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' 11111 nil 111\\ II1~ 11111 nl ~n 11111 I111I ~ 11111 11111 5 0 0 5 0 0 0 2 2 0 	 5 J S 

-rD p-oc.l 	-<85 

-.. 

VRF.Om .ATORY/RF.PORT 
90 DAY INHALATION TOXICITY 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 ofAmerica. ' 

STATEMENT OF NO DATA CONFIDENTIALITY CLAIM 

No claim of confidentiality 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 of these data in compliance with FIFRA does not constitute a waiver of any right 

to confidentiality which may exist under any other provision of common law or statute or in 

any other country. 

2) The following statement applies to submissions to regulatory agencies other than in 

the United States ofAmerica. 

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 of this product or 

any Qther product without the written permission of 

REGULATORYnffiPORT . 2 
90 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 Laboratory Practice, re"ised 1997 

(ENV!MC!CHEM(98)17). 

24 January 2005 

5:tudy Director Date 

~GULATORYffiEPORT - 3 
90 DAY INHAlATION TOXICITY STUDY IN THE RAT wrtH RECOVERY PHASE 

! I This page 


may be required 


by some 


regulatory authorities . 


./REGUlATORY/REPORT - 4 
90 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 ""port has been aurulCd 

and the conduct ofthis study hill! been inspected as follows: 

Date AuditlInspection Date of QA 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 of custody 2611112004 

11 Nov 2004 Draft report 26 Nov 2004 

07neclOO4 Orail report 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 of custody 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, PR1302 

24 January 2005 

Quality Assumnce Unit) 

~GULATORY~PORT - 5 
90 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 • 6 
90 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 of atmospheric concentrations ............................................................... 14 


2.5 Dates of the 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 of exposure ............................................................................................. 20 


4.3.8 Duration of recovery 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 • 7 

90 DAY INHAlATION TOXICITY STIlDY IN THE RAT wrm RECOVERY PHASE 

4.10.1 Urinalysis............................................................................................................... 23 


4.10.2 HaematoJogy.......................................................................................................... 24 


4.10.3 Blood clinical chemistry ........................................................................................ 24 


4.11 Investigations post mortem .................................................................................... 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 of cyanide 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 post mortem ..: ................................................................................. 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 


IREGULATORY/REPORT - 8 
34 

90 DAY lNHAlATION TOXICITY srUDY IN 1lIE RAT 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 of bodyweight 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 FOR TABLES 2 AND 6 ................................................................................. 52 


TABLE 2: Clinical observations .......................................................................... 53 


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


TABLE 3: Intergroup comparison of bodyweights.............................................. SS 


TABLE 4: Intergroup com~son of food consumption ..................................... 61 


TABLE S: Intergroup comparison of foon utilisation .......................................... 65 


TABLE 6: Ophthalmoscopy................................................................................. 66 


GLOSSARY FOR TABU 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 of time to tail flick ........................................ 77 


TABLE 12: Intergroup comparison of motor activity ........................................... 78 


TABLE 13: Intergroup comparison of haematology ............................................. 80 


TABLE 14: Intergroup comparison of blood clinical chemistry ... : ....................... 85 


TABLE 15: Intergroup comparison of urine clinical chemistry ............................ 92 


GLOSSARY FOR TABLE 16 .............................................................................................. 93 


I 


IREGULATORY!REPORT 1- 9 

90 DAY INHAlATION TOXICITY STUDY IN THE RAT wrrn RECOVERY PHASE 

TABLE 16: Intergroup comparison of urine data - qUalitative tests ...................... 94 


TABLEt7: Group range urinary sediments .......................................................... 95 


TABLEtS: Intergroup comparison of organ weights ........................................... 96 


TABLE 19: Intergroup comparison of palmitoyl CoA ........................................ 111 


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


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


APPENDICES 

APPENDIX A: Chamber validation .......................................................................... 124 


APPENDIX B: The determination of In test atmospheres .................. 126 


APPENDIX C: Allocation of rats to experimental groups ........................................ 129 


APPENDIX D: Arrangement of animals 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 of stAtistk.:d methods_.. ................................................ 145 


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


INDIVIDUAL ANIMAL DATA 

INDIVIDUAL ANIMAL DATA VOLUME I ................................................................... 148 


APPENDIX 1: Individual clinical observations ......................L.............................. 149 


APPENDIX 2: Individal bodyweights (g) ................................................................ 151 


APPENDIX 3: 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 10 

90 DAY INHAlATION TOXICITY STUDY IN TIlE RAT wrm RECOVERY PHASE 

APPENDIX 11: Individual organ weights (g) ............................................................ 350 


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


APPENDIX 13: Individual pathology data ................................................................. 399 


REOULATORY/REPORT - 11 

90 DAY INHALATION TOXICITY STUDY IN THE RAT wrm RECOVERY PHASE 


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 of recovery. Recovery 

. animals were retained without treatment at the end of the 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 of grip strength, time to tail-flick, landing foot splay and motor activity were 

conducted during week 12 of the study. Urine samples collected during weeks 13 (main 

study) or 17 (recovery) were analysed. At the end of the study, the rats were killed and 

examinedpost mortem. Cardiac blood samples were taken for clinical pathology, selected 

organs were weighed, liver samples were taken for the determination of palmitoyl co enzyme 

A activity and specified tissues weretak.en for histopathological examination. 

1.2 Results 

Analysis of the test atmospheres gave the following results. 

Group Target (ppm) MeaD of Means 

(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 of the recovery period or were within the historical 

'REGUlATORY/REPORT - 12 
90 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 of the 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 of no toxicological significance. 

The pathological no-effect level was 1000 ppm of 

1.3 Conclusion 

Administration of up to 1000 ppm by inhalation for up to 90 consecutive days 

resulted in no adverse treatment-related findings. 

'REGULATORY/REPORT • 13 

90 DAY INHALATION TOXICITY STUDY IN TIm RAT WITH RECOVERY PHASE 

2. INTRODUCTION 

2.1 Purpose 

The purpose of this 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 of laws, 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 of the species generally recommended for the assessment of toxicity. The 

Alpk:APtSD strain of rat was used because of the substantial baCkground data available for 

this strain, in this Laboratory, relating to studies of this type. The inhalation route was 

selected for the administration of the test substance as this is a possible route of exposure. 

2.4 Selection of atmospheric concentrations 

The atmospheric concentrations were selected by the sponsor on tbe basis of a 2H-day 

preliminary inhalation study performed by the sponsor. 

REGUlATORY/REPORT - 14 
90 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 of toxicity 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 of 5 years from the date of issue of the final report. At the end of this period 

the Sponsor will be contacted regarding the further retention, return.to the Sponsor or . 

destruction of the archived materials. 

'REGULATORY/REPORT ~ 15 
3.1 

90 DAY INHALATION TOXICITY STUDY IN THB 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: 

CfL test 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 of analysis (dated 31 March 20(4) and re-analysis (dated 26 November 

2004) are retained in the The test substance characterisation is the 

responsibility of the Sponsor. 

4. EXPERIMENTAL PROCEDURES 

4.1 Atmosphere concentration 

4.1.1 Trial ganeratlon 


Trial generations were carried out prior to the start of exposure 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 of atmosphere gene~tion. 

\ 

iii) Determine the most appropriate method of analysis. 

1lHOULATORY/REPORT - 1~ 

\ 
90 DAY INHAlATION TOXICITY STUDY IN THE RAT WI1H RECOVERY PHASE 

iv) Determine the distribution of test substance in the exposure chambers. (Appendix A) 

4.1.2 GeneraUOn conditions 

Test atmospheres were generated by metering appropriate amounts of liquid test substance 

onto the top of a jacketed 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 of the 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 

of 500 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 of test 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 of the 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 17 
90 DAY INHALATION TOXICITY STIJDY IN THE RAT wrm RECOVERY PHASE 
 I 

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 of freshly prepared standards prior 

to the study and at intervals thereafter. The peak obtained was used to calculate the 

atmosphere concentration. 

Control atmospheres and room air were 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 of the study animals were 

accommodated in cages in stainless steel holding chambers of approximately 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 - 18 
90 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°C and relative humidities of 25-29% 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 of the study. 

The diet and mains water were supplied ad libitum, except during exposure. Diet was 

withheld during urine collection. 

Bach batoh of diet is routinely analysed for composition and the pxesence of any 

contaminants that could affect the purpose or integrity of the study. Water is also routinely 

WlalYSed COl the prcscnce of contaminants. Certificates of onnlysis 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 of the 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 of each cage of animals 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 - 19 

90 DAY INHALATION TOXICITY STIJDY IN TIm RAT WITH RECOVERY PHASE 

4.3.5 exposure concentrations 

The main study consisted of one 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 of the 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 of five 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 per week, 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. 

REGULATORY/REPORT - 20 
90 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 of the 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 of each rat was recorded immediately prior to exposure on day 1, then 

weekly. 

4.6 Food consumption and utilisation 

Food consumption was recorded continuously throughout the study for each cage of rats 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 of food eaten. 

4.7 Ophthalmoscopy 

The eyes of all main stutly ruumals were examined prior to the stnrt of exposures. The eyes 

of the 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 - 21 
90 DAY INHAlATION TOXICITY S11JDY IN 1lIE RAT wrrH RECOVERY PHASE 

recorded on a computer system by personnel not directly involved in the clinical 

observations. The presence andlorabsence of all listed observations was recorded and the 

degree of condition 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, walking backwanls, 

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 of the spine, downward curvature of the 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 of splay when animal lifted by base of tail), visual placing response 

(animal is lifted by base of tail and slowly moved downwards towards the edge of arena). 

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 - 22 

90 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 [cconiing apparatus. A111llain 

study animals were tested in week 12 of the study, immediately after the FOB. Each 

observation period was divided into ten scans of five 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 prior to 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 - 23 

90 DAY INHALATION TOXICITY STUDY IN 'I'HB RAT WITH RECOVERY PHASB 


Ifthe appearance of the urine sample was considered to be abnormal, a portion of the 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 of potential clotting (prothrombin time and activated partial thromboplastin 

time) were made on samples of blood 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 - 24 
90 DAY INHAlATION TOXICITY STIJDY IN THE RAT WITH RECOVERY PHASE 

4.11 Investigations post mortem 

4.11.1 Termination 

All rats were killed by over-exposure to halothane Ph Eur vapour followed by 

exsanguination. The animals were examined post mortem. This involved an external 

observation and detailed examination of thoracic 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 glandspleen 

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 -25 
90 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 of palmitoyl CoA An accurately weighed sample of approximately 58 was 

placed in 15ml ice cold O.25M sucrose, bomogenised and centrifuged. The oxidation of 

palmitoyl CoA isa measure of the degradation of saturated 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 post mertem, the lungs (with trachea and larynx attached) were excised, 

trimmed and weighed following removal of the 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 of larynx were produced, taken at the level of the base of the 

epiglottis, through the ventral pouch and the cricoid cartilage to include all different epithelial 

cell types of the 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 of variance 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-f were within 8% of the target 

concentratio~ daily values are presented in Table 1. 

Group Target (ppm) Mean of Meaas 

(ppm) 

Standard Deviation of 

Meaas(ppm) ._.... ----' 

IREGUlATORY/RBPORT • 27 
90 DAY INHAlATION TOXICITY snIDY IN TIlE RAT WITH RECOVERY PHASE 

2 100 104 7 


300 310 22

4&6 1000 1000 60 

The distribution of the 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 or immediately 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 300 ppm did not form part of a 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 

1000 ppm was lower than control in weeks 2, 3,4, 6 and 15 (recovery only). The 

/REGULATORY/REPORT - 28 

90 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 of all animals examined pre-study were normal. The eyes of all animals in control 

and 1000 ppm exposure groups (main study) examined in week 13 were normal. 

Consequently, the eyes of the intermediate and recovery groups were not examined prior to 

termination. (Table 6) 

6.6 Functional observation battery 

6.6.1 Clinical assessments 

There wen:; DO treatment-related dluiosl obscrvatiumI during the cUn1cal assessments made in 

week 12 as part of the FOB. (Table 7) 

6.6.2 landing foot splay meaaurementa 

There were no effects of treatment 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 of treatment on the grip strength measurements. (fables 9 and 10) 

6.6.4 Time to tall nick 

There were no effects of treatment 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 RAT WlTH 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 an considered to be incide.ntal to 

treatment. 

At week 18, in males exposed to 1000 ppm, 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 of recovery; In addition, mc;an cell haemoglobin and MC4lD cell haemosIobio 

concentration were higher than oontrol. 

None of the 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 300 ppm (glucose in 

females, phosopholipid andcholestero} in males). None of these 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 • 30 

90 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH 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 liver were 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 eoA oxidation 

There were no effects on liver palmitoyl CoA activity measured in the main study animals. 

(fable 19) 

6.9.3 Macroscopic findings 

A small number of lesions was observed, none of which were rela.ted to treatment. (Table 

20) 

REGUlATORY/REPORT - 31 
90 DAY INHALATION TOXICITY S'IUDY IN TIlE RAT WJI'H RECOVERY PHASE 

1.9A Microscopic findings 

A small number of spontaneous lesions was observed, none of which was related to 

treatment. There was a minimal increase (3/10 compared with 0/10 in controls) in the 

incidence of eosinophilic casts (unilateral) in the kidney of males exposed to 1000 ppm. 

There was however, A decrea~e in the incidence of tubular ba400philia in the kidney of males 

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 of this 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 of the rats was satisfactory 

and there was no evidence of disease or infection which might have compromised the 

interpretation of the tindin~. 

Analyses of the 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 of the 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 of no toxicological sjgnlflcance. The 

pathological no-effect level was 1000 ppm of 

'REGUlATORY/REPORT - 32 
90 DAY lNHAI.ATlON TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE 

8. CONCLUSION 

Administration of up to 1000 ppm by inbalation for up to 90 conse~tive days 

resulted in no adverse treatment-related findings. 

!/REGUIATORY/REPORT • 33 

90 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 of statistical methods for the analysis of general 

toxico1ogy data. In Statistics in Toxicology (cd. B J T MorSan). Oxford University Press, 

Oxford. 

Doe JE and Tinston DJ (1981), 'Novel Chambers for long term inhalation studies'. In 

Proceedings of the 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 sruDY IN 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 

3001 

j

~ 2901 270j -1 - :-:::c:::~-: -::.; . ~ c.~" . /-..-.-------- ­ ~/ /-­

260 " / //...---~/-' 

____ l:j! .7".-:'-...-.­ j /~ 

230 // 

--- 100 JlPn 

----- 800 JIPD

:jI~/ r-:.m -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 - 36 
90 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 - 37 

90 DAY INH.uATION TOXlcrrY SI1.DY IN THE RAT 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) 

2101' 
 DlO pp:o

200 
 -"""r'''''',, ".-,", ''',-i r"'l~-T"""I I ....'·,...~

2 8 4 5 6 7 8 9 10 n 12 13 14 lD 16 17 18 


Week 


REGUIATORY/REPORT - 38 

1 
90 DAY INHAlATION TOXICITY STUDY IN TIlE RAT Wrffi RECOVERY PHASE 

AQURE 3 - STAnsTlCAL ANALVS'S OF eoOYWElGHT ADJUSTEO FOR INITIAL WEIGHT 

..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 ~ ·:JL:jl]ntt. j

.. -w 

-1IIO

-~~ ""..'''~ ."•• t 	 I r r t-··""f""'""l'"-~"''1~"f'''''''''''''''' -80 " ,,', ~'T 8 • W "-'-'-""'" M rr ..c llilB4S I " 	 _ 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 .LLJ...L1nJ.. .J n1 1 I 1 I ... -10 

-:M) --, 

-~~~~~~~~~~~~~~ -80~ , i~"r""'rr>""""''"'""T~ 

1 2 a 4 6 ~ Tap m u ~ Dum MW. 1 a a 4 •• 7 •• 10 U m _ um _ tt ~ 

""'"* 

'REGULATO.RYIREPORT - 40 

90 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 

, .5' I ao ' ... ~ /'~/ . \ \ // ' '. ". '. ~ ~ ...... .x.....oc .~~ \ / 
 V 

. 29' - .... ,"-, 

'........" \ '-', / , //.: ""'-" ,,~ "..,
 .. . - "~: "

' '. ,, ,, j " I ',- .

l ! 2Jl ./ ... """"""" ':5 

'ZT 1 

I 

26~, ~--r~~~~,--~~~...,-~-' --1-·....... r,~~,--,....,~~~~--~~-,

1 2 8 4 5 6 'T s 9 10 n 12 18 

Week 

REGULATORY/RE1'ORT - 41 

DAY 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 ./ ," - /\ 1 22}" / / . \, ,~ I / , '--... ..... 1 _" i 11 ~,~:--- '_./7\'''', \ 

,,/" / 

/ ',.\ \ _-, .... ~ 1' .... , 

~m/ .' . \

" ,/,.. .. _" ~l""", ~'-\ .......... \. ,I ......- - "'" " \ '\ 1" , 

,I , , 

\ 

\ 

, , I .. \ ...... / " , \

~ ',I \~ ooj '\ 

., 

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

{ ~-~~.-:~ == 

\'

lB~ --~I 

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

1 2 8 I) 6 7 8 9 10 n 12 lSI '" 

Week 

IllBGULATORY/RBPORT . 42 
90 DAY INHAlATION TOXICITY STUDY IN TIlE RAT WITH RECOVERY PHASE 

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 - 43 
90 DAY INHAlATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

122 I ml , , 

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 - 44 
90 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 - 45 
90 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 - 46 

90 DAY INHAlATION TOXICITY STIIDY IN TIlE RAT WITIf RECOVERY 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 1 S-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 - 47 

90 DAY INHALATION TOXICITY SIUDY IN THE RAT WITH RECOVERY PHASE 


TABLE 1 - ATMOSPHERIC CONCENTRAnONS 

GAOUP3 


Group 3 I Target 30t ppm 

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--­ - ll-May-2004 7 288 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 - 48 

90 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 - 49 

90 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 .~ 

9 21-Apr-2004 6 -1020 71 7.0

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 ... 

21 U3-May-2004 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 wml RECOVERY PHASB 

TABLE 1 • ATMOSPHERIC CONCENTRAnONS 

GROUPS 4 .. 6 - CONTINUED 
 ~-. 

Groups 4&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 - 51 

90 DAY INHAlATION TOXICITY STUDY IN TIm RAT wrm RECOVERY PHASE 

GLOSSARY FOR TABLES 2 and 6 

Key:­

NO.OFOBS.- Number of obscrvatioll~. This may n::present the recording of an 

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 In this Table. 

/REGULATORY/REPORT - S2 
90 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.,. ... psJaLLBD !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 

8IDtI 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 - 53 
90 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 of covariance. 

The size of the adjustment is determined by the size of the inter-group difference in group 

mean initial bodyweight and the strength of the relationship between initial bodyweight and 

subsequent bodyweights. 

Orgaa. weight atijusted for bodywefght: 

Group mean organ weights corrected for inter-group differences in group mean terminal 

bodyweight. The adjusted means are calculated statistically using analysis of covariance. 

The size of the adjustment is determined by the size of the inter-group difference in group 

mean terminal bodyweight and the strength of the relationship between organ weight and 

terminal bodyweight. 

Key to results of statistical 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 - 54 
90 DAY INHALATION TOXICITY STUDY IN1HE 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 to1.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 

10 6011.11 

..... 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 

18 

no.' 

_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 

18 tt••• 

...... 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 ... .. .. .. .. ... ... ... ... .... ... ... 

J 
90 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 • _ 551.' 5&4,.

REGULATORY/REPORT • 57 

90 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. 0 -=-,_1) 1000 -.. -~~..--.-.-.......................-.-.-.~-...................................................................


...... 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 

10a42 .• 

26." 

10 

21•• 1 

11.2 

.0 

2..... 

11.2 

10 

2311.1 

....... 

.... , 

..... , 

• MIt 7 

IIIWI 

S.I>,

aN1IftD 

•...

••

-

1>.

DolV81111D •_ 

UJV8'IIID •

8.1>.

-.....

-

: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 

10 

21•• 2 

2•••• 

10•• 10 

2.1.'· 

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 

102.,..' 

.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 - 58 
90 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 

10 

211.7 

... 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 - 59 
90 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 -60 

90 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 

1 

21.1 

~.I 

1 

U .• 1.1 

I 

21.' ',I

J 

2'.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 INHALATION TOXICITY 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:rolI 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 - 62 
90 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 

2 

12.1 

0.1 

2 

22.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 

2 

22•• 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 

2 

21.' 

0.7 

2 

111.2 

0.1 

2 

111.2 

0.1 

2 

llEGULATORY/R3PORT - 63 
90 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 -64 

90 DAY INHAlATION IDXICITI STUDY IN TIlE RAT 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) 1GO 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 -65 
90 DAY INHAlATION TOXICITY sruDY IN THE RAT wrm RECOVERY PHASE 

TABLE6-0PHTHALMOSCOPY 

SUa DLB 

:nJ:(8) IIOIIDl. 

110. OJ' OBI. 

110. OF AllDllL8 

..... :nOH-~ 

0 

Ps20 

10 

-2 

100

,.. 

10 

10 

13 -2 

IIUII ftIIDl' 

301 

ppa 

10 

10 

-1 -2 

1000 

.J1III 

20 

11 

-1 -2 

0 

PsUI 

10 

13 -2 

1000

.... 10 

10 

-1 -2 

IlICOVDI' 

-1 

SU, rllmLll 

:nJ:(S) aomw. 

11). OJ' OIlS. 

110. OJ' AIIDIlL8 

..... I'Rmt - ~ 

0 

ps20 

10 

-2 

100 

JIIIII 

10 

10 

13 -2 

300 

Ps10 

10 

-2 -2 

1000 

PJIII 

20 

10 

-2 -2 

0 

ppa 

II 

10 

13 -2 

1000

.... 10 

10 

-2 -2 -2 

'REGULATORY/RBPORT - 66 

90 DAY INHAlATION TOXICITY STUDY IN DIE RAT 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 of animals noted to display the condition listed. 

All incidences of no abnormalities detected for each parameter assessed are included. 

REGUlATORY/REPORT - 67 
90 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 - 68 
90 DAY Il\HALATION TOXICITY STUDY IN THE 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 - 69 
90 DAY INHALATION TOXICITY STIIDY IN THE RAT WITH RECOVERY PHASE 

TABLE 7 • FUNCTIONAL OBSERVATION BATTERY CUNICAL ASSESSMENTS 

DPU 

BJD[ 	

DOSII J.BVIIL (PH) -------.---~---------------I---·-----·--~·------···--I • 100 :SOO 10~0 0 100 SOD ltOO _ U'AIlClIDM 

I:1I¥IIItlft COIIII " 10 10 LO 10 10 10 10 10 

IIUIICDD 

I:1I¥IIItJft COIIII " 10 10 lO 10 10 10 10 10

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 . 70 
9{) DAY INHAlATION TOXICITY STUDY IN mE RAT wrm RECOVERY PHASE 

TABLE 7 - FUNCTIONAL OBSERVATION BATTERY CUNICAL ASSESSMENTS 

_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 -71 
90 DAY INHALAnON TOXICITY STUDY 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 -72 
i)() 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 

UMIIIOOIID SJmDtIft 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:IBftlS 

RV'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....) 

o tColltrol) 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 - 74 
90 DAY INHALATION TOXICITYSTUDYIN 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 ....................--.................................................................................. " 


.. ... 	 603 521 570 4.,

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 - 76 
90 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 - 77 
90 DAY INI:IALATION TOXICITYSTUDY 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.'

10 

18.6 

U.S 

10 

77.0 

aa.40 

10H.l a •• 1 

10 

1'.7 

IUIItlt.. II-3~ 

S.D.

•

-

:&7.' 

10 

71.1 

Z;II.S 

10 

81.0 

a3.1 

10 

Sll.' 

.II.t 

10 

13.2 

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 

10 

1:1.7 27•• 

10 

"'.S ala.' 

10 

fREGULATORY/REPORT - 78 
90DA 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 

10n.I 

11.D 

tel 

73.1 

1l.2 

10 

11.3· 

13.0 

10 

13.0· 

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 - 79 
90 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 - 80 

90 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 .....................-.--.......................-.~-..-...--................................................................... 

Plat;elet; COGat (zIo*.'/l) 	 ". 1f1 ,U '31 ,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) 	 au 1." 	 1.31 1.112 1.75· 1.U 1.1'··

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 WflH REOOVERY 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) 	 .... 	 ".1 "'.1 11.3 11.0 11.' 11.3· ••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 . 82 

90 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) 	 '21 '11 .76 '66 1006 '22 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.• l'.~ 16.0 16.3· 16.1 16•• 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 . 83 
90 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 - 84 
It1 

~ 

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•••••

I •I•I .. ••

• 0 .. • I ~ ..; 

II ... .. ... .. .. 
 I 0 .. 0 .. 

... 

f 

I 

• 

'. .. '. ... ... .. ~ -I 

" .. ... .. 
 , .. "'SI-I• .....
 •• ...... = ...... ., I •

1 .. ... • .; II! .. :10: t=0l "",.. .. ~l ... '1 ... " ..... j ! ... : I ~ 

. 

.; 

hi ". ... .. ... .. •• •• ..-. .....-. .. .... .. ... 

0

fi 0" 

.. ... ... 

.... ..... .... .. N

'... 

.. ~= ~ • .. II! . Ii> 

... -: "! .. .. .. ... :: .. t·;.. 

.... .. .. .... ":. ... 0 .. , 1 ~.

0 

.... ". ... ..... 

-. <"IOC o. <'tri 0"

:

• 

"'. 0 

0" D" 

.. ..
 .. .. =<1 ..

... ... 

"! 

.- .,

.. ..; ..

~ ,.; III 2 I .. .. : ..:.,.. .. "' .. A: ".., • 0 

... ~~ ~~ .;9- ~= 

0

~= ..... oj,

, I, ·1 _ i i I I. i i I Q c:i c:i Go Go Go 

Q

,;.,.

·

• 

I 

... m. .:. ... .;.. • lit I 

1 


I 
•

I 

1 •• ;j ..

.. ..

"- ... N 

::; .. .I .... .... ... ! ... ~ 

..

t J ! 

.... 

@ 

~ ;:4 i :: 

::l 

- ...

i ..• 


! ;: ~ !
 ! •• " ':I., J J ! 2 ~ ! 

'II 

j J 

.. .. ":

.. ~ ": ., ~ .. .. .. .. • .. .. .. .. .. .. • .... .. :a '... .4S '. '... "' ... 

... 

'0 

.. 

•.. 0 

~ ...

•... ..;. .. to ... .. = ... '" II 

...... .... 

-

'0 

.. ..

'. 

•-... '. .:a .. .. .... ~ 

.. ": "! .. .. .. .. ., ... .. .. '0 

.. ..... ... ,

. ~ ...... ·co .... . ... """ "'0</ . 

.. • .: 

ot 

.. "l t'! • • 

1111 I I .. II 

J ! J lil 

J ! l ! ..J 
90 VAYlNHALATlON TOXIcrrY ~yIN 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." :t. ::l'1 3,lS .).41 3.'1. 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

• l4J i' 10 111 1. 10

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 • ... 1t U IJ) 1. 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

.-......-.--.............. ....---.---.-.-.-.......•-........••...--...... ....--

, 

.............................................. 
 • 10_ CEeaU•• E:I.II... (IV/l) IIIIWI 1".3 137.' 131.1 lU.l 1••& 101.1 

S.D. 	 201.6 61.' 37.1 51.7 1'.' 41.1 

10 10 10 IJ 10 10 • 

.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 '.62 B.D. 	 0.66 0.60 0.'. 0.71 0.75 0.66 

10 10 10 U 10 10 • 

:r1_ Chlor:l..... (_111) IIIIWI lOa.6 In.O 1.1.' 102.4 100.' 100.3 

III.D. 	 1.5 1.2 1.:1. 1.5 1.' 1.1 

10 10 10 11 1. 10 • 

Pla_ Calo:l.... (_1./1) 	 IIIIWI 2." 2.72 -:ill. 7. :ill. 75 :ill.11 a.,.. S.D. 0.1. 0.1111 0.12 0.07 0 ••' 10 10 10 U 10 10 • 

1'1._ Pbo.pborv.a (_111) IIIIWI 1.t. 1 ••5 1." 1.13 1.tI 1.16

III.D. 	 0.:lI2 0.31$ 0.6. 0.43 0.31 0.31 

10 10 10 If 1. 10 • 

.1._ PboaPbol:l.p:l.4 (../41) IIIIWI 140.' It•. 2 15'.0· 143.7 166.& lIt.a II.D. 	 12.6 16.2 21.1 21.6 u.a :iIIO.7 

10 10 10 It 10 10 • 

fREGUlATORY/REPORT - 87 
~ "... 

~ 

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I ••
 :E I 


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I 

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tit .. ., ~ • :::i ...... ... N:!: 0 ... '. 0 '. ...... 0 "... "'= '. '.

Q ;:ii z .... lit ': ~ :It •.. .; ... lit ., 

~ 1'1 ..; .. ... lit .. 0 I !: ... ... •.. .. .. .. ~ -s= '0 '0 9 •'0 •'0 •'0 1-= ...... 0 ... ...... '. "'''' _0. ...... ... ... .... 2:. '. - ID f .. .. ., 0 

II. !! ... '" ... . "'! I't ... , ... "? ... .; .. ... 0 ... :: '" .. • ... .... .. .. 1ft 

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0 

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po -I ••

• .. .. lit I .. ..• )! .. 5 ... .; ... ... '"! ..

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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 ....•....-...••.•.-....--.--.--...--..-.....--...~.-.-.....•..__............................................................... 


']a... Cbol••tarol 1-.01/1) 	 2.11 2.01 2.11 2.2' 2,"" 1 •••• S.D. - 0.27 O.:tl O.U ••:to 0.22 0.3' 

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.' ".. S.P. 	 27.11 n.t 10.7 1••' ••1 68.5 

10 10 1~ 10 10 10 • .:a- ~.t. :aaaotr6AlJ~U'_. (IV!l) .... 108.1 .... ,... ,... 1117.7 111.'· S.D.. 11.' 11.1 12.3 33.' 37.0 

".. 10 10 11) 10 10 10 • 

REGUlATORY/REPORT • 89 
90 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 .....----_.._----..._-............-......................._...•...•••-_........................................................ 

"a- cr..tllle Ittaue (IV/II .... lt6•• 7••5 10'.5 '7.' n.7 7••' S.D. 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) 

• IIIIWI 1111 •• 102.11 102.' 10'.1 101.1 101. '7 

B.D. 	 1 ... 2.' 1.3 1.3 2.2 1.' 

10 10 10 10 10 10 • 

.a- Cal.cd_ (_1/1) 	 ..... 2.77 2.79 2.77 a.11 2 •• 2.'11 

I.D. 	 0.0' 0.0' 0,01 0.0'7 0.09 0.11 

10 10 10 10 10 10 • 

.a-l'IIo.pbol:'llll (_1/11 ..... 1.015 1.'11 1.71 1.7t 1.U 1.61 

S.D. 0.&5 0.2' 0.&'7 0.'" 0." 0.33 

10 10 10 10 10 10 • 

.a-tboqIballpld (../41) KDII 153.7 14•• a 13'.a* lSI.' 171 •• 175.' 

S.D. 	 1".5 11.' at.l 10.' It•• aO.1I 

10 10 Ib 10 10 10 • 

REGULATORY/REPORT • 90 

90 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 ..........__..........................................--_...................................... 


II~ ~·1I111~1 ~r...f_... IIV/l) 

lIIal•• 7.0 6.7 

B.D. 

- 0.5 0.6 II II • J'~. 7.1 6 •• S.D. 

-- 0.6 0.7 

10 10 • 

'REGTJIATORY/REPORT - 91 

90 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' ...----......--...............--.~..... -~.......-....--........................................................................ 
 1IIIlA_ 

17riDa '9'01_ (101) U.0i5 17.71 16.70 11.111 II.S0 11.10·· ••111. 6.40 10.15 7.Z!I 10." 7." 2." 

10 10 10 11 10 10 • 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 • "r1ae S.....,.l:fJ.o '1"..11:7 1.01' 1.021 1.023 1.0:1:1 1.024 1.021 ••P. - 0.004 0.00' o.on O.Oot •• 00S 0.011 

10 10 10 It 10 10 • 

a:l.a... 6.12 6.1& .,.. 6.74 ',U ..SO ••

-

D. 0.26 0.'. 0." 0.32 ~.32 0.17 

10 10 10 It 10 10 • 

/REGlILATORYIREPORT - 92 
90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 


GLOSSARY FOR TABLE 16 


NEG = negative 

The following represent an arbitrary scale of increasing presence of a urinary parameter as 

measured by a oolour change of the relevant portion of a test strip. 

+ 

++ 

+++ 

The number against each analysed level denotes the number of observations. 

:/REGULATORY/REPORT - 93 

90 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 - 94 
90 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 of view. 


++ =Few in most fields of view. 


Only urine samples with cloudy appearance were examined (one control male, two control 


females). 

~GULATORY~RT - 95 
90 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 C8} 	 • 

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 • 96 
90 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." 0.03 0 ••' 0••1

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 I.', 1._ 1.97

REGUlATORY/REPORT . 97 
90 DAY INHALA.fION TOXICITY STUDY IN THE RAT 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 •• I." 1."

S.D. 

-- '.11 0.17 0.10 0.115 G.l' 0.12 

10 1. 10 10 10 10 

ora- to ....,..1..1: lat20

•

It)

...- '.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 • 98 
90 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 ............_----.-_.--.----._-------...--......-........-.............................................. ..... 
 o.u.r 

1IIlIU8 

BcMI:r-.1lJllt '.1 .... n •.l U ••, sa.•• 102.1 slS.a !lt5.' 

S.D. 	 a..' 32.a '5.2 11.1 ".'7 10 10 10 1. 10 1. 

Oli:g- 1fej,..... '.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

•

(tJ IIIIIUI I.atl O.a.' o.an 0.2'4 I.atl ••au ••0. a.ou o.on 0.011 O.t23 I ••U •••:a,

• 	 10 10 10 1. lG 1. 

0J:pIl ••.1....\ .II.4;Jun.. Par IIocJ.7wa;1l11lt 

1.'11 1 •••0 1.4" 1 ..... 1.111'7 1.UO 

PllDLD 

'l'uallULl. ~""t [II) .... 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 
•• 

~ ~ 

~ 

~ 

~ 

.~ 

~ 2:i 

>­

~ 

§ 


~ f-< 

6 


•

=,
 -4. •-"001"

I

_... 2i •

I 

_ lSI .... 1 •

! 

II 

J" 

G. 


1=
 I •

i 

•flO 

.. :: 

i 


~ 

•

" •I

" 

• I•

" r " III 

~ " " 

i

•

• ;: I 

....... ....0 .. . .... •• ..
 ••• • 0 .. ••• .... -4 .;c:= • 0 ... .. N

.... .... 

.... .,0 .... Ii: .. '" ...... • '0 . · .... ... "'! 

'" 

"'! .. .... ~R .. ft •• • .0 ~~. : ..... .,0" 00'" " 

~ .. .... :10 .,• ...... .. '. ... 

'" 

..... ~~~ 00"" ..; 
 ... .... .., .. 
 • '0 ..... 0 .... .. ,...... .. ... ·... ·.,.. o. " ft

.... ..• .... ., ...... ~~= ~~= .. ..." .... ... ='" 


i~_ II:i _jA
 1Ii_; .l. 

..
 ..... : ... .. ..• 

f, i 

• .. ....• 

-

J.. ... ..to I ... 

'; I 

i .. I}

I.. J I 

0 

If i 

.. 

...... .,.,

001 

.... .. "0

D · ...

' . ~ "OS M

=== 

.... 0 ... 

.

"0.. ... ..... .....

.......0 NO 

..• ... 00 ·.... 

• 

~ 

N 

"! .. ...•.. ... .. .... .... -:~. ~~O • ~N'" .. 0"- 00" ... 

.... ....
 ,,; .. :::1. ..• 0 .... ~~= fI" ";0'" .0 .. 

"'fI ... .. ... .... ·.... ...;: ~ 0... .... ..• : ... .0 .. ....... .. .. ==. .... "0· ....0 ..

0 

"0'" ... ... 


N ='" 

Q ... tI

I~. I'ci.:-I'•• .. ,

.... 

1 .. .. 

f, 

.. 


= ~ i .. .. t. I ..

i i 0

I , .. I}
 f I If 

8.... 

i 


~ 0 

S 


::l 

~ 

i a: 

CI

a: 

w 

I­

~ Q 

~ 

f!!

:c 

c" 

iii 

3= 

~ CJ 

IX 

0 

u.. 

0 

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 41'.' Sat.' loa.l 513.a 5U.6

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 1••' 17.3 1'.0 n.3

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.ALATION TOXICITY 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 [ul 

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 • 102 
90 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 - 103 
90 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 t".. 52••' 4'6.3 113.2 161.6

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 - 104 

90 DAY INHALATION TOXICITY STUDY IN TIIE RAT wrm REroVERY PHASE 

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 .".11 521.' 501.1 !1'.2 1"5.' 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 ....3· 1.024 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

10 1. 11 1. 1.

Orgu. We.1g1Jt 	 (II:) • 	 I'

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. 	 10 10 	 I.
 10 10 

Orgu. WetlJllt Mjut.a 	 • J'OE~"'t 

o 76. 0.1111 0.,., 0.747 o.nl 0.1" 

REGUIATORY/REPORT - lOS 
90 DAY INHALATION TOXICrrY STUDY IN THE RAT wml RECOVERY 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••• sa•• loa.l S.~.2 lIU.' ' 

-

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 (')

.... 0.7. ..75 	 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 

~ ~ ~ :c 

~ 

iii 

~ 

~ ~ ~ i ~ 0 

u. ~ 0

as 

z

0 

U)

~ 

- I'I.l ~ § :E

0 

S< 

u

g a. 

j 

0 

I 

s a: 

a:" J!! 

Z 

>< 

­ ~ CD.,.. ~ w 

...J 

III 

:! 

I 


I 


a 

•

0 

..

0 -.. _I


IS


--•!

..Sl

... 


! 

50 

i~ 

i:.... 


-
..


! 

~ • 

.. ....
 ...,.. ... '" ..... 

0 

"'0 o • 00 00 

"·0 00 .

• "' ... .'... 0.: 

.. o • "' .. 00 ~ ... ' ... '" 0 00 

•... ' '0 1111= 00" 00:1 0 

oe .. ... a II 

.... • ...• ...... 0. 0 :pt'" 001"4 00'" 0 

.... .... "! ... .... 00 ... 0.0 .0. ..

0 

e" 00 oe e ........ '. .... .... 


.... ... ... .....'" 000 

• ...... ... ~c: .. ~~ ... 00 o. <! 0 ='" 

..... "WI ... .... .. 00 go. .. 0." '!~ ... . ... ::" .... .. .. • 

I~. la ·ili 

••; iii.

...... .. 

I .. .. ! 

i I 

•.,

.. 

~i ! I ! 

i I 

t\l I i 

I I J 

n! 

i 

a Hi 

.. 


",. 

• ... 0 "' 

.", 

.... 

"!,.. 

.. ' ;I AlIS .,.. i.-·
 ...... i

.... ..'0... fO!'" 

.. .,;, • '0 

""''' $I" ...
 • • 0 

S"'" 

I~ . .. 

.. 

i 

i 

.a .. ..0

I i 

a i .. 0 

i I Hi 

.. .. ... .. ~g 00 •• .. ' ' . 0 

00 .. 00 .. ' '. 

0

..... e .. 

::8 :1 := 

O"!a C! .. ollS 0 

..... .. .. .... :1. 110 

00" 00" 0 

0 

... .. . ... 

0 

.. 0 

• 000 00. .. ••.... ... ' 00 .0 0 ... .. ... "·0 ··0 ..• ~~ ... c:~ ... e eo .0 0 

e ... .... "'''' .0

• ~~ ... '" ... C!~ ... 0 ...... -0" 0 

Iii. 

-;;Ia, ··0 .• 


, 

... 

! 

1 .. .. 
 i J of .... ...

caJ.. ... it. i " ,1 

s.... 

" 

~ ~ 

3 


~ 
•• 

I 

-• 

i 

i 

I 

g 

• "0 ..... .. ... o • ..... III ... .0 ..• .., .. ··0 • '0 • '0 • ...... ..... 00 .. ..

I

_i... ..... ••

... 00 

.... ..... 

•

.. ..

...... ... -" ...... .. 

.. 

.; 

=t..;. 

• . ... .... .. ... .... "1C!. -14!. 00'" ci ........

U .. .., .. ",0 

00" ...... 00" ....
 o 

J 

o 

• a:s ... •:; 5i ...• ...

J" 
 00 ~~= o .. 

-fit •• ... ... .. 


, ';"0 1:0 000 .. oO

· ... ... =:.. 00'" 00 

0 ...

.

o 

• I ... 

J! ... ... ... .., ..... .. I • '0 III • ....

II 

I 

,..... .. ,,!~ .. .. .. .... '0 

o. :;toO .; 

- ..... ... ...
 ... .... ... , ..• .... ...... 

.... . ... 0 ...... ....... ... ..... 
 .".T"i rl ....

..... I .. 

... ;t .. 00 00 o • -.. c; 

..... 

... 

•

I 

I 


I 


I 

I I I•

I 

i 

I 

I I I I I 
90 DAY INHALATION TOXICITY STUDY IN nIB RATWITH 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 • U9 
90 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 .-... ..--.----..-.--........---......~-............-.............................................--_.. . 
 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 - 110 

90 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 - 111 
DAY INHAlATION TOXICITY STUDYIN TIlE RAT WITH REroVERY PHASE 

TABLE 20 - MACROSCOPIC FINDINGS 

RBIIOVAL 1llWIOIt'. RI1HIDL 

o 1------------------------ 100 300 100f) MILB8 0 --------------·----------1 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 

SUlKIftJlD" ................................... " .... " <I ........ 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 - 112 
90 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 - 113 
90 DAY INHALATION TOXICITY 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 

o 1------------·---------- 100 lOO 1000 FIMILI8 0 ------------------------1 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 - 114 
90 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 

lOCI 

lis10 

30. 

~ 

10 

lOCO 

~ 

10 

•

PJIII 

10 

1000 

IPs10 

.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 115 
90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 


TABLE 21 .. MICROSCOPIC FINDINGS 

JIJIIIOYAL aJIASOlfI 'fIOIIa1Ol.L 

• 1------------------------ 100 300 UOO MaLIS 0 -------------------------1 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 ....t1tt. "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 1 o o 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 - 116 
90 DAY INHALATION TOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 


TABLE 21 - MICROSCOPIC FINDINGS 

I!IIHOftL lIJlASOIII, 'rIUIIIJDL 

o 1·----------------------- 100 300 1000 MALZa 0 -------------------------1 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 - 11i 
90 DAY INHAlATION TOXICITY STUDY IN THE RAT WrrH RECOVERY PHASE 

TABLE 21 - MICROSCOPIC FINDINGS 

IUDICWAL auso., 'fJI.ItIIJJDl, 

o 1------------------------ 101» 3()O 1000 MILIB 0 --------------------·----1 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 - 118 
90 DAY INHALATION rOXICITY STUDY IN THE RAT WITH RECOVERY PHASE 

TABLE 21 • MICROSCOPIC FINDINGS 

ItIDIOVAL 1IBASOIr. HIIIIIlU.L 

o 1------------------------ 100 300 1100 ..... 0 --------------------·----1 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.:Ltbe1.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 - 119 
90 DAY INHAlATION 70XICITY STUDY IN THE RAT WITH RECOVERY PHASE 

TABLE 21 - MICROSCOPIC FINDINGS 

RIIIO'IAL DABOR. 'l'IIJIIaIIaJ. 

o 1---------------··------ 100 300 1000 0 ------------------------1 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 - 120 

90 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 - 121 
90 DAY INHALATION TOXICITY sruDV IN TIlE RAT WITH RECOVERY PHASE 

TABLE 21 - MICROSCOPIC FINDINGS 

~v.u. UA80Ir c 'l':DIIllfAIo 

o 1----------------------- 101 300 10tO 0 ------------------------1 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 .. " ...................................................... 

., ....-asII'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 - 122 

90 DAY INHALATION TOXICITY STUDY IN 'IlE RAT WITH RECOVERY PHASE 

TABLE 21 - MICROSCOPIC FINDINGS 

RBIIOVAt 1III.I.SOa, 'l'Bma1lU. 

Cl 1----------------------- 110 31)0 1000 PBHaLBS 0 ------------------------1 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 - 123 
90 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 - 124 

90 DAY INHALATION TOXICITY S1lIDY 'IN 1HE RAT WITH 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 • 125 

90 DAY INHALATION TOXICITY STUDY IN mE RAT 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/off valve. 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 of 99.9% w/w was used. 

The purity of the test substance was nnt t~ken into acx:ount in the preparation of gaseow 

standards. 

Known quantities of were added to known volumes of air 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 of test substance (td) 

'D = Oen!llity of test substance (1.47g1ml) 

Mv = Molar gas volume @ 18-24°C (241) 

Mw = Molecular weight of test substance (200.05) 

V2 = Total gas bag volume (1) 

'REGUlATORY/REPORT - 126 
90 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 of the relevant exposure chamber, 

using a 5ml gas-tight syringe equipped with an integral on-off valve 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 25mx 530pm 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 - 127 
90 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 of standards to determine thc.linearity of 

response. An appropriate standard of known concentration was used to check the 

calibration at least three times during the first week of exposure and subsequently on a 

weekly basis. 

CALCULATION OF RESULTS 

The analysed concentration was calculated directly by the data system in units of ppm (v/v). 

LIMIT OF DETECTION 

The limit of detection 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 of the 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 of the weight range were 

discarded. 

The sexes were randomised separately. A JJltin Sqtutre Wl'I!II generl'ltt".cil'lnd wa~ used fOT the 

allocation of animals to the experimental groups. The heaviest animal was allocated the 

lowest number in the group of replicate 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 - 129 
90 DAY INHALATION TOXICITY STUDY IN TIlE RAT WlTII RECOVER.Y PHASE 

APPENDIX D· ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING 


INDMDUAL ANIMAL 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 .. Repleate 4, 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 WITIf RECOVERY 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 - 131 
90 DAY INHALATION TOXICITY SlUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX D • ARRANGEMENT OF ANIMALS ON THE RACKS SHOWING 


INDMDUAL ANIMAL 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 

81 82 83 Level 2

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 


88 
90 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 

31 32 33 Level 1· 36 37 38 

34 35 39 40

Cage 0019 KepUeate 1, M, G6 Cage ttll KepUeate 3, M, 

G6 

51 52 53 Level 2 56 57 58 

55 59 60 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 

98 
90 DAY INHALAnON TOXICITY S1UDY IN TIlE RAT WITH 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 - 134 
90 DAY lNHAlATION TOXICITY STUDY IN TIm llAT W1THRECOVERY PHASE 

APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RElATIVE MUMIDITY 

Key: 

The mean temperature and relative humidity, together with the minimum and maximum for 


each day of exposure 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 - 135 

90 DAY INHALATION TOXICITY sruoy.IN TIlE 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 Minimum Maximum 

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 • 136 

90 DAY INHAlATION TOXICITY sruDY IN TIlE RAT WITH RECOVERY PHASE 

APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RELA"rIVE HUMIDITY 

Groups 1 and 5 

Temperature Relative humidity 

Date Mean Minimum Maximum Date Mean Minimum Maximum 


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 24 Overall 45 30 68 

REGULATORY/REPORT • 137 
90 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 Minimum Maximum 

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 - 138 

90 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 IN THE 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 • 140 
90 DAY 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 MinimumMaximumDate Mean MinimumMaximum 

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 - 141 

90 DAY INHALATION TOXICITY SI1JDV IN TIlE 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 - 142 
90 DAY INHALATION TOXIOTY STUDY IN TIm RAT WITH RECOVERY PHASE 

APPENDIX E - GROUP MEAN DAILY TEMPERATURE AND RELAnVE 

HUMIDITY 

Groups 4 and 6 

Temperature . Relative humidity 

Date Mean Minimum Maximum Date Mean Minimum Maximum 

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 IN THE 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 2 Femaie Rep 3 Male Rep 4 Female 

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 - 144 
90 DAY INHALATION TOXlOTY STIJDY IN 1HE RAT WITH RECOVERY PHASE 

APPENDIX G • DETAILS OF STAnSnCAL METHODS 

Bodyweights were considered by analysis of covariance 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 of variance, 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 of variance, separately for males and 

females. 

Haematology, blood and urine clinical chemistry were considered by analysis of variance. 

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 of variance and analysis of covariance 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 better method of allowing for differences in terminal bodyweights (Shirley~ 1996). 

All analyses were carried out separately for the main study and recovery groups. 

Analyses of variance and covariance were carried out using the MIXED procedure hI SAS 

(1999) and, with the exception of recovery food consumption, recovery food utilisation and 

PCOA values, allowed for the replicate structure of the study design. Least-squares means 

for each group were calculated using the LSMEAN option in SAS PROC MIXED. 

Unbiased estimates of differences 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 IN TIlE RAT wrm RBCOVERY PHASE 

APPENDIX G • DETAILS OF STATISTICAL METHODS 

The differences from control based on the analysis of bodyweigbt are also presented 

grapbically (in figs. 3). The centre of each bar represents the mean percentage difference 

between control and treated group least-squares meaDS, and the top and bottom of ecach bar 

represent the upper and lower 95% confidence limits for this difference. A statistically 

significant diffOlen" betwccn the treated group and the control group is prescnt when the bal 

does not cross the zero difference line. For ease of reference, lines have been added to the 

plots to show differences of:l: 10%. 

IREGUlATORY/RBPORT • 146 
90 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 - 147 

90 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 • 148 

90 DAY INHALATION TOXICfY STUDY IN nmRAT WITH RECOVERY PHASE. 

APPENDIX 1 • INDIVIDUAL CUNICAL OBSERVATIONS 

Key: 

Some or all of the fonowing abbreviations may appear in the appendix. 

N • no abnormalities 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 are presented in this appendix. 


ObselVations made during week 12 at the FOB clinical assessment are presented in Appendix * . 

REGULATORY/REPORT - 149 


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I)() DAY INHALATION TOXICfYSTUDY IN TIm RAT WITH RECOVERY PHASE 

APPENDIX 2 • INDIVIDUAL BODVWBGHTS (9) 

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REGUlATORY/REPORT - 158 
90 DAY INHALATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX2 - INDIVIDUAL BODYWEIGHTS (9) 

DOIIII. 0 JIIIII 

AllIIIUIL ..... IIUIIDIt 11 

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REGULATORY~ORT - 159 
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APPENDIX 2 • INDIVIDUAL BODVWEIGHTS (9) 

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ltEGUlATORY/REPORT - 162 
90 DAY INHALATION IDXIcrY STUDY IN THE. RAT WITH RECOVERY PHASE 

APPENDIX 2 • INDIVIDUAL BODYWEIGHTS (g) 

DOS. • 1000 PIIII 

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REGULATORY~'ORT - 163 
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APPENDIX 3 • INDIVIDUAL BODYWEIGHT GAINS (g) 

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IREGULATORY/REPORT - 165 

90 DAY INHAIATION TOXICTY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 3 - INDIVIDUAL BODYWEIGHT GAINS (g) 

1)()lD, 1000 

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APPENDIX 3 .. INDIVIDUAL BODYWEIGHT GAINS (9) 

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~GULATORY~ORT - 170 
90 DAY INHALATION TOXIcn' STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 3 .. INDIVIDUAL BODYWEIQHT GAINS (g) 

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'REGULATOllYIREPORT - 166 
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APPENDIX 3· INDIVIDUAL BODYWEIGHT GAINS (9) 

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IREOULATORY/REPORT - 171 

90 DAY INHALATION TOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 


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RBGULATORYIREPORT - 172 
90 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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APPENDIX 4 - INDIVIDUAL FOOD CONSUMPTION (glrat/day) 

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REGULATORY/REPORT • 175 

• • 

• • 

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

90 DAY INHAlATION TOXICTY STIIDY IN THE RAT WITH RECOVERY PIIASE 

APPENDIX 4 .. INDIVIDUAL FOOD CONSUMPTION (glratlday) 

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24 22 Z1 21 21 20 ao 21 l' l' :18 l' UI l' 20 20 1. UI 

REGULATORY/REPORT ~ 176 
90 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 of the animals listed overleaf, all animals had 'no abnormalities detected' during the FOB clinical assessment, see 

Table 7 for full list ()f FOB assessm.ents. 

REOULATORY/lEPORT • 177 
90 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 SPIAY REFLEX 

M 

F SPIAY REFLEX 

87 	 : 300 F SPlAY REFLEX 

F 12 

84 300 F 12 SCABS (1ll1derside of tail) 

REGULATORY/REPORT - 178 

90 DAY lNHAlATIONTOXIcrY SnJDY IN THE 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 - 119 

90 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 - 180 

90 DAY INHALATION 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 - 181 
90 DAY INHAIATION TOXICI'Y STUDY IN TIlE RAT 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 • 182 

90 DAY INHALATION TOXICrY STUDY IN TIm RAT 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 DAY INHALATION 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 - 184 
90 DAY INHALAll0NTOXICfY 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) 


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 1lIE RAT 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 - 186 
90 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 - 187 
90 DAY INHALATION TOXIcrY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 6 • INDMDUALFUNCTIONAL 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 'I 3.71

, I 10.00 

, , " 17 11.20 

'RBGULATORY/REPORT - 188 

90 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 - 189 

90 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 - ISO 

90 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 IN THE 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:<:&: 

"'1'. GUll JW.I: - .. 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 - 192 

90 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 - 193 

90 DAY INHAlADON TOXICIY 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 - 194 

90 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 THE RAT 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