time of scheduled necropsy. Standard tissues were harvested from all animals at necropsy and preserved, but were not examined microscopically.



# 1.2. S TUDY 

# D ESIGN 

## was administered as a vapor via whole-body inhalation for a

6-hour/da y exposure period once daily for up to 5 consecutive days to 3 groups (Groups 2-4) of Crl:CD(SD) rats. The first day of administration was study day 0. The target exposure levels were 1250, 2500 and 5000 ppm. A concurrent control group (Group 1) was exposed to the vehicle, filtered air, on a comparable regimen. Based on excessive toxicity, test substance exposure for all Group 4 animals was discontinued after the study day 1 exposure period and an additional group (Group 5) was added to the study. Group 5 was administered the test substance, via whole-body inhalation at a target exposure level of 1800 ppm according to the same regimen as Groups 2-4. Each group (Groups 1-5) consisted of 5 animals/sex. Following 5 days of test substance exposure, all rats in Groups 1, 2, 3 and 5 were euthanized and subjected to necropsy. All surviving Group 4 animals were euthanized and subjected to necropsy after 2 days of test substance exposure and a 3-day non-exposure period.

All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed prior to exposure, approximately 15-30 minutes after the initiation of exposure and 0-1 hour following exposure on exposure days. Detailed physical examinations were performed prior to test substance exposure for randomization and twice during the exposure phase (including prior to scheduled necropsy). Individual body weights were recorded during pretest and prior to the first, third and fifth exposures, and food consumption was recorded on study day 4. Clinical pathology evaluations

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## (hematolog y, coagulation and serum chemistry) were performed on all animals at the time of necropsy. Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsies.



# 1.3. R ESULTS 

## There were no test substance-related effects on body weights, organ weights or clinical pathology parameters, nor were there any macroscopic findings in the test substance-exposed groups.

One male in the 5000 ppm group was found dead on study day 1. All other animals survived to the scheduled necropsy. Test substance-related clinical observations consisted of convulsions and/or tremors in the 2500 and 5000 ppm males and females and dried and/or wet red, yellow and/or brown material on various body surfaces in the 5000 ppm group males and females. Slightly lower food consumption was noted in the 2500 ppm males and females from study days 0 to 4.



# 1.4. C ONCLUSIONS 

## Based on the results of this study, systemic toxicity of administered via whole-body inhalation exposure to Crl:CD(SD) rats for up to 5 days was observed at dose levels of 2500 and 5000 ppm as evidenced by lethality in the 5000 ppm group, convulsions and/or tremors in the 2500 and 5000 ppm groups and decreased food consumption in the 2500 ppm group males and females. The no-observed-effect level (NOEL) for administered via whole-body inhalation exposure to Crl:CD(SD) rats for up to 5 days was 1800 ppm. Therefore, the maximum concentration for a subsequent 28-day study should be no higher than 2500 ppm.

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# 2. I NTRODUCTION


# 2.1. G ENERAL 

# S TUDY 

# I NFORMATION 

## This report presents the data from “A 5-Day Repeated-Dose Inhalation Toxicity Study Of In Sprague-Dawley Rats”. Due to software spacing constraints, the study title appears as “A 5-Day Inhalation Study In Rats” on the report tables.

The following computer protocols were used for data collection during the study:

Computer Protocol Type of Data Collected ........................................... Main study data (Groups 1-4) 534011A ........................................ Main study data (Group 5) 534011P......................................... Pretest data 534011U ........................................ Unscheduled Clinical Observations



# 2.2. K EY 

# S TUDY 

# D ATES 

## Date(s) Event(s)

22 January 2008...................................... Experimental starting date (animal receipt for Group 1-5 animals) 4 February 2008...................................... Assignment to study groups (Groups 1-4) 6 February 2008...................................... Experimental start date (initiation of dose administration for Groups 1-4; study day 0) 8 February 2008...................................... Transfer of Group 5 females from stock colony; randomization of Group 5 animals 9 February 2008...................................... Initiation of dose administration for Group 5; study day 0 11 February 2008.................................... Primary necropsy (study day 5; Groups 1-4) 14 February 2008.................................... Experimental termination (completion) date (Group 5 Primary necropsy, study day 5)

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# 3. S TUDY 

# D ESIGN

5 animals/sex/group (Group 4) exposed for 2 days; 5 animals/sex/group (Groups 1, 2, 3 and 5) for 5 consecutive days

Clinical observations recorded daily; body weights recorded prior to the first,

third and fifth exposures; food intake recorded on study day 4

Clinical pathology evaluations

conducted prior to necropsy Necropsies performed on animal found dead; selected tissues retained for possible histological examination

Necropsies performed on all animals/sex/group on study day 5; selected organs weighed; selected tissues retained for possible histological

e x a min at i on Acclimation/pretest period

Assignment of animals to study groups



## 16 of 435

# 4. E XPERIMENTAL 

# P ROCEDURES 

# - M ATERIALS 

# A ND 

# M ETHODS


# 4.1. T EST 

# S UBSTANCE 

# I DENTIFICATION 

## The test substance, (chemical name

was received from via Nippon EXP ORD, Des Plaines, Illinois, on 21 January 2008, as follows:

Identification Quantity Received Physical Description

[ 15 drums Total gross weight: 330.0 lb Clear, colorless liquid

Documentation regarding the purity and stability of the test substance are on file with the sponsor and A Certificate of Analysis for the test substance was provided by the sponsor and is presented in Appendix B. The test substance was stored at room temperature and was considered stable under this condition. A reserve sample of the test substance (22.7 g) was collected on 28 January 2008, and

stored in the Archives of



# 4.2. E XPOSURE 

# M ETHODS 

## Exposures were conducted in four 500-L stainless steel and glass whole-body inhalation exposure chambers. One chamber was dedicated for each group with the exception of Chamber 4. Following the termination of Group 4, an additional group (Group 5) was added to the study and was exposed in Chamber 4. The following table presents the chambers used for each group:

Group Number 1 2 3 4 5
Chamber Number 1 2 3 4 4 Target Exposure Concentration (ppm) 0 1250 2500 5000 1800

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## Chamber suppl y air was provided from a HEPA- and charcoal-filtered, temperature- and humidity-controlled source. All test atmosphere chamber exhaust passed through carbon scrubbers (Environtrol, Inc., Sewickley, PA) prior to the facility exhaust system, which consisted of charcoal and HEPA filtration. The exposure period was 6 hours per day for 5 consecutive days for Groups 1-3 and 5 and 6 hours per day for 2 consecutive days for Group 4. For the exposure each day, the animals were transferred to exposure caging, transported to the exposure chamber room, exposed for the requisite duration and returned to their home cages in the animal colony room. The cage batteries were rotated on a daily basis between 2 battery positions in the chambers to help ensure a similar exposure for all animals within each group over the duration of the exposure period. Food and water were withheld during each daily exposure period. Exposure methods and conditions are detailed in Appendix C.



# 4.3. T EST 

# A TMOSPHERE 

# G ENERATION 

# A ND 

# M ONITORING 

## Vapors of the test substance were generated using a glass-bead column-type vaporization system. The vaporization column was wrapped with an electric heating tape (Omega Engineering Co., Stamford, CT) controlled using a J-type thermocouple and digital temperature controller. Using a regulator and calibrated rotameter-type flowmeters, nitrogen was metered to the bottom of each vaporization column. Vaporization occurred as the liquid test substance coated the surface of the heated beads and nitrogen flowed up through the column. The concentrated vapors were piped to the chamber inlet and diluted to the desired concentration by mixing with the chamber supply air. For Group 1, nitrogen was supplied to the chamber inlet and dilated with chamber supply air. Refer to Appendix C for a complete description of the generation and exposure systems.



# 4.4. M ETHODS 

# F OR 

# C HARACTERIZATION 

# O F 

# E XPOSURE 

# A TMOSPHERES


# 4.4.1. N OMINAL 

# E XPOSURE 

# C ONCENTRATIONS 

## A nominal exposure concentration was calculated daily for each test substance group from the total amount of test substance used during the exposure and the total volume of air passed through the chamber during that day’s exposure. The amount of test substance

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## used was obtained b y weighing the test substance reservoir prior to and after each day’s exposure. The total volume of air passed through each chamber was calculated from the daily average chamber ventilation flowrate in LPM and the exposure duration. The

nominal concentration was calculated as follows.

WT × MV × 10 6 

## Concentration (ppm) = GMW × CVR × DUR
Where: WT = Weight of test substance used, grams MV = Molar volume at 730 mmHg and 21oC, 25.11 L/mole

10 6 

## = ppm conversion factor GMW = Test substance gram molecular weight, 200.05 g/mole

CVR = Daily mean chamber ventilation rate for a given day, LPM DUR = Duration of the daily exposure, minutes



# 4.4.2. A NALYZED 

# E XPOSURE 

# C ONCENTRATIONS 

## Analyzed exposure concentrations were determined at approximately 30-minute intervals using a gas chromatograph (GC). Samples were collected from the approximate animal-breathing zone of the inhalation exposure chambers via 1/8-inch Teflon ® 

## tubing. Samples were collected manually using an external multi-position valve (Model E16, Valco Instruments Co., Inc., Houston, TX) and a Hewlett Packard Model 3396 Series II integrator (with BASIC program). Gas sample injection onto the chromatography column occurred via an internal gas-sampling valve with a sample loop. The chromatograph was displayed and the area under the sample peak was calculated and stored. The concentration in parts per million (ppm) was calculated using an ln-quadratic equation based on the GC calibration curve. Refer to Appendix C for a complete description of the exposure analyses.



# 4.5. T EST 

# S YSTEM 

## Crl:CD(SD) rats from Charles River Laboratories, Inc., Raleigh, North Carolina were used as the test system on this study. This species and strain of animal is recognized to be appropriate for inhalation toxicity studies. The Sprague Dawley rat was selected

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## because it is a widely used strain for which historical control data are available. The animals were approximately 9 weeks old at the initiation of exposure.



# 4.6. O RGANIZATION 

# O F 

# T EST 

# G ROUPS 

# , E XPOSURE 

# L EVELS 

# A ND 

# T REATMENT 

# R EGIMEN 

## Five males and 5 females per group in Groups 1-3 and 5 were exposed for 6 hours daily for 5 days, through the day prior to the scheduled necropsy. Animals in Group 4 were exposed for 6 hours daily for 2 days and euthanized 4 days later on study day 5. The first day of exposure was study day 0.

The following table presents the study group assignment:

Number of Animals Group Number Test Substance Target Exposure Level (ppm) Males Females

1 Filtered Air 0 5 5

2 1250 5 5

3 2500 5 5

4 5000 5 5

5 1800 5 5

The target exposure levels for Groups 1-4 were selected by the sponsor representative based on the results of previous inhalation toxicology studies. The target exposure level for Group 5 was selected based on the excessive toxicity in the 2500 and 5000 ppm

groups.

The selected route of administration for this study was inhalation exposure since this is a potential route of human exposure. The number of animals selected for this study was the minimum number required to yield statistically valid and scientifically meaningful

data.

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# 4.7. A NIMAL 

# R ECEIPT 

# A ND 

# A CCLIMATION 

# /P RETEST 

# P ERIOD 

## For Groups 1-4 and the Group 5 males, 25 male and 25 female Crl:CD(SD) rats were received in good health on 22 January 2008 from Charles River Laboratories, Inc., Raleigh, North Carolina. The animals were approximately 7 weeks old at receipt. Each animal was examined by a qualified technician on the day of receipt and weighed 3 days later. Five females for use in Group 5 were transferred from the stock rat colony on 8 February 2008.

Each animal was uniquely identified by a Monel ® 

## metal ear tag displaying the permanent identification number. In addition to an ear tag, each Group 5 female had a subcutaneous microchip (BMDS system). All animals in Groups 1-4 and 5 were housed for an acclimation/pretest period of 15 or 18 days, respectively. During this period, each animal was observed twice daily for mortality and changes in general appearance or behavior.

Pretest data collection began on 25 January 2008. Individual body weights were recorded and detailed physical examinations were performed periodically during the pretest period for animals in Groups 1-4. Food consumption data was also recorded for pretest animals in Groups 1-4 prior to the initiation of dose administration. Pretest clinical data are presented in Appendix D. Pretest data collection was not performed for the Group 5

females.



# 4.8. A NIMAL 

# H OUSING 

## Upon arrival, all animals were single-housed in clean, stainless steel, wire mesh cages suspended above cage board. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). The animal

facilities at are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).



# 4.9. D IET 

# , D RINKING 

# W ATER 

# A ND 

# M AINTENANCE 

## The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent

LabDiet ® 

## 5002 (meal), is a certified feed with appropriate analyses performed by the

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## manufactur er and provided to Reverse osmosis treated (on site) drinking water, delivered by an automatic watering system, and the basal diet were provided ad libitum throughout the study, except during exposures and the period of fasting prior to blood collection when food, but not water, was withheld. Food was also withheld overnight from all Group 4 animals on study day 1 for possible blood collection on study day 2; food was replaced the following morning because animals were held for blood collection on study day 5 instead of study day 2. Municipal water supplying the facility was sampled for contaminants according to the standard operating procedures. The results of the diet and water analyses are maintained at No contaminants were present in animal feed or water at concentrations sufficient to interfere with the objectives of this study.



# 4.10. E NVIRONMENTAL 

# C ONDITIONS 

## All animals were housed throughout the acclimation period and during the study in an environmentally controlled room. The room temperature and humidity controls were set to maintain daily averages of 71 ± 5oF (22 ± 3oC) and 50 ± 20% relative humidity. Room temperature and relative humidity were controlled and monitored using the Metasys ®


## DDC Electronic Environmental control system. These data were recorded approximately hourly and are summarized in Appendix E. Actual mean daily temperature ranged from 70.0oF to 72.0oF (21.1oC to 22.2oC) and mean daily relative humidity ranged from 36.1% to 41.6% during the study. Fluorescent lighting provided illumination for a 12 hour light (0600 hours to 1800 hours)/12 hour dark photoperiod. Air handling units were set to provide a minimum of 10 fresh air changes per hour.



# 4.11. A SSIGNMENT 

# O F 

# A NIMALS 

# T O 

# T REATMENT 

# G ROUPS 

## Two days prior to the initiation of exposure for Groups 1-4 (4 February 2008), all available rats were weighed and examined in detail for physical abnormalities. These data were collected using the Toxicology Data Management System (WTDMS TM 

## ) and reviewed by the study director. The animals judged suitable for assignment to the study were selected for use in a computerized randomization procedure. A printout

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## containing the animal numbers, corresponding body weights and individual group assignments was generated based on body weight stratification in a block design. The animals were then arranged into groups according to the printout. On 8 February 2008, the males excluded from Groups 1-4 were returned to the study and additional females from the stock rat colony were selected for the study in the same fashion as Groups 1-4 (randomized by computer program). Individual body weights at randomization were within ± 20% of the mean for each sex. Each group consisted of 5 males and 5 females. Individual body weights on study day 0 ranged from 288 g to 367 g for males and from 186 g to 240 g for females.

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# 5. P ARAMETERS 

# E VALUATED


# 5.1. C LINICAL 

# O BSERVATIONS 

# A ND 

# S URVIVAL 

## All animals were observed twice daily, once in the morning and once in the afternoon, for mortality and moribundity.

Clinical observations were performed 3 times daily on the days of exposure. Time points included an observation prior to exposure and 0-1 hour following exposure (designated as1 hour following exposure for report presentation purposes). In addition, an observation was performed 15-30 minutes after the initiation of exposure (Groups 1-3 and 5 only). This observation time point was initiated on 8 February 2008 (study day 3); however, observations had been recorded as unscheduled observations during this time point on study days 0-2. The unscheduled observations recorded 15-30 minutes after the initiation of exposure on study days 0-2 are presented with observations from this time point on study days 3 and 4. Because an official observational time point was not designated for the first 3 days of dosing, the absence of findings (designated as no significant clinical observations) was not recorded for any animals 15-30 minutes after the initiation of exposure until study day 3. During the non-exposure days for Group 4 animals, examinations were performed at the same time as the observations for the animals being exposed to the test substance. Detailed physical examinations were conducted on all animals prior to test substance administration for randomization and twice during the exposure phase, including an examination prior to the scheduled necropsy. Observations prior to exposure were not performed on the days of detailed physical examinations. The presence or absence of significant findings were recorded for

individual animals.



# 5.2. B ODY 

# W EIGHTS 

## Individual body weights were recorded during the pretest period beginning approximately 2 weeks prior to test substance exposure, at randomization (Groups 1-4 only), and prior to the first, third and fifth exposures. Mean body weights and mean body weight changes were calculated for the corresponding intervals. Final body weights (fasted) were

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## record ed prior to the scheduled necropsies. The exposures for the 5000 ppm group were terminated following the second exposure (study day 1). To prepare for possible blood collection and necropsy on the following day, the animals in this group were fasted overnight from study day 1 to 2. On study day 2, the decision was made to evaluate the 5000 ppm group animals for clinical pathology and necropsy on study day 5 according to the original schedule. However, the scheduled study day 2 body weight for the 5000 ppm group animals was effectively a fasted body weight.



# 5.3. F OOD 

# C ONSUMPTION 

## Individual food consumption was recorded during pretest and on study day 4 for all animals in Groups 1-3 and 5, and on study days 1 and 4 for Group 4 animals. Food intake was calculated as g/animal/day. Due to food consumption data collection on study day 1, additional food consumption data for Group 4 animals is located in Appendix F.



# 5.4. C LINICAL 

# P ATHOLOGY 

## Blood samples for clinical pathology evaluations (hematology, coagulation and serum chemistry) were collected from all animals at the scheduled necropsy (study day 5). The animals were fasted overnight prior to blood collection. Blood was collected for hematology and serum chemistry evaluation via the retro-orbital sinus of animals anesthetized by inhalation of isoflurane. Blood was collected for coagulation parameters at the time of euthanasia via the vena cava of animals euthanized by inhalation of isoflurane. Blood was collected into tubes containing EDTA (hematology), sodium citrate (clotting determinations) or no anticoagulant (serum chemistry). Clinical pathology methods, procedures and references are presented in Appendix G. The following parameters were evaluated:

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# 5.4.1. H EMATOLOGY 

# A ND 

# C OAGULATION 

## Total leukocyte count (White Cells) Erythrocyte count (Red Cells) Hemoglobin Hematocrit Mean corpuscular volume (MCV) Mean corpuscular hemoglobin

(MCH) Mean corpuscular hemoglobin

concentration (MCHC) Platelet count (Platelet) Prothrombin time (ProTime) Activated partial thromboplastin time

(APTT) Reticulocyte count

Percent (Reticulocyte) Absolute (Retic Absolute) Differential leukocyte count - Percent and absolute

-Neutrophil -Lymphocyte -Monocyte -Eosinophil -Basophil -Large unstained cell Platelet estimate a 

## Red cell morphology

(RBC Morphology) a



## ( ) - Designates tabular abbreviation

a 

## - Presented on individual tables if a manual differential was performed, and the manual data were accepted and reported instead of the automated differential data



# 5.4.2. S ERUM 

# C HEMISTRY


## Albumin Total protein Globulin [by calculation] Albumin/globulin ratio (A/G Ratio)

[by calculation] Total bilirubin (Total Bili) Urea nitrogen Creatinine Alkaline phosphatase

(AlkalinePhos’tse) Alanine aminotransferase

(Alanine Transfer) Aspartate aminotransferase (AspartatTransfer) Glucose Total cholesterol (Cholesterol) Calcium Chloride Phosphorus Potassium Sodium Triglycerides (Triglyceride)

( ) - Designates tabular abbreviation

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# 5.5. A NATOMIC 

# P ATHOLOGY


# 5.5.1. M ACROSCOPIC 

# E XAMINATION 

## A complete necropsy was conducted on all animals. Animals were euthanized by isoflurane anesthesia and exsanguinated. The necropsies included, but were not limited
to, examination of the external surface, all orifices, and the cranial, thoracic, abdominal and pelvic cavities, including viscera. Clinical findings that were confirmed macroscopically were designated CEO (correlates with externally observed) on the individual macroscopic data tables. The following tissues and organs were collected and placed in 10% neutral-buffered formalin (except as noted):

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## Adrenal s (2) Aorta Bone with marrow (sternebrae) Bone with marrow (femur with joint) Bone marrow smear (taken from

femur) a 

## Brain

Cerebrum 2 levels Cerebellum with medulla/pons Cervix Epididymides (2) b 

## Exorbital lacrimal glands (2) Eyes with optic nerves (2) c 

## Gastrointestinal tract

Esophagus Stomach Duodenum Jejunum Ileum with Peyer’s patches Cecum Colon Rectum Harderian glands (2) Heart Kidneys (2) Larynx Liver (sections of 2 lobes) Lungs (including bronchi, fixed by inflation with fixative) Lymph nodes

Mediastinal and bronchial (if visible) Mesenteric and mandibular (2) Mammary gland (females only) Nasal Cavity d 

## Ovaries/oviducts (2) e 

## Pancreas Peripheral nerve (sciatic) Pituitary Pharynx Prostate Salivary glands [mandibular (2)] Seminal vesicles (2) Skeletal muscle (rectus femoris) Skin Spinal cord (cervical, thoracic, lumbar) Spleen Testes (2) b 

## Thymus Thyroid [with parathyroids (2)] e 

## Trachea Urinary bladder Uterus Vagina Gross lesions (when possible)

a 

## - Bone marrow smears were obtained at scheduled necropsy, but not placed in formalin; slides were not examined. b 

## - Fixed in Bouin’s solution

c 

## - Fixed in Davidson’s solution d 

## - Following collection of the appropriate protocol-specified tissues, the entire head was removed and preserved.

e 

## - Parathyroids and oviducts were retained for possible microscopic examination if in the plane of section and in all cases when a gross lesion of the organ was present.

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# 5.5.2. O RGAN 

# W EIGHTS 

## The following organs were weighed from all animals at the scheduled necropsy:

Brain Kidneys Liver Lungs* * = Weighed prior to inflation with fixative

Paired organs were weighed together. Organ-to-final-body-weight and organ-to-brain-weight ratios were calculated.



# 5.6. S TATISTICAL 

# M ETHODS 

## All statistical tests were performed using appropriate computing devices or programs. Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Each mean was presented with the standard deviation (S.D.), standard error (S.E.) and the number of animals (N) used to calculate the mean. In addition, percent difference from control is presented for body weights, clinical pathology and organ weight values. Statistical analyses were not conducted if the number of animals was 2 or less. Due to the different rounding conventions inherent in the types of software used, the means and standard deviations on the summary and individual tables may differ by ±1 in the last significant figure.

Due to the absence of a concurrent control group, all Group 5 data was qualitatively compared to the appropriate version of historical control data.

Body weight, body weight change, food consumption, clinical pathology and organ weight data from Groups 1-4 were subjected to a parametric one way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance treated groups to the control

group.

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# 5.7. D ATA 

# R ETENTION 

## The sponsor has title to all documentation records, raw data, specimens, slides or other work product generated during the performance of the study. All work product generated by including raw paper data and specimens, are

retained in the Archives at as specified in the study protocol.

Reserve samples of the test substance, pertinent electronic storage media and the original final report are retained in the Archives at in compliance with regulatory requirements.

30 of 435

# 6. R ESULTS 

# A ND 

# D ISCUSSION


# 6.1. C LINICAL 

# O BSERVATIONS 

# A ND 

# S URVIVAL 

## Summary Data: Tables 1 through 10 Individual Data: Tables A1 through A10

Male no. 95554 (Group 4, 5000 ppm) was found dead on study day 1. This animal had been noted with intermittent tremors during exposure on study day 0 and intermittent and continuous convulsions during exposure on study day 1. These observations and the

animal’s death were considered to be test substance-related.

All other animals survived to the scheduled necropsies. Intermittent tremors and intermittent/continuous convulsions were noted during the exposure period in the 5000 ppm group males and females. Intermittent convulsions were also noted in one 2500 ppm group male on study days 2, 3 and 4 and in one 2500 ppm group female on study days 2 and 4. Dried and/or wet red, yellow and/or brown material on various body surfaces was noted in the 5000 ppm group males and females and was considered to be likely related to the stress of convulsions and/or tremors.

There were no other test substance-related clinical observations. All clinical findings in the test substance-treated groups were not noted in a dose-related manner and/or were common findings for laboratory rats of this age and strain.



# 6.2. B ODY 

# W EIGHTS 

## Summary Data: Tables 11, 12, 13, 14, 15 16 Individual Data: T ables A11, A12, A13, A14, A15 A16

There were no test substance-related effects on body weights throughout the study. A significantly lower mean body weight was noted in the 5000 ppm group males and females on study day 2; however, these animals had been fasted for possible blood collection and this is likely the cause of the difference from the control group (see Section 5.3 for further explanation).

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# 6.3. F OOD 

# C ONSUMPTION 

## Summary Data: Tables 17, 18 Individual Data: Tables A17, A18

Statistically significantly lower mean food consumption was noted from study days 0 to 4 in the 2500 ppm group males and females. Food consumption was unaffected by test substance exposure in the 1250 and 1800 ppm group males and females.



# 6.4. C LINICAL 

# P ATHOLOGY


# 6.4.1. H EMATOLOGY 

# A ND 

# C OAGULATION 

## Summary Data: Tables 19, 20
Individual Data: Tables A19, A20

Hematology parameters were unaffected by test substance administration. When compared to the control group, mean absolute and percent reticulocyte values were statistically significantly lower in the 2500 ppm group males; in addition, mean absolute reticulocyte values were also statistically significantly lower in the 1250 ppm group females. There were no effects on other red blood cell parameters and because all absolute and percent reticulocyte values for all groups fell within the range of historical control data (version 2.5); therefore, these findings were not considered to be test substance-related. The mean percent basophil count was statistically significantly higher in the 1250 ppm group males; however, this value was within the range of

historical control data and was not considered test substance-related. There were no other effects on hematology and coagulation parameters. Due to the absence of a concurrent control group, all 1800 ppm group data was qualitatively compared to the appropriate version of historical control data. Based on these comparisons, there were no effects on hematology and coagulation parameters in the 1800 ppm group.

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# 6.4.2. S ERUM 

# C HEMISTRY 

## Summary Data: Tables 21, 22 Individual Data: Tables A21, A22

Serum chemistry parameters were unaffected by test substance administration. When the control and test substance-treated groups were compared there were statistically significant lower values in the 5000 ppm group female mean total protein value, the 2500 ppm group female urea nitrogen value and the 1250 ppm male glucose value.
However, these differences were not noted in a dose-related trend and/or all were within the range of the historical control data (version 2.5) and were not considered test substance-related. Due to the absence of a concurrent control group, all 1800 ppm group data was qualitatively compared to the appropriate version of historical control data. Based on these comparisons, there were no effects on serum chemistry parameters in the 1800 ppm group.



# 6.5. A NATOMIC 

# P ATHOLOGY


# 6.5.1. M ACROSCOPIC 

# E XAMINATION 

## Summary Data: Tables 23, 24, 25 Individual Data: Tables A23, A24, A25

There were no test substance-related macroscopic findings at the scheduled necropsy. All macroscopic findings noted were considered to be spontaneous and/or incidental in

nature and unrelated to test substance administration.



# 6.5.2. O RGAN 

# W EIGHTS 

## Summary Data: Tables 26, 27
Individual Data: Tables A26, A27, A28, A29, A30, A31

Organ weights were unaffected by exposure to There were no statistically significant differences when Groups 2-4 were compared to the control group, nor were there any remarkable organ weight effects noted in the Group 5 (1800 ppm) males and females based on comparison to historical control data (version 2.4). In

33 of 435

## a ddition, all mean organ weight values were within the range of the historical

control data.

34 of 435

# 7. C ONCLUSIONS 

## Based on the results of this study, systemic toxicity of administered via whole-body inhalation exposure to Crl:CD(SD) rats for up to 5 days was observed at dose levels of 2500 and 5000 ppm as evidenced by lethality in the 5000 ppm group, convulsions and/or tremors in the 2500 and 5000 ppm groups and decreased food consumption in the 2500 ppm group males and females. The no-observed-effect level (NOEL) for administered via whole-body inhalation exposure to Crl:CD(SD) rats for up to 5 days was 1800 ppm. Therefore, the maximum concentration for a subsequent 28-day study should be no higher than 2500 ppm.

35 of 435

# 8.

435

# 9. Q UALITY 

# A SSURANCE 

# U NIT 

# S TATEMENT


# 9.1. P HASES 

# I NSPECTED

Date(s) of Inspection(s) Phase Inspected Date(s) Fi ndings Reported to Study Director Date(s) Fi ndings Reported to Management Auditor(s)

06-Feb-2008 Test Substance Exposure 06-Feb-2008 26-Mar-2008 M.Stauffer

14-Apr-2008 1 5-Apr-2008 16-Apr-2008 17-Apr-2008 Study Records (I-1) 17-Apr-2008 14-May-2008 J.Godby

16-Apr-2008 Study Records (C-1) 16-Apr-2008 14-May-2008 J.Godby

16-Apr-2008 Study Records (N-1) 16-Apr-2008 14-May-2008 J.Godby

16-Apr-2008 1 7-Apr-2008 Draft Report without Inh alation Report 17-Apr-2008 14-May-2008 J.Godby

28-Apr-2008 2 9-Apr-2008 30-Apr-2008 Inhalation Report 30-Apr-2008 14-May-2008 J.Godby

28-Apr-2008 2 9-Apr-2008 30-Apr-2008 Study Records (EX-1, EX-2) 30-Apr-2008 14-May-2008 J.Godby



## This study was inspected in accordance wi th the U.S. EPA Good Laboratory Practice Standards (40 CFR Parts 160 and 792), the OECD Principles of Good Laboratory Practice, the standard operating procedures of and the sponsor's protocol and protocol amendments , with the following exception. The data located in Appendix B (Certificate Of Analysis ) were the responsibility of the sponsor. Quality Assurance findings, derived from the inspections during the conduct of the study and from the inspections of the raw data a nd draft report, are documented and have been reported to the study director. A status report is submitted to management monthly.

This report accurately reflects the data ge n erated during the study. The methods and procedures used in the study we re those specified in the prot ocol, its amendments and the standard operating procedures of

37 of 435

## The raw data, the retention sample and the final report will be stored in the Archives at or another location specified by the sponsor.

38 of 435

## 53401 1



# 9.2. APPROVAL

This study was inspected according to the criteria discussed in Section 9.1.



## 39 of 435

# 10. R EFERENCES 

## Dunnett, C.W. New tables for multiple comparisons with a control. Biometrics 1964, 20, 482-491.

National Research Council. Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, Commission on Life Sciences; National Academy Press: Washington, DC, 1996

. Snedecor, G.W.; Cochran, W.G. One Way Classifications; Analysis of Variance. In Statistical Methods , 7th ed.; The Iowa State University Press: Ames, IA, 1980 ; pp 215-237.

40 of 435

# 11. D EVIATIONS 

# F ROM 

# T HE 

# P ROTOCOL 

## This study was conducted in accordance with the protocol and protocol amendments, except for the following.

• Protocol Section 5.5 states that at the initiation of exposure, male rat body weights will range from 250 to 350 g. Body weights for male nos. 95577, 95554, 95562 and 95575 were above 350 g on study day 0.

• Protocol Section 7.1 states that animals will be allowed a pretreatment week (as part of the acclimation period) during which body weights and food consumption will be recorded and general health will be monitored, but they will not receive the test substance. Because the Group 5 females were originally received for use on another study, pretest data for these animals was collected but not transferred for use on this study.

• Protocol Section 7.7.1 states that the nominal test substance concentration will be within ± 10% of the measured chamber concentration. The nominal concentration for Group 5 was not within this range.

• Protocol Section 8.4 states that a final body weight will be determined prior to necropsy. On 7 February 2008 (study day 1), a final body weight was recorded for male no. 95554 (Group 4, 5000 ppm) which was found dead.

• Protocol Section 8.4 states that individual body weights will be recorded during the pretest phase for randomization and group assignment. On 8 February 2008 (study day -1), weights for the 5 female animals used for Group 5 were hand-entered to allow for randomization. The weights entered were collected on 6 February 2008; weights from 8 February 2008 should have been used.

These deviations did not negatively impact the quality or integrity of the data nor the outcome of the study.

.

41 of 435

# F IGURES 

# 1 - 2

42 of 435PROJECT NO.:FIGURE 1SUMMARY OF BODY WEIGHTS (G) - MALESa = Test substance exposure was discontinued for the 5000 ppm group following exposure on study day 1; these animals werefasted for possible blood collection from study day 1-2BW v1.00 03/25/2008150200250300350-12-8-2024**STUDY DAY**

**BODY WEIGHT (GRAMS)**0 PPM1250 PPM2500 PPM5000 PPM1800 PPMa



## 43 of 435PROJECT NO.:FIGURE 2SUMMARY OF BODY WEIGHTS (G) - FEMALESa = Test substance exposure was discontinued for the 5000 ppm group following exposure on study day 1; these animals werefasted for possible blood collection from study day 1-2BW v1.00 03/25/2008150200250300350-12-8-2024**STUDY DAY**

**BODY WEIGHT (GRAMS)**0 PPM1250 PPM2500 PPM5000 PPM1800 PPMa



## 44 of 435

# TABLES 1 - 27

45 of 435TABLE 1 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF SURVIVAL AND DISPOSITION

MALES GROUP : 1 2 3 4

----------------------------------------------------------------------------------------------------------------------------------- DAY LIVE FD EE SE LIVE FD EE SE LIVE FD EE SE LIVE FD EE SE

----------------------------------------------------------------------------------------------------------------------------------- 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 1 5 0 0 0 5 0 0 0 5 0 0 0 4 1 0 0 2 5 0 0 0 5 0 0 0 5 0 0 0 4 0 0 0 3 5 0 0 0 5 0 0 0 5 0 0 0 4 0 0 0 4 5 0 0 0 5 0 0 0 5 0 0 0 4 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 4

----------------------------------------------------------------------------------------------------------------------------------- DAY = DAY OF STUDY FD = FOUND DEAD EE = EUTHANIZED IN EXTREMIS SE = SCHEDULED EUTHANASIA

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM46of435TABLE 1 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF SURVIVAL AND DISPOSITION

FEMALES GROUP : 1 2 3 4

----------------------------------------------------------------------------------------------------------------------------------- DAY LIVE FD EE SE LIVE FD EE SE LIVE FD EE SE LIVE FD EE SE

----------------------------------------------------------------------------------------------------------------------------------- 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 1 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 2 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 3 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 4 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5 0 0 0 5

----------------------------------------------------------------------------------------------------------------------------------- DAY = DAY OF STUDY FD = FOUND DEAD EE = EUTHANIZED IN EXTREMIS SE = SCHEDULED EUTHANASIA

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PSURVv4.09 03/19/200847of435TABLE 2 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF SURVIVAL AND DISPOSITION

MALES GROUP : 5 DAY LIVE FD EE SE

----------------------------------------------------------------------------------------------------------------------------------- 0 5 0 0 0 1 5 0 0 0 2 5 0 0 0 3 5 0 0 0 4 5 0 0 0 5 0 0 0 5

----------------------------------------------------------------------------------------------------------------------------------- DAY = DAY OF STUDY FD = FOUND DEAD EE = EUTHANIZED IN EXTREMIS SE = SCHEDULED EUTHANASIA

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM48of435TABLE 2 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF SURVIVAL AND DISPOSITION

FEMALES GROUP : 5 DAY LIVE FD EE SE

----------------------------------------------------------------------------------------------------------------------------------- 0 5 0 0 0 1 5 0 0 0 2 5 0 0 0 3 5 0 0 0 4 5 0 0 0 5 0 0 0 5

----------------------------------------------------------------------------------------------------------------------------------- DAY = DAY OF STUDY FD = FOUND DEAD EE = EUTHANIZED IN EXTREMIS SE = SCHEDULED EUTHANASIA

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM PSURVv4.09 03/19/2008 R:03/24/200849of435TABLE 3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 005 GROUP: 1 2 3 4

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 9/ 5 10/ 5 10/ 5 8/ 5

DISPOSITION -FOUND DEAD 0/ 0 0/ 0 0/ 0 1/ 1 -PRIMARY NECROPSY (DAY 5) 5/ 5 5/ 5 5/ 5 4/ 4

EXCRETA -SOFT FECES 1/ 1 0/ 0 0/ 0 0/ 0

ORAL/DENTAL -UPPER INCISOR(S) MALALIGNED 0/ 0 0/ 0 0/ 0 1/ 1

BODY/INTEG III -DRIED RED MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM50of435TABLE 3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 005 GROUP: 1 2 3 4

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 10/ 5 10/ 5 9/ 5 9/ 5

DISPOSITION -PRIMARY NECROPSY (DAY 5) 5/ 5 5/ 5 5/ 5 5/ 5

BODY/INTEGUMENT -HAIR LOSS FORELIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1 -HAIR LOSS HINDLIMB(S) 0/ 0 0/ 0 1/ 1 0/ 0 -HAIR LOSS VENTRAL NECK 0/ 0 0/ 0 0/ 0 1/ 1 -HAIR LOSS UROGENITAL AREA 0/ 0 0/ 0 1/ 1 0/ 0

BODY/INTEG II -SCABBING FORELIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1 -SCABBING VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1

BODY/INTEG III -DRIED YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PCSUv4.07 03/19/2008 R:03/19/200851of435TABLE 4 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 005 GROUP: 5

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 10/ 5

DISPOSITION -PRIMARY NECROPSY (DAY 5) 5/ 5

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM52of435TABLE 4 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 005 GROUP: 5

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 6/ 4

DISPOSITION -PRIMARY NECROPSY (DAY 5) 5/ 5

BODY/INTEGUMENT -HAIR LOSS FORELIMB(S) 2/ 1 -HAIR LOSS VENTRAL TRUNK 2/ 2

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM PCSUv4.07 03/19/2008 R:03/24/200853of435TABLE 5 (AT TIME OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

EYES/EARS/NOSE -DRIED RED MATERIAL AROUND RIGHT EYE 0/ 0 0/ 0 0/ 0 3/ 1 -DRIED RED MATERIAL AROUND NOSE 0/ 0 0/ 0 0/ 0 3/ 1

EXCRETA -RED PENILE DISCHARGE 0/ 0 1/ 1 0/ 0 0/ 0

ORAL/DENTAL -DRIED RED MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 3/ 1 -DRIED RED MATERIAL VENTRAL NECK 0/ 0 0/ 0 0/ 0 1/ 1

SPECIAL -SWOLLEN FACIAL AREA 0/ 0 0/ 0 0/ 0 2/ 1

BODY/INTEG III -WET YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -WET YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 3/ 1 -DRIED YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 2/ 1 -DRIED RED MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL FORELIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM54of435TABLE 5 (AT TIME OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

EYES/EARS/NOSE -DRIED RED MATERIAL AROUND NOSE 0/ 0 0/ 0 0/ 0 7/ 3

ORAL/DENTAL -DRIED RED MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 5/ 3 -DRIED RED MATERIAL VENTRAL NECK 0/ 0 0/ 0 0/ 0 2/ 1

BODY/INTEG III -WET YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -WET YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 4/ 2 -DRIED YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 4/ 2 -DRIED RED MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 3/ 2 -DRIED RED MATERIAL HINDLIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL FORELIMB(S) 0/ 0 0/ 0 0/ 0 4/ 2 -DRIED BROWN MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PCSUv4.07 03/19/2008 R:03/19/200855of435TABLE 6 (AT TIME OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 5

----------------------------------------------------------------------------------------------------------------------------------- NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM56of435TABLE 6 (AT TIME OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 5

----------------------------------------------------------------------------------------------------------------------------------- NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM PCSUv4.07 03/19/2008 R:03/24/200857of435TABLE 7 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

BEHAVIOR/CNS -TREMORS, INTERMITTENT 0/ 0 0/ 0 0/ 0 2/ 2 -CONVULSIONS, INTERMITTENT 0/ 0 0/ 0 3/ 1 2/ 2 -CONVULSIONS, CONTINUOUS 0/ 0 0/ 0 0/ 0 2/ 2

ORAL/DENTAL -WET CLEAR MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 3/ 2

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM58of435TABLE 7 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

BEHAVIOR/CNS -TREMORS, INTERMITTENT 0/ 0 0/ 0 0/ 0 1/ 1 -CONVULSIONS, INTERMITTENT 0/ 0 0/ 0 2/ 1 2/ 2 -CONVULSIONS, CONTINUOUS 0/ 0 0/ 0 0/ 0 2/ 2

ORAL/DENTAL -WET CLEAR MATERIAL AROUND MOUTH 0/ 0 0/ 0 1/ 1 0/ 0

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PCSUv4.07 04/16/2008 R:04/16/200859of435TABLE 8 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1

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

ORAL/DENTAL -WET CLEAR MATERIAL AROUND MOUTH 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 1800 PPM60of435TABLE 8 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1

----------------------------------------------------------------------------------------------------------------------------------- NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 1- 1800 PPM PCSUv4.07 04/16/2008 R:04/16/200861of435TABLE 9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

EYES/EARS/NOSE -DRIED RED MATERIAL AROUND LEFT EYE 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL AROUND RIGHT EYE 0/ 0 0/ 0 0/ 0 3/ 1 -DRIED RED MATERIAL AROUND NOSE 0/ 0 0/ 0 1/ 1 2/ 1

ORAL/DENTAL -WET CLEAR MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 1/ 1 -WET YELLOW MATERIAL VENTRAL NECK 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 4/ 2 -DRIED RED MATERIAL VENTRAL NECK 0/ 0 0/ 0 0/ 0 1/ 1

SPECIAL -SWOLLEN FACIAL AREA 0/ 0 0/ 0 0/ 0 2/ 1

BODY/INTEG III -WET YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 1/ 1 2/ 2 -WET YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 2/ 2 -WET YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 2/ 2 2/ 2 -WET YELLOW MATERIAL FORELIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 1/ 1 6/ 4 -DRIED YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 2/ 2 -DRIED YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 4/ 3

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM62of435TABLE 9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

BODY/INTEG III -DRIED RED MATERIAL FORELIMB(S) 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED BROWN MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED BROWN MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED BROWN MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM63of435TABLE 9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

BEHAVIOR/CNS -HYPOACTIVITY 0/ 0 0/ 0 0/ 0 2/ 1

EYES/EARS/NOSE -DRIED RED MATERIAL AROUND NOSE 0/ 0 0/ 0 2/ 1 5/ 2

ORAL/DENTAL -WET RED MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 1/ 1 -DRIED RED MATERIAL AROUND MOUTH 0/ 0 0/ 0 0/ 0 6/ 3 -DRIED RED MATERIAL VENTRAL NECK 0/ 0 0/ 0 0/ 0 4/ 2

SPECIAL -SWOLLEN FACIAL AREA 0/ 0 0/ 0 0/ 0 4/ 3 -SWOLLEN LEFT FORELIMB 0/ 0 0/ 0 0/ 0 1/ 1 -SWOLLEN RIGHT FORELIMB 0/ 0 0/ 0 0/ 0 1/ 1 -REDDENED LEFT FORELIMB 0/ 0 0/ 0 0/ 0 1/ 1 -REDDENED RIGHT FORELIMB 0/ 0 0/ 0 0/ 0 1/ 1

BODY/INTEG III -WET YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 8/ 5 -WET YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 2/ 2 -WET YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 6/ 4

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM64of435TABLE 9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 1 2 3 4

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

BODY/INTEG III -DRIED YELLOW MATERIAL UROGENITAL AREA 0/ 0 0/ 0 0/ 0 5/ 2 -DRIED YELLOW MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 2/ 2 -DRIED YELLOW MATERIAL ANOGENITAL AREA 0/ 0 0/ 0 0/ 0 4/ 2 -DRIED YELLOW MATERIAL HINDLIMB(S) 0/ 0 0/ 0 0/ 0 2/ 1 -DRIED RED MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 2/ 2 -DRIED RED MATERIAL FORELIMB(S) 0/ 0 0/ 0 0/ 0 5/ 2 -DRIED BROWN MATERIAL VENTRAL TRUNK 0/ 0 0/ 0 0/ 0 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PCSUv4.07 03/19/2008 R:03/19/200865of435TABLE 10 (END OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 5

----------------------------------------------------------------------------------------------------------------------------------- NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM66of435TABLE 10 (END OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: DAY 000 TO DAY 004 GROUP: 5

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

ORAL/DENTAL -DRIED RED MATERIAL AROUND MOUTH 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 5- 1800 PPM PCSUv4.07 03/19/2008 R:03/24/200867of435TABLE 11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY -12 MEAN 211. 217. 215. 214. % DIFFERENCE 2.8 1.9 1.4 S.D. 12.5 11.5 9.7 7.7 S.E. 5.6 5.2 4.3 3.4 N 5 5 5 5

-8 MEAN 252. 255. 253. 253. % DIFFERENCE 1.2 0.4 0.4 S.D. 12.3 13.8 11.6 12.9 S.E. 5.5 6.2 5.2 5.8 N 5 5 5 5

-2 MEAN 309. 306. 307. 309. % DIFFERENCE -1.0 -0.6 0.0 S.D. 18.2 16.9 15.3 20.7 S.E. 8.1 7.5 6.8 9.3 N 5 5 5 5

0 MEAN 330. 321. 327. 327. % DIFFERENCE -2.7 -0.9 -0.9 S.D. 21.6 19.5 13.5 26.2 S.E. 9.7 8.7 6.0 11.7 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group68of435TABLE 11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY 2 MEAN 338. 321. 320. 275.** % DIFFERENCE -5.0 -5.3 -18.6 S.D. 23.0 22.3 16.6 20.2 S.E. 10.3 10.0 7.4 10.1 N 5 5 5 4

4 MEAN 344. 325. 321. 317. % DIFFERENCE -5.5 -6.7 -7.8 S.D. 25.8 22.1 18.3 22.9 S.E. 11.6 9.9 8.2 11.5 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection69of435TABLE 11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY -12 MEAN 169. 172. 170. 170. % DIFFERENCE 1.8 0.6 0.6 S.D. 7.0 6.7 11.0 5.2 S.E. 3.1 3.0 4.9 2.3 N 5 5 5 5

-8 MEAN 186. 188. 187. 186. % DIFFERENCE 1.1 0.5 0.0 S.D. 8.3 6.1 13.2 6.6 S.E. 3.7 2.7 5.9 2.9 N 5 5 5 5

-2 MEAN 209. 208. 211. 210. % DIFFERENCE -0.5 1.0 0.5 S.D. 9.7 6.7 14.0 11.1 S.E. 4.3 3.0 6.2 5.0 N 5 5 5 5

0 MEAN 219. 214. 215. 217. % DIFFERENCE -2.3 -1.8 -0.9 S.D. 9.9 8.5 14.5 15.8 S.E. 4.4 3.8 6.5 7.0 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group70of435TABLE 11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY 2 MEAN 219. 215. 215. 192.** % DIFFERENCE -1.8 -1.8 -12.3 S.D. 11.5 8.4 16.0 10.3 S.E. 5.2 3.8 7.2 4.6 N 5 5 5 5

4 MEAN 224. 220. 219. 215. % DIFFERENCE -1.8 -2.2 -4.0 S.D. 9.6 6.5 13.9 11.1 S.E. 4.3 2.9 6.2 5.0 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection PBFSTv5.28 03/19/2008 R:05/08/200871of435TABLE 12 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 MEAN 346. S.D. 20.6 S.E. 9.2 N 5

2 MEAN 341. S.D. 20.5 S.E. 9.2 N 5

4 MEAN 346. S.D. 19.3 S.E. 8.6 N 5

-----------------------------------------------------------------------------------------------------------------------------------72of435TABLE 12 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF BODY WEIGHTS [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 MEAN 213. S.D. 18.9 S.E. 8.5 N 5

2 MEAN 214. S.D. 15.2 S.E. 6.8 N 5

4 MEAN 216. S.D. 15.3 S.E. 6.8 N 5

----------------------------------------------------------------------------------------------------------------------------------- PBFSTv5.28 03/25/200873of435TABLE 13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY -12 TO -8 MEAN 40. 38. 38. 39. S.D. 1.5 3.9 2.8 5.8 S.E. 0.7 1.7 1.2 2.6 N 5 5 5 5

-8 TO -2 MEAN 57. 51. 54. 56. S.D. 7.9 5.1 3.9 7.9 S.E. 3.5 2.3 1.7 3.5 N 5 5 5 5

-2 TO 0 MEAN 22. 15. 20. 18. S.D. 4.9 4.8 2.9 6.2 S.E. 2.2 2.2 1.3 2.8 N 5 5 5 5

0 TO 2 MEAN 8. 0. -7.** -44.** S.D. 1.5 5.8 5.7 11.6 S.E. 0.7 2.6 2.5 5.8 N 5 5 5 4

2 TO 4 MEAN 7. 4. 1. 42.** S.D. 3.4 1.6 4.5 3.6 S.E. 1.5 0.7 2.0 1.8 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection74of435TABLE 13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY -12 TO -8 MEAN 17. 16. 17. 16. S.D. 1.6 4.1 3.1 2.6 S.E. 0.7 1.8 1.4 1.2 N 5 5 5 5

-8 TO -2 MEAN 22. 19. 24. 23. S.D. 3.8 4.7 5.5 7.4 S.E. 1.7 2.1 2.5 3.3 N 5 5 5 5

-2 TO 0 MEAN 10. 6. 4. 8. S.D. 6.2 3.8 5.9 6.1 S.E. 2.8 1.7 2.6 2.7 N 5 5 5 5

0 TO 2 MEAN 0. 1. 0. -26.** S.D. 8.3 5.1 3.8 14.9 S.E. 3.7 2.3 1.7 6.7 N 5 5 5 5

2 TO 4 MEAN 5. 4. 4. 24.** S.D. 5.0 3.4 3.7 7.4 S.E. 2.2 1.5 1.7 3.3 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection PBFSTv5.28 03/19/2008 R:05/08/200875of435TABLE 14 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN -5. S.D. 3.3 S.E. 1.5 N 5

2 TO 4 MEAN 6. S.D. 4.2 S.E. 1.9 N 5

-----------------------------------------------------------------------------------------------------------------------------------76of435TABLE 14 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN 1. S.D. 5.5 S.E. 2.5 N 5

2 TO 4 MEAN 2. S.D. 4.7 S.E. 2.1 N 5

----------------------------------------------------------------------------------------------------------------------------------- PBFSTv5.28 03/19/200877of435TABLE 15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CUMULATIVE BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN 8. 0. -7.** -44.** S.D. 1.5 5.8 5.7 11.6 S.E. 0.7 2.6 2.5 5.8 N 5 5 5 4

0 TO 4 MEAN 14. 4. -6.** -2.* S.D. 4.8 6.2 9.9 13.1 S.E. 2.2 2.8 4.4 6.5 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection78of435TABLE 15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CUMULATIVE BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM-A

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN 0. 1. 0. -26.** S.D. 8.3 5.1 3.8 14.9 S.E. 3.7 2.3 1.7 6.7 N 5 5 5 5

0 TO 4 MEAN 5. 6. 4. -2. S.D. 3.6 3.4 3.7 7.6 S.E. 1.6 1.5 1.7 3.4 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test A = 5000 ppm group animals were fasted from study day 1-2 for possible blood collection PBFSTv5.28 03/19/2008 R:05/08/200879of435TABLE 16 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CUMULATIVE BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN -5. S.D. 3.3 S.E. 1.5 N 5

0 TO 4 MEAN 1. S.D. 3.2 S.E. 1.4 N 5

-----------------------------------------------------------------------------------------------------------------------------------80of435TABLE 16 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CUMULATIVE BODY WEIGHT CHANGES [G]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 2 MEAN 1. S.D. 5.5 S.E. 2.5 N 5

0 TO 4 MEAN 3. S.D. 6.0 S.E. 2.7 N 5

----------------------------------------------------------------------------------------------------------------------------------- PBFSTv5.28 03/19/200881of435TABLE 17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF FOOD CONSUMPTION [G/ANIMAL/DAY]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY -8 TO -2 MEAN 27. 27. 27. 27. S.D. 1.6 3.0 1.1 2.4 S.E. 0.7 1.3 0.5 1.1 N 5 5 5 5

0 TO 4 MEAN 26. 23. 20.** NA S.D. 1.6 2.2 2.6 S.E. 0.7 1.0 1.2 N 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test NA = NOT APPLICABLE82of435TABLE 17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF FOOD CONSUMPTION [G/ANIMAL/DAY]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY -8 TO -2 MEAN 19. 19. 20. 19. S.D. 1.0 2.7 1.2 1.9 S.E. 0.4 1.2 0.6 0.9 N 5 5 4 5

0 TO 4 MEAN 17. 16. 15.* NA S.D. 1.1 0.8 1.9 S.E. 0.5 0.4 0.8 N 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test NA = NOT APPLICABLE PBFSTv5.28 03/19/200883of435TABLE 18 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF FOOD CONSUMPTION [G/ANIMAL/DAY]

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 4 MEAN 23. S.D. 1.5 S.E. 0.7 N 5

-----------------------------------------------------------------------------------------------------------------------------------84of435TABLE 18 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF FOOD CONSUMPTION [G/ANIMAL/DAY]

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- DAY 0 TO 4 MEAN 16. S.D. 1.2 S.E. 0.5 N 5

----------------------------------------------------------------------------------------------------------------------------------- PBFSTv5.28 03/19/200885of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- WHITE CELLS (thous/uL) DAY 5 MEAN 9.91 11.26 9.44 11.11 % DIFFERENCE 13.6 -4.7 12.1 S.D. 1.463 2.808 2.487 2.580 S.E. 0.654 1.256 1.112 1.290 N 5 5 5 4

RED CELLS (mil/uL) DAY 5 MEAN 7.85 8.11 8.13 7.87 % DIFFERENCE 3.3 3.6 0.3 S.D. 0.320 0.418 0.261 0.298 S.E. 0.143 0.187 0.117 0.149 N 5 5 5 4

HEMOGLOBIN (g/dL) DAY 5 MEAN 16.1 16.3 16.6 15.8 % DIFFERENCE 1.2 3.1 -1.9 S.D. 0.44 0.51 0.60 0.45 S.E. 0.20 0.23 0.27 0.23 N 5 5 5 4

HEMATOCRIT (%) DAY 5 MEAN 45.7 45.8 46.8 44.5 % DIFFERENCE 0.2 2.4 -2.6 S.D. 1.77 1.30 1.83 1.37 S.E. 0.79 0.58 0.82 0.68 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group86of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- MCV (fL) DAY 5 MEAN 58.3 56.5 57.5 56.5 % DIFFERENCE -3.1 -1.4 -3.1 S.D. 1.65 1.58 1.88 0.70 S.E. 0.74 0.71 0.84 0.35 N 5 5 5 4

MCH (pg) DAY 5 MEAN 20.5 20.1 20.4 20.1 % DIFFERENCE -2.0 -0.5 -2.0 S.D. 0.71 0.73 0.61 0.45 S.E. 0.32 0.33 0.27 0.23 N 5 5 5 4

MCHC (g/dL) DAY 5 MEAN 35.2 35.6 35.4 35.6 % DIFFERENCE 1.1 0.6 1.1 S.D. 0.50 0.54 0.38 0.36 S.E. 0.22 0.24 0.17 0.18 N 5 5 5 4

PLATELET (thous/uL) DAY 5 MEAN 1510. 1269. 1312. 1501. % DIFFERENCE -16.0 -13.1 -0.6 S.D. 145.9 210.0 363.1 147.6 S.E. 65.2 93.9 162.4 73.8 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group87of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- PROTIME (seconds) DAY 5 MEAN 13.8 13.3 13.3 13.0 % DIFFERENCE -3.6 -3.6 -5.8 S.D. 0.88 0.41 0.89 0.67 S.E. 0.44 0.18 0.40 0.33 N 4 5 5 4

APTT (seconds) DAY 5 MEAN 19.7 18.4 18.4 19.0 % DIFFERENCE -6.6 -6.6 -3.6 S.D. 0.75 1.34 0.95 0.75 S.E. 0.37 0.60 0.42 0.38 N 4 5 5 4

RETICULOCYTE (%) DAY 5 MEAN 2.8 2.3 2.0** 2.8 % DIFFERENCE -17.9 -28.6 0.0 S.D. 0.38 0.33 0.47 0.16 S.E. 0.17 0.15 0.21 0.08 N 5 5 5 4

RETIC ABSOLUTE (thous/uL) DAY 5 MEAN 226.4 186.6 167.0* 223.0 % DIFFERENCE -17.6 -26.2 -1.5 S.D. 37.39 21.12 34.00 21.08 S.E. 16.72 9.44 15.21 10.54 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test ** = Significantly different from the control group at 0.01 using Dunnett’s test88of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- NEUTROPHIL (%) DAY 5 MEAN 11.8 11.5 10.5 14.7 % DIFFERENCE -2.5 -11.0 24.6 S.D. 2.03 5.42 3.91 4.29 S.E. 0.91 2.42 1.75 2.14 N 5 5 5 4

LYMPHOCYTE (%) DAY 5 MEAN 84.3 85.0 85.9 81.6 % DIFFERENCE 0.8 1.9 -3.2 S.D. 1.88 6.05 4.49 4.31 S.E. 0.84 2.70 2.01 2.15 N 5 5 5 4

MONOCYTE (%) DAY 5 MEAN 1.8 1.6 2.0 2.0 % DIFFERENCE -11.1 11.1 11.1 S.D. 0.25 0.36 0.66 0.34 S.E. 0.11 0.16 0.30 0.17 N 5 5 5 4

EOSINOPHIL (%) DAY 5 MEAN 1.1 0.8 0.6 0.8 % DIFFERENCE -27.3 -45.5 -27.3 S.D. 0.34 0.37 0.16 0.44 S.E. 0.15 0.17 0.07 0.22 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group89of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- BASOPHIL (%) DAY 5 MEAN 0.3 0.4** 0.3 0.3 % DIFFERENCE 33.3 0.0 0.0 S.D. 0.05 0.07 0.07 0.05 S.E. 0.02 0.03 0.03 0.02 N 5 5 5 4

LG UNSTAIN CELL (%) DAY 5 MEAN 0.7 0.7 0.7 0.7 % DIFFERENCE 0.0 0.0 0.0 S.D. 0.19 0.11 0.16 0.22 S.E. 0.09 0.05 0.07 0.11 N 5 5 5 4

NEU ABSOLUTE (thous/uL) DAY 5 MEAN 1.16 1.20 0.96 1.70 % DIFFERENCE 3.4 -17.2 46.6 S.D. 0.189 0.288 0.295 0.882 S.E. 0.084 0.129 0.132 0.441 N 5 5 5 4

LYMPH ABSOLUTE (thous/uL) DAY 5 MEAN 8.37 9.69 8.15 9.00 % DIFFERENCE 15.8 -2.6 7.5 S.D. 1.352 2.944 2.420 1.670 S.E. 0.605 1.317 1.082 0.835 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test90of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- MONO ABSOLUTE (thous/uL) DAY 5 MEAN 0.18 0.18 0.18 0.22 % DIFFERENCE 0.0 0.0 22.2 S.D. 0.028 0.056 0.050 0.021 S.E. 0.012 0.025 0.022 0.010 N 5 5 5 4

EOS ABSOLUTE (thous/uL) DAY 5 MEAN 0.11 0.08 0.05 0.09 % DIFFERENCE -27.3 -54.5 -18.2 S.D. 0.044 0.028 0.015 0.067 S.E. 0.020 0.013 0.007 0.033 N 5 5 5 4

BASO ABSOLUTE (thous/uL) DAY 5 MEAN 0.03 0.04 0.03 0.03 % DIFFERENCE 33.3 0.0 0.0 S.D. 0.008 0.011 0.009 0.013 S.E. 0.004 0.005 0.004 0.006 N 5 5 5 4

LUC ABSOLUTE (thous/uL) DAY 5 MEAN 0.07 0.07 0.06 0.08 % DIFFERENCE 0.0 -14.3 14.3 S.D. 0.018 0.013 0.015 0.024 S.E. 0.008 0.006 0.007 0.012 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group91of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- WHITE CELLS (thous/uL) DAY 5 MEAN 7.56 7.11 7.02 6.82 % DIFFERENCE -6.0 -7.1 -9.8 S.D. 2.568 2.286 0.585 1.137 S.E. 1.148 1.022 0.262 0.509 N 5 5 5 5

RED CELLS (mil/uL) DAY 5 MEAN 8.02 7.98 7.76 7.70 % DIFFERENCE -0.5 -3.2 -4.0 S.D. 0.229 0.381 0.210 0.398 S.E. 0.102 0.170 0.094 0.178 N 5 5 5 5

HEMOGLOBIN (g/dL) DAY 5 MEAN 16.1 15.8 16.0 15.4 % DIFFERENCE -1.9 -0.6 -4.3 S.D. 0.56 0.36 0.45 0.61 S.E. 0.25 0.16 0.20 0.27 N 5 5 5 5

HEMATOCRIT (%) DAY 5 MEAN 43.7 42.9 43.3 42.2 % DIFFERENCE -1.8 -0.9 -3.4 S.D. 1.52 1.78 0.92 1.99 S.E. 0.68 0.80 0.41 0.89 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group92of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- MCV (fL) DAY 5 MEAN 54.5 53.8 55.8 54.9 % DIFFERENCE -1.3 2.4 0.7 S.D. 1.33 1.29 1.26 0.43 S.E. 0.59 0.58 0.56 0.19 N 5 5 5 5

MCH (pg) DAY 5 MEAN 20.1 19.8 20.6 20.0 % DIFFERENCE -1.5 2.5 -0.5 S.D. 0.35 0.72 0.71 0.44 S.E. 0.16 0.32 0.32 0.20 N 5 5 5 5

MCHC (g/dL) DAY 5 MEAN 36.9 36.8 36.8 36.5 % DIFFERENCE -0.3 -0.3 -1.1 S.D. 0.41 0.74 0.78 0.60 S.E. 0.18 0.33 0.35 0.27 N 5 5 5 5

PLATELET (thous/uL) DAY 5 MEAN 1391. 1363. 1496. 1423. % DIFFERENCE -2.0 7.5 2.3 S.D. 116.8 148.5 189.5 250.3 S.E. 52.2 66.4 84.7 111.9 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group93of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 9 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- PROTIME (seconds) DAY 5 MEAN 11.8 12.2 12.5 12.1 % DIFFERENCE 3.4 5.9 2.5 S.D. 0.79 0.43 0.71 0.71 S.E. 0.35 0.19 0.32 0.32 N 5 5 5 5

APTT (seconds) DAY 5 MEAN 15.2 17.4 17.1 16.2 % DIFFERENCE 14.5 12.5 6.6 S.D. 3.47 0.82 1.47 0.80 S.E. 1.55 0.37 0.66 0.36 N 5 5 5 5

RETICULOCYTE (%) DAY 5 MEAN 2.3 1.9 2.1 2.7 % DIFFERENCE -17.4 -8.7 17.4 S.D. 0.25 0.35 0.19 0.24 S.E. 0.11 0.16 0.08 0.11 N 5 5 5 5

RETIC ABSOLUTE (thous/uL) DAY 5 MEAN 185.7 150.5* 162.9 202.7 % DIFFERENCE -19.0 -12.3 9.2 S.D. 18.14 23.45 10.56 18.84 S.E. 8.11 10.49 4.72 8.43 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test94of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 10 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- NEUTROPHIL (%) DAY 5 MEAN 15.4 10.4 10.9 15.8 % DIFFERENCE -32.5 -29.2 2.6 S.D. 9.06 2.13 2.61 1.82 S.E. 4.05 0.95 1.17 0.81 N 5 5 5 5

LYMPHOCYTE (%) DAY 5 MEAN 79.1 86.6 85.8 80.9 % DIFFERENCE 9.5 8.5 2.3 S.D. 12.54 2.47 2.72 1.87 S.E. 5.61 1.10 1.22 0.84 N 5 5 5 5

MONOCYTE (%) DAY 5 MEAN 3.7 1.2 1.4 1.8 % DIFFERENCE -67.6 -62.2 -51.4 S.D. 4.36 0.46 0.26 0.24 S.E. 1.95 0.21 0.12 0.11 N 5 5 5 5

EOSINOPHIL (%) DAY 5 MEAN 0.8 0.9 1.2 0.9 % DIFFERENCE 12.5 50.0 12.5 S.D. 0.31 0.19 0.48 0.27 S.E. 0.14 0.08 0.22 0.12 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group95of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 11 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- BASOPHIL (%) DAY 5 MEAN 0.3 0.3 0.2 0.2 % DIFFERENCE 0.0 -33.3 -33.3 S.D. 0.08 0.09 0.08 0.08 S.E. 0.04 0.04 0.04 0.04 N 5 5 5 5

LG UNSTAIN CELL (%) DAY 5 MEAN 0.7 0.6 0.5 0.5 % DIFFERENCE -14.3 -28.6 -28.6 S.D. 0.12 0.18 0.24 0.07 S.E. 0.05 0.08 0.11 0.03 N 5 5 5 5

NEU ABSOLUTE (thous/uL) DAY 5 MEAN 1.01 0.75 0.75 1.07 % DIFFERENCE -25.7 -25.7 5.9 S.D. 0.364 0.330 0.150 0.208 S.E. 0.163 0.148 0.067 0.093 N 5 5 5 5

LYMPH ABSOLUTE (thous/uL) DAY 5 MEAN 6.21 6.14 6.03 5.52 % DIFFERENCE -1.1 -2.9 -11.1 S.D. 2.671 1.890 0.651 0.942 S.E. 1.195 0.845 0.291 0.421 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group96of435TABLE 19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 12 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- MONO ABSOLUTE (thous/uL) DAY 5 MEAN 0.20 0.09 0.10 0.12 % DIFFERENCE -55.0 -50.0 -40.0 S.D. 0.134 0.064 0.023 0.029 S.E. 0.060 0.029 0.010 0.013 N 5 5 5 5

EOS ABSOLUTE (thous/uL) DAY 5 MEAN 0.06 0.06 0.08 0.06 % DIFFERENCE 0.0 33.3 0.0 S.D. 0.031 0.021 0.031 0.021 S.E. 0.014 0.009 0.014 0.009 N 5 5 5 5

BASO ABSOLUTE (thous/uL) DAY 5 MEAN 0.03 0.02 0.01 0.01 % DIFFERENCE -33.3 -66.7 -66.7 S.D. 0.011 0.008 0.005 0.011 S.E. 0.005 0.004 0.002 0.005 N 5 5 5 5

LUC ABSOLUTE (thous/uL) DAY 5 MEAN 0.05 0.04 0.04 0.03 % DIFFERENCE -20.0 -20.0 -40.0 S.D. 0.024 0.029 0.019 0.005 S.E. 0.011 0.013 0.008 0.002 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group PCPSv5.24 03/24/200897of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- WHITE CELLS (thous/uL) DAY 5 MEAN 9.67 S.D. 1.649 S.E. 0.825 N 4

RED CELLS (mil/uL) DAY 5 MEAN 8.12 S.D. 0.192 S.E. 0.096 N 4

HEMOGLOBIN (g/dL) DAY 5 MEAN 16.9 S.D. 0.32 S.E. 0.16 N 4

HEMATOCRIT (%) DAY 5 MEAN 47.4 S.D. 0.94 S.E. 0.47 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------98of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- MCV (fL) DAY 5 MEAN 58.4 S.D. 0.61 S.E. 0.31 N 4

MCH (pg) DAY 5 MEAN 20.8 S.D. 0.43 S.E. 0.22 N 4

MCHC (g/dL) DAY 5 MEAN 35.7 S.D. 0.50 S.E. 0.25 N 4

PLATELET (thous/uL) DAY 5 MEAN 1235. S.D. 257.4 S.E. 128.7 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------99of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- PROTIME (seconds) DAY 5 MEAN 13.3 S.D. 1.06 S.E. 0.48 N 5

APTT (seconds) DAY 5 MEAN 18.1 S.D. 1.78 S.E. 0.80 N 5

RETICULOCYTE (%) DAY 5 MEAN 1.9 S.D. 0.50 S.E. 0.25 N 4

RETIC ABSOLUTE (thous/uL) DAY 5 MEAN 156.9 S.D. 38.72 S.E. 19.36 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------100of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- NEUTROPHIL (%) DAY 5 MEAN 10.0 S.D. 1.90 S.E. 0.95 N 4

LYMPHOCYTE (%) DAY 5 MEAN 85.6 S.D. 1.68 S.E. 0.84 N 4

MONOCYTE (%) DAY 5 MEAN 2.3 S.D. 0.42 S.E. 0.21 N 4

EOSINOPHIL (%) DAY 5 MEAN 1.2 S.D. 0.58 S.E. 0.29 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------101of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- BASOPHIL (%) DAY 5 MEAN 0.4 S.D. 0.13 S.E. 0.06 N 4

LG UNSTAIN CELL (%) DAY 5 MEAN 0.8 S.D. 0.24 S.E. 0.12 N 4

NEU ABSOLUTE (thous/uL) DAY 5 MEAN 0.94 S.D. 0.068 S.E. 0.034 N 4

LYMPH ABSOLUTE (thous/uL) DAY 5 MEAN 8.29 S.D. 1.534 S.E. 0.767 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------102of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- MONO ABSOLUTE (thous/uL) DAY 5 MEAN 0.22 S.D. 0.075 S.E. 0.038 N 4

EOS ABSOLUTE (thous/uL) DAY 5 MEAN 0.11 S.D. 0.055 S.E. 0.027 N 4

BASO ABSOLUTE (thous/uL) DAY 5 MEAN 0.04 S.D. 0.017 S.E. 0.009 N 4

LUC ABSOLUTE (thous/uL) DAY 5 MEAN 0.07 S.D. 0.032 S.E. 0.016 N 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------103of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 7 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- WHITE CELLS (thous/uL) DAY 5 MEAN 8.45 S.D. 0.335 S.E. 0.150 N 5

RED CELLS (mil/uL) DAY 5 MEAN 8.12 S.D. 0.251 S.E. 0.112 N 5

HEMOGLOBIN (g/dL) DAY 5 MEAN 16.3 S.D. 0.59 S.E. 0.27 N 5

HEMATOCRIT (%) DAY 5 MEAN 44.7 S.D. 2.23 S.E. 1.00 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------104of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 8 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- MCV (fL) DAY 5 MEAN 55.0 S.D. 1.88 S.E. 0.84 N 5

MCH (pg) DAY 5 MEAN 20.1 S.D. 0.57 S.E. 0.26 N 5

MCHC (g/dL) DAY 5 MEAN 36.6 S.D. 0.63 S.E. 0.28 N 5

PLATELET (thous/uL) DAY 5 MEAN 1413. S.D. 187.1 S.E. 83.7 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------105of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 9 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- PROTIME (seconds) DAY 5 MEAN 12.3 S.D. 0.44 S.E. 0.22 N 4

APTT (seconds) DAY 5 MEAN 17.2 S.D. 0.46 S.E. 0.23 N 4

RETICULOCYTE (%) DAY 5 MEAN 1.9 S.D. 0.40 S.E. 0.18 N 5

RETIC ABSOLUTE (thous/uL) DAY 5 MEAN 151.9 S.D. 35.13 S.E. 15.71 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------106of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 10 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- NEUTROPHIL (%) DAY 5 MEAN 9.8 S.D. 4.10 S.E. 1.83 N 5

LYMPHOCYTE (%) DAY 5 MEAN 86.3 S.D. 4.88 S.E. 2.18 N 5

MONOCYTE (%) DAY 5 MEAN 2.1 S.D. 0.53 S.E. 0.24 N 5

EOSINOPHIL (%) DAY 5 MEAN 1.0 S.D. 0.42 S.E. 0.19 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------107of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 11 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- BASOPHIL (%) DAY 5 MEAN 0.2 S.D. 0.08 S.E. 0.04 N 5

LG UNSTAIN CELL (%) DAY 5 MEAN 0.5 S.D. 0.11 S.E. 0.05 N 5

NEU ABSOLUTE (thous/uL) DAY 5 MEAN 0.84 S.D. 0.386 S.E. 0.173 N 5

LYMPH ABSOLUTE (thous/uL) DAY 5 MEAN 7.28 S.D. 0.235 S.E. 0.105 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

-----------------------------------------------------------------------------------------------------------------------------------108of435TABLE 20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 12 SUMMARY OF HEMATOLOGY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- MONO ABSOLUTE (thous/uL) DAY 5 MEAN 0.18 S.D. 0.054 S.E. 0.024 N 5

EOS ABSOLUTE (thous/uL) DAY 5 MEAN 0.09 S.D. 0.035 S.E. 0.016 N 5

BASO ABSOLUTE (thous/uL) DAY 5 MEAN 0.02 S.D. 0.008 S.E. 0.004 N 5

LUC ABSOLUTE (thous/uL) DAY 5 MEAN 0.05 S.D. 0.009 S.E. 0.004 N 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER

----------------------------------------------------------------------------------------------------------------------------------- PCPSv5.24 03/25/2008109of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALBUMIN (g/dL) DAY 5 MEAN 4.3 4.3 4.4 4.3 % DIFFERENCE 0.0 2.3 0.0 S.D. 0.05 0.10 0.19 0.37 S.E. 0.02 0.04 0.09 0.18 N 5 5 5 4

TOTAL PROTEIN (g/dL) DAY 5 MEAN 6.3 6.3 6.5 6.3 % DIFFERENCE 0.0 3.2 0.0 S.D. 0.22 0.17 0.25 0.30 S.E. 0.10 0.07 0.11 0.15 N 5 5 5 4

GLOBULIN (g/dL) DAY 5 MEAN 2.0 2.0 2.0 2.1 % DIFFERENCE 0.0 0.0 5.0 S.D. 0.29 0.15 0.18 0.17 S.E. 0.13 0.07 0.08 0.09 N 5 5 5 4

A/G RATIO DAY 5 MEAN 2.22 2.18 2.23 2.08 % DIFFERENCE -1.8 0.5 -6.3 S.D. 0.388 0.186 0.209 0.261 S.E. 0.173 0.083 0.093 0.130 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group110of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- TOTAL BILI (mg/dL) DAY 5 MEAN 0.09 0.09 0.09 0.11 % DIFFERENCE 0.0 0.0 22.2 S.D. 0.019 0.021 0.013 0.036 S.E. 0.009 0.009 0.006 0.018 N 5 5 5 4

UREA NITROGEN (mg/dL) DAY 5 MEAN 11.2 11.8 11.2 10.0 % DIFFERENCE 5.4 0.0 -10.7 S.D. 1.80 1.10 1.06 1.17 S.E. 0.81 0.49 0.47 0.58 N 5 5 5 4

CREATININE (mg/dL) DAY 5 MEAN 0.2 0.2 0.2 0.2 % DIFFERENCE 0.0 0.0 0.0 S.D. 0.05 0.05 0.04 0.05 S.E. 0.02 0.02 0.02 0.03 N 5 5 5 4

ALKALINEPHOS’TSE (U/L) DAY 5 MEAN 260. 222. 219. 231. % DIFFERENCE -14.6 -15.8 -11.2 S.D. 61.8 82.5 38.0 45.4 S.E. 27.6 36.9 17.0 22.7 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group111of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALANINE TRANSFER (U/L) DAY 5 MEAN 34. 35. 50. 38. % DIFFERENCE 2.9 47.1 11.8 S.D. 5.9 4.8 20.3 5.9 S.E. 2.6 2.1 9.1 2.9 N 5 5 5 4

ASPARTATTRANSFER (U/L) DAY 5 MEAN 87. 94. 100. 88. % DIFFERENCE 8.0 14.9 1.1 S.D. 9.9 6.0 45.4 21.0 S.E. 4.4 2.7 20.3 10.5 N 5 5 5 4

GLUCOSE (mg/dL) DAY 5 MEAN 123. 105.* 118. 108. % DIFFERENCE -14.6 -4.1 -12.2 S.D. 8.9 9.9 12.5 5.0 S.E. 4.0 4.4 5.6 2.5 N 5 5 5 4

CHOLESTEROL (mg/dL) DAY 5 MEAN 54. 63. 68. 62. % DIFFERENCE 16.7 25.9 14.8 S.D. 7.0 13.1 15.8 9.4 S.E. 3.2 5.9 7.1 4.7 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test112of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- CALCIUM (mg/dL) DAY 5 MEAN 10.8 11.0 11.0 10.8 % DIFFERENCE 1.9 1.9 0.0 S.D. 0.12 0.18 0.23 0.24 S.E. 0.05 0.08 0.10 0.12 N 5 5 5 4

CHLORIDE (mEq/L) DAY 5 MEAN 103. 103. 104. 103. % DIFFERENCE 0.0 1.0 0.0 S.D. 1.1 0.8 1.1 0.8 S.E. 0.5 0.4 0.5 0.4 N 5 5 5 4

PHOSPHORUS (mg/dL) DAY 5 MEAN 9.4 9.1 9.0 9.0 % DIFFERENCE -3.2 -4.3 -4.3 S.D. 0.46 0.47 0.18 0.38 S.E. 0.20 0.21 0.08 0.19 N 5 5 5 4

POTASSIUM (mEq/L) DAY 5 MEAN 4.71 4.77 4.91 4.69 % DIFFERENCE 1.3 4.2 -0.4 S.D. 0.325 0.269 0.320 0.110 S.E. 0.145 0.120 0.143 0.055 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group113of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- SODIUM (mEq/L) DAY 5 MEAN 146. 146. 146. 146. % DIFFERENCE 0.0 0.0 0.0 S.D. 0.4 0.8 1.3 0.6 S.E. 0.2 0.4 0.6 0.3 N 5 5 5 4

TRIGLYCERIDE (mg/dL) DAY 5 MEAN 60. 47. 54. 42. % DIFFERENCE -21.7 -10.0 -30.0 S.D. 26.6 5.5 17.9 5.9 S.E. 11.9 2.5 8.0 3.0 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group114of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALBUMIN (g/dL) DAY 5 MEAN 4.6 4.6 4.6 4.3 % DIFFERENCE 0.0 0.0 -6.5 S.D. 0.16 0.28 0.15 0.21 S.E. 0.07 0.12 0.07 0.09 N 5 5 5 5

TOTAL PROTEIN (g/dL) DAY 5 MEAN 6.9 6.8 6.7 6.4** % DIFFERENCE -1.4 -2.9 -7.2 S.D. 0.28 0.18 0.10 0.38 S.E. 0.12 0.08 0.04 0.17 N 5 5 5 5

GLOBULIN (g/dL) DAY 5 MEAN 2.3 2.3 2.1 2.1 % DIFFERENCE 0.0 -8.7 -8.7 S.D. 0.25 0.17 0.08 0.22 S.E. 0.11 0.07 0.04 0.10 N 5 5 5 5

A/G RATIO DAY 5 MEAN 2.01 2.03 2.16 2.04 % DIFFERENCE 1.0 7.5 1.5 S.D. 0.228 0.293 0.162 0.147 S.E. 0.102 0.131 0.073 0.066 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- ** = Significantly different from the control group at 0.01 using Dunnett’s test115of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- TOTAL BILI (mg/dL) DAY 5 MEAN 0.09 0.08 0.10 0.09 % DIFFERENCE -11.1 11.1 0.0 S.D. 0.030 0.019 0.023 0.030 S.E. 0.013 0.009 0.010 0.014 N 5 5 5 5

UREA NITROGEN (mg/dL) DAY 5 MEAN 13.6 13.9 10.8* 13.8 % DIFFERENCE 2.2 -20.6 1.5 S.D. 0.75 0.84 2.12 1.70 S.E. 0.33 0.37 0.95 0.76 N 5 5 5 5

CREATININE (mg/dL) DAY 5 MEAN 0.3 0.3 0.2 0.2 % DIFFERENCE 0.0 -33.3 -33.3 S.D. 0.04 0.05 0.05 0.04 S.E. 0.02 0.02 0.02 0.02 N 5 5 5 5

ALKALINEPHOS’TSE (U/L) DAY 5 MEAN 117. 119. 143. 107. % DIFFERENCE 1.7 22.2 -8.5 S.D. 28.9 9.7 17.5 16.2 S.E. 12.9 4.3 7.8 7.2 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- * = Significantly different from the control group at 0.05 using Dunnett’s test116of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALANINE TRANSFER (U/L) DAY 5 MEAN 32. 30. 41. 33. % DIFFERENCE -6.3 28.1 3.1 S.D. 6.5 3.6 15.3 8.1 S.E. 2.9 1.6 6.8 3.6 N 5 5 5 5

ASPARTATTRANSFER (U/L) DAY 5 MEAN 84. 81. 84. 92. % DIFFERENCE -3.6 0.0 9.5 S.D. 11.8 10.2 12.5 18.8 S.E. 5.3 4.5 5.6 8.4 N 5 5 5 5

GLUCOSE (mg/dL) DAY 5 MEAN 112. 113. 121. 110. % DIFFERENCE 0.9 8.0 -1.8 S.D. 6.5 8.9 12.7 3.7 S.E. 2.9 4.0 5.7 1.7 N 5 5 5 5

CHOLESTEROL (mg/dL) DAY 5 MEAN 78. 88. 78. 70. % DIFFERENCE 12.8 0.0 -10.3 S.D. 17.1 26.1 10.8 10.8 S.E. 7.7 11.7 4.8 4.8 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group117of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 9 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- CALCIUM (mg/dL) DAY 5 MEAN 11.0 11.0 11.0 10.6 % DIFFERENCE 0.0 0.0 -3.6 S.D. 0.44 0.13 0.40 0.29 S.E. 0.20 0.06 0.18 0.13 N 5 5 5 5

CHLORIDE (mEq/L) DAY 5 MEAN 102. 104. 103. 103. % DIFFERENCE 2.0 1.0 1.0 S.D. 1.9 1.1 1.8 1.1 S.E. 0.9 0.5 0.8 0.5 N 5 5 5 5

PHOSPHORUS (mg/dL) DAY 5 MEAN 8.0 7.9 8.2 8.5 % DIFFERENCE -1.3 2.5 6.3 S.D. 1.03 0.30 0.65 0.39 S.E. 0.46 0.14 0.29 0.17 N 5 5 5 5

POTASSIUM (mEq/L) DAY 5 MEAN 4.76 4.69 5.00 4.88 % DIFFERENCE -1.5 5.0 2.5 S.D. 0.419 0.264 0.137 0.346 S.E. 0.187 0.118 0.061 0.155 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group118of435TABLE 21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 10 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- SODIUM (mEq/L) DAY 5 MEAN 146. 145. 145. 145. % DIFFERENCE -0.7 -0.7 -0.7 S.D. 1.1 1.1 2.3 1.5 S.E. 0.5 0.5 1.0 0.7 N 5 5 5 5

TRIGLYCERIDE (mg/dL) DAY 5 MEAN 43. 43. 37. 43. % DIFFERENCE 0.0 -14.0 0.0 S.D. 11.2 15.8 4.3 6.7 S.E. 5.0 7.1 1.9 3.0 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group PCPSv5.24 03/24/2008119of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALBUMIN (g/dL) DAY 5 MEAN 4.4 S.D. 0.11 S.E. 0.05 N 5

TOTAL PROTEIN (g/dL) DAY 5 MEAN 6.6 S.D. 0.22 S.E. 0.10 N 5

GLOBULIN (g/dL) DAY 5 MEAN 2.2 S.D. 0.10 S.E. 0.04 N 5

A/G RATIO DAY 5 MEAN 2.02 S.D. 0.068 S.E. 0.031 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------120of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- TOTAL BILI (mg/dL) DAY 5 MEAN 0.10 S.D. 0.022 S.E. 0.010 N 5

UREA NITROGEN (mg/dL) DAY 5 MEAN 11.7 S.D. 1.70 S.E. 0.76 N 5

CREATININE (mg/dL) DAY 5 MEAN 0.2 S.D. 0.08 S.E. 0.04 N 5

ALKALINEPHOS’TSE (U/L) DAY 5 MEAN 184. S.D. 26.7 S.E. 11.9 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------121of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALANINE TRANSFER (U/L) DAY 5 MEAN 40. S.D. 11.6 S.E. 5.2 N 5

ASPARTATTRANSFER (U/L) DAY 5 MEAN 92. S.D. 17.1 S.E. 7.6 N 5

GLUCOSE (mg/dL) DAY 5 MEAN 132. S.D. 16.8 S.E. 7.5 N 5

CHOLESTEROL (mg/dL) DAY 5 MEAN 72. S.D. 7.6 S.E. 3.4 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------122of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- CALCIUM (mg/dL) DAY 5 MEAN 11.2 S.D. 0.44 S.E. 0.20 N 5

CHLORIDE (mEq/L) DAY 5 MEAN 100. S.D. 1.6 S.E. 0.7 N 5

PHOSPHORUS (mg/dL) DAY 5 MEAN 9.9 S.D. 0.79 S.E. 0.35 N 5

POTASSIUM (mEq/L) DAY 5 MEAN 5.40 S.D. 0.728 S.E. 0.326 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------123of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- MALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- SODIUM (mEq/L) DAY 5 MEAN 145. S.D. 2.3 S.E. 1.0 N 5

TRIGLYCERIDE (mg/dL) DAY 5 MEAN 52. S.D. 13.4 S.E. 6.0 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------124of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALBUMIN (g/dL) DAY 5 MEAN 4.5 S.D. 0.13 S.E. 0.06 N 5

TOTAL PROTEIN (g/dL) DAY 5 MEAN 6.4 S.D. 0.22 S.E. 0.10 N 5

GLOBULIN (g/dL) DAY 5 MEAN 1.9 S.D. 0.09 S.E. 0.04 N 5

A/G RATIO DAY 5 MEAN 2.37 S.D. 0.065 S.E. 0.029 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------125of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 7 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- TOTAL BILI (mg/dL) DAY 5 MEAN 0.12 S.D. 0.029 S.E. 0.013 N 5

UREA NITROGEN (mg/dL) DAY 5 MEAN 12.9 S.D. 1.50 S.E. 0.67 N 5

CREATININE (mg/dL) DAY 5 MEAN 0.2 S.D. 0.04 S.E. 0.02 N 5

ALKALINEPHOS’TSE (U/L) DAY 5 MEAN 115. S.D. 35.9 S.E. 16.0 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------126of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 8 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- ALANINE TRANSFER (U/L) DAY 5 MEAN 38. S.D. 10.6 S.E. 4.7 N 5

ASPARTATTRANSFER (U/L) DAY 5 MEAN 89. S.D. 13.3 S.E. 5.9 N 5

GLUCOSE (mg/dL) DAY 5 MEAN 117. S.D. 16.0 S.E. 7.2 N 5

CHOLESTEROL (mg/dL) DAY 5 MEAN 72. S.D. 20.0 S.E. 9.0 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------127of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 9 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- CALCIUM (mg/dL) DAY 5 MEAN 10.7 S.D. 0.27 S.E. 0.12 N 5

CHLORIDE (mEq/L) DAY 5 MEAN 100. S.D. 1.7 S.E. 0.8 N 5

PHOSPHORUS (mg/dL) DAY 5 MEAN 8.6 S.D. 0.59 S.E. 0.26 N 5

POTASSIUM (mEq/L) DAY 5 MEAN 4.80 S.D. 0.191 S.E. 0.085 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

-----------------------------------------------------------------------------------------------------------------------------------128of435TABLE 22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 10 SUMMARY OF SERUM CHEMISTRY VALUES

----------------------------------------------------------------------------------------------------------------------------------- FEMALES ANALYSIS GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- SODIUM (mEq/L) DAY 5 MEAN 143. S.D. 0.8 S.E. 0.4 N 5

TRIGLYCERIDE (mg/dL) DAY 5 MEAN 36. S.D. 12.0 S.E. 5.4 N 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER

----------------------------------------------------------------------------------------------------------------------------------- PCPSv5.24 03/25/2008129of435TABLE 23 (UNSCHEDULED DEATH) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF MACROSCOPIC FINDINGS

FOUND DEAD OR EUTHANIZED MORIBUND OR IN EXTREMIS

----------------------------------------------------------------------------------------------------------------------------------- ----- M A L E ----- GROUP: 1 2 3 4

----------------------------------------------------------------------------------------------------------------------------------- NUMBER OF ANIMALS IN DOSE GROUP 5 5 5 5 NUMBER OF ANIMALS EXAMINED 0 0 0 1

LUNGS -NOT FULLY COLLAPSED 0 0 0 1

SKIN -MATTING, RED 0 0 0 1

SPLEEN -AREA(S), WHITE 0 0 0 1

NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES 0 0 0 0

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PGRSI2v4.07 03/19/2008 R:04/04/2008130of435TABLE 24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF MACROSCOPIC FINDINGS

SCHEDULED NECROPSY

----------------------------------------------------------------------------------------------------------------------------------- ----- M A L E ----- GROUP: 1 2 3 4

----------------------------------------------------------------------------------------------------------------------------------- NUMBER OF ANIMALS IN DOSE GROUP 5 5 5 5 NUMBER OF ANIMALS EXAMINED 5 5 5 4

KIDNEYS -AREA(S), DEPRESSED 1 1 0 0

LUNGS -AREA(S), DARK RED 1 0 0 0

STOMACH -CYST(S) 0 0 1 0

TEETH -MALALIGNED 0 0 0 1

THYMUS -AREA(S), DARK RED 0 1 0 0

NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES 4 3 4 3

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM131of435TABLE 24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF MACROSCOPIC FINDINGS

SCHEDULED NECROPSY

----------------------------------------------------------------------------------------------------------------------------------- ----- F E M A L E ----- GROUP: 1 2 3 4

----------------------------------------------------------------------------------------------------------------------------------- NUMBER OF ANIMALS IN DOSE GROUP 5 5 5 5 NUMBER OF ANIMALS EXAMINED 5 5 5 5

SKIN -SCABBING 0 0 0 1

STOMACH -CONTENTS, YELLOW 0 0 0 1

UTERUS -CONTENTS, CLEAR FLUID 3 1 0 0

NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES 2 4 5 4

----------------------------------------------------------------------------------------------------------------------------------- 1- 0 PPM 2- 1250 PPM 3- 2500 PPM 4- 5000 PPM PGRSI2v4.07 03/19/2008132of435TABLE 25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF MACROSCOPIC FINDINGS

SCHEDULED NECROPSY

----------------------------------------------------------------------------------------------------------------------------------- ----- M A L E ----- GROUP: 1

----------------------------------------------------------------------------------------------------------------------------------- NUMBER OF ANIMALS IN DOSE GROUP 5 NUMBER OF ANIMALS EXAMINED 5

DUODENUM -CONTENTS, DARK RED 1

ILEUM -CONTENTS, DARK RED 1

PANCREAS -PALE 1

STOMACH -CONTENTS, DARK RED 1

NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES 4

----------------------------------------------------------------------------------------------------------------------------------- 1- 1800 PPM133of435TABLE 25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF MACROSCOPIC FINDINGS

SCHEDULED NECROPSY

----------------------------------------------------------------------------------------------------------------------------------- ----- F E M A L E ----- GROUP: 1

----------------------------------------------------------------------------------------------------------------------------------- NUMBER OF ANIMALS IN DOSE GROUP 5 NUMBER OF ANIMALS EXAMINED 5

UTERUS -CONTENTS, CLEAR FLUID 1

NO SIGNIFICANT CHANGES OBSERVED - ALL EXAMINED TISSUES 4

----------------------------------------------------------------------------------------------------------------------------------- 1- 1800 PPM PGRSI2v4.07 03/19/2008134of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- FINAL BODY WT (G) MEAN 309. 294. 289. 286. % DIFFERENCE -4.9 -6.5 -7.4 S.D. 21.9 18.6 16.3 20.8 S.E. 9.8 8.3 7.3 10.4 N 5 5 5 4

BRAIN (G) MEAN 2.00 1.96 1.93 1.97 % DIFFERENCE -2.0 -3.5 -1.5 S.D. 0.089 0.026 0.093 0.039 S.E. 0.040 0.012 0.041 0.020 N 5 5 5 4

BRAIN (G/100 G FINAL BODY WEIGHT) MEAN 0.648 0.668 0.670 0.693 % DIFFERENCE 3.1 3.4 6.9 S.D. 0.0250 0.0367 0.0359 0.0567 S.E. 0.0112 0.0164 0.0161 0.0284 N 5 5 5 4

KIDNEYS (G) MEAN 2.40 2.30 2.23 2.27 % DIFFERENCE -4.2 -7.1 -5.4 S.D. 0.248 0.211 0.050 0.182 S.E. 0.111 0.094 0.022 0.091 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group135of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- KIDNEYS (G/100 G FINAL BODY WEIGHT) MEAN 0.775 0.782 0.775 0.793 % DIFFERENCE 0.9 0.0 2.3 S.D. 0.0382 0.0373 0.0471 0.0266 S.E. 0.0171 0.0167 0.0211 0.0133 N 5 5 5 4

KIDNEYS (G/100 G BRAIN) MEAN 119.783 117.460 115.848 115.090 % DIFFERENCE -1.9 -3.3 -3.9 S.D. 7.3943 9.3517 6.1710 10.8478 S.E. 3.3069 4.1822 2.7598 5.4239 N 5 5 5 4

LIVER (G) MEAN 9.60 8.69 8.40 8.32 % DIFFERENCE -9.5 -12.5 -13.3 S.D. 1.074 1.107 0.691 0.866 S.E. 0.480 0.495 0.309 0.433 N 5 5 5 4

LIVER (G/100 G FINAL BODY WEIGHT) MEAN 3.100 2.943 2.907 2.908 % DIFFERENCE -5.1 -6.2 -6.2 S.D. 0.1655 0.2150 0.1662 0.0954 S.E. 0.0740 0.0961 0.0743 0.0477 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group136of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- LIVER (G/100 G BRAIN) MEAN 479.883 443.089 435.640 423.003 % DIFFERENCE -7.7 -9.2 -11.9 S.D. 42.5966 51.9746 41.7697 50.5074 S.E. 19.0498 23.2437 18.6800 25.2537 N 5 5 5 4

LUNGS (G) MEAN 1.27 1.21 1.16 1.25 % DIFFERENCE -4.7 -8.7 -1.6 S.D. 0.084 0.104 0.073 0.172 S.E. 0.038 0.046 0.033 0.086 N 5 5 5 4

LUNGS (G/100 G FINAL BODY WEIGHT) MEAN 0.411 0.412 0.402 0.436 % DIFFERENCE 0.2 -2.2 6.1 S.D. 0.0237 0.0249 0.0167 0.0417 S.E. 0.0106 0.0111 0.0075 0.0208 N 5 5 5 4

LUNGS (G/100 G BRAIN) MEAN 63.500 61.916 60.059 63.375 % DIFFERENCE -2.5 -5.4 -0.2 S.D. 3.8135 4.8528 2.9720 9.1579 S.E. 1.7054 2.1702 1.3291 4.5789 N 5 5 5 4

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group137of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- FINAL BODY WT (G) MEAN 198. 195. 196. 193. % DIFFERENCE -1.5 -1.0 -2.5 S.D. 10.7 6.6 13.9 9.9 S.E. 4.8 3.0 6.2 4.4 N 5 5 5 5

BRAIN (G) MEAN 1.86 1.82 1.82 1.85 % DIFFERENCE -2.2 -2.2 -0.5 S.D. 0.108 0.083 0.103 0.081 S.E. 0.048 0.037 0.046 0.036 N 5 5 5 5

BRAIN (G/100 G FINAL BODY WEIGHT) MEAN 0.942 0.935 0.932 0.957 % DIFFERENCE -0.7 -1.1 1.6 S.D. 0.0868 0.0371 0.0629 0.0329 S.E. 0.0388 0.0166 0.0281 0.0147 N 5 5 5 5

KIDNEYS (G) MEAN 1.43 1.46 1.43 1.39 % DIFFERENCE 2.1 0.0 -2.8 S.D. 0.103 0.075 0.149 0.074 S.E. 0.046 0.034 0.067 0.033 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group138of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- KIDNEYS (G/100 G FINAL BODY WEIGHT) MEAN 0.722 0.747 0.732 0.718 % DIFFERENCE 3.5 1.4 -0.6 S.D. 0.0411 0.0277 0.0535 0.0406 S.E. 0.0184 0.0124 0.0239 0.0181 N 5 5 5 5

KIDNEYS (G/100 G BRAIN) MEAN 76.887 80.030 78.756 75.141 % DIFFERENCE 4.1 2.4 -2.3 S.D. 5.2959 5.2666 6.3120 5.6593 S.E. 2.3684 2.3553 2.8228 2.5309 N 5 5 5 5

LIVER (G) MEAN 6.08 6.08 5.94 5.71 % DIFFERENCE 0.0 -2.3 -6.1 S.D. 0.522 0.292 0.554 0.461 S.E. 0.234 0.130 0.248 0.206 N 5 5 5 5

LIVER (G/100 G FINAL BODY WEIGHT) MEAN 3.063 3.117 3.033 2.953 % DIFFERENCE 1.8 -1.0 -3.6 S.D. 0.1296 0.1030 0.1815 0.1091 S.E. 0.0580 0.0461 0.0812 0.0488 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group139of435TABLE 26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- LIVER (G/100 G BRAIN) MEAN 327.709 334.124 326.021 309.014 % DIFFERENCE 2.0 -0.5 -5.7 S.D. 37.5578 21.5431 19.7120 19.9120 S.E. 16.7964 9.6344 8.8155 8.9049 N 5 5 5 5

LUNGS (G) MEAN 1.04 1.05 0.93 1.01 % DIFFERENCE 1.0 -10.6 -2.9 S.D. 0.064 0.109 0.114 0.060 S.E. 0.029 0.049 0.051 0.027 N 5 5 5 5

LUNGS (G/100 G FINAL BODY WEIGHT) MEAN 0.527 0.535 0.476 0.526 % DIFFERENCE 1.5 -9.7 -0.2 S.D. 0.0296 0.0417 0.0505 0.0416 S.E. 0.0132 0.0186 0.0226 0.0186 N 5 5 5 5

LUNGS (G/100 G BRAIN) MEAN 56.203 57.405 50.956 55.018 % DIFFERENCE 2.1 -9.3 -2.1 S.D. 4.4167 5.4744 3.2086 4.9709 S.E. 1.9752 2.4482 1.4349 2.2231 N 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- None significantly different from control group POFBSTv5.11 03/19/2008140of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- FINAL BODY WT (G) MEAN 319. S.D. 16.2 S.E. 7.2 N 5

BRAIN (G) MEAN 2.07 S.D. 0.075 S.E. 0.034 N 5

BRAIN (G/100 G FINAL BODY WEIGHT) MEAN 0.649 S.D. 0.0304 S.E. 0.0136 N 5

KIDNEYS (G) MEAN 2.59 S.D. 0.114 S.E. 0.051 N 5

KIDNEYS (G/100 G FINAL BODY WEIGHT) MEAN 0.814 S.D. 0.0535 S.E. 0.0239 N 5

-----------------------------------------------------------------------------------------------------------------------------------141of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- KIDNEYS (G/100 G BRAIN) MEAN 125.427 S.D. 7.8017 S.E. 3.4890 N 5

LIVER (G) MEAN 9.83 S.D. 0.585 S.E. 0.262 N 5

LIVER (G/100 G FINAL BODY WEIGHT) MEAN 3.087 S.D. 0.1226 S.E. 0.0548 N 5

LIVER (G/100 G BRAIN) MEAN 475.824 S.D. 21.3577 S.E. 9.5514 N 5

LUNGS (G) MEAN 1.34 S.D. 0.058 S.E. 0.026 N 5

-----------------------------------------------------------------------------------------------------------------------------------142of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- MALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- LUNGS (G/100 G FINAL BODY WEIGHT) MEAN 0.421 S.D. 0.0327 S.E. 0.0146 N 5

LUNGS (G/100 G BRAIN) MEAN 64.809 S.D. 3.1640 S.E. 1.4150 N 5

-----------------------------------------------------------------------------------------------------------------------------------143of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- FINAL BODY WT (G) MEAN 194. S.D. 16.3 S.E. 7.3 N 5

BRAIN (G) MEAN 1.83 S.D. 0.045 S.E. 0.020 N 5

BRAIN (G/100 G FINAL BODY WEIGHT) MEAN 0.945 S.D. 0.0716 S.E. 0.0320 N 5

KIDNEYS (G) MEAN 1.58 S.D. 0.131 S.E. 0.059 N 5

KIDNEYS (G/100 G FINAL BODY WEIGHT) MEAN 0.816 S.D. 0.0455 S.E. 0.0203 N 5

-----------------------------------------------------------------------------------------------------------------------------------144of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 5 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- KIDNEYS (G/100 G BRAIN) MEAN 86.642 S.D. 6.8673 S.E. 3.0711 N 5

LIVER (G) MEAN 6.03 S.D. 0.547 S.E. 0.245 N 5

LIVER (G/100 G FINAL BODY WEIGHT) MEAN 3.106 S.D. 0.0610 S.E. 0.0273 N 5

LIVER (G/100 G BRAIN) MEAN 330.258 S.D. 25.8708 S.E. 11.5698 N 5

LUNGS (G) MEAN 1.04 S.D. 0.068 S.E. 0.031 N 5

-----------------------------------------------------------------------------------------------------------------------------------145of435TABLE 27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 6 SUMMARY OF ORGAN WEIGHTS AND RELATIVE ORGAN WEIGHTS

----------------------------------------------------------------------------------------------------------------------------------- FEMALES GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- LUNGS (G/100 G FINAL BODY WEIGHT) MEAN 0.537 S.D. 0.0460 S.E. 0.0206 N 5

LUNGS (G/100 G BRAIN) MEAN 56.855 S.D. 3.6102 S.E. 1.6145 N 5

----------------------------------------------------------------------------------------------------------------------------------- POFBSTv5.11 03/25/2008146of435

# APPENDIX A

Individual Animal Data

147 of 435TABLE A1 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL SURVIVAL AND DISPOSITION

----------------------------------------------------------------------------------------------------------------------------------- TYPE OF AGE IN DATE OF DAYS ON ANIMAL SEX GROUP DEATH WEEKS A DEATH STUDY

----------------------------------------------------------------------------------------------------------------------------------- 95555 M 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95556 M 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95558 M 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95574 M 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95577 M 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95559 M 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95561 M 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95566 M 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95573 M 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95576 M 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95560 M 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95564 M 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95565 M 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95569 M 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95578 M 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95554 M 5000 PPM FOUND DEAD 9 07-FEB-08 1 95563 M 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95568 M 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95570 M 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95572 M 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

----------------------------------------------------------------------------------------------------------------------------------- A = CALCULATED TO THE NEAREST WHOLE WEEK USING THE MEAN AGE IN WEEKS AT INITIATION OF DOSING (9)148of435TABLE A1 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL SURVIVAL AND DISPOSITION

----------------------------------------------------------------------------------------------------------------------------------- TYPE OF AGE IN DATE OF DAYS ON ANIMAL SEX GROUP DEATH WEEKS A DEATH STUDY

----------------------------------------------------------------------------------------------------------------------------------- 95587 F 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95591 F 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95594 F 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95599 F 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95600 F 0 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95579 F 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95586 F 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95588 F 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95595 F 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95603 F 1250 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95580 F 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95589 F 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95593 F 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95597 F 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95598 F 2500 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

95581 F 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95583 F 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95590 F 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95592 F 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5 95601 F 5000 PPM SCHEDULED EUTHANASIA 9 11-FEB-08 5

----------------------------------------------------------------------------------------------------------------------------------- A = CALCULATED TO THE NEAREST WHOLE WEEK USING THE MEAN AGE IN WEEKS AT INITIATION OF DOSING (9) PDEADv4.05 03/20/2008149of435TABLE A2 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL SURVIVAL AND DISPOSITION

----------------------------------------------------------------------------------------------------------------------------------- TYPE OF AGE IN DATE OF DAYS ON ANIMAL SEX GROUP DEATH WEEKS A DEATH STUDY

----------------------------------------------------------------------------------------------------------------------------------- 95557 M 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 95562 M 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 95567 M 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 95571 M 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 95575 M 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5

----------------------------------------------------------------------------------------------------------------------------------- A = CALCULATED TO THE NEAREST WHOLE WEEK USING THE MEAN AGE IN WEEKS AT INITIATION OF DOSING (9)150of435TABLE A2 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL SURVIVAL AND DISPOSITION

----------------------------------------------------------------------------------------------------------------------------------- TYPE OF AGE IN DATE OF DAYS ON ANIMAL SEX GROUP DEATH WEEKS A DEATH STUDY

----------------------------------------------------------------------------------------------------------------------------------- 6664 F 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 6674 F 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 6686 F 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 6712 F 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5 6717 F 1800 PPM SCHEDULED EUTHANASIA 9 14-FEB-08 5

----------------------------------------------------------------------------------------------------------------------------------- A = CALCULATED TO THE NEAREST WHOLE WEEK USING THE MEAN AGE IN WEEKS AT INITIATION OF DOSING (9) PDEADv4.05 03/20/2008151of435TABLE A3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95555 M 0 PPM NORMAL 0 6:21 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:38 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95555 M 0 PPM DISPOSITION 5 9:06 P PRIMARY NECROPSY (DAY 5) 95556 M 0 PPM NORMAL 0 6:22 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:38 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95556 M 0 PPM DISPOSITION 5 9:06 P PRIMARY NECROPSY (DAY 5) 95558 M 0 PPM NORMAL 0 6:22 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95558 M 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95558 M 0 PPM EXCRETA 5 7:39 P SOFT FECES 95574 M 0 PPM NORMAL 0 6:22 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95574 M 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95577 M 0 PPM NORMAL 0 6:23 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95577 M 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95559 M 1250 PPM NORMAL 0 6:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95559 M 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95561 M 1250 PPM NORMAL 0 6:26 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95561 M 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95566 M 1250 PPM NORMAL 0 6:26 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95566 M 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95573 M 1250 PPM NORMAL 0 6:26 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95573 M 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95576 M 1250 PPM NORMAL 0 6:27 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT152of435TABLE A3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95576 M 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95560 M 2500 PPM NORMAL 0 6:29 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95560 M 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95564 M 2500 PPM NORMAL 0 6:29 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95564 M 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95565 M 2500 PPM NORMAL 0 6:30 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95565 M 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95569 M 2500 PPM NORMAL 0 6:30 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95569 M 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95578 M 2500 PPM NORMAL 0 6:31 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95578 M 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95554 M 5000 PPM NORMAL 0 6:33 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95554 M 5000 PPM DISPOSITION 1 8:37 P FOUND DEAD 95563 M 5000 PPM NORMAL 0 6:33 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:43 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95563 M 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95568 M 5000 PPM NORMAL 0 6:33 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:43 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95568 M 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95570 M 5000 PPM NORMAL 0 6:34 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95570 M 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95570 M 5000 PPM ORAL/DENTAL 5 7:43 P UPPER INCISOR(S) MALALIGNED 95570 M 5000 PPM BODY/INTEG III 5 7:43 P DRIED RED MATERIAL UROGENITAL AREA 95572 M 5000 PPM NORMAL 0 6:34 P NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT153of435TABLE A3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95572 M 5000 PPM NORMAL 5 7:43 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95572 M 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95587 F 0 PPM NORMAL 0 6:23 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95587 F 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95591 F 0 PPM NORMAL 0 6:24 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95591 F 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95594 F 0 PPM NORMAL 0 6:24 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95594 F 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95599 F 0 PPM NORMAL 0 6:24 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95599 F 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95600 F 0 PPM NORMAL 0 6:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:39 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95600 F 0 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95579 F 1250 PPM NORMAL 0 6:27 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95579 F 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95586 F 1250 PPM NORMAL 0 6:27 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95586 F 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95588 F 1250 PPM NORMAL 0 6:28 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:40 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95588 F 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95595 F 1250 PPM NORMAL 0 6:28 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95595 F 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5)

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT154of435TABLE A3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95603 F 1250 PPM NORMAL 0 6:29 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:41 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95603 F 1250 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95580 F 2500 PPM NORMAL 0 6:31 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:42 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95580 F 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95589 F 2500 PPM NORMAL 0 6:31 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95589 F 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95589 F 2500 PPM BODY/INTEGUMENT 5 7:42 P HAIR LOSS UROGENITAL AREA 5 7:42 P HAIR LOSS HINDLIMB(S) 95593 F 2500 PPM NORMAL 0 6:32 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:42 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95593 F 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95597 F 2500 PPM NORMAL 0 6:32 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:42 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95597 F 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95598 F 2500 PPM NORMAL 0 6:32 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:42 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95598 F 2500 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95581 F 5000 PPM NORMAL 0 6:35 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:43 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95581 F 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95583 F 5000 PPM NORMAL 0 6:35 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:44 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95583 F 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95590 F 5000 PPM NORMAL 0 6:35 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:44 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95590 F 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95592 F 5000 PPM NORMAL 0 6:36 P NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT155of435TABLE A3 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95592 F 5000 PPM NORMAL 5 7:44 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95592 F 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95601 F 5000 PPM NORMAL 0 6:36 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95601 F 5000 PPM DISPOSITION 5 9:07 P PRIMARY NECROPSY (DAY 5) 95601 F 5000 PPM BODY/INTEGUMENT 5 7:44 P HAIR LOSS FORELIMB(S) 5 7:44 P HAIR LOSS VENTRAL NECK 95601 F 5000 PPM BODY/INTEG II 5 7:44 P SCABBING FORELIMB(S) 5 7:45 P SCABBING VENTRAL TRUNK 95601 F 5000 PPM BODY/INTEG III 5 7:44 P DRIED YELLOW MATERIAL ANOGENITAL AREA

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008 R:03/24/2008156of435TABLE A4 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95557 M 1800 PPM NORMAL 0 6:17 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:24 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95557 M 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 95562 M 1800 PPM NORMAL 0 6:17 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95562 M 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 95567 M 1800 PPM NORMAL 0 6:18 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95567 M 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 95571 M 1800 PPM NORMAL 0 6:19 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95571 M 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 95575 M 1800 PPM NORMAL 0 6:19 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:25 P NO SIGNIFICANT CLINICAL OBSERVATIONS 95575 M 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 6664 F 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 6664 F 1800 PPM BODY/INTEGUMENT 0 6:20 P HAIR LOSS FORELIMB(S) 5 7:26 P HAIR LOSS FORELIMB(S) 6674 F 1800 PPM NORMAL 0 6:21 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:26 P NO SIGNIFICANT CLINICAL OBSERVATIONS 6674 F 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 6686 F 1800 PPM NORMAL 0 6:21 P NO SIGNIFICANT CLINICAL OBSERVATIONS 6686 F 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 6686 F 1800 PPM BODY/INTEGUMENT 5 7:26 P HAIR LOSS VENTRAL TRUNK 6712 F 1800 PPM NORMAL 0 6:22 P NO SIGNIFICANT CLINICAL OBSERVATIONS 5 7:27 P NO SIGNIFICANT CLINICAL OBSERVATIONS 6712 F 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5) 6717 F 1800 PPM NORMAL 0 6:23 P NO SIGNIFICANT CLINICAL OBSERVATIONS 6717 F 1800 PPM DISPOSITION 5 7:53 P PRIMARY NECROPSY (DAY 5)

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT157of435TABLE A4 (DETAILED PHYSICAL EXAMINATIONS/DISPOSITIONS - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 6717 F 1800 PPM BODY/INTEGUMENT 5 7:27 P HAIR LOSS VENTRAL TRUNK

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008158of435TABLE A5 (AT TIME OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95561 M 1250 PPM EXCRETA 1 7:30 P RED PENILE DISCHARGE 95570 M 5000 PPM EYES/EARS/NOSE 1 7:45 P DRIED RED MATERIAL AROUND NOSE 2 7:34 P DRIED RED MATERIAL AROUND NOSE 2 7:35 P DRIED RED MATERIAL AROUND RIGHT EYE 3 6:35 P DRIED RED MATERIAL AROUND RIGHT EYE 4 6:21 P DRIED RED MATERIAL AROUND RIGHT EYE 4 6:21 P DRIED RED MATERIAL AROUND NOSE 95570 M 5000 PPM ORAL/DENTAL 1 7:45 P DRIED RED MATERIAL AROUND MOUTH 1 7:45 P DRIED RED MATERIAL VENTRAL NECK 2 7:35 P DRIED RED MATERIAL AROUND MOUTH 3 6:35 P DRIED RED MATERIAL AROUND MOUTH 95570 M 5000 PPM SPECIAL 1 7:45 P SWOLLEN FACIAL AREA 2 7:34 P SWOLLEN FACIAL AREA 95570 M 5000 PPM BODY/INTEG III 1 7:45 P DRIED RED MATERIAL FORELIMB(S) 1 7:45 P DRIED RED MATERIAL VENTRAL TRUNK 1 7:45 P WET YELLOW MATERIAL UROGENITAL AREA 1 7:45 P WET YELLOW MATERIAL ANOGENITAL AREA 2 7:35 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 7:35 P DRIED YELLOW MATERIAL VENTRAL TRUNK 2 7:35 P DRIED YELLOW MATERIAL ANOGENITAL AREA 3 6:36 P DRIED YELLOW MATERIAL UROGENITAL AREA 4 6:22 P DRIED YELLOW MATERIAL UROGENITAL AREA 4 6:22 P DRIED YELLOW MATERIAL ANOGENITAL AREA 95590 F 5000 PPM EYES/EARS/NOSE 1 7:47 P DRIED RED MATERIAL AROUND NOSE 2 7:36 P DRIED RED MATERIAL AROUND NOSE 95590 F 5000 PPM ORAL/DENTAL 1 7:47 P DRIED RED MATERIAL AROUND MOUTH 95590 F 5000 PPM BODY/INTEG III 1 7:47 P DRIED RED MATERIAL FORELIMB(S) 1 7:47 P DRIED RED MATERIAL VENTRAL TRUNK 1 7:47 P DRIED RED MATERIAL UROGENITAL AREA

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT159of435TABLE A5 (AT TIME OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95590 F 5000 PPM BODY/INTEG III 2 7:35 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 7:36 P DRIED YELLOW MATERIAL VENTRAL TRUNK 2 7:36 P DRIED YELLOW MATERIAL ANOGENITAL AREA 3 6:38 P DRIED YELLOW MATERIAL ANOGENITAL AREA 4 6:24 P DRIED YELLOW MATERIAL UROGENITAL AREA 95592 F 5000 PPM EYES/EARS/NOSE 2 7:36 P DRIED RED MATERIAL AROUND NOSE 95592 F 5000 PPM ORAL/DENTAL 1 7:48 P DRIED RED MATERIAL AROUND MOUTH 95601 F 5000 PPM EYES/EARS/NOSE 1 7:48 P DRIED RED MATERIAL AROUND NOSE 2 7:37 P DRIED RED MATERIAL AROUND NOSE 3 6:39 P DRIED RED MATERIAL AROUND NOSE 4 6:26 P DRIED RED MATERIAL AROUND NOSE 95601 F 5000 PPM ORAL/DENTAL 1 7:48 P DRIED RED MATERIAL AROUND MOUTH 1 7:48 P DRIED RED MATERIAL VENTRAL NECK 2 7:37 P DRIED RED MATERIAL VENTRAL NECK 2 7:38 P DRIED RED MATERIAL AROUND MOUTH 3 6:40 P DRIED RED MATERIAL AROUND MOUTH 95601 F 5000 PPM BODY/INTEG III 1 7:48 P DRIED RED MATERIAL FORELIMB(S) 1 7:48 P DRIED RED MATERIAL VENTRAL TRUNK 1 7:48 P WET YELLOW MATERIAL UROGENITAL AREA 1 7:48 P WET YELLOW MATERIAL ANOGENITAL AREA 2 7:37 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 7:37 P DRIED YELLOW MATERIAL ANOGENITAL AREA 2 7:37 P DRIED RED MATERIAL VENTRAL TRUNK 2 7:37 P DRIED RED MATERIAL FORELIMB(S) 3 6:40 P DRIED RED MATERIAL HINDLIMB(S) 3 6:40 P DRIED RED MATERIAL FORELIMB(S) 3 6:44 P DRIED BROWN MATERIAL ANOGENITAL AREA 4 6:27 P DRIED YELLOW MATERIAL UROGENITAL AREA 4 6:28 P DRIED YELLOW MATERIAL ANOGENITAL AREA

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008 R:03/24/2008160of435TABLE A6 (AT TIME OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- NO SIGNIFICANT CLINICAL OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008 R:03/24/2008161of435TABLE A7 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95564 M 2500 PPM BEHAVIOR/CNS 2 8:13 P CONVULSIONS, INTERMITTENT 3 7:35 P CONVULSIONS, INTERMITTENT 4 7:22 P CONVULSIONS, INTERMITTENT 95554 M 5000 PPM BEHAVIOR/CNS 0 8:16 P TREMORS, INTERMITTENT 1 8:09 P CONVULSIONS, INTERMITTENT 1 8:13 P CONVULSIONS, CONTINUOUS 95554 M 5000 PPM ORAL/DENTAL 1 8:11 P WET CLEAR MATERIAL AROUND MOUTH 95563 M 5000 PPM BEHAVIOR/CNS 1 8:12 P CONVULSIONS, INTERMITTENT 95563 M 5000 PPM ORAL/DENTAL 0 8:17 P WET CLEAR MATERIAL AROUND MOUTH 1 8:12 P WET CLEAR MATERIAL AROUND MOUTH 95572 M 5000 PPM BEHAVIOR/CNS 0 8:18 P TREMORS, INTERMITTENT 1 8:16 P CONVULSIONS, CONTINUOUS 95597 F 2500 PPM BEHAVIOR/CNS 2 8:18 P CONVULSIONS, INTERMITTENT 4 7:29 P CONVULSIONS, INTERMITTENT 95597 F 2500 PPM ORAL/DENTAL 4 7:23 P WET CLEAR MATERIAL AROUND MOUTH 95581 F 5000 PPM BEHAVIOR/CNS 1 8:17 P CONVULSIONS, CONTINUOUS 95583 F 5000 PPM BEHAVIOR/CNS 1 8:24 P CONVULSIONS, CONTINUOUS 95590 F 5000 PPM BEHAVIOR/CNS 0 8:17 P TREMORS, INTERMITTENT 1 8:18 P CONVULSIONS, INTERMITTENT 95592 F 5000 PPM BEHAVIOR/CNS 1 8:10 P CONVULSIONS, INTERMITTENT

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 04/16/2008 R:04/16/2008162of435TABLE A8 (APPROXIMATELY 15-30 MINUTES INTO EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95557 M 1800 PPM ORAL/DENTAL 4 8:02 P WET CLEAR MATERIAL AROUND MOUTH

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 04/16/2008163of435TABLE A9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95560 M 2500 PPM EYES/EARS/NOSE 1 14:38 P DRIED RED MATERIAL AROUND NOSE 95565 M 2500 PPM BODY/INTEG III 0 14:25 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:25 P WET YELLOW MATERIAL ANOGENITAL AREA 2 14:28 P DRIED YELLOW MATERIAL UROGENITAL AREA 95578 M 2500 PPM BODY/INTEG III 0 14:26 P WET YELLOW MATERIAL ANOGENITAL AREA 95554 M 5000 PPM ORAL/DENTAL 0 14:41 P DRIED RED MATERIAL AROUND MOUTH 95554 M 5000 PPM BODY/INTEG III 0 14:41 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:41 P WET YELLOW MATERIAL VENTRAL TRUNK 0 14:41 P WET YELLOW MATERIAL ANOGENITAL AREA 95563 M 5000 PPM BODY/INTEG III 0 14:41 P DRIED YELLOW MATERIAL UROGENITAL AREA 0 14:41 P DRIED YELLOW MATERIAL VENTRAL TRUNK 0 14:41 P DRIED YELLOW MATERIAL ANOGENITAL AREA 95568 M 5000 PPM BODY/INTEG III 0 14:42 P DRIED YELLOW MATERIAL UROGENITAL AREA 0 14:42 P DRIED YELLOW MATERIAL ANOGENITAL AREA 95570 M 5000 PPM EYES/EARS/NOSE 1 14:51 P DRIED RED MATERIAL AROUND LEFT EYE 1 14:51 P DRIED RED MATERIAL AROUND RIGHT EYE 1 14:51 P DRIED RED MATERIAL AROUND NOSE 3 13:51 P DRIED RED MATERIAL AROUND RIGHT EYE 3 13:52 P DRIED RED MATERIAL AROUND NOSE 4 13:17 P DRIED RED MATERIAL AROUND RIGHT EYE 95570 M 5000 PPM ORAL/DENTAL 0 14:43 P WET CLEAR MATERIAL AROUND MOUTH 0 14:43 P WET YELLOW MATERIAL VENTRAL NECK 1 14:52 P DRIED RED MATERIAL AROUND MOUTH 1 14:52 P DRIED RED MATERIAL VENTRAL NECK 2 14:31 P DRIED RED MATERIAL AROUND MOUTH 3 13:52 P DRIED RED MATERIAL AROUND MOUTH 95570 M 5000 PPM SPECIAL 0 14:43 P SWOLLEN FACIAL AREA 1 14:50 P SWOLLEN FACIAL AREA 95570 M 5000 PPM BODY/INTEG III 0 14:44 P WET YELLOW MATERIAL FORELIMB(S)

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT164of435TABLE A9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95570 M 5000 PPM BODY/INTEG III 0 14:44 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:44 P WET YELLOW MATERIAL VENTRAL TRUNK 0 14:44 P WET YELLOW MATERIAL ANOGENITAL AREA 1 14:51 P DRIED BROWN MATERIAL UROGENITAL AREA 1 14:51 P DRIED BROWN MATERIAL VENTRAL TRUNK 1 14:51 P DRIED BROWN MATERIAL ANOGENITAL AREA 1 14:51 P DRIED RED MATERIAL FORELIMB(S) 2 14:30 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 14:30 P DRIED YELLOW MATERIAL ANOGENITAL AREA 2 14:30 P DRIED YELLOW MATERIAL VENTRAL TRUNK 3 13:50 P DRIED YELLOW MATERIAL UROGENITAL AREA 3 13:51 P DRIED YELLOW MATERIAL ANOGENITAL AREA 4 13:17 P DRIED YELLOW MATERIAL UROGENITAL AREA 95572 M 5000 PPM BODY/INTEG III 0 14:45 P DRIED YELLOW MATERIAL UROGENITAL AREA 95597 F 2500 PPM EYES/EARS/NOSE 3 13:44 P DRIED RED MATERIAL AROUND NOSE 4 13:37 P DRIED RED MATERIAL AROUND NOSE 95581 F 5000 PPM BODY/INTEG III 0 14:37 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:37 P WET YELLOW MATERIAL VENTRAL TRUNK 0 14:37 P WET YELLOW MATERIAL ANOGENITAL AREA 95583 F 5000 PPM BODY/INTEG III 0 14:38 P WET YELLOW MATERIAL UROGENITAL AREA 95590 F 5000 PPM EYES/EARS/NOSE 0 14:38 P DRIED RED MATERIAL AROUND NOSE 95590 F 5000 PPM ORAL/DENTAL 0 14:39 P DRIED RED MATERIAL AROUND MOUTH 1 14:58 P DRIED RED MATERIAL AROUND MOUTH 1 14:58 P DRIED RED MATERIAL VENTRAL NECK 95590 F 5000 PPM SPECIAL 1 14:58 P SWOLLEN FACIAL AREA 95590 F 5000 PPM BODY/INTEG III 0 14:39 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:39 P WET YELLOW MATERIAL VENTRAL TRUNK 0 14:39 P DRIED RED MATERIAL FORELIMB(S) 1 14:57 P WET YELLOW MATERIAL UROGENITAL AREA

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT165of435TABLE A9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95590 F 5000 PPM BODY/INTEG III 1 14:57 P WET YELLOW MATERIAL ANOGENITAL AREA 1 14:57 P DRIED RED MATERIAL FORELIMB(S) 1 14:57 P DRIED RED MATERIAL VENTRAL TRUNK 2 14:32 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 14:32 P DRIED YELLOW MATERIAL VENTRAL TRUNK 2 14:32 P DRIED YELLOW MATERIAL ANOGENITAL AREA 3 13:57 P DRIED YELLOW MATERIAL UROGENITAL AREA 95592 F 5000 PPM ORAL/DENTAL 0 14:40 P WET RED MATERIAL AROUND MOUTH 1 14:59 P DRIED RED MATERIAL AROUND MOUTH 95592 F 5000 PPM SPECIAL 0 14:40 P SWOLLEN FACIAL AREA 1 14:59 P SWOLLEN FACIAL AREA 95592 F 5000 PPM BODY/INTEG III 0 14:39 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:39 P WET YELLOW MATERIAL ANOGENITAL AREA 1 14:59 P WET YELLOW MATERIAL UROGENITAL AREA 1 14:59 P WET YELLOW MATERIAL ANOGENITAL AREA 95601 F 5000 PPM BEHAVIOR/CNS 0 14:45 P HYPOACTIVITY 1 15:00 P HYPOACTIVITY 95601 F 5000 PPM EYES/EARS/NOSE 0 14:35 P DRIED RED MATERIAL AROUND NOSE 1 15:02 P DRIED RED MATERIAL AROUND NOSE 3 13:58 P DRIED RED MATERIAL AROUND NOSE 4 13:20 P DRIED RED MATERIAL AROUND NOSE 95601 F 5000 PPM ORAL/DENTAL 0 14:36 P DRIED RED MATERIAL AROUND MOUTH 0 14:36 P DRIED RED MATERIAL VENTRAL NECK 1 15:01 P DRIED RED MATERIAL AROUND MOUTH 1 15:01 P DRIED RED MATERIAL VENTRAL NECK 2 14:33 P DRIED RED MATERIAL AROUND MOUTH 2 14:33 P DRIED RED MATERIAL VENTRAL NECK 95601 F 5000 PPM SPECIAL 0 14:34 P SWOLLEN LEFT FORELIMB 0 14:34 P SWOLLEN RIGHT FORELIMB

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT166of435TABLE A9 (END OF EXPOSURE - GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95601 F 5000 PPM SPECIAL 0 14:35 P REDDENED LEFT FORELIMB 0 14:35 P REDDENED RIGHT FORELIMB 1 15:02 P SWOLLEN FACIAL AREA 95601 F 5000 PPM BODY/INTEG III 0 14:35 P DRIED RED MATERIAL VENTRAL TRUNK 0 14:35 P DRIED RED MATERIAL FORELIMB(S) 0 14:36 P WET YELLOW MATERIAL UROGENITAL AREA 0 14:36 P WET YELLOW MATERIAL ANOGENITAL AREA 1 15:00 P WET YELLOW MATERIAL UROGENITAL AREA 1 15:01 P WET YELLOW MATERIAL ANOGENITAL AREA 1 15:01 P DRIED BROWN MATERIAL VENTRAL TRUNK 1 15:01 P DRIED RED MATERIAL FORELIMB(S) 2 14:33 P DRIED YELLOW MATERIAL UROGENITAL AREA 2 14:33 P DRIED YELLOW MATERIAL VENTRAL TRUNK 2 14:33 P DRIED YELLOW MATERIAL ANOGENITAL AREA 2 14:33 P DRIED YELLOW MATERIAL HINDLIMB(S) 2 14:33 P DRIED RED MATERIAL FORELIMB(S) 3 13:58 P DRIED YELLOW MATERIAL UROGENITAL AREA 3 13:58 P DRIED YELLOW MATERIAL ANOGENITAL AREA 3 13:58 P DRIED YELLOW MATERIAL HINDLIMB(S) 4 13:20 P DRIED YELLOW MATERIAL UROGENITAL AREA 4 13:21 P DRIED YELLOW MATERIAL ANOGENITAL AREA

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008167of435TABLE A10 (END OF EXPOSURE - GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 4

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 6712 F 1800 PPM ORAL/DENTAL 2 14:21 P DRIED RED MATERIAL AROUND MOUTH

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 03/24/2008168of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL BODY WEIGHTS [G]

MALE GROUP: 0 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95555 205. 248. 313. 338. 347. 358. 95556 210. 250. 307. 331. 339. 345. 95558 205. 245. 291. 304. 310. 313. 95574 203. 242. 295. 317. 323. 327. 95577 233. 273. 337. 361. 370. 379.

MEAN 211. 252. 309. 330. 338. 344. S.D. 12.5 12.3 18.2 21.6 23.0 25.8 S.E. 5.6 5.5 8.1 9.7 10.3 11.6 N 5 5 5 5 5 5169of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL BODY WEIGHTS [G]

MALE GROUP: 1250 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95559 216. 256. 308. 327. 324. 329. 95561 220. 260. 305. 325. 332. 338. 95566 202. 233. 280. 288. 286. 290. 95573 214. 254. 310. 325. 319. 322. 95576 234. 271. 327. 340. 346. 348.

MEAN 217. 255. 306. 321. 321. 325. S.D. 11.5 13.8 16.9 19.5 22.3 22.1 S.E. 5.2 6.2 7.5 8.7 10.0 9.9 N 5 5 5 5 5 5170of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL BODY WEIGHTS [G]

MALE GROUP: 2500 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95560 205. 241. 293. 316. 302. 298. 95564 215. 254. 310. 332. 333. 340. 95565 230. 272. 332. 348. 341. 339. 95569 217. 252. 305. 323. 312. 312. 95578 208. 247. 297. 316. 310. 314.

MEAN 215. 253. 307. 327. 320. 321. S.D. 9.7 11.6 15.3 13.5 16.6 18.3 S.E. 4.3 5.2 6.8 6.0 7.4 8.2 N 5 5 5 5 5 5171of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL BODY WEIGHTS [G]

MALE GROUP: 5000 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95554 226. 272. 338. 360. 95563 215. 259. 320. 343. 303. 350. 95568 211. 247. 298. 314. 276. 315. 95570 215. 250. 306. 327. 266. 306. 95572 205. 238. 284. 292. 256. 298.

MEAN 214. 253. 309. 327. 275. 317. S.D. 7.7 12.9 20.7 26.2 20.2 22.9 S.E. 3.4 5.8 9.3 11.7 10.1 11.5 N 5 5 5 5 4 4172of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL BODY WEIGHTS [G]

FEMALE GROUP: 0 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95587 158. 173. 196. 207. 206. 213. 95591 175. 193. 221. 227. 237. 236. 95594 174. 191. 214. 230. 220. 232. 95599 167. 183. 203. 219. 213. 220. 95600 172. 191. 209. 211. 217. 219.

MEAN 169. 186. 209. 219. 219. 224. S.D. 7.0 8.3 9.7 9.9 11.5 9.6 S.E. 3.1 3.7 4.3 4.4 5.2 4.3 N 5 5 5 5 5 5173of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL BODY WEIGHTS [G]

FEMALE GROUP: 1250 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95579 169. 184. 200. 207. 207. 213. 95586 180. 192. 216. 220. 228. 227. 95588 179. 194. 207. 215. 214. 222. 95595 169. 192. 213. 224. 219. 224. 95603 165. 180. 203. 204. 209. 213.

MEAN 172. 188. 208. 214. 215. 220. S.D. 6.7 6.1 6.7 8.5 8.4 6.5 S.E. 3.0 2.7 3.0 3.8 3.8 2.9 N 5 5 5 5 5 5174of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL BODY WEIGHTS [G]

FEMALE GROUP: 2500 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95580 170. 190. 210. 213. 217. 222. 95589 166. 181. 209. 210. 209. 217. 95593 174. 188. 204. 218. 213. 218. 95597 186. 206. 234. 236. 240. 238. 95598 156. 170. 197. 196. 196. 199.

MEAN 170. 187. 211. 215. 215. 219. S.D. 11.0 13.2 14.0 14.5 16.0 13.9 S.E. 4.9 5.9 6.2 6.5 7.2 6.2 N 5 5 5 5 5 5175of435TABLE A11 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL BODY WEIGHTS [G]

FEMALE GROUP: 5000 PPM DAY -12 -8 -2 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95581 163. 176. 195. 196. 178. 198. 95583 171. 191. 208. 213. 198. 215. 95590 168. 184. 206. 219. 187. 214. 95592 177. 192. 215. 219. 205. 224. 95601 172. 189. 225. 240. 191. 226.

MEAN 170. 186. 210. 217. 192. 215. S.D. 5.2 6.6 11.1 15.8 10.3 11.1 S.E. 2.3 2.9 5.0 7.0 4.6 5.0 N 5 5 5 5 5 5 PBFTSv4.44 03/24/2008176of435TABLE A12 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL BODY WEIGHTS [G]

MALE GROUP: 1800 PPM DAY 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95557 324. 321. 329. 95562 367. 360. 364. 95567 325. 317. 325. 95571 348. 348. 347. 95575 364. 358. 367.

MEAN 346. 341. 346. S.D. 20.6 20.5 19.3 S.E. 9.2 9.2 8.6 N 5 5 5177of435TABLE A12 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL BODY WEIGHTS [G]

FEMALE GROUP: 1800 PPM DAY 0 2 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 6664 209. 214. 216. 6674 234. 232. 228. 6686 208. 204. 208. 6712 186. 194. 195. 6717 228. 224. 233.

MEAN 213. 214. 216. S.D. 18.9 15.2 15.3 S.E. 8.5 6.8 6.8 N 5 5 5 PBFTSv4.44 03/24/2008178of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL BODY WEIGHT CHANGES [G]

MALE GROUP: 0 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95555 43. 65. 25. 9. 11. 95556 40. 57. 24. 8. 6. 95558 40. 46. 13. 6. 3. 95574 39. 53. 22. 6. 4. 95577 40. 64. 24. 9. 9.

MEAN 40. 57. 22. 8. 7. S.D. 1.5 7.9 4.9 1.5 3.4 S.E. 0.7 3.5 2.2 0.7 1.5 N 5 5 5 5 5179of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL BODY WEIGHT CHANGES [G]

MALE GROUP: 1250 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95559 40. 52. 19. -3. 5. 95561 40. 45. 20. 7. 6. 95566 31. 47. 8. -2. 4. 95573 40. 56. 15. -6. 3. 95576 37. 56. 13. 6. 2.

MEAN 38. 51. 15. 0. 4. S.D. 3.9 5.1 4.8 5.8 1.6 S.E. 1.7 2.3 2.2 2.6 0.7 N 5 5 5 5 5180of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL BODY WEIGHT CHANGES [G]

MALE GROUP: 2500 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95560 36. 52. 23. -14. -4. 95564 39. 56. 22. 1. 7. 95565 42. 60. 16. -7. -2. 95569 35. 53. 18. -11. 0. 95578 39. 50. 19. -6. 4.

MEAN 38. 54. 20. -7. 1. S.D. 2.8 3.9 2.9 5.7 4.5 S.E. 1.2 1.7 1.3 2.5 2.0 N 5 5 5 5 5181of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL BODY WEIGHT CHANGES [G]

MALE GROUP: 5000 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95554 46. 66. 22. 95563 44. 61. 23. -40. 47. 95568 36. 51. 16. -38. 39. 95570 35. 56. 21. -61. 40. 95572 33. 46. 8. -36. 42.

MEAN 39. 56. 18. -44. 42. S.D. 5.8 7.9 6.2 11.6 3.6 S.E. 2.6 3.5 2.8 5.8 1.8 N 5 5 5 4 4182of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL BODY WEIGHT CHANGES [G]

FEMALE GROUP: 0 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95587 15. 23. 11. -1. 7. 95591 18. 28. 6. 10. -1. 95594 17. 23. 16. -10. 12. 95599 16. 20. 16. -6. 7. 95600 19. 18. 2. 6. 2.

MEAN 17. 22. 10. 0. 5. S.D. 1.6 3.8 6.2 8.3 5.0 S.E. 0.7 1.7 2.8 3.7 2.2 N 5 5 5 5 5183of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL BODY WEIGHT CHANGES [G]

FEMALE GROUP: 1250 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95579 15. 16. 7. 0. 6. 95586 12. 24. 4. 8. -1. 95588 15. 13. 8. -1. 8. 95595 23. 21. 11. -5. 5. 95603 15. 23. 1. 5. 4.

MEAN 16. 19. 6. 1. 4. S.D. 4.1 4.7 3.8 5.1 3.4 S.E. 1.8 2.1 1.7 2.3 1.5 N 5 5 5 5 5184of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL BODY WEIGHT CHANGES [G]

FEMALE GROUP: 2500 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95580 20. 20. 3. 4. 5. 95589 15. 28. 1. -1. 8. 95593 14. 16. 14. -5. 5. 95597 20. 28. 2. 4. -2. 95598 14. 27. -1. 0. 3.

MEAN 17. 24. 4. 0. 4. S.D. 3.1 5.5 5.9 3.8 3.7 S.E. 1.4 2.5 2.6 1.7 1.7 N 5 5 5 5 5185of435TABLE A13 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL BODY WEIGHT CHANGES [G]

FEMALE GROUP: 5000 PPM DAY -12 TO -8 -8 TO -2 -2 TO 0 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95581 13. 19. 1. -18. 20. 95583 20. 17. 5. -15. 17. 95590 16. 22. 13. -32. 27. 95592 15. 23. 4. -14. 19. 95601 17. 36. 15. -49. 35.

MEAN 16. 23. 8. -26. 24. S.D. 2.6 7.4 6.1 14.9 7.4 S.E. 1.2 3.3 2.7 6.7 3.3 N 5 5 5 5 5 PBFTSv4.44 03/24/2008186of435TABLE A14 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL BODY WEIGHT CHANGES [G]

MALE GROUP: 1800 PPM DAY 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95557 -3. 8. 95562 -7. 4. 95567 -8. 8. 95571 0. -1. 95575 -6. 9.

MEAN -5. 6. S.D. 3.3 4.2 S.E. 1.5 1.9 N 5 5187of435TABLE A14 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL BODY WEIGHT CHANGES [G]

FEMALE GROUP: 1800 PPM DAY 0 TO 2 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 6664 5. 2. 6674 -2. -4. 6686 -4. 4. 6712 8. 1. 6717 -4. 9.

MEAN 1. 2. S.D. 5.5 4.7 S.E. 2.5 2.1 N 5 5 PBFTSv4.44 03/24/2008188of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

MALE GROUP: 0 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95555 9. 20. 95556 8. 14. 95558 6. 9. 95574 6. 10. 95577 9. 18.

MEAN 8. 14. S.D. 1.5 4.8 S.E. 0.7 2.2 N 5 5189of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

MALE GROUP: 1250 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95559 -3. 2. 95561 7. 13. 95566 -2. 2. 95573 -6. -3. 95576 6. 8.

MEAN 0. 4. S.D. 5.8 6.2 S.E. 2.6 2.8 N 5 5190of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

MALE GROUP: 2500 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95560 -14. -18. 95564 1. 8. 95565 -7. -9. 95569 -11. -11. 95578 -6. -2.

MEAN -7. -6. S.D. 5.7 9.9 S.E. 2.5 4.4 N 5 5191of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

MALE GROUP: 5000 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95554 95563 -40. 7. 95568 -38. 1. 95570 -61. -21. 95572 -36. 6.

MEAN -44. -2. S.D. 11.6 13.1 S.E. 5.8 6.5 N 4 4192of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

FEMALE GROUP: 0 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95587 -1. 6. 95591 10. 9. 95594 -10. 2. 95599 -6. 1. 95600 6. 8.

MEAN 0. 5. S.D. 8.3 3.6 S.E. 3.7 1.6 N 5 5193of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

FEMALE GROUP: 1250 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95579 0. 6. 95586 8. 7. 95588 -1. 7. 95595 -5. 0. 95603 5. 9.

MEAN 1. 6. S.D. 5.1 3.4 S.E. 2.3 1.5 N 5 5194of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

FEMALE GROUP: 2500 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95580 4. 9. 95589 -1. 7. 95593 -5. 0. 95597 4. 2. 95598 0. 3.

MEAN 0. 4. S.D. 3.8 3.7 S.E. 1.7 1.7 N 5 5195of435TABLE A15 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

FEMALE GROUP: 5000 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95581 -18. 2. 95583 -15. 2. 95590 -32. -5. 95592 -14. 5. 95601 -49. -14.

MEAN -26. -2. S.D. 14.9 7.6 S.E. 6.7 3.4 N 5 5 PBFTSv4.44 03/24/2008196of435TABLE A16 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

MALE GROUP: 1800 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95557 -3. 5. 95562 -7. -3. 95567 -8. 0. 95571 0. -1. 95575 -6. 3.

MEAN -5. 1. S.D. 3.3 3.2 S.E. 1.5 1.4 N 5 5197of435TABLE A16 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CUMULATIVE BODY WEIGHT CHANGES [G]

FEMALE GROUP: 1800 PPM DAY 0 TO 2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 6664 5. 7. 6674 -2. -6. 6686 -4. 0. 6712 8. 9. 6717 -4. 5.

MEAN 1. 3. S.D. 5.5 6.0 S.E. 2.5 2.7 N 5 5 PBFTSv4.44 03/24/2008198of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 0 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95555 28. 28. 95556 26. 25. 95558 26. 24. 95574 25. 25. 95577 29. 27.

MEAN 27. 26. S.D. 1.6 1.6 S.E. 0.7 0.7 N 5 5199of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 1250 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95559 27. 22. 95561 26. 23. 95566 22. 20. 95573 30. 23. 95576 28. 26.

MEAN 27. 23. S.D. 3.0 2.2 S.E. 1.3 1.0 N 5 5200of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 2500 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95560 25. 17. 95564 27. 24. 95565 28. 21. 95569 26. 19. 95578 27. 19.

MEAN 27. 20. S.D. 1.1 2.6 S.E. 0.5 1.2 N 5 5201of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 5000 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95554 30. 95563 29. NA 95568 26. NA 95570 26. NA 95572 24. NA

MEAN 27. NA S.D. 2.4 S.E. 1.1 N 5

NA = NOT APPLICABLE202of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 0 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95587 18. 16. 95591 20. 19. 95594 20. 17. 95599 19. 17. 95600 18. 18.

MEAN 19. 17. S.D. 1.0 1.1 S.E. 0.4 0.5 N 5 5203of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 1250 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95579 17. 16. 95586 21. 17. 95588 18. 16. 95595 17. 15. 95603 23. 17.

MEAN 19. 16. S.D. 2.7 0.8 S.E. 1.2 0.4 N 5 5204of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 2500 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95580 NA 17. 95589 19. 15. 95593 21. 12. 95597 21. 16. 95598 19. 15.

MEAN 20. 15. S.D. 1.2 1.9 S.E. 0.6 0.8 N 4 5

NA = NOT APPLICABLE205of435TABLE A17 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 5000 PPM DAY -8 TO -2 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95581 18. NA 95583 17. NA 95590 18. NA 95592 18. NA 95601 22. NA

MEAN 19. NA S.D. 1.9 S.E. 0.9 N 5

NA = NOT APPLICABLE PBFTSv4.44 03/24/2008206of435TABLE A18 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 1800 PPM DAY 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95557 23. 95562 25. 95567 21. 95571 22. 95575 23.

MEAN 23. S.D. 1.5 S.E. 0.7 N 5207of435TABLE A18 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 1800 PPM DAY 0 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 6664 16. 6674 15. 6686 15. 6712 16. 6717 18.

MEAN 16. S.D. 1.2 S.E. 0.5 N 5 PBFTSv4.44 03/24/2008208of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM MALES

95555 11.79 8.03 16.8 48.5 60.3 20.9 34.7 1623. 14.8 19.8 95556 8.89 8.08 15.9 45.8 56.7 19.7 34.7 1426. 12.7 19.5 95558 10.85 7.31 15.7 43.7 59.8 21.5 35.9 1471. CLT CLT 95574 8.15 7.79 15.8 44.9 57.7 20.3 35.2 1336. 13.5 18.8 95577 9.87 8.02 16.2 45.7 57.0 20.1 35.3 1693. 14.0 20.6

MEAN 9.91 7.85 16.1 45.7 58.3 20.5 35.2 1510. 13.8 19.7 S.D. 1.463 0.320 0.44 1.77 1.65 0.71 0.50 145.9 0.88 0.75 S.E. 0.654 0.143 0.20 0.79 0.74 0.32 0.22 65.2 0.44 0.37 N 5 5 5 5 5 5 5 5 4 4

----------------------------------------------------------------------------------------------------------------------------------- CLT = CLOTTED

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER209of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM MALES

95555 3.3 269.0 9.7 86.3 1.6 1.5 0.3 0.6 95556 3.1 250.4 13.1 83.2 1.6 0.7 0.3 1.0 95558 2.4 178.7 10.3 85.7 2.0 0.8 0.3 0.9 95574 2.5 197.6 11.2 84.8 2.1 1.2 0.2 0.6 95577 2.9 236.2 14.6 81.7 1.6 1.3 0.2 0.6

MEAN 2.8 226.4 11.8 84.3 1.8 1.1 0.3 0.7 S.D. 0.38 37.39 2.03 1.88 0.25 0.34 0.05 0.19 S.E. 0.17 16.72 0.91 0.84 0.11 0.15 0.02 0.09 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER210of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM MALES

95555 1.15 10.18 0.19 0.18 0.03 0.07 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95556 1.17 7.40 0.15 0.07 0.03 0.09 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95558 1.12 9.30 0.22 0.09 0.04 0.09 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95574 0.91 6.91 0.17 0.09 0.02 0.05 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95577 1.44 8.06 0.16 0.13 0.02 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 1.16 8.37 0.18 0.11 0.03 0.07 S.D. 0.189 1.352 0.028 0.044 0.008 0.018 S.E. 0.084 0.605 0.012 0.020 0.004 0.008 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER211of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM MALES

95559 12.36 7.50 15.9 44.1 58.8 21.2 36.1 1076. 13.3 18.6 95561 9.25 7.94 15.7 44.7 56.3 19.8 35.2 1006. 12.8 18.0 95566 11.52 8.50 16.9 46.7 54.9 19.9 36.1 1412. 13.0 16.8 95573 7.99 8.14 16.7 46.6 57.3 20.5 35.8 1446. 13.6 18.3 95576 15.20 8.49 16.4 46.9 55.3 19.3 34.9 1404. 13.8 20.5

MEAN 11.26 8.11 16.3 45.8 56.5 20.1 35.6 1269. 13.3 18.4 S.D. 2.808 0.418 0.51 1.30 1.58 0.73 0.54 210.0 0.41 1.34 S.E. 1.256 0.187 0.23 0.58 0.71 0.33 0.24 93.9 0.18 0.60 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER212of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM MALES

95559 2.5 185.4 6.3 91.2 1.1 0.4 0.4 0.5 95561 2.8 221.2 13.5 82.3 2.1 1.0 0.5 0.7 95566 2.1 177.7 10.3 86.6 1.5 0.5 0.4 0.7 95573 2.0 164.2 19.9 75.9 1.6 1.3 0.4 0.8 95576 2.2 184.5 7.7 88.9 1.7 0.7 0.3 0.6

MEAN 2.3 186.6 11.5 85.0 1.6 0.8 0.4 0.7 S.D. 0.33 21.12 5.42 6.05 0.36 0.37 0.07 0.11 S.E. 0.15 9.44 2.42 2.70 0.16 0.17 0.03 0.05 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER213of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM MALES

95559 0.78 11.27 0.14 0.05 0.06 0.07 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95561 1.25 7.61 0.19 0.09 0.04 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95566 1.19 9.98 0.17 0.05 0.04 0.08 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95573 1.59 6.07 0.13 0.10 0.03 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95576 1.17 13.52 0.27 0.11 0.05 0.09 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 1.20 9.69 0.18 0.08 0.04 0.07 S.D. 0.288 2.944 0.056 0.028 0.011 0.013 S.E. 0.129 1.317 0.025 0.013 0.005 0.006 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER214of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM MALES

95560 8.17 8.13 17.2 47.9 59.0 21.1 35.8 990. 14.5 17.7 95564 13.74 7.70 15.9 45.2 58.6 20.7 35.3 1245. 12.7 18.9 95565 8.94 8.30 16.3 46.2 55.6 19.7 35.4 1378. 14.0 17.9 95569 7.40 8.37 17.2 49.4 59.0 20.6 34.9 1049. 12.7 19.8 95578 8.96 8.17 16.2 45.2 55.3 19.8 35.8 1900. 12.6 17.6

MEAN 9.44 8.13 16.6 46.8 57.5 20.4 35.4 1312. 13.3 18.4 S.D. 2.487 0.261 0.60 1.83 1.88 0.61 0.38 363.1 0.89 0.95 S.E. 1.112 0.117 0.27 0.82 0.84 0.27 0.17 162.4 0.40 0.42 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER215of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM MALES

95560 1.7 142.0 17.2 78.1 2.8 0.8 0.4 0.8 95564 2.8 218.4 8.0 89.4 1.2 0.5 0.3 0.5 95565 1.6 130.9 7.8 88.2 2.2 0.6 0.3 0.9 95569 2.0 170.2 10.7 86.6 1.4 0.4 0.3 0.6 95578 2.1 173.6 8.9 87.2 2.3 0.7 0.2 0.7

MEAN 2.0 167.0 10.5 85.9 2.0 0.6 0.3 0.7 S.D. 0.47 34.00 3.91 4.49 0.66 0.16 0.07 0.16 S.E. 0.21 15.21 1.75 2.01 0.30 0.07 0.03 0.07 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER216of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 9 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM MALES

95560 1.41 6.38 0.23 0.06 0.03 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95564 1.11 12.28 0.17 0.07 0.04 0.07 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95565 0.70 7.89 0.19 0.05 0.02 0.08 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95569 0.79 6.40 0.10 0.03 0.02 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95578 0.80 7.82 0.21 0.06 0.02 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 0.96 8.15 0.18 0.05 0.03 0.06 S.D. 0.295 2.420 0.050 0.015 0.009 0.015 S.E. 0.132 1.082 0.022 0.007 0.004 0.007 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER217of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 10 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM MALES

95563 9.55 7.85 15.5 44.0 56.1 19.8 35.3 1705. 12.6 18.3 95568 9.78 8.07 15.9 45.0 55.7 19.7 35.4 1359. 13.0 19.6 95570 14.96 7.46 15.4 42.8 57.3 20.7 36.1 1497. 13.9 18.4 95572 10.14 8.11 16.4 46.0 56.7 20.2 35.6 1441. 12.4 19.7

MEAN 11.11 7.87 15.8 44.5 56.5 20.1 35.6 1501. 13.0 19.0 S.D. 2.580 0.298 0.45 1.37 0.70 0.45 0.36 147.6 0.67 0.75 S.E. 1.290 0.149 0.23 0.68 0.35 0.23 0.18 73.8 0.33 0.38 N 4 4 4 4 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER218of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 11 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM MALES

95563 2.8 223.5 16.5 79.7 2.1 1.1 0.2 0.5 95568 3.0 243.9 10.8 85.6 2.4 0.3 0.3 0.6 95570 2.6 194.0 19.9 76.4 1.6 1.2 0.3 0.6 95572 2.8 230.4 11.6 84.6 1.9 0.5 0.3 1.0

MEAN 2.8 223.0 14.7 81.6 2.0 0.8 0.3 0.7 S.D. 0.16 21.08 4.29 4.31 0.34 0.44 0.05 0.22 S.E. 0.08 10.54 2.14 2.15 0.17 0.22 0.02 0.11 N 4 4 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER219of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 12 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM MALES

95563 1.57 7.61 0.20 0.10 0.02 0.05 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95568 1.06 8.37 0.23 0.03 0.03 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95570 2.98 11.42 0.24 0.18 0.05 0.09 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95572 1.18 8.58 0.20 0.05 0.03 0.10 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 1.70 9.00 0.22 0.09 0.03 0.08 S.D. 0.882 1.670 0.021 0.067 0.013 0.024 S.E. 0.441 0.835 0.010 0.033 0.006 0.012 N 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER220of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 13 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM FEMALES

95587 6.60 8.27 16.3 43.5 52.7 19.7 37.3 1575. 12.1 18.4 95591 7.80 8.11 16.6 45.7 56.4 20.5 36.4 1333. 11.1 11.7 95594 10.46 7.76 15.6 42.3 54.5 20.1 36.9 1320. 12.0 16.4 95599 9.18 8.17 16.7 44.7 54.7 20.4 37.3 1437. 11.0 11.3 95600 3.77 7.80 15.5 42.2 54.1 19.8 36.6 1290. 12.9 18.2

MEAN 7.56 8.02 16.1 43.7 54.5 20.1 36.9 1391. 11.8 15.2 S.D. 2.568 0.229 0.56 1.52 1.33 0.35 0.41 116.8 0.79 3.47 S.E. 1.148 0.102 0.25 0.68 0.59 0.16 0.18 52.2 0.35 1.55 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER221of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 14 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM FEMALES

95587 1.9 154.9 19.9 76.5 2.0 0.6 0.4 0.5 95591 2.4 195.6 8.9 86.4 2.2 1.3 0.4 0.8 95594 2.5 197.4 13.3 84.0 0.9 0.7 0.3 0.8 95599 2.2 183.6 6.2 90.1 1.8 0.8 0.3 0.7 95600 2.5 197.0 28.7 58.5 11.4 0.5 0.2 0.7

MEAN 2.3 185.7 15.4 79.1 3.7 0.8 0.3 0.7 S.D. 0.25 18.14 9.06 12.54 4.36 0.31 0.08 0.12 S.E. 0.11 8.11 4.05 5.61 1.95 0.14 0.04 0.05 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER222of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 15 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM FEMALES

95587 1.31 5.05 0.13 0.04 0.03 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95591 0.70 6.75 0.17 0.10 0.03 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95594 1.39 8.79 0.09 0.07 0.04 0.08 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95599 0.57 8.27 0.17 0.07 0.03 0.07 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95600 1.08 2.21 0.43 0.02 0.01 0.02 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 1.01 6.21 0.20 0.06 0.03 0.05 S.D. 0.364 2.671 0.134 0.031 0.011 0.024 S.E. 0.163 1.195 0.060 0.014 0.005 0.011 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER223of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 16 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM FEMALES

95579 7.77 8.33 16.4 45.6 54.7 19.7 36.0 1205. 12.6 17.9 95586 10.62 7.93 15.6 42.1 53.2 19.7 37.0 1368. 12.4 16.0 95588 5.38 7.84 15.6 41.7 53.2 19.9 37.4 1243. 12.2 17.7 95595 6.91 7.44 15.5 41.3 55.5 20.9 37.6 1575. 12.4 18.0 95603 4.85 8.36 15.8 43.8 52.3 18.9 36.1 1425. 11.5 17.3

MEAN 7.11 7.98 15.8 42.9 53.8 19.8 36.8 1363. 12.2 17.4 S.D. 2.286 0.381 0.36 1.78 1.29 0.72 0.74 148.5 0.43 0.82 S.E. 1.022 0.170 0.16 0.80 0.58 0.32 0.33 66.4 0.19 0.37 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER224of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 17 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM FEMALES

95579 2.0 164.4 10.4 86.5 1.6 0.6 0.4 0.5 95586 1.9 152.0 12.2 84.0 1.8 0.9 0.2 0.8 95588 2.2 169.2 9.9 86.9 1.2 1.1 0.2 0.7 95595 2.1 156.7 7.2 90.5 0.9 0.9 0.2 0.4 95603 1.3 110.3 12.5 85.1 0.7 1.0 0.3 0.4

MEAN 1.9 150.5 10.4 86.6 1.2 0.9 0.3 0.6 S.D. 0.35 23.45 2.13 2.47 0.46 0.19 0.09 0.18 S.E. 0.16 10.49 0.95 1.10 0.21 0.08 0.04 0.08 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER225of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 18 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM FEMALES

95579 0.81 6.72 0.12 0.05 0.03 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95586 1.30 8.92 0.19 0.10 0.02 0.09 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95588 0.53 4.68 0.06 0.06 0.01 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95595 0.50 6.25 0.06 0.06 0.01 0.02 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95603 0.61 4.12 0.03 0.05 0.02 0.02 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 0.75 6.14 0.09 0.06 0.02 0.04 S.D. 0.330 1.890 0.064 0.021 0.008 0.029 S.E. 0.148 0.845 0.029 0.009 0.004 0.013 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER226of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 19 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM FEMALES

95580 6.38 7.68 16.0 44.1 57.4 20.8 36.2 1272. 12.2 15.1 95589 7.92 7.77 15.2 42.2 54.4 19.6 36.0 1430. 12.3 16.1 95593 7.06 8.11 16.3 44.4 54.7 20.1 36.8 1644. 13.0 18.1 95597 7.08 7.65 16.3 43.0 56.2 21.3 37.9 1736. 13.4 18.5 95598 6.64 7.57 16.0 42.8 56.5 21.1 37.3 1398. 11.6 17.9

MEAN 7.02 7.76 16.0 43.3 55.8 20.6 36.8 1496. 12.5 17.1 S.D. 0.585 0.210 0.45 0.92 1.26 0.71 0.78 189.5 0.71 1.47 S.E. 0.262 0.094 0.20 0.41 0.56 0.32 0.35 84.7 0.32 0.66 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER227of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 20 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM FEMALES

95580 2.1 163.2 10.5 86.3 1.3 1.4 0.1 0.3 95589 2.2 174.7 7.8 88.9 1.5 0.8 0.2 0.8 95593 1.8 148.5 10.9 86.2 1.8 0.6 0.1 0.4 95597 2.1 157.1 10.1 86.2 1.4 1.3 0.2 0.8 95598 2.3 171.0 15.0 81.4 1.1 1.8 0.3 0.4

MEAN 2.1 162.9 10.9 85.8 1.4 1.2 0.2 0.5 S.D. 0.19 10.56 2.61 2.72 0.26 0.48 0.08 0.24 S.E. 0.08 4.72 1.17 1.22 0.12 0.22 0.04 0.11 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER228of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 21 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM FEMALES

95580 0.67 5.50 0.08 0.09 0.01 0.02 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95589 0.61 7.04 0.12 0.06 0.02 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95593 0.77 6.08 0.12 0.04 0.01 0.03 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95597 0.72 6.10 0.10 0.09 0.01 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95598 1.00 5.41 0.07 0.12 0.02 0.03 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 0.75 6.03 0.10 0.08 0.01 0.04 S.D. 0.150 0.651 0.023 0.031 0.005 0.019 S.E. 0.067 0.291 0.010 0.014 0.002 0.008 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER229of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 22 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM FEMALES

95581 6.45 7.50 15.5 41.5 55.4 20.7 37.4 1389. 11.9 15.9 95583 6.49 8.24 16.2 45.1 54.7 19.6 35.9 1458. 12.7 17.2 95590 5.33 7.77 15.3 42.4 54.7 19.7 36.0 1492. 12.5 16.9 95592 7.54 7.83 15.6 42.6 54.4 19.9 36.6 1734. 12.3 15.8 95601 8.30 7.17 14.5 39.6 55.3 20.2 36.5 1040. 10.9 15.3

MEAN 6.82 7.70 15.4 42.2 54.9 20.0 36.5 1423. 12.1 16.2 S.D. 1.137 0.398 0.61 1.99 0.43 0.44 0.60 250.3 0.71 0.80 S.E. 0.509 0.178 0.27 0.89 0.19 0.20 0.27 111.9 0.32 0.36 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER230of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 23 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM FEMALES

95581 2.4 176.4 15.7 80.7 1.7 1.3 0.2 0.4 95583 2.4 198.1 15.0 82.0 1.6 0.8 0.1 0.5 95590 2.8 218.2 17.6 79.1 1.9 0.7 0.1 0.6 95592 2.9 223.6 13.2 83.4 1.5 1.1 0.3 0.5 95601 2.8 197.2 17.4 79.1 2.1 0.7 0.2 0.5

MEAN 2.7 202.7 15.8 80.9 1.8 0.9 0.2 0.5 S.D. 0.24 18.84 1.82 1.87 0.24 0.27 0.08 0.07 S.E. 0.11 8.43 0.81 0.84 0.11 0.12 0.04 0.03 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER231of435TABLE A19 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 24 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM FEMALES

95581 1.01 5.21 0.11 0.09 0.01 0.03 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95583 0.97 5.32 0.10 0.05 0.01 0.03 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95590 0.94 4.21 0.10 0.04 0.00 0.03 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95592 0.99 6.29 0.11 0.08 0.03 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95601 1.44 6.57 0.17 0.06 0.01 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 1.07 5.52 0.12 0.06 0.01 0.03 S.D. 0.208 0.942 0.029 0.021 0.011 0.005 S.E. 0.093 0.421 0.013 0.009 0.005 0.002 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER PHEMAv1.34 03/24/2008232of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM MALES

95557 11.63 8.18 17.2 48.3 59.0 21.0 35.6 1394. 13.9 17.7 95562 8.20 8.20 17.2 47.5 57.9 20.9 36.1 955. 14.4 17.2 95567 8.42 7.84 16.6 46.1 58.8 21.2 36.0 1086. 13.9 19.9 95571 10.44 8.27 16.7 47.8 57.8 20.2 35.0 1505. 11.8 15.9 95575 CLT CLT CLT CLT CLT CLT CLT CLT 12.7 20.0

MEAN 9.67 8.12 16.9 47.4 58.4 20.8 35.7 1235. 13.3 18.1 S.D. 1.649 0.192 0.32 0.94 0.61 0.43 0.50 257.4 1.06 1.78 S.E. 0.825 0.096 0.16 0.47 0.31 0.22 0.25 128.7 0.48 0.80 N 4 4 4 4 4 4 4 4 5 5

----------------------------------------------------------------------------------------------------------------------------------- CLT = CLOTTED

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER233of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM MALES

95557 2.6 211.5 8.5 86.2 2.7 1.3 0.5 0.9 95562 1.5 125.1 12.4 83.6 1.7 1.4 0.4 0.6 95567 2.0 156.5 10.5 84.9 2.2 1.6 0.2 0.5 95571 1.6 134.4 8.4 87.5 2.4 0.3 0.3 1.0 95575 CLT CLT CLT CLT CLT CLT CLT CLT

MEAN 1.9 156.9 10.0 85.6 2.3 1.2 0.4 0.8 S.D. 0.50 38.72 1.90 1.68 0.42 0.58 0.13 0.24 S.E. 0.25 19.36 0.95 0.84 0.21 0.29 0.06 0.12 N 4 4 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- CLT = CLOTTED

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER234of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM MALES

95557 0.98 10.02 0.31 0.15 0.06 0.10 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95562 1.01 6.86 0.14 0.12 0.03 0.05 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95567 0.88 7.15 0.18 0.14 0.02 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95571 0.88 9.14 0.25 0.03 0.03 0.10 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 95575 CLT CLT CLT CLT CLT CLT PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 0.94 8.29 0.22 0.11 0.04 0.07 S.D. 0.068 1.534 0.075 0.055 0.017 0.032 S.E. 0.034 0.767 0.038 0.027 0.009 0.016 N 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- CLT = CLOTTED

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER235of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- WHITE RED HEMO- HEMATO- ANIMAL CELLS CELLS GLOBIN CRIT MCV MCH MCHC PLATELET PROTIME APTT

----------------------------------------------------------------------------------------------------------------------------------- thous/uL mil/uL g/dL % fL pg g/dL thous/uL seconds seconds

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM FEMALES

6664 8.64 8.18 16.6 44.9 54.9 20.3 37.0 1608. 12.4 17.0 6674 8.06 8.11 17.0 47.2 58.2 21.0 36.1 1220. 12.8 16.7 6686 8.19 7.82 15.6 41.9 53.5 20.0 37.3 1584. CLT CLT 6712 8.89 8.50 16.6 46.4 54.6 19.5 35.8 1225. 11.8 17.7 6717 8.46 8.00 15.8 43.0 53.8 19.8 36.8 1426. 12.0 17.5

MEAN 8.45 8.12 16.3 44.7 55.0 20.1 36.6 1413. 12.3 17.2 S.D. 0.335 0.251 0.59 2.23 1.88 0.57 0.63 187.1 0.44 0.46 S.E. 0.150 0.112 0.27 1.00 0.84 0.26 0.28 83.7 0.22 0.23 N 5 5 5 5 5 5 5 5 4 4

----------------------------------------------------------------------------------------------------------------------------------- CLT = CLOTTED

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER, mil/uL = MILLIONS/MICROLITER, fL = FEMTOLITERS, pg = PICOGRAMS, g/dL = GRAMS/DECILITER236of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- RETIC- RETIC NEUTRO- LYMPH- EOSIN- LG UNST- ANIMAL ULOCYTE ABSOLUTE PHIL OCYTE MONOCYTE OPHIL BASOPHIL AIN CELL

----------------------------------------------------------------------------------------------------------------------------------- % thous/uL % % % % % %

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM FEMALES

6664 2.2 177.8 9.0 87.8 1.9 0.5 0.3 0.5 6674 2.0 163.2 7.1 89.5 1.8 0.9 0.2 0.6 6686 1.2 95.1 6.4 90.2 1.7 0.8 0.1 0.7 6712 2.1 180.7 16.7 78.1 3.0 1.4 0.3 0.5 6717 1.8 142.9 9.7 85.9 2.2 1.5 0.2 0.4

MEAN 1.9 151.9 9.8 86.3 2.1 1.0 0.2 0.5 S.D. 0.40 35.13 4.10 4.88 0.53 0.42 0.08 0.11 S.E. 0.18 15.71 1.83 2.18 0.24 0.19 0.04 0.05 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER237of435TABLE A20 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL HEMATOLOGY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- NEU LYMPH MONO EOS BASO LUC PLATELET RBC ANIMAL ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ABSOLUTE ESTIMATE MORPHOLOGY

----------------------------------------------------------------------------------------------------------------------------------- thous/uL thous/uL thous/uL thous/uL thous/uL thous/uL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM FEMALES

6664 0.78 7.59 0.16 0.05 0.02 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 6674 0.57 7.22 0.14 0.07 0.01 0.05 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 6686 0.53 7.39 0.14 0.07 0.01 0.06 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 6712 1.49 6.95 0.27 0.12 0.03 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED 6717 0.82 7.27 0.19 0.13 0.02 0.04 PLATELET ESTIMATE AND MORPHOLOGY NOT REVIEWED

MEAN 0.84 7.28 0.18 0.09 0.02 0.05 S.D. 0.386 0.235 0.054 0.035 0.008 0.009 S.E. 0.173 0.105 0.024 0.016 0.004 0.004 N 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- thous/uL = THOUSANDS/MICROLITER PHEMAv1.34 03/24/2008238of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM MALES

95555 4.3 6.4 2.1 2.06 0.09 13.0 0.2 320. 40. 89. 95556 4.3 6.5 2.2 1.92 0.10 10.2 0.2 276. 37. 88. 95558 4.4 6.0 1.5 2.86 0.11 12.9 0.2 297. 37. 101. 95574 4.4 6.2 1.9 2.31 0.08 10.9 0.1 244. 27. 80. 95577 4.3 6.5 2.2 1.96 0.06 8.8 0.1 161. 28. 75.

MEAN 4.3 6.3 2.0 2.22 0.09 11.2 0.2 260. 34. 87. S.D. 0.05 0.22 0.29 0.388 0.019 1.80 0.05 61.8 5.9 9.9 S.E. 0.02 0.10 0.13 0.173 0.009 0.81 0.02 27.6 2.6 4.4 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER239of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM MALES

95555 127. 57. 10.8 101. 9.8 4.93 145. 104. 95556 132. 64. 10.6 102. 9.5 5.00 146. 60. 95558 109. 49. 10.9 103. 9.7 4.92 146. 35. 95574 126. 46. 10.9 103. 8.7 4.34 146. 45. 95577 119. 55. 10.8 104. 9.1 4.38 146. 54.

MEAN 123. 54. 10.8 103. 9.4 4.71 146. 60. S.D. 8.9 7.0 0.12 1.1 0.46 0.325 0.4 26.6 S.E. 4.0 3.2 0.05 0.5 0.20 0.145 0.2 11.9 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER240of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM MALES

95559 4.2 6.3 2.1 2.02 0.12 12.9 0.2 114. 40. 104. 95561 4.2 6.0 1.8 2.29 0.11 10.9 0.2 206. 34. 93. 95566 4.4 6.2 1.8 2.44 0.09 13.0 0.1 290. 35. 89. 95573 4.3 6.4 2.1 2.00 0.08 10.7 0.1 184. 39. 91. 95576 4.4 6.4 2.0 2.16 0.07 11.4 0.2 318. 28. 91.

MEAN 4.3 6.3 2.0 2.18 0.09 11.8 0.2 222. 35. 94. S.D. 0.10 0.17 0.15 0.186 0.021 1.10 0.05 82.5 4.8 6.0 S.E. 0.04 0.07 0.07 0.083 0.009 0.49 0.02 36.9 2.1 2.7 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER241of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM MALES

95559 106. 69. 10.8 102. 8.7 4.61 145. 40. 95561 117. 77. 11.1 103. 8.8 4.81 146. 51. 95566 90. 53. 11.0 104. 9.0 4.97 147. 52. 95573 103. 69. 11.2 103. 9.1 4.39 146. 51. 95576 109. 45. 10.8 104. 9.9 5.05 147. 43.

MEAN 105. 63. 11.0 103. 9.1 4.77 146. 47. S.D. 9.9 13.1 0.18 0.8 0.47 0.269 0.8 5.5 S.E. 4.4 5.9 0.08 0.4 0.21 0.120 0.4 2.5 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER242of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM MALES

95560 4.5 6.4 1.9 2.42 0.10 11.4 0.1 184. 57. 89. 95564 4.2 6.4 2.2 1.94 0.07 10.5 0.2 174. 28. 66. 95565 4.4 6.3 1.8 2.43 0.10 13.0 0.2 261. 71. 180. 95569 4.7 6.9 2.2 2.11 0.10 10.6 0.2 237. 28. 80. 95578 4.3 6.3 2.0 2.23 0.10 10.6 0.2 240. 64. 87.

MEAN 4.4 6.5 2.0 2.23 0.09 11.2 0.2 219. 50. 100. S.D. 0.19 0.25 0.18 0.209 0.013 1.06 0.04 38.0 20.3 45.4 S.E. 0.09 0.11 0.08 0.093 0.006 0.47 0.02 17.0 9.1 20.3 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER243of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM MALES

95560 110. 55. 10.9 104. 8.9 4.89 145. 45. 95564 131. 95. 11.4 103. 9.0 4.38 147. 82. 95565 108. 59. 11.0 106. 9.2 4.97 146. 62. 95569 132. 64. 11.1 104. 8.8 5.16 148. 44. 95578 108. 69. 10.8 104. 9.2 5.16 145. 38.

MEAN 118. 68. 11.0 104. 9.0 4.91 146. 54. S.D. 12.5 15.8 0.23 1.1 0.18 0.320 1.3 17.9 S.E. 5.6 7.1 0.10 0.5 0.08 0.143 0.6 8.0 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER244of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM MALES

95563 4.4 6.2 1.8 2.36 0.08 8.5 0.2 187. 45. 113. 95568 4.4 6.4 2.1 2.12 0.09 11.2 0.2 285. 40. 79. 95570 3.7 5.9 2.2 1.73 0.16 9.6 0.2 201. 31. 64. 95572 4.5 6.6 2.1 2.12 0.12 10.5 0.1 252. 37. 94.

MEAN 4.3 6.3 2.1 2.08 0.11 10.0 0.2 231. 38. 88. S.D. 0.37 0.30 0.17 0.261 0.036 1.17 0.05 45.4 5.9 21.0 S.E. 0.18 0.15 0.09 0.130 0.018 0.58 0.03 22.7 2.9 10.5 N 4 4 4 4 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER245of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM MALES

95563 105. 63. 10.4 103. 8.5 4.70 145. 50. 95568 103. 58. 10.9 104. 9.1 4.84 146. 38. 95570 110. 53. 10.8 103. 9.4 4.59 145. 37. 95572 114. 75. 10.9 102. 9.1 4.63 146. 41.

MEAN 108. 62. 10.8 103. 9.0 4.69 146. 42. S.D. 5.0 9.4 0.24 0.8 0.38 0.110 0.6 5.9 S.E. 2.5 4.7 0.12 0.4 0.19 0.055 0.3 3.0 N 4 4 4 4 4 4 4 4

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER246of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 9 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM FEMALES

95587 4.5 6.8 2.3 1.95 0.06 13.9 0.2 143. 37. 103. 95591 4.7 7.1 2.5 1.89 0.10 13.4 0.3 116. 37. 74. 95594 4.8 7.3 2.5 1.92 0.08 13.3 0.3 72. 35. 83. 95599 4.4 6.8 2.4 1.89 0.09 12.7 0.3 112. 25. 74. 95600 4.7 6.6 1.9 2.42 0.14 14.7 0.3 142. 24. 84.

MEAN 4.6 6.9 2.3 2.01 0.09 13.6 0.3 117. 32. 84. S.D. 0.16 0.28 0.25 0.228 0.030 0.75 0.04 28.9 6.5 11.8 S.E. 0.07 0.12 0.11 0.102 0.013 0.33 0.02 12.9 2.9 5.3 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER247of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 10 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM FEMALES

95587 119. 89. 11.1 103. 8.3 5.26 146. 50. 95591 107. 82. 11.3 103. 8.6 5.15 146. 39. 95594 104. 92. 11.1 99. 7.7 4.42 144. 59. 95599 116. 79. 11.2 104. 8.9 4.63 147. 33. 95600 116. 49. 10.2 103. 6.3 4.35 146. 34.

MEAN 112. 78. 11.0 102. 8.0 4.76 146. 43. S.D. 6.5 17.1 0.44 1.9 1.03 0.419 1.1 11.2 S.E. 2.9 7.7 0.20 0.9 0.46 0.187 0.5 5.0 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER248of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 11 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM FEMALES

95579 4.4 6.8 2.4 1.81 0.07 14.3 0.3 135. 26. 78. 95586 4.5 6.9 2.4 1.85 0.11 13.0 0.3 120. 33. 68. 95588 4.3 6.6 2.3 1.84 0.06 15.1 0.2 113. 31. 84. 95595 4.7 6.8 2.2 2.15 0.08 13.3 0.2 115. 34. 96. 95603 5.0 7.1 2.0 2.49 0.09 13.7 0.3 111. 27. 80.

MEAN 4.6 6.8 2.3 2.03 0.08 13.9 0.3 119. 30. 81. S.D. 0.28 0.18 0.17 0.293 0.019 0.84 0.05 9.7 3.6 10.2 S.E. 0.12 0.08 0.07 0.131 0.009 0.37 0.02 4.3 1.6 4.5 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER249of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 12 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1250 PPM FEMALES

95579 106. 115. 11.0 104. 8.2 4.84 147. 56. 95586 104. 109. 11.1 102. 7.7 4.32 145. 63. 95588 126. 94. 10.9 105. 7.6 4.95 144. 26. 95595 113. 61. 11.1 104. 7.9 4.84 145. 38. 95603 117. 60. 10.8 104. 8.3 4.52 146. 32.

MEAN 113. 88. 11.0 104. 7.9 4.69 145. 43. S.D. 8.9 26.1 0.13 1.1 0.30 0.264 1.1 15.8 S.E. 4.0 11.7 0.06 0.5 0.14 0.118 0.5 7.1 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER250of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 13 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM FEMALES

95580 4.4 6.7 2.2 1.98 0.11 11.7 0.3 124. 42. 87. 95589 4.7 6.8 2.1 2.24 0.13 9.3 0.3 153. 66. 84. 95593 4.4 6.6 2.2 2.00 0.11 14.1 0.2 150. 34. 65. 95597 4.6 6.6 2.1 2.23 0.07 10.1 0.2 124. 40. 84. 95598 4.7 6.8 2.0 2.35 0.09 8.9 0.2 162. 25. 100.

MEAN 4.6 6.7 2.1 2.16 0.10 10.8 0.2 143. 41. 84. S.D. 0.15 0.10 0.08 0.162 0.023 2.12 0.05 17.5 15.3 12.5 S.E. 0.07 0.04 0.04 0.073 0.010 0.95 0.02 7.8 6.8 5.6 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER251of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 14 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 2500 PPM FEMALES

95580 139. 77. 11.3 102. 8.3 4.95 146. 37. 95589 130. 95. 11.1 100. 7.3 5.22 141. 43. 95593 114. 82. 11.2 104. 9.1 5.04 147. 37. 95597 114. 68. 11.0 104. 8.2 4.91 145. 39. 95598 109. 70. 10.3 104. 8.0 4.88 144. 31.

MEAN 121. 78. 11.0 103. 8.2 5.00 145. 37. S.D. 12.7 10.8 0.40 1.8 0.65 0.137 2.3 4.3 S.E. 5.7 4.8 0.18 0.8 0.29 0.061 1.0 1.9 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER252of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 15 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM FEMALES

95581 4.3 6.4 2.1 2.01 0.09 14.4 0.2 110. 43. 94. 95583 4.3 6.7 2.4 1.80 0.13 15.8 0.3 128. 30. 91. 95590 4.4 6.5 2.1 2.08 0.08 12.2 0.2 87. 22. 66. 95592 4.4 6.5 2.0 2.17 0.11 14.6 0.2 116. 33. 119. 95601 3.9 5.7 1.8 2.14 0.05 11.8 0.2 96. 39. 91.

MEAN 4.3 6.4 2.1 2.04 0.09 13.8 0.2 107. 33. 92. S.D. 0.21 0.38 0.22 0.147 0.030 1.70 0.04 16.2 8.1 18.8 S.E. 0.09 0.17 0.10 0.066 0.014 0.76 0.02 7.2 3.6 8.4 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER253of435TABLE A21 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 16 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 5000 PPM FEMALES

95581 109. 63. 10.8 103. 7.8 4.69 145. 40. 95583 114. 75. 10.9 103. 8.8 5.45 146. 37. 95590 111. 57. 10.5 105. 8.6 4.91 146. 38. 95592 104. 85. 10.8 102. 8.6 4.83 143. 53. 95601 111. 70. 10.2 103. 8.6 4.54 143. 46.

MEAN 110. 70. 10.6 103. 8.5 4.88 145. 43. S.D. 3.7 10.8 0.29 1.1 0.39 0.346 1.5 6.7 S.E. 1.7 4.8 0.13 0.5 0.17 0.155 0.7 3.0 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER PCHEv4.03 03/24/2008254of435TABLE A22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM MALES

95557 4.4 6.5 2.2 1.99 0.14 12.0 0.3 220. 44. 100. 95562 4.3 6.3 2.1 2.06 0.10 13.4 0.1 163. 36. 118. 95567 4.4 6.5 2.1 2.11 0.10 10.7 0.2 169. 32. 79. 95571 4.5 6.8 2.3 1.93 0.10 13.2 0.2 164. 59. 86. 95575 4.6 6.8 2.3 2.02 0.08 9.4 0.3 206. 31. 77.

MEAN 4.4 6.6 2.2 2.02 0.10 11.7 0.2 184. 40. 92. S.D. 0.11 0.22 0.10 0.068 0.022 1.70 0.08 26.7 11.6 17.1 S.E. 0.05 0.10 0.04 0.031 0.010 0.76 0.04 11.9 5.2 7.6 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER255of435TABLE A22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM MALES

95557 155. 65. 11.0 98. 10.4 5.17 143. 35. 95562 125. 77. 10.7 101. 8.7 4.60 144. 67. 95567 111. 66. 11.2 100. 9.6 4.91 145. 41. 95571 142. 83. 11.3 99. 10.4 6.15 145. 56. 95575 129. 71. 11.9 102. 10.6 6.19 149. 60.

MEAN 132. 72. 11.2 100. 9.9 5.40 145. 52. S.D. 16.8 7.6 0.44 1.6 0.79 0.728 2.3 13.4 S.E. 7.5 3.4 0.20 0.7 0.35 0.326 1.0 6.0 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER256of435TABLE A22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- TOTAL A/G TOTAL UREA CREAT- ALKALINE ALANINE ASPARTAT ANIMAL ALBUMIN PROTEIN GLOBULIN RATIO BILI NITROGEN ININE PHOS’TSE TRANSFER TRANSFER

----------------------------------------------------------------------------------------------------------------------------------- g/dL g/dL g/dL mg/dL mg/dL mg/dL U/L U/L U/L

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM FEMALES

6664 4.7 6.6 2.0 2.37 0.12 15.5 0.2 76. 33. 105. 6674 4.6 6.5 2.0 2.35 0.15 12.0 0.3 170. 31. 73. 6686 4.4 6.1 1.8 2.47 0.14 12.4 0.2 106. 43. 101. 6712 4.5 6.5 2.0 2.29 0.08 12.5 0.2 126. 30. 85. 6717 4.4 6.2 1.9 2.35 0.10 11.9 0.2 95. 55. 83.

MEAN 4.5 6.4 1.9 2.37 0.12 12.9 0.2 115. 38. 89. S.D. 0.13 0.22 0.09 0.065 0.029 1.50 0.04 35.9 10.6 13.3 S.E. 0.06 0.10 0.04 0.029 0.013 0.67 0.02 16.0 4.7 5.9 N 5 5 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, U/L = INTERNATIONAL UNIT/LITER, g/dL = GRAMS/DECILITER257of435TABLE A22 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL SERUM CHEMISTRY VALUES DAY 5

----------------------------------------------------------------------------------------------------------------------------------- CHOL- PHOS- POTAS- TRIGLY- ANIMAL GLUCOSE ESTEROL CALCIUM CHLORIDE PHORUS SIUM SODIUM CERIDE

----------------------------------------------------------------------------------------------------------------------------------- mg/dL mg/dL mg/dL mEq/L mg/dL mEq/L mEq/L mg/dL

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 1800 PPM FEMALES

6664 144. 91. 10.5 97. 7.9 4.77 143. 32. 6674 109. 95. 10.9 100. 9.1 5.00 144. 57. 6686 119. 69. 10.6 101. 8.1 4.94 142. 30. 6712 109. 57. 10.5 101. 9.0 4.77 143. 34. 6717 104. 50. 11.1 101. 9.1 4.51 142. 27.

MEAN 117. 72. 10.7 100. 8.6 4.80 143. 36. S.D. 16.0 20.0 0.27 1.7 0.59 0.191 0.8 12.0 S.E. 7.2 9.0 0.12 0.8 0.26 0.085 0.4 5.4 N 5 5 5 5 5 5 5 5

----------------------------------------------------------------------------------------------------------------------------------- mg/dL = MILLIGRAMS/DECILITER, mEq/L = MILLIEQUIVALENTS/LITER PCHEv4.03 03/24/2008258of435TABLE A23 (UNSCHEDULED DEATH) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95554 GROUP 4: 5000 PPM MALE FOUND DEAD 02/07/08 DATE OF DEATH: 02/07/08 GRADE

----------------------------------------------------------------------------------------------------------------------------------- GENERAL COMMENT GROSS: NOT POSITIVELY IDENTIFIED P FINAL BODY WT(G) 336. BRONCHIAL LYMPH NODES LUNGS GROSS: NOT FULLY COLLAPSED P ALL LOBES SKIN GROSS: MATTING, RED P NASAL; BUCCAL SPLEEN GROSS: AREA(S), WHITE P MULTIPLE, IRREGULARLY SHAPED NO SIGNIFICANT CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR JOINT BRAIN CECUM COLON DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT PGRHv4.59 03/24/2008259of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95555 GROUP 1: 0 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.02 0.633 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 10.55 3.307 JOINT BRAIN CECUM COLON KIDNEYS 2.39 0.749 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.26 0.395 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 319. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT260of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95556 GROUP 1: 0 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. KIDNEYS GROSS: AREA(S), DEPRESSED P BRAIN 2.08 0.665 FEW, IRREGULARLY SHAPED, IN CORTEX, RIGHT LIVER 9.20 2.939 LUNGS GROSS: AREA(S), DARK RED P KIDNEYS 2.56 0.818 FEW, IRREGULARLY SHAPED, ALL LOBES LUNGS 1.20 0.383 NO SIGNIFICANT FINAL BODY WT(G) 313. CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR JOINT BRAIN CECUM COLON DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT261of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95558 GROUP 1: 0 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.92 0.678 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 8.30 2.933 JOINT BRAIN CECUM COLON KIDNEYS 2.20 0.777 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.26 0.445 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 283. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT262of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95574 GROUP 1: 0 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.89 0.647 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 9.08 3.110 JOINT BRAIN CECUM COLON KIDNEYS 2.12 0.726 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.21 0.414 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 292. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT263of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95577 GROUP 1: 0 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.08 0.615 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 10.86 3.213 JOINT BRAIN CECUM COLON KIDNEYS 2.72 0.805 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.41 0.417 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 338. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT264of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95559 GROUP 2: 1250 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.97 0.659 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 8.91 2.980 JOINT BRAIN CECUM COLON KIDNEYS 2.24 0.749 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.10 0.368 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 299. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT265of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95561 GROUP 2: 1250 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. THYMUS GROSS: AREA(S), DARK RED P BRAIN 1.95 0.644 MULTIPLE, PINPOINT LIVER 9.16 3.023 NO SIGNIFICANT KIDNEYS 2.28 0.752 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.28 0.422 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 303. DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT266of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95566 GROUP 2: 1250 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.92 0.730 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.75 2.567 JOINT BRAIN CECUM COLON KIDNEYS 2.01 0.764 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.11 0.422 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 263. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT267of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 9 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95573 GROUP 2: 1250 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.97 0.668 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 9.15 3.102 JOINT BRAIN CECUM COLON KIDNEYS 2.41 0.817 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.25 0.424 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 295. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT268of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 10 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95576 GROUP 2: 1250 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. KIDNEYS GROSS: AREA(S), DEPRESSED P BRAIN 1.99 0.638 FEW, PINPOINT, IN CORTEX, LEFT LIVER 9.50 3.045 NO SIGNIFICANT KIDNEYS 2.58 0.827 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.33 0.426 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 312. DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT269of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 11 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95560 GROUP 3: 2500 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.78 0.667 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 7.98 2.989 JOINT BRAIN CECUM COLON KIDNEYS 2.23 0.835 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.05 0.393 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 267. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT270of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 12 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95564 GROUP 3: 2500 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.92 0.636 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 9.55 3.162 JOINT BRAIN CECUM COLON KIDNEYS 2.22 0.735 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.25 0.414 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 302. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT271of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 13 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95565 GROUP 3: 2500 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.95 0.633 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 8.55 2.776 JOINT BRAIN CECUM COLON KIDNEYS 2.24 0.727 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.16 0.377 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 308. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT272of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 14 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95569 GROUP 3: 2500 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. STOMACH GROSS: CYST(S) P BRAIN 2.00 0.702 FEW, IRREGULARLY SHAPED, NONGLANDULAR PORTION LIVER 7.99 2.804 NO SIGNIFICANT KIDNEYS 2.31 0.811 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.19 0.418 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 285. DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT273of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 15 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95578 GROUP 3: 2500 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.01 0.710 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 7.93 2.802 JOINT BRAIN CECUM COLON KIDNEYS 2.17 0.767 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.15 0.406 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 283. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT274of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 16 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95563 GROUP 4: 5000 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.92 0.610 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 9.54 3.029 JOINT BRAIN CECUM COLON KIDNEYS 2.48 0.787 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.39 0.441 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 315. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT275of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 17 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95568 GROUP 4: 5000 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.99 0.703 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 8.05 2.845 JOINT BRAIN CECUM COLON KIDNEYS 2.35 0.830 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.38 0.488 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 283. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT276of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 18 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95570 GROUP 4: 5000 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. TEETH GROSS: MALALIGNED P BRAIN 2.01 0.720 UPPER INCISOR, BILATERAL; CEO MALALIGNED LIVER 8.20 2.939 NO SIGNIFICANT KIDNEYS 2.14 0.767 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.19 0.427 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 279. DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT277of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 19 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95572 GROUP 4: 5000 PPM MALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.96 0.737 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 7.50 2.820 JOINT BRAIN CECUM COLON KIDNEYS 2.09 0.786 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.03 0.387 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 266. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT278of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 20 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95587 GROUP 1: 0 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.00 1.087 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.46 2.967 JOINT BRAIN CECUM COLON KIDNEYS 1.43 0.777 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.01 0.549 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 184. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT279of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 21 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95591 GROUP 1: 0 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.85 0.881 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.89 3.281 JOINT BRAIN CECUM COLON KIDNEYS 1.57 0.748 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.14 0.543 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 210. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT280of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 22 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95594 GROUP 1: 0 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. UTERUS GROSS: CONTENTS, CLEAR FLUID P BRAIN 1.86 0.899 BOTH HORNS LIVER 6.17 2.981 NO SIGNIFICANT KIDNEYS 1.47 0.710 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 0.99 0.478 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 207. DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT281of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 23 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95599 GROUP 1: 0 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. UTERUS GROSS: CONTENTS, CLEAR FLUID P BRAIN 1.70 0.885 BOTH HORNS LIVER 5.92 3.083 NO SIGNIFICANT KIDNEYS 1.29 0.672 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.00 0.521 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 192. DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT282of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 24 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95600 GROUP 1: 0 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. UTERUS GROSS: CONTENTS, CLEAR FLUID P BRAIN 1.90 0.960 BOTH HORNS LIVER 5.95 3.005 NO SIGNIFICANT KIDNEYS 1.39 0.702 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.08 0.545 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 198. DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT283of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 25 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95579 GROUP 2: 1250 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.78 0.942 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.12 3.238 JOINT BRAIN CECUM COLON KIDNEYS 1.34 0.709 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.01 0.534 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 189. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT284of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 26 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95586 GROUP 2: 1250 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.81 0.887 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.52 3.196 JOINT BRAIN CECUM COLON KIDNEYS 1.55 0.760 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.16 0.569 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 204. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT285of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 27 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95588 GROUP 2: 1250 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. UTERUS GROSS: CONTENTS, CLEAR FLUID P BRAIN 1.82 0.929 BOTH HORNS LIVER 6.10 3.112 NO SIGNIFICANT KIDNEYS 1.47 0.750 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.12 0.571 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 196. DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT286of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 28 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95595 GROUP 2: 1250 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.96 0.990 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.91 2.985 JOINT BRAIN CECUM COLON KIDNEYS 1.45 0.732 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.06 0.535 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 198. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT287of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 29 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95603 GROUP 2: 1250 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.74 0.926 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.74 3.053 JOINT BRAIN CECUM COLON KIDNEYS 1.47 0.782 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.88 0.468 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 188. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT288of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 30 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95580 GROUP 3: 2500 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.77 0.908 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.74 2.944 JOINT BRAIN CECUM COLON KIDNEYS 1.55 0.795 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.88 0.451 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 195. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT289of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 31 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95589 GROUP 3: 2500 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.77 0.868 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.26 3.069 JOINT BRAIN CECUM COLON KIDNEYS 1.34 0.657 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.86 0.422 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 204. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT290of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 32 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95593 GROUP 3: 2500 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.75 0.907 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.34 2.767 JOINT BRAIN CECUM COLON KIDNEYS 1.37 0.710 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.86 0.446 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 193. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT291of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 33 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95597 GROUP 3: 2500 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.00 0.943 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.73 3.175 JOINT BRAIN CECUM COLON KIDNEYS 1.63 0.769 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.13 0.533 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 212. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT292of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 34 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95598 GROUP 3: 2500 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.81 1.034 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.62 3.211 JOINT BRAIN CECUM COLON KIDNEYS 1.28 0.731 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.92 0.526 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 175. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT293of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 35 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95581 GROUP 4: 5000 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.73 0.961 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.08 2.822 JOINT BRAIN CECUM COLON KIDNEYS 1.41 0.783 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.02 0.567 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 180. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT294of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 36 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95583 GROUP 4: 5000 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.89 0.969 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.59 2.867 JOINT BRAIN CECUM COLON KIDNEYS 1.34 0.687 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.03 0.528 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 195. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT295of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 37 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95590 GROUP 4: 5000 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.87 1.000 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.56 2.973 JOINT BRAIN CECUM COLON KIDNEYS 1.28 0.684 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.98 0.524 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 187. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT296of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 38 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95592 GROUP 4: 5000 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.94 0.946 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.18 3.015 JOINT BRAIN CECUM COLON KIDNEYS 1.45 0.707 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.94 0.459 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 205. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT297of435TABLE A24 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 39 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95601 GROUP 4: 5000 PPM FEMALE SCHEDULED EUTH 02/11/08 DATE OF DEATH: 02/11/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. STOMACH GROSS: CONTENTS, YELLOW P BRAIN 1.81 0.910 SKIN GROSS: SCABBING P LIVER 6.15 3.090 VENTRAL THORACIC; CEO SCABBING KIDNEYS 1.45 0.729 NO SIGNIFICANT LUNGS 1.10 0.553 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR FINAL BODY WT(G) 199. JOINT BRAIN CECUM COLON DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND SKELETAL MUSCLE SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT PGRHv4.59 03/24/2008298of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95557 GROUP 1: 1800 PPM MALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.12 0.697 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 9.90 3.257 JOINT BRAIN CECUM COLON KIDNEYS 2.49 0.819 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.39 0.457 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 304. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT299of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95562 GROUP 1: 1800 PPM MALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. GENERAL COMMENT GROSS: ORGAN DAMAGED AT NECROPSY P BRAIN 2.05 0.623 THYROID GLANDS, BILATERAL LIVER 9.89 3.006 NO SIGNIFICANT KIDNEYS 2.44 0.742 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.37 0.416 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 329. DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT300of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95567 GROUP 1: 1800 PPM MALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.97 0.659 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 8.84 2.957 JOINT BRAIN CECUM COLON KIDNEYS 2.66 0.890 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.35 0.452 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 299. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT301of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95571 GROUP 1: 1800 PPM MALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. DUODENUM GROSS: CONTENTS, DARK RED P BRAIN 2.03 0.625 ILEUM GROSS: CONTENTS, DARK RED P LIVER 10.29 3.166 PANCREAS GROSS: PALE P KIDNEYS 2.68 0.825 STOMACH GROSS: CONTENTS, DARK RED P LUNGS 1.24 0.382 NO SIGNIFICANT FINAL BODY WT(G) 325. CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR JOINT BRAIN CECUM COLON EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT302of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 95575 GROUP 1: 1800 PPM MALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 2.16 0.643 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 10.24 3.048 JOINT BRAIN CECUM COLON KIDNEYS 2.67 0.795 DUODENUM EPIDIDYMIDES ESOPHAGUS EYES/OPTIC N. LUNGS 1.34 0.399 HEART HARDERIAN GLANDS ILEUM JEJUNUM FINAL BODY WT(G) 336. KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX NERVE, SCIATIC PANCREAS PHARYNX PITUITARY PROSTATE RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN SEMINAL VESICLES TESTES THYROID GLANDS THYMUS TRACHEA URINARY BLADDER PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT303of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 6664 GROUP 1: 1800 PPM FEMALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. UTERUS GROSS: CONTENTS, CLEAR FLUID P BRAIN 1.79 0.923 BOTH HORNS LIVER 6.14 3.165 NO SIGNIFICANT KIDNEYS 1.51 0.778 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LUNGS 1.02 0.526 JOINT BRAIN CECUM COLON FINAL BODY WT(G) 194. DUODENUM ESOPHAGUS EYES/OPTIC N. HEART HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT304of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 6674 GROUP 1: 1800 PPM FEMALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.89 0.922 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.52 3.180 JOINT BRAIN CECUM COLON KIDNEYS 1.55 0.756 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.99 0.483 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 205. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT305of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 6686 GROUP 1: 1800 PPM FEMALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.78 0.957 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.70 3.065 JOINT BRAIN CECUM COLON KIDNEYS 1.59 0.855 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 0.98 0.527 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 186. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT306of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 9 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 6712 GROUP 1: 1800 PPM FEMALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.82 1.058 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 5.27 3.064 JOINT BRAIN CECUM COLON KIDNEYS 1.46 0.849 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.05 0.610 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 172. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT307of435TABLE A25 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 10 INDIVIDUAL MACROSCOPIC FINDINGS

ANIMAL NO. 6717 GROUP 1: 1800 PPM FEMALE SCHEDULED EUTH 02/14/08 DATE OF DEATH: 02/14/08 STUDY DAY: 5 GRADE

----------------------------------------------------------------------------------------------------------------------------------- ORGAN WEIGHT ABS.(G) REL. NO SIGNIFICANT BRAIN 1.85 0.864 CHANGES OBSERVED GROSS:ADRENAL GLANDS AORTA STERNEBRAE FEMUR LIVER 6.54 3.056 JOINT BRAIN CECUM COLON KIDNEYS 1.80 0.841 DUODENUM ESOPHAGUS EYES/OPTIC N. HEART LUNGS 1.15 0.537 HARDERIAN GLANDS ILEUM JEJUNUM KIDNEYS FINAL BODY WT(G) 214. LYMPH NODE, MAND LAC. GLAND EXOR LIVER LYMPH NODE, MES LUNGS LARYNX MAMMARY GLAND NERVE, SCIATIC OVIDUCTS OVARIES PANCREAS PHARYNX PITUITARY RECTUM SPINAL CORD SAL. GLAND MAND STOMACH SKELETAL MUSCLE SKIN SPLEEN THYROID GLANDS THYMUS TRACHEA URINARY BLADDER UTERUS VAGINA CERVIX PEYER’S PATCHES LYMPH NODE, MED LYMPH NODE, BRON NASAL CAVITY

GROSS GRADE CODE: 1-SLIGHT, 2-MODERATE, 3-MARKED, P-PRESENT PGRHv4.59 03/24/2008308of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

MALE GROUP: 0 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95555 319. 2.02 10.55 2.39 1.26 95556 313. 2.08 9.20 2.56 1.20 95558 283. 1.92 8.30 2.20 1.26 95574 292. 1.89 9.08 2.12 1.21 95577 338. 2.08 10.86 2.72 1.41

MEAN 309. 2.00 9.60 2.40 1.27 S.D. 21.9 0.089 1.074 0.248 0.084 S.E. 9.8 0.040 0.480 0.111 0.038 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT309of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

MALE GROUP: 1250 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95559 299. 1.97 8.91 2.24 1.10 95561 303. 1.95 9.16 2.28 1.28 95566 263. 1.92 6.75 2.01 1.11 95573 295. 1.97 9.15 2.41 1.25 95576 312. 1.99 9.50 2.58 1.33

MEAN 294. 1.96 8.69 2.30 1.21 S.D. 18.6 0.026 1.107 0.211 0.104 S.E. 8.3 0.012 0.495 0.094 0.046 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT310of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

MALE GROUP: 2500 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95560 267. 1.78 7.98 2.23 1.05 95564 302. 1.92 9.55 2.22 1.25 95565 308. 1.95 8.55 2.24 1.16 95569 285. 2.00 7.99 2.31 1.19 95578 283. 2.01 7.93 2.17 1.15

MEAN 289. 1.93 8.40 2.23 1.16 S.D. 16.3 0.093 0.691 0.050 0.073 S.E. 7.3 0.041 0.309 0.022 0.033 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT311of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

MALE GROUP: 5000 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95563 315. 1.92 9.54 2.48 1.39 95568 283. 1.99 8.05 2.35 1.38 95570 279. 2.01 8.20 2.14 1.19 95572 266. 1.96 7.50 2.09 1.03

MEAN 286. 1.97 8.32 2.27 1.25 S.D. 20.8 0.039 0.866 0.182 0.172 S.E. 10.4 0.020 0.433 0.091 0.086 N 4 4 4 4 4

FBW = FINAL BODY WEIGHT312of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

FEMALE GROUP: 0 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95587 184. 2.00 5.46 1.43 1.01 95591 210. 1.85 6.89 1.57 1.14 95594 207. 1.86 6.17 1.47 0.99 95599 192. 1.70 5.92 1.29 1.00 95600 198. 1.90 5.95 1.39 1.08

MEAN 198. 1.86 6.08 1.43 1.04 S.D. 10.7 0.108 0.522 0.103 0.064 S.E. 4.8 0.048 0.234 0.046 0.029 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT313of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

FEMALE GROUP: 1250 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95579 189. 1.78 6.12 1.34 1.01 95586 204. 1.81 6.52 1.55 1.16 95588 196. 1.82 6.10 1.47 1.12 95595 198. 1.96 5.91 1.45 1.06 95603 188. 1.74 5.74 1.47 0.88

MEAN 195. 1.82 6.08 1.46 1.05 S.D. 6.6 0.083 0.292 0.075 0.109 S.E. 3.0 0.037 0.130 0.034 0.049 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT314of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

FEMALE GROUP: 2500 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95580 195. 1.77 5.74 1.55 0.88 95589 204. 1.77 6.26 1.34 0.86 95593 193. 1.75 5.34 1.37 0.86 95597 212. 2.00 6.73 1.63 1.13 95598 175. 1.81 5.62 1.28 0.92

MEAN 196. 1.82 5.94 1.43 0.93 S.D. 13.9 0.103 0.554 0.149 0.114 S.E. 6.2 0.046 0.248 0.067 0.051 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT315of435TABLE A26 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

FEMALE GROUP: 5000 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95581 180. 1.73 5.08 1.41 1.02 95583 195. 1.89 5.59 1.34 1.03 95590 187. 1.87 5.56 1.28 0.98 95592 205. 1.94 6.18 1.45 0.94 95601 199. 1.81 6.15 1.45 1.10

MEAN 193. 1.85 5.71 1.39 1.01 S.D. 9.9 0.081 0.461 0.074 0.060 S.E. 4.4 0.036 0.206 0.033 0.027 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008316of435TABLE A27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

MALE GROUP: 1800 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95557 304. 2.12 9.90 2.49 1.39 95562 329. 2.05 9.89 2.44 1.37 95567 299. 1.97 8.84 2.66 1.35 95571 325. 2.03 10.29 2.68 1.24 95575 336. 2.16 10.24 2.67 1.34

MEAN 319. 2.07 9.83 2.59 1.34 S.D. 16.2 0.075 0.585 0.114 0.058 S.E. 7.2 0.034 0.262 0.051 0.026 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT317of435TABLE A27 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL ORGAN WEIGHTS AND FINAL BODY WEIGHTS [G] DAY 5

FEMALE GROUP: 1800 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 6664 194. 1.79 6.14 1.51 1.02 6674 205. 1.89 6.52 1.55 0.99 6686 186. 1.78 5.70 1.59 0.98 6712 172. 1.82 5.27 1.46 1.05 6717 214. 1.85 6.54 1.80 1.15

MEAN 194. 1.83 6.03 1.58 1.04 S.D. 16.3 0.045 0.547 0.131 0.068 S.E. 7.3 0.020 0.245 0.059 0.031 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008318of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 1 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

MALE GROUP: 0 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95555 319. 0.633 3.307 0.749 0.395 95556 313. 0.665 2.939 0.818 0.383 95558 283. 0.678 2.933 0.777 0.445 95574 292. 0.647 3.110 0.726 0.414 95577 338. 0.615 3.213 0.805 0.417

MEAN 309. 0.648 3.100 0.775 0.411 S.D. 21.9 0.0250 0.1655 0.0382 0.0237 S.E. 9.8 0.0112 0.0740 0.0171 0.0106 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT319of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 2 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

MALE GROUP: 1250 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95559 299. 0.659 2.980 0.749 0.368 95561 303. 0.644 3.023 0.752 0.422 95566 263. 0.730 2.567 0.764 0.422 95573 295. 0.668 3.102 0.817 0.424 95576 312. 0.638 3.045 0.827 0.426

MEAN 294. 0.668 2.943 0.782 0.412 S.D. 18.6 0.0367 0.2150 0.0373 0.0249 S.E. 8.3 0.0164 0.0961 0.0167 0.0111 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT320of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 3 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

MALE GROUP: 2500 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95560 267. 0.667 2.989 0.835 0.393 95564 302. 0.636 3.162 0.735 0.414 95565 308. 0.633 2.776 0.727 0.377 95569 285. 0.702 2.804 0.811 0.418 95578 283. 0.710 2.802 0.767 0.406

MEAN 289. 0.670 2.907 0.775 0.402 S.D. 16.3 0.0359 0.1662 0.0471 0.0167 S.E. 7.3 0.0161 0.0743 0.0211 0.0075 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT321of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 4 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

MALE GROUP: 5000 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95563 315. 0.610 3.029 0.787 0.441 95568 283. 0.703 2.845 0.830 0.488 95570 279. 0.720 2.939 0.767 0.427 95572 266. 0.737 2.820 0.786 0.387

MEAN 286. 0.693 2.908 0.793 0.436 S.D. 20.8 0.0567 0.0954 0.0266 0.0417 S.E. 10.4 0.0284 0.0477 0.0133 0.0208 N 4 4 4 4 4

FBW = FINAL BODY WEIGHT322of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 5 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

FEMALE GROUP: 0 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95587 184. 1.087 2.967 0.777 0.549 95591 210. 0.881 3.281 0.748 0.543 95594 207. 0.899 2.981 0.710 0.478 95599 192. 0.885 3.083 0.672 0.521 95600 198. 0.960 3.005 0.702 0.545

MEAN 198. 0.942 3.063 0.722 0.527 S.D. 10.7 0.0868 0.1296 0.0411 0.0296 S.E. 4.8 0.0388 0.0580 0.0184 0.0132 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT323of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 6 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

FEMALE GROUP: 1250 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95579 189. 0.942 3.238 0.709 0.534 95586 204. 0.887 3.196 0.760 0.569 95588 196. 0.929 3.112 0.750 0.571 95595 198. 0.990 2.985 0.732 0.535 95603 188. 0.926 3.053 0.782 0.468

MEAN 195. 0.935 3.117 0.747 0.535 S.D. 6.6 0.0371 0.1030 0.0277 0.0417 S.E. 3.0 0.0166 0.0461 0.0124 0.0186 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT324of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 7 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

FEMALE GROUP: 2500 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95580 195. 0.908 2.944 0.795 0.451 95589 204. 0.868 3.069 0.657 0.422 95593 193. 0.907 2.767 0.710 0.446 95597 212. 0.943 3.175 0.769 0.533 95598 175. 1.034 3.211 0.731 0.526

MEAN 196. 0.932 3.033 0.732 0.476 S.D. 13.9 0.0629 0.1815 0.0535 0.0505 S.E. 6.2 0.0281 0.0812 0.0239 0.0226 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT325of435TABLE A28 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS 10:14 24-MAR-08 PAGE 8 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

FEMALE GROUP: 5000 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95581 180. 0.961 2.822 0.783 0.567 95583 195. 0.969 2.867 0.687 0.528 95590 187. 1.000 2.973 0.684 0.524 95592 205. 0.946 3.015 0.707 0.459 95601 199. 0.910 3.090 0.729 0.553

MEAN 193. 0.957 2.953 0.718 0.526 S.D. 9.9 0.0329 0.1091 0.0406 0.0416 S.E. 4.4 0.0147 0.0488 0.0181 0.0186 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008326of435TABLE A29 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

MALE GROUP: 1800 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95557 304. 0.697 3.257 0.819 0.457 95562 329. 0.623 3.006 0.742 0.416 95567 299. 0.659 2.957 0.890 0.452 95571 325. 0.625 3.166 0.825 0.382 95575 336. 0.643 3.048 0.795 0.399

MEAN 319. 0.649 3.087 0.814 0.421 S.D. 16.2 0.0304 0.1226 0.0535 0.0327 S.E. 7.2 0.0136 0.0548 0.0239 0.0146 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT327of435TABLE A29 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL ORGAN WTS. RELATIVE TO FINAL BODY WTS. [G/100 G] DAY 5

FEMALE GROUP: 1800 PPM

-----------------------------------------------------------------------------------------------------------------------------------
ANIMAL FBW(G) BRAIN LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 6664 194. 0.923 3.165 0.778 0.526 6674 205. 0.922 3.180 0.756 0.483 6686 186. 0.957 3.065 0.855 0.527 6712 172. 1.058 3.064 0.849 0.610 6717 214. 0.864 3.056 0.841 0.537

MEAN 194. 0.945 3.106 0.816 0.537 S.D. 16.3 0.0716 0.0610 0.0455 0.0460 S.E. 7.3 0.0320 0.0273 0.0203 0.0206 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008328of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

MALE GROUP: 0 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95555 319. 2.02 522.277 118.317 62.376 95556 313. 2.08 442.308 123.077 57.692 95558 283. 1.92 432.292 114.583 65.625 95574 292. 1.89 480.423 112.169 64.021 95577 338. 2.08 522.115 130.769 67.788

MEAN 309. 2.00 479.883 119.783 63.500 S.D. 21.9 0.089 42.5966 7.3943 3.8135 S.E. 9.8 0.040 19.0498 3.3069 1.7054 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT329of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

MALE GROUP: 1250 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95559 299. 1.97 452.284 113.706 55.838 95561 303. 1.95 469.744 116.923 65.641 95566 263. 1.92 351.563 104.688 57.813 95573 295. 1.97 464.467 122.335 63.452 95576 312. 1.99 477.387 129.648 66.834

MEAN 294. 1.96 443.089 117.460 61.916 S.D. 18.6 0.026 51.9746 9.3517 4.8528 S.E. 8.3 0.012 23.2437 4.1822 2.1702 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT330of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

MALE GROUP: 2500 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95560 267. 1.78 448.315 125.281 58.989 95564 302. 1.92 497.396 115.625 65.104 95565 308. 1.95 438.462 114.872 59.487 95569 285. 2.00 399.500 115.500 59.500 95578 283. 2.01 394.527 107.960 57.214

MEAN 289. 1.93 435.640 115.848 60.059 S.D. 16.3 0.093 41.7697 6.1710 2.9720 S.E. 7.3 0.041 18.6800 2.7598 1.3291 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT331of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 4 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

MALE GROUP: 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95563 315. 1.92 496.875 129.167 72.396 95568 283. 1.99 404.523 118.090 69.347 95570 279. 2.01 407.960 106.468 59.204 95572 266. 1.96 382.653 106.633 52.551

MEAN 286. 1.97 423.003 115.090 63.375 S.D. 20.8 0.039 50.5074 10.8478 9.1579 S.E. 10.4 0.020 25.2537 5.4239 4.5789 N 4 4 4 4 4

FBW = FINAL BODY WEIGHT332of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 5 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

FEMALE GROUP: 0 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95587 184. 2.00 273.000 71.500 50.500 95591 210. 1.85 372.432 84.865 61.622 95594 207. 1.86 331.720 79.032 53.226 95599 192. 1.70 348.235 75.882 58.824 95600 198. 1.90 313.158 73.158 56.842

MEAN 198. 1.86 327.709 76.887 56.203 S.D. 10.7 0.108 37.5578 5.2959 4.4167 S.E. 4.8 0.048 16.7964 2.3684 1.9752 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT333of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 6 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

FEMALE GROUP: 1250 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95579 189. 1.78 343.820 75.281 56.742 95586 204. 1.81 360.221 85.635 64.088 95588 196. 1.82 335.165 80.769 61.538 95595 198. 1.96 301.531 73.980 54.082 95603 188. 1.74 329.885 84.483 50.575

MEAN 195. 1.82 334.124 80.030 57.405 S.D. 6.6 0.083 21.5431 5.2666 5.4744 S.E. 3.0 0.037 9.6344 2.3553 2.4482 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT334of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 7 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

FEMALE GROUP: 2500 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95580 195. 1.77 324.294 87.571 49.718 95589 204. 1.77 353.672 75.706 48.588 95593 193. 1.75 305.143 78.286 49.143 95597 212. 2.00 336.500 81.500 56.500 95598 175. 1.81 310.497 70.718 50.829

MEAN 196. 1.82 326.021 78.756 50.956 S.D. 13.9 0.103 19.7120 6.3120 3.2086 S.E. 6.2 0.046 8.8155 2.8228 1.4349 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT335of435TABLE A30 (GROUPS 1-4) PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 8 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

FEMALE GROUP: 5000 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95581 180. 1.73 293.642 81.503 58.960 95583 195. 1.89 295.767 70.899 54.497 95590 187. 1.87 297.326 68.449 52.406 95592 205. 1.94 318.557 74.742 48.454 95601 199. 1.81 339.779 80.111 60.773

MEAN 193. 1.85 309.014 75.141 55.018 S.D. 9.9 0.081 19.9120 5.6593 4.9709 S.E. 4.4 0.036 8.9049 2.5309 2.2231 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008336of435TABLE A31 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

MALE GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 95557 304. 2.12 466.981 117.453 65.566 95562 329. 2.05 482.439 119.024 66.829 95567 299. 1.97 448.731 135.025 68.528 95571 325. 2.03 506.897 132.020 61.084 95575 336. 2.16 474.074 123.611 62.037

MEAN 319. 2.07 475.824 125.427 64.809 S.D. 16.2 0.075 21.3577 7.8017 3.1640 S.E. 7.2 0.034 9.5514 3.4890 1.4150 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT337of435TABLE A31 (GROUP 5) PROJECT NO.: 534011A A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL ORGAN WEIGHTS RELATIVE TO BRAIN WEIGHTS [G/100 G] DAY 5

FEMALE GROUP: 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- BRAIN WT ANIMAL FBW(G) (GRAMS) LIVER KIDNEYS LUNGS

----------------------------------------------------------------------------------------------------------------------------------- 6664 194. 1.79 343.017 84.358 56.983 6674 205. 1.89 344.974 82.011 52.381 6686 186. 1.78 320.225 89.326 55.056 6712 172. 1.82 289.560 80.220 57.692 6717 214. 1.85 353.514 97.297 62.162

MEAN 194. 1.83 330.258 86.642 56.855 S.D. 16.3 0.045 25.8708 6.8673 3.6102 S.E. 7.3 0.020 11.5698 3.0711 1.6145 N 5 5 5 5 5

FBW = FINAL BODY WEIGHT

POFBWv4.14 03/24/2008338of435

## FINAL REPORT

Volume 2 of 2 (Appendices B through I)

STUDY TITLE

A 5-DAY REPEATED-DOSE INHALATION TOXICITY STUDY OF IN SPRAGUE-DAWLEY RATS

STUDY NUMBER

S TUDY DIRECTOR

S TUDY INITIATION DATE

9 January 2008

STUDY COMPLETION DATE

14 May 2008

PERFORMING LABORATORY

SP ONSOR

339 of 435

# APPENDIX B

Certificate Of Analysis (Sponsor-Provided Data)

340 of 435

# CERTIFICATE OF ANALYSIS

jttn:

**- r** 



### .341of435

# APPENDIX C

Exposure Atmosphere Generation Report (

342 of 435

## A 5-DAY REPEATED-DOSE INHALATION TOXICITY STUDY OF IN SPRAGUE-DAWLEY RATS

Exposure Atmosphere Generation Report

Inhalation Department

- 1 -
343 of 435

# T ABLE 

# O F 

# C ONTENTS 

## Page

Table Of Contents......................................................................................2 Index Of Figures ........................................................................................3

Index Of Tables..........................................................................................3 1. Exposure Methods .....................................................................................4 1.1. Exposure Regimen.......................................................................................4 1.2. Inhalation Exposure System Description.....................................................4 1.3. Animal Transport And Placement ...............................................................5 1.4. Exposure Environmental Conditions ...........................................................5

2. Test Atmosphere Generation Methods ....................................................6 3. Methods Of Characterization Of Exposure Atmospheres.....................8 3.1. Nominal Exposure Concentrations ..............................................................8 3.2. Analyzed Exposure Concentrations.............................................................8 3.2.1. Analytical Methods......................................................................................8 3.2.2. Gas Chromatograph Calibration ..................................................................9

3.3. Determination Of Homogeneity Of Exposure Atmospheres.....................11

4. Results Of Characterization Of Actual Exposure Concentrations .........................................................................................12 4.1. Nominal Exposure Concentrations ............................................................12 4.2. Analyzed Exposure Concentrations...........................................................13

5. Key Study Personnel And Report Submission......................................14

- 2 -
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# I NDEX 

# O F 

# F IGURES 

## Page

1. Atmosphere Generation And Exposure System ........................................................16



# I NDEX 

# O F 

# T ABLES



## 1. Daily Mean Chamber Temperature [Degrees Celsius]..............................................18

2. Daily Mean Chamber Relative Humidity [%] ...........................................................19

3. Daily Mean Chamber Ventilation Rate [SLPM] .......................................................20

4. Test Atmosphere Homogeneity Determination .........................................................21

5. Daily Nominal Concentrations [PPM].......................................................................24

6. Daily Mean Test Atmosphere Concentrations...........................................................25

- 3 - 345 of 435

# 1. E XPOSURE 

# M ETHODS


# 1.1. E XPOSURE 

# R EGIMEN 

## The test substance or filtered air (control group) was administered as a daily 6-hour whole-body inhalation exposure. Exposures were conducted for 5 consecutive days for Groups 1, 2, 3 and 5 and 2 consecutive days for Group 4. A detailed description of the study design and exposure schedule is presented in the main report. The following table presents the overall schedule for inhalation exposures:

Study Day Date First Exposure (Groups 1-4) 0 6 February 2008

Last Exposure (Group 4) 1 7 February 2008 Last Exposure (Groups 1-3) 4 10 February 2008

First Exposure (Group 5) 3 9 February 2008 Last Exposure (Group 5) 7 13 February 2008



# 1.2. I NHALATION 

# E XPOSURE 

# S YSTEM 

# D ESCRIPTION 

## Exposures were conducted in four 500-L stainless steel and glass whole-body inhalation exposure chambers. One chamber was dedicated for each group with the exception of Chamber 4. Following the termination of Group 4, an additional group (Group 5) was added to the study and was exposed in Chamber 4. The following table presents the chambers use for each group:

Group Number 1 2 3 4 5
Chamber Number 1 2 3 4 4 Target Exposure Concentration (ppm) 0 1250 2500 5000 1800

Chamber supply air was provided from a HEPA- and charcoal-filtered, temperature- and humidity-controlled source. All test atmosphere chamber exhaust passed through carbon scrubbers (Environtrol, Inc., Sewickley, PA) prior to the facility exhaust system, which

consisted of charcoal and HEPA filtration.

- 4 -
346 of 435

# 1.3. A NIMAL 

# T RANSPORT 

# A ND 

# P LACEMENT 

## Animals were individually housed in stainless steel wire-mesh caging during the exposures. Food and water were withheld during the exposure periods. Animals were housed in a normal animal colony room during non-exposure hours. For the exposure each day, the animals were transferred to exposure caging, transported to the exposure chamber room, exposed for the requisite duration and returned to their home cages in the animal colony room.

The cage batteries were rotated on a daily basis between 2 battery positions in the chambers to help ensure a similar exposure for all animals within each group over the duration of the exposure period.



# 1.4. E XPOSURE 

# E NVIRONMENTAL 

# C ONDITIONS 

## Chamber temperature, relative humidity, ventilation rate and negative pressure within each chamber were continually monitored and manually recorded at approximately 35-minute intervals. For each 6-hour exposure period, at least 10 data points were collected per chamber. Chamber temperature and relative humidity were monitored with an Omega Model No. HX94C Humidity and Temperature transmitter probe (Omega Engineering, Inc., Stamford, CT). The mean temperature and mean relative humidity were to be between 20°C to 24°C and 30% to 70%, respectively.

All chambers were operated under dynamic conditions, at least 12 to 15 air changes per hour (100 to 125 liters per minute [LPM]) at a slight negative pressure. Chamber airflow was monitored by a sharp-edge orifice plate and Dwyer Magnehelic ® 

## Indicating Transmitter pressure gauge (Michigan City, IN). Each gauge was calibrated under the conditions of exposure for conversion from pressure to airflow in standard liters per minute (SLPM) through the use of a Fox Gas Mass Flowmeter Transmitter (Model FT2, Fox Thermal Instruments, Marina, CA). Daily means for chamber temperature, relative humidity and ventilation rate over the study period are presented in Tables 1 through 3 of

- 5 -
347 of 435

## this appendix. The following table summarizes the grand mean environmental conditions for all groups:

Group 1 Group 2 Group 3 Group 4 Group 5 Temperature (oC): 21 21 20 21 21 Standard Deviation: 0.4 0.0 0.0 0.0 0.0

Relative Humidity (%): 56 58 53 56 51 Standard Deviation: 1.4 1.1 1.9 2.8 2.1

Chamber Ventilation Rate (SLPM): 113 111 111 113 112 Standard Deviation: 0.9 0.4 1.1 2.1 1.5

Exposure Days: 5 5 5 2 5

Oxygen content was measured during the method development phase for Groups 1 through 4 and during animal exposure for Group 5 using a Drager Pac III equipped with a calibrated oxygen sensor (Draeger Safety, Pittsburgh, PA). Oxygen content was at least 19% for all groups.

The high concentration chamber was monitored for aerosol formation on 31 January 2008 during the method development phase of the study using an MIE High Pressure Industrial Particulates Monitor (Model HPM-1000, Thermo Fisher Scientific, Franklin, MA) and an Omega RD6110 chart recorder. No aerosol formation was observed.



# 2. T EST 

# A TMOSPHERE 

# G ENERATION 

# M ETHODS 

## A test substance atmosphere generation and exposure system is shown in Figure 1. Vapors of the test substance were generated using a glass-bead column-type vaporization system operated as follows: Liquid test substance was metered using a calibrated FMI Lab Pump (Fluid Metering Inc., Syosset, NY) to the top of the vaporization column filled with various sized glass beads. The following table summarizes the specifications for the test substance delivery:

- 6 -
348 of 435

## Group FMI Pump Model No. FMI Pump Piston Head Size Test Substance Flowrate (mL/minute)
2 QG-20 1/8-inch 0.8
3 QG-6 1/4-inch 1.7
4 QG-20 1/4-inch 3.4
5 QG-20 1/4-inch 1.3

The vaporization column was wrapped with an electric heating tape (Omega Engineering Co., Stamford, CT) controlled using a J-type thermocouple and digital temperature controller. Using a Coilhose Pneumatics Regulator (model no. 8802K, East Brunswick, NJ) and calibrated rotameter-type flowmeters (serial no. 115010-2, Cole-Parmer, Vernon Hills, IL for Group 2 and model no. GF-4542-1225, Barnant Co./Gilmont Instruments, Barrington, IL for Groups 3, 4 and 5), nitrogen was metered to the bottom of each vaporization column. Vaporization occurred as the liquid test substance coated the surface of the heated beads and nitrogen flowed up through the column. The concentrated vapors were piped to the chamber inlet and diluted to the desired concentration by mixing with the chamber supply air. For Group 1, nitrogen was supplied to the chamber inlet using the aforementioned Coilhose Pneumatics Regulator (model no. 8802K) and a calibrated Gilmont rotameter-type flowmeter and diluted with chamber supply air. The parameters used for this study are summarized in the following

table:

Group Column Dimensions (ID × height) (cm) Column Temperature (°C) Nitrogen Flowrate (LPM)
1 N A N A 5

. 5
2 2.4 × 20 55 2.5
3 2.4 × 35 65 4.7
4 2.4 × 35 69 4.5
5 2.4 × 35 69 4.5
NA = Not Applicable

- 7 - 349 of 435

# 3. M ETHODS 

# O F 

# C HARACTERIZATION 

# O F 

# E XPOSURE 

# A TMOSPHERES


# 3.1. N OMINAL 

# E XPOSURE 

# C ONCENTRATIONS 

## A nominal exposure concentration was calculated daily for each test substance group from the total amount of test substance used during the exposure and the total volume of air passed through the chamber during that day’s exposure. The amount of test substance used was obtained by weighing the test substance reservoir prior to and after each day’s exposure. The total volume of air passed through each chamber was calculated from the daily average chamber ventilation flowrate in LPM and the exposure duration. The

nominal concentration was calculated as follows.

WT × MV × 10 6 

## Concentration (ppm) = GMW × CVR × DUR
Where: WT = Weight of test substance used, grams MV = Molar volume at 730 mmHg and 21oC, 25.11 L/mole

10 6 

## = ppm conversion factor GMW = Test substance gram molecular weight, 200.05 g/mole

CVR = Daily mean chamber ventilation rate for a given day, LPM DUR = Duration of the daily exposure, minutes



# 3.2. A NALYZED 

# E XPOSURE 

# C ONCENTRATIONS


# 3.2.1. A NALYTICAL 

# M ETHODS 

## Analyzed exposure concentrations were determined at approximately 30-minute intervals using a gas chromatograph (GC). Samples were collected from the approximate animal-breathing zone of the inhalation exposure chambers via 1/8-inch Teflon ® 

## tubing. Samples were collected manually using an external multi-position valve (Model E16, Valco Instruments Co., Inc., Houston, TX) and a Hewlett Packard Model 3396 Series II integrator (with BASIC program). Gas sample injection onto the chromatography column occurred via an internal gas-sampling valve with a sample loop. The chromatograph was displayed and the area under the sample peak was calculated and

- 8 - 350 of 435

## stored. The concentration in parts per million (ppm) was calculated using an ln-quadratic equation based on the GC calibration curve. The following table summarizes the operational parameters for the gas chromatography methods:

Instrument: Hewlett Packard 5890 Series II Detector: Flame Ionization (FID) Column: J&W Scientific, DB-5, 30m × 0.530mm ID, 0.5-micron film thickness

Gases Pressure (psig) Flow Rate (mL/minute)
Carrier - Helium: 14 10 Fuel - Hydrogen: 18 31
Air: 35 294 Temperatures (oC)
Column: 100
Detector: 250 Injector: 100 Auxiliary: 100

Integrator: Hewlett Packard Model 3396 Series II
Run Parameters
Chart Zero Offset: 0
Chart Attenuation: 8 Chart Speed: 2.0 cm/minute Peak Area Rejection Value: 0
Peak Threshold: 4
Peak Width: 0.04 Retention Time (minutes): Approximately 0.757



# 3.2.2. G AS 

# C HROMATOGRAPH 

# C ALIBRATION 

## The GC was calibrated using gas-phase standards prepared to contain a known vapor

concentrations of the test substance in 5- and 10-L Tedlar ® 

## gas bags (SKC, Inc., Eighty Four, PA). Standard bags were prepared by metering a known volume of air into the bag using a dry test meter (Model DTM-200A, Elster American Meter Co., Nebraska

- 9 - 351 of 435

## City, NE) and then injecting a known volume of test substance into the bag. Using a hand-held heated blower, the bag was warmed until total volatilization of the test substance was visually observed. Concentrations of the gas-phase standards are

calculated as follows:

VOL × R × T × D × 10 -3 

## × 10 6 

## Concentration (ppm) = L × GMW × P
Where: VOL = Volume of test substance vaporized into bag, μL R = Universal constant, 62.36 L mmHg/mole K T = Nominal laboratory temperature in K (273 + 21°C = 294 K) D = Density of the test substance, 1.487 g/mL L = Volume of air used to prepare bag, 30 L GMW = Gram molecular weight, 200.05 g/mole P = Nominal laboratory barometric pressure, 730 mmHg 10 -3 

## = μL to mL conversion factor 10 6 

## = Conversion factor to ppm

Prior to initiation of animal exposures, the GC was calibrated with standards prepared and analyzed in triplicate. The calibration curve was defined using standards prepared at 5 vapor concentrations spanning an appropriate range relative to the target exposure concentrations for the study. The prime calibration curve was prepared using the quadratic formula and was used to calculate exposure concentrations for all groups. The peak area (y) and the theoretical concentrations of the calibration standards (x) were fit with least-squares regression analysis to the ln-quadratic function:

ln (y) = a × [ln (x)]2 + b × ln (x) + c

Each day, prior to the initiation of exposure, 1 of the 5 standards was prepared and analyzed, and the prime calibration curve was used to perform a calibration check of the GC. The GC was considered to be within normal calibration limits if the analyzed concentration of the prepared standard was within ± 10% of the known concentration. The following table summarizes the standard parameters:

- 10 - 352 of 435

## Standard (ppm) Volume of Test Substance (μL) Total Dilution Air Volume (L)

933 40 8

2240 60 5

3360 90 5

4978 80 3

6223 100 3



# 3.3. D ETERMINATION 

# O F 

# H OMOGENEITY 

# O F 

# E XPOSURE 

# A TMOSPHERES 

## Homogeneity of exposure concentrations was evaluated during the method development phase of the study. Four test locations and a reference location were used for these determinations. The test locations were Lower Front, Lower Rear, Upper Front and Upper Rear. Samples were collected and analyzed on the GC as rapidly as possible by alternating from the reference location and then to a test location. The measured concentration was calculated as a percent difference for each position from the reference location. Homogeneity was performed in triplicate for each test substance exposure chamber. The results are presented in Table 4 of this appendix. The following table summarizes the mean data of the replicates for each test substance chamber:

- 11 - 353 of 435

## Chamber Number Test Location Mean % From Reference
2 Lower Front -2.1
Lower Rear 0.9 Upper Front 0.1 Upper Rear -2.0

3 Lower Front -0.7
Lower Rear 0.2 Upper Front -0.7 Upper Rear -0.4

4 Lower Front 1.2
Lower Rear 0.9 Upper Front 1.2 Upper Rear -0.7

These data indicate that the homogeneity of each exposure chamber atmosphere was adequate for the purpose of this study.



# 4. R ESULTS 

# O F 

# C HARACTERIZATION 

# O F 

# A CTUAL 

# E XPOSURE 

# C ONCENTRATIONS


# 4.1. N OMINAL 

# E XPOSURE 

# C ONCENTRATIONS 

## Daily nominal concentrations for each test substance group are presented in Table 5 of this appendix. The following table summarizes the overall mean nominal concentrations for each test substance group:

Group 2 Group 3 Group 4 Group 5 Mean Concentration (ppm): 1303 2700 5323 2186

Standard Deviation: 7.7 38.1 78.5 16.9

N: 5 5 2 5

- 12 - 354 of 435

# 4.2. A NALYZED 

# E XPOSURE 

# C ONCENTRATIONS 

## Daily mean analyzed concentrations for each group are presented in Table 6 of this appendix. The following table summarizes the overall mean analyzed concentrations for each group:

Group 1 Group 2 Group 3 Group 4 Group 5 Mean Concentration (ppm): 0 1247 2536 5039 1793

Standard Deviation: 0.0 5.8 32.4 14.8 7.2

N: 5 5 5 2 5

- 13 - 355 of 435

## 53401 1



# 5. KEY STUDY PERSONNEL 

# AND REPORT SUBMISSION



## Report Prepared By:-,



## Report Reviewed By:

Study Personnel:

-14-

356 of 435

# FIGURE 1

- 15 - 357 of 435

# F IGURE 

# 1: A TMOSPHERE 

# G ENERATION 

# A ND 

# E XPOSURE 

# S YSTEM

500-Liter Chamber Supply Air

Rotameter and Regulator Glass Bead

Column

Nitrogen Source Test Article

Reservoir Temp. Controller 123 

## Inlet

FMI Pump

To Exhaust Activated Carbon Scrubber

Orifice Meter



## - 16 - 358 of 435

# TABLES 1-6

- 17 - 359 of 435INHALATION TABLE 1 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 DAILY MEAN CHAMBER TEMPERATURE [DEGREES CELSIUS]

----------------------------------------------------------------------------------------------------------------------------------- DATE GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM 1800 PPM

---------------------------------------------------------------------------------------------------------------------------------- 02/06/08 21. 21. 20. 21. NA 02/07/08 21. 21. 20. 21. NA 02/08/08 21. 21. 20. NA NA 02/09/08 20. 21. 20. NA 21. 02/10/08 21. 21. 20. NA 21. 02/11/08 NA NA NA NA 21. 02/12/08 NA NA NA NA 21. 02/13/08 NA NA NA NA 21.

----------------------------------------------------------------------------------------------------------------------------------- GRAND MEAN 21. 21. 20. 21. 21. S.D. 0.4 0.0 0.0 0.0 0.0 C.V.(%) 1.90 0.00 0.00 0.00 0.00 N 5 5 5 2 5

NA = NOT APPLICABLE

MANUALv1.0 03/17/2008 R:05/14/2008-18-360of435INHALATION TABLE 2 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 DAILY MEAN CHAMBER RELATIVE HUMIDITY [%]

----------------------------------------------------------------------------------------------------------------------------------- DATE GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM 1800 PPM

---------------------------------------------------------------------------------------------------------------------------------- 02/06/08 57. 60. 53. 58. NA 02/07/08 57. 58. 53. 54. NA 02/08/08 55. 57. 52. NA NA 02/09/08 57. 59. 56. NA 55. 02/10/08 54. 58. 51. NA 51. 02/11/08 NA NA NA NA 51. 02/12/08 NA NA NA NA 50. 02/13/08 NA NA NA NA 50.

----------------------------------------------------------------------------------------------------------------------------------- GRAND MEAN 56. 58. 53. 56. 51. S.D. 1.4 1.1 1.9 2.8 2.1 C.V.(%) 2.50 1.90 3.58 5.00 4.12 N 5 5 5 2 5

NA = NOT APPLICABLE

MANUALv1.0 03/17/2008 R:05/14/2008-19-361of435INHALATION TABLE 3 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 DAILY MEAN CHAMBER VENTILATION RATE [SLPM]

----------------------------------------------------------------------------------------------------------------------------------- DATE GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM 1800 PPM

---------------------------------------------------------------------------------------------------------------------------------- 02/06/08 111. 112. 110. 114. NA 02/07/08 113. 111. 110. 111. NA 02/08/08 113. 111. 110. NA NA 02/09/08 113. 111. 112. NA 113. 02/10/08 113. 111. 112. NA 113. 02/11/08 NA NA NA NA 112. 02/12/08 NA NA NA NA 110. 02/13/08 NA NA NA NA 110.

----------------------------------------------------------------------------------------------------------------------------------- GRAND MEAN 113. 111. 111. 113. 112. S.D. 0.9 0.4 1.1 2.1 1.5 C.V.(%) 0.80 0.36 0.99 1.86 1.34 N 5 5 5 2 5

NA = NOT APPLICABLE

MANUALv1.0 03/17/2008 R:05/14/2008-20-362of435INHALATION TABLE 4 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 TEST ATMOSPHERE HOMOGENEITY DETERMINATION

--------------------------------------------------------------------------------------------------------------------------------- TARGET: 1250 PPM CHAMBER #2

--------------------------------------------------------------------------------------------------------------------------------- DATE SAMPLING LOCATION CONCENTRATION (PPM) % FROM REFERENCE MEAN %

--------------------------------------------------------------------------------------------------------------------------------- 01/30/08 REFERENCE PORT 1244 LOWER FRONT 1229 -1.2

REFERENCE PORT 1235 LOWER FRONT 1217 -1.5

REFERENCE PORT 1234 LOWER FRONT 1189 -3.6 -2.1

REFERENCE PORT 1180 LOWER REAR 1221 3.5

REFERENCE PORT 1227 LOWER REAR 1220 -0.6

REFERENCE PORT 1230 LOWER REAR 1227 -0.2 0.9

REFERENCE PORT 1242 UPPER FRONT 1221 -1.7

REFERENCE PORT 1170 UPPER FRONT 1202 2.7

REFERENCE PORT 1220 UPPER FRONT 1211 -0.7 0.1

REFERENCE PORT 1240 UPPER REAR 1213 -2.2

REFERENCE PORT 1227 UPPER REAR 1179 -3.9

REFERENCE PORT 1214 UPPER REAR 1216 0.2 -2.0

-------------------------------------------------------------------------------------------------------------------------------- PPM = PARTS PER MILLION-21-363of435INHALATION TABLE 4 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 TEST ATMOSPHERE HOMOGENEITY DETERMINATION

--------------------------------------------------------------------------------------------------------------------------------- TARGET: 2500 PPM CHAMBER #3

--------------------------------------------------------------------------------------------------------------------------------- DATE SAMPLING LOCATION CONCENTRATION (PPM) % FROM REFERENCE MEAN %

--------------------------------------------------------------------------------------------------------------------------------- 01/30/08 REFERENCE PORT 2591 LOWER FRONT 2585 -0.2

REFERENCE PORT 2516 LOWER FRONT 2470 -1.8

REFERENCE PORT 2474 LOWER FRONT 2473 0.0 -0.7

REFERENCE PORT 2599 LOWER REAR 2609 0.4

REFERENCE PORT 2489 LOWER REAR 2470 -0.8

REFERENCE PORT 2484 LOWER REAR 2511 1.1 0.2

REFERENCE PORT 2596 UPPER FRONT 2584 -0.5

REFERENCE PORT 2477 UPPER FRONT 2479 0.1

REFERENCE PORT 2517 UPPER FRONT 2471 -1.8 -0.7

REFERENCE PORT 2596 UPPER REAR 2564 -1.2

REFERENCE PORT 2478 UPPER REAR 2466 -0.5

REFERENCE PORT 2463 UPPER REAR 2473 0.4 -0.4

--------------------------------------------------------------------------------------------------------------------------------- PPM = PARTS PER MILLION-22-364of435INHALATION TABLE 4 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 3 TEST ATMOSPHERE HOMOGENEITY DETERMINATION

--------------------------------------------------------------------------------------------------------------------------------- TARGET: 5000 PPM CHAMBER #4

--------------------------------------------------------------------------------------------------------------------------------- DATE SAMPLING LOCATION CONCENTRATION (PPM) % FROM REFERENCE MEAN %

--------------------------------------------------------------------------------------------------------------------------------- 01/29/08 REFERENCE PORT 5107 LOWER FRONT 5204 1.9

REFERENCE PORT 5103 LOWER FRONT 5205 2.0

REFERENCE PORT 5132 LOWER FRONT 5119 -0.3 1.2

REFERENCE PORT 5117 LOWER REAR 5201 1.6

REFERENCE PORT 5122 LOWER REAR 5202 1.6

REFERENCE PORT 5126 LOWER REAR 5093 -0.6 0.9

REFERENCE PORT 5170 UPPER FRONT 5203 0.6

REFERENCE PORT 5075 UPPER FRONT 5108 0.7

REFERENCE PORT 5111 UPPER FRONT 5226 2.3 1.2

REFERENCE PORT 5166 UPPER REAR 5119 -0.9

REFERENCE PORT 5204 UPPER REAR 5140 -1.2

REFERENCE PORT 5222 UPPER REAR 5219 -0.1 -0.7

--------------------------------------------------------------------------------------------------------------------------------- PPM = PARTS PER MILLION MANUALv1.0 03/17/2008 R:05/14/2008-23-365of435INHALATION TABLE 5 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 DAILY NOMINAL CONCENTRATIONS [PPM]

----------------------------------------------------------------------------------------------------------------------------------- DATE GROUP: 1250 PPM 2500 PPM 5000 PPM 1800 PPM

---------------------------------------------------------------------------------------------------------------------------------- 02/06/08 1292 2735 5267 NA 02/07/08 1307 2710 5378 NA 02/08/08 1297 2735 NA NA 02/09/08 1310 2655 NA 2175 02/10/08 1307 2665 NA 2169 02/11/08 NA NA NA 2179 02/12/08 NA NA NA 2206 02/13/08 NA NA NA 2203

----------------------------------------------------------------------------------------------------------------------------------- GRAND MEAN 1303 2700 5323 2186 S.D. 7.7 38.1 78.5 16.9 C.V.(%) 0.59 1.41 1.47 0.77 N 5 5 2 5

NA = NOT APPLICABLE

MANUALv1.0 03/17/2008 R:05/14/2008-24-366of435INHALATION TABLE 6 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 1 DAILY MEAN TEST ATMOSPHERE CONCENTRATIONS

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- CHAMBER 1 (0.5M3) CHAMBER 2 (0.5M3) CHAMBER 3 (0.5M3) CHAMBER 4 (0.5M3) CHAMBER 4 (0.5M3) CONCENTRATION CONCENTRATION CONCENTRATION CONCENTRATION CONCENTRATION

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

STUDY DAY: 0 MEAN 0. 1244. 2560. 5049. NA SD 0.0 27.3 35.2 94.0 CV(%) 0.00 2.19 1.37 1.86 N 10 10 10 10

STUDY DAY: 1 MEAN 0. 1243. 2555. 5028. NA SD 0.0 11.6 46.8 71.6 CV(%) 0.00 0.93 1.83 1.42 N 10 10 10 10

STUDY DAY: 2 MEAN 0. 1242. 2557. NA NA SD 0.0 15.6 23.3 CV(%) 0.00 1.26 0.91 N 10 10 10

STUDY DAY: 3 MEAN 0. 1254. 2521. NA 1784. SD 0.0 17.2 24.2 26.4 CV(%) 0.00 1.37 0.96 1.48 N 10 10 10 10

STUDY DAY: 4 MEAN 0. 1253. 2485. NA 1797. SD 0.0 12.8 28.0 21.0 CV(%) 0.00 1.02 1.13 1.17 N 10 10 10 10

CV (%) = COEFFICIENT OF VARIATION, NA = NOT APPLICABLE CONCENTRATION IN: PPM-25-367of435INHALATION TABLE 6 PROJECT NO.: A 5-DAY INHALATION STUDY IN RATS PAGE 2 DAILY MEAN TEST ATMOSPHERE CONCENTRATIONS

----------------------------------------------------------------------------------------------------------------------------------- GROUP: 0 PPM 1250 PPM 2500 PPM 5000 PPM 1800 PPM

----------------------------------------------------------------------------------------------------------------------------------- CHAMBER 1 (0.5M3) CHAMBER 2 (0.5M3) CHAMBER 3 (0.5M3) CHAMBER 4 (0.5M3) CHAMBER 4 (0.5M3) CONCENTRATION CONCENTRATION CONCENTRATION CONCENTRATION CONCENTRATION

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

STUDY DAY: 5 MEAN NA NA NA NA 1792. SD 22.6 CV(%) 1.26 N 10

STUDY DAY: 6 MEAN NA NA NA NA 1790. SD 25.0 CV(%) 1.40 N 10

STUDY DAY: 7 MEAN NA NA NA NA 1803. SD 14.2 CV(%) 0.79 N 10

ALL STUDY DAYS COMBINED MEAN 0. 1247. 2536. 5039. 1793. SD 0.0 5.8 32.4 14.8 7.2 CV(%) 0.00 0.47 1.28 0.29 0.40 N 5 5 5 2 5

-----------------------------------------------------------------------------------------------------------------------------------
CV (%) = COEFFICIENT OF VARIATION, NA = NOT APPLICABLE CONCENTRATION IN: PPM PCHCSUv4.06 03/17/2008 R:05/14/2008-26-368of435

# APPENDIX D

Pretest Clinical Observations

369 of 435PRETEST CLINICAL OBSERVATIONS (GROUPS 1-4) PROJECT NO.: 534011P A 5-DAY INHALATION STUDY IN RATS PAGE 1 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: 01-25-08 TO 02-04-08 GROUP: 1

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 72/25

BODY/INTEG II -SCABBING DORSAL HEAD 2/ 2 -SCABBING VENTRAL NECK 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- PRETEST370of435PRETEST CLINICAL OBSERVATIONS (GROUPS 1-4) PROJECT NO.: 534011P A 5-DAY INHALATION STUDY IN RATS PAGE 2 SUMMARY OF CLINICAL FINDINGS: TOTAL OCCURRENCE/NO. OF ANIMALS

----- F E M A L E -----

----------------------------------------------------------------------------------------------------------------------------------- TABLE RANGE: 01-25-08 TO 02-04-08 GROUP: 1

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

NORMAL -NO SIGNIFICANT CLINICAL OBSERVATIONS 74/25

BODY/INTEGUMENT -HAIR LOSS FORELIMB(S) 1/ 1

----------------------------------------------------------------------------------------------------------------------------------- 1- PRETEST PCSUv4.07 03/24/2008371of435

# APPENDIX E

Animal Room Environmental Conditions

372 of 435TEMPERATURE/HUMIDITY - DAILY SUMMARY REPORT BY STUDYA5-DAY INHALATION STUDY IN RATSPROJECT NO.:PAGE 101/22/087:0016:0002/14/08STUDY SPECIFICATIONS:DATE IN:TIME IN:DATE OUT:TIME OUT:B ROOM 44RATLOW TEMPERATURE oF:66.0 HIGH TEMPERATURE oF:76.0LOW HUMIDITY:30.0HIGH HUMIDITY:70.0ROOM SPECIFICATIONS:SPECIES:TEMPERATUREHUMIDITYMEAN (oF)DATEMEAN (%RH)LOW TEMPERATURE oC:18.9 HIGH TEMPERATURE oC:24.4MEAN (oC)71.7 36.822-Jan-08 22.171.0 36.823-Jan-08 21.670.1 36.924-Jan-08 21.270.8 37.025-Jan-08 21.670.8 36.626-Jan-08 21.671.8 36.127-Jan-08 22.171.2 37.128-Jan-08 21.871.6 37.129-Jan-08 22.070.0 36.830-Jan-08 21.170.3 36.231-Jan-08 21.370.7 37.201-Feb-08 21.570.3 37.102-Feb-08 21.370.9 37.103-Feb-08 21.671.3 38.204-Feb-08 21.871.7 41.605-Feb-08 22.170.6 38.206-Feb-08 21.570.8 37.607-Feb-08 21.671.6 37.408-Feb-08 22.071.3 37.809-Feb-08 21.871.0 36.110-Feb-08 21.772.0 37.411-Feb-08 22.270.9 36.312-Feb-08 21.671.5 37.013-Feb-08 22.05/14/2008 16:35REPORT 4VERSION 1.09NOTE: + = VALUE WAS GREATER THAN HIGH RANGE- = VALUE WAS LESS THAN LOW RANGENOTE: MEANS REPRESENT THE MEAN OF THE DAILY VALUES



## 373 of 435TEMPERATURE/HUMIDITY - DAILY SUMMARY REPORT BY STUDYA5-DAY INHALATION STUDY IN RATSPROJECT NO.:PAGE 201/22/087:0016:0002/14/08STUDY SPECIFICATIONS:DATE IN:TIME IN:DATE OUT:TIME OUT:B ROOM 44RATLOW TEMPERATURE oF:66.0 HIGH TEMPERATURE oF:76.0LOW HUMIDITY:30.0HIGH HUMIDITY:70.0ROOM SPECIFICATIONS:SPECIES:TEMPERATUREHUMIDITYMEAN (oF)DATEMEAN (%RH)LOW TEMPERATURE oC:18.9 HIGH TEMPERATURE oC:24.4MEAN (oC)71.8 40.914-Feb-08 22.171.1TEMPERATURE oF 70.0 72.041.636.137.424MEAN MINMAX21.7TEMPERATURE oC21.1 22.2HUMIDITY (%RH)**GRAND STATS**N DAYS5/14/2008 16:35REPORT 4VERSION 1.09NOTE: + = VALUE WAS GREATER THAN HIGH RANGE- = VALUE WAS LESS THAN LOW RANGENOTE: MEANS REPRESENT THE MEAN OF THE DAILY VALUES



## 374 of 435TEMPERATURE/HUMIDITY - END OF STUDY SUMMARY REPORTA5-DAY INHALATION STUDY IN RATSPROJECT NO.:16:3514-May-08PAGE 1B ROOM 44RATLOW TEMPERATURE: 66.0HIGH TEMPERATURE: 76.0LOW HUMIDITY: 30.0HIGH HUMIDITY: 70.0ROOM SPECIFICATIONS:SPECIES:TEMPERATURE HUMIDITY01/22/087:0016:0002/14/08DATE IN:TIME IN:DATE OUT:TIME OUT:**ROOM B ROOM 44 SUMMARY**MEANMINMAX71.168.573.637.48.168.21.562.78SDNSAMPLES561560NDAYSFIRST DAYLAST DAY01/22/0802/14/08245/14/2008 16:35REPORT 5VERSION 1.10NOTE: TEMPERATURE UNITS = DEGREES FAHRENHEITHUMIDITY UNITS = % RELATIVE HUMIDITYNOTE: MEANS REPRESENT THE MEAN OF ALL VALUES



## 375 of 435TEMPERATURE/HUMIDITY - END OF STUDY SUMMARY REPORTA5-DAY INHALATION STUDY IN RATSPROJECT NO.:16:3514-May-08PAGE 2**STUDY SUMMARY**MEANMINMAX71.168.573.637.48.168.21.562.78SDNSAMPLES561560FIRST DAYLAST DAY01/22/0802/14/08NDAYS245/14/2008 16:35REPORT 5VERSION 1.10NOTE: TEMPERATURE UNITS = DEGREES FAHRENHEITHUMIDITY UNITS = % RELATIVE HUMIDITYNOTE: MEANS REPRESENT THE MEAN OF ALL VALUES



## 376 of 435

# APPENDIX F

Unscheduled Clinical Observations

377 of 435UNSCHEDULED CLINICAL OBSERVATIONS PROJECT NO.: 534011U A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95563 M 5000 PPM SPECIAL II 2 7:55 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95568 M 5000 PPM BEHAVIOR/CNS 1 8:35 P CONVULSIONS, CONTINUOUS 95568 M 5000 PPM SPECIAL II 2 7:55 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95570 M 5000 PPM BEHAVIOR/CNS 0 8:31 P TREMORS, INTERMITTENT 0 8:33 P CONVULSIONS, INTERMITTENT 1 8:34 P CONVULSIONS, CONTINUOUS 95570 M 5000 PPM ORAL/DENTAL 0 8:33 P WET CLEAR MATERIAL AROUND MOUTH 0 8:33 P WET CLEAR MATERIAL VENTRAL NECK 0 8:33 P WET CLEAR MATERIAL FORELIMB(S) 1 8:35 P WET CLEAR MATERIAL AROUND MOUTH 1 8:35 P WET CLEAR MATERIAL VENTRAL NECK 3 6:35 P UPPER INCISOR(S) MALALIGNED 95570 M 5000 PPM SPECIAL II 2 7:55 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95572 M 5000 PPM SPECIAL II 2 7:55 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95581 F 5000 PPM SPECIAL II 2 7:56 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95583 F 5000 PPM SPECIAL II 2 7:56 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95590 F 5000 PPM BEHAVIOR/CNS 0 8:29 P TREMORS, INTERMITTENT 1 8:47 P CONVULSIONS, CONTINUOUS 95590 F 5000 PPM EYES/EARS/NOSE 0 9:07 P WET RED MATERIAL AROUND NOSE 95590 F 5000 PPM ORAL/DENTAL 0 8:30 P WET RED MATERIAL AROUND MOUTH 95590 F 5000 PPM SPECIAL II 2 7:56 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95592 F 5000 PPM BEHAVIOR/CNS 0 8:29 P CONVULSIONS, INTERMITTENT 95592 F 5000 PPM SPECIAL II 2 7:56 P WATER BOTTLE ADDED-BODY WEIGHT LOSS 95601 F 5000 PPM BODY/INTEG II 3 6:45 P SCABBING VENTRAL NECK 3 6:45 P SCABBING FORELIMB(S) 4 6:27 P SCABBING VENTRAL NECK 4 6:27 P SCABBING FORELIMB(S) 4 13:20 P SCABBING VENTRAL NECK 4 13:20 P SCABBING FORELIMB(S)

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT378of435UNSCHEDULED CLINICAL OBSERVATIONS PROJECT NO.: 534011U A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL CLINICAL OBSERVATIONS

STUDY DAYS: 0 THROUGH 5

----------------------------------------------------------------------------------------------------------------------------------- STUDY ANIMAL SEX GROUP CATEGORY DAY TIME GRADE OBSERVATIONS

----------------------------------------------------------------------------------------------------------------------------------- 95601 F 5000 PPM SPECIAL II 0 14:57 P WATER BOTTLE ADDED - POOR BODY CONDITION 2 7:56 P WATER BOTTLE ADDED-BODY WEIGHT LOSS

----------------------------------------------------------------------------------------------------------------------------------- GRADE CODE: 1 - SLIGHT 2 - MODERATE 3 - SEVERE P - PRESENT PCRDv4.11 04/16/2008379of435UNSCHEDULED DATA (GROUP 4) PROJECT NO.: 534011U A 5-DAY INHALATION STUDY IN RATS PAGE 1 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

MALE GROUP: 5000 PPM DAY 0 TO 1 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95554 NA NA 95563 24. 31. 95568 20. 30. 95570 1. 23. 95572 12. 26.

MEAN 14. 28. S.D. 10.1 3.7 N 4 4

NA = NOT APPLICABLE380of435UNSCHEDULED DATA (GROUP 4) PROJECT NO.: 534011U A 5-DAY INHALATION STUDY IN RATS PAGE 2 INDIVIDUAL FOOD CONSUMPTION [G/ANIMAL/DAY]

FEMALE GROUP: 5000 PPM DAY 0 TO 1 2 TO 4

----------------------------------------------------------------------------------------------------------------------------------- ANIMAL 95581 16. 32. 95583 16. 19. 95590 2. 17. 95592 19. 22. 95601 1. 22.

MEAN 11. 22. S.D. 8.6 5.8 N 5 5 PBFTSv4.44 05/08/2008 R:05/08/2008381of435

# APPENDIX G

Clinical Pathology Methods, Procedures And References

382 of 435

## C LINICAL PATHOLOGY METHODS, PROCEDURES AND REFERENCES

Serum Chemistry - Hitachi 912

Albumin - Bromcresol Green (BCG) Method, Modification of the Doumas reaction. Default unit: g/dL. Hitachi 912 Application Code 413. Roche Reagent, catalog number 11970569.

A/G Ratio - Calculated from Albumin and Globulin Results. Default unit: %.

Alkaline Phosphatase - based on the International Federation of Clinical Chemistry (IFCC) Method (Tietz et al. J Clin Chem Clin Biochem 1983; 21:731-748). Default unit: U/L. Hitachi 912 Application Code 158. Roche Reagent, catalog number 2172933.

Alanine Aminotransferase - Modification of the International Federation of Clinical Chemistry (IFCC) recommended method. Default unit: U/L. Hitachi 912 Application Code 706. Roche Reagent, catalog number 450065.

Aspartate Aminotransferase - Kinetic method based on the International Federation of Clinical Chemistry (IFCC) recommendations. Default unit: U/L. Hitachi 912 Application Code 713. Roche Reagent, catalog number 450064.

Bilirubin (Total) - Diazo method developed by Wahlefeld et al . Scand J Clin Lab Invest 1972; 29: Supplement 126. Default unit: mg/dL. Hitachi 912 Application Code 018. Roche Reagent, catalog number 1822730.

Blood Urea Nitrogen (BUN) - A urease-triggered methodology based upon the method of Talke and Schubert Klin Wschr, 1965; 43:174. Default unit: mg/dL. Hitachi 912 Application Code 427. Roche Reagent, catalog number 1489321.

Calcium - Modified method using a gamma-amino-butyric acid (GABA) buffer. Default unit: mg/dL. Hitachi 912 Application Code 180. Roche Reagent, catalog number 1125621.

Chloride - An ion-selective electrode that measures the electrical potential of the ions present in solution. Default unit: mEq/L. Hitachi 912 Application. Roche Reagent, catalog numbers 450043,450042, and 450041.

Cholesterol - Enzymatic reaction as described by Trinder. Ann Clin Biochem 1974; 12:266. Default unit: mg/dL. Hitachi 912 Application Code 722. Roche Reagent, catalog number 450061.

383 of 435

## Creatinine - Modified J affe reaction based on the work of Poper et al. Biochem Z 1937; 291:354, and Seelig and Wuest. Aerztl Labor 1969; 15:34. Default unit: mg/dL. Hitachi 912 Application Code 727. Roche Reagent, catalog number 450019.

Globulin - Calculation obtained by subtracting Albumin from Total Protein. Default unit: g/dL.

Glucose - Glucose hexokinase method based on the work of Schmidt, Peterson and Young. Klin Wschr 1961; 39:1244. Methods of Enzymatic Analysis , 2 nd 

## Eng ed. New York, Academic Press, 1974; 1196. Anal Biochemistry 1958; 23:301. Default unit: mg/dL. Hitachi 912 Application Code 767. Roche Reagent, catalog number 450058.

Phosphorus - Method involves the formation of ammonium phosphomolybdate. Default unit: mg/dL. Hitachi 912 Application Code 714. Roche Reagent, catalog number 1040898.

Potassium - An ion-selective electrode that measures the electrical potential of the ions present in solution. Default unit: mEq/L. Hitachi 912 Application. Roche Reagent, catalog numbers 450043,450042, and 450041.

Sodium - An ion-selective electrode that measures the electrical potential of the ions present in solution. Default unit: mEq/L. Hitachi 912 Application. Roche Reagent, catalog number 450043,450042, and 450041.

Total Protein - Endpoint biuret method that utilizes a sample blank. Default unit: g/dL. Hitachi 912 Application Code 756. Roche Reagent, catalog number 1040901.

Triglycerides - Method that utilizes lipase from a microorganism to promote rapid and complete hydrolysis of triglycerides to glycerol. Default unit: mg/dL. Hitachi 912 Application Code 781. Roche Reagent, catalog number 1488899.

Hematology - Manual Methods

White Cell Differential - Manual method of counting 100 white cells stained with Wright Giemsa and entered on-line into the data files.

Reticulocyte Count - Manual method of counting the reticulocytes present in 1000 red blood cells stained with New Methylene Blue and entered on-line into the data files.

Red Blood Cell Morphology - Manual method of evaluating red blood cells on a Wright Giemsa-stained slide and entered on-line into the data files.

384 of 435

## Platelet Estimate- Manual method of evaluating platelets on a Wright Giemsa-stained slide. Platelet estimation is evaluated and entered on-line into the data files as decreased, adequate or increased. Platelet clumps present on the slide will be reported as part of the RBC morphology.

AMAX Destiny Amelung Coagulation

Mechanical (Ball Method) Measurement – Mechanical measurement methods depend on the physical formation of fibrin strands that attach to a moving mechanical device that either completes or opens an electrical circuit. The elapsed time from the addition of the starting reagent, up to the beginning of fibrin formation is measured.

Prothrombin Time (Protime-PT)/(PTM)- mechanical clot detection is used to measure and record the time required for plasma specimens to clot by adding an excess of thromboplastin reagent and an optional amount of calcium to citrated plasma. The PT measures from factor VII through fibrin formation (extrinsic and common pathways of coagulation). Default unit:

sec.
Activated Partial Thromboplastin Time (APTT)/(PTTM)- mechanical clot detection is used to measure and record clotting time in a one-stage procedure which consists of recalcifying plasma in the presence of an excess of platelet-like reagent (cephalin) containing a plasma activator. The APTT measures the clotting time from factor XII through fibrin formation (intrinsic and common pathways of coagulation) Default unit: sec.

Hematology-Bayer Advia® 120-Siemens Healthcare Diagnostics/(Formerly: Bayer Advia®120)

WBC Count - The whole blood sample is mixed with ADVIA ® 

## 120 BASO reagent that contains acid and surfactant. The red cells are hemolyzed, and the white blood cells are then analyzed using two angle laser light scatter signals. Default unit: x 103 cells/ μ L

RBC / Platelet Count - Both red blood cells and platelets are analyzed by a single optical cytometer after appropriate dilution of the blood sample with ADVIA ® 

## 120 RBC/PLT reagent. The red blood cells are isovolumetrically sphered and lightly fixed with glutaraldehyde to preserve the spherical shape. Red cells and platelets are counted from the signals from a common detector with 2 different gain settings. Default unit RBC: x 10 6 

## cells/ μ L. Default unit PLT: x 103 cells/ μ L

385 of 435

## Hg b - Hemoglobin: The hemoglobin method is a modification of the manual cyanmethemoglobin method developed by the International Committee for standardization in Hematology (ICSH). Default unit: g/dL.

Hematocrit - The percentage of blood volume that is occupied by red blood cells. Also referred to as the packed red cell volume. On the ADVIA ® 

## 120 Hematology System this parameter is derived from the measured red cell volume (MCV) and the red cell count (RBC). Default unit: %.

MCH - Mean Corpuscular Hemoglobin: the average weight of hemoglobin in the red blood cells, calculated from the RBC and Hgb measurements. Default unit: pg.

MCHC - Mean Corpuscular Hemoglobin Concentration: the average concentration of hemoglobin in the red blood cells. This parameter is computed from the measured hemoglobin and the computed hematocrit. Default unit: g/dL.

MCV - Mean Corpuscular Volume: the average volume of the red blood cells. Default unit: fL

White blood cell differential - The ADVIA ® 

## 120 Hematology System White Blood Cell Differential (WBC DIFF) methods, consists of both the Peroxidase method and the Basophil/Lobularity method. The ADVIA ® 

## 120 Hematology System performs a six-part differential that consists of basophils, eosinophils, large unstained cells, lymphocytes, monocytes, and neutrophils. The white blood cell differential count is reported in percent and the actual number of each type of cell per microliter of blood.

Reticulocyte - This method uses a nucleic acid dye (oxazine 750) to stain cellular RNA. The ADVIA ® 

## 120 autoRETIC reagent isovolumetrically spheres the erythroid cells and stains cellular RNA. Low-angle laser light scatter, high-angle laser light scatter, and absorption characteristics of all cells are counted and measured. The absorption data are used to classify each cell as a reticulocyte or mature red blood cell based on its RNA content. The reticulocyte is reported in percent and actual number x 10 9 

## cells/Liter = thous/ μ l.

References:

ADVIA ® 

## 120 Hematology System Operator's Guide: Copyright © 

## 1997, 1998. Siemens Healthcare Diagnostics/ (Formerly: Bayer Corporation Diagnostics Division).

AMAX Destiny Operation Manual SW V 1.1.4, 31/08/05. Trinity Biotech Plc.

386 of 435

# APPENDIX H

Historical Control Data (

387 of 435Sex:
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Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 3

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Age: RAT
Crl:CD(SD) SUBCHRONIC 52

12/02 02/07

- M

9 12

- Weeks / 52

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Serum Chemistry Values

Mean Reference Range
1.98 1.56 2.47 N
411 S.D.
0.208 

## A/G Ratio

/

Mean Reference Range
40 25 60 N
411 S.D.
7.3 

## Alanine Aminotransferase (U/L)

/

Mean Reference Range
4.3 3.9 4.7 N
411 S.D.
0.19 

## Albumin (g/dL)

/

Mean Reference Range
203 122 322 N
411 S.D.
44.3 

## Alkaline Phosphatase (U/L)

/

Mean Reference Range
95 67 154 N
411 S.D.
17.1 

## Aspartate Aminotransferase (UL)

/

Mean Reference Range
11.1 10.3 12.7 N
411 S.D.
0.50 

## Calcium (mg/dL)

/

Mean Reference Range
102 99 106 N
411 S.D.
1.6 

## Chloride (mEq/L)

/

Mean Reference Range
50 30 74 N
393 S.D.
9.8 

## Cholesterol (mg/dL)

/

Mean Reference Range
471 136 1562 N
106 S.D.
280.3 

## Creatine Kinase (U/L)

/

Mean Reference Range
0.2 0.1 0.3 N
412 S.D.
0.06 

## Creatinine (mg/dL)

/



## 388 of 435Sex:
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Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 2 of 3

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Crl:CD(SD) SUBCHRONIC 52

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Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
0.5 0.1 1.4 N
60 S.D.
0.36 

## GGT (U/L)

/

Mean Reference Range
2.2 1.7 2.6 N
411 S.D.
0.21 

## Globulin (g/dL)

/

Mean Reference Range
116 81 181 N
822 S.D.
20.9 

## Glucose (mg/dL)

/

Mean Reference Range
9.8 7.8 13.7 N
411 S.D.
1.30 

## Phosphorus (mg/dL)

/

Mean Reference Range
5.36 4.17 8.46 N
411 S.D.
0.905 

## Potassium (mEq/L)

/

Mean Reference Range
145 142 151 N
411 S.D.
1.8 

## Sodium (mEq/L)

/

Mean Reference Range
0.1 0.1 0.2 N
393 S.D.
0.04 

## Total Bilirubin (mg/dL)

/

Mean Reference Range
6.4 5.8 7.1 N
411 S.D.
0.29 

## Total Protein (g/dL)

/

Mean Reference Range
48 18 97 N
355 S.D.
17.3 

## Triglyceride (mg/dL)

/

Mean Reference Range
14.1 9.8 19.7 N
411 S.D.
2.17 

## Urea Nitrogen (mg/dL)

/



## 389 of 435Sex:
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Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 3 of 3

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Crl:CD(SD) SUBCHRONIC 52

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Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



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### Version 2.5



## 390 of 435Sex:
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Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 3

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Age: RAT
Crl:CD(SD) SUBCHRONIC 53

12/02 02/07

- F

9 12

- Weeks / 53

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Serum Chemistry Values

Mean Reference Range
2.10 1.64 2.66 N
422 S.D.
0.227 

## A/G Ratio

/

Mean Reference Range
34 21 67 N
424 S.D.
8.4 

## Alanine Aminotransferase (U/L)

/

Mean Reference Range
4.6 4.1 5.2 N
423 S.D.
0.26 

## Albumin (g/dL)

/

Mean Reference Range
125 67 191 N
424 S.D.
29.0 

## Alkaline Phosphatase (U/L)

/

Mean Reference Range
96 66 160 N
424 S.D.
19.0 

## Aspartate Aminotransferase (UL)

/

Mean Reference Range
11.1 10.0 12.8 N
423 S.D.
0.60 

## Calcium (mg/dL)

/

Mean Reference Range
103 99 107 N
424 S.D.
1.6 

## Chloride (mEq/L)

/

Mean Reference Range
64 39 97 N
403 S.D.
12.5 

## Cholesterol (mg/dL)

/

Mean Reference Range
452 137 1441 N
103 S.D.
275.2 

## Creatine Kinase (U/L)

/

Mean Reference Range
0.3 0.2 0.4 N
423 S.D.
0.07 

## Creatinine (mg/dL)

/



## 391 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 2 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 53

12/02 02/07

- F

9 12

- Weeks / 53

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
0.7 0.2 2.3 N
90 S.D.
0.45 

## GGT (U/L)

/

Mean Reference Range
2.2 1.7 2.7 N
422 S.D.
0.22 

## Globulin (g/dL)

/

Mean Reference Range
112 79 165 N
846 S.D.
15.1 

## Glucose (mg/dL)

/

Mean Reference Range
9.2 6.2 14.8 N
424 S.D.
1.76 

## Phosphorus (mg/dL)

/

Mean Reference Range
5.35 4.07 8.94 N
424 S.D.
1.070 

## Potassium (mEq/L)

/

Mean Reference Range
144 140 150 N
424 S.D.
1.9 

## Sodium (mEq/L)

/

Mean Reference Range
0.1 0.1 0.3 N
403 S.D.
0.06 

## Total Bilirubin (mg/dL)

/

Mean Reference Range
6.8 6.0 7.7 N
423 S.D.
0.37 

## Total Protein (g/dL)

/

Mean Reference Range
42 19 75 N
365 S.D.
12.4 

## Triglyceride (mg/dL)

/

Mean Reference Range
15.8 11.3 22.4 N
423 S.D.
2.25 

## Urea Nitrogen (mg/dL)

/



## 392 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 3 of 3

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Age: RAT
Crl:CD(SD) SUBCHRONIC 53

12/02 02/07

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9 12

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Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



### 26-Sep-07 

### Version 2.5



## 393 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 35

06/04 02/07

- M

9 12

- Weeks / 35

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Hematology Values

Mean Reference Range
0.04 0.01 0.14 N
273 S.D.
0.025 

## Basophil - Abs (thous/uL)

/

Mean Reference Range
0.4 0.1 1.1 N
273 S.D.
0.18 

## Basophil (%)

/

Mean Reference Range
1.1 0.3 3.7 N
273 S.D.
0.69 

## Eosiniphil (%)

/

Mean Reference Range
0.11 0.03 0.43 N
273 S.D.
0.063 

## Eosinophil - Abs (thous/uL)

/

Mean Reference Range
46.6 39.8 53.4 N
273 S.D.
2.88 

## Hematocrit (%)

/

Mean Reference Range
15.6 13.5 17.1 N
273 S.D.
0.72 

## Hemoglobin (g/dL)

/

Mean Reference Range
0.8 0.2 1.5 N
273 S.D.
0.28 

## LG Unstain Cell

/

Mean Reference Range
0.08 0.02 0.22 N
273 S.D.
0.041 

## Luc Absolute (thous/uL)

/

Mean Reference Range
8.07 4.19 14.33 N
273 S.D.
2.233 

## Lymphocyte - Abs (thous/uL)

/

Mean Reference Range
82.8 69.9 89.8 N
273 S.D.
4.19 

## Lymphocyte (%)

/



## 394 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 2 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 35

06/04 02/07

- M

9 12

- Weeks / 35

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
19.6 18.3 21.3 N
273 S.D.
0.68 

## MCH (pg)

/

Mean Reference Range
33.5 30.1 36.6 N
273 S.D.
1.48 

## MCHC (g/dL)

/

Mean Reference Range
58.7 52.5 66.2 N
273 S.D.
3.13 

## MCV (fL)

/

Mean Reference Range
0.18 0.07 0.42 N
273 S.D.
0.074 

## Monocyte - Abs (thous/uL)

/

Mean Reference Range
1.8 0.8 3.4 N
273 S.D.
0.59 

## Monocyte (%)

/

Mean Reference Range
1.25 0.57 2.50 N
273 S.D.
0.429 

## Neutrophil - Abs (thous/uL)

/

Mean Reference Range
12.9 6.8 26.0 N
273 S.D.
3.68 

## Neutrophil (%)

/

Mean Reference Range
1102 653 1502 N
273 S.D.
174.8 

## Platelet (thous/uL)

/

Mean Reference Range
11.2 11.0 12.0 N
5 S.D.
0.45 

## Red Cell Width (%)

/



## 395 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 3 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 35

06/04 02/07

- M

9 12

- Weeks / 35

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
7.96 6.77 9.04 N
273 S.D.
0.494 

## Red Cells (mil/uL)

/

Mean Reference Range
0.184 0.106 0.283 N
179 S.D.
0.0423 

## Reticulocyte - Abs (mil/uL)

/

Mean Reference Range
69.5 0.1 312.7 N
273 S.D.
101.78 

## Reticulocyte - Abs (thous/uL)

/

Mean Reference Range
2.5 1.3 4.5 N
273 S.D.
0.66 

## Reticulocyte (%)

/

Mean Reference Range
9.7 5.2 17.1 N
273 S.D.
2.56 

## White Cells (thous/uL)

/



### 25-Sep-07 

### Version 2.5



## 396 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 1

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 21

10/05 02/07

- M

9 12

- Weeks / 21

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Hematology Values

Mean Reference Range
20.3 16.4 26.6 N
151 S.D.
2.16 

## APTT (seconds)

/

Mean Reference Range
246.40 211.00 287.00 N
10 S.D.
20.178 

## Fibrinogen (mg/dL)

/

Mean Reference Range
16.4 13.2 20.1 N
151 S.D.
1.83 

## Prothrombin Time (seconds)

/



### 24-Sep-07 

### Version 2.5



## 397 of 435Sex:
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Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 37

06/04 02/07

- F

9 12

- Weeks / 37

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Hematology Values

Mean Reference Range
0.03 0.00 0.14 N
282 S.D.
0.020 

## Basophil - Abs (thous/uL)

/

Mean Reference Range
0.3 0.0 1.2 N
282 S.D.
0.18 

## Basophil (%)

/

Mean Reference Range
1.3 0.4 4.2 N
282 S.D.
0.72 

## Eosiniphil (%)

/

Mean Reference Range
0.10 0.03 0.34 N
282 S.D.
0.055 

## Eosinophil - Abs (thous/uL)

/

Mean Reference Range
44.3 38.4 51.1 N
282 S.D.
2.99 

## Hematocrit (%)

/

Mean Reference Range
15.1 13.1 16.7 N
282 S.D.
0.77 

## Hemoglobin (g/dL)

/

Mean Reference Range
0.7 0.0 1.6 N
282 S.D.
0.30 

## LG Unstain Cell

/

Mean Reference Range
0.06 0.00 0.16 N
282 S.D.
0.034 

## Luc Absolute (thous/uL)

/

Mean Reference Range
6.41 3.05 12.93 N
282 S.D.
2.079 

## Lymphocyte - Abs (thous/uL)

/

Mean Reference Range
83.0 65.1 90.7 N
282 S.D.
5.25 

## Lymphocyte (%)

/



## 398 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 2 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 37

06/04 02/07

- F

9 12

- Weeks / 37

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
19.6 18.3 21.2 N
282 S.D.
0.67 

## MCH (pg)

/

Mean Reference Range
34.2 30.4 37.6 N
282 S.D.
1.70 

## MCHC (g/dL)

/

Mean Reference Range
57.4 51.7 63.9 N
282 S.D.
2.85 

## MCV (fL)

/

Mean Reference Range
0.13 0.04 0.34 N
282 S.D.
0.063 

## Monocyte - Abs (thous/uL)

/

Mean Reference Range
1.6 0.7 3.9 N
282 S.D.
0.61 

## Monocyte (%)

/

Mean Reference Range
0.95 0.38 2.30 N
282 S.D.
0.373 

## Neutrophil - Abs (thous/uL)

/

Mean Reference Range
12.9 5.7 29.7 N
282 S.D.
4.95 

## Neutrophil (%)

/

Mean Reference Range
1144 734 1531 N
282 S.D.
167.3 

## Platelet (thous/uL)

/

Mean Reference Range
10.4 10.0 11.0 N
5 S.D.
0.55 

## Red Cell Width (%)

/



## 399 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 3 of 3

Range of Study Dates: Number of Studies/Control Groups: Study Type:
Age: RAT
Crl:CD(SD) SUBCHRONIC 37

06/04 02/07

- F

9 12

- Weeks / 37

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX

Mean Reference Range
7.72 6.61 8.55 N
282 S.D.
0.461 

## Red Cells (mil/uL)

/

Mean Reference Range
0.144 0.088 0.225 N
175 S.D.
0.0321 

## Reticulocyte - Abs (mil/uL)

/

Mean Reference Range
62.1 0.1 289.4 N
282 S.D.
84.74 

## Reticulocyte - Abs (thous/uL)

/

Mean Reference Range
2.0 1.1 4.0 N
282 S.D.
0.52 

## Reticulocyte (%)

/

Mean Reference Range
7.7 3.8 15.1 N
282 S.D.
2.33 

## White Cells (thous/uL)

/



### 25-Sep-07 

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## 400 of 435Sex:
Species:

Strain: 

### - Historical Control Summary of Clinical Pathology Values Page 1 of 1

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Age: RAT
Crl:CD(SD) SUBCHRONIC 24

10/05 02/07

- F

9 12

- Weeks / 24

Serum/Hematology/Coagulation Instrument: 912/ADVIA/AMAX



## Hematology Values

Mean Reference Range
19.0 15.0 24.8 N
176 S.D.
2.14 

## APTT (seconds)

/

Mean Reference Range
197.40 169.00 228.00 N
10 S.D.
18.846 

## Fibrinogen (mg/dL)

/

Mean Reference Range
14.3 11.9 17.1 N
176 S.D.
1.62 

## Prothrombin Time (seconds)

/



### 24-Sep-07 

### Version 2.5



## 401 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC4806/03 03/07-M/ 48Age: 9 12-Page 1 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksADRENAL GLANDSMeanObserved Low/High Value0.06080.04 0.10N318S.D.0.00995Mean +/- 2 S.D.0.0409 0.0807 0.0310 0.0907Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0190.01 0.033180.00310.012 0.025 0.009 0.0283.1172.06 4.833080.48072.156 4.078 1.675 4.559/////////BRAINMeanObserved Low/High Value1.951.61 2.26N324S.D.0.105Mean +/- 2 S.D.1.74 2.16 1.63 2.26Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.5990.45 0.843240.07140.456 0.741 0.384 0.8130.000.00NA//////EPIDIDYMIDESMeanObserved Low/High Value0.880.49 1.21N259S.D.0.166Mean +/- 2 S.D.0.55 1.21 0.38 1.38Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2640.17 0.362590.03540.193 0.334 0.157 0.37044.84825.51 64.742597.960128.928 60.769 20.968 68.729/////////



## 402 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC4806/03 03/07-M/ 48Age: 9 12-Page 2 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksHEARTMeanObserved Low/High Value1.300.89 1.93N300S.D.0.177Mean +/- 2 S.D.0.95 1.66 0.77 1.83Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.3990.30 0.593000.04520.308 0.489 0.263 0.53566.93848.90 96.023008.309150.320 83.556 42.011 91.865/////////KIDNEYSMeanObserved Low/High Value2.842.00 4.14N329S.D.0.440Mean +/- 2 S.D.1.96 3.71 1.52 4.15Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.8680.63 1.143290.08480.698 1.038 0.614 1.122146.455103.50 196.6731919.6824107.091 185.820 87.408 205.503/////////LIVERMeanObserved Low/High Value10.86.95 20.27N329S.D.2.03Mean +/- 2 S.D.6.7 14.9 4.7 16.9Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.3.2992.61 4.733290.37342.552 4.045 2.179 4.419557.885376.50 1018.5931994.2772369.331 746.440 275.054 840.717/////////



## 403 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC4806/03 03/07-M/ 48Age: 9 12-Page 3 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksLUNGSMeanObserved Low/High Value1.321.07 1.62N30S.D.0.121Mean +/- 2 S.D.1.08 1.57 0.96 1.69Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.4650.37 0.58300.03940.386 0.544 0.347 0.58369.84060.00 78.06204.803760.233 79.448 55.429 84.251/////////PITUITARYMeanObserved Low/High Value0.01170.01 0.02N171S.D.0.00200Mean +/- 2 S.D.0.0077 0.0157 0.0057 0.0177Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0040.00 0.001710.00060.002 0.005 0.002 0.0050.5990.27 0.881710.09550.408 0.790 0.313 0.886/////////PROSTATEMeanObserved Low/High Value0.660.35 1.31N111S.D.0.169Mean +/- 2 S.D.0.32 1.00 0.16 1.17Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2040.12 0.431110.04710.110 0.299 0.063 0.34634.06617.50 75.291118.911116.244 51.888 7.333 60.799/////////



## 404 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC4806/03 03/07-M/ 48Age: 9 12-Page 4 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksSEM VES/COAG GL.MeanObserved Low/High Value1.31080.81 1.97N13S.D.0.33555Mean +/- 2 S.D.0.6397 1.9819 0.3041 2.3174Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.3910.28 0.50130.07410.242 0.539 0.168 0.61366.72642.86 104.231316.693633.339 100.113 16.646 116.807/////////SPLEENMeanObserved Low/High Value0.670.38 1.15N281S.D.0.122Mean +/- 2 S.D.0.43 0.92 0.31 1.04Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2060.14 0.302810.03100.144 0.268 0.113 0.29934.57720.99 59.582815.838822.899 46.255 17.060 52.093/////////TESTESMeanObserved Low/High Value3.162.05 3.88N327S.D.0.281Mean +/- 2 S.D.2.60 3.72 2.32 4.00Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.9770.70 1.413270.11590.746 1.209 0.630 1.325162.749112.02 211.5431713.5416135.666 189.832 122.124 203.374/////////



## 405 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC4806/03 03/07-M/ 48Age: 9 12-Page 5 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksTHYMUS GLANDMeanObserved Low/High Value0.53230.28 1.03N261S.D.0.12763Mean +/- 2 S.D.0.2771 0.7876 0.1494 0.9152Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.1630.07 0.312610.04350.076 0.250 0.033 0.29427.39613.35 52.622616.691714.012 40.779 7.321 47.471/////////THYROID/PARATHYROIDMeanObserved Low/High Value0.02080.01 0.04N267S.D.0.00511Mean +/- 2 S.D.0.0106 0.0310 0.0055 0.0361Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0060.00 0.012670.00150.003 0.009 0.002 0.0111.0670.50 2.012670.26650.534 1.600 0.267 1.866/////////13-Aug-07Version 2.4



## 406 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC5006/03 03/07-F/ 50Age: 9 12-Page 1 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksADRENAL GLANDSMeanObserved Low/High Value0.07050.05 0.11N334S.D.0.01056Mean +/- 2 S.D.0.0494 0.0916 0.0388 0.1022Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0340.02 0.053340.00510.024 0.044 0.018 0.0493.8542.51 5.733240.55692.740 4.967 2.183 5.524/////////BRAINMeanObserved Low/High Value1.831.54 2.03N339S.D.0.087Mean +/- 2 S.D.1.65 2.00 1.57 2.09Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.8780.64 1.303390.09310.692 1.065 0.599 1.1580.000.00NA//////HEARTMeanObserved Low/High Value0.900.57 1.29N316S.D.0.110Mean +/- 2 S.D.0.68 1.12 0.57 1.23Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.4290.34 0.573160.03960.349 0.508 0.310 0.54849.04233.93 65.823165.486138.070 60.014 32.584 65.500/////////



## 407 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC5006/03 03/07-F/ 50Age: 9 12-Page 2 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksKIDNEYSMeanObserved Low/High Value1.821.24 2.58N344S.D.0.232Mean +/- 2 S.D.1.36 2.29 1.12 2.52Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.8710.61 1.123440.08570.699 1.042 0.613 1.12899.79672.38 137.7133411.481176.834 122.758 65.353 134.240/////////LIVERMeanObserved Low/High Value7.24.51 12.02N344S.D.1.08Mean +/- 2 S.D.5.1 9.4 4.0 10.5Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.3.4452.62 4.733440.35322.739 4.151 2.385 4.504395.963265.56 656.8333457.4247281.114 510.812 223.689 568.237/////////LUNGSMeanObserved Low/High Value1.160.94 1.53N40S.D.0.126Mean +/- 2 S.D.0.91 1.42 0.79 1.54Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.5750.50 0.69400.05100.473 0.677 0.422 0.72862.22550.81 75.74306.204749.816 74.635 43.611 80.840/////////



## 408 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC5006/03 03/07-F/ 50Age: 9 12-Page 3 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksOVARIESMeanObserved Low/High Value0.13030.10 0.18N25S.D.0.01917Mean +/- 2 S.D.0.0919 0.1686 0.0728 0.1878Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0610.04 0.08250.00830.044 0.077 0.036 0.0867.1115.39 9.60251.10434.903 9.320 3.798 10.424/////////OVARIES/OVIDUCTSMeanObserved Low/High Value0.13080.08 0.21N281S.D.0.02028Mean +/- 2 S.D.0.0903 0.1714 0.0700 0.1917Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0630.04 0.092810.00900.045 0.081 0.036 0.0907.1664.93 11.132811.06475.037 9.296 3.972 10.360/////////PITUITARYMeanObserved Low/High Value0.01450.01 0.02N182S.D.0.00269Mean +/- 2 S.D.0.0091 0.0198 0.0064 0.0225Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0070.00 0.011820.00110.005 0.009 0.004 0.0100.7880.51 1.311820.13740.513 1.063 0.376 1.200/////////



## 409 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC5006/03 03/07-F/ 50Age: 9 12-Page 4 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksSPLEENMeanObserved Low/High Value0.480.30 0.79N296S.D.0.086Mean +/- 2 S.D.0.31 0.65 0.23 0.74Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2310.16 0.362960.03510.161 0.302 0.126 0.33726.36917.10 44.252964.440917.487 35.251 13.046 39.692/////////THYMUS GLANDMeanObserved Low/High Value0.44910.15 0.75N276S.D.0.09537Mean +/- 2 S.D.0.2583 0.6398 0.1630 0.7352Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2150.08 0.352760.04540.124 0.305 0.079 0.35124.5908.26 40.302765.167914.254 34.926 9.087 40.094/////////THYROID/PARATHYROIDMeanObserved Low/High Value0.01820.01 0.03N275S.D.0.00447Mean +/- 2 S.D.0.0093 0.0272 0.0048 0.0316Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.0090.00 0.012750.00210.005 0.013 0.003 0.0150.9990.51 1.882750.24360.512 1.486 0.268 1.730/////////



## 410 of 435Sex:Species:- Historical Control Summary of Organ WeightsRange of Study Dates:Number of Studies/Control Groups:Study Type:RATCrl:CD(SD)SUBCHRONIC5006/03 03/07-F/ 50Age: 9 12-Page 5 of 5Strain:Excluding +/- 5 S.D.Report Type:WeeksUTERUSMeanObserved Low/High Value0.520.28 1.06N229S.D.0.167Mean +/- 2 S.D.0.19 0.86 0.02 1.02Absolute OW:OW relative to brain:OW relative to FBW:Mean +/- 3 S.D.0.2490.14 0.512290.07980.089 0.408 0.009 0.48828.51914.81 56.252298.893210.732 46.305 1.839 55.198/////////13-Aug-07Version 2.4



## 411 of 435

# APPENDIX I

Study Protocol

412 of 435

## Study 

## Number:

PROTOCOL 

## AMENDMENT KKI

Sponsor:

A. 

## Title of 

## Study:

A 

## S-Day Repeated-Dose Inhalation Toxicity 

## Study of 

## in Sprague-Dawley Rats



## B. Protocol Modification:

1) 

## The 

## Sponsor Name is 

## corrected to 

## , 

## 2) 3 STUDY 

## SCHEDULE:

The following information adds to 

## that currently 

## in the 

## protocol.

Proposed Experimental TerminatiodCompletion Date: February 14,2008



## Proposed Audited 

## Draft Report Date: May 14,2008



## 3) 9 

## STATISTICAL METHODS:



## The following 

## information clarifies to 

## that 

## currently in 

## the 

## protocol.



## For the 1800 ppm 

## group (Group S), 

## statistical 

## analysis will 

## not 

## be performed by comparison to 

## the study 

## control 

## group (Group 

## I) 

## since endpoint evaluations for 

## Group 5 

## were separated 

## from those 

## for a11 

## ather groups by 

## 3 

## days. historical 

## coritrol 

## information wil1 

## be 

## used to 

## aid in 

## interpretation of the 1800 

## ppm group results, as 

## needed.

C. 

## Reason for Protocol Modification:

1) 

## To 

## correct the Sponsor Name.

2) 

## To add 

## study 

## schedule information.

Improving 

### human health 

### and pmtectlng 

### nment thmugh sclent fflc 

### research services,@ 

## 413 of 435

## ndmcnt 

## I11 Page 2



## 3) To 

## clarify that statistical analysis 

## will not be 

## performed for Group 5.

Approved 

## By:

,

Sponsor 

## Representative

Prepared 

## By:



## 414 of 435

### Study Number:

PROTOCOL AMENDMENT II

Sponsor:

A. Title of Study :

A 5-Day Repeated-Dose Inhalation Toxi city Study of in Sprague-Dawley Rats

B. Protocol Modification :

1) 5.4 Number of Animals:

In accordance with the study dir ector notification dated January 30, 2008, animals ordered for this study but not selected for use on this study will be transferred for use on other studies or euthanized via CO 2 

### inhalation.

2) 7.4.1 Organization of Test Groups:

In accordance with the study director notification dated February 8, 2008, an additional group of five animals/sex w ill be added to the study and exposed at a target concentration of 1800 ppm.

7.4.3 Treatment Regimen:

3) In accordance with the study dir ector notification dated February 7, 2008, exposures for the 5000 ppm group (Group 4) will be terminated effective at the end of exposure on February 7, 2008.

4) In accordance with the study dir ector notification dated February 8, 2008, exposures for the additional (1800 ppm) group will be initiated on Saturday, February 9, 2008 and will end on Wednesday, February 13, 2008. All protocol-defined observations will be performed for this group. Necropsy will take place on February 14, 2008.

5) 8.2 Clinical Observations:

In accordance with the study direct or notification dated February 7, 2008, a scheduled clinical observation session will be added to the study for Groups 1, 2 and 3 and any additional groups, if needed. Animals will be observed in the exposure chambers near the beginning of each day’s exposure (approximately 15-30 minutes into the expos ure. Only clinical signs that can



## 415 of 435

## Protocol Amendment 11 Page 2



## be observed clearly through the chamber windows will be recorded 

## (in those animals that are visible through the chamber windows).

C. 

## Reason for Protocol Modification:

1) Clarification of disposition of animals ordered but not selected for study.

2) Addition of exposure group.

3) Termination of exposure for 5000 

## ppm group (Group 4).

4) Addition of treatment regimen for added group.

5) 

## Addition of clinical observation during exposure period.

Approved By:

Prepared By:



## 416 of 435

## Study Number:

PROTOCOL AMENDMENT I

Sponsor:

A. Title of Study:

A 5-Day Repeated-Dose Inhalation Toxicity Study of in 

## Sprague-Dawley Rats



## B. Protocol Modification:

1) 4.1 Identification:

Trade name: Chemical name:

2) 

## 4.2 Lot Number:

3) 4.3 

## Puritv:

99.99% (as 

## shown in 

## the Certificate of Analysis)

4) 4.4 Stability:

Stable for one year when stored at room temperature.

C. Reason for Protocol Modification:

1) Correction of test article identification.

2) 

## Addition of lot number.

3) Addition of purity information.

Tmnrnvin~ human health and nrntecti nment through scientjfjc research services.@ 

## 417 of 435

## Protocol Amendment 

## I Page 2

4) Addition of stability information.

Approved By:

Prepared By:



## 418 of 435Page 1 of17 January 8,2008



## PROTOCOL

A 5-DAY REPEATED-DOSE INHALATION TOXICITY STUDY OF IN SPRAGUE-DAWLEY RATS

Submitted To:

Testing Facility:

Improving human health and protecting the environment through scientific research services.@ 

## 419 of 435Page 2 of 17 January 8,2008



### 1 OBJECTIVE:


## The objective of this dose range-finding study is to evaluate potential toxic effects of the test article when administered via whole-body inhalation to rats for 5 consecutive days. Standard hematology and serum chemistry evaluations will be performed at the time of scheduled necropsy. Standard tissues will be harvested from all animals at necropsy and preserved, but will not be examined microscopically.
This study will be conducted in compliance with the following Good Laboratory Practice Regulations:
Organisation for Economic Cooperation and Development: [C(97) 186lFinall
U.S. Environmental Protection Agency 

## - TSCA: 40 CFR Part 792 Japan 

## MAFF Good Laboratory Practice Standards 1 1 Nousan No. 6283, October 

## 1, 1999.

2 PERSONNEL INVOLVED 

## IN THE STUDY:

2.1 Sponsor Representative:

2.2 Studv Director:

2.3 Deputv Director:



## 420 of 435Page 3 of 17 January 8,2008



### 2.4 

### Departmental Responsibilities:

3 

## STUDY SCHEDULE:



## 421 of 435Paae 4 of 17 January 8,2008



## Proposed Audited Report Date: To be added by protocol amendment.

4 TEST ARTICLE DATA:



## 4.1 Identification:



## (

4.2 Lot Number:



## To be provided by the Sponsor.

4.3 Puritv:


## To be provided by the Sponsor in Certificate of Analysis.

4.4 Stabilitv:



## Stable under conditions of storage. Expiration date: to be added by protocol amendment.

4.5 Physical Description:



## To be documented by

4.6 Storage Conditions:


## Ambient conditions in Inhalation Department test article storage area.

4.7 Reserve Samples:



## A reserve sample of each lot of the test article will be taken in accordance with Standard Operating Procedures and stored in the Archives at indefinitely, unless otherwise specified.

4.8 Personnel Safety Information:


## To be provided by the Sponsor, preferably in the form of a Material Safety Data Sheet (MSDS).

At a minimum, technical staff will wear safety glasses, appropriate gloves, and facility clothing when handling or working with the test article. Additional personal protective equipment, such as a respirator, protective coveralls or sleeve covers, may be required. Specific equipment and its use will be defined by study management and communicated to technical staff, as appropriate.



## 422 of 435Page 5 of 17 January 8,2008



## 5 TEST SYSTEM:



## 5.1 Species:



## Rat

5.2 

### Strain:


## Sprague-Dawley c~~:cD@(sD).

5.3 Source:



## Charles River Laboratories (Facility to be documented in study records)

5.4 Number on Studv:



## Five males and 5 females per exposure level (40 animals on study). Twenty-five animalslsex will be purchased.

The n er of animals used will be the minim eded to meet the objectives of the study.

5.5 Approximate Weight:



## 250 to 350 grams for males and 170 to 300 grams for females at initiation of
exposure, 

# + 20% of the mean for each sex.

5.6 

### Approximate Ape:



## 8-12 weeks at the time of exposure



## 5.7 Identification Svstem:



## mals will be uniquely identified by a metal ear tag displaying the animal number. Individual cage cards will be affixed to each cage and will display the study number, animal number and group (exposure level).

5.8 Justification for Selection:



## This species and strain is generally recognized to be appropriate for inhalation studies. The Crl:CD(SD) rat will be utilized because it is a widely-used strain for which significant historical control data are available. The number of



## 423 of 435Page 6 of 17 January 8,2008



## animals selected is the minimum needed to yield statistically valid and scientifically meaningful data.



## 6 SPECIFIC WON-EXPOSURE PERIOD) MAINTENANCE SCHEDULE:



## 6.1 Animal Housing:

The animals will be individually housed in suspended wire-mesh cages in an environmentally controlled room. The cages will be elevated above cage-board or other suitable material. The cages will be subject to routine cleaning at a frequency consistent with maintaining good animal health. The facilities at are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

6.2 

## Environmental Conditions:

Controls will be set to maintain an average daily temperature of 71 

# * 5°F (approximately 22 

# + 3°C) and an average daily relative humidity of 50 

# * 20%. Temperature and relative humidity will be monitored continuously. Data for these two parameters will be scheduled for automatic collection on an hourly basis. Fluorescent lighting will provide illumination for a 12 hour lighvdark photoperiod. Temporary adjustments to the lighvdark cycles may be made to accommodate protocol-specified activities. The ventilation rate will be set at a minimum of 10 room air changes per hour, 1'00% fresh air.

6.3 

## Drinkinp Water:

Reverse osmosis-treated tap water will be available ad libitum 

## via an automatic watering system throughout the study, except during exposure periods. Filters servicing the automatic watering system are changed regularly according to Standard Operating Procedures. Water supplying the laboratory is analyzed for contaminants according to Standard Operating Procedures to ascertain that none are present at concentrations that would be expected to affect the outcome of the study.



## 6.4 Basal Diet:

PMI Nutition International, LLC Certified Rodent ~ab~iet@ 5002 will be offered ad libitum 

## throughout the study, except during exposure periods or any scheduled period of fasting. Each lot utilized will be identified and recorded. Standard Operating Procedures provide specifications for acceptable levels of heavy metals and pesticides that are reasonably expected to be present in the diet without interfering with the purpose or conduct of the study. Each lot of feed has been analyzed to assure specifications are met. Feeders will be



## 424 of 435Page 7 of 17 WnJanuary 8,2008



## changed and sanitized once per week. Copies of the appropriate analyses will be maintained on file at

.7 EXPERIMENTAL DESIGN:



## 7.1 Animal Recei~t and Acclimation
'


## Each animal will be inspected by a qualified technician upon receipt. Animals judged to be in good health and suitable as test subjects will be acclimated for a minimum of seven days. All animals will be weighed and permanently identified with an ear tag.
During the acclimation period, each animal will be observed twice daily for changes in general appearance and behavior. The animals will be allowed a pretreatment week (as part of the acclimation period) during which body weights and food consumption will be recorded and general health will be monitored, but they will not receive the test article. All animals will receive a detailed physical examination approximately one week prior to initiation of dosing and at the time of animal selection for randomization.

7.2 

## Randomization:

Near the end of the acclimation period, animals judged to be suitable for testing will be assigned to groups at random based on body weight stratification into a block design using a computer program. 

## A printout containing the animal numbers and individual group assignments will be generated. Animals will then be arranged into groups according to the printout. Body weights at randomization will be within A 

### 20% 

## of the mean for each sex. If, after randomization, significant differences between groups exist, new randomizations will be generated until group mean body weights are not statistically different between groups by sex.

7.3 

## Route and Rationale of Test Article Administration:

The route of administration will be inhalation exposure since this is a potential
route of human exposure.



## 425 of 435Page 8 of 17 January 8,2008



### 7.4 Organization of Test Groups, Exposure Levels and Treatment Regimen:
7.4.1 Organization of Test Groups:


## The following table presents the study group arrangement.

7.4.2 Exposure Levels: Group Number 

### 1 2 3 

### 4



## The three test article exposure concentrations were selected by the Sponsor based on the results of previous inhalation toxicity studies.

7.4.3 Treatment Regimen: Test Article Filtered Air



## Filtered-air and test article vapor atmospheres will be administered as six-hour, whole-body exposures for 5 consecutive days. On the day following the fifth exposure, all animals will be euthanized and necropsied. The first day of exposure is defined as exposure day zero.

7.5 Exposure Methods:


## Exposures will be conducted in 500-L stainless-steel and glass whole-body exposure chambers. The exposure systems will be operated under dynamic conditions from a HEPA- and charcoal-filtered air source or breathing quality in-house compressed air source. Air flow rate through the chamber will be such that there will be 12-15 air changes per hour. Mean chamber temperature and relative humidity will be 22 

# * 2°C and 30-70%, respectively. These parameters will be monitored continuously and recorded approximately every 30-40 minutes throughout the exposure. Readings outside the average range will be documented. Oxygen content of the exposure atmosphere will be measured during the methods development phase of the study, while operating at the above targeted conditions, and will be at least 

## 19%. Target Exposure Level (ppm) 

### 0 1250" 2500 5000



## All animals will be housed in a normal animal colony room during non-exposure hours. For each day's exposure, the animals will be placed in exposure batteries, transported to the exposure room, exposed for the requisite duration, and returned to their home cages. Food and water will not be availa ng the exposures. Number of Animals Males



### 5 5 5 5 Females 

### 5 

### 5 5 5



## 426 of 4355340 1 1 Page 9 of 17 January 8,2008



## 7.6 Test Material Generation Methods:
Vapors of the test article will be generated using a bead-filled vaporization column or a gas-washing bottle, or other appropriate generation system. Prior to entering the test chambers, the vapors will be mixed with dilution air to achieve desired exposure levels. Further details of generation systems and methodologies, including specific types andlor models and operating conditions for the system, will be defined during pre-study method development and included in a description of exposure, test atmosphere generation and monitoring methods, which 

## will be approved by the Study Director.

7.7 Methods of Characterization of Exposure Atmospheres:

7.7.1 Nominal Concentrations:
Nominal exposure concentrations will be calculated for each day's exposure using the following formula:

PPm - 

## Wt. Mol. Vol. lo6 MW Ch. Flow Exp. Dur.

Where:

Wt. = 

## the weight of test article used during a given day's exposure, grams Mol. Vol. = 

## molar volume of test article at 730 

## mrn Hg and 21°C 1 

# o6
= 

## ppm conversion factor 

## MW = 

## molecular weight of test article Ch. Flow = 

## daily average chamber flow rate for a given day, in L/min Exp. Dur. = 

## duration of a given days' exposure, in minutes

Given the physical characteristics of the test article, it is expected that the nominal concentration will be within *lo% of the measured chamber concentration. Variation outside this range will be investigated as potential system performance problems.

7.7.2 Analyzed Exposure Concentrations:
Analyzed concentrations of the test article(s) in the exposure chamber will be determined by a specific on-line gas chromatographic method and will be measured approximately every 30-40 minutes throughout the exposure period. Details concerning these specific methods to be used will be defined during pre-study method development and included in a



## 427 of 435Page 10 of 17 January 8,2008



## description of exposure, test atmosphere generation and monitoring methods, which 

## will be approved by the Study Director.

The calibration of the gas chromatograph will be considered acceptable if the r2 value is 

# > 0.98 and the individual points of the calibration are within 

## 10% of their target concentrations. Daily mean analyzed concentrations of test article will be maintained within 

# * 10% get exposure concentrations.

8 

### EXPERIMENTAL OBSERVATIONS:

8.1 Viability Observations:



## All animals will be observed for mortalitylmoribundity twice daily, once in the morning and once in the afternoon, except on the day of scheduled necropsy. Moribund animals will be euthanized to ensure that tissues will not be lost due
to autolysis.

8.2 

### Clinical Observations:



## Clinical observations will be conducted prior to exposure and 0-1 hour following the exposure on exposure days. The clinical observations prior to exposure will not be performed on the days of detailed physical examinations. Observations will include, but are not limited to, changes in the skin, fur, eyes and mucous membranes, respiratory, circulatory and autonomic and central nervous system functions, somatomotor activity and behavior patterns. Findings noted at the clinical examination will be recorded for individual animals; the condition of animals without signs will be documented as a general
comment.

8.3 

### Detailed Physical Examination:



## All animals will receive a detailed physical examination prior to test article administration for randomization and group assignment and twice during the exposufe phase (including prior to scheduled necropsy). Animals to be euthanized prior to scheduled necropsy will undergo an additional detailed physical examination prior to euthanasia to issist in determination of the cause of death.

The animals will be removed fiom their home cages and placed in a standard

arena for observation. Observations will be detailed and carefully noted. When appropriate, explicitly defined scoring systems will be used if, in the opinion of the Study Director, doing so increases the utility of the data. Signs noted shall include, but are not limited to, changes in skin, fur, eyes, mucous membranes,

occurrence of secretions and excretions, and autonomic activity (e.g.,



## 428 of 435Page 11 of 17 January 8,2008



## lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling, as well as the presence of clonic or tonic movements, stereotypes (e.g., excessive grooming, repetitive circling) or bizarre behavior (e.g., self-mutilation, walking backwards) will be recorded. The absence or presence of findings will be recorded for individual animals.

8.4 Individual Bodv Weights:



## Individual body weights will be recorded during the pretest phase for randomization and group assignment and prior to the first, third and fifth exposures. The animals will be fasted overnight prior to scheduled necropsy. A final body weight will be determined prior to necropsy.

8.5 Individual Food Consum~tion:



## Individual food consumption will be recorded weekly for all animals, beginning at least one week prior to test article administration.

8.6 Clinical Patholow:


## Hematology, serum chemistry and coagulation parameters will be evaluated fiom all surviving animals on the day of the scheduled necropsy. The animals will be fasted overnight before blood collection and necropsy. For hematology (except clotting parameters) and standard serum chemistry evaluations, blood samples will be collected fiom the retro-orbital sinus fiom animals anesthetized using isoflurane. Blood samples for clotting evaluations will be collected via the vena cava at necropsy (animals anesthetized using isoflurane). EDTA will be used for the anticoagulant on samples collected for hematology, and sodium citrate will be used for samples collected for clotting determinations. Serum collection tubes will be used for blood samples collected for serum chemistry.
8.6.1 Hematology:



## Differential leukocyte counta Mean corpuscular hemoglobin Erythrocyte count Concentration Hematocrit Mean corpuscular volume Hemoglobin Platelet Count Mean corpuscular hemoglobin Reticulocyte count Total leukocyte count

a 

### - If performed manually, results will include platelet estimates and 

### RBC morphology.


### 8.6.2 Coagulation Parameters:



## Activated partial thromboplastin time Prothrombin time



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### 8.6.3 Serum Chemistry:



## A/G ratio Alanine aminotransferase Albumin Alkaline phosphatase Aspartate aminotransferase Calcium ChlorideCreatinineGlobulin Glucose Phosphorus Potassium Sodium Total bilirubin Total cholesterol Total protein Triglycerides Urea nitrogen

8.7 Anatomic Pathology:
8.7.1 Macroscopic Examination:


## A complete necropsy will be conducted on all animals dying spontaneously, euthanized in extremis 

## or at the scheduled necropsy. Animals euthanized in extremis 

## or at the scheduled necropsy will be anesthetized with isoflurane and exsanguinated. Necropsy will include examination of the external surface; all orifices; and the cranial, thoracic, abdominal and pelvic cavities including viscera. The following tissues will be collected and placed in 10% 

## neutral-buffered formalin:



## 430 of 435Page 13 of 17 January 8,2008



## Adrenal glands (2) Aorta Bone with marrow (sternebrae) Bone with marrow (femur with joint) Bone marrow smear (taken fiom femur") Brain

Cerebrum Level 1 Cerebrum Level 2 Cerebellum with ponslmedulla Cervix Epididymides (21b Eyes with optic nerves (2)' Gastrointestinal tract

Esophagus Stomach Duodenum Jejunum Ileum Peyer's patches Cecum Colon Rectum Harderian glands (2) Heart Kidneys (2) Lacrimal glands [exorbital (2)] Larynx 

## Liver (sections of two lobes) Lungs (including bronchi, fixed by

inflation with fixative) Lymph node Mediastinal and bronchial (if visible) Mesenteric and mandibular (2) ~a'krnar~ gland (females only) Nasal cavityd Ovaries/oviducts (2)" Pancreas Peripheral nerve (sciatic) Peyer's patches Pharynx Pituitary Prostate Salivary glands [mandibular (2)] Seminal vesicles (2) Skeletal muscle (rectus femoris) Skin Spinal cord

Cervical Thoracic Lumbar Spleen Testes (2)b Thymus Thyroid gland [with parathyroids (2)Ie Trachea Urinary bladder Uterus Vagina All gross lesions

a 

## - Bone marrow smears will be obtained at scheduled necropsy and fiom all anirilals euthanized in extrernis 

### (not placed in formalin). To be examined only if scientifically warranted. b 

## - Placed in Bouin's solution.

c 

### - Placed in Davidson's solution. d 

## - Following collection of the appropriate protocol-specified tissues, the entire head will be removed and preserved.

e 

### - Parathyroids and oviducts will be examined microscopically if in the plane of section and in all cases when a gross lesion of the organ is present.



## 431 of 435Page 14 of 17 January 8,2008



## 8.7.2 Organ Weights:


## The following organs fiom all animals at the scheduled necropsy will be weighed:

Liver Kidneys Lungs (prior to inflation with fixative) Brain

Paired organs will be weighed together. Organ-to-body-weight and organ-to-brain-weight ratios will be calculated fiom animals euthanized
at the scheduled necropsy.



## 8.7.3 Microscopic Examination:


## Microscopic examination of hematoxylin-eosin stained tissue sections will not be conducted, but may be performed at a later date at additional
cost.

9 

### STATISTICAL METHODS:



## All statistical tests for experi ata will be performed using appropriate cpmputing devices or programs as referenced below. All analyses will be two-tailed for significance levels of 5% and 1%. Mean values will be presented with standard deviations. Body weights, body weight changes and food consumption as well as clinical pathology values and absolute and relative organ weights will be subjected to

a one-way analysis of variance (Snedecor and Cochran, 1980). If a statistically significant difference (pC0.05) is present in this ANOVA, a comparison of the control group to each treated group by Dunnett's test (Dunnett, 1964) will be performed. Statistical analysis will not be performed on groups with an 

## N of two (2) or less.

10 REPORT:


## The Final Report will contain a summary, test material data, methods and procedures, appropriate individual animal and summary data tables, methods and results of test atmosphere generation and characterization, a copy of the protocol and amendments (if any) and an interpretation and discussion of the study results. The report will be comprehensive and shall attempt to define toxicity and the no-observed-effect level(s) under the conditions of this investigation.

will submit one copy of an audited draft report in a timely manner upon completion of data collection prior to issuance of the final report. One revision will be permitted as part of the cost of the study, fiom which the Sponsor's reasonable revisions and suggestions will be incorporated into the final report, as appropriate. Additional changes or revisions may be made, at an extra cost. It is expected that the Sponsor will review the draft report and provide comments to



## 432 of 435Pace 15 of 17 January 8,2008



## within a two-month time frame following submission. will submit the final report within one month following receipt of comments. If the Sponsor's comments and/or authorization to finalize the report have not been received at within one year following submission of the draft report, may elect to finalize the report following appropriate written notification to the Sponsor. The original paper final report (containing original signatures) and two electronic copies (one in PDF and one in MS Word format) of the final report on CD-R will be provided. Requests for additional paper copies of the final report may result in additional charges.



## 11 QUALITY ASSURANCE:
The study will be audited by the Quality Assurance Unit while in progress to

assure complisince with Good Laboratory Practice Regulations, adherence to the protocol and to Standard Operating Procedures. The raw data and draft report will be audited by the Quality Assurance Unit prior to submission to the Sponsor to assure that the final report accurately describes the conduct and the findings of the study.

12 

## RECORDS TO BE MAINTAINED:
All original raw data, as defined by SOPs and the applicable GLPs, will be maintained in permanently bound notebooks or in loose-leaf notebooks and at study completion will be stored in the Archives at

13 

## WORK PRODUCT:
Sponsor will have title to all documentation records, raw data, slides, specimens, or other work product generated during the performance of the study. All work product including raw paper data and pertinent electronic storage media will be retained for a period of ten (10) 

## years following issuance of the final report in the archives at Thereafter, will charge a monthly archiving fee for retention of all work product. All work product will be stored in compliance with regulatory requirements.
Any work product, including documents, specimens, and samples, that are required by this protocol, its amendments, or other written instructions of the Sponsor, to be shipped by to another location will be appropriately packaged and labeled as defined by SOPs and delivered to a common carrier for shipment. will not be responsible for shipment following delivery to the common carrier.



## 433 of 435Paae 16 of 17



## 14 

## ANIMAL WELFARE ACT COMPLIANCE:
This study will comply with all applicable sections of the Final Rules of the Animal Welfare ~ct regulations (9 

## CFR). The Sponsor should make particular note of the following:

The Sponsor signature on this protocol documents for the Study Director the Sponsor's assurance that the study described in this protocol does not unnecessarily duplicate previous experiments.

Whenever possible, procedures used in this study have been designed to avoid or minimize discomfort, distress or pain to animals. All methods are described in this study protocol or in written laboratory Standard Operating Procedures.

Animals that experience severe or chronic pain or distress that cannot be relieved will be painlessly euthanized as deemed appropriate by the veterinary staff and Study Director. The Sponsor will be advised by the Study Director of all circumstances which could lead to this action in as timely a manner as possible.

Methods of euthanasia used during this study are in conformance with the above referenced regulation.

The SponsorIStudy Director has considered alternatives to procedures that may
cause more than momentary or slight pain or distress to the animals and has provided a written narrative description (AWA covered species) of the methods and

sources used to determine that alternatives are not available.

15 REFERENCES:

Dunnett, C.W. New tables for multiple comparisons with a control. Biometries 

## 1964, 20, 

## pp. 482-491.



## 434 of 435Page 17 of 17 January 8,2008



## Snedecor, G.W. and Cochran, W.G. One Way Classifications; Analysis of Variance. 

## In Statistical Methods, 7th ed.; The Iowa State University Press: Arnes, 

## IA, 1980; pp. 21 5-237.

16 PROTOCOL APPROVAL:
Sponsor approval received via email on 08 January 2008.



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