Document 4aZZjemoyLr1BXgOgg2202kmV
i cro
ART-0) 39
o.
A T=2
International Research and Development Corporation
SPONSOR:
COMPOUND:
suBECT:
3M Company
Fluorad Fluorochemical Surfactant FC-95
Ninety Day Subacute Rat Toxicity Study.
:
<<; RC
,
oer
EVidcweinPrI.esGiodlnicentahnadl, Ph.D.
Director Sf Research
Collaborators: D. C. Jessup, Ph.D., Assoctate R.DiG.recGteoilr,ofD.VR.eMs.e,arcVhice President N.`aDn.d DJeifrfeecrtsoorn,ofB.PSa.t,holAocgtying Director R. ofJ. 'SAazaclelo,AntMw.Da.l Toxicology
Statf Pathologist
137-085>
Date:Nove 10,m19b78er
ECEIVENn
JIN - 3 1997 1I
002094
International Research and Development Corporation
TABLE OF CONTENTS
TIRES + eee eee eae Page
BE
|
nical Studies vv vv vena nae e eae eee
b
CMEEMOd te ei eee. b I. Gemeral Procedure. + ee vv essa ea uenn 4 2. Compound Admini+stvrseavtviseonnsa.. bh 3. Observations + svete eeaanenanaaaas 5
4. Laboratory TeStS + + + eee e sete sea nea 5 ab.o HBeLmOaCtRoElRIoSgEyEY 4se4 sssauseeessauesa eanncaeaanaasa 55 e4l. UrSeirnuamlSyasmipsle+s.i+v.ai aauuet eeuneeeaaaiiccaa... 56
5. StatisticalAnalysis + oes eevee nenees 6 J1
1. General Behavior, AppaendaSurrvivaal.n+ +c+e +. 6 2. Body Weights ves sve sue e nue enaenn 8
3. Food Consumption + + es ss esse anaes 8
4. Laboratory Tests + ss se ese saan neae 8
ab.l HeBmatl ologo y c+.sh isase suem eeeei uees a at neenr eaaayse 89
Co Urinalysis ov ve eee ae aaanaae 9
athological Studies + ov va aa eae nnn e eee 10
CMehods. eau heeaee eee aes. 10
1. Gross Pachologye + oo vv ose es one enn. 10
2. Histo + +vpsa vvt sshseosslouosg eey es 10
ReSulES. + eee eeaaeaae eae. 10
I. GrossPathology and Organ Weights. + + 10
2. Eisto +p+vasetvvhveovl oeo eege y IL
a. Ver. sa en eeea e e. FE
1D 11
c&l BTohnyemMuasr.mo.wv. a+.iesainseaeaaeeeeaaanecceanen.n 1A
FS FE
37-085
|
002095
International Research and Development Corporation
TABLE OF CONTENTS
T(=Coutimued
fgo. MSeosaelnltIenrtiecstLiynmep.h Nodesvo+ o+oo cceosnseoso. h1o0 SSkKeElQeteaelMuesvclrea. noao evaeee ooo ese
Page
1 1122 12
Table Yo. 1. Group Mean Body Weights; Weight Ranges; and Survival . . 14 2. Individual Weekly Body Weights + oo + vo oo 1516 3. CT-otnessutmptCioomnparofisoCnonBtreotlweeaandATvreeraatgeedFGoroodups. + + + + + + + 17 4. Mean Food COSUBPELOR. + + + + + sss senses 18 5. Means and Significance of Hematological Values . . . + 19-20
6-8. Individual Hematological Values. ov + + oo + 2126 9. Means and Significance of Blochemical Values . + + 27-28
10-12. Individual Biochemical Values. + oo oo ov oo oo 2934 13. Means of Sigiificance of Urinalysis Values . . + + + + + 35
16-16. Individual Urinalysis Values oo oo oo oo oo 36-61 17. Summary of Gross Necropsy Observations + + + + + 42743 18. Absolute and Relative Organ Weights. oo oo ++ 4b 19. Individual Organ Weights + + oc oo eos sooo 45 20. Histomorphologic Observations. + + + + + + ++ 4651
137-085
002096
`
International Research and Development Corporation
.
Page 1
;
1. SYNOPSIS
Fluorocheatcal Surfactant was fed in the diet ac
levels of 30, 100, 300, 1,000 and 3,000-ppm to Charles River CD rats for
3 months. Five male and 5 female rats were initiated at each dosage level and in the control group. The rats were observed twice daily for overt signs of toxicity and mortality. Individual body weights and sex group food consumptions were recorded weekly. Hematological, blocheai-
cal and urinalysis studies were conducted during the pretest period and
at 1 and 3 months of study.
At dosage levels of 300, 1,000 and 3,000 ppm, all rats died prior
to scheduled termination of the study. Overt signs of toxicity focluding: emactation, comvulsions, altered posture, red material
(right eye and/or mouth), yellow material (anogenital region),
increased sensitivity to external stimuli and reduced motor activity were evident prior `to most deaths. Time of death was directly related
to the dosage level with the earliest deaths seen in the 3,000-ppm
treatment group. At the 30-ppm dosage level, neither male nor female rats showed
any compound related changes ia appearance or behavior. Mean body
weights were slightly lower for the rats at the 30-ppm dosage level when
compared to the controls. At the 30-ppam dosage level, one female rat
showed a slightly elevated glucose level and one male rat shoved a slightly elevated alkaline phosphatase value at 1 month of study. At 3
months of study, one male rat at the 30-ppm dosage level showed slight
to moderate elevations in glucose, blood urea nitrogen and Y-glutamyl transpeptidase activity.
At the 100-ppm dosage level at 3 months, body weight means when compared to the controls were lover for males and for females. Food consumption means when compared to the controls were lower
(statistically significant) for males and females. At the 100-ppm
137-085
002097
International Research and Development Corporation Page 2
dosage level, slight increases in creatinine phosphokinase (CPK) and alkaline phosphatase activity, slight to moderate increases in glucose and blood urea nitrogen, and slight to marked increases in plasaa glutanic oxalacetic and pyruvic transaminase activities (PGOT and PGPT) were seen at 1 month of study. At 3 mouths of study, slight to moderate decreases in hemoglobin, hematocrit and erythrocyte counts were seen for male and female rats and slight to moderate increases in PGOT and PGPT activities vere seen for tvo of the three surviving female rats at the 100-ppm dosage level.
Conpound-related gross changes such as emactation, areas of discoloration involving ths stomach and liver were observed among treated rats that died prior to sacrifice. Similar changes were also observed in the liver of a few rats sacrificed at teratnation of study from the 30- and 100-ppa groups.
Microscopically, compound-related lesions were observed among all test groups. Morphological changes consisting of centrilobular to nidzonal cytoplasaic enlargement (hypertrophy) of hepatocytes were observed in the livers. Necrosis of liver cells vas also preset among these rats. The incidence and relative severity of the above lesions were more evident among male test rats.
In addition, especially among rats froa the 300-, 1,000-, and 3,000ppm dosage level that died prior to sacrifice, changes iavolving the primary (thymus, bone marrow) and secondary (spleen, mesenteric lymph nodes) lymphoid organs, stomach, intestines, muscle and skin, were observed and were all considered as compound related.
The other changes described in the tissues of these rats were lesions of naturally occurring diseases.
137-085
002C98
International Research and Development Corporation
.
Page 3
-
1m. coromn
The compound was received from 3 Company, Saint Paul, Minnesota
on October 24, 1977 as indicated below:
Label Fluorochenical Surfactant
Description
white 6x5
1pbowdteirns
137-085
002099
International Research and Development Corporation Page 4
III. CLINICAL STUDIES A. METHOD: 1. General Procedure:
Thirty male (196 to 232 g each) and 30 female (165 to 206 g each) Charles River CD rats purchased as veanlings from The Charles River Breeding Laboratories, Inc., Portage, Michigan were used in this study. The rats were distributed among the groups, based upon a
computer-generated table of random nubers. The rats were housed individually in suspended wire-mesh cages and maintained in a temperature-, humidity and light-controlled room. During the pretest period, rats were provided ground Purtns Laboratory Chos and water ad libitua. During the actual study, the rats were provided the appropriate test
dtet and vater ad libitua. This study vas initiated November 2, 1977 and terminated by
sacrifice of all remaining rats on January 31, 1978. 2. Compound Aduintstration: The compound was mixed weekly with ground Purina Labora=
tory Chowd (L.e., ground basal diet) on a weight/weight basis to provide dosage levels of 30, 100, 300, 1,000 and 3,000 ppa for feeding. Five
male and five female rats were used at each dosage level and in a
control group. Control rats received the ground basal diet. Diet
samples (100 each) were taken immediately after preparation of each diet
and after 7 days standing in weeks 1, 4 and 12. The samples were frozen
and subsequently shipped to the sponsor. Diets vere prepared in the
folloving manner: before veightng, the compound vas ground using a
mortar with pestle. The appropriate quantity of
* Fluorocheatcal
Surfactant
as mixed with 500 g of the ground basal diet in a Hobart
blender to provide the preaix. The proper quantity of premix vas sub-
sequently blended in a tuin-shell blender, equipped with an intensifier
bar, with the amount of ground Purina Laboratory Chow necessary to
137-085
002100
International Research and Development Corporation
Page 5
provide the appropriate quantity by group of prepared diet. Control rats recetved the ground basal diet.
3. Observations:
The rats were observed twice daily for overt signs of toxicity and for mortality. Detailed observations were recorded weekly or daily when a specific condition existed. Individual body veights and food consumption vere recorded weekly during the pretest and treatment periods.
4. Laboratory Tests: Once during the pretest period and at 1 month and 3 months of
the study, blood (orbital sinus puncture techaique) aad overnight urine samples vere obtained from all surviving rats for analysis. Food and water were withheld prior to the collection of samples.
a. Hematology: Hematological studies included: hemoglobin!,
hematocrit2, total erythrocytesd, reticulocytes, and totald and differential leucocyte counts.
b. Biochemistry:
Blocheatcal studies included: fasting glucoseS, blood
urea nitrogen (BUN), plasma glutamic pyruvic (PGPT) and plasma glutamic
oxalacetic (PGOT) transaminase activities', plasua alkaline phospha-
tase activity', y-glutaayl transpeptidase (r=GTP), creatinine
phosphokinase (CPK)' and calciumd. Plasma alkaline phosphatase
values were mot obtained for the pretest (baseline) period because of
faterference fron the anticoagulant. ec. Urinalysts: Urinalysis included: measurement of volume, pH, and
specific gravity; description of color and appearance; qualitative tests
for protetnd, glucose, ketones?, bilirubtnd, and occult blood%;
and microscopic examination of sediment.
.
137-085
.
002101
International Research and Development Corporation
Page 6
4. Serum samples: Serum samples were obtained for all survivisg rats at 13
weeks of study. The samples were pooled by sex and group, frozen, aod subsequently shipped to the sponsor.
5. Statistical Analysis: ALL statistical analyses compared the treatment groups with
the control group, by sex. Body weights (week 13), food consumption (1-13 weeks), hematological, biochemical and urinalysis parameters (1 and 3 months) and absolute and relative organ weights (terainal) were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torriel using Dunnett sl! multiple comparison tables to judge the significance of differences. B. RESULTS:
1. General Behavior, Appearance and Survival: Control rats exhibited no behavioral anomalies related to the
testing procedure. Rats given the compound at 30 ppm of the diet exhibited no specific behavioral signs of toxicity and there vas no mortality. Changes in general behavior and appearance for male rats at the 100-ppm dosage level included the following: increased sensitivity to external stimuli and red material around the mouth vere observed for one rat; increased sensitivity to external stimuli, leans to left and convulsions following handling were noted for a second rat; and one rat was cold to the touch (ome day after collection of blood) and died. No compound-related signs of overt toxicity vere noted for any of the females at 100-ppa dosage level.
137-085
002102
International Research and Development Corporation
Page 7
ALL rats fa the 300-, 1,000- and 3,000-ppa dosage levels died
Prior to the scheduled sacrifice. Most exhibited one or more of the
folloving signs of overt toxicity: emactation, convulsions following
handling, altered posture (hunched back), red material around right
eve, yellow material around the anogenital region, increased sen-
sitivity to external stimuli, reduced motor activity and moist red
material around the mouth or mose. At 300 ppa, death for males
occurred from day 13 through day 25 and for females from day 18
through day 28. At 1,000 ppm, death for males and females occurred
from day 8 through day 14. At 3,000 ppm, death for males and females
occurred from day 7 through day 8.
Observation
TO Npurmbaer30of0Rpatse/Obaser1v,at0i0op0np/Do3sa,ge0L0ev0elPPR
Enactation CAolatveurlesdiopnosition Red(hmuantcehreidalback) Yel(lroiwghtmateeyre)ial Inc(raenaosgeednitsaelnsrietgiivoint)y Reduced motor activity Motst red material
(mouth) Survival (prior to
istration was as follows: Dosage Level Control 13000 ppppPE 1,030000 ppppam 3,000 ppa
5
10
6
1
10
3
1
1
1
7
6
2
1
2
22
3
"
1
1
1
sacrifice) after 3 months of coupound adatn-
No. Surviving/No. Initiated
Yale
Fesale
5/5
s/s
25//55
35//55
oo//ss
oo//ss
o/s
ors
137-085
.
002103
International Research and Development Corporation Page 8
2. Body Weights (Tables 1-2): Comparison of mean body weights of the 30-ppm and 100-ppm
groups indicate a lover body weight gain at both dosage levels when compared to the controls. Moderate to marked losses of body weight were seen prior to death for rats at the 300-, 1,000- aad 3,000-ppa
dosage level.
.
Group mean body weights after 90 days of compound administra-
tion were as follows:
Dosage Level
Group Mean Male
Body
WeigFhetmsa,leg
Con30trpoplm
472 a1 (-8.7)
266 263 (- 8.0)
100 ppm
393 (16.7) 221 (-16.3)
3. Food Consumption (Tables 3-4):
Group mean averages for food consumption declined consistently
as the dosage level was increased.
AvCeornasguemptFiooond
Dosage Level
Tal(egrans/rat/daFye)male
Control 30 ppm)
27.4
19.7
26.0
19.0
310000 ppppmm \S
1223:.89
195..38
13,,000000 ppppaa*t
75..05
6a.26
*values for 1 week only
4. Laboratory Tests (Tables 5-8):
a. Hematology:
At the 30-ppm dosage level (1 and 3 months) and at the 100-ppm dosage level (1 month) hematologic values vere within the expected range.
For the 100-ppn dosage level at 3 months, the two surviving male rats had lover erythrocyte, hemoglobin, hematocrit and leucocyte counts (differences when compared to controls were statistically significant, p0.01). The three surviviag fesale rats had slightly
137-085
002104
International Research and Development Corporation
Page 9
.
lover hemoglobin and reticulocyte couats (statistically significant,
P<0.05) as well as slightly lower erythrocyte, hematocrit and leuco-
cyte counts. ALL other hematologic values of male and female rats at
this dosage level were within the expected range.
b. Biocheatstry:
One control rat showed moderately elevated PGOT and BGPT
.
activity at 3 months of study.
At the 30-ppa dosage level, one female rat shoved a slightly elevated glucose level and one male rat showed a slightly elevated alkaline phosphatase value at 1 month of study. At 3 months of study, one male rat at the 0-ppa dosage level shoved slight to moderate elevations in glucose, blood urea nitrogen and Y-glutamyl transpeptidase activity.
Ac the 100-ppm dosage level, slight to moderate increases 1n glucose (3 males, 1 female) and blood urea nitrogen (5 males, &
females) were seen at 1 month of study. Also noted at 1 month of study, for 3 males and 2 females at the 100-ppa dosage level, were slight to marked increases ia PGOT and PGP. The creatinine phosphokinase (CPR) levels generally were slightly increased for rats at the
100-ppa dosage level at 1 month of study. Alkaline phosphatase scti= vity also vas slightly elevated for a few rats at the 100-ppa dosage
level ac 1 monch of study. The group mean glucose values for males, blood urea nitrogen values for males and females, and CEK and alkaline Phosphatase values for females at the 100-ppa dosage level were signi= f1cantly higher (p<0.05) than the control means at 1 month of study.
At 3 months of study, 2 of the 3 surviving female rats at
the 100-ppa dosage level showed slight to moderate increases in PGOT
and PGPT activity. One of these females also shoved a slight eleva-
tion in CIK activity.
ec. Ucinalysts:
.
No changes considered to be related to compound were seen
in the urinalysis studies.
137-085
002105
|
oo
!
International Research and Development Corporation
r
i
Page 10
f
IV. PATHOLOGICAL STUDIES
|
A. METHODS:
1
1. Gross Pathology:
After 90 days of compound administration, five rats/sex in the
control and 30-ppm groups, and two and three female rats in the 100-
PPa groups were sacrificed with carbon dioxide and mecropsied. At
necropsy, organs aud tissues were examined for gross abnormalities and
collected in 10% neutral buffered formalin (eyes in Russell's
fixative). Liver samples, obtained from all of the rats at terminal
sacrifice, were frozen and subsequently shipped to the sponsor.
ALL rats that died prior to termination, were also necropsied,
and tissues were collected as above.
2. Bistopathology:
Microscopic examination of formalin-fixed, hematoxylin and
eosin stained, paraffin sections was performed for all rats in the
control, 30-, 100-, 300-, 1,000~ and 3,000-ppm dosage levels. The
following tissues were examined histologically:
bLruambianrwistphinaclervciocradl cord sapolretean
pLainvecrreas
epyeersipheral nerve
tmheysmeunsteric lyaph nodes kuirdinneayrsy bladder
ptihtyuriottadry
b(osnetewrintuhm)marrow
testes ovaries
paadrraetnhaylrsiod
stsaolmiavcahry gland
uptreorsutsate
hleuanrgt with
saaGll leivnetless)tine
asnkdinal(lsamtmiassruyesgland)
coronary vessels colon
with gross lesions
5. RESULTS:
1. Gross Pathology (Table 17) and Organ Weights (Tables 18-19):
Compound-related gross necropsy lesions and/or observations
were present among rats in all experimental groups. The livers of
these rats showed varying degrees of discoloration and/or ealargement,
while in the stomach, foci of discoloration in glandular mucosa,
137-085
002106
|
.
International Research and Development Corporation
.
Page 11
presumably hemorrhages were also observed. In addition to the above gross observation, emactation was evident especially among rats that died prior to sacrifice (300-, 1,000- and 3,000-ppn levels).
2. Bistopathology (Table 20): Conpound-related lesions were observed histologically in the
folloving organs and tissues. a. Liver: Slight to marked, focal necrosis of liver cells
with no lobular distribution vas seen among rats at the 100-ppm and higher treataeat levels. The above lesion was accompanied by focal to multifocal, very slight to slight, cytoplasnic enlargement (hypertrophy) of hepatocytes in the centrilobular to midzonal regions of the affected liver lobules in all test groups, especially amone male rats. There was a slight increase in cytoplasmic vaculoation of hepatocytes in 30-ppu treated rats, but this finding was mot evident at the higher dose levels; therefore, this lesion was considered instgatficant.
b. Stomach: Mucosal hyperkeratosis and/or acanthosis vas observed in the forestomach (nonglandular portion) while mucosal hemorrhages and/or erosions vere observed fn the glandular portion.
. Bome Marrow: Hypocellularity vas noted. 4. Ihymus: Depletion in nuaber ans size of lympoid follicles was noted. e. Spleen: Decrease fn size of the organ (atrophy) with a corresponding decrease ia size and nuaber of lymphoid follicles and cells vas observed. . Mesenteric Lymph Nodes: Depletion in size and number of 1yaphotd follicles was noted. 8. Small Intestine (duodeous, jejunum, ileum): Decreased atrophy in the height and thickness of the villi were noted.
137-085
002107
International Research and Development Corporation
-
Page 12
h. Skeletal Muscle: Atrophy was evident. i. Skin: Epidermal hyperkeratosis and/or acanthosis was noted. The findings in the stomach, lymphoid organs, intestine, muscle and skin, were prominent among all rats (300-, 1,000- and 3,000-ppm levels) that died prior to sacrifice.
137-085
002108
International Research and Development Corporation
Page 13
References
1. BCioaulletaehr,HeFmloorgildoab.inometer, Coulter Electronics, 590 W. 20th Street,
2. MCoimcpraonhye,matpo.cr1i1t5,6.John B. Male, 3rd Ed., 1967, The C. V. Mosby
-
3. WC.oul2t0etrh PStarreteitc,leHiSailzeeahC,ounFtleorr,idaM.odel Zg, Coulter Electronics, 590
4. RGeriatdmwahno,l'sEdiCtloirnsica6lthLaEbd.o,rat1o9r6y3,MeTthheodCs. aV.ndMDoisabgynoCsoimsp,anyF,ranp.kel113a2n.d
5. Techatcon Auto Analyzer 6/60 Micro Methodology.
6. Signa GOTP Procedure Bulletin #545. Sigma Chemical Co., St. Louis, Missouri.
7. Micro Auto Analyzer II, 6/60 Micro Methodology.
8. Photovolt PV4, Photovolt Corporation.
9. Multistix (Ames Reagent Strips).
10. SSttaeetli,stiR.cs,G. YDc.Graanwd-ATlolr,rieN,ewJ.YorHk., (1N.960Y.), Principles and Procedures of
11. Dunnete, C. W., New Tables for Multiple Conparisons With a Control, Biometrics, Sept. 1964.
i
137-085
.
no.
002109
.
Cn mm -- --
mw
oPuomBuEmEyG PPoomMmRnEhn
mmm
mBAERmGuE RBEEDEES
mm
MER D
mBEEERAN RBOEERRR
mn
Mmm mmm
BaRnEnEy GMRR
gem
LED BR
vee
2 E TE
aw Mp
TOW Mm
me wim us
homeo
We
Mea
om
SWWWLM I ws
0mm mpamm ws
oun wwen wosp
{PoommEmREaon wbEaRdEdU BBEERRSS GENE
=,
PCoommmmman BOMEER
BMEEERRE BESY
EORMRAR EERE
@g S
=
82
g
| stI mcestnltFronts ----lSer erSaSse sytasp or tc set. BESTCOPY AVAILABEE
mEwF=VTryryeeT a ewe
PoE 1 generals OLE MOB OB OBOE BBS SRE om ome
me Lome
1 73889
x
oEam
Ww
EON is 30
W300
OE38
322
NOM we dos
Wz IT
ONG dos ted
32 S06
88288 see as ib dap ae
42% A422 442 eal 448
na se 4%
458 438
mAEor ooMm mOMomOB NOBROROBBOE OMB DOM comm oroaom BOEOE OBR OB
OomRMmoo@hDoommoomw oowmo@w RoR oB REESE
[
C[p; OooRpMJmRmsELOfoxL doBoOummRe Ooo2 OBmmM moBO2mONoNEo30nE0 dOM3ON2BOMMOOMM3ROMOOoMMRe MBo3Oo8MLB2 MoME3N% omoOE40o8 wonB423 oooo4sm2 osmo4 monmooamwsi41
mBmeeErTrooowWm ooonmw moommomoOoNm oOONMw oOONmm OmMMoOmBmoomRomomoommomoooRm obmmeomoweommmoomm
E me Lx EmomOB BmEEXOL HOBmOE
oOBmR EOmR
OoBm oBmOBow OoEw EmOoEw mOEoEm
wm as
omou om om
om om
ow om
ow om wom
m Mooor mob oomb ooRb oBmOBoonOB oOEm mom ow om ow ome mom
_----
pie
002111
Page 16
[ TguostsuenslFu" srebes ies ieHoney sueyySeeeeesvaaswootseetyvsoayrBDEOSTLCIOPTY ARVUARIILLAFBOLPEE
| J BpEEYeba roae.wEy TTeadividualedaakdlybtoS dy dVeesgghesese,iparrimmese. ,
[eme rerwomoommoomm oowm ow wa
[ mE Hsios xX1h8E ooa2mo2m0) om200 a192mopined
C| ommETeoEa rTF1E8E mu3mom1Eoo2E momw16m8
me vw oloem om1m8 oDeied
C[ommmeo eTLy mmeommom omom oooeoe
[I E awe rE oyomE BmmommoEmE-mo:eo
Commmooorrroo omooowmm wou ooonoa
Sama
P LPo or mmmoe eeaomN oom2 roE8 m noB4mm2 oaoo1m6 wDoeiead ,
mm mm Teeoroe rooror omwmoowommn ooowimme oamee
sins
0000000000
002112
i
-
. SurfactantFluorochentcal Ninety Day Subacute Rat Toxicity Study.
| mms.
T-test ComopfariCsoonntroBletwaenednTArveaetreadgeGrFoouopds.Consumption
- WeTeetk
Study
Sex
Control
30 ppm
13
x
27.4
26.00
F
19.7
19.0
100 ppm 23.9%
15.84%
137-085
i+SSiiggnaiitfiiccaanntcllyy ddiiffffeerreenntt tthhaasn CCoonnttrrooll ggrroouupp mseeaans,, pp<e00..0051..
002113
wpm m Pm pm =
aw
au
mw
mw
sa
A
Ugly,
Senet scenTc msoeot SScecrenriattemperateee eee ee es5
PoE Emm BOW
Pi om oE: OBiosoH BHOBE
:
CBi2
Egl
====
i
rei AVAILABLE f f--
Stacy Say Sabacuse tac Toxicity Scud.
To
Waizs: Sesas 1nd Stgmsticaace of Bmasolopieal veiw,
Semscotony
pseeuedr
concror
30 050
100 350
seysgescrses,
aces
5.96
oi
a0
[I
Toe
13
65.550
f6.r28
p30e
J |
[--+
reas37ase
iu5ss
PLsaf
iwSome
i Resiogeuobsas,
Prac31asc
1io5ts5s
1is8s
11ea3e
LaescgeTrcas,
reag3}ent
nn23ha%
1p0x5.80
2St0ha.ie
-
i
7 Neutrophils,
Prec37ast
i07
B31
ui
Lrepma7cyses,
Peac31e
pH=
5buwe
G&e
a 7
roc3pa
o?i
::1
i31
snscy7ces,
rea37ans
o0i
aoo
y
- f-- T
rracF3alaee
5:o
o:.
Rectesttacyzas,
rec3ai se
55u2e
5u1n3
sbfxex
.sre0n
"sFiSrimmimtiitciacnucnllLyy 4dE1ifffSeurreaTnntsEtthhRaann CCEoonncteraoRll sgrraoEvuTyp B mmeewnne,, e p5<00..0015,.. 002115
| . p--.[--. Sis a ssc a Tce sv BEST COPY AVAILABE
P-- PsE--oi [x ceorns wome wosx ASLE 5. 4...
FEMALES: Means and Significance' of Bematologicai Values.
[--
see;ms
ai
"Fi
ai
I pTohs
I:.
bews
ihe
5ie
I Fe erga,
r--e;;"n
3iTiaH
iiwan :
E[ea "
smn,
rams
"
"
| tr:a, [--?
ee;;3 s -i
3:.::;
.$:i=
i3db: :.
[
:
3:
3:
:;
3;
7-085
Seasiscical analyses vere not periorass on the sracesc valve. Q0R116
Eo. FEY EOE TER WOW OE Rou
BO worwoEem
ow
of
Be
om
BoEr.i o2moowoomowBmg
somo
om
#Awm 8Aow oA F"
28woiofs
oa bor o%
3 ..
ff
#"w 38|
411po 18on5E
rr BR
,
.
:
.
oe mm mm ey
Bfne
se
WeEeLa T eJeETW
eTiy i
Wm TR
ie
AR
ee
op
ame
al
ei
Tow
w -- ormE " wt wa 5 : u 20mm
Ime od" oraz moo" fo5me ownrs op. obo F"
Swomy r+ ommw8
BBoOnRLnLEL pen "a"
JwEeoomwA oom aon
fiied wanmon a`
"
wi oun . "
i soe e" onna 2
oF p b ww E=g
P Fo Ern
.5
.. o. iFie g
' . ER |
me
ree
repens ee
Me whe TU WNT ER ge me ee geo
mor te = Fe
Ei#
S
Bm
HS
wom mo hos omo3 soo 8
8 HELL: 4B
8
3 md
:
i
ST
:`
3
pre
TT rere
-- wa im
en been Jee afm
werabile bbe BEM ee
feats Mw fa Rathore ol Me
jem
BoE
mow
=BZ ii ==
Bed om
Bi =
888
s
mn
g
g==
==
een
i5
,
ne
on
Foner
wwe bem FT
we VT Time rer me ne besten
MR GL FF MS ome my
oe i
Boi
EoboB Ti v ae
om
an
oF o
Fos
we
"
wo
#5 PF
HGF omen
sew
.H
o
"
1 iii og
foi i
ios
'
.
og 2 rd 8
wn g
FR
gm
n
SO
7 om
on. wa a F---
. oe
Sp --
10 matt etm mtse me 20
"
staat
Go
Metre emt
MFeor sex able
enemy
Wea Geo Mestiomila who fester Mem fn
dene SCT
ES
Sethe oe
2 mo 18 DRo eeio
nn " bea
BiB
83
s
B= g=
=
g
i
_
BESTE
. JSaurtracscas:t[----_------ Staacy bay SubacuI te fac Tostetey Scudy.
Ta r ee
HALES: Sains smd Sigatticenca' of Biochemical Values. Seusy
DLoo ocmticry
eSeaech
CGonetroel l CL Wwoepe
PGlR ucose,
Peac73ese
n="z
1u1mmo
see/i,30 m1
Precast
5
mw3ia
11w.s24
rSoira.tessa
Prac13esc
1i2
151
CrSaisoctaanaetcPaos/pahokiasse, Pre1cesc
nrl
3
n
u1
cfoa.e'.).dates
PrecTese
w95
3
01
1w0m6 3
PoLarcti.laters
PrecTese
3
i9
sai
Catneetalum,
racTesc 3
foa5r.d5
wa5.is0
Alktaalei'nlewPardoesaslhacase,
PacT es 3
166]
k1e30
rage 27
w10o0 mpra n15a80 un 221559.0535 211 @1 5091 % a33s 1070.1s61 2193
-- e7-e08e3 e -- i -- S"Stignattttiiccaann-- cciisy ddiifttfaecraannet-- tchhaann CCoonncsiooll-- Tgrroouupp sss eeaann:,-- epp 0OO03.. ------ ---------- ---- {5octiedsnatsairoamliantdnut1yaaspsraasecaet ssoecracdondeuccactaads53ofchseacplriaocaegsutanv:alumeess.cterase. 002423
; sualFuses
BEST COPY AVAILABLETM** ** ity sy ues be ete sr.
-
CE --
[Crp ry eT,
Fw=o
ae:
0
0 1e
Sorta re
gA;e enn
82=2
@w@ wa
"p8e at
Siow
T3
53
EFHo]
+o8n
i wires
v
:
i
:
Cortmten Pompeione, Fe$3et
$::
43:
3E;
. When
agT:
25
Fiw3
z-x
_i-- in
rr
stm.
eae
a3o
Ph83 2
oaFi oa
un
t:
E2S1
321
&3
ie Alkalise Phosphatase,
Pracesc
"
"
um
--a_--r--s
SE inn eT m ne ae -- mm nTpY2
Sm nm
hsE! STCOPY AVAILABLE I te5een?d[-- s sim soy ee em i- r
- so= _ tun. lpoemeairPsTO tnrsoy T Stesr.E 3.ex.TeestdTeS. tcr. BEtS. TiCoip .. .I .J*
CoI=mBe tsee wRoiwRes wSvilenesseweirSmeihnae wSiHEEdT.e wJ iEeNn wEUlRDEDd WcHiE
Ho: og H
i
mwpoolarroowwIm n3-g:
}:;
pmZooloorron=oz E=s
:3i
LTeeorx oomm owma
13
morgan
f
pw wohlor rm m- Emge
:{.
=o:
i
i
foee
5 ea . :
3: % 4: 82 5i8 -22 "4 "5
7
P 8 =y B3 32
ym
2E "uo sWn vFIFE ou2 5wusoH 8 n I nuoa gu nm
-
TTI nnn
He
002126
;1 sseeteaserims
Er
MsTteoontoyotwiysSSuabceaseemeaicseamleTvoaeniisCodc- f1eooswkseys:.,- BEST C0OPYTAyRaAjiDpEg- *
e MBae se aGfeion anumaEee EsecVriseeit TctSiEEfwieaTEiRn nR ereerRD a Ce m El
poet ncests
a
TT ee) we wl wen
Tae x ome wa mein i
s i
1 1s PET : 2 3 ow
Waey wmo omwe
::
25 Fwd 5o0w0e0 aBe
mn rom me
:
w as ow
mmsoorromwm Bolm
fpropl)
wwe
jiTdmeaewwooyo4 w aaim
nBads 8
-
wo wa
ii
4: 23 # FR 8 9
:
. 0 w wi ow
:iii
885: 35%5 i s FL E or umm aow
: 10 po was ae
jWoe FR2 wieH
i:
3u wir B a WaR m
me BM
}
3 mom nom
ase
wo ws
:
" mows ve ome
BEoFO 8
i
i aon oB
ererrinin Samora wre
002127
- BESTCOPY AVAILABLE * ;
|
susmutrtamaacananet
-- BNE..n.ay5.Ouy subacute tsaiTosniite iTest.: Cotividual tiocvmicet vets - Lene
BL ce
Si He ee
--
o fGoMreoersseu wsGhpeieoreslswwnswe .e stsehwwwoiirnreee waliimef weiemn weiTiEdnT CcCaleel wEiS5ed0n
20m
Lommary hnme EEA
mE
ua
mEor oud
Fran 1,000pom: mA h oi he
WET um 2.W000EgmF: ou
mwmemeaory ooonuee
Er ----
hi
.
002128
. stJ otA Fry
mea ae s say aseee ssaFTooss e 3siitB:Et STCOPYe AVAILABr LE cc -.
[dm BpH=yaawssee wSmiSeLhwMiandeBaeeseWerwIoerlhesieaedewdBeimEfsaeewwSEi0wNT0hwmTiCTETNnT SmaesTee wrTiMErRiTThp
emMTeEorxoioBwom owOomH Fr
ii1:
5s T0ow%n03 p8oBow oBoBweer omw83m
mm mooenroomyoooma"m oewoem
:: ;!
B4C Powd8 = 3oxn m owBm uh Bsom
mwemoe orrA oooomW moo oEoh
:i} :
JL p ommoa 8 o8em o8 nwns do4w
Fm m Toeeeoxrnoow usEome meooyow i
y:3}
iPPsooooweE o8a8r3 mwo0sn8 omomouBm
Wmmoemel oorioomwxwm oama:mOeH
moro
HE
3;i ::
P; ORO0p RR8A 8 BBHH oipn= Poop og EB
mm--eoorroooo%m- =Eodm yell
:I:
4 S ;om a2 x8% eBBYD on8&
ma B m=oooI rr WOnoem B. :. sw omwow wese womm
=Bmwaooes rrrI owEeOwmR b=e
:: .
w Snwwa m ower aom om ee we we
moeore-
:. Bsoowm mwowwen wm
- n rp -- nn
ara
002129
- sb urtace tanFtluorocheate cal Hiw ncy Duy Subcace taw c Tovi2tsy fger.BEw ST COPY AV: A. ILABLE +..ee.
FmoEolTNCoivtiont Sivvmetoiese3Saontar Lo IFbrme Ssee sGBieOeeOsnS i smwaiaW Rw stsevsmewariieenalld wciSUinLTf weiTIneENnnT wwiTisidEEsSDeO.El wSMiLLDn
20 am:
mhooi ou
EEA mE
1
ooues
j mmEEE oror hhee
1.000om:
wWmhooyy oonnee
mor oa 2W.00ozenre one
Jr
[JeEr
.
mio ous
mobo
= rere
Ee
+57003
002130
BESTCOPY AVAILABLE =
mw s=J at=eorPTe unTees tTe ses se mSeaenarys sol eabeeu to tt oc rtaee mst u a ewase r
w--e a
WEES
eewee
woem
ewomm
_--
g3en
1i
i2
23
t
2
i
i
otis armas. g}en
hHEo
fbodu
tHeeu
om IRMLES:
oan
1
1
1s
ste cami, og:ee
iton
jo3n
WTe
ran
FLAa RE mrete
he NT am ow HRMDOSDOMEONIY OLUN ERR NDR ae
Jit
mero
owe aim
mBooir HTboomR oHm EE
ogBom
Guo
BEL
HER
or 31 11
or Pro OYvu
RIES DTD
FEST SAR
"
;
PnLaA T
P[I E
g2
#
i.
CoE iid BHEF DIODE PE
v
v
i
eo
Bd ommy HE
" " -=
ig
EL nr
homo
omomowe mom EE ee
. g :
:
ETOH
!5
Brom m[TEeTsornos u
mB Seb EEE wes
Ams ow
vom ow
for o@oroe oe. omy
~
LE ow y w
Ww
-
Ey
id Vw
~~
ro 2
Pg "
=
"
L
WER Mn momororoioh od
- 7a
]
P=
BIE mam: ror 2 =
oa 1 B
s
g
8
me A Fo
Tree
eT i
Ea
a
ay
mitre
i -
2
B un
< ig 8
o& n hr fTA aImeEr orm. B2 EEe iTnE
TT ------
8'
8g
- tz
Eve mom momo nome mom ow
FE
rs
. "3
gig HEE
B[EEa E La
IIL.
1 01
a. .
g
88
EW bie
=
BEDE ee we a
ww
[EE
moo
i 2 g 1.3
=
E
B8 op emt
8m
Eiffen, Slew FES
z
EL om Emo
pr
omomnow mow mom Mowe
TT
TT
sm
miyoE
gg
m Zeionw
g=E
<8Bo
E
Firw
EI Ew OE
EEETTTTEEAL RE
,
4
.
Starts
estes ee
TU
HintBoySobbaa Toney Sty.
eT
'
my on
a
eee
tra
n A SHEastt.n eTs T , T t' of ypeseatafcongestion
RE ne : RL LILLI FE ------------
+ 2 compat to oo 22 B E LSL aycecleinitambetbdrfmombuilaattbeontock
'
------------
Ct.
8B
Tr aa22
Las
N'
E =
: Po !
E
sd
Tr
tntn ty se
fr --------
a Stb aebitinne t
5
g
=
g
==
8
-
Eg
:
medTr neet sch
TE
eee emer SS ott) Mite Oty Msg ep enges"
SE TT
me EF gee pws pte pene peep olin peep --
Wo
--
cy BR nN LL
:
:
mm mn sn oru orn
!
28
Bo
; a
8 = =
=
TR Wt at: e "EhEtSSrsfo8 iSey=2e STO
Is
:
CE ros om omowmo# 1%
:
i
RB
Bom BoE FF ig
i
Ber
meee
ee
mmm
TT
TT
E ow RE TT ee epee cl TTT TNT
EET neo eter i og A eet 3 32Brz east2 ? 2s " faats
EEE L tbyt i w 1P Te To TeE iinnccah!secpiuvratsbcraonecshiyayompphtost.dFI mt
1D22E 2 TTE III
!
=
b: igg
oEeE
LX E KNXSEEEXEREE E E NE RRR a ARN
EoEnE Tee : Jorn 58
eT TIT re mr rE --------------ree
deers
e2 ee=
8BetEelemmepeemegees
ar
EE EE
mand
Mtn
cL ee mm Cm OPRRPPONPPPPRR................-~. SOC Sa BERARRLELL KEfhRtiite krsksteses
ety
TT TTT rT
io Bo Rm
Shit itn Liriin, 3 a aa 8
T srrT p--ini +g rie
nT R=B
rh Tan motor el afGrnn 1a
:
s*
=
estaes esse seeseeses5e ERE 524303 tot Hea erate RTA
E
88RO
ibsee inm- mmoo-rooem eerree oers
meee dd LALLY
TI$I3I5I0I3III0G3 T
ALINLAIN IIIA IAINNY.,
TIIRIITSIIIEIINRLELE OSL2T0T5000
= 2
i5
8-
bm ne a 30 Sd
:
.
TTT
e xrr r sr errn a en Miai eiin n.
re
ad BREERSEREE BRIRIIIMR ppiisiees
J CmteSmS eeI TTIL RE y ve
mcm pg,
TRI i fii
:
>
t EpI p risen 1000 0TaTre
EE ad SUPRIALE ICCA
88
og
E HEE E.. ees. 00
yy
ree patsr rarer
&
2
3 aes nee]E .
TTTTTT LFLRRReLeLeEALE RrtRmRoeepemeret nrrsEewnpieiire
ls
Sattar
TE rrr ae
ittetaes terioeirirAtreteee
AAP i i daa ta aan
Se, a a aaa,
' i PB oanrw FcrtansTRm See t ren,on TiaiCmhmEeEE rEs3EEes. Tea mestnsin. 2es8a
TE BT I swe * 12301
=
mE facetytmtasaesacra of Lpatocytes
: ie Bay vrs te
Cor
= or =
B 5 E eee =
Co
:
oe
merfrees cexerxa xannnn Bhakaetten
"re
Ga BRRRRSEEAE PRERRRRRR RRRERH508E
Eopene
TL
Me
Tr
TTT TTT
ST. Te. =
=
i
B
3
`
Coke nti pnt = mre
| od
ewes
Mc ----
SSE
|
HERE REALEAL RRERKALLEE RERRRALEEE
m rr FLdAS BERL RRRRERERRPRENRRBEERERERRSRRERRERERIRAEEGRRRRREAIRRRRRBRRBRERRIM$RE3OA3RR3NI3YE
EE fo Rp------
2
or
:
yor
[ret
Co
.
Sw
ET I Tucal cpldarml -- scotiian
5gg 2
Tia
EEE
=
Doorn
IMM 1 31332 aa at1e ar
TB
conn: b7 ea4dss !sr - BB
=
I
-B
:
4
