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					                                                   ORIGINAL
      TSCA NON-CONFIDENTIAL BUSINESS INFORMATION
  DOCUMENT DESCRIPTION   DOCUMENT CONTROL NUMBER   DATE RECEIVED

                                                   la5
COMMENTS:




                DO[S NOT CONTAIN CBI
*Mexichem*
 Ftuor

 SENT VIA FEDERAL EXPRESS
 TRACKING NUMBER       lqq Z-KZ                            (o


 December 14, 2010                                        II11111111liiI
                                                         8BE    HQ0-O07                  19111   7


 TSCA Confidential Business Information Center (7407M)               8EHQ-1210-16917D
 EPA East - Room 6428. Attn: Section 8(e)                            DCN:89110000048
 US Environmental Protection Agency
 1201 Constitution Avenue NW11111                                              I         IliiI
 Washington, DC 20004-3302
 Phone: 202-564-8940
                                                        111111 1111
                                                                91
                                                                           il 1111 10I11 ii
                                                                          00       004
                                                                                                 II

           Toxic Substances Control Act (TSCA) Section 8(e) Substantial Risk Notification

                                Re: 8EHQ-07-16917. Supplemental Information

                 Subject Chemical: 1.2.3.3.3 -pentafluorop~rovene (CAS No. 5528-43-8)
                         Alternative Name: Refrigerant 1225ye-Z (R- I225ye-Z)


 Dear Sir or Madam:

 On December 17, 2007 TNEOS Fluor Americas LLC submitted a supplemental notification under
 Section 8(e) of the Toxic Substances Control Act (TSCA) regarding preliminary findings from a
 28-day inhalation study in the rat employing relatively low levels of R-1225ye-Z. In that same
 letter, INEOS Fluor Americas LLC also informed you of a parallel 90-day inhalation study of r-
 1225ye-Z in the rat. INEOS Fluor Americas LLC also indicated that the full results of the 90-day
 study and its 28-day satellite would be submitted to the TSCA 8(e) Coordinator. The final report
 is enclosed.

 On April 1, 2010, the INEOS group sold its fluorochemicals group, which included INEOS Fluor
 Americas LLC, to Mexichem S.A.B. de C.V. As part of that transaction, INEOS Fluor Americas
 LLC, and its associated refrigerant development component, became Mexichem. Fluor Inc.

 Mexichemn Fluor Inc., previously INEOS Fluor Americas LLC, hereby withdraws its requests for
 confidentiality regarding all information previously submitted regarding R- 1225ye-Z toxicity.


 Mexichemn Fluor Inc                                                                                  6
 P.O. Box 30, 4990B IC1 Road
 St. Gabriel, Louisiana 70776                                                                         ECM
 Tel +1(225) 642-0094
 Fax + 1 (225) 642-8629


                                                       CONTAINS NO C81
TSCA 8(e) Notification
December 14, 2010
Page 1 of 2


Sincerely,




Joel R. Hall
Security, Safety, Health & Environmental Manager
Mexichem Fluor Inc.

cc:    Ms. Karleen James
       SHE Assurance Manager
       INEOS Nitriles
       2600 South Shore Blvd, Suite 250
       League City, Texas 77573
                                                                                                                                               Page 1 of 1


  From: Ongin ID: OPLA (225) 642-6289                                Ship Date: 14DEC10
   Joel H-ALL                                      i.            ;   ActWgt 3.5 LB
   MEXICHEM FLUOR INC.                                               CAD: 388454M/NET3090
   4990 BICI
           ROAD
  ST. GABRIEL, LA 10716                                                     IIi 111111 I 111111111]I II 11
                                                                      Delivery Address Bar Code



  SHIP TO:   (202) 564-8940             BILL SENDER                     Ref # 155192210
  TSCA Conf. Bus. Info Center (7407M)                                   Invoice#
                                                                        P0 #
  EPA E. - RM 6428 Attn: Sec 8 (e)                                      Dept #
  1201 CONSTITUTION AVE NW

  WASHINGTON, DC 20460
                                                                                                                  WED       -15        DEC        Al
                                                                     TRK#
                               I                        i02011                7942 1527 1260                       STANDARD            OVERNIGHT


                                                                                                                                      20460
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Huntingdon




 R-1 225 yeZ: Toxicity Study by Inhalation Administration to
                 CD Rats for 28 or 90 Days




                            HLS study number:   ATS0022

                            Version ID:         Final

                            Issue date:         24 November 2010




                         Page 1 of 677
                                                          Huntingdon Life Sciences
                                                                         ATS0022

Details of Sponsor, Test Facilities and Test Site
    Sponsor            Ineos, Fluor Limited
                       P0 Box 13
                       The Heath
                       Runcorn
                       Cheshire
                       WA7 4QF
                       UK
    Test facility      Huntingdon Life Sciences
                       Huntingdon Research Centre
                       Woolley Road
                       Alconbury
                       Huntingdon
                       Cambridgeshire
                       PE28 4HS
                       UK
    Test facility      Huntingdon Life Sciences
    Histology          Eye Research Centre
                       Eye
                       Suffolk
                       IP23 7PX
                       UK


    Test site          Butterworth Laboratories Limited
    Urinary fluoride   54-56 Waldegrave Road
                       Teddington
                       Middlesex
                       TWII1 8LG
                       UK




                                      2
                                                                             Huntingdon Life Sciences
                                                                                             ATS0022

Table of Contents
Details of Sponsor, Test Facilities and Test Site................................................. 2
Compliance with Good Laboratory Practice...................................................... 6
Contributing Scientists............................................................................. 7
Summary .........................................................................................     9
1. Introduction .................................................................................     12
      1.1    Objective ...........................................................................   12
      1.2    Regulatory compliance ............................................................      12
      1.3    Test system......................................................................... 12
      1.4    Route of administration............................................................ 12
      1.5    Treatment groups and dosages................................................... 12
2. Experimental Procedure ...................................................................        13
      2.1    Study schedule and structure .....................................................      13
             2.1.1 Duration of treatment ......................................................      13
             2.1.2 Time schedule .............................................................       13
             2.1.3 Identity of treatment groups ...............................................       13
      2.2    Test substance and formulation................................................... 14
             2.2.1 Test substance............................................................. 14
             2.2.2 Control...................................................................... 15
      2.3    Animal management...............................................................        15
             2.3.1 Animal supply, acclimatisation and allocation .......................... 15
             2.3.2 Animal housing, diet and water supply ...................................         16
             2.3.3 Administration.............................................................. 17
             2.3.4 Post exposure washing ...................................................         17
      2.4    Serial observations................................................................. 17
             2.4.1 Clinical observations....................................................... 18
             2.4.2 Mortality ....................................................................    18
             2.4.3 Bodyweight................................................................. 18
             2.4.4 Food consumption......................................................... 18
             2.4.5 Water consumption ........................................................        19
             2.4.6 Haemnatology, peripheral blood ...........................................        19
             2.4.7 Blood chemistry............................................................ 20
             2.4.8 Urinalysis................................................................... 21
     2.5     Necropsy and Histology ...........................................................      22
             2.5.1 Method of kill............................................................... 22
             2.5.2 Macroscopic pathology.................................................... 22
             2.5.3 Organ weights .............................................................       22
             2.5.4 Fixation..................................................................... 23
             2.5.5 Histology ...................................................................     23
     2.6     Pathology........................................................................... 24
             2.6.1 Light microscopy........................................................... 24
     2.7     Data treatment...................................................................... 24
             2.7.1 Definition of "Week"........................................................ 24
             2.7.2 Signs........................................................................ 25
             2.7.3 Bodyweight................................................................. 25
             2.7.4 Food consumption......................................................... 25
             2.7.5 Water consumption ........................................................        25
             2.7.6 Haemnatology............................................................... 25
             2.7.7 Blood chemistry............................................................ 25
             2.7.8 Urinalysis................................................................... 25

                                                  3
                                                                            Huntingdon Life Sciences
                                                                                            ATS0022
            2.7.9 Organ weights .............................................................      26
            2.7.10 Pathology................................................................... 26
            2.7.11 Statistical analysis......................................................... 27
     2.8    Quality assurance and archiving procedures ....................................         28
            2.8.1 Quality assurance.......................................................... 28
            2.8.2 Archives ....................................................................    29
     2.9    Deviations from protocol........................................................... 29
3.   Results....................................................................................   31
     3.1    Chamber atmosphere conditions .................................................        31
     3.2    Signs and mortality................................................................. 31
     3.3    Bodyweight .........................................................................    32
     3.4    Food consumption .................................................................     33
     3.5    Water consumption ................................................................      33
     3.6    Haemnatology .......................................................................    33
     3.7    Blood chemistry ....................................................................   34
     3.8    Urinalysis ........................................................................... 35
     3.9    Urinary fluoride..................................................................... 36
     3.10 Organ weights...................................................................... 36
     3.11 Macropathology ....................................................................      36
     3.12 Histopathology...................................................................... 38
4.   Discussion .................................................................................. 40
5.   Conclusion.................................................................................. 42
6.   References..................................................................................   43

List of Figures
Figure 1       Bodyweight.......................................................................   44

List of Tables
Table 1        Bodyweight....................................................................... 46
Table 2        Haematology..................................................................... 52
Table 3        Blood chemistry ..................................................................    64
Table 4        Urinalysis .........................................................................  76
Table 5        Urinary fluoride................................................................... 80
Table 6        Organ weights.................................................................... 84
Table 7        Macropathology................................................................. 100
Table 8        Histopathology ..................................................................    108
                                                                                   Huntingdon Life Sciences
                                                                                                     ATS0022

List of Appendices
Appendix 1    Signs ..............................................................................      113
Appendix 2    Dose observations ...............................................................         144
Appendix 3    Bodyweight .......................................................................        250
Appendix 4    Food consumption ...............................................................          268
Appendix 5    Water consumption ..............................................................          274
Appendix 6    Haematology .....................................................................         280
Appendix 7    Blood chemistry ..................................................................        316
Appendix 8    Urinalysis..........................................................................      370
Appendix 9    Organ weights....................................................................         406
Appendix 10   Macropathology and histopathology............................................ 430


List of Annexes
Annex 1       Administration of R-1225 yeZ by inhalation to rats........................... 624
Annex 2       Urinary fluoride analysis......................................................... 652
Annex 3       Pathology report..................................................................        666
Annex 4       Certificates of analysis ..........................................................       674




                                                    5
                                                                      Huntingdon Life Sciences
                                                                                      ATS0022

Compliance with Good Laboratory Practice

R-1 225 yeZ: Toxicity study by inhalation administration to CD rats for 28
or 90 days
The study described in this report generally followed the principles of Good Laboratory
Practice. However, the study report and study data were not audited.
The urinary fluoride phase of the study also followed the principles of Good Laboratory
Practice.

No claim of Good laboratory Practice compliance is made in respect of this study.

Prior to the final protocol being signed by the Study Director on 05 September 2007, animal
arrival/allocation to groups/identification, routine husbandry procedures and analytical
method development were carried out using the authorised draft protocol 3 dated
30 August 2007. In addition, the recording of clinical observations, bodyweights, food and
water consumption commenced as did sham dosing, using this draft protocol. The authorised
draft protocol dated 30 August 2007 has been retained in the study file.




                       ____
                      _____              ____               2L~      ~     -10
 Anthony M Bowden BSc (Hons) CIAT                          Date
 Study Director
 Huntingdon Life Sciences




                                                6
                                                                Huntingdon Life Sciences
                                                                               ATS0022

Contributing Scientists
R-1 225 yeZ: Toxicity study by inhalation administration to CD rats for 28
or 90 days
Study management
Amanda J Brooker BSc (Hons) MSc CBiol MlBiol (05 September to 26 September 207)
Study Director

Anthony M Bowden BSc (Hons) CIAT (30 August to 05 September 2007, prior to issue of
the final protocol, and from 26 September 2007)
Study Director

Colin J Hardy BSc (Hons) PhD MIBiol CBiol DipRCPath (Toxicology)
Principal Consulting Toxicologist

Inhalation analysis
Paul Mann BSc (Hons)
Head Formulation & Inhalation Analysis

Aerosol technology
Simon A Moore BSc (Hons) PhD MRSC
Head of Aerosol Technology

Ophthalmic examination
Helmut Ehall MagMed Vet DrMed Vet MRCVS
Named Veterinary Surgeon

Clinical pathology
Emma Mann BSc (Hons) MRSC
Head of Central Laboratory Services Operations

Pathology
Helen Hasler BVMS MRCVS
Study Pathologist

Statistics
Gareth D Thomas BSc
Senior Statistician




                                            7
                                   Huntingdon Life Sciences
                                                  ATS0022

Principal Investigator
David Riches BSc CChem MRSC
Butterworth Laboratories Ltd




                               8
                                                                        Huntingdon Life Sciences
                                                                                       ATS0022

Summary
The systemic toxic potential of R- 1225 yeZ (a refrigerant) to Cr1 :CDO (SD) LOS BR rats by
inhalation administration was assessed over a period of 28 or 90 days.

Three groups, each comprising eight male and eight female rats and a fourth group
comprising ten male and ten female rats were exposed snout-only to R- 1225 yeZ at target
exposure levels of 0.25, 0.5, 0.75 or 1.0% (vlv), respectively, for 28 days. A fifth group
comprising five male and five female rats was exposed whole-body to R- 1225 yeZ at a target
exposure level of 1.0% (v/v) and a Control group comprising six male and six female rats
received air only (snout-only exposure) for 6 hours a day, 5 days a week for 28 days.

A further four groups comprising ten male and ten female rats were exposed snout-only to
R- 1225 yeZ at target exposure levels of 0.25, 0.5, 0.75 or 1.0% (v/v) together with a similarly
constituted Control group which received air only for 6 hours a day, 5 days a week for 90
days.

During the study, clinical condition, bodyweight, food consumption, water consumption,
ophthalmic examination, haematology, blood chemistry, urinalysis, urinary fluoride analysis,
organ weight, macropathology and histopathology investigations were undertaken.

Results
The achieved mean exposure levels were 0.261, 0.512, 0.743 or 1.0 1% (v/v) R- 1225 yeZ for
the 28-day snout-only groups and 0.948% (v/v) for the 28-day whole-body group. For the
90-day snout-only groups mean exposure levels were 0.251, 0.482, 0.722 or 1.02% (v/v).

Animal 38M (Group 3 90-day snout only) was found dead in the cage on Day 89. Necropsy
findings comprised congestion of the mandibular lymph node, dark area(s) on the liver and
pale teeth.

Myocardial vacuolation was noted in male rats exposed to 0.261 % (vlv) and all female
groups exposed for 28 days. Myocardial vacuolation was noted in one female rat exposed to
0.251% (vlv) for 90 days. Myocardial necrosis/inflammation/vacuolation was observed in all
male and female groups exposed for 28 days. Similar findings were observed in all male and
female groups exposed for 90 days. Myocardial fibrosis was seen in all male groups and in
females exposed to 0.251, 0.722 or 1.02% (v/v) for 90 days. Atrial thrombi were seen in
male rats exposed to 0.251 or 0.482% (v/v) for 90 days. Fluid in the thorax was seen in one
male exposed to 0.25 1% (v/v) and one male exposed to 0.482% (v/v).

Pale teeth were seen in all treated groups after 28 days of exposure. Tooth abnormalities
comprising pale colouring, loss of enamel and increased wearing down were seen in all
treated groups after 90 days of exposure. At necropsy an increased incidence of pallor of the
incisors was observed together with an increased incidence of shortening of the lower
incisors and/or elongation of the upper incisors in treated rats. Histopathological examination
revealed ameloblastic dysplasia in the teeth of male treated rats and females exposed to
0.251, 0.722 or 1.02% (v/v) for 90 days. Periodontal inflammation was seen in male and
female rats exposed for 90 days.




                                               9
                                                                       Huntingdon Life Sciences
                                                                                       ATS0022

Urinary fluoride levels were increased (up to I11 OX control in males and 53X in females) in
all groups exposed for 28 days. After 90 days fluoride levels were increased (up to 105X
control in males and 62X in females) in all exposed groups.
Increases in urine volume (up to 2.4X control), associated in most cases with a decrease in
specific gravity were evident for all 28-day female groups. A decrease in urine volume (up to
0.49X control), associated in most cases with an increase in specific gravity was evident for
all treated groups, except males exposed at 0.722% (v/v) after 13 weeks of treatment. Total
urinary potassium levels were increased (up to I1.5X control) in animals exposed to 0.948%
(vlv) for 28 days whole-body. Levels were decreased (up to 0.42X control) for all 90-day
groups. Total sodium levels were increased (up to 1.6X control) for all 28-day female
groups. Levels were decreased (up to 0.49X control) for all 90-day groups, except males
exposed at 0.722% (v/v). Total chloride levels were increased (up to 1.9X control) in animals
exposed to 0.948% (v/v) whole-body for 28 days. Protein levels were increased (up to 1.5X
control) for all 90-day female groups.

A decreased group mean bodyweight gain was evident for all 28-day snout-only exposed
male groups (up to 0.76X control) and in all male groups (up to 0.59X control) and female
groups (up to 0.80X control) exposed for 90 days.
A slight reduction in food consumption was evident for all 28-day snout-only treated male
groups (up to 0.88X control) after 4 weeks of treatment.
An increase in water consumption (1.X control) was evident for the 28-day whole-body
females and (up to 1.2X control) for all 28-day snout-only female groups. A slight decrease
in water consumption (up to 0.79X control) was evident for all 90-day male groups.

Prothrombin time was increased (up to 1.2X control) in 28-day snout-only males exposed at
0.5 12 or 1.0 1%(v/v) and in all 28-day females (up to 1.IX control). After 90 days of
exposure prothrombin time remained slightly increased in most treated groups (up to 1.1X
control) of both sexes. White blood cell counts were increased in all 28-day snout-only
exposed females (up to 1.6X control), this being primarily due to increases in lymphocytes
(up to 1.7X control). Platelet counts were increased for all 28-day male groups (up to 1.23X
control) and in all male 90-day groups (up to 1A.X control) and in females (up to 1.3X
control) exposed to 0.482% (v/v) and above. Reticulocytes were decreased (up to 0.65X
control) for all treated male groups after 13 weeks.
Aspartate aminotransferase levels were increased (up to 1.7X control) in all 28-day male
groups and (up to 2.6X control) in all 90-day groups, except females exposed at 0.251 %
(v/v). Urea levels were increased (up to IA.X control) in all 28-day groups of both sexes and
(up to IA.X control) in all males exposed at 0.251 or 0.482% (v/v) for 90 days. Creatinine
kinase levels were increased (up to 4.OX control) for some rats in all 90-day treated groups,
except males exposed at 1.02% (vlv). Creatinine levels were increased (up to 1.2X control)
for all 90-day treated groups, except animals exposed at 0.25 1%(v/v).
At necropsy heart weights were decreased (up to 0.82X control) in males exposed at 0.722 or
 1.02% (v/v) after 90 days of treatment. Prostate weights were decreased for all treated males
(up to 0.57X control) after 90 days of treatment. Thymus weights were decreased for all
treated males (up to 0.79X control) and females (up to 0.78X control) exposed at 0.482 or
 1.02% (v/v) for 90 days. A reduced incidence of pale areas on the lungs with associated
tracheobronchial lymph node enlargement was seen in male rats exposed to 0.482, 0.722 or


                                              10
                                                                       Huntingdon Life Sciences
                                                                                      ATS0022

1.02% (v/v) and all treated female rats. A thin appearance was noted in some treated male
rats compared with none in control rats.

Conclusion
In the heart, myocardial necrosis/inflammationlvacuolation and myocardial vacuolation were
noted in rats exposed to R- 1225 yeZ over a 28-day period.
In the heart, myocardial necrosis/inflammation/vacuolation, myocardial fibrosis, myocardial
vacuolation and atrial thrombi were observed in rats exposed to R- 1225 yeZ over a 90-day
period.

In the teeth, ameloblastic dysplasia and periodontal inflammation were seen in rats exposed
to R- 1225 yeZ over a 90-day period.

There was no difference in the treatment-related findings between rats undergoing snout-only
exposure and those undergoing whole-body exposure. There was no difference in the
treatment-related findings between rats that were washed following exposure and those that
were not.

A no adverse effect level (NOAEL) was not established in this study.
                                                                       Huntingdon Life Sciences

                                                                                       ATS0022

      1. Introduction
1.1      Objective
The objective of this study was to assess the systemic toxic potential of R- 1225 yeZ, a
material under consideration for use as a refigerant, when administered by inhalation to rats
snout-only or whole-body for 28 days or snout-only for 90 days. The 28-day exposure was
used to investigate the effects of exposure at levels lower than those used in a previous
28-day study. The whole-body exposure was used to investigate any differences between this
method and snout-only exposure over 28 days, in particular any potential adverse effect of
post exposure grooming and ingestion of excreted metabolites.

1.2      Regulatory compliance
The study was designed to meet the requirements of the following guidelines:

        Guidelines for the Testing of Chemicals - 412;
        European Union.

The study was conducted in accordance with the requirements of current, internationally
recognised Good Laboratory Practice (GLP) Standards. However, the study report and study
data were not audited and no GLP compliance is claimed in respect of this study. The study
was also conducted in accordance with the applicable sections of the United Kingdom
Animals (Scientific Procedures) Act 1986.

1.3     Test system
The rat was chosen as the test species because of its acceptance as a predictor of toxic change
in man and the requirement for a rodent species by regulatory agencies. The Crl:CDt
(SD) IGS BR strain was used because of the historical control data available in this
laboratory.

1.4      Route of administration
The inhalation route of administration was chosen to simulate the conditions of potential
human exposure.

1.5     Treatment groups and dosages
The target exposure levels used in this study (0, 0.25, 0.5, 0.75 and 1.0 (by snout-only
exposure or whole-body exposure) %(v/v)) were selected in conjunction with the Sponsor
with reference to previous work with this compound performed in these laboratories
(Huntingdon Life Sciences Report Number: ATSOO 10/072600). In the previous study the test
substance showed toxic effects following exposure to concentrations of 1.0% (v/v) and
above. The target exposure level of 1.0% (v/v) has been selected as the highest concentration
in this study as a reference point to the previous study. The lower concentrations of 0.25, 0.5
and 0.75% (v/v) were selected with a view to identifying a no adverse effect level for the test
substance.




                                              12
                                                                                      Huntingdon Life Sciences

                                                                                                      ATS0022

2.        Experimental Procedure
2.1       Study schedule and structure
2.1.1     Duration of treatment
The test substance, R- 1225 yeZ, was administered over a period of 28 or 90 days. In each
case the necropsy procedures were completed over several days, during which time treatment
continued, and serial observations were recorded at appropriate intervals. The duration of
treatment is reported as 28 or 90 days.

2.1.2     Time schedule
Study initiation:                             05 September 2007
(Protocol signed by Study Director)
Experimental start date:                      30 August 2007

Animal arrival:                               30 August 2007

Treatment commenced:                          09 September 2007

Necropsy completed:
       28-day Study                           08-09 October 2007
       90-day Study                           10- 12 December 2007

Experimental completion date:
(Pathology)                                   26 February 2008

Study completion:                             24 November 20 10

2.1.3     Identity of treatment groups
The study consisted of one Control and five treated groups of rats for the 28-day study and
one Control and four treated groups of rats for the 90-day study, identified as follows:

                                                                  Number of animals
                            Exposure                 Snout-only exposure                      Whole-body
 Group     Treatment                                                                           exposure
                          level % (vlv)       90-day study        28-day studyt              28 day studyt
                                            Male      Female       Male       Female        Male      Female

     1       Control            0            10          10           6          6           0               0
     2     R- 1225 yeZ        0.25           10          10           8           8          0               0
     3     R-1225 yeZ          0.5           10          10           8           8          0               0
     4     R-1225 yeZ         0.75           10          10           8           8          0               0
     5     R-1225 yeZ          1.0           10          10          10          10          0               0
     6     R-l1225 yeZ         1.0           0           0           0           0           5               5

 t 28-day animals used to investigate the effects of exposure at levels lower than a previous 28-day study
  tWhole-body animals used to investigate any differences between whole-body and snout-only exposure




                                                       13
                                                                            Huntingdon Life Sciences
                                                                                            ATS0022


                                                Snout-only exposure
           Gop90-day                  study                               28-day study
       Gop        Cage numbers             Animal numbers       Cage numbers       Animal numbers
               Male         Female         Male     Female     Male    Female      Male    Female

           1    1-2         22-23          1-10    96-105       3-4     24-25      11-16   106-111
   2            5-6         26-27         17-26    112-121      7-8     28-29      27-34   122-129
   3           9-10         30-31         35-44    130-139     11-12    32-33      45-52   140-147
   4           13-14        34-35         53-62    148-157     15-16    36-37      63-70   158-165
   5           17-18        38-39         71-80    166-175     19-20    40-41      81-90   176-185


                       Whole-body exposure
 Group                   28 day exposure
                 Cage numbers         Animal numbers
               Male      Female       Male     Female

   6            21            42          91-95    186-190


2.2        Test substance and formulation
2.2.1      Test substance
Information supplied by the Sponsor regarding the test substance is contained in the test
substance data sheet, which is retained in study records, and the certificates of analysis,
which are presented in Annex 4.

The following information is given in summary:

         Identification:            R- 1225 yeZ

         Chemical name:             I ,2,3,3,3-Pentafluoropropene

         Alternative name:          HFC 1225 ye

         Action:                    Refrigerant

         Description:              Liquefied gas

         Storage conditions:       At ambient temperature

         Supplier:                  Sponsor
         Batch number:             1F240807 1, IF240907 and IF2 609072

         Date of receipt:           24 August 2007, 28 September 2007 and 28 September 2007

         Quantity received:         57948 g, 29368 g and 28228 g (gross weights)
         Expiry date:              24 August 2008, 24 September 2008 and 26 September 2008

         Purity:                   99.544%, 99.542% and 99.3 89%



                                                    14
                                                                        Huntingdon Life Sciences
                                                                                        ATS0022

The Sponsor was responsible for the characterisation of the test substance and the
documentation of the methods of synthesis, fabrication or derivation and stability.
It was not practical for a small sample to be taken and stored in Archives since the test
substance was contained in a pressurised cylinder.
2.2.2    Control
Air only using snout-only exposure chamber.

2.3      Animal management
2.3.1    Animal supply, acclimatisation and allocation
A total of 100 male and 100 female Crl:CDO (SD) IGS BR rats were received from Charles
River (UK) Ltd. The rats were ordered at approximately 36 to 42 days of age and within an
approximate weight range of 180 to 222 g for males and 142 to 166 g for females.
On arrival, the animals were removed from the transit boxes and allocated to study cages.
Using the sequence of cages in the battery, one animal at a time was placed in each cage with
the procedure being repeated until each cage held the appropriate number of animals. Each
sex was allocated separately.
The cages constituting each group were housed on separate batteries.
Each animal was assigned a number and identified uniquely within the study by a tail tattoo.
Each cage label was colour-coded according to group and was numbered uniquely with cage
and study number, as well as the identity of the occupants.
The animals were allowed to acclimatise to the conditions described below for 10 days before
treatment commenced. Each group of animals (including spares) were acclimated to the
restraint procedure used for inhalation snout-only exposure on 5 occasions prior to the
commencement of the first test substance exposure. For those animals selected for this study,
their age at the start of treatment was 46 to 52 days and their bodyweights were in the range
of 249 to 317 g for males and 163 to 222 g for females.
An ophthalmic examination, using a binocular indirect ophthalmoscope, was performed
during the pretreatment period in order to ensure that there were no animals with adverse
ocular abnormalities on study. Mydriasis was induced with 0.5% tropicamide prior to
examination.
The spare animals (5 males and 5 females) were removed from the study after treatment
commenced.




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2.3.2   Animal housing, diet and water supply
Animals were housed inside a restricted access rodent facility (Building Y 14, Room 008).
The facility was designed and operated to minimise the entry of external biological and
chemical agents and to minimise the transference of such agents between rooms. Before the
study the room was cleaned and disinfected.

Each animal room was kept at positive pressure with respect to the outside by its own supply
of filtered fresh air, which was passed to atmosphere and not re-circulated. The temperature
and relative humidity controls were maintained, where possible, within the range of 19 to
23*C and 40 to 70%, respectively. Artificial lighting was controlled to give a cycle of 12
hours continuous light and 12 hours continuous dark per 24 hours.

Periodic checks were made on the number of air changes in the animal rooms. Temperature
and humidity were monitored continuously. These data were in good agreement with the
target values and although rare and short deviations occurred they were considered not to
influence the integrity of the study and have not been presented.

Alarms were activated if there was any failure of the ventilation system, or temperature limits
were exceeded. A stand-by electricity supply was available to be automatically brought into
operation should the public supply fail.
The animals for the 90-day snout-only study were housed five of the same sex per cage, the
Group I 28-day snout-only study animals were housed three of the same sex per cage,
Groups 2 to 4 were housed four of the same sex per cage, Group 5 was housed five of the
same sex per cage and Group 6 28-day whole-body study animals were housed five of the
same sex per cage, unless this number was reduced by mortality or isolation. The cages were
made of a polycarbonate body with a stainless steel mesh lid. Wood shavings (Lignocel 3/4)
were used as bedding and were sterilised by autoclaving and changed at appropriate intervals
each week. Cages, food hoppers and water bottles were changed at appropriate intervals.

The animals were allowed free access to a standard rodent diet (Rat and Mouse No. I
Maintenance Diet), except during exposure and the period when urine was being collected
and overnight before routine blood sampling. This diet contained no added antibiotic or other
chemotherapeutic or prophylactic agent.

Potable water taken from the public supply was freely available via polycarbonate bottles
fitted with sipper tubes, except during exposure and when urine was being collected.
Each cage of animals was provided with an Aspen chew block for environmental enrichment.
Chew blocks were provided throughout the study, except during exposure, when urine was
being collected and overnight before routine blood sampling. They were replaced when
necessary.




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Each batch of diet was analysed routinely by the supplier for various nutritional components
and chemical and microbiological contaminants. Supplier's analytical certificates were
scrutinised and approved before any batch of diet was released for use. The quality of the
water supply is governed by regulations published by the Department for Environment, Food
and Rural Affairs. Certificates of analysis were received routinely from the water supplier.
Certificates of analysis were received routinely from the supplier of the wood shavings and
aspen chew blocks. Since the results of these various analyses did not provide evidence of
contamination that might have prejudiced the study, they are not presented.
No other specific contaminants that were likely to have been present in the wood shavings,
chew blocks, diet or water were analysed, as none that may have interfered with or prejudiced
the outcome of the study was known.
2.3.3    Administration

The gaseous test substance was administered for 6 hours a day for 5 consecutive days a week
over a 28- or 90-day period (total of 20 or 65 exposures). Control animals were exposed to
air only for the periods described previously. The test rats were exposed to an atmosphere
containing the test gas in a snout-only inhalation chamber over a period of 28 or 90 days
(Groups I to 5) or in a whole-body exposure chamber over a period of 28 days (Group 6).
The test atmosphere was produced by metering the test gas from a pressure resistant cylinder,
followed by dilution with clean air prior to the resultant test atmosphere passing into the
exposure chamber.
Details of administration and analysis of the test gas, together with the results obtained are
presented in ADMINISTRATION OF R- 1225 yeZ BY INHALATION TO RATS appended
to this report (Annex 1).
2.3.4    Post exposure washing

All of the 90 day study animals and a sub-group of snout-only 28-day study animals from
Group 5 (animal numbers males 86-90; females 181-185) were washed daily on removal
from the restraint tube in an attempt to remove excreta from the fur. This was carried out in
order to investigate whether ingestion of metabolites from post exposure grooming
contributed to any toxicity of R- 1225 yeZ. There was a minor deviation from this procedure
that is considered not to have affected the integrity of the study (see section 2.9)

2.4      Serial observations
Dated and signed records of all activities relating to the day by day running and maintenance
of the study within the animal unit as well as to the group observations and examinations
outlined in this experimental procedure were recorded in the Study Day Book. In addition,
observations relating to individual animals made throughout the day were recorded.
All observations described below were performed in cage number sequence except where
otherwise indicated.




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2.4.1    Clinical observations
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to
treatment. Cages were inspected daily for evidence of ill-health amongst the occupant(s).
Any deviation from normal was recorded at the time in respect of nature and severity, date
and time of onset, duration and progress of the observed condition, as appropriate.

On days of exposure, detailed observations were recorded daily at the following times in
relation to exposure:
        Pre-exposure observation;
        As each animal was returned to its home cage;
        As late as possible in the working day.

On days of non-exposure, detailed observations were recorded daily at the following
frequency:
        Early in the working day (equivalent to pre-exposure observation);
        As late as possible in the working day.

In addition, a more detailed weekly physical examination was performed on each animal to
monitor general health. Particular attention was paid to the teeth and any changes in colour.
The colour of the teeth from test group animals were compared with that of the control
animals and an assessment of any colour change was recorded.
During the acclimatisation period, observations of the animals and their cages were recorded
at least once per day.
2.4.2    Mortality
Animals were killed for reasons of animal welfare, where necessary and sent to necropsy.
Animals found dead were sent to necropsy. A complete macroscopic examination was
performed in all cases as described below.
2.4.3    Bodyweight
The weight of each rat was recorded one week before treatment commenced (Week -1), on
the day that treatment commenced (Week 0), weekly throughout the treatment period, and
before necropsy. There was a minor deviation from protocol that is considered not to have
affected the integrity of the study (see section 2.9)

2.4.4    Food consumption
The weight of food supplied to each cage, that remaining and an estimate of any spilled was
recorded for the week before treatment started (Week -I1), and each week throughout the
treatment period. From these records the mean weekly consumption per animal
(glanimal/week) was calculated for each cage. There was a minor deviation from protocol
that is considered not to have affected the integrity of the study (see section 2.9).




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2.4.5    Water consumption
Water consumption was recorded daily for each cage, by weight, from Day -6 until
termination, using water bottles fitted with sipper tubes. This was a minor deviation from
protocol that does not affect the integrity of the study (see section 2.9 for details). From these
records the mean weekly consumption per animal (glanimal/week) was calculated for each
cage.
2.4.6    Haematology, peripheral blood
During Week 4 for 28-day study animals (snout-only and whole-body) and during Week 13
for 90-day study animals (before dosing on each occasion), blood samples were obtained
from all animals after overnight withdrawal of food and chew blocks. Animals were held
under light general anaesthesia induced by isoflurane and blood samples were withdrawn
from the retro-orbital sinus. For a few 90-day animals, repeat blood samples were collected
due to the original samples clotting before analysis could be performed.
Blood samples (nominally 0.5 mL) were collected into tubes containing EDTA as
anticoagulant and examined for the following characteristics:
The following were measured using a Bayer Advia 120 haemnatology analyser

         Haematocrit (Hct)
         Haemoglobin concentration (Hb)
         Erythrocyte count (RBC)
         Reticulocyte counts (Retic)
         Mean cell haemoglobin (MCH)
         Mean cell haemoglobin concentration (MCIIC)
         Mean cell volume (MCV)
         Total white cell count (WBC)
         Differential WVBC count
                 Neutrophils (N)
                 Lymphocytes (L)
                 Eosinophils (E)
                 Basophils (B)
                 Monocytes (M)
                 Large unstained cells (LUC)
         Platelet count (Pit)

Morphology flags were generated by the Advia 120 analyser. The most common
morphological changes, anisocytosis, micro/macrocytosis and hypolhyperchromasia were
recorded as follows:
            -   =      no abnormalities detected

Blood film (prepared for all samples) - Romanowsky stain, examined for abnormalities by
light microscopy, in the case of flags from the Advia 120 analyser. Confirmation or a written
description from the blood film was made where appropriate.




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Additional blood samples (nominally 0.5 mL) were taken into tubes containing citrate
anticoagulant and examined in respect of:
         Prothrombin time (PT) - using an ACL 3000 Plus analyser and IL PT-Fibrinogen
         reagent.
         Activated partial thromboplastin time (APTT) - using an ACL 3000 Plus Analyser
         and IL APTT reagent.

2.4.7    Blood chemistry
At the same time and using the same animals as for peripheral haematology, further blood
samples (nominally 0.7 mL) were collected into tubes containing lithium heparin as
anticoagulant. All tubes were mechanically agitated for at least two minutes and the sample
subsequently centrifuged at 3000 rpm for 10 minutes in order to separate the plasma. After
separation, the plasma was examined in respect of:
Using a Hitachi 917 Clinical Chemistry Analyser:

         Alkaline phosphatase (ALP)
         Alanine aminotransferase (ALT)
         Aspartate aminotransferase (AST)
         Gamma-glutamyl transpeptidase (gGT)
         Creatinine kinase (CK)
         Total bilirubin (Bili)
         Urea
         Creatinine (Creat)
         Glucose (Gluc)
         Total cholesterol (Chol)
         Triglycerides (Trig)
         Sodium (Na)
         Potassium (K)
         Chloride (Cl)
         Calcium (Ca)
         Inorganic phosphorus (Phos)
         Total protein (Total Prot)

Electrophoretic protein fractions; albumin (Alb), al globulin (al), cE2 globulin (a2),
P3globulin (Beta) and yI globulin (Gamma) were analysed with agarose gel and scanning with
a suitable densitometer.
Due to an analytical error that required some Week 4 samples to be reanalysed for the Hitachi
917 parameters, there was insufficient volume remaining to be able to conduct protein
electrophoresis for animals 91-95 (Group 6 males), 106-111 (Group I females), 122-129
(Group 2 females), 140-147 (Group 3 females), 158-165 (Group 4 females) and 176-177
(Group 5 females). In addition, insufficient volume was found for animal 190 (Group 6)
following the first analytical run so electrophoresis was not performed. As data exists from a
previous 28-day study and of the changes seen in the previous 28-day study, the
electrophoresis changes were considered to be the least important and as 90-day data was
generated in this study, it is considered that this unforeseen event does not affect the integrity
of the study.

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Albumin/globulin ratio (AG) was calculated from total protein concentration and
electrophoretic albumin concentration.

2.4.8    Urinalysis
During Week 4 for all 28-day study animals (snout-only and whole-body) and during
Week 13 for all 90-day study animals, overnight urine samples were collected. Animals were
placed in an individual metabolism cage without food or water at approximately 16.00 hours;
urine was collected until approximately 08.30 hours the following day.

The individual samples were examined for the following characteristics:

Appearance (App) - by visual assessment using the following abbreviations:

         PY           Pale yellow                     MY     Medium yellow
         CPY          Cloudy, pale yellow             CMY    Cloudy, medium yellow
Volume (Vol)
pH - using a Radiometer PHM 92 pH meter
Specific gravity (SG) - using Atago UR- I digital refractometer
Protein (Prot) sodium (U-Na), potassium (U-K) and chloride (U-Cl)         -   using Hitachi 917
Clinical Chemistry Analyser

Glucose (Gluc), ketones (Keto), bile pigments (Bili), blood pigments (UJBId) by Multistix.
Multistix are diagnostic reagents and were used as qualitative indicators of analyte
concentration. Results for blood pigments are reported as positive (+) or negative (0) only
whilst results for glucose, ketones and bile pigments are reported according to the following
convention:

         0        =        negative
         TR       =        trace
         +        =         small amount' of analyte
         +H-      =         moderate amount' of analyte
             ++            'large amount' of analyte

A microscopic examination of the urine sediment was performed. An aliquot of the urine
sample was centrifuged, stained with Kova stain and the resulting deposit spread on a
microscope slide. The deposit was examined for the presence of the following:

         Epithelia] cells (Epi)
         Leucocytes (Leuc)
         Erythrocytes (RBC)
         Crystals (Cryst)
         Spermatozoa and precursors (Sperm)
         Casts
         Other abnormal components (A)

The grading of cell frequency in the centrifuged deposit is as follows:

         0        =        None found in any field examined
         I        =        A few found in some fields examined
         2        =        A few found in all fields examined



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Following the analysis of urine samples collected in Weeks 4 and 13, the residual urine was
frozen immediately over solid carbon dioxide or in a freezer at approximately -20*C, prior to
despatch, frozen on dry ice, to the Principal Investigator for urinary fluoride analysis. The
method used and the results of the assay by the Principal Investigator are included in the
phase report presented in Annex 2.

2.5      Necropsy and Histology
2.5.1    Method of kill
Animals killed during the study and those surviving until the end of the scheduled treatment
period were killed by intraperitoneal sodium pentobarbitone followed by exsanguination.
The sequence in which the animals were killed after completion of treatment was selected to
allow satisfactory inter-group comparison.
2.5.2    Macroscopic pathology
All animals were subject to a detailed necropsy.

After a review of the history of each animal, a full macroscopic examination of the tissues
was performed. All external features and orifices were examined visually. The cranial roof
was removed to allow observation of the brain, pituitary gland and cranial nerves. After
ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and
pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position,
morphology or interaction was recorded.

The requisite organs were weighed and external and cut surfaces of the organs and tissues
were examined as appropriate. Any abnormality in the appearance or size of any organ and
tissue was recorded and the required tissue samples preserved in appropriate fixative.

The retained tissues were checked before disposal of the carcass.
2.5.3    Organ weights
The following organs, taken from each animal killed after 28 or 90 days of treatment, were
dissected free of adjacent fat and other contiguous tissue and the weights recorded:
        Adrenals                                       Prostate
        Brain                                          Salivary glands
        Epididymides                                   Seminal vesicles
        Heart                                          Spleen
        Kidneys                                        Testes
        Liver                                          Thymus
        Lungs with mainstemn bronchi                   Thyroid with parathyroids*
        Ovaries                                        Uterus with cervix
        Pituitary
         *Weighed after partial fixation.


Bilateral organs were weighed together. Organ weights were also adjusted for terminal
bodyweight, using the weight recorded immediately before necropsy. Organ weights were
not recorded for decedents.


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2.5.4      Fixation
Testes and epididymides, were fixed in Bouin's solution prior to transfer to 70% industrial
methylated spirit and eyes were fixed in Davidson's fluid. Samples (or the whole) of the
other tissues listed below from all animals were preserved in 10% neutral buffered formalin:
        Adrenals                             Ovaries
        Aorta - thoracic                     Pancreas
        Brain                                Peyer's patches
        Caecum                               Pituitary
        Colon                                Prostate
        Duodenum                             Rectum
        Epididymides                         Salivary glands - submandibular
        Eyes                                                 - sublingual
        Femur including joint                Sciatic nerves
        Harderian glands                     Seminal vesicles
        Head#                                Skeletal muscle (thigh)
        Heart                                Skin with mammary gland (caudal)
        Ileum                                Spinal cord
        Jejunumn                             Spleen
        Kidneys                              Sternum
        Lachrymal glands                     Stomach
        Larynx                               Testes
        Liver                                Teetht
        Lungs including bronchi              Thymus
        Lymph nodes - mandibular             Thyroid with parathyroids
                       - mesenteric          Tongue
                       - tracheobronchial    Trachea (including birfiircation)
                       - left axillary       Urinary bladder
        Nasal turbinates                     Uterus and cervix
        Oesophagus                           Vagina
        Optic nerves
         # Including nasal cavity, paranasal sinuses and nasopharynx
         t Only for 90-day animals; collected with head
         Animal identity retained

Samples of any abnormal tissues were also retained and processed for examination. In those
cases where a lesion was not clearly delineated, contiguous tissue was fixed with the grossly
affected region and sectioned as appropriate.
2.5.5      Histology

For those animals specified in the Pathology section, the relevant tissues were subject to
histological processing.
Tissue samples were dehydrated, embedded in paraffin wax, sectioned at approximately four
to five micron thickness and stained with haemnatoxylin and eosin.




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2.6      Pathology
2.6A1    Light microscopy
Microscopic examination was performed as follows:
         All tissues preserved for examination (as specified above) were examined for all
         premature deaths from all groups. Heart and teeth only were examined for all
         90-day study animals and heart only was examined for all 28-day study animals
         (snout-only and whole-body).

Findings were either reported as "present" or assigned a severity grade. In the latter case one
of the following four grades was used - minimal, slight, moderate or marked. A reviewing
pathologist undertook a peer review of the microscopic findings.

2.7      Data treatment
This report contains serial observations pertaining to all weeks of treatment completed,
together with signs data collected during the necropsy period. The only serial observations
relating to the acclimatisation period included in this report relate to the Week -I
bodyweights and food consumption.
Summary statistics (e.g. means and standard deviations) presented in this report were
calculated from computer-stored individual raw data. The summary statistics and the
individual data were stored in the computer to a certain number of decimal places, different
for each parameter. For presentation purposes, however, they were usually rounded to fewer
places. It is, therefore, not generally possible to reproduce the presented means and standard
deviations exactly using the presented individual data.

The death codes in the appendices have the following meaning:
         T             Scheduled kill
         F             Found dead
         S             Suspect fertility

Throughout the report the following abbreviations are used:
         M            Male
         F            Female
         N [or n]     Number of animals/cages examined
         SD [or sd]   Standard deviation

2.7.1    Definition of "Week"
The first week of treatment started at midnight prior to treatment commencing and ended at
midnight on the seventh day following. Subsequent experimental weeks of treatment were of
the same duration.




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2.7.2   Signs
Signs are considered in two parts: observations made in association with treatment, classified
as "dosing signs" and extended changes in condition, classified as "clinical signs". Both are
presented for each animal that showed signs, providing detail of type of sign, day of
occurrence and information on the duration of the sign applicable.
2.7.3   Bodyweight
Group mean weight changes were calculated from the weight changes of individual animals
surviving the specified period.
2.7.4   Food consumption
Values presented for the amount of food consumed in each cage in each experimental week
allow for any animal that died or was killed during the week.
2.7.5   Water consumption
Water consumption was calculated from measurements of initial and final weights (g) of the
water bottle and contents for each cage (it was assumed that 1 mL of water weighed I g).
2.7.6   Haemnatology
The abbreviations used in the Appendix have the following meanings:
        CTD           Clotted sample
        NVR           No valid result
        INS           Insufficient sample
        NSR           No sample received

2.7.7   Blood chemistry
The abbreviations used in the Appendix have the following meanings:
        NVR           No valid result
        NSR           No sample received
        INS           Insufficient sample

Albumin to globulin (A/G) ratios were calculated as:

                             A/G          Albumin concentration
                                   Total protein - albumin concentration

2.7.8   Urinalysis
The abbreviations used in the Appendix have the following meanings:
        NSR           No sample received
        INS           Insufficient sample



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Group means and standard deviations are presented for volume, pH, specific gravity, protein
and electrolytes only.
2.7.9    Organ weights
The abbreviation used in the Table and Appendix has the following meanings:

         Paras           Parathyroids
2.7.10 Pathology

The abbreviations used in the Tables and Appendix have the following meanings:

         LnILN           Lymph node
         Lt.             Left
         gi/GI           Gastrointestinal
         Fac con         Factors contributing

The absence of a comment for a tissue scheduled for examination therefore indicates that the
tissue was considered to be normal. Tissues recorded as abnormal macroscopically but found
to be normal microscopically are described as 'No significant lesion' in the microscopic
pathology appendix. In all tabular presentations of data the tissues specified in the protocol
for histopathological examination precede other tissues.




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-   2.7.11 Statistical analysis
    All statistical analyses were carried out separately for males and females.

    All analyses were carried out using the individual animal as the basic experimental unit.
    The following data types were analysed at each timepoint separately:
             Bodyweight, using gains over appropriate study periods
             Blood chemistry, haemnatology and urinalysis
             Urinary flouride
             Organ weights, both absolute and adjusted for terminal bodyweight
    The following sequence of statistical tests was used for bodyweight, organ weight and
    clinical pathology data:

            If 75% of the data (across all groups) were the same value, for example c, then a
            frequency analysis was applied. Treatment groups were compared using pairwise
            Fisher's Exact tests (Fisher 1973) for each dose group against the control both for
            i) values <c versus values >=c, and for ii) values <=c versus values >c, as applicable.

            If Bartlett's test for variance homogeneity (Bartlett 1937) was not significant at the
             1%level, then parametric analysis was applied. For comparisons involving two
            groups only, t-tests were used. The FI approximate test was applied. This test is
            designed to detect significant departure from monotonicity of means when the main
            test for the comparison of the means is a parametric monotonic trend test, such as
            Williams' test (Williams 1971, 1972). The test statistic compares the mean square,
            NMS, for the deviations of the observed means from the maximum likelihood
            means, calculated under a constraint of monotonicity with the usual error mean
            square, EMS. The null hypothesis is that the true means are monotonically ordered.
            The test statistic is FlI = NMSIEMS which can be compared with standard tables of
            the F distribution with 1 and EDF degrees of freedom. If the F I approximate test for
            monotonicity of dose-response was not significant at the 1%level, Williams' test for
            a monotonic trend was applied. If the F I approximate test was significant,
            suggesting that the dose response was not monotone, Dunnett's test (Dunnett 1955,
            1964) was performed instead.

            If Bartlett's test was significant at the 1%level, then logarithmic and square-root
            transformations were tried. If Bartlett's test was still significant, then non-parametric
            tests were applied. For comparisons involving two groups only, Kruskal-Wallis
            tests were used (Kruskal and Wallis 1952). The HI approximate test, the non-
            parametric equivalent of the F I test described above, was applied. This test is
            designed to be used when the main test for comparison of the means is a non-
            parametric monotonic trend test, such as Shirley's test. The test statistic compares
            the non-monotonicity sums of squares, NRSS, for the deviations of the observed
            mean ranks from the maximum likelihood mean ranks with the non-parametric
            equivalent of the error sums of squares, ERSS (=N*(N+1)112). The test statistic is
            H I = NRS S/ERSS which can be compared to standard tables of the X2-distribution
            with 1 degree of freedom. If the H I approximate test for monotonicity of dose-
            response was not significant at the 1%level, Shirley's test for a monotonic trend
            (Shirley 1977) was applied. If the H I approximate test was significant, suggesting


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      IL   ~                                 .-                   _




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               that the dose-response was not monotone, Steel's test (Steel 1959) was performed
               instead.

      For organ weight data, analysis of covariance was initially performed using terminal
      bodyweight as covariate. If the within group relationship between organ weight and
      bodyweight was significant at the 10% level (AngervallI and Carlstrom, 1963), then the
      treatment comparisons were made on adjusted group means in order to allow for differences
      in bodyweight which might influence the organ weights.
      Key to tables

      Significant differences between Control and treated groups were expressed at the 5%
      (p<0.05) or 1%(p<0.01) level. The key to the annotation used on the tables that contain
      statistical results is given below.
               Statistical test8     Treated groups (Groups 2, 3, 4 and 5) compared with Group 1
                                     using a trend test.
                                      *p<0.05
                                      **P<
                                             0 .0 1


               Statistical test b    Group 6 (whole-body exposure) with Group 5 (snout-only
                                     exposure) using a pairwise comparison.
                                     # p<0 .0 5
                                     ## p<0. 0 l

               1              Data were log transformed for the statistical analysis.
               Du             Treated groups compared with Control using Dunnett's test.
               Sh             Treated groups compared with Control using Shirley's test.
               St             Treated groups compared with Control using Steel's test.
               Wi             Treated groups compared with Control using Williams' test
               Fe             Treated groups compared with Control using Williams' test.
               Tt             Group 6 compared with Group 5 using Student's t test.
               Kw             Group 6 compared with Group 5 using Kruskal-Wallis test.
               Fe             Group 6 compared with Group 5 using Fisher's Exact test.
      Codes placed above adjusted means indicate that the comparisons were based on adjusted
      means.

      2.8      Quality assurance and archiving procedures
      2.8.1    Quality assurance
      Details of the Quality Assurance inspections and audits (undertaken at Huntingdon Life
      Sciences) are retained in the archives. They are not reported as the study report and study
      data were not audited, and as a result no claim for Good laboratory Practice compliance is
      being made with respect to this study.

      Details of the Quality Assurance inspections and audits undertaken at the Test Site are
      presented in the Principal Investigator's report contribution (Annex 2).




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2.8.2    Archives
Following completion of this study all raw data, specimens and samples, except those
generated or used during any Sponsor's or supplier's analysis, were stored in the archives of
Hluntingdon Life Sciences. Types of sample and specimen which are unsuitable, by reason of
instability, for long term retention and archiving may be disposed of after the periods stated
in Huntingdon Life Sciences Standard Operating Procedures.
A copy of the final report and all Quality Assurance inspection records will be retained
indefinitely. All other appropriate specimens and records will be retained for a minimum
period of one year from the date of issue of the final report. At the end of the one year
retention period the Sponsor will be contacted and advice sought on the above requirements.
Under no circumstances will any item be discarded without the Sponsor's knowledge.
All study specific experimental raw data generated by the Principal Investigator and certified
copies of the electronic data was forwarded to the Study Director for retention in the archive
facility at H-untingdon Life Sciences, following issue of the Principal Investigator's final
expert report. Authorised copies of the report as issued, together with the original electronic
data, instrument calibration records, documented in-house methods and standard operating
procedures will be stored in the Principal Investigator's archive facility for a period of not
less than 6 years.

2.9      Deviations from protocol
The following deviations from protocol occurred:

        1. The whole-body exposure chamber was housed in the same extract cabinet as the
           high dose snout-only exposure chamber rather than in a separate cabinet. This
           deviation had no impact on the integrity of the study as the animals undergoing
           whole body exposures were housed in a sealed exposure chamber.

        2. In Week 1 of this study and Day I of week 2, animals were removed from the
           restraint tubes and placed in a holding cage and taken to a washing area and
           washed rather than being washed immediately on removal from the restraint tube.
           There may have been an opportunity for animals to groom for a short period
           before washing. The purpose of washing was to remove any potential urinary
           metabolites before the animal had an opportunity to groom and potentially ingest
           any metabolites excreted in the urine and depositing on the animal's fur during
           exposure. Procedures were changed to ensure that animals were washed
           immediately on removal from the tubes. The impact on the study was assessed
           after 28 days of exposure when the groups of rats which were not being washed
           were sacrificed and the clinical data set from the washed and unwashed animals
           were compared. There was no differences in the results of washed and unwashed
           animals.
        3. On Day I post exposure washing of Group 1, the use of the warming chamber was
           found to be of no benefit so was not subsequently required.
        4. On the morning of 18 September 2007, a male animal was found in a cage (cage
           number 35) of 5 female animals. The contents of cage 35 were examined for any
           evidence of copulation plugs (evidence of mating) and none were found. The 5


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           females were smeared and the smears examined for evidence of mating. Female
           154 appeared to have mated. Three of the females appeared to be in oestrous but
           did not appear to have mated, and the last female had leucocytes present and some
           cornified epithelial cells. Female 154 was retained and regular weights reviewed
           to determine if the animal was pregnant or not. The other females were smeared
           on a daily basis to establish if the animals came back into oestrous, indicating they
           had not mated. Subsequent examination of smears suggested that females 153 and
           156 may have mated and weights were reviewed and animals observed to
           determine whether there was any other evidence of pregnancy. It was determined
           that only one animal (I54F, Group 4, 90-day study) was pregnant. This animal
           was removed from the study, killed and necropsied. As only one animal (from a
           group size of 10) was lost from this test group, the impact on the study was
           considered to be minimal.
       5. On Day 1, due to the length of time in loading animals to restraint tubes and onto
          the exposure chambers together with a technical problem noted at switching on
          the exposure equipment, it was determined that there would be insufficient time to
          expose all animals for 6 hours, and remove them from their individual restraint
          tubes within the 7 hour maximum time for which an animal may be held in a
          restraint tube according to the Project Licence issued under the United Kingdom
          Animals (Scientific Procedures) Act 1986. Consequently animals from Groups 2
          and 3 were removed from the exposure chambers approximately 35 and 25
          minutes early.

       6. Pretreatment bodyweight, food consumption and water consumption recordings
          were not commenced on Day -7 as required by the protocol. These were actually
          commenced on Day -6. Although the available data is for 6 days, rather than 7, it
          is still possible to make a meaningful comparison of the data in the treatment and
          pre-treatment phases.

These deviations were considered not to have affected the integrity or validity of the study.




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3.         Results
3.1        Chamber atmosphere conditions
Annex I
The achieved chamber concentrations are summarised as follows:
                 Group                       Chamber concentration 1%(v/vl
                             Target                              Achieved
                                                After 4 weeks                After 13 weeks
                                            Mean             sd      -Mean                 sd
                    2          0.25         0.261         0.0159          0.251         0.0203
                    3          0.5          0.512         0.0402          0.482         0.0514
                    4          0.75         0.743         0.0407          0.722         0.0566
                    5           1.0          1.01          0.100           1.02         0.098
                   6w           1.0         0,948         0.0780     -     n/a            n/a
                  sd       Standard deviation
                  n/a      Not applicable
                  w        Whole body exposure

These were 104, 102, 99, 101 and 95% of the targets for Groups 2 to 6, respectively after
4 weeks and 100, 96, 96 and 102% of the targets for Groups 2 to 5, respectively after
13 weeks.

3.2        Signs and mortality
Appendices I and 2
Animal 154F (Group 4 90-day snout-only study) was suspected to be pregnant and sent to
necropsy (Day 26) (See section 2.9). Pregnancy was confirmed. No other findings were
noted.

Animal 38M (Group 3 90-day snout-only study) was found dead in the cage at the morning
inspection on Day 89. Necropsy findings comprised congestion of the mandibular lymph
node, dark area(s) on the liver and pale teeth.
28-day study animals
Pale teeth were seen in animals from all treated groups after 4 weeks of treatment. There was
no clear relationship to exposure levels.
             Group/sex                   iM          2M           3M           4M           SM        6Mc
      Exposure level 1%(v/v)I             0         0.261        0.512        0.743         1.01      0.948
    Teeth - abnormal colour, pale         0           7             6           7            8a         2
     No. of animals examined              6           8            8            8            10         5


             Group/sex                   IF          2F           3F           4F            5F        6F
      Exposure level l%(v/v)l             0         0.261        0.512        0.743         1.01      0.948
    Teeth - abnormal colour, pale         0           3             1            1           4b
     No. of animals examined              6           8            8            8            10         5

a        Of the total incidence 5 were 'washed' animals
b        Of the total incidence I was a 'washed' animal
c        Whole-body exposure, all other groups snout-only



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Wet fur and red staining (head/around eyes) were observed in animals from all snout-only
groups during the study. These signs are considered to be a non-specific effect associated
with the method of restraint used and to be of no toxicological importance.
90-day study animals
Tooth abnormalities comprising pale colouring, loss of enamel and increased wearing down
were seen in animals from all treated groups after 13 weeks of treatment, with no clear
relationship to exposure level. Other tooth abnormalities seen comprised overgrowth and
broken and missing teeth, although these observations were generally of a lower incidence.

               Group/sex              im           2M       3M        4M         5M
        Exposure level I%(v/v)]        0        0.251      0.482     0.772       1.02
      Teeth -abnormal colour, pale     0          10         10        10         10
         Teeth -loss of enamel         0           8          4         6         10
              Teeth - worn             0          6           5         6         10
           Teeth -overgrown            0           7          5         0         0
             Teeth -broken             0          2           2         0          1
              Teeth -absent            0          0           0         0         2
       No. of animals examined         10         10         10        10         10

                Group/sex             11F         2F        3F        4F          5F
        Exposure level [%(vlv)l        0        0.251      0.482     0.772       1.02
      Teeth - abnormal colour, pale    0          6          10         9          9
         Teeth -loss of enamel         0           1         4          4          5
               Teeth -worn             0          2          3          2          8
           Teeth -overgrown            0          0           1         0          5
              Teeth -broken            0          0           1         0          0
              Teeth -absent            0          0          0          0          0
       No. of animals examined        10          10         10        10         10
       NB all animals were 'washed'

Wet fur and red/brown staining (head/around eyes) were observed in all 90-day animals.
These signs are considered to be a non-specific effect associated with the method of restraint
used and to be of no toxicological importance. Other signs observed were considered to be
incidental and not related to treatment.

3.3      Bodyweight
Figure 1, Table 1, and Appendix 3

28-day study animals

A slightly higher than control group mean bodyweight gain (up to 1.6X control) was evident
for the 28-day whole-body animals exposed at 0.948% (v/v) after 4 weeks of treatment. This
may be due to slight suppression of weight gain in the control group as a result of tube
restraint.

A decreased group mean bodyweight gain was evident for all 28-day snout-only treated male
groups (up to 0.76X control) after 4 weeks of treatment. This was not exposure level-related.




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90-day study animals

A decreased group mean bodyweight gain was evident for all 90-day snout-only treated male
groups (up to 0.59X control) and all 90-day snout-only treated female groups (up to 0.81IX
control) after 13 weeks of treatment. This was not exposure level-related.

3.4      Food consumption
Appendix 4

28-day study animals

A slight reduction in food consumption was evident for all 28-day snout-only treated male
groups (up to 0.88X control) after 4 weeks of treatment. This was not exposure level-related.

90-day study animals

There were no test article-related effects on food consumption for 90-day study animals after
13 weeks of treatment.

3.5      Water consumption
Appendix 5

28-day study animals

An increase in water consumption (1 .X control) was evident for the 28-day whole-body
females exposed at 0.948% (v/v) after 4 weeks of treatment.

A slight'increase in water consumption (up to 1.2X control) was also evident for all 28-day
snout-only treated female groups. This was not exposure level-related.

90-day study animals

A slight decrease in water consumption (up to 0.79X control) was evident for all treated male
groups after 13 weeks of treatment. This was not exposure level related.

3.6      Haemnatology
Table 2 and Appendix 6

28-day study animals

Prothrombin time was significantly increased (up to 1.2X control) in snout-only males
exposed at 0.512 or 1.0 1%(v/v) and in all treated females (up to 1.1 X control), attaining
statistical significance in females exposed at 0.512% (v/v) or higher.

White blood cell counts were statistically significantly increased in all snout-only exposed
females (up to 1.6X control), this increase was primarily due to increases (up to 1.7X control)
in lymphocytes. These changes were not related to exposure level.




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Platelet counts were increased (up to 1.23X control) for all treated male groups. This was not
exposure level-related.

Other differences seen were generally small, largely inconsistent between the sexes,
dose-relationships and considered to be of no toxicological importance.

90-day study animals

Prothrombin time remained slightly increased (up to 1.1X control) in most treated groups of
both sexes compared with controls but none of the differences were statistically significant.

Platelet counts were increased in all male treated groups (up to IA.X control) and all female
treated groups (up to 1.3X control) exposed to 0.482% (v/v) and above. This was exposure
level-related.

Reticulocytes were decreased (up to 0.65X control) for all male treated groups. This was not
related to exposure level.
Other differences seen were generally small, largely inconsistent between the sexes, unrelated
to exposure level and considered to be of no toxicological importance.

3.7      Blood chemistry
Table 3 and Appendix 7

28-day study animals

Aspartate aminotransferase levels were significantly increased (up to 1.7X control) in all
treated male groups.
Urea levels were statistically significantly increased (up to 1.X control) in all treated male
groups. Levels were also increased (up to 1.3X control) in all treated female groups. In
females there was no statistical significance. This change was not related to exposure level.
Other differences seen were generally small, largely inconsistent between the sexes,
dose-relationships and considered to be of no toxicological importance.

90-day study animals

Aspartate aminotransferase levels were increased in all male treated groups (up to 2.6X
control), and in all female groups (up to 1.6X control) exposed to 0.482% (v/v) and above.
This change was not related to exposure levels.

Creatinine kinase levels were increased (up to 4.OX control) for all treated groups, except
males exposed at 1.02% (v/v) after 13 weeks of treatment. This change was not related to
exposure levels and was noted in only certain rats within the test groups.

Urea levels were increased (up to I .X control) in males exposed to 0.251 or 0.482% (v/v)
after 13 weeks of treatment.



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Creatinine levels were increased (up to 1.2X control) for all treated groups, except animals
exposed to 0.25 1%(v/v) after 13 weeks of treatment. This change was not related to
exposure levels.

Other differences seen were generally small, largely inconsistent between the sexes, unrelated
to exposure level and considered to be of no toxicological importance.

3.8      Urinalysis
Table 4 and Appendix 8

28-day study animals
Statistically significant increases in urine volume (up to 2.4X control), associated in most
cases with a decrease in specific gravity (control 1046g/L- 103 3g/L group 6) were evident for
all treated female groups. This was not exposure level-related.

Total potassium levels were increased (up to 1.5X control) in animals exposed to 0.948%
(v/v) whole body, attaining statistical significance in males.

Total chloride levels were increased (up to 1.9X control) in animals exposed to 0.948% (v/v)
whole-body, attaining statistical significance in females.

Total sodium levels were increased (up to 1.6X control) for all treated female groups. This
was not statistically significant or exposure level-related.

Other differences seen were generally small, largely inconsistent between the sexes,
dose-relationships and considered to be of no toxicological importance.

90-day study animals

A lower than control urine volume (up to 0.49X control), associated in most cases with an
increase in specific gravity (control I 032g/L- 1047gIL group 4M) was evident for all treated
groups, except males exposed at 0.722% (v/v) after 13 weeks of treatment. This was not
exposure level-related.
Total potassium levels were decreased (up to 0.42X control) for all treated groups after 13
weeks of treatment. This was not exposure level-related.

Total sodium levels were decreased (up to 0.49X control) for all treated groups, except males
exposed at 0.722% (v/v) after 13 weeks of treatment. This was not exposure level-related.

Protein levels were increased (up to 1.5X control) for all treated female groups after 13 weeks
of treatment. This was not exposure level-related.

Other differences seen were generally small, largely inconsistent between the sexes,
dose-relationships and considered to be of no toxicological importance.




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3.9      Urinary fluoride
Table 5 and Annex 2
28-day study animals

After 28 days of exposure fluoride levels were markedly increased (from 76 to 11 OX control
in males and from 27 to 53X in females) in all groups exposed to R- 1225 yeZ. There was
some evidence of a dose relationship in males only but the increases were not proportional to
increases in the exposure level.
90-day study animals

After 90 days of exposure fluoride levels were markedly increased (from 75 to 105X control
in males and from 55 to 62X in females) in all groups exposed to R- 1225 yeZ. There was
little evidence of a dose relationship.

3.10     Organ weights
Table 6 and Appendix 9

Animals killed after 28 days of treatment

There were no test article-related effects on organ weights for animals killed after 28 days of
exposure.
Animals killed after 90 days of treatment
Heart weights were decreased (up to 0.82X control) in males exposed at 0.722 or 1.02% (v/v)
after 13 weeks of treatment. This was related to exposure level.

Prostate weights were decreased for all treated males (up to 0.57X control) after 13 weeks of
treatment. This was not related to the exposure levels.
Thymus weights were decreased for all treated males (up to 0.79X control) and females (up
to 0.78X control) exposed at 0.482 or 1.02% (v/v). This was not related to the exposure
level.

3.11     Macropathology
Table 7 and Appendix 10

Animals killed after 28 days of treatment

The macroscopic examination performed after 28 days of treatment revealed no test
substance-related lesions.
The incidence and distribution of all findings were consistent with the common background
of macroscopic changes.




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Animals killed after 90 days of treatment

The macroscopic examination performed after 90 days of treatment revealed the following
changes in the teeth, lungs and tracheobronchial lymph nodes, heart, thorax and general
appearance.

Teeth
An increased incidence of pallor of the incisors was observed in treated rats. Also there was
an increased incidence of shortening of the lower incisors and/or elongation of the upper
incisors in treated rats.

        Group/Sex            IM     2M      3M         4M     5M     IF    2F       3F     4F      5F
   Exposure level [%(v/v)l    0    0.251   0.482      0.722   1.02   0    0.251   0.482   0.722   1.02
         Incisor(s) pale      0      9       9         10      10    0      9       9       9      10
     Incisor(s) overgrown     0      6       3         6       8     0      2       1       1      6
        lncisorqs) short      0      4       4         3       4     0      2       1       1      6
  No. of animals examined    10     10       9         10     10     10    10      10       9     10

Lungs and tracheobronchial lymph nodes

There was a reduced incidence of pale areas on the lungs with associated tracheobronchial
lymph node enlargement in male rats exposed to 0.482, 0.722 or 1.02% (v/v) and treated
female rats, compared with male and female control rats.
        Group/Sex            IM     2M      3M         4M     5M     IF    2F      3F      4F     5F
   Exposure level [%(vlv)l     0   0.251   0.482      0.722   1.02    0   0.251   0.482   0.722   1.02
     Lungs pale area(s)       10     2       0          1       1     6     0       0       0       1
   Bronchial LN enlarged      4      4       0          0      0      6     0       0       0     0
  No. of animals examined    10     10       9         10     10     10    10      10       9     10

Thorax

The thorax contained fluid in two male animals, one from each group exposed to 0.251 or
0.482% (vlv).

Heart

Atrial thombus was noted in a male animal in the 0.482% (v/v) treatment group.

General comments

A thin appearance was noted in some treated male rats compared with none in control rats.
         Group/Sex           1M     2M      3M         4M     5M     IF    2F      3F      4F     5F
  Exposure level [%(v/v)I     0    0.251   0.482      0.722   1.02    0   0.251   0.482   0.722   1.02
         Animal thin          0       1       3          1      3    0      0        0      0      0
  No. of animals examined    10      10      9          10     10    10    10       10      9      10

The incidence and distribution of all other findings were consistent with the common
background of macroscopic changes.



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3.12       Histopathology
Table 8 and Appendix 10

Animals killed after 28 days of treatment

Treatment-related findings

Histopathological changes related to exposure to R-1225 yeZ occurred in the heart.

Myocardial vacuolation was noted in male rats exposed to 0.261 % (v/v) and females
receiving 0.261, 0.512, 0.743, 1.01 and 0.948% (v/v).
Myocardial necrosis/inflammation/vacuolation was observed in male and female rats exposed
to 0.261, 0.5 12, 0.743, 1.01 and 0.948% (v/v). A dose-related increase in incidence was noted
in male rats only.
   Group/sex           IM    2M      3M      4M     5M      6M     1F    2F       3F      4F     5F      61F
  Exposure level        0   0.261   0.512   0.743   1.01   0.948   0    0.261    0.512   0.743   1.01   0.948
     1%(v/v)l
Myocardial
vacuolation
            Minimal    0      2       0       0      0       0     0      2        2       1      6
               Total   0      2       0       0      0       0     0      2        2       1      6        1
Myocardial
necrosis/inflammat
ion/ vacuolation
            Minimal    0      3       4       6       7      5     0      3        5       2      3        1
              Slight   0      3       3       2      3       0     0      0        0       0      0        0
               Total   0      6       7       8      10      5     0      3        5       2      3        1

   Number of           6      8       8       8      10      5     6      8        8       8      10       5
animals examined

Incidental findings

All other findings were considered to be incidental and unrelated to the test substance.
Animals killed after 90 days of treatment

Histopathological changes related to exposure to R- 1225 yeZ occurred in the heart and teeth.

Heart

Myocardial necrosis/inflammation/vacuolation was observed in male and female rats exposed
to 0.251, 0.482, 0.722 or 1.02% (v/v).

Myocardial fibrosis was seen in male rats exposed to 0.251, 0.482, 0.722 or 1.02% (v/v) and
female rats exposed to 0.251, 0.722 or 1.02% (v/v).

Myocardial vacuolation was noted in one female rat exposed to 0.25 1%(v/v).



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Atrial thrombi were seen in male rats exposed to 0.251 or 0.482% (v/v).

No dose-relationship was seen with these findings.

      Group/sex               IM    2M      3M      4M     5M     IF     2F        3F      4F      SF
     Exposure level            0   0.251   0.482   0.722   1.02    0   0.251     0.482   0.722    1.02
        1%(v/v')l
Myocardial
necrosis/inflammation!
vacuolation
                Minimal       0      4       4       5      3     0      4         7       7       8
                    Slight    0      3       4       2      2     0      0         0       0       0
               Moderate       0      3       1       0      0     0      0         0       0       0
                    Total     0     10       9       7      5     0      4         7       7       8
Myocardial fibrosis
                Minimal       0      2       3       2      2     0       1        0       1       1
                  Slight      0      2       1       0      0     0      0         0       0       0
                   Total      0      4       4       2      2     0       1        0       1       1
Myocardial vacuolation
                Minimal       0      0       0       0      0     0      1         0       0       0
                   Total      0      0       0       0      0     0      1         0       0       0
Atrial thrombus
                    Present   0      3       3       0      0     0      0         0       0       0

  Number of animals           10    10       9      10      10    10    10         10      9       10
     examined

Teeth

Ameloblastic dysplasia was observed in male treated rats and females exposed to 0.251,
0.722 or 1.02% (v/v).

Periodontal inflammation was seen in male and female rats exposed to R- 1225 yeZ.

No dose-relationship was seen with these findings.
      Group/sex               iM    2M      3M      4M     5M     IF     2F        3F      4F      SF
    Exposure level             0   0.251   0.482   0.722   1.02    0   0.251     0.482   0.722    1.02
        1%(v/v)l
Ameloblastic dysplasia
                   Minimal    0      2      2        3      2     0      1         0       2       2
                     Slight   0      1      0        0      1     0      0         0       0       1
                     Total    0      3      2        3      3     0      1         0       2       3
Periodontal
inflammation
                   Minimal    0     4       2        1      5     0     2          3       2       4
                     Slight   0     0       1        0      0     0     0          0       1       0
                      Total   0     4       3        1      5     0     2          3       3       4

  Number of animals           10    10      9       10      10    10    10        10       9       10
     examined




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    4. Discussion
In this study, 4 groups of rats were exposed by snout-only inhalation to test atmospheres
containing R- 1225 yeZ for 6 hours daily for 5 consecutive days each week for either 4 or 13
consecutive weeks. In order to investigate the differences between whole-body and
snout-only exposure, a further group of animals were exposed for 28 days only by
whole-body exposure. A sixth group of animals acting as controls was exposed to air only
using a snout-only exposure system.

The achieved exposure levels were 0.261, 0.5 12, 0.743 or 1.01% (v/v) R-1225 yeZ after
4 weeks for animals exposed snout-only and 0.948% (vlv) for animals exposed whole-body
for 4 weeks. After 13 weeks of exposure the achieved mean exposure levels for those
animals exposed by snout-only exposure were 0.251, 0.482, 0.722 or 1.02% (v/v).
In order to investigate whether ingestion of excreta during post-exposure grooming
contributed to any adverse effects of exposure, all animals exposed for 13 weeks and a
sub-group of snout-only 4-week study animals from the highest exposure level were washed
daily on removal from the restraint tube in an attempt to remove excreta from the fur.
Animal 38M (Groups 3 90-day snout-only study), which was found dead on the morning of
Day 89, had no cause of death established.
Microscopic examination was restricted to the heart of animals killed after 28 days, and the
heart and teeth of those killed after 90 days exposure.

In animals killed after 4 or 13 weeks exposure myocardial vacuolation, necrosis and/or
inflammation were seen in a proportion of animals at all exposure levels. Myocardial
vacuolation is thought to be an early stage of the same pathological process which ultimately
leads to necrosis/inflammation/vacuolation. Therefore the myocardial vacuolation can be
considered a milder or primary response to the test substance. The more severe myocardial
damage is considered to be the likely source of the increased serum aspartate
aminotransferase levels noted in some treated rats. Similar myocardial damage has been
reported in experimental fluorosis in the rabbit (Shashi and Thapar 2001) and it is postulated
that the myocardial damage seen in the present study results from the metabolic release of
free fluoride ions from the test article.
Atrial thrombi observed in some male rats exposed to R- 1225 yeZ are secondary to the
inflammation and fibrosis seen in the myocardium of the atria affected and are indicative of
heart failure. Fluid seen in the thorax of two males at macroscopic examination correlates
with the severity of myocardial damage seen in these animals and is also indicative of heart
failure.

The increased level of creatinine kinase (CK) was in some rats from all 90-day exposed
groups, except males exposed to 1.02% (v/v), may correlate with the myocardial damage
identified. CK is leaked from damaged muscle cells; however, the magnitude of increase did
not necessarily correlate with the extent of injury. Increases in creatinine levels may be
associated with this change in CK.
Heart weights were decreased in males exposed to 0.722 or 1.02% (v/v), no abnormality
detected could be correlated with this.


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Pallor of the teeth observed clinically and macroscopically correlates with ameloblastic
dysplasia. Periodontal inflammation (and the other tooth abnormalities observed) which was
seen in animals exposed to R- 1225 yeZ may be secondary to the damaged enamel which has
a protective role in the teeth. This type of effect on the teeth is a long-recognised
consequence to exposure to high levels of fluoride (Schlour and Smith 1934) and in the
present study, is considered to result from the metabolic release of free fluoride ions from the
test article.
Water consumption was increased in females exposed for 4 weeks and decreased in males
exposed for 13 weeks. There was limited correlation with urinary output but it is likely that
the increase in water consumption is a compensatory response to increased urine output; the
changes in urinary specific gravity, potassium, chloride, sodium and protein levels and
plasma urea levels being secondary to this increased urine output. Higher levels of urinary
fluoride at all exposure levels is consistent with the metabolic breakdown of
fluorine-containing compounds, such as R- 1225 yeZ and a common observation in animals
exposed to such compounds is polyuria (Whitford and Taves 1973).

Treatment-related reductions in bodyweight gain were seen at all levels of snout-only
exposed males exposed for 4 weeks and in all groups exposed for 13 weeks. Reductions in
weight gain were not exposure level related but are considered to be treatment-related and
correlate to some extent with macroscopic observations of thin appearance in some treated
males. The reduced food consumption seen early in the present study is consistent with the
appetite suppression which has been reported as a result of fluoride toxicity in cattle
(Stoddart et a] 1963).
As the microscopic examination was restricted to the heart and teeth, the toxicological
significance of a reduced incidence of pale areas on the lungs, bronchial lymph node
enlargement and decreased prostate and thymus weights is unknown. The disturbances in
haemnatology parameters also have no known aetiology in light of the limited pathology
performed.




                                              41
                                                                       Huntingdon Life Sciences
                                                                                      ATS0022

5.      Conclusion
In the heart, myocardial necrosis/intlammation/vacuolation and myocardial vacuolation were
noted in rats exposed to R- 1225 yeZ over a 28-day period.
In the heart, myocardial necrosis/inflammation/vacuolation, myocardial fibrosis, myocardial
vacuolation and atrial thrombi were observed in rats exposed to R- 1225 yeZ over a 90-day
period.

In the teeth, ameloblastic dysplasia and periodontal inflammation were seen in rats exposed
to R- 1225 yeZ over a 90-day period.
There was no difference in the treatment-related findings between rats undergoing snout-only
exposure and those undergoing whole-body exposure. There was no difference in the
treatment-related findings between rats that were washed following exposure and those that
were not.
A no adverse effect level (NOAEL) was not established in this study.




                                             42
                                                                      Huntingdon Life Sciences
                                                                                     ATS0022

6.       References
ANGERVALL, L. and CARLSTROM, E. (1963) Theoretical criteria for the use of relative
organ weights and similar ratios in biology. Journalof Theoretical Biology, 4, 254-259.

BARTLETT, M.S. (193 7) Properties of sufficiency and statistical tests. Proceedingsof the
Royal Society. Series A, 160, 268-282.
DTJNNETT, C.W. (1955) A multiple comparison procedure for comparing several treatments
with a control. Journalof the American StatisticalAssociation, 50, 1096-112 1.

DUNNETT, C.W. (1964) New tables for multiple comparisons with a control. Biometrics,
20, 482-491.

FISHER, R.A. (1973) StatisticalMethods for Research Workers, 14th edn., p.96. Hafner
Publishing Company, New York, USA.

KRUSKAL, W.H. and WALLIS, W.A (1952) Use of ranks in one-criterion variance analysis.
Journalof the American StatisticalAssociation. 47, 583-62 1.

SCHLOUR, 1. and SMITH, M.C. (1934) The histologic changes in the enamel and dentin of
the rat incisor in acute and chronic experimental fluorosis. University ofArizona Agricultural
Experimental Station Technical Bulletin, 52, 69-9 1.

SHASHI, A. and THAPAR, S.P. (200 1) Histopathology of myocardial damage in
experimental fluorosis in rabbits. Fluoride,34 (1), 43-50.

SHIRLEY, E.A.C. (1977) A non-parametric equivalent of Williams' test for contrasting
increasing dose levels of a treatment. Biometrics, 33, 386-389.

STEEL, R.G.D. (1959) A multiple comparison rank sum test: treatments versus control.
Biometrics, 15, 560-572.

STODDARD. G.E., HARRIS, L.E. BATEMEN G.Q., SHUPE, J.L., and GREENWOOD,
D.A. (1963) Effects of fluorine on dairy cattle I. Growth and feed consumption. Journalof
DairyScience, 46, 1094-1102.

WHITFORD, G.M. and TAVES, D.R. (1973) Fluoride-induced diuresis: renal-tissue solute
concentrations, functional, haemodynamic and histologic correlated in the rat.
Anaesthesiology, 39 (4), 416-427.

WILLIAMS, D.A. (1971) A test for differences between treatment means when several dose
levels are compared with a zero dose control. Biometrics, 27, 103-1 17.

WILLIAMS, D.A. (1972) The comparison of several dose levels with a zero dose control.
Biometrics, 28, 519-53 1.

Huntingdon Life Sciences Number ATSOO 10
R- 1225 yeZ: Toxicity Study by Inhalation Administration to CD Rats for 5 Days or 4 weeks.




                                             43
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                              02
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                                                                         ATS0022

Annex I   Administration of R-1225 yeZ to rats by inhalation




                                   624
                                              Huntingdon Life Sciences
                                                              ATS0022


Huntingdon




   Administration of R-1 225 yeZ to rats by inhalation




                         HLS study number:       ATS0022

                         Author:                 Simon Moore




                           625
                                                                         Huntingdon Life Sciences
                                                                                         ATS0022

        1. Administration
Rats were exposed to air or a test atmosphere containing the test gas either by snout-only
exposure for 6 hours a day, 5 consecutive days/week over a period of 4 or 13 weeks (Groups
1-5) (20 or 65 exposures) or by whole-body exposure for 6 hours a day, 5 consecutive
days/week over a period of 4 weeks only (Group 6) (20 exposures).

1.1       Exposure system
The inhalation system comprised an ADG snout-only inhalation exposure chamber and
rodent restraining tubes or a whole-body inhalation exposure chamber each with an
atmosphere generation system. Accessories included air supply and extract lines, attached to
the top and bottom of the chamber, respectively and a filtration system which was
incorporated in the extract line.

Each inhalation chamber was connected to an atmosphere generation system supplying a flow
of test atmosphere or air. An air flow differential was maintained between the inlet and outlet
to provide a small negative pressure within the exposure system. Separate exposure systems
were used for the test and control groups.

Schematics of the exposure systems are presented in Figures A and B. The exposure system
operating conditions are presented in Table A. The component parts of the systems are
described in further detail as follows:

1.1.1     Test atmosphere generation
The test gas was dispensed directly from the test cylinder supplied. The test cylinder was
fitted with a cylinder regulator to allow isolation of the test gas supply. The flow of test gas
to each dose group was regulated with a Porter flowmeter and toggle valve, prior to dilution
in the exposure chamber.

1.1.2     Inhalation chamber (Snout-only (Groups I to 5))
The ADG snout-only inhalation chamber was a modular apparatus of aluminium alloy
construction comprising a base unit, a variable number of animal exposure sections and a top
section incorporating a central aerosol inlet surrounded by a tangential air inlet.

1.1.3     Rat restraining tubes (Snout-only (Groups I to 5))
The restraining tubes were moulded polycarbonate tubes tapered at one end to allow only the
snout to project from the tapered end. The other end was closed by insertion of an expanded
plastic bung. A push rod passed through the centre of the bung and was adjustable to
maintain the position of the rat during restraint. Tubes were attached to the chamber by
means of push fit "0" ring seals located in the exposure ports of the animal exposure
sections.

1.1.4     Inhalation chamber (Whole-body (Group 6))
The whole-body inhalation chamber was of stainless steel and perspex construction and
consisted of a cuboidal body fitted with a pyramidal top incorporating a central aerosol inlet.



                                               626
                                                                      Huntingdon Life Sciences
                                                                                      ATS0022

The internal volume was approximately 120 litres. During dosing the chamber was housed in
an enclosed ventilated cabinet.
1.1.5 Air supply and extract
The compressed air supply was filtered to remove any residual particulate and dried. This
was used to operate the supplementary tangential air inlet at the top of the inhalation
chamber.
Air extract, attached to the base of the inhalation exposure system, was provided by vacuum
pumps and incorporated a filtration system to remove water vapour. Downstream of the
filtration system were charcoal drums to partially remove the test gas from the airstream.
Air supply and extract were monitored using in-line flowmeters. The in-line flowmeters were
calibrated daily against high quality tapered tube rotameters and were used to measure the
free flow of air at the points of attachment of the supply and extract lines to the exposure
system.

1.2         Exposure conditions
1.2.1       Gas concentration
The samples were collected directly from the exposure chambers using gas tight syringes.
The gas concentration of the R- 1225 yeZ within the exposure chambers was measured by
Inhalation Chemistry and details are given in Appendix A.
1.2.2       Nominal concentration
A mean daily nominal concentration was calculated for all test groups from the mass of test
gas used over the exposure period and the airflow through the exposure chamber. The ideal
gas equation was used with the molecular weight of the test gas and the measured chamber
conditions to compute the volume of gas produced from the mass of test gas used. The
calculation is detailed in Table C.
1.2.3 Temperature
This parameter was recorded manually, every 30 minutes during exposure.
1.2.4       Airflow
These parameters were checked manually, as described above under the Exposure System
sections.




                                            627
                                                                          Huntingdon Life Sciences

                                                                                         ATS0022

2.       Results
2.1      Gas concentration
The data are presented as follows and are summarised below:

       Mean gas concentrations          -     Table B
       Individual gas concentrations    -     Appendix B
              Group                    Chamber concentration 1%(vlv)l
                                    Target                      Analysed

                2                      0.25                       0.251
                3                      0.50                       0.482
                4                      0.75                       0.722
                5                      1.0                         1.02
                6                      1.0                        0.948


The mean analysed concentrations were all very close to the target concentrations.

The coefficient of variation for each test group is less than 10%. This confirms consistent
generation throughout the duration of the study.

2.2      Nominal concentration
The nominal concentrations are presented in Table C.

The daily analysed and nominal concentrations for the test groups were generally in good
agreement.

2.3      Chamber temperature
The daily mean chamber temperatures are presented in Table D.

The chamber temperatures were similar for each group on each day of the study. The observed
temperatures for all groups remained within the normally accepted range for inhalation
exposure of rats.

3.       Discussion
Consistency of the delivery of R- 1225 yeZ gas to the exposure chambers was good for all test
groups.

4.       Calculations
In order to minimise the cumulative errors which result from repeated rounding of numbers,
much of the data in this report has been calculated continuously using unrounded numbers
and only rounded for printing. Consequently, these rounded numbers may include rounding
errors in the last significant figure, possibly leading to small apparent discrepancies with
other data in the report.



                                              628
                                                                           Huntingdon Life Sciences
                                                                                          ATS0022

Figure A     Schematic of a rodent snout-only inhalation dosing system
             (Groups I to 5)




                                            0                               B



                                                                             A




   Key
   A       Test cylinder                        G     ADG chamber
   B       Regulator/gauges                     H     Blanking bungs
   C       Porter flow meter and toggle valve   I     Rat restraint tube
   D       Test gas feed line                   J     Extract plenum
   E       Test gas connection to chamber       K     Filtration system
   F       Diluent line




                                                629
                                                                           Huntingdon Life Sciences
                                                                                           ATS0022

Figure B     Schematic of a rodent whole-body inhalation dosing system
             (Group 6)




                                            E                                B




             Key




  A        Test cylinder                        G     Whole body chamber
  B        Regulator/gauges                     H     Internal caging
  C        Porter flow meter and toggle valve   I     Sampling port
  D        Test gas feed line                   J     Extract connection
  E        Test gas connection to chamber       K     Filtration system
  F        Diluent line




                                                630
                                                                                                          Huntingdon Life Sciences
                                                                                                                          ATS0022

Table A           Operating conditions for the inhalation exposure system



(L/minute)

Exposures 1-20
        Inlet                    19                  19                     19               19                    19                   N/A
        Extract                  20                  20                     20               20                    20                   N/A
Exposures 26-65
        Inlet                    14                  14                     14               14                    14                   N/A

        Extract                  15                  15                     15               15                    15                   N/A

Chamber level ofthe          2 and 3               2 and 3            2 and 3            2 and 3              2 and 3                    1
rats                     _   _    _    _   _   _     _    _   _   _     _    _   _   _   _   _    _   _   _    _        _   _   _   _    _    _

N/A     Not Applicable




                                                                  631
                                                                        Huntingdon Life Sciences
                                                                                       ATS0022

Table B           Chamber concentrations of R-1 225 yeZ - mean exposure values
 Exposure                             Atmosphere concentration 1%(vlv)I
  number          Group 1   Group 2        Group 3       Group 4        Group 5     Group 6
            1ND              0.259          0.528         0.771          1.15        0.957
      2              ND      0.283          0.539         0.772          1.18        0.913
      3               ND     0.273          0.558         0.793          1.17        0.898
      4               ND     0.278          0.557         0.805          1.16        0.937
      5               ND     0.259          0.554         0.767          1.05         1.03
      6               ND     0.258          0.493         0.737         0.894        0.878
      7               ND     0.262          0.469         0.708         0.875        0.738
      8               ND     0.281          0.475         0.750         0.89 1       0.878
      9               ND     0.278          0.467         0.723         0.986        0.942
     10               ND     0.279          0.483         0.728          1.09         1.01
     I1I              ND     0.235          0.437         0.635         0.95 1       0.899
     12               ND     0.233          0.449         0.682         0.946        0.924
     13               ND     0.244          0.503         0.718         0.946        0.908
     14               ND     0.243          0.526         0.716         0.966        0.918
     15               ND     0.242          0.505         0.717         0.965        0.950
     16               ND     0.254          0.564         0.753          1.00         1.00
     17               ND     0.265          0.573         0.768          1.02         1.04
     18               ND     0.2 70         0.534         0.777         0.856         1.07
     19               ND     0.276          0.500         0.777          1.03         1.04
     20               ND     0.257          0.527         0.768          1.02         1.04
     21               ND     0.255          0.428         0.730          1.08
     22               ND     0.255          0.439         0.728         0.968
     23               ND     0.263          0.466         0.741          1.01
     24               ND     0.258          0.413         0.759          1.02
     25               ND     0.266          0.449         0.753          1.03
     26               ND     0.228          0.438         0.639         0.892
     27               ND     0.229          0.433         0.622         0.924
     28               ND     0.220          0.430         0.645         0.954
     29               ND     0.256          0.496         0.699         0.896
     30               ND     0.222          0.457         0.698         0.967
     31               ND     0.260          0.470         0.699          1.00
     32               ND     0.247          0.469         0.7 14        0.959
     33               ND     0.27 1         0.503         0.746         0.975
     34               ND     0.292          0.542         0.746          1.01
     35               ND     0.267          0.5 19        0.753         0.949
     36               ND     0.257          0.542         0.798          1.08
     37               ND     0.256          0.470         0.768          1.02
     38               ND     0.243          0.479         0.758         0.955
     39               ND     0.238          0.493         0.782         0.875
     40               ND     0.236          0.484         0.733         0.95 1
ND         Not detected




                                              632
                                                                            Huntingdon Life Sciences
                                                                                            ATS0022

Table B         Chamber concentrations of R-1 225 yeZ - mean exposure values
                (continued)
 Exposure                                Atmosphere concentration 1% (vlv)I
  number        Group 1        Group 2        Group 3       Group 4         Group 5     Group 6
    41            ND            0.227           0.486         0.726          0.956
    42            ND            0.264           0.564         0.924           1.15
    43            ND            0.242           0.493         0.720           1.44
    44            ND            0.256          0.513          0.754           1.20
    45            ND            0.223           0.414         0.608          0.994
    46            ND            0.251           0.470         0.697           1.11
    47            ND            0.233           0.422         0.604           1.04
    48            ND            0.229           0.365         0.636           1.00
    49            ND            0.23 3         0.399          0.709           1.01
     50           ND            0.222          0.451          0,673          0.973
     51           ND            0.230          0.503          0.752           1.15
     52           ND            0.221          0.472          0.614          0.967
     53           ND            0.261          0.567          0.722           1.06
     54           ND            0.293          0.609          0.757           1.08
     55           ND            0.282          0.545          0.710           1.05
     56           ND            0.233          0.446          0.752           1.11
     57           ND            0.228          0.445          0.683           1.13
     58           ND            0.253          0.456          0.741           1.13
     59           ND            0.249          0.482          0.739           1.08
     60           ND            0.237          0.381          0.580           1.00
     61           ND            0.287          0.4 19         0.708          0.946
     62           ND            0.237          0.399          0.657          0,979
     63           ND            0.240          0.444          0.699           1.01
     64           ND            0.206          0.472          0.704           1.07
     65           ND            0.225          0.475          0.716           1.03
    Mean                        0.25 1         0.482          0.722           1.02       0.948
     sd                        0.0203          0.05 14       0.0566          0.098       0.0780
   CV %)                         8.1            10.7            7.8           9.6          8.2
ND      Not detected
sd      Standard deviation
CV ()Coefficient of variation (sd x 100/mean)




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Table C       Nominal concentrations of R-1225 yeZ - individual and mean
              exposure values
Exposure      Mean          Barometric    Test gas         Analysed    Nominal        A/N
 number    temperature       pressure    usage (kg)         conc,       conc.         ratio
             of dose         (mmHg)                        1%(V/V)j   1% (V/V)j b      %
           groups    C~C)                                 _____

   1          22.1             770         1.297              0.734     0.648         113
   2          22.7             765         1.267              0.736     0.638         115
   3          21.6             770         1.262              0.739     0.630         117
   4          21.5             772         1.233              0.748     0.613         122
   5          21.6             772         1.219              0.731     0.607         120
   6          21.6             762         1.206              0.652     0.608         107
   7          21.6             758          1.057             0.610     0.536         114
   8          21.3             768          1.285             0.655     0.642         102
   9          21.4             765          1.319             0.679     0.662         103
   10         22.3             762          1.293             0.718     0.653         110
   11         21.1             765          1.350             0.631     0.676          93
   12         22.0             754          1.368             0.647     0.697          93
   13         22.4             759          1.368             0.664     0.694          96
   14         22.1             768          1.394             0.674     0.698          97
   15         22.1             768          1.012             0.676     0.508         133
   16         22.2             768          1.432             0.716     0.717         100
  17          21.8             769          1.354             0.732     0.677         108
  18          22.0             768          1.240             0.701     0.621         113
  19          21.4             765         1.355              0.725     0.679         107
  20          21.6             767          1.288             0.722     0.645         112
  21          21.0             769         0.985              0.624     0.614         102
  22          20.9             770         0.951              0.597     0.592         101
  23          20.7             769         0.987              0.621     0.614         101
  24          19.4             769         0.962              0.612     0.596         103
  25          20.6             773         0.972              0.624     0.602         104
  26          20.7             767         0.698              0.549     0.581         94
  27          21.0             762         0.680              0.552     0.570         97
  28          20.7             762         0.658              0.562     0.552         102
  29          20.1             763         0.773              0.587     0.645         91
  30          20.4             774         0.731              0.586     0.602         97
  31          19.6             776         0.762              0.607     0.624         97
  32          19.6             770         0.740              0.597     0.611         98
  33          19.7             770         0.776              0.624     0.641         97
  34          19.7             773         0.798              0.648     0.656         99
  35          19.8             771         0.772              0.622     0.637         98
  36          21.6             762         0.776              0.670     0.652         103
  37          21.7             760         0.760              0.628     0.640         98
  38          22.0             766         0.744              0.609     0.623         98
  39          21.7             772         0.794              0.597     0.658         91
  40          21.7             774         0.730              0.601     0.604         100




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Table C          Nominal concentrations of R-1225 yeZ - individual and mean
                 exposure values (continued)
Exposure        Mean          Barometric       Test gas     Analysed        Nominal           A/N
 number      temperature       pressure       usage (kg)     conc.           conc.           ratio
                of dose        (mmllg)                      1%(V/v)j        %
                                                                           1 (V/V)I b         %
              groups (*Q                                                   _____           ____

    41            22.0            775           0.794          0.599          0.657            91
    42            22.3            772           0.840           0.725         0.698           104
    43            22.1            775           0.704          0.725          0.583           124
    44            22.0            770           0.762          0.680          0.634           107
    45            21.8            766           0.659          0.560          0.552           101
    46            22.5            760           0.781          0.631          0.660            96
    47            22.6            770           0.711          0.575          0.593            97
    48            22.7            762           0.715          0.558          0.603            93
    49            22.8            765           0.761          0.587          0.639            92
    50            22.7            772           0.758          0.580          0.631            92
    51            22.9            757           0.784          0.657          0.666            99
    52            22.8            750           0.676          0.568          0.580            98
    53            22.6            755           0.766          0.652          0.652           100
    54            22.5            750           0.795          0.684          0.680           101
    55            22.7            752           0.774          0.647          0.66 1           98
    56            22.8            768           0.732          0.636          0.613           104
    57            22.4            775           0.702          0.62 1         0.582           107
    58            22.5            774           0.733          0.646          0.608           106
    59            22.7            765           0.732          0.638          0.6 15          104
    60            22.5            755           0.558          0.550          0.475           116
    61            22.7            747           0.712          0.590          0.613           96
    62            22.8            751           0.613          0.568          0.525           108
    63            22.6            761           0.744          0.598          0.628           95
    64            22.2            753           0.792          0.6 14         0.674           91
    65            22.1            75            075            0.611          0.649           94
                                                Mean           0.639          0.625           102
                                                  sd           0.0559        0.0466           8.
                                              CV %               8.8           7.5            8 .7
    a    Analysed concentration is the mean of the values for the individual groups
b        Nominal concentrations were calculated from the following equations:

                  Concentration (%       =          X1 02      V = WxRxT X76Omm Hg
                                           V.a+V                         M           Atm
        where             V                 gaseous volume of R- 1225 yeZ
                          W        =        mass ofR- 1225 yeZ
                          M        =        molecular weight R- 1225 yeZ (132.1 glmole)
                          R        =        gas constant (0.08205 1 atm mol' K-)
                          T        =        temperature (K), =temperature ('C, see Table D) + 273
                          Atm      =        atmospheric pressure (mmHg)
                          Va                volume of air (litres) passing through the chamber during the
Exposure (airflow (see Table A) x duration)
AJN     Analysed/nominal concentration ratio expressed as a percentage
sd      Standard deviation
CV ()Coefficient of variation (sd x 100/mean)




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Table D             Chamber temperature (OC)       -   exposure mean values
 Exposure                                               Group
 number                1                2      3                 4       5            6
       1              21.8             22.1   22.1              19.4    22.9         23.9
       2              22.6             22.7   22.9              20.0    23.4         24.3
       3              21.3             21.6   21.6              18.9    22.6         23.5
       4              21.4             21.7   21.7              19.1    22.7         22.2
       5              21.2             21.6   21.7              19.0    22.6         23.2
       6              21.7             21.6   21.8              19.3    22.7         22.8
       7              21.2             21.6   21.9              19.1    22.7         22.6
       8              21.1             21.4   21.5              18.8    22.4         22.4
       9              21.7             21.7   21.5              19.0    22.8         22.2
       10             22.1             22.3   22.5              20.0    23.4         23.1
       11             21.3             21.3   21.3              19.2    22.6
       12              C               21.3   21.4              20.8    22.7         23.6
       13               C21.5                 21.7              22.1    22.7         24.2
       14             21.5             21.5   21.4              21.5    22.4         23.5
       15             21.4             21.4   21.6              21.6    22.3         23.5
       16             21.2             21.6   21.8              21.8    22.6         23.0
       17             21.0             21.2   21.6              21.5    22.5         22.4
       18             21.0             21.0   21.5              22.0    22.5         23.0
       19             21.1             21.4   21.5              21.5    22.3         20.2
       20             21.3             22.0   21.8               C      22.4         20.1
       21             20.8             20.7   20.9               C      21.3
       22             20.3             20.8   20.8               C      21.2
       23             20.1             20.6   20.7               C      20.7
       24             20.2             17.1   20.5               C      20.7
       25             20.3             20.5   20.5               C      20.9
       26             20.7             20.5   20.6               C      20.9
       27             20.3             20.8   21.0              20.8    21.2
       28             20.0             20.9   20.8              20.3    20.8
       29             19.3             20.2   20.0              19.9    20.2
       30             19.0             20.1   21.5              19.9    20.1
       31             18.9             19.7   19.7              19.3    19.8
       32             18.9             19.6   19.7              19.3    19.6
       33             18.9             19.7   19.7              19.5    19.7
       34             19.0             19.7   19.7              19.6    19.8
       35             18.9             19.9   19.7              19.7    20.0
       36             21.0             21.7   21.7              21.1    21.8
       37             21.1             21.7   21.8              21.4    22.0
       38             21.5             21.8   22.0              21.8    22.3
       39             21.2             21.8   21.7              21.4    21.8
       40             21.2             21.8   21.8              21.4    21.8
   C        Temperature not recorded




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Table D          Chamber temperature (*C)                -   exposure mean values (continued)
  Exposure                                                   Group
  number             1               2              3                 4         5            6
    41             21.8            22.3            22.0              21.8     21.9
    42             22.0            22.0            22.5              22.0     22.5
    43             21.8            22.1            22.1              21.8     22.2
    44             21.4            22.2            21.7              21.7     22.2
    45             21.2            21.8            21.8              21.5     22.1
    46             22.0            22.3            22.3              22.3     23.2
    47             22.1            22.3            22.6              22.5     23.1
    48             22.3            22.7            22.7              22.7     22.8
    49             22.2            22.7            22.7              22.7     23.1
    50             22.3            22.6            22.6              22.6     23.0
    51             22.2            22.8            22.8              22.7     23.1
    52             22.3            22.8            22.8              22.7     22.8
    53             22.0            22.6            22.5              22.5     22.7
    54             21.9            22.5            22.5              22.2     22.6
    55             22.2            22.7            22.7              22.5     22.7
    56             22.0            22.8            22.8              22.7     22.8
    57             22.0            22.3            22.4              22.3     22.6
    58             22.0            22.4            22.4              22.4     22.7
    59             22.0            22.7            22.7              22.7     22.8
    60             22.0            22.5            22.5              22.4     22.6
    61             22.3            22.7            22.8              22.6     22.8
    62             22.0            22.7            22.8              22.7     22.8
    63             22.0            22.5            22.7              22.5     22.6
    64             21.9            22.2            22.2              22.0     22.3
    65             22.0            22.0            22.1              22.0     22.3
   Mean            21.2            21.6            21.7              21.1     22.1          22.8
    sd             1.01            1.07            0.90              1.35     1.02          1.13
  CV (%) ,          4.8             5.0            4.2               6.4       4.6          4.9
sd      Standard deviation
CV (%/) Coefficient of variation (sd x 100/mean)




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Appendix A Methods of analysis for R-1 225 yeZ
Flow diagram summary of the method for the analysis of R-1225 yeZ in gas bags

                   Sample Assay                                                   Calibration
  Syringe containing R- 1225 yeZ, extracted directly        Dispense at least 250 ml, of R- 1225 yeZ into a gas bag
             from animal dose chamber.                               that has been purged with test item.

            Inject onto the GC in duplicate.               Using gas tight syringes add appropriate volumes of air
                                                            to clean gas bags, followed by appropriate volumes of
                                                               R- 1225 yeZ from the stock gas bag, or previously
                                                           prepared standard. Standards should be prepared at 0.2,
                                                                 0.25, 0.5, 0.75, 1.0 and 2.0% v/v R- 1225 yeZ.
                                                                                       I
                                                           Inject the six standards onto the GC prior to sample assay,
                                                               to ensure GC system is operating correctly, and an
                                                            appropriate bracketing standard during sample assay, for
                                                                                    calibration.




GC conditions

Analytical column:                 SPB-5, 30m x 0.32 mm id, 0.25 pim film

Injection mode:                    Manual injection in split mode

Injector temperature:              150 0 C

Injection volume:                  250 jiL

Detector type                      Flame lonisation

Detector temperature:              1750 C

Range:                             2

Oven temperature programme:        Isothermal at 50'C

Run Time:                          1.50 min

Gases:                            Carrer:             Helium at 4 mL/min
                                  Split vent:         Helium at 200 mL/min (split ratio 1:50)
                                  Septum purge:       Helium at 5.5 mL/min
                                  Make up:            Helium at 30 mL/min
                                  Oxidant:            Air at 350 mL/min
                                  Fuel:               Hydrogen at 40 mL/min

The GC system was calibrated using external standards. Peak area data acquired by the data capture software
using a 1' order fit was subjected to least squares regression analysis.




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Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values

    Exposure 1                                     Group
     Sample                1           2         3        4            5         6
        1                 ND        0.2 52     0.50 1   0.722        1.09     0.954
        2                 ND        0.245      0.521    0.745        1.08     0.972
        3                 ND        0.258      0.526    0.797        1.18     0.977
        4                 ND        0.259      0.530    0.779        1.14     0.955
         5                ND        0.273      0.560    0.795        1.23     0.942
         6                ND        0.269      0.532    0.790        1.19     0.943

    Exposure 2                                     Group
     Sample                1           2         3        4           5         6
        1                 ND        0.289      0.570    0.738         d       0.935
        2                 ND        0.279      0.516    0.815        1.11     0.909
         3                ND        0.277      0.567      0.762      1.21     0.873
        4                 ND        0.275     0.543       0.754      1.15        d

        5                 ND        0.282     0.532       0.784      1.20     0.941
        6                 ND        0.293     0.507       0.780      1.21     0.905

    Exposure 3                                    Group
     Sample                 1         2          3          4         5         6
        1                 ND        0.245      0.523      0.755      1.09     0.878
        2                 ND        0.278     0.555      0.790       1.23     0.924
        3                 ND        0.278     0.565      0.805       1.20     0.919
        4                 ND        0.288     0.562      0.808       1.22     0.859
        5                 ND        0.261     0.581      0.795       1.20        d

        6                 ND        0.285     0.564      0.807       1.09     0.910

    Exposure 4                                    Group
     Sample                1          2         3        4            5          6
        1                 ND        0.260     0.544    0.841         1.09     0.828
        2                 ND        0.261     0.537    0.826         1.26     0.882
        3                 ND        0.280     0.554    0.820         1.26     0.914
        4                 ND        0.297     0.587    0.819          d       0.955
        5                 ND        0.288     0.560    0.730         1.11      1.02
        6                 ND        0.279     0.559    0.796         1.09      1.02

    Exposure 5                                     Group
     Sample                1          2          3        4            5         6
         1                ND        0.2 59    0.642     0.776        1.03     0.996
        2                 ND        0.265     0.537     0.777        1.01      1.02
        3                 ND        0.260     0.536     0.742        1.06      1.04
        4                 ND        0.255     0.547      0.769       1.10      1.05
        5                 ND        0.261     0.529         d        1.03        d

        6                ND        0.255      0.534     0.769       1.07       1.02
     Analytical problem due to high variation between injections, no results available




                                                  639
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Appendix B Chamber concentrations of R-1225 yeZ - individual exposure
           values (continued)
     Exposure 6                                    Group
      Sample                 1         2         3        4            5           6
             1ND                     0.269     0.499    0.744       0.828        0.826
         2                 ND        0.258     0.47 1   0.733       0.840        0.875
         3                 ND          d       0.477    0.708       0.796        0.85 1
         4                 ND        0.261     0.478    0.683       0.912        0.853
         5                 ND        0.250     0.521    0.781        1.01        0.912
         6                 ND        0.252     0.510    0.771       0.977        0.951

     Exposure 7                                     Group
      Sample                 1         2          3         4         5             6
             1ND                    0.257      0.493      0.721     0.627         1.08
         2                 ND       0.252      0.447      0.686     0.897        0.579
         3                 ND       0.270      0.431     0.640      0.935        0.596
         4                 ND       0.254      0.469      0.722     0.903        0.601
         5                 ND       0.269      0.482      0.720     0.939        0.822
         6                 ND       0.269      0.494     0.760      0.946        0.744

     Exposure 8                                     Group
      Sample                1          2         3         4          5            6
             1ND                     0.287     0.479     0.776      0.838        0.860
         2                 ND        0.288     0.476     0.770      0.95 1       0.779
         3                 ND          d          d      0.728      0.907           d
         4                 ND        0.271     0.461     0.726      0.909        0.943
         5                 ND        0.278        d         d       0.848           d
         6                 ND          d       0.484        d         d          0.931

    Exposure 9                                      Group
     Sample                 1          2         3          4         5            6
        1                  ND          d       0.431     0.715      0.807        0.914
        2                  ND       0.269      0.488     0.725       1.02        0.924
        3                  ND       0.278      0.475     0.735       1.00        0.939
        4                  ND       0.278      0.475     0.736       1.04        0.990
        5                  ND       0.286         d      0.718         d            d
        6                  ND          d         d       0.707       1.06          d


    Exposure 10                                     Group
      Sample               1           2         3          4          5            6
         1                ND        0.256         d       0.715       1.04       0.994
         2                ND        0.276      0.475      0.693       1.06       0.979
         3                ND        0.292      0.465         e          e        0.992
         4                ND        0.285      0.487      0.748       1.10        1.05
         5                ND        0.286      0.491      0.732       1.10        1.05
         6                ND        0.279      0.495      0.753       1.13        1.01
      Analytical problem due to high variation between injections, no results   available
      Analytical problem due to insufficient sample, no results available




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Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)
    Exposure I1I                                         Group
      Sample               1            2            3           4          5          6
         1                ND          0.234        0.424       0.607      0.947      0.875
         2                ND          0.242        0.441       0.624      0.946      0.883
         3                ND          0.217        0.429       0.630      0.961      0.904
         4                ND          0.239        0.433       0.632      0.966      0.884
         5                ND          0.240        0.459       0.653      0.959      0.924
         6                ND          0.237        0.433       0.665      0.927      0.924

    Exposure 12                                         Group
      Sample               1            2             3        4            5           6
         1                ND          0.239        0.440     0.649        0.961      0.906
         2                ND          0.240        0.447     0.662        0.936      0.922
         3                ND          0.233        0.425     0.658        0.962      0.928
         4                ND          0.221        0.443     0.720        0.939      0.918
         5                ND          0.230        0.47 1    0.696        0.940      0.946
         6                ND          0.232        0.465     0.709        0.936      0.926

    Exposure 13                                          Group
      Sample               1            2            3           4           5          6
         1                ND          0.246        0.485       0.663      0.893      0.9 13
        2                 ND          0.245        0.493       0.672      0.898      0.911
        3                 ND          0.244        0.491       0.698      0.941      0.903
        4                 ND          0.237        0.529       0.820      0.973      0.885
        5                 ND          0.244        0.499       0.730      0.962      0.894
        6                 ND          0.249        0.519       0.722       1.01      0.939

    Exposure 14                                        Group
      Sample               1            2            3         4            5          6
         1                ND          0.258        0.521    0.698         0.953      0.943
        2                 ND          0.254        0.584    0.709         0.974        d
        3                 ND          0.239        0.545     0.724        0.972      0.943
        4                 ND          0.234        0.52 1   0.747         0.926      0.90 1
        5                 ND          0.236        0.492    0.669         0.988      0.874
        6                 ND          0.234        0.490    0.751         0.982      0.931

    Exposure 15                                         Group
      Sample               1            2            3          4            5          6
             1ND                      0.225        0.505     0.707        0.843      0.894
         2                ND          0.255        0.5 10    0.735         1.01      0.925
         3                ND          0.247        0.520     0.724        0.969      0.95 1
         4                ND          0.252        0.509      0.725        1.03       1.01
         5                ND          0.222        0.48 1     0.697       0.984      0.953
         6                ND          0.248        0.504     0.711        0.956      0.964
      Analytical problem due to   high variation   between injections,   no results available




                                                         641
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Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)

    Exposure 16                                       Group
      Sample                 1          2           3         4           5          6
             1ND                     0.247        0.567    0.744       0.992      0.966
        2                  ND        0.252        0.571    0.754        1.00       1.01
        3                  ND        0.255        0.561    0.749        1.01      0.985
        4                  ND        0.259        0.555    0.757       0.972       1.01
        5                  ND        0.256        0.569    0.762        1.03       1.03
        6                  ND        0.253        0.562    0.750        1.02       1.02

    Exposure 17                                        Group
      Sample                1           2            3         4          5          6
             1ND                     0.255        0.586     0.745      0.999      0.996
        2                  ND        0.2 72       0.5 97    0.788       1.06       1.05
        3                  ND        0.277        0.5 82    0.767       1.05       1.06
        4                  ND        0.250        0.550     0.744      0.974       1.01
        5                  ND        0.262        0.5 82     0.774      1.05       1.06
        6                  ND        0.272        0.540     0.791      0.978       1.05

    Exposure 18                                        Group
      Sample                1          2             3         4           5          6
         1                 ND        0.270        0.555     0.786      0.00387      1.08
         2                 ND          d             d      0.736        1.02       1.17
         3                 ND        0.274        0.591     0.829        1.03       1.02
        4                  ND        0.278        0.534     0.800       0.990       1.04
         5                 ND        0.261        0.476     0.746        1.02       1.02
        6                  ND        0.269        0.515     0.765        1.07        d



    Exposure 19                                       Group
      Sample                1           2           3        4           5           6
         1                 ND        0.289        0.514    0.802        1.06       1.05
        2                  ND        0.269        0.486    0.768       0.992       1.02
        3                  ND        0.270        0.460    0.794       0.990      0.980
        4                  ND        0.277        0.506    0.777        1.04       1.09
        5                  ND        0.278        0.520    0.778        1.08       1.08
        6                  ND        0.272        0.511    0.740       1.04       1.03

    Exposure 20                                        Group
      Sample                1           2            3        4           5          6
         1                 ND        0.271        0.477     0.794       1.04       1.03
        2                  ND        0.233        0.490     0.793       1.06       1.07
        3                  ND        0.263        0.565     0.801       1.00       1.09
        4                  ND        0.252        0.537     0.714      0.979       1.00
        5                  ND        0.276        0.551     0.764       1.02       1.03
        6                  ND        0.246        0.543     0.739       1.02       1.01
     Analytical problem   due to high variation   between injections, no results available




                                                     642
                                                              Huntingdon Life Sciences
                                                                              ATS0022

Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)
    Exposure 21                    Group
      Sample         1      2         3        4        5
             IND          0.241     0.396    0.699    1.01
         2          ND    0.244     0.395    0.728   0.994
         3          ND    0.245     0.427    0.726    1.01
         4          ND    0.257     0.439    0.719    1.38
         5          ND    0.263     0.438    0.768   0.996
         6          ND    0.268     0.439    0.707    1.041

    Exposure 22                    Group
      Sample         1       2         3       4        5
         1          ND    0.27 1    0.450    0.734   0.996
        2           ND    0.251     0.442    0.734   0.980
        3           ND    0.260     0.444    0.758   0.974
        4           ND    0.246     0.436    0.723   0.943
         5          ND    0.250     0.444    0.720   0.96 1
         6          ND    0.250     0.416    0.699   0.952

    Exposure 23                    Group
      Sample         1       2         3        4       5
         1          ND    0.267     0.454    0.750   0.999
         2          ND    0.260     0.470    0.733   0.996
         3          ND    0.266     0.470    0.747    1.02
        4           ND    0.261     0.472    0.722    1.03
         5          ND    0.265     0.457    0.755    1.03
        6           ND    0.259     0.474    0.737   1.01

    Exposure 24                    Group
      Sample         1      2         3        4       5
         1          ND    0.237     0.391    0.770   1.04
         2          ND    0.233     0.383    0.759   1.01
         3          ND    0.236     0.357    0.752   1.02
         4          ND    0.269     0.450    0.758   1.00
         5          ND    0.297     0.454    0.745   1.03
         6          ND    0.277     0.442    0.770   1.01

    Exposure 25                    Group
      Sample         1      2          3        4      5
         1          ND    0.258     0.429    0.727   1.01
         2          ND    0.261     0.447    0.743   1.00
         3          ND    0.269     0.458    0.758   1.04
         4          ND    0.272     0.457    0.764   1.03
         5          ND    0.264     0.446    0.757   1.01
         6          ND    0.273     0.454    0.771   1.07




                                       643
                                                                                     Huntingdon Life Sciences
                                                                                                     ATS0022

Appendix B Chamber concentrations of R-1225 yeZ - individual exposure
           values (continued)

    Exposure 26                               Group
      Sample                1          2         3          4            5
               1ND                   0.232     0.443      0.608        0.856
         2                 ND        0.227     0.433      0.585        0.808
         3                 ND        0.234     0.44 1     0.672        0.934
         4                 ND        0.232     0.434        d            d

         5                 ND        0.230     0.443      0.629        0.888
         6                 ND        0.217     0.437      0.669        0.9361

    Exposure 27                               Group
      Sample                1          2         3          4            5
               1ND                   0.217     0.391      0.605        0.910
         2                 ND        0.211     0.407      0.612        0.893
         3                 ND        0.229     0.430      0.607        0.897
         4                 ND        0.238     0.456      0.62 1       0.905
         5                 ND        0.240     0.452      0.631        0.918
         6                 ND        0.239     0.461      0.653         1.02

    Exposure 28                               Group
      Sample                1          2         3          4             5
         1                 ND        0.231     0.459      0.673         1.04
         2                 ND        0.227     0.443      0.668         1.04
         3                 ND        0.2 16    0.423      0.635        0.995
         4                 ND        0.226     0.432      0.661         1.01
         5                 ND        0.223     0.430      0.645        0.824
         6                 ND        0.198     0.391      0.588        0.816

    Exposure 29                               Group
      Sample                1          2         3          4            5
         I                 ND        0.283     0.476      0.678        0.871
        2                  ND        0.242     0.471      0.599        0.871
        3                  ND        0.241     0.464      0.667        0.864
        4                  ND        0.239     0.468      0.611        0.893
        5                  ND        0.267     0.554      0.8 18         d

        6                  ND        0.264     0.543      0.823        0.982

    Exposure 30                                Group
      Sample                1          2          3         4             5
             1ND                     0.225      0.464     0.706        0.974
        2                  ND        0.206      0.461     0.704        0.950
        3                  ND        0.222      0.464     0.697        0.983
        4                  ND        0.224      0.447     0.690        0.941
        5                  ND        0.219      0.451     0.695        0.972
        6                  ND        0.233      0.455     0.696        0.981 1
     Analytical problem   due to high variation between injections,   no results available




                                                   644
                                                                             Huntingdon Life Sciences
                                                                                            ATS0022

Appendix B Chamber concentrations of R-1225 yeZ - individual exposure
           values (continued)
    Exposure 31                               Group
      Sample                1          2         3         4          5
         1                 ND       0.239      0.441     0.652     0.917
         2                 ND       0.236      0.437     0.647     0.976
         3                 ND       0.246      0.448     0.631     0.937
         4                 ND       0.2 72     0.484     0.728      1.04
         5                 ND       0.270      0.480     0.718      1.02
         6                 ND       0.2 78     0.500     0.772      1.02 _

    Exposure 32                              Group
      Sample                1          2        3          4          5
             IND                    0.225     0.45 1     0.689     0.942
         2                 ND       0.228     0.434      0.698     0.960
         3                 ND       0.243     0.449      0.68 1    0.949
        4                  ND       0.265     0.492      0.722     0.950
         5                 ND       0.259     0.495      0.755     0.975
        6                  ND       0.260     0.495      0.737     0.9791

    Exposure 33                              Group
      Sample                1          2         3         4          5
         1                 ND       0.274     0.501      0.750     0.985
         2                 ND       0.270     0.500      0.756     0.995
         3                 ND       0.267     0.502      0.750     0.981
         4                 ND       0.276     0.507      0.735     0.957
         5                 ND       0.269     0.508      0.750     0.989
         6                 ND       0.270     0.498      0.734     0.942

    Exposure 34                              Group
      Sample                1         2         3          4         5
         1                 ND       0.284     0.511      0.725     0.990
        2                  ND       0.302     0.555      0.766      1.03
        3                  ND       0.293
        4                  ND       0.293     0.552      0.752      1.02
        5                  ND       0.294     0.55 1     0.737     0.999
        6                  ND       0.286     0.543      0.752     1.01

    Exposure 35                            Group
      Sample              1           2         3          4          5
         1               ND        0.25 1    0.480      0.692       0.933
         2               ND        0.246     0.485      0.705       0.908
         3               ND        0.273     0.539      0.783      0.967
        4                ND        0.282     0.536      0.778      0.970
         5               ND        0.275     0.538      0.782      0.953
         6            1ND          0.277     0.538      0.778      0.963
     Analytical problem due to leaking samples, no results available




                                                  645
                                                                                    Huntingdon Life Sciences
                                                                                                    ATS0022

Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)
    Exposure 36                                Group
      Sample                 1          2         3             4        5
         1                  ND        0.228      0.485       0.811     1.01
         2                  ND        0.245      0.544       0.881     1.10
         3                  ND        0.264      0.545       0.773     1.09
         4                  ND        0.251      0.548       0.771     1.08
         5                  ND        0.262      0.551       0.774     1.08
         6                  ND        0.261      0.523       0.791     1.07

    Exposure 37                                Group
      Sample                  1         2         3            4         5
             1ND                      0.252     0.46 1       0.744    0.997
         2                  ND        0.243     0.446        0.728    0.947
         3                  ND        0.261     0.477        0.780     1.04
         4                  ND        0.240     0.461        0.765     1.01
         5                  ND        0.271     0.491        0.779     1.06
         6                  ND        0.266     0.483        0.809     1.05

    Exposure 38                                Group
      Sample                  1         2         3            4         5
             1ND                      0.223     0.466        0.767    0.969
        2                   ND        0.2 14    0.453        0.72 1   0.854
              3                         g          g           g         g

         4                  ND        0.265      0.493       0.764    0.975
         5                  ND        0.256      0.490       0.78 1   0.985
         6                  ND        0.259      0.495       0.756    0.993

    Exposure 39                                Group
      Sample                 1          2         3             4       5
        1                   ND        0.211     0.467        0.761    0.724
        2                   ND        0.188     0.443        0.747    0.772
        3                   ND        0.256     0.503        0.795    0.950
        4                   ND        0.255     0.529        0.795    0.925
        5                   ND        0.254     0.506        0.810    0.900
        6                   ND        0.263     0.511        0.784    0.9761

    Exposure 40                                  Group
      Sample                  1          2          3           4          5
              1             ND        0.2 16      0.446      0.763       0.895
         2                  ND        0.195          d       0.673       0.945
         3                  ND        0.24 1      0.447      0.725       0.960
         4                  ND        0.263       0.469      0.693       0.967
         5                  ND        0.252       0.521      0.743       0.94 1
         6                  ND        0.25 1      0.537      0.802       0.998
  d   Analytical problem   due to high variation between injections, no results available
  9 Analytical problem     due to error in injections, no results available




                                                       646
                                                                                     Huntingdon Life Sciences
                                                                                                     ATS0022

Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)
       Exposure 41                              Group
         Sample               1           2        3           4           5
            1                ND        0.206     0.401       0.657      0.855
            2                ND          d       0.397       0.66 1     0.854
            3                ND        0.235     0.483         d        0.948
            4                ND        0.237     0.508       0.755      0.96 1
            5                ND        0.193     0.515       0.752        d
            6                ND        0.241     0.525       0.736       1.06 _

       Exposure 42                              Group
         Sample               1           2        3           4           5
            1                ND        0.266     0.606       0.894       1.16
            2                ND        0.255     0.548       0.927       1.19
            3                ND        0.274       d         0.948       1.21
           4                 ND        0.275     0.591         d          d

            5                ND        0.249     0.525       0.888       1.03
            6                ND          d       0.550       0.965       1.14

       Exposure 43                              Group
         Sample                1         2         3           4          5
            1                ND          h         h           h          h

            2                ND        0.251     0.491       0.745       1.64
            3                ND        0.245     0.500       0.710       1.65
            4                ND        0.246     0.502       0.739       1.61
            5                ND        0.236     0.506       0.700       1.16
            6                ND        0.231     0.468       0.706       1.16

       Exposure 44                              Group
         Sample               1          2         3           4           5
            1                ND        0.242     0.448       0.754       1.23
            2                ND        0.275     0.5 58      0.780       1.29
            3                ND        0.268     0.514       0.817       1.24
            4                ND        0.266     0.587       0.710       1.15
            5                ND        0.250     0.505       0.758       1.19
            6                ND        0.23 6    0.465       0.707       1.09

       Exposure 45                              Group
         Sample              1          2          3         4            5
            1               ND        0.234      0.414        d          1.01
            2               ND        0.224      0.4 15    0.629        0.989
            3               ND        0.214      0.416     0.585        0.953
            4               ND           d       0.418     0.617         1.02
            5               ND        0.228      0.414        d          1.00
            6               ND        0.215      0.405     0.601        0.9921
        Analytical problem due to high variation between injections,   no results available
   h    No compound detected




                                                       647
                                                                                        Huntingdon Life Sciences
                                                                                                        ATS0022

Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)
    Exposure 46                                Group
      Sample                 1           2        3              4           5
             1ND                      0.256     0.461          0.705       1.11
         2                  ND        0.254        0.464       0.696       1.11
         3                  ND        0.250        0.475       0.689       1.12
         4                  ND        0.250        0.468       0.708       1.11
         5                  ND        0.250        0.472       0.696       1.11
         6                  ND        0.251        0.471       0.695       1.08

    Exposure 47                                Group
      Sample                 1          2         3              4          5
             1ND                      0.229        0.398         d         1.01
         2                  ND        NR2          0.400       0.649      0.954
         3                  ND        0.220        0.383       0.590      0.983
         4                  ND        0.231        0.458       0.594       1.12
         5                  ND        0.249        0.464       0.501       1.05
         6                  ND        0.236        0.432       0.684      1.12

    Exposure 48                                Group
      Sample                 1          2           3           4           5
         1                  N~D         d            d         0.588       1.02
         2                  ND        0.232        0.404       0.667      0.968
         3                  ND        0.230        0.390       0.641       1.03
         4                  ND        0.234        0.317       0.612        d

         5                  ND        0.224        0.366       0.652      0.932
         6                  ND        0.226        0.346       0.657      1.06

    Exposure 49                                Group
      Sample                 1          2         3              4          5
         1                  ND        0.240     0.312          0.659       1.00
        2                   ND        0.230     0.389            d         1.02
        3                   ND        0.239     0.471          0.700      0.916
         4                  ND        0.230        0.367         d         1.01
         5                  ND        0.231        0.405       0.730       1.02
         6                  ND        0.230        0.448       0.748       1.08   1

    Exposure 50                                Group
      Sample                 1          2        3              4           5
         1                  ND          d          0.497         d        0.968
         2                  ND        0.225        0.469     0.668        0.979
         3                  ND           d         0.497     0.639        0.948
         4                  ND        0.209        0.384     0.683        0.998
         5                  ND        0.225        0.3 84    0.631        0.904
         6                  ND        0.228        0.474     0.746         1.04
      Analytical problem   due to high variation   between injections,   no results available




                                                         648
                                                                                   Huntingdon Life Sciences
                                                                                                  ATS0022

Appendix B Chamber concentrations of R-1 225 yeZ - individual exposure
           values (continued)

    Exposure 51                                Group
      Sample                1           2         3          4          5
         1                 ND        0.244      0.421      0.738      1.15
         2                 ND        0.228      0.516      0.738      1.13
         3                 ND        0.228      0.496      0.763        d

         4                 ND        0.217      0.492      0.746      1.12
         5                 ND        0.227      0.485      0.756      1.18
         6                 ND        0.251      0.525      0.756      1.15

    Exposure 52                               Group
      Sample                1          2         3           4          5
         1                 ND        0.230     0.42 1      0.603     0.997
         2                 ND        0.228     0.493       0.603     0.937
         3                 ND        0.215     0.485       0.617     0.983
         4                 ND        0.219     0.475       0.608     0.972
         5                 ND          d       0.49 1      0.604     0.970
         6                 ND        0.213     0.465       0.648     0.9431

    Exposure 53                               Group
      Sample                1          2         3          4           5
         1                 ND        0.253     0.560      0.701       1.02
         2                 ND        0.245     0.526      0.709       1.02
         3                 ND        0.248     0.550      0.706       1.06
         4                 ND        0.248     0.531      0.706       1.14
         5                 ND        0.293     0.624      0.772       1.05
         6                 ND        0.276     0.609      0.736       1.06

    Exposure 54                               Group
      Sample                1          2          3         4          5
             IND                     0.293     0.634      0.744       1.04
         2                 ND        0.292     0.623      0.750       1.04
         3                 ND        0.289     0.622      0.749       1.04
         4                 ND        0.297     0.587      0.787       1.13
         5                 ND        0.3 05    0.607      0.769       1.09
         6                 ND        0.284     0.581      0.741       1.12 _

    Exposure 55                                Group
      Sample                1          2          3         4           5
          1                ND        0.275      0.543     0.665      0.995
         2                 ND        0.277      0.517     0.666      0.988
         3                 ND        0.298      0.566     0.746       1.09
         4                 ND        0.300      0.572     0.734       1.07
         5                 ND        0.298      0.575     0.733       1.08
         6                 ND        0.245      0.494     0.716       1.09
     Analytical problem   due to high variation between injections, no results available




                                                    649
                                                                                       Huntingdon Life Sciences
                                                                                                       ATS0022

Appendix B Chamber concentrations of R-1225 yeZ - individual exposure
           values (continued)
      Exposure 56                               Group
        Sample                1           2        3          4             5
          1                  ND        0.236     0.433      0.759         1.05
          2                  ND        0.218     0.437      0.760         1.10
          3                  ND        0.211     0.427      0.750         1.11
          4                  ND        0.2 10    0.425      0.729           d

          5                  ND        0.249     0.447      0.724         1.10
          6                  ND        0.277     0.492      0.796         1.14

      Exposure 57                               Group
        Sample                1          2         3          4            5
               1ND                     NR1       0.491      0.784           d

          2                  ND        0.199     0.459      0.740         1.12
          3                  ND        0.212     0.448      0.784         1.21
          4                  ND        0.248     0.418      0.717         1.10
           5                 ND        0.234     0.416      0.526         1.06
           6                 ND        0.245     0.440      0.547         1.15

      Exposure 58                               Group
        Sample                1          2         3          4            5
           1                 ND        0.239     0.501      0.790         1.24
          2                  ND        0.213     0.464      0.755         1.14
          3                  ND        0.273     0.437      0.699         1.08
          4                  ND        0.268     0.434      0.691         1.11
          5                  ND        0.246     0.407      0.692         1.03
          6                  ND        0.276     0.492      0.816         1.20

      Exposure 59                               Group
        Sample                1          2         3          4             5
           1                 ND        0.260     0.487      0.761         1.05
          2                  ND        0.256     0.489      0.736         1.07
          3                  ND        0.252     0.488      0.757         1.10
          4                  ND        0.248     0.482      0.743         1.10
          5                  ND        0.240     0.475      0.727         1.08
          6                  ND        0.236     0.468      0.708         1.10

      Exposure 60                                Group
        Sample                1           2          3         4            5
           1                 ND        0.263      0.45 3                  1.18
           2                 ND        0.232      0 .339       d         0.889
           3                 ND        0.260      0.454     0.736         1.15
           4                 ND        0.220      0.404     0.605        0.922
           5                 ND           d       0.289     0.400         1.01
           6                 ND        0.211      0.349        d         0.855
  d    Analytical problem   due to high variation between injections,   no results available




                                                     650
                                                                                 Huntingdon Life Sciences
                                                                                                 ATS0022

Appendix B Chamber concentrations of R-1225 yeZ - individual exposure
           values (continued)
    Exposure 61                              Group
      Sample                1         2         3          4          5
             IND                    0.278     0.399      0.680      0.646
        2                 ND        0.265     0.406      0.679      0.790
         3                ND        0.313     0.427      0.716        d

        4                 ND        0.3 12    0.424      0.711      0.982
         5                ND        0.307     0.411      0.707      0.941
         6                ND        0.238     0.427      0.729       1.07

    Exposure 62                              Group
      Sample               1          2          3         4          5
         1                ND        0.23 1    0.391      0.657      0.941
         2                ND        0.2 14    0.328      0.565      0.791
         3                ND        0.245     0.414         h         h
         4                ND        0.237     0.410      0.686       1.15
         5                ND        0.230     0.3 93     0.683       1.07
         6                ND        0.264     0.456      0.695      0.944

    Exposure 63                              Group
      Sample               1           2        3          4           5
         1                ND        0.220     0.420      0.70 1     0.992-
         2                ND        0.201     0.429      0.687      0.989
         3                ND        0.189     0.434      0.687      0.990
         4                ND        0.390     0.431      0.685       1.01
         5                ND        0.218     0.481      0.727       1.04
         6                ND        0.224     0.470      0.705      1.04

    Exposure 64                              Group
      Sample               1           2         3          4         5
         1                ND        0.212     0.463      0.717      1.08
        2                 ND        0.205     0.474      0.706      1.08
         3                ND        0.201     0.477      0.707      1.09
        4                 ND        0.198     0.467      0.703      1.09
         5                ND          d       0.478      0.690      1.05
        6                 ND        0.212     0.471      0.701      1.051

    Exposure 65                              Group
      Sample                1         2          3         4          5
         1                ND        0.198     0.456      0.718      1.04
         2                ND        0.232     0.481      0.720      1.02
         3                ND        0.230     0.468      0.726      1.01
         4                ND        0.228     0.479      0.713      1.02
         S                ND        0.226     0.474      0.709      1.04
         6                ND        0.234     0.489      0.709      1.05
     Analytical problem due to high variation between injections, no results available
h    Suspected sample swap, values excluded




                                                  651
1 RLI I III I   I   I,   II~   ii   *IIv*j                     j----k




                                                                              Huntingdon Life Sciences
                                                                                              ATS0022

          Annex 2                        Urinary fluoride analysis




                                                                        652
                                                                  Huntingdon Life Sciences
                                                                                 ATS0022




                   Butterworth Laboratories Ltd

                               GLP Study Report
                                  Delegated Phase


                                    Study Title:
R-1225 yeZ; Toxicity Study by Inhalation Administration to CD Rats for 28 or 90 Days


                                      Study ID:
                                      ATSIOO22


                       Objective of the Delegated Phase:
               Determination of inorganic fluoride in the test materials


                                 BLL Schedule No:
                                    9/0088(07)



                                  Study Director:
                                  Anthony Bowden




                                       653
                                                            Huntingdon Life Sciences
                                                                           ATS0022

Butterworth Laboratories Ltd                                       BIL Schedule No9/0058(07)
                                                                     Study 10: ATS/0022


Contents                                                    Pacie No

Cover Page                                                    1

Contents Page                                                 2

Summary of Results                                            3-11

28 day study
Sample/test item types                                        3
Date(s) of receipt of sample(s)                               3
Date(s) of analysis                                           3
Identification of Reference Items                             3
Test Results including the Identification of Test Items       3- 6
                3-7
90 day study
Sample/test item types                                        7
Date(s) of receipt of sample(s)                               7
Date(s) of analysis                                           7
Identification of Reference Items                             7
Test Results including the Identification of Test Items       7 -10

Methodology                                                   11
Contributing Scientists                                       11
Discussion of results                                         11


Archiving Requirements                                        12

GLP Compliance Statement                                      12

QA Report                                                     13




                                             Page 2 of 13



                                              654
                                                                       Huntingdon Life Sciences
                                                                                       ATS0022

Butterworth Laboratories Ltd                                                BLL Schedule N09I0088(07)
                                                                               Study ID: ATS10022



Test Items:                    Rat Urine 28 day study

Date Received:                 15 October 2007

Date Analysed:                 2 November 2007

Reference Items:               lOO0ppm fluoride standard solution supplied by Romil. Product
                               S194, lot U550455
BLL-1 Reference                       Sample Reference              Fluoride expressed as F
                                                                          (mg/I)
BL1
  10/0401 (07)                        11 M Group 1                             0.9

  10/0402 (07)
BL1                                   12 M Group 1                             0.6
  10/0403 (07)
BL1                                   13 M Group 1                             1.2

131-I1/0404 (07)                      14 MGroupl1                              1.1

  10/0405 (07)
BL1                                   15 M Group 1                             0.6
                                                                               0.6

13110/0406 (07)                       16 MGroupI1                              0.7

  10/0407 (07)
BL1                                   106 FGroupl1                             1.9

13110/0408 (07)                       107 FGroupl1                             1.2

B3L 10/0409 (07)                      108 FGroupI1                           <5

  10/0410 (07)
BL1                                   109 FGroupI1                           <5

B13O1/0411 (07)                       110F GroupI1                           <5

  10/0412 (07)
BL1                                   111 FEGroupi1                            1.4

13110/0413 (07)                       27 MGroup 2                            77

BL 10/0414 (07)                       28 MGroup 2                            28

  10/0415 (07)
BL1                                   29 MGroup 2                            45
                                                                             46
BL 10/0416 (07)                       3OM Group 2                            68

BL 10/0417 (07)                       31 M Group 2                           30

  10/0418 (07)
BL1                                   32 MGroup 2                            72

B13O1/0419 (07)                       33 MGroup 2                            110

  10/0420 (07)
BL1                                   34 MGroup 2                            87



                                            Page 3 of 13



                                            655
                                                     Huntingdon Life Sciences
                                                                     ATS0022

Butterworth Laboratories Ltd                              BLL Schedule NoglOO88(07)
                                                             Study 10: ATS/0022


BIL Reference                  Sample Reference    Fluoride expressed as F
                                                        (mg/I)

BL 10/0421 (07)                122 F Group 2                46

BL 10/0422 (07)                123 F Group 2                48

B31
  10/0423 (07)                 124 F Group 2                48

  10/0424 (07)
BL1                            125 F Group 2                54

BL 10/0425 (07)                126 FGroup 2                 61

BLI1/0426 (07)                 127 FGroup 2               110

BL 10/0427 (07)                128 F Group 2                59

BL110/0428 (07)                129 F Group 2                55

BL 10/0429 (07)                45 M Group 3                 89

BL 10/0430 (07)                46 M Group 3                 51
                                                            52
BL110/0431 (07)                47 M Group 3                 74
                                                            76
BL110/0432 (07)                48 MGroup 3                  70

BL 10/0433 (07)                49 MGroup 3                  43

BL 10/0434 (07)                50 M Group 3                 78

BLI1/0435 (07)                 51lMGroup 3                 110

  10/0436 (07)
BL1                            52 MGroup 3                 100

BIL 10/0437 (07)               140OFGroup 3                 58

BL 10/0438 (07)                141 F Group 3                58

BLI10/0439 (07)                142 F Group 3                29

BL 10/0440 (07)                143 FGroup 3                 37

BL 10/0441 (07)                144 F Group 3                46

BL 10/0442 (07)                145 F Group 3                73

BL 10/0443 (07)                146 F Group 3                69

  10/0444 (07)
BL1                            147 FGroup 3                 81




                                    Page 4 of 13


                                     656
                                                     Huntingdon Life Sciences
                                                                     ATS0022

Butterworth Laboratories Lid                              BLL Schedule N09J0O88(07)
                                                            Study ID: ATS10022


BLL Reference                  Sample Reference    Fluoride expressed as F
                                                        (mgII)

BL 10/0445 (07)                63 MGroup 4                120
131 10/0446 (07)               64 M Group 4                 70
                                                           69
BL 10/0447 (07)                65 MGroup 4                130

BL 10/0448 (07)                66 MGroup 4                  87
BL 10/0449 (07)                67 MGroup 4                 61

BL 10/0450 (07)                68 MGroup 4                 96

  10/0451 (07)
BL1                            69 M Group 4                47
                                                           46
131 10/0452 (07)               70 M Group 4                77

BL 10/0453 (07)                158 FGroup 4                 15

  10/0454 (07)
BL1                            159 F Group 4               57
BL 10/0455 (07)                160 F Group 4               49

BLI10/0456 (07)                16IF Group 4                 17

BL 10/0457 (07)                162 FGroup 4                26

BL 10/0458 (07)                163 F Group 4               71

BL 10/0459 (07)                164 F Group 4               32

  10/0460 (07)
BL1                            165 F Group 4               61

BL 10/0461 (07)                81 M Group 5               130
BL 10/0462 (07)                82 MGroup 5                 36

BL 10/0463 (07)                83 MGroup 5                 75
                                                           75

BL 1/0464 (07)                 84 MGroup 5                110

BL 10/0465 (07)                85 M Group 5               120

BL 10/0466 (07)                86 MGroup 5                 74

  10/0467 (07)
BL1                            87 M Group 5               110

B13O1/0468 (07)                88 MGroup 5                 72



                                    Page 5 of 13


                                     657
                                                            Huntingdon Life Sciences
                                                                            ATS0022

Butterworth Laboratories Ltd                                     611 Schedule No9l0088(07)
                                                                    Study ID: ATSIOO22


BLL Reference                        Sample Reference     Fluoride expressed as F
                                                               (mgII)

BL1
  10/0469 (07)                       89 MGroup 5                  100

BL 10/0470 (07)                      90 M Group 5                 110

BL 10/0471 (07)                      176 FGroup 5                  78

BL 10/0472 (07)                      177 FGroup 5                 140

BL1
  10/0473 (07)                       178 F Group 5                 64

131 10/0474 (07)                     179 F Group 5                 48

BL 10/0475 (07)                      180 F Group 5                 46

  10/0476 (07)
BL1                                  181 F Group 5                 76

BL1
  10/0477 (07)                       182 FGroup 5                  80

BL 10/0478 (07)                      183 F Group 5                 59

B13O1/0479 (07)                      184 FGroup 5                 110

BL 10/0480 (07)                      185 F Group 5                 87

BL 10/0481 (07)                      9lM Group 6                 110
BL 10/0482 (07)                      92 M Group 6                  70

  10/0483 (07)
BL1                                  93 M Group 6                  65
                                                                   65

13110/0484 (07)                      94 M Group 6                  44
                                                                   45

  10/0485 (07)
BL1                                  95 M Group 6                  86

BL 10/0486 (07)                      186 F Group 6                 58

BL 10/0487 (07)                      187 FGroup 6                  54

BL 10/0488 (07)                      188 F Group 6                 76

  10/0489 (07)
BL1                                  189 FGroup 6                  52

131 10/0490 (07)                     190OFGroup 6                  80


Results expressed in mg/I relate to sample as received.




                                           Page 6 of 13



                                            658
                                                                        Huntingdon Life Sciences
                                                                                        ATS0022

Butterworth Laboratories Ltd                                                 511 Schedule No9IOO88(07)
                                                                                Study ID: ATSIOO22


Test Items:                    Rat Urine 90 day study

Date Received:                 17 December 2007

Date Analysed:                 11   -   14 January 2008
Reference Items:               1OO0ppmn fluoride standard solution supplied by Romil. Product
                               S194, lot U550455
BLL Reference                             Sample Reference           Fluoride expressed as F
                                                                           (mg/I)

  12/0306 (07)
BL1                                         1M Groupl1                          1.1
                                                                                1.1

BL1
  12/0307 (07)                              2M Group 1                          1.4

B3L 12/0308 (07)                            3M Group 1                          1.0

  12/0309 (07)
BL1                                         4M Group 1                          0.8

  12/0310 (07)
BL1                                         5M Group 1                          0.9
                                                                                0.5

BL 12/0311 (07)                             6 M Group 1                         0.7

  12/0312 (07)
BL1                                         7M Group 1                          1.1

B3L 12/0313 (07)                            8M Group 1                          1.0

13112/0314 (07)                             9M Group 1                          2.6

131-12/0315 (07)                            10M Groupl1                         1.2

BL 12/0316 (07)                             96F Groupl1                         1.6

BL 12/0317 (07)                             97F Group 1                         1.0

BL 12/0318 (07)                             98F Group 1                       <2.5


BL 12/0319 (07)                             99F GroupI1                         0.8

BL 12/0320 (07)                             101F Groupl1                        1.0

BL 12/0321 (07)                             102F Group 1                        1.8
13112/0322 (07)                             103F Group 1                        1.4

B3L 12/0323 (07)                            104F GroupI1                        1.0

B3L 12/0324 (07)                            18M Group 2                       95




                                                Page 7 of 13



                                                659
                                                    Huntingdon Life Sciences
                                                                    ATS0022

Butterworth Laboratories Ltd                              BIL Schedule NoglOO88(07)
                                                             Study ID: ATS/0022


BLL Reference                  Sample Reference    Fluoride expressed as F
                                                        (mg/I)
BL 12/0325 (07)                  19M Group 2               90

BL 12/0326 (07)                  20M Group 2               83

  12/0327 (07)
BL1                              22M Group 2              190

  12/0328 (07)
BL1                              23M Group 2               51

BL 12/0329 (07)                  25M Group 2              160

  12/0330 (07)
BL1                              26M Group 2                75

131-12/0331 (07)                 113F Group 2              48

BL 12/0332 (07)                  115F Group 2             120

  12/0333 (07)
BL1                              119F Group 2              61

131 12/0334 (07)                 121 F Group 2             42

  12/0335 (07)
BL1                              35M Group 3              140

  12/0336 (07)
BL1                              37M Group 3              150

  12/0337 (07)
BL1                              39M Group 3              190

BL 12/0338 (07)                  40M Group 3               50

  12/0339 (07)
B31                              41M Group 3               31
                                                           32
  12/0340 (07)
BL1                              42M Group 3                74

  12/0341 (07)
BL1                              43M Group 3              150

BL 12/0342 (07)                  44M Group 3              170

13112/0343 (07)                  130F Group 3               78

BL 12/0344 (07)                  132F Group 3              43

BL1
  1210345 (07)                   134F Group 3             130

BL 12/0346 (07)                  135F Group 3       no sample

BL 12/0347 (07)                  136F Group 3               61

BL 12/0348 (07)                  137F Group 3               65

BL 12/0349 (07)                  138F Group 3               71



                                    Page 8Sot 13



                                     660
                                                     Huntingdon Life Sciences
                                                                     ATS0022

Butterworth Laboratories Lid                              BLL Schedule No9IOO88(07)
                                                            Study ID: ATSIOO22



BLL Reference                  Sample Reference    Fluoride expressed as F
                                                        (mg/l)

BL 12/0350 (07)                  139F Group 3               57

131-12/0351 (07)                 54M Group 4              110

  12/0352 (07)
BL1                              55M Group 4              120

BL 12/0353 (07)                  56M Group 4                19
                                                            19
BL 12/0354 (07)                  57M Group 4              110

BL 12/0355 (07)                  58M Group 4               82

  12/0356 (07)
BL1                              59M Group 4               87

  12/0357 (07)
BL1                              60M Group 4              120

BL 12/0358 (07)                  6lM Group 4              120

  12/0359 (07)
BL1                              62M Group 4               32
                                                           32
BL 12/0360 (07)                  149F Group 4              51

  12/0361 (07)
BL1                              150F Group 4              86

BL 12/0362 (07)                  15lF Group 4             140

  12/0363 (07)
BL1                              152F Group 4              98

  12/0364 (07)
BL1                              155F Group 4              66

  12/0365 (07)
BL1                              156F Group 4               12

BL 12/0366 (07)                  157F Group 4              83

BL 12/0367 (07)                  71 M Group 5             160

  12/0368 (07)
BL1                              75M Group 5              160

BL 12/0369 (07)                  76M Group 5                95

BL 12/0370 (07)                  77M Group 5                52

BL 12/0371 (07)                  78M Group 5                88

BL 12/0372 (07)                  79M Group 5              190

131 12/0373 (07)                 80M Group 5              120



                                    Page 9 of 13


                                     661
                                                             Huntingdon Life Sciences
                                                                            ATS0022

Butterworth LaboratoriesLtd                                       BLL Schedule No9IOO88(07)
                                                                    Study 10: ATSIOO22



BLL Reference                        Sample Reference      Fluoride expressed as F
                                                                (mgII)

BL112/0374 (07)                         167F Group 5               56

BL112/0375 (07)                         169F Group 5               87

BL112/0376 (07)                         170F Group 5               90

BL112/0377 (07)                         173F Group 5               47

B3L 12/0378 (07)                        174F Group 5               94


Results in mg/I and relate to samples as received.




                                           Page 10 of 13


                                            662
                                                                        Huntingdon Life Sciences
                                                                                       ATS0022

Butterworth LaboratoriesLtd                                                  BLL Schedule No9IOO55(07)
                                                                               Study ID: AT510022




Methodology:

BLM 147 issue 5. Fluoride was determined using an ion selective electrode.


Contributing Scientists

T Goddard      Analytical Chemist
D Riches       Principal Investigator


Discussion of Results:

The theoretical quantitation limit for the method is 0.25ppm. Same samples were reported to a
higher limit than specified in the method due to a reduced volume available requiring a larger
dilution for analysis.

For analytical quality control purposes, approximately 10% of samples were analysed in
duplicate.

Duplicate results have been included in the results summary above. This is performed every 10
samples for QC purposes subject to sufficient volume available. The duplicates, where performed
meet the method QC requirements, except for sample 12/0310(07). This is probably because
measurements were close to the quantification limit of the method.

A single preparation was spiked with fluoride for each batch of samples. The recovery was 101 %
and 95% respectively.




                                          Page I1I of 13



                                           663
                                                                            Huntingdon Life Sciences
                                                                                            ATS0022

Butterworth Laboratories Ltd                                                      BLL Schedule No9IOO88(07)
                                                                                    Study ID: ATS10022



Archivina Requirements
An authorised copy of this report together with copies of raw data, original electronic data,
instrument calibration records, documented in-house methods, standard operating procedures
and any other associated documentation will be held in the Archives of Butterworth Laboratories
 Limited for a period of not less than six years. Original documentation including Raw Data and
copies of the QA inspection forms are to be archived by Huntingdon Life Sciences Ltd.


GLP Compliance: Statement
1,the undersigned, accept responsibility for the conduct of this delegated phase of the Study and
for validity of the data produced. I confirm that this was conducted at a facility that is part of the
UK GLP Compliance Programme. The work has been conducted in compliance with the
Principles of Good Laboratory Practice (GLP) as set forth in *The Good Laboratory Practice
Regulations 1999" - Statutory Instrument 1999 No 3106 and the Good Laboratory Practice
(Codification Amendments Etc.) Regulations 2004 No 994.


Signed by: _           _ _         _ _            _     _                 Date      ~
             David Riches BSc cChemn MRSC
             Principal Investigator- Butterworth Laboratories Ltd




                                                Page 12 of 13


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                                                                         Huntingdon Life Sciences
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Butterworth Laboratories Ltd                                                  BLL Schedule No9IOO88(07)
                                                                                Study ID: ATSIOO22


CIA Report:
The CIA unit has audited this work for the aspects listed below. Details of observations and
findings made are located in the QA inspection form which has been provided to the Study
Director for forwarding on to lead QA.


Aspect Monitored                            Date Performed                    Date Reported


Verification of Study Plan                   11 September 2007                11 September 2007
                                             5 October 2007                   5 October 2007
                                             10 October 2007                  10 October 2007
                                             5 December 2007                  5 December 2007
                                             18 December 2007                 18 December 2007


Analysis                                     2 November 2007                  2 November 2007
                                             11 January 2008                  11 January 2008


Analytical Results                           10 December 2007                 10 December 2007
                                             13 December 2007
                                             19 February 2008                 19 February 2008


Draft Report                                 19 February 2008


Report                                       27 February 2008                 27 February 2008



*All findings reported to the Study Director, Lead QA at Huntingdon Life Sciences and
Butterworth Laboratories Ltd. Management. Lead QA at Huntingdon Life Sciences report findings
to Huntingdon Life Sciences Management.

In addition the above study specific inspections, a number of scheduled process based
inspections are performed by Butterworth QA throughout the calendar year. The most recent
process based inspection was carried out on: 0 April 2007 and 1e~ May 2007.

Facility based inspections are also performed on an annual schedule covering all operations.
This report complies with the requirements of the Study Plan and any corrective actions required
have been completed to the satisfaction of the QA department of Butterworth Laboratories Ltd.
This report accurately reflects the raw data generated by Butterworth Laboratories Ltd.



Signed by _"~                                                          Date   27 ~         O
         John Welch OSci OChemn MRSC MRQA
         Deputy QA Manager - Butterworth Laboratories Ltd




                                           Page 13 of 13


                                             665
                                   Huntingdon Life Sciences
                                                   ATS0022

Annex 3   Pathology report




                             666
                                                   Huntingdon Life Sciences
                                                                  ATS0022



Pathology Report
R-1225 yeZ: TOXICITY STUDY BY INHALATION ADMINISTRATION TO CD
RATS FOR 28 OR 90 DAYS




Helen Hasler BVMS MRCVS                   26th February 2008
Study pathologist
Huntingdon Life Sciences




                              667
                                                                         Huntingdon Life Sciences
                                                                                         ATS0022



1.         Introduction
1.1        ObjectiveL
Assessment of systemic toxic potential in a 28- or 90-day inhalation study in CD Rats. The
28-day exposure period was conducted to investigate the effect of exposure at levels lower
than in a previous 28-day study. The whole-body exposure was used to investigate any
differences between this method and snout-only exposure over 28-days. The washed
sub-group of rats was used to investigate the effects of post-exposure preening and ingestion
of excreted metabolites.

                            Exposure level                     Number of animals
                              1% 'V/V'l              Snout-only exposure            Whole-body
 Group      Treatment                                                                 exposure
                           28 day     90 day   90 day study    28 day study         28 day study
                           study      study    Male   Female   Male Female         Male    Female

      1       Control         0          0      10      10        6      6          0        0
     2      R- 1225 yeZ    0.261      0.251     10      10        8       8         0        0
     3      R-1225 yeZ     0.512      0.482     10      10        8      8          0        0
     4      R-1225 yeZ     0.743      0.722     10      10        8       8         0        0
     5      R- 1225 yeZ     1.01       1.02     10      10       10      10         0        0
     6*     R-1225 yeZ     0.948        -       0       0        0       0          5        5

  *Whole   body exposure


2.         Results

2.1        Decedents
Animal 154F was confirmed to be pregnant during the macroscopic examination on Day 26.
No treatment-related findings were observed during the microscopic examination.
Animal 38M was found dead on Day 89. Myocardial necrosis/inflammation/vacuolation was
observed. However, the cause of death was undetermined.

2.2        Macroscopic Pathology
2.2.1      Animals killed after 28 days of treatment
The macroscopic examination performed after 28 days of treatment revealed no test
substance-related lesions.
The incidence and distribution of all findings were consistent with the common background
of macroscopic changes.




                                               668
                                                                         Huntingdon Life Sciences
                                                                                        ATS0022


2.2.2     Animals killed after 90 days of treatment
The macroscopic examination performed after 90 days of treatment revealed the following
changes in the teeth, lungs and tracheobronchial lymph nodes, heart, thorax and general
appearance.
Teeth
An increased incidence of pallor of the incisors was observed in treated rats. Also there was
an increased incidence of shortening of the lower incisors and/or elongation of the upper
incisors in treated rats.
Group/Sex                   IM     2M      3M      4M      5M     IF    2F      3F      4F     5F
Exposure level [%(v/v)I      0    0.251   0.482   0.722    1.02    0   0.251   0.482   0.722   1.02

Incisor(s) pale              0      9       9         10    10    0      9       9       9      10
Incisor(s) overgrown         0      6       3         6      8    0      2       1       1      6
Incisor(s) short             0      4       4         3     4      0    2        1       1      6
No. of animals examined      10     10      9         10    10    10    10      10       9      10


Lungs and tracheobronchial lymph nodes

There was a reduced incidence of pale areas on the lungs with associated tracheobronchial
lymph node enlargement in male rats exposed to 0.482, 0.722 or 1.02% (v/v) and treated
female rats, compared with male and female control rats.

Group/Sex                   1M     2M      3M         4M   5M     IF    2F      3F      4F     5F
Exposure level l%(v/v)i      0    0.251   0.482   0.722    1.02   0    0.251   0.482   0.722   1.02

Lungs pale area(s)           10     2       0          1     1    6     0       0        0      1
Bronchial LN enlarged        4     4        0         0     0     6     0       0        0      0
No. of animals examined      10    10       9         10    10    10    10      10       9      10



Thorax

The thorax contained fluid in two male animals, one from each group exposed to 0.251 or
0.482% (v/v).

Heart

Atrial thombus was noted in a male animal in the 0.482% (vlv) treatment group.




                                                669
                                                                                                           Huntingdon Life Sciences
                                                                                                                          ATS0022


General comments

A thin appearance was noted in some treated male rats compared with none in control rats.
 Group/Sex                       1M           2M            3M           4M        5M        IF       2F       3F       4F      5F
 Exposure level [%(v/v)l          0          0.251         0.482        0.722      1.02       0      0.251    0.482    0.722    1.02

 Animal thin                       0             1           3            1         3         0       0         0        0       0
 No. of animals examined           10           10           9           10         10        10      10        10       9       10


The incidence and distribution of all findings were consistent with the common background
of macroscopic changes.

2.3        Microscopic Pathology
2.3.1      Animals killed after 28 days of treatment
Treatment related findings

Histopatho logical changes related to exposure to R- 1225 yeZ occurred in the heart.
Heart

Myocardial vacuolation was noted in male rats exposed to 0.261% (vlv) and females
receiving 0.261, 0.512, 0.743, 1.01 and 0.948% (vlv).
Myocardial necrosis/inflammation/vacuolation was observed in male and female rats exposed
to 0.261, 0.5 12, 0.743, 1.01 and 0.948% (v/v). A dose-related increase in incidence was
noted in male rats only.

Group/sex           IM 2M               3M            4M         5M           6M     IF       2F      3F        4F      5F      6F
Exposure level       0     0.261        0.512        0.743       1.01     0.948          0   0.261   0.512     0.743   1.01    0.948
1%(v/v)l
Myocardial vacuolation
         MinimalO0           2           0             0           0          0          0     2       2         1       6       1
            TotalO0          2           0             0           0          0          0     2       2         1       6       1

Myocardial necrosis/inflammation! vacuolation
         Minimal     0     3       4        6                       7         5          0     3       5         2       3       1
           SlightO0        3       3        2                       3         0          0     0       0         0       0       0
            TotalO0        6       7        8                      10         5          0     3       5         2       3       1

Number of            6       8           8             8           10         5          6     8       8         8       10      5
animals examined


Incidental findings

All other findings were considered to be incidental and unrelated to the test substance.




                                                                   670
                                                                                 Huntingdon Life Sciences
                                                                                                ATS0022


2.3.2        Animals killed after 90 days of treatment
1-istopathological changes related to exposure to R-1225 yeZ occurred in the heart and teeth.

Heart

Myocardial necrosis/inflammation/vacuolation was observed in male and female rats exposed
to 0.251, 0.482, 0.722 or 1.02% (v/v).

Myocardial fibrosis was seen in male rats exposed to 0.251, 0.482, 0.722 or 1.02% (v/v) and
female rats exposed to 0.251, 0.722 or 1.02% (v/v).

Myocardial vacuolation was noted in one female rat exposed to 0.25 1% (v/v).

Atria] thrombi were seen in male rats exposed to 0.251 or 0.482% (v/v).

No dose-relationship was seen with these findings.

 Group/sex                     1M    2M      3M        4M      5M     IF     2F      3F       4F     5F
 Exposure level                 0   0.251   0.482     0.722    1.02    0   0.251    0.482   0.722   1.02
 1% (v/V)l

 Myocardial necrosis/inflammation/ vacuolation
                   Minimal     0      4          4         5    3     0      4        7       7      8
                     Slight    0      3          4         2    2     0      0        0       0      0
                   Moderate    0      3          1         0    0     0      0        0       0      0
                      Total    0      10         9         7    5     0      4        7       7      8

 Myocardial fibrosis
                   Minimal     0      2          3         2    2     0      1        0       1      1
                     Slight    0      2          1         0    0     0      0        0       0      0
                     Total     0      4          4         2    2     0      1        0       1      1

 Myocardial vacuolation
                  Minimal      0      0          0     0        0     0      1        0       0      0
                      Total    0      0          0     0        0     0      1        0       0      0

 Atrial thrombus
                     Present   0      3          3     0        0     0      0        0       0      0

 Number of animals             10    10          9     10       10    10    10        10      9      10
 examined




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Teeth
Ameloblastic dysplasia was observed in male treated rats and females exposed to 0.25 1,
0.722 or 1.02% (v/v).

Periodontal inflammation was seen in male and female rats exposed to R- 1225 yeZ.

No dose-relationship was seen with these findings.

 Group/sex             IM     2M      3M      4M     SM      IF      2F        3F      4F      SF
 Exposure level         0    0.251   0.482   0.722   1.02     0    0.251     0.482   0.722    1.02
 1%(v/v)J

 Ameloblastic dysplasia
           Minimal      0      2       2      3       2      0       1         0       2       2
              Slight    0      1       0      0       1      0       0         0       0       1
              Total     0      3       2      3       3      0       1         0       2       3

 Periodontal inflammation
           Minimal      0      4       2      1       5      0       2         3       2       4
             Slight     0      0       1      0       0      0       0         0       1       0
             Total      0      4       3      1       5      0       2         3       3       4

 Number of animals      10    10       9      10      10     10      10       10       9       10
 examined



3.        Discussion
Microscopic examination was restricted to the heart of animals killed after 28 days, and the
heart and teeth of those killed after 90 days exposure.

Myocardial findings were seen in both the left and right ventricles and atria of the heart.

Myocardial vacuolation is thought to be an early stage of the same pathological process
which ultimately leads to necrosis/inflammation/vacuolation. Therefore the myocardial
vacuiolation can be considered a milder or primary response to the test substance.

Animals killed after 28 days of treatment
The more severe myocardial damage is considered to be the likely source of the increased
AST noted in all treated male rats.

No changes were seen in the heart to account for the increased urea seen in treated rats or the
increase in white bloods cells noted in females.

There was no significant difference in the treatment-related findings between rats undergoing
either snout-only or whole-body exposure.




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Animals killed after 90 days of treatment
The myocardial damage is considered to be the likely source of the increased blood level of
AST noted in all treated groups except females exposed to 0.25 1% (v/v).

Atria] thrombi observed in some males exposed to R- 1225 yeZ are secondary to the
inflammation and fibrosis seen in the myocardium of the atria affected and are indicative of
heart failure. Fluid seen in the thorax of two males at macroscopic examination correlates
with the severity of myocardial damage seen in these animals and is indicative of heart
failure.

The level of CK was increased in all treated groups, except males exposed to 1.02% (v/v) and
this could correlate with the myocardial damage identified. CK is leaked from damaged
muscle cells, however, the magnitude of increase does not necessarily correlate with the
extent of injury.

Heart weights were decreased in males exposed to 0.722 or 1.02% (v/v), no abnormality
detected could be correlated with this.

Pallor of teeth observed macroscopically correlates with ameloblastic dysplasia. Periodontal
inflammation which was seen in animals exposed to R- 1225 yeZ may be secondary to the
damaged enamel which has a protective role in the teeth.

The increase seen in blood urea and creatinine could not be correlated with the findings seen
in the heart and teeth.

4.       Conclusion
Animals killed after 28 days of treatment
In the heart, myocardial necrosis/inflammation/vacuolation and myocardial vacuolation were
noted in rats exposed to R- 1225 yeZ for 28 days.
Animals killed after 90 days of treatment
In the heart, myocardial necrosis/inflammation/vacuolation, myocardial fibrosis, myocardial
vacuolation and atrial thrombi were observed in rats exposed to R-1225 yeZ for 90 days.

In the teeth, ameloblastic dysplasia and periodontal inflammation were seen in rats exposed
to R-1225 yeZ for 90 days.




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Annex 4   Certificates of analysis




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                                                                                                                             ATS0022


IN E(Z)S                      Fluor
                                                  INEOS FLUOR R&TLABORATORY
                                                      Name: 1,2,3,3,3-Pentaluoropropene


                                                            Synonymns:HFCI 225ye

                                                                                         Sample Status: Authorized
LIMtS        No:
     Reference            81973

Botch No:                 90 DayHLS               IneosR&T Reference       IF2409071
Doleof Manufacture;       24-Aug.2007             Expiry Date              24-Aug-2008

Date/Time ofSampling:     24/081207 10:3300O      Date/Tiue Logged:                 10
                                                                           24/0812007 35 52
Quality:                  PASS                                Ref:
                                                  Specification            1225YEZ                                Issue,
                                                                                                                       No:
4nalyte                                  Result                 Units                         Spec.
                                                                                                  Status       Analyst

I225ye(E)                               0.2336                  %wt                                          AWEIR
23                                      N/D                     ppmn/v.                                      AWEIR
32                                      N/D                     Pionww                                       AWEIR
143a                                    N/D                     PionW/W                                      AWEIR
125                                     N/D                     piomwiw                                      AWEIR
Hexatoocopropene                        N/D                     pionv.1                                      AWEIR
134a                                    N/D                     planv./W                                     AWEIR
frrifluoroielylaceylene                 N/D                        v.1
                                                                Pion                                         AWEIR
!225w                                   N/V                     ppmv.1w                                      AWEIR
22
 7uo                                    0.2196                  %wt                                          AWEIR
   5
122 yc                                  N/V                     Piomv.1                                      AWEIR
23(ach                                  N/D                     ppm v.1w                                     AWEIR
136ta                                   N/D                     ppmv.1w                                      AWEIR
isobautasc                              N/D                        v.1
                                                                ppmn                                         AWEIR
i.Methlsytttane                         N/V                                                                  AWEIR
227co                                   19.1                    ppmW/W                                       AWEIR
U~nknown]                               N/D                     ppmi
                                                                   v.1w                                      AWEIR
Unkwwons2                               N/D                     ppmw/w                                       AWEiR
Usknown3                                N/D                     Ppion
                                                                    /v                                       AWEIR
Unkow"4                                 53                         v.4
                                                                Piom                                         AWEIR
Uonkwnov5                               N/D                     ppmw.                                        AWEIR
Total OrganicImpurities                 0,456                   %wt                                          LIMS Caic
TotalUnknowns                           5.3                     ppmw/W                                       LIMS Cate
    ye
1225 (Z) Purity                         99544                   %wv.                                         LIMS Cole

Notes:

ReviewedBy:;   AWEIR
Date Reviewed: 24-Aug.2007 10 39a                                                      Dat Repo"t Printed:    24.Aug-284t7




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                  IN        EZCi)S FlIu or
                                                                        INKOS FLUOR R&T LABORATORY
                                                                           CERTIFICATE OF ANALYSIS


                                                                        Nam:           1,2,3,3,3-Pentafluoropropene

                                                                        Synonyrm: HFC1225ye

                                                                                                                 Samp c tatus: Xtt onz
                                No
                  LIMS Refore.* Me           93126

                  BatchNO:                                    (1)
                                             90 Day ilLS 240907          lawsROT Reference          IF240907
                                                                                                     4     00
                  Dateafmatiafaeture         24-Scp-2007                 Expiry Dale                2 -Sep-2 8

                  Dea~fme of Sampfln:        24/091207 08:32!00          Dat*flvw Loted:            25/02007 08:32:30
                  Quality:                   PASS                        Spodfleaon Ref:            1225yEzz                        slusN:1

                                 AnRyeBaat                                             13.t"                          Spec.Slafts      Analyst
                   12 2 5
                        ye (E)                                 0.1694                   %Wt                                           AWEIR
                  23                                           NID                      PlaW.                                         AWEIR
                  32                                           N/P                      p951W/a                                       AWEIR
                   143a                                        N/D                      ppmW/a                                        AWEIR
                   'S                                          NID                      ppan
                                                                                           w/a                                        AWEIR
                   l~exafluoropmpene                           NWP                      ppmaia                                        AWEIR
                   i34m                                        NID                      ppla                                          A1VEJR
                  Trnfluosmethytacetylese                      NOP                      ppmala                                        AWEIR
                   1225c                                       1410                     peon a/a                                      AWEtR
                   227as                                       0.2972                   %. t                                          AWEIR
                   t225ye                                      NOP                      ppm  ala                                      AWEiR
                   236eb                                       NIP                         a/a
                                                                                        ppTs                                          AWEIR
                   236mx                                       N/P                      ppmn
                                                                                           W/a                                        AWEIR
                   loobutans                                   NIP                      plas a/a                                      AWEIR
                   2-Methylbutaoc                              NIP                                                                    AWEIR
                   227ca                                       M19                      ppmfw                                         AWER
                   Unknowal                                    0.9                       pmw                                          AWER
                   Unknoan2                                    NWP                      pp- waa                                       AWER
                   tUnkmwn3                                    NID                      ppm ala                                       AWEIR
                   tUnknooa4                                   4.2                      ppmalw                                        AWEIR
                   unknoWnS                                    NIP                      ppm ala                                       AWEIR
                   -'oltOrgnie lsuipdtics                      0.458                    %at                                           UIMSCole.
                   .0at Usksoas                                51                       ppm W/a                                       LIMS Cok
                   1225 ye (Z) Paity                           99.542                   % wt                                          LIMS Calc

                   Notes:

                   Reviewed By:     AWEIR
                                                                                                                                        27
                   DateReviewed t26-Sep-2007         2:28 im                                                     Dat Report
                                                                                                                          Prited,            -Sep-2MO




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TNE(C)S                       Fluor
                                                    INEOS FLUOR R&T LABORATORY
                                                       CERTIFICATE OF ANALYSIS


                                                    Name.          11,2,3,21,3-Pentafluoropropene,

                                                    Synonyms: HFC1225ye

                                                                                                Sample      tatus:      Authorized

LI'A3R ei cx Me
        ..                 83182

Botch. No:                                 (2)
                           9oflsy HIS 260907         lnam R&T Reference          IF2609072

Doleof Maenericlure:       26-Sep.2007               Expiry Dale                 26-Sep.2000

Date/TimceaSonpling:       26/09/2007
                                    14:24.00         Dale/The Loged:             2&09/200714:25,59
Quality:                   PASS                      specification ReL           1225YE Z                           Issue No: I

Ana!yl.                                    Result                  Unit.                             Spec.
                                                                                                         slates          Analyst
  2
12 !.ye (E)                              02520                     % c/I                                               AWEIRl
23                                       N/fl                      ppmc/lw                                             AWEIR
32                                       N/P                       ppmc/W                                              AWEIR
143a                                     N/fl                         c/w
                                                                   ppee                                                AWEIR
123                                      N/fl                         c/l
                                                                   ppmn                                                AWEIR
Hexaflecmpmopene                         N/fl                      ppmw/,c                                             AWEIR
1341                                     N/D                       ppmoW/c/                                            AWEIR
Triluororacthylaeetylece                 N/fl                      ppm clw                                             AWEIR
1223mc                                   N/fl                      ppmnW/w                                             AWEIR
227ca                                    0.3557                    % t                                                 AWEIR
1225yc                                   N/D                       ppm /w                                               AWEIR
236cb                                    N/fl                          W/W
                                                                    ppmn                                                AWEIR
236cs                                    N/fl                       ppmwew                                              AWEIR
lee/celcec                               N/I)                          c/w
                                                                    ppmn                                                AWEIR
2-Methylbelse                            N/I)                                                                           AWEIR
227ca                                    27.4                          wtw
                                                                    ppmn                                                AWEIR
Unkeewel                                 N/fl                       ppmc//w                                             AWEIR
Uelecown2                                N/I)                       ppm.1.                                              AWEIR
Unknown.3                                N/fl                          w/o,
                                                                    ppmn                                                AWEIR
Unlteowc4                                32                         ppmn
                                                                       w/cc                                             AWEIR
Unkrow5                                  N/fl                       ppmw/w                                              AWEIR
Total Organic
            biprqities                   0.611                      V. ct                                               LIMS Ceic.
Tom)l Unknoiwns                          32                         ppmw/w                                              LMS Cale
     yc
1225 (Z) Purity                          "9.389                     %c/t                                                LIMSCsie.

Notes:

Reslewed By:       AW1IR
DaleRevtewed:      26-p-2007 3 12pM                                                           Dale Report Prited:         27-Sep-2007




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