Document YpOqk1pggqw5aBnQKjOwqnqE
FINAL REPORT
PROTOCOL 418-010 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE
IN RABBITS SPONSOR'S STUDY NUMBER: 6316.8
FINAL REPORT DATE: 11 JANUARY 1999
PROTOCOL 418-010
ORAL (STOMACH
TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS
SPONSOR'S STUDY NUMBER: 6316.8
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's Study Number A.5. Purpose of the Study A.6. Study Design A.7. Regulatory Compliance A.8. Ownership ofthe Study A.9. Study Monitor
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 11-1 11-2 11-2
SUBJECT 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 F.9. Water Analysis G. Methods G. 1. Dosage Administration
iv
PAGE 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 11-7 11-8 11-8 11-8 11-8
allBJECT
G.2. RationalfeorDosageSelection
G.3. RouteofAdministration
G.4. RationalfeorRouteofAdministration
G.5. FrequencyofAdministration
G.6. LengthofStudy
G.7. MethodofStudyPerformance
G.8. GrossNecropsy
G.9 StatistiAcnaallyses
111. RESULTS A. MortalitAyb,ortionCsl,inicanld NecropsyObservations
A.1. Mortality
A.2. Abortions
A.3. ClinicOablservations
A.4. NecropsyObservations
B. MaternaBlody Weightsand Body WeightChanges
C. Maternal Absolute (g/day)and Relative(g/kg/day)
Feed Consumption Values
D. Caesarean-Sectioning
and Lifter Observations
E. Fetal Alterations
E. 1. Summary of Fetal Alterations
E.2. Fetal Gross External Alterations
E.3. Fetal Soft Tissue Alterations
E.4. Fetal Skeletal Alterations v
PAGE 11-8 11-9 11-9 11-9 11-9 11-10 11-10 11-12 111-1 111-1 111-1 111-1 111-3 111-4 111-4
111-4 111-5 111-5 111-5 111-6 111-6 111-8
SUBJECT
F. SatelliRtaebbits
REFERENCES
APPENDIX A -REPORT FIGURE
Figure1. MaternaBlodyWeights
APPENDIX B -REPORT TABLES
Table1. ClinicOablservation-sSummary
Table 2.
UterinCeontentsand LifteDrataforRabbittshat DiedorAborted
Table 3. Table 4. Table 5. Table 6.
Table 7.
NecropsyObservation-sSummary
MaternaBlody Weights-Summary MaternaBlodyWeightChanges-Summary
MaternaAlbsoluteFeed ConsumptionValues (g/day-)Summary MaternaRlelativFeeed ConsumptionValues (g/kg/da-yS)ummary
Table 8. Table 9.
Caesarean-SectioniOnbgservation-sSummary
LifteOrbservation(sCaesarean-Delivered
Fetuses)-Summary
Table 10. Table 11. Table 12. Table 13. Table 14.
FetalAlteration-s Summary FetalGross ExternalAlteration-sSummary FetalSoftTissue Alteration-s Summary FetalSkeletalAlteration-s Summary FetalOssificatioSnites- Caesarean-Delivered LiveFetuses (Day 29 ofGestation)- Summary
Table 15.
ClinicaOlbservations - IndividuaDlata vi
PAGE 111-10 111-12
A-1
B-1
B-3 B-5 B-6 B-8
B-9
B-10 B-11
B-12 B-13 B-14 B-1 5
B-17
B-22 B-23
PAGE SUBJECT
Table 16. Table 17. Table 18.
Necropsy Observations- IndividuaDlata
Maternal Body Weights - IndividuaDlata
MaternalFeed Consumption Values IndividuaDlata
B-35 B-41 B-56
Table 19. Caesarean-SectioningObservations- B-71 IndividuaDlata
Table 20. LifteOrbservations(Caesarean-Delivered
Fetuses)- IndividuaDlata
B-77
Table 21. FetalSex, VitalStatusand Body Weight -
IndividuaDlata
B-83
Table 22. FetalAlteration-sIndividuaDlata APPENDIX C - PROTOCOL AND AMENDMENT
B-95 C-1 to C-31
APPENDIX D - DEVIATIONS FROM THE PROTOCOL AND THE
STANDARD OPERATING PROCEDURES OF THE
TESTING FACILITY
D-1
APPENDIX E - TEMPERATURE AND RELATIVE HUMIDITY REPORTS AND DEVIATIONS REPORT
APPENDIX F - PILOT REPORT
APPENDIX G - HISTORICAL CONTROL DATA
APPENDIX H - STATEMENT OF THE STUDY DIRECTOR
APPENDIX
I- QUALITY ASSURANCE STATEMENT
UNIT FINAL REPORT
E-1 to E-4 F-1 to F-98 G-1 to G-15
H-1 1-1to 1-4
vii
418-010:PAGE 1-1
TITLE:
ORAL (STOMACH TUBE) DEVELOPMENTAL STUDY OF N-ETFOSE IN RABBITS
TOXICITY
ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-010 SPONSOR'S STUDY NUMBER: 6316.8
1. SUMMARY
AND CONCLUSION
A. Meth-ods@
Twenty-two New Zealand White [Hra:(NZV4)SPF]
timed-pregnant female rabbits
were assignedtoeach offivedosage groups (Groups IthroughV). Nineteen
additionaflemale rabbitswere assigned to one offivedosage groups forthe
satellitsetudy(threef,ive,three,threeand fiverabbitsassignedto Groups I
throughV, respectively)T.he testarticleN,-ETFOSE, orvehicle,2% Tween@ 80
inReverse Osmosis Membrane Processed DeionizedWater (R.O. Deionized
Water),was administeredorally(viastomach tube)once dailyto these naturally-
bred rabbitson days 7 through20 of presumed gestation(DGs 7 through 20).
Dosages of 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day were administeredata
dosage volume of 5 mukg, adjusteddailyon the basisofthe individuablody
weights.
The female rabbitswere observed forviabilitayt leasttwiceeach day ofthe study. The rabbitswere alsoexamined forclinicaolbservationsofeffectsofthe testarticlea,bortions,premature deliverieasnd deaths beforeand approximately 60 minutes afterdosage and once dailyduringthe postdosage period.Body weightswere recordedon DG 0,the day ofarrivaaltthe TestingFacilitaynd on DGs 7 through 29. Feed consumption values were recordeddailyafterarrivaalt
the TestingFacility.
On DG 21, toxicokinetiscamples were collectedfrom the satellitreabbits assigned tothe toxicokinetiecvaluation.Blood samples were collectedfrom the inferiovrena cava and centrifuged.The resultingserum was shipped tothe
a. Detaileddescriptionosf allproceduresused inthe conduct ofthisstudyare providedinthe appropriatesectionsofthisreportand inAPPENDIX C (PROTOCOL AND AMENDMENT).
418-010: PAGE 1-2
Sponsor foranalysis.The livewras excised,weighed and a sample was taken from the rightlateralobeand shipped to the Sponsor foranalysis.Rabbitswere Caesarean-sectionedand fetuseswere examined grosslytothe extentpossible as describedforrabbitsassigned to the main study. Fetuses and placentae were pooled by liftesrhipped tothe Sponsor foranalysis.
On DG 29, rabbitsinthe main study were sacrificedC,aesarea n-sectionedand a gross necropsy ofthe thoracica,bdominal and pelvicviscerawas performed. The number of corporaluteaineach ovary was recorded.The uteruswas excisedand examined forpregnancy,number and distributiofn implantations, earlyand lateresorptionsand liveand dead fetuses.Each fetuswas identified, weighed and examined forgross externalalterationsA.llfetuseswere examined internalltyo identifsyex and visceralalterationsc;avitatedorgans were evaluated by dissectiona;nd the brainwas cross-sectionedand examined insitu.All fetuseswere examined forskeletalalterationasfterstainingwith alizarin red S.
B. Results
No compound-related deaths occurred during the study. One, two and fivedoes abortedand were sacrificeidnthe 0 (Vehicle)2,.5 and 3.75 mg/kg/day dosage groups,respectivelyT.hese abortionsoccurredatthe end ofor afterthe completionofthe dosing period.The abortionsinthe 2.5 and 3.75 mg/kg/day dosage groups were consideredrelatedto the testarticlbeecause they occurred atdosage-dependent incidencesinthe two highestdosage groups. Allother rabbitsurviveduntilscheduled sacrificoen gestationday 29 (DG 29).
Increasednumbers of does inthe 0.1,1.0,2.5 and 3.75 mg/kg/day dosage groups had observationsofabnormal stool(no,scant,and softor liquidfeces). Allotheradverse clinicaolbservationswere consideredunrelatedtothe test article.
One 3.75 mg/kg/day dosage doe had a pale livetrhatwas consideredpossibly relatedtothe testarticlbeecause itoccurredina highdosage group.
Groups administeredthe 1.0,2.5 and 3.75 mg/kg/day dosages ofthe testarticle had statisticalsliygnificanrteductionsinbody weight gain or body weight losses on DGs 7 to 10 and 10 to 13. Reflectingthese effectsofthe testarticleb,ody weight gains were significantrleyduced inthe 2.5 and 3.75 mg/kg/day dosage groups forthe entiredosage period.The 2.5 and 3.75 mg/kg/day dosage groups had significantrleyduced body weights on DGs 14 through25.
418-010:PAGE 1-3
Absoluteand relativfeeed consumption values were significantrleyduced at severaltabulatedintervaldsuringthe dosage periodinthe 2.5 and/or 3.75 mg/kg/day dosage groups. Reflectingthese effectsofthe testarticlet,he 3.75 mg/kg/day dosage group had significantrleyduced absoluteand relative feed consumption valuesforthe entiredosage period.
The liftearverages forlateresorptionswere increasedinthe 2.5 and 3.75 mg/kg/day dosage groups. These increasesinthe number of late resorptionswere consideredtreatment-relatebdecause they occurredat the two highestdosages. No grossexternal,softtissueor skeletalfetalalterations (malformationsor variationsw)ere caused by dosages ofthe testarticlaes high as 3.75 mg/kg/day.
C. Conclusion
On the basis ofthese data,the maternal no-observable-effect-lev(eNlOEL) of N-ETFOSE is0.1 mg/kg/day (the1.0 mg/kg/day and higherdosages caused statisticaslilgynificanrteductionsinbody weight gains orweight lossesand the 2.5 and 3.75 mg/kg/day dosages also significantrleyduced absoluteand relative feed consumption values).The developmentalNOEL is1.0mg/kg/day (the2.5 and 3.75 mg/kg/day dosages caused increasedincidencesof lateresorptions and abortions).Based on these data,N-ETFOSE should not be identifieads a selectivedevelopmental toxicantt;he compound was notfound to be teratogenic inthe rabbit.
MildredS. ChristianP,h.D.,Fellow,ATS
Date
ExecutiveDirectorof Research
@Q --'- ----------4----------------------- - -------- -
Alan M. Hoberman, Ph.D.,DABT
Date
Directorof Research
I
------------------
-oonntcdi-GG. Yo
D., DABT
,;A@sssooccii@aateeD:ieir-le-ccott !@rr-e-R@-@esearch and
Study Director
99
Date
418-010:PAGE 11-1
li. DESCRIPTION OF TEST PROCEDURES
A. Conduct of Study:
A.I. Sponso: 3M Corporate Toxicology,3M Center Building220-2E-02, St.Paul, Minnesota 55144-1000
A.2. Testing Facilily: Argus Research LaboratoriesI,nc.,905 Sheehy Drive,BuildingA, Horsham, Pennsylvania 19044-1297
A.3. Study Numbe
418-010
A.4. Sponsor's Study Number:
6316.8
A.S. Purpose otibp Study: The purpose ofthisstudywas to detectadverse effectsofN-ETFOSE on New Zealand White [Hra:(NZW)SPF] presumed pregnantfemale rabbitsand development ofthe embryo and fetusconsequent to exposure ofthe doe from implantatiotnoclosureofthe hard palate.This studywas designed to evaluate ICH Harmonised TripartitGeuidelinestages C and D ofthe reproductiveprocess ina nonrodent species.
A.6. Study Desicin: The requirementsofthe InternationaClonference on Harmonisation (ICH)
HarmonisedTripartiGtueideline(w)ere used asthebasisforstudydesign.
A.7. Regulato!y ComRiiance: The study was conducted in compliance with Good Laboratory Practice (GLP) regulationosf the U.S. Food and Drug Administratio(nFDA)(')t,he Japanese Ministryof Healthand Welfare(MHW)(')and the European Economic Community (EEC)(')T.here were no deviationfsrom the GLP regulationtshataffectedthe qualityof integritoyfthe study. QualityAssurance Unitfindingsderivedfrom the
418-010:PAGE 11-2
inspectionsduringthe conduct ofthisstudy are documented and have been providedto the Study Directorand the TestingFacilitmyanagement.
A.8. Ownership of the Styjy: 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. (Directorof LaboratoryOperations) Joseph W. Lech, B.S.(Team Leader - General Laboratory) Betsy J.Kerns,B.S. (LaboratoryTechnician)
A.13. Report Preparation: Raymond G. York,Ph.D.,DABT Jo Ann Frazee,M.S. (StudyCoordinator) Susan K. Bradshaw, B.S. (DataManagement 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 (ExecutiveDirectorof Research)
A.15. Date Protocol Signed:
11 August 1998
418-010:PAGE 11-3
A.16. Date 5 of Technical Performance:
Rabbit ArrivalDate Dosage Period [Days 7 through20 of presumed gestation(DGs 7 through20)] ToxicokinetiScample Collectio(nDG 21) Caesarean-SectioningPeriod(DG 29)
28 AUG 98
30 AUG 98 - 16 SEP 98 17 SEP 98
21 SEP 98 -25 SEP 98
A.17. Records Maintained:
The originarleport,raw data and reservesamples ofthe testarticlaend vehicle are retainedinthe archivesofArgus Research LaboratoriesI,nc.Any preserved tissuesare retainedinthe archivesofthe TestingFacilitfyorone year afterthe mailingofthe draftfinalreport,afterwhich time the Sponsor willdecide theirfinal dispositionA.llunused testarticlseuspensionswere discardedatthe Testing FacilityU.nused bulktestarticlweillbe returnedto the Study Monitorupon completionof allwork withthe testarticle.
B. Test ArticleInfoEmation: B.I. Description:
N-ETFOSE - a waxy solid
B.2. Lot/BatchNumber: FM-3929 [30035,30037, 30039 (Expiratiodnate:May 2000)]
B.3. Date Received and Storage Conditions: The testarticlweas receivedon 20 May 1998, and storedatroom temperature.
B.4. SpecialHandling Instructions:
Standard safetyprecautions(use ofprotectivcelothingg,loves,dust-mist respirators,afetygoggles or safetyglassesand a face-shieldw)ere taken when handlingthe bulktestarticlaend prepared suspensions.
B.5. Analysis of Puritt:
Informationregardingthe identityc,omposition,strength,purityand stabilitoyf the testarticlieson filweiththe Sponsor.
418-010:PAGE 11-4
C. VehicleInformation:
C.I. Description: 2% TweenO 80 inReverse Osmosis Membrane Processed Deionized Water (R.O.DeionizedWater).
C.2. Lot Numbers:
M03HO5 and L06662 C.3. Date Received and Storaue Condifions: The Tween(& 80 was receivedon 22 May 1998 and 8 July1998 (lotM03HO5) and 1 September 1998 (lotL06662),from J.T.Baker,PhillipsburgN,ew Jersey, and storedatroom temperature.R.O. DeionizedWater isavailablefrom a continuoussource atthe TestingFacilitaynd ismaintainedat room temperature.
C.4. SpecialHandling Instructions: Standard safetyprecautions(use ofprotectivcelothingg,loves,dust-mist respirators,afetygoggles or safetyglassesand a face-shieldw)ere taken when handlingthe vehicle.
C.5. Analysis of Purity: Neitherthe Sponsor nor the Study Directorwas aware ofany potential contaminants likeltyo be presentinthe vehiclethatwould interferweiththe resultsofthisstudy. D. Test ArticlePreparation: Suspensions of N-ETFOSE were prepared dailyatconcentrationsof0, 0.02,0.2, 0.5 and 0.75 mg/mL. Prepared formulationswere storedatroom temperature.
418-010:PAGE 11-5
D.I. Sample Information:
Sample Type
Components
Concentration (alllevels) BulkTest Article Reserve VehicleReserve
N/A
N/A
TweenOD 80 (lotM03HO5)
Tween(& 80 (lotL06662) R.O. Deionized
Water
Size 2 mLl Ig 5 mL 5 mL 5mL
Date Retained 30 AUG 9811 16 SEP 98c 03 SEP 98
Storage Conditions Frozen (dryice) Room temperature
03 SEP 98 Room t mperature
09 SEP 98 Room temperature
03 SEP 98 Room temperature
Shipped To
Sponsor
Testing Facility Archives Testing Facility Archives Testing Facility Archives Testing Facility Archives
Date Shipped 31 AUG 98 16 SEP 98 01 OCT 98
01 OCT 98
ol OCT 98
01 OCT 98
N/A = Not applicable a. Duplicatesamples were taken from thefirsatnd lastpreparationon the day prepared. One sample ofeach setwas
shipped tothe Sponsor foranalysis.The remainingsamples were retainedattheTesting Facilitays backups.
b. Firstpreparation. c. Last preparation.
Homogeneity and stabilitoyfprepared formulationsare on filewiththe Sponsor.
D.2. AnalvticalResults:
Concentrationsamples (2 mL) were taken on the firsatnd lastdays suspensions were prepared. Analyses were performed by 3M EnvironmentalTechnology and SafetyServices.The resultsofthese analyses have not yet been forwardedto the TestingFacility.
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
418-010:PAGE 11-6
E.S. RationaleforTest System:
The New Zealand White [Hra:(NZW)SPF] rabbitwas selectedas the Test System because: 1)itisone non-rodentmammalian speciesacceptedand widelyused throughouttheindustrfyornonclinicasltudiesof developmental toxicit(yembryo-fetatloxicity/teratogeni2c)ithyi)s;strainofrabbithas been demonstratedtobe sensitivteodevelopmentaltoxins;3)historicdaalta and experienceexistattheTestingFacility(5-7;)and 4) thetestarticlies pharmacologicallayctiveinthespeciesand strain.
E.6. Test System Data:
Number of Rabbits Approximate Date of Birth ApproximateAge atArrival Weight(kg)on DG 0 Weight (kg)atArrival
129 28 FEB 98,07 MAR 98, 28 MAR 98
5 -6 months 2.8-4.4 2.9-4.2
E.7. Method ofRandomization:
Upon arrivarla,bbitwsereassignedtoindividuhaolusingon thebasisof computer-generatedrandom units.Rabbitswere assignedtoone offivedosage groups (GroupsIthroughV),22 rabbitpser dosage group,forthe main portionof the study.An additiona1l9 satellirtaebbitswere assignedfortoxicokinetic evaluationf;iverabbitswere assignedtoeach ofthe low and highdosage groups (Groups 11and V),and threerabbitswere assigned to each ofthe remaining dosage groups (Groups 1,111and IV).Rabbitswere assignedto dosage groups usinga computer-generated(weight-orderedr)andomizationprocedurebased on body weightsrecordedby and atthe Supplier(Covance Research Products, Inc.)on DG 0.
E.8. System of Identification:
Each rabbitwas individualildyentifiweidtha Monel@)self-piercienagrtag (Gey Band and Tag Co.,Inc.,No. MSPT 20103) inscribewdiththe rabbit'dsesignated unique permanent number. Cage tagswere marked withthestudynumber, permanent rabbitnumber, sex,testarticliedentificatiaonnd dosage level.
418-010:PAGE 11-7
F. Husband!y:
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 conditionsof positiveairflowrelativeto a hallwayand independentlysuppliedwitha minimum oftenchanges per hour of 100% freshairthathad been passed through99.97% HEPA filter(sAiroCleans rooms). Room temperatureand humiditywere monitoredconstantltyhroughout thestudy.Room temperaturewas targetedat61OF to72"F (160C to22'C); relativheumiditywas targetedat 30% to 70%. See APPENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORTS).
F.3. Housing:
Rabbitswere individualhloyused. Allcage sizesand housingconditionasre in compliancewiththe Guide forthe Care and Use ofLaboratoryAnimals(8).
F.4. Lighting:
An automatically-controlflleudorescenltightcyclewas maintainedat 12-hours light1:2-hoursdark,witheach dark periodbeginningat 1900 hours EST.
F.5. Sanitization:
Cage pan linerwsere changed approximatelythreetimeseach week. Cages were changed approximatelyevery otherweek.
F.6. Feed:
Approximately150 g of CertifieRdabbitChovvS #5322 (PMI Nutrition InternationaSlt,.Louis,Missouriw)as availablteoeach rabbiteach day untitlhe firsdtay of dosage,atwhich timeapproximately180 g ofthesame certifiefdeed was offeredtoeach rabbiteach day. The certifiefdeedwas availablferom individuasltainlessteel"J-typef"eedersattachedto each cage.
F.7. Feed Analysis:
Analyses were routinelpyerformedby thefeed supplier.No contaminantsat levelsexceedingthemaximum concentratiofnorcertifiefdeedor deviationsfrom
418-010:PAGE 11-8
expectednutritionraelquirementswere detectedby theseanalyses. Copies of theresultsofthefeed analysesare availableintheraw data.
Neitherthe Sponsor northeStudy Directorwas aware ofany agent presentin thefeed thatwas known to interferweiththe resultsofthisstudy.
F.8. Water:
Localwaterthathad been processed by passage througha reverseosmosis membrane (R.O.water)was availabletothe rabbitsad libitufmrom an automatic wateringsystem (individusailppertubes).Chlorinewas added tothe processed water as a bacteriostat.
F.9. Water AnaiyiLs:
The processedwater isanalyzedtwiceannuallyforpossiblechemical contamination(LancasterLaboratoriesL,ancaster,Pennsylvania)and monthly forpossiblebacteriaclontamination(AnalyticaLlaboratoriesI,nc.C,halfont, Pennsylvania).Copies ofthe resultosfthewateranalysesare availablienthe raw data,
Neitherthe Sponsor northeStudy Directorwas aware ofany agent presentin thewater thatwas known to interferweiththeresultsofthisstudy.
G. Methods:
G.I. Dosage Administration:
Dosage Group
Number of Rabbits
Dosage Concentration Dosage (mg/kg/day) (mg/mL) Volume
(mukg)
Assigned RabbitNumbers Main Study Satellite
Studya
I
22+3a
0 (Vehicle)
0
11
22+5a
0.1
0.02
111
22+33
1.0
0.2
IV
22+3a
2.5
0.5
v
22+58
3.75
0.75
5 18572-8593 8682-8684
5
8594-8615 8685-8689
5
8616-8637 8690-8692
5
8638-8659 8693-8695
5 8660-8681 8696-8700
The testarticlweas considered100% pureforthepurposeofdosage calculations.
a. Rabbitsassigned totoxicokineteivcaluation.
G.2. RationaleforDosage Selection:
Dosages were selectedon thebasisofa dosage-rangestudy[ArgusResearch LaboratoriesI,nc.P,rotocol418-010P (seeAPPENDIX F)I.
418-010: PAGE 11-9
Inthe418-010P study,severe maternalbody weight lossoccurredinthe 10,25, 50 and 75 mg/kg/day dosage groups;therewere no survivingrabbitsinthese groups. Abortionsoccurredinthe 5 and 10 mglkg/day dosage groups. Caesarean-sectionobservationsrevealedincreasedlateresorptionsand reduced fetalbody weightsat 5 mg/kg/day. Increasesinearlyresorptionswere found at 1 mg/kg/day; however,therewas no decrease inmean liftesrize. G.3. Route ofAdministration: Oral(stomach tube) G.4. RationaleforRoute 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.5. Frequency of Administration: Appropriatedosages ofthe testarticloer vehiclewere administeredorally(via stomach tube)once dailyto naturally-brerdabbitson DGs 7 through 20a. Dosages of0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day ofthe testarticlweere administeredata dosage volume of5 mukg, adjusteddailyon the basisofthe individuablody weightsrecordedbeforeintubationT.he rabbitswere intubated atapproximatelythe same timeeach day. G.6. Length of Study: Approximately4 weeks
a . See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1.
418-010:PAGE 11-10
G.7. Method of Study Performance:
The female rabbitswere naturallybred by breeder male rabbitsofthe same source and strainbeforeshipment tothe TestingFacilityT.he rabbitswere mated on fiveconsecutivedays and shipped to the TestingFacilitoyn the day afterthe lastday of mating. The day of mating was consideredto be DG 0. A computer-generated(weight-orderedr)andomizationprocedurewas used to assignthe rabbitsto fivedosage groups based on body weights recorded on DG 0 and suppliedby Covance Research Products,Inc.
Allrabbitswere observed forviabiliattyleasttwiceeach day ofthe study and for generalappearance atleastonce duringacclimation.Additionalexaminations forclinicaolbservationsofeffectsofthe testarticlea,bortions,premature deliverieasnd deaths were made beforeeach dailyintubatio(nDGs 7 through 20) and approximately60 minutes afterintubatiodnuringthe dosage period. These observationswere alsomade once dailyduringthe postdosage period (DG 21 through29).
Body weights were recordedon DG 0,the day of arrivaaltthe TestingFacility and on DGs 7 through29. Feed consumption valueswere recorded dailyafter arrivaaltthe TestingFacility.
G.8. Gross Necroppy:
G.8.a. SatelliteRabbits Assigned to Toxicokinetic Sample Collection:
On DG 21 (theday followingthe lastdosage),toxicokinetiscamples were collectedfrom the rabbitsassignedto thetoxicokinetiecvaluation.Following anesthesiawithpentobarbitalb,lood samples (approximately4 mL per rabbit) were collectedfrom the inferiovrena cava intoserum separatortubes and centrifuged.The resultinsgerum (approximately2 mL) was immediatelyfrozen on dry iceand maintainedfrozen(-70'C)untislhipment tothe Sponsor for analysis.The liverwas excised,weighed, and a sample was taken from the right lateralobe,frozenand retainedat-700C untilshipment to the Sponsor for analysis.
Rabbitswere Caesarean-sectionedand fetuseswere examined grosslytothe extentpossible,as describedforrabbitsassignedto the main study. Fetuses and placentaewere pooled by liftearnd retainedfrozen(-700C)untilshipment to the Sponsor foranalysis.
Aftercompletionofsample collections,erum, livesrections,fetaland placental samples were shipped (frozenon dry ice)to 3M EnvironmentalTechnology and SafetyServices,St.Paul,Minnesota.
418-01 O:PAGE 11-11
G.8.b. Scheduled Sacrifice:
Allsurvivingrabbitswere sacrificedby intravenous injectionof Beuthanasia&D Specialeuthanasiasolutionon DG 29. The rabbitswere Caesarean-sectioned and a gross necropsy ofthe thoracic,abdominal and pelvicviscerawas performed. Gross lesionswere preservedinneutralbuffered10% formalinfor possiblefutureevaluation(withthe exceptionof parovariancysts,which are common, spontaneous lesionsinrabbits)a;llothertissueswere discarded.
The number ofcorporaluteaineach ovarywas recorded.The uteruswas excised and examined forpregnancy, number and distributionf implantations, earlyand lateresorptionsand liveand dead fetuses.Uterifrom does that appeared nonpregnant were stainedwith 10% ammonium sulfideto confirmthe absence of implantatiosnites(9A)n. earlyresorptionwas definedas one inwhich organogenesis was notgrosslyevident.A lateresorptionwas definedas one in which the occurrenceoforganogenesis was grosslyevident.A livefetuswas definedas a term fetusthatresponded to mechanicalstimuli.Nonresponding term fetusesare consideredto be dead (therewere no dead fetuses).Dead fetusesand lateresorptionsare differentiatbeyd the degree of autolysispresent; marked to extreme autolysisindicatedthatthe fetuswas a lateresorption.
Each Caesarean-deliveredfetuswas weighed, examined forgross external alterationasnd individualildyentifiewditha tag notingstudy number, lifter number, and uterinedistributioLni.vefetuseswere sacrificebdy an intraperitoneailnjectioonfBeuthanasiaO-D Special.Allfetuseswere examined internalltyo identifsyex and visceralalterationcsa;vitatedorgans were evaluated by dissection(laon)d; the brainwas cross-sectioned(asinglecross-sectiownas made between the parietaalnd the frontablones) and examined in situ.Fetal gross lesionswere preservedinneutralbuffered10% formalinforpossiblefuture evaluation.
Allfetuseswere examined forskeletalalterationasfterstainingwith alizarin red S(").Skeletalpreparationswere retainedinglycerinwiththymol added as a preservative.Late resorptionwsere examined to the extentpossible. Representativephotographs offetalalterationasre availableinthe raw data.
Rabbitsthatdied or were sacrificebdecause ofabortionor premature delivery were examined forcause ofdeath on the day the observationwas made. Pregnancy statusand uterinecontentswere recorded.Aborted fetusesand/or deliveredpups were examined to the extentpossible,using the same methods described forfetuses.
418-010:PAGE 11-12
G.9. StatisticalAnalyses: The followingschematic representsthe statisticanlalyses of the data: Tyt)eofTesta
1. ParametriCb A. Bartlett'Tsestd
F-
Significant at p!@0.05
I Not Significant
li.Nonparametricc
A. Kruskal-WalliTsest (:g75%ties)
Significant at p:@0.05
Not Significant
I
Nonp arametric AnalysisofVariance
I
Dunn's Test
F- Significant
I
-1 Not Significant
B. Fisher'sExact Test
at p:@0.05
(>75% ties)
I Dunneft'sTest
I11.Test forProportionData
Variance Test forHomogeneity ofthe BinomialDistribution
- --- -------
a. Statisticalsliygnificanptrobabilitieasre reportedas eitherp:@0.05or p.-@0.01. b. Used onlytoanalyze data withhomogeneity ofvariance. c. Proportiondata are notincludedinthiscategory. d. Test forhomogeneity ofvariance.
418-010:PAGE 11-13
Clinicaolbservationand otherproportiondata were analyzed usingthe Variance Test forHomogeneity ofthe BinomialDistributi(o1n2)
Continuousdata (e.g.,maternalbody weights,body weightchanges, feed consumption values and liftearverages forpercentmale fetuses,percent resorbedconceptuses,fetalbody weights,fetalanomaly data and fetal ossificatiosnitedata)were analyzed using BartieftT'esst of Homogeneity of Variances"')and the AnalysisofVariance(14),when appropriate[i.e.B,artieft's Testwas not significan(tp>0.05)].Ifthe AnalysisofVariancewas significant (p:@0.05)D,unneft'sTest(")was used to identiftyhe statisticsailgnificancoefthe individuaglroups. IftheAnalysisofVariance was notappropriate[i.e.B,artiefts Testwas significan(tp!50.05)t]h,e Kruskal-WalliTs6st(")was used, when less than or equal to 75% tieswere present;when more than 75% tieswere present, Fisher'sExact Test(17w)as used. incases inwhich the Kruskal-WalliTsest was statisticaslilgynifican(tp:50.05)D,unn's Method of MultipleComparisons('8w)as used to identiftyhe statisticsailgnificancoefthe individuaglroups.
Count data obtained atCaesarea n-sectioningwere evaluatedusing the procedurespreviouslydescribedforthe Kruskal-WalliTsest(").
418-010:PAGE 111-1
111. RESULTS
A. Mortalily, Abortions, Clinical and Necropsy Observations
(Summaries
-Tables land 3: Individual Data -Tables 2. 15 an 16)
A.l. Mortalily
No deaths were attributable to ETFOSE. The only death occurred in a vehicle controlgroup doe, an event attributablteo an intubationaccident.Vehicle controlgroup doe 8587 was found dead approximatelyone hour afterthe seventhdailydosage on gestationday 13 (DG 13). No otheradverse clinical observationsoccurredinthisdoe. This doe lostweight afterDG 9 and itsfeed consumption was reduced afterDG 10. Necropsy ofthe doe revealeda perforatio(n0.5cm x 0.1 cm) inthe rightdiaphragmaticlung lobe;allother tissuesappeared normal. The liftecronsistedof eightfetuses thatappeared normal fortheirdevelopmentalages at gross externalexamination.
A.2. Abortions
One, two and five**does abortedatthe end of or afterthe completionofthe dosage period(on DGs 19,20, 21, 23, 26 or 29) inthe 0 (Vehicle)2,.5 and 3.75 mg/kg/day dosage groups,respectivelyT.he abortionsinthe 2.5 and 3.75 mg/kg/day dosage groups were consideredeffectsofthe testarticle because the incidenceswere dosage-dependent.
0 (Vehicle)mg/kq/dgy
Doe 8581 abortedon DG 26, sixdays afterthe lastdosage was administered. No otheradverse clinicaolbservationsoccurredinthisdoe, and itsbody weight gain and feed consumption were comparable to othercontrolgroup does. No gross lesionswere revealedby necropsy ofthe doe. The littecronsistedof nine lateresorptionsa;utolysisofthese specimens precludedfurtherevaluation.
2.5 mg/kg/day
Doe 8647 abortedon DG 21, one day afterthe lastdosage was administered. Additionaladverse clinicaolbservationsinthisdoe includedscantfeces (DGs 14 to 21),softor liquifdeces(DGs 16 to20) and red substance incage pan (DG 21). Thisdoe generallylostweightand had severelyreduced feed consumption afterDG 7. No gross lesionswere revealedby necropsy ofthe doe. The littecronsistedoftwo lateresorptionsa,nd two dead and nine livefetuses. Autolysisprecludedevaluationofthe lateresorptions.The liveand dead fetuses
Significantdliyfferenftrom the vehiclecontrolgroup value(p:50.01).
418-010:PAGE111-2
appearednormalfortheidrevelopmentaalges atgrossexternaalnd softissue examinationT.en oftheelevenfetuseshad notossifiepdubesatskeletal examination.
Doe 8652 abortedon DG 26,sixdaysaftetrhelasdtosagewas administered. Additionaadlverseclinicoablservatioinnsthisdoe includeadredperioral substance(DG 8)thatwas probablayssociatewdithan intubatipornoblem,no fecesincage pan (DGs 12,22 and 24),softorliquifdeces(DGs 13 to21),scant feces(DGs 13 to21,23,25 and 26)and ungroomedcoat(DGs 14to15 and 20 to21).Thisdoe loswteightand had severelryeducedfeedconsumptioanfter DG 10.No grosslesionwsererevealebdy necropsyofthedoe. The lifter consisteodftwolivfeetuseso,ne dead fetusand one lateresorptioTnh.e fetuseasnd thelateresorptiaopnpearednormalfortheidrevelopmentaalgesat grossexternaslo,ftissuaend skeletaelxaminations.
3.76mg/kg/day
Doe 8660 abortedon DG 20 beforeadministratoifotnhe14thdaildyosage. Additionaadlverseclinicoablservationisnthisdoe includesdoftorliquifdeces (DGs 8 to10),ungroomedcoat(DGs 8 to11),scantfeces(DGs 11 to14and 16),no fecesincage pan (DGs 15 and 17to19),tanperianaslubstance (DG 19)and redsubstanciencage pan (DG 20).Thisdoe generalllyoswteight and had severelryeducedfeedconsumptioanfteDrG 7. No grosslesionwsere revealebdy necropsy.The liftceornsisteodfthreedead and sevenlivfeetuses. Allfetuseasppearednormalfortheidrevelopmentaalgesatgrossexternal examinationS.ofttissuaend skeletaelxaminationwserenotperformedue to theearlydevelopmentaalgesofthefetuses.
Doe 8661abortedon DG 23,threedaysaftetrhelasdtosagewas administered. Additionadlverseclinicoablservationisnthisdoe includesdoftorliquifdeces (DGs 10to12),scantfeces(DGs 11 to15 and 21 to23),localizaeldopecioan theundersid(eDGs 11to23),no fecesincage pan (DGs 16to20),ungroomed coat(DGs 20 to23)and redsubstanceincage pan (DG 23).Thisdoe generally loswteightand had severelryeducedfeedconsumptioanfteDrG 7. No gross lesionwsere revealebdy necropsyofthedoe. The liftceornsisteodfsixlive fetuseso,ne dead fetusandtwo lateresorptionOsn.e fetuswas edematousat grossexternaelxaminatioanl;lotherfetuseasppearednormalfortheir developmentaalgesatgrossexternaelxaminationA.llfetuseasppearednormal atsoftissuexaminationA.llfetusehsad notossifiepdubesand one ofthese fetuseaslsohad splirtibsatskeletaelxamination.
Doe 8663 abortedon DG 26,sixdaysaftetrhelasdtosagewas administered Additionaadlverseclinicoablservationisnthisdoe includesdoftorliquifdeces (DGs 11 and 13to15),scantfeces(DGs 11 to19,21 and 25),ungroomedcoat (DGs 13 to15 and 25)and nofecesincage pan (DGs 20 and 22 to24).This
418-010:PAGE 111-3
doe generallylostweightand had severelyreduced feed consumption. After DG 7. No gross lesionswere revealedby necropsy ofthe doe. The litter consistedof nine dead fetusesand one lateresorptionA.utolysisprecluded evaluationofthe lateresorption.Allabortedfetuseswere partiallcyannibalized but,withinthe limitosfevaluation,appeared normal fortheirdevelopmental ages atgrossexternaland softtissueexaminations. Seven ofthe fetuseshad not ossifiedpubes and one ofthese fetusesalso had splirtibsat skeletal examination.
Doe 8667 abortedon DG 19, afterthe 13th dailydosage was administered. Additionaladverse clinicaolbservationsinthisdoe includedscant feces(DGs 12 and 14 to 19) and red substance incage pan (DG 19).Thisdoe generallylost weight afterDG 7, and itsfeed consumption was severelyreduced afterDG 10. No gross lesionswere revealedby necropsy ofthe doe. The liftecronsistedof fourfetusesthatappeared normal fortheirdevelopmentalages atgross external examination.Softtissueand skeletalexaminationswere not performed due to the earlydevelopmental ages ofthe fetuses.
Doe 8669 abortedon DG 29, nine days afterthe lastdosage was administered. Additionaladverse clinicaolbservationsinthisdoe includedscant feces (DGs 11 to 17,20 and 23 to 26),softor liquifdeces (DGs 13 and 15 to 16) and no feces incage pan (DGs 18 to 19,21 to22 and 27 to 28). Thisdoe generallylost weightthroughoutthe studyand feed consumption was severelyreduced after DG 9. No gross lesionswere revealedby necropsy. The littecronsistedoften lateresorptionsthatwere too autolyzedforfurtherevaluation.
A.3. ClinicalObservations
The incidencesof scant,orsoftor liquidfetuseswere increasedindoes inthe 0.1,1.0,2.5 and 3.75 mg/kglday dosage groups;the incidenceofscant feces was significan(tp:!@0.0i1n)these fourdosage groups. No feces inthe cage pan alsooccurredinone, one and six**does inthe 1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyA.dditionaladverse clinicaolbservations attributablteothe testarticloeccurred indoes thatabortedand includedred substance inthe can pan inone doe inthe 2.5mg/kg/day and threedoes inthe 3.75 mg/kg/day dosage group and a tan perianalsubstance inone doe inthe 3.75 mg/kg/day dosage group.
Allotheradverse clinicaolbservationswere consideredunrelatedtothe test articlbeecause the incidenceswere not dosage-dependent. These observations includeda red perioraslubstance,localizedalopeciaon the limbs,neck and/or underside,ungroomed coat,lacrimatioannd a scab or mass on the hindpaws.
Significantdliyfferenftrom the vehiclecontrolvalue(p:50.01).
418-010P:AGE 1114
A.4. NecropsyObservations
One 3.75mg/kg/daydosagedoe (8662)thathad a palelivetrhatwas consideredpossiblyrelatedto the testarticlbeecause itoccurredina high dosage group rabbit.Controlrabbit8587 had a perforatioinnthe right diaphragmaticlung lobe as the resultofan intubatioenrror,as previously described.
B. Maternal Body Weights and Body Weight Changes (Figure 1; Summaries -Tables 4 and 5: IndividualData -Table 17)
Groups administeredthe 1.0,2.5 and 3.75 mg/kg/day dosages ofthe testarticle had statisticaslilgynifican(tp--,0.0o5r p:@0.01)reductionsinbody weight gains or body weight losseson DGs 7 to 10 and 10 to 13 (2.5and 3.75 mg/kg/day only), as compared tothe controlgroup values. Reflectintghese effectsof the test articleb,ody weight gains were significantrleyduced (p!gO.01)inthe 2.5 and 3.75 mg/kg/day dosage groups forthe entiredosage period(calculatedas DGs 7 to 21).
The 2.5 and 3.75 mg/kg/day dosage groups had significantrleyduced (p:@0.05or p:@0.01)body weightson DGs 14 through 25, as compared withthe controlgroup values.
Body weightsand body weight gains were unaffectedby the 0.1 mg/kg/day dosage ofthe testarticle.
C. Maternal Absolute (giday) and Relative (g/kgiday) Feed Consumption Values (Summaries -Tables 6 and 7: IndividualData - Table 18)
Absolute(g/day)and relativ(eg/kg/dayf)eed consumptionvalueswere reduced duringthe dosage periodinthe 2.5 and/or 3.75 mg/kg/day dosage groups. These reductionswere significan(tp:50.05orp:@0.01)forabsolutefeed consumption values on DGs 10 to 13 and 13 to 16 inthe 2.5 mg/kg/day dosage group and DGs 7 to 10, 10 to 13 and 13 to 16 inthe 3.75 mg/kg/day dosage group. Significanrteductions(p:50.05orp:!@0.01i)nrelativfeeed consumption valuesoccurredon DGs 10 to 13 and 13 to 16 inthe 3.75 mg/kg/day dosage group.
Reflectingthese effectsofthe testarticlet,he 3.75 mg/kg/day dosage group had significantrleyduced (p:@0.01a)bsoluteand relativfeeed consumption values for theentiredosage period(calculateads DGs 7 to21).
Feed consumption values were unaffectedby dosages ofthe testarticlaes high as 1.0 mg/kg/day.
418-010:PAGE 111-5
D. Caesarea i-Sectionin_qand LitterObservations (Summaries -Tables 8 and 9: in lividualData -Tables 19 throuqh 211
Pregnancy occurred in 18 (81.8%), 20 (90.9%), 20 (90.9%), 21 (95.4%) and 21 (95.4%) rabbitsineach dosage group. Caesarean-sectioningobservations on DG 29 were based on 16,20, 20, 19 and 16 pregnant rabbitsineach of the fiverespectivedosage groups. One, two and fivedoes aborted inthe 0 (Vehicle)2,.5 and 3.75 mg/kg/day dosage groups,respectivelya,nd one vehiclecontrolgroup rabbitwas found dead on DG 13.
The liftearverages forlateresorptionwsere increasedinthe 2.5 and 3.75 mg/kg/day dosage groups. These increasesinthe number of late resorptionswere consideredtreatment-relatebdecause they occurred atthe two highestdosages.
No biologicalliymportantor statisticaslilgynificandtifferencesoccurred inthe littearverages forcorporalutea,implantationsl,ivefetuses,totalor early resorptionsand fetalbody weights.There were no dead fetuses,no does with allconceptuses resorbed.Allplacentaeappeared normal.
E. Fetal Alterations (Summaries - Tables 10 through 14: Individual Data - Table 22)
Fetal alterationswere defined as: 1) malformations (irreversiblcehanges that occur atlow incidencesinthisspeciesand strain)a;nd 2) variation(scommon findingsinthisspecies/straina,nd reversibldeelays or accelerationsin development). Liftearverages were calculatedforspecififcetalossificatiosnites as partofthe evaluationofthe degree offetalossification.
Fetalevaluationswere based on 133, 167, 165, 141 and 129 DG 29 Caesareandeliveredlivefetusesin16,20, 20, 19 and 16 lifterisnthe 0 (Vehicle)0,.1,1.0, 2.5 and 3.75 mg/kg/day dosage groups,respectivelyE.ach fetuswas examined forgross external,softtissueand skeletalalterationasnd fetalossificatiosnite averages.
E.I. Summa!y of FetalAlterations(Summa!y -Table 10; IndividualData Table 221
Combination of malformationsand variationsresultedinthe followingincidences forfetalalterationsI.nthe 0 (Vehicle)0,.1,1.0,2.5and 3.75 mg/kg/day dosage groups,respectively1,0 (62.5%),11 (55.0%),10 (50.0%),12 (63.2%)and 9 (56.2%) lifterhsad fetuseswithone or more alterationosbserved. Inthese same respectivedosage groups,the totalnumbers offetuseswith any identified alteratiownesre 23 (17.3%),22 (13.2%),29 (17.6%),23 (16.3%)and 14 (10.8%). One ormore alterationosccurredinaverages of 17.0%, 13.6%,
418-010:PAGE 111-6
16.5%, 16.1% and 11.7% ofthe fetusesper lifteirnthe fiverespectivedosage groups.
No grossexternal,softtissueor skeletalfetalalteration(smalformationsor variationsw)ere caused by dosages ofthe testarticlaes high as 3.75 mg/kg/day. There were no dosage-dependent or significandtifferencesinthe lifteorrfetal incidencesof any gross external,softtissueor skeletalalterations.
E.2. FetalGross ExternalAlterations(Summary -Table 11: Individual Data -Table L21
E.2.a. Malformations
Controlgroup fetus8586-8 had a shorttrunkand absent tailatgross external examination.Softtissueexaminationrevealedfused,displacedand small kidneysand situsinversus.Skeletalexaminationofthisfetusrevealedfused 1st through4th sternalcentra,fusionofthe xiphoidand 4th sternalcentrum,only six thoracicvertebraepresent,no ossificatioonfthe centraand arches ofthe 5th and 6ththoracicvertebrae,fused 4th and 5th leftribs,an extraossificatiosnite attachedtothe 6th ribsand absence ofalllumbar,sacraland caudal vertebrae.
One fetusinthe 2.5 mg/kg/day dosage group (8644-5)had a shortsnoutwitha protrudingtongue as the onlyalteration.
High dosage group (3.75mg/kg/day)fetus8665-8 had an edematous neck,a shortsnout witha protrudingtongue and smallears atgross external examination.Softtissueexaminationrevealedno additionaallterations. Skeletalexaminationofthisfetusrevealedfused 3rd and 4th sternalcentraand angulated alae ofthe hyoid.
E.2.b.Variations
One 0.1 mg/kg/day dosage group fetus(8600-11)had a distended abdomen. Softtissueand skeletalexaminationsrevealedno otheradditionalalterations.
E.3. FetalSoftTissueAlterations(Summary -Table 12: IndividualData Table 22)
E.3.a.Malformations
Externallmyalformed controlgroup fetus8586-8 had fused,displacedand small kidneysand situsinversus.Thisfetushad a shorttrunkand absent taialtgross externalexamination and associatedskeletalmalformations,as previously described.
418-010:PAGE 111-7
Small and fused lung lobes occurredinone 2.5 mg/kg/day dosage group fetus (8646-1).This fetushad common truncusarteriousas the onlyotheralteration.
Allothersofttissuemalformationshave been previouslydescribed.
E.3.b. Variations
E.3.b.i.E X-es
One controlgroup fetus(8579-4),one 0.1 mg/kg/day dosage group fetus (8597-8)and one 2.5 mg/kg/day dosage group fetus(8646-2)had a circumcornealhemorrhage ofone or both eyes, a variationgenerallyattributable totrauma duringprocessing.Fetus 8597-8 also had absence ofthe intermediate lobe ofthe lungs. No otheralterationosccurred inthese fetuses.
E.3.b.2.Vessels
Common truncusarteriosuosccurredinone 2.5 mg/kg/day dosage group fetus (8646-1).This fetusalsohad lung malformations,as previouslydescribed.
E.3.b.3.Lungs
Absence ofthe intermediatelobe ofthe lungsoccurred in2, 5,1, 1 and 4 fetuses from 2,4, 1, 1 and 4 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyO.ne ofthe 0.1 mg/kg/day dosage group fetuses (8597-8)also had circumcornealhemorrhage of the righteye, as previously described.One ofthe 3.75 mg/kg/day dosage group fetuses(8672-6)also had a variatioinnskullossificatio(ninternasalf)u,sed sternalcentraand misaligned caudal vertebrae.
E.3.b.4.Kidneys
The leftkidney was displacedcaudallyin 12, 1,17 and 5 fetusesfrom 2, 1,2, and 2 litterisnthe 0 (Vehicle)0,.1,1.0 and 2.5 mg/kg/day dosage groups. The externallmyalformed vehiclecontrolgroup fetusalso had fused and small kidneys,as previouslydescribed.Another vehiclecontrolgroup fetus(8590-8) also had a variatioinnskullossificatio(ninternasal).
E.3.b.5.Hindlimb
The skinwas constricteodn the righthindlimbofone 3.75 mg/kg/day dosage group fetus(8673-3).No additionaallterationosccurredinthisfetus.
418-010:PAGE 111-8
E.4. Fetal Skeletal Alterations (Summaries -Tables 13 and 14: Individual Data - Ta )le22)
E.4.a.Malformations
E.4.a.l.Vertebrae/Ribs/Sternum
Externallymalformed vehiclecontrolgroup fetus8586-8 had skeletal malformationsofthe sternum,vertebraeand ribsrelatedtothe observationsofa shorttrunkand absent tailatgross externalexamination.The lstthrough4th sternalcentrawere fused,fusionofthe xiphoidand 4th sternalcentrum,only six thoracicvertebraepresent,absent ossificatioonfthe centraand arches ofthe 5th and 6th thoracicvertebrae,fused 4th and 5th leftribs,an extraossification siteattachedto6th ribsand absence ofalllumbar,sacraland caudal vertebrae.
E.4.a.2.Thoracic Vertebrae/Ribs
Interrelatevdertebral/rmiablformationor malformationsofthe thoracicvertebrae and ribsoccurredinone 0 (Vehicle)mg/kg/day,two 1.0mg/kg/day and one 3.75 mg/kg/day dosage group fetuses.These types ofvertebral/rib malformationsare relativelcyommon atmaternallytoxicdosages inrabbitsand generallyconsideredto be secondary to maternalstress('gE)a.ch ofthese fetusesisdescribed below.
Fetus 8582-8 (vehiclecontrolgroup) had a smallleftarch and unilateral ossificatio(nlefto)fthe centrum of the 1Oth thoracicvertebraand fusionofthe 1Oth and 11th ribs
Fetus 8625-5 (1.0mg/kg/day dosage group)had fused centraofthe 8thand 9th thoracicvertebrae,a bifidcentrum inthe 9th thoracicvertebraand fused 8th and 9th rightribs.
Fetus8628-8 (1.0mg/kg/day dosage group)had only11 thoracicvertebraeand 11 ribspresent;the 7th rightriband the 8th leftribwere split.
Fetus8670-1 (3.75mg/kg/day dosage group)had a righthemivertebrapresent as the 12ththoracicvertebraand a split10th leftrib.
E.4.a.3.Lum )arVertebrae
One 0.1 mg/kg/day dosage group fetus(8612-6)had a righthemivertebra, presentbetween the 6th and 7th lumbar vertebrae,as the onlyalteration.
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E.4.a.4. Caudal Ve brae
Misaligned caudal vertebrae occurred in three 0.1mg/kg/day dosage group fetusesand 1 3.75 mg/kg/day dosage group fetus. One 0.1 mg/kg/day dosage
group fetusand the 3.75 mg/kg/day dosage group fetushad additionaslkeletal alterationsa,s previouslydescribed.
E.4.b. Variations
E.4.b.l.Skull
Common small irregularitiensossificatioonfthe skull("[)thepresence of small ossificatiosniteswithinthe suturesor calvaria(nasal,frontaolr parietablones) and/orirregulasrhaping or fusionofthe bones] occurredin5,4, 4, 5 and 2 fetusesin5, 3,4,4 and 2 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyI.rregulaorssificationfthe nasal bones (midlinesuturedisplacedor internasaolssificatiosnite)were the most common ofthese smallirregularitiiensossificatiopnatterns,occurringin3,4, 3, 4 and 2 fetusesin3,3, 3,3 and 2 lifterisnthe fiverespectivedosage groups. One ofthe 2.5 mg/kg/day dosage group fetuses(8648-18)also had fused sternal centraand one 3.5 mg/kg/day dosage group fetusalso had fused sternalcentra and misalignedcaudal vertebrae.No otherskeletalalterationosccurredinthese fetuses.
E.4.b.2.Hyoid
One or both alae ofthe hyoidwere angulated in3,4, 1,2 and 6 fetusesin2,4, 1,1 and 4 lifterisnthe 0 (Vehicle)0,.1,1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyO.ne 0.1 mg/kg/day dosage group fetus(8596-1)and two 3.75 mg/kg/day dosage group fetuses(8665-8;8678-7)also had fused sternal centra.Another 0.1 mg/kg/day dosage group fetus(8614-4)also had shorthyoid alae and a misalignedcaudal vertebra.
E.4.b.3.Vertebrae
One 0.1 mg/kg/day dosage group fetus(8601-5)had unilateraolssificatioonfthe centrum ofthe 13ththoracicvertebraas the onlyalteration.
The centrum ofthe 12ththoracicvertebrawas fusedtothe centrum ofthe lst lumbar vertebra;the centrum ofthe 1stlumbar vertebrawas bifidinone 1.0mg/kg/day dosage group fetus(8628-6).
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E.4.b.4.Sternum
Fused 3rd and 4th sternalcentra occurred in1,4,3, 5 and 4 fetuses from 1,4, 1, 3 and 3 lifterisnthe fiverespectivedosage groups. Additionalalterationisn these fetuseswere describedpreviously.
E.4.b.5.Pelvis
Three fetusesfrom two 2.5 mg/kg/day dosage group lifterhsad unossifiedpubes as the onlyalterationT.he significanitncrease(p:50.01i)nthe fetalincidenceof thisalteratiownas consideredunrelatedto the testarticlbeecause itwas not dosage-dependent.
E.4.b.6.Fetal OssificationSiteAverages
The average numbers ofossificatiosnitesinthe hyoid,vertebrae(cervical, thoracicl,umbar,sacraland caudal),ribs,sternum (manubrium, sternalcenters and xiphoid)f,orelimbs(carpalsm,etacarpalsand phalanges)and hindlimbs (tarsalsm,etatarsalsand phalanges)occurredatsimilarincidencesinlifterisnall dosage groups and did not significantdliyffer.
F. SatelliteRabbits (Individual Data - Tables 15 through 20)
One satellitdeoe inthe 1.0 mg/kg/day dosage group and another satellitdeoe in the 3.75 mg/kg/day dosage group abortedand were sacrificed.
Satellitdeoe 8691 aborted on DG 18 afterthe 12th dailydosage was administered.No otheradverse clinicaolbservationsoccurredinthisdoe. This doe lostweight afterDG 16; itsfeed consumption values were unremarkable. No grosslesionswere revealedby necropsy ofthe doe. The liftecronsistedof threeearlyresorptions.
Satellitdeoe 8700 abortedon DG 19 after12 dailydosages had been administered.Additionaladverse clinicaolbservationsinthisdoe includedscant feces(DGs 7, 11, 13 and 17 to 18),no feces incage pan (DGs 12 and 14 to 16), localizeadlopeciaon the underside(DGs 12 to 18) and softor liquifdeces (DG 13). Body weight lossoccurredinthisdoe afterDG 8, and itsfeed consumption was severelyreduced afterDG 10. No gross lesionswere revealed by necropsy ofthe doe. The liftecronsistedoffourdead fetusesand two conceptuses thatwere presumed cannibalized.
Adverse clinicaolbservationsinthe satellitgeroups were similarto those inthe main study groups. Observationsofscant feces and softor liquifdeces occurred inthe 0.1,1,2.5 and/or3.75 mg/kg/day dosage groups. One doe inthe 3.75 mg/kg/day dosage group had observationsofno feces incage pan.
418-01 O:PAGE 111-11
Patternsof body weight gain and feed consumption were generallycomparable tothe rabbitsinthe main studyatthe same dosage levels.Only one rabbitin the 2.5 mg/kg/day dosage group was not pregnant atCaesarean-sectioningon DG 21. Caesarean-sectioningand lifteprarameterswere comparable among the fivedosage groups. One doe inthe 0.1 mg/kg/day dosage group had blackand brown moftiingof the lungs atnecropsy;allotherdoes appeared normal. Average liverweightsforpregnantdoes on DG 21 were 134.4 10.0, 128.9 4.2,106.6 42.2,117.8 35.5 and 109.0 37.5 inthe 0 (Vehicle)0,.1, 1.0,2.5 and 3.75 mg/kg/day dosage groups,respectivelyT.he data forrabbits assigned to the satellitpeortionofthe study are providedinindividuatlables
only.
418-010:PAGE 111-12
REFERENCES
1. U.S. Food and Drug Administratio(n1994).InternationaClonference on Harmonisation;Guidelineon detectionoftoxicittyo reproductionmedicinal products.FederalRegister,September 22, 1994, Vol.59, No. 183.
2. U.S. Food and Drug Administration.Good 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 decisiorilrecommendation on compliance with ptinciplesof 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 oftheteratogenicpotentialofsuspensions oftrinitrofluorenone (TNF) administeredoralltyo New Zealand White rabbits.Toxicologist 2(l):4(0#143).
6. ChristianM,.S. (1984).Reproductivetoxicitaynd teratologyevaluationsof naltrexone(ProceedingsofNaltrexoneSymposium, 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 for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
9. Salewski,E. (1964).Farbemethode zum makroskopischen Nachweis von lmplantationsstellaemn 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.
418-010:PAGE 111-13
12. Snedecor, G.W. and Cochran,W.G. (1967).Variancetestfor homogeneity ofthe binomialdistributionS.tatisticMaelthods, 6th Edition, Iowa StateUniversityPress,Ames, pp. 240-241.
13. Sokal,R.R. and Rohif,F.J.(1969).Bartieftt'esstofhomogeneity of variances.Biometry,W.H. Freeman and Co.,San Francisco,pp. 370371.
14. Snedecor,G.W. and Cochran, W.G. (1967).AnalysisofVariance. StatisticMaelthods,6th EditionI,owa StateUniversitPyress,Ames, pp. 258-275.
15. Dunnett,C.W. (1955).A multiplecomparison procedureforcomparing severaltreatmentswitha control.J.Amer. Stat.Assoc. 50:1096-1129.
16. Sokal, R.R. and Rohif,F.J.(1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389.
17. Siegel,S. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
18. Dunn, O.J.(1964).Multiplecomparisons usingranksums. Technometrics6(3):241-252.
19. Khera,K.S. (1985).MaternaltoxicityA: possibleetiologicaflactorin embryo-fetaldeaths and fetalmalformationsof rodent-rabbistpecies. Teratology31:129-153.
20. 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).
APPENDIX A REPORT FIGURE
MATERNAL BODY WEIGHTS
Figure 1
4.00
3.90
3.80
3.70
3,60
-VI
I X--N-r
3.50
A
X,
A&-
A AL'
3.40
0
7
9
10
11
12
13 14
15 16
1'7 18
19
iO 21
22
23 24
25 216 27
28 2
DAY OF GESTATION
APPENDIX B REPORT TABLES
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE I (PAGE 1): CLINICAL OBSERVATIONS
- SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
487/ 22
S06/ 22
506/22
495/ 22
FOUND DEAD
lb
0
0
0
ABORTED SCANT FECES
SOFT OR LIQUID FECES
NO FECES IN CAGE PAN
LOCALIZED ALOPECIA:
TOTAL LIMBS NECK UNDERSIDE
UNGROOMED COAT
RED SUBSTANCE
IN CAGE PAN
lc 16/ 6
14/ 4
0/ 0
6/ 4 S/ 3 o/ o 4/ 3
11/ 5
0/ 0
0
58/ 13**
40/ 10 0/ 0
14/ 2 0/ 0 0/ 0
14/ 2
14/ S
0/ 0
0
62/ 15**
36/ 10
1
11/ 3 2/ 1 2/ 1 7/ 1
27/ 4
0/ 0
2d,e
ioB/ i6**d,e
si/ ed,e
3/ le
33-/ 4 12/ 2
1/ 1 21/ 2
10/ 3e
1/ id
TAN PERIANAL
SUBSTANCE
0/ 0
0/ 0
0/ 0
0/ 0
RED PERIORAL SUBSTANCE
0/ 0
a/ 0
0/ 0
1/ le
LACRIMATION
0/ 0
2/ 1
0/ 0
2/ 1
- - - -- - - -- - -- - - - - -- - -- - - -- - - - -- - -- - - -- - -- - -- - - -- - - -- - -- - -- - -- - -- - - -- - -- - - -- - -- - - -- - - -- - - -- -- - - -- - -- - - -- - -- -- - -- --
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 8587 was found dead on day 13 of gestation.
C. Doe 8581 aborted on day 26 of gestation.
d. Doe 8647 aborted on day 21 of gestation.
e. Doe 8652 aborted on day 26 of gestation. f. Doe 8660 aborted on day 20 of gestation. g. Doe 8661 aborted on day 23 of gestation. h. Doe 8663 aborted on day 26 of gestation. i. Doe 8667 aborted on day 19 of gestation. j. Doe 8669 aborted on day 29 of gestation. ** Significaintlydifferent from the vehicle control group value (p<0.01).
RABBITS ON DAYS
WITH OBSERVATIONS. 7 THROUGH 29 OF PRES
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 1 (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
487/ 22
506/ 22
506/22
495/ 22
FOUND DEAI)
lb
0
0
0
ABORTED
lc
0
0
2d,e
HINDPAWS: SCAB
0/ 0
0/ 0
7/ 1
0/ 0
HINDPAWS: MASS
0/ 0
0/ 0
4/ 1
0/ 0
----------------------------------------------------------------------------------------------------------------
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 8587 was found dead on day 13 of gestation.
C. Doe 8581 aborted on day 26 of gestation.
d. Doe 8647 aborted on day 21 of gestation.
e. Doe 8652 aborted on day 26 of gestation.
f. Doe 8660 aborted on day 20 of gestation.
g. Doe 8661 aborted on day 23 of gestation. h. Doe 8663 aborted on day 26 of gestation. i. Doe 8667 aborted on day 19 of gestation.
j. Doe 8669 aborted on day 29 of gestation.
Significantly different from the vehicle control group value (p<0.01) .
RABBITS ON DAYS
WITH OBSERVATIONS. 7 THROUGH 29 OF PRES
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 2 (PAGE 1): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT DIED OR ABORTED
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
RABBIT
CORPORA LUTEA
IMPLANTATIONS
EMBRYOS OR FETUSES b
R
DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH
R
L
T
R
L
T
R
L
A
T
R
-----------------------------------------------------------------------------------------------------------------
I 0 (VEHICLE)
8581
ABORTED ON DAY 26 OF GESTATION
5
4
9
5
4
9
0
0
0
0
5
8587
FOUND DEAD ON DAY 13 OF GESTATION
5
4
9
4
4
8
4
4
0
8d
0
0.1
-
-
-
-
-
-
-
-
-
-
-
-
III 1.0
869le
ABORTED ON DAY 18 OF GESTATION
3
5
8
0
3
3
0
0
0
0
0
IV
2.5
0647
ABORTED ON DAY 21
6
7
13
6
7
13
4
6
1 lif 1
OF GESTATION
8652
ABORTED ON DAY 26 OF GESTATION
8
6
14
2
2
4
1
1
1
3g
0
v 3.75
8660
ABORTED ON DAY 20 OF GESTATION
6
4
10
6
4
10
4
3
3 loh
0
8661
ABORTED ON DAY 23
0
3
11
6
3
9
5
1
1
7i
1
OF GESTATION ----------------------------------------------------------------------------------------------------------------
R = RIGHT
L = LEFT A = ABORTED
T = TOTAL
a. Dosage occurred on day 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages.
C. Late resc)rptions unless otherwise noted.
d. Viability of fetuses unable to be determined because of
e. Doe 8691 was a satellite animal.
f. Litter 8647 had two dead fetuses.
g. Litter 8652 had one dead fetus.
h. Litter 8660 had three dead fetuses.
i. Fetus 8661-6 had edema on the dorsal and ventral neck.
maternal
death.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 2 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT DIED OR ABORTED
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP DOSAGE (MG/KG/DAY)a
RABBIT NUMBER
DAY OF DEATH
CORPORA LUTEA
R
L
T
IMPLANTATIONS
R
L
T
EMBRYOS OR FETUSES b
R
R
L
A
T
R
-----------------------------------------------------------------------------------------------------------------
v 3.75
8663
ABORTED ON DAY 26 OF GESTATION
8
4
12
7
3
10
0
0
9
9d
0
8667
ABORTED ON DAY 19 OF GESTATION
2
3
5
2
2
4
1
1
2
4
0
8669
ABORTED ON DAY 29 OF GESTATION
5
6
11
4
6
10
0
0
0
0
4
8700e
ABORTED ON DAY 19
6
1
7
5
1
6
0
0
4
4f
0
OF GESTATION
----------------------------------------------------------------------------------------------------------------
R = RIGHT
L = LEFT A = ABORTED
T = TOTAL
a. Dosage occurred on day 7 through 20 of gestation.
b. Conceptuses appeared normal for developmental ages.
C. Late resorptions unless otherwise noted.
d. All fetuses were partially cannibalized.
e. Doe 8700 was a satellite animal.
f. Two aborted conceptuses were presumed to have been cannibalized.
PROTOCOL 418-010; ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TA.BLE 3 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
RABBITS EXAMINED b
N
22
22
22
22
FOUND DEAD
N
Ic
0
0
0
ABORTED
N
id
0
0
2e,f
APPEARED NORMAL
N
21
22
22
22
LUNGS: RIGHT DIAPHRAGMATIC
LOBE, PERFORATION
N
lc
0
0
0
LIVER: PALE
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 15) for external observations confirmed at necrop
C. Doe 8587 was found dead on day 13 of gestation. d. Doe 8581 aborted on day 26 of gestation.
e. Doe 8647 aborted on day 21 of gestation.
f. Doe 8652 aborted on day 26 of gestation. g. Doe 8660 aborted on day 20 of gestation. h. Doe 8661 aborted on day 23 of gestation. i. Doe 8663 aborted on day 26 of gestation. j. Doe 8667 aborted on day 19 of gestation. k. Doe 8669 aborted on day 29 of gestation. ** Significantly different from the vehicle control group value (p@0.01).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 4 (PACE 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
18
20
20
21
MATERNAL BODY WEIGHT (KG)
DAY
0
MEA.N+S. D.
3.43 + 0.33
3.40 + 0.27
3.42 + 0.30
3.40 + 0.32
DAY
7
DAY
8
MEA.N+S. D. MEAN+S.D.
3.55 + 0.34 3.59 + 0.33
3.50 + 0.29 3.51 + 0.25
3.51 + 0.26 3.53 + 0.27
3.50 + 0.30 3.50 + 0.31
DAY
9
ME"+S.D.
3.60 + 0.32
3.54 + 0.26
3.54 + 0.28
3.50 + 0.30
DAY 10
MEAN+S. D.
3.64 + 0.32
3.54 + 0.27
3.53 + 0.29
3.48 + 0.31
DAY 11
MEA.N+S.D.
3.66 + 0.34
3.55 + 0.26
3.54 + 0.28
3.47 + 0.32
DAY 12
MEAN+S.D.
3.67 + 0.35
3.56 + 0.27
3.54 + 0.28
3.47 + 0.31
DAY 13
MEA@N+S.D.
3.70 + 0.36
3.58 + 0.29
3.57 + 0.29
3.46 + 0.30
DAY 14
MEAN+S.D.
3.74 + 0.37 ( 17]b
3.61 + 0.28
3.61 + 0.28
3.47 + 0.30*
DAY 15
MEA14+S.D.
3.77 + 0.39 1 17]b
3.66 + 0.28
3.64 + 0.29
3.49 + 0.30**
DAY 16
MEAN+ S. D.
3.81 + 0.38 t 17)b
3.68 + 0.26
3.66 + 0.30
3.50 + 0.32**
DAY 17
MEAN+S. D.
3.79 + 0.36 [ 17]b
3.68 + 0.28
3.65 + 0.28
3.50 + 0.30**
DAY 18
MEAN+S.D.
3.78 + 0.36 [ 17]b
3.68 + 0.28
3.64 + 0.29
3.52 + 0.30*
DAY 19
MEA34+S.D.
3.80 + 0.35 t 17)b
3.69 + 0.28
3.65 + 0.29
3.51 + 0.30**
DAY 20
ME"+S.D.
3.82 + 0.35
3.71 + 0.28
3.67 + 0.28
3.51 + 0.32**
1 17]b
----------------------------------------------------------------------------------------------------------------
DAY = DAY 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.
Significantly different from the vehicle control group value (p<O.OS) .
Significantly different from the vehicle control group value (p<0.01).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 4 (PAGE 2): 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
18
20
20
21
INCLUDED IN ANALYSES
N
17b
20
20
21
MATERNAL DAY
BODY WEIGHT 21
(KG) MEAN+S.D.
3.86 + 0.33
3.74 + 0.28
3.71 + 0.28
3.52 + 0.34**
DAY 22
MEAN+S.D.
3.86 + 0.35
3.77 + 0.29
3.72 + 0.29
3.58 + 0.30*
DAY 23 DAY 24 DAY 25 DAY 26
MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D.
3.87 + 0.35 3.89 + 0.35 3.90 + 0.36 3.93 + 0.35
3.79 + 0.30 3.81 + 0.31 3.84 + 0.32 3.85 + 0.34
3.74 + 0.29 3.75 + 0.29 3.78 + 0.30 3.78 + 0.31
3.60 + 0.31* 3.62 + 0.32* 3.64 + 0.32* 3.67 + 0.33
DAY 27
MEAN+S.D.
3.94 + 0.36
3.85 + 0.35
3.80 + 0.33
3.72 + 0.29
DAY 28
MEAN+S.D.
3.93 + 0.36
3.85 + 0.36
3.81 + 0.33
3.73 + 0.29
DAY 29
MEAN+S.D.
3.96 + 0.35
3.87 + 0.37
3.84 + 0.33
3.76 + 0.29
----------------------------------------------------------------------------------------------------------------
DAY - DAY OF GESTATION
a. Dosage occurred on days 7 through 20 of gestation.
b. Excludes values for rabbits that died or aborted. Significantly different from the vehicle control group value (p:SO.05)
Significantly different from the vehicle control group value (p:So.ol).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 5 (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
18
20
20
21
MATERNAL BODY WEIGHT CHANGE
(KG)
DAYS 0 - 7
MEA.N+S.D.
+0.13 + 0.17
+0.10 + 0.15
+0.10 + 0.11
+0.10 + 0.09
DAYS 7 - 10
MEAN+S.D.
+0.08 + 0.08
+0.05 + 0.10
+0.01 + 0.08*
-0.03 + 0.11*
DAYS 10 - 13
MEAN+S.D.
+0.06 + 0.07
+0.03 + 0.07
+0.04 + 0.06
-0.01 + 0.11**
DAYS 13 - 16
MEAN+S.D.
+0.10 + 0.06
+0.10 + 0.05
+0.09 + 0.07
+0.03 + 0.10
I 17)b
DAYS 16 - 19
MEAN+S.D.
+0.00 + 0.07
+0.01 + 0.06
+0.00 + 0.09
+0.01 + 0.11
( 17)b
DAYS 19 - 21
MEAN+S.D.
+0.05 + 0.10
+0.05 + 0.03
+0.05 + 0.04
+0.01 + 0.06
[ 17]b
DAYS 21 - 24
MEAN+S.D.
+0.04 + 0.10
+0.07 + 0.07
+0.04 + 0.07
+0.06 + 0.07
1 17]b
I 20]b
DAYS 24 - 29
MEAN+S.D.
+0.05 + 0.14
+0.06 + 0.12
+0.08 + 0.12
+0.11 + 0.07
1 16]b
I lg)b
DAYS 7 - 21
MEAN+S.D.
+0.31 + 0.17
+0.24 + 0.14
+0.20 + 0.17
+0.01 + 0.32**
[ 17]b
DAYS 21 - 29
MEAN+S.D.
+0.09 + 0.18 [ 16)b
+0.14 + 0.14
+0.13 + 0.17
+0.18 + 0.09 [ 19)b
DAYS 7 - 29
MEAN+S.D.
+0.39 + 0.19 1 16]b
+0.38 + 0.21
+0.32 + 0.23
+0.26 + 0.26 [ 19]b
DAYS 0 - 29
MEAN+S.D.
+0.49 + 0.19
+0.48 + 0.27
+0.42 + 0.26
+0.36 + 0.26
( 16]b
[ 19]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.
Significantly different from the vehicle control group Significantly different from the vehicle control group
value value
(p@0.05). (p,!EO.01)
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE
6 (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
18
20
20
21
14ATERNAL FEED
CONSUMPTION
(G/DAY)
DAYS 7 - 10
MEAN+S.D.
163.5 + 28.2
165.1 + 24.6
147.8 + 45.3
135.8 + 52.6
DAYS 10 - 13
MEAN+S.D.
158.7 + 22.2
153.8 + 27.2
131.7 + 46.4
103.4 + 65.9*
[ 17)b
[ 19]c
DAYS 13 - 16
MEAN+S.D.
162.2 + 22.3
156.4 + 35.6
139.4 + 54.9
97.1 + 73.6*
( 17]b
DAYS 16 - 19
MEAN+S.D.
146.5 + 40.1
148.6 + 50.8
144.5 + 61.6
117.5 + 74.8
[ 17)b
DAYS 19 - 21
MEAN+S.D.
149.2 + 32.4
155.4 + 39.7
147.1 + 52.9
130.4 + 65.0
( 17]b
[ 20]b
DAYS 21 - 24
MEAN+S.D.
138.2 + 28.3
148.7 + 36.1
134.7 + 51.3
130.7 + 55.9
( 17]b
[ 20]b
DAYS 24 - 29
MEAN+S.D.
116.6 + 48.2
117.4 + 41.4
117.8 + 45.4
128.1 + 33.6
[ 16)b
[ 18)b,c
DAYS
7 - 21
MEA.N+S.D.
157.0 + 24.4
156.0 + 28.8
142.4 + 45.0
119.7 + 58.1
( 17)b
( 20)b
DAYS 21 - 29
MEAN+S.D.
124.7 + 36.8
129.1 + 35.5
124.3 + 45.0
130.9 + 37.7
( 16]b
[ 18]b,c
DAYS
7 - 29
MEAN+S.D.
144.9 + 19.9
146.2 + 26.6
135.8 + 41.1
124.5 + 46.6
1 16]b
( 18)b,c
---------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION [ I = NUMBER OF VALUES AVERAGED a. DOBage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. C. Excludes values that were associated with spillage or wet feed.
Significantly different from the vehicle control group value (p@S0.05) Significantly different from the vehicle control group value (p@S0.01)
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 7 (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
18
20
20
21
MATERNAL
FEED
CONSUMPTION
(G/KG/DAY)
DAYS
7 - 10
MEAN+S.D.
4S.8 + 9.0
47.2 + 8.0
41.8 + 12.2
39.0 + 15.0
DAYS 10 - 13
MEAN+S.D.
43.3 + 5.9 [ 17]b
43.2 + 6.8
37.1 + 12.6 i igic
29.8 + 18.9
DAYS 13 - 16
MEAN+S-D.
43.4 + 6.6
43.4 + 10.3
38.5 + 15.0
21.4 + 20.5
1 17]b
DAYS 16 - 19
MEAN+S.D.
38.8 + 11.1
40.4 + 13.4
39.6 + 16.8
33.3 + 21.3
[ 17]b
DAYS 19 - 21
MEAN+S.D.
39.2 + 8.7 1 17]b
41.8 + 10.0
39.9 + 14.4
36.4 + 18.2 [ 201)b
DAYS 21 - 24
MEAN+S.D.
36.0 + 8.1 [ 17]b
39.3 + 8.8
35.9 + 13.5
35.9 + 14.8 ( 20]b
DAYS 24 - 29
MEAN+S.D.
29.7 + 12.3
30.0 + 9.6
30.7 + 11.1
34.6 + 8.5
[ 16)b
( 18)b,c
DAYS
7 - 21
MEAN+S.D.
42.4 + 7.2
43.3 + 7.8
39.6 + 12.2
34.1 + 16.3
( 17)b
( 20]b
DAYS 21 - 29
MEAN+S.D.
32.0 + 9.8
33.5 + 8.1
32.7 + 11.2
35.6 + 9.5
[ 16]b
( 18)b,c
DAYS
7 - 29
MEAN+S.D.
38.3 + 6.0
39.6 + 6.4
37.0 + 10.8
34.8 + 12.6
( 16]b
( 18]b,c
---------------------------------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION f I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. c. Excludes values that were associated with spillage or wet feed.
Significantly different from the vehicle control group value (p<0.05) significantly different from the vehicle control group value (p<0.01) .
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 8 (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 FOUND DEAD ABORTED
N(t) N(%) N(%)
18( 81.8) 1( 5.6) 1( 5.6)
20( 90.9) 0( 0.0) 0( 0-0)
20( 90.9) o( o.o) 0( 0-0)
21( 95.4) 0( 0-0) 2( 9.5)
RABBITS PREGNANT AND CAESAREAN-SECTIONED ON DAY 29 OF GESTATION CORPORA LUTEA IMPLANTATIONS LITTER SIZES
LIVE FETUSES
DEAD FETUSES RESORPTIONS
EARLY RESORPTIONS
N MEAN+S.D. MEAN+S.D. MEAN+S.D.
N MEAN+S.D.
N MEAN+S.D.
N MEAN+S.D.
16 10.9 +
9.0 + 8.3 +
133 8.3 +
0 0.7 +
10 0.6 +
2.3 1.8 2.2 2.2
1.8 1.8
20 10.8 +
8.6 + 8.4 +
167 8.4 +
0 0.3 +
4 0.2 +
2.0 2.0 2.0 2.0
0.9 0.7
20 10.3 +
8.6 + 8.2 +
165 8.2 +
0 0.3 +
3 0.2 +
2.3 1.9 1.9 1.9
0.7 0.4
19 9.4 + 7.8 + 7.4 +
141 7.4 +
0 0.4 +
1 0.0 +
3.8 3.1 2.2 2.2
1.2 0.2
LATE RESORPTIONS
N MEAN+S.D.
1 0.1 + 0.2
2 0.1 + 0.4
3 0.2 + 0.7
6 0.3 + 1.0
DOES WITH ANY RESORPTIONS
N(t)
3( 18.8)
2( 10.0)
4( 20.0)
2( 10.5)
DOES WITH ALL CONCEPTUSES
RESORBED
N(t)
0( 0.0)
o( o.o)
0( 0.0)
0( 0.0)
DOES WITH VIABLE FETUSES
N(t)
16(100.0)
20(100.0)
20(100.0)
19(100.0)
PLACENTAE APPEARED NORMAL
N (t)
16(100.0)
20(100.0)
20(100.0)
19(100.0)
- -- - - -- - -- -- - - - - -- - -- - - - - - -- - -- - - - --- - -- - -- - - -- - - -- - - -- - -- -- - - -- - -- - -- - - - -- - - -- - - -- - - -- -- - - -- - - -- - - - -- - - ----- -- -
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 9 (PAGE 1): LITTER OBSERVATIONS
(CAESAREAN-DELIVERED
FETUSES) - SUMMARY
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
-----------------------------------------------------------------------------------------------------------------
LITTERS WITH ONE OR
MORE LIVE FETUSES
N
16
20
20
19
IMPLANTATIONS
MEAN+S.D.
9.0 +
1.8
8.6 +
2.0
8.6 +
1.9
7.8 + 3.1
LIVE FETUSES
N MEA.N+S.D.
133 8.3 + 2.2
167
8.4 +
2.0
165 8.2 + 1.9
141 7.4 + 2.2
LIVE MALE FETUSES
N
65
85
77
76
t LIVE MALE FETUSES/LITTER
MEAN+S.D.
46.6 + 20.0
51.0 + 11.8
48.3 + 16.3
52.9 + 21.2
LIVE
FETAL BODY WEIGHTS (GRAMS)/LITTER
MALE FETUSES
FEMALE FETUSES
MEAN+S.D. MEAN+S.D. MEAN+S.D.
40.17 + 12.51
40.37 + 12.68 1 15]b
39.50 + 12.77
43.37 + 5.25 43.36 + 5.51 43.55 + 5.26
42.54 + 4.50 43.70 + 5.08 42.02 + 4.70
41.54 + 7.87
41.07 + 7.08 [ 18]c
41.66 + 8.18
t RESORBED
CONCEPTUSES/LITTER
MEAN+S.D.
6.9 + 18.3
3.1 +
9.8
3.3 +
8.8
2.6 +
7.7
----------------------------------------------------------------------------------------------------------------
fI a. b. c.
= NUMBER OF VALUES Dosage occurred on Litter 8582 had no Litter 8655 had no
AVERAGED days 7 through male fetuses. male fetuses.
20 of gestation.
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 10 (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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
-----------------------------------------------------------------------------------------------------------------
LITTERS WITH ANY ALTERATION
FETUSES WITH OBSERVED
N(%)
10( 62.5)
ll( 55.0)
10( 50.0)
12( 63.2)
FETUSES WITH ANY
ALTERATION
OBSERVED
N(%)
23( 17.3)
22( 13.2)
29( 17.6)
23( 16.3)
t FETUSES WITH ANY
ALTERATION/LITTER
MEAN+S.D.
17.0 + 25.2
13.6 + 16.5
16.5 + 29.8
16.1 + 18.2
----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 11 (PAGE 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
-----------------------------------------------------------------------------------------------------------------
SNOUT:
SHORT
LITTER INCIDENCE
FETAL INCIDENCE
N(t) N(%)
o( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
o( o.o) 0( 0.0)
1( 5.3) 1( 0.7)
ABDOMEN: LITTER FETAL
DISTENDED INCIDENCE
INCIDENCE
N(t) N(t)
0( 0-0) 0( 0.0)
1( 5.0) 1( 0.6)
0( 010) 0( 0.0)
0( 0.0) 0( 0.0)
TRLTNK: SHORT LITTER INCIDENCE FETAL INCIDENCE
N(%) N (%)
1( 6.2) 1( 0.8)c
0( 0-0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
TAIL: ABSENT LITTER INCIDENCE FETAL INCIDENCE
N
1( 6.2)
N
1( 0.8)c
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
BODY. EDEMA LITTER INCIDENCE FETAL INCIDENCE
N N(%)
0( 0.0) 0( 0-0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
EARS: SMALL
LITTER INCIDENCE
N(%)
o( o.o)
0( 0.0)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N (!k)
0( 0.0)
0( 0-0)
0( 0.0)
o( o.o)
- - - -- - - -- - -- - - - -- - - -- - -- - - - -- -- - - - -- -- - -- - - - -- - - -- - -- - -- - -- - - -- - -- - - - -- - -- - - -- - -- - -- - -- - - -- - - -- - -- - - -- - -- - - -- -- -
a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 8665-8 had other gross external alterations. C. Fetus 8586-8 had other gross external alterations.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NL7?
TABLE 12 (PAGE
1) : FETAL SOFT TISSUE ALTERATIONS - SUMMARY (See footnotes on the last pacjeof this table.)
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EVALUATED
N
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
EYES: CIRCLTMCORNEAL LITTER INCIDENCE FETAL INCIDENCE
HEMORRHAGE
N (!k) N(t)
1( 6.2) 1( 0-8)
1( 5.0) 1( 0.6)b
0( 0.0) 0( 0.0)
1( 5.3) 1( 0.7)
VESSELS: COMMON TRUNCUS LITTER INCIDENCE FETAL INCIDENCE
ARTERIOSUS N (t) N (t)
o( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 5.3) 1( 0.7)c
LUNGS: SMALL
LITTER INCIDENCE FETAL INCIDENCE
N (t) N (t)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 5.3) 1( 0.7)c
LUNGS: FUSED LITTER INCIDENCE FETAL INCIDENCE
N (t) N(%)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 5.3) 1( 0.7)c
LUNGS: INTERMEDIATE LITTER INCIDENCE FETAL INCIDENCE
LOBE
ABSENT N(t) N(t)
2( 12.5) 2( 1.5)
4( 20.0) 5( 3.0)b
1( 5.0) 1( 0.6)
1( 5.3) 1( 0.7)
KIDNEYS: DISPLACED LITTER INCIDENCE
FETAL INCIDENCE
N N(%)
2( 12.S) 12( 9.0)d
1( S.0) 1( 0.6)**
2( 10.0) 17( 10.3)
2( 10.5) 5( 3.5)*
KIDNEYS: SMALL LITTER INCIDENCE FETAL INCIDENCE
N N(%)
1( 6.2) 1( 0.8)d
0( 0.0) 0( 0.0)
0( 010) 0( 0.0)
0( 0.0) 0( 0.0)
KIDNEYS: FUSED
LITTER INCIDENCE
N(t)
1( 6.2)
0( O.o)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(t)
1( 0.8)d
0( 0.0)
0( 0-0)
0( 0.0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NU@
TABLE 12 (PAGE 2): 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
ABDOMEN: SITUS INVERSUS LITTER INCIDENCE FETAL INCIDENCE
N(t) N(t)
1( 6.2) 1( 0.8)d
0( 0-0) o( o.o)
o( o.o) o( o.o)
0( 0.0) 0( 0.0)
HINDLIMB: SKIN CONSTRICTED
LITTER INCIDENCE
N (1;)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(t)
0( 0.0)
o( o.o)
0( 0.0)
0( 0.0)
----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 8597-8 had other soft tissue alterations.
C. Fetus 8646-1 had other soft tissue alterations.
d. Fetus 8S86-8 had other soft tissue alterations.
Significantly different from the vehicle control group value (p<0.05).
Significantly different from the vehicle control group value (p@SO0.1) .
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUME
TABLE 13 (PAGE
1): FETAL SKELETAL ALTERATIONS
- 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
SKULL - IRREGULAR OSSIFICATION:B
(SUMMARIZATION
OF ALL IRREGULAR OSSIFICATION
OF THE SKULL c; INDIVIDUAL SUBCATEGORIES
CITED BELOW) L'ITTER INCIDENCE FETAL INCIDENCE
N(l) N(%)
S( 31.0) 5( 3.B)
3( 15.0) 4( 2.4)
4( 20.0) 4( 2.4)
4( 21.0) 5( 3.5)
SKULL:
NASAL(S),
(SUMMARIZATION
IRREGULAR OSSIFICATION
OF INTERNASAL;
MIDLINE
DISPLACED) LITTER INCIDENCE
N(%)
FETAL INCIDENCE
N(%)
SUTURE
3( 18.8) 3( 2.2)
3( 15.0) 4( 2.4)
3( 15.0) 3( 1.6)
3( 15.8) 4( 2.8)
SKULL:
NASALS, MIDLINE
LITTER INCIDENCE
FETAL INCIDENCE
SUTURE DISPLACED
N(t)
1(
N(%)
1(
6.2) 0.8)
2( 10.0) 3( 1.8)
1( 5.0) 1( 0.6)
2( 10.5) 3( 2.1)k
SKULL: NASALS, CONTAIN LITTER INCIDENCE FETAL INCIDENCE
AN INTERNASAL N(t) N(!k)
2( 12.S) 2( 1.5)
1( 5.0) 1( 0.6)
2( 10.0) 2( 1.2)
1( 5.3) 1( 0.7)
SKULL:
FRONTALS,
CONTAIN
LITTER INCIDENCE
FETAL INCIDENCE
AN INTERFRONTAL N(%) N(t)
2( 12.5) 2( 1.5)
1( 5.0) 1( 0.6)
1( 5.0) 1( 0.6)
1( 5.3) 1( 0.7)
SKULL - OTHER ALTEPATIONS:B
HYOID:
ALA, ANGULATED
LITTER INCIDENCE
FETAL INCIDENCE
N(%) N(%)
2( 12.5) 3( 2.2)
4( 20.0) 4( 2.4)f,g
1( 5.0) 1( 0.6)
1( 5.3) 2( 1.4)
HYOID:
ALA, SHORT
LITTER INCIDENCE
N(t)
0( 0.0)
1( 5.0)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N(t)
0( 0-0)
1( 0.6)g
0( 0-0)
0( 0-0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 13 (PAGE 2): FETAL SKELETAL ALTERATIONS - 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
-----------------------------------------------------------------------------------------------------------------
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
HEMIVERTEBRA N(%) 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)
THORACIC VERTEBRAE! LITTER INCIDENCE FETAL INCIDENCE
CENTRA,
FUSED N (%) N (t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
2( 10.0) 2( 1.2)h,i
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRUM,
BIFID N (t) N (t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 5.0) 1( 0.6)h
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
11 PRESENT N (%) N (t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 5.0) 1( 0.6)j
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRUM,
UNILATERAL N (%) N (%)
OSSIFICATION 1( 6.2) 1( 0.0)d
1( 5.0) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
6 PRESENT
N (t) N (%)
1( 6.2) 1( 0.8)e
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRLTM,
NOT OSSIFIED
N (t)
1(
N (%)
1(
6.2) 0.8)e
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,
NOT OSSIFIED
N
1(
N
1(
6.2) 0.8)e
0( 0-0) 0( 0.0)
0( 0-0) 0( 0.0)
o( o.o) 0( 0-0)
THORACIC VERTEBRAE:
ARCH, SMALL
LITTER INCIDENCE
N (%)
1( 6.2)
0( 0.0)
0( 0.0)
0( 0.0)
FETAL INCIDENCE
N (%)
1( 0.8)d
0( 0-0)
0( 0.0)
0( 0-0)
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUM
TABLE 13 (PAGE
3): FETAL SKELETAL ALTERATIONS
- 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
LUMBAR VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
CENTRLIM,
BIFID N(t) N (!k)
0( 0.0) 0( 0.0)
o( o.o) 0( 0.0)
1( 5.0) 1( 0.6)i
0( 0.0) 0( 0.0)
LUMBAR VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
HEMIVERTEBRA
N(t) N (!k)
0( 0-0) 0( 0.0)
1( 5.0) 1( 0.6)
0( 0.0) 0( 0.0)
0( 0.0) 0.0)
LUMBAR VERTEBRAE:
0 PRESENT
LITTER INCIDENCE
FETAL INCIDENCE
N(%) N (!k)
1( 6.2) 1( 0.8)e
0( 0.0) o( o.o)
o( o.o) 0( 0.0)
0( 0-0) 0( 0.0)
SACRAL VERTEBRAE:
0 PRESENT
LITTER INCIDENCE
FETAL INCIDENCE
N(%) N(t)
1( 6.2) 1( 0.8)e
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0.0) o( o.o)
CAUDAL VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE
MISALIGNED
CAUDAL VERTEBRAE:
0 PRESENT
LITTER INCIDENCE
FETAL INCIDENCE
N(%) N(%)
N(%) N(%)
0( 0.0) 0( 0.0)
1( 6.2) 1( 0.8)e
2( 10.0) 3( 1-B)g
o( o.o) 0( 0.0)
o( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
o( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
RIBS: SPLIT LITTER INCIDENCE FETAL INCIDENCE
N(%) N(%)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
1( 5.0) 1( 0.6)j
0( 0.0) 0( 0.0)
RIBS: FUSEE) LITTER INCIDENCE FETAL INCIDENCE
N(%) N(%)
2( 12.5) 2( 1.5)d,e
0( 0.0) 0( 0.0)
1( 5.0) 1( 0.6)h
0( 0.0) 0( 0.0)
RIBS: 11 PRESENT
LITTER ]INCIDENCE
N (!k)
0( 0-0)
0( 0.0)
1( 5.0)
0( 0.0)
FETAL INCIDENCE
N(t)
0( 0-0)
0( 0.0)
1( 0 .6) j
0( 0.0)
- - -- - -- - -- - - - - - -- - - -- - -- - - - -- - -- - - - -- -- - - -- - -- - -- - - -- -- - - - -- - -- - - -- - - -- - -- - -- - - - -- - -- - -- - -- - - -- - - - -- - - -- - --- - -- -
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY N
TABLE 13 (PAGE 4): FETAL SKELETAL ALTERATIONS
- 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
16
20
20
19
FETUSES EVALUATED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
RIBS: EXTRA OSSIFICATION LITTER INCIDENCE FETAL INCIDENCE
N(%) N(t)
1( 6.2) 1( 0.8)e
0( 0-0) 0( 0.0)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
STERNAL CENTRA:
FUSED
LITTER INCIDENCE
FETAL INCIDENCE
N(t) N(t)
1( 6.2) 1( 0.8)e
4( 20.0) 4( 2 .4 ) f
1( S.0) 3( 1.8)
3( 15.8) 3.5)k
XIPHOID: LITTER FETAL
FUSED INCIDENCE
INCIDENCE
N(t) N(%)
1( 6.2) 1( 0.8)e
0( 0.0) 0( 0.0)
0( o.o) 0( 0.0)
0( 0.0) 0( 0.0)
PELVIS:
PUBIS, NOT OSSIFIED
LITTER INCIDENCE
N(t)
0( 0-0)
0( 0-0)
0( 0.0)
2( 10.5)
FETAL INCIDENCE
N(t)
o( o.o)
o( O.o)
0( 0.0)
3( 2.1)**
----------------------------------------------------------------------------------------------------------------
PROTOCOL 418-010; ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 13 (PAGE 5) : FETAL SKELETAL ALTERATIONS - SUMMARY
-----------------------------------------------------------------------------------------------------------------
FOOTNOTES: -----------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation. b. Fetuses with alterations of the skull and/or hyoid are not separately identified in this summary table, exce
alterations of other OSBification sites were also present. C. includes all alterations noted for the skull except hyoid, ala, angulated and ala, short. These categories
because these alterations do not result from irregular ossification. d. Fetus 8582-8 had other skeletal alterations. e. Fetus 8586-8 had other skeletal alterations. f. Fetus 0596-1 had other skeletal alterations. g. Fetus 8614-4 had other skeletal alterations. h. Fetus 8625-5 had other skeletal alterations. i. Fetus 8628-6 had other skeletal alterations. j. Fetus 8626-8 had other skeletal alterations. k- Fetus 8648-18 had other skeletal alterations. 1. Fetus 8665-8 had other skeletal alterations. M. Fetus 8670-1 had other skeletal alterations. n. Fetus 8672-6 had other skeletal alterations. o. Fetus 8678-7 had other skeletal alterations.
Significantly different from the vehicle control group value (p<0.01).
PROTOCOL 418-010: ORAL (STOKACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY N
TABLE 14 (PAGE 1) : FETAL OSSIFICATION SITES - CAESAREAN -DELIVERED LIVE FETUSES (DAY 29 OF GESTATION) - SUMMAR
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
0.1
1.0
2.5
----------------------------------------------------------------------------------------------------------------
LITTERS EXAMINED
N
16
20
20
19
FETUSES EXAMINED
N
133
167
165
141
LIVE
N
133
167
165
141
----------------------------------------------------------------------------------------------------------------
OSSIFICATION SITES PER FETUS PER LITTER
HYOID
MEAN+S.D.
1.00 + 0.00
1.00 + 0.00
1.00 + 0.00
0.97 + 0.14
VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL
MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D.
7.00 + 12.77 +
6.22 + 3.00 + 17.04 +
0.00 0.19 0.20 0.00 0.45
7.00 + 12.68 +
6.32 + 3.00 + 17.00 +
0.00 0.30 0.30 0.00 0.37
7.00 + 12.60
6.38 + 3.00 16.90 +
0.00 0.26 0.26 0.00 0.31
7.00 + 12.73 +
6.27 + 3.00 + 16.78 +
0.00 0.26 0.26 0.00 0.37
RIBS (PAIRS)
MEAN+S.D.
12.68 + 0.25
12.62 + 0.28
12.50 + 0.33
12.67 + 0.30
STERNUM MAUUBRILIM STERNAL CENTERS XIPHOID
FORELIMB b CARPALS METACARPALS DIGITS PHALANGES
MEAN+S.D. MEAN+S.D. MEAN+S.D.
MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D.
1.00 + 3.95 + 0.89 +
0.00 0.10 0.14
0.00 + 4.99 + 5.00 + 13.86 +
0.00 0.02 0.00 0.25
1.00 + 3.94 + 0.96 +
0.00 0.09 0.06
0.00 + 4.98 + 5,00 + 13.91 +
0.00 0.04 0.00 0.17
1.00 + 3.88 0.96 +
0.00 0.16 0.14
0.00 + 4.96 + 5.00 13.90 +
0.00 0.16 0.00 0.24
1.00 + 3.92 + 0.83 +
0.00 0.14 0.26
0.00 + 4.95 + 5.00 + 13.84 +
0.00 0.14 0.00 0.26
HINDLIMB b
TARSALS
MEAN+S.D.
2.00 + 0.00
2.00 + 0.00
2.00 + 0.00
1.98 + 0.05
METATARSALS
MEAN+S.D.
4.00 + 0.00
4.00 + 0.00
4.00 0.00
4.00 + 0.00
DIGITS
MEAN+S.D.
4.00 + 0.00
4.00 + 0.00
4.00 + 0.00
4.00 + 0.00
PHALANGES
MEAN+S.D.
12.00 + 0.00
12.00 + 0.00
11.99 + 0.04
11.97 + 0.08
- -- - -- - - -- - -- - - -- - - - -- - - - ---- -- - -- - -- - -- -- - - - -- - -- - - - -- - -- - -- - - -- - - -- - - -- - -- - -- - - - -- - -- - -- - -- - - -- - - -- - - -- - -- - --
a. Dosage occurred on days 7 throucgh 20 of gestation. b. Calculated as average per limb.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
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TABLE 15 (PAGE 1): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8572
DG( 16- 18)
UNGROOMED
COAT
DG( 17- 19)
SOFT OR LIQUID FECES
DG( 17- 20)
SCANT FECES
DG(
23 )
SCANT FECES
DG( 23- 24)
SOFT OR LIQUID FECES
DG( 26- 29) DG( 28- 29)
LOCALIZED LOCALIZED
ALOPECIA: ALOPECIA:
UNDERSIDE
a
LIMBS a
8573
DG(
29
LOCALIZED ALOPECIA:
UNDERSIDE
a
BS74
NO ADVERSE
FINDINGS
857S
NO ADVERSE FINDINGS
8576
NO ADVERSE FINDINGS
8577
NO ADVERSE FINDINGS
8578
NO ADVERSE FINDINGS
8579
NO ADVERSE FINDINGS
8580
DG( 26- 27)
SCANT FECES
8581
DG(
26
ABORTED AND SACRIFICED
BS82
NO ADVERSE FINDINGS
8583
NO ADVERSE FINDINGS
8S84
NO ADVERSE FINDINGS
as8s
DG( 27- 29)
SCANT FECES
DG(
28 )
UNGROOMED
COAT
DG( 28- 29)
SOFT OR LIQUID FECES
8586
DG( 28- 29)
LOCALIZED ALOPECIA:
LIMBS a
DG(
29
SCANT FECES
8587
DG(
13
FOUND DEAD
8588
DG(
29
UNGROOMED
COAT a
BS89
DG( 25- 26)
SCANT FECES
DG( 27- 29)
UNGROOMED
COAT a
DG( 28- 29)
SOFT OR LIQUID FECES
DG( 28- 29)
SCANT FECES
DG(
29
LOCALIZED ALOPECIA:
UNDERSIDE
a
DG(
29
LOCALIZED ALOPECIA:
LIMBS a
8590
NO ADVERSE FINDINGS
8591
DG( 23- 27)
SOFT OR LIQUID FECES
DG( 25- 27)
UNGROOMED
COAT
DG(
28
SCANT FECES
8592
NO ADVERSE FINDINGS
8593
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMI
TABLE 15 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8594
DG( 16- 23)
SCANT FECES
DG( 21- 23)
SOFT OR LIQUID FECES
DG( 28- 29)
UNGROOMED COAT a
DG( 29
SOFT OR LIQUID FECES
DG( 29
SCANT FECES
8595
DG( 21- 25)
SOFT OR LIQUID FECES
DG( 22- 29)
SCANT FECES
DG( 29
SOFT OR LIQUID FECES
8596
NO ADVERSE FINDINGS
8597
NO ADVERSE FINDINGS
8598
NO ADVERSE FINDINGS
8599
DG( 28- 29)
SCANT FECES
8600
DG( 12- 14)
SOFT OR LIQUID FECES
DG( 21- 29)
SOFT OR LIQUID FECES
8601
DG( 24- 29)
SCANT FECES
8602
DG(
17 )
SCANT FECES
DG( 28- 29)
LOCALIZED ALOPECIA: UNDERSIDE a
DG( 28- 29)
SCANT FECES
8603
DG( 19 )
SOFT OR LIQUID FECES
DG( 27- 28)
UNGROOMED COAT
DG( 27- 29)
SOFT OR LIQUID FECES
DG( 27- 29)
SCANT FECES
6604
DG( 7- 8)
UNGROOMED COAT
DG( 14
SOFT OR LIQUID FECES
DG( 18
SOFT OR LIQUID FECES
DG( 21- 22)
LACRIKATION
DG( 26 )
UNGROOMED COAT
DG( 27- 29)
SCANT FECES
8605
DG( 25- 29)
SCANT FECES
8606
DG( 21- 22)
SOFT OR LIQUID FECES
8607
DG( 27- 28)
SOFT OR LIQUID FECES
DG( 27- 28)
SCANT FECES
8608
DG(
19
SOFT OR LIQUID FECES
DG( 20
SCANT FECES
DG( 26- 29)
SOFT OR LIQUID FECES
DG( 26- 29)
SCANT FECES
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION a. observation confirmed at necropsy.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8609
DG( 15 )
SCANT FECES
8610 8611 8612 8613
DG( 26- 27) DG( 24- 29) DG( 16- 18)
SCANT FECES NO ADVERSE FINDINGS SCANT FECES NO ADVERSE FINDINGS UNGROOMED COAT
DG( 17- 19)
SCANT FECES
DG( 18- 29)
LOCALIZED ALOPECIA: UNDERSIDE a
DG( 27- 29)
UNGROOMED COAT
8614
DG( 28- 29) DG( 24
SOFT OR LIQUID FECES UNGROOMED COAT
DG( 24
SOFT OR LIQUID FECES
8615
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
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TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 4); CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
- - - -- - - -- - -- - - -- - -- - - - - - - - ---- - -- - -- - -- - - -- - -- - -- - - -- - -- - - - -- - -- - - - -- -- - - -- - -- - - -- - - -- - - -- - - -- - -- -- - - -- - -- - -- - - -
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8616
DG( 17- 23)
SCANT FECES
DG( 18- 24)
SOFT OR LIQUID FECES
DG( DG(
28- 29) 29
LOCALIZED ALOPECIA: SOFT OR LIQUID FECES
LIMBS a
8617
DG( DG( DG(
29 17- 19) 17- 24)
SCANT SOFT SCANT
FECES OR LIQUID
FECES
FECES
DG(
29 )
SOFT OR LIQUID FECES
8618
DG( 16- 18)
SCANT FECES
8619
DG( 23- 24) DG( 16- 17)
SOFT SOFT
OR LIQUID OR LIQUID
FECES FECES
DG( 16- 17)
SCANT FECES
DG(
18 )
NO FECES IN CAGE PAN
DG( 19- 22)
SOFT OR LIQUID FECES
DG( 19- 29)
SCANT FECES
8620 8621 8622 8623 8624 8625
DG( 23- 29)
DG(
11
DG(
24
DG(
28
DG(
14
LOCALIZED ALOPECIA:
UNDERSIDE
a
NO ADVERSE FINDINGS
SCANT FECES
SCANT FECES
NO ADVERSE FINDINGS
SOFT OR LIQUID FECES
SOFT OR LIQUID FECES
DG( 14- 21) DG( 23- 29)
UNGROOMED UNGROOMED
COAT COAT
DG( 23DG( 23-
29) 29)
SOFT OR LIQUID SCANT FECES
FECES
8626
DG( 28DG( 27-
29) 26)
LOCALIZED ALOPECIA: SCANT FECES
NECK a
8627
DG(
27 )
SOFT OR LIQUID FECES
DG( 27- 28)
SCANT FECES
8628 8629
DG( 27- 29)
DG( 27- 29)
DG(
26 )
UNGROOMED
COAT
SCANT FECES
SOFT OR LIQUID
a FECES
8630 8631
DG( 26- 26)
DG(
10
SCANT FECES
NO ADVERSE FINDINGS
UNGROOMED
COAT
DG(
14
UNGROOMED
COAT
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Num
TABLE 15 (PAGE 5): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8632 8633
8634 8635
DG( 16 )
DG( 22- 29)
DG( 23
DG(
28
DG(
28
DG( 9- 10)
SCANT SCANT SOFT SOFT SCANT SOFT
FECES FECES OR LIQUID OR LIQUID FECES OR LIQUID
FECES FECES
FECES
DG( 9- 13)
UNGROOMED COAT
DG(
18
UNGROOMED COAT
DG(
18
SOFT OR LIQUID FECES
DG( 19- 22)
HINDPAWS: MASS (1.0 CM X 1.0 CM X 0.5 CM)
DG( 23- 29)
HINDPAWS: SCAB (0.5 CM X 0.5 CM X 0.5 CM)a
DG(
24
UNGROOMED COAT
8636
NO ADVERSE FINDINGS
8637
DG(
28
SCANT FECES
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Num
TABLE 15 (PAGE 6): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
------ RABBIT #
----------------------------------------------------------------------------
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8638
DG( 10- 11)
UNGROOMED COAT
DG( 10- 29)
LOCALIZED ALOPECIA: UNDERSIDE a
DG( 11- 12)
SCANT FECES
DG( 16- 19)
SOFT OR LIQUID FECES
DG( 16- 22)
SCANT FECES
DG(
17 )
UNGROOMED COAT
DG( 22- 24) DG( 24
SOFT OR LIQUID FECES UNGROOMED COAT
DG( 29
SCANT FECES
8639
DG( 11- 29)
SCANT FECES
DG( 17- 22)
SOFT OR LIQUID FECES
8640
DG( 27- 29) DG( 11- 22)
SOFT OR LIQUID FECES SCANT FECES
DG( 19- 20) DG( 22- 23)
SOFT OR LIQUID FECES LACRI14ATION
8641
DG( 25 ) DG( 16- 29)
SOFT OR LIQUID FECES SCANT FECES
DG( 17- 18)
UNGROOMED COAT
DG( 17- 22)
SOFT OR LIQUID FECES
8642
DG( 26- 29)
DG(
29 )
DG( 17 )
LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: SOFT OR LIQUID FECES
LIMBS a NECK a
DG(
19 )
SOFT OR LIQUID FECES
DG( 21- 23)
SOFT OR LIQUID FECES
DG( 25- 29)
SOFT OR LIQUID FECES
8643 8644 8645 8646
DG( 29 DG( 10- 16)
SCANT FECES NO ADVERSE NO ADVERSE NO ADVERSE SCANT FECES
FINDINGS FINDINGS FINDINGS
8647
DG( 22 ) DG( 14- 21)
SCANT FECES SCANT FECES
DG( 16- 20)
SOFT OR LIQUID FECES
DG( 21 )
RED SUBSTANCE IN CAGE PAN
DG( 21 )
ABORTED AND SACRIFICED
8648
DG( 14- 16)
SCANT FECES
-- - --- -- -------- ---------
----------------------------------------------------------------------------------
DG DAY OF PRESUMED GESTATION
a. observation confirmed at necropsy.
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TN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 7): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
- -- - - -- - -- - - -- - -- - - - -- - - - --- -- -- -- -- - - -- - - -- - - - -- - -- - -- - -- - -- - -- - - -- - - -- - - -- - - -- - -- - - -- - - -- - -- - -- - - -- - - -- - -- -- - -
RABBIT #
DESCRIPTION
- -- - - -- - -- - - -- - -- - - - -- - - - - -- --- - -- -- -- -- - - -- - - -- - - -- - -- - -- - -- - -- - - -- - - -- - - -- - - -- - -- - - -- - - -- - -- - -- - - -- - -- - - -- -- - -
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
0649
DG( 15- 16)
SCANT FECES
DG( 26- 27)
SCANT FECES
8650
DG(
27 )
SCANT FECES
86Sl
DG( 26- 27)
SCANT FECES
DG(
29
LOCALIZED ALOPECIA:
UNDERSIDE a
8652
DG(
a
RED PERIORAL SUBSTANCE
DG(
12
DG( 13- 21)
NO FECES IN CAGE PAN SOFT OR LIQUID FECES
DG( 13- 21)
SCANT FECES
DG( 14- 15)
UNGROOMED
COAT
DG( 20- 21)
UNGROOMED
COAT
DG(
22
NO FECES IN CAGE PAN
DG(
23
SCANT FECES
DG(
24
DG( 25- 26)
NO FECES IN CAGE PAN SCANT FECES
DG(
26 )
ABORTED AND SACRIFICED
8653
DG( 15- 16)
SCANT FECES
DG(
27
SCANT FECES
DG(
29
SCANT FECES
8654
DG(
16
SCANT FECES
8655
DG(
28
SCANT FECES
8656
DG( 22- 29)
LOCALIZED ALOPECIA:
LIMBS a
8657
NO ADVERSE FINDINGS
8658 8659
DG( 12- 17)
NO ADVERSE FINDINGS SCANT FECES
DG( 16- 17)
SOFT OR LIQUID FECES
DG( 28- 29)
SCANT FECES
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED
GE:STATION
a. observation confirmed at necropsy.
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TABLE 15 (PAGE 8): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8660
DG( 8- 10)
SOFT OR LIQUID FECES
DG( 8- 11)
UNGROOMED COAT
DG( 11- 14) DG( 15 DG( 16 DG( 17- 19)
SCANT FECES NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN
DG( 19
TAN PERIANAL SUBSTANCE
DG( 20
RED SUBSTANCE IN CAGE PAN
8661
DG( 20 DG( 10- 12) DG( 11- 15) DG( 11- 23)
ABORTED AND SACRIFICED SOFT OR LIQUID FECES
SCANT FECES LOCALIZED ALOPECIA:
UNDERSIDE a
DG( 16- 20) DG( 20- 23)
NO FECES IN CAGE PAN LTNGROOMED COAT
DG( 21- 23) DG( 23
SCANT FECES RED SUBSTANCE
IN CAGE PAN
DG( 23
ABORTED AND SACRIFICED
8662
DG( 9- 12)
SCANT FECES
DG( 10- 12)
UNGROOMED COAT
DG( -DG( DG(
12 ) 13- 19) 20- 22)
SOFT OR LIQUID FECES NO FECES IN CAGE PAN SOFT OR LIQUID FECES
DG( 20- 22)
SCANT FECES
DG( 23- 29)
NO FECES IN CAGE PAN
8663
DG( 11 )
SOFT OR LIQUID FECES
DG( 11- 19)
SCANT FECES
DG( 13- 15)
UNGROOMED COAT
DG( 13- 15)
SOFT OR LIQUID FECES
DG( 20
NO FECES IN CAGE PAN
DG( 21
SCANT FECES
DG( 22- 24)
NO FECES IN CAGE PAN
DG( 25
UNGROOMED COAT
DG( 25
SCANT FECES
DG( 26
ABORTED AND SACRIFICED
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. observation confirmed at necropsy.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 9): CLINICAL OBSERVATIONS
- INDIVIDUAL
DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
- -- -- -- - - -- - - - -- - --- - - - -- -- -- -- - -- - - -- - -- - - -- - -- - - -- - -- - - -- - -- - - -- -- - - -- - - -- - - - -- - - - -- - -- - -- - -- - - -- -- - - -- - -- - -- -
DOSAGE GROUP V
3.75 MG/KG/DAY
- - -- - -- - - -- - - - -- - --- - - - -- -- -- -- - - -- - -- - -- - -- - - -- - -- - - -- - - -- - -- - - -- -- - - -- - - -- - - - -- - - - -- - -- - -- - -- - - -- -- - - -- - -- - -- -
8664
DG(
7- 29)
DG(
9- 23)
DG( 17- 19)
DG( 27- 29)
LOCALIZED ALOPECIA:
NECK a
SCANT FECES
SOFT OR LIQUID FECES
SOFT OR LIQUID FECES
8665
DG(
29 )
DG( 11- 15)
SCANT SCANT
FECES FECES
8666
DG(
18 )
DG( 27- 29)
SCANT FECES LOCALIZED ALOPECIA: NO ADVERSE FINDINGS
LIMBS
8667
DG(
12
SCANT FECES
DG( 14- 19)
SCANT FECES
DG(
19
RED SUBSTANCE
IN CAGE PAN
8668 8669
DG(
19
DG( 15- 29)
DG( 11- 17)
DG(
13 )
DG( IS- 16)
DG( 18- 19)
DG(
20 )
ABORTED AND SACRIFICED
LOCALIZED ALOPECIA:
LIMBS a
SCANT FECES
SOFT OR LIQUID FECES
SOFT OR LIQUID FECES
NO FECES IN CAGE PAN
SCANT FECES
DG( 21- 22)
NO FECES IN CAGE PAN
DG( 23- 26)
SCANT FECES
DG( 27- 28)
NO FECES IN CAGE PAN
8670 8671
DG(
29
DG(
28
DG(
7- 8)
ABORTED AND SACRIFICED SCANT FECES SOFT OR LIQUID FECES
8672
DG(
10
DG(
27
DG(
8
DG( 10- 11)
SCANT FECES SCANT FECES RED PERIORAL SCANT FECES
SUBSTANCE
DG(
12 )
NO FECES IN CAGE PAN
DG( 13- 16)
SCANT FECES
8673
DG(
27 )
DG( 12- 25)
SCANT SCANT
FECES FECES
DG( 19- 25)
SOFT OR LIQUID FECES
- -- - - -- - - -- - - - - - - -- - - -- -- -- -- -- - -- - -- - - -- - -- -- -- - -- - -- - - - -- - -- - -- - - -- - -- - - -- - -- -- -- - - - -- - -- - - -- - -- - - -- - -- - - - -- - -
DG = DAY OF PRESUMED
GESTATION
a. Observation confirmed at necropsy.
PROTOCOL 418-010: OR-AL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 10): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
- -- - -- - - -- - -- -- - -- - -- - - - - --- --- - -- - -- - - -- - - -- - - - -- - -- - -- - -- - -- - -- - -- - - - -- - - -- - - -- - -- - -- - -- - - - -- - -- - - -- - - -- - -- -- -
RABBIT #
DESCRIPTION
- -- - -- - - -- - -- -- - -- - - -- - - - --- -- -- -- - -- - - -- - - -- - - - -- - -- - -- - -- - -- - -- - - -- - - - -- - - -- - -- - -- - - -- - -- - - -- - -- -- - -- - -- - -- -- -
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8673
DG(
27
SOFT OR LIQUID FECES
8674
NO ADVERSE FINDINGS
8675
DG( 12- 19)
SCANT FECES
DG(
26 )
SCANT FECES
DG( 28- 29)
SCANT FECES
8676
DG(
14 )
SOFT OR LIQUID FECES
DG( 14- 15)
SCANT FECES
DG(
29 )
LOCALIZED ALOPECIA: LIMBS a
8677
DG( 18- 29)
LOCALIZED ALOPECIA:
LIMBS a
8678
DG(
19
SOFT OR LIQUID FECES
DG(
19
SCANT FECES
8679
NO ADVERSE FINDINGS
8680
DG( 14- 15)
SCANT FECES
DG(
15 )
SOFT OR LIQUID FECES
DG( 18- 19)
SOFT OR LIQUID FECES
8681
DG( 14- 22)
SCANT FECES
DG( 18- 20)
SOFT OR LIQUID FECES
DG(
26 )
SCANT FECES
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy.
PROTOCOL 418-olo:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Num
TABLE 15 (PAGE 11): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8682 8683 8664
NO ADVERSE NO ADVERSE NO ADVERSE
FINDINGS FINDINGS FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8685
8686 8687 8688 8689
DG(
14 )
DG( 14- 15)
DG(
21
SOFT OR LIQUID SCANT FECES
FECES
NO ADVERSE FINDINGS SCANT FECES
NO ADVERSE FINDINGS
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8690 8691
8692
DG(
18
DG( 13- 16)
NO ADVERSE NO ADVERSE ABORTED AND SCANT FECES
FINDINGS FINDINGS
SACRIFICED
DO(
19 )
SOFT OR LIQUID FECES
----------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 15 (PAGE 12): CLINICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
RABBIT #
DESCRIPTION
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8693
NO ADVERSE FINDINGS
8694
DG( 14
SCANT FECES
8695
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8696 8697
DG( 14- 21) DG( 15 ) DG( 18- 19) DG( 7- 10)
LOCALIZED ALOPECIA: UNDERSIDE a SOFT OR LIQUID FECES SOFT OR LIQUID FECES UNGROOMED COAT
8698
DG( 12- 18) DG( 14- 21)
SCANT FECES SCANT FECES
DG( 17- 20)
SOFT OR LIQUID FECES
8699 8700
DG( 19- 21)
DG(
7
DG( 11
DG( 12
LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS SCANT FECES SCANT FECES NO FECES IN CAGE PAN
DG( 12- 18)
DG(
13
LOCALIZED ALOPECIA: SCANT FECES
UNDERSIDE
DG( 13
SOFT OR LIQUID FECES
DG( 14- 16)
NO FECES IN CAGE PAN
DG( 17- 18)
SCANT FECES
DG( 19 )
ABORTED AND SACRIFICED
---------------------------------------------------------------------------------------------------------------
DG = DAY OF PRESUMED GESTATION
a. observation confirmed at necropsy.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 16 (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)
8S72
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8573
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8574
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
857S
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8576
DG 29
NP
14
ALL TISSUES APPEARED
NORMAL.
8577
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8578
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8579
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8580
DG 29
NP
14
ALL TISSUES APPEARED
NORMAL.
8581
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
ALL TISSUES APPEARED
NORMAL.
8582
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8583
DG 29
NP
14
ALL TISSUES APPEARED
NORMAL.
8584
DG 29
NP
14
ALL TISSUES APPEARED
NORMAL.
8585
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8586
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8587
DG 13
p
7
FOUND DEAD ON DAY 13 OF GESTATION
(57 MINUTES AFTER DOSAGE).
LUNGS:
RIGHT DIAPHRAGMATIC
LOBE,
PERFORATION
(0.5 CM X 0.1 CM).
ALL OTHER TISSUES APPEARED NORMAL.
8588
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8589
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8590
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8591
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8592
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8593
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 15) for external observations confirmed at necro
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY TABLE 16 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA
STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR-S
STUDY N
- - -- - - - -- -- - - - -- - - -- - - - -- ---- - -- - -- - -- - - -- - - -- - -- - - - -- - -- - -- - -- - -- - - -- - - -- - - - -- - -- - - -- - -- - -- - -- - - -- - - -- - - -- -- - -
DOSAGE GROUP
RABBIT
DAY OF PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS a
- - -- - - -- -- - - - -- - - -- -- - - - -- --- -- -- - - -- - - -- - -- - - - -- - - -- - -- - -- - -- - -- - -- - - -- - - -- - - - -- - - -- - -- - -- - -- - - -- - -- - - -- - - -- - -
ii
0.1
8594
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8595
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8596
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8597
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8598
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8599
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8600
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8601
DC 29
p
14
ALL TISSUES APPEARED NORMAL.
8602
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8603
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8604
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8605
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8606
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8607
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8608
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8609
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8610
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8611
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8612
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8613
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8614
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8615
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 15) for external observations confirmed at necr
PROTOCOL 418-olo: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NU
TABLE 16 (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
8616
DG 29
p
14
ALL TISSUES APPEARED
8617
DG 29
p
14
ALL TISSUES APPEARED
8618
DG 29
p
14
ALL TISSUES APPEARED
8619
DG 29
p
14
ALL TISSUES APPEARED
8620
DG 29
NP
14
ALL TISSUES APPEARED
8621
DG 29
p
14
ALL TISSUES APPEARED
8622
DG 29
p
14
ALL TISSUES APPEARED
8623
DG 29
NP
14
ALL TISSUES APPEARED
8624
DG 29
p
14
ALL TISSUES APPEARED
8625
DG 29
p
14
ALL TISSUES APPEARED
8626
DG 29
p
14
ALL TISSUES APPEARED
8627
DG 29
p
14
ALL TISSUES APPEARED
8628
DG 29
p
14
ALL TISSUES APPEARED
8629
DG 29
p
14
ALL TISSUES APPEARED
8630
DG 29
p
14
ALL TISSUES APPEARED
8631
DG 29
p
14
ALL TISSUES APPEARED
8632
DG 29
p
14
ALL TISSUES APPEARED
8633
DG 29
p
14
ALL TISSUES APPEARED
8634
DG 29
p
14
ALL TISSUES APPEARED
8635
DG 29
p
14
ALL TISSUES APPEARED
8636
DG 29
p
14
ALL TISSUES APPEARED
8637
DG 29
p
14
ALL TISSUES APPEARED
---------------------------------------------------------------------------------------------------------------
NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL.
NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL. NORMAL.
NORMAL. NORMAL. NORMAL.
P = PREGNANT NP = NOT PREGNANT
DG = DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necr
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 16 (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
8638
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8639
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8640
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8641
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8642
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8643
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8644
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8645
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8646
DC 29
p
14
ALL TISSUES APPEARED NORMAL.
8647
DG 21
p
14
ABORTED ON DAY 21 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8648
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8649
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8650
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8651
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8652
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8653
DG 29
NP
14
ALL TISSUES APPEARED NORMAL.
8654
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8655
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8656
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8657
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8658
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8659
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 15) for external observations confirmed at necro
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 16 (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
8660
DG 20
p
13
ABORTED ON DAY 20 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8661
DG 23
p
14
ABORTED ON DAY 23 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8662
DG 29
p
14
LIVER: PALE
ALL OTHER TISSUES APPEARED
NORMAL.
8663
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8664
DG 29
p
14
8665
DG 29
p
14
8666
DG 29
p
14
ALL TISSUES ALL TISSUES ALL TISSUES
APPEARED APPEARED APPEARED
NORMAL. NORMAL. NORMAL.
8667
DG 19
p
13
ABORTED ON DAY 19 OF GESTATION. ALL TISSUES APPEARED NORMAL.
8668
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8669
DG 29
p
14
ABORTED ON DAY 29 OF GESTATION.
ALL TISSUES APPEARED
NORMAL.
8670
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8671
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8672
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8673
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8674
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8675
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8676
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8677
DG 29
NP
14
ALL TISSUES APPEARED
NORMAL.
8678
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8679
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8680
DG 29
p
14
ALL TISSUES APPEARED
NORMAL.
8661
DG 29
p
14
ALL TISSUES APPEARED
NORMAI,.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT
DG = DAY OF PRESUMED GESTATION
a. Refer tQ the individual clinical observations table (Table 15) for external observations confirmed at necro
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NLR
TABLE 16 (PAGE 6): 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)
8682
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8683
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8684
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
0.1
8685
DG 21
p
14
LUNGS: ALL LOBES, MOTTLED BLACK
AND BROWN (PINPOINT TO 1.0 CM
IN DIAMETER).
ALL OTHER TISSUES APPEARED NORMAL.
8686
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8687
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8688
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8689
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
III 1.0
8690
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8691
DG 18
p
12
ABORTED ON DAY 18 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8692
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
IV
2.5
8693
DG 21
NP
14
ALL TISSUES APPEARED NORMAL.
8694
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8695
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
v 3.75
8696
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8697
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8698
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8699
DG 21
p
14
ALL TISSUES APPEARED NORMAL.
8700
DG 19
p
12
ABORTED ON DAY 19 OF GESTATION.
ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------
P = PREGNANT NP = NOT PREGNANT
DG = DAY OF PRESUMED GESTATION
a. Refer tc@,the individual clinical observations table (Table 15) for external observations confirmed at necr
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 1): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8572 P
3.60
3.42
3.36
3.44
3.49
3.54
3.55
3.58
3.63
3.68
3.5
8573 P
3.95
4.12
4.14
4.18
4.14
4.14
4.20
4.23
4.26
4.28
4.28
8574 P
3.89
4.22
4.18
4.15
4.12
4.19
4.25
4.33
4.35
4.38
4.3
8575 P
3.58
3.76
3.78
3.82
3.83
3.8S
3.82
3.84
3.88
3.91
3.9
8576 NP
3.34
3.22
3.47
3.53
3.55
3.51
3.55
3.62
3.62
3.60
3.6
8577 P
2.92
3.11
3.10
3.16
3.18
3.18
3.20
3.21
3.24
3.26
3.3
8578 P
2.85
3.06
3.11
3.12
3.12
3.09
3.10
3.14
3.20
3.23
3.2
8579 P
3.23
3.07
3.27
3.28
3.34
3.33
3.34
3.39
3.36
3.34
3.5
8580 NP
3.29
3.52
3.44
3.48
3 .44
3.42
3.45
3.50
3.53
3.56
3.S
8581 P
3.11
3.23
3.27
3.30
3.36
3.37
3.43
3.45
3.50
3.52
3.5
8582 P
3.32
3.29
3.30
3.35
3.37
3.40
3.36
3.35
3.38
3.39
3.3
85e3 NP
3.17
3.34
3.34
3.34
3.25
3.30
3.32
3.40
3.42
3.44
3.4
8584 NP
3.41
3.56
3.51
3.69
3.59
3.60
3.65
3.64
3.77
3.74
3.8
8585 P
3.57
3.64
3.72
3.77
3.84
3.81
3.82
3.82
3.88
3.96
3.9
8586 P
3.36
3.42
3.44
3.48
3.47
3.53
3.57
3.58
3.61
3.53
3.6
8587 P
3.02
3.61
3.56
3.60
3.59
3.58
3.51
3.50
FOUND DEAD ON DAY 13
8588 P
3.72
3.80
3.86
3.76
3.89
3.89
3.90
3.96
4.02
4.07
4.0
8589 P
3.51
3.70
3.73
3.74
3.80
3.83
3.84
3.85
3.90
3.93
3.9
8590 P
3.82
3.95
4.04
4.07
4.17
4.28
4.29
4.35
4.40
4.50
4.6
es91 p
3.65
3.68
3.70
3.72
3.76
3.78
3.83
3.85
3.85
3.88
3.9
8592 P
3.17
3.39
3.45
3.40
3.42
3.47
3.51
3.50
3.57
3.63
3.6
8593 P
3.40
3.51
3.58
3.53
3.54
3.54
3.60
3.65
3.60
3.64
3.6
- - -- - -- - - -- - - - - -- - - - -- - -- - - -- - -- - -- - -- - - -- - - -- - -- - -- - - -- - - -- -- - - -- - - -- - -- - - -- - -- - - -- - -- - -- - - -- - -- - -- - - -- - - -- - --
P = PREGNANT
NP = NOT PREGNANT
DAY = DAY OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
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 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY TABLE 17 (PAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR'S
STUDY Nu
---------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 19
20
21
22
23
24
25
26
27
28
29
---------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8572 P 8573 P 8574 P 8575 P 8576 NP 8577 P 8578 P 8579 P 8580 NP 8581 P 8582 P 8583 NP 8584 NP 8585 P 8586 P 8587 P
3.55 4.20 4.34 4.01 3.57 3.41 3.29 3.58 3.56 3.60
3.38 3.47
3.89 3.98 3.59 FOUND
3.62 4.24 4.35 4.01 3.58 3.35 3.31 3.61 3.59 3.66 3.37 3.46 3.83 3.98 3.62 DEAD ON DAY
3.64 4.19 4.21 4.00 3.62 3.40 3.34 3.64 3.54 3.66 3.42 3.47 3.90 4.05 3.64 13 OF
3.70 4.18 4.25 4.03 3.68 3.38 3.31 3.70 3.56 3.68 3.42 3.46 3.89 4.08 3.66 GESTATION
3.67 4.21 4.34 4.03 3.70 3.39 3.36 3.72 3.58 3.57 3.47 3.49 3.88 4.09 3.70
3.64 4.26 4.34 4.00 3.71 3.43 3.35 3.76 3.53 3.67 3.55 3.54 3.96 4.12 3.75
3.71 4.32 4.38 4.04 3.73 3.51 3.34 3.81 3.48 3.49 3.54 3.58 4.10 4.10 3.7S
3.80 4.34 4.38 4.02 3.73 3.56 3.33 3.86 3.39
ABORTED 3.53 3.54 3.98 3.96 3.73
3.83 4.34 4.44 4.05 3.76 3.57 3.31 3.89 3.45 ON DAY 3.52 3.56 3.97 3.87 3.78
3.84
3.8
4.33
4.3
4.45
4.4
4.00
4.0
3.77
3.7
3.54
3.6
3.35
3.3
3.88
3.9
3.51
3.5
26 OF GESTATION
3.54
3.5
3.59
3.5
3.92
3.9
3.79
3.7
3.81
3.8
8588 P
4.10
4.06
4.11
4.16
4.18
4.24
4.25
4.27
4.30
4.29
4.3
8589 P
4.02
4.00
4.04
4.04
4.07
4.09
4.08
4.09
4.04
3.96
3.9
8590 p
4.47
4.50
4.52
4.59
4.60
4.65
4.67
4.66
4.68
4.72
4.6
8591 P
3.97
4.02
4.05
4.07
4.05
3.98
3.91
3.88
3.92
3.93
3.9
8592 P
3.58
3.64
3.99
3.72
3.70
3.70
3.69
3.71
3.73
3.74
3.8
8593 P
3.62
3.65
3.70
3.70
3.71
3.68
3.69
3.78
3.77
3.78
3.8
---------------------------------------------------------------------------------------------------------------
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 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL
DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
- -- - -- - -- - - -- - -- - -- - - - - -- --- -- - -- - - -- -- - - -- - - -- - -- - - -- - -- - - -- - -- - -- - - -- - -- - - - -- - - -- - - -- - -- - - -- - -- - -- - -- - - -- - - -- -
RABBIT #
DOSAGE GROUP Il
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8594 P 8595 P 8596 P
3.91 3.43 3.10
3.95 3.48 3.31
3.86 3.52 3.31
3.92 3.54 3.32
3.93 3.50 3.35
3.96 3.50 3.41
3.95 3.52 3.43
3.93 3.51 3.43
3.90 3.SS 3.45
3.91 3.58 3.48
3.88 3.60 3.54
8597 P 8598 P 8599 P 8600 p 8601 P 8602 P 8603 P 8604 NP 8605 P 8606 p
3.28 3.22 3.37 3.34 3.26 2.89 3.73
3.99 3.58 3.76
3.61 3.44 3.61 3.55 3.03 3.00 3.79 4.04 3.65 3.81
3.68 3.43 3.58 3.58 3.26 3.01 3.76 4.01 3.64 3.83
3.69 3.48 3.60 3.66 3.30 2.99 3.83 3.94 3.63 3.84
3.69 3.49 3.64 3.73 3.38 2.98 3.83 3.97 3.70 3.80
3.71 3.49 3.66 3.65 3.39 2.99 3.85 4.01 3.66 3.79
3.72 3.46 3.71 3.66 3.37 2.96 3.90 4.06 3.65 3.83
3.73 3.53 3.81 3.70 3.36 2.98 3.96 4.03 3.70 3.87
3.82 3.53 3.84 3.67 3.37 3.00 3.97 3.98 3.81 3.95
3.83 3.56 3.87 3.71 3.44 3.04 3.99 3.96 3.85 4.00
3.87 3.66 3.90 3.75 3.49 3.07 4.03 3.98 3.87 3.93
8607 NP 8608 P
3.03 2.91
3.24 3.08
3.29 3.11
3.32 3.06
3.30 3.03
3.33 3.03
3.35 3.07
3.38 3.12
3.42 3.19
3.40 3.20
3.43 3.24
8609 P 8610 P 8611 P 8612 P 8613 P 8614 P
3.32 3.16 3.53 3.47
3.59 3.70
3.42 3.16 3.20 3.72
3.80 3.80
3.52 3.18 3.22 3.72 3.77 3.72
3.52 3.29 3.23 3.74 3.76 3.76
3.55 3.29 3.19 3.69 3.72 3.81
3.56 3.32 3.16 3.69 3.72 3.82
3.55 3.36 3.19 3.74 3.68 3.87
3.47 3.18 3.22 3.73 3.74 3.80
3.45 3.28 3.27 3.82 3.79 3.88
3.48 3.42 3.33 3.87 3.86 3.96
3.59 3.36 3.36 3.90 3.80 3.95
8615 P
3.40
3.53
3.48
3.59
3.56
3.58
3.65
3.69
3.69
3.75
3.73
----------------------------------------------------------------------------------------------------------------
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 418-010: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (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
----------------------------------------------------------------------------------------------------------------
8594 P 8595 P 8596 P 8597 P 8598 P
3.80 3.65 3.57 3.92 3.66
3.79 3.65 3.58 3.98 3.68
3.84 3.68 3.63 3.98 3.72
3.88 3.63 3.64 4.02 3.73
3.99 3.63 3.63 4.06
3.71
4.05 3.61 3.69 4.02 3.74
4.11 3.60 3.75 4.02 3.74
4.17 3.60 3.75 4.01 3.75
4.13 3.60 3.77 3.98 3.75
4.09 3.55 3.75 4.02 3.78
4.02 3.46 3.78 4.05 3.81
8599 P
3.90
3.94
3.96
3.98
4.00
3.99
4.04
4.05
4.04
4.03
4.07
8600 P
3.76
3.74
3.83
3.86
3.81
3.84
3.90
3.93
3.96
3.97
4.07
8601 P
3.48
3.53
3.52
3.56
3.58
3.58
3.60
3.61
3.63
3.63
3.69
8602 P
3.05
3.03
3.05
3.07
3.08
3.09
3.06
3.07
3.08
3.05
3.05
8603 P
4.02
4.01
4.09
4.14
4.17
4.24
4.26
4.28
4.20
4.20
4.16
8604 NP
4.05
4.04
4.06
4.12
4.16
4.16
4.20
4.26
4.11
4.06
4.09
8605 P
3.86
3.87
3.91
3.95
3.96
4.06
4.08
4.07
4.09
4.10
4.16
8606 P
4.02
4.06
4.03
4.04
4.07
4.15
4.16
4.17
4.18
4.22
4.31
8607 NP
3.49
3.51
3.53
3.54
3.57
3.56
3.61
3.68
3.51
3.50
3.48
8608 p
3.12
3.16
3.24
3.31
3.32
3.36
3.38
3.28
3.22
3.18
3.16
8609 P
3.63
3.65
3.66
3.75
3.71
3.73
3.71
3.78
3.79
3.82
3.81
8610 P
3.48
3.51
3.S4
3.57
3.62
3.64
3.66
3.67
3.70
3.74
3.80
8611 P
3.37
3.41
3.40
3.36
3.41
3.37
3.42
3.33
3.25
3.29
3.38
8612 P
3.94
3.95
3.98
4.00
4.03
4.01
4.12
4.11
4.16
4.20
4.28
8613 P
3.69
3.72
3.76
3.73
3.78
3.82
3.89
3.96
4.03
3.95
3.98
8614 P
4.02
4.00
4.04
4.14
4.15
4.18
4.24
4.28
4.32
4.30
4.30
8615 P
3.84
3.89
3.91
3.97
4.00
4.04
4.08
4.05
4.06
4.08
4.15
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT
DAY = DAY OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
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 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Nut
TABLE 17 (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
---------------------------------------------------------------------------------------------------------------
8616 P 8617 P 8618 P 8619 P 8620 NP 8621 P
3.70 3.76 3.64 3.52 3.07 2.84
3.95 3.73 3.55 3.53 3.31 3.21
3.94 3.78 3.52 3.57 3.32 3.12
3.99 3.80 3.55 3.58 3.34 3.15
3.92 3.74 3.47 3.58 3.36 3.03
3.94 3.81 3.42 3.56 3.36 3.07
3.87 3.80 3.41 3.53 3.32 3.04
3.92
3.90
3.93
3.9
3.84
3.83
3.80
3.7
3.44
3.47
3.48
3.5
3.48
3.49
3.44
3.4
3.32
3.27
3.30
3.3
3.05
3.16
3.14
3.1
8622 P
3.45
3.59
3.62
3.66
3.65
3.71
3.68
3.73
3.75
3.81
3.8
8623 NP 8624 P 8625 P 8626 P 8627 P 8628 P 8629 P 8630 P
3.33
3.53
3.62
3.58
3.59
3.61
3.63
3.65
3.69
3.67
3.7
3.07
3.16
3.24
3.25
3.29
3.30
3.32
3.34
3.32
3.36
3.3
3.60
3.63
3.70
3.74
3.78
3.76
3.77
3.72
3.65
3.73
3.8
3.12
3.29
3.35
3.30
3.22
3.26
3.30
3.35
3.45
3.49
3.5
2.96
3.15
3.03
3.02
3.07
3.11
3.14
3.10
3.13
3.16
3.2
3.26
3.34
3.46
3.50
3.51
3.57
3.54
3.61
3.69
3.71
3.7
3.36
3.48
3.49
3.51
3.51
3.56
3.56
3.60
3.63
3.66
3.7
3.31.
3.48
3.46
3.47
3.46
3.47
3.47
3.53
3.62
3.67
3.7
8631 P
3.18
3.27
3.29
3.29
3.21
3.25
3.26
3.31
3.37
3.47
3.4
8632 P
3.59
3.73
3.70
3.75
3.78
3.78
3.78
3.85
3.93
3.95
4.0
8633 P
3.23
3.22
3.21
3.21
3.22
3.19
3.14
3.18
3.20
3.21
3.2
8634 P
3.83
3.92
3.96
3.95
3.97
3.98
4.03
4.06
4.09
4.11
4.1
8635 P
3.57
3.71
3.71
3.66
3.72
3.73
3.76
3.81
3.82
3.86
3.8
8636 P
3.40
3.44
3.50
3.45
3.47
3.50
3.53
3.52
3.57
3.64
3.6
8637 P
3.96
3.91
3.94
3.97
3.93
3.92
3.94
3.97
4.07
4.15
4.1
- -- - - -- - - -- - - - - - -- - -- - - - -- ---- -- - - -- -- - - -- - -- - - - -- - - -- - -- - -- - - -- -- - - -- - -- - - - -- - - -- - -- - - -- - -- - - -- - -- - - -- - - -- - -- -
P = PREGNANT
NP = NOT PREGNANT
DAY = DAY OF PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
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 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 17 (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
- -- -- - -- - - -- - - - -- - - -- - - -- - - -- -- --- - -- - -- -- - - - -- - -- - - - -- - -- - -- - -- - -- - -- - - -- - - -- - - -- - - - -- -- - -- - -- - -- - - -- - -- - -- - - -- -
8616 P
3.73
8617 P
3.67
061B P
3.55
8619 P
3.28
8620 NP
3.39
8621 P
3.29
8622 P
3.77
8623 NP
3.70
8624 P
3.39
8625 P
3.90
8626 P
3.38
8627 P
3.22
8628 P
3.77
8629 P
3.74
8630 P
3.67
8631 P
3.50
8632 P
3.97
8633 P
3.28
8634 P
4.19
8635 P
3.90
8636 P
3.66
8637 P
4.21
- -- -- - - - -- - - - - - - -- - -- -- -- -
3.68
3.86
3.86
3.89
3.91
3.93
3.96
3.99
3.96
3.93
3.69
3.70
3.72
3.73
3.74
3.80
3.84
3.85
3.86
3.88
3.61
3.64
3.64
3.66
3.66
3.65
3.68
3.67
3.70
3.73
3.24
3.27
3.28
3.19
3.24
3.34
3.29
3.32
3.38
3.46
3.41
3.44
3.48
3.49
3.51
3.53
3.53
3.58
3.58
3.59
3.36
3.36
3.41
3.42
3.49
3.48
3.39
3.41
3.46
3.48
3.79
3.80
3.80
3.77
3.80
3.83
3.83
3.87
3.85
3.87
3.72
3.74
3.81
3.81
3.82
3.86
3.94
3.92
3.94
4.04
3.40
3.43
3.45
3.52
3.51
3.52
3.54
3.62
3.65
3.64
3.91
3.92
3.80
3.70
3.73
3.70
3.62
3.55
3.49
3.47
3.42
3.46
3.47
3.52
3.50
3.51
3.52
3.53
3.59
3.62
3.26
3.28
3.30
3.31
3.33
3.32
3.28
3.19
3.17
3.23
3.75
3.84
3.88
3.93
3.91
3.94
3.98
3.96
3.96
3.95
3.78
3.81
3.85
3.88
3.92
3.92
3.90
3.90
3.90
3.90
3.67
3.71
3.76
3.7B
3.76
3.80
3.89
3.95
3.99
4.00
3.55
3.58
3.64
3.65
3.66
3.70
3.71
3.79
3.84
3.B3
4.00
4.02
4.04
4.02
4.04
4.04
3.91
3.99
4.03
4.09
3.31
3.36
3.31
3.39
3.40
3.44
3.44
3.46
3.47
3.48
4.20
4.20
4.22
4.25
4.26
4.35
4.36
4.43
4.43
4.45
3.89
3.91
3.96
4.00
4.03
4.08
4.13
4.17
4.21
4.24
3.72
3.78
3.80
3.78
3.86
3.87
3.94
3.99
3.99
4.05
4.20
4.23
4.28
4.28
4.32
4.38
4.34
4.32
4.36
4.42
- -- -- --- -- - -- - - -- - - -- - -- - -- - - - -- - -- - - -- -- - - -- - -- - - - -- - -- - - -- - -- - - -- -- - - -- - - -- - - - -- -- - -
P = PREGNANT
NP = NOT PREGNANT
(VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDEIE) IN GRAMS
ALL CALCULATIONS
EXCEPT BODY WEIGHT
BODY WEIGHT AVERAGES
ARE CALCULATED
(G) , ROUNDED TO THREE SIGNIFICANT
DIGITS
AVERAGES ARE PERFORMED
WITH THE UNROUNDED
WITH THE ROUNDED KILOGRAM
(KG) VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG)
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP IV
2.S MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8638 P
3.42
3.45
3.42
3.34
3.26
3.22
3.26
3.34
3.44
3.39
3.37
8639 P
3.73
4.02
4.00
3.90
3.79
3.76
3.78
3.67
3.72
3.64
3.65
8640 P
3.92
4 .08
4.07
3.97
3.90
3.85
3.84
3.77
3.7S
3.66
3.70
8641 P
3.46
3.40
3.38
3.35
3.34
3.33
3.34
3.35
3.39
3.42
3.42
8642 P
4.09
4.05
4.07
4.07
4.09
4.06
4.07
4.02
4.00
3.96
3.94
8643 P
3.39
3.52
3.58
3.53
3.58
3.52
3.53
3.50
3.56
3.62
3.64
8644 P
3.22
3.41
3.36
3.39
3.40
3.40
3.42
3.36
3.35
3.42
3.47
8645 P
3.31
3.48
3.44
3.52
3.51
3.55
3.57
3.59
3.61
3.68
3.65
8646 P
2.91
3.01
3.00
2.98
2.90
2.87
2.77
2.79
2.72
2.74
2.68
8647 P
3.13
3 .36
3.30
3.41
3.33
3.23
3.28
3.06
3.08
3.10
2.94
8648 P
3.53
3.71
3.74
3.66
3.75
3.77
3.77
3.69
3.61
3.62
3.70
8649 P
3.36
3.51
3.48
3.39
3.29
3.32
3.37
3.42
3.46
3.50
3.63
8650 P
3.10
3.22
3.19
3.10
3.14
3.14
3.16
3.18
3.19
3.25
3.26
8651 p
3.26
3.38
3.42
3.47
3.42
3.47
3.45
3.47
3.49
3.60
3.61
8652 P 8653 NP
3.60 3.64
3.66 3.73
3.68 3.73
3.72 3.78
3.74 3.77
3.74 3.80
3.63 3.64
3.56 3.59
3.47 3.58
3.45 3.62
3.43 3.62
8654 P
2.87
3.01
3.00
3.01
3.01
2.92
2.95
3.01
3.08
3.07
3.06
865S p
3.59
3 .56
3.62
3.62
3.62
3.63
3.65
3.71
3.72
3.75
3.74
8656 P
3.80
3.81
3.88
3.88
3.95
3.96
3.95
3.99
4.01
4.07
4.10
8657 P
3.25
3.36
3.34
3.43
3.44
3.45
3.47
3.55
3.53
3.58
3.62
8658 P
3.05
3.19
3.20
3.27
3.26
3.28
3.32
3.34
3.42
3.46
3.48
8659 P
3.41
3.36
3.39
3.40
3.30
3.33
3.37
3.39
3.27
3.29
3.31
-- - -- - - - -- - - - - - - -- - -- - - - -- - -- - - -- - -- - - -- - - -- - - -- -- - -- - - - -- -- - - -- - - -- - - -- - - -- -- - - -- - -- - -- - - -- - - -- - - -- - - -- -- - -- -- -
P = PREGNANT
NP = NOT PREGNANT
(VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS
ALL CALCULATIONS
EXCEPT BODY WEIGHT
BODY WEIGHT AVERAGES
ARE CALCULATED
(G) , ROUNDED TO THREE SIGNIFICANT
DIGITS
AVERAGES ARE PERFORMED WITH THE UNROUNDED
WITH THE ROUNDED KILOGRAM
(KG) VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG)
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 8) ! KATERNAL 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
----------------------------------------------------------------------------------------------------------------
8638 P 8639 P
8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P
3.30 3.57 3.55 3.29 3.94 3.70
3.42 3.73 2.98 2.82
3 .30 3 .58 3 .57 3 .22 3 .92 3 .71 3.44 3.72 3 .02 2.70
3.34 3.54 3.61 3.17 3.97 3.76 3.47 3.75 3.03 2.66
3.38 3.48 3.68 3.16 3.96 3.77 3.50 3.78 3.00 ABORTED
3.41 3.48 3.75
3.18 4.00 3.82 3.51 3.80 3.02 ON DAY
3.48
3.55
3.48
3.51
3.83
3.89
3.24
3.29
4.03
4.03
3.84
3.88
3.52
3.51
3.83
3.88
3.02
3.05
21 OF GESTATION
3.61 3.51 3.95 3.32 4.02 3.89 3.52 3.92 3.07
3.65 3.44 3.94 3.37 4.03 3.92 3.50 3.92 3.10
3.68 3.52 3.98 3.37 4.02 3.94 3.50 3.92 3.10
3.67 3.59 3.96 3.39 4.06 3.97 3.49 3.95 3.15
8648 P
3.75
3 .76
3.79
3.85
3.88
3.83
3.89
3.89
3.90
3.91
3.99
8649 P
3.72
3.74
3.75
3.78
3.80
3.81
3.82
3.84
3.86
3.07
3.88
8650 P
3.29
3 .31
3.35
3.32
3.33
3.36
3.39
3.42
3.4S
3.50
3.47
8651 p
3.67
3.70
3.71
3.73
3.75
3.78
3.72
3.73
3.70
3.78
3.77
8652 P
3.27
3.20
3.17
3.14
3.08
3.04
3.01
2.97
ABORTED ON DAY 26 OF G
8653 NP
3.74
3.72
3.80
3.80
3.85
3.84
3.81
3.89
3.92
3.94
4.00
8654 P
3.18
3 .20
3.18
3.24
3.26
3.26
3.30
3.35
3.39
3.40
3.42
8655 P
3.72
3 .74
3.76
3.80
3.83
3 .82
3.86
3.89
3.91
3.87
3.91
8656 P
4.08
4.08
4.10
4.lS
4.18
4.22
4.24
4.33
4.35
4.35
4.41
8657 P
3.64
3.71
3.68
3.72
3.74
3.76
3.77
3.78
3.80
3.80
3.83
8658 P
3.55
3 .56
3.57
3.63
3.64
3.69
3.72
3.73
3.75
3.71
3.73
8659 P
3.47
3 .46
3.S2
3.53
3.54
3.56
3.53
3.58
3.63
3.67
3.76
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT
DAY = DAY OF PRESUMED GESTATION
(VALUES EXCLUDED FROM AVERAGES)
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 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 9): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8660 P
3.76
3.92
3.63
3.69
3.42
3.54
3.41
3.50
3.52
3.56
3.40
8661 P
3.44
3.55
3.47
3.35
3.29
3.31
3.17
3.24
3.17
3.18
3.12
8662 P
3.49
3.68
3.55
3.51
3.41
3.39
3.34
3.33
3.23
3.22
3.21
8663 P
3.95
4.04
4.00
3.84
3.84
3.83
3.68
3.68
3.69
3.60
3.63
8664 P
4.18
4.12
4.04
3.99
3.98
3.86
3.86
3.79
3.81
3.73
3.64
8665 P
2.99
3.24
3.19
3.11
3.12
3.09
2.96
2.97
2.87
3.01
3.13
8666 P
3.58
3.78
3.71
3.73
3.89
3.82
3.86
3.80
3.93
3.99
3.99
8667 P
2.97
3.26
3.20
3.17
3.22
3.11
3.14
3.07
3.03
3.01
2.93
8668 P
2.89
3.26
3.20
3.29
3.35
3.30
3.30
3.35
3.44
3.48
3.49
8669 P
3.70
3.81
3.78
3.76
3.72
3.66
3.55
3.59
3.54
@.54
3.49
8670 P
3.12
3.24
3.28
3.32
3.22
3.25
3.23
3.27
3.31
3.36
3.38
0671 P
3.35
3.41
3.44
3.33
3.36
3.38
3.42
3.50
3.56
3.60
3.62
8672 P
3.21
3.40
3.31
3.23
3.11
3.09
3.09
3.05
3.03
3.09
3.21
8673 P
3.23
3.38
3.40
3.39
3.44
3.38
3.33
3.28
3.19
3.12
3.10
8674 P
3.55
3.57
3.55
3.61
3.58
3.56
3.58
3.62
3.66
3.67
3.64
8675 p
3.26
3.30
3.29
3.24
3.21
3.22
3.25
3.27
3.31
3.33
3.32
8676 P
3.70
3.71
3.75
3.80
3.76
3.76
3.78
3.80
3.79
3.82
3.79
8677 NP
3.09
3.12
3.15
3.18
3.26
3.22
3.22
3.21
3.22
3.23
3.23
8678 P
3.37
3.58
3.61
3.60
3.59
3.61
3.63
3.66
3.70
3.73
3.77
8679 p
3.61
3.64
3.72
3.86
3.67
3.65
3.62
3.66
3.69
3.70
3.83
8680 p
3.31
3.39
3.43
3.43
3.S3
3.51
3.49
3.48
3.48
3.46
3.48
8681 p
3.39
3.54
3.54
3.61
3.69
3.62
3.60
3.56
3.50
3.40
3.40
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAY = DAY OF
NP = NOT PREGNANT PRESUMED GESTATION
(VALUES EXCLUDED
FROM AVERAGES)
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 418-010: OP-AL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 17 (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
-----------------------------------------------------------------------------------------------------------------
8660 p
3.37
ABORTED ON DAY 20 OF GESTATION
8661 P
3.07
3.03
3.10
3.12
3.02
ABORTED ON DAY 23 OF GESTATION
8662 P
3.07
3.05
3.05
2.97
2.96
2.90
2.90
2.86
2.81
2.76
2.74
8663 P
3.56
3.57
3.48
3.48
3.54
3.47
3.42
ABORTED ON DAY 26 OF GESTATION
8664 P
3.63
3.62
3.63
3.71
3.82
3.90
3.89
3.93
3.92
3.95
4.00
8665 P
3.14
3.13
3.17
3.22
3.24
3.29
3.27
3.28
3.31
3.31
3.35
8666 P
4.00
4.00
4.05
4.08
4.12
4.17
4.22
4.25
4.28
4.27
4.32
8667 P
ABORTED ON DAY 19 OF GESTATION
86@8 p
3.57
3.61
3.48
3.55
S.S2
3.60
3.62
3.63
3.65
3.64
3.7S
8669 P
3.41
3.37
3.35
3.30
3.25
3.23
3.20
3.18
3.17
3.11
a
8670 P
3.37
3.34
3.35
3.42
3.48
3.40
3.54
3.56
3.53
3.58
3.62
8671 P
3.68
3.71
3.74
3.75
3.75
3.77
3.82
3.91
3.92
3.94
3.92
8672 P
3.25
3.28
3.35
3.37
3.38
3.39
3.42
3.49
3.57
3.54
3.60
8673 P
3.05
2.98
3.01
3.01
3.06
3.10
3.18
3.25
3.32
3.37
3.36
8674 P
3.63
3.63
3.63
3.66
3.69
3.71
3.71
3.77
3.80
3.84
3.07
8675 P
3.29
3.33
3.39
3.38
3.39
3.40
3.41
3.42
3.40
3.42
3.44
8676 p
3.87
3.88
3.91
3.92
3.97
4.02
3.97
4.01
4.02
4.06
4.14
8677 NP
3.26
3.26
3.29
3.38
3.41
3.38
3.40
3.41
3.44
3.48
3.53
8678 P
3.88
3.83
3.81
3.89
3.84
3.88
3.96
3.95
3.98
4.02
4.10
8679 P
3.81
3.84
3.91
3.90
3.97
4.01
4.OS
4.10
4.12
4.16
4.11
8680 p
3.52
3.54
3.62
3.61
3.62
3.63
3.63
3.66
3.67
3.69
3.70
8681 P
3.32
3.26
3.31
3.29
3.43
3.55
3.63
3.64
3.64
3.66
3.71
----------------------------------------------------------------------------------------------------------------
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
ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE
DIGITS AND REPORTED IN KILOGRAMS UNROUNDED GRAM (G) VALUE.
(KG)
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED a. Doe 8669 aborted on day 29 of gestation.
KILOGRAM
(KG) VALUE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 17 (PAGE 11); MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
-----------------------------------------------------------------------------------------------------------------
RABBIT #
SARELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8682 P
3.IS6
3.78
3.81
3.84
3.86
3.94
3.96
3.96
3.98
4.04
4.02
8683 P
3.44
3.59
3.65
3.65
3.69
3.71
3.77
3.80
3.86
3.91
3.91
8684 P
3.26
3.49
3.56
3.55
3.58
3.60
3.62
3.66
3.63
3.72
3.77
----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
- -- -- - -- - - -- - - - - - --- - - ---- -- -- -- - - -- -- - - - -- - - -- - -- - -- - -- - -- - -- - - -- - - -- - - -- - - -- - -- - - -- - -- - - -- - -- - - - -- - -- - - -- - -- - -
8682 P
4. :L2
4.12
4.20
8683 P
3. 96
3.98
4.10
8684 P
3. '76
3.80
3.86
----------------------------------------------------------------------------------------------------------------
P= DAY ALL ALL BODY
PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
= DAY OF PRESUME:D 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 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (PAGE 12): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
- -- - -- - - -- - - -- - -- -- - - - - - ---- -- - -- - - -- - -- - -- - -- - - -- - -- - -- - - - -- - -- - -- - -- - - -- -- -- - - -- - -- - - -- - -- - -- - -- - -- - -- - - -- - - --
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP Il
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8685 P
3.68
3.75
3.75
3.76
3.75
3.77
3.72
3.76
3.73
3.74
3.86
8686 p
3.48
3.44
3.46
3.50
3.55
3.54
3.60
3.62
3.62
3.70
3.70
8687 P
3.51
3.67
3.70
3.70
3.72
3.74
3.83
3.85
3.85
3.91
3.92
8688 p
3.57
3.61
3.67
3.68
3.71
3.68
3.64
3.64
3.67
3.74
3.73
8689 P
3.27
3.47
3.48
3.53
3.50
3.46
3.44
3.51
3.54
3.64
3.70
----------------------------------------------------------------------------------------------------------------
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8685 P
3.94
3.94
3.99
8686 P
3.79
3.80
3.90
8687 P
4.00
4.09
3.97
8688 p
3.84
3.86
3.94
8689 p
3.71
3.73
3.74
----------------------------------------------------------------------------------------------------------------
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 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (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
----------------------------------------------------------------------------------------------------------------
8690 p
4.05
4.03
4.00
4.04
4.01
3.99
4.07
4.15
4.21
4.21
4.26
8691 p
3.46
3.59
3.57
3.54
3.61
3.65
3.64
3.68
3.69
3.74
3.80
8692 P
3.01
3.30
3.33
3.29
3.22
3.17
3.19
3.17
3.18
3.20
3.23
----------------------------------------------------------------------------------------------------------------
STATUS
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8690 P
4.28
4.30
4.35
8691 P
ABORTED ON DAY 18 OF GESTATION
8692 P
3.30
3.34
3.26
-- - - -- - -- - -- - - -- - -- - - - -- - -- -- - - - --- - -- -- - - - -- - - - -- - -- -- - -- - -- - -- - - -- - - -- - - -- - - - -- -- - - -- - -- - -- - -- - - -- - - - -- -- - -- - -
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.
(KG)
BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 17 (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
----------------------------------------------------------------------------------------------------------------
8693 NP
3.70
3.79
3.81
3.84
3.84
3.85
3.89
3.87
3.92
3.98
3.81
8694 P
3.42
3.47
3.48
3.55
3.56
3.56
3.54
3.56
3.61
3.68
3.64
8695 P
2.88
3.03
3.06
3.02
2.99
3.04
3.05
3.04
3.10
3.11
3.14
----------------------------------------------------------------------------------------------------------------
STATUS
DAY 19
20
21
----------------------------------------------------------------------------------------------------------------
8693 NP
3.74
3.78
3.86
8694 P
3.70
3.73
3.84
8695 p
3.18
3.18
3.25
----------------------------------------------------------------------------------------------------------------
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 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 17 (PAGE 15) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
-----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8696 P
4.18
4.12
4.13
4.17
4.21
4.20
4.20
4.28
4.31
4.32
4.34
8697 P
3.42
3.34
3.31
3.24
3.27
3.24
3.26
3.23
3.24
3.20
3.22
8698 p
3.53
3.76
3.77
3.75
3.80
3.64
3.82
3.85
3.80
3.80
3.73
8699 p
3.63
3.71
3.73
3.73
3.76
3.72
3.74
3.79
3.90
3.95
3.93
8700 P
3.24
3.25
3.42
3.39
3.35
3.26
3.27
3.24
3.12
3.27
3.21
-----------------------------------------------------------------------------------------------------------------
STATUS
DAY 19
20
21
-----------------------------------------------------------------------------------------------------------------
8696 P
4.42
4.38
4.50
8697 P
3.29
3.28
3.34
8698 P
3.50
3.46
3.51
8699 P
3.94
3.98
4.03
8700 P
ABORTED ON DAY 19 OF GESTATION
-----------------------------------------------------------------------------------------------------------------
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 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (PAGE 1): 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 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8572 P 8573 P 8574 P 8575 P
B.
86.
126.
96.
110.
141.
125.
145.
67.
13.
31
184.
185.
144.
123.
160.
179.
182.
181.
183.
181.
162
124.
a
158.
184.
166.
166.
141.
162.
162.
72.
156
152.
173.
169.
164.
113.
160.
151.
180.
174.
153.
167
8576 NP 8577 P 8578 P B579 P
8580 NP
182.
182.
185.
180.
185.
185.
185.
185.
180.
178.
164
183.
177.
174.
159.
185.
145.
175.
180.
185.
184.
185
185.
181.
176.
134.
163.
135.
183.
182.
173.
175.
163
184.
173.
139.
133.
185.
136.
156.
127.
182.
183.
182
180.
176.
124.
164.
165.
182.
181.
157.
143.
128.
169
8581 p
180.
185.
182.
185.
175.
180.
153.
162.
179.
167.
67
8582 P
142.
171.
151.
121.
92,
112.
103.
110.
137.
113.
97
8583 NP 8584 NP 8585 P 8506 P 8587 P
161.
160.
0.
147.
170.
181.
185.
183.
178.
162.
114
182.
181.
181.
181.
184.
180.
182.
183.
185.
183.
183
185.
184.
185.
182.
181.
180.
181.
iss.
185.
183.
184
182.
167.
176.
166.
176.
134,
133.
158.
162.
102.
133
112.
133.
121.
78.
51.
FOUND DEAD ON DAY 13 OF GESTATION
8588 P
185.
181.
180.
181.
180.
182.
185.
184.
182.
182.
181
8589 p
168.
181.
185.
170.
171.
152.
174.
164.
ISO.
182,
180
8590 P
161.
180.
185.
185.
183.
181.
183.
184.
155.
141.
142
8591 P
184.
184.
180.
180.
185.
182.
185.
181,
182.
182.
185
8592 P
130.
158.
163.
185.
162.
153.
185.
163.
120.
87.
116
8593 P
182.
162.
ISO.
185.
100.
155.
141.
130.
149.
141.
141
- - -- - - -- - - -- - - - -- - -- - - - -- --- -- -- - - -- - -- - -- - - -- - -- - -- - - - -- - - -- - -- - -- - -- - - -- - - -- - - -- - - - -- - -- - -- - - -- -- - - -- - - -- - - -- -
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESL7f4ED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Spilled feed precluded the calculation of this value.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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
----------------------------------------------------------------------------------------------------------------
8572 P 8573 P 8574 P 8575 P 8576 NP
126.
73. 10. 132. 143.
139. 86. 53.
128. 177.
74. 124. 101. 104. 180.
65. 170. 157.
95. 164.
104, 146. 102.
84. 154.
134. 152. 132.
51. 166.
161. 124. 146.
84. 174.
136. 131. 131.
85. 182.
160. 129. 135. ill. 133.
8577 P
156.
181.
181.
181.
182.
183.
184.
183.
181.
8578 P
148.
142.
136.
109.
89.
58.
61.
114.
70.
8579 P
173.
176.
183.
162.
138.
146.
123.
148.
95.
8580 NP
123.
167.
ill.
32.
16.
80.
156.
165.
Ill.
8581 P
151.
162.
a
114.
51.
ABORTED ON DAY 26 OF GESTATION
8582 P
lie.
145.
149.
183.
180.
182.
182.
164.
106.
8583 NP
142.
130.
115.
143.
147.
135.
168.
151.
93.
8584 NP
160.
182.
184.
185.
182.
183.
182.
183.
181.
8585 P
184.
163.
145.
113.
81.
11.
0.
0.
1.
8586 P
146.
122.
138.
124.
135.
140.
110.
103.
87.
8587 P
FOUND DEAD ON DAY 13 OF GESTATION
8588 p
184.
184.
a
184.
185.
183.
182.
181.
147.
8589 P
148.
116.
119.
136.
91.
114.
34.
4.
6.
8590 p
184.
184.
185.
181.
181.
185.
183.
172.
152.
8591 P
184.
153.
144.
93.
6.
73.
78.
89.
43.
8592 P
166.
131.
122.
108.
ill.
108.
86.
109.
119.
8593 P
142.
122.
128.
133.
103.
155.
122.
130.
124.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESLYMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G).
a. Spilled feed precluded the calculation of this value.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 18 (PAGE 3): 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 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8594 P
95.
147.
157.
177.
113.
185.
63.
64.
26.
30.
15.
8595 P
136.
168.
101.
133.
140.
149.
142.
171.
126.
77.
a
8596 p
184.
181.
182.
181.
182.
183.
185.
183.
185.
184.
184.
8597 P
182.
184.
182.
182.
182.
180.
185.
180.
181.
164.
185.
8598 P
183.
184.
166.
140.
183.
185.
183.
180.
180.
185.
185.
8599 p
182.
lB4.
184.
180.
181.
185.
180.
180.
184.
185.
185.
8600 P
184.
174.
161.
148.
154.
116.
180.
168.
148.
164.
137.
8601 P
183.
184.
184.
176.
170.
145.
180.
182.
182.
103.
121.
8602 P
180.
150.
125.
105.
126.
Ill.
151.
150.
157.
68.
149.
8603 P
184.
181.
183.
181.
180.
185.
126.
90.
127.
119.
118.
8604 NP
51.
86.
89.
162.
138.
183.
130.
124.
172.
162.
141.
8605 P
183.
183.
164.
185.
126.
169.
185.
184.
183.
183.
185.
8606 P
182.
122.
100.
129.
122.
143.
157.
159.
168.
185.
182.
8607 NP
181.
184.
ISO.
184.
182.
185.
184.
184.
182.
181.
184.
8608 P
181.
160.
152.
119.
147.
153.
142.
161.
155.
110.
7.
8609 p
182.
174.
180.
146.
132.
87.
62.
109.
isa.
181.
181.
8610 P
183.
180.
169.
170.
184.
92.
156.
183.
180.
184.
185.
8611 P
170.
141.
114.
73.
125.
135.
104.
164.
168.
185.
184
8612 P
185.
183.
182.
182.
181.
183.
185.
184.
182.
184.
181
8613 P
95.
100.
94.
97.
93.
121.
140.
148.
46.
18.
89
8614 P
182.
182.
182.
185.
181.
181.
185.
183.
181.
183.
180
8615 P
181.
180.
184.
184.
180.
182.
185.
185.
184.
181.
182
----------------------------------------------------------------------------------------------------------------
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 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE IS (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
----------------------------------------------------------------------------------------------------------------
8594 P
53.
74.
124.
164.
182.
167.
165.
142.
100.
8595 P
150.
106.
90.
73.
67.
71.
76.
41.
9.
8596 P
180.
184.
184.
181.
164.
149.
151.
152.
109.
8597 P
182.
184.
182.
119.
103.
104.
82.
134.
107.
8598 P
180.
184.
182.
181.
172.
183.
182.
183.
122.
8599 p
180.
181.
180.
141.
145.
139.
136.
141.
100.
8600 P
142.
175.
173.
121.
151.
147.
132.
176.
95.
8601 P
110.
134.
152.
73.
83.
86.
88.
122.
103.
8602 P
74.
101.
130.
110.
37.
66.
67.
101.
25.
8603 P
176.
184.
157.
159.
182.
145.
49.
71.
56.
8604 NP
163.
159.
165.
161.
159.
169.
97.
94.
69.
8605 P
180.
185.
184.
166.
102.
112.
116.
118.
100.
8606 P
184.
3.
158.
158.
155.
143.
166.
144.
121.
8607 NP
184.
184.
183.
184.
183.
184.
83.
132.
91.
8608 P
184.
146.
143.
146.
99.
43.
19.
9.
29.
8609 P
180.
181.
159.
147.
92.
132.
130.
113.
90.
8610 P
181.
181.
185.
172.
150.
146.
123.
128.
141.
8611 P
124.
43.
98.
45.
63.
9.
6.
55.
88.
8612 P
181.
182.
183.
184.
184.
180.
184.
181.
172.
8613 P
141.
49.
160.
183.
185.
183.
183.
117.
109.
8614 P
180.
183.
185.
184.
183.
172.
151.
118.
96.
8615 P
182.
181.
182.
103.
184.
117.
99.
110.
125.
- - -- - - -- - -- - - - - -- -- - -- -- - - -- -- - -- - -- - -- - -- - - -- - -- - - -- - -- - -- - - -- - - -- - - -- -- - - -- - - -- - - -- - - -- - -- - -- - -- - -- - -- - - -- - - --
P = PREGNANT
NP = NOT PREGNANT
(VALUES EXCLUDED
FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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
----------------------------------------------------------------------------------------------------------------
8616 P
149.
173.
150.
95.
34.
79.
57.
72.
76.
35.
1
8617 P
154.
144.
92.
138.
126.
ill.
81.
99.
21.
10.
22
8618 P
37.
2.
0.
0.
60.
49.
30.
40.
66.
77.
109
8619 P
121.
129.
104.
69.
4.
34.
11.
B.
2.
0.
0
8620 NP
182.
182.
182.
98.
14S.
135.
106.
167.
185.
176.
184
8621 P
182.
175.
46.
a
79.
95.
180.
180.
183.
185.
164
8622 P
185.
185.
183.
180.
184.
185.
180.
180.
181.
126.
115
8623 NP
183.
184.
126.
185.
181.
178.
174.
182.
184.
185.
181
8624 P
185.
180.
172.
174.
160.
171.
112.
127.
135.
160.
182
8625 P
180.
183.
185.
167.
130.
113.
59.
133.
164.
183.
182
8626 P
156.
89.
35.
133.
159.
113.
163.
144.
174.
185.
147
8627 P
52.
92.
126.
156.
134.
114.
110.
94.
148.
162.
157
8628 P
184.
182.
181.
183.
182.
180.
185.
174.
185.
185.
184
8629 P
iss.
181.
181.
180.
154.
125.
134.
151.
185.
185.
184
8630 P
184.
172.
168.
141.
122.
120,
154.
182.
182.
182.
185
8631 P
182.
5.
135.
143.
145.
149.
185.
185.
184.
180.
183
8632 P
183.
183.
183.
184.
180.
184.
185.
185.
185.
180.
182
8633 P
146.
125.
149.
86.
109.
117.
101.
107.
117.
149.
135
8634 P
185.
181.
182.
185.
180.
182.
184.
185.
iso.
180.
185
8635 P
182.
163.
143.
155.
151.
181.
184.
185.
183.
182.
185
8636 P
184.
183.
162.
183.
150.
b
176.
185.
184.
100.
lei
8637 P
182.
183.
183.
146.
144.
164.
182.
181.
181.
182.
185
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESLYMED GESTATION
ALL WEIGHTS WERE RECORDED
IN GRAMS (G) .
a. Spilled feed precluded the calculation of this value.
b. Wet feed precluded the calculation of this value.
PROTOCOL 418-010; ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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
----------------------------------------------------------------------------------------------------------------
8616 P 8617 P 8618 p 8619 P
74. 53. 127.
3.
43.
56. 131.
1.
76. 65. 122.
3.
103. ill. 117.
17.
95. 104.
80. 8.
109. 100.
109. 35.
133. 99. 91. 66.
100. 87.
112. 96.
71. 114. 109. 106.
8620 NP 8621 P
174. 182.
170. 182.
182. 183.
166. 180.
156. 156.
154. a
170. 102.
185. 154.
128. 118.
8622 P 8623 NP 8624 P 8625 P
8626 P
145. 184. 182. 137. 126.
140. 184. 184.
93. 143.
139. 183. 158.
39. 116.
109. 183. 150.
13. 134.
116. 183. 129.
15. 125.
122. 183.
93. 2.
140.
135. 181. 167.
2. 167.
160. 181. 154.
7. 151.
139. 184.
86. 2.
96.
8627 P
135.
157.
119.
93.
54.
34.
3.
82.
63.
8628 P
182.
175.
174.
159.
146.
166.
129.
89.
87.
8629 P
184.
172.
163.
173.
140.
112.
89.
47.
88.
8630 P
183.
174.
153.
161.
171.
180.
183.
159.
132,
8631 P
182.
169.
184.
182.
184.
184.
185.
165.
126.
8632 P
181.
181.
184.
185.
181.
184.
183.
a
180.
8633 P
166.
43.
128.
130.
116.
108.
68.
54.
51.
8634 P
180.
183.
185,
184.
184.
183.
169.
160.
142.
8635 P
184.
183.
183.
185.
184.
149.
143.
139.
120.
8636 P
177.
181.
180.
184.
183.
182.
174.
153.
142.
8637 P
146.
3.
181.
184.
169.
98.
86.
112.
113.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES
DAYS = DAYS OF PRESUMED GESTATION
EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Spilled feed precluded the calculation of this value.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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
----------------------------------------------------------------------------------------------------------------
8638 P
59.
10.
5.
2.
48.
84.
83.
5.
23.
16.
21
8639 P
154.
60.
2.
0.
3.
2.
4.
2.
0.
1.
0
8640 P
146.
54.
7.
0.
1.
3.
5.
3.
2.
3.
0
8641 P
71.
57.
52.
48.
59.
62.
55.
49.
24.
2.
0
8642 P
184.
185.
174.
158.
139.
151.
120.
113.
89.
101.
100
8643 P
181.
182.
183.
131.
122.
124.
165,
180.
182.
185.
184
8644 P
182.
169.
183.
109.
128.
80.
82.
130.
168.
154.
165
0645 P
185.
181.
185.
184.
183.
162.
168.
169.
182.
185.
185
6646 P
180.
114.
is.
1.
3.
1.
3.
1.
36.
127.
183
8647 P
104.
99.
2.
42.
14.
1.
1.
2.
0.
4.
1
8648 P
180.
155.
137.
136.
101.
37.
14.
49.
84.
109.
152
8649 P
139.
76.
36.
113.
151.
130.
133.
131.
182.
185.
183
8650 P
152.
63.
132.
124.
169.
112.
102.
102.
130.
123.
122
8651 P
104.
180.
185.
180.
185.
162.
162.
181.
154.
174.
184
8652 P
183.
178.
181.
119.
0.
1.
2.
0.
2.
0.
10
8653 NP
185.
182.
174.
118.
26.
73.
87.
129.
127.
184,
173
8654 P
184.
161.
144.
183.
138.
140.
141.
142.
127.
176.
181
8655 P
18!5.
144.
183.
182.
180.
181.
184.
182.
183.
170.
148
8656 P
185.
184.
181.
185.
183.
183.
185.
183.
180.
185.
184
8657 P
181.
178.
165.
152.
136.
140.
185.
161.
181.
185.
ISO
8658 P
184.
168.
159.
185.
182.
184.
185.
180.
181.
182.
185
8659 P
183.
185.
69.
101.
59.
57.
4.
2.
55.
114.
150
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 410-010: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUME
TABLE 18 (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
-----------------------------------------------------------------------------------------------------------------
8638 P 8639 P 8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P
74. 5.
105. 3.
123. 184147. 185. 146. ABORTED
86.
89.
120.
2.
4.
12.
147.
167.
182.
37.
33.
89.
123.
129.
156.
185.
185.
181.
152.
164.
116.
182.
184.
182.
113.
134.
100.
ON DAY 21 OF GESTATION
109.
11. 174.
75. ill. 176. 113. 184. 122.
117. 24.
184. 74.
107. 165. 106. 183. 109.
110. 44.
184. 100. 114. 159. 101. 165. 115.
91. 93. 154. 115. 31. 184. 110. 182. 162.
105. 96.
112.
121. 71.
147. 58.
142. 134.
8648 P
112.
122.
112.
89.
97.
95.
135.
95.
73.
8649 P
163.
129.
124.
130.
119.
160.
132.
127.
121.
8650 P
150.
107.
108.
127.
145.
169.
134.
118.
ill.
8651 P
182.
139.
123.
143.
54.
101.
138.
132.
130.
8652 P
0.
5.
0.
1.
1.
ABORTED ON DAY 26 OF GESTATION
8653 NP
103.
149.
157.
159.
180.
184.
185.
166.
129.
8654 P
159.
149.
126.
159.
152.
173.
14S.
106.
116.
8655 P
181.
184.
182.
181.
184.
170.
135.
130.
129.
8656 P
181.
170.
180.
185.
183.
185.
178.
168.
164.
8657 P
163.
170.
164.
183.
170.
a
a
a
a
8658 P
185.
182.
183.
185.
181.
150.
130.
119.
96.
8659 P
182.
183.
184.
180.
120.
182.
170.
160.
174.
----------------------------------------------------------------------------------------------------------------
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 418-010: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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
----------------------------------------------------------------------------------------------------------------
8660 P
0.
0.
1.
0.
1.
3.
10.
3.
0.
0.
0
8661 P
23.
1.
1.
1.
2.
2.
2.
4.
0.
0.
0
8662 P
14.
0.
0.
0.
1.
1.
0.
1.
1.
1.
0
8663 P
38.
2.
0.
1.
0.
0.
2.
5.
1.
1.
0
8664 P
20.
2.
0.
2.
1.
1.
4.
2.
1.
1.
0
8665 P
183.
97.
41.
2.
12.
3.
6.
ill.
154.
148.
133
8666 p
183.
182.
183.
163.
181.
132.
184.
184.
185.
184.
184
8667 P
161.
162.
141.
1.
64.
41.
23.
17.
1.
0.
3
8668 P
183.
185.
185.
183.
182.
184.
183.
180.
185.
184.
181
8669 p
158.
109.
12.
4.
1.
2.
116.
0.
0.
4.
1
8670 P
184.
181.
1.
124.
74.
110.
113.
110.
133.
153.
127
8671 P
182.
1.
72.
88.
160.
181.
185.
185.
183.
184.
183
8672 P
95.
2.
6.
7.
B.
0.
4.
119.
168.
182.
156
8673 P
184.
152.
174.
59.
48.
1.
1.
0.
1.
0.
9
8674 P
180.
185.
163.
147.
168.
185.
lS6.
169.
164.
165.
155
8675 P
184.
138.
97.
81.
52.
80.
96.
120.
133.
94.
86
8676 P
184.
143.
ill.
118.
101.
93.
43.
53.
120.
150.
169
8677 NP
181.
181.
182.
184.
182.
150.
155.
180.
181.
120.
139
8678 P
183.
165.
125.
154.
123.
140.
163.
185.
182.
183.
183
8679 P
183.
182.
104.
69.
63.
ill.
156.
183.
184.
182.
180
8680 P
182.
181.
180.
177.
123.
99.
78.
72.
138.
143.
146
8681 P
183.
182.
168.
170.
110.
90.
34.
7.
2.
0.
0
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Doe 8660 aborted on day 20 of gestation.
b. Doe 8667 aborted on day 19 of gestation.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Num
TABLE 18 (PACE 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
----------------------------------------------------------------------------------------------------------------
8660 P
ABORTED ON DAY 20 OF GESTATION
8661 P
7.
0.
ABORTED ON DAY 23 OF GESTATION
8662 P
8663 P 8664 P 8665 P 8666 P 8667 P
7. 9. 43. 134. 185.
ABORTED
0.
0.
1.
0.
0.
1.
91.
101.
125.
162.
182.
148.
183.
iss.
181.
ON DAY 19 OF GESTATION
0. 0. 119. 120. 185.
0. ABORTED 123. 107. 174.
5.
0.
0.
ON DAY 26 OF GESTATION
131.
162.
160.
136.
181.
130.
168.
182.
157.
8668 p
180.
182.
182.
181.
185.
182.
180.
180.
148.
8669 P
0.
0.
1.
4.
2.
6.
3.
2.
ABORTED ON DAY 29 OF
8670 P
129.
181.
172.
170.
180.
170.
182.
185.
114.
8671 P
182.
133.
164.
158.
166.
183.
116.
a
b
8672 P
181.
185.
184.
182.
184.
182.
184.
180.
182.
8673 P
66.
83.
93.
91.
144.
181.
181.
177.
118.
8674 P
120.
115.
151.
164.
154.
185.
168.
155.
164.
8675 P
142.
115.
128.
126.
114.
73.
b
88.
81,
8676 P
134.
116.
127.
131.
96.
151.
131.
136.
150.
8677 NP
181.
183.
184.
182.
185.
180.
183.
184.
185.
8678 P
181.
b
181.
181.
176.
b
b
180.
140.
8679 P
183.
183.
185.
185.
182.
171,
ISO.
135.
77.
8680 P
155.
133.
131.
143.
127.
121.
118.
129.
108.
8681 P
113.
84.
162.
184.
180.
183.
151.
159.
144.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Value was not recorded.
b. Spilled feed precluded the calculation of this value.
PROTOCOL 418-010: OPAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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 ----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8682 P
183.
181.
182.
181.
176.
183.
184.
185.
182.
172.
184
8603 P
184.
109.
171.
180.
184.
180.
184.
143.
172.
180.
185
8684 P
184.
184.
180.
181.
184.
155.
140.
181.
184.
181.
156
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ----------------------------------------------------------------------------------------------------------------
8682 P
180.
8683 P
174.
8684 P
162.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NLT?
TABLE 18 (PAGE 12) : 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 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8685 P 8686 P 8687 P 8688 P
180.
180.
ISO.
157.
113.
112.
55.
67.
168.
181.
157
181.
184.
182.
180.
181.
157.
163.
183.
185.
183.
ISO
182.
184.
183.
180.
181.
183.
182,
184.
181.
181.
181
181.
184.
153.
154.
123.
92.
150.
181.
181.
180.
181
8689 P
160.
176.
164.
73.
80.
142.
168.
168.
183.
182.
146
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21
----------------------------------------------------------------------------------------------------------------
8685 P
138.
8686 P
184.
8687 P
33.
8688 P
184.
8689 p
131.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (C)
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY Nu@
TABLE 18 (PAGE 13): 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 111
1.0 MG/KG/DAY
- -- - - -- - -- - - -- - - - -- -- - - - - ---- -- -- - -- - - - -- - - -- - - -- - -- - - -- - -- -- - -- - - - -- - - -- - - -- - - - -- -- - -- - - -- - -- - - -- - - -- - - -- - -- --
8690 p
180.
181.
182.
184.
182.
164.
183.
184.
183.
184.
18
8691 P
180.
182.
182.
180.
181.
182.
184.
185.
184.
183.
8692 P
157.
137.
100.
77.
78.
47.
51.
53.
95.
116.
12
---------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ---------------------------------------------------------------------------------------------------------------
8690 P 8691 p
180. ABORTED
ON DAY 16 OF GESTATION
8692 P
67.
---------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Doe 8691 aborted on day 18 of gestation.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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 -
----------------------------------------------------------------------------------------------------------------
RABBIT #
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8693 NP
181.
181.
181.
181.
181.
181.
183.
165.
103.
51.
78
8694 P
181.
180.
172.
161.
115.
127.
183.
185.
181.
185.
183
8695 P
181.
144.
124.
141.
148.
128.
146.
134.
147.
162.
155
----------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 ----------------------------------------------------------------------------------------------------------------
8693 MP
122.
8694 P
175.
8695 P
144.
----------------------------------------------------------------------------------------------------------------
P = PREGNANT DAYS = DAYS ALL WEIGHTS
NP = NOT PREGNANT (VALUES
OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 18 (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 #
SATIELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
- - -- - -- - -- - - -- -- - - -- - - - - --- -- -- - - -- - -- -- -- -- - - -- - - -- - - -- - -- - -- - -- - -- - -- - - -- - - - -- - - -- - -- - - -- - -- -- - - -- - - -- - - -- - -- -
8696 P
181.
185.
136.
180.
163.
156.
184.
185.
164.
180.
177
8697 P
106 .
51.
75.
60.
76.
39.
34.
17.
84.
95.
134
8698 P
ISO.
182.
182.
176.
130.
130.
62.
46.
13.
3.
1
8699 P
183.
181.
156.
156.
109.
128.
183.
182.
181.
184.
184
8700 p
184.
134.
121.
2.
1.
0.
2.
0.
0.
0.
1
-- - -- - -- - -- - - - -- - - -- - - - - --- -- -- - -- - -- -- - - -- - - -- - -- - - -- - - -- - -- -- - - -- - -- - -- - - - -- - - -- - - -- - - -- - -- - -- - -- - - - -- -- - - -- - -
DAYS 20 - 21 -- - - -- - -- -- - - - -- - - -- - - - - --- -- -- - -- - -- - -- - - -- - - -- - - -- - -- - -- - -- - -- - -- - - -- - -- - - - -- - - -- - - -- - - -- - -- -- - - -- - - -- - - -- -- - -
8696 P
181.
8697 P
101.
8698 P
4.
8699 P
182.
8700 P
ABORTED ON DAY 19 OF GESTATION
- - -- - -- - -- -- - -- - - -- - - - - --- -- -- - -- - -- - -- -- - - - -- - -- - - -- - - -- -- - -- - - -- - -- - - -- - - -- - - - -- - -- - - -- - -- - -- - - -- - -- - - -- - -- - --
P = PREGNANT
NP = NOT PREGNANT (VALUES EXCLUDED
DAYS = DAYS OF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED IN GRAMS (G)
a. Doe 8700 aborted on day 19 of gestation.
FROM AVERAGES)
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 19 (PAGE 1) : 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
HOP-N
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
0
- - -- - - -- - - -- - - - -- - -- - - -- - - -- -- -- -- - -- - -- - -- - - -- - - -- - -- - - - -- -- - - -- - -- - -- - -- - - - -- - - -- - - - -- -- - -- - -- -- - - -- - -- - -- - - -- -
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8572 1
6
3
8573 5
2
6
8574 4
5
6
8575 5
5
8
4
7
0
0
0
0
1
7
0
0
0
0
3
9
0
0
0
0
2
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
4
7
4
0
0
0
6
1
7
6
0
0
0
6
3
9
7
0
0
0
8
2
10
8
8576 NOT PREGNANT
8577 4
3
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
2
8578 4
3
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
3
8579 5
2
s
2
7
0
0
0
0
0
0
0
0
0
5
2
7
6
8580 NOT PREGNANT
8581 ABORTED ON DAY 26 OF GESTATION
8582 0
3
1
2
3
0
0
0
6
1
7
0
0
0
7
3
10
8
8583 NOT PREGNANT
8584 NOT PREGNANT
8585 4
4
7
1
8
0
0
0
0
2
2
1
0
1
8
3
11
8
8586 5
5
8
2
10
0
0
0
0
0
0
0
0
0
8
2
10
9
8587 FOUND DEAD ON DAY 13 OF GESTATION
8588 2
5
4
3
7
0
0
0
0
1
1
0
0
0
4
4
8
4
8589 5
4
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
5
6590 8
3
4
7
11
0
0
0
0
0
0
0
0
0
4
7
11
6
8591 3
6
2
7
9
0
0
0
0
0
0
0
0
0
2
7
9
6
8592 6
7
7
6
13
0
0
0
0
0
0
0
0
0
7
6
13
7
8593 4
5
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
4
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
PLACENTAE
APPEARED
NOR14AL UNLESS NOTED OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 19 (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 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8594 2 3
2
3
5
0
0
0
1
2
3
0
0
0
3
5
8
3
8595 3 2
3
2
5
0
0
0
0
0
0
0
0
0
3
2
5
3
8596 3 4
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
5
8597 5 4
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
s
8598 2 1
0
3
3
0
0
0
0
0
0
0
0
0
0
3
3
4
8599 3 6
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
5
8600 3 6
4
5
9
0
0
0
1
0
1
0
2
2
5
7
12
5
8601 4 5
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
3
8602 3 4
0
7
7
0
0
0
0
0
0
0
0
0
0
7
7
3
8603 6 3
7
2
9
0
0
0
0
0
0
0
0
0
7
2
9
8604 NOT PREGNANT
8605 6 4
8
2
10
0
0
0
0
0
0
0
0
0
8
2
10
8606 5 4
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
8607 NOT PREGNANT
8608 6 5
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
8609 5 4
2
7
9
0
0
0
0
0
0
0
0
0
2
7
9
8610 4
5
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
8611 3 6
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
8612 4
4
5
3
8
0
0
0
0
0
0
0
0
0
5
3
8
8613 7 3
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
8614 6 3
4
5
9
0
0
0
0
0
0
0
0
0
4
5
9
8615 5 6
3
8
11
0
0
0
0
0
0
0
0
0
3
8
11
---------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMI
TABLE 19 (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
----------------------------------------------------------------------------------------------------------------
8616 3 2
4
1
5
0
0
0
0
0
0
2
1
3
6
2
8
6
8617 3 5
4
4
8
0
0
0
1
0
1
0
0
0
5
4
9
7
8618 5 5
4
6
10
0
0
0
0
0
0
0
0
0
4
6
10
6
8619 4 3
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
6
8620 NOT PREGNANT
8621 5 4
3
6
8622 3 1
3
1
9
0
0
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
6
9
4
0
3
1
4
4
8623 NOT PREGNANT
8624 3 6
3
6
9
0
0
0
1
0
1
0
0
0
4
6
10
4
8625 5 2
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
4
8626 4 3
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
4
8627 4 6
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
6
8628 6 3
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
5
8629 5 5
4
6
10
0
0
0
0
0
0
0
0
0
4
6
10
5
8630 3 5
5
3
8
0
0
0
0
0
0
0
0
0
5
3
a
5
8631 1 8
7
2
9
0
0
0
0
0
0
0
0
0
7
2
9
8
8632 3 s
4
4
8
0
0
0
0
0
0
0
0
0
4
4
8
4
8633 5 3
4
4
8
0
0
0
0
0
0
0
0
0
4
4
8
4
8634 3 6
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
6
8635 5 3
4
4
8
0
0
0
0
0
0
0
0
0
4
4
8
6
8636 2 5
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
4
8637 5 8
9
4
13
0
0
0
1
0
1
0
0
0
10
4
14
12
----------------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE APPEARED NORMAL UNLESS
NOTED OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 19 (PAGE 4): 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 IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8638 2 5
2
5
7
0
0
0
0
0
0
0
0
0
2
5
7
2
8639 2 5
4
3
7
0
0
0
0
0
0
1
1
2
s
4
9
6
8640 3 3
0
6
6
0
0
0
0
0
0
0
0
0
0
6
6
1
8641 7 2
3
6
8642 5 3
5
3
9
0
8
0
0
0
0
0
0
0
0
0
0
0
0
0
3
6
9
4
0
0
0
0
5
3
8
6
8643 5 2
5
2
7
0
0
0
0
0
0
0
0
0
5
2
7
5
8644 6 3
3
6
9
0
0
0
0
0
0
0
0
0
3
6
9
3
8645 6 1
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
4
8646 4 2
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
3
8647 ABORTED ON DAY 21 OF GESTATION
8648 4 10
7
7
14
0
0
0
0
1
1
0
4
4
7
12
19
9
8649 2 4
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
3
8650 4 2
2
4
6
0
0
0
0
0
0
0
0
0
2
4
6
2
8651 5 2
3
4
7
0
0
0
0
0
0
0
0
0
3
4
7
4
8652 ABORTED ON DAY 26 OF GESTATION
8653 NOT PREGNANT
8654 4 3
2
5
7
0
0
0
0
0
0
0
0
0
2
s
7
3
8655 0 3
1
2
3
0
0
0
0
0
0
0
0
0
1
2
3
6
8656 6 4
4
6
10
0
0
0
0
0
0
0
0
0
4
6
10
8657 4 4
4
4
8
0
0
0
0
0
0
0
0
0
4
4
a
8658 4 4
3
5
8
0
0
0
0
0
0
0
0
0
3
5
8
8659 3 3
3
3
6
0
0
0
0
0
0
0
0
0
3
3
6
---------------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE APPEARED NORMAL
UNLESS
NOTED OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 19 (PAGE 5): 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 V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8660 ABORTED ON DAY 20 OF GESTATION
88666621 A1BORTE3D ON 2 DAY 232 OF GE4STATION0 0 0 0 0 0 1 2 3 3 4 7 3
8663
ABORTED
ON DAY 26 OF GESTATION
5
7
0
0
0
0
0
0
0
3
3
2
8
10
4
8664 3 4
2
0
0
0
0
0
0
0
6
4
10
6
88666665 35 76 68 43 1110 00 00 0 0 0 0 0 0 0 8 3 11
88666678 A2BORTE4D ON 2 DAY 194 OF GE6STATION0 0 0 0 1 1 1 1 2 3 6 9
8669
ABORTED
ON DAY 29 OF GESTATION
5
0
0
0
0
0
0
0
1
1
2
4
6
8670 2 3
2
3
0
0
0
0
0
0
6
3
9
88667712 56 43 62 37 99 00 00 00 0 1 1 0 1 1 2 9 11
8673 4 4 4 4 8 0 0 0 00 00 00 00 00 00 43 43 86
8674 2 4
3
3
8675 4 4
5
3
6
0
0
0
8
0
0
0
0
0
0
0
0
0
5
3
8
8676 8 3
4
7
11
0
0
0
0
0
0
1
0
1
5
7
12
8677 NOT PREGNANT
8678 2 6
3
5
8
0
0
0
0
0
0
0
0
0
3
5
8
8679 7 4 4 7 11 0 0 0 00 00 00 00 00 00 44 74 11a
88668801 35 53 44 44 88 00 00 00 0 0 0 0 0 0 4 4 8
----------------------------------------------------------------------------------------------------------
M = MALE PLACENTAE
F = FEMALE APPEARED NORMAL
UNLESS
NOTED
OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 19 (PAGE 6): CAESAREAN- SECTIONING OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
VIABLE FETUSES
DEAD FETUSES
EARLY RESORPTIONS LATE RESORPTIONS
IMPLANTATION SITES c
------------------------ ---------------- ---------------- ---------------- ---------------- ---
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIG
RABBIT
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8682
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
5
8683
3
5
8
0
0
0
0
0
0
0
0
0
3
5
8
3
86B4
9
0
9
0
0
0
0
0
0
0
0
0
9
0
9
9
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8685
9
4
13
0
0
0
0
0
0
0
0
0
9
4
13
9
8686
6
3
9
0
0
0
0
1
1
0
0
0
6
4
10
6
86e7
6
3
9
0
0
0
0
0
0
0
0
0
6
3
9
6
8688
5
5
10
0
0
0
0
0
0
0
0
0
5
5
10
5
8689
4
6
10
0
0
0
0
0
0
1
0
1
5
6
11
6
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8690
7
6
13
0
0
0
0
0
0
0
0
0
7
6
13
7
8691
ABORTED ON DAY 18 OF GESTATION
8692
3
5
8
0
0
0
0
0
0
0
0
0
3
5
8
3
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8693
NOT PREGNANT
8694
3
7
10
0
0
0
0
0
0
0
0
0
3
7
10
3
8695
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
6
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8696
6
4
10
0
0
0
0
0
0
0
0
0
6
4
10
6
8697
2
2
4
0
0
0
0
0
0
0
0
0
2
2
4
2
8698
4
3
7
0
0
0
0
0
0
0
0
0
4
3
7
5
8699
5
6
11
0
0
0
0
0
0
0
0
0
5
6
11
6
8700
ABORTED ON DAY 19 OF GESTATION
-----------------------------------------------------------------------------------------I-----------------------
PLACENTAE APPEARED NOR14AL UNLESS NOTED OTHERWISE.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 20 (PAGE 1) ; LITTER OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
RESORBED
-----------------------------------------------------------------------------------------------------------------
RABBIT #
KALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
t
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8572
1
6
7
43.53
49.55
48.69
7
0
0.0
8573
5
2
7
47.62
51.76
48.80
7
0
0.0
8574
4
5
9
46.23
45.97
46.09
9
0
0.0
8575
5
5
10
49.26
49.60
49.43
10
0
0.0
8576
NOT PREGNANT
8577
4
3
7
47.30
45.97
46.77
7
0
0.0
8578
4
3
7
42.95
41.32
42.25
7
0
0.0
8579
5
2
7
53.07
49.48
52.04
7
0
0.0
8580
NOT PREGNANT
8581 8582
ABORTED ON DAY 26 OF GESTATION
0
3
3
----
47.26
47.26
10
7
70.0
8583
NOT PREGNANT
8584
NOT PREGNANT
8585
4
4
8
36.96
28.55
32.75
11
3
27.3
8586
5
5
10
36.42
32.98
34.70
10
0
0.0
8587
FOUND DEAD ON DAY 13 OF GESTATION
8588
2
s
7
50.22
50.92
50.72
8
1
12.5
8589
5
4
9
35.40
35.12
3S.27
9
0
0.0
8590
8
3
11
41.82
40.81
41.54
11
0
0.0
8591
3
6
9
38.50
39.62
39.24
9
0
0.0
8592
6
7
13
33.41
31.14
32.19
13
0
0.0
8593
4
5
9
46.37
41.46
43.64
9
0
0.0
----------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 20 (PAGE 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
N
N
t
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
8594 8595 8596 8597 8598 8599 8600 8601 8602 8603
2
3
5
52.83
51.01
51.74
8
3
37.5
3
2
5
50.16
48.91
49.66
5
0
0.0
3
4
7
41.29
40.53
40.86
7
0
0.0
5
4
9
37.25
40.29
38.60
9
0
0.0
2
1
3
50.72
49.07
50.17
3
0
0.0
3
6
9
37.81
39.44
38.90
9
0
0.0
3
6
9
43.30
43.35
43.33
12
3
25.0
4
5
9
43.08
41.06
41.96
9
0
0.0
3
4
7
35.41
37.97
36.87
7
0
0.0
6
3
9
45.86
47.66
46.46
9
0
0.0
8604 8605 8606
NOT PREGNANT
6
4
10
44.98
49.26
46.69
10
5
4
9
51.78
49.54
50.79
9
0
0.0
0
0.0
8607
NOT PREGNANT
8608
6
5
11
32.37
33.51
32.89
11
0
0.0
8609
5
4
9
43.88
39.60
41.98
9
0
0.0
8610
4
5
9
40.08
42.68
41.52
9
0
0.0
8611
3
6
9
40.54
34.81
36.72
9
0
0.0
8612
4
4
8
47.92
49.91
48.92
8
0
0.0
8613
7
3
10
40.52
41.04
40.68
10
0
0.0
8614
6
3
9
42.46
46.68
43.86
9
0
0.0
6615
5
6
11
44.92
44.74
44.82
11
0
0.0
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 20 (PAGE 3): 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
N
N
t
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8616 8617 8618 8619
3
2
5
40.05
47.74
43.13
8
3
37.5
3
5
8
46.14
48.29
47.48
9
1
11.1
5
5
10
37.87
38.60
38.23
10
0
0.0
4
3
7
30.79
32.05
31.33
7
0
0.0
8620 8621 0622
NOT PREGNANT
5
4
3
1
9
42.08
4
45.20
42.82 45.02
42.41 45.16
9
0
0.0
4
0
0.0
8623
NOT PREGNANT
8624
3
6
9
46.70
42.91
44.17
10
1
10.0
8625
5
2
7
36.79
36.38
36.67
7
0
0.0
8626
4
3
7
50.61
46.28
48.75
7
0
0.0
8627
4
6
10
40.45
37.46
38.66
10
0
0.0
8628
6
3
9
43.27
42.23
42.92
9
0
0.0
8629
5
5
10
39.54
35.42
37.48
10
0
0.0
8630
3
5
8
49.55
44.33
46.29
8
0
0.0
8631
1
8
9
50.67
41.77
42.76
9
0
0.0
8632
3
5
8
42-71
42.87
42.81
8
0
0.0
8633
5
3
8
46.72
46.72
46.72
8
0
0.0
8634
3
6
9
45.63
40.56
42.25
9
0
0.0
8635
5
3
8
47.21
44.37
46.14
8
0
0.0
8636
2
5
7
48.70
48.43
48.50
7
0
0.0
8637
5
8
13
43-34
36.16
38.92
14
1
7.1
----------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 20 (PAGE 4): 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
N
N
t
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8638 8639 8640 8641 8642 8643 8644 8645 8646
2
5
7
39.30
41.20
40.66
2
5
7
28.30
21.15
23.19
3
3
6
38.83
36.92
37.88
7
2
9
38.93
44-42
40.15
5
3
8
29.41
27.29
20.62
5
2
7
44.31
47.06
45.09
6
3
9
33.66
39.04
35.45
6
1
7
46.81
46.20
46.72
4
2
6
44.36
41.34
43.35
7
0
0.0
9
2
22.2
6
0
0.0
9
0
0.0
8
0
0.0
7
0
0.0
9
0
0.0
7
0
0.0
6
0
0.0
8647 8648 8649 8650 8651
ABORTED ON DAY 21 OF GESTATION
4
10
14
31.64
32.64
32.35
19
2
4
6
50.56
47.86
48.76
6
4
2
6
39.30
38.74
39.12
6
5
2
7
47.49
47.44
47.48
7
5
26.3
0
0.0
0
0.0
0
0.0
8652
ABORTED ON DAY 26 OF GESTATION
8653 8654 8655 8656 8657 8658 8659
NOT PREGNANT
4
3
7
47.50
50.89
48.95
7
0
3
3
----
55.17
55.17
3
6
4
10
35.96
38.16
36.84
10
4
4
8
48.11
47.03
47.57
8
4
4
8
44.99
45.96
45.47
8
3
3
6
49.84
42.97
46.40
6
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
0
0.0
---------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 20 (PAGE 5): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
RESORBED
-----------------------------------------------------------------------------------------------------------------
RABBIT #
KALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
t
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V
3.75 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
8660
ABORTED ON DAY 20 OF GESTATION
8661
ABORTED ON DAY 23 OF GESTATION
8662
1
3
4
19.01
15.77
16.58
7
3
42.8
8663 8664
ABORTED ON DAY 26 OF GESTATION
3
4
7
44.OS
30.09
36.07
10
3
30.0
8665
3
7
10
34.61
34.43
34.48
10
0
0.0
8666
5
6
11
42.90
44.00
43.50
11
0
0.0
8667
ABORTED ON DAY 19 OF GESTATION
8668
2
4
6
47.20
47.91
47.68
9
3
33.3
8669
ABORTED ON DAY 29 OF GESTATION
8670
2
3
5
50.20
51.33
50.88
6
1
16.7
8671
5
4
9
38.32
41.36
39.67
9
0
0.0
8672 8673 8674
6
3
9
29.33
34.07
30.91
11
2
18.2
4
4
8
35.84
33.07
34.46
8
0
0.0
2
4
6
52.72
50.08
50.96
6
0
0.0
8675
4
4
8
42.89
36.69
39.79
a
0
0.0
8676
8
3
11
39.19
39.02
39.14
12
1
8.3
8677
NOT PREGNANT
8678
2
6
8
50.63
46.32
47.40
8
0
0.0
8679
7
4
11
42.01
47.04
43.84
11
0
0.0
8680
3
5
8
43.71
41.13
42.10
8
0
0.0
8681
5
3
8
41.90
39.44
40.98
a
0
0.0
----------------------------------------------------------------------------------------------------------------
a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 20 (PAGE 6): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
NUMBER OF LIVE
AVERAGE FETAL
---- CONCEPTUSES
------
FETUSES
BODY WEIGHT (G)
RESORBED
-----------------------------------------------------------------------------------------------------------------
RABBIT #
TOTAL
TOTAL
N
N
%
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8682
11
4.65
11
0
0.0
8683
8
4.S9
8
0
0.0
8684
9
4.41
9
0
0.0
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8685
13
5.50
13
0
0.0
8686
9
4.81
10
1
10.0
8687
9
4.52
9
0
0.0
8688
10
5.17
10
a
0.0
8689
10
4.76
11
1
9.1
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8690
13
5.11
13
0
0.0
8691
ABORTED ON DAY 18 OF GESTATION
8692
8
4.69
a
0
0.0
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8693
NOT PREGNANT
8694
10
4.81
10
0
0.0
8695
9
5.45
9
0
0.0
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
8696
10
4.74
10
0
0.0
8697
4
S.15
4
0
0.0
8698
7
4.18
7
0
0.0
8699
11
S.16
11
0
0.0
8700
ABORTED ON DAY 19 OF GESTATION
---------------------------------------------------------------------------------------------------------------
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMBE
TABLE 21 (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 # 8572 8573 8574 8575 8576
CLs 4/ 5
6/ 3
7/ 4
8/ 3
MA 43.53
FA 52.56
MA 40.53
FA 54.15
NOT
FA
FA
50.14 49 .78
MA
FA
51.49 50.96
MA
FA
45.04 50 .45
MA
MA
54.58 51 .71
PREGNANT
FA 54.40
MA 47-26
MA 53.16
MA 49.10
FA 50.22
MA 51.36
FA 44-29
MA 38.16
FA 47.14
MA 38.53
FA 47.55
FA 32.73
FA 45.60
MA 49.44
FA 50.74
FA 48.47
MA 46.20
FA 55.37
FA 36.84
MA 52.75
FA 57.31
8577 8578 8579 8580
2/ 7 3/ 6 6/ 3
MA 52.03
FA 38.84
MA 56.80
NOT
MA
FA
50.09 46.67
FA
MA
42.66 44.36
MA
MA
52.82 55.31
PREGNANT
FA 44.60
MA 45.46
FA 43.40
MA
FA
41.97 46.65
MA
MA
42.37 39.60
KA / FA
47.53 S5.55
MA 45.41
FA 42.45
KA 52.91
8581
ABORTED ON DAY 26 OF GESTATION
8582 8/ 4
E
E
E
E
E
E
FA
FA
FA
E
46.39 46.23 49.15
8583
NOT PREGNANT
8584
NOT PREGNANT
-----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
E = EARLY RESORPTION
L = LATE RESORPTION
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) .
DENOTES POSITION OF CERVIX
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (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
15
16
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # 8585
8586
8587
CLs B/ 4
9/ 4
MA
MA
44.74 32.38
MA
FA
44.88 42.44
FOUND DEAD
L
FA
MA
FA
6.56 34.83 33.94 25.22
FA
FA
MA
MA
31.76 25.46 37.67 27.94
ON DAY 13 OF GESTATION
FA
22.73 MA
32.46
FA
31.43 FA
26.05
E
MA 39.15
E
FA 39.19
MA 36.77
8588 4/ 4
FA
FA
FA
MA
FA
MA
FA
E
51.46 48.08 52.60 50.53 51.20 49.91 51.26
8589 5/ 5
FA
FA
MA
FA
MA
MA
MA
MA
FA
39.63 33.12 37.70 37.56 37.35 35.47 32.25 34.21 30.17
8590 6/ 9
f4A
FA
FA
FA
MA
MA
MA
MA
MA
MA
MA
SO.64 43.50 36.13 42.80 40.31 39.34 44.89 41.01 34.61 37.65 46.09
8591 6/ 9
FA
FA
FA
FA
MA
MA
MA
FA
FA
43.91 44.15 41.70 39.60 36.33 40.91 38.25 33.96 34.37
6592
7/ 7
FA
FA
FA
14A
MA
FA
FA
MA
FA
MA
FA
MA
KA
33.92 29.84 32.76 34.39 23.52 27.72 33.05 41.56 3S.46 36.32 25.25 32.26 32.43
8593 4/ 5
MA
PA
MA
FA / MA
MA
FA
FA
FA
50.75 44.57 43.60 39.79 46.34 44.7B 44.80 37.41 40.74 ----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
CLs = CORPORA LUTEA/OVARY
FETAL
E = EARLY RESORPTION
L - LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITION OF CERVIX
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMBE
TABLE 21 (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
is
16
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # 8594 8595 8596 8597 8598 8599 8600 8601 8602 8603 8604
CLs 3/ 8 3/ 4 S/ 7 5/ 4 4/ 3 S/ 6 5/ 8 3/ 6 3/ 7 7/ 4
FA 51.81
MA 53.84
FA 41.24
MA 40.80
MA 52.37
FA 38.27
FA 53.78
FA 47.44
FA
44.17 FA
54.44 NOT
FA
E
50.44
FA
FA
52.62 45.20
MA
MA
39.09 42.15
FA
MA
44.99 26.59
MA
FA
49.06 49.07
FA
MA
38.66 42.15
MA
FA
48.89 50.99
MA
KA
46.88 45.46
MA
FA
43.13 42.87
FA
MA
49.57 47.59
PREGNANT
RA 53.16
MA 42.19
FA 45.46
FA 32.16
FA 40.74
E
FA 35.75
FA 39.54
MA 46.87
E
MA 54.46
MA 42.63
KA 37.79
FA 50.79
FA 38.59
FA 43.76
MA 52.50
FA 36.84
MA 41.54
FA 38.85
FA 38.27
FA 42.16
MA 28.66
MA 39.59
FA 36.72
FA 46.74
FA 38.11
FA 2S.30
MA 30.92
FA 43.38
MA 41.57
FA 41.86
MA 34.45
FA 38.97
E
FA 40.26
MA 35.19
FA 34.23
MA 35.18
MA 58.13
MA 39.52
MA 36.10
ML 20.58
MA 44.78
MA 52.04
FL 23.54
FA 36.00
MA 39.45
8605 9/ 6
MA
MA
MA
14A
MA
FA
MA
FA / FA
FA
8606
4/ 6
53.06 44.45 45.12 38.74 45.05 46.61 43.45 47.60 52.98 49.83
FA
MA
FA / MA
KA
FA
MA
MA
FA
48.63 54.94 50.24 55.13 48.58 50.38 48.18 52.08 48.92 -------- -------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
E = EARLY RESORPTION
L = LATE RESORPTION
DENOTES POSITION OF CERVIX
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMBE
TABLE 21 (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
15
16
------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 11
0.1 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # CLS 8607
NOT PREGNANT
8608 5/ 7
FA
MA
KA
FA
KA / MA
KA
FA
FA
FA
MA
43.30 31.39 33.84 31.67 30.93 35-26 34.20 36.33 32.75 23.52 28.58
8609 8610 8611
2/ 8 6/ 6 S/ 4
MA 44.13
FA 36.34
FA 40.66
MA 44.89
FA 42.52
MA 43.12
FA 39.28
MA 27.21
FA 40.79
MA 44.56
MA 40.71
MA 35.11
FA
MA
41.78 44.34
FA / MA
42.69 47.04
FA / MA
35.66 43.40
FA 42.98
KA 45.35
FA 28.02
MA 41.48
FA 45.61
FA 27.52
FA 34.34
FA 46.26
FA 36-19
8612 6/ 5
MA
MA
FA
FA
FA / MA
FA
MA
51.69 SO.94 49.90 44.28 53.91 41.29 51.55 47.76
8613 6/ 5
MA
MA
KA
MA
FA / MA
FA
MA
FA
MA
42.83 44.11 40.54 37.12 41.99 43.20 44.29 38.29 36.84 37.57
8614 6/ 7
KA
FA
MA
14A / FA
FA
MA
MA
MA
40.11 47.24 46.33 33.10 45.92 46.89 50.85 40.71 43.63
8615 4/ 8
FA
KA
FA / MA
FA
MA
FA
MA
FA
FA
KA
53.71 51.10 47.25 49.38 50.56 44.52 48.24 39.77 34.76 33.95 39.83
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A - ALIVE
CLS = CORPORA LUTEA/OVARY
FETAL
E . EARLY RESORPTION
L = LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITION OF CERVIX
PROTOCOL 418-010-. ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (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
is
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # 8616 8617 8618 8619 8620
CLs 6/ 3
7/ 6 6/ 8
6/ 5
FA 48.33
FA 54.55
MA 40.04
MA 33.99
NOT
L
MA
1.92 45.61
FA
14A
48.00 42.79
FA
FA
40.05 45.18
MA
MA
32.96 28.62
PREGNANT
KA 38.05
FA 42.87
KA 36.97
KA 27.60
L
MA / FA
10.57 36.49 47.16
E / MA
FA
54.77 47.12
MA
FA
FA
40.35 32.58 38.95
FA
FA
FA
32.40 30.64 33.12
L 4.50
FA 48.89
FA 36.22
MA 40.87
MA 35.03
MA 36.96
8621 8622 8623
4/ 6 4/ 3
FA 42.88
MA 44.17
NOT
FA
MA
48.02 44.46
FA
KA
45.02 46.73
PREGNANT
MA 46.03
MA 44.70
FA 42.56
MA
FA
MA
MA
35.43 37.84 41.41 43.07
8624 4/ 8
FA
FA
MA
E
FA
MA
FA
MA
FA
FA
37.03 43.12 47.31
43.84 47.81 41.56 44.99 48.09 43.80
8625 4/ 5
FA
14A
MA
MA
MA
MA
PA
40.93 35.34 35.11 40.93 39.22 33.34 31.83
8626 4/ 3
FA
KA
FA
FA
KA
MA
MA
40.34 51.83 43.13 47.37 50.33 51.14 49.13
8627 6/ 4
FA
MA
FA
FA
MA
FA / MA
MA
FA
FA
36.52 43.40 39.31 37.29 39.97 38.19 34.40 44.02 34.86 38.60
8628 S/ 6
MA
MA
MA
MA
FA / MA
FA
MA
FA
45.66 43.14 42.88 39.23 45.20 45.20 39.54 43.S4 41.94 -- - - -- - - -- - -- - -- - -- - -- - - - - -- - - - - --- --- - -- - -- - -- - - -- - - -- - - -- - -- - -- - -- - - -- - -- - - -- - - -- - - -- -- - - -- - - -- - -- - - - -- -- - - --
M = MALE
F = FEMALE
A = ALIVE E = EARLY RESORPTION
L = LATE RESORPTION
CLs = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) .
DENOTES POSITION OF CERVI
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (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 # 8629
CLa 5/ 6
FA
MA
MA
MA / MA
FA
MA
PA
FA
FA
38.26 40.62 39.71 34.07 42.91 32.68 40.37 37.01 32.04 37.10
8630 5/ 4
MA
MA
FA
FA
FA / FA
FA
MA
54.05 48.56 47.43 39.21 42.17 4S.38 47.48 46.03
8631 8/ 3
FA
FA
FA
FA
FA
FA
FA / MA
FA
35.24 43.84 44.36 47.44 43.31 40.76 34.09 50.67 45.15
8632 4/ 4
MA
FA
FA
MA
FA
FA
MA
FA
43.79 43.37 41.80 38.67 45.68 41.58 45.68 41.90
8633 4/ 5
FA
MA
MA
MA
FA
MA
MA
FA
51.73 52.61 49.99 49.08 44.96 43.98 37.95 43.48
8634 6/ 5
FA
FA
14A
FA
FA
MA
MA
FA
FA
46.72 38.26 41.76 40.70 37.00 46.46 48.68 38.21 42.46
8635 6/ 5
FA
MA
FA
MA
MA
MA
FA
MA
45.78 47.55 45.96 48.28 48.49 50.50 41.38 41.22
8636 4/ 3
MA
FA
FA
MA
FA
FA
FA
50.28 51.03 46.05 47.12 52.01 42.71 49.53
8637 12/ 4
E
FA
MA
FA
FA
MA
FA
FA
FA
MA
MA
FA
FA
MA
45.74 42.00 36.06 44.82 41.26 34.68 2S.38 24.35 38.22 50.86 37.05 41.21 44.37
----------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE E - EARLY RESORPTION
L = LATE RESORPTION
DENOTES POSITION OF CERVIX
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G).
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (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
15
16
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
------------------------------------------------------------------------
RABBIT # 8638 8639 8640 8641 8642 8643 8644 8645 8646 8647
CLS 2/ 5 6/ 5 1/ 6 4/ 6 6/ 4 5/ 4 3/ 6 4/ 5 3/ 3
FA
FA / FA
40.28 32.90 38.25
FA
FA
L
23.26 24.69 5.15
MA
FA
FA
44.53 33.60 38.80
MA
FA
FA
39,77 42.81 46.04
FA
MA
FA
35.34 30.14 30.91
MA
FA
14A
50.36 45.62 42.69
FA
FA
MA
42.26 39.28 41.03
MA
MA
MA
48.81 46.23 43.18
FA
FA
14A
41.73 40.94 47.24
ABORTED ON DAY
MA 46.95
FA 18.43
MA 34.42
14A 39.08
MA 27.71
MA 45.99
MA 35.48
14A
48.91 MA
48.25 21 OF
FA
MA
43.41 31.64 MA / MA
29.94 FA
38.36
26.65 MA
37.55
MA
MA
33.05 MA
28.84 MA
37.18
37.62 MA
29.20 MA
45.32
MA
MA
31.24 29.67
14A
MA
47.45 46.30
MA
MA
43.29 38.67
GESTATION
FA 51.17
FA 26.53
MA 36.19
FA 15.63
FA 48.50
MA 29.85
FA 46.20
L 16.40
MA 38.17
MA 31.16
FA 35.59
FA 12.83
MA 48.66
MA 34.66
8648
9/14
FA 31.21
FA 36.66
FA
FA
MA
30.62 35.19 35.13
FA
FA / FA
FA
29.89 38.65 39.35 29.65
ML
ML
12.63 15.99
MA
KA
29.30 36.20
L 0.57
L
FA
3.81 28.4
8649 3/ 3
FA
MA
MA / FA
FA
FA
45.80 48.91 52.20 50.56 46.91 48-16
8650 2/ 4
MA
MA / MA MA
FA
FA
40.62 34.76 47.05 34.78 36.42 41.06 ---------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE E = EARLY RESORPTION
L = LATE RESORPTION
CLS = CORPORA LUTEA/OVARY
FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) .
DENOTES POSITION OF CERVI
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 21 (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 # 8651
8652
CLs 4/ 5
MA
FA
FA / MA
MA
MA
47.52 50.95 43.93 52.77 47.93 45.91
ABORTED ON DAY 26 OF GESTATION
MA 43.32
8653
NOT PREGNANT
8654
3/ 7
FA
MA / FA
FA
MA
MA
MA
51.69 50.86 50.69 50.28 50.69 43.80 44.66
8655 6/ 4
FA
FA
FA
56.63 55.06 53.82
8656 5/ 8
MA
FA
MA
MA
FA
MA
MA
FA
MA
PA
37.66 40.21 41.71 32.74 43.55 39.48 33.27 33.61 30.92 35.29
8657 4/ 4
MA
MA
FA
KA
PA
FA
MA
FA
49.99 49.18 44.11 43.64 46.72 48.48 49.62 48.01
8658 3/ 5
FA
FA
KA
MA
MA
MA
FA
FA
47.86 47.10 44.22 46.38 45.20 44.16 45.44 43.43
8659 4/ 4
FA
MA
FA
MA
FA
MA
47.92 45.38 41.33 56.20 39.65 47.95 ----------------------------------------------------------------------------------------------------------------
M = KALE
F = FEMALE
A = ALIVE
CLS = CORPORA LUTEA/OVARY
FETAL
E - EARLY RESORPTION
L = LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITION OF CERVI)
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 21 (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 # CLs 8660
ABORTED ON DAY 20 OF GESTATION
8661
ABORTED ON DAY 23 OF GESTATION
8662 8663 8664 8665 8666 8667
3/ 5
L
FA
MA / L
FA
FA
14.24 18.19 19.01 17.85 14.21 14.92
ABORTED ON DAY 26 OF GESTATION
ML 21.94
4/ 9 6/ 5 9/ 3
MA 48.71
FA 30.36
FA / FA
42.52 18.62
FA
FA
32.81 37.90
MA 44.75
FA 33.12
FA 27.39
FA 30.14
L 0.66
MA 33.64
MA
FA
FA
FA
FA
MA
48.23 42.22 44.74 42.32 4S.72 40.93
ABORTED ON DAY 19 OF GESTATION
L
0.64 FA
36.87 MA
38.45
L
0.67 MA
36.62 MA
41.81
MA
38.68 PA
39.80 FA
47.19
FA
31.83 MA
33.S7 FA
41.82
MA 45.10
8668 8669
5/ 6
MA
FA
49.75 49.19
ABORTED ON
L / FA
L
FA
2.11 52.64 4.54 46.18
DAY 29 OF GESTATION
E
FA
MA
43.63 44.66
8670 2/ 5
FA
MA
FA
FA
L
MA
8671
6/ 5
52.67 40.51 51.90 49.43 3.38 51.89
FA
FA
FA
MA
MA
FA / MA
MA
MA
48.01 36.65 41.41 37.76 34.86 39.38 39.77 40.59 38.63
8672 3/ 9
MA
MA
MA
E
PA
MA
MA
L
FA
MA
FA
35.46 24.22 29.95
36.85 30.08 32.11 0.42 29.92 24.17 35.43
---------------------------------------------------------------------------------------------------------------
M = MALE
F = FEMALE
A = ALIVE
CLs = CORPORA LUTEA/OVARY
FETAL
E = EARLY RESORPTION
L - LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITION OF CERVI
PROTOCOL 418-010: ORAL (STOKACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (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 # 8673 8674 8675 a676 8677
CLS S/ 6 3/ 3
S/ 3 6/ 8
FA 30.95
FA 49.59
MA 46.05
KA 50.42
NOT
FA
MA
38.53 39.90
PA
FA
54.01 46.52
MA
FA
44.30 36.36
L
MA
20.57 43.22
PREGNANT
14A 38.87
/ 14A 53.09 FA 36.46 MA 39.04
t4A
KA
31.37 33.22
FA
KA
50.20 52.36
FA / MA
38.11 40.70
MA / MA
34.96 50.88
FA 30.59
FA 35.83
FA 37.16
FA 32.22
MA 40.51
FA 42.56
FA
MA
MA
37.34 31.27 28.67
MA 35.07
8678 5/ 6
FA
FA
FA / FA
FA
MA
FA
MA
8679
6/ 8
46.40 FA
49.58
48.47 FA
51.39
46.74 RA
46.44
44.42 45.12 FA / MA
45.11 46.38
55.24 MA
44.28
46.76 MA
41.01
46.02 FA
42.09
MA 38.65
MA 40.91
MA 36.42
8680
4/ 4
t4A 42.43
FA 43.95
FA
PA / MA
MA
39.22 39.32 45.29 43.40
FA 38.22
FA 44.94
8681 4/ 5
MA
t4A
MA
FA / MA
MA
FA
FA
48.74 40.64 37.25 35.10 35.94 46.95 42.29 40.92
--------------------------------------------------------------------------------------------------------------
M = KALE
P = FEMALE
A - ALIVE
CLS = CORPORA LUTEA/OVARY
FETAL
E = EARLY RESORPTION
L = LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
DENOTES POSITION OF CERVIX
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TA,BLE 21 (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
8682 5/ 6
A
A
A
A
A
A
A
A
A
A
A
4.69 4.09 4.36 4.52 4.67 4.81 4.33 4.92 5.01 4.87 4.90
8683 3/ 5
A 4.50
A 4.73
A/ A 4.74 4.74
A 4.50
A 4.27
A 4.49
A 4.75
8684 9/ 0
A
A
A
A
A
A
A
A
A
4.18 5.37 3.72 4.35 3.83 5.46 4.06 3.82 4.88
--------------------------------- -------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 11
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # CLs
8685 9/ 4
A
A
A
A
A
A
A
A
A
A
A
A
A
S.07 4.86 5.30 5.67 5.76 6.00 5.61 5.56 5.00 5.86 5.76 5.47 5.55
8686 6/ 5
A
A
A
A
A
A
A
E
A
A
4.69 4.83 4.95 4.86 4.47 5.06 4.82
4.84 4.79
8687 6/ 3
A
A
A
A
A
A
A
A
A
4.75 4.55 4 .69 4.36 4.52 4.37 4.60 4.53 4.30
8688 S/ 5
A
A
A
A
A
A
A
A
A
A
4.98 5.59 5.05 5.26 5.24 4.79 5.30 5.36 4.90 5.21
8689 6/ 7
A
A
A
L
A
A
A
A
A
A
A
5.10 4.52 4 .90
4.41 5.11 4.77 4.81 4.33 4.64 5.05
---------------------------------------------------------------------------------------------------------------
SATELLITE
DOSAGE GROUP 111
1.0 MG/KG/DAY
---------------------------------------------------------------------------------------------------------------
RABBIT # 8690
CLs 7/ 6
8691
A 5.70
A 5.41
A 3.85
ABORTED ON DAY
A 5.32 18 OF
A 5.39
A 5.08
GESTATION
A 5.84
A 4.52
A 4.97
A 5.22
A 5.01
A 5.10
A 5.07
8692 3/ 6
A
A
A/ A
A
A
A
A
4.93 4.89 4 .79 4.51 4.73 4.80 4.84 4.03
---------------------------------------------------------------------------------------------------------------
A = ALIVE
E = EARLY RESORPTION
CLS - CORPORA LUTEA/OVARY
FETAL
L = LATE RESORPTION
../" DENOTES POSITION
BODY WEIGHTS WERE RECORDED IN GRAMS (G) .
OF CERVIX
PROTOCOL 418-010; ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 21 (PAGE 12): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
-------- --------------------------------------------------------------------------------------------------------
FETUS #
1
2
3
4
5
6
7
a
9
10
11
12
13
14
is
16
-------- --------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP IV
2.5 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
RABBIT # CLs 8693
NOT PREGNANT
8694 3/ 7
A S.54
A 4.57
A/ A 4 .70 5.39
A 5.40
A 4.46
A 5.18
A 4.60
A 3.59
A 4.66
8695 6/ 4
A
A
A
A
A
A
A
A
A
5.30 5.59 5.70 6.23 4.71 5.52 5.21 5.65 5.17
----------------------------------------------------------------------------------------------------------------
SATELLITE DOSAGE GROUP V
3.75 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
RABBIT # CLs 8696 6/ 5
A 5.34
A 4.62
A 4.39
A 4.43
A 3.60
A 5.22
A 5.12
A 5.09
A 4.78
A 4.76
8697 2/ 4
A
A
A
A
5.03 5.32 5.26 5.00
8698 8699
5/ 3 6/ 7
A 3.94
A 5.30
A 4.33
A 5.62
A 4.03
A 5.10
A 4.58
A 5.11
A 4.11
A S.17
A 4.21
A 5.29
A 4.07
A S-53
A 5.38
A 5.34
A 4.29
A 4.67
8700
ABORTED ON DAY 19 OF GESTATION
----------------------------------------------------------------------------------------------------------------
A = ALIVE
E = EARLY RESORPTION
CLs = CORPORA LUTFA/OVARY
FETAL
L = LATE RESORPTION
"/" DENOTES POSITION
BODY WEIGHTS WERE RECORDED IN GRAMS (G) .
OF CERVIX
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUMB
TABLE 22 (PAGE 1) : FETAL ALTERATIONS - INDIVIDUAL DATA
---------------------- -------------------------------------------------------------------------------------------
DOSAGE GROUP 1 ----------------------
SPECIMENS
0 (VEHICLE) MG/KG/DAY
------------------------------------------------------------------------------------------
C;ROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
HIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8572
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS SKULL:
CONTAI
INTERP
1.0 mm
8573
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS SKULL: AN INT 1.0 mm
8574 8575
0( 0.0) 1( 10.0)
0/ 9 0/10
0/ 9 1/10
FETUS 10
LUNGS:
INTERMEDIATE
LOBE ABSENT
0/ 9 0/10
8576 8577
NOT PREGNANT 1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS HYOID bilat
8578 8579
0( 0-0) 3( 42.8)
0/ 7 0/ 7
0/ 7 1/ 7
FETUS 4
EYES;
CIRCUMCORNEAL
HEMORRHAGE,
right eye
0/ 7 2/ 7
FETUS HYOID bilat
FETUS HYOID bilat
- - - - -- - -- - - - - - -- - - -- - - - - ---- -- - - -- - -- - -- - -- - - -- -- - - -- - - - -- - -- - - -- - -- - -- - -- - -- - - -- - -- - - - -- -- - - -- - - - -- - -- - -- - -- - -
NIN = NUMBER OF SPECIMENS
WITH ALTERATIONS /NUMBER OF SPECIMENS
EXAMINED
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUM
TABLE 22 (PAGE 2): FETAL ALTERATIONS
- INDIVIDUAL DATA
---------------------------- -------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------- ------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
- - -- - - -- - - -- - - - - -- -- - - - - -- - - --- -- -- - - -- - - -- - - -- -- - -- - - -- - - -- - - - -- -- - - -- - -- - -- - -- - - - -- - - -- - - -- -- - -- - - -- - - -- - -- - - -
8580
NOT PREGNANT
8581 8582
ABORTED ON DAY 26 OF GESTATION a
1( 33.3)
0/ 3
0/ 3
1/ 3
FETUS THORAC SMALL, CENTR OSSIFI RIBS: lith
8583
NOT PREGNANT
8584
NOT PREGNANT
8585
0( 0.0)
0/ 8
FETUS 3 LATE RESORPTION,
C/ 8
0/ 8
autolysis precluded
further evaluation ---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED a. Doe 8581 aborted one late resorption and had eight late resorptions in utero on day 26 of gestation;
autoly
further evaluation.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUM
TABLE 22 (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
DESCRI
----------------------------------------------------------------------------------------------------------------
6586
1( 10-0)
1/10
FETUS TRUNK: TAIL:
8 SHORT
ABSENT
1/10
FETUS 8 KIDNEYS: bilateral; bilateral caudally;
FUSED, DISPLACED,
kidneys, SMALL,
1/10
FETUS STERNA FUSED, XIPHOI sterna
bilateral
THORAC
ABDOMEN:
SITUS
PRESEN
INVERSUS
CENTRU
5th an
ARCH,
bilate
RIBS:
and 5t
to eac
EXTRA
attach LUMBAR PRESEN SACRAL PRESEN CAUDAL PRESEN
8587
FOUND DEAD ON DAY 13 OF GESTATION b
8588
0( o.o)
0/ 7
0/ 7
0/ 7
8589
0( o.o)
0/ 9
0/ 9
0/ 9
---------------------------------------------------------------------------------------------------------------
NIN a. b.
= NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
Excluded from ossification site group averages and statistical analyses.
Doe 8587 was found dead on day 13 of gestation.
Eight fetuses were present
because of their early developmental ages. All fetuses appeared normal for
in utero; viability could not b developmental ages at gross ext
Soft tissue and skeletal examinations were not performed because of the early developmental ages of the fet
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUMB
TABLE 22 (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 NUMBER
ALTERATIONS N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8590
11(100.0)
0/11
11/11
FETUS 1 KIDNEYS:
DISPLACED,
1/11
FETUS SKULL:
left kidney, caudally
AN INT 1.5 mm
FETUS 2
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 3
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 4
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 5
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 6
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 7
KIDNEYS:
DISPLACED,
left kidney, caudally
-------------------
FETUS 8
KIDNEYS:
DISPLACED,
left kidney, caudally
-------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 5) t FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
N-UM-B-ER-------------------------------------------------------------------------------------------------------------
8590 (Cont.)
FETUS 9 KIDNEYS: DISPLACED, left kidney, caudally
FETUS 10 KIDNEYS: DISPLACED, left kidney, caudally
8591
2( 22.2)
0/ 9
1/ 9
FETUS 11 KIDNEYS: DISPLACED, left kidney, caudally
FETUS 9 LUNGS: INTERMEDIATE LOBE ABSENT
1/ 9
FETUS SKULL CONTA INTER 2.5 mi
8592
0( 0.0)
0/13
0/13
0/13
8593
1( 11.1)
0/ 9
0/ 9
1/ 9
FETUS SKULL
SUTUR
left
--------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUM
TABLE 22 (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 N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
N-U-MB-E-R ----------------------------------------------------------------------------------------------------------
8594
3( 60-0)
0/ 5
0/ 5
3/ 5
FETUS CAUDAL
MISALI
FETUS SKULL: CONTAI INTERF 4.5 mm
FETUS CAUDAL MISALI
8595 8596
0( 0.0) 1( 14.3)
0/ 5 0/ 7
0/ 5 0/ 7
0/ I/ 7
FETUS HYOID bilat STERN FUSED
8597
2( 22.2)
0/ 9
1/ 9
FETUS 8 EYES: CIRCUMCORNEAL HEMORRHAGE, right eye LUNGS: INTERMEDIATE LOBE ABSENT
1/ 9
FETUS STERN FUSED
8598
0( 0-0)
0/ 3
0/ 3
0/
-------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
N-ETFOSE STUDY OF
IN RABBITS
(SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 7): FETAL ALTERATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP Il
0.1 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NIN
DESCRIPTION
NIN
DESCRI
NUMBER
N(%)
NIN
DESCRIPTION
--------------------------------- -----------------------------------------------------------------------------
8599
1( 11.1)
0/ 9
1/ 9
FETUS 3
LUNGS:
INTERMEDIATE
0/ 9
LOBE ABSENT
8600
3( 33.3)
1/ 9
FETUS 9 LATE RESORPTION, autolysis precluded further evaluation
FETUS 10 LATE RESORPTION autolysis preclded further evaluation
0/ 9
2/ 9
FETUS SKULL: SUTURE right
FETUS STERNA FUSED,
FETUS 11
ABDOMEN:
DISTENDED
----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 410-010:
OP-AL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
STUDY OF N-ETFOSE
IN RABB ITS
(SPONSOR'S
STUDY NUMB
TABLE 22 (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(%)
--------------------
8601
2( 22.2)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
-------------------------------------------------------------------------------------------
0/ 9
1/ 9
FETUS 8
KIDNEYS:
DISPLACED,
left kidney, caudally
1/ 9
FETUS THORAC CENTRU OSSIFI
13th
8602 8603
0( 0-0) 1( 11.1)
0/ 7 0/ 9
0/ 7 0/ 9
0/ 7 1/ 9
FETUS HYOID: bilate
8604 0605 8606
NOT PREGNANT 0( 0.0) 3 ( 33 .3)
0/10 C/ 9
0/10 1/ 9
FETUS 4
LUNGS:
INTERMEDIATE
LOBE ABSENT
0/10 2/ 9
FETUS HYOID right
FETUS STERN FUSED
8607
NOT PREGNANT
8608
0( 0-0)
0/11
0/11
0/11
8609
0
0.0)
0/ 9
0/ 9
0/ 9
8610
0
0.0)
0/ 9
0/ 9
0/ 9
8611
0
0.0)
-------------------
0/ 9
0/ 9
0/ 9
------------ ------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF H-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 22 (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
DESCRI
----------------------------------------------------------------------------------------------------------------
8612
1( 12.5)
0/ 8
0/ B
1/ 8
FETUS LUMBAR
HEMIVE
betwee
arch a
8613 8614
0( 0.0) 3 ( 33 .3)
0/10 0/ 9
861S
2( 18.2)
0/11
0/10 2/ 9
0/11
FETUS 3 LUNGS: INTERMEDIATE LOBE ABSENT
FETUS 8 LUNGS: INTERMEDIATE LOBE ABSENT
0/10 1/ 9
FETUS HYOID left; ALA, S CAUDAL MISALI
2/11
FETUS SKULL
AN IN 4. 5 mi
NASAL DISPU
FETUS SKULL SUTUR right
--------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATION/SNUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR'S
STUDY NUMB
TABLE 22 (PAGE 10) : FETAL ALTERATIONS
- INDIVIDUAL DATA
---------------------------------- ------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
- -- - - -- - - -- - -- - - -- - - -- - - - - --- -- -- - - - - -- - -- - - -- - -- - -- - - -- - -- - - -- - - - -- -- - --
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE
EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
---------------------------------------------------------------------------------------------------
8616
o( o.0)
0/ 5
FETUS 2 LATE RESORPTION,
0/ 5
NIN
DESCRIP
--------------
0/ 5
autolysis precluded further evaluation
FETUS 5 LATE RESORPTION, autolySiS precluded further evaluation
FETUS 8 LATE RESORPTION, autolysis precluded further evaluation
8617
1( 12.5)
0/ 8
0/ 8
1/ 8
FETUS SKULL: SUTURE
8618 8619
0( 0.0) 0( 0.0)
0/10 0/ 7
0/10 0/ 7
0/10 0/
8620
NOT PREGNANT
---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TA,BLE 22 (PAGE 11) : FETAL ALTERATIONS - INDIVIDUAL DATA
- -- - - - -- - -- - - - -- - - -- - -- - - - - ----- - -- - - -- - - -- - - -- - - -- - -- - -- - -- - - - -- - -- - - -- - - -- - - -- - -- - -- - - -- - - -- -- -- - -- - -- - -- - -- - -
1.0 MG/KG/DAY DOSAGE GROUP 111 - - - -- - - -- - - -- - - - -- - -- - - - - - - ---- -- - - -- - -- - -- - - - -- - - -- - - -- -- - - -- - -- - -- -- - -- - - -- - - -- - -- - -- - - -- - - -- - - -- - -- - -- - -- - -- -
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
--------------------------------- -----------------------------------------------------------------------------
8621
1( 11.1)
0/ 9
0/ 9
1/ 9
FETUS SKULL:
CONTAI
INTERF 7.5 mm
8622 8623 8624
0( 0.0) NOT PREGNANT 1( 11.1)
0/ 4 0/ 9
0/ 4 0/ 9
0/ 4
1/ 9
FETUS SKULL AN IN 4. 0 mi
862S
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS THORA CENTR right CENTR RIBS: and 9
8626
0( 0.0)
0/ 7
0/ 7
0/ 7
8627
1( 10.0)
0/10
0/10
1/10
FETUS HYOID left
---------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTEPATIONS/NLTMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 12): FETAL ALTERATIONS - INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
-------- ---------------------------------------------------
SPECIMENS
(3ROSS EXTERNAL EXAMINATION
SOFT
TISSUE
EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
-- - -- - -- -- - - - -- - - -- - - -- - - -- - -- - ----- -- - - -- - - -- - - -- - - -- - -- - - -- - -- - -- - -- - - -- - - - -- - - -- - -- - -- - - -- - - -- -- - - - -- - - -- - -- -
8628
2( 22.2)
0/ 9
0/ 9
2/ 9
FETUS THORAC
CENTRA
lumbar
LUMBAR
CENTRU
FETUS THORAC PRESEN RIBS-. bilate SPLIT, distal medial
8629 8630 8631 8632
o( O.o) 0( 0-0) 0( 0-0) 2( 25.0)
0/10 0/ 8 0/ 9 0/ 8
0/10 0/ 6 0/ 9 1/ 8
FETUS I LLTNGS: INTERMEDIATE LOBE ABSENT
0/10 0/ 8 0/ 9 1/ 8
FETUS SKULL AN IN 4. 0 mi
8633
0( 0.0)
0/ 8
0/ 8
0/ 8
-------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATION/SNUMBER OF SPECIMENS EXAMINED a. Excluded from ossification site group averages and statistical analyses.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 22 (PAGE 13) : FETAL ALTERATIONS
- INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP 111
1.0 MG/KG/DAY
-------------------------------------------------------------------------------------
--------------------------
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
-- - - -- - - -- - - - -- - -- - - -- - - -- --- -- - -- - - - -- - - -- - -- - -- - -- - - -- - -- - - -- - - -- - - -- - -- - - -- - -- - - - -- - - -- - - - -- -- - -- - - -- - -- - -- --
8634
9(100.0)
0/ 9
9/ 9
FETUS 1 KIDNEYS:
DISPLACED,
0/ 9
left kidney, caudally
FETUS 2
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 3
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 4
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 5
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 6
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 7
KIDNEYS:
DISPLACED,
left kidney, caudally
-------------------
FETUS 8
KIDNEYS:
DISPLACED,
left kidney, caudally
-------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/ NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUM
TABLE 22 (PAGE 14): FETAL ALTERATIONS
- INDIVIDUAL
DATA
--------------------------------- ------------------------------------------------------------------------------
DOSAGE GROUP 111 --------------------
SPECIMENS
1.0 MG/KG/DAY
---------------------------------------------------
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE
EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
--------------------------------- ----------------------------------------------------------------------------
8634 (Cont.)
FETUS 9
KIDNEYS:
DISPLACED,
left kidney, caudally
8635
8(100.0)
0/ a
B/ 8
FETUS 1
KIDNEYS:
DISPLACED,
left kidney, caudally
0/ 8
FETUS 2
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 3
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 4
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 5
KIDNEYS:
DISPLACED,
left kidney, caudally
-------------------------------- ------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 22 (PAGE 15) ! FETAL ALTERATIONS
- INDIVIDUAL DATA
- - - -- - - -- - - - -- - - -- -- - - - - -- ---- - - -- - - -- - -- - -- - -- - - -- - - -- - -- - - -- - - -- - -- - -- -- -- - - -- - -- - - -- - - -- - -- - - -- - -- - -- - - -- - -- -
DOSAGE GROUP 111
1.0 MG/KG/DAY
-------------------------------------------------------------------------------------
--------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
N-U-MB-E-R -
-
-
-
--
-
-
-N-(%-)-
-
-
--
-
-
-
- N-I-N - - -
--
- D-E-SC-R-IP-T-IO-N-
-
--
--
-
--
-
-
--
-
-
--
-
--
-
-N-I-N
-
--
-
-
-D-E-SC-R-IP-T-IO-N-
-
--
-
-
-
--
-
-
--
-
--
-
--
-
NIN -- - -
--
-
--
DESCRI - -- - - --
8635 (cont.)
FETUS 6
KIDNEYS:
DISPLACED,
left kidney, caudally
FETUS 7
KIDNEYS:
DISPLACED,
left kidney, caudally
8636 8637
0( 0.0) 3( 23.1)
0/ 7 0/13
0/ 7 0/13
FETUS 8
KIDNEYS:
DISPLACED,
left kidney, caudally
0/ 7 3/13
FETUS STERN FUSED
FETUS STERN FUSED
FETUS STERN FUSED -------------------------------- ------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERAT IONS/NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR'S
STUDY NUMB
TABLE 22 (PAGE 16) : FETAL ALTERATIONS
- INDIVIDUAL DATA
- - -- - - -- - -- - -- - -- - -- - - - - -- -- -- - -- - - -- -- - -- - - -- - - -- - -- - - -- - -- - - - -- -- - - -- - - -- - - -- - - -- - -- - -- - -- - -- - -- - - -- - - -- - -- - -- -
DOSAGE GROUP IV
2.5 MG/KG/DAY
----------------------------------------------------------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8638
o( o.o)
0/ 7
0/ 7
0/ 7
8639
2( 28.6)
0/ 7
FETUS 3 LATE RESORPTION, autolysis precluded further evaluation
FETUS 8 LATE RESORPTION, autolysis precluded further evaluation
0/ 7
2/ 7
FETUS PELVIS OSSIFI
FETUS PELVIS OSSIFI
8640
2( 33.3)
0/ 6
0/ 6
2/ 6
FETUS HYOID: left
FETUS HYOID right
8641
0( 0.0)
0/ 9
0/ 9
0/ 9
8642
1( 12.5)
0/ 8
0/ 8
1/ 8
FETUS PELVI OSSIF
------------------- -------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 17) : FETAL ALTERATIONS
- INDIVIDUAL DATA
- - - -- - - -- -- - -- - - -- - - -- - - - --- -- -- - -- - -- - -- - - -- - -- -- - -- - -- - - -- -- - -- - - - -- - -- - - - -- - - -- - -- - - -- - -- - -- - -- - - -- - - -- - -- - --
DOSAGE GROUP IV
2.5 MG/KG/DAY
- - - -- - - -- - -- -- - - - -- - -- - - - - -- -- - -- - -- - -- - - -- -- - - - -- - -- - - -- - -- - -- - -- - - -- - - -- - - -- - - - -- - -- - - -- - -- - -- - -- - - -- - - -- -- - --
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N (!k)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8643
1( 14.3)
0/ 7
0/ 7
1/ 7
FETUS SKULL:
AN INT
1.5 mm
8644 8645
1( 11.1) 3( 42.8)
1/ 9 0/ 7
FETUS 5
SNOUT:
SHORT,
protrudes
tongue
0/ 9
1/ 7
FETUS 6
LUNGS:
INTERMEDIATE
LOBE ABSENT
0/ 9
2/ 7
FETUS SKULL: SUTURE
FETUS SKULL: SUTURE
8646
3( 50-0)
0/ 6
3/ 6
FETUS 1 VESSELS:
COMMON TRUNCUS
0/ 6
ARTERIOSUS
LUNGS: SMALL, all lobes;
FUSED, all lobes
----------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 18) : FETAL ALTERATIONS - INDIVIDUAL DATA
---------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV
2.5 MG/KG/DAY
-------- ---------------------------------------------------------------
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
- -- - - -- - -- - - -- - - -- - - - - - - - ---- - -- - -- - - -- - -- - - -- - - -- - -- - - -- - -- - - -- - -- - - -- - -- - - -- - - - -- - - - -- -- - -- - -- - -- - - -- - -- - - -- - -
8646 (Cont.)
FETUS 2 EYES: CIRCLTMCORNEAL HEMORRHAGE,
bilateral,
FETUS 6 KIDNEYS: DISPLACED, left kidney, caudally
8647 8648
ABORTED ON DAY 21 OF GESTATION a
3( 21.4)
0/14
FETUS 10 LATE RESORPTION, autolysis precluded further evaluation
0/14
3/14
FETUS 11
LATE RESORPTION
autolysis precluded
further evaluation ------- ------------------------------------------------------------------------------------------
FETUS STERNA FUSED,
FETUS STERN; FUSED,
NIN a.
= NUMBER Doe 8647 in utero appeared 1, 2, 4,
OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED aborted one live fetus and one late resorption and had eight live fetuses, 2 dead fetuses and one on day 21 of gestation. Autolysis precluded further evaluation of the late resorptions. All rema normal at gross external examination for developmental ages and appeared normal at soft tissue exa 5, 6, 8, 9, 10, 11 and 12 had pelvis, pubis not ossified (bilateral) at skeletal examination.
PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STUDY NUMB
TABLE 22 (PAGE 19): FETAL ALTERATIONS - INDIVIDUAL DATA
----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP IV -------------------
SPECIMENS
2.5 MG/KG/DAY ------ -------- ----------- --------------------------------------------------------
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
RABBIT NUMBER
WITH ANY ALTERATIONS
N(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
8648 (Cont.)
FETUS 14 LATE RESORPTION, autolysis precluded further evaluation
FETUS SKULL: SUTURE STERNA FUSED,
FETUS 15 LATE RESORPTION,
autolysis precluded futher evaluation
8649 8650 6651
0( 0.0) 0( 0.0) 4( 57.1)
0/ 6 0/ 6 0/ 7
0/ 6 0/ 6 4/ 7
FETUS 1 KIDNEYS: DISPLACED, left kidney, caudally
0/ 7
FETUS 2 KIDNEYS: DISPLACED, left kidney, caudally
FETUS 5 KIDNEYS: DISPLACED, left kidney, caudally --------------------------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENSEXAMINED
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR'S
STUDY NUMB
TABLE 22 (PAGE 20): FETAL ALTERATIONS
- INDIVIDUAL
DATA
- -- - -- - - -- - -- - - -- - --- - - - ---- -- - -- - -- - -- - - -- - -- - - -- - - -- - -- - -- - -- - - -- - - -- - -- - - - -- - - -- - -- - -- - -- - - -- - - - -- - - -- -- - -- - --
DOSAGE GROUP IV
2.5 MG/KG/DAY
- - -- --- --- - - - - -- - - --- - - ------ -- -- - ---- ----- - - ----- --- --- -- - - --- - -- -- -- ---- - -- -- - -- -- - -- -- -- --- ----- -- -- --- -- -- --
SPECIMENS
GROSS EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NIN
DESCRIP
NUMBER
N (%)
NIN
DESCRIPTION
NIN
DESCRIPTION
-------- --------------------------------------------------------------------------------------------------------
8651 (Cont.)
FETUS 7
KIDNEYS:
DISPLACED,
left kidney, caudally
8652
ABORTED ON DAY 26 OF GESTATION
a
8653 8654 8655 8656
NOT PREGNANT 0( 0.0) 0( 0.0) 1( 10.0)
0/ 7 0/ 3 0/10
0/ 7 0/ 3 0/10
0/ 7 0/ 3 1/10
FETUS SKULL: CONTAI INTERF 3.5 mm
8657
1( 12.5)
0/ 8
0/ 8
1/ 8
FETUS STERNA FUSED,
8658
1( 12.5)
0/ 8
0/ 8
1/ 8
FETUS STERNA FUSED,
8659
0( 0.0)
0/ 6
0/ 6
0/ 6
--- --------- - --- - --- - - ----------- ------------- ------ -- ----------- ------- --- ----- --- --- - ------ --- ---- -- - - - -- - --
NIN a.
= NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED Doe 8652 aborted one dead fetus and had 2 live fetuses and one late resorption in utero and the late resorption appeared normal at gross external examination for developmental
on day 26 of gestati ages. All fetuses a
soft tissue and skeletal examinations.
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 22 (PAGE 21): FETAL ALTERATIONS - INDIVIDUAL DATA
- -- - -- - -- - - -- - - - - -- - - -- - - - - ---- --- - - -- - - -- -- - - -- - - -- - - -- - -- - -- - -- - - -- - -- - - -- - - - -- - - -- - -- -- - - -- - - -- - - -- - -- - - -- -- -
DOSAGE GROUP V
3.75 MG/KG/DAY
- - -- -- - - -- - - -- -- - - -- - - -- - - - -- -- -- -- - - -- - - -- - - -- - -- - -- - - -- - -- - -- - -- - - -- - - -- - -- - - - -- - -- - - -- - -- - -- - - -- - - -- - - -- - -- --
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT NUMBER
ALTERATIONS N(t)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8660
ABORTED ON DAY 20 OF GESTATION
a
8661 8662
ABORTED
ON DAY 23 OF GESTATION
b
0( 0.0)
0/ 4
FETUS 1 LATE RESORPTION, autolysis precluded further evaluation
0/ 4
0/ 4
FETUS 4 LATE RESORPTION, autolysis precluded further evaluation
FETUS 7 LATE RESORPTION, autolysis precluded further evaluation
8663
ABORTED ON DAY 26 OF GESTATION c
---------------------------------------------------------------------------------------------------------------
NIN a. b.
C.
= NUMBER OF SPECIMENS WITH ALTERATIONS/ NUMBER OF SPECIMENS EXAMINED
Doe 8660 aborted fetuses appeared
three dead fetuses and had seven fetuses of undetermined viability normal for their developmental ages at gross external examination.
in utero on day 20 of g Soft tissue and skelet
were not performed because of the early developmental ages of the fetuses.
Doe 8661 aborted one dead fetus and had six live fetuses and
precluded further evaluation of the late resorptions.
Fetus
two late resorptions 6 had edema (dorsal
in utero on day 23 of ges and ventral neck) at gross
examination.
All remaining fetuses appeared normal at gross external examination for developmental age. A
normal at soft tissue examination. Fetuses 1, 2, 3, 5, 6, 7 and 9 had pelvis, pubis not ossified (bilatera
examination. Doe 8663 aborted
nine
dead fetuses and one late resorption
on day
of the late resorption.
All fetuses were partially cannibalized.
26 of gestation. Fetuses 1, 2, 3,
gross external examination for developmental age and appeared normal at soft tissue
Autolysis precluded fur
4, 5, 6, 8 and 10 appea
examination.
Fetuses 2
10 had pelvis, pubis not ossified (bilateral) and fetus 4 had ribs, split (right 12th, medial-distal) at sk
PROTOCOL 418-010:
OPAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S STUDY Numi
TABLE 22 (PAGE 22): 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(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8664
3( 42.8)
0/ 7
FETUS 6 LATE RESORPTION, autolysis precluded
0/ 7
3/ 7
FETUS HYOID: left
further evaluation
FETUS
FETUS 7 LATE RESORPTION,
HYOID: right
autolysis precluded further evaluation
FETUS HYOID:
FETUS 8
bilate
LATE RESORPTION,
autolysis precluded
further evaluation
8665
2( 20.0)
1/10
FETUS 8
BODY: EDEMA,
SNOUT:
SHORT,
protrudes
EARS: SMALL,
bilateral
neck tongue
0/10
2/10
FETUS STERN FUSED
FETUS STERN FUSED HYOID bilat
8666
0( o.o)
-------------------
0/11
0/11
0/11
-------------------------------------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
STUDY OF N-ETFOSE
IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 22 (PAGE 23) : FETAL ALTERATIONS
- INDIVIDUAL DATA
----------------- - --- - ----------- - -------- ------------- ----- ------------------- - ----- --- ------ ----------- - -----
DOSAGE GROUP V
3.75 MG/KG/DAY
-- - - - -- - -- - -- - - -- - - -- - - - --- -- -- - - -- - -- - -- - - -- - -- - -- - - - -- - - -
SPECIMENS
GROSS EXTERNAL EXAMINATION
WITH ANY
RABBIT
ALTERATIONS
NUMBER
N(%)
NIN
DESCRIPTION
- -- - - -- - - -- -- - - - -- - -- - - - --- -- - -- - -- - -- - -- - - -- -
SOFT TISSUE EXAMINATION
NIN
DESCRIPTION
-------------SKELETAL
NIN
DESCR
8667
ABORTED ON DAY 19 OF GESTATION
a
8668
2( 33 .3)
0/ 6
FETUS 3 LATE RESORPTION, autolysis precluded further evaluation
1/ 6
FETUS 2
LUNGS:
INTERMEDIATE
LOBE ABSENT
1/ 6
FETUS HYOID left
FETUS 5 LATE RESORPTION, autolysis precluded further evaluation
8669 8670
ABORTED
ON DAY 29 OF GESTATION
b
1( 20.0)
0/ 5
FETUS 5 LATE RESORPTION, autolysis precluded further evaluation
0/ 5
FETUS THORA HEMIV 12th, attac RIBS medi
8671
2( 22.2)
0/ 9
1/ 9
FETUS 5
LUNGS:
INTERMEDIATE
LOBE ABSENT
1/ 9
FETU SKUL SUTU righ
-------------------------------------------- -----------------------------------------------------------------
NIN a.
b.
= NUMBER Doe 8667
appeared
performed Doe 8669
OF SPECIMENS WITH ALTERATIONS/ NUMBER OF SPECIMENS EXAMINED
aborted two dead fetuses and had two fetuses of undetermined viability in utero
normal for their developmental ages at gross external examination.
Soft tissue
on day 19 of and skeletal
because of the early developmental ages of the fetuses. aborted five late resorptions and had five late resorptions
in utero on day 29 of gestation;
further evaluation.
gest exam
auto
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY
N-ETFOSE STUDY OF
IN RABBITS
(SPONSOR 'S STUDY NUMB
TABLE 22 (PAGE 24): FETAL ALTERATIONS
- INDIVIDUAL DATA
-----------------------------------------------------------------------------------------------------------------
DOSAGE GROUP V ----------------------------------
3.75 MG/KG/DAY ---------------------------------------------------
SPECIMENS
GROSS EXTERNAL
EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL
WITH ANY
RABBIT
ALTERATIONS
NIN
DESCRIPTION
NIN
DESCRIP
NUMBER
N(%)
NIN
DESCRIPTION
---------------------------------- -------------------------------------- ---------------------------------------
8672
1( 11.1)
0/ 9
FETUS 8 LATE RESORPTION, autolysib precluded
1/ 9
FETUS 6
LUNGS:
INTERMEDIATE
LOBE ABSENT
1/ 9
FETUS 6 SKULL: AN INTE 3.0 n=
further evaluation
STERNAL
FUSED,
CAUDAL
MISALI(
15th
8673
8674 8675 8676
1( 12.5)
0/ a
0( 0.0) 0( 0.0) 0( 0.0)
0/ 6 0/ 8 0/11
FETUS 2 LATE RESORPTION, autolysis precluded further evaluation
1/ 8
0/ 6 0/ 8 0/11
FETUS 3 HINDLIMB: CONSTRICTED,
SKIN right
0/ 8
0/ 6 0/ 8 0/11
8677
NOT PREGNANT
------- ----------------------------------------------------------------
NIN = NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED
PROTOCOL 418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS
(SPONSOR'S
STUDY NUM
TABLE 22 (PAGE 25):
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(%)
NIN
DESCRIPTION
NIN
DESCRIPTION
NIN
DESCRI
----------------------------------------------------------------------------------------------------------------
8678
1( 12.5)
0/ 8
0/ 8
1/ 8
FETUS HYOID:
right STERNA
FUSED,
8679 8680
0( 0.0) 1( 12.5)
0/11 0/ 8
0/11 1/ 8
FETUS 6
LUNGS:
INTERMEDIATE
LOBE ABSENT
0/11 0/ 8
8681
0( 0.0)
0/ 8
0/ 8
0/ 8
- -- - - -- - - -- - - -- - - -- - - - - ---- - -- -- - - -- - -- - -- -- -- - - - -- - -- - - -- - -- - -- - - -- - - -- - - - -- - -- - - -- - - -- - -- - -- - -- - - -- - -- - -- - - --
NIN = NUMBER OF SPECIMENS
WITH ALTERATIONS /NUMBER OF SPECIMENS
EXAMINED
APPENDIX C PROTOCOL AND AMENDMENT
418-010:PAGE C-1
icPiRLNUDICA
Argus Research Laboratories,Inc. 905 Sheehy Drive.BuildingA Horsham, PA 19044 Telephone: (215)443-8710 Telefax:(215)443-8587
PROTOCOL 418-010 SPONSOR'S STUDY NUMBER: 6316.8
STUDY TITLE: PURPOSE:
TESTING FACILITY:
STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATIVE STUDY MONITOR:
oral(Stomach Tube) Developmental ToxicityStudy of N-ETFOSE inRabbits
The purpose ofthisstudy isto detectadverse effectsof N-ETFOSE on New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbitsand development ofthe embryo and fetusconsequent to exposure of the doe from implantatiotno closureofthe hard palate.This study evaluatesICH Harmonised TripartitGeuidelinestages C and D ofthe reproductiveprocess ina nonrodent species.
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 AssociateDirectorof Research
3M ToxicologyServices 3M Center Building220-2E-02 St.Paul,Minnesota 55144-1000
Marvin T. Case, D.V.M.,Ph.D. Telephone: (651)733-5180 Telefax: (651)733-1773
Andrew M. Seacat,Ph.D. Telephone: (651)575-3161 Telefax: (651)733-1773
41"10:PAGE C-2
Protocol41"l 0 Page 2
REGULATORY
CITATIONS:
U.S. Food and Drug Administration(1994). InternationaClonference 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 Practice Standard 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 study willbe conducted incompliance withthe Good LaboratoryPractice(GLP) regulationscitedabove.
Allchanges or revisionsofthisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained withthe protocol.
The QualityAssurance Unit(OAU) willauditthe protocol,the raw data and the report, and willinspectcriticaplhases ofthe study inaccordance withthe Standard Operating Procedures ofArgus 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 ofthe study. Should significandteviationsfrom GLP regulationsoccur,each willbe described indetail, togetherwith how the deviationmight affectthe qualityor integritoyfthe study.
SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE:
See ATTACHMENT
I to the protocol.
41"10:PAGE C-3
Protocol418-010 Page 3
TEST ARTICLE AND VEHICL
identification:
Test Article:
Name: Physical Description: Lot/Batch Number: SpecificGravity: Purity:
ExpirationDate:
N-ETFOSE. Waxy solid. FM-3929(30035, -1.7. 99.1%. May, 2000.
30037, 30039).
informationon the identityc,omposition,strengthand purityof the testarticleison file with the Sponsor.
Vehicle:
2% TweenG) 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplierand lotidentificatioofnTween 80 tobe documented inthe raw data.
Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present in the vehiclethatwould interferewith the resultsof thisstudy. Therefore, no analyses other than those mentioned inthisprotocolwillbe conducted.
Safety Precautions:
Gloves, mask, appropriateeye protectionand a uniform/labcoat are to be worn during formulationpreparationand administration.The MaterialSafety Data Sheet (MSDS) is attachedto the protocol(seeATTACHMENT 2).
Storage:
Bulk Test Article: Vehicle Components:
Prepared Vehicle:
Prepared Formulations:
Room Room
Room
Room
Temperature. Temperature.
Temperature.
temperature (samples to be frozen).
Alltestarticleshipments 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 cartonsshould be labeledappropriately.The recipientshould be notifiedin advance of shipment.
418-010:PAGE C-4
PmtoCol 41 B-010 Page 4
FORMULATION: Frequency of Preparabon: Formulations(suspensions)willbe prepared dailyatthe TestingFacility. Detailedpreparationprocedures are attachedtothisprotocol(ATTACHMENT 3).
Ad*ustment forPuri : The testarticlweillbe considered 100% pure forthe purpose ofdosage calculations.
Testing FacilityReserve Samples: The TestingFacilitwyillreservea sample (1 g) ofeach lotofbulktestarticlaend a sample (5 mL) of each lotofvehicleused duringthe course ofthe study. Samples will be storedunder the previouslycitedconditions.
ANALYSE : Samples additionatlothose describedbelow may be taken ifdeemed necessary during the course ofthe study.
Bulk Test ArticleSamt)ling: No analyses ofthe bulktestarticlweillbe conducted duringthe course ofthisstudy. Informationon the stabilitoyfthe bulktestarticlieson filweiththe Sponsor.
Analyses of Prepared Formulation : Homogeneity and stabilitoyf prepared formulationson filewiththe Sponsor. However, recordswillbe maintained to document how the testarticlfeormulationswere prepared.
ConcentrationofTest ArticleFormulations:
Concentration of the prepared formulations wilibe verified during the course of this
study. Duplicatesamples (2mL each) willbe taken from the firsatnd lastpreparation on the day prepared. One sample ofeach setwillbe shipped foranalysis;the remainingsamples willbe retainedatthe Testing Facilitays backup samples. Backup samples willbe stored under the previouslycitedconditionsand discardedatthe Testing Facilituypon requestofthe Sponsor.
418-010:PAGE C-5
Pmtocol 41 B-010 Page 5
ShiPRina Instructions:
Samples to be analyzed willbe shipped (frozen on dry ice)to:
Kris J. Hansen, Ph.D. 3M Environmental Technology and Safety Services
935 Bush Avenue
Building2-3E-09 St.Paul, Minnesota 55133-3331
Telephone: (612)778-6018
Telefax:
(612)778-6176
The recipientwillbe notifiedinadvance of sample shipment.
DISPOSITION:
Prepared formulationswillbe discarded at the Testing Facility.Allremaining bulk test articlweillbe returned to the Study Monitor at the previouslycitedaddress upon completion of allwork with the testarticle.
TEST SYSTEM:
Species/Strain and Reason for Se ection:
The New Zealand White [Hra:(NZW)SPF] rabbitwas selectedas 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;hisstrainofrabbithas been demonstrated to be sensitiveto
('-3);
developmental toxins;3) historicadlata and experience existat the Testing Facility and 4) the testarticleispharmacologicallyactiveinthe species and strain.
Number and Sex: Population evaluated:
110 timed-pregnant female rabbits(22 per dosage group).
Population selected for toxicokinetiecvaluation:
19 satellitfeemale rabbits(fiveat the low and high dose levelsplus three at 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 in the raw data,and the weight range willbe included in the finalreport.
418-010:PAGE C-6
Protoool41 "10 Page 6
Source:
Covance Research Products, Inc. Swampbridge Road, Box 7200 Denver, Pennsylvania 17517
The rabbitswillbe shipped infilterecdartons by truckfrom Covance Research Products,Inc.,Denver, Pennsylvania, to the Testing Facility.
Identification: Rabbits are permanently identifieudsing MonelS self-piercinegar tags (Gey Band and Tag Co., Inc.,No. MSPT 20103). Female rabbitsare given unique permanent identificationnumbers when assigned to the study on the basis of day 0 of presumed gestationbody weights.
ANIMAL HUSBANDRY:
Allcage sizes are in compliance with the Guide forthe Care and Use of Laboratory
AnimaiS(4).
Housing: The rabbitswillbe individuallhyoused in unitsof sixto eightstainlesssteelcages. No nestingmaterialswillbe suppliedbecause the female rabbitswillbe sacrificedbefore parturitioinsexpected.
Room Air,Temperature and Humidi The animal room isindependently suppliedwith at leastten changes per hour of 100% freshairthathas been passed through 99.97% HEPA filtersR.oom temperature willbe maintained at61 OF (160C) to 720F (220C) and monitored constantly.Room humidity willalso be monitored constantlyand maintained at 30% to 70%.
Light:
An automaticallcyontrolle1d2-hourlight1:2-hourdarkfluorescenltightcyclewillbe
maintained. Each dark periodwillbegin at 1900 hours EST.
Diet: Approximately 150 g ofCertifiedRabbit ChowS #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.
418-010:PAGE C-7
Pmtocol41Ml 0 Page 7
Water:
Water willbe available ad 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 is analyzed monthly forpossible bacterialcontamination and twice annuallyforpossiblechemical contamination.
Contamina
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 Supplierby breeder male rabbitsof the same source and strainbefore shipment to the Testing FacilityT.he day mating occurs willbe designated day 0 of presumed gestation.The rabbitswillbe mated on five consecutivedays 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 records and 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 withthe dietaryroute,the exact dosage can be accuratelyadministered;and 2) itisone of the possible routes of human exposure.
Method and Freguency:
Female rabbitswillbe given the testarticleonce 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 selected on the basis of a dosage-range study (Argus Research Laboratories,Inc.,Protocol 41 B-01OP).
418-010:PAGE C-8
PmtoCol41"10 Page 8
Dosaae Levels.Concentrationsand Volumes:
Dosage
Number
Of R:abbds
Dosage
Concentration (mg/mL)
Dosage Voiunw
Arous Batch Number
22+3*
0 (Ve icle)
0
5
B-41B-01O-A(Day.Month.Year)
22+5*
0.1
0.02
5
B-418-01O-B(Day.Month Year)
111
22+3'
1.0
0.2
5
B-418-01O-C(Day.Month.Year)
IV
22+31
2.5
0.5
5
B@41 8-01G-D(Day.Month.Year)
v
22+5.
3.75
0.75
5
B-41 B-01O-E(DaX.Month. earl
a. Rabbitsassignedto toxicokomw evaluation.
The testarticlweillbe considered1()0% pure forthe purpose ofdosage calculations.
TESTS, ANALYSES AND MEASUREMENT
Viability: AllPeriods:
At leasttwice daily.
ClinicalObservations and/or General At)g)earance:
Predosage Period: Dosage Period:
At leastonce.
Twice daily.Priorto dosage administrationand once approximately one hour postdosage.
Postdosage 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 atthe Testing Facility.
Dosage Period:
Postdosage Period:
Daily.
Daily.
Feed ConsumRtion Values: Predosage Period:
Recorded dailyafterarrivalat the Testing Facility (valuesnot tabulated).
Dosage Period:
Recorded daily.
418-010:PAGE C-9
Pmtocol 418-010 Page 9
Postdosage Period:
Recorded daily.
Feed consumption values duringthe dosing period willbe tabulatedforthe same intervalsas body weight evaluations.
Caesarean -SectionIng Observations:
Rabbits willbe Caesarean-sectioned on day 29 of presumed gestation. The fetuses will be removed from the uterus and placed in individuaclontainers.The rabbitswillbe examined fornumber and distributioonf:
Corpora Lutea.
ImplantationSites [Placentaeappearance (size,coloror shape ifabnormal) 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 fetuses demonstrating marked to extreme autolysisare considered to be lateresorptions.)
Earlyand Late Resorptions. (A conceptus isdefined as a lateresorptionifitisgrosslyevidentthat organogenesis has occurred;ifthisisnot the case, the conceptus is identifieads an earlyresorption.)
Fetal Observations:
Body Weiahts and Identification:
The body weight of each fetuswillbe recorded. Only body weights of livefetuses will be used to determine littefretalbody weight averages. Fetuses willbe tagged with identificationnoting study number, littenrumber and uterinedistribution.
Gross ExternalAlterations:
Allfetuseswillbe examined forgross externalalterations.Late resorptionsand dead fetuses also willbe examined forgross externalalterationtso the extent possible but
suchobservatiownislnlotbe includeidneithedratasummarizatioornstatistical
analyses.
418-010: PAGE C-1 0
Pmtocol 418-010 Page 10
SoftTissue Examinationand Sex:
Allfetuseswillbe examined internalltyo determine sex. Cavitatedorgans willbe evaluated inallfetuses by dissection@'@A. singlecross-sectionwillbe made between the parietaland frontalbones, and the brain willbe examined in situ.
SkeletalExamination:
Allfetuses willbe examined forskeletalalterationsafterstainingwith alizarinred S('). Skeletalpreparationswillbe retainedinglycerinwiththymol added as a preservative.
Representative photographs of fetalgross, softtissueand skeletalalterationswillbe taken.
METHOD OF SACRIFICE:
Beuthanasia&D Special (manufactured by Schering-Plough Health) willbe used to sacrificreabbits(viaintravenousinjectiona)nd livefetuses(viaintraperftoneailnjection).
NECROPSY:
Gross lesionswillbe retainedinneutralbuffered10% formalinforpossiblefuture evaluation(corresponding tissueswillbe retainedfrom rabbitsin the vehiclecontrol group atthe discretionofthe Study Director).(Exception: Parovarian cysts willbe discarded;these are common, spontaneous lesionsinrabbits.)Unless specifically citedbelow, allother tissueswillbe discarded.
SatelliteRabbits Assianed to Toxicokinetic Sample Collection:
On day 21 of presumed gestation(theday followingthe lastdosage), toxicokinetic samples willbe collectedfrom the rabbitsassigned to the toxicokinetiecvaluation. Followinganesthesia of pentobarbitalb,lood samples (approximately4 mL per rabbit) willbe collectedfrom the inferiovrena cava intoserum separatortubes and centrifuged. The resultingserum (approximately2 mL) willbe immediately frozenon dry iceand maintained frozen (-700C) untilshipment tothe Sponsor foranalysis.The liverwillbe excised, weighed, and a sample willbe taken from the rightlateralobe,frozen and retainedat -700C untilshipment to the Sponsor foranalysis.
Rabbits willbe Caesarea n-sectionedand fetuses willbe examined grossly to the extent possibleas described above forrabbitsassigned to the main study. Fetuses and placentae willbe pooled per liftearnd 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.,atthe previouslycited
418-010: PAGE C-1 1
Pmtoool 418-010 Page I I
address foranalysis.Both the recipienatnd the Study Monitorwillbe notifieidn advance ofsample 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 sulfideto confirm the absence of implantationsftes(7)
Rabbits Found Dead or Moribund:
Rabbits thatdie or are sacrificedbecause of moribund condition,abortionor premature deliverywillbe examined forthe cause of death or moribund conditionon the day the observation ismade. Pregnancy statusand uterinecontentswillbe recorded. Aborted fetuses and/or deliveredpups willbe examined to the extent possible,using the same methods described forfetuses. Uteriof apparently nonpregnant does willbe stained with 10% ammonium sulfideto confirm the absence of implantationsftes(7)
418-010:PAG E C-12
Pmtocol 418-010 Page 12
PROPOSED STATISTICAL METHOD (6-14):
Averages and percentages willbe calculated.Liftervalues willbe used where appropriate.Additionalprocedures and/or analyses may be performed, ifappropriate.
Tyl2e of Tes?
1. Parametric A. Bartlett'TseStr-d
11.Nont)arametriCb
A. Kruskal-WallisTest
(--.75%ties) 1
Signfficat at p:50.05 Not Sig ificant
Significatat p@.0.05 Not Significant
Nonparametric
Analysisof Variance
Dunn's Test
F-
Significantat p.-qO.05
1 Liu,,i,eft'Tsest
Not Significant
B. Fishers Exact Test (>75% ties)
111.Test for Pror)ortionData
Variance Test forHomogeneity of the Binomial Distribution
a. Statisticalsliygnificanptrobabilitieasre reported as eitherp:50.05 or p!@0.01. b. Proportiondata are not included inthiscategory. c. Used only to analyze data with homogeneity of variance. d. Test forhomogeneity of variance.
418-010:PAGE C-13
Pmtocol 418-010 Page 13
DATA ACQUISITION, VERIFICATION AND STORAGE:
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 archives of the Testing FacilityA.lloriginaldata will be bound and indexed. A copy of allraw data willbe suppliedto the Sponsor upon request. Preserved tissueswillbe stored at the Testing Facilitayt no charge forone year aftermailingof the draftfinalreport,afterwhich time the Sponsor willbe contacted to determine the dispositionof these materials.
RECORDS TO BE MAINTAINE
Protocoland Amendments. Test ArticleV,ehicle and/or Reagent Receipt, Preparationand Use. Animal Acquisition. Randomization Schedules. VeterinarianExamination. Mating History. Treatment (ifprescribedby StaffVeterinarian). General Comments. ClinicalObservations and/or General Appearance. Blood Sample Collection,Processing and Shipment. Body Weights. Feed Consumption Values. Caesarean-Sectioning and FetalObservations. Gross Necropsy Observations. Organ Weights. Photographs (ifrequired). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists.
KEY PERSONNEL:
Executive Directorof Research: Mildred S. Christian,Ph.D., Fellow,ATS Directorof Research: Alan M. Hoberman, Ph.D., DABT Associate Directorof Research and Study Director:Raymond G. York, Ph.D.,DABT Directorof Laboratory Operations: John F. Barnett,B.S. Manager of Study Coordination: ValerieA. Sharper, M.S. Manager of Animal Operations and Member, InstitutionAanlimal Care and
Use Committee: Dena C. Lebo, V.M.D. Manager of Regulatory Compliance: Kathleen A. Moran, M.S. Consultant,Veterinary Pathology: W. Ray Brown, D.V.M., Ph.D.,ACVP
418-010:PAGE C-14
PmtoCol 41 B-010 Page 14
FINAL REPORT:
A comprehensive draftfinalreport 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 IndividualTables Summarizing the Above Data, Protocoland Associated Amendments and Deviations,Study Directoes GLP Compliance Statement, Reports of Supporting Data (ifappropriate)and QAU Statement.
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMEN
The procedures described in thisprotocolhave 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 alternative(invitro) 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.Toxicologis2t(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(g):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 for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
5. Staples,R.E. (1974). Detectionofvisceralalterationisnmammalian fetuses. Teratology9(3):A37-38.
418-010:PAGE C-15
Pmtocol 41 B-010 Page 15
6. Staples,R.E. and Schnell,V.L.(1964).Refinementinrapidclearingtechniquein
the KOH-alizarinred S 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). Bartleftstestof homogeneity ofvariances. Biometry,W.H. Freeman and Co., San Francisco,pp. 370-371.
10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition,Iowa State UniversityPress, Ames, pp. 258-275.
11. Dunneft,C.W. (1955). A multiplecomparison procedure forcomparing several treatments with 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). Nonparametfic Statisticsfor the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
PROTOCOL APPROVA FOR THE TESTING FACILITY
GGee@4g PC-D@ear@lo@ovvee,, Ph.D., @D@ABBTT Associate Directorof Research
mR4d m dG.Y or h! DABT Associate Directorof Research 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
418-010:PAGE C-16
Pmtoool 418-010 Page 16
Date Date Date
Date
418-010:PAGE C-17
ATTACHMENT I SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE
ATTACHMENT 1
418-010:PAGE C-18
Pmtoool 418-010 Page I of2
STUDY SCHEMATIC
RABBIT DEVELOPMENTAL
TOXICITY STUDY'
Timed-Pregnant Rabbits
Startof Dosage
Day 0 of Presumed Gestation
Day 7 of Presumed Gestation
End of Dosage
CaesareanSectioningb
Day 20 of Presumed Gestation
Day 29 of Presumed Gestation
Dosage Period
a. For additionaldetailss,ee 'ITestsA,nalyses and Measurements" sectionof the protocol.
b. Fetalevaluations(externalsofttissueand skeletal).
ATTACHMENT 1
418-010:PAGE C-19
PMtocol 418-010 Page 2 of2
SCHEDULEA
28 AUG 98 30 AUG 98 - 16 SEP 98 13 SEP 98 - 17 SEP 98 21 SEP 98 - 25 SEP 98
22 DEC 98
Animals Arrive- AcclimationBegins.
Dosage Period (Days 7 through 20 of presumed gestation).
ToxicokineticSample Collection(Day 21 of presumed gestation).
Caesarean-Sectioning Period (Day 29 of presumed gestation).
Draft FinalReport.
a. The study initiatiodnate isthe date the Study Directorsignsthe protocol.
418-010:PAGE C-20
ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
MATERIAL SAFETY DA7,-A SHEET
41M10: PAGE C-21
3M 3M Center
St. Paul, Minnesota
55144-1000 i-800-364.3S77 or (612) 737-6501
N-L-+@05L (24 hours)
Copyright, 1998, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this informationfor the purpose of properly utilizing 3M products
is allowed provided that: the information is copied in full with no changes unless-
1) prior agreement is obtained from 3M, and
2) neither the copy nor the original is resold or otherwise distributedwith the intentionof earning a profit thereon.
DIVISION: 3M CHEMICALS TRADE NAME:
FC-10 FLUORAD Brand Fluorochomical Alcohol
ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2 98-0211-1183-0 00-51135-09542-3 98-0211-1575-7 00-51135-02145-3 96-0211-6620-6 00-51135-10439-2 ZF-0002-0572-2 , -
ISSUED: January 29 1998 SUPERSEDES: November 05, 1997
D-O-CU-M-E-NT-:---1-0--3-77-8---7-----------------------------------------------------------
C.A.S. NO.
PERCENT
--1-.--IN-G-R-E-DI-E-N-T---------------------------------------------------------------
PERFLUDROOCTANESULFONAMIDO PERFLUOROHEXANESULFONAMIDO PERFLUOROHEPTANESULFONAMIDO PERFLUOROBUTANESULFONAMIDO PERFLUOROPENTANESULFONAMIDO
ALCOHOL ...... ALCOHOL ......
ALCOHOL ..... ALCOHOL ......
ALCOHOL .....
1691-99-2 34455-03-3 68555-73-7 34449-89-3 68555-72-6
80.0 3.0 2.0 2.0 1.0
90.0 7.0 6.0 6.0 3.0
---------------- ----------------------------------------------------------
--2-.--PH-Y-S-IC-A-L--D-AT-A------------------------------------------------------------
BOILING POINT: ..............c.a...118 C @ 1 mm Mg
VAPOR PRESSURE: ..............<.1.0 mmHg Calc @ 20 C
VAPOR DENSITY: ..............>..1..0 Air=l Calc @ 20 C.
EVAPORATION RATE: ............<..1.0 BuOAc=l SOLUBILITY IN WATER: ..........n.eglig. SPECIFIC GRAVITY: ............c.a.. 1.7 Water=l
(of melt)
PERCENT VOLATILE: ............0..% pH: .......................N/.A.... VISCOSITY: ..................N/.D.. MELTING POINT: ..............N./.D.
....................................................................... Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-010:PAGE C-22
MSDS: Fe-10 FLUORAD Brand Fluorochmical A]Lcohol innuary 29, 1998
PAGE 2
....................................................................
2. PHYSICAL DATA
(continued)
-----------------------------------------------------------------------------
APPEARANCE AND ODOR: Amber waxy solid
----------------------------------------------------------------------------3. FIRE AND EXPLOSION MAZARD DATA
-----------------------------------------------------------------------------
FLASH POINT: ..................>. 148 C Setaflash FLAMMABLELIMITS 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 and pants, bands around arms, waist and legs, face mask, and protective covering for exposed areas of the head.
coat
UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion.
-----------------------------------------------------------------------------
4. REACTIVITY DATA -----------------------------------------------------------------------------
STABILITY: Stable
INCOMPATIBILITY - MATERIALSICONDRTIONS Not applicable.
TO AVOID:
HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur.
HAZARDOUS DECOMPOSITION
PRODUCTS:
Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Oxides of
Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates.
-----------------------------------------------------------------------------
5. ENVIRONMENTAL INFORMATION ---------------------------------------------------------------------------
SPILL RESPONSE: Refer to other sections of this MSDS for information regarding physical and health hazards, respiratory protection, ventilation, and personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container.
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA Approximately
418-010:PAGE C-23
MSDS: FC-10 FLUORAD Brand Flucrochomical Alcohol
january 29, 1998
PAGE 3
-----------------------------------------------------------------------------
5. ENVIRONMENTAL INFORMATION
(continued)
-----------------
------------------------------------------------------------
RECOMMENDED DISPOSAL:
aste incinerator in the presence
Incinerate in a permitted hazardous w
of a combustible material. Combustion products will include HF.
Dispose of waste product in a facility permitted to accept chemical
waste.
ENVIRONMENTAL DATA: Laboratory tests showed no biodegradation. 96-Hr. LD50 Fathead Minnow (Pimephales promelas) - No mortality at water saturation. No statistically significant effect on % hatch, % survival, weight, and length in 30 day Fathead Minnow egg try study. Lab tests showed 200 fold bioconcentration of FO-10 into muscle fillets of channel catfish.
REGULATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A.
This product complies with the chemical registration requirements of TSCA, EINECS, CDSL, AICS and Korea.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes
-----------------------------------------------------------------------------6-.--S-UG-G-E-ST-E-D--F-I-R-ST---AI-D--------------------------------------------------------
EYE CONTACT: Immediately flush eyes with large amounts of water. Get immediate medical attention.
SKIN CONTACT: Immediately wash skin with soap and large amounts of water. Remove contaminated clothing. If signs/symptoms occur, call a physician. Wash contaminated clothing before reuse and dispose of contaminated shoes.
INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician.
IF SWALLOWED: Call a physician IMMEDIATELY. If swallowed, induce vomiting immediately as directed by medical personnel. Never give anything by mouth to an unconscious person.
------ --------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-010:PAGE C-24
MSDS: FC-10 FLUORAD Brand FluorachosiCal AjLcohol
jar.uary 29, 1998 -----------------------------------------------------------------------------
7. PRECAUTIONARY INFORMATION ---------------------------------------
PAGE 4
EYE PROTECTION: Avoid eye contact.
Wear safety glasses with side shields.
SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of gloves made from the following material(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: coveralls.
RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. 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 airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust 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: Store away from heat. Keep container closed when not in use.
FIRE AND EXPLOSION Nonflammable.
AVOIDANCE:
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: 1 FLAMMABILITY: 1 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.)
EXPOSURE LIMITS
VALUE UNIT
TYPE
AUTH SKIN*
INGREDIENT
-----------------------------------------------------------------------------
PERFLUOROOCTANESULFONAMIDO
ALCOHOL ... 0.1 MMGG//MM33. TTWWAA 33MM yy
PERFLUOROHEXANESULFONAMIDO
ALCOHOL...
0.1
PERFLUOROHEPTANESULFONAMIDO
0.1
MG/M3
TWA
3M
y
ALCOHOL ............................
---------------------------------------------------------------------------
N/A - Not Applicable CA - Approximately Abbreviations: N/D - Not Determined
418-010:PAGE C-25
msDS: FC-10 FLUOP-ADBrand Fluarochnical Alcohol jacuary 29, 1998
PAGE 5
EXPOSURE LIMITS (continued)
VALUE UNIT
TYPE AUTH SKIN*
I-N-G-R-E-DI-E-N-T---------------------------------------------------------------
PERFLUOROBUTANESULFONAMIE)O ALCOHOL ... 0.1 MG/M3
TWA 3M
y
PERFLUOROPENTANESULFONAMIDO
0.1 MG/M3
TWA 3M
y
ALCOHOL ...............**.*.*.".*"
SKIN NOTATION: Listed substances indicated with 'Y' under SKIN refer to
the potentialcontributionto the overallexposureby the cutaneousroute
including mucous membrane and eye, either by airborneor, more particularly,
by direct contactwith the substance. Vehiclescan alter skin absorption.
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines ------------------------------------------------------------------------S-.-H-E-A-L-T-H -H-A-ZA-R-D--D-AT-A---------------------------------------------------------
EYE CONTACT: No adverse health effects are expected from eye contact.
SKIN CONTACT: Productis not expectedto be irritatingto the skin. May be absorbedthrough the skin and persist in the body for an extended time.
INHMAaLyATbIeON:absorbedby inhalation and persist in the body for an extended time.
IF SWALLOWED: Ingestionis not a likely route of exposureto this product.
Illnessmay occur after a singleswallowingof relativelylarge quantitiesof this material.
MUTAGENICITY: Not mutagenicin in-vitro assays.
REPRODUCTIVE/DEVELOPMENTAL TOXINS: Substancewas not teratogenicin the rat at doses as high as 30 milligramsper kilogram per day via oral route.
OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substancesregulated under CaliforniaProposition65. A ProductToxicity Summary Sheet is available.
-----------------------------------------------------------------------Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
418-010:PAGE C-26
MSDS: FC-10 FLUORAD Brand Fluoroohoaica3,Aleohol
PAGE 6
january 29, 1996
-----------------------------------------------------------------------------
SECTION CHMGE DATES
-------------------------------------
----------------------------------------
HEADING
SECTIONCHANGEDSINCENovember05, 1997 ISSUE
---------------------------------------------------------------------------Abbreviations:N/D - Not Determined N/A - Not Applicable CA - Approximately
-----------------------------------------------------------------------
The informationin this materialSafety Data Sheet (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 whetherthe 3M product is fit for a particularpurposeand suitablefor user'smethod of use or application. Given the varietyof factorsthat can affect the use and applicationof a 3M product, some of which are uniquelywithinthe user's knowledgeand control,it is essentialthat the user evaluatethe 3M productto determinewhetherit is fit for a particularpurpose and suitablefor user's method of use or application.
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418-010:PAGE C-27
ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE
418-010:PAGE C-28
ATTACHMENT
3
TEST ARTICLE AND VEHICLE PREPARATION
Pmtocol 41 B-010 Version:418-010 (09AUG 98)
Page 1 of 3
PROCEDURE
Test Article:
N-ETFOSE
Vehicle:
2% TweenO 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 N-ETFOSE and the vehicle for oral administration to rabbits on Argus Study 418-010.
B. General Information:
1 . All suspension containers willbe labeled and color coded. Each label will specify the protocol number, test articleidentification,Argus batch number, concentration, dosage level,preparation date, expiration date and storage conditions.
2a. Suspensions willbe prepared:
-X
Daily
-
Weekly
- For
days of use
2b. Vehicle willbe prepared:
Daily
X Weekly
- For
days of use
3. Suspensions willbe prepared at a finaldosage volume of 5 mukg.
4. Safety:
X
Gloves, lab coat, goggles or safety glasses and faceshield
x
Dust-Mist Respirator
-
Half-Face Respirator
-
Full-Face Respirator/Posftive Pressure Hood
-
Tyvek Suit/Apron
5. Dosage suspensionsadjustedforFree base and % Purity.
Yes
X No (Calculations based on 100%)
Free Base
Purity
6. Sampling requirements: Cited in protocol.
7. Storage: Cited in protocol.
418-010:PAGE C-29
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Protocol418-010 Version:41 B-010 (09 AUG 98)
Page 2 of3
PROCEDURE
NOTE:
The testarticlewillbe 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 t5"C, then 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 oftestarticl(eSee TEST ARTICLE CALCULATIONS) intoan appropriatelysized,labeledcontainer.Add the requiredamount of vehicleand heat the mixtureto 80'C 5"C forapproximately 30 minutes or untilthe TAIS dissolves.
2. Once the testarticlehas dissolved;spin over nightwhile the suspension cools. (Be sure there isa visiblevortex,thiswillachieve the desired
emulsion.)
3. To prepare the 0.5 mg/mL, Group IV suspension, remove the required amount ofstock suspension (Group V) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicleand mix.
4. To prepare the 0.2 mg/mL, Group IIIsuspensiorne,movetherequired
amount ofstock suspension (Group M (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), OS ad with the vehicleand mix.
418-010:PAGE C-30
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Protocol418-010 Version:418-010 (09AUG 98)
Page 3 of3
PROCEDURE
6. To prepare the 0 mg/mL, Group Isuspension, add the required amount of vehicleto an appropriatelysized,labeledcontainer(See TEST ARTICLE
CALCULATIONS) and mix.
Written by:
o .ca""".
Approved by: ,@ 0
ClarificationX: No
Date:
US(See attachedclarificatifonrm.)
Initials/Date:L((-
ifPiR@IMIDICA
418-010:PAGE C-31
Argus Research Laboratories. Inc. 905 Sheehy Drive, Building A Homham, PA 19044 Telephone: (215) 443-8710 Tolefax: (215) 443-8587
PROTOCOL 418-010 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY
OF N-ETFOSE IN RABBITS SPONSOR'S STUDY NUMBER: 6316.8
Amendment 1 -22 December 1998
1 . S2onso (page 1 ofthe protocol): The Sponsor is3M Corporate Toxicology,ratherthan 3M ToxicologyServices. Reason forChange: This change was made atthe requestofthe Sponsor.
G4G@d rige*-.Dearlove,Ph.D.,DABT Date Raym'oRg G. York,Ph.D ,D
Date
AssociateDirectorof Research
AssociateDirectorof Re@ h
Study Director
Den
kb,oI v.m.6)
Date
Cha ailr@@son.0'1b nstitutionAanlimal Care
and Use Committee
Marvin T. Case, D.V.M.,Ph.D. Study Monitor
Date
APPENDIX D
DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
418-010:PAGE D-1
DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
On 2 September 1998 (Day 11 ofpresumed gestationo)ne rabbitin Group V (3.75mg/kg/daydosage group,rabbi8t675) was inadvertently notdosed. This deviatiodnoes notadverselyaffectheoutcome ofthe studybecause thisrepresentsonlya smalllossofdataand was a single event.
Alldeviationsaredocumented inthe raw data.
RRaa4d 'ee d G. Yo @,,@PPhhj .,DABT AssociateDirecto ee.s,earch
and Study Director
-.;kw1,99 Date
APPENDIX E
TEMPERATURE AND RELATIVE HUMIDITY REPORTS AND DEVIATIONS REPORT
418-010:PAGE E-1
ARGUS
Temperature and RelativeHumidity Report Location:Room 07
ProtocolNumber. 41"10
Range of Dates: 28-Aug-I 998 14:00 to 21 -Sep-I998 13:53
TargetRange: Species:RABBIT
TotalNumber of Days: TotalNumber of Hours: TotalNumber ofData Points:
Mean (:tSD):
Maximum: Median: Minimum:
Number of PointsinRange Number of PointsHigh Number of PointsLow
Tompomture 61OF to72*F
RelativeHumidity 30% to70%
25 575.74
576
25 575.74
576
67.4 (t0.4) 60.4
3.0)
68.6
68.7
67.4
60.5
66.3
53.1
576 (100.0) 576 (100.0)
0
(0.0) 0
(0.0)
0
(0-0) 0
(0-0)
Report Generated:28-Sep-1993at13:48
COMMENTS:
REVIEWED BY:-.
DATE:
Cumulativeby Location(v04.01.97)
418-010:PAGE E-2
ARGUS
Temperature and RelativeHumidityReport Location:Room 08
protocolNumber. 418-010
Range of Dates:28-Aug-1998 14:00to 25-Sep-1998 11:50
Target Range: Species: RABBIT
Total Number of Days: Total Number of Hours: Total Number of Data Points:
Temperature 61 OF to 720F
29 669.75
670
RelativeHumidity 30% to 70%
29 669.15
670
Mean (SD):
Maximum: Median: Minimum:
Number of Points in Range Number ofPoints High (%): Number of Points Low
67.0
69.3 66.8 65.6
670 0 0
0.7)
(100.0) (0-0) (0-0)
62.5
70.0 63.0 47.7
669 1 0
3.6)
(99.9) (0-1) (0-0)
Report Generated: 28-Sep-1998 at 13:56
COMMENTS:
REVIEWED BY: !5
DATE:
Cumulative by Location(v04.01.97)
418-010:PAGE E-3
ARGUS
Temperature and RelativeHumidity Report Location:Room 09
Protocol Number: 418-010
Range of Dates: 28-Aug-1998 14:00 to 26-Sep-1998 11:50
TargetRange: Species:RABBIT
TotalNumber ofDays: TotalNumber ofHours: TotalNumber of DataPoints:
Mean (:tSD):
Maximum: Median: Minimum:
Number ofPointsinRange (%): Number ofPointsHigh (%): Number of PointsLow
Temperature 61OF to 720F
RelativeHumidity 30% to70%
29 669.75 670
29 669.75
670
66.7 (:0t.9) 63.7 (:4t.2)
69.7
73.7
66.5
64.1
64.7
44.8
670 (100.0) 640
0
(0.0) 30
0
(0.0) 0
(95.5) (4.5)
(0-0)
Report Generated:28-Sep-1998at13:57
COMMENTS:
REVIEWED BY:
-DATE:
Cumulativeby Location(v04.01.97)
ARGUS
418-010:PAGE E-4
RelativeHumidity DeviationsReport Location:Room 09
ProtocolNumber: 418-010
Range of Dates:28-Aug-1998 14:00 to 25-Sep-1998 11:50
Humidity Target Range: Species: Rabbit
30% to 70%
Date
29-Aug-1998 30-Aug-1998 30-Aug-1998 30-Aug-1998 31-Aug-1998 31-Aug-1998 02-Sep-1998 02-Sep-1998 04-Sep-1998 14-Sep-1998 14-Sep-1998 15-Sep-1998 15-Sep-1998 15-Sep-1998 16-Sep-1998 16-Sep-1998 17-Sep-1998 17-Sep-1998
Time
09:00 00:00 01:00 22:00 08:00 19:00 01:00 20:00 20:00 11:00 13:00 16:00 19:00 21:00 09:00 21:00 00:00 14:00
R.H. 70.6H 70.2H 70.2H 70.9H 72.2H 71.0H 70.9H 70.6H 70.6H 70.2H 70.4H
70.3H 70.1H 71.0H 70.7H 73.7H 71.5H 72.2H
Date
17-Sep-1998 18-Sep-1998 18-Sep-1998 18-Sep-1998 19-Sep-1998 19-Sep-1998 20-Sep-1998 20-Sep-1998 21 -Sep-1998 22-Sep-1998
Time 23:00 10:00 11:00 21:00 21:00 22:00 10:00 13:00 10:00 10:00
H = Valueoutofrange-High L Value out of range - Low R.H.= RelativeHumidity
Report Generated: 03-Dec-1998at 10:02
R.H. 70.2H 73.1H 70.9H 70.1H 70.2 H 71.3H 70.4H 70.4H
72.8H 70.4H
@,-'Thesedeviationdsidnotadverselayffectheoutcomeorinterpretatoifotnhestudy. The followindgeviation(ism)pactedon theoutcomeofthestudyas described:
StudyDirector:
Date: 0 1 -Drc -")8
Deviationbsy Locatio(nv04.01.97)
APPENDIX F PILOT REPORT
418-010:PAGE F-1
FINAL PILOT REPORT
Study Title Oral (Stomach Tube) Dosage-Range Developmental ToxicityStudy of
N-ETFOSE inRabbits
SPONSOR'S STUDY NUMBER: T-6316.8
Author Raymond G. York, Ph.D.,DABT
(StudyDirector)
Study Comi2leted On 6 January 1999
(FinalPilotReport)
Performing Laboratory Argus Research LaboratoriesI,nc.
905 Sheehy Drive,BuildingA Horsham, Pennsylvania 19044-1297
Laborato[yProiectID Argus Research LaboratoriesI,nc.,ProtocolNumber: 418-01 OP
418-010:PAGE F-2
PROTOCOL 418-010P
418-01 OP: PAGE 2
ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS
SPONSOR'S STUDY NUMBER: T-6316.8
SUBJECT ABSTRACT 1. Purpose li. Methods Ill. Results
TABLE OF CONTENTS
PAGE 4 6 6 7
IV. Conclusion
12
Figure 1. Maternal Body Weights
13
Table 1. ClinicalObservations - Summary
14
Table 2. Necropsy Observations - Summary
18
Table 3.
Uterine Contents and LifterData forthe IndividualRabbits that
were Found Dead, Moribund Sacrificedor Aborted
20
Table 4. Maternal Body Weights - Summary
23
Table 5. Maternal Body Weight Changes - Summary
26
Table6. MaternAablsolutFeedConsumptiVoanlue(sg/day-)
Summary
28
Table 7. Maternal RelativeFeed Consumption Values (g/kg/day)-
Summary
30
Table 8. Caesarean-Sectioning Observations - Summary
32
41"10:PAGE F-3
418-01OP:PAGE 3
Table 9. LifteOrbservations(Caesarean-DeliveredFetuses)-
Summary
34
Table 10. FetalGross ExternalAlterations- Summary
36
Table 11. ClinicalObservations - IndividualData
38
Table 12. Necropsy Observations - IndividualData
44
Table 13. Maternal Body Weights - IndividualData
48
Table 14. Maternal Feed Consumption Values - IndividualData
55
Table 15. Caesarean-Sectioning Observations - IndividualData
62
Table 16. LitterObservations (Caesarea n-De Iivered Fetuses) -
IndividualData
64
Table 17. Fetal Sex, VitalStatus and Body Weight -
IndividualData
66
ATTACHMENT
1 - PROTOCOL AND AMENDMENT
69
41B-010:PAGE F4
418-01 OP:PAGE 4
TITLE: ORAL(STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS
ARGUS RESEARCH LABORATORIES, INC., PROTOCOL NUMBER: 418-010P SPONSOR'S STUDY NUMBER: T-6316.8
ABSTRACT
The purpose ofthisstudywas to provideinformationforthe selectionofdosages to be used inthe developmentaltoxicit(yembryo-fetatloxicitaynd teratogenic potentials)tudy of N-ETFOSE administeredorallyviastomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnantfemale rabbits.
Thirty-fivperesumed pregnant New Zealand White [Hra:(NZW)SPF) rabbitswere randomly assigned to seven dosage groups,fiveper group. Suspensions of N-ETFOSE were administeredorallyonce dailyon days 7 through 20 of gestation (DGs 7 to 20) atdosages of0 (Vehicle)1,,5, 10,25,50 and 75 mg/kg/day. The vehiclewas 2% TweenS 80 inreverseosmosis membrane processed deionized Water. The dosage volume was 5 mukg, adjusteddailyon the basisofthe individuablody weights.
Checks forviabilitwyere 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 values were recordeddailyduringthe dosage and postdosage periods.
Allsurvivingrabbitswere sacrificeodn DG 29 of presumed gestationand examined forthe number and distributiofn corporalutea,implantationsitesand uterinecontents.A gross necropsy ofthe thoracica,bdominal and pelvicviscera was performed. Fetuses were weighed and examined forgross external alterationasnd sex.
Severe maternal body weight lossoccurredinthe 10,25, 50 and 75 mg/kg/day dosage groups;therewere no survivingrabbitsinthese groups. Abortions occurredin5 and 10 mg/kg/day dosage groups. Caesarean-section
418-010:PAGE F-5
418-01OP: PAGE 5
observationsrevealedincreasinglateresorptionsand reduced fetalbody weights at5 mg/kg/day. Increasesinearlyresorptionswere found at 1 mg/kg/day;
however, there was no decrease in mean littesrize.
Based on the resultsof thisdosage-range findingstudy, dosages of 0, 0.1, 1.0, 2.5 and 3.75 mg/kg/day were recommended for the fulldevelopmental toxicity study of N-ETFOSE inrabbits.
418-010:PAGE F-6
41 B-01 OP:PAGE 6
1. PurRose:
The purpose of thisstudy was to provide informationforthe selectionof dosages
to be used inthe developmental toxicity(embryo-fetaltoxicityand teratogenic potential)study of N- ETFOSE administered orallyvia stomach tube to New Zealand White [Hra:(NZMSPF] presumed pregnant female rabbits.
li. Methods":
The testarticleN,-ETFOSE (lotFM-3932), an off-whitewax, was received on 20 May 1998, and stored at room temperature. The vehicle,2% Tween@ 80 (lot3HO5), a clearviscous liquidw,as received on 22 May 1998, and stored at room temperature. The vehicle diluent,reverse osmosis membrane processed deionized water (R.O. Deionized Water) isavailablefrom a continuous source at the Testing Facilityand ismaintained at room temperature.
Thirty-fivepresumed pregnant New Zealand White [Hra:(NZW)SPF] rabbitswere randomly assigned to seven dosage groups [fiveper group (Groups Ithrough Vil)].Suspensions of N-ETFOSE were administered orally(stomach tube) once dailyto these timed-pregnant rabbitson days 7 through 20 of gestation (DGs 7 to 20) at dosages of 0 (Vehicle),1,5, 10, 25, 50 and 75 mg/kg/day. The vehicle was 2% TweenS 80 in reverse osmosis membrane processed deionized Water (R.O. Deionized Water). The dosage volume was 5 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.
Allsurviving rabbitswere sacrificedon DG 29 of presumed gestation and examined forthe number and distributioonf corpora lutea,implantationsitesand
uterinceontents.A grossnecropsyofthethoracica,bdominaland pelvicviscera
was performed. Fetuses were weighed and examined forgross external alterationsand sex.
a.
Detailed descriptionsof allprocedures used inthe conduct of thisstudy
are provided inthe appropriate sections of thisreportand inthe attached
protocol and amendments. Deviations from the Protocol and Standard
Operating Procedures of the Testing Facilityare availablein the raw data.
418-010:PAGE F-7
418-OIOP:PAGE 7
111. Results:
A.
Mortalily, Moribund Sacrifices, Abortions, Clinical and NecroRsy
Observations (Summaries - Tables I and 2: IndividualData - Tables
11, 12 and 3)
A.l. Mortality
One, two and one rabbitswere found dead in the 1, 50 and 75 mg/kg/day dosage groups, respectively.The remaining rabbitsinthe 50 and 75 mg/kg/day dosage groups and allfiverabbitsinthe 25 mg/kg/day dosage group were moribund sacrificed.
1 mg/kg/day Dosage Group
Doe 8206 was found dead on DG 16, within an hour followingdosage administration,after10 dosages of the testarticle.The rabbithad no adverse clinicasligns during the dosing period. The rabbitgained weight during the dosage period,but feed consumption values were reduced on DGs 12 through 15. The uterus contained eightfetuses,which appeared normal fortheir developmental ages. Viabilitoyf the fetuses could not be determined because of the death of the dam. Alltissues appeared normal at necropsy.
50 mci/kq/day Dosage Group
Doe 8226 was found dead on DG 14, withinthree hours followingdosage administration,afternine dosages of the testarticle.The rabbithad softor liquid feces and scant or no feces between DGs 9 and 14 and lostweight and had reduced feed consumption during the dosage period. The uterus contained six fetuses and one earlyresorption.Viabilitoyf the fetuses could not be determined because of the death of the dam. Necropsy revealed the stomach mucosa contained black viscous material;allother tissuesappeared normal.
Doe 8229 was founddead beforedosage administratioonn DG 12,afterfive
dosages of the testarticle.The rabbit had softor liquidfeces or scant feces on DGs 9 to 12 and lostweight and had reduced feed consumption during the dosage period. The uteruscontained 13 fetuses. Viabilitoyf the fetuses could not be determined because of the death of the dam. Necropsy revealed greenish-gray areas on alllobes of the liverand 30 mL of fluidinthe thoracic cavity.Allother tissues appeared normal forthe slightdegree of autolysis.
41 B-010:PAGE F-8
418-01 OP:PAGE 8
iy Dosage Group
3s found dead beforedosage administratioonn DG 15,afternine -ietestarticleT.he rabbithad softor liquifdecesor scantfeceson decreased motor activitoyn DGs 13 and 14 and excess salivation -herabbitlostweightand had reduced feed consumption duringthe ,d.The uteruscontainedninefetusesand one earlyresorption. e fetusescouldnotbe determinedbecause ofthedeath ofthe dam. nalcavitycontainedapproximately18 mL ofthin,brown fluiadnd mucosa containeda viscous,brown material.Allothertissues rmal.
.und Sacrificed
the 25, 50 and 75 mg/kg/day dosage groups were moribund DG 15. Clinicaolbservationsintheserabbitsincludeddecreased .,i,mpairedrightinrgeflexc,oldtotouch,emaciation,red substance an,perioraslubstance,excess salivationu,ngroomed coat,and @es(scant,softor liquida,bsent).
ad and Sacrificed
inthe5 mg/kg/day dosages group and allfiverabbitsinthe dosages group abortedand were sacrificed.
Dosage Group
ortedon DG 26. The rabbithad scantfeces,softor liquifdecesor DGs 10 through25. There was a redsubstanceinthecage pan on rabbitlostweightand had reducedfeed consumption duringthe d. There were one abortedlateresorptioannd fivelateresorptions @issuesappeared normal at necropsy.
ortedon DG 24. The rabbithad scantfecesorsoftorliquifdeces )23. There was a redsubstanceinthe cage pan on DG 20. The @ightand had reduced feed consumption duringthe dosage period. ie abortedlateresorptionT.here threelivefetusesand eightlate i utero.Alltissuesappeared normalatnecropsy.
ortedon DG 26. The rabbithad scantfecesor no feceson DGs 17 was a redsubstance inthecage pan on DG 26. The rabbitlost the dosage periodand had reducedfeed consumption on DGs 10
418-010:PAGE F-9
418-01OP: PAGE 9
to26. There were fourimplantationasnd threeaborteddead fetuses.The fourthconceptuswas presumed cannibalizedA.lltissuesappeared normal at necropsy.
10 mglkg/day Dosage Group
Doe 8216 aborted on DG 26. The rabbithad scantfeces,softor liquifdeces or no feceson DGs 10 through25 and darkorange urineon DG 24. There was a redsubstanceinthe cage pan on DG 26. The rabbitlostweightand had reducedfeed consumptionduringthe dosage period.There were eightaborted lateresorptionsT.he livehrad pale,tanareas on alllobes,ranginginsizefrom 1.5cm x 1.0cm to4.0 cm x 1.6cm. Allothertissuesappeared normal at necropsy.
Doe 8217 abortedDG 22. The rabbithad scantfecesorno feceson DGs 9 to21 and a red substanceinthe cage pan on DG 21. The rabbitlostweightand had reduced feed consumptionduringthedosage period.There were two abortedlateresorptionasnd fourearlyand fourlateresorptionisnutero.All tissuesappeared normal atnecropsy.
Doe 8218 abortedon DG 24. The rabbithad scantfeces,softor liquifdecesor no feceson DGs 9 to23. The rabbitlostweightand had reducedfeed consumption duringthedosage period.There were eightabortedlate resorptionasnd two lateresorptionisnutero.Alltissuesappeared normal at necropsy.
Doe 8219 abortedon DG 22. The rabbithad scantfecesorno feceson DGs 9 through21 and a redsubstance inthecage pan and darkorange urineon DG 21. The rabbitlostweightand had reducedfeed consumption duringthe dosage period.There were eightabortedearlyresorptionsf,ourabortedlate resorptionasnd one earlyresorptioinnutero.Necropsy revealedthatalllobesof the livewrere pale.Allothertissuesappeared normal.
Doe 8220 abortedon DG 23. The rabbithad scantfecesorsoftorliquifdeces on DGs 9 to22. The rabbitlostweightand had reducedfeed consumption duringthe dosage period.There were threeabortedlateresorptionasnd seven livefetusesinutero.Alltissuesappeared normalatnecropsy.
A.4. ClinicalObservations
Clinicaolbservationsconsideredtobe testarticlreelatedincludedscantfeces, softor liquifdecesor no fecesin5, 10,25,50 and/or75 mg/kg/day dosage
418-010:PAGE F-10
418-01OP:PAGE 10
groups,and dark urineinthe10 mg/kg/day dosage group. Ungroomed coat, decreased motor activitiym,pairedrightinrgeflexc,oldtotouch,lostrighting reflexe,maciation,perioraslubstanceand excess salivatioonccurredinrabbits thatwere found dead ormoribund sacrificeidnthe25, 50 and/or75 mg/kg/day dosage groups. Red substanceincage pan was correlatewdithabortionand/or moribund conditioninthe5, 10 and 75 mg/kg/day dosage groups.
Allotherclinicaolbservationwsere consideredunrelatedtothetestarticle because: 1)theincidenceswere notdosage-dependent;and/or2)theyoccurred inonlyone rat.These observationsincludedabrasionand localizeadlopeciaon the limbsand/orback.
A.S. Necropsy
Necropsy observationsfrom allunscheduled deathsor sacrificehsave been previousldyescribed.One 5 mg/kg/daydosage groupdoe (7385)had paleliver lobes.The onlyothernecropsyobservationswere confirmatioonfclinical observationsof localizeadlopecia.
B. Maternal Body Weights and Body Weight Changes (Fi-gur1e: Summaries -Tables 4 and 5:IndividualData -Table 1_;j
Severe maternalbody weightlossesoccurredinthe 10,25, 50 and 75 mg/kg/day dosage groups;therewere no survivinrgabbitsinthese groups afterDGs 26, 15,15 and 15,respectively.
Maternalbody weightlossesoccurredforthe5 mg/kg/day dosage group forthe entirethe dosage period(calculateads DGs 7 to21),thepostdosage period (DGs 21 to29) and theentiregestatiopneriod(DGs 0 to29).
Maternal body weights and body weight gains forthe 1 mg/kg/day dosage group were generally comparable to controlvalues during the dosage and postdosage
periods(DGs 7 to21).
C. Absolute (g/day) and Relative (glkg/day) Feed Consumption Values (Summaries - Tables 6 and 7: Individual Data -Table 14)
Absoluteand relativfeeedconsumption valueswere severelyreduced inthe 10, 25,50 and 75 mglkg/daydosage groups;therewere no survivingrabbitsin thesegroups afterDGs 26, 15,15 and 15,respectively.
41 B-010:PAGE F-11
418-01 OP:PAGE 11
Absoluteand relativfeeed consumptionvaluesforthe 5 mg/kg/day dosage group were severelyreduced,compared tothe controlgroup,duringthedosage and postdosage periods.
Absoluteand relativfeeed consumptionvaluesforthe 1 mg/kg/day dosage group were generallycomparable tocontrolvaluesover each intervatlabulated.
D. Caesarean-Sectioning and LitterObservations (Summaries -Tables 8 through 10,-IndividualData -Tables IS through 17)
Caesarean-sectioninogbservationswere based on 5,4 and 2 pregnant rabbits withlivelitteirnsthe0 (Vehicle)1,and 5 mg/kg/daydosage groups. There were no survivingdoes inthe 10,25,50 or 75 mg/kg/day dosage groups.
An increaseinearlyresorptionosccurredinthe 1 mg/kg/day dosage group, relativteothe controglroup. Thisobservationwas consideredan effectofthe testarticlbeecause itwas outsidethe historiccaolntrolrange fortheTesting FacilityA.n increaseinlateresorption(sand a concomitantdecrease inlifter size)and reducedfetalbody weightsoccurredatthe 5 mg/kg/day dosage, relativteothe controlgroup. These observationswere alsoconsideredan effect ofthetestarticlbeecause theywere dosage-dependent and occurredat maternallytoxicdosages (decreasedbody weightand feed consumption values).
No dams had allresorbedconceptusesand therewere no dead fetuses.
Totalsof 36,34 and 13 livefetuseswere evaluatedforexternalgross alterations inthethreerespectivdeosage groupswithlifterOsn.e fetus(8207-7)inthe 1 mg/kg/daydosage group had a distendedabdomen. One fetus(7385-1)inthe 5 mg/kg/day dosage group had open eyelidsand protrudingtongue and another inthesame lift(e7r385-4)had downward flexedforepaws,cleftsnout,absent incisorasnd a largerighteye. This liftaelrsocontainedthreelateresorptions and threenormal fetuses.No fetalgrossexternalalterationwsere observed in the vehiclecontrolgroup fetuses.
418-010:PAGE F-12
418-01OP:PAGE 12
IV. Conclusion:
Based on the results of this study, dosages of 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day of N-ETFOSE were recommended forthe developmental toxicity studyinrabbits(418-010).The 0.1 mg/kg/day dosage isexpected to be a no-observable-effect-le(vNeOlEL) forboth maternaland embryo-fetaltoxicity, and the 3.75 mg/kg/day dosage isexpected toproduce maternaltoxicity (decreasedmaternalbody weight and feed consumption values)and may produce minimal developmentaltoxicit(ydecreasedfetalbody weight and delayed ossification).
.114)@-
Alan M. Hoberman, Ph.D., DABT
Dire
Research
-TPau 1,7 Date
aRa4n nd G. York, h. ,DABT
Date
AssociateDirectokro@ff0'essetarch
and Study Director
4.60 4.40 4.20 4.00 3: 3.80 3.60 3.40 3.20 3.00
MATERNAL BODY WEIGHT
FIGURE 1
x- x x@ X
0 (VEHICLE) I MGIKG/DA) 5 MG/KG/DA 10 MGIKGID 25 MGIKG/ 50 MGIKG/D 75 MG/KGID
l'o I'l 1'2 1'3 1'4 1'5 1'6 17 1'8 1'9 2@O 2'1 22 213 214 2'5 2;6 @7 28 2@9
DAY OF GESTATION
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) DOSAGE-RANGE NUMBER: T 6316.8)
DEVELOPMENTAL
i'oxici'ry STUDY OF N ETFOSE IN RABBITS (SPONSOR'S ST
TABLE I (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY
--------------------- ------ -- ----------------------- ------------- ----- - ----- ---------- ----------------------
DOSAGE GROUP
I
ir
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
10
------------------------------------------------------------------------------------------------ ----------------------
MAXIMUM POSSIBLE INCIDENCE
IIS/ 5
102/ 5
104/ 5
87/ 5
MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD
0
1
3
5
0
0
0
0
0
0
3b
5b
0
lb
0
0
SCANT FECES
0/ a
0/ 0
62/ 5
59/ 5
DECREASED MOTOR ACTIVITY
0/ 0
0/ 0
0/ 0
0/ 6
UNGROOMED
COAT
0/ 0
0/ 0
11/ 1
0/ 0
SOFT OR LIQUID FECES
0/ 0
0/ 0
4/ 3
7/ 3
DRIED YELLOW, BROWN OR YELLOW-BROWN
PERIORAL SUBSTANCE
0/ 0
0/ 0
0/ 0
0/ 0
NO FECES
0/ 0
o/ o
10/ 3
10/ 4
RED SUBSTANCE
IN CAGE PAN
0/ 0
1/ 1
3/ 3
3/ 3
IMPAIRED RIGHTING REFLEX
0/ 0
0/ 0
0/ 0
0/ 0
COLD TO TOUCH
0/ 0
0/ 0
0/ 0
0/ 0
EMACIATION
0/ 0
o/ o
0/ 0
0/ 0
EXCESS SALIVATION
0/ 0
0/ 0
0/ 0
0/ 0
LOST RIGHTING REFLEX
0/ 0
0/ 0
0/ 0
0/ 0
DARK URINE --------------------------
0/ 0 ----- -------------------- - -------------------
0/ 0
0/ 0
2/ 2
------ - -----
MAXIMUM POSSIBLE INCIDENCE = (DAYS x RABBITS)/NUMBER
OF RABBITS EXAMINED PER GPOUP ON DAYS 7 THROUGH 29 OF PRESUMED e
NIN - TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS WITH OBSERVATION.
a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or abotled.
PROTOCOL 416-OIOP:
ORAL ISTOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS ISPONSOR'S ST
TABLE I (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY
---------------------
----------------------- -- --------- ------------ ------------ ---------------- ---
DOSAGE GROUP
v
vi
vii
DOSAGE IMG/KG/DAY)a
25
50
75
----------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE
45/ 5
41/ 5
45/ 5
MORTALITY
MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD
5
5
5
5b
3b
4b
0
0
0
0
2b
lb
SCANT FECES DECREASED MOTOR ACTIVITY
25/ 5 1/ 1
20/ 5 4/ 4
22/ 5 13/ 5
UNGROOMED
COAT
SOFT OR LIQUID FECES
5/ 2 0/ 0
0/ 0 10/ 3
15/ 4 13/ 4
DRIED YELLOW, NO FECES
BROWN OR YELLOW-BROWN
PERIOPAL SUBSTANCE
0/ 0 2/ 1
3/ 3 2/ 2
5/ 2 4/ 2
RED SUBSTANCE
IN CAGE PAN
0/ 0
0/ 0
2/ 2
IMPAIRED RIGHTING REFLEX
1/ 1
0/ 0
3/ 1
COLD TO TOUCH EMACIATION
0/ 0 0/ 0
0/ 0 0/ 0
1/ 1 2/ 1
EXCESS SALIVATION
0/ 0
0/ 0
1/ 1
LOST RIGHTING REFLEX
o/ o
1/ 1
0/ 0
DARK URINE
0/ 0
o/ o
------------------------------------------------------------------ --------------
0/ 0
MAXIMUM POSSIBLE INCIDENCE = (DAYS x RABBITS)/NLIMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH
HIN = TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS WITH OBSERVATION.
&. Dosage occurred on days 7 through 20 of presumed gestation.
b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that
sacrificed.
29 OF PRESI]MED r, died or were mor
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 1 (PAGE 3) : CLINICAL OBSERVATIONS
- SUMMARY
------------------- ---------------------------------------- ----- ------------ --- --------------------
DOSAGE GROUP
I
ii
III
IV
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
10
------------------------------------------------------------------------------------- ----------------------- ----------
MAXIMUM POSSIBLE INCIDENCE
115/ 5
102/ 5
104/ 5
87/ 5
MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD
0
1
3
5
0
0
0
0
0
0
3b
Sb
0
lb
0
0
ABRASION c
0/ 0
o/ o
17/ 2
0/ 0
LA)CALIZED ALOPECIA:
TOTAL
1/ 1
2/ 1
0/ 0
o/ 6
LIMBS
0/ 0
2/ 1
0/ 0
0/ 0
BACK
1/ 1
1/ 1
0/ 0
G/ 0
-------------------------------------------------------------------------------------- --------------------------------
MAXIMUM POSSIBLE INCIDENCE - (DAYS x RABBITS)/NUMBER
OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GE
MIN - TOTAL NUMBER OF OBSERVATIONS/NUMBER
OF RABBITS WITH OBSERVATION.
a. Dosage occurred on days 7 through 20 of presumed gestation.
b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or aborted.
C. Located on the left forepaw or left hindpaw.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) DOSAGE NUMBER: T-6316.8)
RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S S
TABLE I IPAGE 4): CLINICAL OBSERVATIONS - SUMMARY
-------------------I ----------
---------------------------- -------- -- - ----
---- --------
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
25
50
75
---------------------------------------------- -------------------------------------------------------- --------------
KA.XIMUM POSSIBLE INCIDENCE
45/ 5
41/ 5
45/ 5
MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIPICED FOUND DEAD
5
5
5
Sb
3b
4b
0
0
0
0
2b
lb
ABRASION
0/ 0
0/ 0
0/ 0
LOCALIZED ALOPECIA:
TOTAL
0/ 0
0/ 0
0/ 0
LIMBS
o/ o
0/ 0
0/ 0
BACK
0/ 0
0/ 0
0/ 0
----------------------------------------------------------------------------------------------------------------------
MAXIMUM POSSIBLE INCIDENCE - (DAYS x RABBITS) /NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED G
NIN - TOTAL NUMBER OF OBSERVAT3[ONS/NUMBER
OF RABBITS WITH OBSERVATION.
a. Dosage occurred on days 7 through 20 of presumed gestation.
b. Refer to the Individual clinical observations table (Table 11) for observations for rabbits that died or were mor
sacrificed.
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE
RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 2 (PAGE 1); NECROPSY OBSERVATIONS
- SUMMARY
-------------- ---
DOSAGE GROUP DOSAGE (MG/KG/DAY)a -------------------
RABBITS EXAMINED b
------------------ ------ ------------------
- ---- --------------- ---------- -----
I
ii
III
I
0 (VEHICLE)
1
5
1
----------------------------------- ---------------------------------------------------------------
N
5
5
5
MORTALITY MORIBUND SACRIFICED ABORTED FOUND DF.AD
N
0
N
0
H
0
N
0
1
3
0
0
0
3c
Ic
0
APPEARED NOR14AL
N
5
5
4
STOMACH:
MUCOSA, BLACK OR BROWN
VISCOUS MATERIAL
N
0
0
0
FRIABLE
N
0
0
0
ABDOMINAL
CAVITY:
THIN BROWN FLUID
N
0
0
0
LIVER:
ALL LOBES, GREEN-GREY AREAS
N
0
0
0
ALL LOBES, PALE OR
PALE TAN AREAS
N
0
0
1
THORACIC CAVITY:
TAN-GREY FLUID
N
0
0
0
LUNGS:
ALL LOBES, TAN-GREY
N
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. C. Refer to the individual necropsy observations table (Table 12) for observations for rabbits that died or aborted.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 2 (PAGE 2): NECROPSY OBSERVATIONS
- SUMMARY
-------------------------------------------- - -------------------------- --- --------- ------- ------ ------
-----
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
25
so
75
-- - --- - -- - --- - - --- -- -- --- -- -- -- -- - - ---- -- -- --- -- -- --- -- -- -- -- -- -- -- -- -- --- --- - --- -- -- -- -- --- -- -- -- -- --- - ---- -- -- --- ----
RABBITS EXAMINED b
N
5
5
5
MORTALITY
N
5
5
5
MORIBUND SACRIFICED
N
Sc
3c
4c
ABORTED
N
0
0
0
FOUND DEAD
N
0
2c
Ic
APPEARED NORMAL
N
5
3
3
STOMACH:
MUCOSA, BLACK OR BROWN
VISCOUS 14ATERIAL
N
0
1
2
FRIABLE
N
0
0
1
ABDOMINAL
CAVITY:
THIN BROWN FLUID
N
0
0
1
LIVER:
ALL LOBES, GREEN-GREY AREAS
N
0
1
0
ALL LOBES, PALE OR
PALE TAN AREAS
N
0
0
0
THORACIC CAVITY:
TAN-GREY FLUID
N
0
1
0
LUNGS:
ALL LOBES, TAN-GREY
N
0
1
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. Refer to the individual necropsy observations table (Table 12) for observations for rabbits that died or were mor
sacrificed.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T- 6316, 8)
DOSAGE-RANGE
DEVEI,OPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 3 (PAGE 1)! UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED
OR ABORTED
----- ---------- ---------
------------------------- - - - -------- --------
---------------------- --
DOSAGE GROUP
RABBIT
CORPORA L.UTEA
IMPLANTATIONS
DOSAGE (MG/KG/DAY)c NUMBER DAY OF DEATH
R
L
T
R
L
T
-------------------------------------------------------------------------------------
EMBRYOS/FETUSES
a
RESORP
R
L
A
T
R
L
------------------------- ------
I
0 (VEHICLE)
-
-
-
-
-
-
-
-
11
1
8206
FOUND DEAD ON DAY
4
5
9
3
5
8
3
5
0
Bd
0
0
16 OF GESTATION
III 5
8211 8212 8214
ABORTED ON DAY 26 OF GESTATION
ABORTED ON DAY 24 OF GESTATION
ABORTED ON DAY 26 OF GESTATION
6
4
10
6
7
13
4
4
8
3
3
6
6
6
12
2
2
4
0
0
0
1
2
0
0
0
3
0
2
3
3
4
4
3f,g
0
IV
10
8216
ABORTED ON DAY 26
5
7
12
4
4
OF GESTATION
8217
ABORTED ON DAY 22 OF GESTATION
5
6
11
5
5
8218
ABORTED ON DAY 24 OF GESTATION
5
6
11
5
s
8219
ABORTED ON DAY 22 OF GESTATION
6
7
13
6
7
8220
ABORTED ON DAY 23
6
5
OF GESTATION
----------------------------------------------------------
11
6
4
---- ------------
R= a. b. c. d. e. f. g.
RIGHT
L = LEFT
T = TOTAL
A = ABORTED
Conceptuses appeared normal for developmental ages.
Early resorptions, unless noted otherwise.
Dosage occurred on days 7 through 20 of presumed gestation.
Unable to determine viability of conceptuses because of death
AUtolysis precluded further evaluation.
One conceptus was presumed cannibalized.
Dead fetuses.
of doe.
B
0
0
0
0
10
0
0
0
0
10
0
0
0
0
13
0
0
0
0
10
5
2
0
7
- -- -- --------- - --- -
0
4 (ILR)(3
0
0
0
PROTOCOL 418 OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316-6)
DOSAGE
RANGE DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 3 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED OR ABORTED
------------- ------ ------------------- - ---- ------------------ ------------------------ ----- ----- --------------
DOSAGE DOSAGE
GROUP (MG/KG/DAY)c
RABBIT NUMBER
DAY OF DEATH
CORPORA LUTEA
R
L
T
IMPLANTATIONS
R
L
T
EMBRYOS/FETUSES
a
R
L
A
T
RESORP
R
L
-- -- -- -- -- -- -- -- - --- - -- -- - --- - ---- -- -- --- - --- -- -- -- -- -- -- --- -- --- - --- - --- -- -- -- -- --- - --- -- -- --- -- --- -- -- --- -- -- -- --- ---
25v 7371 MORIBUND SACRIFICED 3 5 8 2 5 7 2 3 0 5 0 2 ON DAY 15 OF GESTATION
8222
MORIBUND SACRIFICED
6
4
10
6
4
10
6
4
0
10
0
ON DAY 15 OF GESTATION
8223
MORIBUND SACRIFICED
5
s
10
ON DAY 15 OF GESTATION
4
3
7
4
3
0
7
0
8224
MORIBUND SACRIFICED
5
s
10
5
5
10
5
5
0
10
0
ON DAY 15 OF GESTATION
8225
MORIBUND SACRIFICED
5
6
11
5
6
11
5
6
0
11
0
ON DAY 15 OF GESTATION
vi
so
8226
FOUND DEAD ON DAY
7
4
11
3
4
7
14 OF GESTATION
8227
MORIBUND SACRIFICED
5
6
11
ON DAY IS OF GESTATION
5
6
11
8228
MORIBUND SACRIFICED
2
1
3
ON DAY IS OF GESTATION
1
1
2
8229
FOUND DEAD ON DAY 12 OF GESTATION
7
6
13
7
6
13
8230
MORIBUND SACRIFICED
7
5
12
3
2
5
ON DAY 15 OF GESTATION ---------------------------------------- --------------------------------------
R - RIGHT
L = LEFT
T = TOTAL
A = ABORTED
a. Conceptuses appeared normal for developmental ages. b. Early resorptions. unless noted otherwise. c. Dosage occurred on days 7 through 20 of presumed gestation. d. Unable to determine viability of conceptuses because of death of doe.
3
3
0
6d
0
5
6
0
11
0
1
1
0
2
0
7
6
0
13d
0
3
2
0
s
0
-------- -
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE)
NUMBER:
T-6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 3 (PAGE 3) : UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED OR ABORTED
--------- - -- - -------------------------------------------------- -------------------------------------------------
DOSAGE DOSAGE
GROUP (MG/KG/DAY)C
RABBIT NUMBER
DAY OF DEATH
CORPORA LUTEA
R
L
T
IMPLANTATIONS
R
b
T
EMBRYOS/FETUSES
a
R
L
A
T
RESORP
R
L
---------------- ------------------------------------------------------------------------------------------------------
Vil 75
8231
MORIBUND SACRIFICED
0
4
4
ON DAY 15 OF GESTATION
0
4
4
0
0
0
0
0
4
8232
MORIBUND SACRIFICED
0
0
0
ON DAY 15 OF PRESUMED GESTATION
0
0
0
0
0
0
0
0
0
8233
FOUND DEAD ON DAY 15 OF GESTATION
2
9
11
1
9
10
1
8
0
9d
0
1
8234
MORIBUND SACRIFICED
4
3
7
ON DAY 15 OF GESTATION
3
3
6
3
3
0
6
0
0
8235
MORIBUND SACRIFICED
6
5
11
6
4
10
6
4
0
10
0
ON DAY 15 OF GESTATION ----------------------------------------------------------------------------------------------------------------------
Rm a. b. c. d.
RIGHT L m LEFT
T - TOTAL
A - ABORTED
Conceptuses appeared normal for developmental ages.
Early resorptions, unleso noted otherwise.
Dosage occurred on days 7 through 20 of presumed gestation.
Unable to determine viability of conceptuses because of death
of doe.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T 6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ELPOSE IN RABBITS (SPONSOR'S ST
TABLE 4 (PAGE 1) : MATERNAL BODY WEIGHTS - SUMMARY
--------------- ---- - ----- ---------- -- - - -- --- --------- ----- ------ ----------- --- - -- -- - -- - - -------- - -- - --- - --------
DOSAGE GROUP
I
ii
III
I
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
1
-- -- -- -- -- -- -- -- -- - --- - --- - --- -- -- -- -- --- --- -- -- --- -- - -- -- -- -- -- -- --- -- -- --- -- -- -- -- - --- --- - ---- --- -- -- -- - --- -- -- -- ----
RABBITS TESTED
N
5
5
PREGNANT
N
5
5
14ATERNAL BODY WEIGHT (KG)
DAY
0
MEAN+S.D.
3.80 + 0.36
3.84 + 0.24
3.95 + 0.28
DAY
7
MEAN+S.D.
3.76 + 0.17
3.97 + 0.18
4.10 + 0.30
DAY
8
MEAN+S.D.
3.77 + 0.18
4.00 + 0.17
4.06 + 0.30
DAY
9
HEAN+S.D.
3.82 + 0.19
4.02 + 0.17
4.06 + 0.33
DAY 10
MEAN+S.D.
3.83 + 0.17
4.05 + 0.18
3.98 + 0.30
DAY 11
HEAN+S.D.
3.81 + 0.16
4.05 + 0.15
3.93 + 0.30
DAY 12
HEAN+S.D.
3.83 + 0.16
4.07 + 0.14
3.68 + 0.24
DAY 13
MEAN+S.D.
3.86 + 0.15
4.09 + 0.13
3.93 + 0.28
DAY 14
MEAN+S.D.
3.90 + 0.17
4.13 + 0.12
3.85 + 0.24
DAY 15
MEAN+S.D.
3.92 + 0.18
4.17 + 0.14
3.86 + 0.23
DAY 16
MEAN+S.D.
3.92 + 0.16
4.21 + 0.10
3.76 4 0.24
DAY 17
MEAN+S.D.
DAY 18
MEAN+S.D.
DAY 19
MEAN+S.D.
DAY 20
MEAN+S.D.
----------------------------------------
3.94 + 0.16
4.22 + 0.10
( 4]b
3.96 + 0.17
4.20 + 0. 10
[ 4)b
3.98 + 0.16
4.22 + 0.10
1 41b
3.99 + 0.15
4.24 + 0.12
[ 4]b -------------------------------------- ----
DAY (I a. b.
= DAY OF GESTATION = NUMBER OF VALUES AVERAGED Dosage occurred on days 7 through Excludes values for a rabbit that
20 of gestation. was found dead.
3.78 + 0.18
3,76 + 0.12
3,'77 + 0.16
3.75 + 0.14
----
------I - -----
3.79 3.98 3.88 3.81 3.70 3.61 3.54 3.51 3.46 3.45 3 .42 3 .42 3 .40
3.37 3 . 36
PROTOCOL 418-01OP!
ORAL (STOMACH TUBE) DOSAGE NUMBER: T-6316.8)
RANGE DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S S
TABLE 4 IPAGE 2): MATERNAL BODY WEIGHTS - SUMMARY
----------------------------------------------- ------ ---------------- -- ---- --- ------------ ---- --- ----
DOSAGE GROUP
I
ii
III
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
------------------------------------------------------ ------------------------------------------------ --------------
RABBITS TESTED
N
5
5
5
PREGNANT
N
s
5
5
INCLUDED IN ANALYSES
N
5
4b
s
MATERNAL
BODY WEIGHT (KG)
DAY 21
MEAN+S.D.
4.02 + 0.15
4.27 + 0.13
3.72 + 0.15
3.29
DAY 22
HEAN+S.D.
4.03 + 0.14
4.28 + 0.11
3.69 + 0.19
3.18
DAY 23
MEAN+S.D.
4.03 + 0.13
4.34 + 0.10
3.63 + 0.20
3.22
DAY 24
MEAN+S.D.
4.02 + 0.14
4.35 + 0.10
3.69 + 0.11
3.28
1 4]b
I
DAY 25
MFAN+S.D.
4.01 + 0.14
4.38 + 0.10
3.68 + 0.15
3.25
i 4)b
DAY 26
MEAN+S.D.
4.03 + 0.16
4.41 + 0.08
3.70 + 0.16
1 i)b
DAY 27
MEAN+S.D.
4.04 + 0.17
4.42 + 0.07
3.70 + 0.23
( 21b
DAY 28
HEAN+S.D.
4.06 + 0.19
4.40 + 0.03
3.70 + 0.29
( 2]b
DAY 29
MEAN+S.D.
4.07 + 0.24
4.42 + 0.05
3.70 + 0.36
( 2)b - -- - --- - -- -- -- - --- -- --- - -- - -- -- --- - ---- -- -- -- -- -- -- -- --- - -- -- -- -- -- -- --- -- -- --- -- --- -- - --- -- -- -- --- - --- -- -- --- - --- --- -
DAY (I a. b.
= DAY OF GESTATION - NUMBER OF VALUES AVERAGED Dosage occurred on days 7 through Excludes values for rabbits that
20 of gestation. died or aborted.
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER: T 6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS ISPONSOR'S ST
TABLE 4 (PAGE 3): MATERNAL BODY WEIGHTS - SUMMARY
-------------------------------------------------------- -- -I -- ------------ ----
DOSAGE GROUP
DOSAGE (MG/KG/DAY)a -----------------------------
v
vi
25
so
---------------------------------- -----------------
RABBITS TESTED
N
5
5
--------------------------- --vii 75
--- -------------------------------
s
PREGNANT
N
5
5
4
14ATERNAL BODY WEIGHT (KG)
DAY
0
HEAN+S.D.
3.49 + 0.25
3.81 + 0.31
3.65 + 0.39
DAY
7
MEAN+S.D.
3.60 + 0.18
3.89 + 0.25
3.76 + 0.34
DAY
8
MEAN+S.D.
3.50 + 0.17
3.78 + 0.27
3.70 + 0.29
DAY
9
MEAN+S.D.
3.41 + 0.13
3.65 + 0.24
3.63 + 0.32
DAY 10
MEAN+S.D.
3.33 + 0.16
3.56 + 0.25
3.48 + 0.40
DAY 11
MEAN+S.D.
3.26 + 0.16
3.46 + 0.22
3.34 + 0.38
DAY 12
MEAN+S.D.
3.20 + 0.13
3.39 + 0.23
3.28 + 0.37
DAY 13
MEAN+S.D.
3.15 + 0.14
3.26 1
+ 0.22 4)b
DAY 14
MEAN+S.D.
3.09 + 0.14
3.17 + 0.24 1 41b
DAY 15
MEAN+S.D.
b
b
---------------------------------------------------------------------------------- ----
3.17 + 0.34
3.12 + 0.31
b ------------------------ -----
DAY (I a. b.
= DAY OF GESTATION = NUMBER OF VALUES AVERAGED Dosage occurred on days 7 through Excludes values for rabbits that
20 of gestation. died or were moribund
sacrificed.
I
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS (SPONSOR'S ST
TABLE S (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - SUMMARY
----------------- -
--------------------------- -- ----------
------- ---------- - ----
DOSAGE GROUP
I
ii
III
I
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
1
- -- -- -- -- - -- -- - --- -- -- ---- - - - ------ -- -- -- -- --- -- -- --- -- -- -- -- -- -- -- -- -- -- -- -- ---- -- -- -- -- --- - --- -- -- -- --- --- - --- -- -- --
RABBITS TESTED
N
5
5
s
PREGNANT
N
5
5
MATERNAL BODY WEIGHT CHANGE
(KG)
DAYS 0
7
MEAN+S.D.
-0.04 + 0.36
+0.14 + 0.08
+0.16 + 0.09
+0.19
DAYS
7
10
t4EAN+S. D.
40.07 + 0.02
+0.08 + 0.04
-0.13 + 0.08
-0.28
DAYS 10
13
MEAN+S. D.
+0.03 + 0.03
*0.04 + 0.08
-0.14 + O.OS
-0.19
DAYS 13
16
14EAN+S.D.
+0.06 + 0.04
+0.12 + 0.04
-0.07 + 0.12
-0.09
DAYS 16 - 19
MEAN + S. D.
+O.OS + 0.02
+0.04 + 0.03
+0.01 + 0.12
-0.04
DAYS 19 - 21
HEAN+S. D.
+0.04 + 0.02
[ 4)b +0.04 + 0.04
-0.05 + 0.04
-0.09
( 4]b
DAYS 21 - 25
MEAN+S. D.
-0.01 + 0.08
+0.12 + 0.05
-0.09 + 0.14
-0.22
DAYS 25 - 29
HEAN+S.D.
+0.06 + 0.12
1 +0.04
4)b + 0.06
( 4)b +0.00 + 0.25
1 4)b
I 2)b
DAYS
7 - 21
MEAN+ S. D.
+0.26 + 0.08
+0.34 + 0.07
0.38 + 0.21
-0.69
1 4)b
DAYS
7 - 29
MEAN+S. D.
+0.31 + 0.11
+0.51 + 0.14
-0.58 + 0.74
DAYS
0 - 29
MEAN+ S. D.
+0.27 + 0.38
1 +0.66
4)b + 0.18
( 2)b -0.36 + 0.74
1 4]b
[ 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 418-01OP:
ORAL (STOMACH TUBE) NUt4BER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 5 (PAGE 2) : MATERNAL BODY WEIGHT CHANGES - SUMMARY
--------------------- -- ---- ----------------- --------------------------
---- ---
------
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
25
50
75
-- -- -- -- -- --- - -- -- -- - --- - - - ------ --- -- --- -- -- -- -- -- -- -- -- --- - --- -- -- --- -- -- -- -- -- --- -- -- --- -- -- --- -- --- --- - --- -- -- -- ---
RABBITS TESTED
N
5
5
s
PREGNANT
N
5
s
4
MATERNAL BODY WEIGHT CHANGE
(KG)
DAYS 0
7
MEAN+S.D.
+0.11 + 0.07
+0.09 + 0.10
+0.11 + 0.06
DAYS 7
10
HEAN+S.D.
-0.27 + 0.04
-0.33 + 0.04
-0-28 + 0.07
DAYS 10
13
MEAN+S.D.
-0.18 + 0.12
-0.27 + 0.05
-0.32 + 0.07
( 4)b
DAYS 13
16
MEAN+S. D.
b
b
b
-----------------------------------------------------------------------------------------------------------------------
DAYS - DAYS OF GESTATION [ I - NUMBER OF VALUES
AVEP.AGED
a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or were moribund sacrificed.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS ISPONSOR'S ST
TABLE 6 (PAGE 1)! MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY
----------------------------- -------------------- - ---------------------------- --------------- ------ -- ---------
DOSAGE GROUP
I
ii
III
I
DOSAGE (MG/K(;/DAY)a
0 (VEHICLE)
1
5
1
------------------------------------------------------------------------------------------------------------- ---------
RABBITS TESTED
N
5
5
5
PREGNANT
N
5
5
5
MATERNAL FEED
CONSUMPTION
(G/DAY)
DAYS 7 - 10
MEAN+S.D.
165.2 + 20.2
167.6 + 14.1
111.9 + 47.8
19.5
DAYS 10 - 13
MEAN+S.D.
165.9 + 21.1
158.9 + 17.7
21.1 + 29.0
0.7
DAYS 13 - 16
MF.AN+s. D.
169.2 + 21.6
163.6 + 20.8
9.1 + 15.8
7.2
( 4)b
DAYS 16 - 19
MEAN+S.D.
167.2 + 17.2
155.5 + 40.1
2.6 + 1.1
9.1
( 4]b
DAYS 19 - 21
HEAN+S.D.
IS6.6 + 25.4
161.4 + 25.0
1.9 + 1.3
1.4
( 4]b
DAYS 21 - 25
HEAN+S.D.
114.1 + 58.5
164.6 + 8.7
25.5 + 46.6
1.0
I 4)b
I 4)b
DAYS 25 - 29
HEAN+S.D.
101.9 + 47.2
123.4 + 26.0 ( 4]b
79.6 +110.1 ( i)b
DAYS 7 - 21
MEAN4s.D.
165.4 + 17.9
162.0 + 21.9
31.3 + 17.7
8.0
I 4)b
DAYS 7 - 29
MEAN+S.D.
144.5 + 24.5
155.4 + 11.8
46.2 + 40.6
( 4]b
( ilb
---------------------------------------------------------------------------------- -------------------------- --
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 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 6 (PAGE 2): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY
----------------------------- - ----------------------- ----- -- -------- - ---- ---
----------------------- - ----
DOSAGE GROUP
v
vi
vii
DOSAGE (MG/KG/DAY)a
25
so
75
------------------------ - ------------------------------- ----------------- - ------------- -------------------------------
RABBITS TESTED
N
5
5
5
PREGNANT
N
5
5
4
MATERNAL CONSUMPTION
FEED (G/DAY)
DAYS 7
10
MEAN+S.D.
12.1 + 6.7
5.4 + 3.4
4.5 + 2.6
DAYS 10
13
MEAN+S.D.
1.4 + 1.9
0.8 + 0.2
0.1 + 0.2
1 41b
DAYS 13
16
HEAN4S.D.
b
b
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 were moribund
sacrificed.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 7 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY
--------- --- ----- ---------- ------ ---------------------- ----------------- - - -- ------------------------ -- --
DOSAGE GROUP
I
ii
III
I
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
1
----- - ---- -- - -- -- -- ---- - --- -- -- - -- - -- --- -- --- --- --- - -- -- --- -- -- -- --- - ---- ---- - --- -- -- -- --- -- -- ----- ---- --- -- -- --- --- --
RABBITS TESTED
N
5
5
5
PREGNANT
N
s
5
5
14ATERNAL FEEI)
CONSUMPTION
(G/KG/DAY)
DAYS 7
10
MEAN. S. D.
43.5 + 4.8
41.9 + 4.6
27.4 + 11.4
5.1
DAYS 10
13
MEAN+S.D.
43.2 + 4.8
39.1 + 4.9
5.3 + 7.3
0.2
DAYS 13
16
MEAN+ S. D.
43.3 + 5.1
39.6 + 4.7
DAYS 16
IS
MEAN+ S. D.
42.2 + 4.6
[ 4]b 36.5 + 9.0
DAYS 16 - 19
MEAN+ S. D.
42.3 + 4.3
( 4]b 36.9 + 9.4
DAYS 19 - 21
DAYS 21 - 25
DAYS 25 - 29
DAYS
7 - 21
DAYS
7 - 29
MEAN+ S. D. MEAN*S.D. MEAN+S.D. MEAN+ S. D. MEAN+ S. D.
39.2 + 6.4 28.3 + 14.2 24.9 + 10.4 42.5 + 4.2 36.6 + 5.5
( 38.0
1 38.0
1 28.0
( 39.4
i 37.0
4]b + S.4 4]b + 1.1 4]b + 6.1 41b + 5.2 4]b + 2.7
( 4]b ------------------------------------------------------------------------------------
DAYS = DAYS OF GESTATION ( ) = NUMBER OF VALUES
AVERAC;ED
a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted.
2.4 + 4.0
2.2
0.8 + 0.5
3.0
0.7 + 0.3
2.8
0.5 + 0.3
0.4
7.0 (
20.6 (
8.0
+ 12.7 4)b + 28.4 2)b + 4 .4
0. 3 2.3
12.0 + 10.7 ( ilb
-- - -- --------- -------- ---
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NTJMBER: T-6316.8)
DOSAGE
RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 7 (PAGE 2) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KC/DAY) - SUMMARY
------------------------------------------ ---- --------------------------------------------------- ---------------- --
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
25
so
75
----------- --- - --- - --- - --- - --- ---- ---- --- - --- -- -- --- -- - -- -- -- ---- - --- - -- --- -- -- -- --- - --- -- -- - --- --- -- --- ---- --- - ---- -- -
RABBITS TESTED
N
5
s
5
PREGNANT
N
5
5
4
MATERNAL FEED
CONSUMPTION
(G/KG/DAY)
DAYS 7 - 10
MEAN+S.D.
3.5 + 1.9
1.5 + 1.0
1.3 + 0.9
DAYS 10 - 13
MEAN+S.D.
0.4 + 0.6
0.2 + 0.0
0.0 + 0.0
DAYS 13 - 16
MEAN+S.D.
-------------- ---- ---- -----------------
( 4)b
b
b
b
---- --- --- --- - ---- --- ----- ---- - --------- -- --- -- -- -- --- - --- -- -- --- --- - --- - -- -----
DAYS - DAYS OF GESTArioN
( I - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or were moribund
sacrificed.
PROTOCOL 418-OIOP:
ORAL, (STOMACH TUBE) DOSAGE-RANGE NUMBER: T 6316.8)
DEVELOPMENTAL
TOXICITY STUDY OF N-ETPOSE IN RABBITS (SPONSOR'S ST
TABLE 8 (PAGE 1): CAESAREAN-SECTIONING
OBSERVATIONS
SUMMARY
---------------------
---------------- ------
---------------------
DO-SA-G-E---G-R-OU-P----------------
1
11
111
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
I
s
---------------------------- -- ---------- ---------------- - ------------------------- - ------------------------ --------
RABBITS TESTED
N
5
5
5
PREGNANT FOUND DEAD ABORTED MORIBUND SACRIFICED
N(t) N(t) N(t) N(t)
5(100.0) 0( 0.0) 0( 0-0) 0( 0.0)
5(100.0) 1( 20.0) 0( 0.0) 0( 0.0)
5(100.0) 0( 0-0) 3( 60.0) 0( 0-0)
S(10 0( 5(10 0(
RABBITS PREGNANT AND
CAESAREAN-SECTIONED
ON DAY 29 OF GESTATION
N
5
4
2
CORPORA LUTRA
MEAN+S.D.
10.8 +
2.6
11.2 +
1.5
11.0 +
2.6
IMPLANTATIONS
HEAN+S.D.
8.2 +
3.8
10.2 +
1.0
10.0 +
2.8
LITTER SIZES
HEAN*S.D.
7.0 +
3.4
8.5 +
3.1
6.5 +
2.1
LIVE FETUSES
N MEAN+S.D.
35
7.0 +
3.4
34
8.5 +
3.1
13 6.5 + 2.1
DEAD FETUSES
N
0
0
0
RESORPTIONS
MEAN+S.D.
1.2 + 0.8
1.8 +
2.9
3.5 +
0.7
EARLY RESORPTIONS
N MEAN+S.D.
4
0.8 +
0.8
7
1.8 +
2.9
0
0.0 +
0.0
LATE RESORPTIONS
N MEAN+S.D.
2 0.4 + 0.5
0
0.0 +
0.0
DOES WITH ANY RESORPTIONS
N(%)
4( 80.0)
2( 50.0)
DOES WITH ALL CONCEPTUSES
RESORBED
N
0
0
DOES WITH VIABLE FETUSES
N(t)
5(100.0)
4(100.0)
PLACENTAE APPEARED
NORMAL
N(t)
5(100.0)
4(100.0)
------------------------------------------------------- - --- ---------------------
a. Dosage OCCurred on days 7 through 20 of gestation.
7
3.5 +
0.7
2(100.0)
0
2(100.0)
2(100.0) ---- ------- -- -
PROTOCOL 418-01OP:
ORAL ISTOMACH TUBE) NUT-IBER: T-6316.6)
DOSAGE-RA.NGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS (SPONSOR'S S
TABLE 8 (PAGE 2): CAESAREAN -SECTION ING OBSERVATIONS
- SUMMARY
------- -------- ------- - - --- ------------------ ------ ------------ --- ---
--- -------- ------------ ---
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
25
50
75
------------------------------------------------------------ -------------------------- ---------------- -------------
RABBITS TESTED
N
5
5
5
PREGNANT FOUND DEAD ABORTED MORIBUND SACRIFICED
N(t) N(t) N(t) N(l)
S(100.0) 0( 0.0) 0( 0.01 5(100.0)
5(100.0) 2( 40.0) 0( 0.0) 3( 60.0)
4( 80.0) 11 20.0) 0( 0.0) 3( 60.0)
RABBITS PREGNANT AND
CAESAREAN-SECTIONED
ON DAY 29 OF GESTATION
N
0
0
0
--------------------------------------------------------------------------------------- ---------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 9 (PAGE 1): LITTER OBSERVATIONS
(CAESAREAN-DELIVERED
FETUSES) - SUMMARY
----------- ------------------------- - ------------ --- -- --- ----------------
--------------
DOSAGE GROUP
I
ii
III
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
5
-------------------------------------- ---------------------------------------------------- -----------------
LITTERS WITH ONE OR
MORE LIVE FETUSES
N
s
4
2
----
I 1 --------
IMPLANTATIONS LIVE FETUSES
MEAN+S.D.
N MEAN+S.D.
8.2 +
3.8
35 1.0 + 3.4
10.2 +
1.0
34 8.5 + 3.1
10.0 +
2.8
13 6.5 + 2.1
LIVE 14ALE FETUSES
N
24
is
5
t LIVE MALE FETUSES/LITTER
MEAN+S.D.
73.1 + 20.3
45.0 + 4.1
38.8 +
1.8
LIVE
PETAL BODY WEIGHTS (GRAMS)/LITTER
MEAN+S.D.
45.66 + 5.70
46.50 + 6.26
23.80 + 6.68
MALE FETUSES
MEAN+S.D.
46.30 + 5.33
46.75 + 4.SS
25.51 + 3.55
FEMALE FETUSES
MEAN+S.D.
44.74
+ 7.45 4)b
46.44 + 7.60
22.64 + 8.73
t RESORBED
CONCEPTUSES /LITTER
MEAN+S.D.
15.0 + 10.9
17.3 + 28.8
35.4 4
3.0
-------------------------------------------------------------------------------------------------------------
( I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Litter 8201 had no female fetuses.
PROTOCOL 416-01OP;
ORAL (STOMACH TUBE) NUMBER: T-6316.6)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY S'I'IJDYOF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 9 (PACE 2); LITTER OBSERVATIONS
(CAESAREAN-DELIVERED
FETUSES) - SUMMARY
----------------------- I -
DOSAGE GROUP DOSAGE (MG/KG/DAY)a -------------------------
-------- ------ ---------- ---- 1-@ --- --------------
v
vi
25
so
----------------------------------------------------
--- -- ------------- --- - --------
Vil 75
---------------------------------------
LlrrERS WITH ONE OR
MORE LIVE FETUSES
N
0
0
0
-- - -- -- -- - --- - --- -- -- -- - -- - --- --- - ---- - --- -- -- --- -- -- -- -- - -- -- -- -- --- -- --- --- - --- -- -- --- - --- -- -- --- -- -- --- -- -- -- --- --- -
a. Dosage occurred on days 7 through 17 of gestation.
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NLlt4BER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S S
TABLE 10 (PAGE 1) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY
---------------- --I --------------------
---- -- I ------- ------ -------- - ----I -- --- -- ---- -- --------
DOSAGE GROUP
1
11
111
DOSAGE (MG/KG/DAY)a
0 (VEHICLE)
1
s
----------------------------------------------------------------------------------------------- ----------------------
LITTERS EVALUATED
N
5
4
2
FETUSES EVALUATED
N
35
34
13
LIVE
N
35
34
13
----------------------------------------------------------------------------------------------------------------------
BODY: ABDOMINAL DISTENTION
LITTER INCIDENCE FETAL INCIDENCE
N(t) N(t)
0( 0.0) 0( 0.0)
1( 25.0) 1( 2.9)
0( 0.0) 0( 0.0)
TONGUE:
PROTRUDED
LITTER INCIDENCE
FETAL INCIDENCE
N(t) N(t)
0( 0-0) 0( 0.01
0( 0.0) of 0-0)
1( 50.0) 1( 7.7)b
EYELIDS: LITTER FETAL
OPENED INCIDENCE
INCIDENCE
N(l) N(l)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0-0)
1( 50.0) 1( 7.7)b
FORE AND/OR HINDLIMBS.LITTER INCIDENCE FETAL INCIDENCE
FLEXED
DOWNWARD N(t) N(t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 50-0) 1( 7.7)c
INCISORS; LITTER FETAL
ABSENT INCIDENCE INCIDENCE
N(t) N(t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 50.0) 1( 7.7)c
SNOUT; CLEFT LITTER INCIDENCE FETAL INCIDENCE
N(t) N(t)
0( 0.0) 0( 0.0)
0( 0-0) 0( 0.0)
1( 50.0) 1( 7.7)c
EYES: LARGE
LITTER INCIDENCE
N(t)
0( 0-0)
0( 0.0)
FETAL INCIDENCE
N(t)
0( 0.0)
0( 0-0)
------------------------------------------ ------------------------------- ---
a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 7385-1 had other gross external alterations. C. Fetus 7385-4 had other gross external alterations.
1( 50.01 1( 7.7)c
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 10 (PAGE 2): FETAL GROSS EXTERNAL ALTERATIONS
- SUMMARY
----------------
- -------------------- ---- ---- ----- -------- ---
-- ------------- ------
DOSAGE GROUP
v
vi
Vil
DOSAGE (MG/KG/DAY)a
2S
so
7S
-------------------------------------------- ------------------------- ----------------- ------------------------------
LITTERS EVALUATED
N
0
0
0
FETUSES EVALUATED
N
0
0
0
LIVE
N
0
0
0
-----------------------------------------------------------------------------------------------------------------------
a. Dosage occurred on days 7 through 20 of gestation.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 11 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAI@ DATA
----------------- ---- ------ - --------------- -I --- - ------------------------ -- - ---------------- - -------
RABBIT #
DESCRIPTION
-------------------------------------------------------
---------------------- I --------------------------
DOSAGE GROUP 1
0 (VEHICLE)MG/KG/DAY
------------------------------------------------------ - --------------------------- ----- ----------------
--------
8201
8202
DG(
8203
8204
8205 ----------------------
NO ADVERSE FINDINGS
29
LOCALIZED ALOPECIA:
BACK a
NO ADVERSE FINDINGS
NO ADVERSE FINDINGS
NO ADVERSE FINDINGS --- - --- - - - ----- ---- ----- --- -- -- -- -- --- -- --- - ----- - --- -- --- --- - -- -- -- ---- ----- -- -- --- --
- --- -- --- -
DOSAGE GROUP 11
1 MG/KG/DAY
------------------------------------------------------------------------------------------------------------ ----------
8206
DG(
16
FOUND DEAD
8207
DG(
19
RED SUBSTANCE
IN CAGE PAN
8208
NO ADVERSE FINDINGS
8209
DG( 28- 29)
LOCALIZED ALOPECIA:
LIMBS a
DG(
29
LOCALIZED ALIDPECIA:
BACK a
8210
NO ADVERSE FINDINGS
----------------------------------------------------------------------------------------------------------------- -----
DG = DAY OF PRESUMED GESTATION a. observation confirmed at necropsy.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ELFOSE IN RABBITS (SPONSOR'S S
TABLE 11 (PAGE 2): CLINICAL OBSERVATIONS
- INDIVIDUAL DATA
---------------- -------------------------------------------- ---------- - ----------- ------------------------
RABBIT 0
DESCRIPTION
-- -- -- -- -- -- -- - -- -- --- - - ------- --- -- -- --- - -- -- -- --- -- -- -- -- -- -- --- -- -- -- -- -- -- --- -- -- --- -- --- - --- -- -- --- - --- -- -- -- -- --
DOSAGE GROUP 111
5 MG/KG/DAY
------------------------------------------------------------------------------------------------------------------ ---
8211
DG( 10- 25)
DG(
17
SCANT FECES NO FECES
DG(
22
DG(
26
SOFT OR LIQUID FECES RED SUBSTANCE IN CAGE PAN
DG(
26
ABORTED AND SACRIFICED
8212
DO( 10 - 23)
DGI
20 )
SCANT FECES RED SUBSTANCE
IN CAGE PAN
DG( 20 - 21)
LEFT FOREPAW;
ABRASION
DG(
22
ABRASION NO LONGER APPARENT
DG(
22
SOFT OR LIQUID FECES
8213 8214
DG(
24
DG( 13- 25)
DG( 17- 19)
ABORTED AND SCANT FECES NO FECES
SACRIFICED
DG( 20- 25)
SCANT FECES
DGI
26
RED SUBSTANCE IN CAGE PAN
7385
DG4
26
DG( 7- 21)
ABORTED AND SACRIFICED
LEFT HINDPAW:
ABRASION
(DID NOT EXCEED 0.5 CM IN DIAMETER)
DG(
22 )
ABRASION NO LONGER APPARENT
DG( 10- 20)
SCANT FECES
DG( 12 - 13)
SOFT OR LIQUID FECES
DG( 12 - 22) DG( 21 - 24)
UNGROOMED NO FECES
COAT
DG(
26
DG(
27
SCANT FECES NO FECES
DG(
28
SCANT FECES
DG(
29
NO FECES
--------------------------------------------------------------------------------------- --- ---------------------- ---
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NLYMBER: T 6316.8)
DOSAGE-RA.NGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 11 (PAGE 3) : CLINICAL OBSERVATIONS
INDIVIDUAL DATA
----------------------- ----- ------------ --
-- - - - ---------------- ------ ------ - --------------
RABBIT #
DESCRIPTION
-------------------------------------------- --------------------------------------------- - ----- --------------------
DOSAGE GROUP IV
10 MG/KG/DAY
-------------------------------------------------------------------------------------------------- --------------------
8216
DG(
10 )
NO FECES
DG( 11- 15)
SCANT FECES
DG( 17- 19)
SCANT FECES
DG(
20
NO FECES
DG(
21
SCANT FECES
DG(
22
NO FECES
DG( 23- 25)
SCANT FECES
DG(
24
DARK URINE
DG(
25
SOFT OR LIQUID FECES
DG(
26
RED SUBSTANCE
IN CAGE PAN
DG(
26
ABORTED AND SACRIFICED
6217
DG( 9- 18)
SCANT FECES
DG( 19- 20)
NO FECES
DG(
21
RED SUBSTANCE IN CAGE PAN
DG(
21
SCANT FECES
DG(
22
ABORTED AND SACRIFICED
8218
DG( 9- 11)
SOFT OR LIQUID FECES
DG( 10- 21)
SCANT FECES
DG(
22
NO FECES
DG(
23
DG(
24
SCANT FECES ABORTED AND SACRIFICED
8219
DG( 9- 16)
SCANT FECES
DG( 17- 20)
NO FECES
DG(
21
RED SUBSTANCE IN CAGE PAN
DG(
21
SCANT FECES
DG(
21
DARK URINE
DG(
22
ABORTED AND SACRIFICED
8220
DG( 9- 22)
SCANT FECES
DG( 11- 13)
SOFT OR LIQUID FECES
DG(
23 )
ABORTED AND SACRIFICED
--------------------------------------------------------------------------- ----- -
DG = DAY OF PRESUMED GESTATION
PROTOCOL 418-01OP:
ORAL ISTOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 11 (PAGE 4) : CLINICAL OBSERVATIONS
INDIVIDUAL DATA
-------------
------------------ --
-------------- ----
------------- ------ -- --------
RABBIT 4
DESCRIPTION
--------------- ----------------------------------------------- ----- -
------------------------------------------- --
DOSAGE GROUP V
25 MG/KG/DAY
-------------- - --- ---- -- ------ ---------- --- -- ---- --- ------- --- ---- --- -- -- -- -- --- --- ---- ---- ------ -------- -- - -- - - - -
7371
DG( 9- 11)
DG( 12- 13)
DG(
14
SCANT FECES NO FECES SCANT FECES
DG(
is
MORIBUND SACRIFICED
8222
DG( 9- 14)
SCANT FECES
DG(
is )
MORIBUND SACRIFICED
8223
DG( 10- 14)
SCANT FECES
DG(
is )
MORIBUND SACRIFICED
8224
DG( 10- 14)
SCANT FECES
DG(
11
DECREASED MOTOR ACTIVITY
DG(
11
IMPAIRED RIGHTING REFLEX
DG( 13- 14)
UNGROOMED
COAT
DG(
ILS )
MORIBUND SACRIFICED
8225
DG( 10- 14)
SCANT FECES
DG( 12- 14)
UNGROOMED
COAT
DG(
is )
MORIBUND SACRIFICED
----------------------------------------------------------------------------------------------------------------------
DG - DAY OF PRESUMED GESTATION
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T-6316.6@
DOSAGE
RANGE DEVELOPMENTAL
TOXICITY STUDY OF N-ELFOSE IN RABBITS (SPONSOR'S ST
TABLE 11 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA
-----------------------------------------------------
-------------- ---- - -- ---- ---------------
RABBIT N
DESCRIPTION
--- -------------------- - -- -- -------- ------------------------ ------------------------ -------------------- -----
--------
DOSAGE GROUP VI
SO MG/KG/DAY
- - --- -- -- - -- -- -- -- --- -- - - - ------- --- - -- -- --- - --- - --- -- -- -- -- -- -- -- -- --- - ---- -- -- --- - --- - --- - --- -- -- --- -- --- -- -- --- --- --
8226
DG( 9- 13)
SOFT OR LIQUID FECES
D(; 1 10- 13)
SCANT FECES
DG(
14
DECREASED MOTOR ACTIVITY
DG(
14
LOST RIGHTING REFLEX
DG(
14
DG(
14
NO FECES FOUND DEAD
8227
DG( 10- 14)
SCANT FECES
DG(
14
DECREASED MOTOR ACTIVITY
DG(
14
DRIED YELLOW BROWN PERIORAL SUBSTANCE
DG(
is
MORIBUND SACRIFICED
8228
DG( 10- 14)
SCANT FECES
DO(
14
DECREASED MOTOR ACTIVITY
DG(
14
DRIED YELLOW PERIORAL SUBSTANCE
DG(
15
MORIBUND SACRIFICED
8229
DG(
9
SOFT OR LIQUID FECES
DG( 10- 11)
SCANT FECES
DG(
12 )
FOUND DEAD
8230
D(I( 10- 13)
SCANT FECES
DG( 10- 13)
SOFT OR LIQUID FECES
DG(
14
DECREASED MOTOR ACTIVITY
DG(
14
DRIED YELLOW PERIORAL SUBSTANCE
DO(
14
NO FECES
DG(
is
MORIBUND SACRIFICED
- --- - -- -- -- -- - - -- -- --- - - -- ------ -- -- -- -- -- -- -- -- --- -- -- -- --- - --- - -- -- --- -- -- --- -- -- -- --- -- --
--- -- -- -- --- -- --- - ------ ---
DG = DAY OF PRESUMED, GESTATION
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 11 (PAGE 6) : CL.INICAL OBSERVATIONS - INDIVIDUAL DATA
----------------------------- ------------- ------------ - ------ --- --------- ---- ---- -------------------- --
RABBIT 0
DESCRIPTION
---------------------------------------------------------------- - ----------- ---------- -------------------- ------
DOSAGE GROUP VII
75 MG/KG/DAY
------------------------------------------------------------ ----------------------------------------------------------
8231
DG( 9- 14)
SCANT FECES
DG( 12- 14)
UNGROOMED
COAT a
DG( 13- 14)
DECREASED MOTOR ACTIVITY
DG( 13- 14)
DRIED BROWN PERIOPAL SUBSTANCE a
8232
DG(
is )
DG( 9- 14)
MORIBUND SACRIFICED SCANT FECES
DG(
13 )
SOFT OR LIQUID FECES
DG( 13- 14)
DECREASED MOTOR ACTIVITY
DG( 13- IS)
DRIED YELLOW PERIOPAL SUBSTANCE
DG( 13- 14)
UNGROOMED
COAT
DG(
is
RED SUBSTANCE
IN CAGE PAN
DG(
is
MORIBUND SACRIFICED
8233
DG( 9- 13)
SCANT FECES
DG( 9- 23)
SOFT OR LIQUID FECES
DO( 13- 14)
DECREASED MOTOR ACTIVITY
DG(
14
EXCESS SALIVATION
DG(
14
NO FECES
8234
DG(
is
DG( 9- 14)
FOUND DEAD
UNGROOMED
COAT
DG( 9- 14)
SOFT OR LIQUID FECES
DG( 12- 14)
SCANT FECES
DG( 13- 14)
DECREASED MOTOR ACTIVITY
DG(
is
MORIBUND SACRIFICED
823S
DG(
9
SOFT OR LIQUID FECES
DG(
10
IMPAIRED RIGHTING REFLEX
DG( 10- 11)
SCANT FECES
DG( 10- 14)
DECREASED MOTOR ACTIVITY
DG( 12- IS)
UNCROOMED
COAT
DG( 12- 14)
NO FECES
DG( 13- 14)
IMPAIRED RIGHTING REFLEX
DG(
14 )
COLD TO TOUCH
DG( 14- 15)
EMACIATION
DG(
is
RED SUBSTANCE IN CAGE PAN
DG(
is
MORIBUND SACRIFICED
----------------------------- ----------------------------------------------- -- -
---- -------------- -
DG - DAY OF PRESUMED GESTATION
a. observation confirmed at necropsy.
PROTOCOL
418 OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S S
TABLE 12 (PAGE 1): NECROPSY OBSERVATIONS
- INDIVIDUAI, DATA
---- --------- ----------------------- --------------- --
- -- ------- -
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
--------------------------------------------------------
DOSAGES
ADMINISTERED
OBSERVATIONS
a
- ------------------------------------------------- ----- --
I
0 (VEHICLE)
8201
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8202
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8203
DG 29
p
14
ALI, TISSUES APPEARED NORMAL.
8204
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
820S
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
11
1
8206
DG 16
p
10
FOUND DEAD ON DAY 16 OF GESTATION (DEATH OCC
MINUTES AFTER DOSAGE).
ALL TISSUES APPEARED NORMAL.
8207
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8208
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8209
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8210
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
s
8211
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8212
DG 24
p
14
ABORTED ON DAY 24 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8213
DG 29
p
14
ALL TISSUES APPEARED NORMAL.
8214
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
738S
DG 29
p
--------------------------------------- ---------
P
PREGNANT
NP = NOT PREGNANT
DG
DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations
----table
14
LIVER! ALL UOBES, PALE.
ALL OTHER TISSUES -- ----------------
APPEARED
NORMAL.
(Table 11) for external observations confirmed at Fiecroi)sy
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER: T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S Sl
TABLE 12 (PAGE 2): NECROPSY OBSERVATIONS
INDIVIDUAL DATA
-------------- ----- ----------------------- ------------------------- ---------- - - ---- --- -- -------- ---------
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
-------------------------------------------------------------------------------- -------------------------------------
IV
10
8216
DG 26
p
14
ABORTED ON DAY 26 OF GESTATION.
LIVER: ALL LOBES, PALE TAN AREAS (1.5 CM X
4.0 CH X 1.6 CM). ALL OTHER TISSUES APPEARED
NORMAL.
8217
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8218
DG 24
p
14
ABORTED ON DAY 24 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8219
DG 22
p
14
ABORTED ON DAY 22 OF GESTATION.
LIVER: ALL LOBES, PALE.
ALL OTHER TISSUES APPEARED NORMAL.
8220
DG 23
p
14
ABORTED ON DAY 23 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
v
25
7371
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8222
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
B223
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8224
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8225
DG IS
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
------------------------------------------------------------------------------------------- ----------------- -- -----
P
PREGNANT
NP = NOT PREGNPLNT
DG
DAY OF PRESUMED GESTATION
a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy.
PROTOCOL 418-01OP;
ORAL (STOMACH TUBE) NUMBER: T-6316.0)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 12 (PAGE 3): NECROPSY OBSERVATIONS
- INDIVIDUAL DATA
-- --------------------------------------------- --
-----------------
------ --------------
- ------
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/YG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
- -- --- -- -- -- -- - -- -- - --- - - ----- --- -- -- -- --- -- -- - --- - --- -- -- --- -- -- -- -- -- --- -- -- -- -- --- --- - ---- - --- -- -- - --- -- -- -- ---- -- ---
vi
so
8226
DG 14
p
a
FOUND DEAD ON DAY 14 OF GESTATION (DEATH OCCUR
AND 33 MINUTES AFTER DOSAGE).
STOMACH:
MUCOSA, BLACK VISCOUS MATERIAL.
ALL OTHER TISSUES APPEARED NORMAL.
0227
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8228
DG 15
p
9
MORIBUND SACRIFICED ON DAY IS OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8229
DG 12
p
6
FOUND DEAD ON DAY 12 OF GESTATION
(DEATH OCCU
AND 53 MINUTES AFTER DOSAGE).
LIVER: ALL LOBES, GREEN-GREY AREAS.
THORACIC CAVITY:
TAN-GREY FLUID (APPROXIMATE
LUNGS: ALL LOBES, TAN-GREY.
ALL OTHER TISSUES APPEARED NORMAL FOR THE SLI
OF AUTOLYSIS.
8230
D(3 15
p
9
MORIBUND SACRIFICED ON DAY IS 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.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T 6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF H-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 12 (PAGE 4) : NECROPSY OBSERVATIONS
- INDIVIDUAL DATA
---------------------- ---------- -- ---------- --------- ------------------
------------ ---
DOSAGE GROUP
RABBIT
DAY OF
PREGNANCY
DOSAGES
DOSAGE (MG/KG/DAY)
NUMBER
NECROPSY
STATUS
ADMINISTERED
OBSERVATIONS
a
-- -- -- -- -- -- -- -- -- -- -- -- - - --- ----- --- -- -- --- -- -- - --- - -- -- --- - -- -- --- -- -- --- -- -- --- - --- -- -- --- -- -- -- --- -- -- -- -- --- -- --- -
Vil 75
8231
DG 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
ALL TISSUES APPEARED NORMAL.
0232
DG 15
NP
9
MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GES
ALL TISSUES APPEARED NORMAL.
8233
DG 15
p
9
FOUND DEAD ON DAY 15 OF GESTATION (DEATH OCCU
OVERNIGHT).
ABDOMINAL CAVITY:
THIN BROWN FLUID (APPROXIM
STOMACH:
FRIABLE; MUCOSA, VISCOUS BROWN KATE
ALL OTHER TISSUES APPEARED NORMAL.
0234
DG 15
p
9
MORIBUND SACRIFICED ON DAY IS OF GESTATION.
ALL TISSUES APPEARED NORMAL.
8235
DC 15
p
9
MORIBUND SACRIFICED ON DAY 15 OF GESTATION.
STOMACH;
MUCOSA, BLACK VISCOUS MATERIAL.
ALL OTHER 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 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.6)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 13 (PAGE 1): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
---------------------------------------
---- ---- --- - ------------------ -------- ----------------
RABBIT #
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
----------------------------------------------------------------------------------- ----------- -----------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
1
- ---- -------------------- - ----------- -------------- -- --------- ----------------- ----------------------------- ---------
8201 P
4.40
3.72
3.67
3.72
3.75
3.74
3.78
3.80
3 .78
3.79
3 . 01
3.
8202 P
3.69
3.82
3.84
3.92
3.90
3.92
3.95
3.97
4.01
4.03
4.07
4.
8203 P
3.86
4.02
4.06
4.11
4.09
4.05
4.05
4.07
4.15
4.18
4.11
4.
8204 P
3.53
3.58
3.60
3.64
3.67
3.68
3.70
3.72
3.75
3.76
3.76
3.
8205 P
3.51
3.67
3.67
3.70
3.73
3.68
3.69
3.74
3.83
3.86
3.86
3.
- - --- -- -- -- -- -- - --- -- - --- - -- ----- -- -- --- -- -- --- - -- -- -- -- -- -- --- -- --- -- -- -- -- -- -- -- -- -- -- --- -- -- --- --- -- -- -- -- -- --- --- --
DAY 19
20
21
22
23
24
25
26
27
28
29
------------------------------------------------------------------- ----------------------------------------- ---------
8201 P
3.85
3.87
3.08
3.93
8202 P
4.11
4.10
4.12
4.13
8203 P
4.18
4.19
4.22
4.19
8204 P
3.60
3.82
3.86
3.86
8205 P
3.94
3.99
4.01
4.03
---- ---------------------------------------------
3.92
3.93
3.94
3.95
3.93
3.97
4.03
4.11
4.05
3.99
4 .04
4 .09
4.14
4 .10
4.21
4.25
4.26
4.29
4.30
4.34
4.41
3.89
3.90
3.89
3.87
3.87
3.83
3@73
4.01
3.97
3.99
3.98
4.02
4.04
4.09
------ ---------------------------- - --------- ------------ ---- - ----- ---
P = PREGNANT
MP - 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 (KC)
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 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T-6316.8)
DOSAGE-RAN(;E
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 13 IPAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
--------------- --------- --- ------------ --------------------------
RABBIT #
DOSAGE GROUP 11
1 MG/KG/DAY
--------------------------------------------------------------------
PREGNANCY
-- - -- --
----- - --- ------------ - -----
---------------------------------------- ---------
STATUS
DAY 0
7
a
9
10
11
12
13
14
is
16
1
--- - -- -- -- -- -- - -- --- -- -- - - -- ------ -- --- - -- -- --- -- -- -- -- -- -- -- -- -- -- - ---- -- -- --- -- -- -- -- -- -- -- -- -- --- --- -- -- -- -- --- --- --
8206 P
4.13
8207 P
3.73
8208 P
3.83
0209 P
3.98
8210 P
3.51
-------------------------
4.17
4.19
4.19
4.24
4.22
4.26
4.24
4.23
4.30
4.32
3.84
3.89
3.96
3.99
4.00
4.00
4.01
4.08
4.06
4.17
4.
4.04
4.04
4.06
4.09
4.10
4.12
4.20
4.24
4.31
4.28
4.
4.08
4.10
4.14
4.15
4.12
4.10
4.10
4.16
4.18
4.23
4.
3 .72
3.76
3.77
3.78
3.83
3.89
3.92
3.94
4.01
4.06
4.
----------------------------------------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
1 29
------------------------------ --------------------------------------------- ------------------------------------------
8206 P
FOUND DEAD ON DAY 16 OF GESTATION
8207 P 8208 P 8209 P 0210 P
4.17 4.34 4.28 4.21
4.13 4.36 4.32 4.13
4.16 4.39 4.37 4.16
4.17 4.38 4.36 4.20
4.26 4.43 4.42 4.24
4.26 4.47 4.41 4.27
4.32 4.50 4.42 4.29
4.36 4 .49 4.46 4.32
4.38 4.50 4.45 4.34
4.38 4.45 4.41 4.38
4.36 4.47 4.46 4.41
-----------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY - DAY OF PRESUMED GESTATION
ALL ALL BODY a.
WEIGHTS WERE RECORDED IN GRAMS
CALCULATIONS
EXCEPT BODY WEIGHT
WRIGHT AVERAGES ARE CALCULATED
Doe 8206 was found dead on day
(G) , ROUNDED TO THREE SIGNIFICANT AVERAGES ARE PERFORMED WITH THE WITH THE ROUNDED KILOGRAM (KG) 16 of gestation.
DIGITS UNROUNDED VALUE.
AND REPORTED GRAM (C)
IN KILOGRAMS VALUE.
(KG) .
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS ISPONSOR'S ST
TABLE 13 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
-------------- --- -- - ------ --------------- --------------- ----------- --------- ------------- -------- ------ - -
RABBIT 0
DOSAGE GROUP III
5 MG/KG/DAY
-------------------------------------------------------------- --------------------------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
is
16
1
- -- -- -- -- - --- - - -- -- -- - - - ------- --- -- -- -- - --- -- -- -- --- -- -- -- -- - --- -- -- --- - --- --- - --- -- --- -- -- -- -- -- -- -- -- --- -- --- --- --- -
8211 P
4.09
4.11
4.13
4 .01
3 .92
3.80
3.76
3.74
3.86
3.90
3.79
3.
8212 P
3.61
8213 P
3.80
6214 P
3.92
7385 P
4.33
------------------I
3.72
3.64
3 .61
3.S6
3.51
3.54
3.43
3.44
3.49
3.38
3.
4.02
4.00
4.06
4.03
4.02
3.94
3.68
3.93
3.84
3.69
3.
4.10
4.06
4.07
3.99
3.98
3.97
3.92
3.94
3.95
3.94
3.
4.56
4.49
4.53
4.40
4.34
4.18
4.20
4.07
4.11
3 .99
3.
---------------------------.-----------------------------------------------------------------
DAY 19
20
21
22
23
24
25
26
27
28
29
- -- -- -- -- -- -- - - --- --- - - - -------- -- -- -- --- - --- - -- -- --- -- -- -- -- --- - --- - -- -- --- --- -- --- -- -- -- -- -- -- -- -- -- -- --- --- -- -- --- --
6211 P
3.66
8212 P
3.54
8213 P
3.81
8214 P
3.90
7385 P
3.92
-- -- -- -- - -- -- - - --- ----
3.70
3.64
3.64
3.56
3.57
3.48
ABORTED ON DAY 26 OF GESTATION
3.57
3.52
3.41
3.40
ABORTED ON DAY 24 OF GESTATION
3.70 3.87
3.70 3.89
3.66 3.92
3.55 3.91
3.68 3.84
3.79 3.81
3.81 ABORTED
3.87
3.91
3.96
ON DAY 26 OF GESTATION
3.90
3.86
3.60
3.73
3.68
3.63
3.58
3.54
3.50
3.45
- - -------- -- --- -- -- -- -- -- -- -- -- -- -- --- -- -- -- -- -- -- --- -- -- -- --- -- -- --- - -- -- -- -- -- -- --- -- --- --- --- -
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.
PROTOCOI, 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 13 (PAGE 4) ; MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
---------------------------------------------------------------------------------- --
- --------------------
RABBIT 0
DOSAGE GROUP IV
10 MG/KG/DAY
-------------------------------------------------------------------------------------------- -------------------- ---
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
15
16
1
----------------------------------------------------------------------------------------- -- --------------------------
8216 P
4.08
4.26
4.16
4.13
3.98
3.90
3.82
3.75
3 .69
3.71
3.65
3.
8217 P
3.75
4.02
3.93
3.82
3.71
3.65
3.60
3.64
3.55
3.58
3.53
3.
8218 P
3.81
4.09
3.88
3.74
3.75
3.55
3.48
3.41
3.42
3.40
3.34
3.
8219 P
3.96
4.05
4.00
3.90
3.78
3.65
3.61
3.53
3.52
3.46
3.44
3.
8220 P
3.35
3.48
3.42
3.44
3.29
3.32
3.19
3.24
3.12
3.11
3.14
3.
- -- -- --- - --- - -- - -- - -- - --- -- -- ---- --- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --- -- --- -- -- -- -- --- -- -- -- -- --- -- --- - --- - --- -- -- --- -- ---
DAY 19
20
21
22
23
24
2S
26
27
28
29
----------------------------------------------------------------------------------------- -----------------------------
8216 p
3.54
3.47
3.47
3.40
3.36
3.28
3.25
ABORTED ON DAY 26 OF GESTATION
8217 P
3.55
3.56
3.44
ABORTED ON DAY 22 OF GESTATION
8218 P
3.20
3.23
3.16
3.17
3.09
ABORTED ON DAY 24 OF GESTATION
8219 P
3.44
3.45
3.32
ABORTED ON DAY 22 OF GESTATION
8220 P
3.14
3.11
3.06
2.98
ABORTED ON DAY 23 OF GESTATION
- - --- -- -- -- -- - - -- -- -- - --- - --- --- -- --- -- -- --- - --- - -- -- -- -- --- -- -- --- -- -- -- -- -- --- -- -- --- -- -- - --- --- - --- - --- -- -- -- --- -- --
PDAY ALL ALL
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
DIGITS AND REPORTED IN KILOGRAMS UNROUNDED GRAM (G) VALUE.
(KC)
BODY WRIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE.
PROTOCOL 418-010p:
ORAL (STOMACH TUBE)
NUMBER:
T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 13 (PAGE 5) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
----------------------------------- ------------------------- -- --------------- ---- - --------- ------- ------ -----
RABBIT 0
DOSAGE GROUP V
25 MG/KG/DAY
------------- -- ----------- - --------- ------- ------------ ---- - -- --- ------- -------------- -- ------- --------------- ---- - ----
PREGNANCY
STATUS
DAY 0
7
a
9
10
11
12
13
14
is
16
17
-- -- -- -- -- --- - - -- --- -- -- -- - - - -------- - --- -- -- -- -- -- -- -- -- - -- -- --- -- --- --- --- - --- - --- -- -- -- --- -- --- -- -- -- --- - -- -- --- --- --
7371 P
3.14
3.34
3.26
3.28
3.11
3.06
3.10
3.14
2.98
a
8222 P
3.63
3.70
3.56
3.46
3.42
3.30
3.23
3.18
3.15
b
0223 P
3.79
3.82
3.72
3.60
3.53
3.49
3.41
3.38
3.30
c
6224 P
3.52
3.61
3.50
3.38
3.28
3.24
3.14
3.04
2.99
d
8225 P
3.39
3.55
3.47
3.31
3.31
3.19
3.11
3.03
3.02
e
-- -- -- -- -- -- -- - -- -- --- - --- - - - -------- -- -- --- -- - -- -- -- -- -- - --- - ---- -- -- --- -- -- --- - --- -- -- --- -- -- --- -- -- -- --- - -- - ---- --- --
DAY 19
20
21
22
23
24
25
26
27
28
29
-- -- -- --- - --- - - - --- --- - --- - - - ------- -- --- -- -- -- --- - --- - -- -- - -- --- -- --- --- -- -- --- - --- -- -- --- -- -- -- --- -- -- -- -- - --- -- ---- --
7371 P 8222 P
MORIBUND MORIBUND
SACRIFICED SACRIFICED
ON DAY 15 OF GESTATION ON DAY 15 OF GESTATION
0223 P
MORIBUHD SACRIFICED ON DAY 15 OF GESTATION
8224 P
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
8225 P
MORIBUND SACRIFICED ON DAY 15 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 (KG) .
ALL CALCULATIONS
EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE.
BODY a. b.
C. d.
WEIGHT AVERAGES ARE Doe 7371 was moribund Doe 8222 was moribund Doe 8223 was moribund Doe 8224 was moribund
CALCULATED WITH THE ROUNDED KILOGRAM sacrificed on day 15 of gestation. sacrificed on day 15 of gestation. sacrificed on day 15 of gestation. sacrificed on day 15 of gestation.
(KG) VALUE.
e. Doe 8225 was moribund sacrificed on day 15 of gestation.
PROTOCOL 418-OIOP:
OPAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS ISPONSOR'S STU
TABLE 13 (PAGE 6): MATERNAL BODY WEIGHTS
INDIVIDUAL DATA
--------------- --- ------------------------ ------------------------- - --- --- -
-------------- -- ------
RABBIT #
DOSAGE GROUP VI
50 MG/KG/DAY
-------------------------------------------------------------------------------------------------- ---------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
17
------------------------------------------------------------------------------------------------------------------------
8226 P
4.21
4.17
4.07
3.90
3.64
3.70
3.61
3.52
3.43
a
8227 P
3.76
3.89
3.70
3.63
3.51
3.40
3.36
3.26
3.18
b
8228 P
3.83
3.84
3.83
3.63
3.57
3.45
3.35
3.27
3.23
c
6229 P
3.89
4.OS
3.95
3.80
3.72
3.64
3.60
FOUND DEAD ON DAY 12 OF GESTATION
8230 P
3.34
3.51
3.36
3.28
3.17
3.13
3.05
2.97
2.85
d
-- -- - -- -- -- -- -- - -- -- - -- --- - -- ---- -- -- -- -- --- --- -- -- -- -- -- -- -- - --- -- -- -- --- -- --- -- -- -- -- --- -- - --- --- --- - --- -- --- -- -- -- ---
DAY 19
20
21
22
23
24
25
26
27
28
1 29
-- -- - -- -- - --- -- - -- -- - --- -- - --- --- -- -- -- -- --- --- -- -- -- -- -- -- -- - --- - --- -- -- --- --- -- -- -- -- -- --- - --- -- --- -- --- -- -- --- -- -- -- -
8226 P
FOUND DEAD ON DAY 14 OF GESTATION
8227 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8228 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8229 P
FOUND DEAD ON DAY 12 OF GESTATION
8230 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
-------------------------------------------------------------------------------------------- ---------------------------
P - PREGNANT
NP - NOT PREGNANT IVALUES EXCLUDED FROM AVERAGES)
DAY - DAY OF PRESUMED GESTATION
ALL ALL BODY a. b. c. d.
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)
Doe 8226 was found dead on day 14 of gestation
Doe 8227 was moribund sacrificed on day 15 of gestation.
Doe 8228 was moribund sacrificed on day 15 of gestation.
Doe 8230 was moribund sacrificed on day 15 of gestation.
DIGITS UNROUNDED VALUE.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG)
PROTOCOL 416-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOTIMENTAL TOXICITY STUDY OF N-ETPOSE IN RABBITS (SPONSOR'S ST
TABLE 13 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA
------------------------------------------------ ----- - ----- --------------------------------------
RABBIT I
DOSAGE GROUP VII
75 MG/KG/DAY
------------------------------------------------------------------------------ -- -------------------------------------
PREGNANCY
STATUS
DAY 0
7
8
9
10
11
12
13
14
15
16
1
-- -- -- -- -- -- - -- - --- -- - --- - - ------ --- - --- - --- -- -- -- -- -- -- --- -- -- -- --- -- -- -- -- -- -- --- -- -- -- --- -- -- -- -- --- -- -- --- -- --- --- -
8231 P
4.10
4.11
4.00
3.97
3.85
3.72
3.66
3.52
3.41
a
6232 NP
3.60
3.65
3.52
3.42
3 .33
3.22
3.14
3.00
2.93
b
8233 P
3.00
3.92
3.85
3.82
3 .73
3.53
3.40
3.32
3.24
c
8234 P
3.54
3.69
3.64
3.44
3 .41
3.2S
3.26
3.14
3.14
d
8235 P
3.17
3.32
3.33
3.29
2.9S
2.85
2.78
2.71
2.68
e
-- -- -- -- - -- -- -- - -- -- -- --- - - ------ -- -- --- - --- - --- -- -- -- -- -- -- -- -- --- -- -- -- -- --- -- -- -- --- -- -- --- -- --- - --- -- -- --- -- --- --- -
DAY 19
20
21
22
23
24
25
26
27
28
29
---------------------------------------------------------------------------------------------------------------
8231 P 8232 NP 8233 P
MORIBUND SACRIFICED ON DAY 15 OF MORIBUND SACRIFICED ON DAY 15 OF FOUND DEAD ON DAY IS OF GESTATION
GESTATION PRESUMED
GESTATION
8234 P
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
8235 P
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
--------------- ---------- -------------------------------------------------------- ---------------------------- - ----------
P = PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAY = DAY OF PRESUMED GESTATION
ALL ALL BODY a. b. c. d. e.
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.
Doe 8231 was moribund sacrificed on day 15 of gestation.
Rabbit 8232 was moribund sacrificed on day 15 of presumed gestation.
Doe 8233 was found dead on day 15 of gestation.
Doe 8234 was moribund sacrificed on day 15 of gestation.
Doe 8235 was moribund sacrificed on day 15 of gestation.
AND REPORTED IN KILOGRAMS GRAM (G) VALUE.
(KG)
PROTOCOI, 410-OIOP:
ORAL (STOMACH TUBE)
NLTMBER:
T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 14 (PAGE 1) : 14ATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
------------------------------------------ ------------------------------------ - -- ---- - -- -- ------- I ---- -- ----
RABBIT 0
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-- -- -- -- -- -- --- - -- -- --- - - -- -- --- --- -- --- -- -- -- -- -- -- -- -- -- -- --- -- -- -- --- -- - --- - --- -- -- -- --- --- - --- -- -- -- -- --- -- --- --- --
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 -------------------------------------------------------------------------------------------------- --------------------
8201 P
124.
135.
143.
144.
157.
128.
129.
121.
143.
127.
148.
1
8202 P
181.
181.
164.
185.
180.
185.
175.
174.
184.
154.
164.
1
8203 P
180.
182.
185.
180.
183.
181.
185.
184.
180.
180.
183.
1
8204 P
185.
173.
177.
173.
180.
184.
167.
173.
182.
167.
180.
1
e205 P
173.
150.
145.
135.
Ise.
135.
175.
181.
185.
181.
180.
1
- -- -- -- -- --- - --- - -- -- -- - -------- -- -- --- -- -- -- -- -- -- -- -- -- --- - --- -- -- -- --- -- -- -- -- -- -- -- --- -- --- - --- -- -- -- -- -- --- -- ---- -
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 - -- -- -- -- --- - -- -- -- -- -- - ------- --- -- --- - --- -- -- -- -- - --- -- -- -- --- -- -- -- -- --- - --- - -- --- -- -- -- --- -- --- -- -- -- -- -- -- --- ---- -
8201 P
115.
148.
105.
112.
97.
82.
96.
108.
123.
8202 P
126.
105.
61.
3.
1.
37.
81.
92.
68.
8203 P
103.
184.
183.
184.
183.
182.
183.
185.
184.
8204 P
182-
173.
181.
141.
136.
113.
79.
74.
52.
820S P
147.
119.
76.
40.
50.
73.
68.
81.
78.
-----------------------------------------------------------------------------------------------------------------------
P - PREGNANT DAYS - DAYS ALL WEIGHTS
mp - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G).
EXCLUDED
FROM AVERAGES)
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER! T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 14 (PAGE 2); MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
------------------------ --- ---------------- -------- ------------ ---
--------------- ---- ----
RABBIT #
DOSAGE GROUP 11
1 MG/KG/DAY
-------------------------------------------------------------------- -- -----------------------------------------------
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
-----------------------------------------------------------------------------------------------------------------------
6206 P
166.
156.
160.
159.
176.
132.
102.
133.
a
8207 P
143.
171.
148.
165.
157.
114.
140.
114.
146.
74.
119.
8208 P
185.
185.
183.
183.
180.
181.
177.
177.
181.
181.
180.
1
0209 P
171.
163.
139.
138.
150.
131.
171.
172.
184.
169.
174.
1
8210 P
182.
181.
181.
185.
171.
162.
149.
170.
183.
156.
175.
1
-----------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ------------------------------------------------------------------- --- -----------------------------------------------
8206 P
FOUND DEAD ON DAY 16 OF GESTATION
0207 P
136.
135.
101.
154.
156.
152.
170.
135.
115.
0208 P
183.
182.
183.
174.
163.
105.
85.
79.
75.
8209 P
166.
173.
182.
159.
157.
161.
ISI.
137.
108.
8210 P
173.
168.
168.
149.
150.
137.
138.
121.
106.
-- -- --- - --- -- -- - --- - -- - --- - - ---- --- -- -- -- --- -- -- -- - --- - --- -- -- -- --- -- -- --- - -- -- --- -- -- -- -- -- -- --- -- --- -- -- -- -- -- -- --- --
P - PREGNANT DAYS - DAYS ALL WEIGHTS
UP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G)
EXCLUDED
FROM AVERAGES)
a. Doe 8206 was found dead on day 16 of gestation.
PROTOCOL 418-01OP:
ORAI, (STOMACH TUBE) NUMBER: T-6316.6)
DOSAGE-RANGE
DEVELOPMENTAI, TOXICITY STUDY OF N-ETPOSE IN RABBITS (SPONSOR'S ST
TABLE 14 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
-------------- --- ---------- --------- -- -- ---------------- -------------------- -
------------- ----------
RABBIT N
DOSAGE GROUP III
S MG/KG/DAY
------------------- ----------------------------------------------------------------------- --------------------------
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
-----------------------------------------------------------------------------------------------------------------------
8211 P
lel.
14.
0.
2.
0.
0.
1.
0.
2.
1.
1.
8212 P
126.
59.
2.
1.
1.
0.
4.
0.
10.
10.
2.
8213 P
180.
183.
149.
96.
1.
14.
0.
I.
3.
0.
6.
8214 P
172.
156.
102.
113.
0.
82.
44.
46.
22.
0.
5.
7385 P
184.
160.
10.
1.
2.
3.
2.
0.
2.
0.
6.
-- -- - -- -- -- -- -- ---- - - --- -- -- -- --- -- -- --- -- -- -- -- --- - --- - --- -- - -- --- --- -- -- -- --- -- -- -- -- -- -- --- --- -- --- - --- -- -- -- --- -- --
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 --------------- ---- ----- -------------- --- ----- ---- -- ----------- - --------------------- -- -- -- --- ----- -- -------------- -----
6211 P
4.
2.
3.
2.
1.
ABORTED ON DAY 26 OF GESTATION
8212 P
3.
2.
2.
ABORTED ON DAY 24 OF GESTATION
8213 P
3.
17.
98.
114.
lS3.
149.
168.
153.
160.
8214 P
a.
4.
0.
3.
4.
ABORTED ON DAY 26 OF GESTATION
7305 P
0.
1.
2.
3.
1.
2.
2.
1.
2.
---------------------------------------------------------------------------------------------- ------------------------
P - PREGNANT DAYS - DAYS ALL WEIGHTS
NP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G)
EXCLUDED
FROM AVERAGES)
PROTOCOL. 418-Olop:
ORAL (STOMACH TUBE) NUMBER: T-6316.6)
DOSAGE-RANGE
DEVELOPMENTAL, TOXICITY STUDY OF H-ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 14 (PAGE 4): MATERNAL FEED CONSUMPTION
VALUES - INDIVIDUAL DATA
-------------- --------- -------------------------------- -- - ---------- -- - ------- ------------ ------ -- ------
RABBIT N
DOSAGE
-----------------
GROUP IV
10 MG/KG/DAY
------------------------------------------------------------------------------------------
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 -
------------------------------------------------------------------------------------------------------------- ----------
8216 P
82.
2.
1.
2.
0.
0.
1.
1.
3.
S.
0.
8217 P
39.
1.
0.
1.
1.
0.
3.
0.
0.
10.
2.
8218 P
65.
0.
0.
1.
1.
0.
11.
3.
1.
4.
3.
8219 P
42.
0.
0.
1.
0.
0.
S.
7.
1.
1.
4.
0220 P
49.
9.
2.
2.
1.
0.
7.
29.
36.
26.
42.
3
------------------------------------------------------------------------------------------------------------------------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 ------------------------- ----------------------------------------------------- ------------------------------
--- ----
8226 P
0.
2.
0.
1.
1.
ABORTED ON DAY 26 OF GESTATION
8217 P
0.
ABORTED ON DAY 22 OF GESTATION
8218 P
0.
2.
0.
ABORTED ON DAY 24 OF GESTATION
8219 P
0.
ABORTED ON DAY 22 OF GESTATION
8220 P
1.
1.
ABORTED AND SACRIFICED ON DAY 23 OF GESTATION
------------------------------------------------------------------------------------------------------------------------
P - PREGNANT
NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS - DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDEID IN GRAMS (G)
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 14 (PAGE 5): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
------------------------ - -- -- -------------- -- ----------------------
--------- - - - ---------
RABBIT 0
DOSAGE GROUP V
2S MG/KG/DAY
------------------------------------------------- -- ---------------------- ---- -------------------------- - ------
PREGNANCY
STATUS DAYS 7 - 8
8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - IS 15 - 16 16 - 17 17 - 18 10
--------------------------------------------------------------------------- -------------------------------------------
7371 P
14.
1.
0.
11.
0.
3.
0.
1.
a
8222 P
25.
3.
0.
2.
1.
0.
0.
1.
b
8223 P
36.
1.
0.
1.
1.
0.
I.
0.
c
8224 P
31.
0.
2.
0.
0.
0.
0.
0.
d
8225 P
64.
4.
1.
1.
0.
1.
0.
0.
e
----------------------------------------------------------------------------------------------- ------------- ---------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 --------------------------------------------------------------------------------------I ---------------------- ---------
7371 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8222 P 8223 P
MORIBUND MORIBUND
SACRIFICED SACRIFICED
ON DAY 15 OF GESTATION ON DAY 15 OF GESTATION
8224 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8225 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
-------------------------------------------------------------------------------------------------------------- --------
P = PREGNANT
UP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
DAYS - DAYS OIF PRESUMED GESTATION
ALL WEIGHTS WERE RECORDED
IN GRAMS (G).
a. Doe 7371 was moribund sacrificed on day
15 of
gestation.
b. Doe 8222 was moribund sacrificed on day 15 of gestation. c. Doe 8223 was moribund sacrificed on day 15 of gestation.
d. Doe 8224 was moribund sacrificed on day 15 of gestation. e. Doe 8225 was moribund sacrificed on day 15 of gestation.
PROTOCOL 418-01OP:
OPAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 14 (PAGE 6) : MATERNAL FEED CONSUMPTION VALUES
INDIVIDUAI, DATA
- ---------------------------------------------- - -- - ------ -- --------- - ---------------------------
-----
RABBIT N
DOSAGE GROUP VI
50 MG/KG/DAY
----------------------------------------------------------------------------------- -----------------------------------
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
------------------------------------------------------- ------------------------- - -----------------------------------
8226 P
4.
2.
0.
2.
0.
0.
1.
FOUND DEAD ON DAY 14 OF GESTATION
8227 P
14.
1.
0.
1.
1.
1.
2.
0.
a
8228 P
30.
2.
0.
1.
2.
0.
0.
0.
b
8229 P
6.
2.
1.
0.
FOUND DEAD ON DAY 12 OF GESTATION
8230 P
S.
12.
2.
1.
1.
0.
0.
0.
c
--------------------------------------------------------------------------------------------------------------- -------
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 --------------------------------------------------------------------------------------------------------------- ------
8226 P
FOUND DEAD ON DAY 14 OF GESTATION
8227 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8228 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8229 P
FOUND DEAD ON DAY 12 OF GESTATION
8230 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
-----------------------------------------------------------------------------------------------------------------------
P = PREGNANT
NP - NOT PREGNANT
DAYS - DAYS OF PRESUMED GESTATION
(VALUES
EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED a. Doe 8227 was moribund
IN GRAMS (G) sacrificed on day 15 of gestation.
b. Doe 8228 was moribund sacrificed on day 15 of gestation. c. Doe 8230 was moribund sacrificed on day IS of gestation.
PROTOCOL 418-01OP:
ORAI. (STOMACH TUBE)
NUMBER:
T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 14 (PAGE 7): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA
------------------------------- ----------- ------------------- ------------------
----- ------ ----------
RABBIT I
DOSAGE GROUP VII
75 MG/KG/DAY
------------------------------------------- -------------------------------------- ------
--------------------- -- --
PREGNANCY
STATUS DAYS I - 8
8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 15 15
----------------------------------------------------------------------------------- -----
- 16 16 - 17 17 - 18 18 ---------------------------
8231 P
9.
1.
2.
0.
0.
0.
0.
0.
a
9232 MP
2.
2.
1.
0.
0.
0.
0.
0.
b
8233 P
2.
2.
1.
0.
0.
0.
0.
c
e234 P
10.
2.
1.
1.
0.
0.
1.
0.
d
8235 P
22.
2.
0.
0.
0.
0.
1.
0.
e
-- -- --- -- -- -- -- - -- -- -- -- - - - - ---- --- -- -- --- -- -- - --- - --- -- -- -- -- -- --- -- -- -- -- -- -- --- - --- --- - --- --- -- -- -- --- - --- -- -- --- -- -
DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 21 - 28 28 - 29 ---------------------------------------------------------------------------------- ---- - ----------------------
8231 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8232 MP 8233 P
MORIBUND SACRIFICED ON DAY 15 OF PRESUMED FOUND DEAD ON DAY 15 OF GESTATION
GESTATION
8234 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8235 P
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
-- -- -- -- -- -- -- - -- -- -- - --- - - ------ --- -- -- --- -- -- -- -- - --- -- -- --- - --- -- -- -- -- -- --- -- -- --- -- -- -- -- --- - --- -- --- - -- --- -- --- --
P - PREGNANT DAYS - DAYS
NP - NOT OF PRESU149D
PREGNANT GESTATION
(VALUES
EXCLUDED
FROM AVERAGES)
ALL WEIGHTS WERE RECORDED
IN GRAMS (G) .
a. Doe 8231 was moribund sacrificed on day 15 of gestation.
b. Rabbit 0232 was moribund sacrificed on day 15 of presumed
c. Doe 8233 was found dead on day 15 of gestation.
d. Doe 8234 was moribund sacrificed on day 15 of gestation.
gestation.
e. Doe 8235 was moribund sacrificed on day 15 of gestation.
PROTOCOL 418 01OP:
ORAL (STOMACH TUBE) NUMBER: T-6316.8)
DOSAGE-RANGE
DEVEI,OPMEN,RAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 15 (PAGE 1): CAESAREAN-SECTIONING
OBSERVATIONS
INDIVIDUAL DATA
-- - -------- ------------- -- ---- ------ --- -
-
------- ------------- -- ------------ --- -
---
VIABLE FETUSES ------------------------
DEAD FETUSES
EARLY RESORPTIONS
LATE RESORPTIONS
IMPLANTATION
SITES
---------------- --- ----------- ---------------- ----------------
CORPORA - - ------
SEX
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RABBIT N N
F
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
OVARY
-------------------------------------------------------------------------------------------------------------- ------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
--------------------------------------------------------------------------------------------------------------
8201 5
0
1
4
5
0
0
0
0
8202 7
3
6
4
10
0
0
0
1
0203 2
1
2
2
3
0
0
0
1
8204 5
1
1
5
6
0
0
0
0
8205 5
6
5
6
11
0
0
0
0
----------------------------------------------------------
0
0
0
0
0
1
4
5
5
0
1
1
0
1
a
4
12
9
0
1
0
0
0
2
2
4
5
2
2
0
0
0
1
7
8
1
0
0
1
0
1
6
6
12
7
--------------------------------------------------
5
5 4 7
6 ------
DOSAGE GROUP 11
1 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------- - -----
8206 FOUND DEAD ON DAY 16 OF GESTATION
8207 4
6
5
5
10
0
0
0
1
0
1
0
0
0
6
5
11
8
0208 4
5
5
4
9
0
0
0
0
0
0
0
0
0
5
4
9
5
8209 2
2
2
2
4
0
0
0
0
6
6
0
0
0
2
8
10
2
8210 5
6
6
5
11
0
0
0
0
0
0
0
0
0
6
5
11
6
-------------------------------------------------------------------------------------------------------------- -
5 5
8 6 -----
DOSAGE GROUP 111
5 MG/KG/DAY
---------------------------------------------------------- --------------------------------------------------
8211 ABORTED ON DAY 26 OF GESTATION
8212 ABORTED ON DAY 24 OF GESTATION
8213 3
5
4
4
8
0
0
0
0
0
0
1
3
4
5
7
12
6
7
8214 ABORTED ON DAY 26 OF GESTATION
7385 2
3
2
3
5
0
0
0
0
0
0
2
1
3
4
4
a
4
5
---------------------------------------------------------------------------------------------------------- -
DOSAGE GROUP IV
10 MG/KG/DAY
------------------------------------------------------------------ -----------------
- -- - ----- -------
8216 ABORTED ON DAY 26 OF GESTATION
8217 ABORTED ON DAY 22 OF GESTATION 8218 ABORTED ON DAY 24 OF GESTATION
8219 ABORTED ON DAY 22 OF GESTATION 8220 ABORTED ON DAY 23 OF GESTATION -------------------------------------------------------
- ---- -----------------
N = MALE PLACENTAE
P = FEMALE
APPEARED
NORMAL
UNLESS NOTED OTHERWISE.
PROTOCOL 418 OIOP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF N ETFOSE IN RABBITS (SPONSOR'S ST
TABLE 15 (PAGE 2): CAESAREAN SECTIONING OBSERVATIONS
- INDIVIDUAL DATA
------------- --------- -- - -- ------ ------------- --
------ ------
-- ---------------
VIABLE FETUSES ---------------- -------
DEAD FETUSES
EARLY RESORPTIONS
LATE RESORPTIONS
IMPLANTATION
SITES
---------------- ---------------- ---- -------- -- ------------ ---
CORPORA - --------
SEX
RIGHT LEFT
RIGHT LEFT
RABBIT N M
F
HORN
TOTAL
HORN
TOTAL
-----------------------------------------------------
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
RIGHT LEFT
HORN
TOTAL
HORN
TOTAL
HORN
TOTAL
OVARY
------------------------------ ----------------------- -- -----
DOSAGE GROUP V
25 MG/KG/DAY
------------------------------ ---------------------------------------------------- ---------------------------- ------
7371 MORIBUND SACRIFICED ON DAY
6222 MORIBUND SACRIFICED ON DAY 6223 MORIBUND SACRIFICED ON DAY 8224 MORIBUND SACRIFICED ON DAY 8225 MORIBUND SACRIFICED ON DAY ------------------------------------
15 OF GESTATION
15 OF GESTATION 15 OF GESTATION 15 OF GESTATION
15 OF GESTATION -------------------------------------------
----
----------------------- --------
DOSAGE GROUP VI
50 MG/KG/DAY
-------------------------------------------------------------------------------- --------------------------------------
8226 FOUND DEAD ON DAY 14 OF GESTATION
8227 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8220 MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8229 FOUND DEAD ON DAY 12 OF GESTATION 8230 MORIBUND SACRIFICED ON DAY 15 OF GESTATION ------------------------------------------------------
------------------------------------------------------- --------
DOSAGE GROUP VII
75 MG/KG/DAY
----------------------------------------------------------------------------- --- -
-----------------
----
8231 MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
8232 MORIBUND
SACRIFICED ON DAY 15 OF PRESUMED GESTATION
8233 FOUND DEAD ON DAY 15 OF GESTATION
0234 MORIBUND
SACRIFICED
ON DAY 15 OF GESTATION
8235 MORIBUND
SACRIFICED
ON DAY 15 OF GESTATION
------------------------------------------------------------------------------------- - --- ---------------- - - ---
M = MALE PLACENTAE
F = FEMALE
APPEARED
NORMAL
UNI,ESS NOTED OTHERWISE.
PROTOCOL 418 OIOP:
ORAL (STOMACH TUBE) NUM13ER: T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUI)Y OF N ETFOSE IN RABBITS (SPONSOR'S STU
TABLE 16 (PAGE 1): LITTER OBSERVATIONS
(CAESAREAN DELIVERED FETUSES) - INDIVIDUAL DATA
----- ---------------------
-------------
NUMBER OF LIVE
FETUSES ---------------------------------------------------
-- ------------- -
- ---------------
AVERAGE FETAL
---- CONCEPTUSES
------
BODY WEIGHT (G)
RESORBED
------------------------------------------------------- -----------
RABBIT #
MALE
FEMALE
TOTAL
MALE
FEMALE
TOTAL a
N
N
%
--------------------------------------------------------------------------------------------------------------- - -----
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
-- -- - --- -- -- -- - -- -- -- -- - - - ------ --- -- --- - --- - --- - -- -- --- - -- --- -- --- -- -- --- - --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- --- --
8201
5
0
5
49.35
----
8202
7
3
10
37.55
37.81
8203
2
1
3
51.50
51.48
8204
5
1
6
47.19
50.88
8205
5
6
11
45.92
38.79
--------------------------------------------------------------------------
49.35
5
37-63
12
51.50
4
47.60
8
42.03
12
---------------
0
0.0
2
16.7
1
2S.0
2
25.0
1
8.3
----------------------------
DOSAGE GROUP 11
1 MG/KG/DAY
---- ---------- -------- - - - ----------------------- -- - --- -- -------- ----------------- ---- ----- ------- -- -- ----- -- -- -- -- --- --
8206
FOUND DEAD ON DAY 16 OF GESTATION
8207
4
6
10
45.56
42.93
43.98
11
1
9.1
8208
4
5
9
44.68
45.10
44.91
9
0
0.0
6209
2
2
4
53.84
57.44
55.64
10
6
60.0
8210
5
6
11
42.93
40.28
41.49
11
0
0.0
-- -- -- -- -- -- -- - --- - --- - - - ------- -- --- -- -- -- -- -- -- -- -- -- -- -- --- -- -- --- -- -- --- - -- -- --- - --- --- - --- -- -- --- -- -- -- -- --- -- --- -
DOSAGE GROUP 111
5 MG/KG/DAY
--------------------------------------------------------- ---------------------- ---- -
-------- ---------
0211
ABORTED ON DAY 26 OF GESTATION
8212 8213
ABORTED ON DAY 24 OF GESTATION
3
5
8
28.02
28.82
28.52
12
4
33.3
8214
ABORTED ON DAY 26 OF GESTATION
'7385
2
3
5
23.00
16.47
19.08
6
3
37.5
----------------------------------------------------------------------------------------------------- ----- --- -
DOSAGE GROUP IV
10 MG/KG/DAY
--------------------------------------------------------------- --------------------
----
---- --- -----
8216
ABORTED ON DAY 26 OF
8217
ABORTED ON DAY 22 OF
8218
ABORTED ON DAY 24 OF
8219
ABORTED ON DAY 22 OF
B220
ABORTED ON DAY 23 OF
-------------------------------------------------
GESTATION GESTATION GESTATION GESTATION GESTATION -----
a. TOTAL = SUM OF FE:TAL WEIGIITS/NUMBER OF LIVE FETUSES.
PROTOCOI, 418 OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316-8)
DOSAGE-RA.NGE
DEVELOPMENTAI,
*]'OXICITY STUDY OF N ETFOSE IN RABBITS
(SPONSOR'S ST
TABLE 16 (PAGE 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
N
--------- --- ---------- -------------------------------------------------------- --------
N
t
----------------------- -
DOSAGE GROUP V
25 MG/KG/DAY
-----------------------------------------------------------------------------------------------------------------
7371 8222 8223
8224 8225 -------------------
MORIBUND SACRIFICED ON DAY IS OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION
MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION --------------------------------------------------- ------- --
---- ----- - ----------------------
DOSAGE GROUP VI
50 MG/KG/DAY
--------------------------------------------------------------------------------- --- -- ----- ------------------- -- -
8226
FOUND DEAD ON DAY 14 OF GESTATION
8227
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8228
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8229
FOUND DEAD ON DAY 12 OF GESTATION
8230
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
----------------------------------------------------------------------------------------
----------------------------
DOSAGE GROUP VII
75 MG/KG/DAY
-----------------------------------------------------------------------
----- --
- - --------------
0231
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8232
MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION
8233
FOUND DEAD ON DAY 15 OF GESTATION
8234
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8235
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
-------------------------------------------------------------------------------
----
---------
------------------
a. TOTAL - SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES.
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316. 8)
DOSAGE-RANGE
I)EVEI,OPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS (SPONSOR'S S
TABLE 17 (PAGE 1); FETAL SEX, VITAL STATUS AND BODY WEI(;HT - INDIVIDUAL DATA
---- -------- ----------- --- -------- - -----
- ------ ------------ ------ -
FETUS N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
is
16
17
------------------------------- -------- ----------------- ----------------------- -------------------------
DOSAGE GROUP 1
0 (VEHICLE) MG/KG/DAY
---------------------------------------------------I -- - - --- ---------------------- ---- ---------------
RABBIT N CLa
8201 S/ 5
MA
MA
MA
MA
MA
57.56 41.35 47.67 48.21 Sl.98
8202 9/ 5
L
MA
FA
E
FA
MA
MA
FA / MA
MA
MA
MA
39.86 42.07
34.09 29.66 38.33 37.27 44.39 38.89 34.11 37.61
8203 S/ 4
E
MA
MA
FA
52.60 50.41 SI.48
8204 1/ 7
MA
FA
MA
E
MA
E
MA
MA
4 B. 96 50. 88 46. 06
46.18
49.74 45.01
8205 7/ 6
FA
MA
FA
FA
L
FA / MA
MA
FA
MA
MA
FA
43.95 44.94 40.84 43.58
40.44 53.S4 Sl.36 34.22 37.03 42.72 29.69
---------------------------------------------------------- ---------------------------------------------------
DOSAGE GROUP 11
1 MG/KG/DAY
-------------------------------------------------------------------------------------------------------------
8206
FOUND DEAD ON DAY 16 OF GESTATION
8207 B/ 5
FA
MA
E
FA
MA
MA
MA
FA
FA
FA
FA
49.48 48.31
45.78 39.00 4S.12 49.02 42.07 37.73 40.76 41.74
8208 S/ 5
PA
MA
MA
MA
FA / FA
MA
PA
FA
41.55 SO.39 43.05 42.27 45.86 52.04 43.03 40.77 45.27
8209 2/ 8
MA
FA / E
E
E
E
E
E
MA
FA
55.77 58.25
51.91 S6.63
8210 6/ 6
MA
MA
FA
FA
FA
MA
MA
MA
FA
FA
FA
45.50 41.96 34.82 37.56 41.80 41.67 42.70 42.84 44.01 41.20 42.32
------------------------------------------------------------------------------------------------ ----------
DOSAGE GROUP 111
5 MG/KG/DAY
--------------------------------------------------- ----- -------- -------------
8211
ABORTED ON DAY 26 OF GESTATION
8212
ABORTED ON DAY 24 OF GESTATION
8213 6/ '7 FA
MA
FA
L
MA / MA
11
FA
FA
l@
FA
11
38.65 27.40 29.39
26.21 30.46
2'1.18 22.78
26.11
8214
ABORTED ON DAY 26 OF GESTATION
7385 4/ S
FA
L
L
FA / MA
L
FA
MA
18.86
13.20 24.97
17-36 21.03
---------------------------------------- ----- --------
M - MALE
F = FEMALE
A = ALIVE
CLs - CORPORA LUTEA/OVARY
FETAL
E = EARLY RESORPTION
L = LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
"/" DENOTES POSI'1'1()IOiF CERVIX
PROTOCOL 418-01OP:
ORAL (STOMACH TUBE)
NUMBER:
T 6316.8)
DOSAGE-RANGE
DEVELOPMENTAI, TOXICITY STUDY OF N ELFOSE IN RABBITS (SPONSOR'S STU
TABLE 17 (PAGE 2@ : FETAI, SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA
- -- ----- ------- -------
FETUS N
1
2
---------- ----------------
------ -- ---------
3
4
5
6
----I --------------------
-
-
7
8
9
10
11
----------------------------
- - - ---- ----------
12
13
14
is
16
17
----------------------------------
DOSAGE GROUP IV
10 MG/KG/DAY
----------------------------- --------------------------- -------- ----------------- ----------------------------------
RABBIT # CLa 8216
ABORTED ON DAY 26 OF GESTATION
8217
ABORTED
ON DAY 22 OF GESTATION
8218
ABORTED
ON DAY 24 OF GESTATION
8219
ABORTED ON DAY 22 OF GESTATION
8220
ABORTED ON DAY 23 OF GESTATION
------------------------ ------------------------------------------------------------------ ----------------------------
DOSAGE GROUP V
2S MG/KG/DAY
------------------------------------------------------------------------------------ ----------------------------------
7371
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
8222
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8223
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
8224
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8225
MORIBUND SACRIFICED ON DAY IS OF GESTATION
---------------------------------------------- -------------------------------------
DOSAGE GROUP VI
50 MG/KG/DAY
-------------- --------- - -------------------------------- -------------------- ---- - -
------- ------------------ ---------- --- ------------ -------------- -
8226
FOUNE) DEAD ON DAY 14 OF GESTATION
8227
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8228
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8229
FOUNT) DEAD ON DAY 12 OF GESTATION
0230
MORIBUND
SACRIFICED ON DAY 15 OF GESTATION
------------------------------------------------------------ ------- ----- ---
N - MALE
F z FEMALE
CLS = CORPORA LUTEA/OVARY
A = ALIVE FETAL
E = EARLY RESORPTION
L = LATE RESORPTION
BODY WEIGHTS WERE RECORDED IN GRAMS (G).
"/" F)EIIOTES POSITION OF CERVIX
PROTOCOL 418-OIOP:
ORAL (STOMACH TUBE) NUMBER: T-6316-8)
DOSAGE-RANGE
DEVELOPMENTAL
TOXICITY STUDY OF H-ETFOSE IN RABBITS ISPONSOR'S S
TABLE 17 (PAGE 3); 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
17
----------------------------------------------------------------------------------------------------------------------
DOSAGE GROUP VII
75 MG/KG/DAY
- --- -- -- -- --- - -- -- - -- -- -- -- - ----- -- -- -- -- --- -- - -- --- - --- - --- -- -- --- -- -- -- -- - --- -- -- - -- -- --- -- -- -- -- -- -- --- - --- -- ---- --
RABBIT N CLa 8231
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8232
MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION
0233
FOUND DEAD ON DAY 15 OF GESTATION
8234
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
8235
MORIBUND SACRIFICED ON DAY 15 OF GESTATION
---------------------------------------------------------------------------------------------------------------------
N - 14ALE
F - FE14ALS
A - ALIVE
CLO - CORPORA LUTEA/OVARY
FETAL
2 . EARLY RESORPTION
L = LATE RESORPTION
BODY WEI(;HTS WERE RECORDED IN GRAMS (0).
"/" DENOTES POSITION OF CERVIX
418-010:PAGE F-69
418-OIOP:PAGE69
ATTACHMENT 1 PROTOCOL AND AMENDMENT
AA. AF-
REMARCH
418-010:PAGE F-70
416-01 OP:PAGE 70
Argus Reseamh Laboratories, Inc. 905 Sheehy Drive, Building A
Homham, Pennsylvania 19044 T: (215)443-8710 F:(215)"3-8587
PROTOCOL 418-010P SPONSOR'S STUDY NUMBER: T-6316.8
STUDY TITLE: PURPOSE:
TESTING FACILITY:
STUDY DIRECTOR: SPONSOR: STUDY MONITOR:
ALTERNATIV
STUDY MONITOR:
Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of N-ETFOSE in Rabbits
The purpose of thisstudy isto provide information for the
selection of dosages to be used in the developmental
toxicity(embryo-fetal toxicityand teratogenic potential)study
of N-ETFOSE administered orallyvia stomach tube to
New Zealand White [Hra:(NZW)SPF] female rabbits.
presumed pregnant
Argus Research Laboratories, Inc.
905 Sheehy Drive, Building A
Horsham, Pennsylvania 19044-1297
Telephone: (215) 443-8710
Telefax:
(215) 443-8587
Raymond G. York, Ph.D., DABT Associate Director of Research
3M Toxicology Services 3M Center Building 220-2E-02 St. Paul, Minnesota 55144-1000
Marvin T. Case, D.V.M., Ph.D.
Telephone: (612) 733-5180
Telefax:
(612) 733-1773
Andrew M. Seacat, Ph.D.
Telephone: (612) 575-3161
Telefax:
(612) 733-1773
418-010:PAGE F-71
418-01 OP: PAGE 71
Pmtocol41"IOP Page 2
REGULATORY
CITATIONS:
U.S. Food and Drug Administration (1994). International Conference on Harmonisation;Guidelineon detectionof toxicittyo reproductionformedicinal products. Federal Register,September 22, 1994, Vol.59, No. 183.
U.S. Food and Drug Administration.Good LaboratoryPracticeRegulations;FinalRule. 21 CFR Part58.
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 withpfinciplesof good laboratorypractice.OfficiaJlournal of the European Communities: Legislation3.2 (No. L 315; 28 October): 1-17.
REGULATORY COMPLIANCE:
This studywillbe conducted inthe spiriotfthe Good Laboratory Practice(GLP) regulationscitedabove inthatthe Testing Facilitpyersonnel willadhere to the Standard Operating Procedures forlaboratoryoperationsand data collectionT.he Testing FacilitQyualityAssurance Unit(OAU) willnot auditthe protocol,the raw data,the reportsor the criticaplhases of the study.
Allchanges or revisionsofthisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained withthe protocol.
STUDY SCHEDULE: See ATTACHMENT 1 to the protocol.
418-010:PAGE F-72
418-01OP:PAGE 72
Pmt=l 418-01OP Page 3
TEST ARTICLE AND VEHICL
Identification:
Test Article:
Name: Physical Description: Lot/Batch Number: SpecificGravity: Purity: ExpirationDate:
N-ETFOSE. Waxy solid. FM-3929(30035,30037,30039). -1.7. 99.1%. May 2000.
Informationon the identityc,omposition,strengthand purityof the testarticleison file withthe Sponsor.
Vehicle:
2% TweenID 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplierand lotidentificatioofnTweent) 80 to be documented in the raw data.
Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe vehiclethatwould interferweiththe resultsof thisstudy. Therefore, no analyses otherthan those mentioned inthisprotocolwillbe conducted.
Safety Precautions:
Gloves, mask, appropriateeye protectionand a uniform/labcoat are to be wom during formulationpreparationand administrationT.he MaterialSafety Data Sheet (MSDS) is attachedto the protocol(ATTACHMENT 2).
Storage:
Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations:
Room temperature. Room temperature. Room temperature. Frozen (-20*C).
Alltestarticlsehipments to the Testing Facilitsyhould be addressed to the attentionof
JulianGuibinskiM,anager ofFormulationsa,tthepreviouslcyitedaddressand
telephone number.
Shipments should includeinformationconcerning storageconditionsand shipping cartons should be labeledappropriately.The recipiensthould be notifiedinadvance of shipment.
418-010:PAGE F-73
41 B-01 OP:PAGE 73 Protocol418-OIOP
Page 4
FORMULATION: Freguency of Procamtion: Formulations (suspensions) willbe prepared daily at the Testing Facility.Vehicle willbe prepared weekly atthe TestingFacility. Detailedpreparationprocedures are attached to thisprotocol(ATTACHMENT 3).
Ad*ustment forPuri : The testarticlweillbe considered 100% pure forthe purpose of dosage calculations.
Testing FacilityReserve SaMR108: The Sponsor willreserve a sample (1 g) of each lotof the bulk testarticluesed during the course of thisstudy. The Testing Facilitwyillreserve a sample (5 mL) of each lotof the vehiclecomponents used duringthe course of thisstudy. Samples willbe stored under the previouslycitedconditions.
ANALYSE : Samples additionalto those described below may be taken ifdeemed necessary during the course of the study.
Bulk Test ArticleSamplina: No analyses ofthe bulk testarticlweillbe conducted duringthe course ofthisstudy. Informationon the stabilitoyf the bulktestarticlieson filewfththe Sponsor.
Analyses of Prepared Formulation : At the request of the Sponsor, no analyses of prepared testarticlfeormulationswillbe conducted duringthe course of the study. However, recordswillbe maintained to document how the testarticlfeormulationswere prepared.
DISPOSITION: Prepared formulationswillbe discarded at the Testing FacilityA.llremaining bulk test articlweillbe returnedto the Study Monitor at the previouslycitedaddress.
418-010:PAGE F-74
418-OIOP:PAGE 74 Pmtoeol 41B-01OP
Page 5
TEST SYSTEM:
Species/Strain and Reason for Selection: The New Zealand White [Hra:(NZW)SPF) rabbit was selected as the Test System because: 1) itisone non-rodentmammalian species accepted and widely used throughoutthe industryfornonclinicasltudiesof developmental toxicit(yembryo-fetal toxicity/teratogenici2t)yt)h;isstrainof rabbithas been demonstrated to be sensitiveto developmental toxins;3) historicadlata and experience existat the Testing Facility(1-3) and 4) the testarticliespharmacologicallyactiveinthe species and strain.
Number and Sex:
Populationevaluated:35 timed-pregnantfemale rabbits(5 per dosage group).
Body Weight and Acie:
The individuablody weights ofthe female rabbitswillrange from 2.5 kg to 5.5 kg;the rabbitswillbe approximatelyfiveto seven months of age atthe time of study assignment. Actual body weights recorded at receiptand at study assignment willbe documented inthe raw data.
Source:
Covance Research Products,Inc. Swampbridge Road, Box 7200 Denver, Pennsylvania 17517
The rabbitswillbe shipped infifterecdartons by truckfrom Covance Research Products,Inc.,Denver, Pennsylvania,to the Testing Facility.
Identification:
Rabbits are permanently identifieudsing MonelS self-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 HUSBANDRY:
Allcage sizes are in compliance withthe Guide forthe Care and Use of Laboratory Animals"".
418-010:PAGE F-75
418-OIOP:PAGE 75 Pmtocol 418-010P
Page 6
Housinci:
The rabbits willbe individuallyhoused in units of six to eight stainless steel cages. No nestingmaterialswillbe suppliedbecause the female rabbitswillbe sacrificedbefore parturitioinsexpected.
Room Air,TomRemture-and Humidity:
The animal room isindependentlysuppliedwith at leastten changes per hour of 100% freshairthathas 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%.
LLght:
An automaticallycontrolled12-hour light:12-houdrark fluorescentlightcyclewillbe maintained. Each dark periodwillbegin at 1900 hours EST.
Diet:
Approximately 150 g of CertifieRdabbit ChowID #5322 (PMI NutritioInnternationalw)ill be availableto each rabbiteach day untilthe firsdtay of dosage, atwhich 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 individualbottlesattached 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 1.2ppm chlorineat the time of analysis.Water isanalyzed monthly forpossible bacterialcontamination 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 withthe resultsof thisstudy. Therefore,no analyses otherthan those routinely performed by the feed supplieror those mentioned inthisprotocolwillbe conducted.
418-010:PAGE F-76
41 B-01OP:PAGE 76 Pmtocol41"l OP
Page 7
MATING AND RANDOMIZATION:
The female rabbits willbe naturally bred at the Supplier by breeder male rabbits of the same source and strainbefore shipment to the Testing FacilityT.he day mating occurs willbe designated day 0 of presumed gestation.The rabbitswillbe shipped to the Testing Facilitayftermating,to arriveon day 2 of presumed gestation.Before shipment ofthe rabbits,the Supplierwillforward breeding records and day 0 of presumed gestationbody weights. A computer-generated (weight-ordered)randomization procedure willbe used to assign the rabbitsto dosage groups based on this information.
ADMINISTRATION:
Route and Reason for Choice:
The oral(stomach tube) routewas selectedforuse because: 1) in comparison withthe dietaryroute,the exact dosage can be accuratelyadministered;and 2) itisone of the possibleroutes of human exposure.
Method and Freguency:
Female rabbitswillbe given the testarticloence dailyon days 7 through 20 of presumed gestation.Dosages willbe adjustedforthe most recentlyrecorded body weight and given at approximatelythe same time each day.
Rationale for Dosage Selection:
Dosages willbe selectedby the Sponsor on the basis of previous studiesconducted with the testarticle.
418-010:PAGE F-77
418-01 OP:PAGE 77
Protocol41 B-01OP Page 8
Dosage Levels,Concentrations and Volumes:
Dosage Gmup
Number Of
Rabbits
Dosage Concentration Volume (mg/kg/day) (mg/mL)
Argus BatchNumber
1
5
0 (Vehicle)
0
11
5
1
0.2
5
B-418-01OP-A(Day.Month.Year)
5
B-418-01OP-B(Day.Month.Year)
111
5
5
1
5
B-418-01OP-C(Day.Month.Year)
IV
5
10
2
S-418-01OP-D(Day.Month.Year)
v
5
25
5
5
B-418-01OP-E(Day.MonthYear)
vi
5
50
10
5
B-418-01OP-F(Day.Month.Year)
Vil
51
75
1ei
5
B-418-01OP-G(Day. Month.Year)
The testarticlweillbe considered100% pureforthepurposeof dosage calculations.
TESTS, ANALYSES AND MEASUREMENTS:
Viabilily:
AllPeriods:
At leasttwice daily.
ClinicalObservations and/or General ARpearance:
Predosage Period: Dosage Period:
At leastonce.
Twice daily.Priorto dosage administrationand once approximatelyon hour postdosage.
Postdosage Period:
Once daily.
Clinicalobservationsmay be recorded more frequentlythan citedabove, ifdeemed appropriateby the Study Directorand/or Study Monitor.
Body Weights: Predosage Period:
Dosage Period: Postdosage Period:
Day 0 of presumed gestationand on the day of arrival at the Testing Facility.
Daily.
Daily.
418-010:PAGE F-78
418-01OP:PAGE 78
Pmtocol 41 B-01OP Page 9
Feed Consumption Values:
Predosage Period:
Recorded dailyafterarrivaalt the Testing Facility (valuesnot tabulated).
Dosage Period:
Recorded daily.
Postdosage Period:
Recorded daily.
Feed consumption values duringthe dosage periodwillbe tabulatedforthe same intervalsas body weight evaluations.
Caesarean-Sectioning Observations:
Rabbits willbe Caesarean-sectioned on day 29 of presumed gestation.The fetuseswill 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 Gata.]
Liveand Dead Fetuses. (A livefetusisdefined as one thatresponds to stimulia; dead fetusisdefined as a term fetusthatdoes not respond to stimuliand thatisnot markedly autolyzed; dead fetusesdemonstrating marked to extreme autolysisare considered to be lateresorptions.)
Early and Late Resorptions. (A conceptus isdefined as a lateresorptionifitisgrosslyevidentthat organogenesis has occurred;ifthisisnot the case, the conceptus isidentifieads
an eady resorption.)
FetalObservations:
Body Weights:
The body weight of each fetuswillbe recorded. Only body weights of livefetuses will be used to determine liftefretalbody weight averages.
418-010:PAGE F-79
41 B-01OP:PAGE 79
Pmt=l 41"l OP
Page 10
Gross ExternalAlterations:
Allfetuseswillbe examined forgrossexternalalterationsL.ate resorptionsand dead fetusesalsowillbe examined forgross externalalterationtsothe extentpossiblebut such observationswillnot be includedineitherdata summarizationor statistical analyses. Fetuses withgrossexternalalterationwsillbe preservedinneutralbuffered 10% formalin.Allotherfetuseswillbe discarded.
Representativephotographs offetalgross alterationwsillbe taken.
Sex:
Allfetuseswillbe examined intemallyto determine sex.
METHOD OF SACRIFIC :
Beuthanasia(&-DSpecial,manufactured by Schering-PloughAnimal Heafth,willbe used tosacrificreabbits(viaintravenousinjectiona)nd livefetuses(viaintraperftoneal injection).
NECROPSY:
Gross lesionswillbe retainedinneutralbuffered10% formalinforpossiblefuture evaluation(correspondingtissueswillbe retainedfrom rabbitsinthe vehiclecontrol group atthe discretioonfthe Study Director)(.Exception:Parovariancystswillbe discarded;these are common, spontaneous lesionsinrabbits.)Unless specifically citedbelow,allothertissueswillbe discarded.
Scheduled Sacrifice:
On day 29 ofpresumed gestation,female rabbitswillbe Caesarean-sectioned,and a gross necropsy ofthe thoracica,bdominal and pelvicviscerawillbe performed. Uteriof apparentlynonpregnant does willbe stainedwith10% ammonium sulfideto confirmthe absence ofimplantationsites(5).
Rabbits Found Dead or Moribund:
Rabbitsthatdie orare sacrificebdecause ofmoribund conditiona,bortionorpremature deliverywillbe examined forthe cause ofdeath ormodbund conditionon the day the observationismade. Pregnancy statusand uterinecontentswillbe recorded.Aborted fetusesand/ordeliveredpups willbe examined tothe extentpossible,using the same methods describedforfetuses.Uteriof apparentlynonpregnant does willbe stained with10% ammonium sulfidetoconfirmthe absence ofimplantatiosnites(s).
418-010:PAGE F-80
418-01OP:PAGE 80
Pmtocol41"IOP Page 11
STATISTICAL EVALUATION:
Averages and percentages willbe calculated. Littervalues willbe used where appropriate.Additionalprocedures and/or analyses may be performed ifdeemed appropriate.
DATA ACQUISITION. VERIFICATION AND STORAG
Data willbe hand- andior computer-recorded. Records willbe reviewed by the Study Directorand/or appropriatemanagement personnel within21 days aftergeneration.All originalrecordswillbe storedinthe archivesof the Testing FacilityA.lloriginaldata will be bound and indexed. A copy of allraw data willbe suppliedto the Sponsor upon request. Preserved tissueswillbe storedatthe Testing Facilitayt no charge forone year aftermailingof the draftfinalreport,afterwhich time the Sponsor willbe contacted to determine the dispositionof these materials.
RECORDS TO BE MAINTAINED:
Protocoland Amendments. Test ArticleV,ehicle and/or Reagent Receipt,Preparationand Use. Animal Acquisition. Randomization Schedules. VeterinarianExamination. Mating History. Treatment (ifprescribedby StaffVeterinarian). General Comments. ClinicalObservations and/orGeneral Appearance. Body Weights. Feed Consumption Values. Caesarean-Sectioning and FetalObservations. Gross Necropsy Observations. Organ Weights (ifrequired). Photographs (ifrequired).
Study Maintenance (room and environmentalrecords).
Feed and Water Analyses. Packing and/or Shipment Lists.
418-010:PAGE F-81
418-01OP:PAGE 81
Protocol418-010P Page 12
KEY PERSONNE
Executive Director of Research: Mildred S. Christian, Ph.D., ATS Directorof Research: Alan M. Hoberman, Ph.D.,DABT Associate Directorof Research and Study Director:Raymond G. York, Ph.D., DABT Directorof Laboratory Operations: John F. Barnett,B.S. Manager of Study Coordination:ValerieA. Sharper, M.S. Manager of Animal Operations and Member, InstitutionAanlimal Care and
Use Committee: Dena C. Lebo, V.M.D. Manager of Regulatory Compliance: Kathleen A. Moran, M.S. Consultant,VeterinaryPathology: W. Ray Brown, D.V.M., Ph.D.,ACVP
REPORT:
A lettereportforthe purpose of dosage selectionforthe fullstudy willbe prepared immediately followingcompletion ofthe in-lifpehase.
A summary reportwillbe prepared including:abstract,summaries ofthe methods, resultsand conclusion;tableof contents;copy of the protocol;amendments; summary and individuatlables;and reportsof supportingdata (ifappropriate).The reportwillbe includedas an appendix to the fullstudy report.The Sponsor willreceiveone copy of the draftreportand two copies of the finalreport.
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 thatinvolvestudy animals willbe conducted ina manner to avoid or minimize discomfort,distressor pain to the animals.
The Sponsor's signaturebelow documents the factthatinformationconcerning the necessityforconducting thisstudy and the factthatthisisnotan unnecessarily
duplicatsitvuedymay beobtainefdromtheSponsor.No aftemati(vienvitro)
procedures were availableformeeting the statedpurposes ofthe study.
418-010:PAGE F-82
418-01OP:PAGE 82 Protocol418-OIOP
Page 13
REFERENCES:
1 Christian,M.S.,Hoberman, A.M. and Smith, T.H.F.(1982). Dosage-range study ofthe teratogenicpotentialofsuspensions oftrinitrafluoreno(nTeNF) administeredorallyto New Zealand White rabbits.Toxicologis2t(l):40(#143).
2. ChristianM,.S. (1984). Reproducbve 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 of rabbitfbrtilfdtayta: Study of historicaclontrolanimals. Teratology46(4):349-365.
4. Instituteof Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C.
5. Salewski,E. (1964). Farbemethode zum makroskopischen Nachweis von lmplantationsstelieanm Uterus der Ratte. Arch. Pathol.Exp. Pharmakol. 247:367.
PROTOCOL APPROVA
FOR THE TESTING FACILITY
r
George E, earlove,Ph.D.,DABT Associate Directorof Research
Ra\yMoY@d .York, Ph.t-.DR(BT
Associate Directorof R
rch
Study Director
C-
Dena C. Lebo, V.M.D. Member, InstitutionAanlimal Care and
Use Committee
FORTHESPONSOR
MarvinT.Case, D.V.M.,Ph.D.
Study Monitor
418-010:PAGE F-83
418-01 OP: PAGE 83 ProtoCol418-OIOP
Page 14
C.IAI
Date Date Date
Date
418-010:PAGE F-84
418-01 OP:PAGE 84
SCHEMATIC
ATTACHMENT I OF STUDY DESIGN AND STUDY SCHEDULE
ATTACHMENT 1
418-010:PAGE F-85
418-01OP:PAGE 85
Pmtocol 41 " 1OP Page 1 of 2
DOSAGE-RANGE
STUDY SCHEMATIC DEVELOPMENTAL TOXICITY STUDYO
Timed-
Pregnant Rabbits
StartOf
Dosage
CaesareanSectioninc_P
End of
Dosage
Day'O of Presumed Gestation
Day 7 of Presumed Gestation
Day 20 of Presumed Gestation
Day 29 of Presumed Gestation
Dosage Period.
a. For additionaldetailssee "Tests, Analyses and Measurements"
protocol.
b.
Fetalevaluations (allfetuses - externalexaminations).
section of the
ATTACHMENT I
418-010:PAGE F-86
418-01OP:PAGE 86 Pmtocol 41B-01OP
Page 2 of2
26 JUN 98 01 JUL 98 -14 JUL 98
23 JUL 98 30 JUL 98 06 OCT 98
SCHEDULES
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 Directorsigns the protocol.
418-010:PAGE F-87
418-01OP:PAGE 87
ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
418-010:PAGE F-88
MATERIAL SAFETY DA7A SHEET
3M
3M Center
N-E4
@0517418-01 OP:PAGE 88
St. Paul, Minnesota
55144-1000 1-600-36.4-3M 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 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: 3M CHEMICALS
TRADE NAME: FC-10 FLUORAD Brand Fluorochomical
ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2
98-0211-1575-7 00-51135-02145-3
ZF-0002-0572-2
-
ISSUED: January 29, 1998
SUPERSEDES: November 05, 1997
DOCUMENT: 10-3778-7
Alcohol
98-0211-1183-0 98-0211-6620-6
00-51135-09542-3 00-51135-10439-2
-----------------------------------------------------------------------------
1. INGREDIENT
C.A.S. NO.
PERCENT
-----------------------------------------------------------------------------
PERFLUOROOCTANESULFONAMIDO PERFLUOROHEXANESULFONAMIDO PERFLUOROHEPTANESULFONAMIDO PERFLUOROBUTANESULFONAMIDO PERFLUOROPENTANESULFONAMIDO
ALCOHOL ...... ALCOHOL ......
ALCOHOL ..... ALCOHOL ......
ALCOHOL .....
1691-99-2 34455-03-3 68555-73-7 34449-89-3 68555-72-6
80.0 3.0 2.0 2.0 1.0
90.0 7.0 6.0 6.0 3.0
-----------------------------------------------------------------------------
2. PHYSICAL DATA -----------------------------------------------------------------------------
BOILING POINT: ...............c.a.. 118 C @ 1 mm mg
VAPOR PRESSURE: ..............<..10 mmHg Cale @ 20 c
VAPOR DENSITY: ...............>..1.0 Air=l Cale @ 20 C.
EVAPORATION RATE: .............c.1.0 BuOAc=l SOLUBILITY IN WATER: ..........n.eglig. SPECIFIC GRAVITY: .............ca.. 1.7 Water=l
(of melt)
PERCENT VOLATILE: .............0 .% pH: ........................N./A...
VISCOSITY: ..................N./.D . MELTING POINT: ...............N.ID.
........................................................................... Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-010:PAGE F-89
t4SDS: FC-10 FLUORAD Brand Fluorachmical january 29, 1998
Alcohol
418-OIOP:PAGE 89 PAGE 2
-----------------------------------------------------------------------------
2. pmySICAL DATA
(continued)
-----------------------------------------------------------------------------
APPEARANCE AND ODOR: Amber waxy solid
----------------------------------------------------------------------------3. FIRE AND EXPLOSION HAZARD DATA
-----------------------------------------------------------------------------
FLASH POINT: ................>..1.48 C Setaflash 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 Nitrogen, Oxides of
Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates.
----------------------------------------------------------------------------
5. ENVIRONMENTAL INFORMATION -----------------------------------------------------------------------------
SPILL RESPONSE: Refer to other sections of this MSDS for information regarding physical and health hazards, respiratory protection, ventilation, and personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container.
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A . Not Applicable CA - Approximately
418-010:PAGE F-90
msDS: FC-10 FLUOPAD Brand Fluorochadeal Alcohol january 29, 1998
418-OIOP:PAGE 90 PAGE 3
---------------------------------------------a-------------------------------
5. ENVIRONMENTAL INFORMATION
(continued)
-----------------------------------------------------------------------------
RECOMMENDED DISPOSAL: Incinerate in a permitted hazardous we sto incinerator in the presence of a combustible material. Combustion products will include HF. Dispose of waste product in a facility permitted to accept chemical waste.
ENVIRONMENTAL DATA: Laboratory tests showed no biodegradation. 96-Mr. LD50 Fathead Minnow (Pimephalespromelas) - No mortality at water saturation. No statistically significant effect on % hatch, % survival, weight, and length in 30 day Fathead Minnow egg fry study. Lab tests showed 200 fold bioconcentration of FC-10 into muscle fillets of channel catfish.
REGULATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A.
This product complies with the chemical registration requirements of TSCA, EINECS, CDSL, AICS and Korea.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes
-----------------------------------a -----------------a -----------------6. SUGGESTED FIRST AID
-----------------------------------------------------------------------------
EYE CONTACT: Immediately flush eyes with large amounts of water. Get immediate medical attention.
SKIN CONTACT: Immediately wash skin with soap and large amounts of water. Remove contaminated clothing. If signs/symptoms occur, call a physician. wash contaminated clothing before reuse and dispose of contaminated shoes.
INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician.
IF SWALLOWED: Call a physician IMMEDIATELY. If swallowed, induce vomiting immediately as directed by medical personnel. Never give anything by mouth to an unconscious person.
----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A . Not Applicable CA - Approximately
418-010:PAGE F-91
msds: Fe-lo FLUOW jaruary 29, 1998
Brand Fluoroch*sical Alcohol
418-OIOP:PAGE 91 PAGE 4
-----------------------------------------------------------------------------
7. PRECALITIONARY INFORMATION -----------------------------------------------------------------------------
EYE PROTECTION: Avoid eye contact. Wear safety glasses with side shields.
SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of gloves made from the following material(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: coveralls.
RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. 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 airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust 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: Store away from heat. 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: 1 FLAMMABILITY: 1 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.)
EXPOSURE LIMITS
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
- - - - -- - - - -- - - -- - - - - - -- - - - - - - -- - ----------------------------------------------
PERFLUOROOCTANESULFONAMIDO
ALCOHOL ... 0.1 MG/M3-
TWA
3M
y
PERFLUOROHEXANESULFONAMIDO
ALCOHOL ... 0.1 MG/M3
TWA
3M
y
PERFLUOROHEPTANESULFONAMIDO
ALCOHOL ..........................0...1 MG/M3
TWA
3M
y
- - - - -- - - - -- - - -- - - - - - -- - - -- - - - - - ----------------------------------------------
Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-010:PAGE F-92
MSIDS: FC-10 FLUORAD Brand Fluorochosical Jar.uary 29, 1998
EXPOSURE LIMITS
Alcohol (continued)
418-OIOP:PAGE 92 PAGE 5
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
-----------------------------------------------------------------------------
PERFLUOROBUTANESULFONAMIDO
ALCOHOL ... 0.1 14G/f43
TWA
3M
y
PERFLUOROPENTANESULFONAMIDO ALCOHOL ..........................0..1.
MG/M3
TWA
3M
y
SKIN NOTATION: Listed substances indicated with 'Y' under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption.
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines
-----------------------------------------------------------------------------
S. HEALTH HAZARD DATA -----------------------------------------------------------------------------
EYE CONTACT: No adverse health effects are expected from eye contact.
SKIN CONTACT: Product is not expected to be irritating to the skin.
May be absorbed through the skin and persist in the body for an extended time.
INHALATION: May be absorbed by inhalation and persist in the body for an extended time.
IF SWALLOWED: Ingestion is not a likely route of exposure to this product.
Illness may occur after a single swallowing of relatively large quantities of this material.
MUTAGENICITY: Not mutagenic in in-vitro assays.
REPRODUCTIVE/DEVELOPMENTAL
TOXINS:
Substance was not teratogenic in the rat at doses as high as 30
milligrams per kilogram per day via oral route.
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.
.......................................................................... Abbreviations: N/D - Not Determined N/A . Not Applicable CA - Approximately
418-010:PAGE F-93
msos: Fe-lo FLLX)W January 29, 1998
Brand FluoroehoSiCal
Alcohol
418-DIOP:PAGE 93 PAGE 6
-----------------------------------------------------------------------------
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 f rom a database may not be as current as the information in the MSDS available directly from 3M.
418-010:PAGE F-94
418-OIOP:PAGE 94
ATTACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION
PROCEDURE
418-010:PAGE F-95
418-OIOP:PAGE 95
A7rACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION
Pmtocol4lS-OlOP Version:418-010P (12JUN 98)
Page 1 of3 PROCEDURE
Test Article:
N-ETFOSE
Vehicle:
2% TweenO 80, inR.O. Water
A. Purpose: The purpose ofthisprocedure isto providea method forthe preparation of dosage suspensions of N-ETFOSE and the vehiclefororal administrationto rabbitson Argus Study 418-01 OP.
B. General Information:
1 . Allsuspension containerswillbe labeledand colorcoded. Each labelwill specifythe protocolnumber, testarticliedentificatioAnr,gus batch number, concentration,dosage level,preparationdate,expirationdate and storage conditions.
2a. Suspensions willbe prepared:
- x Daily
- Weekly
- For- days ofuse
2b. Vehicle willbe prepared:
- Daily
X Weekly
- For- days ofuse
3. Suspensions willbe prepared at a finaldosage volume of 5 mL/kg.
4. Safety:
X- Gloves, labcoat,goggles or safetyglasses and faceshield
X- Dust-MistRespirator - Half-Face Respirator - Full-FaceRespirator/PositivPeressure Hood - Tyvek Suit/Apron
5. Dosage solutionsadjusted forFree base and % Purity.
Yes
X _ No (Calculationbsased on 100%)
Free Base
Purity
6. Sampling requirements: Cited inprotocol.
7. Storage: Citedinprotocol.
418-010:PAGE F-96
418-OIOP:PAGE 96
ATTACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION
PmtDool 418-OiOP Version:418-OIOP_LlZjMN-9-8-1
Page 2 of3
PROCEDURE
NOTE:
The testarticlweillbe 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 duringsampling and/or administration.
C. Preparationof Vehicle
1 . Add the requiredamount of R.O. deionizedwater to an appropriately labeledcontainer.Heat the water to 500C,:t5oC, add the required amount ofTweenID 80 and mix untiluniform (See TEST ARTICLE CALCULATIONS).
D. Test ArticleSuspension Preparation:
1 . To prepare the 15-mg/mL, Group Vilsuspension, add the required amount oftestarticl(eSee TEST ARTICLE CALCULATIONS) intoan appropriatelysized,labeledcontainer.Add the requiredamount of vehicleand heat the mixtureto 800C, :t5oC forapproximately30 minutes.
2. Once the testarticlheas dissolved;spin over nightwhile the solution cools. (Be sure there isa visiblevortex,thiswillachieve the desired emulsion.)
3. To prepare the 10-mg/mL, Group Vi suspension, remove the required amount of stocksuspension (Group VII)(See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix.
4. To prepare the 5-mg/mL, Group V suspension, remove the required amount of stocksuspension (Group VI)(See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix.
5. To prepare the 2-mg/mL, Group IV suspension, remove the required amount of stocksuspension (Group V) (See TEST ARTICLE
CALCULATIONS), add the requiredamount of vehicleand mix.
418-010:PAGE F-97
418-01OP: PAGE 97
ATTACHMENT 3
TEST ARTICLE AND VEHICLE PREPARATION
Protoool418-010P Vemion:418-OIOP (12 JUN 98)
Page 3 of 3
PROCEDURE
6. To prepare the 1-mg/mL, Group IIIsuspension, remove the required amount of stocksuspension (Group IV)(See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicjeand mix.
7. To prepare the 0.2-mg/mL, Group 11suspension, remove the required amount of stock suspension (Group 111()See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix.
Writtenby
Approved b
Clarificatiyio5.nN-:-X, Nool
Date: 12 -%7aA)-9E ese@sts(eSee attached clarificatifoonrm.)
lnhials/Date:
R ESEA)KH @iqffl"w
A.#-%IWCaNi-.F LAMMATORM
418-010:PAGE F-98
418-01OP:PAGE 98
Argue Research Labomtorl", Inc. 905 Sheehy Drive, Building A
Homham, Pennsylvania 190" T: (215)443-8710 F: (215)443-M7
ORAL (STOMACH
PROTOCOL 418-01 OP
TUBE)DOSAGE-RANGE
DEVELOPMENTAL
OF N-ETFOSE IN RABBITS
TOXICITY STUDY
SPONSOR'S STUDY NUMBER: T-6316.8
Amendment 1 - June 25, 1998
1
ClinicalObservations and/or General At)gearance (page 8 of the protocol):
The postdosage observation willbe made approximately one hour postdosage.
Reason for Chanae: This change corrects a typographical error.
George @Dearlove, Ph.D., DABT Associate Director of Research
Date
RayhVn& G. York, Ph.
BT
Associate Director of Rl.(3-e@r(ch
and Study Director
Date
Dena C. Lebo, V.M.D. Member, InstitutionaAlnimal
Use Committee
Care
Date and
Marvin T. Case, D.V.M., Ph.D. Study Monitor
Date
APPENDIX G HISTORICAL CONTROL
DATA
418-010:PAGE G-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
1
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)
418-010:PAGE G-2
SUMMARY
OF REPRODUCTIVE INDICES NZW RABBIT
MEAN or%
RANGE/STUDY MEAN or %
AVERAGE % DOES WITH ANY RESORPTIONS
26.8
(0-100)
AVERAGE % DOES WITH ALL CONCEPTUSES RESORBED
0.6
(0-20-0)
AVERAGE % DOES WITH ONE OR MORE LIVE FETUSES
99.4 (80.0-100)
AVERAGE SEX RATIO. (% MALES/LITTER)
AVERAGE FETAL BODY WEIGHT (G)
AVERAGE FOR MALES (G)
AVERAGE FOR FEMALES (G)
AVERAGE % DEAD OR RESORBED CONCEPTUSESILITRER
51.2 43.74 44.26 43.08
4.4
(31.4-61-0) (31.85-55-74) (29.5-r,-56.97) (32.25-53.76)
(0-18.8)
418-010:PAGE G-3
SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS
PERIOD
JANUARY 1996 -JANUARY
TOTAL # STUDIES
TOTAL # DOES
#PREGNANT
DIED
ABORTED
DELIVERED PREMATURELY.
DOES WITH 100% RESORPTIONS
1998 67 921 876 6.
22 4 5
% OF PREGNANT 0.6 2.4 0.4 0.5
EXTERNAL OBSERVATIONS
N
Fecalmaterialin
perianalregion
I
Localizedalopecia
2
Leftear,tom
1
GROSS LESIONS
THYMUS
Small
1
LUNGS
Discolored
6
Tear inrightdia-
phragmatc lobe
1
Multiplelesions
1
THORACIC CAVITY
Containedredfluid
I
LIVER
Pale and/ordiscolored 7 Accentuatedlobular
pattemon lobe(s) 1
BACK Break presentin
lumbar regionof
spine
1
-RANGE /STUDY
%N
%
o.i1 D-1 (0-5-0) 0.22 0-1 (D-5.0) 0.11 0-1 (0-5.0)
0.11 D-1 (0-5.0)
0.65 D-4 (0-20.0)
0.11 D-1 (D-4.0) o.11 D-1 (D-4-2)
o.11 D-1 (0-4-0)
0.76 D-4 (D-16.0)
0.
(0-5.0)
0.11 0-1 (0-5.0)
Three were moribund sacrificeosn,e was attributetdoan intubatioanccident
418-010:PAGE G-4
SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS
GROSS LESIONS
N
BACK(CONT.)
Dorsalmuscles,three
hemorrhagicareas
inlumbar region
1
STOMACH
Trichobezoar
2
Mucosa, eroded in
areas
1
SPLEEN
Small
3
Large
1
KIDNEY(S)
Small
1
Right,displaced
caudally
1
ADRENAL GLAND
Right absent
1
UTERUS
Righthom contained
darkbrown fluid
1
Homs containeda
viscous,green-brown
substance
1
Vasculafintion
1
Placentaesurrounded
by a thicky,ellow
substance
1
OVARIES
Parovariacnyst(s) 30
RANGE /STUDY
%N
%
0.11 0-1 (0-12.5)
0.22 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 D-1 (0-5-0)
0.11 0-1 (0-16.7)
0.11 0-1 (0-4.0) 0.11 0-1 (0-4.3) 0.11 0-1 (0-5.0)
3.26 0-5 (0-25.0)
SUMMARY
418-010:PAGE G-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
RANGE/STUDY
N% N
%
L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6)
HEAD
Meningocele
L
F
Cyclops
L
F
Upper jaw intwo
L
segments
F
Nares absent
L
F
Fleshyprotrusion L
F
2 0.24 0-1 3 0.04 0-2 1 0.12 0-1 1 0.01 0-1
1 0.12 0-1 1 0.01 0-1
1 0.12 0-1 i o.oi o-i
1 0.12 0-1 I o.ol 0-1
(0-16.7) (0-3.7) (0-5.9) (D-0.7) (0-5.9) (0-0.7) (0-5.3) (0-0-6) (0-5.3) (0-0.6)
EYES Bulge depressed
Eyelidsopen
L 3 0.37 0-1 (0-5.3)
F 3 0.04 0-1 (0-0-6) L 1 0.12 0-1 (0-5-9) F 1 0.01 o-i (0-0.7)
SNOUT Short
L 2 0.24 0-1 (0-5.9) F 2 0.03 0-1 (0-0.7)
TONGUE Protrudes
L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0-6)
BODY
UmbilicaHlemia
Edema
L 9 1.10 (@2 (0-50.0)
F 10 0.14 0-3 (0-12.0) L 1 0.12 0-1 (0-5-3) F 1 o.oi 0-1 (0-0-6)
L:LITTER INCIDENCE F: FETAL INCIDENCE
418-010:PAGE G-6
SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS NZW RABBITS
ALTERATION
BODY(CONT.)
Skin discolored
L
purple
F
Spina bifida
L
F
Hemorrhagicarea(s) L
F
Meningocele
L
F
Hematoma
L
F
Dark red areas
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 3 0.04 0-3 2 0.24 0-1 2 0.03 0-1 2 0.24 0-1 2 0.03 0-1 2 0.24 D-1 2 0.03 D-1 1 0.12 0-1 1 0.01 0-1 1 0.12 0-1 1 0.01 0-1
(0-5.3) (D-1.9)
(0-20-0) (0-1-9) (0-5.0) (0-0-6) (0-16.7)
(0-2-0) (0-5.9) (0-0.8) (0-5.6) (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 0.01 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
41 B-01 0:PAGE G-7
SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS
PERIOD
JANUARY 1996 -JANUARY 1998
STUDIES
38
LITTERS EXAMINED
674
FETUSES EXAMINED
5739
ALTERATION
BRAIN DilatedlateravlenbiCIOS L (Moderate)(Grade2) F
N%
RANGE/STUDY
N
%
2 0.30 0-1 (0-5.0) 2 0.03 0-1 (0-0.6)
EYE(S) Circumeomeal hemorrhage L
F
Micmphthalmia
L
F
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)
HEART
Large Three ventricles
L 1 0.15 0-1 (0-5.9)
F 1 0.02 0-1 (0-0-6)
L 1 0.15 0-1 (0-5.9) F 1 0.02 0-1 (0-0.6)
VESSELS
Persistentruncus
L
arteriosis
F
lnnominate,absent
L
F
Two pulmonaryarteries L
F
1 0.15 0-1 (0-5.0) 1 0.02 0-1 (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 0-1 (0-0.6)
LUNGS
One or more lobes,partial L
orcompleteagenesis F
Rightapicaland cardiac L
lobesfused
F
69 10-24 0-5 (0-27.8) go 1.57 0-9 (0-5.0)
1 0.15 0-1 (0-5.3) 1 0.02 0-1 (0-0.6)
DIAPHRAGM Hernia
L 1 0.15 0-1 (0-5-0) F 1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
418-010:PAGE G-8
SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS
ALTERATION
KIDNEY(S) Absent Displacedcaudally
SPLEEN Palo
GONADS Righttestidsisplaced caudally
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)
L 1 0.15 0-1 (0-7.1) F 1 0.02 0-1 (0-0.9)
L 1 0.15 0-1 (0-5.9) F 1 0.02 0-1 (0-0.6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
SUMMARY OF FETAL SKELETAL ALTERATIONS NZW RABBITS
418-010:PAGE G-9
PERIOD # STUDIES # LRTTERS EXAMINED # FETUSES EXAMINED
ALTERATIONS SKULL
jANUARy
1996-JANUARY 1998 37
668
RA
OF
STUDIES
RANGE ISTUDY WITH
N%
N % ALTERATION
SummarizatioonfallirregularL
ossificatioofnskull
F
185 27.69 0-11(0-66.7) 35 237 4.17 0-17(0-9.8)
AnterioFrontonelle Irregularslhyaped
L
1 0.15 0-1(0-5.3) 1
F
1 0.02 0-1(D-0.5)
PosterioFrontanelle
Enlarged(Slight)
L
1 0.15 0-1 (0-5.3) 1
(Grade1)
F
1 0.02 0-1 (0-0.6)
Frontals im3gularsuture
L IS 2.69 0-3 (0-16.7) 13
F 20 0.35 0-3 (0-1-8)
Interfrontparlessent L 17 2.54 0-3 (0-15.0) 13
F 17 0.30 0-3(0-1.7)
Fused
L
5 0.75 0-2 (0-10.5) 4
F
5 0.09 0-2(0-1-1)
Two segments
L
1 0.15 0-1 (0-5.9) 1
F
1 0.02 0-1 (0-0.7)
Suturelarge
L
1 0.15 0-1 (0-5.0) 1
F
1 0.02 0-1 (0-0.6)
Small
L
1 0.15 0-1 (0-5.3) 1
F
1 0.02 0-1 (0-0.6)
Paristal(s)
Contaihnoles
L
F
Fused and small
L
F
lnterparistals
L
im3gularly shaped
F
lnterparietianlcsom- L
pleteloyssified
F
3 OA5 0-1 (0-5.6) 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 (D-0.5) 1 0.15 0-1 (0-16.7) 1 1 0.02 0-1 (0-i.g)
L:LITTER INCIDENCE F:FETAL INCIDENCE
418-010:PAGE G-10
SUMMARY
ALTERATIONS SKULL (CONT.) Nasals
lm3gulasrub" lntemasals lntranasais Displacedsuture Fused Small
OF FETAL SKELETAL ALTERATIONS
NZW RABBITS # OF
STUDIES
RANGE ISTUDY WITH
N
%
N % ALTERATION
L
4 0.60 0-2 (0-10-0) 3
F
4 0.07 0-2 (0-1.2)
L
26 3.89 0,3 (0-15-8) 18
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
I1 0.19 0-2 (0-1.3)
L
1 0.15 0-1 (0-5.0)
F
1 0.02 0-1 (0-0.6)
NasaVFrontalsutures:
L
irregulaarnd/ormisaligned F
Premaxillasf:used
L
F
Promaxillaen:ot ossified L F
Maxillaef:used
L
F
Supraoccipitalisr:regularly L
shaped
F
Eye socket small
L
F
Skull:extraossificabon
L
F
12 1.80 0-2 (0-11.1) 9 13 0.23 0-3 (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 (D-5.0)
I
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 G-1 (0-0.6)
HYOID Ala(e),angulated Small Irregularslhyaped
L 108 16.17 0-8 (G40.0) 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)
1
F
1 0.02 0-1 (0-0.6)
L: LITTER INCIDENCE F:FETAL INCIDENCE
418-010: PAGE G-1 1
SUMMARY OF FETAL SKELETAL ALTERATIONS
NZW RABBITS # OF
STUDIES
ALTERATIONS
RANGE /STUDY NTH
N%
N % ALTERATION
VERTEBRAE
cervical
Centrum,unilateral L
ossification
F
Archesand/orContra. L
fused
F
Heniivertebra
L
F
Contrum,asymmetric L
F
Centra,bifid
L
F
2 0.30 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 0.45 0-1 (0-5.9) 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
Archesand/orContra, L
fused
F
Centrum,unilateral L
ossification
F
Centra,one ormore L
asymmetric
F
Centrum,bifid
L
F
Centra,notossified L
F
Arch,absent
L
F
Arch,small
L
F
10 1.50 0-1 (0-5-9) 10
11 0.19 0-2 (0-1-1) 5 0.75 0-2 (0-10.5) 4
6 0.10 G-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 0.60 D-2 (0-10-5) 3
4 0.07 0-2 (0-1.2) 1 0.15 0-1 (04.5) 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 (0-0.6)
Lumbar
Hemivertebra
L
F
Centrum,unilateral L
ossificaton
F
Arch,small
L
F
Centrum,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 (@l (0-0.6) 2 0.30 0-1 (D-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:LMRER INCIDENCE F:FETAL INCIDENCE
41MIO:PAGE G-12
SUMMARY
ALTERATIONS VERTEBRAF-(CONT.) Sacral
Arches open
OF FETAL SKELETAL ALTERATIONS
NZW RABBITS
# OF
STUDIES
RANGE ISTUDY WITH
N
%
N % ALTERATION
L
1 0.15 0-1 (0-5.3)
1
F
1 0.02 0-1 (0-0.5)
Caudal One or more misaligned :Fused 11 present
12 preservt
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
a 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 O.D4 0-2 (0-1-0)
L
3 0.45 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)
VERTEBRAEIRIB
interrelatVeedrtebralIRb
L
malformations
F
3 0.45 0-3 (0-15.8) 1 3 0.05 0-3 (0-1-6)
RIBS
CervicalRib present
L
F
Two or rwre, fused
L
F
Bases proximate
L
F
One ormm, spift
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 (@l ((@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 ((@-5-6) 2
2 0.04 0-1 (0-0.6)
L:LrT7ER INCIDENCE F: FETAL INCIDENCE
418-010:PAGE G-13
SUMMARY
ALTERATIONS RIBS (CONT.) Extrarib Small Broad Bent
OF FETAL SKELETAL ALTERATIONS NZW RABBITS 0 OF
STUDIES
RANGE ISTUDY WITH
N%
N % ALTERATION
L
1 0.15 0-1 (0-4.3) 1
F
1 0.02 0-1 (G-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 .0-1(0-4.5) 1
F
1 0.02 0-1 (0-0.6)
MANUBRIUM Duplicated Fused
L
1 0.15 0-1 (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 ormore.fused
L
F
One ormore,asymmetric L
F
One ormore,incompletely L
ornotossified
F
Duplicated
L
F
64 9.58 0-5 (G-27.8) 31 78 1.37 0-7 (0-3.9) 6 0.90 0-2 (D-10.5) 5 6 0.10 0-2(0-1.2) 11 1.65 0-2 (0-10.5) 9 11 0.19 D-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
ornotossified
F
4 0.60 0-1 (0-5.9) 4 5 0.09 0-2 (0-1-1)
SCAPULAE
Ala(e)i:m3gulady shaped Aia(ew)a:vy
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 (D-0-6)
L:LITTER INCIDENCE F:FETAL INCIDENCE
4lMlO:PAGE G-14
SUMMARY
ALTERATIONS SCAPULAE (CONT.) Misaligned Bent
OF FERAL sw-LETAL ALTERATIONS
NZW RABBITS
# OF
STUDIES
RANGE /STUDY WITH
N
%
N % ALTERATION
L
5 0.75 0-2 (0-10.5) 4
F
5 0.09 0.2(0-1.2)
L
1 0.15 0.1(0-5.0)
1
F
1 0.02 0-1(0-0.6)
FORELIMB(S)
I Phalanx present
L
F
0 Phalanges pmservt
L
F
Humerus, Radius,Ulna,
Carpals,Metacarpals,Fow
digitsand Forephalanges L
absent
F
L: LrrrER INCIDENCE F: FETAL INCIDENCE
1 0.15 0-1 (0-5.6)
1
1 0.02 0-1 (".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)
418-010:PAGE G-15
SUMMARY
OF FETAL OSSIFICATION SITES NZW RABBITS
PERIOD
JANUARY 1996 -JANUARY 1998
# STUDIES
37
# LITTERS EXAMINED
667
FETUSES EXAMINED
5882
FETUS
SKELETAL AVERAGES HYOID
MEAN 1.00
VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL
RIBS (Pairs)
7.00 12.58 6.41 3.00 16.96
12.51
STERNUM
MANUBRIUM
1.00
STERNAL CENTERS
3.92
XIPHOID
0.98
FOREPAWS (Calculateads average perlimb)
CARPALS METACARPALS DIGITS
PHALANGES
0.00 4.99 5.00 13.91
HINDPAWS (Calculateads average perlimb)
TARSALS METATARSALS DIGITS PHALANGES
2.00 4.00 4.00 12.DO
LrrTER RANGEISTUDY (0.98-1.00)
(12.44-12.72) (627-6.57) (16.75-17.13) (12.36-12.67)
(3.83-3.99) (0.92-1.00)
(4.96-5.00) (13.80-13.99)
(1.98-2.00) (11.97-12.00)
STATEMENT
APPENDIX H OF THE STUDY DIRECTOR
iriPUMMICA
418-010: PAGE H-1
Argus ResearchLaboratoriesI,nc. 905 Sheehy Drive,BWlding A Horsham, PA 19044 Telephone:(215)443-8710 Telefax:(215)443-8587
PROTOCOL
418-010:
ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS SPONSOR'S STUDY NUMBER: 6316-8
STATEMENT OF THE STUDY DIRECTOR
This finalreportaccuratelyreflecttshe raw data obtainedduringthe performance ofthe study. No significandteviationsfrom the U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulations;FinalRule',the Japanese MinistryofHealthand Welfare(MHW) Good LaboratoryPractice Standard forSafetyStudieson Dnigs" and the European Economic Community (EEC) Councildecisionon 28 July1989 on the acceptance by the European Economic Community ofan OECD decisiorilrecommendatioonn compliance with ptincipleosfgood laboratorpyracticeo'ccurredthataffectedthe qualityor integritoyfthe study.
Raymond G. Yor4,P@.D.,DABT AssociateDirectorofResearch and Study Director
Date
-------------------
a. U.S. Food and Drug AdministrationG.ood LaboratoryPractice Regulations;FinalRule. 21 CFR Part58.
b. Japanese Ministroyf Healthand Welfare (1988). Good Laboratory PracticeStandard forSafetyStudieson Dnigs, MHW Ordinance
Number 21, March 26, 1997. C. European Economic Community (1989). Council decision on 28 July
1989 on the acceptance by the European Economic Community of an
OECD decisionlrecommendation
on compliance with principles of good
laboratory practice. Official Journal of the European Communities:
Legislation3.2(No.L 315;28 October):1-17.
QUALITY ASSURANCE
APPENDIX I UNIT FINAL REPORT STATEMENT
ijPRIMEDICA
418-010:PAGE 1-1
Argus Research Laboratories,Inc. 905 Sheehy Drive,Building A Horsham, PA 19044 Telephone: (215) 443-8710 Telefax: (215) 443-8587
QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT
Study Director:Raymond G. York,Ph.D.,DABT
ExecutiveDirectorof Research : MildredS. ChristianP,h.D.,Fellow,ATS
Protocol418-010: Oral(Stomach Tube) DevelopmentalToxicityStudy of N-ETFOSE inRabbits Sponsor's Study Number: 6316.8
The draftprotocolforthisstudy was auditedforadherence to U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulations,Japanese Ministryof Healthand Welfare (MHW); Good LaboratoryPracticeStandard for SafetyStudieson Drugs,and European Economic Community (1989)council decisionon 28 July1989 on the acceptance by the European Economic Community ofan OECD decision/recommendationon compliance with principles of good laboratorypracticeon 10 AUG 98.
Criticaplhases ofthisstudy were inspectedfourtimes;study information and raw data were auditedtwice(see tables1 and 2 fordates and phases/data).
The draftfinalreportand the raw data forthisstudy were compared and auditedforaccuracy,foradherence to protocolrequirements,and foradherence to U.S. Food and Drug Administratio(nFDA) Good LaboratoryPractice Regulations,Japanese Ministryof Healthand Welfare (MHW); Good Laboratory PracticeStandard forSafetyStudieson Drugs, and European Economic
Community (1989) councildecision on 28 July 1989 on the acceptance by the
European Economic Community of an OECD decision/recommend ationon compliance withprincipleosf good laboratorypracticebetween 14 DEC 98 and 23 DEC 98, forrevisionsrequested by the Sponsor 07 JAN 99, and for finalizatioonn 11 JAN 99.
418-010:PAGE 1-2
This study was conducted accordingto U.S. Food and Drug Administration(FDA) Good LaboratoryPracticeRegulations,Japanese Ministry ofHealth and Welfare (MHW); Good LaboratoryPracticeStandard forSafety Studieson Drugs, and European Economic Community (1989)councildecision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendationon compliance withprincipleosfgood laboratorypractice.
Bnairblatorra0J.i4erson, B.A.
D irectorof O@erations and Compliance
uate
Heather L.Rabuftino,M.S. Date QualityAssurance Supervisor and PrincipaAluditor
TABLE 1 CRITICAL PHASES INSPECTED
418-010:PAGE 1-3
TestArticlePreparation Date ofinspection:31 AUG 98 Date resultsreportedtothe Study Directorand Management: 31 AUG 98
Test ArticlAedministratio-n Gavage Date of inspection:01 SEP 98 Date resultsreportedtothe Study Directorand Management: 02 SEP 98
Blood Collection Date ofinspection:17 SEP 98 Date resultsreportedtothe Study Directorand Management: 18 SEP 98
Caesarean-Sectioning Date of inspection:21 SEP 98 Date resultsreportedtothe Study Directorand Management: 24 SEP 98
TABLE 2
418-010:PAGE1-4
RAW DATA AUDIT(S)
The followisntgudyinformatiaonnd rawdatawere audited on 11 OCT 98,13OCT 98 to17 OCT 98:
Protocol. Lisotfpersonnealnd computeroperatocrodes. Errorcodesand codesforclinicsailgnobservations. Animalreceiprta,ndomizatioann,d acclimation. Veterinareyxamination. In-litfreansactiroencord. Feed consumption. Caesarean-sectioning. Maternaglrossobservations. Fetalgrossobservations. Fetalfixatiavsesignment. Fetalvisceraelxamination. Fetalskeletaelxamination. Tissuepackinglists. Generalcomments. Studymaintenancerecords. Temperatureand relatihvuemiditryeports. Feed and wateranalyses. Editrequests. Dosagevolumes. Datareviewpage. Bloodcollectidoantaand packinglists. Livewreights. Deviations.
The resultosfthisauditwere reportetdotheStudyDirectoarnd Managementon 19 OCT 98.
The followisntgudyinformatiaonnd rawdatawereaudited on 27 OCT 98:
Vehiclreeceipptr,eparatiaonnd use. Testarticlreceipptr,eparatiaonnd use. Testarticlpeackinglists.
The resultosfthisaudiwtere reportetdotheStudyDirectoarnd Managementon 29 OCT 98.