Document 1qXYeXjwD3xabaQ0ddngLNBq
International Research and Development Corporation
SPONSOR:
COMPOUND: SUBJECT:
3 Company Fluoead Fluorocheatcal Fe-143 Ninety Day Subacute Rat Toxicity Study.
CoFhorAYCa. AsS a
TGT oVZiilcveine2rI.assidinnc eandnBaR l--,
Collaborators:
Director of Research
0.DiC.recJteosrsupo,f PRhe.sDe.a,rchAssoctate
Re anGd. N. D.
DGierlle,ctoDr.V.oXf.,PatVhiocleogPyrestdent Jefferson, B.4., Acting Director
R. ofJ. `SAaraclels,AntMa.Da.l, ToSxtiacffoloPgaythologist
137-089
Date:___ NNoovveember 66.. 3109788
01617
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International Research and Development Corporation
TABLE OF coNTENTS
IoSymopsis
Lo...
Page
IL IIL.
CColmipnofuenald Me.th.ods... ............................................3..
Ao Method LL...
..,
1. 2.
CGoemnpeoruanld PArdomcienduirsetra.ti.o.n.. ................................44..
3. Observations .......................5s
4 LaboratoryTests . ....................s
ba.. BlHoecmahteomliosgtyry......Lo.o.l....[..I.l ..l.......5
d. SUetrmwamlSyasmipsles L.o.. ...D0l0l0l]I1I1I1lI1IllIlI1I10I0I3
5. Statistical Analysis ...................5
Bo Results... LL...
1. General Behavior, Appearance and Sur.v ..i..v.a..l.
2. BodyWeights .......................5
3. Foodand Compound Consumption . . . . ........... 7
Go LaboratoryTests .....................7
bao. BlHeomcahteomltosgtyry..LL........0..0..1..1 ..1 ..1 ..1 ..1 .7
e Urinalysis Lo... 0000111111000
IV. Pathological Studles . ......................
A Methods . LL...
1. Gross Pathology . . . ..................0.
2. Estopathology ......................3
Boo Results... LiL...
1. Gross PathoanldoOrggaynWeights . . . .......... 9
2. Histopathology . .....................1I0
.
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T( TAT C BLo E nOt F hCi ONw TEe NTdS
Table No.
Page
1. Group Mean Body Weights; Weight Ranges; and Survival . ... 2. Individual Weekly Body Weights . . .............
12 1310
3. 4.
MeanFood Sumnary of
Comsumption . . . . . ............... Means and Significance of Hematological Values . .
15 16-17
5-7. Individual Hematological Values . . . . ........... 1823
8. Sumary of Means and Significance of Biochemical Values . . . 9-11. Individual Biochemical Values - . . .. ...........
26-25 2631
12-14. Individual Urinalysis Values . . .............. 15. Sumary of Gross Necropsy Observations . .. ........
32-3 138
16. Absolute and Relative Organ Weights . . . .. ........ 3
17. Individual OrganWefghts . . . ............... 40-60
18. Histomorphologic Observations . . . . . ........... 42-47
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1. stwopsts
30,
Fluorad 100, 300
Fluorocheaical FC-143 was fed in the diet ac levels and 1,000 ppa to Charles River CD rats for 90 days.
of 10, Five
ale and five female rats were taitiated at each dosage level and in
the control of toxicity
group. The rats were observed twice daily for overt signs and mortality. Individual body weights and sex-group food
consumption vere recorded weekly. Hematologic, biochemical and urinal-
ysis studies were conducted during the pretest period and at 1 and 3
months of study.
No changes considered to be directly related to the compound were
seen body
in general behavior, weight gain and food
appearance or survival. consuaption was seen for
A slight decrease male rats ac the
in
300- and 1,000-ppa dosage levels.
Hematologic, blochenical and urinalysis values for the female
rats shoved no changes considered to be related to the compound. A few
values obtained for the males showed a slight deviation from the
control values (.e. slightly lover erythrocyte count, and elevated
blood urea nitrogen and alkaline phosphatase values).
Compound-related gross observations such as enlargement and varying
degrees of discoloration on the surface of the liver were observed
asong male rats in the 1,000-ppm group. There were no such observations
amoung female rats fron the 1,000-ppm group or in males or females from
lover dietary levels.
Statistically significant variations in sex-group sean organ
weights, which were considered compound related, occurred in the liver
of rats in the 300- and 1,000-ppa dosage groups. ALL other variations
were unaccompanied by any morphologic alterations.
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verM.icroTshecopliecsailolnys,cocnosmipsotuendd-rofelaftoecadl lteosimounlstivfeorcealc,onvfeirnyedsltioghttheto
slight, cytoplasaic idzonal regions of
enlargement of hepatocytes the affected liver lobules,
located in centrilobular accompanied in some
1{iapsotfaunsceeisn biyn icnyctroepalsaesdm aomfounhtepaotfocyyetlelsowainsdh-obcrcoawsniopniaglaelayt fnressienmubsloiindgal
aing cells. The fnctdence and relative severity of the above
lesions were 3 1,000 ppa.
predontaancly amoung males and wore The other changes recorded in the
pronounced among racs liver and other tissues
mwoesrte linesstiaonncsesofamnoantgurtahlelycoonctcruorlrinagnd ditessetasersatsa.nd they were present in
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1. cowromp
The October
compound was received 24, 1977 as indicated
from 3M below:
Company,
Saint
Paul,
Misnesota
on
-- LDaabbel
Description
F3MluoSrtoacdk FNol.ur9o8c-h0e2a1t1c-a0l00F8C--0143
white powder
Lot 340
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III. CLINICAL METHODS A. yETHOD: 1. General Procedure: Thicey male (222 to 254 grams) and 30 female (151 to 179 grams) Charles River CD rats purchased from The Charles River Breeding Laboratories, Inc., Portage, Michigan were used in this study. The rats vere distributed asong the groups, based upon a computer-generated table of randoa numbers. The rats were housed individually fn suspended wire-mesh cages and maintained in a temperature-, humidityand light-contzolled room. During the pretest period, rats were provided Purina Laboratory Chow and vater ad libitum. During the test period, the rats were provided the appropriate test diet and water ad
Libteun.
This study was initiated on November 1, 1977 and teratnated by sacrifice of all remaining rats on January 30, 197.
2. Compound Adatnistration: The test compound was mixed weekly with ground Purina Laboratory
Chow (1.e., ground basal diet) to provide dosage levels of 10, 30, 100, 300 and 1,000 ppm. Five male and five female rats were used at each dosage level and in a control group. The control rats received the basal diet only, on the same regimen as treated rats. Samples of diet (100 grass each) were taken immedfately after preparation and after 7 days standing in weeks 1, & and 12. The samples were frozen and subsequently shipped to the sponsor. Diets were prepared in che following manner: to produce a premix, the required amount of Fluoradd Fluorocheatcal FC-143 was mixed with 500 grams of Purins Laboratory Chow using a Hobart bleader. To provide the proper dosage level diets, appropriate quantities of the preaix were combined with additional ground basal diet fn a twin-shell blender. The diets were prepared weekly.
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3. Observations:
city
andTfhoer rmaotrscavleirtey.obsDeertvaeidletduiocbesedravtaltyiofnosr
overt signs of toxivere recorded weekly.
Individual during the
body weights and food pretest and treatmeat
consuapeion periods.
were
recorded
weekly
4. Laboratory Tests:
Once during the pretest period and at 1 month and 3 months of
the
vere
study, blo
obtained
od
for
(orbital
analysts
s
inus
from
withheld overnight prior to the
puncture technique)
all surviving rats. sample collection.
and urine
Food and
samples
water were
a. Hematology:
Heastological stuites fncluded: hesoglobial, hematocric?,
total erythrocytes3,
Leucocyte counts.
reticulocytes',
and
totald
and differential
b. Blochemtstry:
Biochemical studies included: fasting glucoseS, blood urea
nitrogen (3UN)5, plasma glutamic pyruvic transaminase (PGPT)S and
plasma glutamic oxalacetic transaminase (PGOT)S accivicy, plasma alka-
line
phosp
phosphatases
hokinase" and
activity,
caletus.
y-glutamyl
Alkaline
pepcidaseS,
phosphatase
creatinine
activity was
mot
deterined coagulant.
in
the
pretest
period
because
of
interference
by
the
anti-
. Urinalysts:
Urinalysis included: description of color and appearance;
measureaent of voluze, ph', and specific gravityd; qualitative
tests
blood;
for
and
partoetreions'c,opigcluceoxsaemdi,nkaetitoonneo?f,
bilirubin?,
the sediment.
and
occult
d. Serum Samples:
veeks
Of
Serus samples were obtained for study. The samples were pooled by
all sex
surviving rats at 13 and group, frozea, and
subsequently shipped to che sponsor.
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International Research and Development Corporation
age
5. Statistical Analysts:
control
ALL statiseical group, by sex.
analyses compared the Body weights (week 13)
treatment groups with the food consumption (weeks
113), hematological, blocheatcal and urinalysis lute and relacive organ weights vere compared by
parameters and absoanalysis of variance
a(nodne-twheayapcplraospsriifaitceatito-nt)e,st B(afrotrleteqtu'asl toerstunfeoqruahlomvoagreinaenicteys)ofasvariances
described tables to
by Steel and Torrield judge significance of
ustag Dunnett'sll differences.
multiple
comparison
:
5. RESULTS:
1. General Behavior, Appearance and Survival:
No changes considered to be related observed fn general behavior or appearance.
to the compound were Incidental findings
moced
for control tion.
and
treated
rats
fncluded
ocular
discharge
and
pupil
dila-
Survival (prior to suspcion vas as follows:
sacrifice)
after
3
months
of
compound
cone
Dosage Level
No.aSluerviving/No. FIenmiatlieated
Con1t0roplpa
5s//5s
5P/A5
10300 ppppma
55//55
5f7s5
1,030000 ppppaa
s5//s5
s4//55
Both deaths occurred following collection of blood. Neither
death was preceded by any signs of toxicity.
2. Body Weights (Tables 1.3):
Coapartson of group mean body weights, by sex shoved a decrease
in body weight gain for male rats at the 300- and 1,000-ppa dosage
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International Research and Development Corporation
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levels. Changes female rats. Ac
in 13
body weight were weeks, the group
siaflar for control and treated mean body weight for male rats was
mseiagnaibfoidcyanwteliygh(t7s<0.at05)13 lwoeveekrs tohfansctuhdeycwoenrterolas grfoolulpovmse:an. The group
Dosage Level
MeMaanleBody~~WeiFgehmtasl,e g
Con1t0ropla
446786
225690
10300 ppppaa
455070
226788
1,030000 ppppua
a3612
225653
3. Food Consumption (Table 3 ):
levels
Declines in food consumption were noted for male rats (100, 300 and 1,000 ppa).
at the higher dosage Food consumption values
were stailar for control and treated female rats. The average consumption through the Li-week study were as shown below:
food
Dosage Level
Average(g/Froaodt/dCaoyn)sumption
Wale
Female
Con1t0roplpa 30 ppm
2267..70
1199.:72
28.7
20.7
310000 ppppaa 1,000 ppa
2255..87
2191:.65
2300
1905
4. Laboratory Tests (Tables 5.34 ):
a. Hematology:
control
A comparison of male rats, by dosage group, group, showed a slight decrease in erythrocytes
to at
the 3 months
of study. Houever, the individual values were within the normal range
for Charles River CD comparison of fesale
rats rats
of this age {in this laboratory. showed no variations that could
A be
similar actribu-
table to cospound consumption.
.
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b. Biochemistry:
the
control
A comparisan of male rats, male rats, shoveda slight
a the higher dosage levels, to increase fn the BUN and alka
line phosphatase values. variations that could be
A similar cosparison of attributable to compound
female rats showed consumption.
mo
. Urinalysis:
females
The presence of occult blood than males at all dosage levels.
vas No
of a higher frequency changes considered to
ta be
related to compound consumption vere observed in urinalysis values.
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IV. PATHOLOGICAL STUDIES:
A. METHODS:
1. Gross Pathology:
sacrificeAdfcweirth90cadraybsonodfiocxoimdpeounadndavdearteodnsetcrraotiposni,ed.iveAtrmaeccsr/ospesxy/,grooru.p vere
1B0a%nsneauntdratlisbsuufefserveedrefoerxmaamliinned (efyoers girnosRsusasbenlolr'msalfiitxiaetsivaen)d.
collected Liver
fn
samples, obtained from all of the rats frozen and subsequently shipped to the
at terminal sponsor.
sacrifice,
vere
Topsied
Two and
female rats which tissues collected
died prior as above.
to
termination
were
also
mec
2. Histopathology:
statned, Mpiacrraofsfcionpiseecetxiaomnisnawtaisonpeorffofronremdalfionr-fiaxlled,rachsemiantocroynltirnola,nd10e0o-s,in
300-, and 1,000-ppn groups. logically.
The following tissues were examined histor
bcroairndwith cervical lumbar spinal cord
spsloercean
pLiavnecrreas
mesenteric lymph node kidneys
epveersipheral nerve pituitary
btohnyeauswith marrow (sternum)
utersitneasry bladder ovaries
thytrhoyirdoidwich paraadrenals
ssaaallilvariyntegsltainndes uptreorsutsate (duodenum, jejunum, skin (mammary gland)
Lhuenagrt with coronary vessels
ciolloenum)
anylestiiosnssue(s) wich gross
level
In were
addiction, the livers also microscopically
from rats examined.
from
the
10-
and
30-ppa
dosage
5. RESULTS:
1.
Gross Gross
Pathology (Table 15) necropsy observations
and Crean in liver,
Welghes such as
(Tables 16-17): enlargement, and
varyiag Tats ac
degrees of discoloration che 1,000-ppa level and
on the surface were present among vere considered compound related.
male No such
.
ebsecvacion was present among che females females from lover dietary-level groups.
at
1,000
ppm
or
in
males
or
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Page 10
Statistically significant variations several organs occurred between the control
fn sex-group mean weights and experineatal groups.
of
These variations vere of unknown cepcion of the increase in liver
biological significance wich veight moted in males at the
the exe 300- and
1,000-ppm dosage levels. This variation in by morphologic alterations. One female rat
liver weights ac 1,000-ppm,
was accompanied also had
orphologic alterations noted fn the liver.
Osan Liver
Grow sex
Weighe
Change
2c
30300 ppppm MM aabbssoolluuttee,, rreellaactiivvee iinnccrreeaassee 0.01, 0.05
1,000 pa
F
aabbssoolluuttee,, rreellaactiivvee
iinnccrreeaassee
00..0011,, b0..0011 0.05, 0.05
Kidney 3010pPppaa 100 pon
MF absolute relative iinnccrreeaassee 00..0055 relative increase 0.05
1,030000 pppam x
rreellaattiivvee iinnccrreeaassee 00..0015
Brata 1,000 ppm X 2. Histopathology (Table 18):
relacive increase 0.01
Fats
Compound-relaced liver lesions occurred in almosc all ac 100, 300 and 1,000 ppm and one female ac 1,000 ppa.
male test The lesions
consisted lazgement
of focal to multifocal, very (hypertrophy) of hepatocytes
slight to slighc in centrilobular
cycoplasaic to midzonal
en regions
of by
the affected liver lobules. These were accompanied in increased amount of yellowish-brown pigment reseabling
some instances lipofuscin in
Teh7etoipnlcaisdnenocfehaenpdatroeclyatteisveandsevoecrciacsyioonfalltyheianbosvienusloesiidoanls lwienriengmocreells.
pronounced asong male rats at the 1,000-ppm diecary level.
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Page 11
References
I+ HCioaulletaehr,BeFmloogrlidoab.inometer, Coulter Electronics, 590 W. 20h Street, 2+ PMeer1o1h5e6n.atocric, Joha 3. Male, 3rd Bd. 1967, The C. V. Mosby Company, 3. 3C9o0ulWt.er2P0atrhtiSctlreeetS,izeHiaCloeuanht,er,FloMroiddeal. 23, Coulter Electronics, 4. RCeriatdmuahno,l'sEdiCtloirnsica6lthLEadb.o,rat1o96r3y, MTehtehodC.s aV.ndYDoisabgynoCsoimsp,anyF.ramprkel11a3n5d
5. Technicon Auto Analyzer 6/60 MicroMethodology.
6. CGol.u,tamSty.l PLoeupttsi,daNsoe. - Sigma GGTP Procedure Bulletin #545, Sigma Chemical 7. Micro Auto Analyzer II, 6/60 Micro Methodology. 8. Photovolt PV4, Photovole Corporation.
9. Multistix (Ames Reagent Strips).
10. SStteaetli,stiRc.s,G.MeDG.raawn-dfiTlolr,rieN,ewJ.YorHk., (N1.960Y.), Principles and Procedures of 1. DBiuommeecter,icsC,. SWe.,pt.Ne1w96T4a.bles for Multiple Comparisons with a Control,
pr
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. Page 16
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. Page 17
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