Document BRaboBbjqo33x3zK66w00b75w
AR 26 - 0660
N-Et FOSE alcohol
Teratology - [ b
|
|
| @HAZLETON
|
Eo EERTeeth wht Bo 2190 484
, LE an
Fo
t ism
RAT TERATOLOGY STUDY T-3352
FINAL REPORT
Submitted to
3M Company St. Paul, Minnesota
sazeh 21, 1984
000376
@HAZLETONuiconsronesavers ne
OFFICE OF QUALITY ASSURANCE
Project Title: Rat Teratology Study Project No.: 154-161
Quality Assurance inspections of the study and review of the final report
of the above referenced project were conducted according to the standard
tohpeergaetnienrgalprorceeqduuirreesmenotfsthoef tOhfefiGcoeodofLaQbuoalriattyorAyssPurraactniccee anrdegualcactoirodnisngthtaot
were issued on December compliance on and after
22, 1978, by the Food and Drug Administration June 20, 1979. Findings from the inspections
for and
ofninatlhe rfeopolrltowirnegvideawtewse:re reported to management and to the study director
Inspections/Review Protocol 6/15/83 Inspection 8/3-5/83
Report Review
2/11,12,14,15/84
Findings Reported 6/15/83
8/5/83
2/24/84
Inspector/Reviewer E. Burroughs E. Burroughs
P. Miller
Director ny Office of Quality Assurance
00037;
@HAZLETON
SUBJECT: RPartojeTcetratNoo.log1y54-S1t6u1dy We, the undersigned, hereby declare that the work was performed
under our supervision, according to the procedures herein described.
Study Director:
Laboratory Supervision:
HuTWy ETZEL, PRD
Life Sciences Division
Teratology:
DGEiORpGE1dnatAe.,:BAUmReDrOiCKc,an PBhooa.rd Lifoef STcoixeinccoelsogyDivision
RLRiUfTseH kSS.ci$eOnUcReLDsODe,Difv5i.os5.ieon
Study Coordinator:
BT RR RE Life Sciences Division
bm
000378
@HAZLETON
TABLE OF CONTENTS
Page
SUMMARY
1
INTRODUCTION
3
CONTROL AND TEST MATERIALS
3
TEST ANINALS,
4
METMHaOtDiSng Period
55
CGroomupposundandPreDpoasargaetioLnevaenlds Administration
65
CMeastaerrenaanl SOabcsreirfviacteions and Records
77
SVkieslceetraall EExxaammiinnaattiioonn ooff FFeettuusseess
88
STtiastsiusetiPcraelseArnvaaltyiosnes
98
Specimen, Raw Data, and Final Report Storage
n
REMSoUrLTtSali-tyMAaTnEdRNACLlinDiAcTaAl Observations Body Weights and Food Consumption
22 12
GUrtoesrsinePaWtehioglhotgsy
13
RESPUrLeTgSnan~cyCESRAatReEsA,N DCoArTpAora Lutea, and Uterine Implantations Fetal Viability, Weight, and Sex
11 1
Fetal Development.
u
TABTLabElSe 1 - Summary of Maternal Clinical Observations Table 2 - Mean Maternal Body Weights and Body Weight Changes
716
TTaabbllee 43 -- MMeeaann TMeartmeirnnaall BFoodoyd WCeoingshutmsp,tioGnravid Uterine Weights, 18
Table 5 - SanudmmaTrerymionfalMatBeordnyalWeiGgrohstss Key to Tables 6-14
Pathology
Findings
210
Table 6 ~ Summary of Mean Ovarian and Uterine Data
22
000379
@HazLETON
TABLE OF CONTENTS - CONTINUED Page
TABLES - CONTINUED
Table 7 Table 8
- Summary of Mean Litter Data - Summary of External Findings
23 2
Table 9 - Summary of Visceral Findings Table 10 - Summary of Skeletal Findings
25 2
Table Table
11 12
-
Incidence Incidence
of of
External Visceral
Findings Findings
Per Per
Litter Litter
21 28
Table Table
13 14
-
MIenacnideInncceideofnceSkeofletEaxlterFnianld,ingVsiscPeerralL,ittanedr
Skeletal
2
Findings Per Litter
0
APPENDICES.
Appendix 1 - Individual Key to Appendices 2, 3,
Clinical and 4
Signs
3 2
Appendix
2
-
Individual and Mean Body Weight Changes
Maternal
Body
Weights
and
33
Appendix Appendix
3 4
-
Individual Individual
and and
Mean Mean
Food Consumption Terminal Body Weights,
Gravid
31
UGrtaevriidneUtWeeriighntes,WeiagnhdtsTerminal Body Weights Minus
a
Appendix Appendix
5 6
-
Individual Individual
and and
Mean Mean
Ovarian and Litter Data
Uterine
Data
a5 49
Appendix Appendix
7 8
-
Individual Individual
Visceral Skeletal
Findings Findings
in in
Fetuses Fetuses
53 61
Appendix 9 - References
63
eoe3so
@HAZLETONN Se i Rr n R aS eS I T nrLTm T -- trTa aL AT T Ar --arr I t maT 4aeraI nT a otriee eannsin C0 rats on presumed gestation Days 6-15. A fourth group (Group 1) of
0OBIBY
@HAZLETON
sen
Z2-
156-161
The data from this study show that T-3352 1s not teratogenic in rats at doses as high as 30 mg/kg of body weight, although that dose
produced deleterious effects in the dams.
000382
@HAZLETON $300 LEESBURG TumnRE NAVGA 22180 USA
FO.
-3-
INTRODUCTION
This study was designed to evaluate the embryo/fetal toxicity and teratogenic potential of T-3352 when administered by oral gavage to pregnant rats during the period of fetal organogenesis. On July 18, 1983, breeding of the rats was begun, and cesarean sections were completed on August 11, 1983. The study was conducted according to a protocol designed to satisfy existing guidelines of the Food and Drug Administration as well as Good Laboratory Practice Regulations. This report presents and discusses the methods and results from the study.
CONTROL AND TEST MATERIALS
The vehicle and control material, Duke's Corn 011 (Lot No. 80275), a slightly viscous, yellow 1iquid, was received from the C. F. Sauer Co., Richmond, Virginia, and was stored at room temperature.
The test material, T-3352, large chunks of off-white compound, was received from the sponsor on January 5, 1983, and was stored at room temperature. The test material was assumed to be 100% active compound. Information on the methods of synthesis, stability, as well as data on composition, or other characteristics which define the test material, are on file with the sponsor.
000353
@HAZLETO|N
--
-a-
154-161
TEST ANIMALS
TWo hundred Fifty-nine (130 male and 129 female) sexually mature, cesarean-derived Sprague-Dawley Crl:CD (SD)BR rats were received from Charles River Breeding Laboratories, Inc., Kingston, New York, on June 29, 1983. The rat was selected for use in this study because historically this species has been used in teratology studies and 1s required by appropriate regulatory agencies. The animals were housed individually in elevated stainless-steel cages and acclimated to laboratory conditions for approximately three weeks prior to initiation of the study. During this time, one female rat was euthanatized due to an unthrifty appearance and one female was found dead. Following an examination by a staff veterinarian for health status, 120 rats/sex were Placed in breeding on July 18, 1983, and the remaining 7 rats/sex were placed in breeding one day later due to caging limitations.
The rats were housed one male and one female per cage during breeding. Following confirmation of mating, the females were uniquely identified by ear tags and individually housed in elevated stainlesssteel cages. Food (Purina Rodent Laboratory Chowe 5001) and tap water (via an automatic watering system) were available ad libitum. The mean room temperature + the standard deviation was 73.6F + 1.68 and the mean relative humidity + the standard deviation was 59.4% + 3.44 during the study. A twelve-hour light/dark cycle was maintained.
000384
@HazLETon
age
154-161
METHODS
Mating period
During the mating period, one female was paired with one male until mating was confirmed or until two weeks had elapsed. A sufficient number of mated females, during the course of this study, were obtained after four days of cohabitation and mating was discontinued. Daily
vaginal examinations of each female were performed to detect the presence
and viability of sperm or the presence of a copulatory plug. The day of observation of sperm or copulatory plug was designated as "Day 0% of
gestation.
Groups and Dosage Levels
Upon confirmation of mating, each female was assigned to one of
the following groups by use of a table of random numbers (Cochran and
Cox, 1957).
Group
Number of Females
a/Dkoas/ed?ay
1
2
25
0
2
1
3
2
10
4
25
30
Based on individual animal body weights at each weighing interval
pdruersiunmgedthgeesdtoastiinogn. period. Animals were dosed on Days 6 through 15 of
Dose levels were selected based upon information obtained in a range
finding study. The results from that study were reported separately. 000385
@HazLEToN 5200 -CE80TuUmRG nn AG22180 U3 8
_--
"6-
All males and a1) remaining females were sacrificed via carbon dioxide asphyxiation and discarded without necropsy once a sufficient number of matings was confirmed.
CP omporundeparaa ndAt dminiistoratn ion Suspensions of the test material in the corn ofl vehicle were
prepared on a weight per volume basis. The compound was First ground in a mortar and pestle into a workable powder. The required amount of compound for each level was then weighed on an electronic Arbor 126 balance and transferred to a 7 ml tissue grinder. Approximately 3 ml of corn oil was added and the test material was ground into a fine suspension. This suspension was transferred to a precalibrated beaker' and any remaining compound in the tissue grinder was rinsed into the beaker. Additional corn ofl was added to the suspension to produce the desired concentration and the suspension was mixed on a magnetic stirrer.
Females were given the appropriate dosing suspension or vehicle by oral intubation on a daily basis beginning on Day 6 and continuing through Day 15 of presumed gestation. The dose administered to each female was based on the most recently recorded individual body weight. The test material was administered orally because of the relative ease and accuracy of dosing.
one female was euthanized following mating confirmation due to alopecia.
P
tDhuee tcoompthoeundamowuanst transferred to one
dopifrveiccdaoelmdipbourinandtteodrebfqeouauikrreerdt.istsouepregprairnederGsrouapnd4
ssuubsspeeqnsuieonntsl,y
00038
@HazLETo|N
200 EERToh sos moe 32180 038
ann
Sa-
Fresh suspensions of the test substance for dosing were prepared weekly. Samples of each test mixture as well as the vehicle were sent to the sponsor for analysis. A 10 gram sample of compound and a 30 ml
sample of corn ofl were taken on August 4, 1383, and stored at room temperature.
Materna)Observationsand Records
.
AT) animals vere observed twice daily for mortality and moribun-
dity (from day of receipt through animal sacrifice). The females were
also examined once daily for clinical signs of toxicity and pharmacologic
effects (throughout gestation). Individual body weights were recorded at
inftiation and on Days , 8, 12, 16, and 20 of gestation. Food
consumption during gestation was determined on Days 6, 8, 12, 16, and 20.
Sacrifice at Tine of Cesarean Sectioning A gross necropsy was performed on all females. Prior to
terminal sacrifice and cesarean section on Day 20 of gestation, all
females were assigned random numbers so that all personnel performing cesarean sections and/or external, visceral, or skeletal examinations of the fetuses were unaware of the dose level from which the animals were derived.
On Day 20 of gestation, all females were weighed and sacrificed
by carbon dioxide asphyxiation. The uterus from each female was excised, weighed, and examined for the number and placement of implantation sites,
number of 1ive and dead fetuses, number of early and late resorbing 000387
@HAzLEToN,
200 AER Tomek win ogo 12105 4
Toe
a.
fetuses, and any abnormalities. The ovaries were examined for the number of corpora lutea. Each female was examined grossly for any abnormalities.
Each fetus was sexed, weighed, examined externally, and tagged for identification. Beginning at the ovarian end of the left uterine horn and continuing past the cervix into the right uterine horn, the first available fetus was fixed in Bouin's solution for visceral evalua tion. The next tuo fetuses were processed for skeletal evaluation. This process was repeated until all available fetuses were selected for evaluation. Dead fetuses were discarded without examination.
Visceral Examination of Fetuses Approximately one-third of all live fetuses from each litter
were fixed in Bouin's solution and sectioned by the Wilson Technique for assessing soft tissue development (Wilson, 1965). During examination of the fetuses' viscera, particular attention was paid to examination of the eyes, palate, and brain. Stainless-steel razor blades (Gem) were used for sectioning procedures.
Skeletal Examination of Fetuses
The remaining fetuses were eviscerated and placed in 95% ethyl alcohol. After proper fixation, dehydration, and maceration, the skeletons were stained in 1% KOK, with an alizarin red solution and cleared in glycerol (modified Staples and Schnell, 1964). This evaluation included exanfnation of the skull, long bones, vertebral colum, rib cage, extrenfties, and pectoral and pelvic girdles. Bone alignment and degree
of ossification were assessed.
000385
@HAZLETON
Ce-
154-161
Tissue preservation The following are the procedures for preservation of the various
tissues: (1) The uterus and ovaries of each animal were preserved in 10%
neutral buffered formalin; (2) The fetuses examined by Wilson's technique were placed in tissue capsules, preserved in 95% ethyl alcohol, and sealed in plastic bags after sectioning; (3) Fetuses stained for skeletal examination were preserved in plastic bags containing a glycerol:ethyl
bacterial and mold growth. alcohol (1:1) solution with several crystals of thymol to retard
Statistical Analyses
total
Maternal body
food consumtion
weight changes (Days 6-8, 6-16, 16-20, and 0-20),
(Days 7-8, 7-16, 17-20, and 0-20), gravid uterine
weight, and terminal body weight minus gravid uterine weight data of the
control group were compared statistically against the data of the
compound-treated groups of the same sex.
order:
Analyses of the above data were performed in the following
Levene's test for homogeneity of variance (Levene, 1960; Draper
and unter, 1963) was performed and 1f the variances proved to be homo-
geneous, the data were analyzed by one-way classification analysis of
variance (ANOVA) (Winer, 1971). If the varfance proved to be hetero-
geneous, a series of transformations was performed until variance homo-
geneity wes achieved. These transformations were logq. squsre (x2),
square root ox, reciprocal (1/X), angular (arcsine x, and
rank, in that order. If rank transformation was ineffective in removing
000389
@HAZLETON 525 wetBoRG Tum vis VAG T5183 US4
-
"0-
variance heterogeneity, ANOVA of ranked data was completed. If ANOVA of untransforned or transformed data was significant, Dunnett's t-test (Dunnett, 1955 and 1964) was used for control vs. compound-treated group mean comparisons. If ANOVA was not significant, the amalysis was complete.
Data transformations are designated throughout this report as Follows: A = Data analyzed following logyg transformation.
8 = Data analyzed following square (X2) transformation. = Data analyzed following square root (X%) transformation.
0 = Data analyzed following reciprocal (1/X) transformation.
= fDoartamatiaonn.alyzed following angular (arcsine X% transF = Data analyzed following rank transformation.
Mean fetal body weights per litter were statistically analyzed as follows: Bartlett's test for homogeneity of varfances (Bartlett, 1937) was performed by one-way classification of covariance (ANCOVA) (Winer, 1971). If ANCOVA was significant, control vs. treatment group comparisons were analyzed using the Games and Howell Modification of the Tukey-Kramer honestly significant difference test (Games and Howell, 1976).
Tests for homogeneity of variances, ANOVA, and ANCOVA were
evaluated at the 5.05 one-tailed probability level. Control vs.
compound-treated group mean comparisons of the above data were evaluated
at the 5.0% two-tailed probability level.
000390
@HAzZLEToN
-n-
154-161
In addition to the above data, fetal viability was analyzed by nonparametric one-way ANOVA (Kruskal and Wallis, 1952, 1953; Miller, 1966). The litter was used as the experimental unit. The number of fetuses exhibiting skeletal variants of the rib cage and bone alignment and the total number of fetuses affected by skeletal variants were analyzed using the Cochran-Armitage test for linear trend in proportions (Cochran, 1954; Armitage, 1955; Fleiss, 1981) and Fisher's "exact test (Fisher, 1950). If a significant trend was noted, the results of Fisher's "exact" test were evaluated at the one-tailed, 5% level. If a significant trend was not observed, or if there was a significant trend with severe departure from it, the results of Fisher's "exact" test were evaluated at the two-tailed, 5% level. When using these statistical tests on indices, the actual proportions prior to conversion to percentages were the data that were analyzed.
Statistical references are appended to this report, and statistically significant differences, as indicated by the aforementioned tests, are designated throughout this report by the term "significant and/or as follows:
S+ = Significantly higher than the control value. S- = Significantly lower than the control value.
Specimen, Raw Data, and Final Report Storage AN specimens, raw data, and the final report are stored in the
archives of Hazleton Laboratories America, Inc. 000391
@HAzLETON
cz
154-161
RESULTS - MATERNAL DATA
Mortality andClinica)Observations
Individual clinical observations are presented in Appendix 1. A
summary of clinical observations is presented in Table 1. No animals were found dead or sacrificed in extremis during the
study. Clinical observations were considered incidental. These
observations included hunched and/or thin appearance, languid behavior,
anorexia, soft feces, alopecia, and rough haircoat.
Body Welahts and Food Consumption
Individual and mean body weights and body weight changes are
presented in Appendix 2 and Table 2, respectively. Individual and mean food consumption values are presented in Appendix 3 and Table 3, respectively.
Evaluation of the body weight changes revealed a significant
decrease in body weight gain during treatment (Days 6-15) for the Group 4
fenales, resulting fn a significantly lower overall body weight gain
during gestation. Group 3 females also gained less weight than control females during gestation, although that finding was not statistically
stanificant. Body weight gatns during the nontreatment phases (days 0-6 and 16-20) were comarable between the control and compound-treated groups.
000392
@HAazLETON
-13-
154-161
A decrease in overall mean food consumption was noted in the Group 4 females after Day 9 of gestation. Mean total food consumption values for Group 4 were significantly lower than control for Days 7-16 and 17-20. Slightly lower mean food consumption values were noted for Groups 3 and 4 over Days 13-16 and 0-20 and for Group 3 over Days 7-16. AT other food consumption values were comparable to control.
Uterine Weights
Individual and mean terminal body weights, gravid uterine weights, and terminal body weights minus gravid uterine weights are presented in Appendix 4 and Table 4, respectively.
Gravid uterine weights were comparable between the control and treated groups. Terminal body weights were decreased and terminal body weights minus gravid uterine weights were significantly decreased in the Group 4 females when compared to control.
Gross Pathology
A summary of maternal gross pathology findings is presented in Table 5.
Gross pathology findings noted at necropsy were considered incidental.
000393
@HAZLETON,
-1a-
156-161
RESULTS - DATA OBTAINED AT CESAREAN SECTIONING
Individual and mean ovarfan and uterine data are presented in
Appendix 5. Individual and mean litter data are presented in Appendix 6. Individual visceral and skeletal findings in fetuses are presented in Appendices 7 and 8, respectively. Summary ovarian and uterine data are presented in Table 6. Summary litter data are presented in Table 7. Summaries of the external, visceral, and skeletal findings are presented in Tables 8 through 14.
Pregnancy Rates, Corpora Lutea, and Uterine Implantations Pregnancy rates, number of corpora lutea, and
efficiencies were comparable for all groups.
implantation
Feta) Viability, Weight, and Sex
The mean incidences of early, late, and total resorptions, fetal 105s, and the number of dead fetuses were comparable between the control and treated groups. The mean fetal weights of the Group 4 males and females were significantly lower than their respective controls. The percent of male fetuses was 49.54%, 51.24%, and 51.20% for Groups 2, 3, and 4, respectively, and 53.26% for the control group.
Feta) Development
The percents of external and visceral variants and anomalies in fetuses were comparable between the control and treated groups. Gross external examination of fetuses at cesarean section revealed one Group 1
000394
@HAzLETO|N
Tm
154-161
fetus with an undeveloped tail, one Group 3 fetus with a short trunk and
no tail, one Group 3 fetus with a cleft palate, and one Group 4 fetus with an underdeveloped tail.
Cryptorchism was noted in two Group 1 fetuses and in one Group 3
fetus examined viscerally by Wilson's sectioning. One fetus from Group 3 was noted to have fused kidneys. No other visceral anomalies were observed. Visceral variants consisted mainly of dilated renal pelves and distended ureters in Groups 1 and 2 fetuses.
No skeletal anomalies were observed. Comparing the number of fetuses with skeletal variants (treated groups versus control) showed that the number of fetuses affected by skeletal variants was not significantly different than control for any group. However, the number of bone alignment and rib cage variants in fetuses derived from Group 4 dams, animals in which toxicity was observed, was significantly higher than control fetuses.
000395
|
Sumaryhoef rteoronnnohtHe1iaycarsTerAvRations
Tn
Buea; sore eel aokreo: T0m greitreaseTeHS t At F--= e TwFSl aSlsed
RooopmemeeerrrrioOocfFf kfeTemmaireemsisraefptxoeemuainntedose2gs0t soorrs
5U03E) 42 0) 20) EAE 2BE3E0 H2R0 H20D0) 2B0E0 51G3)) 12)0 2an0 a210w0) 000 0000 0a0
niGnneicuhteas ty
a}i
@8
|| RoRSiuopmfetMiiersco
FE '
S\ oe
aa
o syn
0=
&OTrEaetreatdiiocantetottehse sTurmveerroosfpaanntteFsewtlteh tht particular fineg.
<g 882
Hn HaterRso)t TBearyseIoStToaHytSesed2nyd oortdySwieidght changes
en
ty tant
poush
Foannt PgoEw:RE otneyh wgasd
sn eta (a)
. " W3n 2m%s m3e a3ma
` . W5s w5ma m5ew w3e
. " w5w twhns m7e w5w
" w%e tmH a mow e waw
.
" w%n mi)e siee w5ma
54
Wen change (4)
" os
s5e w5e w4w w5Ha wn am owe oa
aoh
aseko oaaRn owwen 3a%m
6W"-ei1hn6F
wWS47.aa7h8 a5wWm1.ee08 dkwna.ehme a1Bw9rh.n3s35
s XK pInrtiicattersthie ample Tze on Ch msn clcuTa: tons were based. Only pregnant fmsles sare sed1 mean
2
33
|
|
InDtaeyrsval
os
w
7-4
w
9-12
w:
146
"
1-20 we
7168
we
o0-20F
"
MeaRnatMaTteerrantaolloTgFayoboldSetuC3doynsuofmpt1i-o3n352(3)
s0rmoawrks1
rTmoaw/k2g
G1r0omugp/k3g
12.a7
1E2l9
1321.05
231.98
i3
u30.62
E1l8.93
820).75
21a3.9
s2ay
28a5.40
28.2
1a04.56
1203.76
10E0).76
221.40
2a02.10
1288.23
aErl m
43a5.50
a2na
1501600
0Gromwarkg
1E3F0).34
236.60
1na
8i.45
92.475
5:
1132.645
'
2n99.16
W: cIanldciuclaatteisonst.he sIanmvpalleidsifzoeodonconWshuimcphtitohne vamleuaens cwaelrceulnaottionIsnclwuedreed biansedm.ean Ocnallycurpartejgonnsa.nt females were used fn mean g2 >Q)
Hea Terminal Body etahtWsih.nTGsrearrctladavt(TioeneraSint4ryveotfBone1sh3,5es2nd Terniol soy etgnes
san
arnomiana
ftTiomrtom
om: g *
25s.16
[E: N .
we5n
10ms g x
0.30
0 m`ins "
u%ss
wertarattehio
GranTetesromBnianritniteytsetae
8w s
sae
na
mns
"an
m%a
w% o
05.5
.
: aIntdiltaittesiotne sample iis on wAICH the man calculations were based. Only pregeant female sere used 1 man
88
SumaryRaotf TMaetreartnoal)oTgaybGlreoSstsu5dyPaotfhol1o-g3y352Findings
190-161
ORGANM0 DESCRIPTION MNoummbbeerr owfithaninmoalgsrosesxampiantehdology wDeark red focal areas veIrrregular shape Lobes adhered to one another KioPneelxv(iss)dilate
oweayvs(tiiecs) clear
cerCvoinxtained yelloutsh-green viscous UTDEiRsUSt/eUnTdEeRdIwNEithHORcNlear fluta
matertal
Lt Group: H2e aBwE wWmy w00m) aTwa
'
)V
.
vos
11
8:
m
:
m
() = Finding present tn nonpregnant females.
33g a32 3
Jae
Key to Tables 6-14
150-160
Pregrante(aperncecnt)y- 1(0n0u.mber of pregnant rats/mumber of rats inseminated) x Survival Rate (percent) - p(lnaucmebderonofsturdaytsat siunrivtiivaitnigon)tox 1D0a0y. 20/mumber of rats Mean Implantation Efficiency (percent) - Gcorropuopra.melaunteaof pe(r[iTmipcltaenrt]atxio1n0s0)p:er 1itter/
Mean Incidence Mean_Inciden Mean Incidence
of Resorptions
(percent)? - Group mean of ([resorptions per litter/ implantations per litter] x 100).
f Fetal Mortalit:
reent;
~- Group mean of ([dead and resorbing fetuses per litter/ implantations per litter] x 100).
of Fetal Viability
114129: FA Wiis td reent;
=Group mean of ([live fetuses per 100).
Mean Incidence of External Variants cent) - eGpnxeruarommubipe"nrVeimdtetaee"norxfteiorftn"nafel(tl[ueynsx)uetmsebxrenr1a6pl0eo)rf.varf1ie1attnuttseser/s
Mean Incidence of External Anomalies (percent) - npGeruromubpeTritmteea"rnof wioftfhe(te[uxnstueemsrbnear)peoarfnofnleaitituetsseesrs
Mean Incidence of Viscers] Variants (percent)
examined externally] x 100).
- pGerroup11m%etaenr woifth([Vniusmcbeerralofvafreitaunstess
nexuammibneerdovfiscefreatlulsye)s x 1p0e0r). 11tter
Mean Incidence of Visceral Anomalies (percent) - pGerroupJitmteearn wiofth (V[insucmebrearl oafnofmeatluiseess
number `of fetuses per 1tter
-
Mean Incidence of Skeletal Variants
(percent)
examined viscerally] x 100).
- pGerroupitmteearn woifth([snkuemlbeetralofvarfietaunsieess
nexuammbienred osfkelefteatlulsye]s x 1p0e0r). 11tter
Mean Incidence of Skeletal Anomalies
(percent)
number of fetuses per 1itter - Group mean of ([number of fetuses per litter with skeletal anomalies/ examined skeletally] x 100).
# Values calculated separately for early, late, and total resorptions.
000401
SomarRyeofTeersitnatDToanerSioeaayandartTerEiAnSg ota
an
|
RanbbearooFfprroemsteest. femtes
Or Goir a 2 som ow a
SnFurreavinrveacflyraFFeoee5nthcurving to oy 20
Wsg3 ooownwRnx uBn aa
Yanttoromraeetr neorts: Ey arptions
Bw oweDwe wwee
TUote rTerepelson
oo0s8s wNh hONo0E) gbm
InHHedeeiakceIsnpccEliohadtdneuetnlnacacetteioeosoffnoSnawaker3etrrgeeursneosritrpsittt3ieloronnbah(s5ya):
aTee eGm umane nwae 8.8
Yen Tctoeneof tateTeveation
OHXoroem a0% abni
#0 Tat resorption was meted for femal No. 2128, therefore, the actu mean vs 0.00,
882 8
RaStumTaerryatoofloTgNayeaeSntuL7diyttoefr 1d-a3t3a5s2
50161
Mean number of:
tose Leven (maGjrkogw):: 01 12 wo3 W4
Fetuses: Idieaed
20s0 o0w0s w0e0e e0o0
InMHgeelaaenns ficnnaccliicddueennlccaeetedooff on`ffeeattaapl emrvoiraitbtaitlleiirttyyba((X3s))is: Hean percent males. (3)
6119 wais m0i8ss srses
Uve fetuses
S26 454 sin sia
MeHealnlesb"ody-weuclnoaauhdatjrutsa(ntgce)edb asdejaunsted sean Females ~ unadjusted mein
I3w: 31mm 3ama aasse 5.
- covariance adlusted mean
FMeTIARs J 30 }sas 8
B SStexa;tispteirccaelntanmaalleyss,isanpdersfeoarmnedboodny cweoivgahrtiandcaetaadIjnucsltuedde mveaalnuse.s for ive fetuses only.
2 28
RaStumTaerryatoofloTgEayxtteSetu8rdmy Fofin1d-i3n3g5s2
15961
Dose Level (mGarokuap:: TO
21 5 5.
MMoosmbbeerr Nosber
ooff of
ffeettuusseess fetuses
wweiixttahhmivinnaerdnoarnmtas
1iaits
Number of fetuses with ancaniies
m20 ]
wwooows am 011
MeTrrunkan=dshtoyrpte of vartants
V
2
0
o1
)
Tail ~ underdeveloped
1
MosPhalearteand- ctlyepfetof anomalies Tall +huondeiveloped
1
2i
o
'
5
2 Finding confirmed at skeletal evaluation.
233 22s
RaStumTmearraytoofloTgVayibslcSeetr5uadly Fofind1i-n3g9s32
tose Level (mGaraowr:: O _1 f
NMMoousmmbbbeeerrr ooofff fffeeetttuuussseeesss wWeiixttahhmiinnveadrnioarnmtasl nits Nosber of fetuses with snomsTies
wi]oom0e1%0 0me3
MosBhrearinan-d letfytpe voefntrviacrlteantds1lated
2 [] 2 1" 3
Liver
= 2
ddaarrkk a1
maarteearsiaoln aTroobuend brain abe appeared dark
11 1
KUriedtneery((=ss))dar-~kadaiir1saettesenddiendreTnitv)erpelvis
1 1
STkeisnte-s edesmaailbetween skin and peritoneal wall
81 5 1 1
MCorRspeedtrnaeryac(nsdh)itsynpefusoefdanomalies
2 o i2
2
1
190-160
a4 %2 2
. '
%|!
o
32 1
RaStumTmaerryatoofloTgSiykneelSettu1ad0ly oFfind1i-n3g3s52
150161
Dose Level (gG/rkogup):: TO
2+ T3o 2o
MMMoommsbbbeeerrr
ooofff
ffeettuusseess fetuses
wweiixttahhmiinnveadnroiramnatls
Halts
Nosber of fetuses WIth anomiies
18is 5
n wom m 9
m1 1
NosLbaegrginagndostsypceatofiovanrtants
4
m wom 195
Skill
==
pIiannrtcleoermtppaaltresiteetoasclsliofosiuscrsaeitfii(oc<na75t%iI)ornreqfunicoemrplete.
- swbraocc pital ossification incomplete
a%4 3
3. 5
3 s
35 fl
Rb cag--ehsy-uoBlsrdtaeoorcncseisbpirifatieaclatbiinopananrftuIisntecedosplete/nafnioesds = Sternebras Sositied
a27 IaH 11
1
-.
2
75
=- rriiibbbssso13s3s1Fppiaactrassttooosnsssiifrflr1eeeddgular
1i1
`1 2 "2
*
Vertebral colum -~ ttlhhuoomrrbaaaccriicc.osccseeinnfttirrcaaati0n3oo3nn1fuifsncecadotmipolneteI/nncoonmopslseitfeies 11 ian =w - mbar arches fused
5) 6v
-- sccaaaucudrdaaalllvv<ee3rrttaeesbbsrrtaaes1n6ondonnoossss flfeedd
51 1
o . n"
1
HPienldvicnbgsir--dl<e4--osptsusibcfihisieuqmosossisfiicfaitciaotnionInicnocommpplleettee/nonfoisesd
`3
5
22
3
BoRniebsali~gnfmuesnetd, forked
'
5
1
22
Sterne-~bsraaanslgaull~iagtcnehededcketrheodracte centra and arches.
'
'1
11 2
z
Vertebrae aalalionsd - thoracic
1
i2
IncidenRcoe oTfercsaatteoTrnayatsFeeiygtoofs1rSrhsLiter
1m
RJe aambeerrtofaMpeetrecreR s eorxfaHmiyenekse: wi--h w--atants
woe ewe arciraops:;
=saa ga oonwwBnow
Waker $34 percent of Meiers Wh snomrits NaTbear snndeperrcent with variants
oVsAmS oOmme uiann d1eAe
To sntrdevtosed NoTstoert4e0 Jtoenth sna tes
van vate
TLSwsetters
ass
van van
4.
+ inti confirmed at skeletal vatunion
2 8 23
IncideRnacte oTferVaitsocleonrgoaytleStFui1dn2ydinogfs1p.e3r357Litter
15018
dose Level GaaGsrkgoyw:: D 1 i2
4
NMoossbeerr Momber
aoonffd
11piiettrttceeerrnsst
eUoixftahmiiHnnietdtneorrsmalwitMhelvtasriants
Nosber 3nd percent of 11tters with snosaies
WA2i L
2is 625.00
220 2/833
2i 219.52
NeBsrbaeirn'and 16pfetrcveennttrwiictlhe vdairltaatnetds
ua 0000 2m 00
Liver
== ddaarrkk 2311
emaarsetaesraiapanpeaaTrroeobduenddarbkrain
[bZyr van
UKriedtneery((~ss))dar~-kdaiaisrlteaetaneddiennrTeivmerpelvis Testes small
ma
som
nm
wey. 8
MES an ae
Skin- edema between skin and peritoneal wall
2 143s
NoKsibdenreya(nsd)'p~erfcuesnetdwith anomalies Cryptarehtsn
2.10
nann
223 2a3
IncidenRcaet oTferaStkoelleoTtgaayblleSFtiu1nd3ydinogfs1.p3e3r52Litter
150160
Dose Level (mGar/okup):: 0 2t 75 El.
NNNooosssbbbeeerrr aooffnd11piiettrttceererssntWeoixftahniiHnnietndteorrs mwit1hiaivtasriants Mosher and percent of Titters with anomaties
2952.1 65 2/0212 60 20/B8l`333 20/9281.20
MoLsabgegriangndospseirfciecnattiwointh vartants
0/000 "0/000 0/000 0/0.00
Skull -~- pfIannrctioeemrtppalalerstieetoacsllsiooFssiuscriaetfii(oc<na1tsKiI)ornregfuntcaorplete - supraoccipital ossification Incomplete
1A6/1633597 2870
132/2550000 250
16572652.10500 520m
143/n6s1..09s0 2s
Rib cag-~eShu-oprlsadtoecroensespbiirftaiacclatbiinoponanrftuIisntecedomplete/nanoss1fied
NAETsE 8 1707 sas IN sa ems ens
&.
- SIritbbessrn<e51b133raeppaati<rr3ssotoosssissfiiiffetideeqd
mAASs3S 28a2mn
A641 em
e2//s9502 ees
:
3s
Vertebral=coilbusmnos=-sttPhhioocrraaatcciiloccncceetnnrttrrreaaguntoaasnrsfiufsiecdation Incomplete - lumbar ossification Incomlete/nonassified
106/469351
18 3/50.17
1i4/z5e8.33
13e01r64e1.s70)60
~- clauumdbaalrsa<r3choesssiffulseedd caudal vertebraenonossfed
117/44.13358
17476
S1/A41M35 5208 anes Tome
Pelvic girdle =- Tpus-bclhasicuromasolssisfvifecriatcteaibtorinaoennncoionnmoclsosemitpfelf/eetmdeonossified Hind tabs - <4 ossifieq
31/7134.3054 28.10
5/20.83
2n9s.5e2
SoneRib3s11gnaFaunsted
an
ane
32
~-
fmoarlkae)aigned ngulated
thoracic
centra
and
arches
114.73766 17078
23
SVteerrtneebbrraaes-malacthieacnkeedred- thoracic
3
was an wvenn aas 7
Mean Incldence of ExtRaetrnaTle,raVtioslcoTegarybaelS,tu1d4ayndofSke1l-e3t3a5]2 Findings er Litter
Dose Level (mGirkoeuyp:: T_1T 2t 73
External
MeauNnumsbbveearrluwWeisitthhcaalvcnaurolimaaintiteesdson a per Mtter basis: Incldence of vartants (x)
0000 o0o0 0010
Incidence of ancaaties (5)
o0s0 oooo 0214
Visceral
MeaNNnaussbbveearrluWweIistthhcaalvncaourmllaaaintiteesdson a per Titter bass: Incidence of variants (x)
o os oooa 0011
Incidence of anseaies (5)
n20 aeoo 2is
Skeletal
Me`MaNnousmvbeaerlruewWsiitthhcavalnacorumilaaalntiteesdson a per Titter basts: Inctdence of variants (x)
000 oa1o oaeb
Incidence of ancaalies (5)
aoso woso aosnh
150100
EDo
00p0 003p
0onp
8:7
b0a0
0ag0 s0e3d
233 22 s
Sa
Muamtebrenarl nu ma ma msz an60 ms
M19 21190
2217220012
21205
2121220181
21212
2211221135 21221
2226
21225 21228
2 A animals
Appendix 1
Individual Clinical Signs? Rat Teratology Study of T-3352
154-161
grow Observation 1 Alopecia
1 AAllooppeecciiaa
1 AAlAllooopppeeeccciiiaaa 1 AlAlooppeecciiaa 2 AlSoofptecfieaces 22 AlAoloppeecciiaa
Alopecia
2
Alopecia
3
Alopecia
33 AAllooppeecciiaa
4
Alopecia
AAlAloloopppeeeccciiiaaa 4" STohfitn. feces 4 HAuTnhnoicrnheexdia
4 AAllRooopupgeehcciihaaaircoat 4` AAllooppeecciiaa
Alopecia
. HAulTnhoicpnheecida LKalnogpuetcdia
a Hunched
. THhuinnched
not included in this table
Body Area Abdonen ALbedgo-fnoerne-right LLLeeeggg-ssh--ihfniodnr-del--beboofttthh LeLge-dfs~ofroer-el-ebfotth Paws -fore-both PaPawws--ffoorree--rbiogthht
Paw-fore-left Paws-fore-both
Leg-hind-left
PLaewg--ffoorree--lleefftt
Abdomen
HHiiLpep-gs-r-hibigonhtdth-right
Paw-fore-left
AbAbddoonmeenn AbChdeosnten
Hips-both
Paws-fore-both
Day(s) 1-20 196--2200
11835--1119250, 1260-19 152--210 768 1n5s7
18-19 18-20 20
1208-19
13-20
111836-0-212050 1306. 18-19 11163--1290 112650-:1290 205-20 15018
1n122-a1250 n16a1z8 14-20 114-18
appeared normal throughout the study.
000411
}
Sa2-
Key to Appendices 2, 3, and4
150-161
P= Pregnant N= Not Pregnant = Cesarean Section Performed (preceded by day of gestation) () = Data excluded from mean calculation.
Explanation of Footnotes 2 osencltyiodnatwaerferoumsedpriengnmaenatn acnailmcaullsatisounrsv.iving to Day 20 cesarean cIanlvcaulliadtionfso.od consumption value not included in mean
Gravid uterine weight inadvertently not recorded.
000412
mt ey E iyric
_
SE
BOGE eb
mile
B2ESE2 BEum Em S
Bo 508s 0 eepoma
we ann um aa
BEG BESES 8 088 EES
g:B:
ns EESE L eo en
_
NE t -- A semen
hme Male 0% 8 ww am
TT
wHoEoRTEEC wOBLaBrD domiEombtodmaidodmiy dopm doub dobm dByowgmbomome
HGR HE mEEERIED
dhooER BOE BD el moan
BOMB BOE BRB
RONORD
dh
EOD ED EBD ED RD
OB
o&
a
OE
o
RmoOmoBE
win dnodaoln da Ba tn Se de de de da
s 222
Ee SE pe vi ra EE SE yo
T re y
tert
al
tegen
it BRCM mY momo mom aoa mow ni a Jie!
BoE oaGdas 4 38a LEY
. 8g2
]]
EHEsne sont - contours.
kr
tert
mma
a
mie 6 4 aw wm
Sa
tegen
ei ew am
em
em
IBoEE EmaInTaInTaI Ra EdEg RRAHEEE IomEE dED Gib Gh Gib Ga SRY GY enn gn di ad gd
BOE BERBER BLOB oO HEE moonROOBDOM me ompomi oan ow 4
WORD Em
PORE dh dh guh Oh (hh deh Oh (Bh AY UD Rb dn Kk)
& Abn dadudn fe Ge Se du be Be be du
5<g B8
Swe
MaNtuemrbnearl
m3a0 mmaa an mm21a335 2an38 240 2mm4aa3z 212144ss 2m7a14r6 27148 am27ns1s4)9 mmsss FE HeNan
S.0.
0-6
QMIls 1n25o7 1238 (WM122s2.3) 1W2s84 3 a 1M20O.0 W1BB W12s8 BT 11132550.576 1M22689 WI
M2IE
17.7161
Appendix 3 IndivRiadtuaTleraatndoloMgeyanStFuodoyd oCfon1s-u3m3p5t2ion?
Group 1 - 0 mg/kg
TitFerovoadl Co(nDsayusmpotfiGoens(tqa)tion
2-6F 9-12 13-1 17-20
GmIs (05865) (700607) (e4.s0)
n3AT 12520 e1l9e8 11006305
388 199 828 113s
(30 342.6) (e503s.0s5) (1J514a.ss6) (8s671s.5)
5 ws als
Bm149 69
ssesss 1119307 153 M16
48234173.84
e76116.100 Ms
8sBe7l.Ts3 111000610.893 767 sz
@ a3 33
3w5z5 360
lsas 7905
essails 920s
400 NIT ele 1a
3s41l3.s8 9g129.s058 1870013.433 1n90i54a18
4a0s ak
M2a0 0elss 1102308 es mez 1057
327.98 128.93 824.43 1020.55
4.988 10.880
8.0m 9.290
2-188
(113109.82) 1d9e5sse 201.5 (A1e4l5w.e7) 2206009 es 21119098..747 2i0i0a 1199514 23s 2213094.036 22105040 zie
22030.40
20.254
156-161
_o-20"
(336m6..s0) a40o1es 436.9 (3a3s3r85..e50) 4s5e5e0 4es0 4a329e5..s60 sdealds 4se3e0s sane 4a48v57e.sa4 a43e07 ase a2sg.72
38.302
000417
Sm-
MaNtuemrbnearl
nmsses nnsse nse 222716166120 2m63 212271711666564 mm26667 2a1n0n nannn n27s4 2a1n17n6 2n1e9 Heuan
s.0.
Group 2 ~ 1 ma/kg Appendix 3 - Continued
Individual and Mean Food Consumption? Rat Teratology Study of T-3352
TaTerFvoaold (CDoanyssumpoftioGnest(a)tion
0-6
2-6F
9-12
13-16
17-20
11264.8 nse
a3l.y6 ses
88.00 7
9852.70 N90.53 als, 10s
a12s3a5 Bmae (m5ss 087.833% (9016.43)
21122093.556 4330.la1s 21T9e.l00s 871089.087 19S0412.179
1203 30 e183 106s
Wn Wea es 3ea0.z4176s43l.s4 e812n6.h8 1e9081e.40
W 12264.29TB 3320.76 1ee28lz.e3 (10sm8e.a5l) e1100s93.78
2W4a amlee W327
e6s8l m0
s88s7 11008s3 ese 917
O 1NS2s 67s 3l9s
mse0z 83
eeells 11006678 93a 1001
W12e62 MS
4a30s3
1129 786s4 m9503 e125 nals
15 38 8 ee 1015
2290.11 320.31 820.75 2835.40 21003.76
7.957
4.222 12.219 6.301 6.289
1-168
22025.66 (2i2s.9s), oad 1e199s39..a39 1940 e2160n78.s86 (21269902..943) 221091015 1241.330 2203335 0en8s z08e.e6
22002.70 14.943
158-161
0-20F
4e2r8.s7 (3a8v9i.l0a), arals a042l14e.ss4 427.8 a438339.,90 (`45a0vz4ee.o1z) saesed saeess asnses 44317s 44a1s6i0e 4325.50
23.804
000418
S39
IndividuaAlppeannddixMea3n - FoCoodntiCnounesdumption? Rat TeGrraotuoplog3y-St10udmyg/ofkgT-3352
MaMteemrbnae-- lr T
TnteFrovoadlC(oDnasvusmopftGieonst(aqt)fom
0-6 28" sz 36 11-20
2880 221n8s32 2270188s8 an8e7s 22781889 2a1n1e30 2n9a3z 22a9ns5s 2277000976 2271000098 2271110010 22110032 2n08
1313.52 11502.67 11284070 2121612 112380410 101821910 M10e0a8 e13s 10 1s8l3a3 10521631 WwSz m100s6 136
31.3 1m2s 7168.58 19026.05 3as.s9 Mm82 eMn0 $8223s a3l4s9 7e6ll.s0 m8887 11003827 363.870 n69s3 5969..94 9989s..9 43231a 7872..40 888040 1e0m825 2367035 seee 16870.)0 9943.70 E31a.0 d52n.4a, T76.2G 99933 G38058 087.6.000 ((4613.)6) 1(0170.23) 3aasn 7894..29 58308 1905872 333s 8 eels 7654.75 9933.s2 a302 s6a5 76001 1905677 4s0s0a0 2079.04) o8sas 1m025s) 1.4 79 00s 1232
HeWan 5.0.
1321.05 328.62 723.69 728.24 1020.76 13.235 6.431 8.43 11.473 8.389
2-168 118986.00 118809027 12080.a0 11761882 120999.58 119603040 l159s06 ((226030050)0 m2232.4 117655.s6 111922.82, (220032..040 23208 18282.23 18.997
15-161
0-20" 443193'.57 440052..73 445143.39 339921.s3 4as2e5..4 436163.62 s369e.5 ((530814..88)) 44861.20 338894.)1 d4e0s0e7 (a5753.4) sos. 41272.40 34.384
000412
|
Sa
MaWtusebrenral
2211220065 21200
27208
2122721009
2121 21212
27213
221722212111564 21217 2221112221908 212222212 21223 212272722222564 2211222281
21229
n MSe5a0n"
0-6
W12I8 0
(106.8)
9u2.e9
143.0 (139.0)
151.3
WW2Es8S (107.8) M12222e.s9 smee wo Ad12Ie9.rD5 my 132.3
(=)
20 ME 130.34
Appendix 3 - Continued IndivRiadtuaTleGrraaotnuodploMg4eyan-St3F0uododmyg/oCfkognTs-u3m3p5t2ion?
TteFrvoaoldCo(nDasysumotfioGens(teatyion
2-8F
n30e.9 2
(29.0)
1a8l.o5
35.3 19.2)
64.7
(m323122E.0305) 2da8l.es5 ams1l we
56.4
Wis o35m.e6
38.7
2 3960.06505
9-12
s50z.6 3
(65.7)
6w0.5s
(106.6) (34.1)
80.5
(6e51l0.a57) wo 6ss0s.s8h, @Eo, geab (2w2s0n.h0))" wr (15.7)
73.0
1 n13.0a23
13-16
5s0e0 Tels
(52.2),
(q86.r4),
(80.9) (2.2),
(99.5)
(755836.9s4) es, (ms84.e10) Ggebd camp (12oa8.en4)
o12a.8
69.5
1 618.5435m
17-20
8933.0 sz
(85.8)
a9o7.e2
99.0 (66.8)
101.9
1(9s6021e.0)27) o9ss8a.se8 a2naeb, las we14h.o8
ad 971.2
95.4
0 ssn 96.4777
154-161
2-16
0-20
d0e.r2s 3s4ese.s ws sore,
(146.9),
ss (165.4)
(339.5),
sd) (355.5)
(222.8)"
(55.5),
(244.7)
(ea14e8k.s1) 2002
(464.8) (261.3),
(503.9)'
(`a310864.s6) ao,
(2e172a3.dr4) (g72z00 (ssp (4e(0149n..88))"
(ma39oe5n.se1), G(snadd (ore 1(`64G9)e.1s),
Gh (184.1) G8) (413.6)
2 oom 181.3 (276.7)
ane 173.647 3s99e.e16m
000420
Sa
Appendix 4 Individual and Mean Terminal Body Weights, Gravid Uterine
Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352
Group 1 - 0 mg/kg
158-161
(g)3
MaNtuemrbnearl mma0 mma3 a2ns 23 m221n13339 m2na40 maz 221121111444583 2m71a46 227714489 m211a50 amnsse mse
Meuan soo.
BoTdeyrmWieniaalnt Not P3r40e.g6nant
36383.s0 Not 3P1r5e.g2nant
350.3 34350224.s5 33101435 1102 30314760.839 343848.87 383086..61 3901.33 3382960.70 3567
23835.16 25.525
UteriGnreaWviegight 68.8
87.s5 740
4.4 786939.30 450513 612 a 6268.s4 5037 [nixs 8650..90 606033 ns
629.52 18.207
WTeeirgmhintalNinBuosdy GravidUterineWeight
me
228823.55 01.2
215.9 33238549.0.215 230848044 23000 322219620...445 238890009 2391140s7 23030.43 232691078 27808
29253.68 20.212
000421
-a2-
Appendix 4 - Continued
158-161
WeightIsn,divanidduaTlermainndalMeaBnodyTeWremiingahlts BMoidnyusWeiGgrhatvsi,d
Gravid Uterine Uterine Weights
(g)a
Rat
Teratology Study of Group 2 - 1 mg/kg
T-3352
Maternal Number 21155 27156 ans? 27158 2n59
27160 21161 21162 2163 27168 27165 27166 2ne7 27168 27169 21700 2am nm 2173 2174 2n7s N76 ann 2n78 an N Mean s.0.
Terminal Body Weight
360.2 389.3 352.5 Not Pregnant 347.0 366.4 365.8 380.4 387.4 338.6 362.3 369.9 373.0 356.1 391.7 387.1 394.7 352.0 361.9 357.6 316.0 360.3 369.1 418.9 374.1 24 368.01 21.094
Gravid Uterine Weight
61.5 61.5 48.6 90.3 5.7 7.8 81.0 84.8 72.4 80.0 0.6 7.8 65.8 83.5
9.8 86.7 88.8 61.1 17.0 80.8 68.9 88.1 86.8 2 73.62 16.288
Terminal Body GraviWdeigUhtteriMnienusWeight
252.7 321.8 303.9
256.7
290.7
288.0
299.4
302.6
266.2
282.3
299.3
205.2
290.3
308.2
-
302.9
285.3
213.1
296.5
299.0
219.5
:
300.2
330.8
287.3
23 293.56 16.285
0004272
Sas
Appendix 4 = Continued
156-161
WeightIsn,divaindduaTlermainndalMeaBnodyTeWrmeiingahltsBMoidnyusWeiGgrhatvsi,d UGrtaevriidneUWteeirgihntes (3)
Rat TerGarotuoplog3y=St10udmyg/okfg1-3352
NMuatmebrenral m211e80 2n1e8x3 a21n1e8s5 2n1s8e7 27a1n8e8 2n11a90 2m1e19z3 aanmees aanmar 221719988 2722120000 2121220032 21208 HeNan 5.0.
BoTdeyrnWienialgnt a36n5.e7 335732.67 383588..93 a33n41s9 36a2.29 35352..03 33202..83
Not 3P7r6e.g5nant 370051.19 333865101 383368..60 339990063 357.9 36720.30 26.79)
UteGrrinaeviwaeight 65400.35 6670..54 679..06 6592..84 6860.5
106.15 5551..80 6723.08 82.4 8518.s0 8330.88 20108.45 612.51 13.989
WTeeirgmhitnalMinBuosdy Gravid Uterine ueignt
33091.32 320027..22 2768917 320822..75 23399..48 228651..98 228641..30 33023..87 2255420.79 23085..41 33018.28 a31ss 20209.78 22.726
000422
4-
Appendix 4 - Continued
154-161
Individual and Mean Terminal Body Weights, Gravid Uterine
Weights, and TerminaR)atBToedryatWoeligohgtys SMtiunduys ofGraTv-i3d352Uterine Weights (g)2
Group 4 - 30 ng/kg
MaNtuemrbneral
TBeordymiWneallgnt
UteGrrinaeviWdeight
WTeeirgmhintalNinBuosdy Gravid Uterine Weight
2211220068 2127220008 2127221009 22211m2 2211221134 2211221165 2211221178 2121222109 2271222212 2217222243 2217222286 2121222218 21229 HeNan 5.0.
23360.37 Not P3r8e4g.n1ant.
3360491.34 Not PNr2eg6nant Not P31r9e.g3nant
336021.77 38364.35.5 363386..63 302907.2 303794..80 Not38Pr6e.g3nant 334266118) 3728 23615.03 21.679
6n509.s189 571..12 02 ns 778..00 n9.a0 6868.104 2590.65 o-e 7n41s9 68121 2606.47 15.015
225710.198 2696 237067.13 2824 300.8 226639..17 32m027a5 22657.169 22318516 202-.6 4mi.s0 125090
22600.335 20.353
000424
geo Eee
Loon, ow dd
nb Bd
Bu BE 8B
an
i)
Hs
Ba Ta Hon
Bo Be
kn i
8ggg<
dma coil on tobete bo0 tobid sities 1 283 23
Rw
ER
lil wi
we
a
aon iE i 3 HE
i3 :
g8 283
gy SEL 0
Boge ;, & + 1 ou PE
Eo hs
HE
HI
8
g3g 83
TMahteerrna'l
tTomtall tta GLE n Ge tem aw EE rWerceEnt die g MN
Boe
DP Ew BE HE
ie
:
goood
dh oad su Booed
:1
Lo
23
BH
He noon
in
:
soa Bo
3i
ay
Ba
&
[----
0 Te fa Be Ha
Te Me
Ba
Ta Ba
2:53 BHrae net fiateSIeN fhe ct ae tape fetes sb.
|| foe
EaStRoYn ln T em aen [EP
Haiidm53
AE g<g2g g
me
EL i
ase EG
ih i RWhae al "
aa rls
Tiha?
oni g pd Gem d uss ues) EE * Umm aie GlCSLer
momar Gp
i
HAdjusEted R5.8. R2SmEe
gg<2 g5
Ge Ba Be Beh te
Rom.
*
ow, ow
ao.
wo
pa p rse n
on
RE wll oe Ghoaeowres mem GE mee
Comm Gn bm Be dn WY Bm in ie
hm
polio
gg$ 58
Fnuh
Tater ttre
of
I
pees win
stHeEnt - Shier pe
acne ters of tse wo Ctra
I
MEL d dE dd
Sw Bo dm tw So se ow he Bn bm bw
oR-
.
Pro e
2`
222 28&
gGLEaEtt
i
mri
d iidi dd
FRATEREITII Tw fe fe Le da te de be de de de te te
| FEmi fd
LE
vox
|| EBg afmbEeorfnfUem tusesIhatviInng ssaeIomr mRoreovTmis.cerOal smoTmalieUs e SeeSe 0de 0fe 8fed. e le fe Le fe .de te *'
23883
|
|
en
Jel TeaI
msds brs yy
FE rEa erm:
.EE
"
;
EtAAg +IoAonTIITe Se fe fe la fe fe fe ln le fe fe fe
2$8
rl
i
me
To
id
dE
rd 3
FEASERRIIINI 0
EE es
de fu fe be be fede fede be be |
-
| smi.
Fa RATiw ERNIT-IES Se fe Je fn fe Se Se fe fe le te te
8
'
238 H3
BLL
ienET0
HEE
EE OE I A A
iar ddd
Se de be Se fe bo to Go fw be fw be de
ettry Apres os
5. .
228 382
--
FER Hr shige
Hr os
TTTTTTTTTT L333 388
"
,
222 2 &
[OAR
Feces bebot se on tr
m T e pr T ds y bT bT a l T s dTd TT
RS, Soo Sen mm Soo bm boo 1 Boo Sem feo
gE
.
.
Ermita
weerie
3gS 88
nn
og iy ies
mel aoa Ld 3 0
-
dG
JEL
a
F pLA a RE fe le fe fe fe fe de a fe fu
2
Fanart
3g2 2
jd add
dE
FEAIRARIVTESA de dein be de ie do de de du be
RE
pO,
[. bor oan
RR em, .
hme Wa
ff. ------
20S PoFIrEmR mts st
.
wr
Pa
me iddd i d
EEE nn, | eB LL
Cee baw
mee ww
em .
rete Giate pansap rebee tans?
SE 222
i
rs DEWir
mrad di TT T d T T i Td
z
am
eg
|
ER
es - EET SEH
.
,
.
,
S& omRaT wo 5
oaLE SI wl tgielon Sa a
ma Trd l iTd T d TTTd
Fr i Ry Tr WT 1 Bo de a shan 00 hw a0 000000 bon hoo thse
teats SUE{TI emt
on
wom
"
| anLEmnt
"Ee =
*
revearte wl Se mine
Ce
ld
3Q32R here ver se shat smmtes ote 10amrofenes.
wp
-
i
FREER
HR
mr pd PE idE
wd de de de de de dude de be de de te
| EER
a
-5
|
Petvic etree- sl
a do tEe :AeR mt cus te
&
rem mm
EE
I wn a
ml
dd ddd
to | VE
3 mi un
:
RR bt mts ts 1
gaJopen ndi8n-SCoHntinues
en
me iiy pd iii
RTA 0 de de de de de Se EET PY
HA mine
|
EEELT
PERT
in
s
3
Cone
-
oo
:3 RRTLRIt,t mts ste 0si tee,
RS
JG
gel es
me Ld sPi EEEi dd
'
"a
- Cw
23 t wuiTl E eh ag...com ron 232BwT e weterergana) somates sted tnsouo
.
.
-69 -
Appendix 9 References Rat Teratology Study of T-3352 STATISTICAL METHODS/LABORATORY PROCEDURES
154-161
ABrimoimteatgrei,cs,P.1,1:"3T7e5s-t3s85,for195L5i.near Trends in Proportions and Frequencies."
ABgarritlceutltt,ureM.
S., and
A"pSpolmieedExaBmipolleosgy.o"f
Statistical J. Royal
Methods Statist.
of
SoRc.eseaSrucphpl.i,n
1v:137-170, 1937.
Cochran, Tests."
BiWo.metGr.i,cs,"S1o0m:e41M7e-t45h1o,ds
of 1954.
Strengthening
the
Common
Chi-Square
CanodchrSaonn,s, W.IncG..,,
and New
Cox, York,
6. M., 1957.
Experimental
Designs,
2nd
Ed.,
John
Wiley
DRreavpiesri,tedN.. RT.e,chnaonmdetrHiucnst,er1,1:2W3.-40G,.,196"9T.ransformations: Some Examples
TDruenanettmte,ntsC.witWh., a "CAontMruollt.i"pleJ.CoAmmp.arSitsaotn. APrsoscoecd.u,re50:f1o0r96C-o1m1p2a1r,in1g855S.everal BDiuonmneetttr,icsC,. 2W0.:,482"-N4e9w1,Ta1b9l6e4s. for Multiple Comparisons with a Control.*
EFdiisnhbeurr,ghR,. 1A95,0. Statistical Methods for Research Workers, Oliver & Boyd,
WFilleefys,s, NeJw.
L., York,
SCtha.ti9s,ti1c9a8l7.Methods
for
Rates
and
Proportions,
2nd
Ed.,
wGiatmehs, UnPe.quAa.l,
and Howell, N's and/or
Statist., 1:113-125, 1976.
J. F., "Pairwise Variances: A
MMounltteiplCearCloompaSrtiusdoyn.* Proco.e. dur4e.s
AKrnuaslkyasli,s.W.
H. J.
and Am.
SWtaaltl.isA,ssWo.c.A,.,47":U5s8e3-6of21,Ran1k9s52.in
One-Criterion
Variance
Kruskal, Variance
WA.nalHy.siasn.d* WalJ.lisA,m. W.StaAt..,
"Errata Assoc.,
4t8o:9U0s7e-9o1f1,Ran1k9s53.fn
One-Criterion
gLoenvetnrei,butHi.o.ns*RotbousPtroTbeasbtisliftoyr Palo Alto, 1960.
aEnqdualSittaytiosfticVsa,riaSntcaensf,o"rdinUnIi.ve0rlskiitny
edited, Press.
000449
- 70 -
Appendix 9 - Continued
Rat
References Teratology Study
of
T-3352
STATISTICAL METHODS/LABORATORY PROCEDURES
158-161
Miller, R. York, 1966,
6., Ch.
Jr., 6.1.
Simultaneous
Statistical
Inference,
McGraw-Hill,
New
Staples, R. Teratology,
9E(.3,):"AD-e3t7e,ct1i9o7n4.of
Visceral
Alterations
in
Mammalian
Fetuses.*
Staples, In the
KOR.H-AE.lizaanrdinSchRneedll,S
V. L., Method
"fRoerfinFeemteanlts Boimne.RapidStCalienariTnegchnToelcohgnyi,c
39:61-63, 1964.
TWeirlastoonl,ogyJ.: GP.rin"cEimpblreysolaongdicaTlechCnoinqsuiedse.ratido.ns J.inG.TeWrialtsoolnogayn.d* JC.h.Wa1r0k.anyI.n The Univ. of Chicago Press, Chicago, 1965.
WMicnGerra,w-HBi.ll,J..N.Y.S,tatCihsst.ic3a-l5,
Principles 1971.
in
Experimental
Design,
2nd
fd.,
WMicnGerra,w-H8i.11,J.N..Y.S,tatCihs.ti1c0a,l
Principles 1971.
in
Experimental
Design,
2nd
Ed.,
000450
