### C;ompany 

### Sanitized



### 90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE

STUDY DETAILS Data Requirement: Guideline Ref: OPPTS 870.3465 (1998) Study Completion Date: 24 

### January 2005 

### Perfonning Laboratory: Laboratory Project ID: Report No: Study No: Document No: 

### AUTHOR



## \

# ~IIII**III~**Ill'11111nil111\\

# II1~11111nl

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# ~11111

## 11111 5 0 0 5 0 0 0 2 2 0 	 5 J S 

# -rD 

# p-oc.l -<85 

# - ..

VRF.Om .ATORY/RF.PORT90 DAY 

### INHALATIONTOXICITY STIJDY IN TI:IE 

### RAT WITH RECOVERY PHASE 

## STATEMENTS OF DATA CONFIDENTIALITY CLAIMS 1) The/ollowinK statement applies to submissions to regulatory agencies in the United States of America. ' STATEMENT OF NO DATA CONFIDENTIALITY CLAIM No claim ofconfidentiality is made for any information contained in this study on the basis of its 

### falling within the scope of

### FIFRA section 

### 10 (d) 

### (1) (A), (B), ot 

### (e). Company: 

### Company Representative: Title:
Signature; 

### Date.:
These data are the property of and, as SUCh, 

### are considered to 

### be confidential for 

### all purposes other than compliance with the regulations implementing FIFRA 

### Section 10. 

### Submission ofthese data in compliance with 

### FIFRA does not constitute a waiver ofany right to 

### confidentiality which 

### may exist under any other provision ofcommon law or statute or in any other country. 

### 2) Thefollowing statement applies to submissions to regulatory agencies other than in 

### the United States of America.
THIS DOCUMENT CONTAINS INFORMATION CONFIDENTIAL AND TRADE SECRET TO It should be not be disclosed in /lOy form to /lO outside 

### party, nor should information 

### contained herein be 

### used by a registration authority to support registration ofthis product or any Qther product without the written permission of



### REGULATORYnffiPORT . 290 DAY INHAlATION TOXICITY STUDY IN THE RAT 

### wrtH RECOVERY PHASE


### STATEMENT OF GLP COMPLIANCE AND AUTHENTICATION I, the undersisned, declare that the**objectiv~** laid down in the protocol were achi",ved And tbat the data generated are valid. The repon funy and accurately reflects the procedures used and the raw data generated in the above study. Tht: lolLiUy (PR1302) was .;;ondu.c;ted ill compliance with the UK Principlc;.s ofGood Laboratory Practice (The Uliited Kingdom GLP Regulations 1999, Statutory Instrument No. 3106, as amended 2004, Statutory Instrument No. 994). These Principles are in accordance with the DEeD Principles ofGood LaboratoryPractice, re"ised 1997 (ENV!MC!CHEM(98)17).

24 January 2005 5:tudy Director Date**~GULATORYffiEPORT** - 390 DAY INHAlATION TOXICITY STUDY IN THE RAT 

### wrtH RECOVERY PHASE

! 

### I 

### This page may be 

### required by 

### some regulatory authorities.

. /REGUlATORY/REPORT - 490 DAY INHALATION TOXICITY STIIDY IN THE RAT WITH RECOVERY PHASE


### QUALITY ASSURANCE STATEMENT
In accordanoe**wH~** pul.h;)' iIIlU QA**JJr~t:U!.Il ~**  (UI Ouuu J....,UUI dlUl)' Pla<otK<o, this ""porthasbeen aurulCd and the conduct ofthis study hill! been inspected as follows:

Date AuditlInspection Date ofQA Report 22 Mar 2004 Protocol 22 Mar 2004 23 Apr 2004 Atmosphere generation, exposure, atmosphere 26 Apr 2004 collel;tion. fllnlOspbc:re analysis 1\ May 1004 Clinical observati.ons, bodyweigbts, food weighing 11 May 2004 03 Jul2004 Functional**()b~Mioo b~"""Y.**  mnlor Rr.'iviry 0,luI2004 08 Jul2004 Urine collection 09 J.12004 12JuI2004 Ophthalmo300PY 1211112004 16Ju12004 Post mortem. blood collection 19 Je12004 26Jul2004 Sample dispaICh chain ofcustody 2611112004 11 Nov 2004 Draft report 26 Nov 2004 07neclOO4 Orailreport 17 Dec 2004 21 Jan 2005 Final report review 21 Ian 2005
In additian, inspections associated with this type ofstudy were made as follows:

13Jul2004 Sample dispatch chain ofcustody 13 Jul2004
Facilities and proct'5S based procedures associated with this type ofstudy were inspected in accordaru:e**~'ith** QA Standard Operating Procedures. So far as can be reasonably established, the methods described and the results given in the final report accurately fe-fleet the raw dam produce-d during the study, PR 1302
24 January 2005 Quality Assumnce Unit)**~GULATORY~PORT** - 590 DAY INHALATION TOXICITY STUDY IN THE RAT 

### wrm RECOVERY PHASE


## STUDY CONTRIBUTORS

The following contributed to this report in the capacities indicated:



### Name Title Study Director

Study Reviewer Chemical Analyst Pathologist! Clinical Pathologist Statistician Study Technician Ophthalmoscopist Principal Investigator (histopathology slide production)

fREGUlATORYIREPORT • 690 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### CONTENTS Page Number 

## 1. SUMMARY 

### 12 1.1 

### Study design........................................................................................................... 12 

### 1.2 Results.................................................................................................................... 12 1.3 Conclusion ............................................................................................................. 13 

### 2. INTRODUCTION 

### 14 2.1 

### Purpose .................................................................................................................. 14 2.2 Regulatory 

### guideline.1i: ............................................................................................ 14 2.3 

### Justification for test system selection .................................................................... 14 2.4 Selection ofatmospheric concentrations ............................................................... 14 2.5 Dates 

### ofthe in-life phase ....................................................................................... 15 

### 2.6 

### Data storage ........................................................................................................... 15 

### 3. TEST SUBSTANCE 

### 16 3.1 

### Test substance ........................................................................................................ 16 

### 4. EXPERIMENTAL PROCEDURES 

### 16 4.1 

### Atmosphere concentration ..................................................................................... 16 4.1.1 

### Trial generation...................................................................................................... 16 

### 4.1.2 Generation conditions............................................................................................ 17 

### 4.2 

### Atmosphere sampling and analysis ....................................................................... 17 

### 4.2.1 Nominal atmosphere concentrations...................................................................... 17 4.2.2 Analysed atmospheric concentrations ................................................................... 18 

### 4.3 

### Experimental design .............................................................................................. 18 4.3.1 

### Animals .................................................................................................................. 18 

### 4.3.2 Accommodation and 

### husbandry ............................................................................ 18 

### 4.3.3 

### Acclimatisation ...................................................................................................... 19 4.3.4 

### Animal randomisation and identification .............................................................. 19 4.3.5 

### Exposure concentrations ........................................................................................ 2U 

### 4.3.6 

### Exposure system .................................................................................................... 20 4.3.7 

### Duration ofexposure ............................................................................................. 20 4.3.8 

### Duration ofrecovery period................................................................................... 21 

### 4.4 Clinical observations ............................................................:................................ 21 

### 4.5 Bodyweights .......................................................................................................... 21 4.6 Food 

### consumption and utilisation.......................................................................... 21 4.7 

### Ophthalmoscopy .................................................................................................... 21 4.8 Functional observation battery .............................................................................. 21 

### 4.9 Motor activity ........................................................................................................ 23 

### 4.10 Clinical pathology.................................................................................................. 23**REGULATORY~ORT** • 790 DAY INHAlATION TOXICITY STIlDY IN THE RAT

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4.10.1 Urinalysis ............................................................................................................... 23 4.10.2 HaematoJogy.......................................................................................................... 24 4.10.3 Blood clinical chemistry ........................................................................................ 24 4.11 Investigations

### postmortem .................................................................................... 25 4.11.1 Tennination............................................................................................................ 

### 25 4.11.2 Organ weights ........................................................................................................ 

### Z5 4.11.3 Tissue submission for main study and recovery groups ........................................ 25 4.11.4 Determination 

### ofcyanide insensitive PaImitoyl CoA oxidation ........................... 

### 26 4.11.5 Tissue processing................................................................................................... 

### 26 4.11.6 Tissue examination ................................................................................................ 

### 27 

### 5. DATA EVALUATION 

### 27 8. RESULTS 

### 27 6.1 Abnosphere analysis .............................................................................................. 

### 27 6.1.1 Nominal concentration........................................................................................... 

### 27 6.1.2 Analy"d atnlospheric concentration ..................................................................... 27 

### 6.2 

### Clinical observations ............................................................................................. 

### 28 6.2.1 Prior to exposure .................................................................................................... 28 6.2.2 DUling eAposW"e and post exposun:: ....................................................................... 28 6.3 Bodyweigbts .......................................................................................................... 28 

### 6.4 Food consumption and utilisation..........................................................................

### 28 0.5 Ophthalmoscopy .................................................................................................... 29 6.6 Functional observation battery
.............................................................................. 29 6.6.1 Clinical assessments .............................................................................................. 29 6.0.2 Landing foot splay measurements ......................................................................... 29 

### 6.6.3 Grip strength measurements .................................................................................. 29 6.6.4 Time to tail flick .................................................................................................... 29 

### 6.1 Motor activity measurements ................................................................................ 29 6.8 Oinical pathology.................................................................................................. 30 6.8.1 Haematology .......................................................................................................... 30**6.~.2** Blood clinical chemistry ........................................................................................ 30 

### 6.8.3 Urine clinical chemistry......................................................................................... 31 6.9 Investigations

### postmortem .. :................................................................................. 31 

### 6.9.1 Organ weights ........................................................................................................ 31 6.9.2 Cyanide insensitive palmitoyl CoA oxidation....................................................... 31 6.9.3 Macroscopic findings............................................................................................. 31 6.9.4 Microscopic findings ............................................................................................. 32 

### 7. DISCUSSION 

### 32 8. CONCLUSION 33

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### 34 90 DAY lNHAlATION TOXICITY srUDY IN 1lIERAT WOH RECOVERY PHASE


### 9. 

## REFERENCES FIGURES FIGURE 1: Group mean bodyweight versus time (main study) ........................... 35 

### F1GURE2: Group mean bodyweight versus time (recovery groups) ................... 37 

### F1GURE3: Statistical analysis ofbodyweight**adj~sted** for initial weight............ 39 

### F1GURE4: Group mean food consumption versus time (main study) ................. 41 

### F1GURES: Group mean food consumption versus time (recovery groups) .........43 

### F1GURE6: Group mean motor activity (main study) ........................................... 45 

### TABLES TABLE 1 : Atmospheric concentrations............................................................... 46 

### GLOSSARY FORTABLES 2 AND 6 .................................................................................52 TABLE 2: Clinical observations .......................................................................... 53 

### GLOSSARY FOR STATISTICAL TABLES ..................................................................... 54 

### TABLE 3 : Intergroup comparison ofbodyweights.............................................. SS 

### TABLE 

### 4: Intergroup**com~son** offood consumption ..................................... 61 

### TABLE S: Intergroup comparison offoon utilisation.......................................... 65 

### TABLE 

### 6: Ophthalmoscopy................................................................................. 66 

### GLOSSARY FORTABU 

### 7 ................................................................................................ 67 

### TABLE 7: Functional observation battery clinical assessments .......................... 68 

### TABLE 8: Intergroup C'nmparison of landing foot splay ..................................... 74 

### TABLE 9: Intergroup comparison of grip strength· forelimb............................. 75 TART:F.**10~** Intergroup comparison of grip strength. hindlimb ............................ 76 

### TABLE 11: Intergroup comparison oftime to tail flick ........................................ 77 

### TABLE 12: Intergroup comparison ofmotor activity ........................................... 78 

### TABLE 13: Intergroup comparison ofhaematology ............................................. 80 

### TABLE 14: Intergroup comparison ofblood clinical chemistry ...:....................... 85 

### TABLE 15: Intergroup comparison ofurine clinical chemistry ............................ 92 

### GLOSSARY FORTABLE 16 .............................................................................................. 93 

## I IREGULATORY!REPORT 

### 1- 990 DAY INHAlATION TOXICITY STUDY IN THE RAT 

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### TABLE 16: Intergroup comparison ofurine data
- qUalitative tests...................... 94 

### TABLEt7 : Group range urinary 

### sediments .......................................................... 95 

### TABLEtS: Intergroup comparison oforgan weights ........................................... 96 

### TABLE 

### 19: Intergroup comparison ofpalmitoyl CoA........................................ 111 

### TABLE 20: Macroscopic findings ....................................................................... 112 

### TABLE 21: Microscopic fmdings ........................................................................ 115 

## APPENDICES APPENDIXA: Chamber validation .......................................................................... 124 APPENDIX B: The determination of In test atmospheres .................. 126 APPENDIX C: Allocation ofrats to experimental groups ........................................ 129 APPENDIX D: Arrangement ofanimals on the racks showing Individual animal numbers" and positions...................................................................... 130 APPENDIX E: Group mean daily temperatures and relative humidity .................... 135 APPENDIX F: Allocation of animals to motor activity............................................ 144 APPENDIX G:**Det~ils** ofstAtistk.:d methods_.................................................. 145 

### APPENDIX H: lIistorical Control Data .................................................................... 147 

## INDIVIDUAL ANIMAL DATA INDIVIDUALANIMAL DATA VOLUME I ................................................................... 148 APPENDIX 

### 1 : Individual clinical observations ...................... 

### L
.............................. 149 

### APPENDIX 2: Individal bodyweights (g) ................................................................ 151 APPENDIX3 : Individual bodyweight gains (g) ...................................................... 164 APPENDIX 4: Individual food consumption (g/rat/day).......................................... 173 APPENDIX S: Individual functional observational battery (clinical observations). 177 APPENDIX 6: Individual functional observational battery (landing foot splay, time to tall-fliCk, 

### fore- and bing-limb grip strength)........................ 179 

### APPENDIX 7: Individual functional observational battery (motor activity) ........... 218 APPENDIX 8: Individual haematology.................................................................... 227 APPENDIX 9: Individual blood clinical chemistry.................................................. 278 APPENDIX 10: Individual urine clinical chemistry................................................... 323**ffiEGULATORY~ORT** 1090 DAY INHAlATION TOXICITY STUDY IN TIlE RAT

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### APPENDIX 11 : Individual organ weights (g) ............................................................ 

### 350 APPENDIX 12: Individual pathology cross reference (microscopic) ........................ 375 APPENDIX 

### 13: Individual pathology data................................................................. 399

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- 1190 DAY INHALATION TOXICITY STUDY IN THE RAT

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## 1. SUMMARY 1.1 Study design Groups of 10 male and 10 female body for 6 

### hours per day to 0 

### (control), 100,**300,.~')l1000** 

### ppm rats were exposed whole for 5 

### days per week over a minimum of 13 

### weeks. An 

### additional control group and treatment group exposed to the highest concentration was included for assessment ofrecovery. Recovery

. animals were retained without treatment at the end ofthe 90 

### day exposure period for a 

### further

28 days. Oinlca1 observations, bodywelgbts and food consumptiun were measured throughuut the study. A functional observation battery (FOB), including clinical assessments, measurements ofgrip strength, time to 

### tail-flick, landing foot splay and motor activity were conducted during week 12 ofthe study. Urine samples collected during weeks 13 (main study) or 17 (recovery) were analysed. At the end ofthe study, the rats were killed and examinedpostmortem. 

### Cardiac blood samples were taken for clinical pathology, selected organs were weighed, liver samples were taken for the determination ofpalmitoyl co enzyme A activity and specified tissues weretak.en for histopathological examination. 

## 1.2 Results Analysis ofthe test atmospheres gave the following results. Group Target (ppm) 

### MeaD ofMeans (ppm) 

### StaDdard Deviation of Means (ppm) 2 

### 100 104 7 

### 3 300 310 22 4&6 1000 

### 1000 60 

### There were no deaths. There were no treatment-related clinical observations during the study. There were no adverse treatment-related effects on bodyweight, food consumption or utilisation. There were no treatment-related effects during the FOB. There were some changes in haematology parameters in animals exposed to 1000 ppm, which 

### had returned to control levels at the end ofthe recovery period or were within the historical 'REGUlATORY/REPORT
- 1290 DAY INHAlATION TOXICITY STUDY IN TIm RAT WITH RECOVERY PHASE
control data base or were different from control after the recovery period only and none are considered to be adverse. Although there were no treatment-related effects on blood or urine clinical chemistry at the end ofthe exposure period, females had higher plasma aspartate transaminase and males had lower urine volume and minimally higher specific gravity following the recovery period. In the absence of any adverse treatment-related effects on organ weights or macroscopic or microscopic 

### findings, these small differences from control are considered to be ofno toxicological significance. The pathological no-effect level was 1000 ppm of 

## 1.3 Conclusion Administration ofup to 1000 ppm by inhalation for up to 90consecutive days resulted in no adverse treatment-related findings.

'REGULATORY/REPORT • 1390 DAY INHALATION TOXICITY STUDY IN TIm RAT WITH RECOVERY PHASE 

## 2. INTRODUCTION 2.1 

## Purpose The purpose ofthis study was to assess the toxicity of to 

### male and female rats following inhalation exposure to 0,100,300 and 1000 ppm for a 

### period of 90 

### days and to monitor recovery after a 

### further 28 

### days. 

## 2.2 Regulatory guidelines This study was conducted according to the following Regulatory Guidelines:­ a) OECO guideline reference 413. (Adopted 12 May 1981)Subchronic Inhalation Toxicity: 

### 90 

### day Study. b) Annex V to 

### Council Directive 67/548/EEC on the approximation oflaws, regulations and administrative provisions relating to the classification, packaging and 

### labelling of dangerous substances, published in the Ninth Adaptation, Commission Directive 87/302!EEC of 18th 

### November 1987, OlEC L133/20-23. 30.5.88 Sub-chronic inhalation toxicity study. 9O-day repeated inhalation dose study using rodent species. c) United States Environmental Protection Agency, Health Effects Test Guidelines, OPPTS 870. 3465 (1998): 9O-Day Inhalation Toxicity. d) In accordance with MITI Handbook 1996
- Guidelines for Industrial Chemicals. 

## 2.3 Justification for test system selection The rat is one ofthe species generally recommended for the assessment oftoxicity. The 

### Alpk:APtSD strain ofrat was used 

### because ofthe substantial baCkground data available for this strain, in this Laboratory, relating to studies ofthis type. The inhalation route 

### was selected for the administration ofthe test substance as this is a possible route ofexposure. 

## 2.4 Selection of atmospheric concentrations The atmospheric concentrations were selected by the sponsor on tbe basis ofa 2H-day preliminary inhalation study performed by the sponsor.

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- 1490 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### The exposure concentrations selected by the Sponsor were 0, 100, 300 and 1000 ppm. The highest concentration was expected to result in some toxic effects, but not death. The intermediate concentration was !i>paced to produce Agraduation of "ny foyil".**~ff~NS,** :mn the 

### lowest concentration was expected to produce no evidence oftoxicity ie. it should be 

### a No Observed Effect 

### Level (NOEL). 

## 2.5 Dates of the In-life phase The study was initiated on 18 March 2004. The experimental phase started on 19 March 2004 and was completed on 29 October 2UU4. 

## 2.6 Data storage An 

### original report. the 

### study protocol and all raw data, 

### samples and specimens pertaining to this study, including any generated at will be retained in the for a minimum of5 years from the date ofissue ofthe final report. At the end ofthis period the Sponsor will be contacted regarding the further retention, return.to the Sponsor or . destruction ofthe archived materials.

'REGULATORY/REPORT**~** 15

## 3.1 90 DAY INHALATION TOXICITY STUDY INTHB RAT WfI'H RECOVERY PHASE 

## 3. 

# TEST SUBSTANCE Test substance Name: Source: Grade of

### material: Colour: Clear colourless Physical state: Uquid Boiling point: 56.Z2"C 

### Vapour pressure: 31 kPa at 25°C Batch reference number: CfLtest 

### substance reference number: Purity (% 

### w/w): 99.9 

### Storage conditions: Ambient temperature 

### in the dark The sample was tested as supplied. From information supplied by the Sponsor, the tesl subStance was used. within tire**~Apity** date. 

### Certificates ofanalysis (dated 31 March 20(4) and re-analysis (dated 

### 26 November 2004) 

### are retained 

### in the The test substance characterisation is 

### the responsibility ofthe Sponsor.


## 4. EXPERIMENTAL PROCEDURES 

## 4.1 Atmosphere concentration 4.1.1 Trial ganeratlon Trial generations were carried out prior to the start ofexposure 

### in order to: i} Determine the requisite air and test compound flow rates to achieve the appropriate concentrations. i 'I 

### ii) 

### Determine the most appropriate method ofatmosphere**gene~tion.** \ 

### iii) 

### Determine the most appropriate method ofanalysis. 

### 1lHOULATORY/REPORT

-**1~** \90 DAY INHAlATION TOXICITY STUDY IN THE RAT WI1H RECOVERY PHASE
iv) 

### Determine the distribution oftest substance in the exposure chambers. (Appendix A) 4.1.2 GeneraUOn conditions 

### Test atmospheres were generated by metering appropriate amounts ofliquid test substance onto the top ofajacketed glass condenser column beated to 40 

## °c using Tecbne water baths. A counter flow 

# of air 

### was used to pass the resultant vapour to the input point ofthe long-term chamber (see 

### section 4.3.2). 

### Watson Marlowe pumps were used 

### to deliver liquid test substance to the condenser. Pump setting were as follows: Group 

### 1 and 

### 5 control, no pump required. Group 2: 

### 5 - 9%; 

### Group 3: 11-**22%~** 

### Groups 4 

### and 6: 37.5
- 

### 60%. 

### Generation settings were 

### 25 I/minute generation air. Conditioned air, 

### into which tbe test substance is introduced, was supplied directly to the exposure cbamber at a 

### nominal flow rate of500 litres/min. The chamber containing control animals was supplied with 

### conditioned air at 

### 500 I/minute only. Atmosphere generation and chamber air flow rates were monitored continuously using variable area flowmeters (KDG Flowmeters, West Sussex, UK). 

## 4.2 Atmosphere sampling and analysis 4.2.1 

### Nominal 

### atmosphere concentrations 

### The nominal concentration is a concentration based on the total Weight oftest substance used during the eAposucc; 

### period. This repre3ents the 

### maximum concentration to which 

### the animals could be exposed, assuming no losses within 

### the generation or exposure systems. The nominal concentration ofthe lest substance (juliug 

### the exposure generation period 

### was calculated from tbe following formulae: Concentration (mg/l) 

### = weight loss (m&) time (minutes x. wlfiow 

### (l/minute) Concentration (ppm) 

## = concentration 

## (msiD x 24000 molecular weight**REGULATORY~ORT** 17I 90 DAY INHALATION TOXICITY STIJDY IN THE RAT

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### 4.2.2 Analysed atmospheric concentrations The test atmospheres were sampled manually using a suitable gas tight syringe and analysed using gas chromatography. 

### Each test atmosphere was analysed approximately hourly during each exposure 

### period. The analysis system was calibrated using an 

### appropriate range offreshly prepared standards 

### prior to 

### the study and at intervals thereafter. The 

### peak obtained 

### was used to calculate the atmosphere concentration. Control atmospheres and 

### room airwere alsu sampled and analysed. 

### The analytical 

### method is 

### given in Appendix B. 

## 4.3 Experimental design 4.3.1 Animals

Species: Strain: Source; Sex: Specification: Delivery date: Rat.



### 60

### Males and 60 

### females, plus 2 per sex as 

### spares [including 20 males and 20 female!'! for 

### recovery &fOups). Approximately 5-6 weeks old on arrival. (125-175g males; 120-150g females). 2 

### April 2004 

### 4.3.2 AccommodatiOn and husbandry 

### Long tenn chambers (whole body exposure): &fore the start 

### ofthe study animals 

### were accommodated in 

### cages in 

### stainless steel holding chambers ofapproximately 3.4m3 

### capacity (Doe 

### &Tinston, 1981) in the 

### long tenn inhalation facility. The cages were labelled with stock cards 

### prior to the study start date. Environmental conditions were maintained as appropriate to 

### the species and study type 

### to the following specification:

Temperature: 22:t3°C Relative humidity: 30-70% Air 

### Cbanges: At least 12 per hour Diet type: 

# cn supplied by Light cycle: Artificial giving 12 hours light, 12 hours dark REGULATORYnffiPORT
- 1890 DAY lNHALATION TOXICITY SfUDY IN THE RAT WITH RECOVEllY PHASE


### Temperature and relative humidity were measured outside exposure periods using maximum/minimum thermometers and dial hygrometers. The recorded values were within the ranges, except for temperature (18°C) on 29 April 2004. 

### In addition temperatures of 17 or 18°Cand relative humidities of25-29% were recorded during the period of acclimatisation (between 4 and 14 April 2004). These deviations from the ranges are consiilert".d 

### not to have 

### affected the 

### integrity ofthe study. The diet and mains water were supplied 

### ad libitum, except during exposure. Diet was withheld during urine collection. Bach batoh 

### ofdiet is routinely analysed for composition and the 

### pxesence of any 

### contaminants that could affect 

### the purpose or integrity ofthe study. Water is also routinely WlalYSed COl 

### the prcscnce 

### ofcontaminants. Certificates ofonnlysis ore retained in 

### the


### For environmental enrichment, the rats were provided with 'nylabones' to play with or chew on and with cardboard 'fun

### tunnels'. Both items were supplied by These 

### items were removed during the exposure periods. Details of analyses for the 'nylabones' and 'fun tunnels' are retained in the 4.3.3 

### Accllmatlaation Animals were acclimatised for at least 1 

### week before the start ofthe study. Excess animals were discarded on 4 May 2004. 4.3A 

### Animal randomlaatlon and Identification During 

### the acciimatisation period, animals were randomly aUocated to holding cages 

### and treatment group by a method based on individual bodyweights (Appendix C). Animals were identified by ear-punching. On 

### the front ofeach cage 

### ofanimals was a card identifying the contained animals by exposure concentration, group number, individual number, sex and study. The cage cards were colour-coded to 

### correspond 

### with exposure concentration. 

### A rack pJlIn 

### is shown in 

### Appendix D.

:/REGULATORY/REPORT
- 1990 DAY INHALATION TOXICITY STIJDY IN TIm RAT WITH RECOVERY PHASE


### 4.3.5 exposure concentrations The main study consisted ofone control and three treatment groups with 

### 10 males and 10 females per group. An 

### additional control group and treatment group exposed to the hiahest concentration. with 

### 10 males and 10 females per group, were included for assessment of recovery. 

### These rats were retained at the end ofthe 90 day exposure period. for 

### a further 

### 28 days without treatment. The rats 

### were housed five per cage. The study had a replicate design, each replicate consisting offive animals per exposure group.

Group Target Exposure Concentration (ppm) 

### Colour code Male numbers Female numbers 1 

## o(Control) Blue 1-10 61-70 2 

### 100 Green 11- 20 71-80

! 

### 3 300 Yellow 21-30



## - 81-90 4 

### 1000 Red 31-40 91-HJO 5 

## o(Control) Blue 41-50 101-110 6 

### 1000 Red 51-60 111-120 

### 4.3.6 Exposure system 

### Animals were exposed whole-body in long-term exposure chambers, for 6 hours per day. S days perweek, over a period of at least 90 days. The last exposure period was the day before necropsy. Control animals were exposed to air only. but were**otherw~e** 

### treated in a similar manner to the test animals. The temperature and relative humidity in the chambers were recorded approximately every 30 minutes during each exposure period. The daily means, minima and maxima are**pra~nted** 

### in Appendix E. 

### 4.3.7 Duration of exposure The animals were first exposed in replicates on 13-16 April 2004 and were exposed for 6 hours per day. 5 days per week for up to 13 weeks.

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- 2090 DAY INHAI.ATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### 4.3.8 Duration of recovery period The recovery period started on 13-16 July until 10-13 August 2004. 

## 4.4 Clinical observations PliO! to the start ofthe study, all rats were examined to ensure that they were physically normal and exhibited normal activity. Detailed clinical observations, included the finding of no abnormalities detected were recorded weekly prior Lo t:XPUSUIC, where appropriate, at the I same time that the bodyweights were recorded. Rats were observed frequently during exposure periods. Rats were checked immediately after exposure periods. All tats were checked at least twice daily for morbidity or mortality during exposure periods and at least once a day during the recovery period. 

### 4.5 

## Bodywelghts The bodyweight ofeach rat was recorded immediately priorto exposure on day 1, then weekly. 

## 4.6 Food consumption and utilisation Food consumption was recorded continuously throughout the study for each cage ofrats and calculated, at weekly intervals, as a mean value (g food/rat/day) for each cage. The food utilisation value per case was calculated as the bodyweight gained by the rats in the cage per l00g offood eaten. 

## 4.7 Ophthalmoscopy The eyes ofall main stutly ruumals were examined prior to the stnrt ofexposures. The eyes ofthe control and high dose rats (main study) were examined during week 13. 

## 4.8 Functional observation battery Detailed clinical assessments (during which each rat was removed from its cage and physically examined for changes in general health status) and quantitative assessments of landing foot splay, muscle weakness (fore- and hind-limb grip strength) and sensory perception (tail-flick test) were made in week 12 on main study animals. The observations were made by one observer who was 'blind' with respect to the animals treatment, and /REGUlATORY/REPORT
- 2190 DAY INHAlATIONTOXICITY S11JDY IN 1lIE RAT wrrH RECOVERY PHASE


### recorded on a computer system by personnel not directly involved in the clinical observations. The presence andlorabsence ofall listed observations was recorded and the degree ofcondition noted (slight, moderate or extreme) where appropriate. The examination proceeded from the least to the most interactive test with observations recorded 

## as follows: a)**A,~!,:p',~,~ment** in the ho1n(" rage: hi7.arre hehaviour (circling, head flicking, head searching, 

### walking backwards, rolling over sideways, paw flicking), vocalisation. b) 

### Removal from the cage: approach response, response to 

### touch (increased, decreased), vocalisation. c) 

### In the standard arena: activity (increased, decreased), comatosed, prostration, hunched posture, bizarre behaviour (circling, head flicking, 

### head sean:hing, walkingbackwanls, 

### rolling over sideways, paw flicking). convulsions (tonic, clonic), vocalisation. ataxia, tremors, reduced stability, abnormal gait, splayed gait, tiptoe gait, reduced limb 

### function (fore, 

### hind). upward 

### curvature ofthe 

### spine, downward 

### curvature ofthe spine. piloerection, sides pinched in, 

### ungroomed appearance, urinary incontinence, dianhoea. d) Handling the animal: response to touch, convulsions, vocalisation,. tremors, piloerection, 

### skin colour (pale, hyperaemia. cyanosis). ungroomed appearance, hyperthermia, hypothermia, chromodacryorrhca, lachrymation,. ptO$is, c.ndophthabnus, exophthalmus, 

### miosis. mydriasis, stains around the mouth, stains around the nose. salivation, respiratory abnormalities (breathing rate. breathJng depth. laboured brealhing, gasping, Irregular breathing, whistling, wheezing, croaking), thin 

### appearance, sides pinched in, dehydrated. abdominal tone (increased. decreased). urinary 

### incontinence, diarrhoea. e)Reflex tesf!iI: 

### righting reflex (from "upine 

### po"ition),**re"pon~** 

### to sound 

### (to finger click/clap), 

### splay reflex (degree ofsplay when animal lifted by base oftail), visual placing response (animal is 

### lifted by base oftail 

### and slowly moved downwards towards the edge ofarena). 

### pupil response to light (after eye has been held closed for 10 seconds), palpebral membrane reflex (palpebral membrdne touched with

### bristle anti 

### blink :response observed). corneal reflex (hair is touched against comea and blink reflex observed
- only performed if 

### palpebral reflex is absent), pinna reflex (bristle poked into ear canal), foot withdrawal reflex (to toe pinch). /REGULATORY/REPORT
- 2290 DAY INHALATION TOXICITY STUDY IN 1HE RAT

## wrm RECOVERY PHASE 

### t)Quantitative measures: fore-limb and hind-limb grip strt'.Dgth, landing foot splay, time to 

### tail-flick. 

## 4.9 Motor activity Loc.:olIlolol activily was mOllilond by an automated activity [cconiingapparatus. A111llain 

### study animals were tested in week 12 ofthe study, immediately after the FOB. Each observation period was divided into ten scans offive minute duration. 'l'reatment groups were counter balanced across test times and across devices (Appendix 1'). Motor activity was assessed in 

### a separate room to minimise disturbances. 

## 4.10 Clinical pathology Urine samples were collected from each rat

### overnight during the week priorto termination (week 13 

### or 17). 

### At scheduled termination all

### rats were bled by cardiac puncture and samples taken as 

### detailed below and analysed by the Clinical Pathology Unit, Parameter Approximate volume Anticoagulant Haematology 1.2 ml 

### potassium EDTA Clinical Chemistry 1.2 

### ml

....

# __....

# __.... 

### 1.4 

### ml 

### lithium heparin Clotting sodium citrate 4.10.1 Urinalysis 

### For environmental enrichment, only nylabones were present during urine collection. The following were measured and recorded: colour appearance volume pH The following were assessed semi-quantitatively: Specific 

### gravity protein glucose ketones urobilinogen blood bilirubin

/REGULATORY/REPORT
- 2390 DAY INHALATION TOXICITY STUDY IN 'I'HB RAT WITH RECOVERY PHASB


### If

### the appearance ofthe urine sample was considered to be abnormal, a portion ofthe sample was centrifuged, the deposit stained and examined microscopically to identify the components. 

### 4.10.2 Haem8tology The following measurements were made or determined on samples collected using EDT A 

### as 

### an anticoagulant: haemoglobin mean 

### cell haemoglobin concentration haematocrit platelet count red blood cell count total white 

### cell count 

### mean cell volume differential white cell count mean 

### cell haemoglobin reticulocyte count Measurements ofpotential clotting (prothrombin time and activated partial thromboplastin time) were made on samples ofblood collected into tubes containing sodium citrate as an anticoagulant. A 

### blood 

### film was prepared when results from the automated analysis suggested this was necessary. 

### 4.10.3 Blood clinical chemistry The following measurements were made on the plasma from 

### blood samples coJlected into tubes 

### containing lithium heparin as an anticoagulant: 

### urea alkaline phosphatase activity creatinine aspartate an$otransferase activity glucose alanine aminotransferase activity albumin 

### gamma-glutamyl transferase 

### activity total protein calcium cholesterol phosphorus (as phosphate) albumin/globulin ratio sodium friglycerides potassium 

### total bilirubin chloride creatine 

### kinase activity phospholipid urea**nitrog~n**

/RBGUlATORY/RBPORT
- 2490 DAY INHAlATION TOXICITY STIJDY IN THE RAT WITH RECOVERY PHASE


## 4.11 Investigations 

## postmortem 4.11.1 Termination All rats were killed by over-exposure to halothane Ph Eur vapour followed by exsanguination. The animals were examinedpostmortem. 

### This involved an external observation and detailed examination ofthoracic and abdominal viscera. 

### 4.11.2 Organ weights The following organs were weighed for all animals at scheduled termination: adrenal glands kidneys liver ovaries pituitary 8lan" 

### brain lungs 

### (tracbea attached but 

### larynx 

### removed) testes uterus with cervix thyroid gland

### spleen thymus heart epididymides Paired organs were weighed, together. Thyroid gland* included parathyroid gland. which was weighed 24 

### hours post-fixation and dissection from the larynx. 

### 4.11.3 

### Tissue submission for main study and 

### recovery groups The following were taken from all main study and recovery animals and preserved in appropriate fixatives: 

### Abnormal tissues Adrenal gland Aorta Bone
-**(f~m"r** inc1lldingjnint) 

### Bone marrow - femur Brain (medulla/pons, cerebellar cortex, cerebal cortex) Caecum 

### Cervix Colon

. Duodenum Epididymus Eyes 

## * (retina, optic nerve) Harderian gland 

### Heart lleum Jejunum Kidney Lachrymal gland 

### Larynx iJver Lullg 

### Oesophagus 

### Oral cavity
- (store) Ovary Pancreas Parathyroid gland Peyer's patches Pharynx Pituitary gland Prostate gland Rectum 

### Salivary gland Seminal vesicle Skin (nghl Flank) 

### Spinal cord 

### (3 levels) (cervical, mid-thoracic & 

### lumbar) Spleen Sternum with bone marrow Stomach Testis Thymus Thyroid gland**~GULATORY~ORT** -2590 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### Lympb node: cervical Tracbea Lympb node: mesenteric Urinary

### bladder 

### Mammary gland (female only) Uterus Nasopharynx Vagina Nerve
- sciatic Voluntary muscle 

## * left for processing, right for store 

### 4.11.4 

### Determination of cyanide Insenaltlve Palmnoyl CoA oxidation liver samples were taken from 5 males and 5 females per 

### group (from replicates 3 and 4) for the assessment ofpalmitoyl CoA An 

### accurately weighed sample ofapproximately 58was placed in 15ml ice cold O.25M sucrose, bomogenised and centrifuged. The oxidation of palmitoyl CoA

### isameasure ofthe degradation ofsaturated fatty acids to acetyl CoA 

### 4.11.5 

### Tissue processing All submitted tissue from control and high exposure main study animals 

### and respiratory tract 

### and abnormal tissues from the remaining main study exposure groups were embedded in paraffin 

### wax, 5j.U1l sections cut and stained with haematoxylin and 

### eosin. At examination

### postmertem, the lungs (with trachea and larynx attached) were excised, 

### trimmed and weighed following removal ofthe larynx. The lungs. inflated with 10% formol saline (approximately 2m1/100g bodyweight) and the trachea and larynx (see below), were fixed in 10% formol saline, routinely processed to paraffin blocks, 5!AJD sections cut and stained with haematoxylin and eosin for histopathologic.al examiDJItion. 

### Three 

### standard sections oflarynx were produced, taken at the level ofthe base ofthe epiglottis, through the ventral pouch and the cricoid cartilage to include all different epithelial cell types ofthe larynx and underlying'seromucinous glands. The heads from all 

### animals were removed, excess skin and muscle removed, the brain excised and the nasal cavity perfused with 10% 

### formol saline through the**D~pharynx.** 

### The head was then immersed in formol saline followed by decalcification with 20% formic acid. After processing, six standard sections were produced to 

### include all different epithelial cell types and accessory nasal structures. The six 

### sections were routinely stained with haematoxylin and eosin for histopathological examination. fREGULATORY/REPORT
- 26

## 6.1 90 DAY INHALATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE

. Tissues from recovery animals were stored 

### in fixative.



### 4.11.6 Tissue examination All submitted tissues from the control and high 

### exposure groups were examined by light microscopy. Lungs, 

### trachea and abnormal tissues were examined from the low and mid exposure groups.


## 5. DATA EVALUATION
All dota were evaluated using analysis ofvariance and/or covariance for each specified 

### parameter using

### the MIXED procedure in 

### SAS (1999). The 

### methods are descn'bed in Appt:ndix O.


## 6. RESULTS 

## Atmosphere analysiS 6.1.1 Nominal concentration Tht: 

### uvt::ndl mean CUlll:ClllraliuWi frUlU 

### 1lIt:: wt::ighlloss of It::sl**sllbslan~** 

### welt:: calculaled 

### lo be 

### as follows. Group Target concentration . (ppm) Nominal concentration (mgll) 

### Nominal concentration (ppm) 2 100 1.26 151.2 3 300 2.65 318.5 

### 4&6 1000 8.64 1036.6 

### 6.1.2 Analysed atmospheric concentration The mean achieved concentrations of HFE-347pc-fwere within 8% ofthe target**concentratio~** 

### daily 

### values are 

### presented in Table 1. 

### Group 

### Target 

### (ppm) 

### Mean ofMeaas (ppm) 

### Standard 

### Deviation of Meaas(ppm)

._.... ----' IREGUlATORY/RBPORT • 2790 DAY INHAlATION TOXICITY snIDYINTIlE RAT WITH RECOVERY PHASE



### 2 

### 100 104 7 

### 22 

### 300 310 4&6 

### 1000 1000 

### 60 The distribution ofthe telit substance within the chamber was acceptable. (Appendix A) 

## 6.2 Clinical observations 6.2.1 Prior to exposure There 

### were no treatment-related clinical 

### observations during the clinical 

### examinations made weekly prior to exposure or during recovery period. (Table 2) 

### 6.2.2 During exposure and post exposure No abnormalities were detected in the animals during exposure periods orimmediately post 

### exposure. 

## 6.3 Bodywelghts Thcre were no trcauncat-ccIatw cffc;;cts all budyweigbt 

### adjusted for In.(lIal weight 

### for males either in the main study or recovery groups. Statistically significant differences from control seen at 

### 100 or

### 300ppm did not form part ofa dose-response relationship and are considered to be incidental to treatment. The difference from control in 

### week 2 for females exposed to 100, 300 or 1000 

### ppm, main study only. was due to a high weight for control female 

### number 67 and is 

### considered incidental to treatment. Bodyweightfor females exposed to 1000 ppm was statistically significantly 

### lower than control in 

### the main study animals in

### weeks 5, 6,12 

### and 14 

### (maximum difference 5%), 

### and in weeks 4 

### and 6 

### (maximum 6%) in 

### the recovery group.**Th~** difference from 

### oontrol was 

### small (5 to 6%), 

### was llul**r~nc;;c~** in 

### the liiamc weeks 

### (except for week 6)

### between main and recovery group and is considered not to be adverse. (Figures 1-3, 

### Table 3) 

### 6.4 Food consumption and utilisation Food consumption for males exposed to 1000 ppm 

## was lower than control in

### week 1 (main study) and weeks 12 

### and 14 

### (recovery). Food consumption for females exposed to 1000ppm was lower than control in weeks 2, 

### 3,4, 6 and 15 (recovery only). The /REGULATORY/REPORT
- 2890 DAY INHALATION TOXICITY STUDY IN TIlE RAT

## wrm RECOVERY PHASE**differe~.f'.s** from control were small and/or were not reflected in the same weeks between 

### main and recovery group and none are considered to be adverse. (Figures 4-5, Table 4) There were no treatment-related effects in food utilisation at 

### any exposure concentration in main study or recovery groups. (Table 5) 

## 6.5 Ophthalmoscopy The eyes ofall animals examined pre-study were normal. The 

### eyes ofall animals in control and 1000 ppm exposure groups (main study) examined in week 13 were normal. Consequently, the eyes ofthe intermediate and recovery groups were not examined prior to termination. (Table 6) 

## 6.6 Functional observation battery 6.6.1 Clinical assessments Therewen:; DO treatment-related dluiosl obscrvatiumI during the cUn1cal assessments made in 

### week 12 as part ofthe FOB. (Table 7) 

### 6.6.2 landing foot 

### splay meaaurementa There were no effects oftreatment on**landi~g** foot splay_ The difference from control in 

### males exposed to 300 ppm was not dose-related and is considered to be 

### incidental to treatment. (Table 8) 

### 6.6.3 Grip strength measurements There were no effects oftreatment on the 

### grip strength measurements. (fables 9 and 10) 6.6.4 Time to tall 

### nick 

### There were no effects oftreatment on the time to tail-flick. (Table 11) 

## 6.7 Motor activity measurements There were no treatment-related effects on motor activity. The occasional differences from 

### control seen at 100 and 300 ppm were not dose-related and are considered to be 

### incidental to treatment. The small difference from control for females exposed to 1000 ppm in minutes 6-10 was isolated and considered to 

### be incidental to treatment (Figure 6, Table 12)

REGUlATORY/REPORT • 29

### 90 DAY INHALATION TOXICITY STUDY IN 1'HB

### RATWlTH RECOVERY PHASE 

## 6.8 Clinical pathology 6.8.1 Haematology At 

### week 14, 

### neutrophil count was higher in

### males exposed to 1000 ppm. The mean value; 

## was within historical control mean data and the difference from control is considered to 

### be incidental to treatment (Appendix H).
- 

### Reticulocyte count and prothrombin time 

### were higher than 

### control in females exposed 

### to 1000 ppm. The isolated 

### statistically significant differences 

### from control 

### seen at week 

### 14 at 100 ppm in 

### males and 300

### ppm in females were 

### not dose-Ielated 

### and anconsideredto

### beincide.ntal to 

### treatment. At week 18, in

### males exposed 

### to 1000ppm, red blood. cell count was highet, 

### mean cell volume., neutrophil, white 

### hlood cell 

### and 

### monocyte counts 

### were lower than controL The difference from control for 

### white blood cell 

### count was 

### exaggerated by 

### a high 

### control value fUf 

### male 43. 

### Data arc; 

### presented with 

### and without this value. In ferolllelli. 

### reticulocyte 

### colint and prothrombin time 

### were not statistically 

### significantly different 

### froID oontrol showing evidence 

### ofrecovery; In addition, mc;an cell 

### haemoglobin and MC4lD 

### cell 

### haemosIobio 

### concentration were higher than oontrol. 

### None ofthe 

### differences from control at week 

### 18 listed above are 

### considered to 

### be of haematological or toxioologlC'..st 

### significance. (Table 13) 

### 6.8.2 Blood clinical chemistry There were no treatment-related differences from control at week 14 in 

### the blood clinical chemistry. A smalJ 

### number of

### differences from control were seen 

### at 300ppm 

### (glucose in 

### females, phosopholipid andcholestero} in 

### males). None ofthese were dose-related and are considered to he incidental to treatment. Ar 1000 ppm after the recovery period, plasma gamma-glutamyl transferase activity was lower than control in 

### males. This was 

### attributed to a 

### high value in control (male 50) and a 

### low value at 1000 ppm (male 51). 

### Data are presented 

### with and 

### without these values. At 

### 1000 ppm after the recovery period, plasma aspartate transaminase activity was higher than control 

### in females. (fable 14)

'REGULATORY/REPORT • 3090 DAY INHAlATION TOXICITY STUDY IN THE RATWITH RECOVERY PHASE


### 6.8.3 Urine clinical chemistry There were no differences from control in 

### urine clinical chemistry in

### males in 

### the main study or in females in 

### main or recovery groups. Urine volume was lower and urine specific gravity was slightly higher than control for males at 1000

### ppm in 

### week 18 (recovery group). The differences from control were small and 

### are considered to be 

### of

### no toxicological significance. (fable 15) 

### There were no treatment-related effects in the qualitative tests. (Table 16) There 

### were no treatment-related effects in the urine sediments. (fable 17) 

## 6.9 Investigations post

## mortem 6.9.1 Organ 

### weights At week 14, spleen weight was lower than control for males 

### exposed to 1000 ppm. 

### However, this was attributed to the high spleen weight for control male number 8. The data 

### are presented excluding and including number 8. The**difference.~** from 

### control in 

### spleen weight at 100 ppm and lung weight at 300 ppm were not dose-related and are considered to be incidental to 

### treatment. Thymus weight was higher than control at all exposure concentrations for females. However, the control mean was low and all treatment group means fell within the historical control data (HCD) range. (Appendix H) Absolule weights for 

### adrenal gland, kidney and 

### liverwere lower than control 

### for**female.~** 

### exposed to 1000 ppm, but not when adjusted for final bodyweight. At week 18, absolute thymus weight was lower than control in 

### females, but there was 

### no difference from control when adjusted for final bodyweight. (Table 18) 

### 6.9.2 Cyanide Insensitive palmHoyi eoAoxidation There were no effects on liverpalmitoyl CoA activity measured in 

### the main study animals. (fable 19) 

### 6.9.3 

### Macroscopic findings A small number oflesions was observed, none ofwhich were rela.ted to treatment. (Table 

### 20) REGUlATORY/REPORT
- 3190 DAY INHALATION TOXICITY S'IUDY IN TIlE RAT WJI'H RECOVERY PHASE


### 1.9A Microscopic findings A small number ofspontaneous lesions was observed, none ofwhich was related to treatment. There was a minimal increase (3/10 

### compared with 0/10 

### in controls) in the incidence ofeosinophilic casts (unilateral) in the kidney ofmales exposed to 

### 1000 ppm. There was however, A**decrea~e** in 

### the incidence of

### tubular ba400philia in the kidney ofmales in 

### this group and they are both therefore considered to be unrelated to 

### treatment. No treatment related changes were observed in 

### the respiratory system. (Table 21)


## 7. 

## DISCUSSION The pmpose ofthis study was to investigate the toxicity of to 

### male and female rats 

### when administered orally by inhalation for up to 

### 90 

### days and to monitor recovery over a further 28 days; 

### this was successfully accomplished. The health ofthe 

### rats was satisfactory and there was no evidence ofdisease or infection which might have compromised the interpretation ofthe**tindin~.** 

### Analyses ofthe test atmospheres showed that the achieved concentrations were satisfactory throughout the study. There were no deaths. There were no treatment-related clinical observations made during 

### the study. There were no adverse treatment-related effects on bodyweight, food consumption or utillisation.**Th~n::** wen:: no 

### treatment-related effects seen during the FOB. 

### There were some changes in haematology parameters in animals exposed to 

### 1000 ppm, which had returned to control levels at the end ofthe recovery period or were within the historical control data 

### base or were different from 

### control after the recovery period 

### only. None of these differences are considered to be adverse. Although there were no treatment-related effects on 

### blood or urine clinical chemistry at the 

### end of

### the expol'llre period, females 

### had higher plasma aspartate transaminase and males had 

### lower urine volume and minimally higher specific gravity following the recovery period. In 

### the absence. of

### any adverse treatment-related effects on organ weights or macroscopic or microscopic findings, these small differences from control are considered to be ofno toxicological sjgnlflcance. The pathological no-effect level was 

### 1000 ppm of 'REGUlATORY/REPORT
- 3290 DAY lNHAI.ATlON TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE



## 8. CONCLUSION Administration ofup to 1000ppm by 

### inbalation for up to 90**conse~tive** 

### days resulted in no adverse treatment-related findings.

!/REGUIATORY/REPORT • 3390 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

## 9. REFERENCES SAS 

### Institute Inc. SAS/STAT User's Guide, Version 

### 8. Cary, NC., SAS 

### Institute Inc., 1999. 

### Shirley E (1996). A 

### literature review 

### ofstatistical methods 

### for the 

### analysis ofgeneral 

### toxico1ogy data. In 

### Statistics in

### Toxicology (cd. B

### J T MorSan). Oxford University 

### Press, Oxford. DoeJE and Tinston DJ (1981), 

### 'Novel Chambers 

### for long

### term inhalation studies'. 

### In Proceedings ofthe Inhalation Toxicity and Technulogy Symposium, Kalamazoo, Michigan, 

### October 23-24, 1980. 

### Edited. by B K leong. Ann Arbour Science Publishers Inc.

IREGULATORY/REPORT • 34

## ----

-- 

## -- 90 DAY INHAlATION TOXICITY sruDYIN THE R4.T 

### wrm RECOVERY PHASE FIGURE 1 • GROUP MEAN BODYWEIGHTVERSUS TIME (MAIN STUDY) MALES

600 

## 1
500 1**---~-=-=-** 

### -,­ 

# -­ -------­**~** 

## 4O(]J. 1 

## -,- .--­ 

# J 1
--­ 1 - - --­ 

# i /%-----;/-­**/~--** 

# --/

# 3OO~1/ ,/ 

# /!:;;»/ y O(Cordrol)**~~** lOOppm ?' BOO ppm 1000 ppnl 200

---..**,,,.~** t' I ,**'~""""-I--'** . r-l-----.--r-r j I 1 

### 2 8 4 6 6 

### 7 8 9 10 11 12 13 14 

### Week REGUIATQRY/REPORT
- 3S

# --- 90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE FIGURE 1 • GROUP MEAN BODYWEIGHT VERSUS 11ME (MAIN STUDV) FEMALES

880 

# :!1

300 

## 1 j

# ~ 2901 

# 270j 

# -1
- :-:::c:::

# ~-: -::.; .

# ~**c.~"**

. /-

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# -.-------- ­**~/** 

# /-­ 260 

# " / //
...

# ---~/-'



# ____



# l :j! .7".-:'- ...-.­ j**/~** 230 //

--- 100 JlPn

----- 800 JIPD 

# :.m .........

# :jI~/ 

# r- -I
1;J**2001~r** I -r.... .,'·**I"~** I I ' I Ii. , ,.....,.-,.-,-..**I"~** .... r r f 1 2 

### a 4 5 6 7 8 9 10 II 12 18 14 

### Week
REGULATORY/REPORT - 3690 DAY INHAlATION TOXlCI'IY SnIDY IN THE RAT WITH RECOVERY PHASE FIGURE 2 • GROUP MEAN BODYWEIGHT VERSUS TIME (RECOVERY GROUPS) MALES

6001 

### 1 

# I ---­ 6001 ."

# ­ 1

## ~ 1 

# 14001

I 1 4

## ~I/

## IU~.~~~**~I** :2()() 11 ' ..- ....,-,.·"-'1· ....**1-..~.** »1 I ' I I ......... , 1 • 

### 1 2 846 678 9 ID 

# n**~** 

# m W ffi 

# m IT W Week
'REGULATORY/REPORT
- 3790 DAY INH.uATIONTOXlcrrY SI1.DY IN THERAT

## wrm RECOVERY PHASE FIGURE 2 • GROUP MEAN BODWIEIGHT VERSUS nilE {RECOVERY GROUPS) FEMALES

820 310 300 290

## ~ 

## j 

# I:' 280 

# /}-/- / 

### --­ 

# :1////
2201 ,/ 

# r Q:CobtrQ1) DlO pp:o 2101' 200 -"""r'''''',, ".-,", ''',-i I
....**'·,...~ r"'l~-T"""I**  2 8 4 5 6 7 8 9 10 

### n 12 13 14 lD 16 17 18 Week
REGUIATORY/REPORT
- 38 190 DAY INHAlATION TOXICITY STUDY IN TIlE RAT Wrffi RECOVERY PHASE AQURE 3 - STAnsTlCALANALVS'S OF eoOYWElGHT ADJUSTEO FOR INITIALWEIGHT

..ALES

1C111OptIr/I 

# 1. JIpIII "-y '10 w



# -**-~** 

# I


# .. -'lOL' -80**,~,~,~.~",~~~~~~~,-~~~~~~~~~~~** )1"'.,..., .( ,j**~** • 8
... f 6**~** • 	 • _ n**~** w 14**~ ~**  »**~ la.4.678.wn.~U~~D_** **~** 

# - 1.ppII\ 100
.....

." ........ . 

# ............... ..... tt- Il1O 

# Ul.·r'··!"'[··I'·'r·'r·'I,url":·"1

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_ I**~m_14l1i** 1 • • 6 6 8 ,.. B • W U » • 14 U**~ ~**  m 'Mook IREGULATORY/REPORT • 39

# --

-- 90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE FIGURE 3 - STAllSTICAL ANALYSIS OF BODlWElGHT ADJUSTED FOR INITIAL WEIGHT FEMALES

toGO JIPIII , .. "'"ItHWtNy 

# J ot---;-- f I , , I " 

# I 

# I I I 1 

# I 1 

# I I '" -10 -10 -110, -80**....,....,..,.,,....-~"T~,....,.,..,..~-,....,.TT"....,.,,.....,,.,....~~T'"·T~,...,..,'** ..... '1 1 • a 4 & • 7 8 e**~** n D m w m**~W.** 1 a a 4 •• 7 •• 10 U D D um M W**~** ""'"***~** 100,.,. 101 ... lIOi 10 

# I j


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### - 4090 DAY INHALATION TOXICITY STUDY IN 

### TIm RAT WITH RECOVERY 'HASE
FlGURE 4 • GROUP MEAN FOOD CONSUMPTION VERSUS TIllE (MAIN STUDy) MALES '

# 82L~, 31 '­ Ir",_ '­ I I , I I \

# "~"" I I

'-''-" 

### --- - 

### - / /'" 

# - .- '-- 

### - \ I 

# , 

# I

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# '

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### \ // 

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# . 

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## s 9 10 

### n 12 18 Week
REGULATORY/RE1'ORT - 41DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE FIGURE 4 • GROUP II£AN 

### FOOD COHSUMPnON VERSUS nuE (MAtH STUD\,) FEMALES 

# 24j j 28·' ;",­

J /"" 

# ---... 1\ 

# i r ./ ," 

### - 

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### .,

### .~''\ "**-~-** 100 ppn, 

## {

# ~-~~.-:~ 

# == \'

# lB~**--~I ~~--'rj** **T............-,.-I~.~I~.,.......,-~·~~·~~~l 1B~**  '--''­ 1 

### 2 8 I) 

### 6 7 8 9 10 

## n 12 lSI 

# '" Week IllBGULATORY/RBPORT . 4290 DAY INHAlATION TOXICITY STUDY IN TIlE RAT WITH RECOVERYPHASE FlGUAE 5 - GROUP MEAN FOOD CONSUMPTION VERSUS TIME (RECOVERY GROUPS) MALES

32 

# " lD., , ... ' , ' , " , 

# i:\ , . ' 

## .. \: 

## .

# ~,
29

# \, 

# ,.,/ ""'" ," \

, ' • .' .f ....,' , 

# . , " 

# I**~** 

# [m_m**~[** 

# ._, 1 2 345 6 7 8 9 ID II**~ ~**  

### W**~ ~**  fl Week
REGUlATORY/REPORT
- 4390 DAY INHAlATION TOXICITY STUDY IN THE RATWITH RECOVERY PHASE



# 122 

# I
m

# l , , FIGURE 5 • GROUP MEAN FOOD CONSUMPTION VERSUS nlE (RECOVERY GROUPS) 

### FEMALES

24

# /\~" I**~** I • : 

# .. "

## ~ 20 , , " 19 

## m

# I~--- 

# .**~I** " i" I ' ii, i ' • 

### 1 234 5 678 9 

## ro II**~** 

## mum ffi fi 

### Week
REGUlATORY/REPORT

- 4490 DAY INHAlATION TOXICITY SJ'UDY IN THE RAT WITH RECOVERY PHASE FIGURE 6 • GROUP MEAN MOTOR ACTlVrTV (MAIN STUDY)

M

.... F .....I ..



# .. :il 

## ,

liC)1

til**~**

----­ 1OOppa: -------. IlOO ppr. .::.:.:.- . .:::.. lDOO ppr.

..**~\**

### \ 

# ,

...

# ~~ \\ ;// 

### '.\'" /' ,/,\',,:, 

# \ \ '\.._­**',c~** 

### \ : " \.\ 

### -" ," " 

# \

'\\

## \.**'~~,~.** '\,: '.,**\~~.~** .,' \........... 

## ;\\/ " ;,F'''-..,::....// '. ,\

" // '" " \ "'.,
....' \ \ , \\\\ /
.....



## ,---­ / .\. I , / 

# ' I I , I !IO

-­ O(CmbaI)

----­ lOll ppm -------. 800
I I

# .~ 

# ........... lDOO: 

# 1101/)., ,**.~** t 

### -/ 

# -'\\'\

, ....

### ".,.**~-** \ 

## } '/ / "" \ ,l 

### '/Ov / ....

# "\~ :1 I 

# I [ /'\'\-"', ,/'"ff.··
lID \

# -.~ .•.. ' /'/ \.:

.. '\ I I \ \! • "",,' I

'-­ I \ I

...... , ..../ \ J \

___ J lie



# .., "**8C~.,** 1,1 ,I' I' .....**'i.'···T~** 8011' "I " r-'O"+-'--jl, 'I' 1" " 2 3 

# " 6 /I '1 8 9 10 2 8 

# " 1\ /I '1 8 I) 10 AIriIod l?IerIod 

# 1**;'.>~"t.~~**

,. ,,/a.....



## .**REGULATORY~ORT** - 4590 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 1 • ATMOSPHERIC CONCENTRATIONS GROUP 2

...**~** .­ 

### Group 2 Target 100 ppm Number 

### Anabsed 

### CoacentrBUon Day Date 

### of Mean StaDdard 

# '*'Reiatin 

### Analyses (ppm) 

### DevlaUon Standard (ppm) 

### Deviation 

### 1 _ 13-Apr-2004 

### 5 103 7 6.8 2 14-Apr-2004 

### 5 101 3 3.0 3 15-APr-2004 5 96.5 7 7.3 4 16-Apr-2004 5 104 

### 11 10.6 7 19-Apr-2004 5 116 18 15.5 8 

### 20-Apr-2004 6 

### 114 2 1.8 

### -9 21-Apr-2004 6 102 7 6.9

--­



### 10 22-Apr-2004 6 100 8 8.0 11 

### 23:APr-2004 8 

### 8.5.7 38 

### 45.5 

### 14 26-Apr-2004 6 104 7 6.7 15 27-Apr-2004 6 107 4 3.7

-­ --­**---~** 

### 16 28-Apr-2004 6 111 

### 11 9.9 17 29-Apr-2004 6 98.0 8 8.2 18 30-Apr-2004 6 98.7 6 tit 

### 21 03-May-2004 6 99.3 11 11.1 22 04-May-2004 7 84.4 18 21.3 23 05-May-2004 

### 6 95.5 7 7.3 24 06-May-2004 

### 6 101 7 6.9 

### 25 07-May-2004 6 101 13 12.9 28 10-May-2004 6 

### 96.5 S 5.2 29 11-May-2004 7 103 

### 11 to.7 30 12-May-2004 6 91.5 12 13.1 31 13-May-2004 7 94.5 12 12.7 32 14-May-2004 6 105 5 4.8 35 

### 17-May-2004 6 99.3 

## is 15.1 

### 36 18-May-2004 6 - 91.8 4 4.4 37 19-May-2004 6 92.9 8 8.6 

### 38 20-May-2004 6 

### 100 14 

### 13.5 

### 39 21-May-2004 6 102 11 10.8 42
.24-May-2004 6 104 7 6.7


### . 43 25-May-2004 6 111 10 9.0 44 

### 26-May-2004 6 107 10 8.4 45 

### 27-May-2004 6 

### 105 12 11.4 

### 46 28-May-2004 6 104 16 15.4

'REGULATORY/REPORT
- 4690 DAY INHAlATION TOXICITY STIIDY IN TIlE RAT WITIfRECOVERY PHASE


### TABLE 1 - ATMOSPHERIC CONCENTRAnONS 

### GROUP 2 - CONTINUED



### - Group 2 Target 100 ppm Number Analysed 

### Concentration

. Maul 

### Standard %Relative 

### Day nate of (ppm) 

### Deviation Standard 

### Analyses (ppm) DeviatioD 49 31-May-2004 6 105 

### 33 31.4 50 01-Joo-2004 6 111 14 12.6 51 02-Joo-2004 6 -116 18 15.5 52 03-Joo-2004 

### 6 109 4 3.7 53 04-Jun-2004 6 111 9 8.1 56 07-Jun-2004 6 105 10**_~·L_** 

### 57 08-Jun-2004 6 103 8 7.8 58 09-Jun-2004 6 99.0 5 5.1 59 1O-Jun-2004 6 

### 99_4 10 

### 10.1 60 11-Joo-2004 

### 7 91.6 

### 7 

### 7.6 63 14-Jun-2004 6 96.6 16 16.5 64­ 

### 15-Jun-2004 6 

### 107 5 

### 4.7 65 16-Jun-2004 

### 8 I 

### 103 39 37.9 66 17-Jun-2004 

### 6 112 12 10.7 67 1S-Jun-2004 5 

### 113 3 2.7 70 21-Jun-2004 6 

### 104 7 6.7 

### 71 22-1un-2004 6 113 16 14.2 72 

### 23-Jun-2004 6 116 11 

### 9.5 73 24-Jun-2004 

### 6 111 9 8.1 74 25-1un-2004­ 6 

### 106 

### 12 11.3



### - --­ 77 28-Jun-2004 6 104 

### 11 10.6 78 29-Jun-2004 6 106 12 11.3 

### 79 30-Jun-2004 6 105 

### 12 1L4 

### 80 01-1ul-2004 6 

### 111 6 

### 5.4 81 02-Jul-2004 6 110 10 9.1 

### 84 05-Jul-2004 6 

### 111 

### 15 13.5 85 06-Jul-2004 6 

### 105 5 4.8 86 07-JuI-2004 

### 6 109 10 9.2 87 08-Jul-2004 b 108 8 

### 7.4 

### 88 09-Jul-2004 6 

### 109 18 16.5 91 12-Jul-2004 

### 6 98 10 10.2

- -­ - , 

### 92 13-Jul-2004 6 98 3 3.1 93 14-Jul-2004 

### 6 103 

### 11 10.7 94 15.1ul-2004 6 101 12 11.9

- 

### Mean of 

### 104

means
/REGUI.ATORY/REPORT
- 4790 DAY INHALATION TOXICITY SIUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 1 - ATMOSPHERIC CONCENTRAnONS GAOUP3 Group3 I 

### Target

### 30tppm Number Analysed 

### CoDc:entratiOD Day Date 

### of Mean 

### Standard % 

### Relaf:iYe 

### Analyses (ppm) 

### Deviation Standard _(ppm) 

### Deviation 1 13-Apc-2004 5 

### 333 

### 6 1.8 

### 2 14-Apr-2004 S 342 15 4.4 3 lS-Apr-2004 5 329 

### 11 0.9 4 16-Apr-2004 

### 5 311 

### 28 9.0 7 19-Apr-2004 5 308 14 4.5 8 20-Apr-2004 6 308 26 8.4 21-Apr-2004 ' ,-­ ..**-~"** 

### 9 6 328 

### 10 3.0 10 22-Apr-2004 6 295 37 12.5 11 

### 23-ADr-2004 Ii 114 

### 12 3.8 14 26-Apr-2004 6 317 14 4.4 15 27-Apr-2004 6 325 12 3.7 

### 16 28-A .pr-2O().1 6 

### 287 17 

### S.9 17 29-Apr-2004 9 211 38 18.0 18 3O-Apr-2004 6 299 28 9.4 

### 21 03-May-2004 

### 6 293 53 

### UU r-­ 

### 22 04-May-2004 6 295 35 11.9 23 05-May

__2004 6 306 44 

### 14.4 24 

### 06-May-2004 6 

### 281 40 14.2 15 07-May-2004 8 310 70 22.6 28 10-May-2004 6 327 20 6.1 29 ' -'-­ 

### -­ c--­ - 

### 288 ll-May-2004 

### 7 74 15.7 30 12-May-2004 6 319 43 13.5 c-, 

### 31 13-t\1ay-2004 

### 6 324 

### 7 

### 2.2 32**14-~-2004** 

### 7 325 

### 22 6.8 3S 17-May-2004 6 323 19 5.9 36 18-May-2004 6 318 

### 27 8.5 

### 37 19-MaY-2004 6 323 12 3.7 38 20-May-2004 

### 8 298 66 22.1 39 21-May-2004 

### 6 323 

### 16 5.0 42 24.:May-2004 7 305 82 26.9 43 15-May-2004 6 

### 340 32 9.4 44 

### 26-May-2004 6 30S 

### 46 15.1 4S 27-May-2004 6 319 26 8.2 

### 46 28-May-2004 

### 6 323 31 Q.6

IRHGULATORY/REPORT
- 4890 DAY INHAlATION TOXICITY SlUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 1 • ATMOSPHERIC CONCENTRATIONS GROUP 3 • CONTINUED



### - Group 3 Target 300 ppm Number 

### Analysed Concentration Day Date of MeaD. StaBdanl %R.ehlUve 

### (ppm) 

### DevIation Standard Analyses (ppm) 

### Deviation 49 

### 31-May-2004 6 296 44 

### 14.9 

### 50 01-Jun-2004 6 280 9 

### 3.2 51 02-1un-2004 6 327 16 4.9

---­ 

### 52 03-Jun-2004 6 295 35 11.9 53 04-1un-2004 8 287 101 35.2 56 07-1un-2004 6 341 2S 7.3 -"57 08-1un-2004 8 250 71 28.4 58 09-Jun-2004 6 324 15 4.6 59 10-1un-2004 

### 6 

### 341 

### 17 5.0 60 

### 11-Jun-2004 6 299 26 8.7 63 14·1un-2004 6 314 47 15.0 64­ 

### 1S-Jun-2004 6 

### 335 

### 22 

### 6.6 65 16-1un-2004 6 326 

### 24 7.4 66 

### 17-1un-2004 6 324 26 8.0



### - 67 

### 18-Jun-2004 5 

### 331 27 

### H.2 

### 70 21-1un-2004 6 313 20 

### 6.4 71 

### 22-1un-2004 6 322 15 4.7**--~".----** 

### 72 

### 23-Jun-2004 6 327 13 4.0 73 24-Jun-2004 6 341 22 6.5 74**25-~un-2004** 

### 6 310 29 

### 9.4 77 28-Jun-2004 6 306 20 

### 6.5 78 29-1un-2004 6 336 23 

### 6.8 79 30-Jun-2004 6 

### 326 17 5.2 80 01-Jul-2004 7 297 32 10.8 81 02-101-2004 6 288 25 

### 8.7 84 

### OS-Jul-2004 6 

### 291 42 

### 14.4 85 06-Jul-2004 6 304 

### 37 12.2 86 07-Jo1-2004 6 302 20 

### 6.6 87 08-Jul-2004 

### 6 

### 300 

### 21 

### 7.0 88 09-Jul-2004 6 297 

### 30 10.1 91 12-1ul-2004 6 281 22 7.8

"""- ..**-~-** - 

### 92 13-Jul-2004 6 300 

### 22 7.3 93 14-101-2004 7 278 59 21.2 94 15-1ul-2004 6 320 9 

### 2.8 Mean of 310 means
IREGULATORY/RBPORT
- 4990 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 1 • ATMOSPHERIC CONCENTRATIONS GROUPS 

## 4Ic 6 Groups 4&6 

### Target 1_ppm Number Aaalysed Concentration Day Date of 

### Meaa Standsnl 

### % Relative 

### (ppm) Deviation 

### Slandard Aaalyses 

### (ppm)**De~ation** 

### 1 13-ApI-2004 

### 5 1110 26 2.3 2 14-Apr-2004 5 1040 33 3.2 

### 3 15-Apr-2004 5 1040 26 2.5 4

## 16-Apr-~ 5 1020 60 

# '.9 7 19-Apr-2004 5 1020 32 3.1

_ .... - 

### 8 2O-Apr-2004 6 1040 

### 24 2.3**.~** 

## -1020 7.0 9 21-Apr-2004 6 71 

### 10 22-Apr-2004 6 1000 36 3.6 

### 11 23-J\pr-2004 

### 6 997 

### 29 2.9 14 26-Apr-2004 6 988 37 3.7 15**27-A~~** 

### 6 999 

### 30 3.0 16 28-Apr-2004 6 954 

### 27 

### 2.8 17 29-Apr-2004 6 957 54 5.6 18 30-Apr-2004 6 1020 39 3.8

... 

### U3-May-2004 21 

### 6 1030 

# '8 5.6 22 04-May-2004 6 1040 113 10.9 23**05-M:4i~004** 

### 6 977 33 3.4 24 06-May-2004 6 1020 33 

### 3.2 25 07-May-2004 6 1010 67 6.6 

### 28 10-May-2004 . 6 

### 990 23 2.3 29 l 

### ll-May-2004 6 1000 58 5.8 

### 30 \ 12-May-2004 6 1020 15 I.S 31 13-May-2004 6 

### 1000 

### 72 7.2 32 14-May-2004 7 979 33 3.4 35 17-May-2004 6 

### 907 208 22.9­ 

### 36 18-May-2004 6 

### 1000 

### 33 3.3 37 19-May-2004 6 986 . 50 5.1 38**20-M~-2004** 

### 6 977 

### 2S 2.6**~-** ...**'--~.** 

### 39 21-May-2004 6 1000 70 7.0 42 24-May-2004 6 934 66 7.1

...­**4~** 

### 25-May-2004 6 1060 47 4.4

- ..

### ­ 44 26-May-2004 6 1040 59 5.7 45 27-May-2004 7 894 273 30.5 46 

### 28-Mo.y-2004 6 

### 1070 

### 80 7.5

REGUlATORY/REPORT
- 50

### 90 DAY INHALATION TOXICITY STUDY IN TIm

### RAT 

### wmlRECOVERY PHASB


### TABLE 1 • ATMOSPHERIC CONCENTRAnONS GROUPS 4
. . 6- CONTINUED**~-.** 

### Groups4&6 Taqet 1000 ppm 

### Number 

### Analysed 

### Concentration Day -Date 

## 01 Meaa Standard %

### Reladve (ppm) 

### Deviation Standard 

### Ao.alyses (DDm) 

### Deviation**~** 

### 49 31-May-2004 6 

### 1050 80 

### 7.6 50 01-Jun-20(}4 6 1070 68 6.4 51 

### 02-Jun-2004 6 

### 991 45 

## 4.5 52 03-Jun-2004 6 1060 22 2.1 53 04-Joo-2004 6 

## 1050 21 2.0 

## '6 07-Jun-2004 8 807 

### 303 37.5

...**~** 

### 57 08-Joo-2004 6 

## 1080 35 3.2 58 09-Joo-2004 6 

### 980 50 5.1 

### 59 10-Joo-2004 

### 6 998 

### 35 3.5 60 11-Joo-2004 6 858 182 21.2 63 

### 14-Jun-2004 6 

### 1050 64 

### 6.1 64 

### 15-Joo-2OO4 6 

### 992 47 4.7 65 16-Joo-2004 6 1010 59 5.8 

### 66 17-Jun-2004 6 

### 1030 47 4.6 67 18-Joo-2004 

## 5 1020 65 6.4 70 21-Joo-2004 7 962 96 10.0 71 22.)00-2004 7 

### 816 274 33.6 

### 72 23-Joo-2004 6 

### 1060 83 

### 7.8 73 24-Joo-209L- I­ 

### 7 832 275 f...
.. 

### 33.1**-.~.-** 

### 1030 .­ 

### 74 25-Joo-2004 6 

### 50 4.9 

### 77 28-Jun-2004 6 

### 976 87 8.9 78 29-Jun-2004 6 

### 999 62 

### 6.2 79 30-Jun-2004 6 1040 38 3.7 80 01-JuI-2OO4 6 1050 77 

### 7.3 

## H1 Ol-Jul-2004 6 

### 1030 31 3.0 

### 84 

### 05-JuI-2004 7 930 309 33.2 85 

### Q.§:-:Jul-2004 6 

### 1030 60 

### 5.8

- .. 

### 86 

### 07-Jul-2004 6 972 43 4.4 

### 87 08-Jul-2004 6 .1020 91 8.9 1-­ 

### 88 09-JuJ-2004 6 

### 986 

### 87 8.8 

## 91 12-Jul-2004 7 970 110 11.3 

### 92 13-JuI-ZOO4 6 1040 

### 57 

### 5.5 93 14-Jul-2()()4. 

### 6 1020 

### 4S 4.4 

### 94 15-JuI-2004 

### 8 905 169 18.7 

### Mean of 1000

means
/REGUIATORY/REPORT
- 5190 DAY INHAlATION TOXICITY STUDY IN TImRAT

## wrm RECOVERY PHASE 

### GLOSSARY FOR TABLES 2 and 6

Key:­ NO.OFOBS.- 

### Number of**obscrvatioll~.** 

### This may n::present the recording ofan observation on more than one occasion during the week for any individual 

### animal.


## NO
- Number

ND Some:; or 

### all of lilt; 

### above abbreviations 

### may appear 

### Inthis 

### Table.

/REGULATORY/REPORT
- S290 DAY INHALATION TOXICITY STUDY IN TIIE RAT WITH REroVERY PHASE 

### TABLE 2 • CUNICAL OBSERVATIONS
1I1.I.. 8'I'DM ucanRl' SUa IOL. 0 100 300 1000 0 1000 ps- PPI ps- p.,. ps

# ... JaLLBD !l'IIIKIlGItOlf
.,. 01' OIlS. 10 10 10 10 10 Ie 110. or DIJIU,S 10 10 10 10 10 11) WIlDS :rJlOII • '10 16 16 16 14 16 16 14 14 1. II II II 8Cl.BS (BJW))
.,. 01' OIlS. I 110. 01 Aa'lXI.LI 2 lIDO I'JlOI( - '10 11 14 IlRDUCU SI'UJ 

### .rr.a
.,. 01' OIlS. 1 110. 01 AIIDf.Udi 1 WIlDS I'JlOI( - '10 12 1<1 S'I'AIIOII! AIIOUIID IIDSII
.,. 01' 088. 1 1 1
.,. 01 NIDIUdI 1 1 1 DU8 rI:QI[
- '10 

### ... 4 111 11 7 7 8IDt I I'IIIUdIi J:ILLBD DIDa...ItOlf
.,. 01' O8S. 11 10 10 10 10 Ie 110. 01 &llJJlU,S 10 10 10 10 10 1(1 DU8 :rJlOII - "to 16 16 16 14 14 14 14 14. 18 1. 1. 11 

### sc.us ( .... 18 01' '!'AlL) 110. or 088. 3 110. 01 MIl'IALS 1

..... :rJlOII - '10 12 It UDUC'BIl Bn.I:r IIIII'LD: 110. 

### or 088. 1 1 ".01 UDALS 1 1 IIUI8 raotI
- '10 12 12 12 12 S'l'A.I1IIUl AJtOUIII) II08B 110. 01' 088. 1 110. 01 AIIDIU.II 1 1IBUS I'Jt()II - .,. 1<1 12 RBGULATOILY/RBPORT 

## - 5390 DAY INHAlATION TOXICITY S11JDY IN THE RAT WITH RECOVERY PHASE


### GLOSSARY FOR STATISTICAL TABLES Adjusted lDean: 

### Group mean bodyweight corrected for inter-group differences in group mean initial bodyweight. The adjusted means are calculated statistically using 

### ana1ysis ofcovariance. The size ofthe adjustment is determined by the size ofthe inter-group difference in group mean initial bodyweight and the strength ofthe relationship between initial bodyweight and subsequent bodyweights. Orgaa. weight atijusted forbodywefght: 

### Group mean organ weights corrected for inter-group differences in group mean terminal bodyweight. The adjusted means are calculated statistically using analysis ofcovariance. The size ofthe adjustment is determined by the size ofthe inter-group difference in group mean terminal bodyweight and the strength ofthe relationship between organ weight and 

### terminal bodyweight.
Key to 

### results ofstatistical tests:­ 

# •• Statistically significant difference from the control group mean at the 1

### % level (Student's t-test, two-sided). 

## • Statb11cally slgnJt1cant dJft'erence from the 

### conttol group mean at the ,% 

### level (Student's t-test, two-sided).

Data excluded from analysis. Female 79
- LUNG weight. fixed prior to weighing Male 33
- PITUITARY weight, damaged at necropsy.**~GUIATORYIREPORT** - 5490 DAY INHALATION TOXICITY STUDY IN 1HE RAT WITH RECOVERY PHASE 

### TABLE 3 - INTERGROUP COMPARISON OF BODVWEIGHTS (g)

IICOVIIU**~. ~t** **-.po.~** CoaoeatraU_ (w-) 

# ....... C!(Coatrol) 100 '00 10.0 o (c.atrol) 1000 

### .............................................

# _ ......................................

# - ................................ _1 DAB •• D. 

# • 2U.t U.t

10 25t.2 

## 11.' 10 2aD •• 12.1 10 2111.6 12.1 10 25•• ' •• 6 10 260.11 10.11 10 _2 

# -, IIIWI S.D. 

# • AD.:nJ
__ 

# ... •. D. 

# • AD.J1J87D au 306.' 16.2

10 '02.' 3U.l U.6

10 ,n.6 296.2 It.1I 10 297.11 

## 32'.' 20.1 10 '211.6·­ 307.' U.O 10 '12.7­ 350.J n.l 10 356.2­ 30l.' 17.1 10 300.7 3'1.11 22.7 10

'!6.0 30'.1 13.11 10

10'.5 lI'.O 21.6 10

'''.1 30'.6 

## It.' 10'0'.2

't•• , 1'.2 10 3U.'

..... 6 IIIWI S.D. 

# • AD.:nJS7D ... 375.2 31.0

10 '69.7 U •. , :111.2 10 '10.1· Jl2.J at.2 10 3".1­ '61.11 27.4 10

'611.1 S77.' 21.6 10

'78.t '12.1 

## a,.' 10 '11.11 _5 IIIWI to 1. I S72.2 607.1 390.' ••• 11 t06.1 S.D. 

# • AD.:nJ.
__ 33.2 10 391.7 26.0 10 37t.l· 27.6 10 tit.l '0.' 10 3".2 n.6 10

'''.1 ao.6 106011.11

..... II au ••D. 

# • ADIUIIftD
_ nll.5 U.,

10 no.6 3".6 2'.11

10 

# "

# .... no.' 2•• ' 10 n •• o 6lCl •• '0.1 10 607.11 G6.0 '1.6 1.

'a6.7 629.0 2'.1 18no.' _7 DAB U7.11 nO.II 651.' t21.1 .1.' U6.6 •• D. 

# • AD.J1IIl'l'IIIIIIDII sa.1 10 ttl.l 28.11 10 622.7 32.' . 10 tII'.1I 2I.J 10 ta5.6 sa.2 1.

4112.6 27.11 18tt••• 

# ...... DAB •. D. 

# • AD.:nJ_ liliiii 6U.' 31.6

10 6117.11 n2.11 21.1 10 6'6.7 U •• ' 

### SII.' ID 6".5 tIIl.1I 31•• 10 66•• 1 671.2 n.1I 1.

472.0 U6.2 1'.6 10

tll•• t

REGULATORY/REPORT . 55

# - s

# ~ CJ 

## iii

# ~ o m u. 

## o 

# z 

# o en

# ~ ::E 

## o U D. ::;) 

## o a:: CJ 

## a::

# ~ o o o 

## ...



## ... 

# ..**:r~** 

### := Ift.o"



## ...

# ­

., o 

## ... 

# .. .. 

# .. 

# .. ... ... ... ... 

# .. 

# .. ... 

## ... 

# J90 DAY INHALATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### TABLE 3· INTERGROUP COMPARISON OF BODYWEIGHTS (g)

.. m ftUDl' ac:cmnrr 'target; SI:po• ..- c:oa-tntiOll IJIII) BLIIB Olco.troll 100 300 1000 OIC_tro1) 1000 

# -

..-.............. 

# ...-

# ..

# - ..................................................................................... WNI< 17 HUll 555.0 5U.4**a.~.** 31 •• 

### :"'.5 10 U 

# • ,u.1VS'tJID IIUII 511 •• 512.' WMk 11 HUll SlI,2 11411.' a.lI. 35.J 3'.7 10 U AJl.JVS'tJID

_ 

# • 5&4,. 551.'

REGULATORY /REPORT • 5790 DAY INHALATIONTOXIClTY STUDY IN THBRAT WITH RECOVERY PHASE 

### TABLE 

### 3 - INTERGROUP COMPARISON OF BODVWEIGHTS (9)

IlIAD 1I'I'U'D1.' IIIC:CmIn !!are-t lIIIpo- CGacMm1:ftlUCIII 

# 'rrc:) Dll&l&B O[COIItrol) 100 100 ltO. 1000 0 

# -=-,_1)


# -**-~~** 

# ..--.-.-.......................**-.-.-.~-** 

### ...................................................................



# ..

...... 1 

# ..... 211 ... 201.7 200.4 202.1 101.1 207.1 B.Il. 12.2 14.1 14.0 1'.4 14.1 ••0 W 10 10 10 10 M 10

..... 2 II1&II 8.11. 

# • AD.lVII'l'IID IIIWI 242.5 11••

10 

# 23'... 220.1 11.4 1. 222 ... t 220 •• 16.2 10 221 ••• 2D.1 lB.2 10

222••• 22•• 0 14 ... M 2at.l 224.1 

# .... 1. 223.0

... ! IIIIWI 2111." 21B.! 23•• 1 2a.3 2....... 260.' 8.11. 

# • .IoIIJVII'I'ID 111M 13.1 10 nO.I 1'.7 10 240 ... 20.3 10 a42 .• 26." 10 21 •• 1 11.2 .0

2 ..... 11.2 10

2311.1 

# .......



# .... ,



# ..... ,

• MIt 7 IIIWI S.I>, 

# • aN1IftD
... 

# - •• 1>. 

# • DolV81111D
_ 

# - 8.1>. 

# • UJV8'IIID
..... 

# - :110.1 1'.2

10 112.' 211 •• 17.1

10 212.7 a07•• Iii ••

10 II ••• 2ts.0 210.7 

## It., 10 211.1 2'••• 1S.7 10 2U.l 272.1 1'.' 10 271.' 202.3 1-1••1 11.4 10 2st.' 210 .. 1'.1 10 264.' :173.2 16•• 10 277.0 271.1 2 •• ' 27.1 10 212.' 2U •.0 2•. 0 10 21t.7· 2".2 21.' 10 2n ••• 21'.7 21t.O ao.o 10

210.1 211.1 2.1.1 10

21 ••0 200 •• 20.2 10 ·2U,O IB7.' 24'.1 1-1.1 1.

247••• 21 •• 7 13.0 1021•• 2

2•••• 10 •• 102.1.'·

271 •• 8.1>. 

# • AIJOIIftD IIIWI 2•• 1 10 207.1 15.2 10 211.1 16 ... 10 2".1 2•. ' 10 21'.2 2:2 •• 10

:a•••• 11.2 10

## 2.,..' .MIt I 

# ..... 8.1). 

# • U.JIJft'BD ..... 101.1 10.2

10 2.11.1 20'.' 13.0 10 21•• 1 211.7 

## 15.' 10 III.' :a..... 2 •. 3 10 211.0 lB•• ' %3.11 10

Itl.3 211.1 14.0 10

2.0.1

fREGULATORY/REPORT
- 5890 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH REOJVERY PHASE 

### TABLE 3 -INTERGROUP COlUPARISON OF BODYWEIGHTS 

### (g)

Dn stun Uc:o¥D!' 

## "...,._t .... ..aN Coaa_uaUoa Cp.-) P\IIIU.lI8 o (Coatrol) 100**3~0** lOOO O(co.trol) 1000 

### ................................................................................................................

.... 9 IIIWI Ii.D. 

# , 301.1 21.0

10 all.' 13.4 10 215.1 20.3 10 

## :'7.' 3•• 1 10 2'3.1 22.' 10 214.7 14.1 10 AD.J'IJa'I'JID IOIU 299.6 1t2.? 290.2 211.1 294.7 213.1

.... 10 

# .... 309.7 294.1 290.0 %90.2 291.' 211.2 Ii.D. 22.7 13.4 17.4 21.1 :U.3 13.1 J 10 10 10 lit 10 10 AD.J'IJ1ft'IiI) IIIWI 301.5 2'1.7 2 .... 0 291.' atl.3 2U.I

.... 11 IIIWI '.D. 

# • AD.J'IJS'I'IID IOIU 311.0 21.3

10 307.' 310.1 14.7 10 302." 2'0.' 16.1 10 2N.1i 1911.1 :u.o 111 297.3 29'.1 24.4 10

a99.1 2911.2 13.4 10

2t.1.7

.... 12 IIIWI I.D. 

# • 

# UIIJ_ IIIWI 319.3 21.1

10 311."6 3D'.1 111.4 11 307.6 a9'.7 17.2 10 301i1.4 196.1 2'.1 10 197.7· 304.0 :11.4 10

301.3 211.2 111.1 10211.7

... 13 

# .... 321.3 30t.' 3Oz.a 1".9 3011.' 30a.I 6.D. 

# .. aO.4 10 14.9 10 11.' 10 :1Il.' 10 22.a 10 15.5 10 AD.IR'IIIID IIIWI 312.2 307." 3 •• 1 'Ol.? 307.1 301.0

.... 14 

# .... 317.9 301.' 300.S**:91.~** 3ot.a 303.2 6.D. 

# , 20.1 10 1$.3 11 11.1 10 11.7 10 23.7 10 13.4 10

.... 11 aD.1VftD IIIWI 

# - Ii.». 309.7 309.0 31N.1I 1'1.5­ 310.7 31N.7 24.9 301.7 2".3 l4.1 J 10 11 ADJV8'ID IIIWI '''.3 297.7

.... 11 

# ..... E.». ' •• 9 13.1 302.0 ll.a



### ... 10 10 AD.J'IJS'ID .... 301.6 300.5

/REGULATORYfREPORT
- 5990 DAY INHAlATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### TABLE 3· INTERGROUP COMPARISON OF BODYWEIGHTS 

### (g)

IIAD .'!IID!' UC09JII'f 'I_
..t ....... COIaOMtata- CPr-' nIIIILIIl o(CoatrolJ 10. ,to 1000 .CCoatrol) 1000


### ................................................................................................................

..... 17 

# ..... 310.0 SOlS. a I.D. 21.0 13.4 10 10 

# • AlJ.1'08'I'IrD ..... 3L2.1 303.'

..... 10 

# ..... :tll.2 303.3 I.D. 

### a2." 12.3 10 10 ADJUBBD 

# •IIIUII :lLa." 301.1

/REGULATORY/REPORT -6090 DAY INHALATION TOXICITY STUD" IN TIIERAT WITH RECOVERY PHASE 

### TABLE 4
.. INTERGROUP COMPARISON OF FOOD CONSUMPTION (g/RAT/DAY)

DDI IftIID1' UCOVDl'**'I'~** lIZpcMIan eaaoa.tl'atloD (a-) JIAL.S • (CoDtrol) 100 '04) UOO o(CoDtrol) 1000 

# ....

# --_...-.-................................................................................................... weeltl IIIIUI 8.D. 

# • 10.2 0.'

2 10.5 1.0 2 I1.S0 •• 2 

# ...­ 0.' 2 30.1 D.7 I 30.1 0 •• 2 WHIr. 2 IIIIUI Ii.D. 

# • 21.' 1.a

2 a •• ' 1.7 :I 31.1 0.0 2 2111.0 0.0 2 30.1 D.3 I 31.1 1.1 2

..... 3



# ....... 

# _II

..... ,



# ..... , WIMIk I IIIIUI S.D. 

# • IIIIUI 8.D. 

# •



# ..... 8.D. 

# •



# ..... ••D. 

# •



# ..... S.D. 

# •



# .... 21 •• I ••

2 29.0 0 ••

2 21.5 0.1

2 '0.0 

# •••

2 2'.3 •• 1

2 21 •• 2'1.1 0.5 2 21.5 0 •• 2 2'.0 1.1 2 21." 1.0 a 21.1 0 •• 2 2'.1 30 •• 0 •• :I 3 ••• 0 •• 2 30.1 0.1 2 30.2 0.1 a 2'.7 

# ••• a 21.1 a'.1 0 •• :z 21.2 1.2 :I 27.S 1.' 2 21.1 1.1 a n.5 '2.3 2 27.1 10.0 D.I J 21.'**~.7** 121.1**~.I** 1U .• 1.1 I 21.' 

### ',I J2'.2 31 •• 0 •• 2 SO.l 0.5 2 2'.1 1.0 2 29 •• 0.' 2 29.3 0.1 2 21.7



# ...... 8.D. 

# •



# ..... '8.D. 

# • 0.' 2 2'.5 0.11

2 0.2 2 2'.1 0 •• a 0 •• 2 2'.1 0.3 2 0.1 2 21.1 a.2 a**~.I** I 21.2**~.,** I 0.1 2 30.0 I •• 2

rREGUlATORY/RBPORT
- 61

# •••

•••• 

# •

•• 90 DAY INHALATIONTOXICITY STUDY IN THB RAT WITH RECOVERY PHASE 

### TABLE 4 - INTERGROUP COMPARISON OF FOOD CONSUMPTION (g/RAT/DAV)

..... S'I1ID1' JmiCU¥'IIIIIl[ 'I'aqet 

# 1iIopO._ COaout_tiOil [lJIIIa) IALI:8 o(Coat:rol I 100 Sto 1000 t(Coab';ol.I 1000 

### ................................................................................................................ 

# ... ..... 10 II.' 21.? 111.0 111.0 2•• ' I.D. 0.' 0.' 0." 1.0 0 •• 0.1 :I I :I a 2 :I

..... 11 30.0 21.1 a.... a •• 3 

# •

# ... n." 

# lIII.' S.D. 0.3 0.' 0.1 1.1 0.1 0.:1 a 2 a 

### a 2 2 

# •

..... 12 11.:1 It.o 21.3 SO.1 

# ... lIII.' :Ia.'­ I.D. 0.1 0.' 0.11 1.2 0.1 0.2 2 a 2 :I a 2 

# •

..... 13 27.' 21.1 II.S 2••• 

# ... at.' a ••' I.D. 0.1 0.' 1.1 1.5 0.' 0 •• 2. 2 :I 

### a 2 a 

# •

..,. ..... 14 10.3 1'.0· I.D. 1.1 0.:1 :I 2 

# •

..... 15 I' •• 

# .... II.' I.D. I.ll 0.1 I a 

# •

..... 11 

# ... a,.' •. D. O.S 2. a 

# • lJeek 11 

# .... n.? 

## 17.' 

# • '.D. 

## '.1 

# • •• a 2



### RBGULATORY/REPORT

- 6290 DAY INHALATION TOXiUTY STUDY IN THE RAT ,\\TI'H RECOVERY PHASB 

### TABLE 4 -INTERGROUP COMPARISON OF FOOD CONSUMPTION (g/RAT/DAY)

!lAW I'IUM DCO¥II:n:**~Uf6t** ltI;pH1Ire CODoAtnt..l_ tpa-) ..-r.JIS o(Coatrd) 10' .0 1000 J(Coatroll 1000 

## ...................

# _-_........................................................................

## -................. .MII 1 _MIl :z 

# _MIl 3 

# .... I.D. 

# •



# - S.D. 

# •



# - 22.' 1.' 2 23.1 1 ••

2 22.7 22.1 1.s 2 21.11 2.2 2 23.0 21.1 0.1 2 21., 1.2 2 21.7 

## 22.' 

# .. a 22.1**~**

# .. 2 22.7 22.' 0.3 212.1 0.1 222.S 21•• 0.<1 2 20.'* 0.3 2 20.11· 

# -MIl,

'IeoIIJI: 5 S.D. 

# •



# ... B.D. 

# •



# ... B.D. 

# • 0.' 2 21.1 1.' 2 22.1 1.' 2 3.1 2 22.1 0.2 2 22.11 0.' 2 1.2 2 2L.O 0.3 2 

# 2L.' 0.7 2 0.2 2 21 •• 11.3 2 22.' 

## 1.' 2 1.1 222•• 1.3 2

## 22.' 1.' 2 0.' 2 20.'· 0.0 2 111.7 0.1 2 

## .-, IIIWI II.D. 

# • 22.1 1.2

2 22.ll 0.3 2 2' • ., O.S 2 22.2 0.1 2 23.0 0.1 2 1'.9* 0.1 2 '-7 IIIWI I.D. 

# •



# - 21.2 1.0

2 21.7 0 •• 2 2'.' 1.1 2 21.7 

## I., 2 21.0 0.' 2 111.7 1.2 a _MIl I _MIl • 8.D. 

# •



# - S.D. 

# • 20.' 0.'

2 21.3 1."

2 21.1 0.7 2 

## 21.' 0.5 2 11 •• 0.3 2 21.0 1.' 2 2.1.1 1.' 2 20.7 1.2 2 21." 1.2 221.' 0.7 2 111.2 0.1 2 111.2 0.1 2

llEGULATORY/R3PORT
- 6390 

### DAY INHALATION roXiCITY STUDY IN TIlE. RAT WITH 

### RECOVERY PHASE 

### TABLE 4· f.jTERGROUP COMPARISON OF FOOD CONSUMPnON (g/RAT/DAY)

IDlII I1'1'III)1: ......,.,.q 7aq.t II:QOnn c:uo..u.t:1_ ..., I'ImI.LlII**O(coat~l)** lot 3D0 1000**'(Coat~ll** 1000



# .......-

# .... ...

# --................................

### --........................................................... ar..Ir; 10 

# ..... 21.2 21 •• lit. 1 20.11 21.! U •• S.D. 1.5 •• 1 O.S t •• 

# .., 0.5 .z .z :t I I I 

# •

...... 11 U .• 

### 22.' 20.! I1.S 

### 11.' U .• a.D. O.S 

### 1.' 0.1 1.S 0.5 1 ••



# -- 2 .I 2 1 I .I 

# •

..... u 

# ..... 20.1 .zo•• ZO.7 20.1i 20.7 19.3 ••D. 1.2 1.0 0.5 0.7 0.1 0.0 :t 2 2 a 2 2 

# • .1M1I: 13 18 •• 10 •• 11.1 "'.0 20.2 U.O 

# .., S.D. .1.1 0.1 0.1 0.' 0 ••



# -- .I 2 2 :I a 2 

# • 

# ........ au 10.7 20 •• ••D. l.1 1.a 

# • .1M1I: 18 11.1 

# .... :t 2 1 •• "­ S.D. C.I 0.1 .I I

...... 11 10 •• u .• 

# • I.D. e•• 0.' 

# •



# ...



# -- 2 2

...... 1' 10 •• 1 •• ' B.D. 1.1 0.' .I 2 

# •

'REGULATORY/REPORT -6490 DAY INHAlATION IDXICITI STUDY INTIlERAT WITH 

### RECOVERY PHASE 

### TABLE 5
.. INTERGROUP COMPARISON OF FOOD UTILISATION 

### (g GROWTH j 

### 100g FOOD)

IO.DI IIftDI' UCOVIIIa**"~t** 1bqIo_ CaAoeDt.c'_t.loll (PIIII) • (Qlmt1'01) 1 GO 3..**lO~..** (Clat::col) 1000 

# ...

# - ...- 

# ..

# --...•....•..••.... 

# .... .....

# --..................................

# - ....••...••...••.......•....••••.•• IIal.ea .&Us 1-4 IIUII 17.05 14.3L la.13 

### 15." 11." 141.17 8.1>. 0.71 0.91 1.11 0 ••1 '.94 1.11 :I 2 2 2 :;. :I 

# •

....... 5-' IIUII 

### '.01 9.47 9.1' 1.111 9.'9 

### '.87
•• 1>. 0.14 41.61 0.23 0.1)3 

## '.41 •• D4 2 :I :II 2 2 2 

# • ••__ '·U 3.4. 4 ••2 •• 26 4.31 1.01 1.1. B.I). 0.22 •• 11 •• 17 •• 13 0.41 

# .." 

# - :I :II 2 2 :;. :I 

# •**~1** I'
.... 1-13) IIU.II 9.3' I.'. 11.15 9.n 1•• 10 9.91 

# . .., 

# .. " 8.11. D.S. 

### ..51 41.21 0.66 :.I a 2 2 2 a 

# • I-a.

.... 1-4 IIDII 1 •• 91 '.42 1 •• 11 

## I." •• 17 1.1t**8.~.** 0.13 1." 1.:11 1.11 '.3.1 S • .I. 2 :I a 2 2 2 

# •

....... I-I MWI 4.11 4.17 4.31 •• 11 

# ...,. 4.11 8.J). •. at •• '1 o.lIa •• 11 '.1' •• 1' 2 a 2 a a 2 

# •

__IE_ .-13 

# .... 1.2• a.22- 2."· 1.2.1 2.20 2.11 8.]). •• 13 •• 39 0.11 •••7 •• 1114 ..a9 a a :I 2 2 2 

# • Owr.tl ( ...... 1-U) IIIUII 1.41 1.21 1.30 '.0' 5.a. 5.21 8.J). •• 07 

## ..:10 •• 20 0.'1 G ••9 •• 3 • 2 a 2 2 2 :I 

# •**REGULATORY~RT** -6590 DAY INHAlATION TOXICITY sruDY IN THE RAT

## wrm RECOVERY PHASE 

## TABLE6-0PHTHALMOSCOPY

SUa DLB :nJ: (8) IIOIIDl. 110. OJ' OBI. 110. OF AllDllL8

.....**:nOH-~** 0Ps20 10 -2 100 

# ,.. 10 10 13 -2 IIUII ftIIDl' 301 ppa 10 10 -1 -2 1000 .J1III 20 11 -1 -2 0PsUI 10 13 -2 1000 

# .... 10 10 -1 -2 IlICOVDI'

-1

SU, 

### rllmLll :nJ: (S) aomw. 11). OJ' OIlS. 110. OJ' AIIDIlL8

..... I'Rmt -**~** 0ps20 10 -2 100 JIIIII 10 10 13 -2 300Ps10 10 -2 -2 1000 PJIII 20 10 -2 -2 0 ppa II 10 13 -2 1000 

# .... 10 10 -2 -2 -2

'REGULATORY/RBPORT
- 6690 DAY INHAlATION TOXICITY STUDY IN DIERAT WITH RECOVERY 

### PHASE GLOSSARY FOR TABLE 7 

### Key:- 

### CONSTRICfD

- constricted INCR/SD

- increased 

### DOWNWD -downward 

### DECISD VISUAL PLAC. RESP.

- decreased visual placement response DECD. PUPIL RESP 

### TO UGIIT


### - decreased pupil response to 

### Ught REDUCEDFOOTWmIDRWLREF



### - reduced foot withdrawal 

### reflex N



### - no abnormalities detected/normal S

- slight X


### - present The values shown are the number ofanimals noted to display 

### the condition listed. All incidences ofno abnormalities detected for 

### each parameter assessed are included.

REGUlATORY/REPORT
- 6790 DAY INHALATION TOXICITY STUDY 

### N THE 

### RAT WITH RECOVERY PHASE


### TABLE 7 - 

### FUNCTIONAL OBSERVATION BATTERY CUNICAL ASSESSMENTS
_12 sa: 

## 1-----.-.. -.MaLIS•••**--------.---I----·--.--.-~---·---···-·I** DOn Llr9BL (PNI 0 100 310 1000 0 100 300 1000 iUlDCllDlIAL '1'0IIII: DllCIIUSlID nvalft COUll: • 10**~o** if 10 10 10 10 10 iUlDCllDlIAL '1'0IIII: DCUI.IIiP IIIIVDI'I'r COO. II 10 10 if 10 10 10 10 10 a.oIUIiU. 1iIIU'f (sa 'nX!') SIIVIIIII'ff CODII: • 10 10 if 10 10 10 ]0 10 M:l'IVI'fY DllCllBAllJII) SS'VImlft COllI: • 10 10 10 10**~O** 10 10 10 M:l'IVI'fY IIICJIDJIJII) ID'VlDllft CODII: II 10 100 10 10 10 10 10 10**AI'~** _III IlIa/lID IIIIVDIft CODII: • 10 10 10 10 10 10 10 10**~1111** IIBDUCIID lD'VlDl(ft CODII: • 10 10 10 10 10 10 10 10 A'l'UIA SIIVD(ft coPII
.. 10 10 10 10 10 10 ]0 10 JlIIUIIB 

## 8"""1_ 8IMIII1ft CODII:
.. 10 10 10 10 10 10 10 10 _UIIIGI I ............

..... 1'11' COW:. 10 10 10 I.D 10 10 10 10 CIIIIOIIIIIMCItIOIUIIII\.\

..... 1'11' CODII: • 10 10 10 10 10 10 10 10 CIIICLDN R1IDtft COlD II 10 10 10 10 10 10 10 10 CLOIfIC COIIYULSICIIS IIIII1/D.lft CODB II 10 10 U 10 10 10 10 10


### REGULATORynmpORT

- 6890 DAY Il\HALATION TOXICITY STUDY INTHE RAf WITH RECOVERY PHASE


### TABLE 7 - FUNCTIONAL OBSERVATION BATTERY CLINICAL ASSESSMENTS
_12 sa:**1·.-····----H1LSs---·-----------I------------~s---------··-1** IIOU LIMIIo (PIlI) 0 100 300 1000 0 lOG 300 lOOt CDIIII.IOSI: QVD:t'l'l' CODI: • 10 10 10 10 141 to 10 10 CROU:llIG QlVDIn OODJI • 10 10 141 10 10 10 10 10 C!'AIlOB:ID 511V111lln .:00:& • 10 10 10 10 10 10 10 10 .e/SD VIIUlU. .LAC. IIBIP. nrvnln <:ODS • 10 10 10 141 10 LO 10 10 .CP. ""II.
_ ft L:IGII'I' _In.:oos. 10 10 10 10 141 141 10 10 IIICIIJI\UIiI) DD'IBIM DJEPl'II nr:YDI'l'I' CODI: • 141 10 141 10 10 10 10 10 IllcaJlASBI) _ftIIR IUI.!'I: nrvnln**~.** 141 III 10 10 141 10 10 141 lIDDIIIAo:rD QlVDIft OOO'S • 141 10 141 141 141 LO 141 141 DOIIIIIID C1JIVa_ Qp UJ:8 D¥Dl'l'l' eoDlI: • 141 141 10 141 141 141 141 10 IBDOftmIlIWIOIl IIIVDIn CODJI • 10 10 141 141 141 141 10 141 D.OJ'Il'fIIAI.M)S SlI'VDln OOJ)B • 10 10 10 141 141 LO 10 10 GIl":. Sll'VDIft 

### ::oDS • 10 10 10 141 141 141 10 141

_ FLICXI. bVDlft ::oD1I • 141 10 10 10 141 141 141 141

/REGULATORY!REPORT
- 6990 DAY INHALATION TOXICITY STIIDY IN THE RAT WITH RECOVERY PHASE


### TABLE 7 • FUNCTIONAL OBSERVATION BATTERY CUNICAL ASSESSMENTS

DPU BJD[**-------.---~---------------I---·-----·--~·------···--I** DOSII J.BVIIL (PH) • 100 :SOO**10~0** 0 100 SOD ltOO

_ U'AIlClIDM I:1I¥IIItlft COIIII " 10 10 LO 10 10 10 10 10 IIUIICDD 10 10 lO 10 10 10 10 10 I:1I¥IIItJft COIIII " 1IftaIIHII:[.I. III9Dlft COIIII • 10 10 10 10 l.I) 10 10 10 1I'fPD'IIIIIIIIIU nvDJft**~"** 10 10 10 10 10 10 10 10 BnO'J'DIIIIIlI. 8IIV1IIllft • 10 10 LO 10 10 10 10 10 Pea/ID '1'0
_ I:1I¥IIItlft COIIIi " 10 10 LO 10 10 10 10 10 PCa/SD ........ '1'0 'l'OOaI Bll9DJft COIIII • 10 10 10 10 10 10 10 10 IJICIIIIl.SIa)**""''111~** DII1"IIII III9Dlft**~.** 10 10 10 10 10 10 10 10 :DICIIJUaD ...".. IMI an: SIIVDI'I'I coar • 10· 10 10 10 10 10 10 10 LUOVDD ..."IIIDIQ

...... 1'1'1 coar. 10 10 10 10 10 10 10 10**L&CKllDlan~**

......lft 

## coar. 10 10 10 10 10 10 10 10 .I08U (,.,.lL awBftIC'III) 8IVIII:lft coar • 10 10 10 10 10 10 10 10 II!DIlUSIS (PUJL DILIoftl) III9Dlft CODI • 10 10 10 10 10 10 10 10

IREGUlATORY/REPORT . 709{) DAY INHAlATION TOXICITY STUDY IN mERAT

## wrm RECOVERY PHASE


### TABLE 7 - FUNCTIONAL OBSERVATION BATTERY CUNICALASSESSMENTS _12 sa: 

### 1-----------DLIIS---------------I------------J'IIIIloU8------------I JOSII r.nn (l'I'IIl 0 100 30' 1000 0 100 !QO lOCO l.t.ldl: 8ftIDtIft ::oDB • 10 10 10 10 10 10 1t 10 lAt.J'I:8U.L IID'LBX US111ft'

..... I'P'f::oDB • 10 1. 10 1D 10 10 1t 10

,_ I'LJc:1C:5 UYIUU'P'f ::oDB • 10 10 1D 10 10 10 10 10 lUoOaBCIla.

..... I'P'f OODB. 10 10 10 10 10 10 10 10 • JlIID. DI'UIJ: IJISJIII'l 1IIrVIatI'P'f ::oDB • 10 10 n 10 10 10 10 1. J'a08TJIA'n 1IIrVDI'P'f OODB • 10 10 10 ID 10 10 1t 10 .IOSIS IIIrVDI'P'f 0CIIlIi • 10 10 10 11 10 10 10 10 UAllDIG SBYbX'P'f ::oDB • 10 10 10 10 10 10 1t 10 J:.IDIJCID)**r~** w:t'I'IIDIJIL ..,

..... 1'P'f OODB. 10 10 10 10 10 10 U 10 IBIIOQD I"tIDLDIB nllC'll'Ia. SIIYD:t'l"f ::oDB'. 10 10 10 10 10 10 10 10 IlIDUCBD IIJlIDLDIB nllC'l'xa. a¥D1'P'f ::oDB,. 10 10 10 10 10 10 tt 10 IlIDUCBD 1'0 IIIOIJIII)

..... I'P'f::oDB • 10 10 10 10 10 10 18 10 II1IDIJCIID Jl.IGIIIIIIG Dl'LIIX S'ft'IDII'P'f 000•• 10 10 10 10 10 10 11 10**~GULATORYnuwORT** -7190 DAY INHALAnON TOXICITYSTUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 7 - FUNCTIONAL OBSERVATION BATTERY CLINICAL ASSESSMENTS 

# _12

lID IIOSII r,rllllo (l'l'II) 

### ;.·.·-------.....---------------I------------EllaLlS------------I 0 100 300 10ClO 0 100 30D 1000 _CD IIPLU aIU'LII1 a.9IIIll'l'l' CODII •

.....J'I'I' CODII S 

# , 1 ID III 1D 

# , 1 ID 

# , 1 ID IIDVCIW S'!&IIILI'I"l

..... 1'1'r CODI\. 10 10 10 ID 10 10 10 10 ROLLI5 OYD BlIIIIU.TI SII9DI'I"I' CODI\ • 10 10 10 10 10 10 10 10 IIIoLl"fA'l'fa. D\'DI'l"I' COIIIl • 10 10 lO 10 10 10 10 10 81 ... JlIJICIID B BnDI'l"I' CODII • 10 1. JO 1D 10 10 10 Ie SIas or »nuwou

__1'1"1' CODII. 1. 10 lD 10 1. 1D 10 ID B'I'.t.DID dOUIID .,.,. IInIIIIW CODI\ • 10 10 )0 10 10 ID 10 10 8'I'.IUlIIID .- Jtlllll 1III9Dl:'l"I' CODII • ......aft CODII x 10 10 lD 10 10 10 I 1 10 II'RIIIKD 0'1'11 UIWIII - DII1'

.....J'I"I' ClODa. 10 10 10 It 10 1D 10 10 HA.IIIKD 0'1'11 UIWIII • ..,. IInIIII'I!f CODI\ • ID 1D 1D 10 10 10 10 10 DB IIII9Dl:ft CIODII • 10 1. 10 10 1. 1D 10 10 ton:c CllnVli.8JGII SJmIJI.lft CODa • ID ID 10 10 10 ID ID ID

REGULATORYnuBPORT -72i)() DAY INHALATION TOXlCITY STUDY IN 

### mE RAT WITH RECOVERY**PR~E** 

### TABLE 7 - 

### FUNCTIONAL OBSERVATION BATTERY CLINICAL ASSESSMENTS

.... u sa: DOB U'II'IIL (1''', 

### 1-----------KlLBS--·------------I----·-.-----PIKlLE8------------I a 100 MO**100~** ., 100 300 1000 

# .,..,.. IIJIVIIIIl:ft COIIII • 10 10 11 10 10 10 10 10 UMIIIOOIIDSJmDtIft COlIS • 10 10 11 10 10 10 J() 10 Ul'1fUD COVI.'J'IIIUt OF DID BIlVDII"f CIIlIIIIII • 10 10 11 10 10 10 lD 10 YUCU.ISAt'IOll IIIIYIIItIft COIIII • 10 10 11 10 10 10 10 10 DIoItUlO IM:J'IUDII BIIY1IItIft COlIS • 10 10 11 10 10 10 10 10

....**I~** BIlVDIft COIIII • 10 111 11 10 10 10 10 10 a:IBftlSRV'RII"f CODB • 10 10 10 111 10 10 10 10

REGUlATOlY/REPORT
- 73

## ro DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 8 • INTERGROUP COMPARISON OF LANDING FOOT SPLAY (mm)

If.UII 81'\11)1 am.'J' "ugat .....__ c::oa-ft'IItJ._ C
....) otColltrol) 100 300 1000 •• • •••• •••••• ..........w•••

__........................................................................... 1Ial._ 

# ... n.4 11••0 

## '3.'· 

# II.' 8.D. 16.5 15.1 II •• U •• 10 U 10 lP 

# • 1'-.1 •• IIIWf 113.1 IIJ.t 

### 61.' 

### n.' B.D. 

### '.1 

## 11.' 7.3 

## III.' W 10 U 10 U

REGULATORY/REPORT - 7490 DAY INHALATIONTOXICITYSTUDYIN THE RAT WITH RECOVERY PHASE


### TABLE 10· INTERGROUP COMPARISON OF GRIP STRENGTH (I) ... 

### HINDLIMB

IIUII I'll1ft 0lIl.1'**~t** lI:wpOoIu. eaa-.trau.a (PIlI)**.(eoat_~1** 100 SOD 1000


### ....................

# --.................................................................................. " 

# .. 

# ... 4., 603 521 570 S.II. 209 120 143 162 10 10 10 10 

# • 

# .., r-u.. HPII 4,., 103 4U S.D. lU .5 10 

# • 10 

# " 10 10 10

'REOULATORY/RElORT
- 7690 DAY Il\1lAI.ATION TOXIOTY STIJDY IN THE RAT WITH RECOVERY PHASE


### TABLE 11 - INTERGROUP COMPARISON OF TIME TO TAIL FLICK (8)

IIAD' S'I'IIDT**~~** 'l'acv.t bponx:1t**~a.tJ.cm** (..-) 0(CoIluo1) 100 3" 1COO 

## ........

# _-.......-.......................

## -.....................

## -.....................................

# --­**~** 

# ... '.3 7.1 7 •• 11.3 S.D. 6.3 

### ".1 

## ••• '.1 10 10 10 Iii 

# •**I'~** •• IIlIU 10.7 7.3 S.D. 6.2 3.: I.T 

# •

•• '.7 

## '.5 10 1 • 10 11i 

# •

IREGUlATORV/REPORT
- 7790 DAYINI:IALATION TOXICITY STUDY IN THE tAT

## wrrn RECOVERY PHASE


### TABLE 12 - INTERGROUP COMPARISON OF MOTOR ACTIVITY

IIU1t 8'IIII)J' c.r.1: 'Iarget -.-.- C
..o ..t_t:ioa In-} 1I&LI:B • (CGatnl.) 10. 300 10.0

•••• ................................................................................................a __ _ lUII.t... 1-5 1Ua.t.. 1-10 IUJatat•• 11-11 lUaut•• l'-;IIO 1UIItat
.. 21-as 

# ...... 8.D. 

# •

# - S.D. 

# •

# ...... •• D. 

# •

# ...... S.D. 

# •

# ...... 72.3 15.a

10 ••• 1 11.5

Ie

't.5 as."

1. 1S.7 :&7.t

10 71.11 72.1 l •• t 10

7'.0 t.3 10



### n.o '.2 10

'a.l n .• 10

....a Ie.t 9.0 10



# .,

# .... t.' 10



# ,

# ... 10.1 10

.1'.1 U.I 10

51.1 77 •• 

## t.' 1018.6 U.S 1077.0 aa.40 10H.l a •• 1 101'.7 IUIItlt..**II-3~** S.D. 

# •

# - :&7.' 10 71.1 Z;II.S 10

81.0 a3.1 10

Sll.' .II.t 1013.2 lUaut
.. n-1I5 lUaut.. J'-"O IUatat.. 

# &1-".
IUIItlt•• "·SO
o-re.ll. Cl-II.) LD. 

# •

# ..... LD. 

# •

# ...... S.D. 

# •

# ...... ••D. 

# •

# ... 8.D. 

# • 

# ...,. I.D. 

# • U.t 10 7.sA 

### 17.'

10



# ,

# .., 10.1

1. 73.9 21.1

10 61.0 10.1

10 70'.2 1'0.1

10 31.0 10



## •••• 31.' 10

.t.' U.O 10



## .5.'· :17.7 10

31.2 11.7 10 602 •• 1:&5.7

10 ;1140.t 10

53.0 It.7 1.

:u •••• :&6.3 10

C4.1" 2C.t 10

"3.a as.C 1.

IIIt.a· 11O ••

1. 30 •• 1.

## 17." 11.2 10 140.1 31.1 10 6'.7 l'.a 101:1.7 27 •• 10"'.S ala.' 10

fREGULATORY/REPORT
- 7890DA Y INHALATION TOXICITY STUDY INTHE RAT WITH RECOVERY PHASE


### TABLE 12 - INTERGROUP COMPARISON OF MOTOR ACTMTV

IIID' S'IOU1' GIlL!' "upt IIlr,ponz';J Coaoeatrat:l.oa 

# 'n-' l"IIiaLBs o U:oatnl) 1110 300 1300 •••••••••••••••••••••••••••••••••••••••••••••w........................................................ __ Ilbet•• 1-5 

# ... 71.1 ".1 66.2 72.1 Ilbet•• I-le B.V. 

# • MUll 7.6 10 

### n.I 11.D tel

73.1 1l.2 10

11.3· 13.0 1013.0· lU.:II.t.. 11-15 S.D. 

# •

# - 11.1 10 711.7 7.3 10

n .• 11.3 10

71.6 ••7 10

51.5 Ilbet.. 11-20 Ilbat•• Zl-u lU.:II.t.. 26-lO S.D. 

# •

# -­ ••D. 

# • MUll 8.D. 

# • IIIWI U.7 10 72.0 U.O

10 65.0 27.1

10 60.S 17.1 10

n.o 23.'

10

IL.O n.?

10

tlD.3 10.2 10



## •••• 16.2 10

112 •• 26.2 10

61.7 20 •• 10

11.1 ".0 10

f ••• :al,6 10

It.l Ilbat.. 31'l5 lU.:IIat.. 36-40 Idnt•• 61-411 IIIbllt..... ·50 s.D. 

# • IIIWI S.D. 

# • DAB S.D. 

# •

# ..... S.D. 

# •

# ... a•. '­ 10 

# -n." 36.1

10 U .• Sll.'

10 "'.3 35.1

10 "'.1 3 .... 10

SD.' 37.l

10

U •• 42,'

10

61 •• 16.' 10

71.6 23.3 10

U.7 21.3 10

S5 •• .n.7 10

",2 22.7 10

10.3 27.7 10

".1 2S.7 10

U.2 23•• 10

II
.... 13.7 10

72.1
0ftZ'a11 (1-10) S.D. 

# •

# - 8.D. 

# • 11 •• 10 "'2.3 13S,O

10 t •• 7 10 623 •• 217.7

10 20.7 10

602.1 1 ....

10 11.6 10

"".6 1",2 10

IREGUlATORY/REPOET
- 7990 DAY INHALATION TOXICITY STUDY IN THE RAT WITII RECOVERY PHASE


### TABLE 13 -INTERGROUP COMPARISON OF HAEMATOLOGY

IIUII SRM lIIIOO'nR'I "-..t: Coaout:r.u_ I..... ' 1111L118 OeCOJlt:n1) 100 .0 100. OeCoBtzol.l 1000 

### ............................................................................................................................... aa-oa1o1tJ.a e./41, U.I 14.1 14.1 14.6 14.0 14.11 S.D. 0.11 0.5 0.5 D.4 •• 4 0.4 

# - 10 10 11 LO 10 10 

# •

# .... _t_lI:lt: 0.<&2' 0.0'**~."I** 0.U4 0.421 O.UII B.D. 0.019 0.021 0.'20 1.015 0.014 0.014 10 10 LO 10 10 

# -- l' 

# •

... 81004 Coaat (zlO--12/1) 1.1t 1.3' •. 22 I.U 1.11 1.57. B.D. 0." 0.:" 0.14 1.3:1 O.U O.a? 10 10 11 LO 10 10 

# • lIMa Ul1 .01_ (f:, 

# .... 51.4 .to.1 10.t 51.0 52.2 81.4­ S.D. 1.4 1.4 1.2 D.' 1.S 1.0 10 10 11 LO 10 10 

## •

.... Ull ---.lolla (PIlI) 

# - 17.1 

## 17.' 17.1 11.0 17.t 

# 11.' S.D. 0.1 0.1 D. .1 D.' 0.4 0 •.1 10 10 11 lO 10 10 

# •

__ Cell**~o'b1a** C::O_trat:J.aa. (,/411 

# ..... lie. 7 34.' 34 •• 31.3 32.1 32•• B.D. 0.' 0.1 0.' 0.1 1.3 1.1 10 10 U to 10 10 

# •

..U_l.OGJ1:_ ecrut (:11110.-1/11 a.1l1 2.11. 2.230 2.3" 2. ItO l.saO B.D. 0 •.181 0.311 0.31' G.346 0.334 o.a:lll 

# - 10 10 U to 10 II 

# •

/REGULATORY/REPORT
- 8090 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 13 -INTERGROUP COMPARISON OF HAEMATOLOGY

IIA:JI II'l'Im1: UCOYIIU'. -..t; bpoeu. c.m-b'aU_ (n-) IIUoa o(Control.) lOt no" 1800 O( Coatroll 1000


### .....................

# -.--.......................**-.~-** 

# ..

# - ...

# --................................................................... 

# ". '31 Plat;elet; COGat (zIo*.'/l) 1f1 ,U ,n 'S! 

# • 

# .....

# - '2 10. lID 

# " 102 '2 10 10 lG 10 10 10 Wllit;e B1004 Ce11 COGat (zIO••'/l) JOWl 5.'0 1.13 5.n 5.15 6.11· '.'0 8.D. 0.10 o.'! 1.2' 1.11 1.n 0.7' 10 10 U 10 10 10 

# • -.at;ZOpb11 coaat (zIO•• "l) 1.31 1.112 1.75· 1.1'·· au 

### 1." 1.U S .... 0.27 0.3. 0.14, t.11 0.'6 0.20 10 1. 1( 10 10 1. 

# •**~.** coaat (zIO""1) IIIWI 3.'0 31.72 6.1.1. 3.315 3.54 3.01 a.D. 0." 0.6' 0.11 '.65 1.01 0.50 10 1. lI: 10 1. 1. 

# • lIDe.c>Oyte Comlt (al.... "1) O.UI •• 1031· 0.117 0.116 '.1. 0.1110·· S.D. 0.063 0.02' o.cn 0.'" '.0116 0.016 

# - 10 1. 1C 10 10 10 

# • _iIlophi1 coaat (zI' ••',].) au 0.160 0.1" 0.1116 0.135 0.U3 O.ln B.D. •• 01lS 0.". 0.Cl3 ....0 0.056 0.061 10 1. IC 10 10 10 

# •**~1** coaat (al0••'/1) 0.026 '.011 0.026 0.026 O.Ott O.fll 

# ..... 0.'" O.OOt '.C12 0.'13 0.001 '.012 

# - 10 10 'lC 10 10 10 

# • Luge UDd.......oo4 Cella (zI'''''l) lIIWI •• 071 0.066 0.0711 O.OU 0.011' •• 1011 B.... 0.021 0.Oa4 O ••U •• 021 0.031 0.212 10 10 1. 10 10 10 

# • .l"Otu-blll '1t.e (0) 

## 11.' 111.4 111 •• 11.5 16.3 U •• B.D. 0.7 0.5 0.' ".1 0.5 0.' 

# - 10 It 10 10 10 JO 

# • AotJ._too4 raruaJ.**~boJil1utill** 'It.e le) 111M 

### :aG." 26.' 

## 211.' u.a 

## at., 25.4 S.D. 1.2 1.2 2.' t.1 1 •• 1.3 10 It 10 10 10 10 

# •
1illGUIATORY/REPORT • 81

## ro DAY L\THALATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE


### TABLE 9 - INTERGROUP COMPARISON OF GRIP STRENGTH (g) • FOREUMB

III.IlI 8'I'IJD'l Clm.!' t'argtlt CoIIoomtraU.. (PIlI) o (Coatro].) UO 300 1100 

### .........................................................

# - .......................................**~-** 

# ..­

..t .. IIIIIWI lUI "I 18111 

# .$. S.D. "9 a!:! 3110 aOI 10 18 10 10 

# • J'eIIIIl•• IIIWI !III

# $ UI 1013 I,. S.D. :zao 110 2'9 212 10 111 10 II 

# •

IREOULATORY/REPORT
- 7S

## •••


# •

•• 90 DAY INHAI..ATION TOXICITY STIIDY IN TIlE RAT WflHREOOVERY PHASE


### TABLE 13 -INTERGROUP COMPARISON OF HAEMATOLOGY

DOl 8'IUD'l' I:IICO¥D.1' 'l'1Ugtl't**~t:nt10111 (~)**  I'IIIIUoIIS o (ca..'tml) 1Il0 tOO 1000 ICCoatr:o:', leOli 

### ............

# --._................................................................................................................ ",-,10• .b (11/41) 

# ..... 1 .. 4 14.' U.7 14.' 

### u.a .14.1 B.D. 0."**o.~** 0." 0.5 

## '.1 0.5 10 10 It 10 10 10 

# • _toar:it au 

# ..... 0.'" • ...0. 0."0' '.Ul 0 ... 2. ••D. 0.014 0.011 '.no '.010 o.ea, 0.017 10 10 U 10 10 10 led**.~** Call. CoIIIIt (.10•• 12/1) 

# .... 7.55 7.5' 7.61 7.65 l.n 

## 1." II.D. 0.21 0.3J 0.:10 0.31 I.U •• :13 II 10 U 10 10 

# • 

# I. •

...... Call. "01_ (fl, 

# .... tn.o 

## lIZ.' 

## lIS.' 53.S 

### "".3 54.' S.D. 1.0 0.1 1.2 0.7 0 •• 1. 10 U 1. 1. 10 

# •

_ e..u.**~o'II4A** (PI) 11.3 11.0 11.3· 

# .... 11.' ".1 "'.1 ••D. O.S 0.1 0.5 

# . ... '.lI 0.11 10 10 1-1 10 10 10 

# •

...... Call. "_1I1obs... eoa_t_tloa (1/41, 

# .... 31.0 36 .... 1I.0 3S.'I' 31.' 33.11· ••D. 1.!11 1.1 '.7 '.11 0.7 10 10 It 10 10 10 

# •
••t1Ga1oa7t_ Count ,al0••'/l, 

# .... a.•

# 'o 2.170 :l.310 2 .....• :a.JOO 2.100 ••D. 0.610 0.1" ' ••2. 

## '.,n 0.516 0.374 10 

# . I • It 10 It 10 

# •

'REGULATORY/REPOR.T . 8290 DAY INHAlATION TOXICITY STUDY IN THE RAT 

### wrrH RECOVERY PHASE


### TABLE 13 -INTERGROUP COMPARISON OF 

### HAEMATOLOGY

IIUJI II'!UD1' UC'OYJIIJ' '1'U:9It lI:qIOau. coa_tratt.oD 

# C..-, I'IIIIILIIB**o,coat.J:()~)** lOG 300**~OOO** I(Coatnll 1000 

## •.........**~.-----** 

# .....

# ----........-................................................................................

# -_..........**~1at.l.t** caaat (al0"./1) '11 '66 1006 '22 '21 .76 I.D. tI 121 12' n 116 

# .. 

# - :I 10 10 10 10 10 10**~t** ••1004 0al1 Coaat Cal0••**'/~'** au 1.37 6.63 3.35· 6.0' 3.12 3.62 I.D. 1.06 0." o.n (.16 0.'3 0.6. I l_ ID 10 !D 10 10

__troplU.l Ccnmt: (alO"'/1) 1.01 1.0S 0.63· 0.'1 0.6' 0.77 I.D. 0.35 0.:17 O.U Ci.22 0.16 0.34 :I 

# - 11 10 10**~o** 10**~O L~.**  Ccnmt (al0"./1) 3.11 3.11 2.13 2.81 2.5t 2.42 I.D. 0.81 0.60 0.'0 (i.'2 O.H 0.61 :I 

# - 10 10 10 :0 10 10

..........,.t. Ccnmt**(al0"'/~)** IIIIU' 0."1 0.0'5 0.0"· 0.010 0.011 0.077 I.D. 0.03' 1.0:lll 0.112 O.IU 0.020 0.021 II 10 1. :0 10 10 

# • 1I:000iaopiaU caaat**(a10"'/~)** 0.11" 0.0'1 0.070 I.Ot! O.UI 0.1" I.D. 1.022 1.031 I.Qu 0.11' 1.017 0.023 

# - :I 10 II II :0 10 11 B..opbll coaat (xl".'/I) 0.134 0.033 0.023· 0.028 0.031 O.las •• D. 0.018 1.008 0.017 0.115 0.012 0.016 

# - 10 10 10 :0 10 10 

# • L-.. uaatdlwwl eeJ.Ja (al0•• "I) 

# .... 0.1.3 0.0&1 0.036 0.03' 0.050 0.041 I.D. 0.011 

## '.00' 0.016 •• 016 0.0:10 0.01t 

# .. 10 10 10**~o** 10 10 pntlu:oal:llll 'l'S- Ca) 

# .... 11 .• 16.0 16.3· 16.1 16 ••**l'.~** 1.0. 0.1 0.5 0.6 1.5 0.' 0.7 I 10 10 10 :0 10 10 AoU.vat.4**IlIrtl~** 'J.'Ir.I:oa.boplaath 'f1_ 'a' 2'.2 22.' 23.' 23.' 25.0 :15.2 1.0. 1.1 1 •• 2.2 1.1 2.1 2.3 

# - 10 II 10 :0 10 10 

# •
REOUlATO:tY/REPORT . 8390 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECO\'ERY PHASE


### TABLE 13 -INTERGROUP COMPARISON OF HAEMATOLOGY

JIJIC098'1'
- bOl
.......11 IIIIH 4" 

## "..,..t: lIQOlI1Ih eoao-u.t1aa**.~}**

O{CGat_l) lOGO 

# ......

# _-•.......•...•......

# - ..........................................

## -........................ calt. Bloo4 c.1l Coaat (_IO--./l)
IIalAIa 

# - S.D. 

# • lI.n 

# . ... • 4.111 0.7' 10 1'-.1 .. 

# .... S.D. 

# • 3.1:1 11.13

10 3.U 

# II." 10

tREGULATORY/REPORT
- 84It1

# ~ 

# i**~** E**~**

# ~

# ~ 

# =

# ~ g 

# i §

# ~**~** Q**~**

## ~ 

# Iii 

# - '2 w 

## :z: 0 

# g - z ::I CJ 

# § 0 

### fA 

## u.. 0 Z 

### 0 tn 

# - 

# i :I 

# 8 a.. ::)

# ~ <!J £C

# ~ 

# -

, 'lilt T'" 

# !**~** 

# I
I ; I I 

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# .. • I**~** ..; 

### II 

# ... 

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...... 

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## • 1 

# .. ... .; 

## • II! 

# .. :10: 

### t=0l "", 

# .. ..**~l** 

# ... '1
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# .....

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## ... 

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# ..**~=**

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### 90 

### VAYlNHALATlON TOXIcrrY**~y** 

### IN 

### TIreRAT Wrt'H RECOVERY lHASE.


### TABLE 14 -INTERGROUP COMPARISON OF BLOOD CUNICAL 

### CHEMISTRY

lOtI IIft'I)'J'**~** hlptr**~tnU_** (...) D10lAJ «UOI4Iots-l.) 1010 )00 1'" '(CoIltNl) 10t0 ••

__.............. .....**_~** •••

_____ ...._ ....**~,** ..............._ ..... ......_._.. _ ......... _ ............**_~._** •••**~M** ...... ... :rUMllo a.lutU"61 1..:1/1) 

# ..., 1.01 

### a.'l 2 •.11* l.U 

# :t." a.sa 

# II.". 0.22 o.::.a 0 .•1 

## '.n I.n 

# • 

# ..". ;ao .10 ;&0. 10 10 10 •.z.u.a**tr.t.l~** t_1./1} 1.02 1.0' 1.20 1.11 1 ••\1. s ... (f• .It o.lJ 

# ..,. 0 • .1.1 

### .1." 11.11 0.&1 

# - 10 111 1t1 18 1. 

# • ,,:r.- NIhil 

# .:UtnII&. <_1/l) 

# ..... 1" 

### :t.n 

### :I." 3.'1. :t. ::l'1 3,lS .).41 III.D. o.u •..n 11·11. 8.75 O.d 

# It.". 10 11 111 111 10 J" 

# • 1'1._ IoJJIteUU**~t:** ... CD/1) IdIIlf 1N 111 :US l • ., ..U 

# ,,. ••• II.EI. .I' 1" 11 2J H 

# • 

# 1. l4J 10 111 10 i' l'lMIM.**~-.I** ..tAIaJ'l**~~** (Ull) 

### 7.' 

## ".1 

# ••• 'I.'**,.~** 

# "'.). 

# ..**~.** 

### 0.' 

### 1.'

.... :1 1 •• 1.1 

## I., 

# - D lit 1. 10 I' 

# • 

# l'**:r~** &1
...., AlU.lMltr
...tow" (3/1) 

# ... .'.2 •.a.3 Uf•• 

## ".CI U ••• '3.7 ••0. 

# I.!l.' ;10 •• -41 •• 

## H.' I., ,. 

# • 14.' l' 1. 10 111 1. .11" "1UIIMo.**"~1:' ~_.**  (nTll.l 1 •••• IOT.e 1 .... ' lOt•• Ut
.... t04•• •• D. 21.2 I.••• II .• 

# ... .3.' II,' 

# ".1 

# • 

# ... IJ) 

# 1. 1t U 

### aD



### !REGULATORY/R.EPOltT**~86**

## •••• 9[) DAY INHALATION TOXICITY S11J])Y IN 

### nIB RAT WITH REOOVERY PHASE


### TABLE 14 • INTERGROUP COMPARISON OF BLOOD CUNICAL CHEMISTRV

IIlI.D 8I'V.DJ' UOCWDr hq.t bpoll1lN caa-uat:l._ [,.., IIlI.LII o[Coatrol) 100**30~** 1000 O(Coat"l) 1000 

# .-......

# -.--.............. 

# ....---.---.-.-.-

# .......•
-........••...

## --

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# • .1_ Bo41_ (_111) 141.6 1&1.' 141.1 lU.3 141 •• 142.3 

# ... S.D. 1.3 1.0 1.e 2.4 1.4 1.7 10 10 10 I' 10 10 

# • .1.- PotJul.:I._**(~/1)** IIIIWI 5.3'**~.OO** 4.'6 5.05 4 ••0 

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- 87

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# --;)() DAY INHALATION TOXICITY STUDY 1N TIlE RAT WITH RECOVERY PHASE


### TABLE 14 • INTERGROUP COMPARISON OF BLOOD CUNICAL CHEMISTRY

1IiU••_ UCOYIIIU !la:qet ..... --.no**~t,...tioR (~)**  r..u.II8 O(Co.trol) 100 300 1000 UCOIltrol.) 1000 

## ....•....

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# --...**~.-.-** 

# .....•..

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# - 10 10 10 10 10 10 

# • .1 .... !lrlg1rOerl4ea (..aI/Ii G.75 0.'0 0.76 0.72 0.1117 0.74. B.D. 0.27 0.2l 0.l3 •• 16 •• 26 0.23 :1:0 10 U 10 10 10 

# • ']a.-. !lotlll. 8U1rUh (-.1;1) III.U 

### '.41 3.011 3.07 3.14 3.27 3.66 S.D. 0.'2 0.31 0.71 0.60 0.33 O.u 18 10 I 10 10 10 

# • ']a.-. IU,b.Uae l'boIIpb.&t_ \IU/l) 

# ..... 1011 111 116 102 lOll 107 S.D. It, 17 U 20 D 10 18 10 U lO 10 10 

# • 1P:a- S--glata.:rl**'I'raa.~u_.** (IV!l) 

# .... '.5 7.2 6.1 

## '.1 7.1 '.1 S.D. 0.1 1 •• 1.2 1 •• 0.' 0.7 10 II U lO 10 10 

# • 1'1_ lUu.1a• .&II1a.tr_.ferU6 (IU/il DIll 73.0 71 •• 70.0 

# .... 73.' 

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# • .:a-**~.t. :aaaotr6AlJ~U'_.**  (IV!l) 

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## 33.' 37.0 

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# •

REGUlATORY/REPORT • 8990 DAY INHALATION TOXICITY STUDY IN THE RAT WITII RECOVERY PHASE


### TABLE 14 - INTERGROUP COMPARISON OF BLOOD CLINICAL CHEMISTRY

II.ID ftUI)'f aeoYIU !'apt IIIIpon.1:oa Caaoat_tt_**(~)** PllllaYI O(Coat.rol) leO '00 1000 0 Coatzol) lOGO 

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## ...•...•••-_........................................................ "a- cr..tllle Ittaue (IV/II 

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## 112.' 20.) 

## ".2 13.' 14.1 at.1 10 10 10 10 10 10 

# • •a- SOti_ (_1/1) IIIDII UL.' L.2.' 142.2 142.' la3 .• 1&2.7 I.D. 1.2 0.' 1.'7 1.3 1.9 1.' 10 10 10 10 10 10 

## • "a- Pot:all.lQ111 (_1/1) IIIDII '.22 •• 111 

# .... ..33

.... 1 •• 79 S.D. 0."" 0." 0.45 0." 0.'5 0.77 10 10 10 10 10 10 

# .la_**~or14.** (_1/1) 

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# • .a- Cal.cd_ (_1/1) 

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# • .a- l'IIo.pbol:'llll (_1/11 

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# •

REGULATORY/REPORT • 9090 DAY INHALATION To.XICITY snJDY IN THE RAT WlTII RECOVERY PHASE


### TABLE 14 • INTERGROUP COMPARISON OF BLOOD CUNICAL CHEMISTRY

UICO'IBIIY • bol1l4hSl -.l.u .0 _4 n 'l'...,..t bpo•• <:Oa_tzaU_ (we)**O(coa~l)** 1000 

## ..........__..........................................

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# •

'REGTJIATORY/REPORT
- 9190 DAY INHALATION TOXICITY srtJI)y IN THE RAT WITH RECOVERY PHASE


### TABLE 15· INTERGROUP COMPARISON OF URINE CUNICAL CHEMISTRY

D.D 8'!11D1: ItIICO'ID1

...."..t a.po__ eoa-trati_ ( .. ,



# - O(CGah'Ol) 100 300 1000 0(Coatral1 1'0' 

# ...

# ----......

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# .......-

# ....

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# • 17ra. SpNU10 4IA'II'1ty 1.011 1.023 1.02. 1.024 1.02. 1.0:12· B.P. 0.010 0.000 0.0" 0.012 

# ..... 0.006 

# - 10 10 10 11 10 10 

# • Vrbe
.. 

# ..... 7.07 7.11 7.2' 1.111 7.04 7.0' S.D. 0." 0.21 0.33 0.35 t.60 0.25 10 10 10 11 10 10 

# •**I~** .. vr1aa Vol_ (101) 16 •• U.20 14.75 16.50 11.00 11.411 •• P. ..20 

## •.3' 11.01 ••:17 1.3' •. n 

# - 10 10 10 It 10 10 

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# - 10 10 10 It 10 10 

# • 

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# •

/REGlILATORYIREPORT - 9290 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

## GLOSSARY FOR TABLE 16

NEG = 

### negative

The following represent 

### an arbitrary scale ofincreasing presence of 

### a urinary parameter 

### as measured by 

### a oolour change ofthe relevant portion ofa test strip.

+ ++ +++


### The number against each analysed level denotes the number ofobservations.

:/REGULATORY/REPORT
- 9390 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### TABLE 16 -INTERGROUP COMPARISON OF URINE DATA ...QUAUTATIVE TESTS



## ..**I~'--** MALES Target Exposure Concentration (ppm) Main Study Recovery i O(Coatrol) 100 300 1000 O(CQDtrnl) 1000 Protein

# ~CE! 0 1 0 0 0 0 3 4 4 6 7 4
, 7 5 6 4 3 6 

### ++ Glucose • NEG 10 10 10 10 10 10 Bilirubin NEG 10 10 10 10 10 10 Ketones NEG 3 3 2 3 S 1 \ TRACE 4 6 7 

## I 5 5 7 

### + 3 1 1 2 0 2 i Blood NEG 9 9 9 9 8 9 TRACE 1 1 0 1 

### 2 1 I 

### + 0 0 1 0 0 0 I Urobilinogen 

### 3.2 10 10 9 9 10 10 

## I (umoJ/l) 16.0 0 0 1 1 0 0

FEMALES Tarset Exposure C-O:Dt!.'.entrlltinn (rpm) Main Study Recovery O(ConIroI) 100 300 1000 O(Coolrol) 1000 Protein . 

## I NEG 

### 4 4 3 4 7 6 TRACE 5 5 3 3 3 3 

### i+ 1 1 4 3 0 1 Glucose NEG 9 10 10 10 10 10 :­ TRACE i 1 0 0 0 0 0

... 

## i BUlIUbin NEO 10 10 10 10 10 10 i Ketones • NEG I 10 10 , 10 10 10 10 I Blood NEG 8 9 10 10 10 10 TRACE 2 1 0 0 0 0 Urobilinogen 

## I 3.2 10 10 10 10 10 10 (umoJ/l) , I

IREGUlATORY/REPORT
- 9490 DAY INHAIATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE


### TABLE 17. GROUP RANGE URINARY SEDIMENTS
MALES Tar.. Exposllre ('.I)l1N'.ntrAtlon (ppm) Main Study Recovery O(Conlrol) 100 300 1000 O(Control) 1000 Number 1 0 0 0 0 0 examined Sperm 

### NEG 0 

### ++ i 1 

### Cryshll 

### NEG 0 + 1 Casts 

### NEG 1 Red blood cells 

### NEG 1 

## I White blood cel1s 

### NEG 1 Epithelial ceJls 

### NEG 1 I

1
! 

# IFEMALES Target Exposure Concentration (ppm) Main Study Recovery O(Coutrol) 100 300 : 1000 O(ControJ) i 1000 Number examined 2 0 0 0 0 0 Sperm 

### NEG 2 Oy);:ta! NF.G 2 I Casts 

### NEG 2 

## I Red blood cells 

### NEG 2 W

bite bJood cells N.I:!:O 2 Epithelial cells NEG 2 

### NEG 

# = Negative 

## + 

# = Very 

### few (lor 2) 

### in some fields ofview. 

## ++ 

# = Few in most fields ofview. Only urine samples 

### with cloudy appearance were examined (one control male, two control 

### females).**~GULATORY~RT** - 9590 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18· 

### INTERGROUP COMPARISON OF ORGAN WEIGHTS

IU..D 8'JUII)Y 1IIrCOVD'f**"a:q.~** II:lqIoII'IIre co-uatJ._ (ppa) o C

CeatnJ.) 100 100**l'O~** O(CciGtzool) 1000 

# -.----...

# - .... .....................................

# - .......................................................**----~** --.:r. GL.IIIID8 DUlS I'UIdIULl**~lght** (IJ) IIIWI SlO.3 an •• 102.1 IU.2 

# ..,., 

# ..... a.D. u .• 32.2 .'.2 3 •• ' 15.1 3'.7 10 10 10 10 10 10 0J:1IIIIl Welgbt C 8} 

# • IIIWI 0.06. 0.0.1 0.065 O.Oill 0.063 0.066 B.D. 0.006 O.ooa '.00' 0.0" 0.00' 0.010 10 10 10 10 10 10 

# • 0J:1IIIIl to BoqwUgbt hUo (.) IIIWI 0.013 0.012 0.012 0.013 0.011 0.012 B.D. 0.001 0.002 0.002 0.0'2 0.001 '.002 10 10 10 n 10 10 0,..... lIUgbt Mjutel 

# • Poz IIo4ptolfbt 0.064 ••061 0.064 0.065 0.063 0.066 I'IIIIII.LD !'ea1aal.**~"'t** Is) IIIWI 317.' 30••• 300.11 2".' 111.2 303.3 I.D. a'.l 15.3 11 •• 21.7 22.' la.3 10 10 10 10 .lG 10 oz.gaa ..:1...t Cs) 

# • 

# .... 0.090 0.0" '.011 0.0"· 0.017 0.'71 S.D. 0.0'. 0.011 0.010 o.oa 0.011 0.00' 10 10 10 10 10 Oqua to**~l"'t "~1o**  

# • U) 

# l' 0.029 0 ••2. •• on '.027 0.021 0.'36 S.D. 0.002 0.003 '.003 0.0" 0.003 0.003 

# - 10 10 10 1. 11 1. 

# • Orpa Ikdght Adj
...tel roz JIod:rwaitbt 0.0" 0.0" 0.017 o.o.a 0.017 0.071

REGUlATORY/REPORT • 9690 DAY INHAlATION TOXICITY STUDY IN THE RAT WrrH RECOVERY PHASE 

### TABLE 18 • 

### INTERGROUP COMPARISON OF ORGAN WEIGHTS

IIUJI 1mIDJ: uccmarr 'I'Ilr1rel: DpD.u:n eo-tnUoa (ppI) • (CQllt:J:ol) 100 300 1000 o(CODt:J:Ol.) 1000 

# ......._-_.....----•...........•...

# _-.......

## -................................................................... IlIAD IIar.D l'e.aa:.DIll JIoc'I.yYe.LgJal: (G) 

# ,

# .... IIII:U 511.3 au .• '02.1 553.2. '45.' B.D. 21.5 n.2 "'.2 3 .... ,n.l ".7 :0 10 10 10 10 10 Orpa
.....l1li1: (D) 

# • HUll 2.1:1 2.12 2.12 2.12 2.l2 1.15 S.D. 0.07 •• 10 0.0. 0.0. 0.07 0.01 :0 10 10 10 10 10 

# • Oq.. 1:0**~gbt:** Ral:1o (') 0.42 0.43 0.40 0.42 0.19 It.<10 

# .... S.D. 0.03 0.02 0.04 •• 03**0.~2** 1t.03 :0 10 10 10 10 10 Oq........111: ....:I_te4 

# • :rOIl ....,.....gbt 2.12 2.13 2.12 2..12 2..12 :1.15 1'IKlWI' 'l'era1DaJ.**~gbt** (fI) 

# ..... 31'.' Jal.4 300.5 2 •••• 311.2 'OS.3 II.D. 2(.1 11.3 

### 16.' 21.7 22..7 12.3 10 10 10 10 10 10 

# • 0.,... .e'lII1: Is) 

# ..... 1.9' 1.n 1.'1 1." 1." 1.n B.D. 0.07 0.07 0.03 0•• 1 0." 0 ••' 10 10 10 10 10 10 

# • Orgu to JIOd:pa1gbl: .. 1:10 (') 

# ..... 

# . .... 0.63 0." 0 ... 0.'3 •• 15 B.D. ••04 0.03 0.04 0 ••' ' ••5 0." 10 10 10 10 10 10 Orga .. ;1l1li1: 14ju.te4 

# •**:ror~t** 1." 1.97 1.16 1._ 1.97 

# I.',

REGUlATORY/REPORT . 9790 DAY INHALA.fION TOXICITY STUDY IN THERAT WITH REroVERY PHASE 

### TABLE 18 .. INTERGROUP COMPARISON OF ORGAN WEIGHTS

KUII I'I'UDY DCOYD1 'I'II.r1Jet 1brpO.a.re Co_t:at1oa (s.-) o (C••i:&'Ol» 100 300 1000 o (Coat&'Ol) 1000 

# ........_ ....................................................................................................... UllIlmODa 1MLJ8 ftZII.1u.l 1I04pe1g1ll: {g) 

# .... 11l0.3 4111.' 1129.' 502.1 lIII3.2 UII.' B.D. 

# ..

# .. , 312.2 

## ".2 

# ,

# ... 31.1 39.7 10 10 10 10 10 10 

# • ora- "1gbt (gl 1.311 1.lII 1.'6 1 •• 1." 

# I." S.D. 

## '.11 0.17 0.10 0.115 G.l' 0.12 

# -- 10 1. 10 10 10 10 

### ora- to ....,..1
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# ...- '.2.7 0.21 0.26 0.Z7 a.2.f 0.2.' 8.D. •• 03 8.03 0.04 O.M 11.02 0.03 10 10 10 10 10 10 ara- w.igbt Wj_tet 

# •**I'or~** ...t 1.3' 1.311 1.317 1.313 1." 1.111**REGULATORY~RT** • 9890 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18 - INTERGROUP COMPARISON OF ORGAN WEIGHTS

Il&JJI I'IVDI' DCO'I1IIII 'l'U'g4It 1:a1IO- CoJiautmtioa**I~) OCCollt_~)**  1.. ,..**10~.** 0(Coatzol1 1000 

## ............_----.-_.--.----._-------

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# ..... o.u.r 1IIlIU8 BcMI:r-.1lJllt '.1 

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..... '.1 

# • IIIIAIII 1.'07 1 .... a 1.5'" 1.01'7. L.UO 1.5" 3 •• ' S.D. a.133 0.171 0.134 O.tl6 1.11' 0.213 10 10 10 10 10 1. OJ:'VUl to lI04ywU
....t :!aUo 

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# .... 317.' 3 ••• lO•• 1I a.••• '11.2 303.3 ' 8.D. :aO.l 11.3 16 •• 26.'1 U. '7 11,.3 1. 10 10 1. 10 10 Oli:gm hlpt (.1 

# • J.O$O 1.010 1 ••1G 1.U' l.OSO G.'" 8.0. 1.110 • •••5 0.0" 0.15' 1.1.' O.OU 

# - 10 10 10 10 10 1. Oli:gm to Bo4pe:lpt hUo

# •C.) 1.333 o.no o.n. 0.U2 1.331 •• 31' •• D. I.OU 0.030 0.01' 0 • .,1 1.022 0,013 

# - 10 10 10 10 tG 10 

# • Qrgaa ••**1~** &4j••t.1 Par lIocJ.7wa;18bt 1.011 1.00' 1.0a, 1 • .,2 1.0IS 0.'01

'REGULATORY/REPORT
- 99

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# ....**-:~. ~~O**  

## •**~N'"** 

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## ...



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# I' ci.: 

# -I' ••


# .. 

# , .. .. 1 

# .. .. f, 

## = 

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# i
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# I , .. 

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# I If 8



## .... 

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# S ::l

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# i a: CI 

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# f!! :c c" 

## iii 

# 3=**~** CJ IX 

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# 5 en 

# - i :IE 0 0 II.. ::;) 

### 0 

## i! I CD 

## ..­**~**

# ~ 

# ...;)() DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18 - INTERGROUP COMPARISON OF ORGAN WEIGHTS

1IloD: 1'l'UD1: lIBCOYDT 'l'argat: lIKpotIun c-t:r&t1_ (Pc-' O(Cat:.rol) 100 300 10..**OCcoat~l'** 1000 

# ...

# --...**~-** 

# ..

# ---..............

# ---....

# - ..............

# - ............................................................ LnD IIAIU 'l'eDI:lDaJ.**lIo(~illht:** ell) NDII. nO.3 Sat.' loa.l 513.a 5U.6 

## 41'.' S.D. 2',!! n.a**~!!.a** 34.1 35.1 3',7 10 10 10 10 10 10 Orvaa .••Sgbt 

### ell' 

# • IIILIII 17.7 17.2 17.3 1'.0 n.3 1 •• ' S.D. 1.1 1.a 2.3 1.5 1.1 1.1 10 10 10 10 10 10 Orvea to BoCywei.-t .atio 

# •

(II BIll 3.5 3.5 3.5 3.' 

### '.3 3.2 ••D. o.a 0.1 0.3 0.1 '.2 o.a 10 10 10 10 JO 10 

# • Oqaa we.1gbt Ujut'" rllll IIOd;rwe1tbt 17.1 

### 17.' 1 •• 1 17.' 

# H.'**17.~** I'IIULU h%a1IIa1**~:I.flllt** e.) IIILIII 317 •• 301.4 300.S 2M•• 111.41 3113.3 S.D.**~0.1** 15.3 16.6 al.7 22.7 12.3 111 111 10 10 III 10 011IPm ..igbt «II) 

# • BIll 11.0 111.' 10.1 '.7· 1•• 6 111.1 S.D. 1.3 1.0 1.1 1.S 1.1 0.' 10 10 10 10 10 10 Oqu to**~iglat** htio 

# •{t, 

# ... 3.5 3.1 3.5 3.'**J.~** 3.3 S.D. 8.2 lI.a 11.2 11.1 

# ..**~** ..2 10 18 111 10 111 10 CII:'IIID 1fe1.-t .ujan... 

# •**rD~ ~Qb.t** **,..~** 111.' 10.1 111.1**1t.~** 111.3

lREGUlATORY/REPORT
- 101

# • 

# • 90 DAY 1NH.ALATIONTOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18 .. INTERGROUP COMPARISON OF ORGAN WEIGHTS

IIIAI'8 8'IVM. ac::o¥a1' lraJ:lJ4lt ...,..an Coac ..uaU_ (JOPI) o (coat::rol) 100 300 lGOO O(::aatrol) 1000 

### --

### ..........

## -................................................................................................... 

# 1._



# ....**'I'~~igbt(g)** IIIIWI 1111.3 4.,., 'U.I 501.1 553.2 !l45.6 S.D. a..11 32.2 .a.2 U.6 35.1 st.'7 10 10 10 10 10 10 orgu ·.at....t Ie) 

# • IIIlIAIr 1." 1.1' 1.12 1.15 1.16 1.U B.I). o.a. 0.31 0.20 0.11 0.16 11.11 10 10 10 18 10 10 o.:pa to II04pe1gbt 'atio 

# •(tJ 101M 0." 0.3' 0.36 0.37 O.:at o.ss S.I). 0.011 0.0' 0.0. O.OS 0.03 11.03 10 10 10 1G 10 10 lfat....t Mjutel 

# • I'o...**~t** 

## 1." l.n 

# I." 1.1'7 

### :." 1.'1 

# ........ ftniDal lIo4peipt [u l 31'7.' 306 •• 300.1 2" •• 111.2 'OS.3 8.D. 20.1 16.2 16.6 26.7 22.7 U.S 

# -- 10 10 10 to 10 Orpa l'atgbt (IJ) 

# .... 1.4" 1 .... 1.U 1.U 1.41 1.33 8.D. 0.21 0.15 0.111 0.11 0.11 0.11 10 9 10 10 10 10 0rgIIa to lICMI:peigbt .at10

# • ('I 0 ••' 0 .... 0.11 0.'0 G.&5 G.44 •• 1). 0.0" 0.05 0.05 0.'. 0.03 0.011 

# - 10 9 18 10 10 10 ort- lfatgbt A4j
...t .. 

# • 1'0... JI04IIJveipt 1.38 1.4' 1.5.... 1.45**~.3'** I.SS

REGULATORY/REl'ORT • 10290 DAY INHALATION TOXlCITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18 - INTERGROUP COMPARISON OF ORGAN WEIGHTS

!lUll 8'rUDY acovar 'I'lI.'qet CoaoMtZ'llUoa (IPI) O(eoatrol) 100 300 1080 O(c:o.tzoolJ 1000 

### ..............................

# ----....._-....................................................................... 0'IIaU1iII

........a 'I'..tul. lI<Idpe.t.aIlt (If) 117.' 30'.4 300.S 2M •• 311.3 :S1l3.3 a.D. 20.1 15.3 

## 16.' 2'.7 12.7 12.3 

# -- 10 10 10 10 10 10 Oqu 1NI:l8l:t (II) 

# • O.U. 0.107 0.10' O.J09 8.111 0.107 S.D. t.030 0.017 '.Oall 0.0111 '.016 0.1121 

# -- III 10 10 III 10 10 

# • Oqu to .8ootywUght "'tlo (., IIIUII 0.017 0.1135 0.03' 0.037 CI.036 0.031 a.D. 0 ••0' 0.00' 0 •••' 0."1 CI.OOS 0.007 III 10 10 10 10 10 01'1_ •• 1_**&4~** ...t:64 

# •**I'or~** .....t •• 114 0.107 0.111 0.112 0.110 0.101

REGUlATORY/REPORT
- 10390 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 18 - INTERGROUP COMPARISON OF ORGAN WEIGHTS 

# _111 .,..., aconalr 'uget CoaG..tntioD (n-J o (CoatP01) 100 300 1000 

# ° (CODtPOIJ 1000

____•

__.................................................. ................................._._...........**_.~** ••M. PIIVI"rUlr GLIIIID IIUoD**'I'~** 804Jwe,1gbt (.)

.... 510.3 52•• ' 4'6.3 113.2 161.6 

# t".. 8.D. 21.5 32.2 45.2 31.1 35.1 U.7 • 10 10 10 • l' 10 ()rplJ WNgbt (II)

.... 0.010 0.010 0.012 O.eo. 0 .•00 0.007 8.D. 0.001 0.001 0.006 0.0'2 0.002 0.002 Gr9- to lIIMJIoe.t.ght bUo • (') U " " • " "

.... 0.002 0.002 0.002 0.012 0.001 0.001 •• D. 0.000 0.000 0.001 0."0 0.000 0.000 Org_ 1IaI.gbt AIIjD.te4 • " " " • " U**I'W~_** 0.110 0.010 0.011 O••Ot 0.001 •••' 

# ........ ,QII1aal.**~gbt** (.)

.... 317.' 306.6 300.1 2".1 311.2 30:1.3 8.D. 20.1 11.3 16.6 26.1 n.1 12.3 OI:IJIIII .. 1
...t (II) 

# · " " 

# " " " "

.... 0.013 0.014 0.013 0.013 0.011 0.016 8.D. 0.00' 0.001 0.001 0.0'2 0.00' 0.001 • 10 10 11 " 11 10 to Bo4,..lgbt ••tl0 (t)

.... 0.00' 0.00' 0.004 0.01' 0.004 0.005 •• D. 0.001 0.000 0.001 0.010 0.001 0.002 oz,pa ft.1gbt AIIj_te4 

# · " " " 

# " 

# " " I'or**~gbt** 0.012**~.014** 0.014 0.011 0.012 "0.014

1RE0000TORY/REPORT
- 10490 DAY INHALATION TOXICITY STUDY IN TIIE RAT

## wrm REroVERYPHASE 

### TABLE 18 -INTERGROUP COMPARISON OF ORGAN WEIGHTS

DO iII'I.'IJPY acovJIIll hz'gat: c-.1:nUCIII (ppa) O(Cmtro1) 100 SOO 10eo o(Qaatrol.) 10M 

# ._......_ .........._ ..•...

_ .._ •...

_ ...._ .._.__.....**~M._** 

# ..•.•.....

_ .. ............ ................_ .._ ....._ ...**~ ~** **~** IID£U 'I'uaJ.aa.l Boq.e,..,t (II) BU !.dO.J 521.' 501.1 !1'.2 1"5.' 

# .".11 a.D. lt9.1 31.20 

## "'.2 3'.6 la.1 n.7 10 10 1. 10 10 OrgIll. 

# We,,,,, (II) 

# • 

# I.

BU 1 ••S. 0 •• 10·· 0 .... 0.,.7· 1.03. 1.02. a.D. G.l" 0.067 0.019 0.'" 1).123 0.137 10 10 10 10 10 0.,.... to**~_t.** 

# ..t.!o

# •(tl 

# l' O.lI'. 0.1" '.119 O.U. 0.117 0.1 .. 

# ... a.D. 0.02' 0.0111 0 •• 15 0.011 D.022 0.01' I. 10 10 I. 10 10 OrgIll. 1Ie:llbt ltoiU_tel 

# •**ror~** ...t 1 .•" 

## •. 12'· 0 • .,1 1.024 .... 3· 1.030 hIIIt.lidIa hn1lIal
...t: (" 

# ... 317.' '.6 •• 300.5 lIII6•• 311.2 303.3 8.P. 10.1 la.3 16 •• 16,7 12.7 1:1.:11 

# 1. 10 1. 11 1. 

# • 

# I' Orgu. We.1g1Jt (II:) IIIWI 41."1 '.7113 0.135 0.n7 D.'51 0.727 

# • 8. 1). 0.0" O.O'H. 0.010 0."" '.07. O.ON 10 IG IG 11 10 11 oz.gu. to**~t:** llaUo CtJ IIBU •• 2.111 O.U. O.lIU 0.2.60 (1.241 0.2." 8.D. e.on 0.0:12 •• 021 •• 1119 '.0111 O.G:as 

# I. I. 10 10 10 10 Orgu. WetlJllt Mjut.a 

# •**J'OE~"'t** o 76. 0.1111 0.,., 0.747 o.nl 0.1"

REGUIATORY/REPORT
- lOS90 DAY INHALATION TOXICrrY STUDY IN THE RAT wmlRECOVERY PHASE 

### TABLE 18 - INTERGROUP COMPARISON OF ORGAN WEIGHTS

HAD lIftD'I' IIIIClOftI1' lI__..t 1IbIpo_**Coaoeaa.1:~_** (ps-' o(Coat:ro.l, 100 300 ICOO O(COII1:II:Ol.J 100• 

### ................................................................-_

### .............................................. RIH8 IAI'.BS 'I'enWIal. ...."..i_t (If) 510.3 tI ••• loa.l**S.~.2** lIU.' sa•• ' 8.D. a•• s 32.2 41.2 :".6 35.1 n.7 

# - 10 10 10 1G 10 10 art- Ifs.t.gbt (til 

# • 

# ... 3.75**~.'40** 3.7S 

## 3." 3.71**~.71** B.D. 0.240 0.30 o.ao O.C. o.a. 0.:&7 10 11 10 IC 10 10 

# • Oqu to**...."..~_t** "Uo (') 

# .... ..75 

# .... 0.7. 0.71 0.7C 0.611 8.D. 0.05 0.07 0.01 0.11 ••01 0.01 10 14' 10 U 10 10 Qq_

# Ifei_ Adj_t414 

# • Por lIodI'WeiGbt 11.711 .1.17 3.7a 3.'70 3.75 3.71

IREGULATORY/REPORT • 106**~** 

# I**~ ~** **~** 

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# I90 DAY INHALATION TOXICITY STUDY IN 

### nIBRATWITH RECOVERY PHASE 

### TABLE 18 • 

### INTERGROUP COMPARISON OF ORGAN WEIGHTS

am 81'11D'f**~** 'fU'Pt IbpOtnIZ'e Coa_tn.u_ (PPI)**~(Coat%01)** 100 UO 1... O(Coatzal) 1••• 

# .....

# - ........ ...-.--.--.-

# ..--.--..

# - .....

# ---.............................................................

## -

# ..

# -_. IJ'IIIIRI8 WI'!II CDVU I'lIIIU.II8**~uaiJl&1 ~vtat**  (III 317 •• 30'.' 300.5 2".1 111.2 II;'.J S.D. 20.1 Ul.3 16.1 21.7 22.7 12.3 

# - 10 10 10 10 10 10 0J:pa •• 1pt (II) 

# • 0.n1 0.1'" 0.132 0.707 0.728 '.7. 8.D. 0.100 0.14$ 0.237 0.237 0.3U '.11t 

# - 10 10 10 10 10 1. 

# • 0J:pa to IIoGJ'WUpt bUo (') 0.1" o.au 0.21' 0.241 0.231 0.231 1.11. O.OSS 0.'''' 0.074 o.on 0.181 '.01' 

# - 10 10 10 10 1. 1. 

# • 0J:pa .. ipt A4jatel/l For IIoc'Ipdpt 0.5" 

# ....., 0.':14 

### '.7" '.701 O.?!U

IlEGULATORY/REPORT • U990 DAY INHALATION 'TOXICITY STUDY IN THE RAT WlTII RECOVERY PHASE 

### TABLE 18 • MERGROUP COMPARISON OF ORGAN WEIGHTS
Dr. 8nor • bal."", -.1-. • orartet

# -.,0-- c:o:a-tzat..... (".) Ofeo.trol) 10D SOD 1000 

# .-... ..

# --.----..

# -.--........---

# ......**~-** 

## ............

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# --_... SI'ldCIDI HALI:II 'l'e:m.iD.al 804pt0j. ...t Orpa Wdgbt (1J) (g) IIUII S.D. 

# • IIUII ••D. "'.2 30.5

t 1.0a2 o.•n 

# ..... 3:1.2 lG a ••lOO 0.067 II•• ' 415.2 10 0.111' D.OII loa.l 3 •• 6 10 0.'.' 0.06.:1 II t 10 10 10 Orpa t. 804pt0j. ...t ..**uC>~** o.u. 0.1" O.U. O.U. ••D. 0.022 0.011 0.011 0.011 II !II 10 10 10 0Ii9aa Wdpt Wj ....tt04 J'u IIo4JWUgbt: 1.001 o.•n­ 0."0 0.'52

IREGUIATORY/REPORT
- 11090 DAY INHALATION TOXICITY STUDY INTHE RAT 

## wrrn RECOVERY PHASE 

### TABLE 19 - INTERGROUP COMPARISON OF PALMITOYL COA (umoVg/mln)

lIAR SftDY on.I 'Iu:.-t bpMnIre eo-_tZ'aU_ (NIl) .CCoatrcl.) 1.0 300 10•• 

### ....................................................................................................................... IlIUM IIIWI 0.2.' •• 232 0.255 O.ln S.D. 0.133 0.07. 0.:l2f 0.10' II II 5 5 

# • I'-.l.u IIIWI 0.21) 0.2.' 0.3515 •. In S.D. 0.14. 0 •••5 0.459 0.0.11 15 15 5 15 

# •

'REGUlATORY/REPORT
- 111DAY INHAlATION TOXICITY STUDYIN TIlERAT WITH REroVERYPHASE 

### TABLE 20 - MACROSCOPIC FINDINGS
RBIIOVAL 1llWIOIt'. RI1HIDL 

## 1------------------------ MILB8 

## --------------·----------1 o 100 300 100f) 0 lOGO PIlla PIlI JIpa ppa ,.,. nAnII'ALS 011 8nD!' 10 10 10 11) 20 10 MJHU.S COICPURD 10 U. 10 1.0 0 0 UIIIIB1' SU8l:IftU......... <I
.. .. • .. .. • ........... "
.. • .. .. • .. .. .. .. .. 10 10, 10 10 0 0 lIO.lfZ'l'II rllDtRCIS •.••••••••••••••. ·•••• • 0 1 1 1 0 0**IIO.WX~** rIBDXBGS •••••••••••••.••••• 10 t 

# , 9 0 0 Ullilat.rlll. pe1v10 411at:at:l.OD••••.••••• 0 1 1 1 0 0 LUIIQ SUIKI'I'l'RD ............................. 10 10 10 10 0 0 110.WX'IB 1'IIDIJIGS ...................... 1 0 0 0 0 0 

# , 110.WXIllOU'l' PIJlDI_.. • • • •• • • • • • • . • •••• 10 10 10 0 0 Da.I'Ir. ........................**~** ......................... " ........... 1 0 0 0 0 

# • LDI'Il 1IO.... cnv:taL
<I SUlKIftJlD"
................................... "
.... "

........ 10 10 10 10 0 0 110.Wl'I'II rDlDIIIG8 ...................... O. 1 0 0 0 0 

# , 1IO.IItBUUf**~xacs** ••••••••••••••••••• 10 10 10 0 0. bl8X'g1114. • • • • • • • • . • • • • • • • • • • • • • • • • • • • • 0 1 0 0 0 0 SKIll CORIa) SUlKIftD
.......... ,. ............. " "
................... "
...... 0 0 0 2 0 0 110 .WI'IB 

# ,IJIDIIIQI...................
... 0 0 0 2 0 0 8o«b/8 .••••••••••.••••••••••••••••.••• 0 0 0 2 0 0 'l'BII'nS BaaIft'BD
... "
............ "
.......... "
...... "
.. "
.......... 10 10 10 10 0 0 110.Uft rIIIDIIIGIS ...................... 0 0 0 1 0 0 

# , 110.WI'I'IIOft rIJlDIIICS..... • ••••••••••••• 10 10 10 0 0 RMuae4••••••••••••••••••••••••••••••• 0 0 0 1 0 0 DDIIJ8 SUlllI.ftD
.... "
.. .. .. .. ..**~** .. " " "
.......... "
.. "
.... " "
........ 10 10 10 10 O. 0 110.WX'IB I'lJII)DIG8 ......... ; •••••••••••• 0 0 1 0 0 0 

# , IIO.WIIROU! PIRDIRIS ••••••••••••••••••• 10 10 10 0 0 SJMCIkl.&4 •••••••••.••••••• , •••••••••••• 0 0 1 0 0 0



### IREGUI.ATORY/REPORT

- 11290 DAY INHALATIONTOXICITY STUDY IN THE RAT WITH REGOVERY PHASE 

### TABLE 20 - MACROSCOPIC FINDINGS
JUD«IV.IL 1IDSOII.1 ftDDlIlIa.L 

## 1----------------------- .BMIL88 

## ----------··------------1 o 100 JOO 2000 0 1000 PPil PJIII PJIII PJIII PPIl PJIII UDDU.S 011 SmD'f 10 10 10 10 10 10 UDDU.s COIIPLB'I'BD 10 10 10 10 0 0 'J.'IIDI1JS S'UlIID:ftBD. • • • • • • • _•••••••••••••••••••• 10 10 10 10 0 0 1ft).ft'IJI r:DIDJlIQ8•••••••••••••••••••••• 0 1 0 1 0 0 RO.WI!H0U7 PIWDlaaB •••••••••.••••••••• 10 10 !J 0 0 lea**~t/. O~**  are.I•••.•••••....••••.. 0 0 0 1 0 0 

# "

................. _. 

# -.......... 0 1 0 0 0 0 

### unaus BUaaftBD ••••••••••••••••••••••••••••• 10 10 10 10 0 0 RO .ft,. r IIIDDICiIB. • • • • • • • • • • • • • • • • • • ••• 0 1 1 0 0 0 RO.ft!8OU! P71D1IGS •••••••••••••••••.• 10 10 0 0 D1.tell4ao4
............................. 0 1 1 0 0 0 

# " "

1tEGULATORY/RBPORT

- 11390 DAY INHALATIONTOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 20 - MACROSCOPIC FINDINGS
IUOIO'f1.L JtBUI(III RBCO\UY 

## 1-------········-·-·-··.· HaLKB 

## ----------------------··-1 o 100 100 1000 0 1000 AllDlilLS 01( In'DDY P.. 10 ppa 10 ppa 10 lis10 ps10 ps10 AllIIfJlLS COHl'I'.ftBD 

### o 0 0 0 10 10 aDJlIUIU. CLAIm BUmI:IftBD
.. " " "II' • .. " " • "
... " " " " " "
.. .. .. .. • .. .. •• " 0 0 0 0 10 10 ItO .IIID J'IJlDlIIG8................ • ••••• ItO.WZrBOU!**.!ID~s** •.••..••...••••.••. 0 0 0 0 0 0 0 0 1 

# , 0 10 UbA.loll/•••••••••••••••••••.••••••••. 0 0 0 0 1 0

JUDIOYU. JIB&S<II. DOOY.IJtY 

## 1------------·---------- FIMILI8 

## ------------------------1 o 100 lOO 1000 0 1000 

### na ppa ps- lis- ps- ps- AlfDClLS 01( 8'lUDY 10 10 10 10 1. 10 AlfDClLS COICPU'l'IID 

### o 0 0 0 10 10



### __u. GL&IID suaJ:ftBD
....... "
............ "'
.. "
............ "
........ ""
.. 0 0 0 10 10 

# • ItO .1ftD .IJlDDlGS ...................... 0 0 0 0 1 0 

# , 1tO.1ftrlDUf rIIDXIGS ••••••••••••••••••• 0 0 0 0 10


# ............................... 0 0 0 0 1 0 U'I'BItUS su.lftIID
........ "
..........................**~** "
.. .. .. .. .. .... .. 0 0 0 0 10 10

................ "
.. _.U.. PIDlMIS ........... " ........ It 0 0 0 0 1 0 

# , 1lO.lIIfBOUr 

### .IIDI-=s•......•...••..•••• 0 0 0 0 10 D1eteaGe4 ............................. 0 0 0 0 1 0

REGULATORY/REPORT

- 11490 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS
RmIOV.U. UASOlI'. I'BRtaIQl, 

## 1------------------------ HILB& 

## -------------------------1 UlDlALB OR BlVD! 0 ppa

10 lOCIlis10 30.**~** 10 lOCO**~** 10 

# • PJIII 10 1000IPs10 .urnar.S <lOIIPLB'r1D 1.0 10 10 10 0 0 ADIlRDL GLUD U'MIaBD ... ,. ............................. ,. ........ ,. ........... 110 AIDIORIIALrrIBB DII'l'BCDD••••••••••••• 10 

# , 0 0 0 0 10 10 0 0 0 0 Botop.t.G boIIe •••••••••••••••••••••••••• 1 0 0 0 0 0 BPJ:D:IDDIlB


# ............................................ 110 ABaOIIIIIl.rfIBS DBOC'I'BD •••••••••••••**.&Aft~ .~tOIO**  •••••••••••••••••••• 10 10 0 0 0 0 0 0 0 10 

# • 1 0 0 0 0 0 0
••RJ>IlU
.... "GLMD Jll,lNIDD..
.. •.• .. .. .. .. ... • .. .. .. ,. ............................. 10 0 0 10 0 0 110 AJIIIIOBI&I.rrIB. DB'1'&C'f8D ••••••••••••• 9 0 0 10 0 0 IIoDODaoalA41: oell**i~.t.ltr.UOll** (!!OtIAL). 1 0 0 0 0 0 _tDt.) ................................................. 1 0 0 0 0 0 IIDR'I' IIDIIIIIBD ................... _•••••••••• 110**.IUmOJIICI.L:I~U.** DftIIC'l'ID ••••••••••••• 10 9 0 0 0 0 10 

# , 0 0 0 0 Det'eDez.oaU"e G.u:4:l-ropetilJ' ('!'OrAL) ••• 1d.D:s.-J.. ••••••••••••••••••••••••••• 1 1 0 0 0 0 3 3 0 0 0 0 lIoaouaolA41: oell id.t.ltrat.t.OIl (!!OtIAL). .;lg1_' ........................... 0 0 0 0 0 0 1 1 0 0 0 0 J:[DIIB'I' lIKIKIlID. • • • • • • • • • • • • • • • • • •••••••••••• 110 JUIIIOIIII.lI.I.IUU**D~** ••••••••••••• 10 3 1 0 1 0 10 

# , 0 0 0 0 Ua.t.l.atenl.**~.t.** ('l'O'I'AL) ••••• " 1d.D:s.-J... • • • • •• • • • • • • • • • • • • • • • • • • • • 0 0 1 0 1 1 1 0 0 0 0 0 .l.ipt •••••••••••••••••••••••••••• 0 1 0 0 0 0 llOihiI:'ata .......................... 0 0 0 1 0 0**Bo.iD~10** a ••t. ('l'O'I'AL) •••••••••••• 0 0 0 3 0 0 UII:s.-J.. ........................... 0 0 0 3 0 0 Pelv10**~l..t.tb1aI.t..** {'l'O'I'AL) ••••••••••• 0 0 0 1 0 0 alJl:s.-J.. ........................... 0 0 0 1 0 0 hba.lJlr ba.oph1.lla ('rO'I.AL).... •••••••• 

## .t"t_, ........................... later.titi.l**~g_~aar** 0.11 6 6 0 0 0 0 3 

### a 0 0 0 0**1.~11tratiOil (~AL)**  •••••••••••••••••• ::I 0 0 1 0 0**alJl~1** ........................... ::I 0 0 1 0 0 Pyal..t.t.t.. ('rO'1'AL) ...................... 0 0 0 1 0 0 alJlt.a1 ••••••••••••••••••••••••••• 0 0 0 1 0 0 

### REOULATORY/RE10RT 11590 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 21
.. MICROSCOPIC FINDINGS

JIJIIIOYAL aJIASOlf I 'fIOIIa1Ol.L 

## 1------------------------ MaLIS 

## -------------------------1 • 100 300 UOO 0 1000 

### .,.**~** 

### n- n- n- PPII AIrDII.LS o. anDY 10 10 10 10 10 10 AIIDGUoS CClIIPIoftBD 10 10 10 10 0 0 LII.CIlllIAL QLAIID :IDIIIIIm......................................**~** ................... .. 10 

### o o 10 o 

### o .0**~I~IS** ••••.•••••••• 10 

### o o I o 

### o lIaQoiauc1ear o.1l at'i1traUOIl (!'MAL). o 

### o o 1 o 

### o 

### .ta'''' ..................................................... .. o o 

### o 1 

### o o LU1'JIX DAllIIIIID. • • • • • • • • • • • • •• • • • • • • • • • • • • • • • 10 

### o o 10 o 

### o ., J.BIRlIII!mJ.rI'IIS 

# DII!'Ika&D............. 10 

### o o t 

### o o**Ia1~t101l (~IL)**  •••••••••.•.••••• _ 0 

### o o 1 

### o o**1I.'lIl~.** • • •• • • • • • • • • • • • • • •• • • • • • • • 0 

### o o 1 

### o o LI'IU DUf'IWID. • •••••••••••••• •• • ••.• •••• ••• 10 

### o o 10 o o RD AllllUlaLI7IIS**~.............** 3 

### o o 6 

### o o 1IoDOIracll.ear or**.ID1~tOZ'J'** 0811 1ar11tratlOD 

### (7OIaL)............. 5 

### o o 1 o o

...pi .. ] .. .. ...... .. .. .. .. .. .. .... .. .. .. .. ...... .. .. .. .. .. .. .. 5 

### o o 1 

### o o

....t1 tt. "ood/.altUooa.l**.ID1~t1OD** 1f1t:Jl _d.) (!'O!'AL)... , 

### o o 3 

### o o**"'D1~J..** ................. .............. .. .. ...... .......... .. 3 

### o o 2 

### o o**.1~_t..** .. .. .. .... .. .. .. .. .. .. .. .. .. .. . .. .. .... .. .. .. .. .. .. .. 1 

### o o 1 

### o o LOR DIMJ"MID ••••••••••••••••••••••••• '.' • • • 10 10 10 10 

### o o 

# , RD IBIORNALI711S**~.............** 10 10 o o 

# • In0r.aM4 puo:ly-..cralu _at£OllllU.l at'11trat1OD**(~AL)..................** 0 

### o 1 

### o o o .'oi ..

# l... ................... .... .. ...... ......... .... 0 

### o o o 1 

### o .IU'noOl.U' .t.D;fU.trat1OD 'I'MAL1••••••••••••. __ •••••••.•**~......** 0 o 

### o 1 

### o o 1Iia.t..a1 . .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 0 

### o o 1 

### o o aa..orrbage 

### (!07AL)................... 0 o 

### o 1 o 

### o**a1.~.** 

## . ... .. . . . . . . . . . . ... . . . . . . . 0 

### o o 1 

### o 

### o

REGUlATORYJREPORT

- 11690 DAY INHALATION TOXICITY 

### STUDY IN THE RAT WITH 

### RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS
I!IIHOftL lIJlASOIII, 'rIUIIIJDL 

## 1·----------------------- MALZa 

## -------------------------1 o 100 300 1000 0 ltOO AIIl'KALS

# o. 8'rUD1' p)a 10**~** 10 .". 10 X10 PIll U ps10 UIllIA.LS CQIIPLftBD 10 10 10 10 0 0 I.!HPII IIO,.-CBRVJOJ.

........ "................................ 10 1 o 

# , o o IIIUx.;....
.. • . •• • ......... . . ..... •••• 110**~I~IBS D~D.............**  0 , o o o o 1 5 o 

### o o 

### o L}'IIPboi.4 proli.feraU.oa ('l'O'I'AL)........ .1Dt_l ....... I
........... "................... 1 1 1 

### o 

### o o o o o 

### o o o .11pt. • • • • . . . . • • • • •• • • • • • . . • • . . . . 0 1 

### o o o o Pl__ CHIll pz:oUrerat1OD «'l'O'I'I.L)..... a:l.at..l.. • • • . • • • • • • • • • • • • • • . . . • . • • 3 1 

### o o 

### o o fo 2 

### o o o o 811pt. •• • • • . . . • • • • . . • •• • • • . • • • • • • .odeDlt.. . • • . . • . . • . . . . . • . • . . . • • • • . a 0 o 

### o o 

### o 1 1 

### o 

### o o o IWI&L CAVIn UAIIDIBD. • • • • • • • • • • • • • • • • • • • • • •• • • • • • • MO**~I~IBS bB!IC~ID.............**  10
, o 

### o o 

### o 10 

# , o 

### o o 

### o**1I.~.ge** :I.D 1_**(~O'.rAL)..........** 1 

### o o o 

### o o 

### --..s. . . . . . . . . . . . . .. . . . . . . . . . . . . . 1 o 

### o o o o Peri.odAiIDtal**111f'~t1oll** ('l'O'I'AI}...... 81.1_ • • • . • • . • • • • • • •• • • • • • • . • . • • • • 0 0 o 

### o o o 1 1 

### o o o o**1I!'UJ:~.ur** GUIlD UIlMDII!\). • • • • • • •• • • • • • • • • • • • • • • • • • • • • • 10 

### o o 10 o o 110**~1'tUS** DftIICftD............ • 8 

### o o 7 o 

### o <l78t/8. •. . • . • • • . • • • • • • • . • • • • • • • • • • • • • • 2 

### o o 3 

### o o .aonAU GLU'D IXAIIIBD. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • MO ABMORlfALI'tIJIS DBRCftD............. 10 , o o 

### o o 10 

# , o 

### o o 

### o IIoDODaol.!NU: oe11 1D111tnat1.oD C'l'O'tAL). .:111 ... 1 •• • • • . • • . • . . •. • • • • • . . . . . • . • 3 1 o 

### o 

### o o o o 

### o o o 

### o 81.1pt. • • • • • • • • • • • • • • • • • • • • . • • • • • • 2 

### o o o o 

### o**,~.t.ti.ti.. (~AL)...................**  3 

### o o 1 

### o o a:l.a:lPl. • • • • • • • • • • • •• . . . • • • . • • • • • • 3 

### o o 1 o 

### o**REGULATORY~ORT** - 11i90 DAY INHAlATION TOXICITY STUDY IN THE RAT WrrH RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS
IUDICWAL 

### auso., 'fJI.ItIIJJDl, 

## 1------------------------ MILIB 

## --------------------·----1 o 101» 3()O 1000 0 1"00 p.v- ..... .... SIs- 

### a- aUIDfUoS OR S'IUJD[ 10 10 10 10 II 10 I1IDfALS ec.PLBBD 10 10 10 10 0 0 sc:u.fIC IIBIl9I: UAKIIIBD
...................................... ,. .. ... .. .. .. .. .. .. 10 

### o o 10 

### o 

### o ID**~I~I.S ~.............**  3 

### o o 5 

### o o 

## o..:r-U-tiOD ('IIO'l'AL} ••••••••• _. • • • • • • 7 

### o o 5 

### o o 1IiD:Iaal. ••••••••• _• • • • • • • • • • . • • • • • • 7 o o 5 

### o o 

## su. (O'J'IID) UAKIIlID. • • • • • • •• • • • • • •• •• • • • • •• • • • • • • 0 

### o o 2 

### o o**AD_1:IM:HI:I../~toal. (~IJ.).....**  0 

### o 

### o 2 o o 111.,_1. • • • • . • • • • • • .. • . • • • • . • • • • • • 0 o 

### o 1 

### o 

### o aU_. • • • • • • • • • • • • •• • • • • . . . . • . • • • 0 

### o o 1 o 

### o lpitMlJAl.**~i8** ('IO\'A£)........... 0 o o 1 

### o 

### o aUght. • • • • • . • • • • • • •. . . . • • • . • • • • • • 0 

### o o 1 

### o 

### o**~l_tlfty** 0811 :l.D1iltr.tiOll
­ ['IO'l'A£) • • • • • • • •• • • • • • • . • • • • • • •• • • • • • • 0 o 

### o 1 o 

### o cUgJat: ... 'I
.. .. .. • .. .. • .. .. .. .. .. .. .. .. .. .. .. I
.. .. .. .. .. .. 0 

### o o 1 o 

### o SIu:l'IIOt u:aclati_/aroatiDg ('I'OUL).... 0 o 

### o 1 

### o o**~t.~.............** 

## ..... ............................. 0 o 

### o 1 o o SIOIG.CII IIIDUIIJIIIU). • • • • • • • • • • • • • • • • • • • • • •• • • • • • • 10 

### o o 10 o 

### o ID ABIORlaLlfl••**~.............** 10 o o 

### o 

### o**~ar dl'-td~**  (!'O'I'AL}.......... 0 o o 2 

### o o 

# • -,.,_1.. .... .. .. ... .. .. .. .. .. ... .. .. .. .. .. .. ... .. .. .. .. .. 0 

### o o 2 

### o o**REGULA10RY~PORT** - 11890 DAY INHALATION rOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 21 • MICROSCOPIC FINDINGS

ItIDIOVAL 1IBASOIr. HIIIIIlU.L 

## 1------------------------ ..... --------------------·----1 o 100 300 1100 0 1000 W- I'ra PJ,a PJ,a ppa. ps­ JUr.[If.I.LS OR ftUl)Y 10 10 10 10 10 10 AllIIIALS COIIPLBI'BD 10 10 10 10 0 0 

### nS'frs IDIC[IIBD ••••

_ •••• _ • • • • • • • • • • • •• • • • • • • • 10 o 

### o 10 o 

### o 10**~1'flBS** 

### DB7IC!BD............. 9 o o t o 

### o**mntlat~~** tabular**4.geaarat~OQ (~AL)..**  • • • • • •• • • • • • • •• • •• • • •• • • • • • • • 1 

# .. o 1 

### o o**atD~l..** • ........ • .••• ••• ....... • 1 

### o o o 

### o 

### o .arJr.e4•••••••••••••••••••• _. • • • • • . 0 

### o o 1 

### o 

### o fII'IJIIJB 1IZMII1IIUl. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 10 

### o 1 10 

### o o 10**~1'fI.S** 

### DBrBCIID............. a 

### o 1 10 

### o o eoa...t.:loD/u-rrbap**(~.u.)........** 1 o 

### o o o o**atD~** ••••••••••••.••••••••••••• _ 1 o 

### o o 

### o 

### o 1p.:L**tbe1.t~** 

## OJ'IItf...................... 1 o 

### o o o 

### o 'rIIDOID GLUm**~.............** ........................ 10 

### o o 10 o 

### o 10 AIIIIOIIIQJ.I'fI&J 

## D'I'BCIBD............. a 

### o o 7 o 

### o**~.** 

## OJ'IIt/....................... . a 

### o o 3 o o**1IoDoD1I.o~** oell :lDUl.t.J:'at:l.oa**[~.u.).** 0 o 

### o 1 

### o o ata:laal.. • • • • • • • • • • • . • • • • • • •• • • • • • • 0 

### o o 1 

### o o '7OL1III'fUJ' IIIIBCU IDIIIII'IUI. • • • • • • • • • • • • • • • • • • • • • . • • • • • • • 10 o 

### o 10 o 

### o 10 A88OJIfALI'fI&' 

## DII'I'IIC'IBD............. " o o 5 o 

### o tlegeD.e.rn.:L_ 1Iif'OP8t:lQ'/_aoDa.Gl.ear 0.11**iDt11tra~:l.0Q C~AL).............**  6 

### o o 5 

### o o .1a1_1 • • • • •• • • • • • • . • • • • • • •• • • • • • • 6 

### o o 5 o 

### o**~GULATORY~ORT** - 11990 DAY INHAlATION 70XICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS
RIIIO'IAL DABOR. 'l'IIJIIaIIaJ. 

## 1---------------··------ ------------------------1 o 100 300 1000 0 1.000 ptIa SIs- ... ....ppI
.... IIIJDLa O. ftUDI' 10 10 10 10 10 10 UIDIU.S CCIIl'LBftD**~ ~**  

### a a 0 0 IlUDUIAI' QLAIID BJ:aKDIIII). • • • • • • • • • • • • • • . • • • • • • • • • • • • • • 10 

### o o 10 

### o o RO**~II~"** D.78CIID............. 9 o o 

# , o o IICmoIlaQl-.r O4tll :I.II.r:l.luat:l.oD ('I'O'I'&I.). 1 

### o o 1 

### o o .:La:lal.1
................. ""
... ,. ......... ,. .. .. • .. • 1 o 

### o 1 

### o o II:[..-r '«IIID:DD. • • • • • • .. • • • • • • . • • • • • • • • • • • • • • 10 

### o 

### o 10 

### o 

### o RO**ABIOIIaLl~18 DI~.............**  1 

### o 

### o o o o Ilitrataba.1.aJ: ai.cu:oUtld.uJ.. ('1'0'1'&1.)... , 

### o o 10 

### o o UD:laLl. • • • • • • • • • • • •• • • • • • • • • • • • • • • 

### o o 

### o o 

# • aU_t
........................ _ • •• 1 

### o 

### o 2 

### o o**"l~o** uzol:l.tId.aIl1.**(~AL)...........** 1 o o 

### o o o Ua:laLl. • • • • • • • • • • • •• • • • • • • • • • • • • • 1 

### o o o 

### o 

# • 'hI:Ial.lIr IIaIJopb.1lla ('1'0'1').1.)............ 1 

### o o 1 

### o o a:l.a:laLl.
.. .. .. • • .. ,. • • • • .... .. .. • • .. .. .. .. • .. • • .. 1 

### o o 1 

### o o 'l"1IInl.1U 4:.lhtatioD ('1'0'1').1.)............ 0 

### o 

### o 1 

### o o .oCIerat............... , •• '" •• .. •• 0 

### o o 1 

### o o latarat:l.t:l.al .oooDaoleer O4tll**11f:l.l~.tJ.OD (~AL)..................**  1 

### o o 2 

### o o .tD:laLl
.........' • • •
.. • • .. • • • • • • • .. 1 

### o o 1 

### o o aUpl:. • • • • • • • • • • • • •• • • • • • • • • • • • • • 0 

### o o 1 

### o o**~T1D.L** GLAIID DlMTaD. .. .. .... • .. ... .. .. ... .. .. .. . .. .. .. .. .. .. .. .. .. .. .. .. .. .. 10 o o 10 

### o o 10**AIROIMlLI~I" D~.............**  10 .0 

### o 9 o 

### o lI:taoaaol-.r O4tll :l.ll.rl1uat:l.OD ('I'O'I'AL). 0 

### o o 1 

### o o at..:a....1. .. .. .. .. .... .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. .. .. .. .. 0 

### o o 1 

### o o Lnn VUfTIIU.. • • •• • •• • • • • •• •••••••••••••• 10 

### o 

### o 10 

### o 

### o 

# , .,**~l~l" ~.............**  7 

### o o o o IIoooI:raol-.r OJ:' at::&ecl**i.af~tOZ'J'** oall :l.ll.rllttatlGD**('I'O'I'~).............** 3 

### o o 4 

### o 

### o 

# , .tD:I.IIL1.. • • • • • • • • • • • .. • • • • • • . • • • • • • 3 o 

### o o 

### o lltlpatltb**(:foo&ll_ltJ.:f~ :I.4:f~tlOD**  fttb. DeGX'Oda) ('1'0'1'&1.)... 1 

### o o o o o .11gbt. • • • • • . • • • • • • •• • • • • • • . • • • • • • 1 

### o o o o o 

### REGULA'IORY!REPORT

- 12090 DAY INHALATION TOXICITY STUDY IN THE RAT

### wrm RECOVERY PHASE 

### TABLE 21 • MICROSCOPIC 

### FINDINGS
UIIOVU. UASOIII mmKIlDL 

## 1---------vv------------PBKIlBS -----------_·_----------1 o 110 300 1100 0 1000 )pi ps- ps- ps- ps- psAIdlfAL8 011 S'fU1)'f 10 10 10 10 10 10 MlIllALS CXIIPLBI'BD 10 10 10 10 0 0 r,1IIIG BZIIIrIID.. .. .. .. .. .. .... • .. .. .. .. .. ,. ..... ,. .. .. .. .. .. • .. .. .. .. .. 10 10 10 10 

### o o 10**ABIOIHAL~~I.a ~crID_............**  

### • 9 9 10 

### o o [1ICI1'eeM4 J!ft'l"...ov.l.ar a_b:opta1l. Laflltcatloa**(y~)..................** 0 

### o 1 

### o o O.**~1M1...** .......... ...... ............. .................. 0 

### o 1 

### o o o**Iat~titlal** pa...oalti.**(~AL)......** 1 1 

### o o o o 1IiD:Iaa1. • • • •• • • • • • • • • • • • • • •• • • • • • • 1 1 

### o 

### o o o

..**{~AL)...................** 1 o 

### o o 

### o o .tpt., ........... to ......**~..........................** 1 o 

### o o 

### o o LDIPII "'.-CIIIlVECAL 1lI:MJlUm. • • • • • •• • • • • • • • • • • • • • • • • • • • • • • 10 

### o o 10 o o 10 UIIIOlID.LrI'I8& DII'IIlCftlD............. • o o 10 

### o 

### o U .... _U pE01..U'eraUoa ('lOI'.1L)..... 2 o 

### o o 

### o o ali_to ........._ • _ . _•••••• _• • • • • . 2 o 

### o o o 

### o :r.DIPII 111J)11-88I111'lDIC D.IIIJ:DI) ........................................... , .. .. .. ...... .. 10 o o 10 o 

### o 10**ABROIHaLI~X.a** ••••••••••••• 9 

### o o 10 

### o o 11004 :rn1e4 .1aa••• (201'&1.)
_ ........ . 1 

### o o o o o .tra'M1 ........ ... ., .................................. '" ... 1 

### o o o o o IWIAL CIV'lft aaHTJllll'l. • • • • • • . . • • • • • • • • • • • • • • • • • • • • • 10 o o 10 

### o 

### o 10**AIIIIO..u.l~l.** 

## DnBC'DD............. 9 o o 10 

### o o

__.n:tIage 111 1_ ('lOI'AL,.......... 1 

### o o o 

### o o ali_t. . . • • •• . • • • • • . • • • • • . •• . . • • • • 1 

### o o o o 

### o pAJlCltJlU IlmHlDD•••••••.••**~** • • • • • • • • • • • . • • • • • • • 10 

### o o 10 o 

### o 10**ABIIOIIIA.L:I~IlI'** DIt'IBC'IBD..... . • • • • • • • • o o 10 

### o o

__lIO:bIar cell**~ilt:z:at1oD.** ('lOI'AL,. 1 o o 

### o o II1D.:1aa1. • • • •• • • • • • • • • • • • • • •• • • • • • • 1 

### o o o o o**~111.** aUOpb:r ('l'CWAL).............. 1 o 

### o o o o _1D:lU' .......... _ • • • • • • • • .. • • • • • • 1 o 

### o o o 

### o o

REGULATORY/RFPORT

- 12190 DAYINHALATION TOXICITY sruDV INTIlE RAT WITH RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS**~v.u.** UA80Irc 'l':DIIllfAIo 

## 1----------------------- ------------------------1 o 101 300 10tO 0 1000 

### umcu.. QI( S'l'UDIr t.IIIIALs CONn.BftI) lIP 10 10 p.­ 10 10 .. ... 10 10 10 10 

### n10 0 PlIII 10 0 PI'fUrI'AIl! GLAIIJ) BIII[[BI) f
.. "
...................................................... 

### ., ....-as II'DI DftBCtID ••••••••••••• cr.t/•••....••............•...•.•..... 10 

# • 2 0 0 0 0 0 0 10 

# , 3 0 0 0 0 0 0 SCUl'IC RJNI: IIZ.II[IRD •••••••••••••••••

_••••

_•••••••
., AIIIIIOJIDLI'l'IU DIUCI'IID.. • • • •• • • ••••**~llDat~oa (IDI'~)**  ••••••••••••••••• -:101-1 ••••••••••..••••••••••••.•• 10 

# , • .. 0 0 0 0 0 0 0 0 10 

# , • 

# • 0 0 0 0 0 0 0 0 staDaI 'IIEUIIIID. • • • • • • • • • • • • • • • • • • • • • •••••••• 10 0 0 10 0 0
.,**~I'l'IB8** Dft&C'I'ID••••••••••••• 10 0 0 t 0 0 QllID4ahr tilat8ttOll.**(~ar.)** .......... 0 0 0 1 0 0 .tn .... l .......... ,. .... ...................... "
............ " 0 0 0 1 0 0 'ZIIIIIU8 

# ....,..., ..... " 

### ....................................... " 

### .......... .,**~I'l'I"** DBnc:'I'aD •••••••••••••**~.UOD/~** !'I'O'rAL, •••••••• _tntMI • ...... ...................... '" ......... ., .. I;
...... 10 

# • 0 0 1 0 1 1 0 0 0 0 10 10 0 0 0 0 0 0 0 0 0 0 Ipltbel1&1**~tl. ('I'O'r~)**  ••••••••••••• Nut .. 1 .......................... ........................... 2 2 0 0 0 0 0 0 0 0 0 0 'IIIDOID GLAJU) gwtnn ........................................................... ., ANIORDLI'l'IJ:. DI&'l'K.flD ••••••••••••• 10 7 0 0 0 0 10 

# , 0 0 0 0**~. ~t'**  

# ........................................ 2 0 0 3 0 0 ll:laoouolM!r ael.l :La.f'ut:nt:l.OD (I'O'DL). ma.:l.all............. ........................ ,. .... ,. ........ 1 1 ·0 0 0 0 0 0 0 0 0 0



### IREGULATORYIRBPORT

- 12290 DAY INHALATION TOXICITY STUDYIN 'IlERAT WITH RECOVERY PHASE 

### TABLE 21 - MICROSCOPIC FINDINGS

RBIIOVAt 1III.I.SOa, 'l'Bma1lU. 

## 1----------------------- PBHaLBS 

## ------------------------1 Cl 110 31)0 1000 0 1000 

### n- ps- 

### na :n- PJIII PaAllDlALI 011 SYmJ.' lO 10 10 10 10 10 AllDD.LI COIIPLftBD 10 10 10 10 0 0 

### unaus



## ..... "'."

# .......................... "' 

### ...... "'. 10 1 1 10 0 0 WO**A8IORNlLI~18** ••••••••••••. 10 0 1 0 0 

# • Glu.dv..1.u 4:1lat.Uoa**(~,** •••••••••. 0 1 0 1 0 0 M'Jg,..l .... WI
............................... "
.............. 0 1 0 1 0 0 Lu.1aa1 411.tat1oa**(~AL)** •••••••••••. 0 0 0 1 0 0 .UgIlt.. ..................... ., .............................. 0 0 0 1 0 0 WLmrrUy JIUBCU WUM:J:Mlr>
...........................**~** .............................. 10 0 0 10 0 0 :wo AUOIIIIaLI'J:DS**~C'!'BD** ••••••••••••• 7 0 0 7 0 0 Degeaqati._ 1QOP8t.br/_DODUol-.r 0.11 tDf11tratioD (.orAL) •••••••.••••• 3 0 0 :3 0 0**1IiD.~1** ••••••••••••••••••••••••••• 3 0 0 :3 0 0**REGULATORYnuB~RT** - 12390 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX A· CHAMBER VALIDAnON Generated atmosphere homogeneity data 

### were produced by sampling a group 4 & 

### 6 trial 

### atmosphere generation. Data were obtained in 

### duplicate from sample points 2 to 5 with reference to the normal sample point 

### 1.


# PI1302 LONG 

# teRM·CHAMBER ATMOSPHERE .SAMPLINQPOINTS

__.pon 1 -+-;..;;,'\ (frut) 

### EmactOutt

IREGULATORY/REPORT
- 12490 DAY INHALATION TOXICITY S1lIDY 'IN 1HE RATWITH RECOVERY PHASE


### APPENDIX A - CHAMBER VALIDATION

nae (hour:JDIDs) SampUng polDt Concentration (ppa) SaDlpllDg point IDeaD 

### Deviation (%) 

### froa Overall Mean 10:37 1 

### 1150 

# - - 

# - 10:45 2 1170 1160 5.5 

### I 10:50 1150 10:58 1 1140 

# - - ,­ 

### 2.7 11:04 3 1140 1130 11:08 1120 

### 11:14 1 1070 

# - 

# - 11:23 4 983 10'30 

### -6.4 11:27 

### 1080 11:32 1 

### 1050 

# - - 11:38 5 1070 1070 -2.7 11:45 1070 11:52 1 1090 

# - - Overall Mean (n = 

### 13) 1100 SD 

### 52 %RSD 4.7



# .. POSItion 1 

### =reference 

### sample point %RSD = 

### %relative standard deviation

IREGULATORYIREPORT • 12590 DAY INHALATION TOXICITY STUDY IN 

### mERAT WITH RECOVERY PHASE


### APPENDIX B • THE DETERMINATION OF IN TEST 

### ATMOSPHERES METHOD SUMMARY Test atmospheres were sampled from each exposure using a suitable gas tight 

### syringe fitted 

### with an 

### integral on/offvalve. Samples were directly introduced into a

### gas chromatograph equipped with flame 

### ionisation detection using an 

### automated gas sampling valve. 

### Atmosphere concentrations of were directly calculated after suitable system calibration and 

### reprocessing.


### CAUBRATIONSTANDARDS with a 

### purity of99.9% w/w was used. The purity ofthe test substance was 

### nnt**t~ken** 

### into 

### acx:ount in the 

### preparation of

### gaseow 

### standards. Known quantities of were added 

### toknown volumes ofair in gas 

### sampling bags (Tedlar, 

### SKq and 

### agitated to 

### produce gaseous standards within the nominal range 5ppm (v/v) to 1400ppm (v/v). Oascous Stundard 

### Concentration ppm (v/V) 

### =VI x U x My x 

## 1009 MwxV2 Where 

### Vl 

# = Volume oftest substance (td) 

### 'D 

# = Oen!llity of

### test substance (1.47g1ml) Mv 

# = Molar gas volume @ 

### 18-24°C (241) Mw 

### = Molecularweight oftest substance (200.05) V2 

# = Total gas bag volume 

### (1)

'REGUlATORY/REPORT
- 12690 DAY INHALATION TOXICITY STUDY IN TIlE RAT wrI'H RECOVERY PHASE


### APPENDIX B - THE DETERMINATION OF 

### IN TEST ATMOSPHERES PROCEDURE 

### -Atmosphere sampling Test atmospheres were sampled from a front-facing 

### port ofthe relevant exposure chamber, using a 5ml gas-tight syringe equipped with 

### an integral on-offvalve and detachable sampling probe. Room air 

### samples were typically taken from areas adjacent to exposure chambers. in a similar fashion to above. 

### Gas Chromatography Conditions Gas 

### chromatograph HP5890 Series U(Hewlett Packard). Column 25mx530pm BP-l, 5,um film (SGE) Oven temperature 50°C 

### Inlet type Packed Injecliull**It:~Ialure** 

### Injection volume 200,ulloop (nominal) Sample introduction 6 

### port gas sampling valve at 2Ufj"'C 

### Detector Flame ionisation detector (F1D) 

### Detector temperature 300°C Carrier gas 

### Helium,lOml1min Auxiliary gas 

### Helium, 20ml1min Detector gases Hydrogen,30ml1min Detector gases 

### Air, 300mVmin (All 

### flow rates are nominal) Data HandHng Millennium 32 CDS (Waters)

iftEOULATORY/REPORT
- 12790 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### APPENDIX B •THE DETERMINATION OF IN TEST ATMOSPHI!RI!S CAUBRAnON 

### The analysis system was calibrated using a range ofstandards to 

### determine thc.linearity of response. An 

### appropriate standard ofknown concentration was used to check the calibration at least three times during the first week ofexposure and subsequently on a weekly basis.
CALCULATION OF RESULTS 

### The analysed concentration was calculated directly by the data system in units 

### ofppm (v/v).


### LIMIT OF DETECTION The limit ofdetection was calculated to be approximately a atmosphere concentration ofO.4ppm (v/v).**~GULATORYmEPORT** -**1~**90 DAY INHALATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE


### APPENDIX C • ALLOCATION OF RATS TO EXPERIMENTAL GROUPS

The animals were distnbuted amongst experimental groups by a method designed to ensure that any unhealthy rats or rats at the extremes ofthe weight range were excluded;­ The weishUi were recorded and sorted using a computer sort feature for each sex separately. 

### All the stock animals were weighed and the data

### recorded directly electronically. The weight:; weretlten SOiled 

### elecllonlcally into OIdcl" 

### with the highest weight listed first, 

### followed by the next highest etc.. Animals at the extremes ofthe weight range were 

### discarded. The 

### sexes were randomised separately. A JJltin Sqtutre Wl'I!II generl'ltt".cil'lnd**wa~** used fOT the 

### allocation ofanimals to the experimental groups. The heaviest animal was allocated the lowest number in

### the group ofreplicate 1 denoted by 

### the number on the Latin 

### Square and oarpunched with the lowest available experimental number for that cage shown on the rack plan. This procedure was carried 

### out until all cages in 

### each replicate contained one rat. The rm('.enure**wa~** then repeated until each cage contained five rat4ll.

/REGUlATORY/REPORT
- 12990 DAY INHALATION TOXICITY STUDY IN TIlE RAT WlTII RECOVER.Y PHASE


### APPENDIX D·ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING INDMDUALANIMAL NUMISI!RS AND POSITIONS ANIMAL HOUSING IN HOLDING/EXPOSURE CHAMISERS 

### GROUP 1 and 5 (CONTROL) Case 0001 Repllc:ate 1. M,
_ Cage OUOZ Replicate 3,M, G1 G1 

### 1 

### 2 

### 3 Level 1 

### 6 7 8 4 

### 5 9 10 Cage ote3 Replcate 1,M, G5 Cage"", ReplIcate 3, M, G5

### 41 

## 42 43 Level 

### 2 

### 46 

## 47 48 44 

### 45 

### 49 50 .RepUc:ate 2, F, G 1 Cage 8006 RepUcate 4, F, G1 

### 61 

### 62 63 Level 

### 3 66 

### 67 68 64 65 

### 69 70 Cage 0007 RepIleate 2, F, G5 Cage .. Repleate4, F, GS 

### 101 

### 102 103 

### 104 105 Level 4 

### 106 107 

### 108 

## 109 110

M 

# = male F 

# = female G 

# = group numher

IREGULATOR.Y/REPORT • 130\90 DAY INHALATION TOXICITY STUDY IN TIlE RAT WITIfRECOVERY PHASE


### APPENDIX D • ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING INDIVIDUAL ANIMAL NUMBERS AND POSITIONS ANIMAL HOUSING IN HOLDING/EXPOSURE CHAMBERS GROUP 2 (100 ppm) Cage 

### 0809 llepllcatt 

### 1. AI, Cage 001. Replicate 3, M, 

### Gl G2 11 

### 12 

### 13 Level 1 16 

### 17 

### 18



### . 14 15 

### 19 20 Cage 0012 Replleatc 4, F, G2 

### 71 

## 72 73**7~** 

### 74 

### Level 2 76 77 

### 78 

### 79 Cage Cage Level 3 

# : I
Cage OIgc Level 4 

# I

M 

# = male F

# = female G

## =group number

IREGUIATORY/REPORT
- 13190 DAY INHALATION TOXICITY SlUDY IN THE RAT WITH RECOVERY PHASE


### APPENDIX D • ARRANGEMENT OF ANIMALS 

### ON THE RACKS SHOWING INDMDUALANIMAL NUMBERS AND POSmONS ANIMAL HOUSING IN HOLDINO/EXPOSUAE CHAMBI!!RS 

### GROUP 3 (300 ppm) Cage G3 

### 0113 Replleate 

### 1, M, Cage 

### G3 0014 Replicate 3, M, 

## 21 24 

## 22 25 

## 23 Level 1 

### 26 

## 29 27 30 28

Cage 

### 0015 RepHcate 

### 2, F. G3 Cage 

### 0116 Replicate 4, 1', 

### G3 

### Level 2 

### 81 

## 82 83 85 84 86 

### 87 ·89 90 Cage Cage 

# ] u,vc) 3

Cage Cage Level 4



### M=male F = female G = group number

JREGULATORY/REPORT
- 132 

### 8890 DAY INHALATION TOXICITY S11JDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX D • ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING INDIVIDUAL ANIMAL NUMBERS AND POSITIONS 

### ANIMAL HOUSING IN HOLDING/EXPOSURI! CHAMBERS GROUPS 4 and 6 (1000 ppm) Cage 0017 ReplIcate 

### 1, M, Cage 0118 Keplk:ate J, M, G4 

### G4 

### Level 1· 31 

### 32 33 

### 36 37 38 

### 39 40 

### 34 35 Cage 0019 KepUeate 1, M, G6 Cage ttll KepUeate 3, M, G6

### 51 

### 52 53 Level 2 56 

### 57 58 59 

### 60 

### 55 54 Cage 0821 Replk:ate 1,. F. G4 Cage 0022 ReplIcate 

### 4, F, G4 

### 91 92 

### 93 Level 3 94 95 

### 96 97 99 

## 100 Cage 0023 RepUCBte 2, F, G6
. Cage 0024 Replicate 4, F. G6 

### 111 112 113 

### Level 4 114 115 116 

### 117 118 

### 119 120

M 

### = male 

### F 

### = female 

### G = group number

:tREGULATORY/REPORT
- 133 

### 9890 DAY INHALAnON TOXICITY S1UDY IN TIlE RATWITH RECOVERY PHASB


### APPENDIX D •ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING INDMDUALANIMAL NUMBERS AND POSITIONS ANIMAL HOUSING IN HOLDING CHAMBER DURING RECOVERY PERIOD GROUPS 5 and 8 Cage 8003 G5

### 41 

### 44 Replicate 1, 

### M., G5


### 42 43 45 

### level 1 Cage 10M


### 46 

### 49 Replkate 3, 

### M.,


### 47 48 

### 50

Case tOO7 Replicate:,P, GS Case 0008 Ileplleate 4, F, G5 

### 101 

### 104 102 

### 105 103 

### Level 

### 2 

## 106 109 107 110 108

Cage G6 1019 Replicate 1,

### M., G6 

### 51 54 

### 52 55 

### 53 Level 

### 3 56 59 57 

### 60 58

Cage 0023 Replicate 

### 2, F, G6 Cage 1024 Replkate 4, P, G6 

### 111 

### 114 112 115 

### 113 

### Level 4 116 

### 119 117 

### 120 118



### M=maIe F =female G

# = group number

1mGULATORY/REPORT
- 13490DAY lNHAlATION TOXICITY STUDY IN TIm llATW1THRECOVERY PHASE


### APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RElATIVE MUMIDITY



### Key:
The 

### mean temperature and relative humidity, togetherwith 

### the minimum and maximum for each day ofexposure are presented in 

### the following tables for each cbamber. Including 

### aU chambers: 

### Overall minimum temperature was 20°C and maximum was 24 °C. Overall minimum relative bumidity 

### was 30% and maximum was 68%.

/REGULATORY/REPORT
- 13590 DAY INHALATIONTOXICITY sruoy.INTIlE RAT

## wrm RECOVERY PHASE


### APPENDIX E • GROUP MEAN DAILY *rEMPERATURE AND RELATIVE HUMIDITY Groups 1 and S Temperature Relative humidity Date 

### Mean Minimum Maximum Date Mean MinimumMaximum l3-Apr 21 20 21 13-Apr 35 

### 33 37 14-Apr 22 21 23 14-Apr 38 38 39 15-Apr 

### 22 22 23 15-Apr 

### 40 

### 38 42 16-Apr 

### 22 22 23 16-Apr 37 

### 36 37 19-Apr 23 22 23 19-Apr 

### 36 33 38 20-Apr 23 

### 22 23 20-Apr 31 30 32 21-Apr 23 

### 22 23 21-Apr 47 46 50 22-Apr 23 22 24 22-Apr 47 

### 46 48 23-Apr 23 

### 22 23 23-Apr 

### 46 45 47 26-Apr 24 23 24 26-Apr 

### 55 54 57 27-Apr 23 22 23 27-Apr 50 50 51 28-Apr 23 22 23 28-Apr 

### 48 48 49 

### 29-Apr 23 

### 22 23 29-Apr 

### 46 

### 45 48 3o-Apr 23 23 23 3O-Apr 47 47 47 3-May 23 22 23 3-May 

### 48 45 50 4-May 23 22 24 4-May 

### 46 43 

### 48 5-May 23 22 23 5-May 47 

### 46 49 6-May 23 22 23 6-May 45 

### 43 47 7-May 

### 22 22 23 7-May 47 47 47 10-May 23 22 23 1o-May 

### 58 56 62 11-May 22 22 23 1l-May 

### 56 S4 

### 58 12-May 23 22 23 12-May 

### 53 52 56 13-May 23 22 23 l3-May 49 48 51 14-May 23 22 23 14-May 52 52 53 17-May 23 23 24 17-May 

### 56 

### 55 57 18.May 23 22 23 l8-May 

### 54 

### 50 57 19-May 23 23 23 19-May 55 54 56 20-May 23 23 23 20-May 51 45 54 21':'May 23 23 23 21-May 43 

### 42 44 24-May 23 22 23 24-May 

### 48 47 

### 48 25-May 23 23 23 25-May 

### 53 49 56 26-May 23 23 23 26-May 41 40 

### 43 27-May 23 23 23 27-May 

### 43 42 

### 44 28-May 23 23 23 28-May 39 38 

### 41 3l-May 23 22 23 31-May 42 

### 40 44

'REGULATORY/REPORT • 13690 DAY INHAlATION TOXICITY sruDY IN TIlE RAT WITH RECOVERY PHASE


### APPENDIX E - GROUP MEAN DAILYTEMPERATURE AND RELA"rIVE 

### HUMIDITY Groups 1 and 5 Temperature Relative humidity Date Mean Minimum Maximum Date Mean MinimumMaximum 1-Jun 23 23 23 1-Jun 51 

### 49 52 2·Jun 23 23 23 2-Jun 

### 48 

### 44 52 3-Jun 23 23 23 3-Jun 45 43 47 4-Jun 23 23 23 4-Jun 55 50 

### 59 7-Jun 23 23 23 7..Jun 47 

### 43 52 8-Jun 23 23 24 8-Jun 59 57 

### 60 9-Jun 23 23 23 9-Jun 

### 48 46 

### 50 10-Jun 23 23 24 10-Jun 

### 56 48 60 11-Jun 

### 23 23 23 11-Jun 40 37 42 14-Jun 23 23 23 

### 14-Jun 

### 49 

### 47 50 15-Jun 23 23 23 15-Jun 52 51 

### 53 16-Jun 23 23 23 16-Jun 51 

### 46 53 17-Jun 23 23 23 17-Jun 42 41 

### 43 18-Jun 23 23 23 18-Jun 

### 40 35 45 21-Jun 23 23 23 21-Jun 37 

### 34 40 22-Jun 23 23 23 22-Jun 39 

### 34 42 23-Jun 23 23 23 23-Jun 51 50 53 24..Jun 23 23 23 24-Jun 

### 46 42 17 25-Jun 23 

### 23 23 25-Jun 

### 39 37 41 28-Jun 23 23 23 28-Jun 47 45 

### 50 29-Jun 23 

### 22 23 29-Jun 

### 48 47 51 30-Jun 22 22 

### 22 3O-Jun 53 51 57 1-Jul 22 22 

### 22 1-Jul 43 41 45 2-Jul 22 22 

### 22 2-Jul 

### 50 47 52 5-Jul 22 22 22 5-Jul 46 43 

### 48 6-Jul 22 

### 22 22 

### 6..Jul 

### 47 46 50 7-Jul 22 22 

### 23 7-Jul 49 47 51 8·Jul 22 22 22 8-Jul 43 41 45 9-Jul 

### 22 22 22 9-Jul 

### 38 37 

### 39 12-Jul 

### 22 22 

### 22 12-Jul 52 46 

### 58 13-Jul 

### 22 22 

### 23 13-Jul 41 

### 39 43 14-Jul 22 

### 22 22 14-Jul 

### 64 62 

### 66 15-Jul 

### 22 22 22 15-Jul 

### 64 57 

### 68 Overall 23 

### 20 24Overall 45 30 68

REGULATORY/REPORT • 13790 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE


### APPENDIX E • GROUP MEAN DAILY TEMPERATURE AND RELATIVE HUMIDITY Group 2 Temperature Relative humidity Date Mean Minimum Maximum Date Mean MinimumMaximum 13-Apr 21 20 22 13-Apr 32 31 34 14-Apr 22 21 

### 22 14-Apr 34 33 35 15-Apr 

### 22 22 23 1S-Apr 41 38 43 

### 16-Apr 23 

### 22 23 16-Apr 39 38 43 19-Apr 23 22 23 19-Apr 35 33 38 20-Apr 23 

### 22 23 2D-Apr 32 32 33 21-Apr 23 22 23 21-Apr 

### 45 44 

### 48 22-Apr 23 

### 22 24 22-Apr 

### 43 42 

### 44 23-Apr 23 

### 22 24 23-Apr 41 

### 40 42 26-Apr 24 22 24 26-Apr 45 

### 44 45 27-Apr 23 22 23 27-Apr 43 

### 42 45 

### 28-Apr 23 

### 22 23 28-Apr 42 42 42 29-Apr 23 22 23 29-Apr 38 

### 38 38 3D-Apr 23 

### 22 24 3D-Apr 41 

### 40 41 3-May 23 

### 22 23 3-May 42 

### 38 43 4-May 23 

### 22 24 4-May 41 38 42 5-May 23 22 23 5-May 39 38 39 6-May 22 22 23 6-May 39 

### 38 39 7-May 23 22 23 7-May 39 39 

### 39 1Q-May 23 22 23 10-May 47 46 

### 48 11-May 22 

### 22 23 11-May 45 

### 44 47 12-May 23 22 23 12-May 45 

### 44 46 13-May 23 22 23 13-May 42 41 

### 43 14-May 

### 23 22 

### 23 14-May 43 

### 42 45 17-May 23 23 24 17-May 47 46 

### 48 18-May 23 22 24 1B-May 

### 44 41 45 19-May 23 23 24 19-May 47 46 47 20-May 23 23 23 20-May 

### 43 39 45 21-May 23 

### 23 23 21-May 37 

### 36 

### 38 24-May 23 22 23 24-May 40 40 

### 40 25-May 23 23 23 25-May 

### 44 

### 40 47 26-May· 23 23 23 2e-May 37 35 38 27-May 23 23 23 27-May 

### 40 40 41 2B-May 23 23 23 28-May 38 37 40 31-May 23 22 23 31-May 

### 40 38 

### 43

IREGULATORY/REPORT
- 13890 DAY INHAlATION TOXlcrrY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX E- GROUP MEAN DAILY TEMPERATURE AND RELATIVE HUMIDITY

Group 2 Temperature Relative humidity

- 

### Date Mean Minimum Maximum Date Mean Minimum Maximum 1-Jun 23 23 23 1-Jun 49 

### 48 49 2-Jun 23 23 23 2-Jun 44 

### 41 46 

### 3-Jun 23 23 23 3-Jun 

### 43 42 45 4-Jun 23 23 23 4-Jun 

### 48 44 51 7-Jun 23 23 23 7-Jun 48 

### 46 52 8-Jun 23 23 24 8-Jun 

### 53 52 54 9-Jun 23 23 23 9-Jun 42 41 

### 45 10-Jun 23 23 24 10-Jun 49 42 

### 53 11-Jun 23 23 24 11-Jun 

### 36 34 40 

### 14-Jun 23 23 23 14-Jun 44 

### 43 45 15-Jun 23 23 23 15-Jun 

### 46 45 46 16-Jun 

### 23 23 23 16-Jun 

### 44 42 45 17-Jun 23 

### 23 23 17-Jun 37 

### 36 38 18-Jun 23 23 23 18-Jun 34 32 

### 38 21-Jun 

### 23 23 23 21-Jun 32 

### 30 35 22-Jun 23 23 23 22-Jun 34 31 36 23-Jun 23 23 23 23-Jun 45 

### 44 46 24-Jun 23 23 23 24-Jun 38 36 39 25-Jun 23 23 23 25-Jun 

### 34 32 35 28-Jun 23 23 23 28-Jun 43 

### 42 45 29-Jun 23 

### 22 23 29-Jun 

### 44 

### 43 46 30-Jun 22 22 22 30-Jun 47 45 

### 48 1-Jul 22 22 

### 22 1-Jul 41 40 

### 43 2-Jul 22 22 22 2-Jul 

### 44 42 

### 45 5-Jul 22 22 22 5-Jul 41 

### 40 42 6-Jul 22 22 22 6-Jul 41 40 42 7-Jul 22 22 23 7-Jul 

### 44 

### 43 45 8-Jul 

### 22 

### 22 22 8-Jul 

### 39 37 41 

### 9-Jul 22 

### 22 22 9-Jul 37 36 37 12-Jul 

### 22 22 22 12-Jul 45 42 

### 48 13-Jul 22 

### 22 23 13-Jul 

### 38 37 40 14-Jul 22 22 22 14-Jul 52 51 

### 53 15-Jul 

### 22 22 

### 22 15-Jul 51 47 55 Overall 23 

### 20 24 Overall 40 30 

### 55

IREGUIATORY/REPORT**~** 139

### . 90 DAY INHALATION TOXlOTY SnJDY INTHE RAT

## wrm: RECOVERY PHASE


### APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND AELAnvE HUMlDrrv

Oroup3 Temperature Relative humidity 

### Date Mean Minimum Maximum Date Mean Minimum Maximum 13·Apr 

### 21 

### 20 22 13-Apr 

### 34 33 

### 36 14-Apr 

### 22 21 22 14-Apr 35 35 

### 36 15-Apr 

### 22 

### 22 23 15-Apr 31 30 

### 33 16-Apr 23 22 23 16-Apr 

### 34 

### 32 39 19-Apr 23 

### 22 23 

### 19-Apr 33 

### 31 35 20-Apr 23 22 23 

### 2O-Apr 30 30 

### 31 21-Apr 23 

### 22 

## 23 21-Apr 

### 41 39 44 

### 22-Apr 23 22 . 24 22-Apr 

### 40 38 

### 42 23-Apr 23 22 24 23·Apr 38 37 38 

### 26-Apr 24 

### 23 24 26-Apr 46 

### 45 47 27-Apr 24 23 24 27-Apr 42 41 42 28-Apr 23 

### 22 

## 23 28-Apr 

## 42 41 42 29-Apr 23 23 23 

### 29-Apr 37 37 38 3Q..Apr 23 

### 22 24 3O-Apr 40 40 

### 41 a-May 

### 23 22 23 a-May 

### 40 37 

## 42 4-May 

### 23 23 24 4-May 

### 38 36 39 5-May 

### 22 22 23 5-May 38 

### 37 

### 39 6-May 23 

### 22 23 6-May 37 36 38 

### 7-May 

### 23 22 

### 23 7-May 

### 38 38 39 

### 10-May 23 

### 22 23 

### 10 May 

### 47 46 49 

### 11-May 23 22 23 ll-May 45 

### 43 47 12-May 23 

### 22 23 12-May 

### 46 45 48 13-May 

### 23 22 

## 23 l3-May 42 41 43 14-May 

### 23 23 23 l4-May 43 42 43 17-May 

### 23 23 24 11-May 48 

### 41 4g 18-May 23 22 24 18-May 

### 44 41 45 19-May 23 23 24 19-May 47 

### 46 47 20-May 

### 23 23 23 2Q-May 4S 

### 39 46 

### 2l-May 23 23 23 21-May 35 34 

### 36 24-May 

### 23 22 23 24-May 41 40 

### 41 25-May 23 23 

### 23 25-May 45 42 48 26-May 23 23 23 26-May 35 34 

### 36 27-May 23**2~** 

### 23 21-May 40 

### 38 44 

### 28-May 23 23 23 28-May 37 36 39 

### 31-May 23 

### 23 23 31-May 42 40 

### 44

IREGULATORY{RBPORT • 14090DAY INHALATION TOXlClTY S1UDY IN

## nm RAT

# wrm RECOVERY PHASE


### APPENDIX E • GROUP MEAN DAILY TEMPERATURE AND RELATIVE HUM'Dnv Group) 

### Temperature Relative humidity 

### Date MeGn 

### Minimum Maximum Date Mean Minimum Maximum 1..Jun 

### 23 23 23 1..Jun 49 47 

### 50 2..Jun 23 23 23 2..Jun 40 37 41 3-Jun 23 23 

### 23 3..Jun 38 36 39 

### 4..Jun 

### 23 23 23 4..Jun 43 

### 38 48 

### 7-Jun 

### 23 23 

### 23 7..Jun 43 41 47 8..Jun 

### 23 23 24 8..Jun 47 

### 45 48 

## &-Jun 24 23 24 9-Jun 36 35 

### 38 1o-Jun 23 23 

### 24 10-Jun 

### 41 36 

### 46 11..Jun 

### 23 23 24 11..Jun 30 28 31 14..Jun 

### 23 23 23 14..Jun 36 34 39 15-Jun 28 

### 23 24 1S..Jun 

### 40 38 

### 41 

### l6..Jun 

### 23 23 23 la-Jun 

### 39 38 40 

### l7-Jun 

### .23 23 23 17..Jun 31 30 32 18..Jun 

### 23 23 23 18-Jun 30 30 

### 31 21..Jun 23 23 

### 2.3 21-Jun 

## SO 30 

### 30 22..Jun 

### 23 23 23 

### 22..Jun 30 30 

### 31 

### 23..Jun 

### 23 23 23 23..Jun 37 37 

### 38 24..Jun 

### 23 23 23 24-Jun 31 30 34 25-Jun 23 23 23 2S-Jun 30 

### 30 

### 30 28..Jun 

### 23 

### 23 23 28..Jun 

### 38 38 40 29-Jun 

### 23 22 23 29..Jun 

### 38 37 39 

### 3ChJun. 22 22 

### 22 SO-Jun 

## 42 41 

### 44 1-Jul 22 22 23 l..Jur 35 34 

### 38 2-Jul 

## 22 22 22 2-Jul 

### 38 36 39 5-Jul 

### 22 

### 22 22 5-Jul 

### 36 

### 35 38 6..Jut 

### 22 22 22 6..Jul 37 

### 36 37 7-Jul 22 22 

### 23 

### 7-Jul 39 

### 38 39 

### 8..Jul 22 

### 22 22 8..Jul 

### 35 33 37**~ul** 

## 22 22 22 9..Jul 31 30 32 12.Jul 22 

### 22 22 12,JUI 

### 39 36 

### 43 13-Jul 22 

### 22 23 13..JuJ 32 31 33 14-Jul 22 22 22 14..Jul 47 46 48 15..Jul 

### 22 22 22 15..Jul 

### 46 41 

## 50 Overall 

### 23 20 

### 24 Overall 

### 38 30 50

REGULATORY/REPORT
- 14190 DAY INHALATION TOXICITY SI1JDV INTIlE RAT WITH RECOVERY PHASE


### APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RELATIVE HUMIDITY 

### Groups 4 and 6 TemperaturA Relative humidity Date Mean Minimum Maximum Date Mean Minimum Maximum 13-Apr 21 20 22 13-Apr 35 33 38 14-Apr 23 21 23 14-Apr 

### 38 37 

### 38 15-Apr 

### 23 22 24 15-Apr 48 45 50 16-Apr 23 23 24 16-Apr 41 38 

### 43 19-Apr 23 

### 22 23 19-Apr 

### 34 31 37 20-Apr 23 

### 22 23 20-Apr 32 

### 30 33 21-Apr 23 22 24 21-Apr 

### 44 

### 43 44 22-Apr 24 

### 22 24 22-Apr 41 

### 39 42 23-Apr 23 23 24 23-Apr 41 41 42 26-Apr 24 23 24 26-Apr 46 

### 44 

### 48 27-Apr 24 22 24 27-Apr 

### 43 42 45 28-Apr 

### 23 23 23**28~Apr** 

### 42 41 42 29;.Apr 23 23 23**29~Apr** 

### 42 41 

### 43 3O-Apr 

### 23 23 24**3O~Apr** 

### 41 40 42 3-May 23 23 23 3-Mo.y 

### 43 39 46 4-May 

### 23 23 24 4-May 40 37 42 5-May 

### 23 23 23 5-May 40 

### 38 42 6-May 

### 23 23 24 6-May 

### 39 38 41 7-May 24 23 24 7-May 41 

### 39 42 10-May 

### 23 

### 22 23 10-May 

### 48 46 50 11-May 

### 23 22 

### 23 11-May 

### 44 

### 43 47 12-May 

### 23 23 23 l2-May 47 

### 44 48 13-May 23 23 23 13-May 43 

### 41 45 

### 14-May 24 23 24 l4-May 

### 43 42 44 17-May 24 23 24 17-May 47 45 49 l8-May 23 23 24 18-May 

### 44 41 48 19-May 24 24 24 19-May 46 45· 48 20-May 

### 23 

### 23 24 20-May 

### 43 39 47 21-May 23 23 23 21-May 41 38 42 24-May 24 23 24 24-May 42 40 

### 43 25-May 23 23 24 25-May 

### 48 44 

### 50 26-May 23 23 23 26-May 

### 36 34 39 27-May 23 23 23 27-May 40 39 41 28-May 23 23 23 28-May 39 37 41 31-May 23 23 23 31-May 41 39 

### 44

JREGUlATORY/REPORT
- 14290 DAY INHALATION TOXIOTY STUDY INTImRAT WITH RECOVERY PHASE


### APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RELAnVE 

### HUMIDITY Groups 4 

### and 6 Temperature
. Relative humidity Date Mean MinimumMaximum Date 

### Mean MinimumMaximum 1-Jun 23 23 23 1-Jun 50 47 51 2-Jun 23 23 23 2..Jun 

### 50 45 

### 54 3-Jun 

## 23 23 

## 23 3.Jun 

### 45 42 46 4-Jun 2S 

### 2:3 24 4-.lun 

### 47 41 49 7-Jun 23 23 23 7..Jun 45 43 49 8-Jun 24 24 24 8-Jun 

### 50 47 52 9-Jun 

### 24 24 24 9-Jun 41 

### 40 43 10-Jun 24 24 24 10..Jun 

### 48 40 

### 53 11-Jun 24 23 24 11..Jun 35 33 38 14-Jun 24 23 24 14-Jun 41 

### 38 46 15-Jun 23 23 24 15-Jun 

### 44 42 46

. 16-Jun 

### 23 2S 

### 23 16-Jun 

### 46 

### 44- 

### 48

17-Jun 23 23 23 17..Jun 38 

### 36 39 18-Jun 

### 23 23 

### 23 18-Jun 36 32 41 21-Jun 23 23 23 21-Jun 

### 33 31 

### 34 22-Jun 23 

### 23 23 22-Jun 35 

### 30 38 2S-Jun 24 23 24 23.Jun 43 41 46 24-Jun 23 23 23 24..Jun 37 35 

### 40 25-Jun 23 

### 23 24 25..Jun 34 30 37 28-Jun 23 23 

### 23 28·Jun 45 

### 44 48 29-Jun 23 23 23 29-Jun 

### 43 40 46 30-Jun 23 23 23 30..Jun 46 45 

### 48 1..Jul 

### 23 23 

### 24 1-Jul 40 38 

### 43 2-Jul 23 23 23 2..Juf 

### 44 42 47 5-Jul 23 

### 23 24 5-Jul 42 

### 40 45 6-Jul 23 22 23 6..Jul 

### 43 41 45 7-Jul 23 23 23 7-Jul 

### 44 42 47 

### 8-Jul 

### 23 23 23 8-Jul 42 

### 39 

### 44 9..Ju\ 23 23 23 9-Jul 39 37 41 12-Jul 23 22 23 12-Jul 45 41 49 13-Jul 

### 23 23 23 13-JuJ 

### 40 

### 39 42 14-JuJ 23 23 23 14-Jul 

### 50 49 51 15-Jul 23 23 23 15..Jul 

### 50 

### 44 56 

### Overall 23 20 24 

### Overall 41 30 56

IREGULATORY/REPORT 143

### 90 DAY INHALATION TOXICITY STUDY INTHE RAT

# wrm RECOVERY PHASE


### APPENDIX F • ALLOCA110N OF ANIMALS TO MOTOR ACTIVITY 

### Cage! 

### Run 1 Run 2 Run 3 Run 4 Device Rep 

### I·Male 

### Rep 2Femaie Rep 3Male Rep 4Female 1 21 -81 16 76 2 31 91 6 66 3 1 61 26 86 4 11 

### 71 36 

### 96 5 

### 32 92 7 67 6 2 62 27 87 7 12 72 37 97 

### 8 22 82 17 77 

### 9 '13 

### 63 28 88 10 3 73 38 98**.~ -~-~~~~~**  .. 

### 11 

### 23 

### 83 18 78 12 ! 

### 33 93 8 68 

### 13 '4 

### 74 

### 39 99 

### 14 24 84 

### 19 79 15 34 94 

### 9 69 16 14 64 29 

### 89 17 2S 

### 85 20 80 

## lR 35 

### 95 10 70 19 5 65 30 90 

### 20 15 75 40 

### 100 Rep
- replicate

'REGUlATORY/REPORT
- 14490 DAY INHALATION TOXlOTY STIJDY IN 1HE RAT WITH RECOVERY PHASE


### APPENDIX G • DETAILS OF STAnSnCAL METHODS Bodyweights were considered by analysis ofcovariance on initial (week 1) bodyweight. separately for males and females. Weeldy food consumption and food utilisation during the periods weeks 1-4, 5-8, 9-13 and 1­ 

### 13 were considered by analysis ofvariance, separately for males and females. Motor activity measurements, time to 

### tail-flick (in 

### the sensory function test), landing foot !Splay and 

### grip !Strengths were considered. by analysis ofvariance, separately for males and females. Haematology, blood and urine clinical chemistry were considered by analysis ofvariance. Palmitoyl 

## e.nA (PCOA) values were also 

### considered by analysis of

### variance. Male and 

### female data 

### were analysed together, and the results examined to determine whether any differences between control and treated groups were 

### consistent between the sexes. 

### Organ weights were considered by analysis ofvariance and analysis ofcovariance 

### on fina1 

### bodyweight, separately for males and females. Summary data 

### are presented for organ to bodyweight ratios but these were 

### not**analy~ed ~tati~ri(".al1y**  

### as. thp. SUlalysis of

### covariance provides a 

### bettermethod of

### allowing for 

### differences in terminal 

### bodyweights**(Shirley~** 

### 1996). All 

### analyses were carried out separately for the main study and recovery groups. Analyses 

### ofvariance and covariance 

### were carried out using 

### the MIXED procedure hI 

### SAS (1999) and, with the exception ofrecovery food 

### consumption, recovery food utilisation and PCOA values, allowed for the replicate structure ofthe study design. Least-squares means for each group were calculated using the LSMEAN option in SAS PROC 

### MIXED. Unbiased estimates ofdifferences from control were provided by the difference between each treatment group least-squares mean and the control group least-squares mean. Differences from control were tested statistically by comparing each treatment group least-squares mean with the control group least-squares mean using a two-sided Student's t-test, based on the error mean square in 

### the analysis.

IREOULATORY/REPORT
- 145

### 90 DAY INHAlATION TOXICITY STUDY INTIlE RAT

## wrm RBCOVERY PHASE


### APPENDIX G • DETAILS OF STATISTICAL METHODS The differences from control based on the analysis ofbodyweigbt are also 

### presented grapbically (in figs. 3). 

### The centre ofeach barrepresents the mean percentage difference between control and treated group least-squares meaDS, and the top 

### and bottom ofecach bar 

### represent the upper and lower 95% confidence limits for this difference. 

### A statistically significant diffOlen" betwccn the treated group and the control group isprescnt when thebal 

### does notcross the zero difference line. For ease ofreference, lines have been added to the plots to 

### show 

### differences of:l: 

### 10%.

IREGUlATORY/RBPORT • 14690 DAY INHAlATION TOXIClTY STUDY IN TIlE RAT WITH REa>VERY PHASE


### APPENDIX H - HISTORICAL CONTROL DATA Neutrophil COunt 

### (x1tJM9n)
- Week 14 

### Males

- Start Date Mean±SD N 

### Range

2002/03 1.8 ±0.61 10 1 -2.8 2002/04 2.45 ±2.57 10 0.93 -9.62 2002/04 1.52 ±0.46 8 0.99 -2.2 2002/04 1.89 ±0.61 12 1.03 -2.94 2002/05 1.46 ±0.48 12 0.83 -2.25 2002/05 1.83 ±0.4 10 1.26 -2.5 2002/10 1.46 ±0.31 12 1-2.03 

### 2002112 1.67
. ::!:O.39 

### 12 1.12 -2.61 

### 2003/06 1.12 ±0.28 12 0.74 -1.61 2003107 i 

### 1.41 ± 

### 0.61 12 0.79 -3.16 

# I Thymus - Week 14 Females 

### Start Date Mean±SD N 

### Range Mean organ to Mean bodyweight terminal ratio bodyweight 2002/03 0.449 :to.OSl 10 0.286 -0.555 0.148 304 2OQ2/04 0.47 ±0.043 

### 8 0.427 -0.S3S 

### 0.169 

### 278 2002104 0.422 :to.067 12 0.264 -0.522 0.153 275 2002105 

### 0.448 

# = 0.076 12 0.338 -0.551 0.16 280 

### 2002/05 0.443 ±0.066 10 0.377 -0.589 0.159 279 2002/10 0.416 ±0.068 12 0.35 -0.552 0.149 278 2002/12 0.434 ± 0.087 12 0.332 -0.632 0.157 277 2003/06 0.449 

## ±0.075 112 0.295 .0.568 : 

### 0.156 287 2003/07 0.459 

## ±0.063 12 0.373 -0.57 

## I 0.162 283

IREGULATORY/REPORT
- 14790 DAY INHAlATION TOXlcrY STUDY IN 11IE RAT WITH RECOVERY PHASE**~EQULATORYmEPORT** 

### 90 DAY INHALAll0N TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE INDMDUAL 

### ANIMAL DATA

STUDY DETAILS 

### Sponsor: Sponsor Reference: Test Substance 

### Reference Number: Study NumbeI: 

### Document Number: 

### AUTHOR

DATE OF ISSUE 24 

### January 2005

IREOUI.ATORY/REPORT • 14890 DAY INHALATION TOXICfY STUDYIN

## nmRAT WITH RECOVERY PHASE. 

### APPENDIX 1 • INDIVIDUAL CUNICAL OBSERVATIONS

Key: Some or 

### all of

### the fonowing abbreviations may appear 

### in the appendix. N • noabnormalities**detect~** 

### cancelling an ooservatnn from the previous week X
- present All uimals in groups 1, 2, 3 and 4 were 'killed termination' 

### in week 14. All3limals in groups 5 and 6 were 'tilled tennination' 

### in week 18. Note only observations made 

### in the weekly detailed examination arepresented 

### in 

### this appendix. ObselVations made during week 12 

### at the FOB clinical assessment are presented in Appendix 

## * .

REGULATORY/REPORT
- 149(;I,J

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# • •• 90 DAY INHAlATION TOXlCIY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### APPENDIX 3· INDIVIDUAL BODYWEIGHT GAINS (9)

DOII.I. 10.0 li'lIIa RIGIl'l' 6&DII AD 81....... WID 1 JIIrD '1'B .... RDftD lIIDIAL au: 

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## 30. 14 0 55 Ilit l53 17. It! a04 220 247 2al 271 273 2.1 214 210 285 51 0 50 102 155 17. 20' 224 au II' ,a.1 207 302 JO' a:at UI 32' 33' 

# .. 0 51 104 144 150 Ial 204 221 134 251 2U 271 184 :at4 213 3•• SO. 17 0 n as' 124 l" 176 1'5 2U 230 U. 243 atl 271 all 210 2n 2'5 21' 18 0 14 IS lla lto III 17. a03 2n 2411 251 2'7 272 211 210 d4 I. 0 lI4 17 It 12. 13' 15. 17' 1.5 201 201 213 :au a21 a23 23. .4 3. 70 II 111 111 1,. 154 114 Ut 174 115 n3 IN 1" ao'7 210'7 

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IREOULATORY/REPORT
- 17190 DAY INHALATION TOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE

MIIII.L

_ ..


# ..... 51 sa 53 5. sa 56 57 I. !I' '0

J'IIQ.LaS

111 112 113 1140 111 nr8lft' GAIn IlII:

..­

11

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10. (0)
., (0) .7 CD) 10e CD)
,. (0) 11"8 (D) 117 " (D) 11. 187 (0) 11' 10e (D) 120 .1 (D) 

### APPENDIX 3 

## -INDIVIDUAL BODYWEIGHT GAINS 

### (g)

DOSIE. 1000 .,.

....... 1fJrIIt 1 II1II ID n:aa ••DII'IID

RBGULATORYIREPORT

- 17290 DAY INHAlATION TOXIcrY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### APPENDIX 4 - INDIVIDUAL FOOD CONSUMPnON (g/RAT/DAY) Cage 

### number Animal 

### numbers Cage number Animal number 1 1..5 . 13 21·25 

### 2 6-10 14 26·30 3 4145 15 81-85 4 

### 46-50 16 

### 86-90 5 61-65 17 31·35 6 6(j..70 18 36-40 7 101-105 19 51·55 8 106-110 20 56·60 9 11-15 21 91·95 

### 10 16-20 

## 22 96-100 

### 11 71-75 

### 23 111-115 

## 12 76-80 24 116-120-_

......._­ -

IREGutATORY/REPORT • 173

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# • • • 90 DAY INHAlATION TOXlCfY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 4 - INDIVIDUAL FOOD CONSUMPTION (glrat/day)

1X8II:. 0

.. IBLB/CIIGI: P:IB-IIl'IIIlDIDIALL!'.. I (,
..... ,
_ no. 

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.... -IXnRDlllllftldilr:... __ (J'aUoI8'

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# ...... 

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# ---­ 1 2 3 II 7 t 10 11 12 13 21 22 21 23 22 'U 22 11 20 20 2. 20 20 111 22 23 2i 23 22 23 23 &3 a2 22 21 22 21 It

REGULATORY/REPORT • 175

# • •

• 

# •



# ----------------- 90DAY INHAlATIONTOXICTY STIIDY IN THE RATWITH RECOVERY PIIASE 

### APPENDIX 4
.. INDIVIDUAL FOOD CONSUMPTION (glratlday)

__ I 0 

# ... AIIDIIILIte&a
... ·IIXJ'DDIIII'l'ALLlI:. !I (1IOI.LI8) CAID _an: DB

___ 

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# • ...... __ 

# • 10 11 1:1 1:1 ...... _ 14 111 U .... 17 __ 3 31 :u 31 a. 3. 30 J1 30 SI 2. 31 30 3D 30 10 31 27 

# , 30 :u a. u a, u 2' U 2' lI' U 30 a. 30 n It .II

. OOlllh 1000 PIlI MlIDLSICIIGK nJI-IIXJ'DDaftALLlI:" I (ICALI:I) CIIa 

# , 1 2 3: 4 I 7 10 11 12 11 14 11 14 17 

# - 

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# 2. II U at at It zt :at 27
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.. II (rDIItI.D)
_ .... _____ na ___ .taI: ....: ______ ...: caa 

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# ..... 1 2 3: 4 7 10 11 12 11 14 111 16 17



# • 7 n 23 22 as 21 23 21 20 ao :21 22 20 20 20 21 20 21 21 23 23 23 24 23 21 21 21 2a 21 21 al 21 21 21 21

IIOIilh 1010 .lllII&L8ICH1r JlU-J:DIDI
....ALLlI:.. II (1'IIlIlIiIoH) CI.IiIII 

# ..... , 

# , , PIlI
1 2 3 4 7 10 11 12 13 14 111 If 17 

# •**~3** at 11 ao 21 If It 20 l' It l' 22 I. n 21 20 20 U 24 22 Z1 21 21 20 ao 21 l' l' :18 l' UI l' 20 20 1. UI

REGULATORY/REPORT**~** 17690 DAY INHALATION TOXiCrY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 5 -INDIVI)UAL FUNCTIONAL OBSERVAnONAL BATTERY (CUNICAl. OBSERVATIONS) 

### Key: The following abbreviations may 

### appear 

### in this Appendix. 

### S
- 

### slight X
- 

### pre;ent M 

### -male 

### F • female With the exception ofthe animals listed overleaf, all 

### animals had 'no abnormalities detected' during the FOB clinical assessment, see Table 7 for full 

### list ()fFOB 

### assessm.ents.

REOULATORY/lEPORT • 17790 DAY INHALATION TOXICFf S11JDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 5 .. INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (CUNICAL OBSERVATIONS)

Animal . 

### Sex Week Text 

### M 12 REDUCED SPIA Y REFLEX 

### M F 

### SPIA Y REFLEX 87 : 300 F 

### SPlAY REFLEX F 

### 12 84 300 F 12 SCABS (1ll1derside 

### oftail)

REGULATORY/REPORT
- 17890 DAY lNHAlATIONTOXIcrY SnJDY INTHE RAT WITH RECOVERY PHASE 

### APPENDIX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL 

### BATTERY (LANDING FOOT SPLAY, TIME TO TAIL-FLICK, FORE- AND HING-UMB GRIP STRENGTH) Key: The following abbreviations may appear in this Appendix. NO numbel REPL 

### replicate FOOTSIY foot 

### splay FL fore-limb HL . hind-limb ASSESS 

### assessment Sec 

### seconds

'REGULATORY/REPORT
- 11990 DAY INHAlATION TOXICfY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### APPENDIX 6 - INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY. TIME TO TAIL-FueK, FORE· AND HIND-UMB GRIP STRENGTH)

an.**~.01** CIWD IAU DOBI LJrVJIL. 

# ... 0 P.­ r.ulDU18 FOOrfIl'f
_ 110 lID UDIU. 12 1 1 1 76 1 1 2 35 1 1 3 It 1 1 4 17 1 1 II 43 3 2 6 63 3 2 7 

# " 1 2 II 80 3 2 

# • 67 3 2 10 80 RIIUdI UIDL 2 II 61 83 2 II 62 66 2 II 63 116 2 II It 55 2 II n 67 4 6 66 66 4 6 67 116

'REGULATORY/REPORT
- 18090 DAYINHALATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 6 -INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAIL-FLICK, FORE· AND HIND-LIMB GRIP STRENGTH)

...". 01 D08II LIYBL. 

# . ... L.UmIIIIII 1'00'1'II/'1'
_ IIIIPL CMlII.......
_

.. 110 iIIIDIIIIl£ 

# . ,. 12 

# "

• •• 62 4 , 70 7.

fREGULATORY/REPORT
- 18190 DAY INHAIATION TOXICI'Y STUDY IN TIlERAT WITH REO)VERY PHASE 

### APPENDIX 8 - INDIVIDUAL FUNCTIONAL OBSERVAnONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAiL-FUCK,

- FORE- AND HIND-UMB GRIP STfENGTH)**~.** 02 DOIUI: 1dV&. 100 

# .... LAllDIM POOf.a/'1
_ 

# ..... 

# ..... CAa III) III) .1III:IIIUt U 

# - 1 11 7. 

# • 1 12 5 ... 

# • 1 13 

# .. • 1 U 43 

# • 1 15 .5 

# • .3 18 16 Sa



### ... 111 17 51 3 111 18 

# .,

... 141 U .0 3 lCI 20 41 ..-r.• .t.m1GL 2 11 71 .0 2 11 72 75 2 11 73 32 2 11 71 60 :I 11 7. 7. 

# , 12 76 72 

# , 12 77 U

'REGULATORY/REPORT • 18290 DAY INHALATION TOXICrYSTUDY IN 

### TImRAT WITH RECOVERYPHASH 

### APPENDIX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATIERY (LANDING FOOT SPLAY, llME TO TAiL-FUCK, FORE· AND HIND-UMB GRIP STRENGTH)

GIIOUI'. 02 DOS8 r.nm.. 100 wa ..... DlG fOOlS/"&'
_ JIIDL C'.AG'I: nII'ltoLIi .... 110 JR) &IIDIA.L 12 4 12 78 T1

.. 12 ,. 43

, 1.2 80 Ta**~ULATORY~ORT** 

### .**l~**90 DAYINHALATION TOXIcn' STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL BAlTERY (LANDING FOOT SPLAY, TIME TO TAiL-FUCK, FORE· AND HIND
..UMB GRIP STRENGTH)

an. 110 GIIOVl'. 03 CMIII DLK 110
.. DIU. D08II LnwL. 

# ...

12 300 ". r.uDDGI l"OO't8/'f
_
1 13 21 U 13 22 100 1 13 23 

# ,. 1 13 U 

# '" 1 13 25 55 

# • 11 

# • I" 2' 27 6. a1 J 14 U 

### u. 1" al aa It 30 I" 

# ,.....,.. .urnar. I 15 at n :I 15 .a aa I 15 

# .., 15 2 2 15 11 

# " 

# .. aT 62



# ..
.. 16 l' 

# ... .'7 '" 55

IREGUlATORY/REPORT
- 18490 DAY INHALAll0NTOXICfY STUDY IN THE RATWITH RECOVERY PHASE 

### APPENDIX 6
.. INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAIL-FLICK, FORE· AND HIND-LIMB GRIP STRENGTH)

GIIOVl',OI P08I L&'nL. aoo PI'" WIIIIOIJIQ I'OO'I1l/I'
_ UPI. c:AO I':IIIALI
_ 110 

### * _DIaL 1:1 4, 15 •• 64, 4, U •• 55 4, 15 10 51

IREGULATORY/REPORT
- 185

# ••

•• •• 90 DAY INHAlATION TOXIcrY S1UDY IN 1lIERAT 

### wrm RECOVERY PHASE 

### APPEI\I)IX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAlL.-FUCK, FORE· AND HIND..LlMB GRIP STRENGTH)

!iIIOVJ'. 0' D08II ucv.r.. 1000 

# ... L.IIIDJIIG POe'I'II/Y
_

.... QGII 

# ..... ., 10 M1IGI'. 12 

# - 1 IT .n 1 17 3lI 17 1 17 33 75 1 17 3. 67 1 17 31 T' 3 1. 31i 100 1 1. n 1 18 31 1 1. n 103 

# .. 1 1. n**~** M1IGI'. :I :11 t1 53 :I 21 02 63 a :u 13



# , 

# .. " " '" :I 21 51 :I 21 57 za 5. 

# , 22 '7 50

REGUlATORY/REPORT
- 18690 DAY INHAlATION TOXICTY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### APPENDIX 6· INDMDUAL FUNCTIONAL OBSERVATIONAL BA'ITERY (LANDING FOOT SPLAY, TIME TO TAIL-FLICK, FORE- AND HIND-UMB,GRIP STRENGTH)

IID'I. fiJIOUJ'. Ot 

# CMI....... IIOBIr r.ir9Go. 

# _ 1000 ps.- LlllDDIG JI'OO'ftI/Y
_ 110 110 AImIAL 12

.. :za ,. 6. t 22 " 65

.. 22 100 51

lREGUlATORY/RBPORT
- 18790 DAY INHALATION TOXIcrYSTUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 6 • INDMDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAiL-FUCK, FORE- AND HIND-LIMB GRIP STRENGTH)

CDOID. 01 DOa ..."... 0 

# .,. lAIr. I'LICl: 

## .- IIIIPr. cata aD: 

# .... JIG JIO lIIIlBIt 1:1

1 1 1 11.'7 1 1 2 1.22 1 1 3 1.13 1 1 

# .. 10••• 1 1 5 '.77 3 :2 1.1' 

# • 3 :2 7 20.00 3 2 2.12 

# • 

# , .s 2 7.50 3 2 10 '.73 l'IIIIIIUoI: IIIIDIIU:. 2 S II 10.st. I II 1:1 2O.0D :2 II '3 

## '.31 2 II 12.24­ 

# " 2 5 3.71 'I 

# , I 10.00 

# , , " 17 11.20

'RBGULATORY/REPORT
- 18890 DAY INHAlATION TOXlCI'Y STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 6 - INDIVIDUAl FUNCTIONAL OBSERVATIONAL BATTERY

## (LANDING FOOT SPLAY, TIME TO TAIL-FLICK, FORE- AND HIND-UMB GRIP STRENGTH)**~.** 01 DOSB**~.** 0 

# .,. '1'1.I1Io PLIca 

# -­ lUI. CAGC rau.a IIIID 110 110 AIIIIIUo 12



# .. 6 'I 13.42



# .. 6 6. 1.11



# .. 6 70 6.56

REGULATORY/REPORT
- 18990 DAY INHAIATION TOXICI'Y STUDY IN THE RAT WlTII RECOVERY PHASE 

### APPENDIX 6· INDIVIDUAL FUNCTIONAL OBSERVATIONAL BAITERY(LANDING FOOT SPLAY, TIME TO TAiL-FUQ<, FORE- AND HIND-UMB GRIP STRENGTH)

IIID'L ItIO 1 1 1 1 1 CJIOUII. all. CAaI 

# ..... ItIO UDIU.



# • 11 

# , 12 

# , 13 

# , U 

# , 15 D08II LJr¥IIL. -....:

12 

# :'I." 11.&' 3.n 

## 15.', 12.23 100 

# ... 'IUL I'LlCit eN



# " 10 11 ••0' 3 10 17 1.:12 I 10 18 7.11 3 10 1. ".43 3 10 20 3.11 FIIIDLI UDAL 2 11 71 •• 11 2 11 ·12 7.32 2 11 73 7.U 2 1:1 7.U 

# '" 2 11 7!S 1.1= 

# • 1:1 7' 10.J3



# ..**1~** 71 2.l0

'REGULATORY/REPORT
- ISO90 DAY INH.ALATION TOXICfY STUDY IN THE RAT WITII RECOVERY PHASE 

### APPENDIX 8 - INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAIL-Fuel(, FORE- AND HIND-UMB GRIP STRENGTH)

GIIOOI'. 02 DOIII: 1ioI:YIIli. 

# - 100· 

# ... 'fAIL rr.:r:CX 

# -­ IJII'L CI.GI nau 110 110 AIIDIU. 12



# " 12 7. 

### 11.'"



# .. 12 

# " 6.U 

# " 12 10 ••110

fREGUlA'IDRY/REPORT
- 19]

### 90 DAY JNHAI.ATION TOXICI'Y STUDY INTHE RAT WITH RECOVERY PHASE 

### APPENDlX 8 -INDIVIDUAL FUNCTIONA\. OBSERVATIONAL BATrERY (LANDING FOOT SPlAY, TIME TO TAiL-FUCK, FORE.. AND HIND-UMB GRIP STRENGTH)

(IIIIQ1tt • O:!l DC:I8r. t.lA'&.. 3<10 wa 

### u.n ""I:<:&: 

# - JW.I: 

# "'1'. GUll 

# .. Ill) IIIDIUo 1'1 

# - 1 13 21 5.33 1 U 

### n 4.1" 1 U 113**2.0~** 1 13 II 9.115 1 U 1.$ '1.'11 .II lot :Ii :aG.II• .II .1.4 :1.7 3 ••• I .1.4 21 20••' 

# , 14 21 2.1. S U SII 

## ",'1, l'IIDU umw. 2 15 11 s.U a 15 12 5,a1 2 11 .,1.) 

# '3 

# ,. :I 1.5 5 .... 2 1lI .a 3.U l' 

# ,/I
•• 21 

# • ,., 4 11 u.u



### REOULA1ORY/REPORT
- 19290 DAY INHALATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAY, TIME TO TAiL-FUCK, FORE.. AND HIND·UMB GRIP STRENGTH)

GIOUP r N DOllIE l.IW.U.. 300 .".**~AU.** !"LICK .. 1IP'L CJo8**~** _ 110 110 AIIDIU. 12

.. 16 •• 13.'1

.. 16.' 1
.... • 16,0 2."

/REOULATORY/REPORT
- 19390 DAY INHAlADONTOXICIY STUDY IN TIlE RAT WITH RECOVERY PHASE 

### APPENDIX 6 • INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY (LANDING FOOT SPLAy' TIME TO TAiL-FueK, FORE· AND HIND-UMB GRIP STRENGTH)

GiIOIIJJ' , 04 D08Ii;.Jn!'II'L, 1000 

# ... un. I'LICIt 

# .- JIIlIIL c..­ IIAL8 -=0 10 110 AIIIDL 12 1 17 11 10••' 1 17 :12**4.s~** 1 17 33 4.6l 1 1'7 34 15.6' 1 17 3S 211.0. 3 18 3. 7.6. :I II n 5.1. :I 11 '31 10.64 3 11 II 4.13 :I 11 40 111.:11 PBIIALII AIIIDL 2 21 01 :zo.o. :z 21 ilia 3.07 :I 21 .3**6.'~** a 21 04 4.01 :z :Ill 

# ... 12.:12



# .. 21 

# ., 4.13 4 :112 t7 6.71



### IREOULATORYIREPORT
- 19490 DAY INHALATION TOXlCIY 

### STUDY IN TIlE RAT \\TI1I RECOVERY PHASE 

### APPENDIX 6 - 

### INDIVIDUAL FUNCTIONAL OBSERVAnONAL BATTERY (LANDING FOOT SPLAY, 

### nUE TO TAiL-PLlCK, FORE· AND HIND-UMB GRIP STRENGTH)

IIII'L GIIOII1' • 04 cam: 

# ....... DOIIIi LS¥B. 

# ... 1000 

# .... 'rAJL J'L!CIt 

# .­ 110 110 UDCI.L 12 

# • 21 

## •• ZO.GO 40 Z2 

## •• 5 •• 

# • Z2 100 Z.:I1

REGULATORY/REPORT • 195

# •• 90 DAY INHALATION TOXICTY STUDY IN THERAT WITH REroVERY PHASE 

### APPENDIX 6 • INDMDUAL FUNCll0NAL OBSERVATIONAL BATTERY 

### (LANDING FOOT SPLAY, TIME 

### TO TAIL-FLICK, FORE- AND HIND-UIIB GRIP STRENGTH)

JtII'L <IDIOVJ', 01 CUIIl IIUoII DIlI8a' DrVn. 

# ... 0 

# ... .... 411U........ 

# • 10 110 IoIIIII.U. 11 1 1 1 ",e 1 1 ::I U. 1 1 3 4:15 1 1 

# • 521 I 1 

# " 4121 :I ::I 41 375 :I ::I 7 621 :I s :a 2 

# • 

# , aso 1111 S ::I 10 UI naw:.s .umAL J 5 III 

## "'I Z 5 6a 525 l 5 13 175 II 375 1 II U 

## .01 32.5 

# • 

# ., •• ISO 

# •**~LATORY~ORT** . 196