Document 6545r4zwEYMxjRj120VyNm4X6
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.FFIIN. NAALL RREEPPOOR. RTT . /
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m LABORATORIES AMERICA, INC. LABORATORIES AMERICA, INC.
9200 LEESBURG TURNPIKE, VIENNA,VIRGINIA 52180, U.S.A.
-::: a ae ~'HONI~ (~'03] B93 5400, TELEX 899436 (HAZLABS VINA), CABLE HAZ/ABS WASH DO
Exhibit
2786
22778866..00000011
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PPIILLOOTT RRAATT TTEERRAATTOOLLOOG6YY SSTTUUDDYY
I1 TT--33335522 II11 FFIINNAALL RREEPPOORRTT
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I1I11I MWaayy 1111,, 11998833
22778866..00000022
m3MA0A002024408226877
I
1I @HAZLETON| I SIRRCT: prio fa Teratology tats SUBJECT: Pilot Rat Teratology Study
Hal Project No. 154-159 Ii Ve, the designed, hereby dslare tat the ork wis pertrend We, the undersigned, hereby declare that the work was performed I nt oS nas Ne str under our supervision, according to the procedures herein described.
Sta ptectars I
Study Director:
I Lit Tierr 1
S[SLttAaaWffRffENSSCEcciiTee.nn-tttii;IssfttjTZEL, Ph.D.
Soar Toxtantony Department of Toxicology
I1I sores pes ---- Laboratory Supervision:
Teratology:
I Gaff 1
Rodent Toxicooay 1 GEORGECA. BURDOCK, Ph.D.
Rodent Toxicology I
I a 5 tatony Department of Toxicology
Bont Duelo RRRUeeTssHeeaarrScc.hhDAUAsRssLsoOoc0ci,iaattBee.S. Sereno Toreatony Department of Toxicology
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Separt raparation:
Report Preparation:
Mpadeong e. MARCIA A. MENSE, B.A. TSeiEl iieorices vparoant Technical Writer
Scientific Resources Department
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22778866..00000033
swsorziasa 3MA00248288
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I @HAZLETONucomrons svenca ne
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TTAABBLLEE OOFF CCOONNTTEENNTTSS
Page
I rRONUCTION 3 1
SSuUMmMAyRY
i 1
INTRODUCTION
1
CCOONNTTRROOLL AANNDD TTEESSTT MMAATTEERRIIAALLSS
3
I1 TEST Avs ` TEST ANIMALS
I WEH0DS . METHODS
4
Hating Period 3 1
GMGrraootuuinppsgs PaanneddrioDDdoossaaggee LLeevveellss
54 5
Conpoing reparation and Adninistration : Compound Preparation and Administration
6
I Haternai Observations and Records s Maternal Observations and Records
Cesarean Sacrifice and Tissue Preservation 7 Cesarean Sacrifice and Tissue Preservation
7
1 Statistical Analyses : Statisti cal Analyses
8
l Spacinen, Rau Data, and Firal Report Storage s Specimen, Raw Data, and Final Report Storage
9
1 RESULTS - MATERML DATA 10 RESULTS - MATERNAL DATA
i0
Crinica1 Signs i Clinical Signs
i0
I Hortaiity 10 Mortal ity BBooddyy W Weeiigghhttss
i0
I100
I1 Foot Consumption 1 GFGrorooosdsss CPPoanatsthhuoomllopogtgioyyn
Ii1Ii
UUtteerriinnee WWeeii gghhttss
uini
1I Regus csi pn 2 RESPPFUerretSLeaTagngaS]dnnaanVn-ITmcicoyaypCpbElmRiRSaalAanatiRtttetEeaisyAst,,Nio,onHnCCDeoAoiErTErgAppfhtooftirir,acaciieeLLannunucctdteeyyaaS,e,xUUtteerriinnee
plantations,
Implantations,
Ix12
12
I FFeettaall Deveroment Viability, Weight, and Sex
i13
13
Fetal Devel opment
!1 aus TATBTTaLaaEbbbSllleee 211 --- HCCollaiinnniiccMaaaltl eOrOnbbassleerrvovaadttiyioonnesstaDDhuutrrsiinnggandGGeesSstotadatytiiooHnneight Change
1115s5
i 1
TTaabbllee TTTaaabbbllleee
Table
452 3 3
4
----
-
MMMeeeaaannn MFFcoaootdderCnCoaonlnssuBumompdptytiiooWnneiVVgaahlltsuueessand Body Weight
MSeuamnarTyermoifnaGlrosBsodpyaNtheoilgohgty,sFGinrdaivnigdsUterine Su,~mary of Gross Pathology Findings
Change
Weights,
and
111u67
18
Tabl e 5 - MeTaanorTmeinrma)inaSol dyBoHdey1gWheisighMtisn, usGrGarvaidvidUtUetreinreinW e eAicghttos,s and 2200
I1 Koy to Tate's 3 TKTTaaaebbybilleeteo's67Ta-= bhSSleeuuaTnmn~6eanrramTryyhincooaiflfenOOBcvoveadaryrfViaaW anlne,l,iegsUUhtttseferorirMinnieenV,ui,sscaaoGnnrddraalLLviiidttattneeUdrrtSekDDreaianltteeaataWleiFgihntsdings 2222123
I 1
Table 7 - Mean Incidence
KKeeyy ttoo TTaabbllee 88
Tablas ~ MeapnerInLciitdteenrce Table 8 - Mean Incidence
of Visceral and Skeletal Findings Values for Visceral and Skeletal Findings
of Visceral and Skeletal Findings
=23
2255
per Litter
26
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1 pagePave
I APPENDICES APPENDICES
1 Key to Aependix 1 7 Key to Appendix i
27
I Aependta 1 Individual end Mean Maternal Body Weights and Appendix I - Individual and Mean Maternal Body Weights and
eign Changes = Weight Changes
28
1 appendix 2 = Individual ang Mean Daily and Total Food Consumption 31 Appendix 2 - Individual and Mean Daily and Total Food Consumption 31
Appendix 3 Individual Body Nelgnts, Gravid Uterine Neignts, and Appendix 3 - Individual Body Weights, Gravid Uterine Weights, and
I Terminal Body el his Minus Gravid Utering Weights 34 Terminal Body Weights Minus Gravid Uterine Weights AAppppeennddiixx 44 -- IInnddiivviidduuaall aanndd MMeeaann OOvvaarriiaann,, UUtteerriinnee,, aanndd LLiitttteerr DDaattaa
3374
37
Ii Ropencix 5 - Individual and Mean Live Feta Data i 1 Appendix 8 - References 3 Appendix AAppppeennddiixx
5
66
-
- -
Individual
IInnddiivviidduuaall
and Mean
VViisscceerraall
FFLiiivnneddiinnFggesstaffloorrDaEEtaaacchh
LLiitttteerr
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AAppppeennddiixx 77 -- IInnddiivviidduuaall SSkkeelleettaall FFiinnddiinnggss ffoorr EEaacchh LLiitttteerr
444a
i Appendix 8 - References
46
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22778866..00000055
aMADO248290
3MA00248290
1
EYHAZLETON uiorurones senca nc
LABORATORIES AMERICA, INC.
1
SSPPOONNSSOORR:: 33M CCoommppaannyy
I MATERIAL: T-3352
DDAATTEE:: tMaayy 1111,, 11998633
1 Pi $S1UJBBJJEECCTT::
FFIINNAALL RREEPPOORRTT PPiilloott RRaatt TTeerraattoollooggyy SSttuuddyy Project No. 154-159
} sonar SUMMARY
1 sn, sh 41 5. pg Ss T-3352, suspended in corn oil at concentrations intended to
I ddeelliivveerr I1,, 1100,, 3377..55,, oorr 7755 mmgg//kkgg//ddaayy ((GGrroouuppss 22,, 33,, 44,, aanndd 55,,
1
rreessppeeccttiivveellyy)),, wwaass aaddmmiinniisstteerreedd bbyy oorraall iinnttuubbaattiioonn ttoo ffoouurr ggrroouuppss ooff
I
mmaatteedd ffeemmaallee SSpprraagguuee--DDaawwlleeyy SS--DD rraattss oonn ggeessttaattiioonn DDaayyss 66 tthhrroouugghh 1155.. AA
ffiifftthh ggrroouupp ((GGrroouupp 11)) ooff mmaatteedd ffeemmaalleess sseerrvveedd aass tthhee ccoonnttrrooll aanndd rreecceeiivveedd
1
tthhee vveehhiiccllee oonnllyy..
I iran tot tres of oon rom tt on ox te ow 1 Apparent ccoommppoouunndd--rreellaatteedd ddeeaatthhss ooccccuurrrreedd iinn sseevveenn ooff sseevveenn Group 5 and three of seven Group 4 females on or before Day 17 of
gestation. Clinical observations in Groups 4 and 5 included hunched,
thin appearance, languid behavior, and apparent anorexia. Body weight
1
ggaaiinn dduurriinngg ttrreeaattmmeenntt wwaass lleessss iinn GGrroouupp 33,, 44,, aanndd 5 ffeemmaalleess ccoommppaarreedd ttoo
control values obtained during that time. The terminal body weight minus
1 tn ets aterm wiih vey ORE S08 4 Sih SEES 0 the gravid uterine weight was decreased in Group 4 females compared to
I control. A number of gross pathology findings at necropsy or sacrifice
1 sre tad fn Groups od 5 on tase clad nonce of Ther, were noted in Groups 4 and 5 and these included incidences of liver,
adrenal, lung, and/or gastrointestinal tract effects.
22778866..00000066
3MA00248291
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@HAZLETONueorronesmma ne ~ H LA~Z'~~r~ LABORATORIES _AMERICA, INC.
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115544--115599
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I1 Elation of nen fetal weight data indicated that feta] Evaluation of mean fetal weight data indicated that fetal
I1 Wits of both sexes decressed with fncreasing dose level. A i
wseiiggnhitfsicanotf debcortehasesefxnesmeadnecrfeetaasled weiwgihtth ocicnucrrreeadsinign Gdroosuep 4lemvaelle.s andA
significant decrease in mean fetal weight occurred in Croup 4 males and
! females, although data for only tio litters were available for that
1
females, although data for only
group. Cleft. palate was fond in
two
two
olfitstiexrs Grwoeurpe
4 afveatiulsaebsle (ofnoer
ftehtauts
group. Cleft palate was found in two of six Group 4 Fetuses (one fetus
! iinn eeaacchh lliitttteerr)) eexxaammiinneedd bbyy WWiillssoonn''ss tteecchhnniiqquuee.. IInnccoommpplleetteellyy ddeesscceennddeedd
1 estes vere oted in ane fetus fram cach Group 4 litter evaluated for testes were noted in one fetus from each Group 4 litter evaluated for
I Visceral defects. Incidences of skeletal varfants were similar for al visceral defects. Incidences of skeletal variants were similar for all
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HAZLETON vscnronessemen ic.
1 Pete unmeonae ots -3-
154-159
!I1 rection INTRODUCTION
I1 This study was designed to determine the maternal and. anbryo/ ffeettaall
This study was designed to determine the maternal and embryo/
ttooxxiicciittyy ooff TT--33335522 wwhheenn aaddmmininiisstteerreedd bbyy ggaavvaaggee ttoo pprreeggnnaanntt rraattss
I during the period of fetal organogenesis for the purpose of setting dose
1 levels for an expanded teratology stuly. The rats were placed in levels for an expanded teratology study. The rats were placed in
! breeding on January 17, 1983, and cesarean sections were completed on breeding on January 17, 1983, and cesarean sections were completed on
1 February 18, 1983. This report presents the methods and results from February 18~ 1983. This report presents the methods and results from
I this study. this study.
!11
CCOONNTTRROOLL AANNDD TTEESSTT MMAATTEERRIIAALLSS
I The vehicle and control material, Duke's Corn OF1 (C. F. Saver The vehicle and control material, Duke's Corn Oil (C. F. Sauer
1
CCoo..,, RRiicchhmmoonndd,, VViirrggiinniiaa)),, lloott 8800223355,, wwaass rreecceeiivveedd oonn JJaannuuaarryy 2244,, 11998833,,
I1 and vas stored at roo temerature. and was stored at room temperature.
i The test material, T-3352, an off-white solid, was received from The test material, T-3352, an off-white solid, was received from
I test material was assumed to be 1004 active compound. Information on 1
tthhee ssppoonnssoorr oonn JJaannuuaarryy 55,, 11998833,, aanndd wwaass ssttoorreedd aatt rroooomm tteemmppeerraattuurree.. TThhee
test material was assumed to be 100% active compound. Information on
I1 methods of synthess and stability, as well as data on composition or other characteristics hich define the test material, are on file with methods of synthesis and stability, as well as data on composition or other characteristics which define the test material, are on file with
1I sr sr the sponsor.
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TTEESSTT AANNIIMMAALLSS
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SSeexxuuaallllyy mmaattuurree cceessaarreeaann--ddeerrivveedd SSoprraagguuee--DDaavwlleeyy CCrrlI::CcDo ((SSDD))SBRR
! rraattss
wweerree
cchhoosseenn
ffoorr
tthhiiss
ssttuuddyy
bbeeccaauussee
tthheeyy
aarree
sseennssiittiivvee
to
to
a
a
nurber
number
of
of
!1 srt hic re ace 15% mg. gor sez. oo agents which are known to be embryotoxic and/or teratogenic. Rats have
! required by the regulatory agencies. Thirty-six tuelve to fourteen-neek 1
hhiissttoorriiccaallllyy bbeeeenn uusseedd iinn ssaaffeettyy eevvaalluuaattiioonn ssttuuddiieess ooff tthhiiss ttyyppee aanndd aarree
required by the regulatory agencies. Thirty-six twelve to fourteen-week
1 O16 male rats and thirty-six eight to tanwesk ola female rats were old male rats and thirty-six eight to ten-week old female rats were
! received fron Charles River Breeding Laboratories, Kingston, New York, on received from Charles River Breeding Laboratories, Kingston, ~ew York, on
1 star 2, 1502. Th ras wre eld in curative for thr and December 22, 1982. The rats were held in quarantine for three and
! oonnee--hhaallff
wweeeekkss,,
dduurriinngg
wwhhiicchh
ttiimnee
a a
health
health
status
status
examination
examination
was
was
I 1
ppeerrffoorrmmeedd bbyy aa ssttaaffff vveetteerriinnaarriiaann..
1
The rats vere haused one male and one female per cage during
The rats were housed one male and one female per cage during
! bbrreeeeddiinngg..
FFoolllloowwiinngg
ccoonnffiirrmmaattiioonn
of
of
meting,
mating,
the
the
females
females
were
were
housed
housed
i
iinnddiivviidduuaallllyy iinn eelleevvaatteedd wwiirree--mneesshh ccaaggeess wwiitthh ffoooodd ((PPuurriinnae RRooddeenntt
! LLaabboorraattoorryy CChhooww~ 55000011)) aanndd ttaapp wwaatteerr aavvaaiillaabbllee aadd lliibbiittuumm.. TThhee ffeemmaalleess
1! ae nicely dun1ed by ar tap ater cating was confirm. Tamera: 1
were uniquely
tures in the
identified
study room
by ear
ranged
tag after mating was confirmed.
from 70 to 78F with a relative
Theummpiedriat-y
tures in the study room ranged from 70 to 78F with a relative humidity
! between 44 and 691. between 44 and 69%.
!1 WETHODS METHODS
1! Mating perio Mating Period
1 during the mating period, one fesale sas paired with one wale During the mating period, one female was paired with one male
1!!!1 uunnttiill mmaattiinngg wwaass ccoonnffiirrmmeedd oorr uunnttiill ttwwoo wweeeekkss hhaadd eellaappsseedd..
Daily vaginal
Daily vaginal
22778866..00000099
aMADO248204
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I 5-
ots
154-159
!
examinations of each female were performed to detect the presence and
1
vviiaabbililiittyy ooff ssppeerrmm oorr tthhee pprreesseennccee ooff aa ccooppuullaattoorryy pplluugg.. TThhee ddaayy ooff
! observation of spera or copulatory plug vas designated as "Day 0 of observation of sperm or copulatory plug was designated as "Day 0" of
I1 gestation. gestation.
1
GGrroouuPpss aanndd. DDoossaaggee LLeevveellss
I Upon confirmation of mating, each female was assigned to one of
Upon confirmation of mating, each female was assigned to one of
i
the following groups.
the following groups.
I GGrroou;up
DDoossee"a
NNuummbbeerr ooff FFeemmaalleess
1 fe wore fuser fei mglkglday
I 11
00
1
2
1
6 s &
2 3
101
76b
1
3 a
a10 s
77
7
4
37.5
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77%5
77
1 during the dosing period. a2BBaasseed on individual animal body weeiigghhttss aatt eeaacchh wweeiigghhiinngg iinntteerrvvaall during the dosing period.
I1 5 hn adttanal Group 2 female was confirmed to have mated on a day shen no 1
b AoGRnativheearrddbiemmteaanottininaknglngsos.wGnrwwoeeuarrptee c2cceoofsnneaffmriiasrrlammneeeddws..aascricBfoSeinecccfaaeiuu,rssmeeesdhttehhtiiowssash.aaannvriieemnnaaomllva''etssdedfddrooonossneeatllhdeeeavvyeesllwthuedwwynoo.uullnddo
have been known at cesarean sacrifice, she was removed from the study.
i The females were placed into the dose groups one at @ tine The females were placed into the dose groups one at a time
1I begiming with the high-dose group and continuing sequentially through 1
beginning with the high-dose group and
the control group until all mated females
were assigned to group. continuing sequentially through
the
control group until all mated females
AL mates vere sacrificed via
cwoerrdeonasdsiigonxeidde toasaphgyrxoiuapt.ion
end
i All males were sacrificed via carbon dioxide asphyxiation and
1
discarded without necropsy once a sufficient musber of matings were
discarded without necropsy once a sufficient number of matings were
/ confirmed.
confirmed.
I
I
22778866..00001100
aMAD0248295
3MA00248295
1
1I HAC ZLETONwomy sronss erica.ne.
6 -
ots
154-159
I RPP Compound Preparation and Administration
prepared on a weignt per volume basis. The required smut of compound 1
SSuussppeennssiioonnss ooff tthhee tteesstt mmaateterriiaall iinn tthhee ccoorrnn ooiill vveehhiiccllee wweerree
prepared on a weight per volume basis. The required amount of compound
1 for Tews 2, 3, or wis weighed nto a homgenizer on an electronic arbor 126 balance. Compound for Group 5 wes weighed on poder paper on for levels 2, 3, or 4 was weighed into a homogenizer on an electronic Arbor 126 balance. Compound for Group 5 was weighed on powder paper on
1 an trbor 126 balance and vised into a Haring Slender. pproxiastely & am Arbor 126 balance and rinsed into a Waring blender. Approximately 4
1 a1 of com ofl was added and the test material was ground into 3 fine ml of corn oil was added and the test material was ground into a fine
I! suspension. This suspension was rinsed fron the homogenizer or the suspension. This suspension was rinsed from the homogenizer or the
1
bblleennddeerr iinnttoo aa bbeeaakkeerr aanndd aaddddiittiioonnaall ccoorrnn ooiill wwaass aaddddeedd ttoo pprroodduuccee tthhee
desired concentration. The sussension was mixed on a stirrer for desired concentration. The suspension was mixed on a stirrer for
1 approcinately fifteen minutes. Prepared suspensions were mixed with 3 approximately fifteen minutes. Prepared suspensions were mixed with a
mugretic stirrer during dosing. magnetic stirrer during dosing.
Females were given the appropriate dosing suspension or vehicle
1 by oral intubation on a daily basis begining on Day 6 and continuing by oral intubation on a daily basis beginning on Day 6 and continuing through Day 16 of gestation. The test material was administered orally through Day 15 of gestation. The test material was administered orally
1 because of th relative ese and accuracy of dosing. Fresh dosing suspensions were prepared weekly and stored under because of the relative ease and accuracy of dosing. Fresh dosing suspensions were prepared weekly and stored under
1 refrigeration (proximately 4%). Swmples of sich test mixture as 1 well ss the vehicle were sent to the sponsor for analysis. refrigeration (approximately 41F). Samples of each test mixture as well as the vehicle were sent to the sponsor for analysis. Vaternal Observations end Records Maternal Observations and Records
All animals were examined twice daily for mortality and mori-
1 bundity (fron day of recefpt through study termination) and once caily bundity (from day of receipt through study termination) and once daily for clinical signs of toxicity and pharmacologic effects (throughout for clinical signs of toxicity and pharmacologic effects (throughout
1
,1!
22778866..00001111
amonziszss
3MA00248296
1
11
HS AZLETONuLsAoBa OmRrAoTOnRsIEsS sAeMnERiICA, nINeC.
ress
154-159
! ashton). iy wih sd fe cansetion ar record on 7, 1 6.8, 12, 16, and 20 of gestation. gestation). Body weights and food consumption were recorded on Days O, 6, 8, 12, 16, and 20 of gestation.
I 1
Cesarean Sacrifice and Tissue Preservation
Cesarean Sacrifice and Tissue Preservation
I AA ggrroossss nneeccrrooppssyy wwaass ppeerrffoorrmmeedd oonn aallll aanniimmaallss ((ffoouunndd ddeeaaddss,,
1 moribund sacrifices, and terminal sacrifices). The uterus and ovaries moribund sacrifices, and terminal sacrifices). The uterus and ovaries
i fron found dead animals and animals sacrificed becasse of moribundity from found dead animals and animals sacrificed because of moribundity
1 were removed and examined for the mmber of implantation sites and were removed and examined for the number of implantation sites and
I corpora utes, respectively. Prior fo gestation Day 2, surviving corpora lutea, respectively. Prior to gestation Day 20, surviving
I females were assigned random numbers and all personnel performing
1 cesarean sections and/or external, visceral, or skeletal examinations of cesarean sections and/or external, visceral, or skeletal examinations of
I the fetuses vere unaware of the dose level fron wnich the antasls vere 1 derived. On Day 20 of gestation, all surviving females were weighed and the fetuses were unaware of the dose level from which the animals were derived. On Day 20 of gestation, all surviving females were weighed and
I sacrificed by carbon dioxide asphyxiation. sacrificed by carbon dioxide asphyxiation.
1 The uterus fron escn fensle as veighed and exomied for the The uterus from each female was weighed and examined for the I nnuummbbeerr aanndd ppllaacceemmeenntt ooff uutteerriinnee iimmppllaannttaattiioonn ssiitteess,, nnuummbbeerr ooff lliivvee aanndd
!
dead fetuses, early and late resorbing fetuses, and any abnormalities.
I The ovaries were examined for the number of corpora lutea. Each live |}
TThhee uutteerruuss ooff eeaacchh aanniimmaall wwaass rreewweeiigghheedd aafftteerr tthhee ccoonntteennttss wweerree rreemmoovveedd..
The ovaries were examined for the number of corpora lutea. Each live
1I fetus vos sexed, weighed, and exsmined for external abnormalities. Findings were recorded. fetus was sexed, weighed, and examined for external abnormalities. Findings were recorded.
1 ego 35 the evrin rd of he rig uterine orn, te Beginning at the ovarian end of the right uterine horn, the
i1 first sic fetuses, regadiess of sex, were selected for further first six fetuses, regardless of sex, were selected for further I11II evaliation. After the external examination was completed, the first, evaluation. After the external examination was completed, the first,
22778866..00001122
swao02eezs7
3MA00248297
1
1 e. 1 @HAZLETONuaonsronessenca nc. LABORATORIES AMERICA, INC. rmmm------ -8-
115544--115599
I 1
nr od 1 fetus rs. red ih 1a ad i 1 ove third, and fifth fetuses were identified with a tag and fixed in Bouin's
! Fourth, and sixth fetuses were eviscerated, tagged, and processed for 1
ssoolluuttiioonn ffoorr ssoofftt ttiissssuuee eevvaalluuaattiioonn ((WWiillssoonn,, eett aall,, 11996655)).. TThhee sseeccoonndd,,
fourth, and sixth fetuses were eviscerated, tagged, and processed for
I 1
sskkeelleettaall eexxaammiinnaattiioonn uussiinngg aa tteecchhnniiqquuee mmooddiiffiieedd ffrroomn tthhaatt rreeppoorrtteedd bbyy
SSttaapplleess ((SSttaapplleess aanndd SScchhnneellll,, 11996644))..
I 1
SSttaattiissttiicacla.l.AA~.naall.yysseess
1
MMeeaann mmaatteerrnnaall bbooddyy wweeiigghhtt gcaaiinnss ((DDaayyss 66--1166 aanndd 00--2200)),, ttoottaall ffoooodd
I ccoonnssuummppttiioonn,, ggrraavviidd uutteerriinnee wweeiigghhtt,, tteerrmmiinnaall bbooddyy wweeiigghhtt mmiinnuuss ggrraavviidd
1 erie vet, reoration fndece, pecan mates nd fetal vihiTity uterine weight, resorption incidence, percent males, and fetal viability
I 1
wweerree aannaallyyzzeedd iinn tthhee ffoolllloowwiinngg oorrddeerr.. LLeevveennee''ss tteesstt ffoorr hhoommooggeenneeiittyy ooff
I vvaarriiaanncceess ((LLeevveennee,, 11996600;; ODrraappeerr aanndd HHuunntteerr,, 11996699)) wwaass ppeerrffoorrmmeedd aanndd iiff
1
tthhee vvaarriiaanncceess pprroovveedd ttoo bbee hhoommooggeenneeoouuss,, tthhee ddaattaa wweerree aannaallyyzzeedd bbyy oonnee--wwaayy
I ccllaassssiiffiiccaattiioonn aannaallyyssiiss ooff vvaarriiaannccee ((AANNOOVVAA)) ((WWiirnieerr,, 11997711)).. IIff tthhee
I variances proved to be heterogeneous, a series of transformations was variances proved to be heterogeneous, a series of transformations was
I ppeerrffoorrmmeedd uunnttiill vvaarriiaannccee hhoommooggeenneeiittyy vwaass aacchhiieevveedd.. TThheessee ttrraannssffoorrmmaattiioonnss
I 1
wweerree:: lloogglyo,, ssqquuaarree ((xX22)),, ssqauarree rroooott ((Xx~9),, rreecciipprrooccaall ((1l7/X%)),,
1
aanngguullaarr ((aarrccssiinnee XX)),, aanndd rraannkk,, finn tthhaatt oorrddeerr.. IIff rraannkk ttrraannssffoorrmmaattiioonn
I wwaass. iinneeffffeeccttiivvee iinn rreemmoovviinngg vvaarriiaannccee hheetteerrooggeenneeiittyy,, AANNOOVVAA ooff rraannkkeedd ddaattaa
1 was comets. If MWA of wtrantored or trinsforsed ta vas was completed. If ANOVA of untransformed or transformed data was
I ssiiggnniiffiiccaanntt,, ODuunmneetttt''ss tt--tteesstt ((DDuunmneetttt,, 11995555 aanndd 11996644)) wwaass uusseedd ffoorr
1 Control vs. compndetrested ro sen compra. If HOW was oot control vs. compound-treated group mean comparisons. If ANOVA was not
1!I1!I1
ssiiggnniiffiiccaanntt,, tthhee aannaallyyssiiss wwaass ccoommpplleettee..
22778866..00001133
a3MMAA000022448229988
1I
I 1
@ !~HHA~ZL.~ ETrO~ NwLsAoenOa.ArToOnR,eEsSmAeMEs.,oCsA. n,NeC..
m----
1I 9 -
115544--115599
I 1
In aketion to the sb deta, amiss of covriame (COW) In addition to the above data, analysis of covariance (ANCOVA)
1
((WWiinneerr,, 11997711)) wwaass uusseedd ttoo aannaallyyzzee mmeeaann ffeettaall wweeiigghhttss.. TThhee lliitttteerr wwaass
I used as the experimental unit. used as the experimental unit.
1 Levene's tests and ANOVA were evaluated at the 5.06 one-tailed Levene's tests and ANOVA were evaluated at the 5.0% one-tailed
I pprroobbaabbiilliittyy lleevveell.. CCoonnttrrooll vvss.. ccoommpoouunndd--ttrreeaatteedd ggrroouupp mmeeaann ccoommppaarriissoonnss
1 ere evaluated at the .0 to-taiTed pranabiliy level. were evaluated at the 5.0% two-tailed probability level. ! Statistical references are appended to this report, and statisti-
Statistical references are appended to this report, and statisti-
I cally significant differences, as indicated by the aforementioned tests,
1
aarree ddeessiiggnnaatteedd tthhrroouugghhoouutt tthhiiss rreeppoorrtt bbyy tthhee tteerrnm ""ssiiggnniiffiiccaanntt"? aanndd//oorr aass
I ffoolnlaowwss::
I 1
5S++ == SSiiggnniiffiiccaannttllyy hhiigghheerr tthhaann tthhee ccoonnttrrooll vvaalluuee..
1
5- = Significantly lover than the control value.
S- = Significantly lower than the control value.
I Speciren, Ra Data, aid Fina) Report Storage
Speci.men, Raw Data, a6d Final Report Storage
1
AAlIl ssppeecciimneennss,, rraaww ddaattaa,, aanndd tthhee ffiinnaall rreeppoorrtt aarree ssttoorreedd iinn, tthhee
I 1
archives of Hazleton Laboratories Anerica, Inc.
I archives of Hazleton Laboratories America, Inc.
I 1
! 1 1 1
1I
1I
1I
22778866..00001144
aMAD024829
3MA00248299
I 1
I1 @HAZLETON usomrories mena ve.
1
mm---- S10-
- 10 -
!1 ners - wr, or !
RESULTS - MATERNAL DATA
115544--115599
1 Simic sans Clinical Signs.
! 1
SSuummmaarryy
cclliinniiccaall
ssiiggnnss
aarree
pprreesseenntteedd
iinn
Table
Table
1.
1.
! TTrreeaattmneenntt--rreellaatteedd
cclliinniiccaall
oobbsseerrvvaattiioonnss
were
were
noted
noted
In
in
the
the
Groups
Groups
1
44
aanndd
55
aanniimmaallss
dduurriinngg
ttrreeaattmmeenntt
aanndd
iinn
GGrroouupp
44
aanniimmaallss
posttreatment.
posttreatment.
I No Group rats survived the treatment phase. Clinical signs for Groups
No Group 5 rats survived the treatment phase. Clinical signs for Groups
1 4 and 5 antaals focluded hunched and thin appearance, Tonguid behavior, 4 and 5 animals included hunched and thin appearance, languid behavior,
I uurriinnee
ssttaaiinnss,,
aanndd
bblloooaddyy
ccrruusstteedd
eyes,
eyes,
eyelids,
eyelids,
rose,
nose,
mouth,
mouth,
legs,
legs,
paws,
paws,
I or genitals. Anorexia, ataxia, dyspnea, rough coat and pale appearance
1
Vers 2150 noted for several Group & or 5 rats. One Grow 4 rat aborted
were also noted for several Group 4 or 5 rats. One Group 4 rat aborted
! tthhiirrtteeeenn
ffeettuusseess
oonn
DDaayy
2200
pprriioorr
to
to
sacrifice.
sacrifice.
Alopecia was noted for
Alopecia was noted for
! 1
Ssoommee rraattss iinn eeaacchh ddoossee ggrroouupp aanndd tthhee ccoonnttrrooll ggrroouwp..
1
MoMorrttaalliittyy
! AAllll
GGrroouupp
5 5
ffeemmaalleess
wweerree
ffoouunndd
dead
dead
on
on
or
or
before
before
Day
Day
16
16
of
of
1
ggeessttaattiioonn
aanndd
tthhrreeee
GGrroouupp
44
ffeemmaalleess
were
were
found
found
dead
dead
on
on
or
or
before
before
Day
Day
17
17
! of gestation. All other animals survived to cesarean sacrifice on Day 20.
of gestation. All other animals survived to cesarean sacrifice on Day 20.
I1 BBooddyy VWeeitgghnttss
1
IInnddiivviidduuaall
aanndd
mmeeaann
body
body
weights
weights
and
and
body
body
weight
weight
changes
changes
are
are
! pprreesseenntteedd iinn AAppppeennddiixx 11..
Mean weight values and body weight changes are
Mean weight values and body weight changes are
1 presented in Tt 2. presented in Table 2.
! 1
DDuurriinngg
ggeessttaattiioonn,,
lloowweerr
than
than
control
control
mean
mean
body
body
weight
weight
values
values
! Wweerree
nnootteedd
iinn
GGrroouupp
5 5
bbeaggiinmniinngg
on
on
Day
Day
8
8
and
and
in
in
Group
Group
4
4
beginning
beginning
on
on
Day
Day
!I11
1122..
DDeeccrreeaasseedd
bbooddyy
wweeiigghhtt
ggaaiinn
during
during
gestation
gestation
was
was
noted
noted
in
in
Groups
Groups
3
3
22778866..00001155
3MMAA002042848330000
I 1
I11 @HAZLETON Nusome ronesmenos te:
ss
I
Su- - 11 -
154-159
I
and 4. The decrease in the Group 4 animals was significantly different
I included tn statistical evaluation. 1
tthhaann tthhee ccoonnttrrooll vvaalluuee.. BBeeccaauussee ooff hhiigghh mmoorrttaalliittyy,, GGrroouupp 55 ddaattaa wweerree rnoott
included in statistical evaluation.
I Food Consumption
~
1
IInnddiivviidduuaall aanndd mmeeaann ffoooodd ccoonnssuummppttiioonn vvaalluueess aarree pprreesseenntteedd iinn
I fopendix 22..
MMeeann
ffoooudd
ccoonnssuumppttiioonn
vvaalluueess
aarree
pprreesseenntteedd
in
in
Table
Table
3.
3.
1
Appendix SH decrassad food consumption values were noted for Groups
I 4 and 5 cSolmipgahrteldy tdoeccroenatsreodl foonodancdonasfutmeprtiDoany 8 of valuesgewsetraetinoont.ed Mfeoarn Grtooutapls
4 and 5 compared to control on and after Day 8 of gestation. Mean total
food consumption values for Groups 2, 3, and 4 were statistically
I1 comparable to control. Total food consumption for Group was not comparable to control. Total food consumption for Group 5 was not I deternined because of orally. determined because of mortality.
I 1
Gross PathSoulmoagryy gross pathology findings are presented in Table 4.
I YSoummgarroyssgroTsestopnasthowleorgey fnionteddingast arneecrporpessyentfeodr inanTiasballes 4f.ron the
No gross lesions were noted at necropsy for animals from the
1 control group or se Groups 2 and 3. Findings noted for Group 4 anil vere discolored Tiver, Kidney, and adrenals; enlarged adrenals; dilated control group or dose Groups 2 and 3. Findings noted for Group 4 animals were discolored liver, kidney, and adrenals; enlarged adrenals; dilated
1I rena bland vessel, and ed vaginal Gichorse. Findins rated for Group S aninats were reddened and/or distended lungs, enlarged and/or friable renal blood vessels, and red vaginal discharge. Findings noted for Group 5 animals were reddened and/or distended lungs, enlarged and/or friable
I liver, enlarged adrenals, discolored and/or thin glandular gastric
1
mmuuccoossaa,,
fflluuiidd
iinn
ssttoommaacchh
oorr
iinntteessttiinneess,,
eanndd
rreedd
vvaaggiinnaall
discharge.
discharge.
I 1
erine eignts
I Uterine WIenidgihvtsidual and mean uterine weights are presented in Appendix
1
3. SumrIynduivtiedruianel waenidghtmseanareutperreinseentewdeiginhtsTaalre 5.presented in Appendix
1II 3. Summary uterine weights are presented in Table 5.
22778866..00001166
Swaouzsesor
3MA00248301
I 1
I 1
HAZLETON visomronessemaine
I 1
m----------
Sie
- 12 -
115544--115599
I
Mean terminal body weights were comparable for Groups i, 2, and
i compared to control animal weights. There was an approximate 9% decrease 1
33,, bbuutt't`hthee mmeeaann tteerrmmiinnaall body wweeiigghhtt ooff tthhee GGrroouupp 44 ffeemmaalleess wwaass ddeeccrreeaasseedd
compared to control animal weights. There was an approximate 9% decrease
1I 1 the sean gravid uterine weights of the Group 2, 5, ard 4 mimals con pared to the control mean weight. For Grow 2, this may be attributeble in the mean gravid uterine weights of the Group 2, 3, and 4 animals compared to the control mean weight. For Group 2, this may be attributable
I1 one dim ith it early resending fetuses. Terminal body weight to one dam with eight early resorbing fetuses. Terminal body weight
1 Sinus gravid uterine weights were comparable for Groups 1, 2, and 3, but minus gravid uterine weights were comparable for Groups I, 2, and 3, but
I that weight was decreased in the Grow 4 animals compared to the control that weight was decreased in the Group 4 animals compared to the control
II
vvaalluuee..
I 1
RESULTS
RESULTS
=
-
CESAREAN
OATA
CESAREAN DATA
! 1
IInnddiivviidduuaall aanndd mmeeaann oovvaarriiaann,, uutteerriinnee,, aanndd lliitttteerr ddaattaa aarree
presented
presented
iinn
AAppepnenddiixx
44..
IInnddiivviidduuaall aanndd mmeeaann lliivvee ffeettaall ddaattaa aarree
1!
presented
presented
iinn
AAppppeennddiixx
55..
SSuummmararyy oovvaarriiaann,, uutteerriinnee,, aanndd lliitttteerr ddaattaa aarree
_
pprreesseenntteedd iinn TTaabbllee 66..
LJ
PPrreemE_a~rnncicycya RRaartetees,sr,orCCoRorropgororrtaaLuLLuuttteeesa,,, UUUtteteerrriiinnneeeImIImnpplplaalanntntaatattitiiooonnnss,s,, aaannnddd InIImpmplplalaannntttaaatttiiiooonnn
Preguancy Efficiency Pregnancy
rraatteess
wweerree
110000
ppeerrcceenntt
ffoorr
GGrroouuppss
11,,
22,,
@anndd
33,,
aanndd
85.7
85.7
percent
percent
ffoorr
GGrroouuppss
44
aanndd
55..
TThhee menmean nnuummbbeerr ooff ccoorrppoorraa lluutteeaa aanndd
tthhee mmeeaann nnuummbbeerr ooff uutteerriinnee iimmppllaannttaattiioonnss wweerree ccoommppaarraabbllee ffoorr aallll ggrroouuppss
aas5 wweerree mmeeaann iimmppllaannttaattiioonn eeffffiicciieenncciieess..
22778866..00001177
amaonzssscz
3MA00248302
1I
I1 EHAZLETONwsorsronss enon we.
1
I
m------ ne - 13 -
115544--115599
I I
FFeettaall VViiaabbiilliittyy,,.. WWeeiigghhtt,,...aan~dd SSeexx
I for the control group, but these differences were not statistically 1
MMeeaann rreessoorrppttiioonn iinncciiddeenncceess wweerree hhiigghheerr ffoorr GGrroouuppss 22 aanndd 44 tthhaann
for the control group, but these differences were not statistically
I1 Sinificant, The increased tcidarce in Grow 2 may be stiributable to ane dm with eight resorbing fetuses. Mean incidence of fetal viability significant. The increased incidence in Group 2 may be attributable to one dam with eight resorbing fetuses. Mean incidence of fetal viability
and percent males were comparable for Groups i-4. Mean live fetal
I1 weights of both sexes decreased with Increasing dose Tevel with Group 4 weights of both sexes decreased with increasing dose level with Group 4 I values significantly over than contr values significantly lower than control.
i sea pero: Fetal Development
1I Individual visceral findings are presented fn Append 5 fndivi- Individual visceral findings are presented in Appendix 6; indiviI dduuaall sskkeelleettaall ffiinnddiinnggss aarree pprreesseenntteedd iinn AAppppeennddiixx 77.. MMeeaann iinncciiddeennccee vvaalluueess
1 for visceral and skeletal findings are presented in Table 7 (based on for visceral and skeletal findings are presented in Table 7 Ibased on
! nnuummbbeerr ooff ffeettuusseess)) aanndd TTaabbllee 88 ((bbaasseedd oonn nnuummbbeerr ooff lliitttteerrss))..
1 Gross extarnal exesimation of fetuses at cesurean section Gross external examination of fetuses at cesarean section
I revealed are abrornal fetus from a Group 3 can. This fetus had 0 tal revealed one abnormal fetus from a Group 3 dam. This fetus had no tail
! and appeared to have no thoracic or lumbar vertebrae. However, no
1 Skeletal evaluation was done on this fetus so that Finding could not be skeletal evaluation was done on this fetus so that finding could not be
I verified. verified.
I1 Setetal exanination of the selected fetes revealed tht the incidence of skeletal variants vas comardble for the control group and Skeletal examination of the selected fetuses revealed that the incidence of skeletal variants was comparable for the control group and
I1 ented oro. lo sels] aoneles vere rotss, The fncdece of 1 visceral variants was markedly hier for Group 4 when compared to the treated groups. No skeletal anomalies were noted. The incidence of III11 visceral variants was markedly higher for Group 4 when compared to the
22778866..00001188
Swaouzsesos
3MA00248303
I 1
11
HE AZE LETRO-- N ueommonesaves =ne.
rn
I
154-159
I 1
ccoonnttrrooll ggrroouupp ((5500 ppeerrcceenntt vvss.. 55..5566 ppeerrcceenntt)).. HHoowweevveerr,, oonnllyy ttwwoo GGrroouupp 44
1
lliittteterrss wweerree aavvaaiillaabbllee ffoorr eevvaalluuaattiioonn ccoommppaarreedd ttoo ssiixx ooff tthhee ccoonnttrrooll
I ggrrooupp.. VVaarriiaannttss nnootteedd wweerree ddiillaatteedd rreemnaall ppeellvveess ((GGrroouupp 22)),, ddiillaatteedd
1 ureters (Groups 1 and 4), and incompletely descended testes (Group 4). ureters (Groups 1 and ~), and incompletely descended testes (Group 4).
I Cleft patate was found in two of six Group 4 fetuses examined by Cleft palate was found in two of six Group 4 fetuses examined by
Wilson sectioning. That anomaly was noted in one fetus from each of the
1I two Hitters fran rich the fetuses selected far visceral examination vers two litters from which the fetuses selected for visceral examination were I derived. No other visceral anomalies were observes. derived. No other visceral anomalies were observed.
1I
1I
1I 1I
1I
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I 1
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22778866..00001199
awaoo2ees0s
3MA00248304
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22778866..00002200
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22778866..00002211
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22778866..00002222
swsorzissn 3MA00248307
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22778866..00002233
3MA00248308
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22778866..00002244
33MMAA0000224488330099
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22778866..00002255
3MA00248310
I Cu- - 21 I1I tse Key to Table 6
Key to Table 6
154-159
I 1
PPrreeggnnaannccyy RRaattee ((ppeerrcceenntt)) == ((.nuummbbeerr ooff pprreeggnnaanntt rraattss//nnuummbbeerr ooff rraattss mmaatteedd))
x i00.
I1 Sti tate (reap) = (uber of rats suring 0 tay Bymaber of Tats pTacedon study) x 100. Survival Rate (percent) = (number of rats surviving to Day 20/number of rats placed on stud~)""x i00.
I1 Mean tnplantat on Efficiency (percent) = Group mean of ({ plantations re Ea Fr fob) Mean Implantation Efficie.cy (percent) = Group mean of ([ implantations
per litter/corpora lutea per litte~ x 100).
1
Men Resorption lncidance (percent) = Group mean of ({resorptions per
MealniTtEttReeerrs//oiirmmpppt'lilaaonn.ttaattIiinoocnnissdeppn'ecerer l(itpteVietrtercr]]e"nxtx")"l1O0:00))..Group mean of ([resorptions per
I MMeeaann
IInncciiddeennccee
ooff
FFeettaall
MMoorrttaalliittyy
(p(eprecrecenntt))
=
=
Group
Group
mean
mean
of
of
(Idead
([dead
1 ee atonsrion paTr ar 100) fetuses per litter/impla.tations per I Mean tncidence of Fetal Viability
litter ]'k
(percent)
=100G)r.oup
mean
of
({live
1 Tomtom Sar Tr 0h: Mean Incidence of Fetal Viability (percent) = Group mean of ([ live
I
ietus6s per li'tter/impla"tation's~ p'er l'itter] x 100).
I
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22778866..00002266
aMA00248311
3MA00248311
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22778866..00002277
-- 3MA00248312
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22778866..00002288
-- 3MA00248313
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22778866..00002299
3MA00248314
I Sos 25-
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I Appendix 8
115540--115599
I 1
Pilot Rat TerRARaepetfpfoeeelrnrodeeginnyxcceeSss8tudy of T-3352
Pilot Rat Teratology Study of T-3352
1
SSTTAATTIISSTTIICCAALL MMEETTHHOODDSS/!LLAABBOORRAATTCORRYY PPRROOCCEEDDIURREESS
I 1
ABBgaarrrittclleuettlttt,,ureMM.. aSSn..d,, A""pSSpaolmnieeedEExxaaBmmippollleeossgy.oo"ff SSttJaa.ttiissRttoiiyccaaalll MMSeetttahhtooiddssst. ooffSoRRcee.sseeaaSrrucchphplii.nn
I AI1gVV:r:i11c33u77-l-11t88u33r,,e 1199a33n77d.. Applied Biology." J. Royal Statist. Soc. Suppl,,
1
RDDerrvaaippseeirr,t,edNN".., RRT..echaannnddoreWWt..riGrc~..s,HHuu1nn1tt:ee2rr3-4((011.9%699)),, ""TTrraannssffoorrmmaattiioonnss:: SSaommee EExxaammpplleess
I Revi sited", Technometrics, 11:23-40.
1
TDDruuennannetettmtte,,ntsCC..wiWWt..h,, a ""CAAonMMtuurllotlt.ii"pplleeJ.CCaoAnmnpp.aarrSiitssaootnn. PPArrsoosccoeecdd.uu,rree50:ff1oo0rr96CC-oo1mm1pp2aa1r,riinn1gg955SS.eevveerraall
Treatments with a Control." J. Am. Star. Assoc., 50:1096-1121, 1955.
I 1
BDDiuuonmmnmeeetttrtti,,cs,CC.. 2WW0..:,,482""-NN4ae9ww1,TTaa1bb9ll6ee4ss. ffoorr MMuullttiippllee CCoommppaarriissoonnss wwiitthh aa CCoonnttrrooll..""
Biometrics, 20:482-491, 1964.
I Gw6aainmteehss,,UnPPe..quAAa..l,, aaWnn'dds HHoo"wwaeenl|d/llo,,r JJ..VarFF..i,,anc""ePPsaa:iirrwwiiAssee MMMouunllttteiippllCeearCClooommppaaSrrtiiussdooynn."PPrrooccJee.dduurrEeedss.
wSSitttaahttiissttU..n,,equ11a::l111133--N'11s2255,,an11d99/77o66r.. Variances.- A Monte Carlo Study." J. Ed.
I 1
LCLeoevvneetnnreei,,butHHi..o,,ns""RRootbbouussPttroTTbeeassbttisslitffyoorr aEEnqqduuaallSiitttaytyisootfficVVsaa,rriiaaSnntccaeenssf,,o""rdiinnUnIIi..veOOrTlskkiiitnny eeddPiirtteeesdds,,
I CPaolnotFRrIiAGblATtuEotS,i,on1s960t.Toom, Probability an.d SSntaat.ltaitstiicces,, Stanford University Press,
1
SSitntaapptllheeess,, KROR..H-AEE..liazannaddrinSSccRhhenndeellllS,, MVVe..thLL.o.,,d ""fRRoeerffiinnFeeemmteeannlttssSoiinnne.RR"aappiiddStCCallieenaarriiTnneggcnTToeelccohhgnnyii,cc
I i33n99::66t11h--e6633,,KOH1199-66A44l..izarin Red S Method for Fetal Bone." Stain Technology,
1I A WTTieeclchshnoniniq,quueess,J., TTGhh.ee UUannniidvv.. WooaffrkCCahhniiycc,aaggooJ.PP,rreessessd,,itCoChnriiscc.aaggoos,Ter1a9t6o5l,ToEobs qppyph:.e 2P5r1i-Bn2Rc7iI7pT.loes oand
1I
HWWeiibnnreearr,,r-HBiB..TT,JJ..,,RoSSotctaattiissChttoeiiccaaSllTO,PPrriinncciippTO lloeesso iinn EExxoppeeerrriiimmneeennntttaaalllfeDDesessiii.ag~nnn,, 22nndd EEdd..,,
McGraw-Hill, ~.Y., Chs. 3-10, 1971.
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