Document B5BxYKMX2NOwK8VwgVJobL4R8
Summary PFOS RabbitTeratology
StudyNumbers: 3M T-6295.10,Argus418-012
Compound & Lot: PFOS (Perfluorooctanesulfona-teL)ot 217, 98.4% pure (SMD AnalyticalRequest 53030) AnalyticalDocumentation filedalong with finalreport.Note - same lotas used in two-yearrat PFOS carcinogenicitsytudy(T-6295,Covance 6329-183).
Study Title:Oral (Stomach Tube) DevelopmentalToxicityStudy of PFOS inRabbits
ReportDate: II January 1999
Study Monitor Summary: (writtenby Marvin T. Case) Pregnantrabbitfemales,22 per group,were given dailyoral(intubationo)f PFOS atdose levelsof 0,0.1,1.0,2.5,and 3.75 mgtkg/day on days 7 through 20 of gestation.The rabbitfetuseswhich had been exposed inuteroduringorganogensis were collectedatday 29 ofgestation.All of the fetuseswere examined forsofttissue(visceralc)hanges usinga dissection microscope and thenallfetuseswere examined forskeletalchanges. A dose relatedbody weight effectoccurredinthe 1.0,2.5.and 3.75mgtkg dose groups. The differencein mean body weightswas statisticalsliygnificanattthe3.75 mgtkg dose. A significanrteductioninfood consumption was alsopresentatthe 2.5 and 3.75mgtkg doses. No compound relateddeathsoccurred at any dose level. Abortions occurred inone 2.5 mgtkg doe, and inten3.75 mgtkg does. The abortionsatthe high dose were consideredto be compound related.Mean pup weights were decreasedinthe2.5 and 3.75 mg/kg groups. The reduced food consumption and adversebody weight effectthatoccurred atthe two highestdose levels were indicativoef dam toxicity.The increasednumber of abortionsand reduced pup weightswere probably secondaryto the dam toxicity. Increasednumber of delayed ossificatiosniteswere found inthe 2.5 and 3.75 mg/kg fetuseswhich is anotherreflectioonf matemal toxicityatthesedose levels. No compound-related softtissueorskeletalmalformationswere found atany dose level.Thus, the compound was not found tobe teratogenicintherabbit. The maternaltoxicNOEL was 0.1 mgtkg. The fetaltoxicNOEL was 1.0mg/kg. TeratogenicNOEL in therabbitwas > 3.75 mg/kg. NOTE: Dose preparationsamples were collectedtwice during thestudy and thesesamples were sentto 3M Evirommental AnalyticallaboratoryinBldg 2. Likewise,samples were collectedfrom extrafemales assignedas toxicokinctiscatellitaenimals (3/groupexceptlow and highdose 5/group).These animals were killedon gestationday 21 (day afterlastdose)and the followingsamples were collecteds:erum and liverfrom pregnantdams, fetusesand placentas(pooledby litterf)rom uterus.These samples were frozen and sentto3M EvirorrunentaAlnalyticallaboratoryinBldg 2. At time of thissummary, March 1999, analysisof thesesamples had not been done; thereforet,heseanalyticarlesultswere notincluded inthe finalreportnor inthissummary.
FINAL REPORT
PROTOCOL 418-012
ORAL (STOMACH TUBE) DEVELOPMENTAL IN RABBITS
TOXICITY STUDY OF PFOS
SPONSOR'S STUDY NUMBER: 6295.10
FINAL REPORT DATE: 11 JANUARY 1999
PROTOCOL 418-012
ORAL (STOMACH TUBE) DEVELOPMENTAL IN RABBITS
TOXICITY STUDY OF PFOS
SPONSOR'S STUDY NUMBER: 6295.10
TABLE OF CONTENTS SUBJECT 1. SUMMARY AND CONCLUSION A. Methods B. Results C. Conclusion li. DESCRIPTION OF TEST PROCEDURES A. Conduct ofStudy A.l. Sponsor A.2. TestingFacility A.3. Study Number A.4. Sponsor'sStudy Number A.5. Purpose ofthe Study A.6. Study Design
PAGE 1-1 1-1 1-2 1-3 11-1 11-1 11-1 11-1 11-1 11-1 11-1 11-1
SUBJECT A.7. RegulatoryCompliance A.8. Ownership ofthe Study A.9. Study Monitor A.10. AlternateStudy Monitor A.11 Study Director A. 12. TechnicalPerformance A. 13. Report Preparation A. 14. Report Review A. 15. Date ProtocolSigned A. 16. Dates ofTechnicalPerformance A.17. Records Maintained B. Test ArticleInformation B.1. Description B.2. Lot Number B.3. Date Received and Storage Conditions B.4. SpecialHandling Instructions B.5. AnalysisofActivity C. VehicleInformation C. 1. Description C.2. Lot Number C.3. Date Received and Storage Conditions C.4. SpecialHandling Instructions
PAGE 11-1 11-2 11-2 11-2 11-2 11-2 11-2 11-2 11-2 11-3 11-3 11-3 11-3 11-3 11-3 11-3 11-3 11-4 11-4 11-4 11-4 11-4
SUBJECT C.5. AnalysisofPurity D. Test ArticlPereparation D.1. Sample Information D.2. AnalyticaRlesults E. Test System E.1. Species E.2. Strain E.3. Supplier(Source) E.4. Sex E.5. RationaleforTest System E.6. Test System Data E.7. Method of Randomization E.8. System of Identification F. Husbandry F.1. Research FacilitRyegistration F.2. Study Rooms F.3. Housing F.4. Lighting F.5. Sanitization F.6. Feed F.7. Feed Analysis F.8. Water
PAGE 11-4 11-4 11-5 11-5 11-5 11-5 11-5 11-5 11-5 11-6 11-6 11-6 11-6 11-7 11-7 11-7 11-7 11-7 11-7 11-7 11-8 11-8
SUBJECT F.9. Water Analysis G. Methods G. 1. Dosage Administration G.2. RationaleforDosage Selection G.3. Route ofAdministration G.4. RationaleforRoute ofAdministration G.5. Frequency ofAdministration G.6. Length ofStudy G.7. Method ofStudy Performance G.8. Gross Necropsy G.9 StatisticAanlalyses Ill. RESULTS A. MortalityA,bortions,Clinicaalnd Necropsy Observations A. 1. Abortions A.2. ClinicaOlbservations A.3. Necropsy Observations B. MaternalBody Weights and Body Weight Changes C. MaternalAbsolute(g/day)and Relative(g/kg/day)
Feed Consumption Values D. Caesarean-Sectioningand LifteOrbservations E. FetalAlterations E. 1. Summary ofFetalAlterations E.2. FetalGross ExternalAlterations
iv
PAGE 11-8 11-9 11-9 11-9 11-9 11-9 11-9 11-9 11-10 11-10
11-12 111-1 111-1 111-1 111-3 111-3 111-3
111-4 111-4 111-5 111-5 111-6
SUBJECT
E.3. FetalSoftTissueAlterations
E.4. FetalSkeletalAlterations
F. SatellitReabbits
REFERENCES
APPENDIX A - REPORT FIGURE
Figure1. MaternalBody Weights
APPENDIX B - REPORT TABLES
Table 1. ClinicaOlbservationsand Necropsy ObservationsSummary
Table 2. UterineContentsand LifteDrata forIndividuaRlabbits That Aborted
Table 3. MaternalBody Weights - Summary
Table 4. MaternalBody Weight Changes -Summary
Table 5.
MaternalAbsoluteFeed Consumption Values (g/day-) Summary
Table 6.
MaternalRelativeFeed Consumption Values (g/kg/day-)Summary
Table 7. Caesarean-SectioningObservations- Summary
Table 8.
LifteOrbservations(Caesarean-Delivreed Fetuses)Summary
Table 9. FetalAlteration-sSummary
Table 10. FetalGross ExternalAlteration-sSummary
Table 11. FetalSoftTissueAlteration-sSummary
Table 12. FetalSkeletalAlteration-sSummary
PAGE 111-6 111-7
111-10 111-12
A-1
B-1
B-2 B-4 B-6
B-7
B-8 B-9
B-1 0 B-1 1 B-1 2 B-13 B-14
v
SUBJECT
PAGE
Table 13. FetalOssificatioSnites-Caesarean-Delivered
Live Fetuses (Day 29 of Gestation)- Summary
B-1 9
Table 14. ClinicaOlbservations- lndivdiual Data
B-20
Table 15. Necropsy Observations- IndividuaDlata
B-26
Table 16. Maternal Body Weights - IndividuaDlata
B-33
Table 17. Maternal Feed Consumption Values -
IndividuaDlata
B-48
Table 18. Caesarea n-SectioningObservations- IndividuaDlata
B-63
Table 19. LifteOrbservations(Caesarean-DeliveredFetuses)-
IndividuaDlata
B-69
Table 20. FetalSex, VitalStatusand Body Weight -
IndividuaDlata
B-75
Table 21. FetalAlteration-sIndividuaDlata
B-87
APPENDX C - PROTOCOL AND AMENDMENT
C-1 toC-32
APPENDIX D - PILOT REPORT
D-1 to D-94
APPENDIX E - HISTORICAL CONTROL DATA
E-1 to E-14
APPENDIX F - STATEMENT OF THE STUDY DIRECTOR
F-1
APPENDIX G - QUALITY ASSURANCE STATEMENT
UNIT FINAL REPORT
G-1 to G-4
vi
418-012:PAGE 1-1
TITLE:
ORAL (STOMACH TUBE) DEVELOPMENTAL OF PFOS IN RABBITS
TOXICITY STUDY
ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-012 SPONSOR'S STUDY NUMBER: 6295.10
1. SUMMARY
AND CONCLUSION
A. Methodso
One hundred ten New Zealand White [Hra(NZW)SPF]
rabbits were assigned to
each offivedosage groups (Groups IthroughV) forthe main portionofthe
study. Nineteen additionaflemale rabbitswere assigned to one offivedosage
groups forthe satellitsetudy (three,fivet,hree,three and fiverabbitsassignedto
Groups IthroughV, respectively)T.he testarticleP,FOS, or vehicle,0.5%
Tween@ 80 inReverse Osmosis Membrane Processed DeionizedWater (R.O.
DeionizedWater),was administeredorally(viastomach tube)once dailyto
female rabbitson days 7 through20 ofpresumed gestation(DGs 7 through20).
Dosages of0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day were administeredat a
dosage volume of5 mukg, adjusteddailyon the basis ofindividuablody
weights.
The female rabbitswere observed forviabiliattyleasttwiceeach day ofthe study. The rabbitswere alsoexamined forclinicaolbservationsof effectsofthe testarticlea,bortionsp,remature deliverieasnd deaths beforeand approximately 60 minutes aftereach dailyintubatiodnuringthe dosage period,and once daily duringthe postdosage period.Body weightswere recorded on DGs 0 and 6 through29. Feed consumption values were recordeddailythroughoutthe study.
Allsurvivingrabbitswere sacrificebdy intravenousadministratioonf Beuthanasia&D Specialeuthanasiasolutionon DG 29 and a gross necropsy of the thoracic,abdominal and pelvicviscerawas performed. The number of corpora luteaineach ovary was recorded.The uterusofeach rabbitwas
a. Detaileddescriptionosf allprocedures used inthe conduct ofthisstudy are providedinthe appropriatesectionsofthisreportand inAPPENDIX C (PROTOCOL AND AMENDMENT).
418-012:PAGE 1-2
examined forpregnancy, number and distributiofn implantationsl,iveand dead fetusesand earlyand lateresorptions.The fetuseswere weighed,examined for gross externalalterationasnd sex. Visceralalterationasnd cavitatedorgans were evaluatedby dissection.The brainsofapproximatelyone halfofthe fetusesineach liftewrere free-handcross-sectionedand examined insitu.All fetuseswere eviscerateds,tainedwithalizarirned S and evaluatedforskeletal alterations.
Rabbitsinthe satellitsetudy were sacrificeodn DG 21. Blood samples were collectedand centrifuged.The livewras excised,weighed and sectioned. Fetuses were examined grosslyto the extentpossibleas describedforrabbits assignedto the main study.Fetuses and placentaewere pooled per lifterA.fter completionof sample collections,erum, liversection,fetaland placentalsamples were shipped to the Sponsor foranalysis.
B. Results
Administratioonfthe 2.5 and 3.75 mg/kg/day dosages ofthe testarticlreesulted inten abortions(one inthe 2.5 mg/kg/day dosage group and nine inthe 3.75 mg/kg/day dosage group).These abortionsoccurredafterthe completion ofthe dosing period(on DGs 22, 24, 25 or 28). Allotherdoes survivedto scheduled sacrifice.
Increasednumbers of does inthe 3.75 mg/kg/day dosage group had observationsofscant or no feces. Scant feces alsooccurredinone and three rabbitsinthe 1.0and 2.5 mg/kg/day dosage groups,respectivelyT.he 1.0mg/kg/day dosage group rabbitalso had softor liquifdeces on one day. One doe inthe 3.75 mg/kg/day dosage group had red substance inthe cage pan associatedwithimpending abortion.No otherclinicaolr necropsy observations relatedtothe testarticloeccurred.
Dosage-dependent, significanbtody weight reductionsor body weight losses occurredinthe 1.0,2.5 and 3.75 mg/kg/day dosage groups forthe entiredosage period(calculateads DGs 7 to21). Dosage-dependent reductionsinbody weight gains occurredinthe 2.5 and 3.75 mg/kg/day dosage groups forthe entiregestationperiod(DGs 0 to29) and forthe gestationperiodafterthe initiatioofndosing (DGs 7 to 29). Average body weightswere significantly reduced on DGs 17 through24 inthe 3.75 mg/kg/day dosage group. Absolute (g/day)and relativ(eg/kg/dayf)eed consumptionvalueswere reduced inthe 2.5 and 3.75 mg/kg/day dosage groups forthe entiredosage period(DGs 7 to 21), and the entireperiodafterthe initiatioofndosage (DGs 7 to29).
Fetalbody weights (totalm,ale and female)were significantrleyduced inthe 2.5 and 3.75 mg/kg/day dosage groups. Delays infetalossificatioanssociatedwith
418-012:PAGE 1-3
the significantrleyduced fetalbody weights inthe 2.5 and 3.75 mg/kg/day dosage groups were evidentas significanrteductionsinthe liftearverages for ossifiedsternalcentersinthe 2.5 and 3.75 mg/kg/day dosage groups and significarnetductionsinthe liftearverages forossifiedhyoidand metacarpals and significanrteductionsinthe liftearnd fetalincidencesof incompletely ossifiedpubes inthe 3.75 mg/kg/day dosage group.
C. Conclusion
Based on these data,the maternalno-observable-effect-lev(eNlOEL) forPFOS is0.1mg/kg/day. The 1.0mg/kg/day and higherdosages reduced maternal body weight gain. Dosages of2.5 and 3.75 mg/kg/day caused abortionsand reduced feed consumption. The developmental NOEL is1.0mg/kglday. Dosages of2.5 and 3.75 mg/kg/day caused reductionsinfetalbody weightsand delaysinossificationB.ased on these data,PFOS should not be identifieads a selectivedevelopmentaltoxicantt;he compound was not found to be teratogenic inthe rabbit.
MildredS. ChristianP,h.D.,Fellow,ATS ExecutiveDirectorof Research
Date
Alan M. Hoberman, Ph.D.,DABT Directorof Research
iwv Date
it;X;Fon@G. Y(,oocrrkt,koO;U D., aABT
Date
Associate Directoor
arch and
Study Director
418-012:PAGE 11-1
li. DESCRIPTION OF TEST PROCEDURES
A. Conduct of Study:
A.l. Spons
3M Corporate Toxicology,3M Center Building220-2E-02 St.Paul,Minnesota 55144-1000
A.2. Testing Facilily:
Argus Research Laboratories,Inc.,905 Sheehy Drive,BuildingA, Horsham, Pennsylvania 19044-1297
A.3. Study Number:
418-012
A.4. Sponsor's Study Number:
6295.10
A.5. Purpose of the Study:
The purpose ofthisstudy was designed todetectadverse effectsof PFOS on New Zealand White [Hra:(NZW)SPF] presumed pregnantfemale rabbitsand development ofthe embryo and fetusconsequent to exposure ofthe doe from implantatiotno closureofthe hard palate.This studywas designed to evaluate ICH Harmonised TripartitGeuidelinestages C and D ofthe reproductiveprocess ina nonrodent species.
A.6. Study Design:
The requirementsofthe InternationaClonference on Harmonisation (ICH) Harmonised TripartitGeuideline('w)ere used as the basisforstudydesign.
A.7. Regulatory-Compliance:
The studywas conducted incompliancewiththe Good LaboratoryPractice
(GLP)
regulationsofthe U.S. Food
and
Drug
Administration(FDA)
12) ,
the
Japanese MinistryofHealthand Welfare(MHW)(1)and the European Economic
Community (EEC)(4) . There were no significadnetviationsfrom the GLP
regulationtshataffectedthe qualityor integritoyfthe study. QualityAssurance
418-012:PAGE 11-2
Unitfindingsderivedfrom the inspectionsduringthe conduct ofthisstudy are documented and have been providedtothe Study Directorand the Testing Facilitmyanagement.
A.8. Ownership of the Study:
The Sponsor owns the study.Allraw data,analyses,reportsand preserved tissuesare the propertyofthe Sponsor.
A.9. Study Monitor:
Marvin T. Case, D-.V.M.,Ph.D.
A.10. AlternateStudy Monitor:
Andrew M. Seacat,Ph.D. A.11. Study Director:
Raymond G. York, Ph.D.,DABT (AssociateDirectorof Research)
A.12. Technical Performance:
John F. Barnett,B.S.(DirectorofLaboratoryOperations) KristenlandolaSherer,B.S.(Research Associate/FetaElvaluation) Matthew J.Vaneman, B.S. (LaboratoryTechnician)
A.13. Report Preparation:
Raymond G. York,Ph.D.,DABT MichelleR. Rzaca, B.S.(StudyCoordinator) Susan K. Bradshaw, B.S.(Data Management Specialist) Karen G. Parker,A.A. (ReportAdministrator)
A.14. Report Review:
Alan M. Hoberman, Ph.D.,DABT (Directoorf Research) MildredS. ChristianP,h.D.,Fellow,ATS (ExecutiveDirectorofResearch)
A.1S. Date Protocol Signed:
11 August 1998
418-012:PAGE 11-3
A.16. Dates of Technical Performance:
Rabbit ArrivalDate Dosage Period[Days 7 through 20 ofpresumed gestation(DGs 7 through20)] ToxicokinetiScample Collectio(nDG 21) Caesarean-SectioningPeriod(DG 29)
21 AUG 98
23 AUG 98 - 09 SEP 98 06 SEP 98 - 10 SEP 98 14 SEP 98 - 18 SEP 98
A.17. Records Maintained:
The originarleport,raw data and reservesamples ofthe testarticlaend vehicle components are retainedinthe archivesofArgus Research LaboratoriesI,nc. Any preserved tissuesare retainedinthe archivesof theTestingFacilitfyorone year afterthe mailingofthe draftfinalreport,afterwhich time the Sponsor will decide theirfinaldispositionA.llunused testarticlseuspensions were discarded atthe TestingFacilityU.nused bulktestarticlweillremain atthe TestingFacility untilitsdispositioinsdecided by the Sponsor.
B. Test ArticleInformation:
B.I. Description:
PFOS - an off-whitepowder
B.2. Lot Number:
217 (Expiratiodnate: May 2000)
B.3. Date Received and Storage Conditions:
The testarticlweas receivedon 20 May 1998, and storedat room temperature. Prepared formulationswere storedrefrigerated.
B.4. Special Handling Instructions:
Standard safetyprecautions(use ofprotectiveclothingg,loves,dust-mist respirators,afetygoggles or safetyglassesand a face-shieldw)ere taken when handlingthe bulktestarticlaend prepared suspensions.
B.5. Analysis of P"i :
Informationregardingthe purityi,dentitys,trengthand compositionofthe test articlieson filweiththe Sponsor.
418-012:PAGE 11-4
C. Vehicle Information:
C.l. Description:
0.5% Tween(m 80 prepared using 2% TweeniD 80, a clearviscous to yellow liquid, inReverse Osmosis Membrane Processed DeionizedWater (R.O. Deionized Water). C.2. Lot Number:
M03HO5
C.3. Date Received and Storage Conditions: The 2% Tweene 80 was receivedon 8 July1998,and storedatroom temperature. R.O. deionizedwater isavailablefrom a continuoussource atthe TestingFacilitaynd ismaintainedat room temperature.
C.4. Special Handling Instructions:
Standard safetyprecautions(use ofprotectivcelothingg,loves,dust-mist respirators,afetygoggles orsafetyglassesand a face-shieldw)ere taken when handlingthe vehicle. C.5. Analysis of Purily:
Neitherthe Sponsor nor the Study Directorwas aware of any potential contaminants likeltyobe presentinthevehiclethatwould interferweiththe resultsof thisstudy.
D. Test ArticlePreparation: Suspensions of PFOS were prepared dailyatconcentrationsof 0,0.02,0.2,0.5 and 0.75 mg/mL. The testarticlweas considered100% pure forthe purpose of dosage calculations.
418-012:PAGE 11-5
D.I. Sample Information:
Sample Type
Storage
Components
Size
Date Retained Conditions Shipped To
Date Shipped
Concentration
N/A
(allevels)
Bulk TestArticle
N/A
Reserve
2 mLa 1g
23 AUG 9811 09 SEP 98c 25 AUG 98
Frozen
Room temperature
Sponsor
23 AUG 98 09 SEP 98
TestingFacility Not available Archives
TweenS 80
5 mL
VehicleReserve R.O. deionized 5 mL
I water
25 AUG 98 25 AUG 98
Room temperature
Room I temperature
TestingFacility Not available Archives
TestingFacility Not available
Archives
I
I
a. Duplicatseamples were takenfrom each concentrationO.ne setofsamples was sentforanalysist;he remaining samples were retainedattheTestingFacilitays backups.
b. Firsdtay ofpreparation. c. Lastday ofpreparation.
Homogeneity and stabilitoyf preparedformulationsare on filewiththe Sponsor.
D.2. AnalyticalResults:
Concentrationsamples (2 mL) were taken on the firsatnd lastdays of preparationforanalyses by 3M EnvironmentalTechnology and SafetyServices. The resultsofthese analyseswere not availableatthe time ofthisreport.
E. Test System:
E.I. Species:
Rabbit
E.2. Strain:
New Zealand White [Hra:(NZW)SPF]
E.3. Supplier(Source):
Covance Research Products,Inc.,Denver, Pennsylvania
E.4. Sex:
Timed-pregnant female
418-012:PAGE 11-6
E.5. Rationale for Test System:
The New Zealand White [Hra:(NZW)SPF] rabbitwas selectedas the Test System because: 1)itisone non-rodentmammalian speciesaccepted and widelyused throughoutthe industryfornonclinicasltudiesofdevelopmental toxicit(yembryo-fetatloxicity/teratogenic2i)ttyh)i;sstrainofrabbithas been demonstrated to be sensitivetodevelopmental toxins;3) historicadlata and experienceexistatthe TestingFacility(5a-n7d);4) the testarticliesbiologically activeinthe speciesand strain.
E.6. Test System Data:
Number ofRabbits Approximate Date of Birth Approximate Age atArrival Weight (kg)on DG 0 Weight (kg)atArrival
133 21 MAR 98 5 months 2.77-4.20 2.84-4.21
E.7. Method of Randomization:
Upon arrivarla,bbitwsere assignedtoindividuahlousingon thebasisof computer-generatedrandom units.Rabbitswere assignedto one offivedosage groups (Groups IthroughV),22 rabbitsper dosage group,forthe main portionof the study. An additiona1l9 satellitreabbitswere assigned fortoxicokinetic evaluationf;iverabbitswere assignedtoeach ofthe low and highdosage groups (Groups 11and V) and threerabbitswere assigned toeach ofthe remaining dosage groups (Groups 1,11a1nd IV).Rabbitswere assignedtodosage groups usinga computer-generated(weight-orderedr)andomizationprocedurebased on body weightsrecorded by and atthe Supplier(Covance Research Products, Inc.)on DG 0.
E.8. System of Identification:
Cage tags were marked withthe studynumber, permanent rabbitnumber, sex, testarticliedentificatiaonnd dosage level.Each rabbitwas individualildyentified witha MoneloDself-piercinegar tag (Gey Band and Tag Co., Inc., No. MSPT 20103) inscribedwiththe rabbit'dsesignatedunique permanent number.
418-012:PAGE 11-7
F. Husbandry:
F.l. Research FacililyRegistration:
USDA RegistrationNo. 23-R-099 under the Animal Welfare Act, 7 U.S.C. 2131 et seq.
F.2. Study Rooms:
The study rooms were maintained under conditions of positiveairflowrelativeto a hallwayand independentlysuppliedwitha minimum often changes per hour of 100% freshairthathad been passed through99.97% HEPA filter(sAiroCleanO rooms). Room temperatureand humiditywere monitoredconstantlythroughout thestudy. Room temperaturewas targetedat61 OF to72"F (160C to 220C); relativheumiditywas targetedat 30% to70%.
F.3. Housing:
Rabbitswere individuallhyoused. Allcage sizesand housing conditionsare in compliance withthe Guide forthe Care and Use of LaboratoryAnimals(8).
F.4. Lighting:
An automatically-contrloeldfluorescentlighctyclewas maintainedat 12-hours light1:2-hours dark,witheach dark periodbeginningat 1900 hours EST.
F.S. Sanitization:
Cage pan linerswere changed approximatelythreetimes each week. Cages were changed approximatelyevery otherweek.
F.6. Feed:
Approximately150 g ofCertifieRdabbitChowS #5322 (PMI Nutrition InternationaSlt,.Louis,Missouri)was availabletoeach rabbiteach day untilthe firsdtay ofdosage, atwhich time approximately180 g ofthe same certifiefdeed was offeredto each rabbiteach day. The certifiefdeed was availablefrom individuasltainlessteel"J-type"feedersattachedtoeach cage.
418-012:PAGE 11-8
F.7. Feed Analysis:
Analyses were routinelyperformed by the feed supplier.No contaminants at levelsexceeding the maximum concentratiofnorcertifiefdeed or deviationsfrom expected nutdtionarlequirementswere detectedby these analyses. Copies of the resultsofthe feed analyses are availableinthe raw data.
Neitherthe Sponsor nor the Study Directorwas aware ofany agent presentin the feed thatwas known to interferweiththe resultsofthisstudy.
F.8. Water:
Localwater thathad been processed by passage througha reverseosmosis membrane (R.O.water)was availabletothe rabbitsad libitumfrom individual water bottlesand/orfrom an automaticwateringsystem (individuaslippertubes). Chlorinewas added tothe processed water as a bacteriostat.
F.9. Water AnalyAiLs:
The processed water isanalyzed twiceannuallyforpossiblechemical contamination(LancasterLaboratoriesL,ancaster,Pennsylvania)and monthly forpossiblebacteriaclontamination(AnalyticaLlaboratoriesI,nc.,Chalfont, Pennsylvania).Copies ofthe resultsofthe water analysesare availableinthe raw data.
Neitherthe Sponsor nor the Study Directorwas aware ofany agent presentin the water thatwas known to interferweiththe resultsofthisstudy.
418-012:PAGE 11-9
G. Methods: G.I. Dosage Administration:
Dosage Group
IV v
Number of Rabbits
22+32 22+58 22+38 22+38 22+52-
Dosage
concentration
(mg/kg/day)
(mg/mL)
Dosage Volume (mL/kg)
0 (Vehicle)
0
5
0.1
0.02
5
1.0
0.2
5
2.5
0.5
5
3.75
0.75
5
1
The testarticlweas considered 100% pure forthepurpose of dosage calculations. a. Rabbitsassigned tothetoxicokinetiecvaluation.
G.2. Rabonale for Dosage Selection:
Assigned Ra bitNumbers
Main
Satellite8
8443-8464 8553-8555
8465-8486 8556-8560
8487-8508 1 8561-8563
8509-8530 8564-8566_
8531-8552 8567-8571 11
Dosages were selectedon the basisofa dosage-range study(Argus Research LaboratoriesI,nc.,Protocol418-012P).
G.3. Route of Administration:
Oral(stomach tube)
G.4. Rationale forRoute of Administration:
The oral(stomach tube)routewas selectedforuse because: 1)incomparison withthe dietaryroute,the exactdosage can be accuratelyadministered;and 2) it isone ofthe possibleroutesof human exposure.
G.S. Freguency of Administration:
Appropriatedosages ofthe testarticlweere administeredorally(viastomach tube)once dailyto naturally-brerdabbitson DGs 7 through20. Dosages of 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day ofthe testarticlweere administered ata dosage volume of 5 mukg, adjusteddailyon the basisofthe individuablody weights recordedbefore intubationT.he rabbitswere intubatedatapproximately
the same time each day.
G.6. Length of StUdE.
Approximately4 weeks
418-012:PAGE 11-10
G.7. Method of Study Performance:
The female rabbitswere naturallybred by breeder male rabbitsofthe same source and strainbefore shipment tothe TestingFacilityT.he rabbitswere mated on fiveconsecutivedays and shipped tothe TestingFacilitoyn the day afterthe lastday of mating. The day ofmating was consideredto be DG 0. A computer-generated(weight-orderedr)andomizationprocedure was used to assignthe rabbitstofivedosage groups based on body weights recordedon DG 0 and suppliedby Covance Research Products,Inc.
Allrabbitswere observed forviabiliattyleasttwiceeach day ofthe study and for generalappearance severaltimesduringacclimationand on DG 0. Additional examinationsforclinicaolbservationsofeffectsofthe testarticlea,bortions, premature deliverieasnd deaths were made atleastonce duringthe predosage period,once before each dailyintubatioannd approximately60 minutes after intubatiodnuringthe dosage period.These observationswere alsomade once dailyduringthe postdosage period(DGs 21 through29).
Body weightswere recorded on DGs 0 and 6 through29. Feed consumption values were recordeddailythroughoutthe study.
G.8. Gross NecropAy:
G.8.a. SatelliteRabbits Assigned to ToxicokineticSample Collection:
On day 21 of presumed gestation(theday followingthe lastdosage), toxicokinetiscamples were collectedfrom the rabbitsassigned tothe toxicokinetiecvaluation.Followinganesthesiaofpentobarbitalb,lood samples (approximately4 mL per rabbitw)ere collectefdrom the inferiovrena cava into serum separatortubes and centrifugedT.he resultinsgerum (approximately 2 mL) was immediatelyfrozenon dry iceand maintainedfrozen(-700C)until shipment tothe Sponsor foranalysis.The livewras excised,weighed, and a sample was taken from the rightlaterallobe,frozenand retainedat-70'C until shipment tothe Sponsor foranalysis.
Rabbitswere Caesarea n-sectionedand fetuseswere examined grosslyto the furthestextent.Fetuses and placentaewere pooled per liftearnd retainedfrozen (-700C)untilshipment to the Sponsor foranalysis.
Aftercompletionofsample collections,erum, livesrections,fetaland placental samples were shipped (frozenon dry ice)to 3M EnvironmentalTechnology and Safety Services,St.Paul,Minnesota,
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G.8.b.ScheduledSacrifice:
Allsurvivinrgabbitwseresacrificbeydintravenouasdministratoifon Beuthanasiao-D Specialeuthanasiasolutionon DG 29. The thoracic,abdominal and pelvicvisceraof each rabbitwere examined forgross lesions.Gross lesions were preserved inneutralbuffered10% formalinforpossiblefutureevaluation (withthe exceptionof parovariancysts,which are common, spontaneous lesions inrabbits)a;llothertissueswere discarded.
The number of corporaluteaineach ovary was recorded. The uteruswas excisedand examined forpregnancy,number and distributionf implantations, earlyand lateresorptionsand liveand dead fetuses.Uterifrom does that appeared nonpregnant were stainedwith10% ammonium sulfideto confirmthe absence of implantatiosnites('A)n. earlyresorptiownas definedas one inwhich organogenesis was not grosslyevident.A lateresorptiownas definedas one in which the occurrence oforganogenesiswas grosslyevident.A livefetuswas definedas a term fetusthatresponded to mechanical stimuli.Nonresponding term fetusesare consideredtobe dead (therewere no dead fetuses).Dead fetusesand lateresorptionsare differentiatbeyd the degree of autolysispresent; marked to extreme autolysisindicatedthatthe fetuswas a lateresorption.
Each Caesarea n-deliveredfetuswas weighed, examined forgross external alterationasnd individualildyentifiewditha tag notingstudy number, lifter number, and uterinedistributioLni.vefetuseswere sacrificebdy an intraperitoneianljectioonf Beuthanasiao-D Special.Allfetuseswere examined internalltyo identifsyex and visceralalterationcsa;vitatedorgans,includingthe brain,were evaluatedby dissection(1a0n)d; the brainwas free-handcrosssectioned(a singlecross-sectiownas made between the parietaland the frontal bones) and examined insitu.Fetalgross lesionswere preserved inneutral buffered10% formalinforpossiblefutureevaluation.
Allfetuseswere eviscerateds,tainedwithalizarirned S(")and evaluatedfor skeletalalterationsA.llskeletalpreparationswere storedin80% glycerinwith thymol crystalsadded to retardfungalgrowth. Late resorptionswere examined to the extentpossible.Representativephotographs offetalalterationasre availableinthe raw data.
Rabbitsthatabortedwere examined on the day the observationwas made. Pregnancy statusand uterinecontentswere recorded.Aborted fetuseswere examined to the extentpossible,usingthe same methods describedforfetuses. Uteriofapparentlynonpregnant does were stainedwith 10% ammonium sulfide to confirmthe absence of implantatiosnites(').
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G.9. StatisticaAlnalyses:
The followingschematic representsthe statisticanlalyses ofthe data:
lyl2eofTes?
1. ParametriCb
11.Nonr)arametricc
A. BartlettT'esstd
Significant at p:!@0.05
I Nonparametric
Not Significant AiioiyzooifzVpariance
I
F- Significant
atp:50.05
-7 Not Significant
A. Kruskal-WalliTsest (:!@75%ties)
F- I Significant I Not Significant
at p:50.05
Dunn's Test
B. Fisher'sExact Test (>75% ties)
I Dunneft's
Test
Ill.Test forProl2ortioDnata
VarianceTest forHomogeneity ofthe BinomialDistribution
---------------
a. Statisticalsliygnificanptrobabilitieasre reportedas eitheratp:50.05orp<-0.01. b. Used onlytoanalyze data withhomogeneity ofvariance. c. Proportiondata are notincludedinthiscategory. d. Test forhomogeneity ofvariance.
418-012:PAGE11-13
Clinicoablservatiaond otherproportidoantawere analyzedusingtheVariance Test forHomogeneity ofthe BinomialDistributi(o1n2)
Continuous data (e.g.,maternalbody weights,body weight changes, feed consumption valuesand liftearverages forpercentmale fetuses,percent resorbed conceptuses,fetalbody weights,fetalanomaly data and fetal ossificatiosnitedata)were analyzed usingBartieft'Tsest of Homogeneity of Variances(13)and the AnalysisofVariance(14,)when appropriate[i.e.B,artlett's Test was not significan(tp>0.05)].Ifthe AnalysisofVariance was significant (p:!@0.05D)u,nneft'sTeSt(15) was used toidentiftyhe statisticsailgnificancoefthe individuaglroups. Ifthe AnalysisofVariancewas notappropriate[i.e.B,artiefts Test was significan(tp@50.05)t]h,e Kruskal-WalliTsest(")was used, when less than or equal to75% tieswere present;when more than 75% tieswere present, Fishees ExactTest(")was used. Incases inwhich the Kruskal-WalliTsest was statisticaslilgynifican(tp-<0.05)D,unn's Method of MultipleComparisons(")was used to identiftyhe statisticsailgnificancoefthe individuaglroups.
Count data obtainedatCaesarean-sectioningwere evaluatedusingthe procedurespreviouslydescribedforthe Kruskal-WalliTsest(").
Group Irabbit8481 had a liftecronsistingoften dead fetuses.Because such occurrencescan abnormallyskew the distributiofnthe data,statisticaanlalyses were made withand withoutthe valuesforthisrabbitand lifterD.ata forthisliter were excluded from summarization and statisticaanlalyses;values are presented on the individuatlables.
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Ill. RESULTS
A. Mortalily,Abortions, Clinicaland Necropsy Observations isummary Table 1: IndividualData - Tables 3. 14 and I
A.1 Abortions
A totaloften rabbitsaborted;one inthe2.5 mg/kg/day dosage group and nine** inthe 3.75 mg/kglday dosage group. These abortionsoccurredafterthe completionofthe dosing period[on days 22, 24, 25 or28 ofgestation(DGs 22, 24, 25 or 28)]and were consideredrelatedtothe testarticlbeecause they occurredatdosage-dependent incidencesinthetwo highestdosage groups. All otherrabbitssurvivedto scheduled sacrifice.
2.5 mg/kg/day -
Doe 8517 abortedeightlateresorptionosn DG 25 and was sacrificedT.here were no adverse clinicaolbservationsbeforeaborting.This doe lostbody weight and feed consumption was severelyreduced afterDG 13. Necropsy revealed eightimplantationsitesand alltissuesappeared normal. Autolysisprecluded furtherevaluationofthe eightlateresorptions.
3.75 mg/kg/day
Doe 8534 abortedone dead fetuson DG 22 and was sacrificedT.here were no adverse clinicaolbservationsbeforeaborting.This doe generallylostweight and had severelyreduced feed consumption valuesthroughoutthe study. Necropsy revealedseven livefetusesinthe uterusand alltissuesappeared normal. All fetusesappeared normal fortheirdevelopmentalages atgross externaland soft tissueexamination. Fetuses 1,2,3,4,5,6,7 and 8 had not ossifiedpubes at skeletalexamination.
Doe 8537 abortedfivelateresorptionosn DG 25 and was sacrificedT.he only adverse clinicaolbservationbeforeabortionwas absent feces(DG 24). This doe generallylostweight and had severelyreducedfeed consumption values throughoutthe study. Necropsy revealedfiveimplantatiosnitesand alltissues appeared normal. Autolysisprecludedfurtherevaluationofthe fivelate resorptions.
Doe 8538 abortedeightlateresorptionosn DG 24 and was sacrificedT.here were no adverse clinicaolbservationsbeforeaborting.Thisdoe generallylost weight and had severelyreduced feed consumption valuesthroughoutthe study. Necropsy revealednine implantatiosnitesand alltissuesappeared normal. One conceptus was presumed cannibalizedand autolysisprecludedfurtherevaluation ofthe eightlateresorptions.
Significantdliyfferenftrom the vehiclecontrolgroup value (p:50.01).
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Doe 8539 abortedseven livefetuseson DG 24 and was sacrificedT.he only adverse clinicaolbservationbeforeabortionwas scantfeces (DGs 22 and 23). This doe generallylostweight and had severelyreduced feed consumption valuesthroughoutthe study. Necropsy revealedseven implantatiosnitesand all tissuesappeared normal. Allfetusesappeared normal fortheirdevelopmental ages atgross externaland softtissueexamination.Fetuses 1,2, 3,4, 5,6 and 7 had not ossifiedpubes and fetuses2 and 3 had notossifiedsternalcentraat skeletalexamination.
Doe 8540 abortedfourdead fetuseson DG 25 and was sacrificedT.here were no adverse clinicaolbservationsbeforeaborting.This doe lostweight and feed consumption values were severelyreduced afterDG 15. Necropsy revealed threelivefetuses,one dead fetusesand sixlateresorptionsinthe uterus.All tissuesappeared normal atnecropsy.Allfetusesappeared normal fortheir developmental ages atgross externaland softtissueexamination. Autolysis precludedfurtherevaluationofthesixlateresorptions.Fetuses 1,2,3, 5,7,8,9, and 10 had not ossifiedpubes and fetus2 had incompletelyossifiednasal bones and shortmaxillaeatskeletalexamination.
Doe 8542 abortedsixdead fetuseson DG 28 and was sacrificedT.he only adverse clinicaolbservationbeforeabortionwas scantfeces (DGs 21 to 23 and 27). This doe lostweightand had severelyreduced feed consumption after DG 18. Necropsy revealedeightimplantatiosnitesand alltissuesappeared normal. Two conceptuses were presumed cannibalizedand allsixaborted fetuseswere partiallcyannibalized.Allfetusesappeared normal atsofttissue examination.
Doe 8544 abortedninedead fetuseson DG 25 and was sacrificedT.he only adverse clinicaolbservationbeforeabortionwas scantfeces (DGs 19 to20 and 22 to24). AfterDG 12,thisdoe lostweightand had severelyreduced feed consumption untilsacrificeN.ecropsy revealednine implantatiosnitesand all tissuesappeared normal. Allfetusesappeared normal atgross externaland soft tissueexamination. Fetuses 1,2, 3,4, 5,6, 7,8 and 9 had not ossifiedpubes and fetus3 had not ossifiedsternalcentraatskeletalexamination.
Doe 8547 abortedeightlateresorptionosn DG 22 and was sacrificedT.he only adverse clinicaolbservationsbeforeabortionwere scantfeces (DG 18) and a red substance inthe cage pan (DG 21). Body weightsand feed consumption values were reduced DGs 11 to21. Necropsy revealedeightimplantatiosnitesand all tissuesappeared normal. Autolysisprecludedevaluationofthe eightlate resorptions.
Doe 8548 abortedone dead fetuson DG 25 and was sacrificedT.he only adverse clinicaolbservationbeforeabortionwas scant feces (DGs 21 and 23 to24). This doe lostweightafterDG 15 and feed consumption was severely reduced afterDG 17. Necropsy revealedseven livefetuses,one dead fetusand
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two lateresorptionisntheuterus.Alltissuesappeared normal atnecropsy.All fetusesappeared normalfortheirdevelopmentalages at grossexternaland soft tissueexamination.The lateresorptionasppeared normal atgross external examination;autolysipsrecludedfurtherevaluation.Fetuses1,2, 3,4,5,6, 7,8 and 11 had notossifiepdubes atskeletaelxamination.
A.2. ClinicalObservations
Increasednumbers ofdoes inthe3.75mg/kg/daydosage group had observationsofscantor no feces;theincidenceofscantfeceswas significant (p<0.01).Scantfecesalsooccurredinone and threerabbitsinthe 1.0and 2.5mg/kg/daydosage groupsrespectivelyT.he 1.0mg/kg/daydosage group rabbitalsohad softor liquifdeceson one day. One doe inthe3.75 mg/kg/day dosage group had redsubstanceinthecage pan associatedwithimpending abortion.
Allotheradverse clinicaolbservationsa,nd any statisticaslilgynifican(tP:!@0.01) increasesinthe incidencesoftheseobservationsw,ere consideredunrelatedto thetestarticlbeecause theincidenceswere notdosage-dependent. These observationsincludedlocalizeadlopeciaon the limbs,back and/orundersideand ungroomed coat.
A.3. Necropsy Observations
VViththeexceptionofpersistenatdverse clinicaolbservationsn,o additionaglross lesionswere identifieadt necropsy.
B. Maternal Body Weights and Body Weight Changes (Figure1: Summaries -Tables 3 and 4: IndividualData -Table 11
Maternalbody weightgainswere reduced or body weightlossesoccurredinthe 1.0,2.5 and 3.75 mg/kg/daydosage groups atmost tabulatedintervaldsuringthe dosage period;these reductionsor body weightlosseswere statistically significan(tp:50.0o5rp:50.01i)nthe3.75 mg/kg/daydosage group on DGs 10 to 13,13 to 16 and 16 to 19.
Duringthefirstthreedays ofthepostdosageperiod(DGs 21 to24),body weight gainscontinuedtobe reduced inthe1.0and 2.5mg/kg/daydosage groups; significan(tp@50.05b)ody weightlossoccurredinthe3.75 mg/kg/day dosage group duringthisperiod.As a resultofthese reductionsd,osage-dependent, significanbtody weightreductionsor body weightlosses(p:50.0o5r p:50.01) occurredinthe 1.0,2.5and 3.75 mg/kg/daydosage groups fortheentiredosage period(calculateads DGs 7 to21).
Dosage-dependent reductionsinbody weightgainsoccurredinthe 2.5and 3.75 mg/kg/daydosage groupsfortheentiregestatiopneriod(DGs 0 to29)and forthegestationperiodaftertheinitiatioofndosing(DGs 7 to29; significaantt
418-012:PAGE 111-4
p<0.01 inthe 2.5 mg/kg/day dosage group).Average body weightswere significantlryeduced (p.0-.@05 orp.-0@.01)on DGs 17 through 24 inthe 3.75 mg/kg/day dosage group,as compared withthe vehiclecontrolgroup values.
Body weightsand body weight gainswere unaffectedby the 0.1 mg/kg/day dosage of PFOS. The significanrteduction(p:50.05i)nbody weight gain inthe 0.1 mg/kg/day dosage group on DGs 10 to 13 was notconsideredtreatmentrelatedbecause itwas transientand notdosage-dependent.
C. Maternal Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables 5 and 6: IndividualData - Table 17)
Absolute (g/day)and relative(g/kg/day)feed consumption values were reduced duringthe dosage-period(afterDG 10) inthe 2.5and 3.75 mg/kg/day dosage groups;these reductionswere statisticaslilgynifican(tp:50.05orp:50.01)inone or both ofthese groups on DGs 13 to 16 (relativoenly),16 to 19 and 19 to21. Absoluteand relativfeeed consumption values continuedto be reduced inthese two groups duringthe postdosage period;the reductionswere generally statisticalsliygnifican(tp:!@0.0o5r p:!@0.01o)n DGs 21 to 24.
Refiectingthese effectsofthe testarticlea,bsoluteand relativfeeed consumption values were reduced or significantrleyduced (p:!@0.0o5rp:50.01)inthe 2.5 and 3.75 mg/kg/day dosage groups forthe entiredosage period(DGs 7 to 21),and the entireperiodafterthe initiatioofndosage (DGs 7 to 29).
Absolute and relativfeeed consumption valueswere unaffectedby the 1.0 mg/kg/day dosage of PFOS.
D. Caesarean -Sectioningand LifterObservations (Summaries -Tables 7 and 8: IndividualData -Tables 18 through 201
Pregnancy occurredin20 (90.9%),19 (86.4%),19 (86.4%),17 (77.3%)and 21 (95.4%) rabbitsineach dosage group. Caesarean-sectioningobservationson DG 29 were based on 20, 18, 19,16 and 12 pregnantrabbitsineach ofthefive respectivedosage groups. One and nine does aborted inthe 2.5 and 3.75 mg/kg/day dosage groups,respectivelyV.alues forone 0.1 mg/kg/day dosage group doe (8481)thathad a liftecronsistingoften dead fetuseswere excluded from data tabulatioannd statisticaanlalyses;thistotalliftedreath was consideredto be a non testarticlreelateds,pontaneous event.
Fetalbody weights(totalm,ale and female)were significantrleyduced (p5O.O5 and p-<0.01,respectivelyi)nthe 2.5and 3.75 mg/kg/day dosage groups, as compared tothe vehiclecontrolgroup values.There were no other biologicalliymportantor statisticaslilgynificadnitfferencesinthe liftearverages forcorporalutea,implantationsl,ivefetusesand earlyor lateresorptions.There were no does withallconceptuses resorbedand allplacentaeappeared normal.
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E. Fetal Alterations (Summaries - Tables 9 through 13, Individual Data Table 21)
Fetalalterationswere defined as: 1) malformations (irreversiblcehanges that occur at low incidencesinthisspeciesand strain)a;nd 2) variation(scommon findingsinthisspecies/straiann,d reversibldeelays or accelerationsin development). Liftearverages were calculatedforspecificfetalossificatiosnites as partofthe evaluationofthe degree offetalossification.
Fetalevaluationswere based on 175, 162, 152, 130 and 108 DG 29 Caesarean deliveredlivefetusesin20, 18, 19, 16 and 12 lifterisnthe 0 (Vehicle)0,.1,1.0, 2.5 and 3.75 mg/kg/day dosage groups,respectivelyA.llfetuseswere examined forgross externals,ofttissueand skeletalalterationasnd fetalossificatiosnite averages. Itwas also possibletoexamine theten dead fetusesfrom litte8r481 inthe 2.5 mg/kg/day dosage group forgross external,softtissueand skeletal alterationsT.he embryonic sacs ofallofthese fetusescontaineda dark red substance. One fetushad downward flexionofthe forelimbs,an observation associatedwithinuterocompression (skeletaolssificationnotaffected)a;nother fetushad angulatedhyoidalae,and two fetuseshad onlyten or sixcaudal vertebrae.T.he remainingsixfetusesappeared normal.
E.I. Summary of FetalAlterations(Summary -Table 10: IndividualData Table 22)
Combination of malformationsand variationrsesultedinthe followingincidences forfetalalterationsI.nthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivel1y4, (70.0%),11 (61.1%),9 (47.3%),4 (25.0%)and 8 (66.7%) lifterhsad fetuseswithone or more alterationosbserved. Inthese same respectivedosage groups,the totalnumbers offetuseswithany identified alterationwsere 25 (14.3%),25 (15.4%),14 (9.2%),5 (3.8%)**and 19 (17.6%). One or more alterationosccurredinaverages of 14.1%, 17.0%, 9.5%, 3.6% and 17.4% ofthe fetusesper lifteirnthe fiverespectivedosage groups. The significanrteduction(p<0.05)inthe totalnumber offetuseswithidentified alterationisnthe 2.5 mg/kg/day dosage group was notconsideredtreatmentrelatedbecause the expected response to a toxicantwould be an increase, ratherthan a decrease, inthe number of alterations.
Delays infetalossificatioanssociatedwiththe significantlryeduced (p@@0.05 or p::@0.01f)etalbody weights inthe 2.5and 3.75 mg/kg/day dosage groups were evidentas significanrteductions(p:!@0.0o5rp:50.01)inthe liftearverages for ossifiedsternalcentersinthe2.5 and 3.75 mg/kg/day dosage groups and significanrteductions(p@50.05or p:50.01)inthe liftearverages forossifiedhyoid and metacarpals and significanrteductions(p@50.01i)nthe liftearnd fetal incidencesof incompletelyossifiedpubes inthe 3.75 mg/kg/day dosage group.
Significantldyifferenftrom the vehiclecontrolgroup value (p@@0.01).
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Allotherfetalgross external,softtissueand skeletalalteration(smalformations and variationsw)ere consideredunrelatedto the testarticlbeecause: 1)the incidenceswere notdosage-dependent;and/or2) the incidenceswere within ranges observed historicalaltythe TestingFacility'.
E.2. FetalGross ExternalAlterations(Summa[y -Table 10; Individual 5-ata-Table 21)
E.2.a.Malformations The firsdtigitwas absent on both forelimbsforvehiclecontrolgroup fetus 8448-1. Skeletalexaminationofthisfetusrevealedabsent lstmedial and distal phalanges and lstmetacarpalon both forelimbs.No additionaallterations occurred inthisfet-us.
E.2.b.Variations One fetus(8473-6)ina 0.1 mg/kg/day dosage group liftearnd anotherfetus (8543-3)ina 3.75 mg/kg/day dosage group liftehrad downward flexedforepaws, an observationassociatedwithinuterocompression. Skeletalexaminationof fetus8543-3 revealeda variatioinnskullossificatio(nholeinthe parietablone). Fetus 8473-6 had no additionaallterations. E.3. FetalSoftTissue Alterations(Summary -Table 11,IndividualData
Table 21) E.3.a.Malformations No softtissuemalformationswere observed.
E.3.b.Variations E.3.b.l.Eyes One controldosage group fetus(8449-6)had a circumcornealhemorrhage ofthe lefetye, a variatiognenerallyattributabtloetrauma duringprocessing.Skeletal evaluationofthisfetusrevealedvariationisnossificationfthe skulland hyoid (irregulanrasal-frontsaultureand angulatedalae).
a. See APPENDIX E (HISTORICAL CONTROL DATA).
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E.3.b.2.Lungs
The intermediatelobe of the lungs was absent in2, 7**,1, 0 and 1 fetuses from 2,4, 1,0 and 1 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5ad 3.75 mg/kg/day dosage groups,respectivelyT.wo ofthe 0.1mg/kg/day dosage group fetuses(8476-8, 8483-4)alsohad fused 3rd and 4th sternalcentra.
The significanitncrease(p.-@0.0i1n)the fetalincidenceofthisobservationinthe 0.1 mg/kg/day dosage group was notconsideredrelatedtothe testarticle because: 1)thisvariatioinnlung development isfrequentinthisrabbitstrain 2) thefetaland lifteirncidencesare withinthe historicarlanges ofthe Testing Facilit3y), itwas not dosage-dependent;and 4) itwas not significantilnycreased forthe unitof measurement, the lifter.
E.4. FetalSkeletalAlterations(Summaries -Tables 12 and 13: Individual Data -Table 21)
E.4.a.Malformations
E.4.a.l.Thoracic Vertebrae/Ribs
Interrelatevdertebral/rimbalformationsor malformationsofonlythe ribsoccurred inone, threeand one fetusesinthe 0 (Vehicle)0,.1and 1.0mg/kg/day dosage groups,respectivelyT.hese types ofvertebral/rmiablformationsare relatively common atmaternallytoxicdosages inrabbitsand generallyconsideredto be secondary tomaternal stress(20)
Fetus 8452-1 inthe vehiclecontrolgroup had a lefthemivertebrapresentas the 3rdthoracicvertebraand'a spli2tnd lefrtib.This fetusalsohad asymmetric lst to 3rd sternalcentraand an angulatedhyoidala. Fetus 8476-1 inthe 0.1 mg/kg/day dosage group had fused centraofthe 11thand 12th thoracic vertebraeand a bifidcentrum ofthe 12ththoracicvertebra,and itsliftermate, fetus8476-7,had fused 5th and 6th ribsas the onlyalterationF.etus 8485-2 in the 0.1 mg/kg/day dosage group had a small leftarch ofthe 11ththoracic vertebra,fused leftcentraofthe 11thand 12th thoracicvertebraeand proximate bases ofthe 10th and 1lthleftribs.Fetus 8500-3 inthe 1.0 mg/kg/day dosage group had spli8tth rightand 7th leftribsas the onlyalteration.
E.4.a.2.Lumbar Vertebrae
Fetus 8500-8 had a lefthemivertebrapresentas the 1stlumbar vertebraand a bifidcentrum ofthe 2nd lumbar vertebra.
Significantdliyfferenftrom the vehiclecontrolgroup value (p:50.01).
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E.4.a.3. Metacarpals/Phalanges
The lst medial and distalphalanges and lstmetacarpal on both forelimbswere absent forvehiclecontrolgroup fetus8448-1 thathad missingfirsdtigitsat externalexamination.
E.4.b. Variations
E.4.b.i.Skull
Common small irregularitiiensossificatioonfthe skull(1[9t)hepresence of small ossificatiosniteswithinthe suturesor calvaria(nasal,frontaolr parietablones) and/orirregulasrhaping or fusionofthe bones] occurredin7, 9,3, 1* and 10** fetusesin6,7, 3, 1 and 3 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyI.rregulaorssificationfthe nasal bones (irregulanrasal-frontasluture,fused,internasalm,idlinesuturedisplaced and intranasalw)ere the most common ofthese smallirregularitiensskull ossificatioonc,curringin6, 9,3, 1 and 1 fetusesin5,7,3, 1 and 1 litterisnthe fiverespectivedosage groups.
The significanrteduction(p@50.05i)nthe fetalincidenceofvariationsinskull ossificatioinnthe 2.5 mg/kg/day dosage group was consideredunrelatedto the testarticlbeecause the expected effectofa toxicantwould be an increasein delayedskullossificatiorna,therthan a decrease. The significanitncrease (p@50.01i)nthe fetalincidenceofvariationisnskullossificatioinnthe 3.75 mg/kg/day dosage group was consideredtoreflectthe significantly increased(p@50.01f)etalincidenceof hole(s)inthe parietaalnd unrelatedtothe testarticlea,s discussed below. The fetalincidenceof nasalmidlinesuture displacedwas significantilnycreased(p:50.01i)nthe 0.1 mg/kg/day dosage group butwas consideredunrelatedtothe testarticlbeecause: 1)itwas not dosage-dependent; and 2) the litteirncidencewas not significantilnycreased.
The fetalincidenceofa hole inthe parietalwas significantilnycreased(p:@0.01i)n the 3.75 mg/kg/day dosage group. This increasewas consideredunrelatedto the testarticlbeecause the observationoccurredinseven fetusesfrom onlyone highdosage group lifte(r8543-1,-3,-4,-5,-6,-8 and -10),so the litteirncidence, the more relevantparamete@1),was not significantT.wo ofthe fetusesinthis liftearlsohad notossifiedpubes; allotherfetuseshad no additionaallterations
One 0.1 mg/kg/day dosage group fetus(8471-1)had unossifiedpremaxillaeas the only alteration.
Significantdliyfferenftrom the vehiclecontrolgroup value (p:@0.05). Significantdliyfferenftrom the vehiclecontrolgroup value (p@50.01).
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E.4.b.2. Hyoid
One or both alae of the hyoid were angulated in 10, 4, 7, 3 and 5 fetuses in6, 3, 3,2 and 3 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5and 3.75 mg/kg/day dosage groups,respectivelyO.ne fetus(8452-1)inthevehiclecontrolgroup alsohad vertebral/rmiablformationsand asymmetric lstto3rd sternalcentra,as previouslydescribed.
E.4.b.3.Vertebrae
E.4.b.3.a.Cervical
One 0.1 mg/kg/day dosage group fetushad unilateraolssificatioonfthe centrum ofthe 2nd cervicalvertebraeas the onlyalteration.
E.4.b.3.b.Thoracic
One vehiclecontrolgroup fetushad unilateraolssificationfthe centrum ofthe 5ththoracicvert'ebraeas the only alteration.
E.4.b.3.c.Lumbar
Bifidcentrum ofa lumbar vertebraoccurredinone fetusinthe 1.0and 3.75 mg/kg/day dosage groups,respectivelyF.etus 8500-8 inthe 1.0mg/kg/day dosage group also had a hemivertebrapresentas a lumbar vertebra,as previouslydescribed.The fetusinthe 3.75 mg/kg/day dosage group had no additionaallterations.
E.4.b.3.d.Caudal
A misaligned17thcaudal vertebraoccurredinone vehiclecontrolgroup fetusas the only alteration.
E.4.b.4.Ribs
Cervicalribswere presentatthe 7th cervicalvertebraforone fetusineach ofthe 0 (Vehicle)and 2.5 mg/kg/day dosage groups. No additionaallterationosccurred inthese fetuses.
Thickened areas intwo or three ribsoccurredinone vehiclecontrolgroup fetus (8456-4)and one 1.0 mg/kg/day dosage group fetus(8493-7).No other alterationosccurredinthese fetuses.
418-012:PAGE 111-10
E.4.b.5.Sternum
Fused 3rd and 4th sternalcentraoccurred as the only skeletalalterationin2 and 3 fetusesfrom differenltifterisnthe 0 (Vehiclea)nd 0.1 mg/kg/day dosage groups,respectively.
Fetus 8452-1 inthe vehiclecontrolgroup had asymmetric lstto 3rd sternal centra.This fetusalso had vertebral/rmiablformationsand an angulated hyoid ala,as previouslydescribed.
E.4.b.6.Pelvis
Four**fetusesfrom two** 3.75 mg/kg/day dosage group lifterhsad incompletely ossifiedpubes. Two ofthese fetusesalsohad a variationinskullossification (holeinparietala)s, describedpreviouslyT.he significanitncrease(p:50.01i)n thefetaland lifteirncidencesofthisobservationwas considereda testarticle relateddelay inossificatioannd to reflectthe significantrleyduced (p@50.01f)etal body weights inthisdosage group.
E.4.b.7.FetalOssificationSiteAverages
The average numbers ofossificatiosnitesper fetuswere significantrleyduced (p:50.05or p:50.01)inthe 3.75 mg/kg/day dosage group forhyoid,sternalcenters and metacarpals. The average numbers ofossifiedsternalcenterswere also significantrleyduced (p:@0.01)inthe 2.5mg/kg/day dosage group,as compared withthe vehiclecontrolgroup value.The valueswere below the ranges observed historicalaltythe TestingFacilityT.hese delays inossificatiownere consideredeffectsofthe testarticlaessociatedwiththe significantrleyduced (p:!@0.0o5rp:!@0.01f)etalbody weights inthese dosage groups.
The average numbers of ossificatisointesinthevertebrae(cervicalt,horacic, lumbar,sacraland caudal),ribs,sternum (manubrium and xiphoid)f,orelimbs (carpalsand phalanges)and hindlimbs(tarsalsm,etatarsalsand phalanges) occurredatsimilarincidencesinlifterisnalldosage groups and didnot significantdliyffer.
F. SatelliteRabbits (IndividualData - Tables 14 through 20)
Allrabbitsinthe satellitdeosage groups survived to scheduled sacrifice.There were no adverse clinicaolbservationsinthese does. Patternsofbody weight gainand feed consumption were comparable tothe rabbitsinthe main study at the same dosage levels.Only one rabbitinthe 3.75 mg/kg/day dosage group was notpregnantat Caesarean-sectioningon DG 21. Caesarean-sectioningand lifteprarameters were comparable among thefivedosage groups. There was nota reductioninfetalbody weightsatthe2.5 and 3.75 mg/kg/day dosages as
Significantdliyfferenftrom the vehiclecontrolgroup value (p:50.01).
418-012:PAGE 111-11
was observed forthe main studyrabbits.Alldoes appeared normal at necropsy. Average liverweightsforpregnantdoes were 140.5 29.2,127.1 15.2, 123.9 33.2,115.7 5.7 and 90.7 22.2 inthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyT.he data forrabbitsassigned to the satellitpeortionofthe studyare providedinindividuatlablesonly.
418-012:PAGE 111-12
REFERENCES:
1. U.S. Food and Drug Administratio(n1994).InternationaClonference on Harmonisation;Guidelineon detectionoftoxicittyo reproductionfor medicinalproducts.FederalRegister,September 22, 1994, Vol.59, No. 183.
2. U.S. Food and Drug AdministrationG.ood LaboratoryPractice Regulations;FinalRule. 21 CFR Part58.
3. Japanese Ministryof Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.
4. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decisionlrecommendation on compliance withprinciplesof good . laboratorypractice. OfficiaJlournal of the European Communities: Legislation3.2(No. L 315;28 October):1-17.
5. ChristianM,.S.,Hoberman, A.M. and Smith,T.H.F.(1982).Dosage-range study ofthe teratogenicpotentiaolfsuspensions oftrinitrofluorenone (TNF) administeredorallyto New Zealand White rabbits.Toxicologist 2(l):4(0#143).
6. ChristianM,.S. (1984).Reproductivetoxicitaynd teratologyevaluationsof naltrexone(Proceedingsof NaltrexoneSymposium, New York Academy of Sciences,November 7,1983),J.Clin.Psychiat.45(9):7-10.
7. Feussner,E.L.,Lightkep,G.E.,Hennesy, R.A.,Hoberman, A.M. and ChristianM,.S. (1992).A decade of rabbitfertilidtayta: Study of historical controlanimals. Teratology46(4):349-365.
8. Instituteof Laboratory Animal Resources (1996). Guide forthe Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
9. Salewski,E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationssteliaemn Uterus der Ratte.Arch. Pathol.Exp. Pharmakol. 247:367.
10. Staples,R.E. (1974).Detectionofvisceralalterationisnmammalian fetuses.Teratology9(3):A37-38.
11. Staples,R.E. and Schnell,V.L.(1964).Refinement inrapidclearing technique inthe KOH-alizarinred S method forfetalbone. StainTechnol. 39:61-63.
418-012: PAG E 1111-3
12. Snedecor, G.W. and Cochran,W.G. (1967).Variancetestfor homogeneity ofthe binomialdistributioSnt.atisticMaelthods, 6th Edition, Iowa State UniversityPress,Ames, pp.240-241.
13. Sokal,R.R. and Rohlf,F.J.(1969).Bartlettt'esstof homogeneity of variances.Biometry,W.H. Freeman and Co.,San Francisco,pp.370-371.
14. Snedecor, G.W. and Cochran,W.G. (1967).AnalysisofVariance. StatisticMaelthods, 6th EditionI,owa StateUniversitPyress,Ames, pp. 258-275.
15. Dunneft,C.W. (1955).A multiplecomparison procedure forcomparing severaltreatmentswitha control.J.Amer. Stat.Assoc. 50:1096-1129.
16. Sokal, R.R. and Rohif,F.J.(1969). Kruskal-WallisTest. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389.
17. Siegel,S. (1956). Nonparamettic Statisticsforthe Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
18. Dunn, O.J. (1964).Multiplceomparisons usingrank sums. Technometrics 6(3):241-252.
19. ChristianM,.S.,McCarty, R.J.,Cox-Sica,D.K. and Cao, C.P. (1987). Recent increasesinthe incidencesofskull,lung and ribalterationisn vehiclecontrolNew Zealand White rabbits.J.Amer. Col.Toxicol. 6(4):562(#126).
20. Khera, K.S.(1985).MaternaltoxicityA: possibleetiologicfaalctorin embryo-fetaldeaths and fetalmalformationsofrodent-rabbistpecies. Teratology31:129-153.
APPENDIX A REPORT FIGURE
MATERNAL BODY WEIGHTS
Figure 1
4.00
3.90 -
3.80-
&3.70 r
3.60 -
3.50 -
3.40
3.31D
o
------
- -----
T
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
DAY OF GESTATION
APPENDIX B REPORT TABLES
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 1 (PAGE 1): CLINICAL AND NECROPSY OBSERVATIONS - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
1
11
111
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
506/ 22
506/ 22
506/ 22
502/ 22
ABORTED
0
0
0
lb
SCANT FECES
NO FECES
RED SUBSTANCE IN CAGE PAN
LOCALIZED ALOPECIA:
TOTAL LIMBS BACK UNDERSIDE
UNGROOMED COAT
0/ 0
0/ 0
0/ 0
0/ 0 0/ 0 0/ 0 0/ 0
0/ 0
0/ 0
0/ 0
0/ 0
ll/ 3** 8/ 2 3/ 1 0/ 0
4/ 2
2/ 1
0/ 0
o/ o
14/ 5** 7/ 2 6/ 2 1/ 1
3/ 1
S/ 3
0/ 0
0/ 0
4/ 2 3/ 2 1/ 1 0/ 0
5/ 1
SOFT OR LIQUID FECES
o/ o
0/ 0
1/ 1
o/ o
WITH THE EXCEPTION OF PERSISTENT ADVERSE CLINICAL OBSERVATIONS, NO ADDITIONAL GROSS LESIONS WERE IDENTIFIED -----------------------------------------------------------------------------------------------------------------
STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF
MAXIMUM POSSIBLE INCIDENCE - (DAYS x RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP
NIN = TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS WITH OBSERVATION,
a. Dosage occurred on days 7 through 20 of presumed gestation.
b. Doe 8517 aborted on day 25 of gestation.
c. Doe 8534 aborted on day 22 of gestation.
d. Doe 8537 aborted on day 25 of gestation.
e. Doe 8538 aborted on day 24 of gestation.
f. Doe 8539 aborted on day 24 of gestation.
g. Doe 8540 aborted on day 25 of gestation.
h. Doe 8542 aborted on day 28 of gestation.
i. Doe 8544 aborted on day 25 of gestation.
J. Doe 8547 aborted on day 22 of gestation.
k. Doe 8548 aborted on day 25 of gestation.
Significantly different from the vehicle control group value (p@S0.01).
RABBITS ON DAYS
WITH OBSERVATIONS. 7 THROUGH 29 OF PRES
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 2 (PAGE 1): UTERINE CONTENTS AND LITTER DATA FOR INDIVIDUAL RAJ3BITS THAT ABORTED
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
CORPORA LUTEA
IMPLANTATIONS
FETUSES b
DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH
R
L
T
R
L
T
R
L
A
T
R
----------------------------------------------------------------------------------------------------------------
I 0 (VEHICLE)
0.1
III 1.0
IV
2.5
8517
ABORTED ON DAY 25
6
3
9
5
3
8
0
0
0
0
0
OF GESTATION ----------------------------------------------------------------------------------------------------------------
R - RIGHT
L - LEFT A - ABORTED
T = TOTAL
a. Dosage occurred on days 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages.
c. Late resorption unless otherWiBe noted.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBE
TABLE 2 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR INDIVIDUAL RABBITS THAT ABORTED
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
CORPORA LUTEA
IMPLANTATIONS
FETUSES b
DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH
R
L
T
R
L
T
R
L
A
T
R
---------------------------------------------------------------------------------------------------------------
v
3.75
8534
ABORTED ON DAY 22 OF GESTATION
5
4
9
5
3
8
5
2
1
8
0
8537
ABORTED ON DAY 25 OF GESTATION
4
2
6
3
2
5
0
0
0
0
0
8538
ABORTED ON DAY 24 OF GESTATION
5
5
10
5
4
9
0
0
0
0
0
8539
ABORTED ON DAY 24 OF GESTATION
4
3
7
4
3
7
0
0
7
7
0
8540
ABORTED ON DAY 25 OF GESTATION
6
8
14
6
8
14
0
4
4
8
2
8542
ABORTED ON DAY 28 OF GESTATION
4
5
9
4
4
8
0
0
6
6e
0
8544
ABORTED ON DAY 25 OF GESTATION
4
5
9
4
5
9
0
0
9
9
0
8547
ABORTED ON DAY 22 OF GESTATION
5
3
a
5
3
8
0
0
0
0
0
8548
ABORTED ON DAY 25
5
7
12
4
7
11
3
5
1
9
0
OF GESTATION
---------------------------------------------------------------------------------------------------------------
R = RIGHT
L = LEFT A = A.BORTED T = TOTAL
a. Dosage occurred on days 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages. C. Late resorptions unless otherwise noted.
d. One aborted conceptus was presumed to have been cannibalized. e. Two aborted conceptuses were presumed to have been cannibalized.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 3 (PAGE 1): MATERNAL BODY WEIGHTS - SUMMARY
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT
N
20
19
19
17
INCLUDED IN ANALYSES
N
20
18b
19
17
MATERNAL BODY WEIGHT (KG)
DAY
0
MEAN+S.D.
3.34 + 0.26
3.33 + 0.27
3.36 + 0.27
3.38 + 0.23
DAY
7
MEA.N+S.D.
3.38 + 0.29
3.43 + 0.22
3.47 + 0.23
3.51 + 0.23
DAY
a
MEAN+S.D.
3.42 + 0.30
3.48 + 0.23
3.50 + 0.22
3.54 + 0.25
DAY
9
MEAN+S.D.
3.43 + 0.30
3.50 + 0.23
3.49 + 0.22
3.56 + 0.24
DAY 10
MEAN+S.D.
3.45 + 0.27
3.52 + 0.23
3.50 + 0.24
3.56 + 0.25
DAY 11
MEAN+S.D.
3.50 + 0.27
3.52 + 0.25
3.53 + 0.24
3.56 + 0.24
DAY 12
MEAN+S.D.
3.53 + 0.29
3.54 + 0.28
3.56 + 0.24
3.58 + 0.28
DAY 13
MEAN+S.D.
3.54 + 0.29
3.55 + 0.25
3.60 + 0.24
3.61 + 0.27
DAY 14
MEAN+S.D.
3.59 + 0.30
3.60 + 0.25
3.64 + 0.26
3.63 + 0.26
DAY 15
MEAN+S.D.
3.62 + 0.29
3.62 + 0.25
3.66 + 0.26
3.67 + 0.28
DAY 16
MEAN+S.D.
3.65 + 0.26
3.64 + 0.27
3.69 + 0.25
3.67 + 0.29
DAY 17
MEAN+S.D.
3.66 + 0.27
3.65 + 0.24
3.69 + 0.25
3.65 + 0.28
DAY 18
MEAN+S.D.
3.69 + 0.28
3.69 + 0.24
3.71 + 0.25
3.66 + 0.29
.DAY 19
MEAN+S.D.
3.72 + 0.28
3.69 + 0.25
3.72 + 0.24
3.67 + 0.29
DAY 20
MEAN+S.D.
3.74 + 0.28
3.73 + 0.24
3.75 + 0.24
3.69 + 0.31
---------------------------------------------------------------------------------------------------------------
DAY - DAY OF GESTATION a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for doe 8481, which had a litter that consisted of ten dead fetuses
Significantly different from the vehicle control group value (p@S0.05). Significantly different from the vehicle control group value (p@0.01).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NTIMBEF
TABLE 3 (PACE 2): MATERNAL BODY WEIGHTS - SUMMARY
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (Mr,/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
---------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT
N
20
19
19
17
INCLUDED IN ANALYSES
N
20
18b
19
17
14ATERNAL BODY WEIGHT (KG)
DAY 21
MEAN+S.D.
3.77 + 0.28
3.76 + 0.24
3.77 + 0.24
3.71 + 0.31
DAY 22
MEAN+S.D.
3.79 + 0.29
3.79 + 0.25
3.80 + 0.25
3.71 + 0.33
DAY 23
MEAN+S.D.
3.82 + 0.30
3.82 + 0.25
3.82 + 0.24
3.72 + 0.33
DAY 24
MEAN+S.D.
3.85 + 0.31
3.85 + 0.28
3.84 + 0.26
3.74 + 0.35
DAY 25
MEAN+S.D.
3.88 + 0.32
3.86 + 0.28
3.88 + 0.26
3.81 + 0.29
[ 16]c
DAY 26
MEAN+S.D.
3.91 + 0.34
3.88 + 0.29
3.88 + 0.26
3.80 + 0.29
[ 16]c
DAY 27
MEAN+S.D.
3.91 + 0.35
3.89 + 0.30
3.88 + 0.25
3.80 + 0.29
f 16)c
DAY 28
MEAN+S.D.
3.91 + 0.35
3.93 + 0.30
3.90 + 0.26
3.82 + 0.28
1 16]c
DAY 29
MEAN+S.D.
3.94 + 0.36
3.93 + 0.30
3.92 + 0.26
3.86 + 0.28
16]c --------------------------------------------------------------------------------------------------------------
DAY [I a. b. c.
= DAY OF GESTATION = NUMBER OF VALUES AVERAGED Dosage occurred on days 7 through 20 of gestation. Excludes values for doe 8481, which had a litter that consisted of ten dead Excludes values for rabbits that aborted. Significantly different from the vehicle control group value (p@E0.01).
fetuses.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 4 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - SUMMARY
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT
N
20
19
19
17
INCLUDED IN ANALYSES
N
20
lob
19
17
MATERNAL BODY WEIGHT CHANGE
(KG)
DAYS 0 - 7
MEAN+S.D.
+0.04 + 0.13
+0.10 + 0.13
+0.11 + 0.08
+0.12 + 0.08
DAYS 7 - 10
MEAN+S.D.
+0.07 + 0.07
+0.08 + 0.06
+0.03 + 0.06
+0.05 + 0.06
DAYS 10 - 13
MEAN+S.D.
+0.09 + 0.08
+0.03 + 0.07*
+0.10 + 0.05
+0.06 + 0.07
DAYS 13 - 16
MEAN+S.D.
+0.11 + 0.09
+0.09 + 0.07
+0.08 + 0.05
+0.05 + 0.09
DAYS 16 - 19
MEAN+S.D.
+0.06 + 0.09
+0.05 + 0.08
+0.03 + 0.06
+0.00 + 0.06
DAYS 19 - 21
MEAN+S.D.
+0.05 + 0.03
+0.07 + 0.07
+0.05 + 0.04
+0.04 + 0.03
DAYS 21 - 24
MEAN+S.D.
+0.09 + 0.05
+0.09 + 0.06
+0.07 + 0.05
+0.04 + 0.08
DAYS 24 - 29 DAYS 7 - 21
MEAN+S.D. MEAN+S.D.
+0.08 + 0.11 +0.38 + 0.10
+0.08 + 0.09 +0.33 + 0.09
+0.08 + 0.08 +0.30 + 0.08*
+0.06 + 0.14 [ 16]c
+0.20 + 0.17**
DAYS 21 - 29 DAYS 7 - 29
MEAN+S.D. MEAN+S.D.
+0.17 + 0.13 +0.55 + 0.18
+0.17 + 0.12 +0.50 + 0.16
+0.15 + 0.07 +0.45 + 0.12
+0.11 + 0.15 t 16)c
+0.34 + 0.16**
DAYS 0 - 29
MEAN+S.D.
+0.59 + 0.21
+0.60 + 0.13
+0.56 + 0.13
[ 16)c +0.46 + 0.14
( 16]c ----------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION ( I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for doe 8481, which had a litter that consisted of ten dead C. Excludes values for rabbits that aborted.
Significantly different from the vehicle control group value (p<0.05). Significantly different from the vehicle control group value (p@io.01).
fetuses.
PROTOCOL 418-012! ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 5 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT
N
20
19
19
17
INCLUDED IN ANALYSES
N
20
18b
19
17
MATERNAL FEED CONSUMPTION (G/DAY)
DAYS 7 - 10 DAYS 10 - 13
MEAN+S.D. MEAN+S.D.
142.6 + 50.4 149.7 + 35.7
171.3 + 19.1 142.0 + 47.8
161.2 + 22.8 1 lelc
158.8 + 24.0
161.2 + 18.9 142.6 + 35.9
DAYS 13 - 16
MEAN+S.D.
162.3 + 24.5
158.1 + 35.7
162.8 + 36.6
143.0 + 45.8
DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 24
MEAN+S.D. MEAN+S.D. MEAN+S.D.
177.5 + 11.6 173.6 + 19.9 160.9 + 32.5
175.2 + 12.8 [ 17]c
180.1 + 7.0 [ 17]C
165.2 + 20.7
163.0 + 33.7 170.2 + 20.5 160.2 + 25.3
145.6 + 43.4** 146.1 + 45.5 130.4 + 41.0
DAYS 24 - 29
MEAN+S.D.
124.5 + 40.5
135.5 + 38.7
131.3 + 33.6
112.8 + 37.2
[ 16]d
DAYS 7 - 21
MEAN+S.D.
160.2 + 20.5
163.3 + 20.8
162.9 + 20.7
147.8 + 28.8
[ 17]c
DAYS 21 - 29
MEAN+S.D.
138.4 + 34.8
146.9 + 29.2
142.1 + 24.8
120.7 + 29.3
( 16]d
DAYS 7 - 29
MEAN+S.D.
152.4 + 21.7
157.8 + 21.2
155.3 + 16.6
141.0 + 20.5
t 16]d ----------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION [ I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for doe 8481, which had a litter that consisted of ten c. Excludes values that were associated with spillage or wet feed. d. Excludes values for rabbits that aborted. ** Significantly different from the vehicle control group value (plO.01).
dead
fetuses.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 6 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
---------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT
N
20
19
19
17
INCLUDED IN ANALYSES
N
20
18b
19
17
MATERNAL FEED CONSUMPTION (G/KG/DAY)
DAYS 7 - 10 DAYS 10 - 13
MEAN+S.D. MEAN+S.D.
41.4 + 14.5 42.5 + 9.1
49.1 + 4.2 39.9 + 12.8
46.0 + 6.5 [ 18]c
44.8 + 6.9
45.5 + 4.5 39.6 + 8.7
DAYS 13 - 16
MEAN+S.D.
45.1 + 6.5
43.7 + 9.1
44.5 + 9.7
39.0 + 11.8
DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 24
MEAN+S.D. MEAN+S.D. MEAN+S.D.
48.4 + 3.9 46.6 + 5.8 42.3 + 8.0
47.8 + 3.7 ( 17]c
48.5 + 3.4 [ 17]c
43.3 + 4.2
44.1 + 9.4 45.5 + 5.7 42.1 + 6.6
39.3 + 11.2** 39.1 + 11.6* 34.6 + 9.3*
DAYS 24 - 29
MEAN+S.D.
31.7 + 9.0
34.5 + 8.6
33.9 + 8.9
29.5 + 9.3
( 16]d
DAYS 7 - 21
MEAN+S.D.
44.8 + 5.1
45.4 + 4.6
45.1 + 5.8
40.6 + 6.4
[ 17]C
DAYS 21 - 29
MEAN+S.D.
35.7 + 7.8
37.9 + 6.0
36.9 + 6.6
31.7 + 6.8
( 16]d
DAYS 7 - 29
MEAN+S.D.
41.4 + 4.9
42.7 + 4.1
42.0 + 4.6
38.1 + 4.0*
[ 16]d ---------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION [ I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for doe 8481, which had a litter that consisted of ten dead c. Excludes values that were associated with spillage or wet feed. d. Excludes values for rabbits that aborted.
Significantly different from the vehicle control group value (p@S0.05). Significantly different from the vehicle control group value (p<0.01).
fetuses.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER-
TABLE 7 (PAGE 1): CAESAREAN-SECTIONING
OBSERVATIONS - SUMMARY
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
22
22
22
22
PREGNANT ABORTED
N (1;) N(t)
20( 90.9) 0( 0.0)
19( 86.4) 0( 0.0)
19( 86.4) o( o.o)
17( 77.3) 1( 5.9)
RABBITS PREGNANT AND
CAESAREAN-SECTIONED
ON DAY 29 OF GESTATION
N
20
19
19
16
INCLUDED IN ANALYSES
N
20
18b
19
16
CORPORA LUTEA
MEAN+S.D.
10.B + 2.5
10.9 + 2.5
10.5 + 2.3
10.4 + 2.2
IMPLANTATIONS
MEAN+S.D.
9.0 + 2.2
9.1 + 1.9
8.4 + 1.8
8.4 + 1.8
LITTER SIZES
MEAN+S.D.
8.8 + 2.2
9.0 + 2.0
8.0 + 1.9
8.1 + 1.8
LIVE FETUSES
N MEAN+S.D.
175 8.8 + 2.2
162 9.0 + 2.0
152 8.0 + 1.9
130 8.1 + 1.6
DEAD FETUSES RESORPTIONS
N MEAN+S.D.
0 0.2 + 0.4
0 0.1 + 0.3
0 0.4 + 0.8
0 0.2 + 0.4
EARLY RESORPTIONS
N MEAN+S.D.
3 0.2 + 0.4
2 0.1 + 0.3
2 0.1 + 0.3
2 0.1 + 0.3
LATE RESORPTIONS
N MEAN+S.D.
1 0.0 + 0.2
0 0.0 + 0.0
5 0.3 + 0.7
2 0.1 + 0.3
DOES WITH ANY RESORPTIONS
N(t)
4( 20.0)
2( 11.1)
5( 26.3)
4( 25.0)
DOES WITH ALL CONCEPTUSES
RESORBED
N(Pi)
0
0
0
0
DOES WITH VIABLE FETUSES
N(%)
20(100.0)
18(loo.0)
19(100.0)
16(loo.0)
PLACENTAE APPEARED NORMAL
N(!k)
20(100.0)
18(loo.0)
19(100.0)
16(100.0)
----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
b. Excludes values for doe 8481, which had a litter that consisted of ten dead fetuses.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PPOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 8 (PAGE 1): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
1
11
111
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS WITH ONE OR
MORE LIVE FETUSES
N
20
is
19
16
IMPLANTATIONS
MEAN+S.D.
9.0 + 2.2
9.1 + 1.9
8.4 + 1.8
8.4 + 1.8
LIVE FETUSES
N MEAN+S.D.
175 8.8 + 2.2
162 9.0 + 2.0
152 8.0 + 1.9
130 8.1 + 1.8
LIVE MALE FETUSES
N
87
74
71
66
% LIVE MALE FETUSES/LITTER
MEAN+S.D.
50.4 + 15.1
45.8 + 19.2
45.6 + 18.0
50.2 + 14.1
LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER
MEAN+S.D.
44.15 + 4.50
41.67 + 3.28
42.37 + 4.34
39.89 + 4.33*
MALE FETUSES
MEAN+S.D.
44.50 + 4.90
41.82 + 2.77
43.12 + 5.13
40.56 + 4.52*
FEMALE FETUSES
MEAN+S.D.
43.86 + 4.84
41.36 + 4.09
41.94 + 4.90
38.98 + 5.28*
t RESORBED
CONCEPTUSES/LITTER
MEAN+S.D.
2.1 + 4.4
1.4 + 4.1
4.4 + 9.4
3.1 + 5.7
---------------------------------------------------------------------------------------------------------------
[ I = NUMBER OF VALUES AVERAGED
a. Dosage occurred on days 7 through 20 of gestation. b. Litter 8546 had no male fetuses.
Significantly different from the vehicle control group value (p<0.05).
Significantly different from the vehicle control group value (p@S0.01).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 9 (PAGE 1): FETAL ALTERATIONS - SUMMARY
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
---------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
10b
0
0
---------------------------------------------------------------------------------------------------------------
LITTERS WITH FETUSES WITH
ANY ALTERATION OBSERVED
N(t)
14( 70.0)
ll( 61.1)
9( 47.4)
4( 25.0)
FETUSES WITH ANY ALTERATION OBSERVED
N(Pi)
25( 14.3)
25( 15.4)
14( 9.2)
5( 3.8)**
FETUSES WITH ANY
ALTERATION/LITTER
MEAN+S.D.
14.1 + 12.9
17.0 + 18.2
9.5 + 11.7
3.6 + 7.0
---------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
b. Litter 8481 consisted of ten dead fetuses; values were excluded from group averageb and statistical
observations
for this litter are cited on Table 21.
analys
Significantly
different
from the vehicle control group value (p@@0.01).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 10 (PACE 1): FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
---------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
162
152
130
LIVE
N
175
162
152
130
DEAD
N
0
lob
0
0
---------------------------------------------------------------------------------------------------------------
FORELIMBS:
FLEXED DOWNWARD
LITTER INCIDENCE
FETAL INCIDENCE
N(t) N(%)
o( o.o) 0( 0.0)
1( 5.3) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
FORELIMB: POLLEX ABSENT
LITTER INCIDENCE
N(t)
1( 5.0)
o( o.o)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(t)
1( 0.6)
0( 0.0)
0( 0.0)
o( o.o)
---------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
b. Litter 8481 consisted of ten dead fetuses; values were excluded from group averages and statistical analys
observations for this litter are cited on Table 21.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 11 (PAGE 1): FETAL SOFT TISSUE ALTERATIONS - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
lob
0
0
-----------------------------------------------------------------------------------------------------------------
EYES: CIRCUMCORNEAL LITTER INCIDENCE FETAL INCIDENCE
HEMORRHAGE N(t) N(t)
1( 5.0) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
LUNGS: INTERMEDIATE LOBE ABSENT
LITTER INCIDENCE
N(t)
2( 10.0)
4( 22.2)
1( 5.3)
0( 0.0)
FETAL INCIDENCE
N(%)
2( 1.1)
7( 4.3)**
1( 0.6)
0( 0.0)
-----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
b. Litter 8481 consisted of ten dead fetuses; values were excluded from group averages and statistical analyses
observations for this litter are cited on Table 21.
Significantly different from the vehicle control group value (pS0.01).
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 12 (PAGE 1): FETAL SKELETAL OBSERVATIONS - SUMMARY (See footnotes on the last page of this table.)
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
17S
162
152
130
DEAD
N
0
lob
0
0
----------------------------------------------------------------------------------------------------------------
SKULL - IRREGULAR OSSIFICATION:C
(SUMMARIZATION OF ALL IRREGULAR OSSIFICATION OF THE SKULL d; INDIVIDUAL SUBCATEGORIES
CITED BELOW)
LITTER INCIDENCE FETAL INCIDENCE
N(t) N(t)
6( 30.0) 7( 4.0)
7( 38.9) 9( 5.6)
3( 15.8) 3( 2.0)
1( 6.2) 1( 0.8)*
SKULL: NASAL(S), IRREGULAR (SUMMARIZATION OF FUSED; MIDLINE SUTURE DISPLACED; LITTER INCIDENCE FETAL INCIDENCE
OSSIFICATION
IRREGULAR StYrURE;
INTRANASAL; INTERNASAL)
N(!k)
5( 25.0)
N(!k)
6( 3.4)
SKULL: NASAL - FRONTAL, LITTER INCIDENCE FETAL INCIDENCE
IRREGULAR N(t) N(t)
SUTURE 1( 1(
5.0) 0.6)f
7( 38.9) 9( 5.6)
2( 11.1) 2( 1.2)
3( 15.8) 3( 2.0)
0( 0.0) 0( 0.0)
1( 6.2) 1( 0.8)
0( 0.0) 0( 0.0)
SKULL: NASALS, FUSED LITTER INCIDENCE FETAL INCIDENCE
N(t) N(%)
1( 5-0) 1( 0-6)
0( 0-0) o( o.o)
0( 0-0) 0( 0.0)
0( 0.0) 0( 0.0)
SKULL: NASALS, CONTAINED LITTER INCIDENCE FETAL INCIDENCE
AN INTERNASAL N(t) N(t)
1( 5.0) 1( 0-6)
2( 11.1) 3( 1.8)
0( 0.0) 0( 0.0)
1( 6.2) 1( 0.8)
SKULL: NASALS, MIDLINE LITTER INCIDENCE FETAL INCIDENCE
SUTURE DISPLACED
N(t)
o(
N(t)
0(
o.o) 0-0)
3( 16.7) 4( 2.5)**
1( 5.3) 1( 0.6)
o( o.o) 0( 0.0)
SKULL: NASAL, CONTAINED AN INTRANASAL
LITTER INCIDENCE
N(t)
3( 15.0)
0( 0.0)
2( 10.5)
0( 0.0)
FETAL INCIDENCE
N(t)
3( 1.7)
o( o.o)
2( 1.3)
0( 0.0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-012:
OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 12 (PAGE 2): FETAL SKELETAL OBSERVATIONS - SUMMARY (See footnotes on the last page of this table.)
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
10b
0
0
----------------------------------------------------------------------------------------------------------------
SKULL: FRONTALS, CONTAINED LITTER INCIDENCE FETAL INCIDENCE
AN INTERFRONTAL
N(ts)
1(
N(t)
1(
5.0) 0.6)
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
0( 0.0) 0( 0-0)
SKULL: PARIETAL, CONTAINED LITTER INCIDENCE FETAL INCIDENCE
A HOLE N(t) N(t)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
SKULL - OTHER ALTERATIONS:B HYOID: ALA, ANGULATED LITTER INCIDENCE FETAL INCIDENCE
N(t) N(%)
6( 30.0) 10( 5.7)f,g
3( 16.7) 4( 2.5)
3( 15.8) 7( 4.6)
2( 12.5) 3( 2.3)
SKULL: PREMA-XILLAE, LITTER INCIDENCE FETAL INCIDENCE
NOT OSSIFIED N(!k) N(t)
0( 0.0) 0( 0.0)
1( 5.6) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
CERVICAL VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CERVICAL
RIB PRESENT AT 7TH CERVICAL
N(t)
1( 5.0)
N(%)
1( 0.6)
VERTEBRA 0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 6.2) 1( 0.8)
CERVICAL VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRUM,
UNILATERAL N(t) N(t)
OSSIFICATION 0( 0.0) 0( 0.0)
1( 5.6) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRUM,
BIFID N(%) N(%)
0( 0.0) 0( 0.0)
1( 5.6) 1( 0.6)h
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
THORACIC VERTEBRAE.
CENTPA, FUSED
LITTER INCIDENCE
N(%)
0( 0.0)
2( 11.1)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(!k)
0( 0.0)
2( 1.2)h,i
0( 0.0)
o( o.o)
---------------------------------------------------------------------------------------------------------------
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 12 (PAGE 3): FETAL SKELETAL OBSERVATIONS - SUMMARY (See footnotes on the last page of this table.)
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
lob
0
0
----------------------------------------------------------------------------------------------------------------
THORACIC VERTEBRAE:
LITTER INCIDENCE FETAL INCIDENCE
HEMIVERTEBRA N(t) N(t)
1( 5.0) 1( 0.6)g
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
ARCH,
SMALL N(t) N(t)
0( 0.0) 0( 0-0)
1( 5.6) 1( 0.6)i
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRUM,
UNILATERAL N(t) N(!k)
OSSIFICATION 1( 5.0) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
LUMBAR VERTEBRAE: CENTRUM, LITTER INCIDENCE FETAL INCIDENCE
BIFID N(4) N(t)
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
1( 5.3) 1( 0.6)j
0( 0.0) 0( 0.0)
LUMBAR VERTEBRAE:
HEMIVERTEBRA
LITTER INCIDENCE
FETAL INCIDENCE
N(%) N(%)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 5.3) 1( 0.6)j
0( 0.0) 0( 0.0)
CAUDAL VERTEBRAE: MISALIGNED LITTER INCIDENCE FETAL INCIDENCE
N(t) N(%)
1( 5.0) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
RIBS: FUSED LITTER INCIDENCE
FETAL INCIDENCE
N(!k) N(%)
0( 0.0) 0( 0.0)
1( 5.6) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
RIBS: SPLIT
LITTER INCIDENCE
N(%)
1( 5.0)
0( 0.0)
1( 5.3)
0( 0.0)
FETAL INCIDENCE
N(%)
1( 0.6)g
0( 0.0)
1( 0.6)
0( 0.0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 12 (PAGE 4): FETAL SKELETAL OBSERVATIONS - SUMMARY (See footnotes on the last page of this table.)
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
20
19b
19
16
FETUSES EVALUATED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
lob
0
0
----------------------------------------------------------------------------------------------------------------
RIBS: THICKENED LITTER INCIDENCE FETAL INCIDENCE
N(t) N(t)
1( 5.0) 1( 0.6)
o( o.o) 0( 0.0)
1( 5.3) 1( 0.6)
0( 0.0) 0( 0.0)
RIBS: PROXIMATE LITTER INCIDENCE FETAL INCIDENCE
STERNAL CENTRA: FUSED LITTER INCIDENCE FETAL INCIDENCE
N(!k) N(t)
N(t) N(li)
0( 0.0) 0( 0.0)
2( 10.0) 2( 1.1)
1( 5.6) 1( 0.6)
3( 16.7) 3( 1.8)
o( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
STERNAL CENTRA: ASYMMETRIC LITTER INCIDENCE FETAL INCIDENCE
N(t) N(!k)
1( 5.0) 1( 0.6)g
0( 0.0) o( o.o)
0( 0.0) 0( 0.0)
o( o.o) 0( 0.0)
METACARPALS:
FORELIMB,
LITTER INCIDENCE
FETAL INCIDENCE
4 METACARPALS N(t)
PRESENT 1( 5.0) 1( 0.6)e
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
FOREDIGITS:
FORELIMB,
LITTER INCIDENCE
FETAL INCIDENCE
4 DIGITS PRESENT N(t) N(t)
1( 5.0) 1( 0.6)e
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
FOREPHALANGES:
FORELIMB,
LITTER INCIDENCE
FETAL INCIDENCE
1ST MEDIAL N(t) N(t)
AND DISTAL PHALANGES 1( 5.0) 1( 0.6)e
ABSENT 0( 0.0) o( o.o)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
PELVIS: PUBIS, NOT OSSIFIED
LITTER INCIDENCE
N(%)
o( o.o)
o( o.o)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(t)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBE
TABLE 12 (PAGE 5): FETAL SKELETAL OBSERVATIONS - SUMMARY
---------------------------------------------------------------------------------------------------------------
FOOTNOTES: ---------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation. b. Litter 8481 consisted of ten dead fetuses; values were excluded from group averages and statistical analys
observations for this litter are cited on Table 21. c. Fetuses with alterations of the skull and/or hyoid are not separately identified in this summary table, ex
alterations of other ossification sites were also present. d. Includes all alterations noted for the skull except hyoid, ala, angulated and skull, premaxillae, not ossi
categories are excluded because these alterations do not result from irregular ossification. e. Fetus 8448-1 had other skeletal alterations. f. Fetus 8449-6 had other skeletal alterations. g. Fetus 8452-1 had other skeletal alterations. h. Fetus 8476-1 had other skeletal alterations. i. Fetus 8485-2 had other skeletal alterations. j. Fetus 8500-8 had other skeletal alterations. k. Fetus 8543-4 had other skeletal alterations. 1. Fetus 8543-6 had other skeletal alterations.
Significantly different from the vehicle control group value (p!0.05). Significantly different from the vehicle control group value (p<0.01).
PROTOCOL 418-012! ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 13 (PAGE 1): FETAL OSSIFICATION SITES - CAESAREAN-DELIVERED LIVE FETUSES (DAY 29 OF GESTATION) - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
LITTERS EXAMINED
N
20
19b
19
16
FETUSES EXAMINED
N
175
172
152
130
LIVE
N
175
162
152
130
DEAD
N
0
lob
0
0
-----------------------------------------------------------------------------------------------------------------
OSSIFICATION SITES PER FETUS PER LITTER
HYOID
MEAN+S.D.
1.00 + 0.00
1.00 + 0.00
1.00 + 0.00
1.00 + 0.00
VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL
MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D.
7.00 + 12.72 +
6.26 + 3.00 + 16.90 7
0.00 0.23 0.23 0.00 0.24
7.00 + 12.58 +
6.42 + 3.00 + 17.03 +
0.00 0.28 0.28 0.00 0.30
7.00 + 12.70 +
6.29 + 3.00 + 16.95 +
0.00 0.29 0.29 0.00 0.38
7.00 + 12.49 +
6.51 + 3.00 + 16.86 +
0.00 0.33 0.33 0.00 0.28
RIBS (PAIRS)
MEAN+S.D.
12.66 + 0.26
12.50 + 0.26
12.60 + 0.29
12.42 + 0.28
STERNUM MANUBRIUM STERNAL
XIPHOID
CENTERS
MEAN+S.D. MEAN+S.D. MEAN+S.D.
1.00 + 3.98 + 0.98 +
0.00 0.05 0.04
1.00 + 3.92 +
0.99 +
0.00 0.11
0.05
1.00 + 3.95 + 0.97 +
0.00 0.12 0.06
1.00 + 3.81 + 0.94 +
0.00 0.17** 0.10
FORELIMB c CARPALS METACARPALS DIGITS PHALANGES
MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D.
0.00 + 4.98 + 5.00 + 13.92 +
0.00 0.05 0.00 0.12
0.00 + 4.97 + 5.00 + 13.92 +
0.00 0.06 0.00 0.17
0.00 + 4.99 + 5.00 + 13.90
0.00 0.04 0.00
0.17
0.00 + 4.97 + 5.00 + 13.96 +
0.00 0.07 0.00 0.07
HINDLIMB c
TARSALS
MEAN+S.D.
2.00 + 0.00
2.00 + 0.00
2.00 + 0.00
2.00 + 0.00
METATARSALS DIGITS
MEAN+S.D. MEAN+S.D.
4.00 + 4.00 +
0.00 0.00
4.00 + 4.00 +
0.00 0.00
4.00 4.00 +
0.00 0.00
4.00 + 4.00 +
0.00 0.00
PHALANGES
MEAN+S.D.
12.00 + 0.00
12.00 + 0.00
12.00 0.00
12.00 + 0.00
----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
b. Litter 8481 consisted of ten dead fetuses; values excluded from group averages and statistical analyses. A( observations for this litter are cited on Table 21.
C. Calculated as average per limb.
Significantly different from the vehicle control group value (p@S0.05).
Significantly different from the vehicle control group value (p@io.01).
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 14 (PAGE 1): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
------------------------------------------------------------------------------------- a-------------------------
RABBIT #
DESCRIPTION
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8443
NO ADVERSE FINDINGS
8444
NO ADVERSE FINDINGS
8445
NO ADVERSE FINDINGS
8446
NO ADVERSE FINDINGS
8447
NO ADVERSE FINDINGS
8448
NO ADVERSE FINDINGS
8449
NO ADVERSE FINDINGS
8450
NO ADVERSE FINDINGS
8451
NO ADVERSE FINDINGS
8452
NO ADVERSE FINDINGS
8453
NO ADVERSE FINDINGS
8454
NO ADVERSE FINDINGS
8455
NO ADVERSE FINDINGS
8456
NO ADVERSE FINDINGS
8457
NO ADVERSE FINDINGS
8458
NO ADVERSE FINDINGS
8459
NO ADVERSE FINDINGS
8460
NO ADVERSE FINDINGS
8461
NO ADVERSE FINDINGS
8462
NO ADVERSE FINDINGS
8463
NO ADVERSE FINDINGS
8464
NO ADVERSE FINDINGS
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 14 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8465
DG( 28- 29)
LOCALIZED ALOPECIA:
LIMBS a
8466
NO ADVERSE FINDINGS
8467 8468 8469 8470
NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE
FINDINGS FINDINGS FINDINGS FINDINGS
8471
NO ADVERSE FINDINGS
8472
NO ADVERSE FINDINGS
8473 8474 847S 8476
DG( 27- 29)
LOCALIZED NO ADVERSE
NO ADVERSE NO ADVERSE
ALOPECIA: FINDINGS
FINDINGS FINDINGS
BACK a
84@77
NO ADVERSE FINDINGS
8478
DG( 28
UNGROOMED COAT
8479 8480
NO ADVERSE NO ADVERSE
FINDINGS FINDINGS
8481
NO ADVERSE FINDINGS
8482
DG( 24- 29)
LOCALIZED ALOPECIA:
LIMBS a
8483
NO ADVERSE FINDINGS
8484
NO ADVERSE FINDINGS
8485
NO ADVERSE FINDINGS
8486
DG( 27- 29)
UNGROOMED COAT
--------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 14 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8487
NO ADVERSE FINDINGS
8488
NO ADVERSE FINDINGS
8489
DG( 29
LOCALIZED ALOPECIA: UNDERSIDE a
8490
NO ADVERSE FINDINGS
8491
NO ADVERSE FINDINGS
8492
DG(
9
SOFT OR LIQUID FECES
DG( 9- 11)
UNGROOMED COAT
DC( 10- 11)
SCANT FECES
8493
DG( 27- 29)
LOCALIZED ALOPECIA:
LIMBS a
8494
NO ADVERSE FINDINGS
8495
NO ADVERSE FINDINGS
8496
DG( 26- 29)
LOCALIZED ALOPECIA:
BACK a
8497
NO ADVERSE FINDINGS
8498
NO ADVERSE FINDINGS
8499
NO ADVERSE FINDINGS
8500
NO ADVERSE FINDINGS
8501
NO ADVERSE FINDINGS
8502
NO ADVERSE FINDINGS
8503
NO ADVERSE FINDINGS
8504
NO ADVERSE FINDINGS
8505
NO ADVERSE FINDINGS
8506
DC( 26- 29)
LOCALIZED ALOPECIA:
LIMBS a
8507
DG( 28- 29)
LOCALIZED ALOPECIA:
BACK a
8508
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. observation confirmed at nec.ropsy.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFO@ IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 14 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8509
NO ADVERSE FINDINGS
8510
NO ADVERSE FINDINGS
8511
NO ADVERSE FINDINGS
8512
NO ADVERSE FINDINGS
8513
NO ADVERSE FINDINGS
8514
NO ADVERSE FINDINGS
8515 8516
DG( 28- 29)
NO ADVERSE FINDINGS LOCALIZED ALOPECIA:
LIMBS a
8517
DG( 25 )
ABORTED AND SACRIFICED
8518
DG( 28- 29)
SCANT FECES
8519
NO ADVERSE FINDINGS
8520 8521
DG( 28 DG( 29
NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS ALOPECIA NO LONGER APPARENT
DG( 29
LOCALIZED ALOPECIA: BACK a
8522
NO ADVERSE FINDINGS
8523 8524
DG( 24- 25)
NO ADVERSE FINDINGS SCANT FECES
8525
DG( 26
SCANT FECES
8526
NO ADVERSE FINDINGS
8527
DG( 24- 28)
UNGROOMED COAT
8528
NO ADVERSE FINDINGS
8529
NO ADVERSE FINDINGS
8530
NO ADVERSE FINDINGS
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. observation confirmed at necropsy.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 14 (PAGE 5): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8531
NO ADVERSE FINDINGS
8532
NO ADVERSE FINDINGS
8533
NO ADVERSE FINDINGS
8534
DG( 22
ABORTED AND SACRIFICED
8535
DG( 26- 27)
SCANT FECES
8536
NO ADVERSE FINDINGS
8537
DG( 24
NO FECES
DC( 25
ABORTED AND SACRIFICED
8538
Do( 24
ABORTED AND SACRIFICED
8539
DG( 22- 23)
SCANT FECES
DG( 24
ABORTED AND SACRIFICED
8540
DG( 25
ABORTED AND SACRIFICED
8541
NO ADVERSE FINDINGS
8542
DG( 21- 23)
SCANT FECES
DG( 27
SCANT FECES
DG( 28
ABORTED AND SACRIFICED
8543
DG( 19- 20)
SCANT FECES
DG( 22- 23)
SCANT FECES
DG( 24 )
NO FECES
DG( 25- 27)
SCANT FECES
8544
DG( 19- 20)
SCANT FECES
DG( 22- 24)
SCANT FECES
DG( 25
ABORTED AND SACRIFICED
8545
NO ADVERSE FINDINGS
8546
NO ADVERSE FINDINGS
8547
DG( 18
SCANT FECES
DG( 21
RED SUBSTANCE IN CAGE PAN
DG( 22
ABORTED AND SACRIFICED
8548
DG( 21
SCANT FECES
DG( 23- 24)
SCANT FECES
DG( 25
ABORTED AND SACRIFICED
8549
NO ADVERSE FINDINGS
8550
NO ADVERSE FINDINGS
8551
NO ADVERSE FINDINGS
8552
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 14 (PAGE 6): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------- -----------------------------------------------------------------------
8553
NO ADVERSE FINDINGS
8554
NO ADVERSE FINDINGS
8555
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8556
NO ADVERSE FINDINGS
8557
NO ADVERSE FINDINGS
8558
NO ADVERSE FINDINGS
8559
NO ADVERSE FINDINGS
8560
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8561
NO ADVERSE FINDINGS
8562
NO ADVERSE FINDINGS
8563
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8564
NO ADVERSE FINDINGS
8565
NO ADVERSE FINDINGS
8566
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8567
NO ADVERSE FINDINGS
8568
NO ADVERSE FINDINGS
8569
NO ADVERSE FINDINGS
8570
NO ADVERSE FINDINGS
8571
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 15 (PAGE 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
----------------------------------------------------------------------------------------------------------------
I
0 (VEHICLE)
8443
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8444
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8445
DG 29
NP
14
ALL TISSUES APPEAREB NORMAL.
8446
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8447
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8448
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8449
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8450
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8451
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8452
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8453
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8454
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8455
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8456
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8457
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8458
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8459
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8460
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8461
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8462
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8463
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8464
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
---------------------------------------------------------------------------------------------------------------
P = PREGNANT NP = NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 14) for external observations confirmed at necr
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 15 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RAJ3BIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
-----------------------------------------------------------------------------------------------------------------
ii
0.1
8465
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8466
DG 29
NP
14
ALL TISSUES APPEARED, NORMAL.
8467
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8468
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8469
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8470
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8471
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8472
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8473
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8474
DC 29
p
14
ALL TISSUES APPEARED NORMAL.
8475
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8476
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8477
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8478
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8479
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8480
DC 29
p
14
ALL TISSUES APPEARED NORMAL.
8481
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8482
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8483
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8484
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8485
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8486
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
----------------------------------------------------------------------------------------------------------------
P - PREGNANT NP - NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 14) for external observations confirmed at necra
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE IS (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
----------------------------------------------------------------------------------------------------------------
III
1.0
8487
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8488
DG 29
p
14
ALL TISSUES APPEARED,NORMAL.
8489
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8490
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8491
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8492
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8493
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8494
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8495
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8496
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8497
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8498
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8499
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8500
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8501
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8502
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8503
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8504
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8505
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8506
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8507
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8508
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
---------------------------------------------------------------------------------------------------------------
P - PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations
table
(Table 14) for external observations
confirmed at necr
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBERI
TABLE 15 (PAGE 4): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
-----------------------------------------------------------------------------------------------------------------
IV 2,.5
8509
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
Oslo
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8511
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8512
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8513
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8514
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
6515
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8516
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8517
DG 25
p
14
ABORTED ON DAY 25 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8518
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8519
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8520
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8521
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8522
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8523 6524
DG 29
NP
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
8525
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8526
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8527
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8528
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8529
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8530
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
----------------------------------------------------------------------------------------------------------------
P - PREGNANT NP - NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations
table
(Table 14) for external observations
confirmed
at necro
PROTOCOL 418-012.- ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 15 (PAGE 5): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
----------------------------------------------------------------------------------------------------------------
v 3.75
8531
DG 29
p
14
8532
DG 29
p
14
8533
DG 29
p
14
ALL TISSUES
ALL TISSUES ALL TISSUES
APPEARED
APPEARED. APPEARED
NORMAL.
NORMAL. NORMAL.
8534
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8535
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8536
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8537
DG 25
p
14
ABORTED ON DAY 25 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8538
DO 24
p
14
ABORTED ON DAY 24 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8539
DG 24
p
14
ABORTED ON DAY 24 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8540
DG 25
p
14
ABORTED ON DAY 25 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8541
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8542
DG 28
p
14
ABORTED ON DAY 28 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8543
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8544
DG 25
p
14
ABORTED ON DAY 25 OF GESTATION. ALL TISSUES APPEARED NORMAL.
8545
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8S46
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
----------------------------------------------------------------------------------------------------------------
P . PREGNANT NP - NOT PREGNANT
DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 14) for external observations confirmed at necro
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER.-
TABLE 15 (PAGE 6): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
-----------------------------------------------------------------------------------------------------------------
v 3.75 (cont.)
8547
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION. ALL TISSUES APPEARED NORMAL.
8548
DG 25
p
14
ABORTED ON DAY 25 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8549
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8550
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8551
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8552
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
-----------------------------------------------------------------------------------------------------------------
P - PREGNANT NP - NOT PREGNANT
DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 14) for external observations confirmed at necrop
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 15 (PAGE 7): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
-----------------------------------------------------------------------------------------------------------------
I 0 (VEHICLE)
8553
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8554
DG 21
p
14
ALL TISSUES APPEAREP NORMAL.
8555
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
0.1
8556
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8557
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
esse
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8559
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8560
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
III 1.0
8561
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8562
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8563
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
IV
2.5
8564
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
856S
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8566
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
v
3.75
8567
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8568
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8569
DG 21
NP
14
ALL TISSUES APPEARED NORMAL.
8570
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8571
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT NP - NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 14) for external observations confirmed at necro
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 1): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8443 NP
3.22
3.35
3.42
3.38
3.41
3.36
3.43
3.46
3.53
3.53
3.63
8444 P
3.40
3.42
3.51
3.52
3.48
3.48
3.46
3.48
3.52
3.53
3.52
8445 NP
3.S8
3.76
3.81
3.91
3.89
3.87
3.94
3.94
3.92
3.93
4.01
8446 P
3.24
3.38
3.4S
3.40
3.29
3.31
3.41
3.50
3.56
3.63
3.68
8447 P
3.44
3.79
3.82
3.82
3.85
3.94
3.97
3.96
4.00
4.05
4.01
8448 P
3.44
3.44
3.54
3.54
3.62
3.61
3.63
3.67
3.74
3.84
3.78
0449 P
3.55
3.50
3.41
3.34
3.40
3.55
3.54
3.66
3.66
3.66
3.66
8450 P
3.07
3.24
3.29
3.32
3.37
3.34
3.39
3.36
3.40
3.43
3.50
8451 P
3.34
3.41
3.43
3.47
3.50
3.51
3.58
3.65
3.80
3.77
3.74
8452 P
3.17
2.86
2.83
2.80
2.97
3.15
3.12
3.11
3.16
3.25
3.31
8453 P
3.66
3.63
3.70
3.73
3.72
3.80
3.82
3.82
3.92
3.86
3.90
8454 P
3.56
3.58
3.58
3.66
3.64
3.73
3.74
3.77
3.77
3.80
3.75
8455 P
3.37
3.44
3.49
3.51
3.56
3.58
3.66
3.67
3.75
3.67
3.72
8456 P
3.31
3.20
3.16
3.13
3.24
3.34
3.37
3.36
3.41
3.44
3.54
8457 P
3.01
3.13
3.19
3.24
3.23
3.24
3.26
3.22
3.26
3.30
3.32
8458 P
3.80
3.89
3.91
3.90
3.85
3.87
3.88
3.98
4.04
4.06
4.08
8459 P
3.76
3.82
3.89
3.86
3.90
3.94
4.08
4.03
4.07
4.11
4.11
8460 P
3.53
3.64
3.64
3.66
3.66
3.74
3.84
3.77
3.81
3.84
3.86
8461 P
2.99
3.06
3.14
3.14
3.17
3.16
3.12
3.15
3.15
3.20
3.55
8462 P
3.18
3.22
3.29
3.34
3.34
3.35
3.34
3.35
3.40
3.41
3.45
8463 P
3.12
3.12
3.21
3.28
3.28
3.34
3.35
3.30
3.32
3.39
3.45
8464 P
2.88
2.93
2.90
2.95
3.01
3.05
3.08
3.10
3.14
3.17
3.16
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
(KG).
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
PROTOCOL 418-012: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
27
28
29
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8443 NP
3.60
3.64
3.70
3.68
3.73
3.70
3.74
3.75
3.80
3.80
3.84
8444 P
3.61
3.61
3.64
3.65
3.65
3.67
3.60
3.70
3.68
3.71
3.76
8445 NP
4.06
4.14
4.17
4.16
4.13
4.16
4.20
4.23
4.20
4.38
4.27
8446 P
3.67
3.67
3.72
3.77
3.80
3.85
3.84
3.78
3.69
3.70
3.74
8447 P
4.13
4.18
4.18
4.27
4.31
4.36
4.44
4.52
4.52
4.61
4.64
8448 P 8449 P
3.85 3.79
3.90 3.83
3.93 3.83
3.96 3.92
4.00 3.93
4.04 3.97
4.13 4.06
4.17 4.09
4.21 4.14
4.24 4.12
4.25 4.12
8450 P
3.S?
3.60
3.63
3.62
3.66
3.67
3.73
3.73
3.Bl
3.81
3.88
8451 P
3.78
3.81
3.82
3.83
3.87
3.92
3.97
3.93
3.91
3.88
3.89
8452 P
3.46
3.49
3.50
3.50
3.51
3.57
3.60
3.67
3.65
3.64
3.66
8453 P 8454 P 8455 P
3.99 3.89 3.82
4.04 3.92 3.86
4.07 3.95 3.90
4.07 4.00 3.91
4.12 4.06 3.95
4.15 4.09 3.98
4.18 4.11 4.00
4.23 4.16 4.05
4.29 4.16 4.07
4.28 4.12 4.05
4.37 4.lS 4.10
8456 P
3.62
3.61
3.66
3.70
3.69
3.72
3.72
3.74
3.71
3.72
3.72
8457 P
3.47
3.50
3.54
3.55
3.61
3.62
3.64
3.66
3.60
3.61
3.58
8458 P
4.10
4.14
4.16
4.17
4.18
4.21
4.23
4.25
4.24
4.16
4.10
8459 P
4.18
4.15
4.18
4.20
4.29
4.33
4.32
4.42
4.39
4.40
4.5
8460 P
3.98
3.96
3.99
3.98
3.99
4.11
4.IS
4.23
4.22
4.24
4.2
8461 P
3.26
3.30
3.29
3.30
3.33
3.33
3.32
3.31
3.34
3.34
3.3
8462 P
3.51
3.50
3.49
3.44
3.50
3.49
3.53
3.53
3.55
3.58
3.6
8463 P
3.52
3.53
3.55
3.58
3.57
3.65
3.68
3.68
3.66
3.67
3.6
8464 P
3.23
3.24
3.29
3.29
3.33
3.35
3.37
3.36
3.37
3.37
3.3
---------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESL44ED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
DIGITS AND REPORTED IN KILOGRAMS UNROUNDED GRM (G) VALUE.
(KG).
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 11
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8465 P
3.58
3.88
3.94
3.91
3.94
3.97
4.02
4.02
4.09
4.07
4.1
8466 NP
3.53
3.63
3.63
3.64
3.57
3.64
3.63
3.66
3.63'
3.64
3.6
8467 NP
3.43
3.63
3.66
3.66
3.68
3.77
3.73
3.77
3.87
3.80
3.9
8468 P
3.23
3.53
3.55
3.57
3.52
3.53
3.60
3.64
3.68
3.72
3.7
8469 P
3.17
3.39
3.45
3.46
3.49
3.47
3.50
3.56
3.62
3.65
3.8
8470 P
3.00
3.17
3.28
3.22
3.17
3.18
3.17
3.16
3.21
3.27
3.2
8471 P
3.10
3.30
3.37
3.40
3.39
3.38
3.30
3.34
3.34
3.40
3.4
8472 P
3.40
3.40
3.47
3.55
3.64
3.64
3.63
3.66
3.69
3.75
3.6
8473 P
2.95
3.15
3.11
3.11
3.25
3.28
3.25
3.30
3.32
3.30
3.2
8474 P
3.28
3.34
3.36
3.41
3.40
3.40
3.42
3.44
3.48
3.54
3.5
8475 P
3.51
3.47
3.54
3.54
3.49
3.56
3.63
3.67
3.77
3.72
3.7
8476 P
3.58
3.46
3.51
3.52
3.64
3.68
3.59
3.61
3.70
3.64
3.6
8477 NP
3.47
3.54
3.58
3.64
3.59
3.57
3.64
3.74
3.78
3.73
3.6
8478 P
2.95
3.21
3.24
3.25
3.22
3.05
2.96
3.15
3.28
3.26
3.2
8479 P
3.11
3.31
3.39
3.39
3.34
3.34
3.34
3.32
3.33
3.27
3.3
8480 P
3.74
3.69
3.76
3.78
3.78
3.84
3.96
3.90
3.94
3.99
4.0
8481 P
3.32
3.43
3.45
3.42
3.35
3.37
3.38
3.46
3.52
3.60
3.5
8482 P
3.25
3.30
3.41
3.37
3.36
3.39
3.41
3.44
3.50
3.57
3.5
8483 P
3.60
3.57
3.61
3.67
3.72
3.71
3.84
3.74
3.80
3.88
3.9
8484 P
3.18
3.25
3.24
3.29
3.34
3.39
3.46
3.39
3.48
3.53
3.5
8485 P
3.47
3.49
3.S4
3.60
3.63
3.64
3.64
3.68
3.72
3.74
3.7
8486 P
3.87
3.90
3.96
3.99
3.97
3.96
3.91
3.89
3.89
3.94
3.9
---------------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY a.
PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (0), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS
CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
Doe 8481 had a litter which consisted on 10 dead fetuses; values excluded from group averages and
(KG). statisti
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 4): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
27
28
29
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
0465 P
4.12
4.15
4.15
4.25
4.23
4.26
4.25
4.32
4.33
4.34
4.34
8466 NP 8467 NP
3.82 3.90
3.87 3.94
3.89 3.98
3.92 3.99
3.95 4.01
3.94 3.98
3.96 4.05
4.01 4.08
4.03'
3.99
4.0
4.07
4.13
4.2
8468 P 8469 P
3.77
3.83
3.09
3.88
3.89
3.92
3.98
3.94
3.97
3.94
3.9
3.66
3.69
3.70
3.75
3.83
3.82
3.88
3.87
3.87
3.96
4.0
8470 P 8471 P 8472 P 8473 P
3.37 3.40 3.82 3.36
3.34 3.50 3.84 3.45
3.36 3.58 3.87 3.48
3.32 3.61 3.93
3.50
3.30 3.64 3.95 3.49
3.28 3.67 3.98 3.51
3.31 3.62 4.03 3.48
3.35 3.63 4.05 3.46
3.37
3.38
3.4
3.66
3.70
3.7
4.10
4.12
4.1
3.46
3.42
3.4
8474 P
3.60
3.65
3.64
3.71
3.74
3.75
3.73
3.77
3.79
4.15
3.8
8475 P
3.85
3.85
3.85
3.87
3.90
3.96
3.99
4.03
4.04
4.11
4.1
8476 P
3.74
3.81
3.91
3.91
3.91
3.97
4.01
4.05
4.10
4.13
4.1
8477 NP
3.74
3.78
3.80
3.82
3.82
3.87
3.88
3.93
3.93
3.97
4.0
8478 P
3.34
3.35
3.42
3.44
3.44
3.48
3.48
3.47
3.40
3.55
3.5
8479 P
3.53
3.57
3.59
3.64
3.72
3.74
3.74
3.80
3.78
3.78
3.7
8480 P
4.03
4.06
4.11
4.18
4.20
4.29
4.26
4.25
4.29
4.29
4.3
8481 P a
3.64
3.65
3.72
3.74
3.78
3.86
3.88
3.93
3.92
3.88
3.8
8482 P
3.51
3.65
3.70
3.70
3.77
3.78
3.81
3.87
3.86
3.89
3.9
8483 P
3.99
3.96
4.02
4.02
4.06
4.13
4.15
4.22
4.21
4.22
4.2
8484 P
3.58
3.62
3.64
3.66
3.71
3.67
3.69
3.62
3.63
3.58
3.5
8485 P
3.80
3.79
3.74
3.80
3.80
3.95
3.88
3.97
4.00
4.02
4.1
8486 P
3.99
4.02
4.07
4.11
4.15
4.20
4.25
4.24
4.15
4.16
4.2
---------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (C), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
ALL CALCUIATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. a. Doe 8481 had a litter which consisted on 10 dead fetuses; values excluded from group averages and
(KG). statisti
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 5): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
-----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 111
1.0 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8487 P
3.37
3.47
3.50
3.49
3.50
3.57
3.60
3.64
3.69
3.68
3.72
8488 P
3.18
3.28
3.33
3.33
3.32
3.35
3.40
3.43
3.38'
3.44
3.48
8489 P
3.09
3.23
3.31
3.34
3.36
3.38
3.40
3.43
3.48
3.50
3.58
8490 P
3.58
3.69
3.68
3.59
3.63
3.69
3.77
3.79
3.87
3.88
3.90
8491 P
3.65
3.61
3.62
3.66
3.72
3.72
3.76
3.83
3.86
3.92
3.82
8492 P
3.16
3.37
3.35
3.29
3.28
3.26
3.29
3.27
3.28
3.34
3.36
8493 P
3.71
3.72
3.78
3.74
3.74
3.81
3.84
3.90
3.94
4.00
4.01
8494 P
3.33
3.39
3.40
3.40
3.39
3.47
3.52
3.57
3.66
3.64
3.64
8495 P
3.43
3.57
3.60
3.66
3.67
3.70
3.64
3.74
3.84
3.82
3.83
8496 P
3.52
3.55
3.60
3.45
3.57
3.62
3.6S
3.71
3.74
3.76
3.78
8497 P
3.25
3.40
3.37
3.35
3.37
3.41
3.44
3.45
3.40
3.28
3.49
8498 P
2.87
2.99
3.04
3.06
3.04
3.07
3.11
3.16
3.17
3.19
3.22
8499 P
3.56
3.60
3.60
3.63
3.67
3.69
3.73
3.78
3.76
3.80
3.85
8500 P
3.17
3.30
3.37
3.34
3.30
3.38
3.44
3.46
3.52
3.53
3.56
8501 P
2.96
3.23
3.17
3.24
3.16
3.15
3.17
3.25
3.34
3.44
3.44
8502 NP
3.02
3.31
3.33
3.31
3.21
3.29
3.28
3.24
3.22
3.20
3.28
8503 P
3.91
4.04
4.03
4.08
4.12
4.10
4.09
4.15
4.20
4.26
4.29
8504 P
3.38
3.48
3.53
3.57
3.60
3.62
3.60
3.61
3.64
3.61
3.61
8505 NP
3.22
3.28
3.37
3.33
3.38
3.42
3.44
3.43
3.49
3.53
3.54
8506 p
3.26
3.50
3.58
3.58
3.53
3.56
3.58
3.64
3.69
3.75
3.79
8507 P
3.57
3.56
3.62
3.58
3.57
3,60
3.65
3.66
3.69
3.70
3.71
8508 NP
3.49
3.58
3.60
3.57
3.63
3.66
3.72
3.71
3.74
3.81
3.84
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
(KG).
ALL CALCULATIONS EXCEPT BODY WEIGHT BODY WEIGHT AVERAGES ARE CALCULATED
AVERAGES ARE PERFORMED WITH THE UNROUNDED WITH THE ROUNDED KILOGRAM (KG) VALUE.
GRAM (G) VALUE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY S71JDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 6): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
.27
28
29
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8487 P
3.76
3.80
3.81
3.86
3.89
3.92
3.94
3.92
3.88
3.88
3.90
8488 P
3.56
3.56
3.59
3.64
3.66
3.69
3.70
3.7@
3.75'
3.72
3.83
8489 P
3.59
3.61
3.64
3.68
3.73
3.73
3.78
3.77
3.82
3.82
3.86
8490 P
3.92
3.97
4.0 2
4.08
4.06
4.09
4.09
4.12
4.12
4.13
4.15
8491 P
3.89
3.91
3.98
4.02
4.04
4.13
4.15
4.17
4.15
4.18
4.20
8492 P
3.46
3.49
3.54
3.57
3.58
3.61
3.61
3.59
3.62
3.68
3.71
8493 P
3.95
3.96
3.95
3.99
3.88
3.98
4.01
4.03
4.03
4.08
4.13
8494 P
3.67
3.70
3.70
3.72
3.75
3.73
3.77
3.76
3.78
3.78
3.81
8495 P
3.82
3.86
3.90
3.96
3.97
3.96
3.96
3.92
3.93
3.93
3.92
8496 P
3.89
3.86
3.92
3.92
3.90
3.68
3.96
3.96
3.96
4.04
4.08
8497 P
3.40
3.50
3.53
3.51
3.58
3.59
3.68
3.66
3.65
3.67
3.65
8498 P
3.33
3.33
3.31
3.33
3.36
3.34
3.37
3.38
3.36
3.37
3.37
8499 P
3.96
3.97
3.97
4.02
4.02
4.05
4.14
4.16
4.24
4.26
4.26
8500 P
3.52
3.64
3.66
3.72
3.73
3.72
3.80
3.82
3.80
3.80
3.79
8501 P
3.46
3.48
3.48
3.46
3.49
3.49
3.51
3.56
3.60
3.65
3.65
8502 NP 8503 P
3.46 4.31
3.44 4.37
3.44 4.34
3.47 4.38
3.48 4.43
3.48 4.46
3.45 4.48
3.42 4.51
3.45 4.42
3.49 4.45
3.51 4.47
8504 P
3.60
3.61
3.62
3.72
3.73
3.78
3.77
3.80
3.72
3.65
3.69
8505 NP
3.54
3.62
3.64
3.69
3.69
3.74
3.76
3.77
3.78
3.86
3.84
8506 P
3.78
3.81
3.84
3.84
3.89
3.94
3.99
4.01
3.99
4.03
4.08
8507 P
3.76
3.81
3.83
3.88
3.89
3.91
3.93
3.91
3.90
3.91
3.98
8508 NP
3.85
3.86
3.86
3.84
3.90
3.99
4.00
3.99
3.88
3.90
3.97
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8509 P
3.00
3.11
3.13
3.13
3.09
3.11
3.13
3.20
3.23
3.24
3.25
8510 p
3.40
3.53
3.53
3.58
3.61
3.60
3.68
3.78
3.80'
3.81
3.78
8511 NP
3.17
3.33
3.47
3.47
3.50
3.54
3.56
3.60
3.55
3.54
3.51
8512 P
3.37
3.54
3.51
3.60
3.60
3.60
3.59
3.62
3.68
3.73
3.78
8513 NP
3.43
3.56
3.57
3.63
3.61
3.59
3.58
3.66
3.67
3.63
3.64
8514 P
3.32
3.57
3.64
3.65
3.60
3.56
3.61
3.68
3.72
3.74
3.72
8515 P
3.58
3.59
3.71
3.71
3.74
3.71
3.74
3.84
3.85
3.93
3.87
8516 P
3.55
3.63
3.67
3.68
3.64
3.62
3.61
3.59
3.68
3.70
3.69
&Fzl7 P
3.14
3.44
3.38
3.37
3.41
3.45
3.49
3.49
3.43
3.32
3.24
8518 P
3.50
3.70
3.69
3.74
3.74
3.78
3.88
3.82
3.88
3.91
3.91
8519 P
3.27
3.32
3.29
3.36
3.41
3.47
3.44
3.46
3.50
3.55
3.56
8520 P
3.08
3.14
3.16
3.18
3.14
3.15
3.17
3.20
3.26
3.28
3.32
8521 P
3.23
3.44
3.48
3.49
3.47
3.47
3.44
3.45
3.51
3.59
3.57
8522 P
3.74
3.81
3.85
3.91
3.93
3.93
3.96
4.11
4.02
4.10
4.18
8523 NP
3.62
3.83
3.82
3.86
3.90
3.88
3.96
3.96
3.93
3.94
3.80
8524 MP
2.88
3.10
3.14
3.14
3.13
3.10
3.12
3.14
3.20
3.24
3.26
8525 P
3.57
3.66
3.73
3.70
3.68
3.68
3.65
3.68
3.56
3.64
3.67
8526 NP
2.83
2.98
2.95
2.93
2.96
2.99
3.00
3.01
3.01
3.00
3.01
8527 P
3.51
3.53
3.62
3.71
3.69
3.61
3.62
3.64
3.63
3.68
3.61
8528 P
3.17
3.29
3.28
3.29
3.29
3.26
3.25
3.25
3.28
3.37
3.39
8529 P
3.26
3.33
3.41
3.40
3.41
3.41
3.45
3.50
3.53
3.56
3.55
8530 P
3.85
4.01
4.07
4.02
4.00
4.03
4.22
4.11
4.19
4.24
4.24
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT
DAY = DAY OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS ALL CALCULATIONS EXCEPT BODY WEIGHT BODY WEIGHT AVERAGES ARE CALCULATED
(G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 8): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
27
28
29
-----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8509 P
3.24
3.29
3.31
3.32
3.34
3.29
3.33
3.34
3.34
3.39
3.42
8510 P
3.75
3.76
3.81
3.80
3.84
3.83
3.89
3.91
3.92'
3.94
3.98
8511 NP
3.58
3.62
3.63
3.64
3.65
3.62
3.63
3.68
3.68
3.73
3.72
8512 P
3.82
3.79
3.83
3.85
3.87
3.91
3.93
3.86
3.88
3.86
3.92
8513 NP
3.65
3.64
3.65
3.68
3.65
3.66
3.70
3.71
3.75
3.77
3.76
8514 P
3.72
3.73
3.77
3.70
3.70
3.80
3.82
3.82
3.83
3.86
3.86
8515 P
3.90
3.94
4.00
4.01
4.03
4.04
4.04
4.07
4.07
4.01
3.95
8516 P
3.70
3.71
3.76
3.77
3.81
3.89
3.86
3.86
3.89
3.90
3.98
8517 P
3.11
3.10
3.09
3.03
3.03
2.98
ABORTED ON DAY 25 OF GESTATION
8518 P
3.92
3.92
3.94
3.96
3.96
3.93
3.86
3.74
3.62
3.56
3.57
8519 p
3.60
3.61
3.66
3.65
3.68
3.69
3.69
3.66
3.73
3.74
3.78
8520 P
3.33
3.33
3.32
3.32
3.35
3.38
3.39
3.39
3.41
3.43
3.49
8521 P
3.51
3.50
3.54
3.57
3.60
3.63
3.68
3.65
3.64
3.71
3.74
8522 P
4.13
4.19
4.18
4.23
4.27
4.33
4.34
4.37
4.39
4.39
4.46
8523 NP
3.60
3.56
3.50
3.46
3.40
3.36
3.32
3.42
3.51
3.63
3.69
8524 NP
3.20
3.25
3.24
3.28
3.24
3.22
3.18
3.25
3.34
3.33
3.36
8525 P
3.70
3.75
3.71
3.70
3.70
3.82
3.83
3.86
3.88
3.84
3.93
8526 NP
3.11
3.15
3.18
3.23
3.26
3.29
3.26
3.26
3.23
3.24
3.26
8527 P
3.79
3.83
3.84
3.89
3.75
3.72
3.77
3.78
3.75
3.86
3.93
8528 P
3.42
3.41
3.43
3.44
3.44
3.44
3.48
3.46
3.46
3.46
3.51
8529 P
3.58
3.60
3.59
3.60
3.58
3.60
3.64
3.68
3.73
3.80
3.81
8530 P
4.19
4.27
4.28
4.31
4.35
4.40
4.41
4.37
4.34
4.34
4.36
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (C), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 9): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8531 P
3.36
3.43
3.47
3.52
3.56
3.61
3.66
3.63
3.68
3.74
3.83
8532 P
3.42
3.55
3.54
3.56
3.53
3.55
3.48
3.60
3.58'
3.52
3.46
8533 P
3.55
3.47
3.54
3.48
3.48
3.46
3.49
3.52
3.55
3.58
3.56
8534 P
3.28
3.52
3.47
3.48
3.38
3.33
3.31
3.29
3.30
3.35
3.19
8535 P
3.42
3.64
3.66
3.63
3.57
3.51
3.63
3.69
3.80
3.82
3.78
8536 P
3.32
3.40
3.33
3.71
3.72
3.77
3.74
3.77
3.74
3.72
3.74
8537 P
3.25
3.37
3.36
3.27
3.31
3.31
3.42
3.40
3.32
3.33
3.22
8538 P
2.86
2.96
2.92
2.84
2.79
2.72
2.74
2.78
2.74
2.68
2.66
8539 P
3.07
3.36
3.43
3.36
3.33
3.29
3.30
3.29
3.23
3.17
3.12
8540 P
3.58
3.47
3.52
3.53
3.65
3.64
3.67
3.76
3.84
3.84
3.73
8541 P
3.16
3.25
3.31
3.34
3.35
3.38
3.42
3.44
3.52
3.53
3.52
8S42 P
3.58
3.69
3.72
3.74
3.71
3.70
3.74
3.71
3.74
3.77
3.76
8543 P
3.68
3.81
3.82
3.86
3.88
3.86
3.79
3.73
3.67
3.62
3.61
8544 P
3.00
3.12
3.18
3.20
3.21
3.27
3.28
3.23
3.14
3.08
3.01
8545 P
3.02
3.2S
3.30
3.35
3.43
3.40
3.42
3.41
3.47
3.50
3.54
8546 P
3.21
3.36
3.38
3.38
3.41
3.46
3.51
3.54
3.56
3.58
3.61
8547 P
3.53
3.50
3.60
3.61
3.63
3.65
3.62
3.58
3.54
3.46
3.42
8548 P
3.59
3.59
3.59
3.65
3.73
3.80
3.88
3.81
3.85
3.89
3.84
8549 P
3.20
3.26
3.32
3.30
3.34
3.40
3.39
3.40
3.43
3.41
3.37
8550 P
3.12
3.25
3.31
3.38
3.45
3.51
3.52
3.54
3.54
3.53
3.57
8551 P
3.49
3.40
3.46
3.49
3.51
3.60
3.69
3.66
3.70
3.77
3.60
8552 NP
3.90
3.98
3.99
4.06
3.94
3.96
3.96
3.93
3.90
3.96
3.90
----------------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY
PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (C), ROUNDED TO THREE SIGNIFICANT
CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG)
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KC).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 10): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
27
28
29
----------------------------------------------------------------------------------------------------------------
RABBIT
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8531 P
3.78
3.84
3.87
3.90
3.97
3.97
3.98
4.08
4.03
4.10
4.13
8532 P
3.30
3.24
3.20
3.36
3.41
3.49
3.49
3.56
3.51'
3.60
3.65
8533 P
3.48
3.46
3.42
3.45
3.48
3.51
3.56
3.59
3.S6
3.57
3.63
8534 P
3.03
3.05
2.93
ABORTED ON DAY 22 OF GESTATION
8535 P
3.82
3.80
3.75
3.66
3.61
3.55
3.49
3.43
3.49
3.53
3.63
8536 P
3.68
3.73
3.82
3.83
3.83
3.92
3.90
3.95
3.92
3.95
4.02
8537 P
3.10
3.10
3.12
3.05
3.07
3.02
ABORTED ON DAY 25 OF GESTATION
8538 P
2.55
2.51
2.49
2.53
2.53
2.32
ABORTED ON DAY 24 OF GESTATION
8539 P
3.02
2.94
2.96
2.85
2.79
ABORTED ON DAY 24 OF GESTATION
8540 P
3.52
3.40
3.36
3.32
3.28
3.21
ABORTED ON DAY 25 OF GESTATION
8541 P
3.57
3.61
3.65
3.66
3.71
3.73
3.73
3.70
3.62
3.64
3.73
8542 P
3.70
3.66
3.66
3.58
3.59
3.54
3.58
3.52
3.57
ABORTED ON D7
8543 P
3.45
3.44
3.40
3.36
3.30
3.25
3.19
3.20
3.16
3.11
3.08
8544 P
2.84
2.88
2.85
2.86
2.80
2.74
ABORTED ON DAY 25 OF GESTATION
8545 P
3.61
3.64
3.66
3.60
3.59
3.66
3.69
3.66
3.69
3.66
3.70
8546 P
3.63
3.65
3.73
3.67
3.67
3.69
3.70
3.70
3.68
3.73
3.76
8547 P
3.25
3.24
3.19
ABORTED ON DAY 22 OF GESTATION
8548 P
3.76
3.67
3.70
3.62
3.58
3.58
ABORTED ON DAY 25 OF GESTATION
8549 P
3.30
3.29
3.33
3.36
3.39
3.46
3.52
3.50
3.56
3.54
3.59
8550 P
3.60
3.62
3.64
3.62
3.68
3.68
3.76
3.76
3.77
3.79
3.73
8551 P
3.76
3.83
3.85
3.82
3.74
3.74
3.80
3.81
3.82
3.87
3.96
8552 NP
3.89
3.88
3.88
3.81
3.92
3.89
3.93
3.89
3.92
3.88
3.93
-----------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY
PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG)
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KC).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 11): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8553 P
3.95
3.96
4.05
4.06
4.09
4.11
3.87
4.07
4.09
4.01
4.18
8554 P
3.36
3.44
3.45
3.52
3.61
3.67
3.60
3.56
3.51'
3.68
3.67
8555 p
3.09
3.05
3.06
3.12
3.13
3.17
3.13
3.09
3.12
3.18
3.29
----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8553 P
4.23
4.25
4.34
8554 P
3.74
3.75
3.84
8555 P
3.33
3.39
3.39
----------------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY
PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG)
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG).
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 12): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
-----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8S56 P
3.80
3.92
3.88
3.88
3.88
3.86
3.80
3.88
3.98
4.00
3.95
8557 P
3.39
3.41
3.45
3.51
3.46
3.47
3.44
3.46
3.44'
3.46
3.51
8558 P
3.56
3.51
3.58
3.61
3.70
3.76
3.66
3.58
3.57
3.67
3.69
8559 P
3.61
3.50
3.60
3.60
3.64
3.63
3.61
3.68
3.72
3.71
3.75
8560 P
3.12
3.22
3.31
3.26
3.28
3.36
3.26
3.34
3.43
3.47
3.52
-----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
-----------------------------------------------------------------------------------------------------------------
8556 P
3.95
3.98
4.03
8557 P
3.63
3.66
3.72
8558 p
3.82
3.83
3.92
8559 P
3.86
3.86
3.88
8560 P
3.50
3.50
3.52
-----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT
(VALUES EXCLUDED
FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS
ALL CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED
BODY WEIGHT AVERAGES ARE CALCULATED
WITH THE ROUNDED KILOGRAM
(KG) VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 13).- MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8561 P
3.98
3.87
3.95
3.96
3.97
4.04
3.92
3.96
3.98
3.98
4.01
8562 P
3.54
3.55
3.58
3.64
3.63
3.65
3.65
3.70
3.73'
3.80
3.81
8563 P
2.98
3.16
3.19
3.15
3.20
3.26
3.23
3.24
3.27
3.30
3.32
----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8561 P
4.12
4.08
4.06
8562 P
3.84
3.84
3.90
8563 P
3.37
3.36
3.35
----------------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY
PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG)
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAN (G) VALUE.
(KG).
PROTOCOL 418-012: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 16 (PAGE 14); MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
---------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8564 P
3.86
3.88
3.91
3.95
3.98
4.03
3.95
3.95
4.02
4.07
4.0
8565 P
3.34
3.36
3.42
3.51
3.49
3.55
3.38
3.37
3.34
3.28
3.2
8566 P
3.08
3.09
3.19
3.24
3.30
3.39
3.30
3.32
3.26
3.23
3.2
---------------------------------------------------------------------------------------------------------------
DAY 19
20
21
---------------------------------------------------------------------------------------------------------------
8564 P
4.10
4.07
4.18
8565 P
3.49
3.57
3.60
8566 P
3.27
3.35
3.39
---------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 16 (PAGE 15): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8567 P
3.91
3.86
3.91
3.94
3.91
3.90
3.97
3.90
3.95
3.96
4.03
8568 P
3.37
3.31
3.34
3.36
3.31
3.30
3.23
3.22
3.28
3.31
3.32
8569 NP
3.60
3.59
3.58
3.59
3.51
3.53
3.37
3.31
3.26
3.20
3.17
8570 P
3.75
3.58
3.59
3.65
3.72
3.78
3.75
3.71
3.62
3.53
3.45
8571 P
2.75
2.85
2.84
2.89
2.88
2.87
2.90
2.91
2.88
2.85
2.84
----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8567 P
3.85
3.70
3.68
6568 P
3.34
3.34
3.39
8569 NP
3.06
3.02
3.00
8570 P
3.52
3.60
3.65
8571 P
2.84
2.88
2.90
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY - DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMENWITH
THE UNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 1 -----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8443 NP
185.
180.
184.
180.
181.
185.
183.
180.
167.
183.
180.
8444 P
183.
146.
96.
89.
53.
87.
41.
ill.
97.
185.
182.
8445 NP
185.
180.
185,
183.
185.
180.
185.
180.
182.
iss.
182.
8446 P
151.
94.
92.
124.
171.
185.
185.
184.
157.
182.
181.
8447 P
183.
180.
180.
183.
183.
177.
180.
166.
185.
182.
180.
8448 P
116.
Ill.
185.
157.
165.
165.
184.
171.
182.
181.
183.
a449 P
80.
12.
81.
169.
151.
184.
150.
127.
127.
152.
180.
8450 P
180.
184.
166.
168.
166.
161.
125.
182,
184.
182.
185.
8451 P
181.
182.
182.
180.
185.
185.
183.
181.
182.
185.
185
8452 P
16.
26.
27.
107.
90.
65.
86.
143.
185.
181.
185
8453 P
183.
180.
180.
185.
182.
181.
185.
182.
182.
185.
184
8454 P 8455 P
184.
180.
15.
100.
185.
160.
107. -
181.
180.
185.
185
185.
180.
180.
169.
180.
185.
ISO.
180.
184.
181.
181
8456 P
4.
S.
107.
159.
118.
90.
169.
185.
183.
185.
185
8457 P
185.
184.
165.
133.
97.
74.
93.
183.
182.
167.
173
8458 P
183.
94.
98.
115.
110.
139.
183.
151.
154.
181.
184
8459 P
180.
184.
ISO.
182.
185.
185.
184..
184.
181.
180.
180
8460 P
180.
183.
183.
184.
185.
183.
181.
183.
182.
iss.
184
8461 P
171.
165.
150.
131.
81.
119.
123.
146.
148.
153.
154
8462 P
184.
185.
167.
130.
110.
114.
152.
166.
182.
172.
181
8463 P
180.
184.
164.
184.
160.
145.
121.
16S.
183.
183.
180
8464 P
90.
134.
164.
185.
148.
181.
185.
165.
165.
ISO.
158
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS
NP = NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 17 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29
---------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8443 NP
182.
ISO.
180.
181.
180.
180,
180.
180.
184.
8444 P
163.
180.
122.
106.
173.
100.
101.
102.
122'.
8445 NP
184.
185.
185.
182.
180.
182.
180.
181.
180.
8446 P
182,
180.
185.
182.
180.
63.
19.
37.
94.
8447 P
180.
185.
184.
182.
182.
185.
167.
185.
181.
8448 P
183.
185.
185.
181.
185.
182.
152.
180.
107.
8449 P
180.
185.
180.
185.
185.
185.
138.
120.
66.
8450 P
175.
172.
174.
147.
172.
158.
180.
153.
137.
8451 P
185.
185.
185.
177.
182.
125.
99.
35.
130.
8452 P
185.
i85.
185.
182.
183.
185.
180.
120.
135.
8453 P
185.
185.
184.
180.
182,
181.
180.
138.
134.
8454 P
182.
180.
182.
166.
159.
132.
154.
104.
83.
8455 P
171.
168.
182.
161.
180.
130.
iss.
100.
96.
8456 P
177.
181.
166.
180.
135.
142.
84.
99.
73.
8457 P
185.
182.
153.
182.
145.
154.
83.
91.
68,
8458 P
116.
87.
55.
69.
51.
66.
15.
2.
1.
8459 P
184.
181.
184.
180.
183.
183.
180.
96.
184.
8460 P
181.
180.
180.
180.
182.
182.
184.
184.
181.
8461 P
141.
128.
148.
117.
98.
45.
77.
95.
89.
8462 P
143.
53.
121.
102.
128.
90.
86.
115.
86.
8463 P
185.
172.
155.
112.
151.
113.
102.
91.
90.
8464 P
185.
140.
157.
125.
2.
105.
a
109.
85.
---------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS a. Spilled
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G). feed precluded the calculation of this value.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 a - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 ----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8465 P
185.
184.
183.
184.
182.
180.
185.
184.
183.
181.
184
8466 NP
164.
180.
184.
165.
143.
129.
70.
118.
121'.
181.
183
8467 NP
185.
185.
183,
184.
180.
135.
185.
181.
185.
184.
183
8468 P
183.
185.
180.
180.
183.
181.
183.
185.
185.
183.
185
8469 P
181.
181.
185.
180.
181.
181.
183.
184.
185.
185.
185
8470 P
180.
139.
79.
55.
97.
51.
95.
116.
182.
183.
182
8471 P
184.
iso.
183.
129.
3.
76.
83.
102.
181.
164.
181
8472 P
184.
183.
183.
181.
148.
173.
183.
185.
184.
180.
185
8473 P
62.
165.
182.
153.
180.
166.
135.
99.
71.
137,
138
8474 P
184.
180.
180.
147.
149.
123.
108.
170.
174.
183.
175
8475 P
184.
181.
180.
159.
185.
185.
185.
180.
185.
182.
185
8476 P
180.
181.
184.
133.
79.
92.
115.
183.
185.
iso.
184
8477 NP
185.
184.
156.
162,
184.
18S.
181.
180.
130.
108.
159
8478 P
180.
125.
95.
17.
14.
81.
184.
185.
144.
116.
181
8479 P
185.
180.
117.
127.
118.
102.
80.
67.
89.
128.
155
8480 P
181.
184.
184.
183.
180.
182.
184.
180.
184.
183.
184
8481 P b
131.
6.
72.
109.
94.
166.
185.
168.
123.
73.
184
8482 P
184.
150.
123.-
158,
130.
182.
185.
184.
180.
185.
184
8483 P
184.
180.
182.
184.
183.
184.
181.
183.
182.
180.
183
8484 P
168.
183.
181.
183.
184.
180.
183.
185.
180.
182.
182
8485 P
182.
184.
182.
185,
138.
181.
185.
181.
180.
iso.
180
8486 P
181.
185.
185.
151.
85.
59.
68.
110.
115.
115.
166
-----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. wet feed precluded the calculation of this value.
b. Doe 8481 had a litter which consisted of 10 dead fetuses; values excluded from group averages and statistic
C. Spilled feed precluded the calculation of this value.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 -----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8465 P
183.
181.
183.
185.
181.
180.
iss.
180.
182.
8466 NP
183.
184.
170.
180.
185.
167.
182.
144.
126'.
8467 NP
180.
184.
184.
183.
182.
180.
180.
180.
180.
8468 P
180.
180.
182.
126.
163.
120.
140.
86.
81.
8469 P
181.
180.
185.
65.
183.
180.
182.
180.
183.
8470 P
132.
93.
172.
50.
81.
123.
98.
134.
90.
8471 P
185.
185.
180.
103.
70.
99.
97.
161.
110.
8472 P
181.
185.
181.
183.
180.
181.
181.
181.
155.
8473 P
185.
159.
157.
158.
134.
119.
112.
104.
81.
8474 P
153.
152.
157.
109.
121.
103.
119.
80.
82.
8475 P
182.
185.
184.
181.
180.
183.
185.
184.
160.
8476 P
185.
183.
180.
lS8.
159.
147.
182.
160.
154.
8477 NP
183.
180.
ISO.
182.
183.
185.
183.
184.
172.
8478 P
185.
184.
131.
164.
147.
75.
19.
96.
98.
8479 P
180.
184.
180.
181.
133.
181.
113.
100.
67.
8480 P
180.
185.
183.
ISO.
185.
168.
172.
167.
140.
8481 P a
185.
160.
182.
185.
180.
153.
154.
132.
0.
8462 P
185.
183.
184.
156.
183.
181.
163.
166.
133.
8483 P
182.
181.
181.
180.
181.
180.
157.
143.
131.
8484 P
185.
160.
162.
118.
98.
40.
50.
64.
48.
8485 P
b
181.
180.
182.
180.
161.
180.
140.
1BI.
8486 P
184.
185.
182.
154.
150.
96.
b
70.
69.
-----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Doe 8481 had a litter which consisted of 10 dead fetuses; values excluded from group averages and statistic b. Spilled feed precluded the calculation of this value.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 5): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 -----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 111
1.0 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8487 P
143.
144.
162.
185.
184.
185.
184.
182.
184.
144.
185.
8488 P
185.
iso.
133.
163.
170.
152.
110.
150.
144'.
183.
185.
8489 P
182.
182.
181.
180.
181.
185.
185.
180.
185.
182.
185.
8490 P
149.
69.
145.
167.
185.
185.
181.
163.
183.
181.
180.
8491 P 8492 P
182. 156.
183. 90.
180. 84.
170. 84.
182. 109.
176. 86.
184. 67.
183. 83.
185. 87.
184. 116.
184. 135.
8493 P
180.
156.
182.
182.
181.
185.
182.
iso.
139.
142.
153.
8494 P
185.
180.
171.
184.
185.
153.
185.
182.
184.
184.
180.
0495 P
185.
185.
182.
180.
118.
183.
185.
183.
184.
125.
115.
8496 P
184.
115.
139.
146.
156.
152.
153.
182.
184.
185.
185.
8497 P
132.
138.
138.
158.
140.
92.
31.
29.
105.
124.
26.
8498 P
185.
184.
142.
173.
173.
158.
148.
183.
184.
184.
183.
8499 P
180.
181.
181.
183.
183.
183.
180.
185.
184.
185.
182.
8500 p
180.
126.
123,
145.
155.
143.
183.
184.
183.
183.
182.
8501 p
180.
184.
a
183.
114.
156.
183.
170.
182.
184.
173.
8502 NP
180.
132.
60.
131.
145.
123.
113.
135.
16S.
160.
149.
8503 P
180.
184.
183.
116.
118.
ise.
180.
181.
183.
181.
180.
8504 P
180.
185.
184.
163.
125.
115.
180.
156.
98.
70.
47.
8505 NP
184.
163.
163.
185.
181.
184.
181.
184.
180.
180.
182.
8506 P
181.
132.
156.
158.
126.
184.
174.
182.
185.
180.
182.
8507 P
183.
170.
154.
166.
168.
181.
170.
157.
iso.
184.
181.
8508 NP
180.
182.
182.
185.
185.
183.
180.
183.
182.
185.
183.
-----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Spilled feed precluded the calculation of this value.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 6): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8487 P
185.
182.
182.
185.
183.
128.
110.
77.
99.
8488 P
184.
184.
180.
185.
185.
181.
181.
181.
181
8489 P
185.
182.
ISO.
182.
185.
183.
185.
168.
173.
8490 P
184.
183.
185.
180.
180.
183.
114.
144.
85.
8491 P
185.
185.
182.
180.
160.
180.
120.
127.
94.
8492 P
170.
178.
173.
182.
133.
157.
138.
184.
120.
8493 P
135.
147.
136.
182.
114.
138.
132.
154.
103.
8494 P
185.
185.
155.
94.
139.
117.
161.
116.
101.
8495 P
162.
181.
162.
109.
83.
56.
90.
66.
62.
8496 P
167.
154.
136.
106.
149.
127.
152.
124.
127.
8497 P
185.
181.
184.
180.
184.
153.
175.
119.
107.
8498 P
164.
162.
165.
109.
183.
BB.
101.
73.
50.
8499 P
185.
185.
180.
183.
184.
180.
184.
180.
157.
8500 p
178.
185.
166.
120.
151.
183.
121.
133.
55.
8501 P
107.
74.
75.
130.
129.
182.
161.
169.
125.
8502 NP
154.
184.
130.
180.
80.
114.
112.
134.
46.
8503 P
184.
181.
184.
167.
153.
165.
103.
119.
94.
8504 P
isi.
147.
142.
183.
84.
98.
B.
7.
52.
8505 NP
181.
184.
184.
182.
185.
165.
174.
175.
146.
8506 p
180.
180.
2.
180.
184.
140.
136.
132.
120.
8507 P
180.
166.
181.
125.
142.
82.
81.
103.
110.
8508 NP
182.
181.
181.
159.
182.
52.
95.
154.
155.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 7): MATERNAL FEED CONSUMPTION
VALUES - INDIVIDUAL
DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8
a- 9
9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 -
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8509 P
146.
130.
72.
102.
85.
140.
125.
50.
108.
130.
180
esio p
182.
185.
183.
180.
184.
183.
182.
130.
106.
153.
167
8511 NP 8512 P
185. 182.
182. 181.
181. 181.
181. 180.
181. 169.
173. 178.
112. 184.
100. 185.
119.
142.
147
ISO.
180.
180
8513 NP
183.
185.
159.
163.
147.
168.
136.
112.
108.
161.
115
8514 P
184.
134.
80.
76.
108.
184.
185.
133.
122.
182.
180
8515 P
182.
125.
182.
180.
182.
183.
185.
185.
185.
182.
182
8516 P
180.
158.
108.
79.
101.
49.
110.
138.
180.
169.
140
8517 P
112.
180.
184.
165.
161.
130.
52.
6.
18.
1.
3
8518 P
179.
184.
185.
182.
185.
127.
133.
129.
184.
171.
92
8519 P
121.
185.
185.
162.
125.
138.
110.
162.
180.
144.
145
8520 P
181.
173.
125.
147.
121.
149.
133.
176.
153.
148.
127
8521 P
180.
153.
136.
133.
88.
100.
137.
182.
166.
124.
99
8522 P
180.
185.
184.
185.
185.
182.
183.
185.
185.
180.
180
8523 NP
185.
183.
164.
149.
185.
iss.
184.
183.
109.
39.
8
8524 NP
184.
167.
155.
127.
140.
Ill.
175.
166.
159.
153.
118
8525 P
185.
133.
124.
154.
164.
151.
181.
184.
183.
180.
180
8526 NP
162.
147.
133.
106.
155.
143.
159.
136.
143.
152.
148
8527 P
180.
184.
147.
150.
88.
80.
57.
81.
20.
89.
155
8528 P 8529 P
159.
145.
156.
106.
84.
62.
113.
146.
143.
132.
135
185.
135.
152.
151.
136.
184.
169.
160.
160.
143.
143
8530 P
183.
184.
181.
185.
184.
183.
184.
180.
183.
180.
182
----------------------------------------------------------------------------------------------------------------
P= DAYS ALL
PREGNANT = DAYS
WEIGHTS
NP = NOT PREGNANT
(VALUES
OF PRESUMED GESTATION
WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 8): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8509 p
184.
119.
87.
59.
114.
94.
117.
93.
86.
8510 P
150.
154.
138.
152.
180.
166.
157.
133.
118'.
8511 NP
143.
153.
146.
135.
150.
144.
159.
147.
132.
8512 P
183.
185.
185.
176.
146.
92.
76.
98.
90.
8513 NP
139.
128.
122.
135.
144.
122.
154.
143.
116.
8514 P
132.
92.
153.
109.
164.
105.
147.
121.
117.
8515 P
183.
185.
185.
180.
110.
154.
106.
90.
10.
8516 P
122.
125.
154.
167.
130.
109.
97.
180.
123.
8517 P
0.
38.
54.
75.
ABORTED ON DAY 25 OF GESTATION
8518 P
132.
118.
119.
52.
2.
0.
0.
7.
26.
8519 p
148.
137.
134.
90.
94.
78.
126.
104.
108.
8520 P
91.
133.
144.
125.
140.
116.
134.
107.
106.
8521 P
120.
137.
147.
126.
134.
108.
136.
118.
120.
8522 P
185.
181.
150.
180.
154.
180.
160.
166.
183.
8523 NP
4.
0.
2.
0.
0.
93.
108.
163.
172.
8524 NP
128.
98.
67.
28.
78.
176.
158.
145.
110.
8525 P
185.
a
185.
181.
108.
138.
102.
106.
88.
8526 NP
160.
185.
166.
183.
133.
133.
116.
158.
141.
8527 P
182.
149.
30.
89.
128.
168.
84.
ISO.
170.
8528 P
140.
101.
105.
73.
62.
74.
66.
79.
go.
8529 P
124.
92.
87.
84.
144.
122.
150.
159.
126.
8530 P
185.
180.
183.
182.
181.
116.
103.
62.
94.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS a. Spilled
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G). feed precluded the calculation of this value.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 9): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 ----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8531 P
181.
185.
184.
181.
181.
152.
135.
185.
184.
184.
185
8532 P
184.
146.
117.
93.
64.
183.
131.
21.
5'.
10.
0
8533 P
183.
139.
102.
ill.
116.
142.
113.
90.
64.
94.
96
8534 P
147.
145.
86.
66.
19.
56.
29.
3.
11.
2.
0
8535 P
167.
93.
65.
105.
185.
185.
iss.
150.
181.
180.
152
8536 P
44.
184.
183.
184.
178.
144.
81.
66.
80.
81.
67
8537 P
134.
73.
99.
102.
165.
73.
3.
0.
12.
0.
4
8538 P
S.
44.
18.
2.
46.
23.
5.
0.
2.
0.
10
8539 P
184.
103.
65.
23.
83.
S.
3.
0.
3.
3.
13
8540 P
184.
184.
185.
183.
180.
18S.
184.
169.
78.
3.
0
8541 P
180.
183.
180.
180.
171.
174.
165.
182.
181.
184.
185
8542 P
184.
182.
149.
147.
113.
100.
107.
158.
76.
121.
84
8543 P
185.
163.
159.
118.
86.
22.
6.
1.
9.
4.
0
8544 P
185.
180.
184.
182.
143.
84.
10.
2.
2.
24.
12
8545 P
180.
180.
179.
165.
159.
129.
175.
183.
185.
184.
183
8546 P
0.
182.
182.
183.
182.
180.
183.
182.
183.
182.
150
8547 P
181.
181.
151.
90.
28.
22.
4.
1.
7.
3.
5
8548 P
180.
183.
183.
185.
183-
184.
150.
147.
140.
121.
104
8549 P
185.
185.
185.
105.
126.
157.
145.
113.
60.
6.
17
8550 P
183.
185.
182.
185.
160.
171.
183.
184.
184.
173.
152
8551 P
183.
183.
ISO.
184.
185.
183.
185.
182.
185.
166.
183
8552 NP
161.
161.
125.
119.
106.
144.
122.
127.
143.
104.
130
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS
NP = NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 10): MATERNAL FEED CONSUMPTION
VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 -----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8531 P
180.
180.
185.
184.
185.
182.
180.
127.
141.
8532 P
0.
89.
124.
137.
183.
180.
182.
185.
182'.
8533 P
17.
46.
81.
78.
114.
92.
108.
70.
103.
8534 P
S.
ABORTED ON DAY 22 OF GESTATION
8535 P
40.
4.
1.
2.
2.
1.
41.
171.
82.
8536 P
166.
167.
180.
185.
164.
182.
124.
183.
121.
8537 P
0.
0.
0.
0.
ABORTED ON DAY 25 OF GESTATION
8538 P
9.
10.
7.
ABORTED
ON DAY 24 OF GESTATION
8539 P
0.
0.
0.
ABORTED
ON DAY 24 OF GESTATION
8540 P
4.
1.
0.
6.
ABORTED ON DAY 25 OF GESTATION
8541 P
185.
180.
183.
147.
138.
70,
23.
56.
107.
8542 P
1.
2.
7.
3.
13.
B.
10.
ABORTED ON DAY 28 OF GESTATION
8543 P
2.
2.
0.
1.
1.
0.
0.
0.
0.
8544 P
1.
4.
4.
0.
ABORTED ON DAY 25 OF GESTATION
8545 P
118.
182.
181.
180.
157.
183.
119.
11.
71.
8546 P
159.
124.
145.
5.
132.
84.
105.
106.
112.
8547 P
0.
ABORTED ON DAY 22 OF GESTATION
8548 P
180.
12.
2.
122.
ABORTED ON DAY 25 OF GESTATION
8549 P
92.
95.
99.
181.
180.
144.
166.
128.
131.
8550 P
175.
Ill.
184.
ill.
181.
131.
136.
127.
65.
8551 P
127.
91.
41.
56.
139.
116.
149.
169.
154,
8552 NP
99.
78.
141.
107.
143.
95.
107.
104.
110.
-----------------------------------------------------------------------------------------------------------------
P= DAYS ALL
PREGNANT = DAYS
WEIGHTS
NP = NOT PREGNANT
(VALUES
OF PRESUMED GESTATION WERE RECORDED IN GRAMS
(G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 11): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 1 -----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8553 P
184.
185.
169.
184.
7.
180.
185.
185.
180.
180.
184
8554 P
185.
184.
180.
185.
185.
183.
184.
184.
ISO .
180.
184
8555 p
103.
142.
114.
97.
87.
113.
85.
126,
107.
150.
171
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ----------------------------------------------------------------------------------------------------------------
8553 P
ISO.
8554 P
182.
8555 p
120.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS - DAYS ALL WEIGHTS
NP = NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 12): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 a - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 ---------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP Il
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8556 P
147.
142.
133.
130.
128.
165.
143.
165.
85.
68.
15
BSS7 P
181.
172.
104.
180.
94.
150.
92.
110.
146 .
154.
is
85SB P
18S.
183.
184.
182.
151.
132.
30.
118.
159.
180.
18
8559 P
182.
180.
183.
185.
83.
182.
184.
183.
185.
185.
is
8560 P
185.
153.
115.
126.
90.
182.
184.
184.
185.
180.
16
---------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ---------------------------------------------------------------------------------------------------------------
8556 P
182.
8557 P
183.
8558 P
159.
8559 p
184.
8560 P
108.
---------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS
NP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (C).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 13): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 a - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 ----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP iir
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8561 P
184.
180.
185.
138.
74.
155.
184.
180.
180.
184.
184
8562 P
181.
180.
180.
184.
134.
185.
185.
183.
180'.
185.
180
8563 P
134.
124.
151.
147.
125.
166.
141.
139.
150.
147.
140
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ----------------------------------------------------------------------------------------------------------------
8561 P 8962 P
180. 173.
8563 P
95.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED
DAYS = DAYS OF PRESUMED GESTATION
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 14): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - I -----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8564 P
164.
180.
177.
141.
116.
158.
125.
139.
127.
132.
180.
8565 P
183.
163.
185.
151.
38.
30.
2.
1.
1.
154.
185.
8566 P
185.
184.
183.
180.
107.
126.
49.
32.
63.
57.
86.
-----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 -----------------------------------------------------------------------------------------------------------------
8564 P
166.
8565 P
123.
8566 P
151.
-----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS
NP = NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 17 (PAGE 15): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 ----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8567 P
182.
183.
114.
116.
153.
65.
182.
143.
129.
34.
109
8568 P
140.
139.
79.
63.
55.
64.
73.
83.
83'.
oil
113
8569 NP
185.
132.
67.
182.
0.
4.
2.
0.
S.
12.
a
8570 P
185.
184.
184.
182.
148.
180.
83.
4.
7.
13.
6
8571 P
119.
lie.
115.
184.
72.
79.
19.
25.
48.
66.
107
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ----------------------------------------------------------------------------------------------------------------
8567 P
0.
8568 P
132.
8569 NP
0.
8570 P
174.
8571 P
84.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 18 (PAGE 1): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
C
------------------------ ---------------- ---------------- ---------------- ---------------- ---
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIG
RABBIT # M F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8443 NOT PREGNANT
8444 5 2
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
2
8445 NOT PREGNANT
8446 3 4
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
6
8447 5 7
5
7
12
0
0
0
0
0
0
0
@o
0
5
7
12
7
8448 6 4
6
4
10
0
0
0
0
0
0
1
0
1
7
4
11
7
8449 7 2
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
6
8450 6 4
6
4
10
0
0
0
0
1
1
0
0
0
6
5
11
7
8451 5 2
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
7
8452 2 4
5
1
6
0
0
0
0
1
1
0
0
0
5
2
7
6
8453 5 4
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
6
8454 3 7
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
7
8455 5 6
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
6
0456 4 2
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
3
8457 4 4
5
3
8
0
0
0
0
0
0
0
0
0
5
3
8
5
84S8 6 8
7
7
14
0
0
0
0
0
0
0
0
0
7
7
14
7
8459 2 5
6
1
7
0
0
0
0
0
0
0
0
0
6
1
7
6
8460 4 3
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
4
8461 3 3
2
4
6
0
0
0
0
0
0
0
0
0
2
4
6
6
8462 3 6
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
6
8463 6 4
9
1
10
0
0
0
1
0
1
0
0
0
10
1
11
10
8464 3 7
7
3
10
0
0
0
0
0
0
0
0
0
7
3
10
7
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 18 (PAGE 2): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
C
------------------------ ---------------- ---------------- ---------------- ----------------
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIG
RABBIT # M F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP Il
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8465 1 5
3
3
6
0
0
0
1
0
1
0
0
0
4
3
7
4
8466 NOT PREGNANT
8467 NOT PREGNANT
8468 3 7
4
6
10
0
0
0
0
0
0
0
0
0
4
6
10
8
8469 2 5
6
1
7
0
0
0
0
0
0
0
0
0
6
1
7
7
8470 6 1
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
4
8471 3 6
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
5
8472 3 6
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
6
8473 4 4
5
3
8
0
0
0
1
0
1
0
0
0
6
3
9
6
8474 4 5
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
5
8475 2 5
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
4
8476 6 4
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
6
8477 NOT PREGNANT
8478 6 4
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
7
8479 6 9
6
9
is
0
0
0
0
0
0
0
0
0
6
9
15
8
8480 6 3
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
6
8481a 0 0
0
0
0
3
7
10
0
0
0
0
0
0
3
7
10
3
8482 4 5
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
3
8483 6 2
5
3
8
0
0
0
0
0
0
0
0
0
5
3
8
7
8484 6 3
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
6
8485 3 6
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
7
8486 3 8
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
7
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE.
a. Doe 8481 had a litter which consisted of 10 dead fetuses; values excluded from group averages and statistic
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 18 (PAGE 3): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
c
------------------------ ---------------- ---------------- ---------------- ---------------- ---
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIG
RABBIT # M F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8487 4 2
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
3
8488 3 4
2
5
7
0
0
0
1
0
1
0
0
0
3
5
8
5
8489 2 4
2
4
6
0
0
0
1
0
1
0
0
0
3
4
7
3
8490 1 4
0
5
5
0
0
0
0
0
0
0
0
0
0
5
5
2
8491 5 4
3
6
9
0
0
0
0
0
0
0
1
1
3
7
10
5
8492 2 7
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
6
8493 2 3
1
4
5
0
0
0
0
0
0
0
3
3
1
7
a
2
8494 2 4
2
4
6
0
0
0
0
0
0
0
0
0
2
4
6
5
8495 7 3
7
3
10
0
0
0
0
0
0
0
0
0
7
3
10
9
8496 1 8
7
2
9
0
0
0
0
0
0
0
0
0
7
2
9
a
8497 4 3
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
3
8498 3 6
1
8
9
0
0
0
0
0
0
0
0
0
1
a
9
1
8499 6 2
3
5
a
0
0
0
0
0
0
0
0
0
3
5
8
3
8500 S 5
2
a
10
0
0
0
0
0
0
0
1
1
2
9
11
3
8501 8 3
6
5
11
0
0
0
0
0
0
0
0
0
6
5
11
8
8502 NOT PREGNANT
8503 5 5
8
2
10
0
0
0
0
0
0
0
0
0
a
2
10
9
8504 4 6
3
7
10
0
0
0
0
0
a
0
0
0
3
7
10
5
8505 NOT PREGNANT
8506 4 5
7
2
9
0
0
0
0
0
0
0
0
0
7
2
9
8
8507 3 3
0
6
6
0
0
0
0
0
0
0
0
0
0
6
6
3
8508 NOT PREGNANT ----------------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE.
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 18 (PAGE 4): CAESAREAN-SECTIONING
OBSERVATIONS
- INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES ------------------------
DEAD FETUSES
EARLY RESORPTIONS
LATE RESORPTIONS
IMPLANTATION
SITES
---------------- ---------------- ---------------- ----------------
co ----
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGH
RABBIT # M
F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
0
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8509
2
s
3
4
7
0
0
0
1
0
1
0
0
0
4
4
a
4
8510 4
4
5
3
8
0
0
0
0
0
0
0
0
0
5
3
a
7
8511 NOT PREGNANT
8512
3
4
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
7
8513 NOT PREGNANT
8514
3
4
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
6
851S 4
5
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
4
8516
4
3
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
3
8517 ABORTED ON DAY 25 OF GESTATION
8518
7
2
4
5
9
0
0
0
0
0
0
1
0
1
5
5
10
7
8519 6 2
3
5
a
0
0
0
0
0
0
0
0
0
3
5
a
3
8520 3
2
2
3
5
0
0
0
0
0
0
0
0
0
2
3
5
2
8521 6 4
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
7
8522
3
6
5
4
9
0
0
0
0
0
0
0
1
1
5
5
10
6
8523 NOT PREGNANT
8524 NOT PREGNANT
8525
5
6
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
6
8526 NOT PREGNANT
8527 7
4
6
5
11
0
0
0
0
0
0
0
0
0
6
s
11
6
8520 3
4
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
6
8529 2
3
1
4
5
0
0
0
1
0
1
0
0
0
2
4
6
3
8530 4
6
7
3
10
0
0
0
0
0
0
0
0
0
7
3
10
7
-----------------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE
APPEARED
NORMAL
UNLESS
NOTED OTHERWISE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NTIMBER:
TABLE 18 (PAGE 5): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
VIA13LE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
c
------------------------ ---------------- ---------------- ---------------- ---------------- ---
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIG
RABBIT # M F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8531 6 3
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
4
8532 4 4
5
3
8
0
0
0
0
0
0
0
0
0
5
3
8
6
8533 2 4
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
7
8534 ABORTED ON DAY 22 OF GESTATION
8535 8 3
8
3
11
0
0
0
0
0
0
0
0
0
a
3
11
8
8536 3 5
2
6
8
0
0
0
1
0
1
0
0
0
3
6
9
3
8537 ABORTED ON DAY 25 OF GESTATION
8538 ABORTED ON DAY 24 OF GESTATION
8539 ABORTED ON DAY 24 OF GESTATION
8540 ABORTED ON DAY 25 OF GESTATION
8541 2 5
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
5
8542 ABORTED ON DAY 28 OF GESTATION
8543 2 7
6
3
9
0
0
0
0
0
0
0
1
1
6
4
10
7
8544 ABORTED ON DAY 25 OF GESTATION
8545 5 8
6
7
13
0
0
0
0
0
0
0
0
0
6
7
13
6
8546 0 7
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
3
$547 ABORTED ON DAY 22 OF GESTATION
0540 ABORTED ON DAY 25 OF GESTATION
8S49 6 4
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
7
8550 7 3
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
7
8551 5 5
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
8552 NOT PREGNANT ----------------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE APPEARED NORMAL
UNLESS NOTED OTHERWISE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 18 (PAGE 6): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
co
------------------------ ---------------- ---------------- ---------------- ---------------- ----
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGH
RABBIT
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
0
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8553
4
9
13
0
0
0
0
0
0
0
0
0
4
9
13
4
8554
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
8555
3
5
8
0
0
0
0
0
0
0
0
0
3
5
a
3
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8556
4
4
8
0
0
0
0
0
0
0
0
0
4
4
8
4
8557
3
4
7
0
0
0
0
0
0
1
0
1
4
4
8
4
8558
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
8559
7
4
11
0
0
0
0
0
0
0
0
0
7
4
11
7
8560
4
7
11
0
0
0
0
0
0
0
0
0
4
7
11
4
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8561
0
2
2
0
0
0
0
0
0
0
0
0
0
2
2
0
8562
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
5
8563
1
6
7
0
0
0
0
0
0
0
0
0
1
6
7
2
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8564
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
8565
7
3
10
0
0
0
0
0
0
0
0
0
7
3
10
7
8566
4
4
8
0
0
0
0
0
0
0
0
0
4
4
a
4
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.7S MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8567
3
7
10
0
0
0
0
0
0
0
0
0
3
7
10
3
8568
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
5
8569 NOT PREGNANT
8570
4
5
9
0
0
0
a
0
0
0
0
0
4
5
9
6
8571
0
2
2
0
0
0
1
0
1
0
0
0
1
2
3
2
-----------------------------------------------------------------------------------------------------------------
PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PPOS IN RABBITS (SPONSOR'S STUDY NUMBER-
TABLE 19 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
-----------------------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
7,
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8443
NOT PREGNANT
8444
5
2
7
51.30
49.86
50.89
7
0
0.0
8445
NOT PREGNANT
8446
3
4
7
51.60
46.62
48.75
7
0
0.0
8447
5
7
12
44.66
42.94
43.66
12
0
0.0
8448
6
4
10
47.24
44.60
46.18
11
1
9.1
8449 8450
.7
2
9
44.62
47.62
45.29
9
6
4
10
44.86
42.48
43.91
11
0
0.0
1
9.1
8451
5
2
7
47.34
49.38
47.92
7
0
0.0
8452
2
4
6
47.98
50.26
49.50
7
1
14.3
8453
5
4
9
50.65
45-67
48.44
9
0
0.0
8454
3
7
10
44.11
39.29
40.74
10
0
0.0
8455
5
6
11
46.24
42.17
44.02
11
0
0.0
8456
4
2
6
46.98
51.80
48.59
6
0
0.0
84S7
4
4
8
44.81
41.70
43.26
a
0
0.0
8458
6
8
14
37.79
36.06
36.80
14
0
0.0
8459
2
5
7
39.94
43.44
42.44
7
0
0.0
8460
4
3
7
44.86
44.63
44.76
7
0
0.0
8461
3
3
6
44.44
47.33
45.88
6
0
0.0
8462
3
6
9
38.30
38.28
38.29
9
0
0.0
8463
6
4
10
40.69
38.04
39.63
11
1
9.1
8464
3
7
10
31.60
34.98
33.97
10
0
0.0
-----------------------------------------------------------------------------------------------------------------
a. TOTAL - SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-012: ORAL ISTOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 19 (PAGE 2): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
---------------------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
06
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8465 8466
1
5
NOT PREGNANT
6
45.60
47.09
46.84
7
1
14.3
8467
NOT PREGNANT
0468 8469 8470 8471 8472 8473 8474 8475 8476 8477
3
7
10
43.49
39.60
40.77
10
2
5
7
43.00
47.51
46.22
7
6
1
7
41.04
36.76
40.43
7
3
6
9
41.56
41.22
41.33
9
3
6
9
44.55
40.00
41.52
9
4
4
8
38.61
39.84
39.23
9
4
5
9
44.18
43.07
43.57
9
2
5
7
41.22
39.68
40.12
7
6
4
10
41.29
36-39
39.33
10
NOT PREGNANT
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
1
11.1
0
0.0
0
0.0
0
0.0
8478
6
4
10
38.49
38.S4
38.51
10
0
0.0.
8479
6
9
15
37.45
34.32
35.57
15
0
0.0
8480 8481b
6
3
9
43.58
44.16
43.78
9
0
0.0
0
0
0
----
----
----
10
10
100.0
8482
4
5
9
37.77
36.95
37.31
9
0
0.0
8483
6
2
8
47.47
48.04
47.61
8
a
0.0
8484
6
3
9
41.16
43.89
42.07
9
0
0.0
8485
3
6
9
42.66
45.71
44.70
9
0
0.0
8486
3
8
11
39.65
41.71
41.14
11
0
0.0
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
b. Doe 8481 had a litter which consisted of 10 dead fetuses; values excluded from group averages and statisti
PROTOCOL 418-012: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 19 (PAGE 3): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
--------------------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
PEMALE
TOTAL a
N
N
!k
-----------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8487 8488 8489 8490 8491 8492 8493 8494 8495 8496 8497 8498 8499 8500 8501 8502
4
2
6
45.08
47.92
46.03
6
3
4
7
44.95
48.43
46.94
a
2
4
6
47.74
45.64
46.34
7
1
4
5
52.43
49.38
49.99
5
5
4
9
43.39
38.25
41.11
10
2
7
9
39.84
39.32
39.44
9
2
3
5
45.12
40.46
42.33
8
2
4
6
40.86
41.00
40.95
6
7
3
10
39.82
37.36
39.09
10
1
8
9
50.85
43.20
44-05
9
4
3
7
44.44
46.43
45.30
7
3
6
9
32.90
35.34
34.52
9
6
2
8
38.95
39.98
39.21
8
5
5
10
40.43
37.51
38.97
11
8
3
11
40.83
35.95
39.50
11
NOT PREGNANT
0
0.0
1
12.5
1
14.3
0
0.0
1
10.0
0
0.0
3
37.5
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
1
9.1
0
0.0
8503
5
5
10
40.58
37.54
39.06
10
0
0.0
8504
4
6
10
34.81
37.76
36.58
10
0
0.0
8505
NOT PREGNANT
8506
4
5
9
49.77
45.23
47.25
9
0
0.0
8507
3
3
6
29.49
50.22
39.85
6
0
0.0
8508
NOT PREGNANT
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 19 (PAGE 4)- LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
---------- -----------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
&
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
---------- -----------------------------------------------------------------------------------------------------
8509 8510 8511
2
5
4
4
NOT PREGNANT
7
42.72
8
46.61
44.49 34.32
43.98 40.46
a
1
12.5
8
0
0.0
8512 8513
3
4
NOT PREGNANT
7
46.69
46.17
46.39
7
0
0.0
8514 8515 8516 8517 8518 8519 8520 8521 8522 8523
3
4
7
44.41
40.65
42.26
7
4
5
9
36.02
35.39
35.67
9
4
3
7
44.57
41.71
43.34
7
ABORTED ON DAY 25 OF GESTATION
7
2
9
33.81
29.02
32.74
10
6
2
8
37.80
36.28
37.42
8
3
2
5
38.96
44.59
41.21
5
6
4
10
41.46
36.27
39.39
10
3
6
9
43.88
44-50
44.29
10
NOT PREGNANT
0
0.0
0
0.0
0
0.0
1
10.0
0
0.0
0
0.0
0
0.0
1
10.0
8524
NOT PREGNANT
8525
5
6
11
35.57
31.32
33.25
11
0
0.0
8526
NOT PREGNANT
8527
7
4
11
32.91
33.76
33.22
11
0
0.0
8528 8529
3
4
7
45.15
43.71
44.32
2
3
5
38.80
41.40
40.36
7
0
0.0
6
1
16.7
8530
4
6
10
39.56
40.17
39.93
10
0
0.0
----------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 19 (PAGE 5): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
---------------------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
t
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8531
6
3
9
40.47
39.78
40.24
9
0
0.0
8532
4
4
a
34.20
34.17
34.18
8
0
0.0
8533
2
4
6
40.65
37.75
38.72
6
0
0.0
8534
ABORTED ON DAY 22 OF GESTATION
8535
8
3
11
32.41
22.67
29.75
11
0
0.0
8536
3
5
8
36.22
36.17
36.19
9
1
11.1
8537
ABORTED ON DAY 25 OF GESTATION
8538
ABORTED ON DAY 24 OF GESTATION
8539
ABORTED ON DAY 24 OF GESTATION
8540
ABORTED ON DAY 25 OF GESTATION
8541
2
5
7
43.72
39.86
40.96
7
0
0.0
8542 8543
ABORTED ON DAY 28 OF GESTATION
2
7
9
17.69
13.84
14.70
10
1
10.0
8544
ABORTED ON DAY 25 OF GESTATION
8545 8546
5
8
13
27.58
25.53
26-32
13
0
0.0
0
7
7
----
38.59
38.59
7
0
0.0
8547
ABORTED ON DAY 22 OF GESTATION
8548
ABORTED ON DAY 25 OF GESTATION
8549 8550
6
4
10
28.54
26.52
27.73
10
0
0.0
7
3
10
36.26
34.96
35.87
10
0
0.0
8551
5
5
10
37.36
37.93
37.64
10
0
0.0
8552
NOT PREGNANT
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-012: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 19 (PAGE 6): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
DEAD OR RESORBED
---------------------------------------------------------------------------------------------------------------
RABBIT #
TOTAL
TOTAL a
N
N
!k
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8553
13
4.96
13
0
0.0
8554
10
4.59
10
0
0.0
8555
8
5.14
8
0
0.0
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 11
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8556
8
5.17
8
0
0.0
8557
7
4.69
8
1
12.5
8558
10
4.56
10
0
0.0
8559
11
5.21
11
0
0.0
8560
11
4.96
11
0
0.0
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8561
2
5.37
2
0
0.0
8562
9
5.12
9
0
0.0
8563
7
5.06
7
0
0.0
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8564
10
4.89
10
0
0.0
8565
10
5.49
10
0
0.0
8566
8
4.14
8
0
0.0
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8567
10
4.30
10
0
0.0
8568
7
4.61
7
0
0.0
8569
NOT PREGNANT
8570
9
5.18
9
0
0.0
8S71
2
5.78
3
1
33.3
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 20 (PAGE 1): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8443
NOT PREGNANT
8444 8445
2/ 6
MA 56.21
NOT
FA / MA 51.03 53.74 PREGNANT
MA 53.50
FA 48.70
MA 49.27
MA 43.80
8446 6/ 7
MA
MA / MA
FA
FA
PA
FA
52.73 45.56 56.50 52.59 46.91 43.50 43.48
8447 7/ 8
FA
FA
MA
FA
MA
MA
MA
FA
FA
FA
FA
MA
52.34 43.91 43.11 44.81 44.16 44.38 43.14 46.06 44.06 32.77 36.63 48.49
8448 7/ 5
?4A
FA
MA
MA
L
MA
FA
FA
MA
FA
MA
44.73 43.94 50.24 48.10
45.20 42.35 48.09 50.37 44.00 44.83
8449 6/ 6
FA
FA
MA
MA
MA
MA
MA
MA
MA
46.84 48.40 42.94 48.11 49.00 46.13 42.21 39.98 44.01
8450 7/ 6
MA
MA
FA
FA
MA
FA
MA
E
FA
MA
MA
50.79 47.41 45.63 41.80 37.55 40.11 50.49
42.39 37.99 44.95
8451 7/ 2
MA
MA
MA
FA
MA
FA
MA
47.90 49.72 44.85 45.48 49.43 53.27 44.79
8452 6/ 3
FA
FA
FA
MA
MA
E
FA
45.63 55.44 52.04 48.77 47.20
47.92
8453 6/ 7
MA
FA
MA
MA
PA
FA
MA
MA
PA
62.37 51.25 52.51 50.58 36.80 48.85 39.38 48.41 45.78
8454 7/ 5
FA
FA
FA
FA
FA
FA
FA
btA
MA
MA
41.88 38.46 37.67 41.55 36.23 39.41 39.85 42.97 45.40 43.97
8455 G/ 7
MA
FA
MA
FA
FA
MA
FA
MA
FA
FA
MA
46.20 43.72 42.71 44.40 46.73 48.40 45.18 45.99 36.63 36.36 47.92 ---------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITI
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 2): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # CLa
8456 3/ 4
FA
MA
MA / FA
MA
KA
50.69 48.39 46.64 52.91 47.19 45.70
8457 5/ 3
MA
MA
FA
FA
MA
FA
MA
FA
49.24 40-91 45.36 41.77 39.57 43.53 49.51 36.15
8458 7/ 7
MA
FA
FA
FA
MA
PA
MA
FA
PA
MA
MA
PA
FA
MA
48.33 34.86 37.64 41.01 30.01 32.55 38.35 41.70 37.67 40.03 35.05 33.42 29.59 34.98
8459 6/ 1
FA
FA
MA
KA
FA
FA
FA
50.26 46.54 43.89 35.98 37.66 40.16 42.57
8460 4/ 4
FA
MA
FA
MA
MA
FA
MA
47.79 45.01 47.77 40.17 49.24 38.33 45.04
8461 6/ 4
MA
FA
FA
FA
MA
MA
43.96 43.13 48.41 50.44 42.14 47.23
8462 61 5
MA
FA
FA
MA
FA
FA
FA
FA
MA
40.36 38.51 38.20 41.28 40.99 39.45 38.36 34.18 33.26
8463 10/ 3
E
FA
MA
PA
MA
MA
FA
FA
MA
14A / MA
41.92 43.20 44.40 38.14 34.30 37.73 28.09 34.76 42.28 51.47
8464 7/ 3
MA
FA
FA
FA
FA
MA
FA
FA
MA
FA
34.27 30.24 35.00 32.69 30.71 26.55 36.96 40.65 33.98 38.63 ----------------------------------------------------------------------------------------------------------------
M = MALE
F - FEMALE
A - ALIVE D = DEAD
E = EARLY RESORPTION
L - LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITIO
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR-S STUDY NUMBER
TABLE 20 (PAGE 3): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
--------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
--------------------------------------------------------------------------------------------------------------
RABBIT # 8465
8466
CLs 4/ 3
MA 45.60
NOT
FA
FA
43.81 48.51
PREGNANT
E
FA
FA
FA
48.37 48.03 46.75
8467
NOT PREGNANT
8468
B/ 7
MA
MA
MA
PA
FA
FA
FA
FA
FA
PA
47.27 40.38 42.81 36.38 44.10 44.88 39.45 35.81 37.69 38.89
8469 8470 8471 8472 8473 8474 8475 8476
7/ 2 4/ 5 S/ 8 6/ 4 6/ 5 5/ 5 4/ 4 6/ 6
FA 53.28
MA 42.48
MA 33.93
FA 44.77
MA 49.18
MA 43.52
FA 33.93
FA 44.27
FA 51.18
FA 36.76
MA 45.03
FA 42.76
FA 38.09
MA 44.47
MA 42.02
MA 44.37
FA 45.06
MA 36.81
FA 40.91
MA 40.73
E
MA 43.89
FA 41.30
FA 38.82
FA 44.83
MA 42.03
FA 38.12
FA 41.27
MA 34.07
FA 38.06
MA 40.42
FA 30.39
MA 39.47
MA 46.43
FA 40.87
FA 32.00
MA 25.96
FA 47.20
FA 38.71
FA 32.09
FA
MA
43.21 46.53
MA
KA
41.31 37.18
MA
FA
45.72 42.20
FA
MA
33.58 52.07
FA
FA
29.61 47.33
FA
FA
45.16 43.96
FA
FA
43.59 40.89
MA / t4A
37.95 47.12
FA 41.34
FA 45.61
FA 44.35
MA 44.86
MA 42.34
FA 43.88
MA 40.86
MA 45.23
FA 40.99
MA 35.65
MA 40.30
8477
NOT PREGNANT
---------------------------------------------------------------------------------------------------------------
M = MALE
F - FEMALE
A = ALIVE D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITI
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 4): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8478 7/ 5
MA
FA
MA
MA
MA
FA / MA
FA
MA
FA
46.49 39.16 38.92 33.12 35.57 41.39 44.32 35.54 32.50 38.05
8479 S/ 9
FA
FA
FA
FA
FA
MA
MA
MA
MA
MA
FA
MA
FA
FA
FA
22.79 35.71 35.64 38.48 43.11 35.88 34.26 42.60 41.00 43.87 45.69 27.08 25.39 32.10 29.98
8480 6/ 3
MA
FA
FA
14A
MA
MA
FA
MA
14A
46.60 41.98 40.91 46.54 39.30 42.05 49.60 45.06 41.95
8481a 3/ 8
FD
FD
FD
FD
MD
FD
FD
FD
FD
FD
45-86 46.91 45.99 51.11 47.50 45.01 38.98 41.14 38.31 41.88
8482 3/ 7
MA
FA
FA
MA
MA
FA
MA
FA
PA
43.89 45.85 37.85 39.97 35.69 31.76 31.53 30-39 38.88
8483 7/ 4
MA
FA
FA
MA
MA
MA
MA
MA
55.20 51.95 44.14 38.19 45.14 45.41 47.60 53.27
8484 6/ 3
FA
MA
MA
MA
FA
MA
MA
FA
MA
48.76 48.13 42.50 46.08 39.88 25.38 42.43 43.02 42.47
8485 7/ 4
FA
MA
FA
FA
MA
FA
FA
FA
MA
49.61 48.36 43.09 44.08 38.45 43.78 52.45 41.27 41.17
8486 7/ 6
FA
MA
FA
PA
FA
FA
FA
MA
FA
MA
FA
45.21 44.96 44.27 37.15 39.12 44.51 45.63 40.85 36.11 33.13 41.65 ----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
DENOTES POSITI(
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
a. Doe 8481 had a litter which consisted of 10 dead fetuses; values excluded from group averages and Btatiati
PROTOCOL 418-012; ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 20 (PAGE 5)- FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8487 3/ 4
FA
MA
MA
FA
MA
MA
46.05 48.00 43.38 49.80 45.05 43.88
8488 S/ 6
E
PA
FA
FA
FA
MA
MA
MA
46.18 49.04 50.97 47.52 43.30 42.11 49.43
8489 3/ 5
MA
FA
E
FA
MA
FA
FA
47.90 46.58
44.56 47.57 43.24 48.17
8490 2/ 5
MA
FA
FA
FA
FA
52.43 50.12 43.68 48.93 54.79
8491 S/ 8
MA
FA
14A
FA
MA
L
MA
MA
FA
FA
46.90 38.03 43.41 45.04 48.94 1.26 41.01 36.71 35.45 34.47
8492 6/ 3
MA
FA
FA
MA
PA
FA
FA
FA
FA
42.28 38.88 39.50 37.41 33.81 36.29 44.06 40.60 42.09
8493 2/10
PA
MA
L
L
L
MA
FA
FA
45.19 45.57 5.95 0.79 0.98 44.67 37.65 38.55
8494 5/ 6
MA
MA
FA
FA
FA
FA
41.15 40.58 43.50 40.57 38.44 41.47
8495 9/ 4
MA
MA
FA
MA
FA
MA
MA / MA
FA
MA
43.56 42.88 35.41 31.44 32.83 28.21 45.91 45.94 43.85 40.84
8496 8/ 5
FA
FA
FA
FA
FA
FA
FA / FA
MA
53.70 48.23 45.40 35.33 41.06 34.07 35.52 52.26 50.85
8497 3/ 5
MA
FA
FA
FA
MA
MA
MA
47.84 47.91 44.18 47.21 47.13 39.11 43.69
8498 1/ 8
MA
PA
FA
FA
MA
FA
FA
MA
FA
38.14 38.40 36.49 35.23 32.16 30.78 32.92 28.40 38.21
8499 3/ 5
MA
MA
MA
PA
PA
MA
MA
MA
42.91 40.01 39.98 41.98 37.98 34.30 37.94 30.55 --------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSIT
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 6): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # 8500
8501
8502
CLs 3/ 9
B/ 6
FA 43.88
MA 43.17
NOT
t4A / FA
42.23 35.01
MA
MA
36.70 41.88
PREGNANT
MA 43.85
MA 42.12
FA 35.53
MA 40.72
MA 36.84
MA 40.73
L 1.33
MA 48.19
FA 38.59
FA 39.68
FA 34.52
FA 33.34
f4A 42.42
MA 33.14
MA 36.79
FA 34.84
8503 8504 8505
9/ 4 S/ 7
MA 49.13
FA 43.92
NOT
MA
MA
46.49 39.69
FA
FA
40.39 34.65
PREGNANT
MA 39.73
MA 39.94
PA 37.16
FA 38.17
FA 28.48
MA 32.76
MA 27.87
MA 35.21
FA 30.10
FA 36.00
FA 47.22
MA 31.32
FA 44.76
FA 33.46
8506 8/ 3
PA
FA
MA
FA
FA
FA
MA
MA
MA
48.96 49.18 52.74 49.93 43.75 34.33 47.69 50.65 48.01
8507 3/ 6 / MA
PA
FA
FA
MA
MA
51.22 52.40 48.86 49.39 47.99 40.47
8508
NOT PREGNANT
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
D = DEAD
E = EARLY RESORPTION
L - LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITIO
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 7): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # 8509
8510
8511
CLs 4/ 7
7/ 5
14A 48.53
MA 52.02
NOT
E
FA
41.94
MA
FA
46.80 33.61
PREGNANT
FA 46.99
FA 35.29
FA 44.40
PA 30.02
FA 40.30
MA 51.25
FA 48.82
FA 38.34
MA 36.91
KA 36.38
8512 8513
7/ 4
MA 52.12
NOT
FA
MA
47.92 42.50
PREGNANT
FA 43.65
MA 45.46
FA 49.14
FA 43.96
6514 8515 8516 8517
6/ 7 4/ 6 3/ 6
FA
FA
FA
MA
MA
FA
44.25 42.18 37.29 44.61 45.67 38.88
FA
FA
MA
FA
MA
FA
39.20 36.77 37.54 34.18 37.55 34.51
MA
FA / MA
MA
FA
MA
45.09 41.03 48.93 42.06 42.55 42.20
ABORTED ON DAY 25 OF GESTATION
MA 42.96
MA 33.67
FA 41.54
FA 32.27
MA 35.34
8518 7/ 5
MA
MA
MA
MA
L / MA
FA
MA
MA
FA
35.13 37.26 33.3S 31.55 0.58 37.57 34.95 30.47 31.32 23.08
8519 3/ 5
MA
MA
FA / MA
FA
MA
KA
MA
40.52 35.27 34.34 37.48 38.23 37.67 36.38 39.47
8520 2/ 4
FA
MA / MA
MA
FA
44.00 43.14 35.80 37.94 45.18
8521 7/ 5
MA
MA
MA
MA
FA
FA / FA
MA
FA
MA
45.57 45.12 37.02 37.95 35.74 36.05 38.45 39.43 34-83 43.70 ----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITIO
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 8): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # 8522
CLs 6/ 7
FA 46.76
FA 45.76
FA 45.05
MA 44.61
MA
MA
38.81 48.21
FA 43.39
FA 43.87
FL
FA
24.30 42.16
8523
NOT PREGNANT
8524
NOT PREGNANT
8525 8526
6/ 7
MA 40.08
NOT
FA
MA
38.03 34.97
PREGNANT
FA 27.49
FA 29.49
FA 36.56
MA 38.99
MA 34.21
MA 29.61
FA 26.10
FA 30.27
8527 6/ 5
MA
MA
MA
MA
MA
MA / FA
FA
FA
MA
FA
41.16 41.97 38.11 30.51 21.05 18.80 35.72 30.23 34.01 38.80 35.06
8528 6/ 3
PA
MA
FA
FA
MA
FA
MA
47.70 45.44 41.92 43.95 42.15 41.26 47.86
8529 3/ 4
E
KA / FA
FA
MA
FA
42.11 42.69 43.75 35.48 37.75
8530 7/ 3
FA
MA
MA
FA
FA
MA
FA
FA
FA
MA
41.58 41.84 34.18 38.16 38.01 38.42 40.79 43.07 39.43 43.79 -----------------------------------------------------------------------------------------------------------------
M = MALE
P = FEMALE
A = ALIVE
CLS - CORPORA LUTEA/OVARY
FETAL
D = DEAD BODY WEIGHTS
E = EARLY RESORPTION
L = LATE
WERE RECORDED IN GRAMS (G).
RESORPTION
DENOTES POSITION
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 20 (PAGE 9): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # 8531
8532
8533
8534
CLa 4/ 7
6/ 6
7/ 5
FA
FA
FA
MA / MA
MA
40.31 40.21 38.81 31.50 49.16 42.77
MA
FA
FA
FA
MA / FA
38.54 34.70 33.13 29.40 30.58 39.44
FA
MA
FA / t4A FA
FA
41.03 39.95 37.99 41.35 36.50 35.49
ABORTED ON DAY 22 OF GESTATION
MA 39.52
MA 33.18
MA 38.03
MA 34.49
MA 41.82
8535 8536 8537
8/ 3 3/ 8
MA
MA
MA
FA
MA
FA
38.06 35.58 37.84 14.27 23.13 21.76
f4A
MA
E / FA
FA
FA
39.65 44.51
46.24 41.41 33.54
ABORTED ON DAY 25 OF GESTATION
KA 24.00
FA 25.63
MA 27.76
MA 24.51
FA 31.98
FA 34.03
MA 34.42
MA 38.48
8538
ABORTED ON DAY 24 OF GESTATION
8539
ABORTED ON DAY 24 OF GESTATION
8540 8541 8542
ABORTED ON DAY 25 OF GESTATION
5/ 3
MA
FA
MA
FA
FA / FA
47.60 42.99 39.85 31.84 38.05 44.51
ABORTED ON DAY 28 OF GESTATION
FA 41.90
8543 7/ 5
FA
MA
MA
FA
FA
FA
L
FA
FA
FA
18.98 21.05 14.33 9.61 12.62 11.15 5.01 13.45 17.13 13.97
---------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITI
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 10): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # CLs 8544
ABORTED ON DAY 25 OF GESTATION
8545 8546 8547
6/ 7 3/ 5
FA
FA
MA
FA
FA
FA / FA
33.44 23.74 31.73 30.19 15.63 14.05 34.34
FA
PA / FA
FA
FA
FA
FA
39.89 43.53 39.73 37.76 40.56 34.02 34.62
ABORTED ON DAY 22 OF GESTATION
FA 29.81
14A 34.38
MA 26.13
f4A 20.57
PA 23.06
14A 25.11
8548
ABORTED ON DAY 25 OF GESTATION
8549 7/ 5
FA
FA
MA
MA
KA
MA
FA
MA
MA
FA
32.68 19.63 27.15 26.92 31.62 32.57 25.28 30.14 22.82 28.47
8550 7/ 6
FA
MA
FA
MA
MA
MA
MA
FA
MA
MA
37.27 36.52 39.52 34.53 34.56 41.67 39.86 28.09 32.32 34.34
8551 5/ 5
FA
MA
MA
MA
FA
FA
FA
MA
MA
FA
41.03 37.47 42.30 33.52 36.51 45.27 36.10 37.49 36.02 30.74
8552
NOT PREGNANT
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
CLa = CORPORA LUTEA/OVARY
FETAL
D - DEAD BODY WEIGHTS
E - EARLY RESORPTION
L = LATE
WERE RECORDED IN GRAMS (G).
RESORPTION
DENOTES POSITIO
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 11): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # CLa
8553 4/ 9
A
A
A
A/ A
A
A
A
A
A
A
A
A
4.78 4.78 4.99 5.18 5.59 4.45 5.56 4.67 4.97 5.12 4.87 4.57 4.89
8554 5/ 5
A
A
A
A
A/ A
A
A
A
A
4.80 3.99 5.19 4.34 4.69 4.63 4.56 4.41 4.25 5.05
8555 3/ 5
A
A
A/ A
A
A
A
A
5.37 5.03 5.58 5.27 5.61 4.18 5.09 5.01 -----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8556 4/ 4
A
A
A
A
A
A
A
A
5.44 5.41 5.49 4.02 4.99 5.31 5.62 5.10
8557 4/ 4
A
A
A
L
A
A
A
A
4.05 4.89 5.05
4.81 4.70 4.87 4.45
8558 S/ 5
A
A
A
A
A
A
A
A
A
A
3.74 4.78 5.08 4.67 4.46 4.09 4.77 4.53 4.93 4.57
-
8559 7/ 4
A
A
A
A
A
A
A
A
A
A
A
5.32 5.54 4.57 5.05 5.54 5.41 4.99 5.33 5.32 5.11 5.10
8560 4/ 7
A
A
A
A
A
A
A
A
A
A
A
4.37 5.19 5.20 4.59 5.43 4.70 4.63 5.77 4.99 4.55 5.20
-----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # CLa
8561 0/ 3
A
A
5.38 5.36
0562 5/ 4
A
A
A
A
A
A
A
A
A
5.24 4.76 5.55 5.27 5.34 4.77 5.48 5.00 4.67
8563 2/ 6
A/ A
A
A
A
A
A
5.24 5.06 4.40 5.13 5.17 4.82 5.64 -----------------------------------------------------------------------------------------------------------------
A = ALIVE
D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
"/" DENOTES
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
POSITION OF CERVIX
PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 20 (PAGE 12): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.S MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8564 5/ 5
A
A
A
A
A/ A
A
A
A
A
4.71 5.07 4.76 4.89 5.06 4.72 4.96 4.84 4.81 5.05
8565 7/ 3
A
A
A
A
A
A
A
A
A
A
6.03 5.78 5.32 5.82 5.76 5.34 4.77 6.15 5.14 4.78
8566 4/ 5
A
A
A
A/ A
A
A
A
4.33 4.06 3.71 3.82 4.42 4.35 4.37 4.10 ---------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # CLa 8567 3/ 7
8568 5/ 3
8569
A 4.82
A 4.64
NOT
A
A/
4.53 4.08
A 4.69
A 4.61
PREGNANT
A 4.65
A 4.46
A
A
4.49 4.44
A/ A
4.41 4.63
A 4.18
A 4.82
A 'A 4.28 3.62
A 3.95
8570 6/ 6
A
A
A
A/ A
A
A
A
A
5.60 5.44 5.43 4.85 5.51 5.34 4.79 4.85 4.86
8571 2/ 3
E
A
A
5.93 5.62 ---------------------------------------------------------------------------------------------------------------
A = ALIVE
D = DEAD
E = EARLY RESORPTION
L = LATE RESORPTION
"/" DENOTES
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (C).
POSITION
OF CERVIX
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 1): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8443
NOT PREGNANT
8444
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS HYOID: bilate
8445 8446 8447
NOT PREGNANT 0( 0.0) 5( 41.7)
0/ 7 0/12
0/ 7 0/12
0/ 7 5/12
FETUS HYOID: bilate
FETUS HYOID: left
FETUS
CAUDAL MISALI
FETUS THORAC CENTR OSSIFI
FETUS HYOID: bilate ------ ---------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 2): FETAL ALTERATIONS - INDIVIDUAL DATA
------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
------------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL E
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRIPI
------------------------------------------------------------------------------------------------------------------
8448
1( 10.0)
1/10
FETUS 1 FORELIMB: POLLEX ABSENT, bilateral
FETUS 5 LATE RESORPTION, autOlyBiS precluded further evaluation
0/10
1/10
FETUS 1 FORELIMI PRESENT, lst met 4 DIGIT bilater absent; lst MED PRALANG bilater
8449
3( 33.3)
0/ 9
1/ 9
FETUS 6 EYES: CIRCUMCORNEAL HEMORRHAGE, left eye
3/ 9
FETUS 2 HYOID: bilater
FETUS 6 SKULL: IRREGU bilater HYOID: bilater
FETUS 7 HYOID: bilater -----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 410-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 3): FETAL ALTERATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRII
-----------------------------------------------------------------------------------------------------------------
8450
3( 30.0)
0/10
1/10
FETUS 7 LUNGS: INTERMEDIATE LOBE ABSENT
2/10
FETUS 2 SKULL: AN INT 2.0 mm 2.5 mm
FETUS 3 SKULL: AN INT x 2.5 nun
8451
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS 1 SKULL: AN INT 3.0 mm
8452
1( 16.7)
0/ 6
0/ 6
1/ 6
FETUS HYOIDleft THORAC HEMIVE arch a RIBS: medial STERNA]
ASYMME
8453
0( 0.0)
0/ 9
0/ 9
0'/ 9
8454
1( 10.0)
0/10
0/10
1/10
FETUS
SKULL:
partia ----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 4): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8455
0( 0.0)
0/11
0/11
0/11
8456
1( 16.7)
0/ 6
0/ 6
1/ 6
FETUS RIBS: 8th an
8457 8458
0( 0.0) 1( 7.1)
0/ 8 0/14
0/ 8 0/14
0/ 8 1/14
FETUS STERNA FUSED,
8459
2( 28.6)
0/ 7
0/ 7
2/ 7
FETUS STERNA FUSED,
FETUS SKULL:
AN INT 1.0 mm 1.5 mm
8460
2( 28.6)
0/ 7
0/ 7
2/ 7
FETUS CERVIC CERVI 7TH Cl bilate
FETUS SKULL CONTA INTER 2.0 mr ---------------------------------------------------------------------------------------------------------------
NIN - NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 5): FETAL ALTERATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRIP
-----------------------------------------------------------------------------------------------------------------
8461
0( 0.0)
0/ 6
0/ 6
0/ 6
8462
0( 0.0)
0/ 9
0/ 9
0/ 9
8463
1( 10.0)
0/10
0/10
1/10
FETUS 8 HYOID: left
8464
2( 20.0)
0/10
1/10
FETUS 1
1/10
FETUS 7
LUNGS: INTERMEDIATE
HYOID:
LOBE ABSENT
right
-----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 6): FETAL ALTERATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8465
2( 33.3)
0/ 6
0/ 6
2/ 6
FETUS SKULL: SUTURE right
FETUS HYOID: bilate
8466 8467 8468 8469
NOT PREGNANT NOT PREGNANT 0( 0.0) 2( 28.6)
0/10 0/ 7
0/10 0/ 7
0/10 2/ 7
FETUS SKULL: AN INT 2.5 mm
FETUS SKULL: AN INT 1.0 mm HYOID: right
8470
2( 28.6)
0/ 7
0/ 7
2/ 7
FETUS SKULL: SUTURE right
FETUS SKULL: SUTURE left ----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 7): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N (t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8471
1( 11.1)
0/ 9
0/ 9
1/ 9
FETUS SKULL: OSSIFI
8472
0( 0.0)
0/ 9
0/ 9
0/ 9
8473
2( 25.0)
1/ s'
FETUS 6 FORELIMBS DOWNWARD, bilateral
FLEXED forepaws
0/ 8
1/ 8
FETUS STERNA FUSED,
8474
1( 11.1)
0/ 9
0/ 9
1/ 9
FETUS SKULL: IRREGU bilate
8475
4( 57.1)
0/ 7
1/ 7
FETUS 2 LUNGS: INTERMEDIATE LOBE ABSENT
3/ 7
FETUS SKULL:
IRREGU bilate
FETUS SKULL: AN INT 1.5 mm HYOID: left
FETUS HYOID: bilate ----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 8): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8476
3( 30.0)
0/10
1/10
FETUS 8 LUNGS: INTERMEDIATE LOBE ABSENT
3/10
FETUS THORAC CENTRU CENTRA left I
FETUS RIBS: and 6t distal
FETUS STERNA FUSED,
8477 8478
NOT PREGNANT 0( 0.0)
0/10
0/10
0/10
8479
3( 20.0)
0/15
2/15
FETUS 4 LUNGS: INTERMEDIATE LOBE ABSENT
FETUS 12 LUNGS: INTERMEDIATE LOBE ABSENT
1/15
FETUS SKULL: SUTURE left
8480
o( o.o)
0/ 9
0/ 9
0/ 9
8481a
4( 40.0)
1/10
FETUS 1 (DEAD)
0/10
3/10
FETUS
FORELIMBS: FLEXED
HYOID:
DOWNWARD
bilate
----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED a. Litter 8481 consisted of ten dead fetuses; all embryonic sacs contained
group averages and statistical analyses.
a dark
red substance.
Values were e
418-012:PAGE C-8
Pmtocol 41 Ml 2 Page 8
Dosaue Levels,Concentrations,Volumes and lnjecfionRates:
Dosage i
Number Of
Rabbits
22+36
Dosage 0 (Vehide)
Concentration IMV!MU
0
Do"p Volume (MLAA)
5
A!Rus Batch Number E"18-012-A(Day.Month.Year)
11 1 22+5'
0.1
0.02
5
B-418-012-B(Day.Month.Year)
111
22+3'
1.0
0.2
5
B-418-012-C(Day.Month.Year)
IV
22+31
2.5
-.0.5
5
8.418-012-D(Doy.Month.Year)
v
22+5*
3.75 1
0.75
6
B-418-012-E(Day.Monft.Year
a. Rabbitsassignedto toxicokinetwiacluawn.
The testarfidewiU be considered100% pure forthepurpose ofdosage cahwlafions.
TESTS, ANALYSES AND MEASUREMENT
Viablilly:
All Periods:
At leasttwice daily.
ClinicalObservations and/or General Ag)Rearance:
Predosage Period:
At leastonce.
Dosage Period:
Twice daily.Priorto dosage administrationand once approximately one hour postdosage.
Posidosage Period:
Once daily.
Clinicalobservations may be recorded more frequentlythan citedabove, ifdeemed appropriateby the Study Directorand/or Study Monitor.
Body Weights: Predosage Period:
Day 0 of presumed gestationand on the day of arrival at the Testing Facility.
Dosage Period:
Daily.
Postdosage Period:
Daily.
Feed Consumption'Values:
Predosage Period:
Recorded dailyafterarrivalat the Testing Facility (valuesnot tabulated).
Dosage Period:
Recorded daily.
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 9): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRIP
-----------------------------------------------------------------------------------------------------------------
8481a (Cont.)
FETUS 7 CAUDAL PRESENT
FETUS 9 CAUDAL PRESENT
8482
0( 0.0)
0/ 9
0/ 9
0/ 9
8483
4( 50.0)
0/ 8
3/ 8
FETUS 3 LUNGS: INTERMEDIATE LOBE ABSENT
FETUS 4 LUNGS: INTERMEDIATE LOBE ABSENT
FETUS 7 LUNGS: INTERMEDIATE LOBE ABSENT
2/ 8
FETUS 1 CERVICA CENTRUM OSSIFIC
FETUS 4 STERNAL FUSED,
8484
0( 0.0)
0/ 9
0/ 9
0/ 9
8485
1( 11.1)
0/ 9
0/ 9
1/ 9
FETUS 2 THORACI SMALL, CENTRA, llth an RIBS: 10th an
8486
o( o.o)
0/11
0/11
0/11
-----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED a. Litter 8481 consisted of ten dead fetuses; all embryonic sacs contained a dark red substance.
group averages and statistical analyses.
values were ex
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 10): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS WITH ANY
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
RABBIT
ALTERATIONS
NUMBER
N(!k)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
-8-4-8-7 -------0-(---0-.-0-)-----0-/--6--------------------------------0/--6--------------------------------0-/--6-----------------
8488
o( o,o)
0/ 7
0/ 7
0/ 7
8489
1( 16.7)
0/ 6
1/ 6
FETUS 6 LUNGS: INTERMEDIATE LOBE ABSENT
0/ 6
8490
o( o.o)
0/ 5
0/ 5
0/ 5
8491
1( 11.1)
0/ 9
FETUS 6 LATE RESORPTION, autolysis precluded further evaluation
0/ 9
1/ 9
FETUS SKULL: AN INT 1.0 mm
8492
0( 0.0)
0/ 9
0/ 9
0/ 9
8493
1( 20.0)
0/ 5
FETUS 3 LATE RESORPTION, autolysis precluded further evaluation
0/ 5
1/ 5
FETUS
RIBS: 6th -
FETUS 4 LATE RESORPTION, autolysis precluded further evaluation
FETUS 5 LATE RESORPTION, autolysib precluded further evaluation -----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTEP-ATIONS/NUMBEORF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 11):
FETAL ALTERATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8494
2( 33.3)
0/ 6
0/ 6
2/ 6
FETUS HYOID: bilate
FETUS HYOID: bilate
8495
1( 10.0)
0/10
0/10
1/10
FETUS SKULL: SUTURE right
8496
3( 33.3)
0/ 9
0/ 9
3/ 9
FETUS HYOID: right
FETUS HYOID: right
FETUS HYOID: bilate
8497
0( 0.0)
0/ 7
0/ 7
0/ 7
8498
0( 0-0)
0/ 9
0/ 9
0/ 9
8499
o( o.o)
0/ 8
0/ 8
0/ 8
----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 12): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS WITH ANY
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
RABBIT
ALTERATIONS
NUMBER
N(I;)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8500
2( 20.0)
0/10
FETUS 7 LATE RESORPTION, autolysis precluded further evaluation
0/10
2/10
FETUS RIBS: proxim left 7
distal
FE111S LUMBAR HENIVE arch a CENTRU
8501
0( 0.0)
0/11
0/11
0/11
8502
NOT PREGNANT
8503
2( 20.0)
0/10
0/10
2/10
FETUS HYOID: bilate
FETUS HYOID: right
8504
0( 010)
0/10
0/10
0/10
8505
NOT PREGNANT
8506
0( 0.0)
0/ 9
0/ 9
0/ 9
8S07
1( 16.7)
0/ 6
0/ 6
1/ 6
FETUS SKULL: AN INT 1.0 mm
8508
NOT PREGNANT
----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER
TABLE 21 (PAGE 13): FETAL ALTERATIONS - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETA
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCR
---------------------------------------------------------------------------------------------------------------
8509
0( 0.0)
0/ 7
0/ 7
0/ 7
8510
0( 0.0)
0/ 8
0/ 8
0/ 8
8511
NOT PREGNANT
8512
0( 0.0)
0/ 7
0/ 7
0/ 7
8513 8514 8515 8516
NOT PREGNANT 0( 0.0) o( o.o) 1( 14.3)
0/ 7 0/ 9 0/ 7
0/ 7 0/ 9 0/ 7
0/ 7 0/ 9 1/ 7
FETUS SKULL AN IN 3.0
8517
ABORTED ON DAY 25 OF GESTATION a
8518
o( o.o)
0/ 9
FETUS 5 LATE RESORPTION, autolysis precluded further evaluation
0/ 9
0/ 9
8519
1( 12.5)
0/ a
0/ 8
I/ 8
FETUS CERVI
CERVI
7TH C
bilat
---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED a. Doe 8517 aborted eight late resorptions on day 25 of gestation; autolysis precluded further evaluation.
PROTOCOL 418-012:
OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PACE 14); FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINAT10N
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8520
0( 0.0)
0/ 5
0/ 5
0/ 5
8521 8522
0( 0.0) 2( 22.2)
0/10 0/ 9
FETUS 9 LATE RESORPTION, autolysis precluded further evaluation
0/10 0/ 9
0/10 2/ 9
FETUS HYOID: bilate
FETUS HYOID: bilate
8523 8524 8525
NOT PREGNANT NOT PREGNANT 1( 9.1)
0/11
0/11
1/11
FETUS HYOID: right
8526
NOT PREGNANT
8527
0( 0.0)
0/11
0/11
0/11
8528
0( 0-0)
0/ 7
0/ 7
0/ 7
8529
0( 0.0)
0/ 5
0/ 5
0/ 5
8530
0( 0.0)
0/10
0/10
0/10
---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 15): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8531
2( 22.2)
0/ 9
0/ 9
2/ 9
FETUS SKULL:
CONTAI
INTERF
3.0 mm
FETUS SKULL: CONTAI INTERF 4.0 m
8532
1( 12.5)
0/ 8
1/ 8
FETUS 5 LUNGS: INTERMEDIATE LOBE ABSENT
0/ a
8533 8534 8535
0( 0.0)
0/ 6
ABORTED ON DAY 22 OF GESTATION a
1( 9.1)
0/11
0/ 6 0/11
0/ 6
1/11
FETUS LUMBA CENTR
8536
3( 37.5)
0/ 8
0/ 8
3/ 8
FETUS SKULL AN IN 2.0 mi
FETUS HYOID bilat ---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED a. Doe 8534 aborted one dead fetus and had seven live fetuses in utero on day 22 of gestation. All fetuses ap
at gross external and soft tissue examination. Fetuses 1, 2, 3, 4, 5, 6, 7, and 8 had pelvis, pubis not os at skeletal examination.
PROTOCOL 418-012;
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 16):
FETAL ALTERATIONS
- INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRIP
-----------------------------------------------------------------------------------------------------------------
8536 (Cont.)
FETUS 7 HYOID: bilatei
8537 8538 8539 8540 8541
ABORTED ON DAY 25 OF GESTATION a
ABORTED ON DAY 24 OF GESTATION b
ABORTED ON DAY 24 OF GESTATION c
ABORTED ON DAY 25 OF GESTATION
d
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS HYOIDbilate
8542
ABORTED ON DAY 28 OF GESTATION
e
8543
7( 77.8)
1/ 9
FETUS 3 FORELIMBS
FLEXED
0/ 9
7/ 9
FETUS SKULL:
DOWNWARD, bilateral
CONTAI
forepaws
right, - larg
4.0 mm
----------------------------------------------------------------------------------------------------------------
NIN a. b. C.
d.
e.
= NUMBER Doe 8537 Doe 8538
OF SPECIMENS WITH ALTEP-ATIONS/NUMBER OF SPECIMENS EXAMINED aborted five late resorptions on day 25 of gestation; autolysib aborted eight late resorptions on day 24 of gestation; autolysis
precluded precluded
further evaluation. further evaluation.
one
fetus was presumed cannibalized.
Doe 8539 aborted seven live fetuses on day 24 of gestation.
All fetuses appeared normal at gross external a
examination.
Fetuses 1, 2, 3, 4, 5, 6 and 7 had pelvis, pubis not ossified (bilateral) and fetuses 2 and 3
centra (first) not ossified at skeletal examination.
Doe 8540 aborted four dead fetuses and had three live fetuses, one dead fetus and six late resorptions in ut
of gestation.
Autolysis precluded further evaluation of the late resorptions.
All remaining fetuses appear
gross external and soft tissue examination.
Fetuses 1, 2, 3, 5, 7, 8, 9 and 10 had pelvis, pubis not ossifi
and fetus 2 had skull, nasals incompletely ossified and maxillae, short at skeletal examination.
Doe 8542 aborted six dead fetuses on day 28 of gestation. All fetuses were partially cannibalized.
All pup
normal at soft tissue examination.
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 17): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(!k)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8543 (Cont.)
FETUS 7 LATE RESORPTION, autolysis precluded further evaluation
FETUS SKULL: CONTAI right, - larg 8.5 mn
FETUS SKULL: CONTAI right, - larg 5.0 mm PELVIS OSSIFI
FETUS SKULL: CONTAI right,
- larg 4.5 mm
FETUS SKULL: CONTAI right, - larg 5.5 mm PELVIS OSSIFI ----------------------------------------------------------------------------------------------------------------
NIN - NUM13EROF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER:
TABLE 21 (PAGE 18):
FETAL ALTERATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8543 (Cont.)
FETUS SKULL: CONTAI right, - smal 2.5 mm
FETUS SKULL-. CONTAI right, - larg 8.5 mm
8544 BS45
ABORTED ON DAY 25 OF GESTATION a
2( 15.4)
0/13
0/13
2/13
FETUS PELVIS OSSIFI
FETUS PELVIS OSSIFI
8546
0( 0.0)
0/ 7
0/ 7
0/ 7
8547
ABORTED ON DAY 22 OF GESTATION b
8548
ABORTED ON DAY 25 OF GESTATION
c
----------------------------------------------------------------------------------------------------------------
NIN a.
- NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED
Doe 8544 aborted nine dead fetuses on day 25 of gestation. All fetuses appeared normal at gross external
examinations.
Fetuses 1, 2, 3, 4, 5, 6, 7, 8 and 9 had pelvis, pubis not ossified (bilateral) and fetus
an 3h
(first) not ossified at skeletal examination.
b. Doe 8547 aborted eight late resorptions on day 22 of gestation; autolysis precluded further evaluation.
C. Doe 8548 aborted one dead fetus and had seven live fetuses, one dead fetus and two late resorption in utero
gestation.
The late resorptions appeared normal at gross external examination; autolysis precluded further
All fetuses appeared normal at gross external and soft tissue examinations.
Fetuses 1, 2, 3, 4, 5, 6, 7, 8
pelvis, pubis not OSBified (bilateral) at skeletal examination.
PROTOCOL 418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NLTMBER:
TABLE 21 (PAGE 19): FETAL ALTERATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
SPECIMENS WITH ANY
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
RABBIT
ALTERATIONS
NUMBER
N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRIP
-----------------------------------------------------------------------------------------------------------------
8549
0( 0.0)
0/10
0/10
0/10
8550
2( 20.0)
0/10
0/10
2/10
FETUS 9 HYOID: left
FETUS 1 HYOIDright
8551
0( 0.0)
0/10
0/10
0/10
8552
NOT PREGNANT
-----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED
--, .,
-;,Wl@
APPENDIX C PROTOCOL AND AMENDMENT
418-012:PAGE C-1
PRLMFDICA
Argus Research Laboratories, Inc. 905 Sheehy Drive, BuildingA Homham, PA 19044 Telephone: (215) 443-8710 Tolefax: (215) 443-8587
PROTOCOL 418-012 SPONSOR'S STUDY NUMBER: 6296-10
STUDY TITLE: PURPOSE:
TESTING FACILITY:
STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATE STUDY MONITOR:
Oral(Stomach Tube) DevelopmentalToxicitSytudy ofPFOS inRabbits
The purpose ofthisstudyistodetectadverseeffectsof PFOS on New Zealand White[Hra:(NZW)SPF] presumed pregnantfemale rabbitsand development ofthe embryo and fetusconsequenttoexposure ofthe doe from implantation toclosureofthe hard palate.This studyevaluatesICH Harmonised TripartitGeuidelinestagesC and D ofthe reproductivperocessina nonrodentspecies.
Argus Research LaboratoriesI,nc. 905 Sheehy Drive,BuildingA Horsham, Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587
Raymond G. York,Ph.D.,DABT AssociateDirectorof Research
3M ToxicologyServices 3M CenterBuilding220-2E-02 St.Paul,Minnesota 55144-1000
MarvinT. Case, D.V.M.,Ph.D. Telephone: (651)733-5180 Teiefax: (651)733-1773
Andrew M. Seacat,Ph. D. Telephone: (651)575-3161 Telefax: (651)733-1773
418-012:PAGE C-2
Protocol418-012 Page 2
REGULATORY CITATIONS:
U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detectionof toxicittyo reproductionformedicinal products. Federal Register,September 22, 1994, Vol.59, No. 183.
U.S. Food and Drug Administration.Good Laboratory PracticeRegulations;FinalRule. 21 CFR Part 58.
Japanese Ministryof Health and Welfare (1997). Good Laboratory PracticeStandard forSafety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.
European Economic Community (1989). Coundil decisionon 28 July 1989 on the acceptance by the European Economic Community of an OECD decisionlrecommendation on compliance withpilnciplesof good laboratorypractice.OfficiaJloumal of the European Communities: Legislation.32(No. L 315; 28 October): 1-17.
REGULATORY
COMPLIANCE:
This study willbe conducted incompliance withthe Good Laboratory Practice(GLP) regulationscitedabove.
Allchanges or revisionsof thisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained withthe protocol.
The QualityAssurance Unit(QAU) willauditthe protocol,the raw data and the report, and willinspectcriticaplhases of the study inaccordance with the Standard Operating Procedures of Argus Research Laboratories,Inc.
The finalreportwillincludea statement signed by the Study Directorthatthe report accuratelyreflectsthe raw data obtained duringthe performance ofthe study and that allapplicableGLP regulationswere followedinthe conduct of the study. Should significandteviationsfrom GLP regulationsoccur,each willbe described indetail, togetherwith how the deviationmight affectthe qualityor integritoyf the study.
SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE:
See ATTACHMENT
1 to the protocol.
418-012:PAGE C-3
Pmtocol 418-012 Page 3
TEST ARTICLE AND VEHICL
Identification:
Test Article:
Name: PhysicalDescription: Lot/BatchNumber: SpecificGravity: Purity: ExpirationDate:
PFOS. Light-colorepdowder. 217. -0.6. 98.9%. May 2000.
Informationon the identityc,omposition,strengthand purityofthe testarticlieson file withthe Sponsor.
Vehicle:
0.5% TweenG) 80 inReverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplierand lotidentificatioofnTweenOD 80 to be documented in the raw data.
Neitherthe Sponsor nor the Study Directorisaware ofany potentiaclontaminants likely tobe presentinthe vehiclethatwould interferweiththe resultsofthisstudy. Therefore, no analysesotherthan those mentioned inthisprotocolwillbe conducted.
Safely Precautions:
Gloves, mask, appropriateeye protectionand a uniform/labcoat are to be worn during formulationpreparationand administrationT.he MaterialSafety Data Sheet (MSDS) is attachedto the protocol(see ATTACHMENT 2).
Storage:
Bulk Test Article: VehicleComponents: Prepared Vehicle: Prepared Formulations:
Room Room Room Room
temperature. temperature. temperature. temperature (samples to be frozen).
Alltestarticlsehipments tothe TestingFacilitsyhould be addressed to the attentionof JulianGuibinski,Manager of Formulations,atthe previouslycitedaddress and telephone number.
Shipments should includeinformationconcerning storageconditionsand shipping cartonsshould be labeledappropriately.The recipiensthould be notifiedinadvance of shipment.
418-012:PAGE C-4
Pmtocol 418-012 Page 4
FORMULATION:
Freauency of PreRaration:
Formulations (suspensions) willbe prepared daily at the Testing Facility.
Detailedpreparationprocedures are attached to thisprotocol(ATTACHMENT 3).
Adoustment for Puri : The-testarticlewillbe considered 100% pure forthe purpose of dosage calculations.
Testin-qFacilityReserve SamRiOs: The Sponsor willreserve a sample (1 g) ofeach lotofthe bulk testarticluesed during the course ofthisstudy. The Testing Facilitwyillreserve a sample (5 mL) ofeach lotof the vehiclecomponents used duringthe course of thisstudy. Samples willbe stored under the previouslycitedconditions.
ANALYSES:
Samples additionalto those described below may be taken ifdeemed necessary during the course of the study.
Bulk Test ArticleSampling: No analyses of the bulk testarticlweillbe conducted during the course of thisstudy. Informationon the stabilitoyf the bulk testarticlieson filewith the Sponsor.
Analyses of PreRared Formulations: Homogeneity and stabilitoyf prepared formulationsison filewith the Sponsor. However, records willbe maintained to document how the testarticlfeormulationswere prepared. Concentration of Test ArticleFormulations:
Concentration of the prepared formulationswillbe verifiedduringthe course of this study. Duplicatesamples (2 mL each) willbe taken from the firsatnd lastpreparation on the day prepared. One sample of each setwillbe shipped foranalysis;the remaining samples willbe retainedat the Testing Facilitays backup samples. Backup samples willbe stored under the previouslycitedconditionsand discarded at the Testing Facilityupon request of the Sponsor.
418-012:PAGE C-5
Protocol418-012 Page 5
ShiRPing Instructions:
Samples to be analyzed willbe shipped (frozenon dry ice)to:
KrisJ.Hansen, Ph.D.
3M Environmental Technology and 935 Bush Avenue
Building2-3E-09
St.Paul, Minnesota 55133-3331 Telephone: (612)778-6018 Telefax: (612)778-6176
Safety Services
The recipientwillbe notifiedinadvance of sample shipment.
DISPOSITION:
Prepared formulationswillbe discarded at the Testing FacilityA.llremaining bulk test articlweillbe returnedto the Study Monitor at the previouslycitedaddress upon completion of allwork with the testarticle.
TEST SYSTEM:
Species/Strain and Reason for Selection:
The-New Zealand White [Hra:(NZW)SPF] rabbitwas selected as the Test System because: 1) itisone non-rodent mammalian species accepted and widely used throughout the industryfornonclinicalstudiesof developmental toxicit(yembryo-fetal toxicity/teratogenici2t)y)t;hisstrainof rabbithas been demonstrated to be sensitiveto developmental toxins;3) historicadlata and experience existatthe Testing Facility('-'); and 4) the testarticleispharmacologicallyactivein the species and strain.
Number and Sex:
Populationevaluated: 110 timed-pregnantfemale rabbits(22 per dosage group).
Populationselected for toxicokinetiecvaluation:
19 satellitfeemale rabbits(fiveat the low and high dose levelsplus threeat the otherdose levels).
Body Weight and Age:
The individualbody weights of the female rabbitswillrange from 2.5 kg to 5.5 kg; the rabbitswillbe approximately fiveto seven months of age at the time of study assignment. Actual body weights recorded at receiptand at study assignment willbe documented inthe raw data,and the weight range willbe included inthe finalreport.
418-012:PAGE C-6
Protocol418-012 Page 6
Source:
Covance Research Products,Inc.
Swampbddge Road, Box 7200 Denver, Pennsylvania 17517
The rabbitswillbe shipped infilterecdartonsby truckfrom Covance Research Products, Inc.,Denver, Pennsylvania,to the Testing Facility.
Identification:
Rabbits are permanently identifieudsing MonelS seff-piercinegar tags (Gey Band and Tag Co., Inc.,No. MSPT 20103). Female rabbitsare given unique permanent identificatinounmbers when assigned to the study on the basis of day 0 of presumed gestationbody weights.
ANIMAL HUSBAND
Allcage sizesare incompliance with the Guide forthe Care and Use of Laboratory Animals"').
Housing:
The rabbitswillbe individuallhyoused in unitsof sixto eightstainlesssteelcages. No nestingmaterialswillbe supplied because the female rabbitswillbe sacdficedbefore parturitioinsexpected.
Room Air,Temperature and Humidi
The animal room isindependently supplied with at leastten changes per hour of 100% freshairthat has been passed through 99.97% HEPA filtersR.oom temperature willbe maintained at61 OF (160C) to 720F (22'C) and monitored constantly.Room humidity willalso be monitored constantlyand maintained at 30% to 70%.
Light:
An automaticallycontrolled12-hour light1:2-hour dark fluorescentlightcycle willbe maintained. Each dark period willbegin at 1900 hours EST.
Diet:
Approximately 150 g ofCertifiedRabbit Chov& #5322 (PMI NutritionInternationalw)ill be availableto each rabbiteach day untilthe firsdtay of dosage, at which time approximately 180 g of the same certifiefdeed willbe offeredto each rabbiteach day. The certifiefdeed willbe availablefrom individualstainlesssteel"J-type"feeders attached to each cage.
418-012:PAGE C-7
Pmtocol 418-012 Page 7
Water:
Water willbe availablead libitumfrom individualboftlesattached to the cages or from an automatic watering access system. Allwater willbe from a localsource and passed through a reverse osmosis membrane before use. Chlorinewillbe added to the processed water as a bacteriostatp;rocessed water isexpected to containno more than 1.2 ppm chlorineat the time of analysis.Water isanalyzed monthly forpossible bacteria[contamination and twice annuallyforpossiblechemical contamination.
Contaminants:
Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe certifieddietor inthe drinkingwater at levelsthatwould interfere with the resultsof thisstudy. Therefore,no analyses otherthan those routinely performed by the feed supplieror those mentioned inthisprotocolwillbe conducted.
MATING AND RANDOMIZATION:
The female rabbitswillbe naturallybred at the Supplier,by breeder male rabbitsof the same source and strain,before shipment to the Testing FacilityT.he day mating occurs willbe designated day 0 of presumed gestation.The rabbitswillbe mated on five consecutive days and shipped to the Testing Facilitayfterthe lastmating day to arrive on day 1,2, 3, 4 or 5 of presumed gestation.Before shipment of the rabbits,the Supplierwillforward breeding recordsand day 0 of presumed gestationbody weights. A computer-generated (weight-ordered)randomization procedure willbe used to assign the rabbitsto dosage groups based on thisinformation.
ADMINISTRATION:
Route and Reason for Choice:
The oral (stomach tube) routewas selectedforuse because: 1) incomparison with the dietaryroute,the exact dosage can be accuratelyadministered;and 2) itisone of the possibleroutesof human exposure.
Method and Freguenc :
Female rabbitswillbe given the testarticloence dailyon days 7 through 20 of presumed gestation.Dosages willbe adjusted dailyforbody weight changes and given at approximately the same time each day.
Rationale for Dosage Selection:
Dosages were selectedon the basis of a dosage-range study (Argus Research Laboratories,Inc.,Protocol418-012P).
418-012:PAGE C-8
Pmtocol 41 M 12 Page 8
Dosage Levels,Concentrabons, Volumes and lnoectionRates:
Dosage Gmup
Number Of
Rabbits
Dosage
Concentration (M2@MLI
Dosage Volunn
A!Rus Batch Number
1
22+3'
0 (Vehicle)
0
11
22+51
0.1
0.02
iii
22+31
1.0
0.2
5
B-418-012-A(Day.Month.Year)
5
B-418-012-8(Day.Month.Year)
5
B-41"I 2-C(Day.Month.Year)
IV
22+3'
2.5
0.5
5
B-418-012-D(Day.Month.Year)
v
22+5*
3.75 1
0.75
1 5 1 B-41!:2@@th.Year)
a. Rabbitsassignedto toxicokirieetviacluation. The testarticlweillbe considered100% pureforthepurpose ofdosage calculations.
TESTS, ANALYSES AND MEASUREMENTS:
Viabill All Periods:
At leasttwice daily.
ClinicalObservations and/or General Apt)earance:
Predosage Period:
At leastonce.
Dosage Period:
Twice daily.Priorto dosage administrationand once approximately one hour postdosage.
Posidosage Period:
Once daily.
Clinicalobservations may be recorded more frequentlythan citedabove, ifdeemed appropriateby the Study Directorand/or Study Monitor.
Body Weights:
Predosage Period:
Day 0 of presumed gestationand on the day of arrival at the Testing Facility.
Dosage Period:
Daily.
Postdosage Period:
Daily.
Feed Consumi)tion Values:
Predosage Period:
Recorded dailyafteranivalat the Testing Facility (valuesnot tabulated).
Dosage Period:
Recorded daily.
418-012P:AGE C-9
Pmtocol 418-012 Page 9
Postdosage Period:
Recorded daily.
Feed consumptionvaluesduringthe dosingperiodwillbe tabulatedforthe same intervalass body weightevaluations.
Caesarea n-Sectioning Observations:
Rabbits willbe Caesarean-sectioned on day 29 of presumed gestation. The fetuses will be removed from the uterusand placed inindividuaclontainers.The rabbitswillbe examined fornumber and distributioonf-
Corpora Lutea.
ImplantationSites. [Placentaethatappear abnormal (size,coloror shape) willbe noted inthe raw
data].
Live and Dead Fetuses. (A livefetusisdefined as one that responds to stimulia; dead fetusisdefined as a term fetusthatdoes not respond to stimuliand thatisnot markedly autolyzed; dead fetusesdemonstrating marked to extreme autolysisare considered to be late resorptions.)
Earlyand Late Resorptions. (A conceptus isdefined as a lateresorptionifitisgrosslyevidentthat organogenesis has occurred;ifthisis notthe case, the conceptus isidentifieads an earlyresorption.)
Fetal Observations:
Body Weights and Identification:
The body weight of each fetuswillbe recorded. Only body weights of livefetuseswill be used to determine liftefretalbody weight averages. Fetuses willbe tagged with identificationnotingstudy number, liftenrumber and uterinedistribution.
Gross ExternalAlterations:
Allfetuseswillbe examined forgross externalalterations.Late resorptionsand dead fetuses also willbe examined forgross externalalterationsto the extent possiblebut such observationswillnot be included ineitherdata summarization or statistical analyses.
418-012:PAGE C-10
Protocol418-012 Page 10
SoftTissue Examination and Sex:
Allfetuseswillbe examined internalltyo determine sex. Cavftatedorgans willbe evaluated inallfetuses by dissection(s@A. singlecross-sectionwillbe made between the parietaland frontalbones, and the brainwillbe examined in situ.
SkeletalExamination:
Allfetuseswillbe examined forskeletalalterationasfterstainingwith alizarirned S(". Skeletalpreparationswillbe retainedin glycerinwiththymol added as a preservative.
Representative photographs of fetalgross,softtissueand skeletalalterationswillbe taken.
METHOD OF SACRIFICE:
Beuthanasia&D Special (manufactured by Schering-Plough Animal Health) willbe used tosacrificreabbits(viaintravenousinjectiona)nd livefetuses (viaintraperitoneal injection).
NECROPSY:
Gross lesionswillbe retainedinneutralbuffered10% formalinforpossiblefuture evaluation(correspondingtissueswillbe retainedfrom rabbitsinthe vehiclecontrol group atthe discretionofthe Study Director).(Exception: Parovarian cystswillbe discarded;these are common, spontaneous lesionsin rabbits.)Unless specifically citedbelow, allothertissueswillbe discarded.
SatelliteRabbits Assigned to Toxicokinetic SamRIe Collection:
On day 21 of presumed gestation(theday followingthe lastdosage), toxicokinetic samples willbe collectedfrom the rabbitsassigned to the toxicokinetiecvaluation. Followinganesthesia of pentobarbital,blood samples (approximately4 mL per rabbit) willbe collectedfrom the inferiovrena cava intoserum separatortubes and centrifuged. The resultingserum (approximately2 mL) willbe immediately frozen on dry iceand maintainedfrozen (-700C) untilshipment tothe Sponsor foranalysis.The livewrillbe excised,weighed, and a sample willbe taken from the rightlaterallobe,frozen and retainedat -70'C untilshipment to the Sponsor foranalysis.
Rabbits willbe Caesarea n-sectioned and fetuses willbe examined grosslyto the extent possibleas described above forrabbitsassigned to the main study. Fetuses and placentae willbe pooled per littearnd retainedfrozen (-700C)untilshipment to the Sponsor foranalysis.
Aftercompletion of sample collections,erum, liversections,fetaland placentalsamples willbe shipped (frozenon dry ice)to KrisJ. Hansen, Ph.D., at the previouslycited
418-012: PAGE C-1 1
Protocol418-012 Page 11
addressforanalysis.Both the recipienatnd the Study Monitorwillbe notifieidn advance of sample shipment.
Scheduled Sacrifice:
On day 29 of presumed gestation,female rabbitswillbe Caesarean-sectioned, and a
gross necropsy of the thoracic,abdominal and pelvicviscerawillbe performed. Uteriof
apparently nonpregnant does willbe stainedwith 10% ammonium absence of implantationsftes(7)
sulfideto confirmthe
Rabbits Found Dead oi Moribund:
Rabbits thatdie or are sacrificedbecause of moribund condition,abortionor premature deliverywillbe examined forthe cause of death or moribund conditionon the day the
observationismade. Pregnancy statusand uterinecontents willbe recorded. Aborted fetusesand/or deliveredpups willbe examined to the extent possible,using the same
methods described forfetuses. Uteriof apparentlynonpregnant does willbe stained with 10% ammonium sulfideto confirmthe absence of implantationsites(7)
418-012:PAGE C-12
Protocol418-012 Page 12
PROPOSED
STATISTICAL METHODS(B-14):
Averages and percentages willbe calculated. Littervalues willbe used where appropriate.Additionalprocedures and/or analyses may be performed, ifappropriate.
Tyr)eof Test'
1. Parametric
li.Nonr)arametriCb
A. Bartieft'TseSf,d I
A. Kruskal-WallisTest (:@75% ties) 1
Significatat p5O.O5 Not Sig ificant
Significatat p.-@0.0 Not Significant
Nonparametric
Analysis of Variance
I
Dunn's Test
F-
Significantat p:5;0.05
I
Not Significant
B. Fishees Exact Test (>75% ties)
1 Liu,,i,ett'Tsest
111.Test for Pror)ortionData
Variance Test forHomogeneity of the Binomial Distribution
a. Statisticalsliygnificanptrobabilitieasre reportedas eitherp:50.05orp:50.01. b. Proportiondata are not included inthiscategory. c. Used only to analyze data with homogeneity of variance. d. Test forhomogeneity of variance.
418-012:PAGE C-13
Pmtocol 418-012
Page13
DATA ACQUISITION, VERIFICATION AND STORAGE:
Data willbe hand- and/orcomputer-recorded.Records willbe reviewedby the Study Directorand/orappropriatmeanagement personnelwithin21 days aftergeneration.All originarlecordswillbe storedinthe archivesoftheTestingFacilityA.lloriginadlata will be bound and indexed.A copy ofallraw data willbe suppliedtothe Sponsor upon request.Preservedtissueswillbe storedatthe TestingFacilitaytno charge forone year aftermailingofthe draftfinalreporta,fterwhich timethe Sponsor willbe contacted todeterminethedispositioonf these materials.
RECORDS TO BE MAINTAINED:
Protocoland Amendments. TestArticlVeehicleand/orReagent Receipt,Preparationand Use. Animal Acquisition. Randomization Schedules. VeterinariaEnxamination. Mating History. Treatment(ifprescribedby StaffVeterinarian). General Comments. ClinicaOlbservationsand/orGeneral Appearance. Blood Sample CollectionP,rocessingand Shipment (ifrequired). Body Weights. Feed Consumption Values. Caesarean-Sectioningand FetalObservations. Gross Necropsy Observations. Organ Weights (irfequired). Photographs(ifrequired). Study Maintenance(room and environmentalrecords). Feed and Water Analyses. Packingand/orShipment Lists.
KEY PERSONNEL:
ExecutiveDirectorof Research: MildredS. ChristianP,h.D.,Fellow,ATS DirectorofResearch: Alan M. Hoberman, Ph.D.,DABT AssociateDirectoorfResearch and Study Director:Raymond G. York, Ph.D.,DABT DirectorofLaboratoryOperations:John F.Barnett,B.S. Manager ofStudy Coordination:ValerieA. Sharper,M.S. Manager ofAnimal Operationsand Member, InstitutioAnnailmal Care and
Use Committee: Dena C. Lebo,V.M.D. Manager ofRegulatoryCompliance: KathleenA. Moran, M.S. ConsultantV,eterinaryPathology:W. Ray Brown, D.V.M.,Ph.D.,ACVP
418-012:PAGE C-14
Protocol418412 Page 14
FINAL REPORT:
A comprehensive draft finalreport willbe prepared on completion of the study and will be finalizedfollowingconsultationwith the Sponsor. The reportwillincludethe following:
Summary and Conclusion. Experimental Design and Method. Evaluationof Test Results. Appendices: Figures,Summary and IndividuaTlables Summarizing the Above Data, Protocoland Associated Amendments and Deviations,Study Director's GLP Compliance Statement, Reports ofSupporting Data (ifappropriate)and QAU Statement.
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT:
The procedures described inthisprotocolhave been reviewed by the Testing Facility's InstitutionAanlimal Care and Use Committee. Allprocedures described inthisprotocol that involvestudy animals willbe conducted in a manner to avoid or minimize discomfort,distressor pain to the animals.
The Sponsor's signaturebelow documents the factthatinformationconcerning the necessityforconducting thisstudy and the factthatthisisnot an unnecessarily duplicativestudy may be obtained from the Sponsor. No alternativ(einvitro) procedures were availableformeeting the stated purposes of the study.
REFERENCES:
1 . Christian,M.S., Hoberman, A.M. and Smith,T.H.F. (1982). Dosage-range study ofthe teratogenicpotentialofsuspensions oftrinitrofluoreno(nTeNF) administeredorallyto New Zealand White rabbits.Toxicologist2(l):40(#143).
2. Christian,M.S. (1984). Reproductive toxicitaynd teratologyevaluationsof naltrexone(Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983),J.Clin.Psychiat.45(9):7-10.
3. Feussner, E.L.,Lightkep,G.E., Hennesy, R.A., Hoberman, A.M. and Christian, M.S. (1992). A decade ofrabbitfertilidtayta: Study of historicaclontrolanimals. Teratology46(4):349-365.
4. Instituteof Laboratory Animal Resources (1996). Guide forthe Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
5. Staples,R.E. (1974). Detectionofvisceralalterationisnmammalian fetuses. Teratology9(3):A37-38.
418-012:PAGE C-1 5
Pmtocol 418-012 Page 15
6. Staples,R.E.and Schnell,V.L.(1964).Refinementinrapidclearingtechniquein the KOH-alizahnredS method forfetalbone. StainTechnol.39:61-63.
7. Salewski,E. (1964). Fgrbemethode zum makroskopischen Nachweis von lmplantationsstelieanm Uterus der Rafte. Arch. Pathol.Exp. Pharmakol. 247:367.
8. Snedecor, G.W. and Cochran, W.G. (1967). Variance testforhomogeneity of the binomialdistributionS.tatisticaMlethods, 6th Edition,Iowa State University Press,Ames, pp.-240-241.
9. Sokal, R.R. and Rohif,F.J.(1969). BartletCstestof homogeneity of variances. Biometry,W.H. Freeman and Co., San Francisco,pp. 370-371.
10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis ofVariance. Statistical Methods, 6th Edition,Iowa State University Press, Ames, pp. 258-275.
11. Dunneft,C.W. (1955). A multiplecomparison procedure forcomparing several treatmentswith a control.J.Amer. Stat.Assoc. 50:1096-1129.
12. Sokal, R.R. and Rohif, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389.
13. Dunn, O.J.(1964). Multiplecomparisons using rank sums. Technometrics 6(3):241-252.
14. Siegel, S. (1956). Nonparametric Statisticsforthe Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
PROTOCOL APPROVAL:
FOR THE TESTING FACILITY
Gel,POrfIe E earloveP,h.D.,DABT
Asso iateDirectorof Research
R4mAd G. York, h ).,DABT Ass'@te Directoro@-@esearch Study Director
Dena C. Lebo, V.M.D. Member, InstitutionAanlimal Care and
Use Committee
FOR THE SPONSOR
@2@4 11Z--c@
Marvin T. Case, D.V.M., Ph.D. Study Monitor
418-012:PAGE C-16
Pmtocol 418-012 Page 16
Date
2L
Date
9i7
Date
/;
Date
418-012:PAGE C-1 7
ATTACHMENT I SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE
I
ATTACHMENT 1
418-012:PAGE C-1 8
Protoco4l18-012 Page 1 of2
STUDY SCHEMATIC RABBIT DEVELOPMENTAL TOXICITY STUDY'
Startof Dosage
Timed-Pregnant Rabbits
Day 7 of Presumed Gestation
CaesareanSectioninbg End of Dosage
Ljay20 of Presumed Gestation
Lidy1-9Of Presumed Gestation
Dosage Period a = For additionadletailssee '7ests,Analyses and Measurements" sectionofthe
protocol. b = Fetalevaluations(externals,ofttissueand skeletal).
ATTACHMENT 1
418-012:PAGE C-1 9
Pmtocol 418-012 Page 2 of2
SCHEDULE'
21 AUG 98 23 AUG 98 - 09 SEP 98 06 SEP 98 - 10 SEP 98 14 SEP 98 - 18 SEP 98
17 DEC 98
Animals Arrive-Acclimation Begins.
Dosage Period (Days 7 through 20 of presumed gestation).
Toxicokinetic Sample Collection(Day 21 of presumed gestation).
Caesarean-Sectioning Period (Day 29 of presumed gestation).
DraftFinalReport.
a. The study initiatidoante isthe date the Study Directorsigns the protocol.
418-012:PAGE C-20
ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
MATERIAL SAFETY DATA SHEET
418-012:PAGE C-21
3m 3m center St. paul, Minnesota
551"-1000 1-800-364-3577 or (612) 737-6501
(24 hours)
Copyright, 1998, Minnesota Mining and Manufacturing Company.
All rights reserved. Copying and/or downloading of this
information for the purpose of properly utilizing 3M products
is allowed provided that: 1) the information is copied in fu3.1with no changes unless
prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise
distributed with the intention of earning a profit thereon.
DIVISION: 3M CHEMICALS TRADE NAME:
FC-95 FLUORAD Brand Fluarachemical
Surfactant
ID NUMBER/U.P.C.: 98-0207-0103-7 00-5113S-09064-1
98-0211-0888-6 00-51135-09362-7
ZF-0002-10"-l
-
ISSUED: January 29, 1998
SUPERSEDES: November OS, 1997
DOCUMENT: 10-3796-9
98-0207-0104-6 98-0211-3916-1
00-51135-09055-8 00-51135-02311-2
-----------------------------------------------------------------------------
1. INGREDIENT
C.A.S. NO.
PERCENT
-----------------------------------------------------------------------------
POTASSIUM PERFLUOROALKYL SULFONATE ...... 2795-39-3
82
86
POTASSIUM PERFLUOROALKYL SULFONATE ...... 3871-99-6
3
8
POTASSIUM PERFLUOROALKYL SULFONATE ...... 29420-49-3
3
7
POTASSIUM PERFLUOROALKYL SULFONATE ...... 60270-55-6
2
6
POTASSIUM PERFLUOROALKYL SULFONATE ...... 3872-25-1
1
3
----------------------------------------------------------------------------2. PHYSICAL DATA
-----------------------------------------------------------------------------
BOILING POINT: ...............N./.A VAPOR PRESSURE: ..............N./.A VAPOR DENSITY: ...............N./.A EVAPORATION RATE: .............N/.A SOLUBILITY IN WATER: ..........s.light SPECIFIC GRAVITY: .............ca.. 0.6
Water=l
(Bulk)
PERCENT VOLATILE: .............0.% pH: ........................7.-..8.
(0.1% Aqueous)
VISCOSITY: ..................N./.D . MELTING POINT: ...............N./.D.
APPEARANCE AND ODOR: Light colored, free flowing powder.
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not-Applicable CA - Approximately
418-012:PAGE C-22
f4SDS: FC-95 FLUORAD Brand Fluorochomical SUrfactant January 29, 1998
PAGE 2
-----------------------------------------------------------------------------
3. FIRE AND EXPLOSIONHAZARDDATA -----------------------------------------------------------------------------
FLASH POINT: .................No.n.e
FLAMMABLE LIMITS - LEL: ........N/A
FLAMMABLE
LIMITS
-
UEL:
........N/A ......
AUTOIGNITION TEMPERATURE:
N/A
EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam
SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat
and pants, bands around arms, waist and legs, face mask, and
protective covering for exposed areas of the head.
UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion.
----------------------------------------------------------------------------4. REACTIVITY DATA
-----------------------------------------------------------------------------
STABILITY: Stable
INCOMPATIBILITY - MATERIALS/CONDITIONS Not applicable.
TO AVOID:
HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur.
HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates.
----------------------------------------------------------------------------S. ENVIRONMENTAL INFORMATION
-----------------------------------------------------------------------------
SPILL RESPONSE: Observe precautions from other sections. Vacuum, use wet sweeping compound or water to avoid dusting. CAUTIONI A vacuum cleaner could be an ignition source. Clean up residue with water. Place in an approved metal container. Seal the container.
RECOMMENDED DISPOSAL: Do not release to waterways or sewer. Do not use in products or processes that could result in aquatic concentrations greater than 1/10 of the lowest ECSO or LCSO concentration. Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-012:PAGE C-23
"BOB: Fr,-95 FLUORAD Brand Fluorachosical January 29, 1998
suffactant
PAGE 3
-----------------------------------------------------------------------------
5. EWIRC)NMENTAL INFORMATION
(continued)
-----------------------------------------------------------------------------
accept chemical waste.
ENVIRONMENTAL DATA: 96-Hr. Aquatic Fish LCSO, Fathead Minnow(Pimephales promelas)=38 mg/l, Bluegill Sunfish(Leponis macrochirus)-68 mg/l,,Rainbow Trout(Saloo gairdneri)-Il mg/l; 46-Mr. EC50, Daphnia Magna - 50 mg/l; COD=.004 g/g; BOD20 = Ni-I.
REGULATORY INFORMATION: Volatile Organic Compounds: NIA. VOC Less H20 & Exempt Solvents: N/A.
Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Number - None (Not U.S. EPA Hazardous).
This product complies with the chemical registration requirements of TSCA, EINECS, CDSL, AICS, MITI and Korea.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes
----------------------------------------------------------------------------6. SUGGESTED FIRST AID
-----------------------------------------------------------------------------
EYE CONTACT: Immediately flush eyes with large amounts of water for at least 15 minutes. Get immediate medical attention.
SKIN CONTACT: Immediately flush skin with large amounts of water. Remove contaminated clothing. If irritation persists, call a physician. Wash contaminated clothing before reuse.
INHALATION: If signsisymptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician.
IF SWALLOWED: Drink two glasses of water. Call a physician.
----------------------------------------------------------------------------7. PRECAUTIONARY INFORMATION
-----------------------------------------------------------------------------
EYE PROTECTION: Avoid eye contact. Wear vented goggles.
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
4lMl2: PAGE C-24
MSDS: FC-95 FLUORAD Brand Fluorochomical Surfactant january 29, 1998
PAGE 4
-----------------------------------------------------------------------------
7. PRECAUTIONARY INFORMATION
(continued)
-----------------------------------------------------------------------------
SKIN PROTECTION: Avoid skin contact. Wear appropriat gloves when handling this material. A pair of gloves made fro: the following material(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garments (other than gloves) should
be made of either of the following materials: polyethylene/polyvinylidenechloride (Saranex).
RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Use in a well-
ventilated area. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation
is not adequate, use appropriate respiratory protection.
RESPIRATORY PROTECTION: Avoid breathing of dust. Select one of the following NIOSM approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust and mist respirator, half-mask supplied air respirator, full-face dust and mist respirator,
full-face supplied air respirator.
PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and
before eating.
RECOMMENDED STORAGE: Keep container dry. Keep container closed when not in use.
FIRE AND EXPLOSION AVOIDANCE: Nonflammable.
OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contamination of the tobacco and/or smoke and lead to the formation of the hazardous decomposition products mentioned in section 4 of this MSDS.
HMIS HAZARD RATINGS: HEALTH: 2 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.)
EXPOSURE LIMITS
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
-----------------------------------------------------------------------------
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1 MG/M3
TWA
3M
y
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1
MG/M3
TWA
3M
y
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1
MG/M3
TWA
3M
y
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1
MG/M3.
TWA
3M
y
-----------------------------------------------------------------------------
Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-012:PAGE C-25
MSDS: FO-95 FLUORAD Brand Fluorochomical Surfactant January 29, 1996
EXPOSURE LIMITS
(continued)
PAGE 5
VALUE UNIT
TYPE AUTH SKIN-
I-N-GR-E-D-IE-N-T------------------------------------------------------------------
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1 MG/M3
TWA 3M
y
* SKIN NOTATION: Listed substancesindicatedwith 'Y' under SKIN refer to the potentialcontributionto the overallexposureby the cutaneousroute including mucous membrane and eye, either by airborne or, more particularly, by directcontactwith the substance. Vehiclescan alter skin absorption.
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines
-------------------------------------------------------------------------
--S-.-H-E-A-LT-H--H-AZ-A-RD--D-A-T-A -------------------------------------------------------
EYE CONTACT: Mild Eye Irritation:signs/symptomscan include redness,swelling, pain, and tearing.
SKIN CONTACT: Mild Skin Irritation(afterprolongedor repeatedcontact): signs/symptomscan include redness, swelling,and itching.
May be absorbedthrough the skin and persistin the body for an extended time.
INHALATION: May be harmfulif inhaled.
May be absorbed by inhalationand persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause:
Irritation(upperrespiratory):signstsymptomcsan include soreness of the nose and throat, coughing and sneezing.
IF SWALLOWED: Ingestionis not a likely route of exposureto this product.
Illnessmay resultfrom a single swallowingof a moderatequantityof this material.
May be harmful if swallowed.
MUTAGENICITY: Mutagenicity-assaysindicatethe productis not mutagenic.
----------------------------------------------------------------------Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
4lMl2:PAGE C-26
MSDS: Fr,-9S FLUORAD Brand Fluarochomical january 29, 1998
Surfactant
PAGE 6
-----------------------------------------------------------------------------
S. HEALTH MAZARD DATA
(continued)
-----------------------------------------------------------------------------
REPRODUCTIVE/DEVELOPMENTAL
TOXINS:
Not teratagenic in the rat at oral doses below maternally toxic
levels.
OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under
California Proposition 65.
A Product Toxicity Summary Sheet is available.
----------------------------------------------------------------------------SECTION CHANGE DATES ----------------------------------------------------------------------------
HEADING
SECTION CHANGED SINCE November 05, 1997 ISSUE
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
-----------------------------------------------------------------------------
The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application.
3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly from 3M.
418-012:PAGE C-27
ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE
418-012:PAGE C-28
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Pmtocol 418-012 Version:418-012 (09AUG 98)
Page 1 of 3
PROCEDURE
Test Article:
PFOS
Vehicle:
0.5% Tweene 80 in R.O. Deionized Water
A. Purpose:
The purpose of this procedure is to provide a method for the preparation of dosage suspensions of PFOS and the vehicle for oral administration to rabbits on Argus Study 418-012.
B. General Information:
1 . All suspension containers willbe labeled and color coded. Each label will specify the protocol number, test articleidentificationA,rgus batch number, concentration, dosage level,preparation date, expiration date and storage conditions.
2a. Suspensions willbe prepared:
X Daily
-
Weekly
2b. Vehicle willbe prepared:
Daily
X Weekly
- For
days of use
- For
days of use
3. Suspensions willbe prepared at a finaldosage volume of 5 mL/kg.
4. Safety:
X
Gloves, lab coat, goggles or safety glasses and faceshield
X
Dust-Mist Respirator
Haff-Face Respirator
Full-Face Respirator/Positive Pressure Hood
Tyvek Suit/Apron
5. Dosage suspensions adjusted for Free base and % Purity.
Yes
X _ No (Calculations based on 100%)
Free Base
Purity
6. Sampling requirements: Cited in protocol.
7. Storage: Cited in protocol.
418-012P:AGE C-29
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Protocol418-012 Version:418-012 (09AUG 98)
Page 2 of3
PROCEDURE
NOTE:
Test articlweillbe prepared as a serialdilutiofnrom the high dosage to the low dosage. Once the finalvolumes are achieved, stirbars are to be added to the containers;mixing should occur during sampling and/or administration.
C. Preparationof Vehicle
1 . Add the requiredamount of R.O. deionized water to an appropriately labeledcontainer.Heat the water to 500C, 50C, add the required amount of Tweens 80 and mix untiluniform (See TEST ARTICLE CALCULATIONS).
D. Test ArticleSuspension Preparation:
1 . To prepare the 0.75 mg/mL, Group V suspension, add the required amount of testarticle(See TEST ARTICLE CALCULATIONS) intoan appropriatelysized,labeledcontainer.QS ad to the requiredamount with vehicleand heat the mixtureto 800C 50C forapproximately 30 minutes or untilthe TA/S dissolves.
2. Once the testarticlehas dissolved;spin whilethe suspension cools. (Be sure there isa visiblevortex,thiswillachieve the desired emulsion. This may be prepared the day before use.)
3. To prepare the 0.5 mg/mL, Group IV suspension, remove the required amount of stock suspension (Group V) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicleand mix.
4. To prepare the 0.2 mg/mL, Group IIIsuspension, remove the required amount of stock suspension (Group IV)(See TEST ARTICLE CALCULATIONS), QS ad with the vehicleand mix.
5. To prepare the 0.02 mg/mL, Group 11suspension, remove the required amount of stock suspension (Group 111()See TEST ARTICLE CALCULATIONS), QS ad with the vehicleand mix.
418-012:PAGE C-30
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Pmtocol 418-012 Version:418-012.(09AUG 98)
Page 3 of 3
PROCEDURE
6. To prepare the 0 mg/mL, Group Isuspension, add requiredamount of vehicleto an appropriatelysized,labeledcontainer(See TEST ARTICLE CALCULATIONS) and mix.
Written by:
Approved b
Date: 11-4@16-9
Clarification: No --@@s (See attachedclarificatifonrm.)
lnftials/Date:
P PJAEDIC A
418-012:PAGE C-31
Afgus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Horshaffn,PA 19044 Telephone: (215)443 -87 10 TelefiLx(:215)443-8587
PROTOCOL 418-012
ORAL (STOMACH TUBE) DEVELOPMENTAL OF PFOS IN RABBITS
TOXICITY STUDY
SPONSOR'S STUDY NUMBER: 6295.10
Amendment I - 11 December 1998
1
S12onso (page 1 ofthe protocol):
The Sponsor is3M CorporateToxicology,ratherthan 3M ToxicologyServices.
Reason forChange:
This change was made atthe requestofthe Sponsor.
2. Species/Strainand Reason forSelection(page 5 ofthe protocol):
The testarticliesbiologicalalcytive,ratherthan pharmacologicallyactiveinthis strain.
Reason forChange:
This change was made atthe requestofthe Sponsor.
3. Route and Reason forChoice (page 7 ofthe protocol):
The oral(gavage)routeisa possiblerouteofhuman exposure,ratherthan the one proposed forclinicaulse.
418-012:PAGE C-32
Reason forChange:
This change was made at the request of the Sponsor.
Amendment 1 Pmtocol 418-012
Page 2
-
61,444@
--I/-)g@z-irf
I- -
n7l@. Hoberman, Ph.D., DABT Date 4d Directorc
nd GY.-.o-r-Y-ko4rk,, 6hfh..D@D nDDAABET3
@ Dire or of Research
Associa-te Director
earch
and Study'Director
Date
I zip De na CI-6@o, V.M.D.@
11:0ze -5y Date
Chairp&f@on, InstitutionaAlnimal Care
and Use Committee
Marvin T. Case, D.V.M., Ph.D. Study Monitor
z m,.-er Date
I -"- .
--
1.7.,
APPENDIX D PILOT REPORT
418-012:PAGE D-1
FINAL PILOT REPORT
Study Title Oral (Stomach Tube) Dosage-Range Developmental ToxicityStudy of PFOS
in Rabbits
SPONSOR'S STUDY NUMBER: T-6295.10
Author Raymond G. York Ph.D.,DABT
(StudyDirector)
Study Comr)letedOn 6 January 1999
(FinalPilotReport)
PerformingLaborato Argus Research LaboratoriesI,nc.
905 Sheehy Drive,BuildingA Horsham, Pennsylvania 19044-1297
Laborato[yPro6ectID Argus Research LaboratoriesI,nc.,ProtocolNumber: 418-012P
418-012:PAGE D-2
PROTOCOL
418-012P:
418-012P:PAGE 2
ORAL (STOMACH DEVELOPMENTAL IN RABBITS
TUBE) DOSAGE-RANGE TOXICITY STUDY OF PFOS
SPONSOR'S STUDY NUMBER: T-6295.10
SUBJECT ABSTRACT 1. Purpose ii. Methods 111. Results
TABLE OF CONTENTS
IV. Conclusion
Figure 1. Maternal Body Weights
Table 1. ClinicalObservations - Summary
Table 2. Necropsy Observations - Summary
Table 3.
Uterine Contents forthe IndividualRabbits that were Found Dead or Aborted
Table 4. Maternal Body Weights - Summary
Table 5. Maternal Body Weight Changes - Summary
Table 6.
Maternal Absolute Feed Consumption Values (g/day) Summary
Table 7.
Maternal Relative Feed Consumption Values (g/kg/day)- Summary
PAGE 4 6 6 7
12 13 14 16
20 22 26
28
30
418-012:PAGE D-3
SUBJECT
418-012P:PAGE 3
PAGE
Table 8. Caesarean-SectioningObservations- Summary
32
Table 9. LitterObservations (Caesarean-Delivered Fetuses) -
Summary
34
Table 10. Fetal Gross ExternalAlterations- Summary
36
Table 11. ClinicalObservations - IndividualData
38
Table 12. Necropsy Observations - IndividualData
42
Table 13. Maternal Body Weights - IndividualData
45
Table 14. Maternal Feed Consumption Values - IndividualData
52
Table 15. Caesarean-Sectioning Observations - IndividualData
59
Table 16. LifterObservations (Caesarea n-De liveredFetuses) -
IndividualData
61
Table 17. FetalSex, VitalStatus and Body Weight -
IndividualData
63
ATTACHMENT
1 - PROTOCOL
66
41 Ml 2:PAGE D-4
418-012P:PAGE 4
TITLE: ORAL (STOMACH TUBE) DOSAGE-RANGE TOXICITY STUDY OF PFOS IN RABBITS
DEVELOPMENTAL
ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-012P SPONSOR'S STUDY NUMBER: T-6295.10
ABSTRACT
Thirty-fipvreesumed pregnant New Zealand White [Hra:(NZW)SPF] rabbitswere randomly assignedto seven dosage groups,fiveper group. Suspensions of PFOS were administeredorallyonce dailyon days 7 through20 of presumed gestation(DGs 7 to20) atdosages of0 (Vehicle)0,.1,1,2.5,5, 10 and 20 mg/kg/day. The vehiclewas 0.5% Tween88O inreverseosmosis membrane processed deionizedwater. The dosage volume was 10 mukg, adjusteddaily on the basisofthe individuablody weights.
Checks forviabiliwteyre made twicedaily.Clinicaolbservationswere recorded twicedailyduringthe dosage period(once priortodosage administratioannd once approximatelyone hour afterdosage administrationa)nd once dailyduring the postdosage period.Body weightsand feed consumption valueswere recordeddailyduringthe dosage and postdosage periods.
Allsurvivingrabbitswere sacrificeodn DG 29 and examined forthe number and distributioofncorporalutea,implantatiosnitesand uterinecontents.A gross necropsy ofthe thoracica,bdominal and pelvicviscerawas performed. Fetuses were weighed and examined forgross externalalterationasnd sex.
Two does inthe 5 mg/kg/day dosage group and fourinthe 10 mg/kg/day dosage group abortedand were sacrificedA.dditionallyf,ourdoes inthe 20 mg/kglday dosage group were found dead and one doe inthe same dosage group aborted and was sacrificedD.osage-dependant increasesinadverse clinical observations(scantor no feces,ungroomed coat and excess salivation) occurredinthe 2.5,5, 10 and 20 mg/kg/day dosage groups.
Rabbitsinthe 10 and 20 mg/kg/day dosage groups had body weight lossesand severelyreduced absoluteand relativfeeed consumption valuesforallrecorded
418-012:PAGE D-5
418-012P:PAGE 5
intervalasfterinitiatioofndosage; therewere no survivingpregnant rabbitsin these groups afterDGs 26 and 19, respectivelyT.he 2.5 and 5 mg/kg/day dosage groups had decreased body weight gainsor body weight lossesforthe entiredosage and gestationperiods.Absolute and relativfeeed consumption valuesforthe entiredosage periodwere reduced inthe 2.5 and 5 mg/kg/day
dosage groups. Feed consumption values were reduced inthe 2.5 and 5 mg/kg/day dosage groups forthe entiregestationperiod afterthe initiatioonf dosing.
Fetalbody weights were severely reduced and the number of early and late resorptionsand the percentage of conceptuses per liftewrere increased inthe 5 mg/kg/day dosage group, however, only two of the four pregnant does inthis dosage group survived to Caesarean-sectioning. Fetalbody weights were reduced inthe 2.5 mg/kg/day dosage group as compared to the concurrent controlsbut were at the lower end ofthe range observed historicallaytthe Testing Facility.Allother Caesarean-sectioning or lifteprarameters were unaffected by administrationofthe testarticleat dosages as high as 5 mg/kg/day.
One fetus inthe 2.5 mg/kg/day dosage group had a cleftsnout and absent incisors.Two fetuses inthe 0.1 mg/kg/day dosage group had fetalgross malformations. One fetus had a short snout, displaced and small nares and the other fetus had abdominal distention.
Based on these data, dosages of 0 (Vehicle),0.1, 1.0,2.5 and 3.75 mg/kg/day
PFOS were recommended Protocol418-012).
for the developmental toxicitystudy in rabbits(Argus
418-012:PAGE D-6
1. PurRose:
418-012P:PAGE 6
The purpose ofthisstudywas to provideinformationforthe selectionof dosages
to be used in the developmental toxicity(embryo-fetaltoxicityand teratogenic potential)study of PFOS administered orallyvia stomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits.
ii. Methods!:
The testarticleP,FOS (Lot217), an offwhite powder, was received on 20 May 1998, and was stored at room temperature. The vehicle,0.5% Tween@80 (lotM03HO5), a clearviscous fluidwas received on 1 July 1998, and was stored at room temperature. The vehiclediluent,reverse osmosis membrane processed deionized water (R.O. Deionized Water) was available from a continuous source at the Testing Facilityand was maintained at room temperature.
Thirty-fivperesumed pregnant New Zealand White [Hra:(NZW)SPF] rabbitswere randomly assigned to seven dosage groups [fiveper group (Groups Ithrough Vil)].Suspensions of PFOS were administered orally(stomach tube) once daily on days 7 through 20 of presumed gestation(DGs 7 to 20) at dosages of 0 (Vehicle),0.1, 1,2.5, 5, 10 and 20 mg/kg/day. The dosage volume was 10 mukg, adjusted dailyon the basis of the individualbody weights recorded immediately before intubationof the testarticle.
Checks forviabilitwyere made twice daily. Clinicalobservations were recorded twice dailyduring the dosage period (once priorto dosage administrationand once approximately one hour afterdosage administration)and once dailyduring the postdosage period. Body weights and feed consumption values were recorded dailyduring the dosage and postdosage periods.
Allsurvivingrabbitswere sacrificedon DG 29 and examined forthe number and distributonof corpora lutea,implantationsitesand uterinecontents. A gross necropsy of the thoracic,abdominal and pelvicviscera was performed. Fetuses were weighed and examined forgross externalalterationsand sex.
a. Detailed descriptionsof allprocedures used inthe conduct of thisstudy are provided inthe attached protocoland amendments. Deviationsfrom the Protocol and Standard Operating Procedures of the Testing Facility are availableinthe raw data.
418-012:PAGE D-7
Ill. Results:
418-012P:PAGE 7
A. Mortalily,Clinicaland NecroRsv Observations (Summaries -Tables I
and 2: Individual Data - Tables 3. 11 and 12)
A.I. Mortalily, Abortions and Uterine Contents of Aborted Rabbits
Two does (8257 and 8259) in the 5 mg/kg/day dosage group and four does (8261, 8262, 8364 and 8265) inthe 10 mg/kg/day dosage group aborted and were sacrificed.Additionallyf,our does (8266, 8267, 8268 and 8270) inthe 20 mg/kg/day dosage group were found dead and one doe (8269) in the same dosage group aborted and was sacrificed.The death of doe 8266 was due to an intubationaccident. These does are described below. Allother does survived to scheduled sacrifice.
5 mg/kg/day dos"e
Doe 8257 inthe 5 mg/kg/day dosage group aborted and was sacrificedon DG 23 after14 dailydosages. The only adverse clinicaolbservation was scant feces (DGs 13 to 22). No gross lesionswere revealed by necropsy and fivelate resorptionswere aborted and one lateresorptionwas in utero. This doe lost body weight and feed consumption values were reduced throughout the dosage period.
Doe 8259 inthe 5 mg/kg/day dosage group aborted and was sacrificedon DG 22 after14 dailydosages. The only adverse clinicaolbservation was scant feces (DGs 14 and 16 to 21). No gross lesionswere revealed by necropsy. This doe aborted seven dead fetuses and two lateresorptions;no conceptuses remained in utero. This doe lostbody weight and feed consumption values were reduced afterDG 11.
10 mg/kci/day dosage
Doe 8261 inthe 10 mg/kg/day dosage group aborted and was sacrificedon DG 26 after14 dailydosages. Adverse clinicaolbservations included scant feces (DGs 12, 16 to 20, 23 and 24),no feces (DG 13 to 15, 21, 22, 25 and 26) and an ungroomed coat (DGs 24 to 26). Alllobes of the liverwere mottled red and tan and the mucosal surface of the stomach had numerous black areas at necropsy. This doe aborted seven dead fetuses and two dead fetuses were in utero. The fetuses that were inutero had edematous heads and necks; allother fetuses appeared normal fortheirdevelopmental ages. This doe generally lost weight and had reduced feed consumption values afterDG 9.
4lMl2:PAGE D-8
418-012P:PAGE 8
Doe 8262 inthe 10 mg/kg/day dosage group abortedand was sacrificeodn DG 22 after14 dailydosages. Adverse clinicaolbservationsincludeda mass on
the nose (DGs 7 to 21),scant feces (DGs 11 to 12, 14 to 21) and no feces (DG 13). At necropsy, the cut surface of the small mass on the nose revealed a smooth pink material. Nine lateresorptionswere aborted and no conceptuses remained in utero. This doe lostbody weight and feed consumption values were reduced afterDG 9.
Doe 8264 inthe 10 mg/kg/day dosage group aborted and was sacrificedon DG 23 after14 dailydosages. Adverse clinicaolbservations included scant feces (DGs 12, 14, 15, 19 and 20),no feces (DGs 13, 16 to 18, 21 and 22) and a red substance inthe cage pan (DG 22). Alltissuesappeared normal at necropsy. Nine lateresorptionswere aborted and no conceptuses remained in utero. This doe lostbody weight afterDG 8 and feed consumption values were reduced afterDG 9.
Doe 8265 inthe 10 mg/kg/day dosage group aborted and was sacrificedon DG 25 after14 dailydosages. Adverse clinicaolbservations included scant feces (DGs 9 to 20, 23 and 24),no feces (DGs 21 and 22) and a red substance inthe cage pan (DG 25). Alltissues appeared normal at necropsy. This doe aborted one dead fetus and fivelivefetuses and one earlyresorptionwere in utero. Allfetuses appeared normal fortheirdevelopmental ages. Body weight losses occurred afterDG 8 and feed consumption values were reduced throughout the dosage period.
20 mg/kglday dos"e
Doe 8266 in the 20 mg/kg/day dosage group was found dead on DG 17 after11 dailydosages. Adverse clinicaolbservations priorto death included scant feces (DGs 12 to 15),a red substance incage pan, no feces,ungroomed coat, a red perivaginalsubstance (DGs 16 and 17) and excess salivation(DG 17). Necropsy revealed a white frothymaterialinthe esophagus and inflatedlungs. Necropsy also revealed tears inthe leftdiaphragmatic lobe and inthe leftlateral lobe of the lungs (approximately2.0 cm in length)and two eroded areas inthe fundic mucosa of the stomach (1.5x 0.5 cm and 1.5 x 0.5 cm). Ten early resorptionswere inutero. Allfetuses appeared normal fortheirdevelopmental ages. Body weight lossoccurred afterDG 8 and itsfeed consumption values were reduced throughout the dosage period. The death of thisdoe was considered an intubationaccident because of the tear inthe leftlung lobe; however, thisdoe had adverse clinicaalnd necropsy observations that indicated the doe was moribund.
418-012:PAGE D-9
418-012P:PAGE 9
Doe 8267 inthe 20 mg/kg/day dosage group was found dead on DG 20 after13 dailydosages. Adverse clinicaolbservationsincludedscant feces (DGs 9, 10
and 16 to 19),no feces (DGs 11 to 15) and excess salivation(DG 19). No gross lesionswere observed by necropsy and thirteendead fetuses were in uter-o.All fetuses appeared normal fortheirdevelopmental ages. Body weight losses occurred afterDG 8 and feed consumption values were reduced throughout the dosage period.
Doe 8268 inthe 20 mg/kg/day dosage group was found dead on DG 17 after 10 dailydosages. Adverse clinicaolbservations included scant feces (DGs 9 to 15),softor liquidfeces (DGs 12 and 13),a tan perivaginalsubstance (DG 16) and no feces (DG 16). Necropsy revealed approximately 18 mL of cloudy green fluidinthe abdominal cavity,a friablestomach and a ruptured gallbladder. Nine dead fetuses and one earlyresorptionwere in utero. Allfetuses appeared normal fortheirdevelopmental ages. Body weight losses occurred afterDG 9 and feed consumption values were reduced throughout the dosage period.
Doe 8269 inthe 20 mg/kg/day dosage group aborted and was sacrificedon DG 19 after13 dailydosages. Adverse clinicaolbservations included scant feces (DGs 11 to 19),excess salivation(DGs 18 and 19) and a red substance in the cage pan (DG 19). Other than an observation of ungroomed coat and confirmationof persistentadverse clinicaolbservations, no gross lesionswere observed by necropsy. This doe aborted three dead fetuses and fivelivefetuses were in utero;allfetuses appeared normal fortheirdevelopmental ages. Body weight losses occurred and feed consumption values were reduced afterDG 8.
Doe 8270 inthe 20 mg/kg/day dosage group was found dead on DG 16 after nine dailydosages. The only adverse clinicaolbservation priorto death was scant feces (DGs 9 to 15). Necropsy revealed the non-glandular mucosal surface of the stomach to be red and diffuse.Five fetuses and one early resorptionwere in utero. Allfetuses appeared normal fortheirdevelopmental ages. Body weight losses occurred afterDG 7 and feed consumption values were reduced throughout the dosage period.
A.2. ClinicaOlbservations
Dosage-dependant increases inadverse clinicaolbservations occurred inthe 2.5,5, 10 and 20 mg/kg/day dosage groups. One rabbitinthe 2.5 dosage group and allrabbitsinthe 5, 10 and 20 mg/kg/day dosage groups had scant feces (firsotbserved on DGs 14, 13, 9 and 9, respectively).One, fiveand three rabbits inthe 5, 10 and 20 mg/kg/day dosage groups had no feces (firsotbserved on
418-012:PAGE D-10
418-012P:PAGE 10
DG 18,12 and 11,respectivelyT)h.ree rabbitsinthe20 mg/kg/daydosage group had excess salivatio(nfirsotbserved on DG 17).Two rabbittshataborted orwere found dead ineach ofthe 10 and 20 mg/kg/day dosage groups had a redsubstanceinthecage pan (firsotbservedon DGs 22 and 16,respectively). Two rabbitsinthe20 mg/kg/daydosage group had a redortanperivaginal substance(firsotbservedon DG 16).One rabbitineach ofthe2.5,5,10 and 20 mg/kg/daydosage groups had an ungroomed coat(firsotbserved on DG 18,23, 24,24 and 16,respectively).
Allotherclinicaolbservationswere consideredunrelatedtothetestarticle because: 1)the incidenceswere notdosage-dependent;or2)theobservations occurredinonlyone rat.These clinicaolbservationsincludedlocalizeadlopecia (undersideh,ead,back and/orlimbs)for2,1,1,0,2,0 and 0 does inthe seven respectivedosage groups,a mass on the nose of one 10 mg/kg/daydosage group doe thataborted,one rabbitineach ofthe 0.1and 20 mg/kg/daydosage groupsthathad softor liquifdeces(firsotbserved on DG 12)and scantfecesin one 0.1mg/kg/daydosage group rabbiton one day ofthestudy.
A.3. NecroRsy Observations
There were no necropsyobservationsforthe rabbitsthatsurviveduntil scheduledsacrificeA.llnecropsyobservationsinrabbitsthatdied oraborted were describedpreviously.
B. Maternal Body Weights and Body Weight Changes (Figure1: Summaries -Tables 4 and S. IndividualData -Table 12)
Rabbitsinthe 10 and 20 mg/kg/daydosage groups had body weightlossesfor allrecordedintervalasfterinitiatioofndosage; therewere no survivinpgregnant rabbitsinthesegroups afterDGs 26 and 19,respectivelyT.he 2.5and 5 mg/kg/daydosage groups had decreased body weightgainsor body weight lossesfortheentiredosage period(calculateads DGs 7 to21). Duringthe postdosageperiod(DGs 21 to29),body weightgainswere increasedinthe 2.5and 5 mg/kg/daydosage groups,a rebound phenomenon thatcommonly occursinthese typesofstudies.Body weightgainsfortheentiregestation period(DGs 0 to29) and theentiregestationperiodafterthe initiatioofndosing (DGs 7 to29) were reducedinthe2.5 and 5 mg/kg/daydosage groups.
Body weightsand body weightgainswere unaffectedby the 1 mg/kg/day dosage ofthetestarticle.
418-012:PAGE D-1 1
418-012P: PAGE 11
C. Absolute (glday)and Relative (g/kgiday)Feed Consumption Values
(Summaries - Tables 6 and 7: Individual Data - Table 14)
Rabbits inthe 10 and 20 mg/kg/day dosage groups had severely reduced absolute and relativefeed consumption values forallrecorded intervalsafter initiatioonf dosage; there were no survivingpregnant rabbitsinthese groups afterDGs 26 and 19, respectively.Absolute and relativefeed consumption values forthe entiredosage period (calculatedas DGs 7 to 21) were reduced in the 2.5 and 5 mg/kg/day dosage groups. During the postdosage period (DGs 21 to 29), feed consumption values were generallycomparable among the five survivinggroups, -althoughthe 5 mg/kg/day dosage group had slightlyincreased feed consumption values during thisperiod,a rebound phenomenon that commonly occurs inthese types of studies. Feed consumption values were reduced inthe 2.5 and 5 mg/kg/day dosage groups forthe entiregestation period afterthe initiationf dosing (DGs 7 to 29).
Absolute and relativefeed consumption values were unaffected by the 1 mg/kg/day dosage of the testarticle.
D. Caesarea n-Sectioning and LitterObservations (Summaries - Tables 8 and 9: IndividualData - Tables 15 through 17)
Caesarean-sectioning observations were based on 5,4, 4, 5 and 2 pregnant rabbitswith one or more livefetuses inthe 0, 0.1, 1,2.5 and 5 mg/kg/day dosage groups, respectively.There were no pregnant rabbitsthatsurvived to DG 29 Caesarean-sectioning inthe 10 and 20 mg/kg/day dosage groups. Fetalbody weights were severely reduced and the number ofearly and lateresorptionsand the percent resorbed conceptuses per liftewrere increased (along with the concomitant decrease inliftesrize)inthe 5 mg/kg/day dosage group. Only two of the four pregnant does inthisdosage group survived to Caesareansectioning. Fetalbody weights were also reduced inthe 2.5 mg/kg/day dosage group as compared to the concurrent controlsbut were at the lower end of the range observed historicallayt the Testing Facility.
Allother Caesarean-sectioning or lifteprarameters were unaffected by administrationof the testarticleat dosages as high as 5 mg/kg/day. The lifter averages for corpora lutea,implantationsand percent livemale fetuses were comparable among the fivesurvivingdosage groups. No does had a lifter consistingof only resorbed conceptuses, there were no dead fetuses and all placentae appeared normal.
418-012:PAGE D-12
E. FetalGross Observations (Summary -Table 10)
418-012P:PAGE 12
Totalsof42,37,34,42 and 11 fetuseswere examined externallfyorgross alterationisnthefiverespectivedosages groupswithliveliftersT.hree fetuses had grossexternalalterationsO.ne fetus(8251-10)inthe2.5 mg/kg/daydosage group had a clefstnoutand absent incisorsT.wo fetuses(8243-8and 8244-7)in the0.1mg/kg/daydosage group had fetaglross malformationsf;etus8243-8 had a shortsnout,displacedand smallnares and fetus8244-7 had abdominal distention.
IV. Recommendation:
Based on thesedata,dosages of0 (Vehicle)0,.1,1.0,2.5and 3.75mg/kg/day PFOS were recommended forthedevelopmentaltoxicitsytudyinrabbits(Argus Protocol418-012).The 0.1mg/kg/daydosage isexpectedtobe a no-observable-effect-le(vNeOlEL) forboth maternaland embryo-fetatloxicity, and the 3.75mg/kg/daydosage isexpectedtoproduce minimalmaternaltoxicity and littolreno developmentaltoxicity.
Alan M. Hoberman, Ph.D.,DABT Date Directorof Research
'&o onnd G. York h. .,DABT AssociateDirecto search and Study Director
99 Date
4.20
4.W
3.80
3.60 -
x 3.40 (9
3.20
3.00
2.50
2.60 '7
MATERNAL BODY WEIGHTS
Figure 1
0 (VEHICLE)
0.1MG/KG/
1 MGIKGIDAY
2.5:GIKG/Dfi
x x
5 MG/KG/DAY
x
10 MG/KGIDN
20 MG/KG/Dk
lio I'l l@2 1'3 1'4 1'5 li6 1'7 1'8 1'9 iO @l 2.2 213 2:4 2!5 2'6 27 2'8 29
DAY OF GESTATION
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR,S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE I (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY
--------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE) 0.1
1
2.5
--------------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
115/ 5
115/ 5
115/ 5
IIS/ 5
MORTALITY FOUND DEAD ABORTED AND
SACRIFICED
0
0
0
0
0
0
0
0
0
0
0
0
SCANT FECES
0/ 0
1/ 1
0/ 0
a/ I
NO FECES
C/ 0
0/ 0
0/ 0
0/ 0
EXCESS SALIVATION
0/ 0
0/ 0
0/ 0
0/ 0
RED SUBSTANCE IN CAGE PAN
0/ 0
0/ 0
0/ 0
0/ 0
RED OR TAN PERIVAC;INAL SUBSTANCE
0/ 0
0/ 0
0/ 0
0/ 0
SOFT OR LIQUID FECES
0/ 0
2/ 1
0/ 0
0/ 0
UNGROO148D COAT
0/ 0
0/ o
0/ 0
12/ 1
NOSE: 14ASS
0/ 0
0/ 0
0/ 0
0/ 0
LOCALIZED ALOPECIA:
TOTAL
15/ 2
3/ 1
2/ 1
0/ 0
UNDERSIDE
2/ 1
0/ o
0/ 0
0/ 0
HEAD
0/ 0
0/ 0
2/ 1
a/ 0
BACK
0/ 0
3/ 1
0/ 0
0/ 0
LIMBS
13/ 1
0/ 0
0/ 0
0/ 0
-------------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE - (DAYS x PABBITS)/NUMBER
OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GEST
U/N - TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS WITH OBSERVATION.
a. Dosage occurred on days 7 through 20 of presumed gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RA.NGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 1 IPAGE 2): CLINICAL OBSERVATIONS - SUMMARY
------------------------------------- ----------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
------------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
102/ 5
95/ 5
59/ 5
MORTALITY FOUND DEAD ABORTED AND
SACRIFICED
SCANT FECES
NO FECES
EXCESS SALIVATION
RED SUBSTANCE IN CAGE PAN
RED OR TAN PERIVAGINAL
SUBSTANCE
2 0 2f,g 50/ 5
2/ 1 0/ 0
0/ 0 0/ 0
4 0 4h-k
5 4b-e 11
49/ 5
33/ 5
23/ 5
S/ 3b-d
0/ 0
4/ 3b,c,l
2/ 2j,k 3/ 2b,l
0/ 0
3/ 2b,d
SOFT OR LIOUID FECES
0/ 0
0/ 0
2/ id
UNGROOMED
COAT
2/ 1
3/ ih
2/ lb
NOSE: MASS
0/ 0
15/ li
0/ 0
LOCALIZED ALOPECIA:
TOTAL
16/ 2
0/ 0
0/ 0
UNDERSIDE
16/ 2
0/ 0
0/ 0
HEAD
0/ 0
0/ 0
0/ 0
BACK
0/ 0
0/ o
0/ 0
LIMBS
0/ 0
0/ o
0/ 0
------------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE - (DAYS x RABBITS)/NUMBER
OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GES
NIN - TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS
a. Dosage occurred on days 7 through 20 of presumed
b. Doe 8266 was found dead on day 17 of gestation.
C. Doe 8267 was found dead on day 20 of gestation.
d. Doe 8268 was found dead on day 17 of gestation.
e. Doe 8270 was found dead on day 16 of gestation.
f. Doe 8257 aborted on day 23 of gestation.
9. Doe 8259 aborted on day 22 of gestation.
h. Doe 8261 aborted on day 26 of gestation.
i. Doe 0262 aborted on day 22 of gestation.
J. Doe 8264 aborted on day 23 of gestation.
k. Doe 0265 aborted on day 2S of gestation.
1. Doe 8269 aborted on day 19 of gestation.
WITH OBSERVATION. gestation.
PROTOCOL 418-012P!
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY
----------------------------------------------------------- ------------------------------------------------------------
DOSAGE GROUP
I
if
III
IV
DOSAGE (14G/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
------------------------------------------------------------------------------------------------------------------------
RABBITS EXAMINED b
N
5
5
5
5
MORTALITY FOUND DEAD
ABORTED
N
0
0
0
0
N
0
0
0
0
N
0
0
0
0
APPEARED NORMAL
N
5
5
5
5
ESOPHAGUS:
WHITE FROTHY MATERIAL
N
0
0
0
0
LUNGS:
APPEARED INFLATED AND LEFT
DIAPHRAGMATIC
LOBS, TEAR
N
0
0
0
0
ABDOMINAL CAVITY:
CLOUDY GREEN FLUID
N
0
0
0
0
GALLBLADDER:
RUPTURED
N
0
0
0
0
------------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of presumed gestation.
b. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
PROTOCOL, 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 2 (PAGE 2): NECROPSY OBSERVATIONS - SUMMARY
-------------------------------------------------------------------------------------------------------------- ----------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
--------------------------------------------------------------------------------------------------------------------------
RABBITS BXAMINED b
N
s
5
5
5
STOMACH:
FUNDIC MUCOSA, TWO ERODED AREAS N
0
0
0
0
NON-GLANDULAR
MUCOSA,
RED AND DIFFUSE
N
0
0
0
0
FRIABLE
N
0
0
0
0
MUCOSAL SURFACE,
NUMEROUS BLACK AREAS
N
0
0
0
0
LIVER-.
LEFT LATERAL LOBE, TEAR
N
0
0
0
0
MOTTLED RED AND TAN
N
0
0
0
0
EXTERNAL OBSERVATIONS:
UNGROOKED
COAT
N
0
0
0
0
NOSE, MASS, CUT SURFACE
REVEALED SMOOTH PINK MATERIAL
N
0
0
0
0
--------------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days I through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 2 (PAGE 3): NECROPSY OBSERVATIONS - SUMMARY
-------------------------------------------------------- --------------------------------------------------------------
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
5
10
io
------------------------------------------------------------------------------------------------------------------------
RABBITS EXAMINED b
N
5
5
5
MORTALITY FOUND DEAD ABORTED
APPEARED NORMAL
N
2
N
0
N
2(j,h
N
Sg,h
4 0 41-1
3k,l
5 4c-f Im
2d,m
ESOPHAGUS:
WHITE FROTHY MATERIAL
u
0
0
Ic
LUNGS:
APPEARED INFLATED AND LEFT
DIAPHRAGMATIC
LOBE, TEAR
N
0
0
lc
ABDOMINAL CAVITY-.
CLOUDY GREEN FLUID
N
0
0
le
GALLOIJUDDER:
RUPTURED
N
0
0
le
-----------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for external observations c. Doe 8266 was found dead on day 17 of gestation. d. Doe 8267 was found dead on day 20 of gestation. e. Doe 8268 was found dead on day 17 of gestation. f. Doe 8270 was found dead on day 16 of gestation. 9. Doe 6257 aborted on day 23 of gestation. h. Doe 82S9 aborted on day 22 of gestation. i. Doe 8261 aborted on day 26 of gestation. J. Doe 8262 aborted on day 22 of gestation. k. Doe 8264 aborted on day 23 of gestation. 1. Doe 8265 aborted on day 25 of gestation. M. Doe 6269 aborted on day 19 of gestation.
confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 2 (PAGE 4): NECROPSY OBSERVATIONS - SUMMARY
--------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
-------------------------------------------------------------------------------------------------------------------------
RABBITS EXAMINED b
N
5
5
5
MORTALITY FOUND DEAD ABORTED
N
2
N
0
N
2g,h
4 0 4i-1
5 4c-f Im
STOMACH:
FUNDIC MUCOSA, TWO ERODED AREAS N
0
0
lc
NON-GLANDULAR
MUCOSA,
RED AND DIFFUSE
N
0
0
if
FRIABLE
N
0
0
le
MUCOSAL NUMEROUS
SURFACE, BLACK AREAS
N
0
ii
0
LIVER:
LEFT LATERAL LOBS, TEAR
N
0
0
Ic
MOTTLED RED AND TAN
N
0
ii
0
EXTERNAL OBSERVATIONS:
UNGROOMED
COAT
N
0
0
lm
NOSE, MASS, CUT SURFACE
REVEALED SMOOTH PINK 14ATERIAL
N
0
ij
0
----------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. c. Doe 8266 was found dead on day 17 of gestation. d. Doe 8267 was found dead on day 20 of gestation. e. Doe 8266 was found dead on day 17 of gestation.
f. Doe 8270 was found dead on day 16 of gestation. 9. Doe 0257 aborted on day 23 of gestation.
h. Doe 8259 aborted on day 22 of gestation. i. Doe 8261 aborted on day 26 of gestation. J. Doe 8262 aborted on day 22 of gestation. k. Doe 8264 aborted on day 23 of gestation.
1. Doe 8265 aborted on day 25 of gestation. M. Doe 8269 aborted on day 19 of gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 3 (PAGE 1): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD OR ABORTED
------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
CORPORA LUTEA
IMPLANTATIONS
EMBRYOS/FETUSES
b
RESORPTIO
DOSAGE (14G/KG/DAY)a NUMBER DAY OF DEATH
R
L
T
R
L
T
R
L
A
T
R
L
--------------------------------------------------------------------------------------------------------------------------
I 0 (VEHICLE)
0.1
III I
IV 2.5
v
5
0257
ABORTED ON DAY 23
2
4
6
2
4
6
0
0
0
0
0
1
OF GESTATION
82S9
ABORTED ON DAY 22 OF GESTATION
4
7
11
3
6
9
0
0
7e
7
0
0
vi
10
8261
ABORTED ON DAY 26
4
7
11
2
7
9
2f 0
7e
9
0
0
OF GESTATION
8262
ABORTED ON DAY 22 OF GESTATION
5
5
10
4
5
9
0
0
0
0
0
0
6264
ABORTED ON DAY 23 OF GESTATION
4
5
9
4
5
9
0
0
0
0
0
0
6265
ABORTED ON DAY 25
4
3
7
4
3
7
2
3
le
6
1
0
OF GESTATION ------------------------------------------------------------------------------------------- -------------------------
R = RIGHT
L = LEFT T = TOTAL
A = ABORTED
a. Dosage occurred on days 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages.
c. Early resorptions, unless noted otherwise.
d. Autolysis precluded further evaluation.
e. Dead fetuses.
f. Fetus 8261-1 and 8261-2 had edema on the dorsal head and ventral
neck.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVEUOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 3 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD OR ABORTED
--- ---------------------------------------------------- ---------------------------------------------------------------
DOSAGE GROUP
RABBIT
CORPORA LUTEA
IMPLANTATIONS
EMBRYOS/FETUSES
b
RESORPTI
DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH
R
L
T
R
L
T
R
L
A
T
R
L
-------------------------------------------------------------------------------------------------------------------------
Vil 20
8266
FOUND DEAD ON DAY 17 OF GESTATION
5
s
10
5
5
10
0
0
0
0
5
s
8267
FOUND DEAD ON DAY 20 OF GESTATION
9
6
15
7
6
13
7
6
0
13d
0
0
8268
FOUND DEAD ON DAY 17 OF GESTATION
6
4
10
6
4
10
6
3
0
9d
0
0269
ABORTED ON DAY 19 OF GESTATION
7
3
10
5
3
8
3
2
3e
8
0
0
8270
POUND DEAD ON DAY
5
2
7
5
1
6
4
1
0
Sd
1
0
16 OF GESTATION -----------------------------------------------------------------------------------------------------------------------
R = RIGHT
L - LEFT
T - TOTAL
A - ABORTED
a. Dosage occurred on days 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages.
C. Early resorption*, unless noted otherwise.
d. Unable to determine viability of conceptuses because of death of doe.
e. Dead fetuses.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR*S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 4 (PAGE 1); MATERNAL BODY WEIGHTS - SUMMARY
-----------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 IVEHICLE)
0.1
1
2.S
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
5
PREGNANT
N
5
4
4
5
14ATERNAL BODY WEIGHT (KG)
DAY
0
MEAN+S.D.
3.45 + 0.22
3.32 + 0.30
3.34 + 0.18
3.49 +
DAY
7
MEAN+S.D.
3.49 + 0.18
3.36 + 0.11
3.49 + 0.23
3.62 +
DAY
8
HEAN*S.D.
3.53 + 0.17
3.42 + 0.21
3.53 4 0.24
3.64 +
DAY
9
MEAN+S.D.
3.54 + 0.17
3.44 + 0.22
3.54 + 0.22
3.65 +
DAY 10
HEAN+S.D.
3.57 + 0.19
3.43 + 0.21
3.57 + 0.22
3.67 +
DAY 21
MEAN+S.D.
3.58 + 0.19
3.42 + 0.24
3.60 + 0.19
3.70 +
DAY 12
HEAN+S.D.
3.61 + 0.20
3.44 + 0.22
3.62 + 0.25
3.72 +
DAY 13
MEAN+S.D.
3.67 + 0.20
3.SO + 0.24
3.66 + 0.27
3.75 +
DAY 14
MEAN+S.D.
3.71 + 0.23
3.S3 + 0.25
3.71 + 0.28
3.74 +
DAY 15
MEAN+S.D.
3.70 + 0.20
3.56 + 0.29
3.74 + 0.28
3.77 +
DAY 16
MEAN+S.D.
3.73 + 0.20
3.60 + 0.31
3.76 + 0.28
3.74 +
DAY 17
MEAN+S.D.
3.75 + 0.22
3.62 + 0.28
3.78 + 0.30
3.73 +
DAY 18
MEAN+S.D.
3.77 + 0.22
3.62 + 0.28
3.81 + 0.28
3.75 +
DAY 19
MEAN+S.D.
3.80 + 0.22
3.66 + 0.28
3.83 + 0.30
3.72 +
DAY 20
MEAN+S.D.
3.81 + 0.21
3.69 + 0.28
3.84 + 0.28
3.72 +
DAY 21
MEA.N+S.D.
3.81 + 0.20
3.71 + 0.25
3.83 + 0.31
3.73 +
------------------------------------------------------------------------------------------------------------------
DAY = DAY OF GESTATION a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 4 IPAGE 2): MATERNAL BODY WEIGHTS - SUMMARY
-------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
5
PREGNANT
5
4
4
5
MATERNAL BODY WEIGHT (KG)
DAY 22
MEAN+S.D.
3.84 + 0.21
3.72 + 0.26
3.87 + 0.29
3.74 +
DAY 23
14EAN+S.D.
3.86 + 0.19
3.74 + 0.26
3.92 + 0.27
3.79 +
DAY 24
HEAN+S.D.
3.87 + 0.20
3.76 + 0.23
3.95 + 0.27
3.81 +
DAY 25
HEAN+S.D.
3.89 + 0.21
3.77 + 0.20
4.01 + 0.28
3.84 +
DAY 26
MEAN+S.D.
3.87 + 0.23
3.76 + 0.20
3.97 + 0.30
3.83 +
DAY 27
HEAN+S.D.
3.91 + 0.23
3.76 + 0.18
4.00 + 0.29
3.88 +
DAY 28
HEAN+S.D.
3.93 + 0.24
3.74 + 0.14
4.03 + 0.30
3.90 +
DAY 29
MEAN+S.D.
3.96 + 0.22
3.75 + 0.16
4.06 + 0.32
3.93 +
-------- ----------------------------------------------------------------------------------------------------------------
DAY - DAY OF GESTATION a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOI, 416-012P:
ORAL, (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER! T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 4 (PAGE 3): MATERNAL BODY WEIGHTS - SUMMARY
-------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
5
10
20
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT
N
4
4
s
MATERNAL BODY WEIGHT (KG)
DAY
0
HEAN+S.D.
3.36 + 0.40
3.28 + 0.41
3.40 + 0.18
DAY
7
MEAN+S.D.
3.44 + 0.33
3.45 + 0.39
3.54 + 0.22
DAY
8
MEAN+S.D.
3.45 + 0.35
3.48 + 0.36
3.S3 + 0.27
DAY
9
HEAN+S.D.
3.49 + 0.36
3.47 + 0.42
3.44 + 0.25
DAY 20
HEAN+S.D.
3.47 + 0.39
3.38 + 0.42
3.34 + 0.24
DAY 11 DAY 12
MEAN+S.D. MEAN+S.D.
3.49 + 0.37 3.44 + 0.37
3.28 + 0.39 3.19 + 0.40
3.27 + 0.24 3.20 + 0.24
DAY 13
HEAN+S.D.
3.44 + 0.39
3.16 + 0.43
3.15 + 0.24
DAY 14
MEAN+S.D.
3.35 + 0.38
3.10 + 0.42
3.10 + 0.25
DAY 15
MEAN+S.D.
3.28 + 0.37
3,06 + 0.42
3.04 + 0.26
DAY 16 DAY 17 DAY 18 DAY 19 DAY 20
MEAN+S.D. MEAN+S.D. HEAN+S.D. MEAN+S.D. MEAN+S.D.
3.25 + 0.36 3.20 + 0.35 3.20 + 0.35 3.16 + 0.34 3.12 + 0.35
3.04 + 0.39 3.00 + 0.38 2.96 + 0.44 2.92 + 0.42 2.90 + 0.44
3.06 [
3.03 (
2.99 I
2.79 (
+ 0.16 4)b + 0.15 3]b + 0.18 ilb + 0.00 ilb b
DAY 21
MEAN+S.D.
3.10 + 0.38
2.87 + 0.43
------------------------------------------------------------------------------------------------------------------------
DAY - DAY OF GESTATION I I = NUMBER OF VALUES
AVERAGED
a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER; T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 4 (PAGE 4); MATERNAL BODY WEIGHTS - SUMMARY
---------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE IMG/KG/DAY)a
5
10
20
---------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
u
5
5
5
PREGNANT
N
4
4
5
INCLUDED IN ANALYSES
u
3b
3b
Ob
MATERNAL BODY WEIGHT (KG)
DAY 22
MEAN+S.D.
3.17 + 0.48
2.05 + 0.52
DAY 23 DAY 24
MEM+S.D. HEAN+S.D.
3.40 i
3.47
+ 0.66 2)b + 0.66
2.78 + 0.71 ( 2)b
2.74 + 0.70
( 2)b
I 2]b
DAY 2S
MEAN+S.D.
3.52 + 0.60 ( 2]b
3.20 + 0.00 ( Ilb
DAY 26
MEAN+S.D.
3.50 + 0.59
3.03 + 0.00
I 2]b
I lib
DAY 27
HEAN+S.D.
3.58 + 0.56
b
( 2)b
DAY 28
MEAN+S.D.
3.56 + 0.64
[ 2)b
DAY 29
HEAN+S.D.
3.58 + 0.66
1 2)b
--------------------------------------------------------------------------------------------------------------------------
DAY II a. b.
= DAY OF GESTATION = NUMBER OF VALUES AVERAGED Dosage occurred on days 7 through 20 of gestation. Excludes values for rabbits that died or aborted.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 5 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - SUMMARY
------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
1
11
111
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
5
PREGNANT
N
5
4
4
5
MATERNAL BODY WEIGHT CHANGE
(KG)
DAYS 0 - 7
MEAN+S.D.
+0.04 + 0.09
+0.04 + 0.14
*0.14 + 0.10
+0.13 +
DAYS 7 - 10 DAYS 10 - 13 DAYS 13 - 16 DAYS 26 - 19 DAYS 19 - 21
HEAN+S.D. MEAN+S.D. HEAN+S.D. HEAN+S.D. HEAN+S.D.
+0.09 + 0.04 +0.10 + 0.04 +0.05 + 0.01 +0.07 + 0.02 +0.01 + 0.04
+0.07 + 0.05 +0.06 + 0.05 +0.10 + 0.08 +0.07 + 0.04 +0.04 + 0.03
+0.08 + 0.02 +0.10 + 0.05 +0.09 + 0.06 +0.08 + 0.05 +0.00 + 0.05
+0.05 + +0.08 + -0.01 + -0.02 + +0.01 +
DAYS 21 - 25 DAYS 25 - 29
HEAH+S.D. MEAN+S.D.
+0.09 + 0.06 +0.06 + 0.04
+0.07 + 0.08 -0.02 + 0.12
+0.18 + 0.05 +0.06 + 0.09
+0.12 + +0.09 +
DAYS 7 - 21
DAYS 21
29
HEAN+S.D. MEAN+S.D.
+0.32 + 0.04 +0.15 + 0.08
+0.34 + 0.10 +0.04 + 0.16
+0.34 + 0.09 +0.23 + 0.09
+0.11 + +0.20 +
DAYS
7
29
MEAN+S.D.
+0.47 + 0.11
+0.38 + 0.07
+O.S7 + 0.12
+0.31 +
DAYS
0 29
MEAN+S.D.
+0.51 + 0.18
+0.43 + 0.21
+0.72 + 0.20
+0.44 +
------- ----------------------7-----------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF Ppos IN RABBITS
TABLE 5 (PAGE 2): MATERNAL BODY WEIGHT CHANGES - SUMMARY
---------------------- ---------------------------- --------------------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT
N
4
4
5
MATERNAL BODY WRIGHT CHANGE
(KG)
DAYS 0 - 7
HEAN+S.D.
+0.08 + 0.08
+0.17 + 0.11
+0.15 + 0.10
DAYS 7 - 10
HEAN+S.D.
+0.02 + 0.10
-0.08 + 0.05
-0.20 + 0.11
DAYS 10 - 13
HEAN+S.D.
-0.03 + 0.04
-0.22 + 0.02
-0.20 + 0.08
DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21
HEAN+S.D. MEM+S.D. HEAN+S.D.
-0.19 + 0.04 -0.00 + 0.07 -0.06 + 0.06
-0.12 + 0.06 -0.12 + 0.03 -0.05 + 0.02
-0.18 I
-0.21 I
+ 0.02 ilb + 0.00 lib b
DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21
HEAN+S.D. HEAN+S.D. MEAN+S.D.
+0.29 I
+0.05 I
-0.34
+ 0.01 2]b + 0.06 2)b + 0.09
-0.16
+ 0.00 lib b
-0.58 + 0.06
DAYS 21 - 29
HEAN+S.D.
+0.35 + 0.04
b
( 2]b
DAYS 7 - 29
MEAN+S.D.
+0.06 + 0.11
I 2)b
DAYS 0 - 29
HEAN+S.D.
+0.10 + 0.01
I 2)b
------------------------------------------------- ----------------------------------------------------------------
DAYS - DAYS OF GESTATION I I - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 6 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) . SUMMARY
--------------------- -----------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ir
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
----------------- --------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
5
PREGNANT
N
5
4
4
5
MATERNAL FEED
CONSUMPTION
(G/DAY)
DAYS 7 - 10
MEAN+S.D.
181.0 + 3.2
163.2 + 21.9
181.8 + 1.3
181.4 +
DAYS 10 - 13
MEM+S.D.
172.5 + 22.9
144.2 + 41.6
169.5 + 21.3
162.8 + 3
DAYS 23 - 16 DAYS 16 - 19
HEAN+S.D. HEAN+S.D.
167.6 + 32.4 176.4 + 12.0
152.1 + 51.5 ( 3]b
178.8 + 8.4
173.9 + 14.0 175.3 + 11.8
135.3 + 7 122.0 + 6
DAYS 19 - 21
MEM+S.D.
172.3 + 17.5
182.5 + 1.8
181.0 + 4.1
114.4 + 8
DAYS 21 - 25
MEAN+S.D.
153.6 + 40.4
158.0 + 37.2
169.6 + 10.8
125.0 + 5
DAYS 25 - 29 DAYS 7 - 21
MFAN+S.D. MEAN+S.D.
130.9 + 37.1 174.1 + 17.5
89.0 + 56.2 163.0 + 23.6
144.2 + 35.8 176.0 + 10.8
143.2 + 2 145.2 + 4
DAYS 21 - 29
MEAN+S.D.
146.2 + 37.4
121.7 + 45.1
156.9 + 23.0
134.1 + 3
DAYS 7 - 29
MEAN+S.D.
164.0 + 22.0
148.4 + 10.6
169.0 + 13.9
141.2 + 4
------------------------------:-------------------7 --------------------------------------------7-------------------------
DAYS = DAYS OF GESTATION a. Dosage occurred on days 7 through 20 of gestation.
b. Excludes a value that was associated with spillage.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 6 (PAGE 2); MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY
---------------- ----------------------------------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
5
10
20
--------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT
N
4
4
5
MATERNAL PEED
CONSUMPTION
(G/DAY)
DAYS 7 - 10
MEAN+S.D.
168.4 + 25.3
111.8 + 42.6
46.2 + 24.0
DAYS 10 - 13
HEAN+S.D.
88.4 + 37.4
3.3 + 3.6
0.7 + 0.4
DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21
MEAN+S.D. MEAN+S.D. MEAN+S.D.
3.7 + 5.7 11.2 + 11.3 27.8 + 27.9
0.7 + 0.5 1.2 + 0.9 0.4 + 0.8
1.2 (
0.7 I
+ 0.2 4]b + 0.0 lib b
DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21
MEAN+S.D. HEAN+S.D. HEAN+S.D.
135.2 + 50.1 I ilb
182.6 + 1.6
( 2]b 60.8 + 17.6
1.8 + 0.0 -11b b
25.1 + 9.3
DAYS 21 - 29
MEAN+S.D.
158.9 + 25.9
b
I 2]b
DAYS 7 - 29
MEAN+S.D.
103.2 + 21.7
1 2]b -------------------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION I I - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted.
PROTOCOL 418-012P:
ORAL ISTOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 7 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUM14ARY
-------------------------------------------------------------------- ----------------------------------------------------
DOSAGE GROUP
1
11
111
TV
DOSAGE (t4G/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
s
5
PREGNANT
N
5
4
4
5
14ATERNAL FEED
CONSUMPTION
(G/KG/DAY)
DAYS
7
10
DAYS 10
13
DAYS 13
16
DAYS 16
19
MEAN+S.D. HEAN+S.D. MEAM+S.D. HEAN+S.D.
51.3 + 2.0 47.7 + 4.8 45.0 + 7.2 46.9 + 1.7
47.0 + 6.0
41.6 + 11.0
42.8 I
49.4
+ 12.0 3]b + 1.8
51.6 + 3.2 46.8 + 3.2 46.8 + 0.7 46.2 + 0.5
50.2 + 43.9 + 35.8 + 32.4 +
DAYS 19 - 21 DAYS 21 - 25
MEAN+S.D. HEAN+S.D.
45.3 + 3.2 39.8 + 9.8
49.6 + 3.2 42.7 + 11.4
47.4 + 2.8 43.4 + 3.4
30.4 + 33.3 +
DAYS 25 - 29 DAYS 7 - 21
HEAN+S.D. HEAN+S.D.
35.4 + 9.1 47.4 + 3.2
24.0 + 15.6 46.0 + 5.0
35.7 + 7.2 47.8 + 0.5
36.8 + 39.2 +
DAYS 21 - 29
MEAN+S.D.
37.6 + 9.1
32.9 + 13.1
39.6 + 4.4
35.1 +
DAYS 7 - 29
MEAN+S.D.
43.7 + 4.9
41.3 + 3.8
44.6 + 1.7
37.6 +
-------------------------------------------------------------------------------------------------------------------------
DAYS - DAYS OF GESTATION I I - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through
20 of gestation.
b. Excludes a value that was associated with spillage.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 7 (PAGE 2); MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY
-------------------- ---------- -----------------------------------------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
-------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT
u
4
4
5
14ATERNAL FEED
CONSUMPTION
(G/KG/DAY)
DAYS 7 10
MEM+S.D.
48.9 + 8.3
31.7 + 9.9
13.1 + 6.0
DAYS 10
13
HEAN+S.D.
25.0 + 7.5
1.0 + 1.1
0.2 + 0.1
DAYS 13
16
DAYS 16
19
DAYS 19 - 21
HEAN+S,D. HEAN+S.D. MEAN+S.D.
1.0 + 1.5 3.5 + 3.6 5.0 + 7.5
0.2 + 0.2 0.4 + 0.4 0.1 + 0.2
0.4 (
0.2 I
+ 0.0 4]b + 0.0 llb b
DAYS 21 - 25 DAYS 2S - 29 DAYS 7 - 21
MEM+S. D. HEAN+S.D. MEM+S.D.
39.3 I
52.2 (
18.1
+ 7.5 21b + 8.6 2)b + 3.6
0.5 + 0.0 llb b
7.8 + 2.2
DAYS 21 - 29
MEAN+S.D.
46.0 + 0.8
b
I 2)b
DAYS 7 - 29
HEAN+S.D.
29.8 + 1.1
I 2]b
-------------------------------------------------------------------------------------------------------------------------
DAYS - DAYS OF GESTATION
( I - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation.
b. Excludes values for rabbits that died or aborted.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 8 (PAGE 1): CAESAREAN-SECTIONING
OBSERVATIONS
- SUMMARY
----------------------------------------------------------------------------I ---------------------------------------------
DOSAGE GROUP
1
11
111
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
--------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
5
PREGNANT FOUND DEAD ABORTED
N(%) N(t) N(t)
S(IOD-0) 0( 0.0) 0( 0-0)
4( 80.0) 0( 0.0) 0( 0.0)
4( 80.0) 0( 0.0) 0( 0.0)
5(100.0 o( o.0 0( 0.0
RABBITS PREGNANT AND
CAESAREAN-SECTIONED
ON DAY 29 OF GESTATION
N
5
4
4
5
CORPORA LUTFA
MEAN+S.D.
10.2 +
1.6
11.8 +
2.9
10.0 + 0.8
11.0 +
IMPLANTATIONS
MEAN+S.D.
8.8 * 1.6
9.5 +
1.7
8.5 + 1.3
0.8 +
LITTER SIZES
MEAN+S.D.
8.4 +
1.1
9.2 +
1.5
8.5 + 1.3
8.4 +
LIVE FETUSES
N HEAN+S.D.
42
8.4 +
1.1
37
9.2 +
1.5
34 8.5 + 1.3
42 8.4 +
DEAD FETUSES
N
0
0
0
0
RESORPTIONS
MEAN+S.D.
0.4 + 0.5
0.2 +
0.5
0.0 + 0.0
0.4 +
EARLY RESORPTIONS
N MEAN+S.D.
0 0.0 + 0.0
0
0.0 +
0.0
0
0.0 +
0.0
1 0.2 +
LATE RESORPTIONS
N MEAN+S.D.
2 0.4 + 0.5
1 0.2 + O.S
0 0.0 + 0.0
1 0.2 +
DOES WITH ANY RESORPTIONS
N(t)
2( 40-0)
1( 25.0)
0( 0.0)
2( 40.
DOES WITH ALL CONCEPTUSES
RESORBED
N
0
0
0
0
DOES WITH VIABLE FETUSES
N(t)
5(100.0)
4(100.0)
4(100.0)
5(100.
PLACENTAE APPEARED NORMAL
N(t)
5(100.0)
4(100.0)
4(100.0)
5(100.
------------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
ORAL ISTOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE
8 (PACE 2): CAESAREAN SECTIONING OBSERVATIONS
- SUMMARY
------------------------------- ------------------------------------------- --------------------------------------
DOSAGE GROUP
v
vi
vil
DOSAGE ING/KG/DAY)a
5
10
20
--------------------------------------------------------------------------------------------------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT FOUND DEAD ABORTED
N(%) N(%) N(%)
4( 80.0) 0( 0.0) 2( 50.0)
4( 80.0) 0( 0.0) 4(100.0)
5(100.0) 4( 80.0) 1( 20.0)
RABBITS PREGNANT AND
CAESAREAN-SECTIONED
ON DAY 29 OF GESTATION
m
2
0
0
CORPORA LUTER
HEAN+S.D.
10.5 + 0.7
IMPLANTATIONS
MEAN+S.D.
9.5 + 0.7
LITTER SIZES
MEAN+S.D.
5.5 + 2.1
LIVE FETUSES
N MEAN+S.D.
11 5.5 + 2.1
DEAD FETUSES
N
0
RESORPTIONS EARLY RESORPTIOtiS
LATE RESORPTIONS
HEAN+S.D.
N MEAN+S.D.
N MEAN+S.D.
4.0 + 1.4
5 2.5 + 3.5
3 1.5 + 2.1
DOES WITH ANY RESORPTIONS
DOES WITH ALL CONCEPTUSES RESORDED
N(%) N
2(100.0) 0
DOES WITH VIABLE FETUSES
N (%)
2(100.0)
PLACENTAE APPEARED NORMAL
N(%)
2(100.0)
------------------------------------------------------------------------------------- - ---------------------- -- --
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-629S.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 9 (PAGE 1): LITTER OBSERVATIONS (CAESAREAN-DELIVERED
FETUSES) - SUMMARY
---------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
rri
IV
DOSAGE (NO/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
--------------------------------------------------------------------------------------------------------------------------
LITTERS WITH ONE OR
MORE LIVE FETUSES
N
5
4
4
5
IMPLANTATIONS LIVE FETUSES
MEAN+S.D.
N HEAN+S.D.
8.8 +
1.6
42 8.4 + 1.1
9.5 + 1.7
37 9.2 + 1.5
8.5 + 1.3
34 8.5 + 1.3
8.8 +
42 8.4 +
LIVE MALE FETUSES
N
23
14
13
20
t LIVE KALE FETUSES/LITTER
LIVE
FETAL BODY WEIGHTS (GRA?48)/LITTER
14ALE FETUSES
MEAN+S.D. MZAN+S.D. MEAN+S.D.
53.9 +
9.4
43.77 + 5.95 44.06 + 5.55
37.2 + 5.7 40.76 + 7.53 41.31 + 7.46
38.0 + 8.9 44.05 + 2.70 45.67 + 2.75
48.5 +
38.18 + 39.44 +
FEMALE FETUSES
MEAN+S.D.
43.37 + 7.09
40.40 + 7.66
42.02 + 3.12
38.04 +
t RESORBED
CONCEPTUSES/LlrrER
MEAN+S.D.
3.8 +
5.2
2.3 + 4.6
0.0 + 0.0
3.6 +
--------------------------------7 ----------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 9 IPAGE 2): I.ITTER OBSERVATIONS (CAESAREAN-DELIVERED
FETUSES) - SUMMARY
----------------------------- ----------------------------------------------- --- --------------------- --- ---------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
--------------------------------- ----------------------- --------------------------------------------------------------
LITTERS WITH ONE OR
MORE IIVE FETUSES
@N
2
0
0
IMPLANTATIONS
MEAN+S.D.
9.5 + 0.7
LIVE FETUSES
N MEAN4S.D.
11 5.5 + 2.1
LIVE MALE FETUSES
N
5
t LIVE MAIE FETUSES/LITTER
MEAN+S.D.
46.4 + 5.1
LIVE
PETAL BODY WEIGHTS (GRAMS)/LITTER
HEAN+S.D.
26.05 + 5.40
MALE FETUSES
MEAN+S.D.
28.52 + 11.60
FE14ALE FETUSES
MEAN+S.D.
23.35 + 0.47
t RESORBED
CONCEPTUSES/bITTER
MEAN+S.D.
42.8 + 18.1
----------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-012P:
OPAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 10 (PAGE 1): PETAL GROSS EXTERNAL ALTERATIONS - SUMMARY
------------------------------------------------------------------------------------------------ -------------- ---------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1
2.5
-------------------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
5
4
4
5
FETUSES EVALUATED
N
42
37
34
42
LIVE
N
42
37
34
42
-------------------------------------------------------------------------------------------------------------------------
SNOUT: CLEFT LITTER INCIDENCE PETAL INCIDENCE
N(ft) N(t)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 20 1( 2
INCISORS: LITTER PETAL
ABSENT INCIDENCE INCIDENCE
N(t) H(t)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
It 20 1( 2
SNOUT:
SHORT
LITTER INCIDENCE
PETAL INCIDENCE
N(t) u(t)
0( 0.0) 0( 0-0)
1( 25.0) 14 2.7)c
0( 0.0) 0( 0.0)
0( 0 0( 0
NARES: DISPLACED LITTER INCIDENCE PETAL INCIDENCE
N(l) H(t)
0( 0.0) 0( 0.0)
1( 25.0) 1( 2.7)c
0( 0-0) 0( 0.0)
0( 0 0( 0
MARES:
S14ALL
LITTER INCIDENCE
PETAL INCIDENCE
N(t) N(t)
0( 0.0) 0( 0.0)
1( 25.0) 1( 2.7)c
0( 0.0) 0( 0.0)
0( 0 0(
BODY: ABDOMINAL DISTENTION
LITTER INCIDENCE
N(t)
0( 0.0)
1( 25.0)
of 0.0)
0(
PETAL INCIDENCE
N(t)
0( 0.0)
1( 2.7)
0( 0.0)
0(
------------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 6251-10 had other gross external alterations.
C. Fetus 8243-8 had other gross external alterations.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER; T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 10 (PAGE 2)! FETAL GROSS EXTERNAL ALTERATIONS
- SUMMARY
------------------------------------------------------------ ---- -------------------------------------------------------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
5
10
20
-------------------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
2
0
0
FETUSES EVALUATED
N
11
0
0
LIVE
N
11
0
0
-------------------------------------------------------------------------------------------------------------------------
SHOUT: CLEFT LITTER INCIDENCE FETAL INCIDENCE
N(96) "(1)
0( 0.0) 0( 0-0)
INCISORS: LITTER FETAL
ABSENT INCIDENCE INCIDENCE
H(t) "(1)
0( 0.0) 0( 0.0)
SNOUT: SHORT LITTER INCIDENCE FETAL INCIDENCE
N(t) u(t)
0( 0.0) o( o.o)
NARES: DISPLACED LITTER INCIDENCE FETAL INCIDENCE
N(t) N(ri)
0( 0.0) 0( 0.0)
MARES: SMALL LITTER INCIDENCE FETAL INCIDENCE
N(t) N(%)
0( 0.0) 0( 0.0)
BODY: ABDOMINAL DISTENTION
LITTER INCIDENCE
N(t)
0( 0-0)
FETAL INCIDENCE
N(t)
o( o.o)
-- -- -- --- -- --- -- -- --- -- -- --- -- ---- -- --- -- -- ---- - --- -- -- --- -- --- -- --- --- ---- --- --- --- - ---- -- ---- -- -- --- -- -- ---- -- ---- --- --
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-022P:
ORAL ISTOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL (SPONSOR'S STUDY NTJMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 11 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------I -------------------------- -------------------------- --------------------
RABBIT #
DESCRIPTION
------------------------------------------------------------------------- ----------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
8236 8237 8238
DG( 17- 29) DG( 28- 29)
LOCALIZED ALA)PECIA: LIMBS a
LOCALIZED ALOPECIA:
UNDERSIDE a
NO ADVERSE FINDINGS
8239
NO ADVERSE FINDINGS
8240
NO ADVERSE FINDINGS
-------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
8241
DG(
28 )
SCANT FECES
DG( 28- 29)
SOFT OR LIOUID FECES
6242
NO ADVERSE FINDINGS
8243
NO ADVERSE FINDINGS
8244
DG( 27- 29)
LOCALIZED ALOPECIA:
BACK a
8245
NO ADVERS19 FINDINGS
------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
8246 8247
DG( 28- 29)
NO ADVERSE FINDINGS LOCALIZED ALOPECIA:
HEAD a
8248
NO ADVERSE FINDINGS
8249
NO ADVERSE FINDINGS
8250
NO ADVERSE FINDINGS
------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
--------------------------------------------------------------- --------------------------------------------------------
8251
NO ADVERSE FINDINGS
8252
NO ADVERSE FINDINGS
7650
NO ADVERSE FINDINGS
82S4
DG(
14
SCANT FECES
DG( 16- 22)
SCANT FECES
DG( 18- 29)
UNCROOMED
COAT
8255
NO ADVERSE FINDINGS
---------------------------------------------------------------------------------------------------
--------------------
DG = DAY OF PRESUMED GESTATION a. observation confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 11 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
---------------- ------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------
RABBIT
DESCRIPTION
-----------------------------------------------------------------------------------------------------------------------
8256
DG(
14 )
SCANT FECES
DGI 16- 21)
SCANT FECES
DO( 19- 29)
LOCALIZED ALOPECIA:
UNDERSIDE a
8257
DG( 13- 22)
DG(
23 )
SCANT FECES ABORTED AND SACRIFICED
8258
DG( 13- 27) DG( 25- 29)
SCANT FECES LOCALIZED ALOPECIA:
UNDERSIDE
DG(
29
SCANT FECES
8259
DG(
14
DG( 16- 21)
SCANT SCANT
FECES FECES
DO(
22 )
ABORTED AND SACRIFICED
8260
DG( 13- 17)
SCANT FECES
Do( Is- 19)
NO FECES
DG( 20- 24)
SCANT FECES
DO( 23- 24)
UNGROOMED
COAT
-----------------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION a. observation coneirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 11 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
--------------------------------------------------------------------------------------- - -----------------------------
DOSAGE GROUP VI
10 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
------------------------------------------------------------------------------------------------------------------------
8261 8262
DG(
12 )
DG( 13- 15)
DG( 16- 20)
DG( 21- 22)
DG( 23- 24)
DO( 24- 26)
DG( 25- 26)
DGI
26 )
DG( 7- 21)
DG( 11- 12)
SCANT FECES
NO FECES
SCANT FECES
NO FECES
SCANT FECES
UNGROOMED
COAT
NO FECES
ABORTED AND SACRIFICED
NOSE: KASS (0.3 CM IN
SCANT FECES
DIAMETER)A
DG(
13 )
NO FECES
DG( 14- 21)
SCANT FECES
DG(
22
ABORTED AND SACRIFICED
8263
Do(
11
SCANT FECES
DO( 12- 13)
NO FECES
DG( 14- 201
SCANT FECES
DG( 21- 23)
NO FECES
DG( 24- 27)
SCANT FECES
Dr.1 28- 29)
NO FECES
8264
DG(
22
SCANT FECES
DG(
13
NO FECES
DG( 14- 15)
SCANT FECES
DG( 16- 18)
NO FECES
DG( 19- 20)
SCANT FECES
DG( 21- 22)
NO FECES
DG(
22
RED SUBSTANCE IN CAGE PAN
DG(
23
ABORTED AND SACRIFICED
8265
DG( 9- 20)
SCANT FECES
DG( 21- 22)
NO FECES
DG( 23- 24)
SCANT FECES
DG(
25
RED SUBSTANCE IN CAGE PAN
DG(
25
ABORTED AND SACRIFICED
--------------------------------------------------------------------------------
-- -- ------------------------- - ---
DG = DAY OF PRESUMED GESTATION a. observation confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 11 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
------------------------------------------------------------------------------------ ------------------------------------
DOSAGE GROUP VII
20 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
-------------------------------------------------------------------------------------------------------------------------
8266
8267 8268 8269 8270 --- ------------
DG( 12- 15)
SCANT FECES
DG( 16- 17)
RED SUBSTANCE IN CAGE PAN
DG( 16- 27)
RED PERIVAGINAL SUBSTANCE a
DG( 16- 17)
UNGROOMED COAT
DG( 16- 17)
NO FECES
DG(
17
EXCESS SALIVATION
DG(
17
FOUND DEAD
DG( 9- 20)
SCANT FECES
DG( 11- 25)
NO FECES
DG( 26- 19)
SCANT FECES
DGI
29
EXCESS SALIVATION
DG(
20
FOUND DEAD
Do( 9- 25)
SCANT FECES
DG( 12- 13)
SOFT OR LIQUID FECES
DO(
16
TAN PERIVAGINAL
SUBSTANCE a
DG(
16
NO FECES
DG(
27
FOUND DEAD
DG( 11- 19)
SCANT FECES
DO( 18- 19)
EXCESS SALIVATION
DG(
19 )
RED SUBSTANCE IN CAGE PAN
DG(
19 )
ABORTED AND SACRIFICED
DG( 9- 15)
SCANT FECES
DG(
16 )
FOUND DEAD
-- ---------- -- ---- -- --- --- - ------------- ----- --- -- ---- --- -- --- --- -- ---- --- --- --- --- -- ---- -- --- -- --- --- ---
DO = DAY OF PRESUMED GESTATION a. Oboervation confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 12 (PAGE 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
--------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
--------------------------------------------------------------------------------------------------------------------------
0 (VEHICLE)
8236
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
0237
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8238
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8239
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8240
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
0.1
8241
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8242
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8243
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8244
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8245
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
III 2
8246 8247 8240 8249 8250
DG 29
NP
DG 29
p
DG 29
p
DG 29
p
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
IV
2.S
8251
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8252
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
7650 8254
DG 29
p
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
14
ALL TISSUES APPEARED NORMAL.
8255
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
--------------------------------------------------------------------------------------------------------------------------
P
PREGNANT
NP - NOT PREGNANT
DG
DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 12 (PAGE 2); NECROPSY OBSERVATIONS - INDIVIDUAL DATA
---------------------------------------- ------- I ------------------ -------------------------- -------------------------
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
-------------------------------------------------------------------------------------------------------------------------
v
5
8256
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8257
DG 23
p
14
ABORTED ON DAY 23 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8258
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8259
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8260
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
vi
10
6261
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
LIVER: MOTTLED RED AND TAN.
STOMACH:
MUCOSAL SURFACE, NUMEROUS BLACK AREAS
(PINPOINT TO 0.2 CH IN DIAMETER).
ALL OTHER TISSUES APPEARED NORMAL.
8262
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION.
EXTERNAL OBSERVATIONS:
NOSE, MASS (1.0 CM X 1.
0.3 CH). CUT SURFACE REVEALED SMOOTH PINK MATEI
ALL OTHER TISSUES APPEARED NORMAL.
8263
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8264
DG 23
p
14
ABORTED ON DAY 23 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8265
DG 2S
p
14
ABORTED ON DAY 25 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
---------------------------------------- - ------------------------------------------ ---- -
P
PREGNANT
NP = NOT PREGNANT
DG
DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
b. Confirms a clinical observation.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RMGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 12 IPACE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
-------------- ----------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
-------------------------------------------------------------------------------------------------------------------------
vil
20
8266
DG 17
p
11
FOUND DEAD ON DAY 17 OF GESTATION (11 MINUTES A
DOSAGE).
ESOPHAGUS:
WHITE FROTHY MATERIAL.
LUNGS: APPEARED INFLATED AND LEFT DIAPHRAGt4ATI
TEAR (2.0 CH IN LENGTH).
LIVER: LEFT LATERAL LOBE, TEAR (2.0 CM IN LENG
STOMACH:
FUNDIC MUCOSA, TWO ERODED AREAS (I.S
AND 1.5 CH X 0.5 CH).
ALL OTHER TISSUES APPEARED NORMAL.
8267
DG 20
p
13
FOUND DEAD ON DAY 20 OF GESTATION
(DEATH OCCURR
OVERNIGHT).
ALL TISSUES APPEMED
NORMAL.
8268
DG 17
p
10
FOUND DEAD ON DAY 17 OF GESTATION (22 HOURS AND
27 MINUTES AFTER DOSAGE).
ABDOMINAL CAVITY:
CLOUDY GREEN FLUID
(APPROXIMATELY
18 ML).
STOMACH:
FRIABLE.
GALLBLADDER:
RUPTURED.
ALL OTHER TISSUES APPEARED NORMAL.
8269
DG 19
p
13
ABORTED ON DAY 19 OF GESTATION.
EXTERNAL OBSERVATIONS:
UNGROOMED COAT.
ALL OTHER TISSUES APPEARED NORMAL.
8270
DG 16
p
9
FOUND DEAD ON DAY 16 OF GESTATION
(DEATH OCCURR
OVERNIGHT).
STOMACH:
NON-GLANDULAR
MUCOSA, RED AND DIFFUSE
ALL OTHER TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------------- -
P
PREGNANT
NP a NOT PREGNANT
DG
DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
PROTOCOL 41e-oi2p:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
ISPONSOR'S STUDY NUMBER:
T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 (PAGE 1): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
17
-------------------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------
8236 P
3.76
3.64
3.71
3.74
3.75
3.74
3.74
3.60
3.86
3.82
3.86
3.67
8237 P
3.38
3.47
3.50
3.54
3.57
3.59
3.62
3.68
3.70
3.72
3.72
3.75
8238 P
3.44
3.49
3.47
3.48
3.50
3.53
3.51
3.61
3.63
3.62
3.66
3.71
8239 P
3.S2
3.64
3.67
3.66
3.76
3.76
3.84
3.91
3.99
3.94
3.96
4.01
8240 P
3.14
3.20
3.28
3.30
3.29
3.30
3.32
3.37
3.38
3.41
3.43
3.43
-------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
-------------------------------------------------------------------------------------------------------------------------
8236 P
3.93
3.94
3.98
4.01
3.97
3.95
3.98
3.96
4.00
4.01
4.04
8237 P
3.82
3.61
3.84
3.SS
3.91
3.96
3.90
4.00
4.01
4.03
4.OS
8238 P
3.74
3.78
3.75
3.80
3.82
3.78
3.83
3.77
3.74
3.83
3.84
8239 P
4.03
4.03
3.97
4.02
4.04
4.08
4.12
4.12
4.18
4.21
4.23
8240 P
3.46
3.48
3.SO
3.SO
3.S4
3.56
3.S6
3.S2
3.61
3.58
3.64
-------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT
DAY - DAY OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS
ALL CALCULATIONS
EXCEPT BODY WEIGHT
BODY WEIGHT AVERAGES ARE CALCULATED
(G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAN (G) VALUE. WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 (PAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-------------------------------------------------- -------------------------------- ------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
17
------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP 11
0.1 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
8241 P
3.68
3.53
3.62
3.62
3.66
3.70
3.71
3.75
3.77
3@85
3.89
3.8
6242 NP
3.36
3.49
3.60
3.56
3.57
3.64
3.62
3.68
3.70
3.71
3.81
3.7
8243 P
3.42
3.49
3.56
3.63
3.54
3.51
3.49
3.58
3.64
3.70
3.74
3.7
6244 P
3.20
3.27
3.30
3.32
3.35
3.34
3.39
3.47
3.53
3.53
3.58
3.6
824S P
2.98
3.17
3.18
3.19
3.18
3.13
3.19
3.18
3.19
3.17
3.17
3.2
------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
------------------------------------------------------------------------------------------------------------------------
8241 P
3.95
3.96
3.99
4.01
4.00
4.00
3.94
3.88
3.82
3.78
3.82
8242 UP
3.82
3.88
3.88
3.88
3.91
3.92
3.91
3.90
3.96
4.03
4.02
8243 P
3.78
3.04
3.79
3.78
3.86
3.85
3.88
3.90
3.92
3.90
3.94
0244 P
3.63
3.63
3.66
3.68
3.72
3.75
3.79
3.77
3.78
3.70
3.65
8245 P
3.30
3.33
3.40
3.39
3.40
3.45
3.48
3.47
3.50
3.56
3.59
-----------------------------------------------------------------------------------------------------------------------
PDAY ALL ALL BODY
PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS
CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
AND REPORTED IN KILOGRAMS GRAN (G) VALUE.
(KG).
PROTOCOL 418-012P;
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 IPAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
17
-------------------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP III
I MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------
8246 NP
3.57
3.63
3.76
3.76
3.79,
3.80
3.84
3.86
3.87
3.86
3.94
3.94
6247 P
3.29
3.57
3.63
3.62
3.65
3.63
3.74
3.76
3.79
3.80
3.82
3.88
8246 P
3.46
3.63
3.64
3.63
3.68
3.68
3.67
3.76
3.87
3.94
3.94
3.94
8249 P
3.52
3.61
3.69
3.69
3.71
3.75
3.81
3.87
3.68
3.90
3.92
3.96
8250 P
3.11
3.15
3.17
3.22
3.25
3.32
3.26
3.27
3.30
3.34
3.34
3.34
-------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
-------------------------------------------------------------------------------------------------------------------------
8246 NP
4.02
4.05
4.03
4.06
4.05
4.09
4.11
4.21
4.16
4.19
4.21
8247 P
3.93
3.94
3.90
3.93
3.96
3.98
4.03
4.01
4.06
4.12
4.16
0246 P
3.97
3.99
4.04
4.06
4.10
4.14
4.23
4.21
4.24
4.29
4.35
8249 P
4.04
4.00
4.02
4.05
4.09
4.12
4.17
4.11
4.22
4.12
4.13
8250 P
3.36
3.41
3.37
3.44
3.53
3.55
3.60
3.54
3.58
3.59
3.60
-------------------------------------------------------------------------------------------------------------------------
PDAY ALL
PREGNANT
MP - NOT PREGNANT (VALUES
- DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G).
EXCLUDED FROM AVERAGES) ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
(KG).
ALL CALCULATIONS
EXCEPT BODY WRIGHT
BODY WEIGHT AVERAGES ARE CALCULATED
AVERAGES ARE PERFORMED WITH THE UNROUNDED WITH THE ROUNDED KILOGRAM (KG) VALUE.
GRAN (G) VALUE.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER! T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 (PAGE 4): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
17
------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP IV
2.5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------
6251 P
3.62
3.80
3.80
3.81
3.86
3.88
3.94
4.01
4.05
4.08
4.11
4.0
8252 P
3.31
3.55
3.56
3.56
3.60
3.64
3.67
3.73
3.64
3.75
3.72
3.7
76SO P
4.05
4.12
4.18
4.18
4.16
4.20
4.23
4.31
4.29
4.30
4.27
4.2
6254 P
3.47
3.52
3.56
3.55
3.59
3.58
3.54
3.SO
3.46
3.39
3.33
3.2
025S P
3.00
3.12
3.12
3.14
3.14
3.20
3.23
3.20
3.2S
3.34
3.28
3.2
------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
------------------------------------------------------------------------------------------------------------------------
62SI P
4.13
4.19
4.20
4.24
4.27
4.29
4.32
4.31
4.34
4.40
4.41
8252 P
3.84
3.63
3.82
3.89
3.88
3.93
3.94
3.92
3.94
3.93
3.94
7650 p
4.16
4.14
4.11
4.08
4.09
4.07
4.14
4.15
4.21
4.26
4.28
82S4 P
3.17
3.13
3.19
3.16
3.30
3.37
3.40
3.40
3.46
3.47
3.48
825S P
3.29
3.29
3.33
3.35
3.35
3.40
3.41
3.39
3.47
3.42
3.54
------------------------------------------------------------------------------------------------------------------------
PDAY ALL ALL
PREGNANT
UP - NOT PREGNANT (VALUES EXCLUDED
- DAY OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED
CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE
FROM AVERAGES)
TO THREE SIGNIFICANT
PERFORMED NM
THE
DIGITS AND REPORTED IN KILOGRAMS UNROUNDED GRAN (G) VALUE.
(KC).
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
PROTOCOL 416-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 13 (PAGE 5): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
is
16
17
-------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP V
5 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------
6256 P
3.93
3.90
3.94
4.01
4.04
4.02
3.97
4.01
3.91
3.82
3.77
3.71
8257 P
3.27
3.44
3.40
3.40
3.34
3.33
3.30
3.25
3.23
3.14
3.12
3.15
62Se NP
3.40
3.44
3.50
3.48
3.46
3.43
3.42
3.3S
3.30
3.24
3.20
3.16
82S9 P
3.22
3.29
3.33
3.35
3.34
3.42
3.31
3.35
3.21
3.17
3.15
3.06
8260 P
3.02
3.14
3.12
3.19
3.15
3.18
3.12
3.14
3.05
2.97
2.95
2.90
-------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
20
29
-------------------------------------------------------------------------------------------------------------------------
02SG P
3.66
3.64
3.66
3.72
3.87
3.94
3.9S
3.92
3.98
4.01
4.04
8257 P
3.00
3.03
2.99
2.94
ABORTED ON DAY 23 OF GESTATION
8258 UP
3.12
2.98
2.93
2.88
2.83
2.80
2.76
2.69
2.69
2.67
2.62
8259 P
2.98
2.96
2.9S
ABORTED ON DAY 22 OF GESTATION
8260 P
2.93
2.04
2.80
2.65
2.93
3.00
3.10
3.08
3.20
3.10
3.11
-------------------------------------------------------------------------------------------------------------------------
PDAY ALL ALL
BODY
PREGNANT
MP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
- DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS
(G), ROUNDED
TO THREE
SIGNIFICANT
CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE PERPORMED WITH THE
WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG)
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 (PAGE 6); MATERNAL BODY WEIGHTS
INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
21
12
13
14
15
16
17
-----------------------------------------------------------------------------------------------------------------------------
RABBIT N
DOSAGE GROUP VI
. 10 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
8261 p
3.77
3.94
3.92
3.95
3.07
3.73
3.64
3.68
3.60
3.54
3.48
3.44
6262 P
3.33
3.35
3.40
3.41
3.28
3.18
3.10
3.04
2.98
2.97
2.97
2.96
8263 UP
3.42
3.45
3.51
3.52
3.41
3.29
3.24
3.17
3.15
3.08
3.00
2.92
6264 P
3.26
3.52
3.60
3.57
3.SO
3.42
3.33
3.27
3.22
3.17
3.15
3.10
8265 P
2.77
3.00
3.02
2.94
2.86
2.91
2.69
2.64
2.59
2.54
2.54
2.51
-----------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
-----------------------------------------------------------------------------------------------------------------------------
8261 P
3.39
3.39
3.36
3.34
3.28
3.24
3.20
3.03
ABORTED ON DAY 26 OF GESTATION
8262 p 6263 UP
2.82 2.91
2.80 2.68
2.74 2.03
ABORTED 2.77
ON DAY 22 OF GESTATION
2.73
2.68
2.64
2.56
2.57
2.56
2.53
0264 P
3.06
3.04
3.03
2.90
ABORTED ON DAY 23 OF GESTATION
6265 P
2.40
2.35
2.34
2.30
2.27
2.25
ABORTED ON DAY 25 OF GESTATION
-----------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY - DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT
DIGITS AND REPORTED IN KILOGRAMS
ALL CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE TJNROUNDED GRAM (G) VALUE.
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 13 (PAGE 7); MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
------------ ------------------------- -------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
17
------------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP VII
20 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
6266 P
3.59
3.70
3.74
3.61
3.51
3.42
3.34
3.29
3.24
3.16
3.10
2.98
8267 P
3.37
3.37
3.37
3.28
3.21
3.18
3.15
3.14
3.13
3.09
3.00
2.92
8268 P
3.43
3.64
3.48
3.36
3.27
3.19
3.12
3.06
3.00
2.94
2.88
b
8269 P
3.49
3.75
3.87
3.77
3.67
3.59
3.51
3.45
3.39
3.34
3.26
3.20
e270 P
3.10
3.26
3.21
3.16
3.06
2.98
2.es
2.80
2.72
2.65
c
-----------------------------------------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
-----------------------------------------------------------------------------------------------------------------------------
8266 P
FOUND DEAD ON DAY 17 OF GESTATION
8267 P
2.79
FOUND DEAD ON DAY 20 OF GESTATION
8266 P
FOUND DEAD ON DAY 17 OF GESTATION
8269 P
ABORTED ON DAY 19 OF GESTATION
8270 P
FOUND DEAD ON DAY 16 OF GESTATION
-----------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
UP - NOT PREGNANT
DAY - DAY OF PRESUMED GESTATION
(VALUES NCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS
ALL CALCULATIONS
EXCEPT BODY WEIGHT
BODY WEIGHT AVERAGES ARE CALCULATED
(G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAN (G) VALUE. WITH THE ROUNDED KILOGRAM (KG) VALUE.
(KG).
a. Doe 8266 was found dead on day 17 of gestation. b. Doe 8268 was found dead on day 17 of gestation. c. Doe 8270 was found dead on day 16 of gestation.
PROTOCOL 418-012P:
ORAL ISTOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 14 IPAGE 1): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 6 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 ------------------------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
6236 P
181.
103.
183.
185.
180.
183.
164.
185.
181.
182.
182.
183.
8237 P
180.
105.
lei.
183.
181.
183.
181.
182.
160.
161.
la4.
181.
8238 P
184.
185.
181.
185.
284.
185.
180.
183.
182.
181.
182.
180.
8239 P
282.
162.
282.
181.
181.
102.
184.
183.
180.
ISO.
164.
261.
8240 P
178.
166.
182.
159.
127.
109.
102.
122.
105.
180.
13S.
150.
------------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ------------------------------------------------------------------------------------------------------------------------------
8236 P
184.
151.
106.
75.
82.
92.
96.
108.
121.
8237 P
264.
185.
185.
184.
182.
170.
119.
124.
125.
8238 P
180.
182.
180.
185.
104.
102.
180.
184.
165.
8239 P
163.
182.
ISO.
182.
184.
162.
170.
152.
180.
8240 P
133.
120.
Ill.
114.
iie.
97.
116.
71.
12S.
------------------------------------------------------------------------------------------------------------------------------
P - PREGNANT DAYS - DAYS ALL WEIGHTS
NP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WEBB RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NLYMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 14 (PAGE 2); MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
--------------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 0 8
9
9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - IS 18 - 19 19
--------------------------------------------------------------------------------------------------------------------------------
RABBIT
DOSAGE GROUP 11
0.1 MG/KG/DAY
--------------------------------------------------------------------------------------------------------------------------------
8241 P
101.
184.
182.
182.
183.
167.
182.
181.
182.
183.
184.
184.
8242 UP
185.
264.
162.
181.
184.
181.
181.
180.
181.
184.
182.
180.
8243 P
181.
165.
98.
126.
102.
123.
125.
185.
a
184.
183.
les.
8244 P
180.
102.
183.
181.
182.
104.
180.
184.
182.
lei.
182.
180.
6245 P
138.
143.
141.
93.
lie.
09.
124.
93.
61.
136.
182.
181.
--------------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 213- 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 --------------------------------------------------------------------------------------------------------------------------------
8241 P
185.
160.
127.
78.
45.
15.
4.
8.
41.
8242 UP
181.
100.
ISO.
182.
185.
181.
185.
185.
185.
8243 P
le5.
181.
182.
181.
184.
152.
124.
83.
132.
8244 P
280.
a
180.
182.
163.
104.
123.
58.
8.
8245 P
182.
153.
173.
183.
182.
145.
140.
135.
152.
--------------------------------------------------------------------------------------------------------------------------------
P - PREGNANT DAYS - DAYS ALL WEIGHTS
UP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
a. Spilled feed precluded the calculation of this value.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 14 (PAGE 3); MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------------------PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 23 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19
------------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP III
I 14G/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
0246 NP
181.
182.
183.
lei.
183.
185.
185.
181.
180.
180.
182.
184.
6247 P
181.
182.
181.
202.
181.
168.
182.
181.
190.
100.
181.
180.
8248 P
182.
181.
182.
181.
181.
182.
185.
183.
169.
180.
180.
184.
8249 P
ISS.
181.
185.
184.
180.
182.
185.
183.
ISO.
181.
184.
181.
8250 P
180.
180.
182.
102.
101.
124.
131.
183.
145.
145.
176.
152.
------------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ------------------------------------------------------------------------------------------------------------------------------
8246 RP
185.
102.
183.
182.
184.
183.
184.
183.
181.
8247 P
183.
182.
183.
283.
lei.
173.
181.
174.
183.
e248 P
le4.
182.
176.
175.
167.
166.
181.
152.
181.
8249 P
le2.
ie2.
167.
146.
143.
150.
115.
115.
126.
82SO P
182.
lei.
175.
153.
138.
114.
113.
93.
90.
------------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
MP - NOT PREGNANT
DAYS - DAYS OF PRESUMED GESTATION
(VALUES
EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER! T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 14 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-- -- --- -- -- -- -- -- --- --- -- -- --- --- -- --- --- - --- --- -- --- --- -- --- --- -- -- --- --- - ---- --- --- -- --- --- -- -- -- --- --- --- ---- --- --- --- -- --
PREGNANCY STATUS DAYS 7 - 8 a - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19
---- -- -- -- -- --- - --- --- -- --- -- -- --- --- -- --- --- -- -- ---- - --- --- --- -- --- -- --- -- ---- -- --- --- --- -- -- --- -- -- ---- --- --- ---- -- -- --- -- -
RABBIT V
DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
8251 P
263.
180.
180.
182.
284.
184.
183.
185.
182.
180.
182.
184.
8252 P
184.
181.
183.
183.
182.
180.
126.
284.
ISO,
183.
181.
183.
7650 P
28S.
182.
182.
184.
283.
184.
167.
181.
110.
102.
76.
So.
8254 P
100.
lei.
176.
153.
122.
43.
17.
1.
2.
0.
2.
0.
82SS P
262.
179.
183.
166.
164.
148.
162.
180.
269.
166.
165.
168.
-----------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 -----------------------------------------------------------------------------------------------------------------------------
8251 P
168.
180.
162.
182.
181.
181.
163.
160.
183.
8252 P
183.
152.
152.
148.
161.
148.
148.
141.
181.
7650 P
37.
30.
30.
10.
94.
123.
161.
155.
269.
8254 P
11.
36.
100.
130.
117.
84.
102.
93.
113.
82SS P
162.
158.
134.
156.
166.
153.
142.
115.
249.
-----------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
UP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS - DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS
(G).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 14 (PAGE 5); MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-------------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 ------------------------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP V
5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8256 P
185.
183.
182.
168.
137.
123.
36.
0.
1.
0.
45.
13.
8257 P
117.
144.
131.
115.
66.
9.
1.
0.
3.
I.
3.
0.
8258 UP
182.
182.
169.
134.
84.
13.
1.
0.
0.
0.
2.
0.
8259 P
184.
280.
182.
173.
56.
21.
0.
0.
0.
2.
2.
1.
8260 P
182.
166.
185.
142.
44.
7.
0.
0.
4.
5.
6.
57.
------------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ------------------------------------------------------------------------------------------------------------------------------
8256 P
79.
133.
181.
164.
185.
184.
185.
181.
185.
8257 P
7.
7.
14.
ABORTED ON DAY 23 OF GESTATION
82SO UP
2.
3.
1.
0.
0.
1.
4.
1.
1.
0259 P
2.
ABORTED ON DAY 22 OF GESTATION
8260 P
0.
55.
62.
223.
169.
180.
181.
182.
183.
------------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT
DAYS - DAYS OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 14 (PAGE 6): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS DAYS 7 - e 0 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 -----------------------------------------------------------------------------------------------------------------------------
RABBIT N
DOSAGE GROUP VI
10 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------------------
8261 P
181.
171.
86.
2.
0.
3.
0.
0.
0.
1.
0.
1.
8262 P
ieo. 145.
28.
1.
0.
2.
0.
2.
0.
0.
0.
1.
8263 UP
180.
164.
28.
2.
1.
2.
0.
0.
0.
1.
0.
1.
8264 P
179.
128.
93.
0.
24.
2.
0.
4.
0.
4.
0.
0.
8265 P
121.
30.
0.
3.
0.
2.
0.
1.
1.
2.
S.
0.
-----------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 -----------------------------------------------------------------------------------------------------------------------------
8261 P
1.
5.
0.
1.
1.
ABORTED ON DAY 26 OF GESTATION
8262 P
0.
ABORTED ON DAY 22 OF GESTATION
0263 UP
0.
2.
1.
0.
2.
4.
3.
0.
0.
e264 P
0.
2.
1.
ABORTED ON DAY 23 OF GESTATION
8265 P
0.
1.
0.
3.
2.
ABORTED ON DAY 25 OF GESTATION
-----------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT (VALUES
DAYS - DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-ILANCE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 14 (PAGE 7): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
------------------------------------------------------------------------------------------------------------------PREGNANCY
STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19
-----------------------------------------------------------------------------------------------------------------------------
RABBIT I
DOSAGE GROUP VII
20 MG/KG/DAY
------------------------------------ ----------------------------------------------------------------------------------------
8266 P
143.
12.
0.
1.
2.
0.
0.
2.
2.
0.
a
8267 P
124.
5.
3.
0.
0.
1.
0.
2.
1.
0.
1.
1.
8268 P
71.
4.
0.
2.
0.
0.
1.
2.
1.
c
8269 P
181.
69.
2.
2.
0.
1.
0.
2.
1.
3.
2.
d
8270 P
52.
27.
0.
I.
0.
0.
0.
2.
e
-----------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29
-----------------------------------------------------------------------------------------------------------------------------
8266 P
FOUND DEAD ON DAY 17 OF GESTATION
8267 P
FOUND DEAD ON DAY 20 OF GESTATION
8268 P
FOUND DEAD ON DAY 17 OF GESTATION
8269 P
ABORTED ON DAY 19 OF GESTATION
8270 P
FOUND DEAD ON DAY 16 OF GESTATION
-----------------------------------------------------------------------------------------------------------------------------
PDAYS ALL a. b. c. d. e.
PREGNANT
UP - NOT PREGNANT (VALUES EXCLUDED FROM
- DAYS OF PRESUMED GESTATION
WEIGHTS WERE RECORDED IN GRAMS (G).
Doe 8266 was found dead on day 27 of gestation.
Doe 8267 was found dead an day 20 of gestation.
Doe 0268 was found dead on day 17 of gestation.
Doe 8269 aborted on day 19 of gestation.
Doe 6270 was found dead on day 16 of gestation.
AVERAGES)
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 15 (PAGE 1); CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
------------------------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES
CORPORA LUTEA
------------------------ ---------------- ---------------- ---------------- ---------------- ----------------
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RABBIT # N p
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
OVARY
TOTAL
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------------
8236 6
4
3
7
10
0
0
0
0
0
0
0
1
1
3
a
11
4
0
12
8237 3
4
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
4
4
a
6238 6
3
4
5
9
0
0
0
0
0
0
1
0
2
5
5
10
s
6
11
8239 4
4
5
3
8
0
0
0
0
0
0
0
0
0
5
3
a
7
4
11
8240 4
4
5
3
a
0
0
0
0
0
0
0
0
0
5
3
a
6
3
9
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------------
8241 4
6
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
7
5
12
8242 NOT PREGNANT
8243 4 6
6
4
20
0
0
0
0
0
0
0
0
0
6
4
10
a
4
12
6244 4 6
5
5
10
0
0
0
0
0
0
0
1
1
5
6
11
6
9
15
8245 2 5
5
2
7
0
0
0
0
0
0
0
0
0
s
2
7
5
3
a
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP III
I MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------------
8246 NOT PREGNANT
8247 2 6
2
6
8
0
0
0
0
0
0
0
0
0
2
6
a
3
7
10
8248 4
6
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
6
11
8249 3 4
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
5
5
10
82SO 4
5
s
4
9
0
0
0
0
0
0
0
0
0
5
4
9
5
4
9
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8251 4
6
7
3
20
0
0
0
0
0
0
1
0
1
a
8252 4
6
2
8
10
0
0
0
0
1
1
0
0
0
2
7650 S
2
4
3
7
0
0
0
0
0
0
0
0
0
4
8254 5
3
4
4
a
0
0
0
0
0
0
0
0
0
4
8255 2
5
6
1
7
0
0
0
0
0
0
0
0
0
6
-------------------------------------------------------------------------------------------------
3
11
9
11
3
7
4
8
1
7
------
9
3
12
4
9
13
5
5
10
6
4
10
7
3
10
- ---- --- -
N - MALE PLACENTAE
F - FEMALE APPEARED NORMAL
UNLESS
NOTED OTHERWISE.
PROTOCOL 418-012P:
OPAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
ISPONSORIS STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 15 (PAGE 2): CAESAREAN-SECTIONING
OBSERVATIONS - INDIVIDUAL DATA
- - - - - - - - - - - - - - - -- - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
VIABLE FETUSES ------------------------
DEAD FETUSES
EARLY RESORPTIONS
LATE RESORPTIONS
IMPLANTATION SITES
---------------- ---------------- ---------------- ----------------
CORPORA LUTEA ----------------
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RABBIT # M
F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
OVARY
TOTAL
------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
6256 2
2
2
2
4
0
0
0
0
5
5
0
0
0
2
7
9
2
a
10
8257 ABORTED ON DAY 23 OF GESTATION
8258 NOT PREGNANT
6259 ABORTED ON DAY 22 OF GESTATION
8260 3
4
2
5
7
0
0
0
0
0
0
2
1
3
4
6
10
4
7
11
------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VI
10 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
6261 8262
ABORTED ABORTED
ON DAY 26 OF GESTATION ON DAY 22 OF GESTATION
8263 NOT PREGNANT 8264 ABORTED ON DAY 23 OF GESTATION 0265 ABORTED ON DAY 2S OF GESTATION ------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VII
20 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8266 8267
FOUND FOUND
DEAD DEAD
ON DAY ON DAY
17 OF GESTATION 20 OF GESTATION
8268 FOUND DEAD ON DAY 17 OF GESTATION 8269 ABORTED ON DAY 19 OF GESTATION 8270 FOUND DEAD ON DAY 16 OF GESTATION ------------------------------------------------------------------------------------------------------------------------------
N = MALE PLACENTAE
F = FEMALE APPEARED NORMAL
UNLESS
NOTED OTHERWISE.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T-6295-10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 16 (PAGE 1): LITTER OBSERVATIONS
(CAESAREAN-DELIVERED
FETUSES) - INDIVIDUAL DATA
-------------------------------------------------- --------------------------------I --------------------- -------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
RESORBED
------------------------------------------------------------------------------------------------------------------------------
RABBIT N
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
t
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8236
6
4
10
41.51
44.35
42.64
11
1
9.1
8237
3
4
7
49.42
48.62
49.08
7
0
0.0
8238
6
3
9
35.68
32.03
34.46
10
1
10.0
8339
4
4
8
47.94
49.68
48.80
a
0
0.0
8240
4
4
8
45.74
41.99
43.87
a
0
0.0
------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP Il
0.1 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8241
4
6
10
31.86
32.38
32.17
10
0
0.0
8242
NOT PREGNANT
8243
4
6
10
40.24
36.62
38.06
10
0
0.0
6244
4
6
10
43.30
42.58
42.86
11
1
9.1
824S
2
5
7
49.83
50.02
49.97
7
0
0.0
------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP III
I MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8246
NOT PREGNANT
8247
2
6
a
43.46
44.07
43.92
8
0
0.0
8248
4
6
10
45.87
40.83
42.84
10
0
0.0
8249
3
4
7
49.48
46.60
47.84
7
0
0.0
8250
4
5
9
43.88
39.77
41.59
9
0
0.0
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
8251
4
6
10
37.63
33.19
34.97
11
1
9.1
8252
4
6
10
36.26
33.94
34.86
11
1
9.1
7650
5
2
7
43.25
48.32
44.70
7
0
0.0
8254
5
3
a
32.69
32.30
32-54
8
0
0.0
8255
2
5
7
47.36
42.44
43.85
7
0
0.0
----------------------------------------------------------------------------------------------------- --
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER
OF LIVE FETUSES.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL (SPONSOR'S STUDY NUMBER: T 6295-10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 16 IPAGE 2); LITTER OBSERVATIONS
(CAESAREAN-DELIVERED
FETUSES) - INDIVIDUAL DATA
---------------------- ------------------------- ----------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
RESORBED
-----------------------------------------------------------------------------------------------------------------------------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
u
N
t
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------------------
8256
2
2
4
36.72
23.02
29.87
9
5
5S.6
8257
ABORTED ON DAY 23 OF GESTATION
8258
NOT PREGNANT
8259
ABORTED ON DAY 22 OF GESTATION
8260
3
4
7
20.31
23.68
22.23
10
3
30.0
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VI
10 14G/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
8261 8262
ABORTED ABORTED
ON DAY 26 OF GESTATION ON DAY 22 OF GESTATION
8263
NOT PREGNANT
8264
ABORTED ON D" 23 OF GESTATION
8265
ABORTED ON DAY 2S OF GESTATION
----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VII
20 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------------------
8266
FOUND DEAD ON DAY 17 OF GESTATION
8261
FOUND DEAD ON DAY 20 OF GESTATION
8268
FOUND DEAD ON DAY 17 OF GESTATION
8269
ABORTED ON DAY 19 OF GESTATION
8270
FOUND DEAD ON DAY 16 OF GESTATION
----------------------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER
OF LIVE FETUSES.
PROTOCOL 418-012P:
ORAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER; T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 17 (PAGE 1); FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------------------
FETUS N
1
2
3
4
5
6
7
a
9
10
11
12
13
14
15
16
17
is
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
RABBIT I 8236
8237
CLa 4/ 8
4/ 4
MA 49.46
FA
MA 45.09
PA
FA / PA
MA
46.98 50.29 40.84
MA
FA / MA
MA 41.52
FA
MA 34.50
MA
MA 37.65
FA 40.06
PA 40.06
L 1.95
51.77 46.72 51.46 50.21 47.56 44.56 49.25
0238 S/ 6
PA
MA
14A
14A
FL
MA
FA
14A
MA
FA
28.71 39.23 34.06 29.22 3.43 37.90 34.83 36.81 36.85 32.S6
8239 7/ 4
FA
FA
MA
MA
14A
PA
14A
FA
52.85 46.42 44-55 46.27 53.37 48.22 47.55 50.21
8240 6/ 3
MA
PA
MA
PA
FA
MA
MA
FA
40.74 46-03 42.61 39.01 41.56 44.95 46.48 41.33
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
------------------------------- ---------------------------------------------------------------------------------------------
8241 0242
7/ 5
FA 35.65
NOT
PA
FA
35.91 34.09
PREGNANT
MA 26.52
MA 29.38
PA 27.65
FA 29.03
FA 31.97
MA 34.81
MA 34.72
8243a 8244b
S/ 4 6/ 9
FA 36.00
KA 47.16
FA 44.04
FA 46.85
FA 41.86
FA 44.45
Ph 31.80
FA 39.22
MA 35.20
FA 32.31
MA 36.12
MA 39.16
14A 44.09
FA 52.80
FA 27.20
MA 51.48
FA 38.79
MA 35.38
MA 45.53
FL 7.32
FA 37.84
8245 5/ 3
FA
FA
FA
FA
FA
MA
MA
52.45 48.54 52.22 46.73 50.17 52.15 47.51
-----------------------------------------------------------------------------------------------------------------------------
N - KALE
F - FEMALE
A - ALIVE
E = EARLY RESORPTION
L - LATE RESORPTION
CLO = CORPORA LUTRA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
a. Fetus 8243-8 had a short snout, and small and displaced nares.
DENOTES POSITION OF CERVIX
b. Fetus 8244-7 had abdominal distention.
PROTOCOL 416-012P:
OPAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PFOS IN RABBITS
TABLE 17 (PAGE 2): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
------------------------------------------ ----- ------ ---------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
a
9
10
11
12
13
14
15
16
11
18
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
RABBIT I CLO 6246
NOT PREGNANT
8247 8248
3/ 7 5/ 6
14A 46.57
MA 51.27
PA / PA
46.46 45.73
PA
FA
39.44 44.56
FA 42.90
MA 37.77
PA 45.12
FA 37.44
PA 46.63
MA 54.03
FA 37.60
PA 44.11
MA 36.34
FA 42.15
PA
MA
37.26 40.42
8249 S/ S
KA
PA
FA
MA
MA
FA
FA
52.58 47.34 42.63 50.08 45.79 49.87 46.SS
82SO S/ 4
NA
MA
PA
MA
FA
MA
PA
FA
FA
46.56 43.22 42.44 40.21 33.62 45.52 38.82 43.04 40.91
-----------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------------------
82SIa 9/ 3
KA
L
PA
FA
MA
PA
FA
MA / PA
MA
PA
47.06 1.21 31.11 31.19 31.49 28.19 29.34 40.49 40.44 31.48 38.87
8252 4/ 9
FA
FA / MA
PA
14A
FA
MA
PA
B
MA
PA
40.31 37.60 39.80 30.92 36.40 30.75 36.62 32.98
32.20 31.05
76SO 5/ 5
t4A
FA
MA
MA
PA
MA
NA
55.61 50.54 45.68 49.64 46.11 34.14 31.18
8254 6/ 4
FA
MA
MA
PA
MA
PA
NA
MA
38.36 37.08 32.34 32.57 38.10 25.98 28.90 27.03
8255 7/ 3
PA
MA
PA
FA
FA
FA / MA
47.02 46.53 41.50 40.14 38.39 45.17 48.19
-----------------------------------------------------------------------------------------------------------------------------
NCLO a.
MALE
F - FE14ALE A - ALIVE
E . EARLY RESORPTION
L
- CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED
Fetus 8251-10 had a cleft snout and no incisors.
- LATE RESORPTION IN GRAMS (G).
./" DENOTES POSITION OF CERVIX
.PROTOCOL 418-012P:
OPAL (STOMACH TUBE) DOSAGE-RANGE
DEVELOPMENTAL
(SPONSOR'S STUDY NUMBER: T-6295.10)
TOXICITY STUDY OF PPOS IN RABBITS
TABLE 17 (PAGE 3): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
-------------------------------------------------------------------------------------------------------------------------------
FETUS 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
is
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------------------
RABBIT I CLe
82S6 2/ 8
MA
MA / FA
E
E
E
E
E
FA
40.97 32.48 32.20
14.84
8257
ABORTED ON DAY 23 OF GESTATION
8258
NOT PREGNANT
62S9
ABORTED ON DAY 22 OF GESTATION
8260 4/ 7
PA
L
FA
L / MA
MA
FA
MA
L
FA
26.90 4.03 28.15 4.33 19.67 20.02 21-85 21.23 3.13 17.82
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VI
10 14G/KG/DAY
-------------------------------------------------------------------------------------------------------------------------------
8261
ABORTED ON DAY 26 OF GESTATION
8262
ABORTED ON DAY 22 OF GESTATION
8263
NOT PREGNANT
8264
ABORTED ON DAY 23 OF GESTATION
8265
ABORTED ON DAY 25 OF GESTATION
-------------------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VII
20 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------------------------
RABBIT # CLo 8266
FOUND DM ON DAY 17 OF GESTATION
8267
FOUND DEAD ON DAY 20 OF GESTATION
8268
FOUND DEAD ON DAY 17 OF GESTATION
8269
ABORTED ON DAY 19 OF GESTATION
8270
FOUND DEAD ON DAY 16 OF GESTATION
-------------------------------------------------------------------------------------------------------- -------
N - MALE
F - PB4ALE
A - ALIVE
E - EARLY RESORPTION
L = LATE RESORPTION
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
"/" DENOTES POSITION OF CERVIX
418-012:PAGE D-66
418-012P:PAGE 66
ATTACHMENT 1 PROTOCOL
418-012:PAGE D-67
.-Argc.s
418-012P:PAGE 67
Argus PAseamh Labomtorl", Inc. 905 Sheehy Drive,BuildingA
Homhom, Pennsylvania 190"
T: (215)4434710 F: (215) "3-8587
PROTOCOL 418-012P SPONSOF;VS STUDY NUMBER: T-6295.10
STUDY TITLE: PURPOSE:
TESTING FACILI
STUDY DIRECTOR: SPONSO STUDY MONITOR: ALTERNAT STUDY MONITO
Oral (Stomach Tube) Dos@age-Range Developmental ToxicityStudy of PFOS inRabbits
The purpose ofthisstudy isto provide informationforthe selectionof dosages to be used inthe developmental toxicit(yembryo-fetaltoxicitaynd teratogenicpotentials)tudy of PFOS administeredorallyviastomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits.
Argus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Horsham, Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587
Raymond G. York, Ph.D., DABT Associate Directorof Research
3M Toxicology Services 3M Center, Building220-2E-02 St.Paul, Minnesota- 55144-1000
Marvin T. Case, D.V.M., Ph.D. Telephone: (612)733-5180 Teleftx: (612)733-1773
Andrew M. Seacat, Ph.D. Telephone: (612)575-3161 Telefax: (612)733-1773
418-012:PAGE D-68
418-012P:PAGE 68 Protocol418-012P
Page 2
REGULATORY CITATION
U.S. Food and Drug Administration(1994). InternationaClonference on Harmonisabon; Guidelineon detectionof toxicittyo reproductionformedicinalproducts. Federal Register,September 22, 1994, Vol.59, No. 183.
U.S. Food and Drug Administration.Good Laboratory PracticeRegulations;FinalRule. 21 CFR Part 58.
Japanese Ministryof Health and Weffare (1997). Good Laboratory PracticeStandard forSafety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.
European Economic Community (1989). Council decisionon 28 July 1989 on the acceptance by the European Economic Community of an OECD decisionlrecommendation on compliance withprinciplesof good laboratorypractice.OfficiaJlournal of the European Communities: Legislation.32 (No.L 315; 28 October): 1-17.
REGULATORY COMPLIANC :
This studywillbe conducted inthe spiriotf the Good Laboratory Practice(GLP) regulationscitedabove inthatthe Testing Facilitpyersonnel willadhere to the Standard Operating Procedures forlaboratoryoperationsand data collection.The Testing FacilitQyualityAssurance Unit(GAU) willnotauditthe protocol,the raw data,the reportsor the criticaplhases of the study.
Allchanges or revisionsof thisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained with the protocol.
SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE:
See ATTACHMENT 1 to the protocol.
418-012:PAGE D-69
418-012P:PAGE 69
Pmtocol 418-012P Page 3
TEST ARTICLE AND VEHIC
Identification:
Test Article:
Name: Physical Description: LotIBatch Number: SpecificGravity:
Purity:
ExpirationDate:
PFOS. Light-coloredpowder. 217. -0.6.
98.9%.
May 2000.
Informationon the identityc,omposition,strengthand purityofthe testarticleison file withthe Sponsor.
Vehicle:
0.5% TweenO 80 in Reversed Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplierand lotidentificatiofnTweenO 80 to be documented in the raw data.
Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe vehiclethatwould interferweith the resultsofthisstudy. Therefore, no analyses otherthan those mentioned inthisprotocolwillbe conducted.
Safely Precautions:
Gloves, mask, appropriateeye protectionand a uniform/labcoat are to be wom during formulationpreparationand dosage administration.The MaterialSafety Data Sheet (MSDS) isattached tothe protocol(ATTACHMENT 2).
Storage:
Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations:
Room temperature. Room temperature. Room temperature. Frozen (-200C).
Alltestarticlsehipments to the Testing Facilitsyhould be addressed to the attentionof JulianGuibinski,Manager of Formulations,at the previouslycitedaddress and telephone number.
Shipments should includeinformationconcerning storage conditionsand shipping cartons should be labeled appropriately.The recipientshould be notifiedinadvance of shipment.
418-012:PAGE D-70
418@-012P:PAGE 70 Pmtocol418-012P
Page 4
FORMULATION: Freauency of Preparaton: Formulations(suspensions)willbe prepared dailyattheTestingFacilityV.ehiclewillbe prepared weekly atthe TestingFacility. Detailedpreparationprocedures are attachedto thisprotocol(ATTACHMENT 3). Adiustment forPurl : The testarticlweillbe considered 100% pure forthe purpose ofdosage calculations.
Testing FaclillyReserve SamRIO : The Sponsor willreservea sample (1 g)ofeach lotofthebulktestarticluesed during the course ofthisstudy.The TestingFacilitwyillreservea sample (5mL) ofeach lotof the vehiclecomponents used duringthe course ofthisstudy. Samples willbe stored under the previouslycitedconditions.
ANALYSE : Samples additionatlothose describedbelow may be taken ifdeemed necessary during the course ofthe study. Bulk Test ArticleSamRiin No analyses ofthe bulktestarticlweillbe conducted duringthe course ofthisstudy. Informationon the stabiliotfythe bulktestarticlieson filewiththe Sponsor. Analyses of Prepared Formulations: At the requestofthe Sponsor, no analyses ofprepared testarticlfeormulationswillbe conducted duringthe course ofthe study. However, recordswillbe maintainedto document how the testarticlfeormulationswere prepared.
DISPOSITION: Prepared formulationswillbe discardedatthe TestingFacilityA.llremainingbulktest articlweillbe returnedto the Study Monitoratthe previouslycitedaddress.
418-012:PAGE D-71
418-012P:PAGE 71 Pmtocol 418-012P
Page 5
TEST SYSTEM:
Species/Strainand Reason for Selection:
The New Zealand White [Hra:(NZW)SPF) rabbitwas selectedas the Test System because: 1)itisone non-rodentmammalian species accepted and widelyused throughoutthe industryfornonclinicasltudiesof developmentaltoxicit(yembryo-fetal toxicitytteratogenic2i)ttyh)i;sstrainof rabbithas been demonstrated to be sensitiveto developmentaltoxins;3) historicadlata and experienceexistatthe TestingFacility("); and 4) the testarticliespharmacologicallyactiveinthe speciesand strain.
Number and Sex:
Populationevaluated: 35 timed-pregnantfemale rabbits(5 per dosage group).
Body Wei-ghtand Age:
The individuablody weights ofthefemale rabbitswillrange from 2.5 kg to 5.5kg;the rabbitswillbe approximatelyfiveto seven months ofage atthe time ofstudy assignment. Actualbody weights recorded atreceiptand atstudy assignment willbe documented inthe raw data.
Source:
Covance Research Products,Inc. Swampbridge Road, Box 7200 Denver, Pennsylvania 17517
The rabbitswillbe shipped infifterecdartonsby truckfrom Covance Research Products,Inc.,Denver, Pennsylvania,to the TestingFacility.
Identification:
Rabbitsare permanently identifieudsingMoneW self-piercinegar tags (Gey Band and Tag Co., Inc.,No. MSPT 20103). Female rabbitsaregiven unique permanent identificatinounmbers when assigned to the studyon the basisofday 0 ofpresumed gestationbody weights.
ANIMAL HUSBANDRY:
Allcage sizesare incompliance withthe Guide forthe Care and Use ofLaboratory Animals("'.
418-012:PAGE D-72
418-012P:PAGE 72 PMtocol 418-012P
Page 6
Housing:
The rabbitswillbe individuallhyoused in unitsof sixto eightstainlesssteelcages. No nesting materialswillbe suppliedbecause the female rabbitswillbe sacrificedbefore parturitioinsexpected.
Room Air.Tomperatum and Humidity:
The animal room isindependently supplied with at leastten changes per hour of 100% freshairthat has been passed through 99.97% HEPA filtersR.oom temperature willbe maintained at 61 OF (160C) to 72*F (220C) and monitored constantly.Room humidity willalso be monitored constantlyand maintained at 30% to 70%.
An automaticallycontrolled12-hour light1:2-hour dark fluorescentlightcycle willbe maintained. Each dark period willbegin at 1900 hours EST.
Diet:
Approximately 150 g of CertifiedRabbit ChowS #5322 (PMI NutritionInternationalw)ill be availableto each rabbiteach day untilthe firsdtay of dosage, at which time approximately 180 g ofthe same certifiefdeed willbe offeredto each rabbiteach day. The certifiefdeed willbe availablefrom individuals,tainlesssteel,"J-type"feeders attached to each cage.
Water:
Water willbe availablead libitumfrom individuabloftlesattached to the cages or from an automatic watering access system. Allwater willbe from a localsource and passed through a reverse osmosis membrane before use. Chlorinewillbe added to the processed water as a bacteriostatp;rocessed water isexpected to contain no more than 1.2 ppm chlorineat the time of analysis.Water isanalyzed monthly forpossible bacterialcontaminationand twice annuallyforpossiblechemical contamination.
Contaminants:
Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe certifieddietor inthe drinkingwater at levelsthatwould interfere with the resultsof thisstudy. Therefore,no analyses other than those routinely performed by the feed supplieror those mentioned inthisprotocolwillbe conducted.
418-012:PAGE D-73
418-012P:PAGE 73 ProtoCol418-012P
Page 7
MATING AND RANDOMIZATION:
The female rabbitswillbe naturallybred atthe Supplier by breeder male rabbitsofthe same sourceand strainbeforeshipmenttothe TestingFacilityT.he day matingoccurs willbe designatedday 0 ofpresumed gestation.The rabbitswillbe shippedtothe TestingFacilitayftermating,toarriveon day 1 of presumed gestation.Beforeshipment oftherabbitst,he Supplierwillforwardbreedingrecordsand day 0 ofpresumed gestatiobnody weights.A computer-generated(weight-orderedr)andomization procedurewillbe used to assignthe rabbitstodosage groups based on this information.
ADMINISTRATION:
Route and Reason for Choice:
The oral(stomachtube)routewas selectedforuse because: 1)incomparisonwiththe dietaryroute,the exactdosage can be accuratelyadministereda;nd 2) itisone ofthe possibleroutesof human exposure.
Method and Freguency:
Female rabbitswillbe giventhe testarticloence dailyon days 7 through20 of presumed gestation.Dosages willbe adjusteddailyforbody weightchanges and given atapproximatelythesame timeeach day.
RationaleforDosage Selection:
Dosages willbe selectedby the Sponsor on thebasisofpreviousstudiesconducted withthe testarticle.
418-012:PAGE D-74
418-012P:PAGE 74
PMtoCol 418-012P Page 8
Dosage Levels,Concentrationsand Volumes:
Dosage Group
1 11 111 IV v vi
Number Of
Animals
Dosage
Concentration Volume
(mgikg/day) (mg/mL) iMUk
Argus Batch Number
5
0 (Vehicle)
0
5
0.1
0.01
10- B-418-012P-A(Day.Month.Year) 10 B-418-012P-B(Day.Month.Year)
5
1
0.1
10 B-418-012P-C(Day.Month.Year)
5
2.5
0.25
10 B-418-012P-D(Day.Month.Year)
5
5
0.5
10 B-418-012P-E(Day.Month.Year)
5
10
1
10 B-418-012P-F(Day.MonthY.ear)
5 1 20
2
1 10 1 B-418-012P-G(Day.Month.Year)
The testarticlweillbe considered100% pureforthepurpose ofdosage calculabons.
TESTS, ANALYSES AND MEASUREMENTS:
Viability:
AllPeriods:
At leasttwice daily.
ClinicalObservations and/or General Appearance:
Predosage Period:
At leastonce.
Dosage Period:
Twice daily.Priorto dosage administrationand once approximately one hour postdosage.
Postdosage Period:
Once daily.
Clinicalobservationsmay be recorded more frequentlythan citedabove, ifdeemed appropriateby the Study Directorand/or Study Monitor.
Body Weights:
Predosage Period:
Day 0 of presumed gestationand on the day of arrival at the Testing Facility.
Dosage Period:
Daily.
Postdosage Period:
Daily.
418-012:PAGE D-75
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Page 9
Food Consumption Values:
Predosage Period:
Recorded dailyafterarrivaaltthe TestingFacility (valuesnottabulated).
Dosage Period:
Recorded'daily.
Postdosage Period:
Recorded daily.
Feed consumption values duringthe dosage periodwillbe tabulatedforthe same intervalass body weight evaluations.
Caesarean-Sectioning Observations:
Rabbitswillbe Caesarean-sectionedon day 29 ofpresumed gestation.The fetuseswill be removed from the uterusand placed inindividuaclontainers.The rabbitswillbe examined fornumber and distributiofn
Corpora Lutea.
ImplantationSites. [Placentaethatappear abnormal (sizec,oloror shape) willbe noted inthe raw data.]
Liveand Dead Fetuses. (A livefetusisdefinedas one thatresponds tostimulia; dead fetusisdefinedas a term fetusthatdoes not respond to stimuliand thatisnot markedly autolyzed; dead fetusesdemonstratingmarked toextreme autolysisare consideredto be lateresorptions.)
Eady and Late Resorptions. (A conceptus isdefinedas a lateresorptionffitisgrosslyevidentthat organogenesis has occurred;ffthisisnot the case,the conceptus isidentifieads an earlyresorption.)
FetalObservations:
Body Weights:
The body weight ofeach fetuswillbe recorded.Only body weights oflivefetuseswill be used todetermine littefretalbody weight averages.
418-012:PAGE D-76
418-012P:PAGE 76
Pmtocol 418-012P
Page 10
Gross ExternalAlterations:
Allfetuseswillbe examined forgrossexternalalterationsL.ate resorptionsand dead fetusesalsowillbe examined forgross externalalterationtsothe extentpossiblebut such observationswillnot be includedineitherdata summarizationor statistical analyses. Fetuses withgross externalalterationwsillbe preserved inneutralbuffered 10% formalin.Allotherfetuseswillbe discarded.
Representativephotographs offetalgross alterationwsillbe taken.
Sex:
Allfetuseswillbe examined intemallytodetermine sex.
METHOD OF SACRIFICE:
BeuthanasiaO-D Special(manufacturedby Schering-PloughAnimal Heafth)willbe used tosacrificreabbits(viaintravenousinjectiona)nd livefetuses(viaintrapedtoneal injection).
NECROPSY:
Gross lesionswillbe retainedinneutralbuffered10% formalinforpossiblefuture evaluation(correspondingtissueswillbe retainedfrom rabbitsinthe vehiclecontrol group atthe discretioonfthe Study Director)(.Exception:Parovadan cystswillbe discarded;these are common, spontaneous lesionsinrabbits.U)nless specifically citedbelow,allothertissueswillbe discarded.
Scheduled Sacrifice:
On day 29 ofpresumed gestation,female rabbitswillbe Caesarean-sectioned,and a gross necropsy ofthe thoracic,abdominal and pelvicviscerawillbe performed. Uteriof apparentlynonpregnant does willbe stainedwith 10% ammonium sulfideto confirmthe absence ofimplantationsftes(S).
Rabbits Found Dead or Moribund:
Rabbitsthatdie or are sacrificebdecause ofmoribund conditiona,bortionor premature deliverywillbe examined forthe cause ofdeath or moribund conditionon the day the observationismade. Pregnancy statusand uterinecontentswillbe recorded.Aborted fetusesand/ordeliveredpups willbe examined tothe extentpossible,usingthe same methods describedforfetuses. Uteriofapparentlynonpregnant does willbe stained with10% ammonium sulfideto confirmthe absence ofimplantatiosnites().
418-012:PAGE D-77
418-012P:PAGE 77
Protocol418-012P Page 11
STATISTICAL EVALUATIO
Averages and percentages willbe calculated.Littervalues willbe used where appropriate.Additionalprocedures and/or analyses may be performed ffdeemed appropriate.
DATA ACQUISITION,VERIFICATIONAND STORAO
Data willbe hand- and/or computer-recorded. Records willbe reviewed by the Study Directorand/or appropriatemanagement personnel within21 days aftergeneration.All originalrecords willbe stored inthe archivesof the Testing FacilityA.lloriginaldata will be bound and indexed. A copy of allraw data willbe suppliedto the Sponsor upon request. Preserved tissueswillbe storedat the Testing Facilitayt no charge forone year aftermailingof the draftfinalreport,afterwhich time the Sponsor willbe contacted to determine the dispositionofthese materials.
RECORDS TO BE MAINTAINE
Protocoland Amendments. Test ArticleV,ehicle and/or Reagent Receipt,Preparationand Animal Acquisition. Randomization Schedules. VeterinarianExamination. Mating History. Treatment (ifprescribedby StaffVeterinarian). General Comments. ClinicalObservations and/or General Appearance. Body Weights. Feed Consumption Values. Caesarean-Sectioning and FetalObservations. Gross Necropsy Observations. Organ Weights (ifrequired). Photographs (ifrequired). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists.
Use.
418-012:PAGE D-78
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Page 12
KEY PERSONNE
Executive Director of Research: Mildred S. Christian,Ph.D., ATS DirectorofResearch: Alan M. Hoberman, Ph.D.,DABT AssociateDirectorof Research and Study Director:Raymond G. York, Ph.D.,DABT DirectorofLaboratoryOperations:John F.Barnett,B.S. Manager ofStudy Coordination:ValerieA. Sharper,M.S. Manager ofAnimal Operationsand Member, InstitutionAanlimal Care and
Use Committee: Dena C. Lebo, V.M.D. Manager ofRegulatoryCompliance: KathleenA. Moran, M.S. Consultant,VeterinaryPathology:W. Ray Brown, D.V.M.,Ph.D.,ACVP
REPO :
A lettereportforthe purpose ofdosage selectionforthe fullstudywillbe prepared immediatelyfollowingcompletionofthe in-Iffpehase.
A summary reportwillbe prepared includinga:bstract,summaries ofthe methods, resultsand conclusion;tableofcontents;copy ofthe protocol;amendments; summary and individuatlables;and reportsofsupportingdata (ffappropriate)T.he reportwillbe includedas an appendix tothe fullstudy report.The Sponsor willreceiveone copy of the draftreportand two copiesofthe finalreport.
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMEN
The procedures describedinthisprotocolhave been reviewed by the TestingFacility's InstitutionAanlimal Care and Use Committee. Allprocedures describedinthisprotocol thatinvolvestudyanimals willbe conducted ina manner toavoidor minimize discomfortd,istressor paintothe animals.
The Sponsoes signaturebelow documents the factthatinformationconcerningthe necessityforconductingthisstudyand the factthatthisisnot an unnecessarily duplicativsetudy may be obtainedfrom the Sponsor. No alternativ(einvitro) procedureswere availableformeeting the statedpurposes ofthe study.
418-012:PAGE D-79
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Page 13
REFERENCES:
1 ChristianM,.S.,Hoberman, A.M. and Smith,T.H.F.(1982). Dosage-range study ofthe teratogenicpotentiaolfsuspensions oftrinitrofluoreno(nTeNF) administeredoralltyoNew Zealand White rabbits.Toxicologis2t(l):40(#143).
2. ChristianM,.S. (1984). Reproductivetoxicitaynd teratologyevaluationsof naftrexone(ProceedingsofNaltrexoneSymposium, New York Academy of Sciences,November 7, 1983).J.Clin.Psychiat.45(g):7-01.
3. Feussner, E.L.,Lightkop,G.E.,Hennesy, R.A.,Hoberman, A.M. and Christian, M.S. (1992).A decade ofrabbitferfilidtayta: Study ofhistoricaclontrolanimals. Teratology46(4):349-365.
4. Institutoef Laboratory Animal Resources (1996). Guide forthe Care and Use of Laboratory Animals. NationalAcademy Press, Washington, D.C.
5. Salewski,E. (1964). F;Irbemethodezum makroskopischen Nachweis von lmplantationssteliaemn Uterusder Ratte.Arch.Pathol.Exp. Pharmakol. 247:367.
PROTOCOL APPROVA FOR THE TESTING FACILITY
2@c,-w 19
/GTorge bearlove,Ph.D.,DABT AssociaifeD.irectorof Research
p-plymond G. York, P@. DABT Ass-d-ciateDirectorof Rt@e@,earch Study Director
Dena C. Lebo, V.M.D. Member, InstitutionAanlimal Care and
Use Committee
FOR THE SPONSOR
Marvin T. Case, D.V.M.,Ph.D. Study Monitor
418-012:PAGE D-80 I
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Page 14
Date /7 - 4aou 9
Date
7
Date
Daie
418-012:PAGE D-81
418-012P:PAGE 81
SCHEMATIC
ATTACHMENT 1 OF STUDY DESIGN AND STUDY SCHEDULE
ATRACHMENT 1
418-012:PAGE D-82
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Protoeol418-012P Page 1 of 2
DOSAGE-RANGE
STUDY SCHEMATIC DEVELOPMENTAL TOXICITY STUDYO
TimedPregnant Rabbits
StartOf Dosage
CaesareanSecbonind'
End of Dosage
Day 0 of Presumed
Gestation
Day 7 of Presumed Gestation
Day 20 of Presumed Gestation
Day 29 of Presumed Gestation
Dosage Pedod.
a.
For additionaldetailssee 'Tests,Analyses and Measurements" section of the
protocol.
b.
Fetalevaluations(allfetuses -externalexaminations).
ATTACHMENT 1
418-012:PAGE D-83
418-012P:PAGE 83 Protocol418-012P
Page 2 of2
26 JUN 98 02JUL98-15JUL98
24JUL98 31 JUL 98 08 OCT 98
SCHEDULE8
Animals Arrive-AcclimationBegins. Dosage Period(Days 7 through 20 of presumed gestation). Caesarean-Sectioning Period (Day 29 of presumed gestation). LetterReport. Summary Report.
a. The study initiatidoante isthe date the Study Directorsignsthe protocol.
418-012:PAGE D-84
418-012P:PAGE 84
ATTACHMENT
2
MATERIAL SAFETY DATA SHEET
418-012:PAGE D-85
MATERIAL SAFETY DATA SHEET
3M 3M Center St. Paul, Kinnesota
551"-Iooo i.soo-364-3577 or (612) 737-5501 (24 hours)
418-012P:PAGE 85 PFC)IS
Copyright, 1998, Minnesota Mining and Manufacturing Company.
All rights reserved. Copying and/or downloading of this
inforaationfor the purpose of properly utl2izing 3M products
is allowed provided that: 1) the information in copied in full with no changes unless
prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise
distributedwith the intention of earning a profit thereon.
DIVISION: 3H CHEMICALS TRADE NAME:
Fe-95 FLUORAD Brand Fluorochanical Surfactant
ID NUMBER/U.P.C.: 98-0207-0103-7 00-51135-09OS4-1 98-0207-0104-5 98-0211-0888-5 00-51135-09362-7 9B-0211-3916-1
ZF-0002-10"-l ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3796-9
00-51135-09OSS-8 00-51135-02311-2
-----------------------------------------------------------------------------
1. INGREDIEN7
C.A.S. NO.
PERCENT
-----------------------------------------------------------------------------
POTASSIUM PERFLUOROALKYL SULFONATE ...... 2795-39-3
82
POTASSIUM PERFLUOROALKYL SULFONATE ...... 3871-99-6
3
POTASSIUM PERFLLIOROALKYL SULFONATE ...... 29420-49-3 3
POTASSIUM PERFLWROALKYL SULFONATE ...... 60270-55-5 2
POTASSIUM PERFLUOROALKYL SULFONATF ...... 3872-25-1
1
- 86 -8 -7 -6 -3
.............................................................................
2. PHYSICAL DATA -----------------------------------------------------------------------------
BOILING POINT: ...............N/.A. VAPOR PRESSURE: ..............N./A. VAPOR DENSITY: ...............N/.A. EVAPORATION RATE: ............N./.A SOLUBILITY IN WATER: ..........a.light SPECIFIC GRAVITY: ............c.a.. 0.6 Water-I
(Sulk) PERCENT VOLATILE: ............0..% PH: .......................7..-.6..
(0.1% Aqueous) VISCOSITY: ..................N/.D.. MELTING POINT: ...............N/.D.
APPEARANCE AND ODOR: Light colored, free flowing powder.
............................................................................. Abbreviations: N/D - Not Deterained N/A - Not Applicable CA Approximately
418-012:PAGE D-86
418-012P:PAGE 86
irr,.96IFLUORADgrand Fluorochgmical surfactant isnuary 29, 1991B
PAGE 2
.............................................................................
--3-.--FI-R-E--A-ND--E-X-Pa-L-O--S-IO-N--H-A-Z-MD---D-A-TA-----a----------------------------------------
FLASH POINT: ................N.on.e. FLAMMABLE LIMITS - LEL: ........N/A FLAMMABLE LIMITS - UEL:..a .....N/A AUTOIGNITION TEMPERATURE: ......N/A
EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam
SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bonds around arms, waist and logs, face mak, and protective covering for exposed areas of the head.
UNUSUAL FIRE AND EXPLOSION HAZARDS: See hazardous Decomposition section for products of combustion.
----------------------------------------------------------------------------4. REACTIVITY DATA
-----------------------------------------------------------------------------
STABILITY: Stable
INCOMPATIBILITY - MATERIALS/CONDITIONS Not applicable.
TO AVOID:
HAZARDOUS POLYMERIZATION: hazardous polymerization will not occur.
HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Sulfur, hydrogen Fluoride, Toxic Vapors, Gases or Particulates.
----------------------------------------------------------------------------S. EWIRONMENTAL INFORMATION
-----------------------------------------------------------------------------
SPILL RESPONSE: Observe precautions from other sections. Vacuum, use wet sweeping compound or water to avoid dusting. CAUTIONI A vacuum cleaner could be an ignition source. Clean up residue with water. Place in an approved metal container. Seal the container.
RECOMMENDED DISPOSAL: Do not release to waterways or sewer. Do not use in products or processes that could result in aquatic concentrations greater than 1110 of the lowest ECSO or LCSO concentration. Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permittedto
-----------------------------------------------------------------------------
Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-012:PAGE D-87
418-012P:PAGE 87
Fe-96 IFLWW Brand Fluorochosima Surfactant January 29, ION
PAGE 3
.....................................a ......................................
5. ENVIRONMENTAL INFORMATION
(continued)
..........................................................
accept chemical waste.
ENVIRONMENTAL DATA: gSaHr. Aquatic Fish LCSO, Fathead Hinnow(Pinsphales promelas)m36 mg/l, BluegillSuntish(Lopomismarochirus)-IM mg/l, RainbowTrout(Salmo gairdneri)-llag/l; 48-Mr. EC50, Daphnis Magna - 50 mg/l; CDD=.004 g/g; 80020- Nil.
REMJLATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less M20 & Exempt Solvents: N/A.
Since regulationsvary, consult applicableregulationsor authorities before disposal. U.S. EPA Hazardous Waste Number - None (Not U.S. EPA hazardous).
This product CDMPli93 with the chemical registration requirements of TSCA, EINECS, CDSL, AICS, MITI and Korea.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRDNIC: Yes
----------------------------------------------------------------------------6. SUGGESTED FIRST AID
-----------------------------------------------------------------------------
EYE CONTACT: Immediatelyflush eyes with large amounts of water for at least 15 minutes. Get immediate medical attention.
SKIN CONTACT: Immediately flush skin with large amounts of water. Remove contaminatedclothing.If irritationpersists,can a physician.Wash contaminatedclothing before rouse.
INHALATION: If signsisymptomsoccur, remove person to fresh air. If signs/symptomscontinue, call a physician.
IF SWALLOWED: Drink two glassesof water. Call a physician.
----------------------------------------a-----------------------------------7. PRECAUTIONARY INFORMATION
-----------------------------------------------------------------------------
EYE PROTECTION: Avoid eye contact. Wear vented gaggles.
----------------------------------------------------------------------------Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
418-012:PAGE D-88
418-012P:PAGE 88
NSDS: Fr,.95IFLWRAD Brand Fluorochosima Surtactunt january 29, 19M
PAGE 4
.......................................................................... 7. PRECAUTIONARY INFOR14ATIONaa ----(-c-o-n-ti-na-au--ed-)-------a---a------------------
.............................
SKIN PROTECTION: Avoid skin contact. Wear appropriategloves when handling this material. A pair of glovesmad* from the followingmaterial(s)are recommended: butyl rubber. Use on* or ro of the following personal protectionitems as necessary to prevent skin contact: head covering,coveralls. Protectivegarments (otherthan gloves)should be made of either of the followingmaterials: polyethylene/palyvinylidencehloride (Saranex).
RECOMMENDED VENTILATION: U30 with appropriate local exhaust ventilation. Use in a wellventilatedarea. Providesufficientventilationto maintain emissions below recommendedexposure limits. If exhaust ventilation is not adequate,use appropriaterespiratoryprotection.
RESPIRATORY PROTECTION:Avoid breathingof dust. Select on* of the followingNIOSM approved respiratorsbased an airborne concentrationof contaminantsand in accordancewith OSHA regulations: half-maskdust and mist respirator, half-masksuppliedair respirator,full-facedust and mist respirator, full-facesuppliedair respirator.
PREVENTION OF ACCIDENTAL INGESTION: Do not sat, drink or smoke when using this product. Wash exposed areas thoroughlywith soap and water. Wash hands after handling and before eating.
RECDMMENDED STORAGE: Keep containerdry. Keep container closed when not in use.
FIRE AND EXPLOSION AVOIDANCE: Nonflammable.
OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contaminationof the tobacco and/or smoke and lead to the formation of the hazardous decompositionproducts mentioned in section 4 of this MSDS.
HMIS HAZARD RATINGS: HEALTH: 2 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.)
EXPOSURE LIMITS
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
........................................................................
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1 MGIM3
TWA 3M
y
POTASSIUM PERFLUORDALKYL SULFONATE ... 0.1 MGIM3
TWA 3M
y
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1 MGIM3
TWA 3M
y
POTASSIUM PERFLUOROALKYL SULFONATE ... 0.1 MGIK3-
TWA 3M
y
-----------------------------------------------------------------------------
Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
4lMl2:PAGE D-89
418-012P:PAGE 89
MSDS: Fr,.95FLuow Brand Flucrochaniml Surfactant January 29, 1998
PAGE 5
EXPOSURE LTHRM
(continued)
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN-
-----------------------------------------------------------------------------
POTASSIUM PERFLUOFTOALKYL SULFONATE...
0.1 MG/K3
TWA 3M
y
w SKIN NOTATION: Listed substances indicatedwith 'Y' under SKIN refer to the potentialcontributionto the overall exposureby the cutaneous route including mucous membrane and my*, either by airborne or, more particularly,
by direct contactwith the substance. Vehiclescan alter skin absorption.
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines
----------------------------------------------------------------------------S. HEALTH HAZARD DATA
-----------------------------------------------------------------------------
EYE CONTACT: Mild Eye Irritation:signstsymptomscan include redness,swelling, pain, and tearing.
SKIN CONTACT: Mild Skin Irritation(afterprolongedor repeatedcontact): signs/symptomscan include redness, swelling, and itching.
May be absorbed through the skin and persist in the body for an extended time.
INHALATION: May be harmful it inhaled.
May be absorbed by inhalation and persist in the body for an extended time.
Single overexposure, above recommended guidelines, may cause:
Irritation(upperrespiratory):signs/symptomscan include soreness of the nose and throat, coughing and sneezing.
IF SWALLOWED: Ingestionis not a likely route of exposureto this product.
Illness may result from a single swallowingof a moderate quantity of this material.
May be harmful if swallowed.
MUTAGENICITY: Mutagenicityassays indicate the product is not autagenic.
----------------------------------------------------a----------------------Abbreviations:N/D - Not Determined N/A Not Applicable CA - Approximately
418-012:PAGE D-90
418-012P:PAGE 90
MSDS: Fr,.96 prLUOW grand fluoroch@mual Surtac't2n't january 29, 1998
PAGE 6
-----------------------------------------------------------------------------
a. HEALTH HAZARD DATA
(continued)
-----------------------------------------------------------------------------
REPRODUCTIVE/DEVELOPMENTAL TDXINS: Not toratogenicin the rat at oral doses below maternallytoxic levels.
OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under CaliforniaProposition65.
A Product Toxicity Summary Sheet is available.
----------------------------------------------------------------------------SECTION CHANGE DATES -----------------------------------------------------------------------------
HEADING
SECTION CHANGED SINCE November 05, 1997 ISSUE
----------------------------------------------------------------------------Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
-----------------------------------------------------------------------------
The informationin this Material Safety Data Shoot (MSDS)is believedto be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particularpurposeand suitablefor user'smethod of use or application. Given the variety of factors that can affect the use and applicationof a 3M product, some of which are uniquelywithin the user's knowledgeand control,it is essentialthat the user evaluatethe 3M product to determinewhether it is fit for a particularpurposeand suitable for user's method of use or application.
3M providesinformationin electronicfare as a service to its customers. Due to the remote possibilitythat electronictransfermay have resulted in errors, omissionsor alterationsin this information,3M makes no representationsas to its completenessor accuracy. In addition, informationobtained from a database may not be as current as the informationin the MSDS available directly from 3M.
418-012:PAGE D-91
418-012P:PAGE 91
ATTACHMENT
3
TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE
418-012:PAGE D-92
418-012P:PAGE 92
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Protocol418-012P Version:418-012P (12 JUN 98)
Page 1 of3
PROCEDURE
TestArticle: PFOS
Vehicle:
0.5% TweerS 80,inR.O.Water
A. Purpose:The purposeofthisprocedureistoprovidea method forthepreparation ofdosage suspensionsofPFOS and thevehiclfeororaladministratitoon rabbitosn Argus Study418-012P.
B. GeneralInformation:
1. Allsuspensioncontainerwsilble labeledand colorcoded. Each labelwill specifytheprotocolnumber,testarticliedentificatAirognu,s batch number,concentratiodno,sage levelp,reparatiodnate,expiratiodnate
and storageconditions.
2a. Suspensionswillbe prepared:
X Daily
- Weekly
2b. Vehiclewilble prepared:
- Daily
X Weekly
- For@__ daysofuse - For_ daysofuse
3. Suspensionswillbe preparedata finadlosage volume of10 mL/kg.
4. Safety: _L_ Gloves,labcoat,gogglesorsafetyglassesand faceshield X Dust-MistRespirator Haff-FaceRespirator Ful@-FaceRespirator/PosftiPvressureHood
Tyvek Suit/Apron
5. Dosage solutionasdjustedforFreebase and % Purity.
Yes
X No (Calculatiobnassedon 100%)
FreeBase - Purity
6. SamplingrequirementsC:itedinprotocol.
7. Storage:Citedinprotocol.
418-012:PAGE D-93
418-012P:PAGE 93
ATTACHMENT
3
TEST ARTICLE AND VEHICLE PREPARATION
Protoeol418-012P Version:418-012P (12JUN 98)
Page 2 of 3
PROCEDURE
NOTE:
Test articlewillbe prepared as a serialdilutionfrom the high dosage to the low dosage. Once the finalvolumes are achieved, stirbars are to be added to the containers; mixing should occur during sampling and/or administration.
C. Preparation of Vehicle
1. Add the required amount of R.O. deionized water to an appropriately labeled container. Heat the water to 500C,:t5oC, add the required amount of TweenO 80 and mix untiluniform (See TEST ARTICLE CALCULATIONS).
D. Test ArticleSuspension Preparation:
1 . To prepare the 2-mg/mL, Group VII suspension, add the required amount
of test article(See TEST ARTICLE CALCULATIONS)
into an
appropriately sized, labeled container. Add the required amount of
vehicle and heat the mixture to 800C, *50C for approximately 30 minutes.
2. Once the test articlehas dissolved; spin while the solution cools. (Be sure there is a visiblevortex, thiswillachieve the desired emulsion. This may be prepared the fty before use.)
3. To prepare the 1-mg/mL, Group Vi suspension, remove the required
amount of stock suspension (Group VII) (See TEST ARTICLE
CALCULATIONS),
add the required amount of vehicle and mix.
4. To prepare the .5-mg/mL, Group V suspension, remove the required
amount of stock suspension (Group VI) (See TEST ARTICLE
CALCULATIONS),
add the required amount of vehicle and mix.
5. To prepare the .25-mg/mL, Group IV suspension, remove the required
amount of stock suspension (Group V) (See TEST ARTICLE
CALCULATIONS),
add the required amount of vehicle and mix.
418-012:PAGE D-94
418-012P:PAGE 94
ATTACHMENT 3 TEST ARTICI 1=AND VEHICLE PREPARATION
Pmtocol418-012P Vemion:418412P_LILJUN 98)
Page 3 of3
PROCEDURE
6. To prepare the 0.1-mg/mL, Group IIIsuspension,remove the required amount ofstocksuspension (Group IV)(See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix.
7. To prepare the 0.01-mg/mL, Group 11suspension,remove the required amount ofstocksuspension (Group 111()See TEST ARTICLE CALCULATIONS), add the requiredamount ofvehicleand mix.
Writtenby-
Appmv b,
/Z July-78
Cla *i tion: No
Yes (See attachedclarificatfiornm.)
A
Initials/Date
APPENDIX E HISTORICAL CONTROL DATA
418-012:PAGEE-1
SUMMARY OF REPRODUCTIVE INDICES NZW RABBIT
PERIOD: JANUARY 1996 -JANUARY 1998
NUMBER OF STUDIES:
66
NUMBER OF RABBITS:
TESTED
901
PREGNANT
861
FOUND DEAD
6*
ABORTED
22
DELIVERED PREMATURELY
4
NUMBER OF RABBITS PREGNANT AT
CAESAREAN-SECTIONING ON
DAY 29 OF GESTATION:
825
NUMBER OF RABBITS WITH
SINGLE CONCEPTUS LiTrER:
LIVE
1
RESORBED
I
ABORTED
2
MEAN or %
% PREGNANT
96.0
AVERAGE # CORPORA LUTEA
9.7
AVERAGE # IMPLANTATIONS
8.9.
AVERAGE LITTER SIZE
AVERAGE # LIVE FETUSES
8.4
AVERAGE # DEAD FETUSES
0.0
AVERAGE # RESORPTIONS
0.4
AVERAGE # EARLY RESORPTIONS
0.3
AVERAGE # LATE RESORPTIONS
0.1
Three were moribund sacrificeosn,e was attributetdoan intubatioanccident
RANGE/STUDY MEAN or % (75.0-100) (7.8-11.7) (3.8-10.6)
(3.2-10.4) (0-0.1) (0-3.2) (0-2.8) (0-1.2)
418-012:PAGE E-2
SUMMARY
OF REPRODUCTIVE INDICES NZW RABBIT
MEAN or %
RANGE/STUDY MEAN or%
AVERAGE % DOES WITH ANY RESORPTIONS
AVERAGE % DOES WITH ALL CONCEPTUSES RESORBED
AVERAGE % DOES WITH ONE OR MORE LIVE FETUSES
26.8 (0-100) 0.6 (0-20.0) 99.4 (80.0-100)
AVERAGE SEX RATIO. (% MALES/LITTER) AVERAGE FETAL BODY WEIGHT (G)
AVERAGE FOR MALES (G)
AVERAGE FOR FEMALES (G)
51.2 43.74 44.26 43.08
(31.4-61-0) (31.85-55.74) (29.55-56-97) (32.25-53.76)
AVERAGE % DEAD OR RESORBED CONCEPTUSES/LITTER
4.4 (0-18.8)
418-012:PAGE E-3
SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS
PERIOD
JANUARY 1996-JANUARY 1998
TOTAL # STUDIES
67
TOTAL # DOES
921
#PREGNANT
876 % OF PREGNANT
DIED
6*
0.6
ABORTED
22
2.4
DELIVERED PREMATURELY
4
0.4
DOES WITH 100% RESORPTIONS
5
0.5
E)CRERNAL OBSERVATIONS
N
Fecalmateriailn
perianalregion
I
Localizedalopecia
2
Leftear,tom
1
GROSS LESIONS
THYMUS
Small
1
LUNGS
Discolored
6
Tear inrightdia-
phragmaticlobe
1
Multiplleesions
1
THORACIC CAVITY
Containedredfluid
1
LIVER
Paleand/ordiscolored 7 Accentuatedlobuiar
patteronn lobe(s) 1
BACK
Break presentin
iumbar regionof
spine
1
RANGE /STUDY
%N
%
o.11 0-1 (0-5.0)
0.22 0-1 (0-5.0) 0.11 0-1 (0-5.0)
0.11 o-i (0-5.0)
0.65 0-4 (0-20.0) 0.11 0-1 (0-4.0) 0.11 o-i (0-4.2)
0.11 0-1 (0-4.0)
0.76 0-4 (0-16.0) 0.11 0-1 (0-5.0)
0.11 0-1 (0-5.0)
Threewere moribundsacrificeosn.e was attributteodan intubatioanccident
418-012:PAGE E-4
SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS
GROSS LESIONS N
BACK(CONT.) Dorsalmuscles,three
hemorrhagicareas
inlumbarregion
1
STOMACH
Trichobazoar
2
Mucosa, eroded in
areas
1
SPLEEN
Small
3
Large
1
KIDNEY(S)
Small
1
Right,displaced
caudally
1
ADRENALGLAND
Right,absent
1
UTERUS
Righthom contained
darkbrown fluid
I
Homs containeda
viscous,green-brown
substance
1
Vascularization
I
Placentaesurrounded
by a thicky,ellow
substance
1
OVARIES Parovariacnyst(s) 30
RANGE /STUDY
%N
%
0.11 0-1 (0-12.5)
o.22 0-1 (0-4.3) 0.11 0-1 (0-4.2)
0.32 0-1 (0-20.0) 0.11 0-1 (0-4.0)
0.11 0-1 (0-20.0) 0.11 0-1 (0-5.0)
0.11 0-1 (0-5.0)
o.11 0-1 (0-16.7)
0.11 0-1 (0-4.0) o.11 0-1 (0-4.3)
0.11 0-1 (0-5.0)
3.26 0-5 (0-25-0)
SUMMARY
418-012:PAGE E-5
OF FETAL GROSS EXTERNAL ALTERATIONS NZW RABBITS
PERIOD
JANUARY 1996 -JANUARY 1998
OF STUDIES
65
LITTERS EXAMINED
816
LIVE FETUSES EXAMINED (DAY 29)
6929
ALTERATION
SKIN
Absent area
L
F
HEAD
Maningocele
L
F
Cyclops
L
F
Upper jaw intwo
L
segments
F
Nares absent
L
F
Fleshyprotrusion L
F
EYES Bulge depressed L
F
Eyelidsopen
L
F
SNOUT
Short
L
F
TONGUE
Protrudes
L
F
BODY
UmbilicaHlemia
L
F
Edema
L
F
L:LITTER INCIDENCE F:FETAL INCIDENCE
RANGE/STUDY
N% N
%
1 0.12 0-1 (0-5.3) 1 0.01 0-1 (0-0.6)
2 0.24 0-1 (0-16.7) 3 0.04 0-2 (D-3.7) 1 0.12 0-1 (0-5.9) 1 0.01 0-1 (D-0.7) 1 0.12 0-1 (0-5.9) 1 0.01 0-1 (0-0.7) 1 0.12 0-1 (0-5.3) 1 0.01 0-1 (0-0.6) 1 0.12 0-1 (0-5.3) 1 o.01 0-1 (0-0.6)
3 0.37 0-1 (0-5.3)
3 0.04 0-1 (0-0.6) 1 0.12 0-1 (0-5.9) 1 0.01 0-1 (0-0.7)
2 0.24 0-1 (0-5-9) 2 0.03 0-1 (0-0.7)
1 0.12 0-1 (0-5.3) 1 0.01 0-1 (0-0.6)
9 1.10 0-2 (0-50.0)
10 0.14 0-3 (0-12.0) 1 0.12 0-1 (0-5.3) 1 0.01 0-1 (0-0.6)
418-012:PAGE E-6
SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS NZW RABBITS
ALTERATION
BODY(CONT.)
skindiscolored L
purple
F
Spina bifida
L
F
Hemorrhagicarea(s) L F
Meningocele
L
F
HematDma
L
F
Dark redareas
L
F
FORELIMBS AND/OR HINDLIMBS
Paw(s):Flexed/ L
Rotated
F
Paw: Shortdigits L
F
Limb(s)R:otated L
F
Limb(s)A:bsent
L
F
TAIL
Short
L
F
RANGE/STUDY
N% N
%
1 0.12 0-1 (0-5.3) 3 0.04 0-3 (0-1.9) 2 0.24 ()-1 (0-20.0) 2 0.03 D-1 (0-1-9) 2 0.24 0-1 (0-5.0)
2 0.03 0-1 (0-0-6) 2 0.24 0-1 (0-16.7) 2 0.03 0-1 (0-2.0) 1 0.12 0-1 (0-5.9) 1 O.Oj 0-1 (0-0.8) 1 0.12 0-1 (0-5.6)
1 0.01 0-1 (0-0-6)
2 0.24 0-1 (0-5.6) 2 0.03 0-1 (0-0.6) 1 0.12 0-1 (0-5.6) 1 o.ol 0-1 (0-0.7)
2 0.24 0-1 (0-16.7)
2 0.03 0-1 (0-1-9) 1 0.12 0-1 (0-5.3) 1 0.01 0-1 (0-0.6)
7 0.86 0-1 (0-20.0) 10 0.14 0-4 (0-2.3)
L:LITTER INCIDENCE F:FETAL INCIDENCE
418-012:PAGE E-7
SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS
PERIOD
JANUARY
STUDIES
LITTERS EXAMINED
FETUSES EXAMINED
1996 -JANUARY
1998 38 674
5739
ALTERATION
BRAIN
Dilatedlateravlentricles L (Moderate)(Grade2) F
EYE(S)
Circumcomeal hemorrhage L
F
Microphthalmia
L
F
HEART
Large
L
F
Three ventricles
L
F
VESSELS
Persistenttruncus
L
arteriosis
F
Innominate,absent
L
F
Two pulmonaryarteries L
F
LUNGS
One or more lobes,parual L
or completeagenesis F
Rightapicaland cardiac L
lobesfused
F
DIAPHRAGM
Hemia
L
F
RANGE/STUDY
N% N
%
2 0.30 0-1 (0-5.0) 2 0.03 0-1 (0-0.6)
20 2.97 0-2 (0-16.7) 21 0.36 0-3 (0-1.9)
1 0.15 0-1 (0-5.0) 1 0.02 0-1 (0-0.6)
1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6)
1 0.15 0-1 (0-5.0) 1 0.02 O@-1 (0-0.6) 1 0.15 0-1 (0-5.3) 1 0.02 0-1 (0-0.7)
1 0.15 0-1 (0-5.9) 1 0.02 D-1 (0-0.6)
69 10.24 0-5 (0-27.8) 90 1.57 0-9 (0-5.0) 1 0.15 0-1 (0-5.3) 1 0.02 0-1 (0-0.6)
1 0.15 0-1 (0-5.0) 1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
418-012:PAGE E-8
SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS
ALTERATION
KIDNEY(S) Absent
Displacedcaudally
RANGE/STUDY
N% N
%
L 1 0.15 0-1 (0-5.6) F 1 0.02 0-1 (0-0.6) L 1 0.15 0-1 (0-4.3) F 1 0.02 0-1 (0-0.5)
SPLEEN Pale
L 1 0.15 0-1 (0-7-1) F 1 0.02 0-1 (0-0-9)
GONADS
Righttestidsisplaced L 1 0.15 0-1 (0-5.9)
caudally
F 1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
SUMMARY
OF FETAL SKELETAL ALTERATIONS NZW RABORTS
418-012:PAGE E-9
PERIOD # STUDIES # LRTTERS EXAMINED # FETUSES EXAMINED
ALTERATIONS SKULL
JANUARY
1996 - JANUARY 1998
37 668 5684
OF STUDIES
RANGE /STUDY WITH
N
%
N % ALTERATION
Summarizabon ofallirregularL lg5 27.eg 0-11 (0-66.7) 35
oufficatioonf skull
F 237 4.17 0-17 (0-9.8)
AnteriorFontansile irregularslhyaped
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 0-1 (0-0-5)
PosteriorFontenelle Enlarged(Slight) (Grade1)
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 0-1 (0-0.6)
Frontals irregulasruture interfrontaplrsesent Fused Two segments Suturelarge Small
L
18 2.69 0-3 (0-16.7) 13
F
20 0.35 0-3 (0-1-8)
L
17 2.54 0-3 (0-15-0) 13
F
17 0.30 0-3 (0-1.7)
L
5 0.75 0-2 (0-10.5) 4
F
5 0.09 0-2 (0-1-1)
L
1 0.15 0-1 (0-5.9)
1
F
1 0.02 0-1 (0-0.7)
L
1 0.15 0-1 (0-5.0)
1
F
1 0.02 0-1 (0-0.6)
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 0-1 (0-0.6)
Parietal(s)
:Containholes
L
F
:Fused and small
L
F
:interparietals
L
irregularsthyaped
F
:lnterparistailnscom-
L
pletelyossffied
F
3 0.45 0-1 (D-5-6)
3
3 0.05 0-1 (0-0.6)
1 0.15 0-1 (0-5.3)
1
1 0.02 0-1 (0-0.6)
1 0.15 0.1 (0-5.3)
1
1 0.02 0-1 (0-0.5)
1 0.15 0-1 (0-16.7) 1
1 0.02 0-1 (0-1.9)
L:LITTER INCIDENCE F: FETAL INCIDENCE
418-012:PAGE E-10
SUMMARY
ALTERATIONS SKULL (CONT.) Nasals
:irregulasrubire :lntemasais lntranssals Displacedsuture Fused Small
OF FETAL SKELETAL ALTERATIONS
NZW RABBITS
# OF
STUDIES
RANGE /STUDY WITH
N%
N % ALTERATION
L
4 0.60 0-2 (0-10-0) 3
F
4 0.07 0-2(0-12)
L 26 3.89 0-3 (0-15.8) is
F 29 0.51 0-4 (0-2.3)
L 16 2.40 0-2 (0-16.7) 13
F
16 0.28 0-2(0-1.9)
L 116 17.36 0-8 (0-40.0) 34
F 129 2.27 0-9 (0-5.2)
L
10 1.50 0-2 (0-10-0) 9
F
11 0.19 0-2(0-1.3)
L
1 0.15 0-1(0-5.0) 1
F
1 0.02 0-1(0-0.6)
Nasal/Fmntalsutures:
L
irregulaarnd/ormisaligned F
Promaxillaef:used
L
F
Promaxillaen:otossified L
F
Maxillaef:used
L
F
Supraoccipitalisr:regularly L
shaped
F
Eye socket.small
L
F
Skulle:xtraossification L
F
12 1.80 0-2 (0-11-1) 9 13 0.23 G-3 (0-1.9)
1 0.15 0-1 (0-5.9) 1 1 0.02 0-1 (0-0.7) 1 0.15 0-1 (0-5.0) 1 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.3) 1 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.3) 1 1 0.02 0-1 (0-0.5) 2 0.30 0-1 (0-5.0) 2 2 0.04 0-1 (0-0.6) 1 0.15 0-1 (0-5.6) 1 1 0.02 0-1 (0-0.6)
HYOID Ala(e)a,ngulated Small Irregularslhyaped
L 108 16.17 0-8 (0-40.0) 34
F 137 2.41 0-18 (0-9-9)
L
1 0.15 0-1 (0-5.3) 1
F
4 0.07 0.4 (0-2.4)
L
1 0.15 0-1 (0-5.3)
F
1 0.02 0-1 (0-0.6)
L:LRMR INCIDENCE F:FETAL INCIDENCE
418-012:PAGE E-11
SUMMARY OF FETAL SPELETAL ALTEmnoNs
NZW RABBITS
# OF
STUDIES
ALTERATIONS
RANGE /STUDY WITH
N
%
N % ALTERATION
VERTEBRAE
CANViC8l
Contrum, unDaWal
L
ossification
F
Ardws and/orContra. L
fww
F
Hemivertabra
L
F
Contrum, asymmetric L F
Contra,bifid
L
F
2 030
0-1 (0-5.6)
2
2 0.04 0-1 (0-0.7)
3 0.45 0-1 (0-5.6)
3
3 0.05 0-1 (0-0.7)
3 OA5
0-1 (".9)
3
3 0.05 0-1 (0-0.6)
1 0.15 0.1 (0-5.6)
1
1 0.02 0-1 (0-0.7)
1 0.15 0-1 (0-5.3)
1
1 0.02 0-1 (0-0.6)
Thoracic
:Hemivertebra
L
F
:Arches and/orContra, L
fused
F
:Centrum, unilateral L
ossification
F
:centra,one or more
L
asymmetric
F
:Centrum, bifid
L
F
:Contra, notOSSiflOd L F
:Arch,absent
L
F
Arch,small
L
F
10 1.50 0-1 (".g)
10
11 0.19 0-2(0-1.1)
5 0.75 0-2 (0-10-5) 4
6 0.10 0-2 (0-1.2)
5 0.75 0-1 (0-5.3)
5
5 0.09 0-1 (0-0.6)
1 0.15 0-1 (0-5.6)
1
1 0.02 0-1 (0-0.6)
4 O-W
0-2 (0-10-5) 3
4 0.07 0-2 (0-1.2)
1 0.15 0-1 (0-4.5)
1
1 0.02 0-1 (0-0.6)
1 0.15 0-1 (0-5.6)
1
1 0.02 0-1 (0-0.6)
3 OA5
0-1 (0-5.9)
3
3 0.05 0-1 (0-0.8)
Lumbar
:Hemivertebra
L
F
:Centrum, unilateral L
ossification
F
:Arch,small
L
F
:Contrum, notossified L
F
2 0.30 0-1 (0-5.9) 2
2 0.04 0-1 (0-0.8)
1 0.15 0-1 (0-5.0)
1
1 0.02 0-1 (0-0-6)
2 0.30 0-1 (0-5.0)
2
2 0.04 0-1 (0-0.6)
1 0.15 0-1 (0-5.0)
1
1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F: FETAL INCIDENCE
418-012:PAGE E-12
SUMMARY
ALTERATIONS VERTEBRAE(CONT.) sacrai
Arches open
OF FETAL SPELETAL ALTERATIONS NZW RABBITS # OF
STUDIES
RANGE /STUDY WITH
N
%
N % ALTERATION
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 ()-(l0-0.5)
Caudal One or more n-isaligned :Fused
11 present
12 present
13 to 14 present
15 present
irregularslhyaped
L
30 4.49 0.3 (0-16.7) 24
F
31 0.54 0-3 (0-2.0)
L
8 1.20 0-1 (0-5.6)
8
F
10 0.18 0-3 (0-1-6)
L
1 0.15 0-1 (0-4.3)
1
F
1 0.02 0-1 (0-0.5)
L
1 0.15 0-1 (0-4.3)
1
F
2 0.04 0-2 (0-1-0)
L
3 OAS
0-1 (0-5.6)
3
F
3 0.05 0-1 (0-0.6)
L
1 0.15 0-1 (0-4.3)
1
F
1 0.02 0-1 (0-0.5)
L
1 0.15 0-1 (0-5.0)
1
F
1 0.02 0-1 (0-0.6)
VERTEBRAE/RIB
interrelatVeedrtebral Rib L
malformations
F
3 0.45 0-3 (0-15.8) 1 3 0.05 0-3 (0-1.6)
RIBS
CervicalPjb present
L
F
Two ormre, fused
L
F
Bases pmximate
L
F
one ormore, split
L
F
One or more, thickenedareas L
F
Flat
L
F
2 0.30 0-1 (0-5.6)
2
2 0.04 0-1 (0-0.6)
6 0.90 0-2 (0-10-5) 5
6 0.10 0-2 (0-1.2)
10 1.50 0-2 (0-9-1)
9
10 0.18 0-2 (0-1-1)
8 1.20 0-1 (0-5.6)
8
8 0.14 0-1 (0-0.6)
27 4.04 0-3 (0-16-7) 19
29 0.51 0-3 (0-2.2)
2 0.30 0-1 (0-5.6)
2
2 0.04 0-1 (D-0.6)
L:LITTER INCIDENCE F: FETAL INCIDENCE
418-012:PAGE E-13
SUMMARY
ALTERATIONS F;UBS(CONT.) Extrarib Small Broad Bent
OF FETAL SPELETAL ALTERATIONS
NZW RABBITS
0 OF
STUDIES
RANGE /STUDY WTRH.
N
%
N % ALTERATION
L
1 0.15 0-1 (0-4.3)
1
F
1 0.02 0-1 (0-0.5)
L
2 0.30 0-1 (0-5.9) 2
F
2 0.04 0-1 (0-0.6)
L
1 0.15 0-1 (0-5.9)
1
F
1 0.02 0-1 (0-0.8)
L
1 0.15 10-1 (04.5)
1
F
1 0.02 0-1 (0-0.6)
MANUBRIUM Duplicated Fused
L
1 0.15 D-1 (0-5.9)
1
F
1 0.02 0-1 (0-0.7)
L
3 0.45 0-2 (0-10.5) 2
F
3 0.05 0-2 (0-1-1)
STERNEBRAE
Two or more, fused
L
F
One ormore, asymmetric
L
F
One ormore, incompletely L
or notossified
F
Duplicated
L
F
64 9.58 0-5 (0-27.8) 31
78 1.37 0-7 (0-3.9)
6 0.90 0-2 (0-10-5) 5 6 0.10 0-2 (0-1.2) 11 1.65 0-2 (0-10.5) 9
11 0.19 0-2 (0-1.2)
1 0.15 0-1 (0-5.9)
1
1 0.02 0-1 (0-0.7)
PELVIS
Pubis(es)i:ncompletely
L
or notossified
F
4 0.60 0-1 (0-5.9)
4
5 0.09 0-2 (0-1-1)
SCAPULAE
Ala(e)i:rregularly shaped Ala(e)w:avy
L
4 0.60 0-2 (0-10.5) 3
F
4 0.07 0-2 (0-1.2)
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 0-1 (0-0.6)
L: LRTTER INCIDENCE F: FETAL INCIDENCE
418-012:PAGE E-14
SUMMARY
ALTERATIONS SCAPULAE (CONT.)
OF FETAL SKELETAL ALTMTIONS
NZW RABBITS
# OF
STUDIES
RANGE /STUDY WITH
N%
N % ALTERATION
Misaligned Bent
L
5 0.75 0-2 (0-10.5) 4
F
5 0.09 0-2(0-12)
L
1 0.15 0-1(()-5.0) 1
F
1 0.02 0-1 (0-0.6)
FORELIMB(S)
I Phalanxpresent
L
F
0 Phalangespresent
L
F
Humerus, Radius,Ulna,
Carpals,Metacarpals,FORG-
digitasnd Forephalanges L
absent
F
1 0.15 0-1 (0-5.6) 1 1 0.02 0-1 (0-0.7) 1 0.15 0-1 (0-5.6) 1 1 0.02 0-1 (0-0.7)
1 0.15 0-1 (0-5.3) 1 1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
STATEMENT
APPENDIX F OF THE STUDY DIRECTOR
riPM,WDICA
418-012:PAGE F-1
Argus ResearchLaboratoriesI,nc. 905 Sheehy Drive,BuildingA Horsham, PA 19044 Telephone:(215)443-8710 Telefax:(215)443-8587
PROTOCOL
418-012:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: 8295.10
STATEMENT OF THE STUDY DIRECTOR
This finalreportaccuratelyreflecttshe raw data obtainedduringthe performance ofthe study.No significandteviationfsrom theU.S.Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulationsF;inalRulea,the Japanese Ministroyf Healthand Welfare(MHW) Good LaboratoiyPractice StandardforSafetyStudieson Drugsband theEuropean Economic Community (EEC) Councildecisionon 28 July1989 on theacceptanceby theEuropean Economic Community ofan OECD decisionlrecommendatioonn compliancewith principleosfgood laboratorpyractic6occcurredthataffectedthe qualityor integritoyfthe study.
alaxco;nd G. Yor Ph DAB Date Ae Aq-- ---'neorecto esearch
and Study Director
a. U.S.Food and Drug AdministrationG.ood LaboratoryPractice Regulations;FinalRule. 21 CFR Part58.
b. Japanese Ministryof Health and Welfare (1988). Good Laboratory Practice Standard forSafety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997.
C. European Economic Community (1989). Councildecisionon 28 July 1989 on the acceptance by the European Economic Community of an OECD decisionlrecommendation on compliance withprinciplesofgood laboratorypractice.OfficiaJlournalofthe European Communities: Legislation3.2(No.L 315;28 October):1-17.
APPENDIX G QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT
@JPRMEDICA
418-012:PAGE G-1
Argus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Horsham, PA 19044 Telephone: (215)443-8710 Tolefax:(215)443-8587
QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT
Study Director:Raymond G. York,Ph.D.,DABT
ExecutiveDirectorofResearch: MildredS. ChristianP,h.D.,Fellow,ATS
Protocol418-012: Oral(Stomach Tube) DevelopmentalToxicitSytudy ofPFOS inRabbits Sponsors Study Number: 6295.10
The draftprotocolforthisstudywas auditedforadherence toU.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulationsJ,apanese MinistroyfHealthand Welfare (MHW); Good LaboratoryPracticeStandardfor SafetyStudieson Drugs,and European Economic Community (1989)council decisionon 28 July1989 on the acceptance by the European Economic Community ofan OECD decision/recommendationon compliancewithprinciples ofgood laboratorpyracticeon 10 AUG 98.
Criticaplhases ofthisstudywere inspectedfivetimes;studyinformation and raw datawere auditedtwice(seetables1 and 2 fordatesand phases/data).
The draftfinalreportand the raw data forthisstudy[exceptfor Appendix F,the PilotReport,which was conducted inthe spiriotfGood LaboratoryPractice(GLP)]were compared and auditedforaccuracy,for adherence toprotocolrequirements,and foradherence to U.S.Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulationsJ,apanese Ministry ofHealthand Welfare(MHW); Good LaboratoryPracticeStandardforSafety Studieson Drugs,and European Economic Community (1989)councildecision on 28 July1989 on the acceptance by the European Economic Community ofan OECD decision/recommendationon compliancewithprincipleosfgood laboratorpyracticebetween 04 DEC 98 and 17 DEC 98,forrevisionsrequested by the Sponsor 23 DEC 98, and forfinalizatioonn 11 JAN 99.
418-012:PAGEG-2
Thisstudywas conducteadccordintgoU.S.FoodandDrug Administrat(iFoDnA)GoodLaboratoPrryacticRegulationJsa,paneseMinistry ofHealtahndWelfar(eMHW);Good LaboratoPrryacticSetandarfdorSafety Studieosn Drugs,andEuropeanEconomicCommunity(1989c)ouncidlecision on 28 July1989on theacceptancbeytheEuropeanEconomicCommunityofan OECD decision/recommendaotnicoonmpliancweithprinciploefgsood laboratoprryactice.
-- /
@BBarcbatareora@r0aJo.,0 ersioonn,sB,.AA,. Date Dir@ecrtofr0 rrraatstions andCompliance
HeatheLr.RabuftinMo.,S. Date
QualitAyssurancSeupervisor and PrincipAaulditor
TABLE 1 CRITICAL PHASES INSPECTED
418-012:PAGE G-3
TestArticlAedministratio-nGavage Date ofinspection:25 AUG 98 Date resultsreportedtothe Study Directorand Management: 12 SEP 98
TestArticlePrel2aration Date ofinspection:04 SEP 98 Date resultsreportedtothe Study Directorand Management: 12 SEP 98
Blood Collection Date ofinspection:10 SEP 98 Date resultsreportedtothe Study Directorand Management: 10 SEP 98
Caesarean-Sectioning
Dates ofinspection:10 SEP 98, 18 SEP 98
Dates resultsreportedtothe Study Directorand Management: 10 SEP 98, 24 SEP 98
418-012:PAGEG-4
TABLE 2
RAW DATA AUDIT(S)
The followingstudyinformatioannd raw datawere audited on 12 OCT 98:
Vehiclereceiptp,reparationand use. Test articlreeceiptp,reparationand use. Test articlpeackinglists.
The resultsofthisauditwere reportedtotheStudy Directorand Management on 13 OCT 98.
The followingstudyinformatioannd raw data were audited on 13 OCT 98:
Protocol. Protocolamendments. Listofpersonneland computer operatorcodes. Errorcodes and codes forclinicaslignobservations. Animal receiptr,andomizationa,nd acclimation. Veterinaryexamination. In-lifteransactionrecord. Feed consumption. Caesarean-sectioning. Maternal gross observations. Fetalgross observations. Fetalfixativaessignment. Fetalvisceralexamination. Fetalskeletalexamination. Necropsy. Organ weights. Tissue packing lists. General comments. Study maintenance records. Tempscribes. Feed and water analyses. Editrequests. Dosage volumes. Deviations. Data reviewpage. Blood collection.
The resultsofthisauditwere reportedtothe Study Directorand Management on 14 OCT 98.