Document NEGrJNLEOvLy3pnZBzXEw9ebp
BEHR - 0800-373 75 OAR26-0958
ogy AL
Draft Report
".
;:
26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic
Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys
ePa-OTS
Le : 000811795V
i
g
& =z
PREPARED FOR:
TM
COVANCESSTUYDY NUMBER:
VOLUME
3 ox
1]
2x 33%
2
CL
003138
SOVANTETM
Sponsor: 3M
St. Paul, Minnesota
"UNAUDITED DRAFT April 12, 2000
FINAL REPORT
Study Title: 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid
Potassium Salt (PFOS; T-6295) in CynomolgusMonkeys Author:
Peter J. Thomford, PhD Study Completion Date:
"To be determined
`Testing Facility:
Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification:
Covance 6329-223 Sponsor Study Identification:
3M Study No. T-6295.7
Volume II of II Page 502 of 821
:
003129
_--
CovaMnIcMer6T3a2299.52273
VOLUME II OF I
CONTENTS
Page
APPENDIX Individual
4 Clinical HEMAOIOEY Datas ... ,
S04. 505
IInnddiivviidduuaall CClliinniiccaallCUHHiEnMaIlySsTiYs DDatae..t. ...o..meoomo5n6s65e37
APIPndEiNviDdIuaXlS Palmitoyc ] COA Oo XidaSer DECTTs UNAIOe NS...s .vcve vrrrr, rnr. 668856
Individual ASOD PathOIOBY DA...
690
APPENDIX6. `SumanmdInadivriduyal Blood HOMMONE Determination...
169 770
(Cell PrOLfETation REPO ovvvvvesessssstsss8,09
:
503
0031490
-_--
MCovTan3ceMe 6Ts3-2692s-92527.37
APPENDIX 4
Individual Clinical Hematology Data Individual Clinical Chemistry Data Individual Clinical Urinalysis Data
504
003141
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:
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Ses 28
BE
MOAN WD. BS BD. 0 em me men we
88gS a2
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Gro tone eral 0.95 song miesmney
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Group: 2 Dose Level: 0.03 DosageUnits markardny
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Group: 3 Dose Level: 0.13 Dosage Units markerdny
:
`
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FOHOCR OF 3d fe Sb de PY
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:
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8
sis
888 8
si
BE HT SL Wa Sh Se rT Tm wm mm we Grow: 1 bose evel: 0
`Dosagetate:warsatons TT
mm me ee
Grow: ose Levels 0.15
`Dosage Unit: me/kasday
:
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5gggs
&
B7
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T + & P of
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Individual Clinical Hematology bata
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BE af BOY WRN Me TE.
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Dosage Unie: marigsdey
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2a28 525
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cores 2383
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&gc 8
&
526
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Dosage Units mararany Cm
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BoM: pb Be Ee bono EY
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888 8
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Be ofl. BOONOR ROT J. TEE.
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1
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82
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:
sams Dose Levels 0.75 `DosageUnit: maraiany
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8g8 35
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Tm mm
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8
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=
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8SEH Ch 888
hw df @
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ossge Unit markarsy
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3 883
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Dosage Unie: markardey
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Grow: 2 bose Level: 0.03 Dosage Unie: saskasdny
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Dosage nse sarkgray
or
Gros ve tts 633 oon nts marr
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8
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s
Boh Mla th
288 3
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Groupr 1 Dose Level
`cosage Units markesay
TE TE ------
Groups 2 Dose Levels 0.00 Dosage Unit: markesny
`
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Groups 3 Dose Levels 9.15 `Dosage Units ma/kasany
:
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Boe HO
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&&88
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Crop 4 bo tots 078 ane is manana
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Grow: 4 tov evel 0.5 ease tn smarty
covey PIE
88 888
3
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Crop 4 oan veh 035 Sona tits moar a3s 88&
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Grow 4 bonbowels 075 Onan ates mer a28 &88
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-
Coop 4 oetel 075 oan ons moartny
eas ate on is mr rt mein sg a &ggg &
Crom 3 oesnes +
tes ou 25 Jp --
g 8&& 3
sree 4 [I
wel US
g8 28
88s 8
i
ress ou 20s
wl RI
oe
78
is my
ggs g &
a Js [a
ws en's
i nen
al E60
Go 4 nets 035 one ts ory
eg 8 &
[UR [---- Gro 4 oetals 075 Drea ties mtorr S&s 8a -
er mit Swi sn -- 8 &8g
:
gs
ag
reer
nl SE
Crs3 tose ahs015 Sonesnk: mus
Grom: 1 boseLevel: 0
Dosage unit: mo/kaiday
or
Fe
s 3gg
|
sermons
wa SET PE
'
bd
Se She Be He be Be Re de
Grom: 3 toe belt 015 nang Snes monary
aS 8q @
ee
PT
.
ort en's
i en
ot rn 00 soi tn
82 G88
g8 38
|
rs
aE PD
Grow: 1 Dose Level:
Dosage Umit: markerday
3 tts 055 ne it, str
Crp4 ts 078 oe es tr
Tm
8 888
| i
|
ie oo 2
Grow1: DoceLevel:
Dosage Unit: morkgsday
meme
' jo He Me tn vn em oe a a, wm. a, ow
88& 88
[mp
>
pass 1 ose evel: 0
Dosage Units ma/kgsday
Tem
re mr 0 ns 883 38
me vier
ET 22
et ein &8&8 &
a
.
ms nt 1 Dorsoe tits martastar
wn 2
TT
Tm ----
g838 38
rai mes se s8 8 3
cows tts 6 wanwitsoro row 3 bn tore 035 nn nis ater oro4 sn ss 038 ae ns sotto
88 &
|
Group: 4 Dose Level: 0.75 Porage vast: markesdny
83 g88
:
:
wren 4
aw slur PEI
Grom 4 oetoed 075 One ics mney 288 8a&
oven 4
aes ou 6
aw sili! FEES
Grower 4 doeteks 035 Sonn ies mney 38 aa8
8g2 88
aes oo a 28a a82
sermon
nS ES
888 &8
oo A
3 888
amon 4
Crops 4 men trek
[oe --
SH PI
28a a83
1
I
moa, aa ene, en, ae ae ow, om
3a @aa
ba
eh Ba Me Bd hh Me
Gr3 tes 035 ongon maar
8&
a& 3
seven 4
ow sel! PEE
Gro 3 tose tev 015 Sonnethts moras Grom tosetev 075 oes ens mana
288 @2
|
soem
Grom: 3 on oats 035 One ties rb Gros 4 oe toed: 035 One tits mbar
238 B42 \
aw aS RE
JA 2&28 8
Crop 3 bon tents 015 Conan ties mba Crop 4 bo toed: 075 Oona ties mbar
832 &a8
Gro1 oretev 6 [op--
Grom3 tosteal. 0.6) esseunits muarter
GED: 3 ctoenes 015 bossatics manastey
.
i
ER
a88
2a
1
[a
8828 &
a
ms
033 mn ts
Geoupr 4 Dose Levels 0.5 Dosage nse: sarkasany :
8&28 3
@
| g8 5&8
ste
cst 22
wee
ee
cm 3 tos 018 se ats mat rp 4 etic 078 mn nits mat
so
es i in
|
og E
ers ir en nn
CA
SA
. 2g
; bo
-
|
[Sp
823 ae
on
:
Gr on tet 8 oan ts sori
Growp 2 bose Levels 8.03
`Dosage tai: ma/kaldey .
A
FS .
&8g8
g
0
Grow: 1 Dose Levels 8
`Bonage tai: ma/haldey Trem
cco 3 ne tres 003 mean ins samt
Group: 3 Dose Levels 0.15, DosageUnit: marngdey
.
Gr retry 075 me nts tt
882 aa8
ou
Grom 3 Doseeve6.s05 Sogn its mbar 222 8&a
os
oor ves a tsmaa a888 8
si
Gro 3 tosetev 0.35 soniesemanan Gr4 Does veh 075 neetne maar
2 a&8 a
67
Group: 3 Dose Levels 0.15, Dosage Units me/koidny
:
g8 aa
os
7 a22 a&
rp [a --
DE
TL J------
Gro3 oa ev 05 Soe iss mbar
ot
Aspentin
Gro 4 bose veh 015 ose ts meatier
Covey BIEN
832 Ja&
650
| &e &a
Iivioun cites risayete sia ress oa
Grom 1 tose vet
J--
Gro 3 tose veh 0.35 neeties maarder
651
Grow: 1 ose Levels
Dosage Unit: ma/karany
Gre 3 entts 3 on ots sein
FT a828 8a
mies ow2
Geo3 Dotloves 0.03 Saniesgmae ny
Go3 Doetere 0.5 Saniesnhe n
8
2
v
3a
88
653
:
Cone4 res70 eemissat
s g 28
ost
vin
ha 1:
Gr toeto0s9 Grr 3 re tvs 013
mitsn rin ona nes sary
FC
&&ge &8
as
|
Geo 3 one tents
TR RE EE
Group3s Dose Levels 0.15 ose tases marmaraey
-
2 8g23 a8
65
Gro 1 ovetev 6 [----
Grom 3 So tevets 0.03 Soapontsurrey
Grom 3 to devel 6.15 Soaponi sere
j= Sho
388
24
657
:
Grom Sotlevels 0.75 Soap nies arta
238 aa
658
cart tos eeeois ren
Group: 3 Dose Levels 0.03 Dosage Unie: mararny : Growp: 3 Dose Levels 0.15 `Dosage Unit: markarday .
Sr tontos 05 em ots eri
mE Lo: Lf
822
82
9
'
:
Gioup: 1 Dose Levels 0
Dosage Dait: ma/kgsny
mm
Groups 3 Dose Levels 0.0 `Cosage Units markarany
:
Groups 4 Dose Levels 0.75) `Dosage Gait: makasey
:
g 28a g
0
38
BBLBoEEh
g88
+ sot ct oy 1.
wl
Grows 4 tot tevets 0.15 Snape nies surrey g22 &&&
62
Po
ons tie, saosin
Grom 3 oe evel 0.05 Gro 3 tote tev 0.15
Sonar ont surrey nage nis sare
Gro tose eal 0.95 Sonne mies sn
2
+ iecoteceeson soeu 2.
3a8
S
os
|
:
2 3g
Appendix 4
or1 teen tov Doesnt: mygrday
Grow: 2 Dose Level: 0.03 `Dosage vate: marva/dey
HL + em
a
cos RE
Tr
.
arp 1 oontev 6 va ies mas ha
Grow: 3 oo tees 0.03 ons ontsurrey
Gomi 3 oot levels 0.15 naan nimenaraey
&2
jo=w 5 a1,Cl 8 ae hns
38
os
Aopentix 4
ores EEE
H &883
66
Gro 3 to tots 0.13 onan ants surrey Go tote teres 0.95 rage nies are
832 >3a
1
|
--
co 22333
ra pm ------
Ff
mt ---- m----
822
d
Ps
|
2 a38 &
Grom 1 to tev6 ona ies man roon Grom 3 So tel 0.03 soap cnt sure
i=
Bx 2
6
Go Dose eve 0.95 fragties mbar
238 aJJ
on
J ---- oon ce, sahastny
Gro 3 mo levels 0.03 Gro: 3 coetel: 0.15
onanont surrey ones tits smarter
Gro 4 oo tevels 0.5 oss wnsmeariny
88 38
on
:
Grow: 1 Dose Levels 0
`Dosage Date: ma/kaldey
rm
:
Grow: 2 Dose Levels 0.00 `Dosage Uait: marha/dey ot
Grou: 3 ose tevel: 0.35 Dosage Units markasdny
:
&882 33
wn
| :
2 &&3S
Geom tometev 6 ne icssro
Sn i 00 i ty
Sd i 025
is ty
iow
BspomWpW Th
on
ste
og 0
:
.
g38 28
a
:
----
Gre 3 sor tev, 0.15 aap cn surrey Grom: 4 oe eels 075 osm tis maar 288 828
1s
tion craton sisavel ova
"
oro1 soe tee 8 [----
Cm
28a 828
6
crs
ona iessrn ry
r
ow Ip
g83
.3
on
&2a on
Fe
Ei in Ei in g5z2
"
Groups 3 Dose Levels 0.15 Dosage vast: makgrtey
:
&328H2 a0
EE TEL, pe wer
3 Doete0v.03 nape nissare
rd ts 035 en ns mi
o
=
Rh Wh
8e3
*&
ot
resis tag 103 Gro tovtev0.a95 coupe nitssane
aSs @@8
2
Group: 1 Dose Lave: 0
`Dosage vai: nares or
Grow: 2 DoseLevels 0.03
re 3 tei 033
Dosage vast: ma/kardey :
enn es mri
Gre 4 on ert 073 tae ics sna
g23 8g
a
pnt
wonegs SUEY
Groups 1 Dose Levels 0
Dosage nic: sarkasdey I
Grow: 2 bose Level 0.03 Group: 3 Dose Levels 0.15
onsge tnsc sarvasny ot Dosage Unie: markarday
.
:
oo . So aves 0.75 Dosage Dait: marka/any
:
88 28
o
| |
2 888 8
a Cran 3 oe ts 0.05 Stan ie: marr
ames iro
nT SEES
g8 8
rats w-- ------------
)
tr 08 sss iy
8 $8g
!
rt ots 075 vn i srry 8888 &
! 8 & &
1
.
rom 3 tretoes + san nies sng
82238 ~
|
|
g8888
we
aE SE
A
| 238 a2@
p--
SER RES
Crop: 4 Soe teks 038 Sonn ties mn
! 288 aS3
!
sti csanronremn+ inte
eT
883g8
,
com +eca 08 Swan nes mv
88 38
amen
)
cr + me cos 08. oven ts rr
com ett 05 se hn, nar
wa
3
28228
23a 232
'
3tere 01 Sone nie. rr
43 a28
88g2 8
crop 1 toe tents oe nies mn Comp Du Lew 6.18 onan nis sorta
382 a33
i
--
EE 2S
3 &288
383 g3
soreane o
wel RE
Gr ton bev 075 onan nis marta 832 iaB
2 8
BR
com mates moe is nar 883 g8
soreore
aw nel PEE
.
PR [--
3a2s a8
!
a Tadtvigual Clinical w_Srinalysie Data
ne
oro oe teks 478 sean ont: sana
288B 5
}
ot ---- so------------
,
om oo v5 i tn
82g8 &
/ ' 238a2 >
wo wes ign on
|
aman +
wT EEE
.
ct rinse mie sen
:
cn 1 owns a vee ns
coer4 vt 874 a tes ttn
g888 5
wre rr 4 nts 078 oe es rir 82g8 &
ped
|
|
. .
B2
orm 4
aw selma: PERE
Crew 1 te sets
op--
Grom 3 oe eels 015 tosage tnes mbar
|
:
8
nti hsnemin re ow
Group: 1 oce Level:
Dosage Unit: markoidny
,
os tein omen
peg
-
g8 &
'
-- we me es
Grom: 3 vto wtr 015 orn ones maha
382 a88
sere
nS PEE
Jy
'
Cow 3 tt 018 ati rr
rnp 4 etic 075 on es mtr
82g3 8
J Grom 4 tn bevels 075 ora nt mana
342 a8
|
reese nu 156
Grow 4 ose tna + one ies mbar
Geo 0 oe els 075 ne ontsmaae r
a32s aa
|
remy +
PT ante
ta
,
CE en ein
a TE
&2
|
3
g8
J
| 83 a8
Crop: 3 one tet ons tse, motor 38 a<Q
ats oem sn pte 388g 8
|
on ne
ncSome EgEeSn
Grn 1 tm 8 toa its mbt Cron 3 foehs 038 ene ni arr
00 et sry
2 882
|
sormre
SrEmp2--3
Cre 1 te sets J------
28 a88
os et
aono 3 bose eves 0s hn 4 Dose taverns 0.5
[I
Dosage Units morkiany Dosage Dat: me/karany
me
: :
2a2 288
APPENDIX
TrConeei 0T2as2s3s
Individual Palmitoyl CoA Oxidase Determinations Individual Anatomic Pathology Data
.
pe
03434
|
Gro 1 tos tes 6 [---- Grow 3 bontel 0.69 nase ntsmeatinr Gro 3 tovseve0r.1,5 oss tntserie 3a2 a88
6
|
eis
ces 5)
38g 3&] I
|
enti wes [----
Cs ie em Cs a on
gg2
~
a
|
Aspentin
cos 23
So is 635 oe ns rig
238 A8
2
o>
BI
A88
83
0
[
38 2BS
I
34 322
0
a832
"INURE, Dw TIOCKTIC, Nn,
&&
0
88
aws &
0
i
23a 22
os
| |
:
"HrrEakrd, LreemonIsTIOCTTIC, INIMAL, WIFE-FOCAL
&
82g8 3
on
288
3
a
382 &%2
2
a88
8
0
238 aa3S
01
ee
ERSET rn te
sire
o888
RT --------------
a[4
TM
EE
382
oti drape
a8
08
23aS aa&
04
238S aa2
05
SEE coma, roam ra 33 aa8
ns
2 a488
o
SO
1.Re
nm
2 &88 3
88 a&&
SEERGy Ny me BE
SR Sm ne
43 8aa
288282
Inti acme athlon Baca
hi
JR
3-1:Ky
nee
882 22
ee ER mnT roc ssc
-
EEER ESEEE Re
8882 ?3
eee
teint ousnie rare maa
0 EYSOF FELT TREpm
EE
nen
8882 83
Inti atts ecstons Bata
RAST FETS cone
Sgt SE
[oe
EEL LEE SERaSal
2ggg3
EE 822a
Indiv dnstentc Baolony Baca
RI
pi isis oemn 3 eosinpos
'
:
22822 2
Individual Anatomic Pathology vata
Ed
EE
MR EEE
.
58g8 2
382 2&2
[Tr ---- ee EST RSS pare
ha 1: er
2882 82
EEUER BNoe BO pnne i
822 3d
tetas suse paratype
pe
I ER REL T snone
ne
- {h g8 a5
CREE
ET rs re
` 828 5
Ei wrmmee rso
o
3
foci hat
a2Se
&
"
238 a33
ns
a8a a3
6
]
s
er ML --------
83
3 m
8383
3
TM
23a a53
"
tris rm seen
52
38832
70
2238@
228 82
TM
I
2
Brits somos, ra,womars
882@8
EE
a28 aI&]
74
I, TR emer
2282 8 ns
pe TTL
&238
&
ns
28& 2*
TM
o
CT ------------
382
%3
EE
3a a2[J
7
382 2@@
0
238 4?3s
1
|
Eividunt ates Fathteny baa
RI
.
LL
22a 82
238 82?
eee ENA TIT eipets mre
ne
SERRE ERI an 5 Hd ey om nc i cir
SHER snanee un 2 nins 1 mnie ens
E
822 &88
re.
rn EELA oT se
ese
-
EEieSae m SNERrSEReAno REm TaR `:
38g3 2
[
g22 g5
ee ET EL re see
i
EERE UOTE EALBLICOER WEIGHT 188.5340chaBv1s1 VoL 15
TTT
3832 33
ee ET nnT ste me
-
Ti,mmm 8822 %5
288 2%
8a82s
mmaris RT LE
nes
&a82 8g
Bimmer cis, wsrins ous se, 12 pre ee TT
2
TEERd aorro
&g
ver cy |
ivi Anatomic Pathology Data
Li
R BTRSEtTHRGEeV t J Sedl o coe,emtIanReaRn an can nn
en BEE BERTR Se RR ME lt,
'
:
228 8
REAR SE EE BitEARAESTTT SEP TY ce
&832 8Z
| 288 aS=
To inumes, sme wesotnwns re. ?38 aa
in tanooaeee on
]
BRLTSR IN, mar mmaomsourceeessoumese,ao
382 3ag
.
ESAT
38
3g =
2
ag8
@
758
382 a23 7%
Er] ce. vomve 82 as2
RT -- "0
FL
8&a22 BE
|
88
a
0
882
aaq
13
76
8 =a4
6
|
828 aa a
765
AER
3
igB
*
6
ga aJ
0
288 aa
768
&388 %
22a8 8
88 8&
8a8 8
_--
wmCorvanIecMe 6wT3.26s92292537
APPENDIX 6
Summary and Individual Blood Hormone Determination
Note: This appendix contains information supplied by Ani Lytics Inc.
769
603523
Sms s-- --------
mE BE Ip BE OER 8 iE
mM
mmo om us
8m
BE
uhh
Group: Wale 4 Dose Level: 0.75 `Dosagevai: makarcey
or roe 1 retris 0 oe nies sears
Gn rte 3 ne at 0.03 oo ie,man ter o mw ak HOH un oi ii
&
m
CT
wi i
ry 1 ngs srr ation
Group: Pesala 3 Dose Level: 8.15 `Dosage Unie: ma/kardey
a488 3
m
Group: Wale 1 Dose Level:
Dosage nic: sarkgrey
ori on es 00 etee mr
anes enn s-- o --
o HE OBE ix EE gE oR im
3
LE: i
TM
CS
[EI }i
Group: Male & Dose Levels 0.75 Dons Unie: sa/korday
oT
A AA.
3o dE EGEE HHEOEE OBERYM IB iom
8a
i Ll
i
TM
o in i
Ty ad
coo rei on os 3 me mis in
Comevi 8 tn et 07 sve in ur
.
g 8&
ms
|
g8
mood
Hem I
ne
8
i if
com intonaen oi
Group: Female 1 Dose Level:
`Dosage Gait: ma/hasey
Bao
ome Bf OH HOHE HO
g m g Ss mwunEh Eamo gmmh owegmosme goma
`
o
o
om oo
H oy imTe
i"
wom
Group: Pemsle 3 Dose Levels 0.15 Dosage nits marke/any
Te
re: re on es 07 ents tr
Eons i BR OWE oi i ws
!
3
8g
TM
Group: Wale 1 Dose Level: 0
`Dosage Vat: mahasdey
CLL nel
Ee tn li
gs BEBE OE B"H OH o
oomn
Em oa
100
om nas as 00
on
Sm
BOB aEss e)be
oe
Elec
Grow: Wale + Goss Levels 0.75 Dosage Unit: marng/any
Group: Femal1e Dose Level: 0
`Dosage Oni: ma/kastay
;
co rte nee os g 83om HoEmE uBOhEmE oOmBoOomH OwEEmE OmmoupFwn gsE ommm Boionmm
TM
B# E 0i w5% hoop
mass tn, pe me scion
Group: Female 3 Dose Levels 9.15 Sosage Units mararday
DE
cro rma4 esto 073 omen nts marr
os
aa
oa
00 mm oe
Lon
10.30.
a
3&2
@8
0
Grow: Nala 1 Dose Level: 0
`Dosage Unit: ma/kardey
Tr
mains, Swan. an
g HE OBE OH om BW
8 8 m~
thE "mn
118.
niaopwmn om
om
8m
BH oz
womi
Em nial Ta Tm TD a TURES TULA me
oS A 5 ag28 mpBeE EuWmEo 8
J pommmonBwhmEouOowBhnE oOe:eMm 0 j}goEum
TM
2wH3 h E% HofiHd
| g g
-
ni
J
--
mn piel Tem Tm mn a TRIS TRL mE
Con em eth 035 roistmeer
2
Emmons i Ry mn 6d i
: P 4 + POE mm
s
Ri.
wh i
J--
aa insmintTs8T
TT
me
men Se
es mon
TUR
TUG
S Smm oopRmh iEm WmEw mmaBm osem gamm
&
3
6
nTrh gh
238 aaB
1G]
mm Tel TT TA A Te TORR Ee me
ns rst8 otee atts
Grow: Wale 3 Dose Levels6.03 osage Units markorany
!
Con ema eth 045 soe is ser
8832
f+
4
B3 ohSIenma oomw
8
:
8g
ns
foiui ew iiixnn
in SL SS
LAE ALR A.
2g2 po omm o@momn Rms a
mw
8
m
J
Grom: reso} Soetevets 0.15 naan tn sure
238 a2a
0
J
Gro vale 2 Soetel: 0.8 name ts merase
o8S
i
Pe
aa2]
1
I
SETA Rae
Grom a 4 sow eels 0.75 nasewets manarier
Gre rest1e oan eve
onene ones mason
Gro remsi3e Dose eve 0.03 Sage nies hey
0
3
a38
a>
og m
e
SEE
Gresresie 3 ose veh 0.35 Sontnsmarhmey
238 aa3
mm
Grow: wal1e Dose Level: 0
J
Dosage nic: sorkgsdey
SR
&882 @4
TM
mo
:
Gro: reasi3e doetel: 0.15 Sosa ones maar
Grom reste4Soetoes 075 onan its manasiey
:
8S2s a
795
|
--
Grou: Wate 3 Dose Level: 0
`Dosage tests makarasy
rp le ne er 038 soe ie ros
or mie en tis 73 aap res sary
22a aag
6
Ea Te
:
Crop: rms 1 se eves [---- Grom rosie3 Sot torts 0.5 oaspetnt meatier Crop: rms4 Soe tel: 0.75 onan iss sahara
a22 2aa
wm
|
cn nen 8 oa es err rp te rn ot 038 soe ie, rir 288 a8
I
crop: pms1 one vets sae nies mao Gro rosie3 Soe tev, 6.35 ons tn, mutiny Gro: rmsie4 coe vets 0.75 ota Ss sahara
2aa aIa]
7
|
.
won
mOBN IB HR BRE I Cs Sr sow mony
M3
mo
im gn
i
382
g
"
Grow: Pessl1e Dose Level:
Dosage nie: sarkgrny
Co re ou ees 045 Ste ms mate
Con ee ots 73 te nts srt
&8g2 aa
wo
|
ie
Gro Mala 3 Soeteats 015 oss tts maar Crop: le 4 ontreks0.73 ons onesmaar
832 ]aa
so
cfs] :
tinBis srr oem Geog rest+e one eve ------------ Crop: rable tosetev 0.15 onspetn, meatier Gros vesi4e bone eve 0.35 Soap nis surrey
928 aa3
03
oo :
|
I
Group: Nale 4 Doss Levels 0.75 `Dosage Vait: ma/ardny
:
aa83
g
04
|
2
-
Soups xale's Dose aves 0.15 toss its sarhosany
:
:
::
Geog: ale seLevels 0.75 onan Sn maar
:
:
382 3a3
806
|
Grp rie 3 oeteh 0.03 Susan nis, mehr Crop:parle tos tev 0.78 aspontmeaty 2
a8
22 807
SL
:
:
-_--
CovanmMceTr66e32299w-52w273
APPENDIX 7
Cell Proliferation Report
Note: This appendix contains information supplied and audited by Pathology `Associates International (PAD).
-
808
C0356
2
_--
- - 0 Sess Covance 6329-223
2r.g 7
Pathology Associates International
==
4 ] A companyoofSciScienence AppliApcliacattionis ons IntIenrtneartationnaall Corporation 73
.
Bl et ind.
DRAFT CELL PROLIFERATION REPORT
26-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID
POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS 'COVANCE STUDY NUMBER 6329-223
PREPARED FOR: 3M
BUITLSODT.IXNPIGACU2OL2L,0O2MEG-NY025S,5E13R4M4V-IC1C0EE0N0STER PREPARED BY:
PAT1H5OWLOORGMYAANS'SSOMCIIALTLECSOIUNRTTE,RSNUAITTIEOINAL
FREDERICK, MD 21701
FEBRUARY 25, 2000
TT Court, SueTrTedeTrck,MarylanTd 31e701e+ (G01) 663-1644 (301) 663.3994 FAX
03563
809
:
"ie
CovDarnaceCSeuldPrNoulmfeerni3n25Re.p5o5r3t
er
`TABLE OF CONTENTS
L Im IL IV. Vv.
CELL PROLIFERATION REPORT TABLES SIGNATURE PAGE QUALITY ASSURANCE STAYEMENT APPENDII X
)
so
03564
.
~ TamTessy
CovDarnacfet SCteuldPyroNluimfebreaxti6on3R2e9p-2o2r3t
Page3
CELL PROLIFERATION REPORT
26:WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUCMCSOAVLANTC(EPFSOTSU;DTY-6N29U5)MIBNECRY6N32O9M-2O2L3 GUS MONKEYS
PURPOSE
`The purposeofthestudywas hormones, and other selected
to assess the biochemical
effoeftchte test parameters when
material on critical administered daily
enzyme levels, by capsule to
`cynomolgus monkeys for at least 26 weeks.
"rTehpirsesreenptosrtt,hesucbemllitptreoldifbeyraPtaitonhofliongdiyngAsssaoncdiaitnetserIpnrteetamtaitoinonfoarl C(oPvAaIn)cteo StthuedystNuudymbSeporn6s3or2,9-32M2,3
entitled (PFOS;
"T2-662-9W5e)ekinCaCpysnuolmeolTogxuisciMtoynSkteuydsy"w.ithAlPlerafslpueocrtosocotfanteheSutlafsoknsicasAscociidatPeodtawsistihuPmASLa'lst
`portion of this study were Good Laboratory Practice
conducted in compliance (GLP) Regulations as set
with forth
the Environmental Protection in Title 40 of the US Codeof
Agency Federal
`Regulations, Part 792, issued applicable amendments.
November
29,
1983
(effective
December
29,
1983),
and
with
any
MATERIALS AND METHODS
Tissue Collection for Cell Proliferation
Fouranimalspersexingroups 1 - 4weresacrificed after atleast26weeksonstudy. A
`representative sampleofthe liver, testes (males only) and pancreas from each animal was fixed
in formalin, processed and embedded to paraffin block by Covance per protocol specifications.
Tissue blocks was prepared
were then for H&E
shipped to evaluation
PAI and
fiomrmsuencothioinsitnogchaenmdicsatalindiengt.ectFironomofeapcrholbilfoecrkat,inagslciedlel
`nuclear antigen (PCNA), a markerofcell proliferation.
Immunohistochemistry for Cell Proliferation
Sections of paraffin-embedded tissues were cut at approximately ym and placed on positively charged slides (Superfrost Plus, Fisher Scientific, Pittsburgh, PA) to ensure adhesion during, processing for PCNA. Standard immunohistochemical methods were used to stain tissues for PCNA (PAT's Standard Operating Procedure for Immunohistochemical Staining (SOP #707). Briefly, tissue sections were incubated with a monoclonal antibody to PCNA (DAKO, lot #107(101), PAI No. A2240) and reagents required for the avidin-biotin peroxidase (ABC Kit, lot #PK6102, PAI No. K444) method for the detectionofthe antigen-antibody complex. PCNA. expression in cells was localized by the chromagen 3,3-diaminobenzidine (DAB; Sigma Chemical Co, lot #49H8204 & 108H8210). Tissue sections were counterstained with `hematoxylin.
811
603565
Draft Cell Proliferation Repart Covance Study Number 632a9g-2e2d3
Cell Proliferation Measurements
`The percentageof hepatocytes in S-phase (labeling index, LI) was determinedbyscoring at least
3000hepatocytes in 10fieolfldivesr. The LIinthetestes (males only)was determinbeyd
Iasbceolriinngg itnhdeexniunmtbheerpaonfcPrCeNaAs-wpaosssictoirveed Lsuebyjdeicgtivceelllyswiatmhon4gbeiatnglbeaostth 1ac0i0naLreaynddiigslceetlslss.taiTnhede
`heavily and 3 being predominant staining in the acinar region. A negative control slide was
included inthe antibody.
staining
run
and
consisted
ofstudy
tissue
thatwas
notincubated
withtheprimary
For cell proliferation evaluations, slides were fist perused at low magnification (100X) to judge quality of staining, processing and sectioning, potential pattems of cellular proliferation, and histomorphologic changes. Cell proliferation was then quantified at higher magnification (200X afsosrelsisveedr abnyd epvaanlcuraetaisn,g atnhde 4H0&0EX fsolridteespterse)paarseddesfcrroimbetdheabsovaem.e Htiissstueombolropchkolfoogryewaachs faunritmhaelr evaluated for cell proliferation.
Statistical Analysis
The Student' t-test (two-sided, unequal variance) was used to test for statistical significance in LwIasbjeutdwgeeedn tcoonbterosltaatinsdtitcralelaytmsiegnntifgircaonutp.s using Microsoft Excel version 5.0. A P value of 0.05
RESULTS
Cell Proliferation
|
Individual animal cell proliferation data are presented in Section II (Table 1). Cell proliferation in the liver, testes and pancreas of control and testmaterialtreated animals was similar.
Histopathology
Sections from the same tissue blocks used for preparation of PCNA-stained slides were stained with hematoxylin and eosin (H&E) for histopathologic evaluation to facilitate the interpretation ofthe immunostained slides. Individual animal findings are presented in Appendix I.
Single sections of liver, pancreas, and testes from 16 adult male monkeys and single sections of
liver and pancreas from 16 adult female monkeys representing control, low-dose (0.03
emvga/lkuga/tdeady)h,ismtiodlo-gdiocsalely(.0.15Eamcgh/ktgi/sdsauey)seacntdiohnigwha-sdossteai(n0e.d75wmigt/hkhg/edmaayt)oxtyrleiantmaenndt geroosiunp.s wTehree
`purpose ofthis evaluation was to determine whether or not morphologic changes were occurring.
in these tissues which may alter or confound the specificity of the PCNA staining observed in these animals.
03566
812
-_ Tew =
`Draft CellProliferationReport:
Covance Study Number 632P9a-ge2s23
`tTehsteicruelsaurlttsissshuoeswefdrotmhatmanloe smiognnikfeicyasntocrhtahnegelsivwereraendobpsaenrcvreedasintiesistuheesr fthoemlifveemr,alpeanmcorneakse,yso,r `which would alter the interpretation ofthe PCNA staininginthis study. DISCUSSION
`Inmtohnekepyrse,seanntdstthuedyl,ivceerllapnrdolpiafnecrarteiaosn owfasfemmeaalseumroednwkietyhsinftrhoem lciovnetr,rotles(t0esmagn/dkgp/adnacyr)e,asloofwmdaolsee
(0.03 mg/kg/day), weekson study to
mid-dose assessthe
(0.15 mg/kg/day) effofethectetst
and high dose (0.75 mg/kg/day) groups after 26 mateonrciritaiclalenzyme levels,hormones, and
other selected biological parameters, including cell proliferation.
``Tphaenrcreedais,dansodteatpepremairnteodbbeyalcaebelllipnrgoliinfdeircaest,ivwehriecshpownesreetso tihmeitielsntaamlraltearniimaallisn.theliver, testesor SUMMARY
In the present study, cell proliferation, as determined by measuring the labeling index, was not
increasedin the liver, testes or pancreas of monkeys.
03567
813
y
Tes)
`CoDvraanfcteCSetladlyPrNoulimfbereatrio6n3R2e9p-o2r2t3
IL TABLE
Legend S=E StanM dard Errofothre Mean
814
03568
DossGroup
MT82957 TABLE 11. CELL PROLIFERATION IN -MONKEYS 'COVANCE STUDY NO. 6328-223
SexiGroup | Number Liver Pancreas Testes
Te Mew o omwm aoss
[[00.0083mmognhpiiommyy((LCoowwddooswee))| | FFzZ Jfiloosssssr___onoiusaskk
34 WNeel|
[0.03mohgiday(Lowdose]| F2--fiosW8e5n0
abwaark
[O18mghideyWiddose)+ FR Tlsoser
ooeos m
[0m:15ahg(/Midddosae) y|
LE FR
-- llossas
00.0028%%
[0:15mghgidey(Mddose) | Fa "lWioosasnas
0o.1s20e%!
(075mofkgleayighdose1)| Fl&liosSsEMod
ozrr 0.000%
[075mandy (High dose)
FA _Joss3 ___oswul
[[00mm..7758ogkhgg((iFiidggdhhddaooassee))yy|| FFiA4 1__f0lo8ss4s10
00.000000!%
Men Teen
sy3Np|
o3s --We|
E)w -- l
33we)Eg
03]
3S|bl
33]
NNpF
mel
[[oommeakkggirddaayy((GCoonrttrood
WWrrii Joosssst0r8 | 0.0106070%
4Sool
[SE
ojos
3
20.75%)
[0mg/kgiday(Contro) |
lMiooassn27-- |" 0O.d1b84a%%
EXHam
[5:3mgikgiday(Cowdose) | Wrz JiSoEssMta Toos0e.005R%
033
7336%)
0[.00033 mamgkgindaydy(Lo(Lowwdodsoes)e) WWzz ----foTsioests1e5 --T--oo0o.0o00%W---- u 3 e
[0.03mejkgiday (Low dose)
Wz fMioosasn21 ~~ o0.00z0e0%%,
3s ree-- wl
[O18magkaliayWiddose)| Wr sleosmst0 oooszen__Tal___o_oaslr_wzzlou
[( 0G.185 rc heimo enkgiday (iids dose etWs s --oJslosssipse--
ooviesn TTS4]
7T1e%w],
[p0:3r5mes ma GeEiDn) WR | {ERR -- -- "oss--) Tis T205767%4)
075 gg Gigidose) | WA Bj055C 06
S0o30w%! | Tar3
17505%%
[0[.0:7755mafmapkgiidaay y(H(iHigghhcdoossee))| Wwii [soss0rs
ooNme
Wp3
T081"%)
[0.75 mkgiday(Fighdose)
Mis w0e8a5n12 ___ GGo0t0s
305
Teoel
[Notdetermined dvs subopimal taking Sem
o0ss
oo) T
S56%]
[ILNiPv:ersiPdoercnaonttage of epatoogies ? = S-phase I
=
~T
[[FPeasntcesr:asP:eSrccoerendtsaoubgjfeecivelroeratwinigh Lsevdielceallns scinar Sed i viy CEO: Ib0189, SASHA
Page 1
815
003569
CovranacfeSCteuldlyPrNoulimfberearti6on32R9e-p2o2r3t
III. SIGNATURE PAGE 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt
(PFOS; T-6295) in Cynomolgus Monkeys (Covance Study Number 6329-223) Submitted by: PAI Project Manager:
SandraR. Eldridge, PRD.
Date
`PAT Project Pathologist:
CarolynMoyer, D.V.M,Diplomate, ACVP.
Dae
816
03570
= CoDvraaafeteCSeluldPrNoluirfiereasti3on35533
IV. QUALITY ASSURANCE STATEMENT
air
CO.3571
.
_
sia
E=H
PaAtChomoplanogofySoArscsAocciaartetsamIanrtaeCronpaorttioonnal -- SAE
_--_--mmmm----------
Cell Proliferation Report
26-WePeoktaCsaspisuumleSaTlotxi(cPiFtOySS;tuTd-y62w9i5t)hiPneCrfylnuoomroologctuasneMoSunlkfeoynisc Acid Covance Study Number: 6329-223
QUALITY ASSURANCE STATEMENT
T`Ahsissurcaenlcle pUrnoiltife(rQaAtiUo)n parsorjeeqcutirheads bbyeethne iGnosopedctLeadboarnadtorayudPirtaecdticbey (tGhLeP)PArIeguQluaatliiotnys pprroolmiuflergaattieodn rebpyortthiseanUaSc.curEantveirreofnlemcetnitoanolftPhreotrecetcioorndedAdgaetna.cyTh(eTSfoClAl)o.wingTthabele cieslal recordofth inspections/audits performedandreported by the QAU.
Date of
Inspection
01221070160909
02/17/00
Phase Inspected
PSrtiumdayrDyaAtnatainbdody Dilution Supporting Documentation
Draft Cell Proliferation Report
Date Findings Reported to PAT
Management/Project Manager
12006199
017100
02/17/00
2 PRI
QualitKyaArsesnurEa.nBcuetlOefrficer
2 [a3 foo
Date
03572
S EI8r 1sNMITET 15Worman's Mill Court, Suit|e + Frederick, Maryland 21701 + (301) 663-1644 (301)663-8994 FAX
Conn 329.23 eeConDrea SCelylcNluimbfTeree6m3eR2te5npi2o2rn3t
APPENDIXT
03573
819
-"
IMT62957
=
Mp se
:
Individual Animal Findings
26.WEEK CGAOPTSAUSLSEIUTMOXSIACLITTY(PSFTOUS;DYT6W29I5T)HINPECRYFNLOUMOORLOGOUCSTAMNOENSKUELYFSONIC ACID
NAUNMIMBAELR~~ SEX DOSE GROUP HISTOLOGIC FINDINGS
105530 F
1
`LiPvaenr- cNrS-EeNaSsF
108531 F
1
LPainv-cNerS-reENaSsE
108535 F
1 LPivaenr-cchrr-oenNaiScsFinflammamtiinoimna,l
108544 F
1
L`Piavn-ceNrS-rFeNaSsF
108537 F
2
LPainv-ceNr-SreENaSsF
105541 F
2 LiPvaern-cchrr-oenNiaScsFinflammatmiinoimna,l
108547 F
2
LPainv-ceNrS-reFNaSsF
105550 F
2
LPainv-ceNrS-rFeN.aSFs.
108532 F 105538 F
3 3
LLPaiinv--vcceNhrer-SreoENnraiScsEinflammation,minimal
105545 F
3
`LiPvearn-cch-rroeNnaSicsFinflammation, minimal Pancr-eNaSsF
105548 F
3 LiPvaern-cchrr-oenNiaScsFinflammamtiinoimna,l
108534 F 105536 F
4 4
LiL`viPevarenr--fcNtSr-FieN.nfaSilsFtration,centrilobular,moderate.
105540 F
4 LiPPvaaernn-ccNrr--SeeENNaaSSssFF
105551 F
4
LPainv-ceNrS-reFNaSsF
--N ET T D`PiavnecrreaGsro-cnhlrcoTnifcaimnaftlioanm,mamtmaiinolimn--a,l
108517 M
1
TLievesr--tNNeSSEsF
Pancr-eNaSsF
108519 M
'
TLesitevs--NecSrFru.sh anifact, focal Pancr-eNaSsF
108527 NM
1
TLeisv--teNNeSrSEsF
Pancr-eNaSsF
108514 iv
2 PTLainecvreser-a-tscNher-SocsnFhirconiincflianmmfatliaonm,mmiantmiiminaoilmna,l
108515 M
2
LiTveers--tchNerSosnFic inflammamtiiniomnal, Pancr-eNaSsF
105516 M
2
LiTveers--tNNeSSEsF Pancr-eNaSsF
108521 M
2
TLievesr--tNNeSSEsF
Pancr-eNaSsF
108510 M
3
LiTveers--tchNerSosnEic inflammamtiinoimna,l Pancr-eNaSFs.
Tes-tNeSsF
Legend: NSF =nosigafican:findings
820
03574
Lo
IM T6295]
ME e623
Individual Animal Findings
26.WEEK CPAOPTSAUSLSEIUTMOXSIACLITTY(PSFTOUS;DYT6W29I5T)HINPECRYFNLOUMOORLOGOUCSTAMNOENSKUELYFSONIC ACID
ANIMAL ~~ SEX DOSE GROUP
HISTOLOGIC FINDINGS
NUMBER
105518 M
3 LiPvaern-cNrS-eENaSsF
105524 M
3
TLesitevs- -NeNSrSEF Pancr-eNaSsF
105528 M
3
TLeisv-t-eNNeSSrFFs.
Pancr-eNaSsF
105507 M
4
T`Leisvtee-rs-faNtSiFn.filtration, centrilobular, moderate.
Pancr-eNaSsF
105512 M
4
LTeisv--teNNeSSrEsF
Pancreas - NSF
105506 M
4
TLievesr-t-NNeSSEFs.
Pancreas - NSF
105509 M
4
TNoemsic-troNesScFso.pic slides available.
(Inventory shows blocks submitted; STPR
doesnotshow blocks sectioned.)
Legends NSF = no significan findings
821
03575
