Document 5bdpwVbg9X7X5QpGnpB17obv8
COVANCE>
Sponsors:
APME Ad-Hoc APFO Toxicology Working Group
PROTOCOL
Study Tite:
26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Date:
September 23, 1998
Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595
Laboratory Study Identification:
Proposal No. w6806a Covance 6329-231
T- (%%9
02518
:
-_--
Covance 6325231
Pag6e2.r
Study
26-Week Capsule Toxicity
Cynomolgus Monkeys
Study
with
Ammonium
Perfluorooctanoate
(APFO)
in
Purpose
To assess the effectofthe test material on critical enzyme levels, hormones, and other
selected biochemical parameters
`monkeys for at least 26 weeks
when
administered
daily
by
capsule
to.
cynomolgus
Sponsors 'APME Ad-Hoc APFO `Toxicology WorkingGroup
Study Monitor
Paul Lieder, PhD, DABT 3M
`Toxicology Services
`Building 220-2E-02, 3M Center
St. Paul, Minnesota, 55144-1000
Telephone No.: 612.737.2678
Facsimile No.: 612.733.1773
Alternate Study Monitor John Butenhoff, PhD, DABT 3M
"Telephone No.: 612.733.1962 Facsimile No.: 612.733.1733
Sponsor's Representative
David Farrar, PhD ICI Chemicals & Polymers Limited Occupational Health `The Heath, Runcorn, PO Box 13 Cheshire, WA7 4QF Telephone No.: 01928.513953 Facsimile No.: 01928.515146
CSotvuadnycLeoLcaabtoiroantories Inc.
3301 Kinsman Boulevard Madison, Wisconsin 53704
coR514
-_--
Mailing Address: PO Box 7545-2595 Madison, Wisconsin 53707-7545
Study Director Peter J. Thomford, PhD
`CToevlaenpchoenLeaNboo.r:ato6r0i8e.s24In1c..7207
Facsimile No.: 608.242.2736
[-- Pages Page3
`Toxicologist Dale Aldridge, BS Covance Laboratories Inc.
EPxrpoeproismeedntSatluSdtyarTtiDmaettea:blSecpiember 29, 1998 In-Life Start Date: September 29, 1998
In-Life End Date: July 2, 1999
AExupdeirtiemdenDrtaafltTReerpmoinrattDiaotne:DaOtec:toTboerb2e2d,e1t9e9r9mined
Regulatory Compliance
"This study will be conducted in compliance with the Environmental ProtectioAn gency `Good Laboratory Practice Regulations as set forthin Title 40 of the US Code of Federal
Rweigtuhlaatniyoanpsp,liPcaarbtl7e9a2,meinsdsumeednNtsoveexmcebpetrt2ha9t, b1i9le83ac(iedffdeectteirvmeiDneatcieomnbsedron2e9,by19U8n3i)v,earsnidty of
Dundee will not be done in compliance with GLPs.
`Animal Care and Use Statement
All procedures in this protocolarein compliance with the Animal Welfare Act
Rneogtuulnanteicoensss,ar9iClyFdRupl1-i4c.atIenatnhye
opinion of the
previous work.
Sponsor
and.
study
director,
the
study
does
Quality Assurance
`ATshseuprraontcoecoUln,istt(uQdyAUc)on.duTchte, aprnodliffienraaltrieopnocretllwinlulcbleeaaruadnittiegdebnyevtahleuCaotivoanncdaetaQuaanlditryeport
`will be audited by the QAU of Pathology Associates International. The serum, urine,
feces, and liver APFO analysis and report will be audited by the QAUof 3M
Environmental
audited by the
Labor
QAU
atories. The
of Ani Lytics
blood hormone
Inc and DuPont
dete
, as
rminations
appropriate
and report
. The rece
will
ptor
be
level
determinations
determinations
and report will be audited
done by the University of
DbuyntdheeeQwAilUlonfotDbuePoaundti.tedB.ile
acid
c02518
"Test Material
Identification Ammonium Perfluorooctanoate (APFO)
Lot Number "The lot number will be maintained in the rawdata.
Cones capess
Responsibility of the Sponsor
Stability Responsibility of the Sponsor
Storage rn. Conditions
Characteristics
tIensftomramtaetriioanl oisnosnynftihleeswiistmhetthheoSdpso,ns`ocro.mposition, or other characteristics that define the
Gelatin Capsules
Ca
be
pssuuplpelsie(dSibzye
tNhoe.m2a)nuofbatcatiunreedr.froGemlaTtoirnpacca,psIuncl.es(Fwaiilrlfibeelds,tNoreedw
aJterrsoeoy)m;
tleomtpneuramtbuerre.wi
ll
A
`copy of the Certificate of Analysis provided by the manufacturer will be maintained in the
data.
Reserve (Archive) Samples
Areserve sampleofeach lot of test material (1 g each) will be taken and stored at room temperature. These samples will be transferred to the Sponsor after completion of the in-life phase.
Disposition of Test Material
`Any remaining test material will bereturned after authorization from the Sponsor.
Animals
Species Cynomolgus monkey
02510
_--
Source Covance Research Products Inc.
Age at Initiation of Treatment
Young adult/adult
Covance 3h2Pu9a2eg3es1s
Weight at InitiationofTreatment 3to5kg
Number and Sex: 22 males
Identification Collar tag
Husbandry
Housing
Individual; animals will be housed in suspended, stainless steel cages.
Diet
not require analysis. Certified
routinely
primate diet
analyzed by
(#8726C, Harlan
the manufacturer
Teklad) once
for nutritional
or twice. daily. The diet is
components and environment
al
contaminants. Results of specified nutrient and contaminant:analyses are on file at
Covance-Madison. Fruit, vegetables, or other supplements may be provided but will
`Water Ad libitum. Samplesofthe water are routinely analyzed for specified microorganisms and environmental contaminants. The results are on file atCovance-Madison.
Contaminants
`There are no known contaminants in the diet or waterat levelsthatmight interfere with
this study.
Environment Environmental controlsforthe animal room will be set to maintain 18 to 29C,a
relative humidityof30 to 70%, and a 12-hour light/12-hour dark cycle.
Acclimation
Minimum of 4 weeks
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Covance 6329231
-_--
Pagce6s
Randomization
bAlnoicmkaslesquwialllbtoetwheeignhuemdb,erstorfataifniiemdablys btoodbey wseeliegchtte,dafnodr eaallcohcgatreodupt.o tAhneinmuamlbseirnoefach
block will then be assigned to groups using computer-gencrated random numbers
Justification AnPoFnhOuimsanakpnriomwatneshe(psaulcihc apserthoexicsyonmoemoplrogluisfemraotnokre(yP)P)reinsptohnedrasti.miWlahrelynteoxhpuomsaendsto PP, s(pie.ec,ielso.w to no hepatic response) and therefore are an appropriate human surrogate.
Group Designations and Dosage Levels
Dose Level
Group
(mg/kg/day)
Number of Males
T (control) 2 (low-dose)
o 3
4
3 (mid-dose)
10
6
4
a
(high-dose)
The control
group
(Group
1)
30
will
receive
empty
gelatin
6
capsules.
b Ttrweaoteadnfiomral2s6iwneGekrso,uptshe1n, t3,reaantdme4ntdewsiilgnbaeteddisacsorneticnouveedr,yaanndimtahlesawniilmlables
twiolxlicbeeffoebcstesrvfoerdaftolreraesvter1s3ibwileietky,s ppeorsstitsrteeantcme,enotr. dBelaasyeedd oonccpulrarsemnaceteosft
rmeatdeurcieadl loerveexltseannddedcliantitcahle pdaistchroeltoigoynoffitndhiengss,tutdhye drierceocvteorryamftaeyr be
`consultation with the Sponsors,
Dosing Procedures
Method of Administration Orally by gelatin capsules, daily (7 days/week) for at least 26 weeks Reason for Dosing Route `To compare with previously conducted toxicology studies using the oral route
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se
Covmee 6e32w9e.e3rr1
Dose Preparation
Capsules will be prepared at least weekly. The size and number of capsules willdepend
on the physical
monkey. Dose
characteristics of the te
levels will be based on
st
th
mater
e test
imaalt,ertihaeldaossesulpepvleile,d.andIntdhieviwdeuiaglhdtaiolfythe
doses will be based on the most recent individual body weights, with the exception of
body weight
preparations
collection days when the previous `body
willbestored at room temperature until
weight
dosed.
will
be
used.
All dose
Dose Analysis
Becausethetest material is not being mixed with a vehicle, dose analyses are not
required.
Observation ofAnimals
Clinical Observations
`Each animal
findings will
will be observe
be recorded as
d twice daily (a.m.
they are observed.
and
p.m.)
for mortality and moribundity;
`Each animal will be observed daily and food consumptionwillbe assessedqualitatively;
abnormal
abnormal
findings
findings,
will be recorded.
oran indication
Once weekly, each animal willbe observed;
that theanimalis normal will be recorded.
`Additional findings willberecorded as theyare observed.
Body Weights
Weekly before initiation of treatment, Day -1(for the Day 1 dose calculations),on the
first day of treatment, and weekly thereafter
Ophthalmic Examinations
Before initiation oftreatmentand before each scheduled sacrifice. The anterior portion
ofthe eye, optic media,
ophthalmoscope.
and
ocular
fundus
will
be
examined
using
an
indirect
Clinical Pathology
Frequency
Unscheduled Collections s`aWchreinfipcoesdsaitbluen,scbhleooddulweidllinbteercvoalllsected for clinical pathology tests from animals
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Covance 6329231 Pages -_------m-------- Pages
Scheduled Collections Before initiation of treatment; and (before the daily dose) afterat least 30, 60, 90, and 180 days of treatment; and after at least 30, 60, and 90 days of recovery
Number of Animals All
Method of Collection
Animals will be fasted overnight; blood willbecollected from afemoral vein. Anticoagulants will be sodium citrate for coagulation tests and potassium EDTA for `hematology tests. No anticoagulant is required for clinical chemistry tests. Urine `will be collected on wet ice ovemight (approximately 16 hours).
Tests
Hematology
red blood cell (erythrocyte) count
platelet count
hemoglobin
`white blood cell (leukocyte) count
`hematocrit
`mean corpuscular volume
differential blood cell count
blood cell morphology
`mean corpuscular hemoglobin
reticulocyte count
`mean corpuscular hemoglobin
`concentration
Coagulation activated partial thromboplastin time ~~ prothrombin time.
fibrinogen
Clinical
glucose
urea nitrogen
creatinine total protein albumin
globulin total bilirubin
direct bilirubin (if total bilirubin is greater than 2.0 mg/dL)
cholesterol triglycerides
alanine aminotransferase
alkaline phosphatase.
Chemistry
aspartate aminotransferase
`gamma glutamyliransferase
sorbitol dehydrogenase creatine kinase calcium
inorganic phosphorus sodium
potassium chloride
bile acids amylase lipase
`pancreatic-specific amylase
cozs20)
_----m
Covance 632P9a2g5e1s Paged
appearance. volume (approximately 16 hours)
pH`specific gravity
protein urobilinogen
Urinalysis
glucose ketones
bbilloiordubin
`microscopic examinationofsediment
Blood Hormone Determination
Frequency
`Three times before initiationoftreatment; afattleearst 30, 60, 90, and 180 days of treatment; and afterat least 30, 60, and 90 days of recovery
Number of Animals All
Method of Collection
Animals will notbefasted; blood will be collected from afemoral vein (an alternative vein may beused if necessary). Approximately 6mLof blood for plasmasamples `willbe collected into tubes with potassium EDTA as theanticoagulant.
Aanptpircooxaigmualatnetl
y
a
n6d
mL of
allow
ebdlotoodc
for
lot.
sBelrouomdssaammpplleesswiwlilllbbeecomlaliencttaeidnweidtahtourtoom
temperature until serum
plasma s harvested.
is
harvested.
Blood samples will be maintained chilled until
Serum Sample Handling
woSamples for serum willbecentrifuged within 1 hour after collection, and serum will
bsethoraerdveisntaedf.reeSzeerrusmetwtiollmabiendtiaviinde-d60inttoo-t8w0oCapupnrtoilxipmaactkeeldy
equal aliquots
on dry ice and
and
shipped
Dr. Saroj Das Ani Lytics Inc.
200 Girard Street, Suite 200
Gaithersburg, Maryland 20877 "Telephone No.: 301.921.0168 Facsimile No.: 301.977.0433
Ani Lytics Inc. will be notified regarding shipment of samples.
cozszf
Covance 6329231
-_-- --
PaPgageel10l
Serum Tests
Sstaimmpulleatsinwiglhl obremaonnael,yztoetdalbaynAdnfireLeyttircisioIdnoc.t,hyfroorneisntera(dTi3o)l,,
estrone,
and total
estriol, thyroid
and free thyroxin
(T4). Results will be provided for inclusion in the final report.
Plasma Sample Handling
`Samples for plasma will be centrifuged
harvested and storedin a freezer set to
within 1
maintain
houraftercollection. Plasma
-60 to -80C until packed on
will
dry
be
ice
and shipped to:
Jon C. Cook, PhD, DABT
E. I du Pont de Nemours & Company, Inc.
Haskell Laboratory for Toxicology
Building 11 Room 1325
and
Industrial
Medicine
1090 Elkton Road
Newark, Delaware 19711-0500
`Telephone No.: 302.366.5495
Facsimile No.: 302.366.5003
DuPont will be notified regarding shipment of`samples.
Plasma Analysis
Samples will be
will be provided
analyzed by DuPont Haskell `Company
for inclusion in the final report,
for
cholecystokinin.
Results
Serum APFO Level Determination
Frequency Afte7r days of treatment and every 2 weeksthereafter during treatment andrecovery
Number of Animals All
Method of Collection
Animals will not be fasted; blood (approximately 2 mL) will be collected from a femoral vein (an aliemative vein may be usedif necessary) without an anticoagulant.
Sample Handling
Samples will be centrifuged within 1 hour after collection, and serum willbe harvested. Serum samples will be stored ina freezersetto maintain -10 10-30C.
00252
-_--
Sample Shipping Serum samples will be packed on dry ice and shipped to:
Kris J. Hansen, PhD 3MET.&S Bldg. 2-3E-09 935 Bush Avenue
St. Paul, Minnesota 55106
Cove 632931 Pmgeeint
Kris J. Hansen, PhDorheralternate will be notified regarding the shipment ofthe samples. Analysisof serum for APFO will be done on the samples. Results will be provided for inclusiion the final report.
possible future analysis. `Additional Blood Collection
At scheduled and unscheduled sacrifices, blood (as much as possible, collected from animals at the time of exsanguination. Approximately
up to 20 mL) equally sized
will
be
samples of serum (collected without anticoagulant) and whole blood and plasma (both
collected using EDTA as an anticoagulant) from each animal will be transferred into
containers (approximately 5 mL each). Whole blood, serum, and plasma samples will be
stored ina freezer set to maintain -60 to -80C until shipped to 3M (Kris Hansen) for
Urine and Feces APFO Level Determination
Frequency
After 7 days oftreatmentand every 2 weeks thercafter during treatment and recovery
(concurrent with serum APFO sample collection)
Number of Animals All
Method of Collection
oAnviemmailgsh.willnot be fasted; urine (collected on wet ice) and feces willbecollected
Sample Handling Samples of urine (at least 2 mL) and feces (at least 5 grams) will be stored in afreezer
set to maintain -10 to 30C.
02528
-_---------- Covn-- ee 63P2a9g2e3r1 Page Sample Shipping `Samples will be packed on dry ice and shipped to:
Kris J. Hansen, PhD
B3lMdgE.T2.38&-S09
935 Bush Avenue St. Paul, Minnesota 55106
Kris J.
sample
sH.anAsneanl,ysPishoDfourrihneer
alternatewill
and feces for
bAePnFoOtiwfiileldbreegdaorndeinognthteheshsiamppmleenst.ofRtehsuelts
will be provided for inclusion in the final report,
`Termination
Unscheduled Sacrifices and Deaths
Necropsies willbedone. Animals tobesacrificed will be anesthetized with ketamine
and xylazine, weighed, and exsanguinated.
Scheduled Sacrifices
After at least 26 weeks of treatment, four animals/sex/group will be fasted overnight,
then anesthetized withketamineand xylazine, weighed, exsanguinated, and`necropsied.
rAefmtearinaitnlgeaasnti2m6alwseweiklls
of
be
ftarsetaetdmeonvetrannigdhta,t
least
then
13
ane
swteheektisze`dwiwtihtohutkterteaamtimneneta,ntdhe
xylazine, weighed, exsanguinated, andnecropsied.
Postmortem Procedures
Necropsy
`The necropsy will include examination of:
al orifices
cranial cavity external surfaceofthe brain; the external surface of the spinal cord and cut surfaces of the brain and spinal cord will be examined whenever tissue trimming is performed cervical tissues and organs thoracic, abdominal, and pelvic cavities and viscera external surface of the body
`nasal cavity and paranasal sinuses
cozs2ff
Covance 325.231
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1 Papen
Organ Weights
pFrreosemnte)acwhilalbniemwaeliagthsecdh;edpualierdeadnodrgaunnsscwhieldlubleedwesiacgrhiefidcseesp,atrhaetefloyl:lowing organs (when
adrenal (2) `brain
epididymis (2)
kidney (2)
liver pancreas
testis (2)
thyroid (2) with parathyroid
Organ-to-body weight percentages and organ-to-brain `weight ratios will be calculated.
Sponsor. Palmitoyl CoA Oxidase Determinations
"The right lateral lobe of liver will be collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in af.reezer setto maintain -60 to -80C until dispositionofthe samples is determined by the
Cell Proliferation Evaluation
Representative samples of left lateral lobeofthe liver, left and right testes, and pancreas
`will be collected
preserved in zinc
from each
formalin.
animal
at
the
scheduled
and
unscheduled
sacrifices,
and
eAfmtbeerdfdiexadtiionn,pasraamfpfilnesmafionrtparionleifdeartataimobniceenlltntuecmlpeearraatnutrieguennti(lPdCiNspAo)sietvioanlouafttihone wsialmlpblees
is determined by the Sponsor.
Bile Acid Determination All available bile (up to 5 mL) will be collected from each animal at the scheduled and unscheduled sacrifices, flash-frozen in liquid nitrogen, and stored in a freezer setto `maintain -60 to -80C. Bile samples will be packed on dry ice and shipped to:
0252
_--
Biomedical Research Centre Level 5
Ninewells Hospital and Medical School
University of Dundee Dundee DD1 9SY UK Dr. Cliff Elcombe Biomedical Research Centre Ninewells Hospital and Medical School University of Dundee Dundee DD1 9SY, UK Telephone: +44 (0)1382-632641 Fax: +44 (0)1382-425586
Counce 2f9o51 Paper
rReepsourltt.s of bile acid determinations analyses will be provided for inclusion inthefinal
Receptor Level Determination
t`hSeamspclheesdu(laeppdraonxidmuantseclhye2dugl)eodfslaicvreirfiacnesd,
pancreas will
flash-frozen
be collected from
in liquid nitrogen,
each animal at
and stored in a
freezerset to maintain -60 to -80C.
ice and shipped to:
Liver and pancreas samples will be packed on dry
Jon C. Cook, PhD, DABT
E. 1 du Pont de Nemours & Company, Inc. Haskell Laboratory for Toxicology and Industrial Medicine
Building 11 Room 1325 1090 Elkton Road
Newark, Delaware 19711-0500 "Telephone No.: 302.366.5495 Facsimile No.: 302.366.5003
DuPont will be
determinations
wnioltlifbieedprroevgiadrdeidnfgorshiinpclmuesnitoonifnstahmeplfeisn.al
Results
report.
of
receptor
level
Tissue Preservation
"aTnhdrereigshatmtpelsetess (taipsspureo,ixifmaantye,ly(d5ivgeidaecdhi)ntooftthhreeeliavperpraonxdiamlaltreelmyaeiqnuianlgspaamnpclreesa)swainlld bleeft collected from each animal at the scheduled and unscheduled sacrifices, weighed,
flash-frozen in liquid nitrogen, and stored ina freezer set to `maintain -60 to -80C for possible future analysis.
02528
Covance 6329231 -_---m Pager1s5
"1T0he%fnoelultorwailn-gbutfifsesrueeds (fowrhmeanlipnr,esuennlte)ssfrotohmeerwaicsheasnpiemcailfiewidl,lfborepporsessiebrlveedfuitnure microscopic examination:
aaodrrteanal (2) bcreaciunm ducooldonenum eespiodpihdaygmuiss (2) eyfeix[a(t2i)vetofrbeomprseacsreirfviecdedinanDiamvaildssoonnl'ys] fesmuurfrawcietohfbtohneedimsatarlreonwd)(articular ghaelalrbtladder ileum jkeijdunneuym2) lleisvieorns lung mammary gland
mpeasnecnrteearsic lymph node. ppirtousittaatrey sraelcitvuarmy gland [mandibular (2)) ssceimaitnicalnevrevsei:cle (2) sskkeilnetal muscle (thigh) splinuamlbacro)rd (cervical, thoracic, and spleen sstteormnaucmh with bone marrow tessotlsut[i(2o)n tforobme sparcersiefrivceedd ainniBmoaulisnso'nly] tthhyyrmouisd (2) with parathyroid turriancahreya bladder
Bone From
tMhaersrteorwnuSmmoefaerach
animal
at
unschedulaend
scheduled
sacrifices
(made
and
held for possible future examination)
LAisvaemrpAlePFofOliDveerte(ramnyinnaotni-ofonrmalin treated liver remaining after sampling for shaicsrtiofpicaetsh,olwoegiyg)hewdi,llfbleascho-lflreoczteendifnrloimqueiadcnhitarnoigmeanl, aatndthsetsocrhedediunleadfraenedzeurnssecthteoduled manaailnytsaisi.n -A6n0altyos-i8s0ofCulinvteirlfosrhiApPpFedOwwiitlhl sbeerduomnseaomnpltehse stoam3plMes(.KriRsesHualntssewni)llfbore provided for inclusion in the final report.
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Covance 6329-231
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PaPaggeel1s6
Histopathology
`Tissues from each animal in the control and high-dose groups and each animal that dies or is sacrificedat unscheduled interval will be embeid n pd arae ffid n, sectioned, stained `with hematoxylin and eosin, and examined.`microscopically.
`The adrenals, pancrea
`mid-dose groups will
s,
be
liver, spleen,
embedded in
and testes from each animal
paraffin, sectioned, stained
in the low-and
with hematoxylin
and
eosin, and examined microscopically.
Suspected target organs noted at the high-dose will be embedded in paraffin, sectioned,
stained with hematoxylin and eosin,and examined `microscopically from all animals (at the Sponsor's request and added by amendment).
Reports
A draft report which includes the following information will be prepared and submitted: Experimental Design and Methods
Results
`mortality
clinical observations
body weights
body weight gains food consumption ophthalmic examination results clinical pathology results
`hormone analyses (provided by Ani Lytics, Inc. and the DuPont Haskell Company)
soerrguamn,wueriignhet,sfeces, and liver APFO levels (provided by 3M)
organ-to-body weight percentages
`organ-to-brain weight ratios
`macroscopic observations
`microscopic observations
palmitoyl CoA oxidase activities (provided by the Sponsor'sdesignee) cell proliferation evaluations (provided by Pathology AssociatesInternational) bile acid determinations (provided by University of Dundee) receptor determination (provided by DuPont)
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Covance 6329231
---
eagee1rr
Statistical Evaluation
Levene's test will be done
heterogeneity of variance
to test for variance homogeneity. In the
atp s 0.05, transformations will be used
case of
to stabilize
the
variance. Comparison tests will take variance heterogeneiinttyo consideration.
One-way analysis
body weights, bod
o
y
f variance (ANOVA)
weight gains, contin
will
uous
be
cli
used
nical
(if applicable)
pathology valu
to analyze initial
es, palmitoyl CoA
`owxilildabseeuascetidviftoiresc,onatnrdolorvgearnsuwsetirgehatteddatgar.ouIpf
the ANOVA is.
comparisons.
significant,
Dunnett's
t-test
One-way analysis of covariance (ANCOVA) willbe used to analyze body weights, with
initial body weights as the covariate. If the ANCOVA is significant, covariate-adjusted `means will be used for control versus treated group `comparisons.
Group comparisons (Groups 2 through 4 versus Group 1) will be evaluatedatthe
5.0% two-tailed probability level. Only data collected on orafterthe first day of
troeradtumreinntgwrielclovbeeryanwailllyzneodt sbteataisntailcyalzleyd.
Data collected
statistically.
before
the
first
day
of
treatment
At the end of 1 year after issuanceofthe audited draft report,if no requested revisions or
instructions to finalize havebeen communicated by the Sponsor, then the audited draft report will be considered`final'and issued as the final report, signed by the study director, and submitted to the Sponsor.
AwinllybmeodpiefrifcoartimoendsaotracddhiatnigoensaltcootshtetaoutdhieteSdpodnrasfotr.report requested 1 year after issuance
Record Retention All raw data, documentation, records, protocol, specimens, and final report generated as a
preesruilotdooffth1isyesatrudfyolwliollwibneg asrucbhmiivsesdiionntohfe tshteorfaignaelfraceiploirttietsootfhCeoSvpaonnscoer-.MaOdniesoyneafrorafater `submission of the final report, allofthe aforementioned materials will be sent to the Sreptoanisnoerd,ian ntdheaCroevtuarnncfeeearwcihlilvebsefcohraarngeadd.diTthioenaSlpopenrsioordomfatyimelee,ctantod hCaovveatnhceemwaitlelcrhiaalrsge
astorage fee. If the Sponsor chooses to have Covance dispose of the materials, a disposal fee will be charged. All raw data stored on `magnetic media will be retained by Covance.
Within oneyearafter submission of the final report, all of the aforementioned materials from the Sponsor's designees (Ani Lytics Inc., E. 1. du Pont de Nemours & Company, Inc, SME.T. & 8, Pathology Associates International, and University of Dundee) will be sent to the Sponsor (Paul Lieder, PhD, DABT, 3M) to be maintained.
conAsg
_-- --
PROTOCOL APPROVAL
Covance 632931 PPaaggeess
Pod Lid
Paul Lieder, PhD Diplomate, ABT Study Monitor 3M
TT erm David Farrar, PhD
ICI Chemicals & Polymers Limited
# I ZsPhD
Z
Study Director
Department of Toxicology
Covance Laboratories Inc.
Yes/zp
Date
_
Date
Date
;>
cc2538