Document jy2Ov6GOOwkkmja8ro0NO72aR
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AR226 _ [0 3
EPA / SPI FMG Meeting
January 30,2002
Agenda
Introduction
=
Toxicology/PK Program Studies underway
Progress o Time line
= Ed 3
Environmental Effects/Fate Testing program * Environmental distribution
Summary
|
PROJECT SUMMARY REF: APFO -2
SPONSOR
(AsahiAGPlMasEs,PDTuFPEonCto,mDmyintetoene,MDeamikbienr,sAuasnidmAonPtF,OSoSluvpapyl,ieArtsoFina 3M, Miteni)
CHEMICAL sTUDY
Ammonium Perfluoro-octanoate (APFO~ FC143)
Preliminary 4 week oral toxicity study in Cynomolgus monkeys. 6 month oral toxicity study in Cynomolgus monkeys to include an
additional 13 week recovery period
PURPOSE
To understand the particular, to study
toxicity of APFO in the effects on the liver,
a on
sub-human pancreatic
primate. function,
In on|
homone levels administered dose
and and
to understand APFO levels in
the body
relationship between fluids (eg plasma) and
tissues.
CONTRACTING LABORATORY
Covance Laboratories Inc, Madison, Wisconsin.
I
STATUS
Study completed. Reports issued and delivered to EPA in January 02 TextPoofstpeurblpirceasteinotnedinatexUtSemSaolTlimteeerattiunrge,nMoawrcfihna0l1ised.
REPORTING DEADLINE
Dec 1999 (COVANCE): Q1 2000 - interim report.
VAoEtoR2dS0Ic ON 1
DATE 18.01.02.
&
APFO - Mammalian Toxicology
90 -- day study in male cynomolgus monkeys * Dose levels -0, 3, 10 & 30/20 mg/kg/day + recovery * Clin obs, clin chem, key hormone levels, cell
biochemistry, cell proliferation, serum & liver PFOA levels.
* Signsoftoxicity, weight loss and reduced food consumption at 30 and then 20 mg/kg.
* One monkey in 30/20 mg/kg group moribund sacrificed -- evidence of liver and muscle toxicity.
* Dose-dependant increase in liver weight, due in part to mitochondrial proliferation, but no evidence of liver
toxicity at 3 or 10 mg/kg. * One monkey in 3mg/kg group found moribund and
sacrificed (Day 153); cause of morbidity unknown. * No clear changes in pathology, hormone levels,
biochemistry or clin chem.
3
PROJECT SUMMARY REF: APFO-9
CHEMICAL STUDY
PURPOSE CLOANBTORRAACTTOIRNYG
EN Ammonium perfluoro-octanoate (APFO ~ FC143)
Two generation reproductive toxicity study in the rat Test run to comply with US EPA Health Effects Test Guidelines.
To study the efnfaetcatlodfevAePlFopOmeonntmaanldesaunrdvifveamlailnetfheertrialtity and on neo-
Argus Research, Pennsylvania.
STATUS REPORTING DEADLINE
Project initiated in November 2000. Project to be reported ~ February 2002.
aVpElRooScION 1
DATE 25.01.02.
u
APFO - Mammalian Toxicology
Multi-generation Reproduction Study in Rats
* The objective of this study is evaluate the effect of APFO on the gonadal function, conception, parturition, and the growth and development of offspring of male and female rats over 2 generations involving the production of at least one set of litters in each generation.
+ Work Plan - Initiated 11/00; in-life phase completed; final report expected 02/02
* Dose levels 1, 3, 10, and 30 mg/kg.
Results
AGEN. -- NOAEL, Male
P
< 1 mg/kg/day (liver &
kidney weight ratio
increases @ | mg/kg/day)
ONOAAEL.,TFeemmaallee 10 mg/kg/day (decreased kidney weight @ 30 mg/kg/day)
Fl
<1 mg/kg/day (decreased BW/BWG and organ weight
10mg/kg/day (increased post-weaning mortality &
changes at | mg/kg/day0 decreased post-weaning
BWG& feed consumption,
delayed sexual maturation,
increased estrous cycling @
30 mg/kg/day)
F2
> 30 mg/kg/day
> 30 mg/kg/day
Study Reproductive NOAEL > 30 mg/kg/day
s
PROJECT SUMMARY REF: APFO-8
CHEMICAL STUDY
PURPOSE CONTRACTING LABORATORY EE STATUS REPORTING DEADLINE
= Ammonium perfluoro-octanoate (APFO ~ FC143) Dermal Sensitisation Test ~ Buehler Method
Test run to comply with US EPA Health Effects Test Guidelines. To study the sensitising effect of APFO on guinea pig skin DuPont Haskell Laboratory, Delaware.
Project initiated in September 2001 Project reported ~ December 2001.
pVoErRtSoION 1
DATE 25.01.02.
6
SPONSOR CHEMICAL STUDY PURPOSE LCAOBNOTRRAATCOTRIYNG
STATUS REPORTING DEADLINE
PPRROOJJEECCTSSUUMMARYY REF: APFO-1
AP(MAEsahPiTGFlEasCs,omDmuiPtotnete, MDeynmeboenr,sAaunsdimAoPntF,ODSaukpipnli,ers Solvay, AtoFina, 3M, Miteni)
Ammonium Perfluoro-octanoate (APFO ~ FC 143)
Mechanistic
studies in rat pancreatic
and human acinar cells.
hepatocytes
and
To understand the pancreatic cancer in
mechanisms rats and its
of APFO-induced relevance to human
health risk assessment.
Unive(rFsaictilyitoyf iDnusnpdeceteioBniobmyeDdiGcFal- RAeusgeuasrtch98C)entre
(Dr CR Elcombe)
Work
commenced focusing
- May 1998. Phase on PPARy received.
II
proposal
18 months from commencement.
VERSION 1 Apfo-1.doc
DATE 18.01.02.
SPONSOR CHEMICAL STUDY
PURPOSE
CLOANBTORRAACTTOIRNYG STATUS REPORTING DEADLINE VoEeRdSoIcON 1
PROJECT SUMMARY REF: APFO-3
(AsahiAGPlMasEs,PDTuFPEonCto,mDmyintetoene,MDeamikbienr,sAuasnidmAonPtF,OSoSluvpapyl,ieArtsoFina 3M, Miteni)
Ammonium perfluoro-octanoate (APFO ~ FC143)
Toxicokinetic Studies
1. 2.
ADME Protein
bmiansdsinbgalsatnucdieeisnirnatrsa.ts
and
humans
3. PBPK modelling in rats and humans
1.
To determine elimination
AinPFOratasbsorfpotliloonw,indgistrisbiuntgiloen,
metabolism and| and repeated,
administration. Will the development and
vfaolrimdaatisocnioenftitfhiecPalBlyPdKefmeondseilb.le
basis
for
2.
To determine protein in rats
the and
extent and humans in
onradteurreto omfakAePFquOalibtiantdiviengandto|l
3. qTuoandteivteatliovpePcoBmPpaKrimsoodnesl.s for APFO in the rat and human. To|
raebllaetetoeqxutaenmtailtadtiovseelytoexitnrtaepmoallatdeotsoehoufmaAnPs.FO in rats and to be,
DuPont Haskell Laboratory, Delaware.
Project initiated in Q2 2001 Targeted reporting date - Q4 2002..
DATE 19.01.02. 8
Ammonium Perfluoro-octanoate
(APFO)
. CF;(CF,),COO- NH,* (acid -- PFOA)
* Solid - sublimes at 130C * Solubility in water - >100 g/I * Vapour pressure - 9.2 x 10-5 HPa
q
APFO -- Aquatic Toxicity
Daphnia: Algae:
Fish:
48 hour EC 4;-- 632 mg/l
chronic study ongoing.
14 day EC 5,-- 73 mg/l
96 hour LC 4;- > 100 mg/l (bluegill sunfish, fathead minnows
orange-red killifish). Chronic study ongoing (early life stage).
10
SPONSOR
CHEMICAL STUDY PURPOSE
CONTRACTING LABORATORY STATUS REPORTING DEADLINE
aVoEeRSdoIcON 1
PROJECT SUMMARY REF: APFO-
(AsahiAPGlMasEs,PDTuFPEonCto,mDmyintetoene,MDeaimkbienr,sAuasnidmAonPtF,OSoSluvpapyl,ieArtsoFina 3M, Miteni)
Ammonium perfluoro-octanoate (APFO ~ FC143)
Reproduction study in Daphnia magna DTaophanssieassmtahgentaoxiinciaty2o1f-dAayPFseOmio-nsttathiecretepsrtodinucctoimvpeleifafnicceacwyiotfh
OECD Test Guideline No 211 Preliminary acute toxicity study (non GLP)
Project initiated in December 2001
Targeted Acute toxicity
reporting dates: study - January
2002
Reproduction study ~ May 2002.
DATE 19.01.02.
1
PROJECT SUMMARY REF: APFO-6
SPONSOR
(AsahiAGPlMasEs,PDTuFPEonCto,mDmyintetoene,MDeamikbienr,sAuasnidmAonPtF,OSoSluvpapyl,ieArtsoFina 3M, Miteni)
CHEMICAL
Ammonium perfluoro-octanoate (APFO ~ FC143)
STUDY
Early-life stage toxicity test in the Rainbow Trout
PURPOSE
Toeaarslys-elsisfethsetalgeetsha(leamnbdrysou,b-llaertvhaael eafnfdecjtusvoenfilAePs)FoOfoOnnchoartchhylnicnhguasnd mykiss in a flow-through test in compliance with OECD Test Guideline No 210. Preliminary acute toxicity study (non GLP)
CONTRACTING LABORATORY
CIT, Evreux, France.
Et
STATUS
Project initiated in December 2001
REPORTING DEADLINE
AcuteTtaorxgiceitteydsrteupdoyrt~inJganduataersy: 2002.. Early-life stage study October 2002.
sVpEcRSdoIcON 1
DATE 19.01.02.
12
SPONSOR CHEMICAL
PURPOSE CONTRACTING LABORATORY STATUS REPORTING DEADLINE VERSION 1
PROJECT SUMMARY REF: APFO-7
(AsahiAGPlMasEs,PDTuFPEonCto,mDmyintetoene,MDeamikbienr,sAuasnidmAonPtF,OSoSluvpapyl,ieArtsoFina 3M, Miteni)
Ammonium perfluoro-octanoate (APFO -- FC143)
AlsGrow abbion stn Scterastram erica
To assess acute toxic effects ofAPFO in algae using OECD Test Guideline No 201.
CIT, Evreux, France (2).
Project to be initiated in Q2 2002 Targeted reporting dates: Q2 2002
DATE 25.01.02.
13
APFO - Environmental Fate
Biodegradation: no evidence of biodegradation (not readily biodegradable - OECD)
Adsorption/Desorption: sediment/sludge -study recently initiated
i
SPONSOR
CHEMICAL
STUDY
[PURPOSE
CONTRACTING LABORATORY
STATUS REPORTING
DEADLINE
PROJECT SUMMARY REF: APFO-4 APME PTFE Committee Members and APFOSuppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni) Ammonium perfluoro-octanoate (APFO -- FC143)
Absorption/Desorption Studies
Test run to comply with US EPA guidelines and OECD Test Guideline 106.
1. aTnod sstluuddygetshewistohrpvtairoyninbgehcahavriaocuterriosftiAcsP.FO in soils, sediments| 2. To provide data for determining the leaching and runof
potential of APFO in soils etc. Determination of Kd, Kom,| Koc and % desorbed. 3. To determine the Freundlich absorption isotherm in all test] soils with >10% adsorption.
DuPont Haskell Laboratory, Delaware.
Project to be initiated in Q1 2002 Targeted reporting date -- December 2002...
"VERSION 1
DATE 19.01.02.
[Ig
APFO -- Bioconcentration Factor
Bioconcentration Factor:
3M Study in minnow: Japanese Study in carp:
BCF 1.8 BCF <9.4
Studies judged to be adequate.
16
APFO -- Environmental Distribution Studies
* Survey in marine mammals, fish-eating birds, fish and oysters (Geisy & Kannan).
* Survey human blood samples from
different human populations (Olsen etal.). * Market basket survey in food. * Survey in different bodies of water in six
selected cities.
17
APFO -- Biota Studies
Maximum PFOS and PFOA concentrations (ng/g wet wt ) and detection frequencies (%) (Geis&y Kannan)
Species
PFOS
PFOA
Marine mammals
1520(77%)
41(4%)
Mink & Otter
Birds
4900(100%) ~~ 110(11%)
2570(60%) 440(3%)
Fish
1000(38%)
46(2%)
Concentrations are in ppb Detection limits varied from 3 to 75 ppb
18
Fish and mink where PFOA was found.
Species
Mink
Fish Species:
Fish Vsapreicioeuss
Fish
Various
species
Source
Tissue
Mass. Liver
- oo
n Samples ng/gwet
~
orm
31 18 184-108
(m=32)
(dry wy)
-
LOQ ng/g wet
wtor ml
188 |
(dry wt)
Begin
Michigan
Inland
Lakes
Med
Eggs* Muscle
26 3 <75-46 75
~
~ (m=17) ]
19
1
13.7
8.03
20.1
a
~
103 3 Detected,
8.03
not
20.1
quantified
11
Marine mammalian species where PFOA was found.
California
Sea Lion
Grey Seal
Botlenose
Dolphin
Ringed Seal
Califomia Liv.
"Baltic Sea Bd ItalianCoast Bld BalicSea Bld
61
a
26 1
679
4 3 234
17
359
498 "mL 62
Cups
Tse Lv.
CasRpuisasniSaea, BI
10 3 8317.41 6 62|
81 2 290,395 188
5 3 na se
Stceinyemlelnae
GMuelxfiocfo Liv.
3 .1
20 TT 7s
20
Fish-eating water birds where PFOA was found
Speci"es
Source Ti"ssue 0 pprs eeoogeme-- Too
@
Fh
Co Newemnne Wm paty nNeoet
Tmo iSoww doiimed Ge 30 mm
Dubos Lkewewes Yok 5 mam we
|:
TosGirevneLakmesed wes 3 1 ws my
| savin srwenitss Yok 32 we emer
| Satan
on eed
3 ae
aw
[--
on LT aiid
| dEathos wen be 0
ba eams Res
2
Summary of species in which PFOA was not detected above the Limit of Quantitation (LOQ)
Species
Twmsow
Source
usa
Tissue n
LOQ ng/g wet
wt
tes wes
Frehhe&ns"ss1w5esdarseh.
| Mspoeancsie,isdGno&elpiehninsom,anmwemhsaallsieeasn || "ndpolarben | Fpie(lvCioccraanmansnbg.awoaTsoeotrnbelrrldn.s,
cae, sok. 9)
PMaicthBiiagtMaene,dnAewsnm.niPesno, Cree Repibie
nMdCdao,iteoAmrann,eAnAlmRtioers,si,, Gulforsiexico
MGroeCaanatanL.askTe,e,aCFslaolrMiiifdoadrn,a Nell Japan ni Koes
VLWiihvloeelre
9 10 5
s77557-a37555ms
TEesvees
5
1800--230519
BvBlroaomwd 112226 s2o4150s96
KiMdunseey
33
n3s9
BoLoirdvepeumrsny T7w
Kidney
'
wi 25-3m 89 1500
2
Market Basket Survey In over 230 samples of foodstuffs, PFOA was detected in only 6 samples above a limit of detectionof 0.5 ng/g.
- ground beef: 1.09 & 0.50 ng/g - bread: 0.52 ng/g - apples: 1.13 & 2.35 ng/g - green beans: 0.54 ng/g
23
Preliminary Descriptive Summaryof Serum Fluorochemical Levels (ppb) in Adult American Red
Cross Blood Donors (N = 652)
Geom. Cumulative
Analyte
Mean* Range
Median _Mean* _ 95 th Percentile
PFOA
5.6
<LLOQ-52.3
4.7
4.6
129
PFOS
437 <LLOQ-1656 358 35.1 905
Values thatar < LLOQ wee snl3ythezmidepoidnt between ze andthe <LLOQ
PFOS <LLOQ = (421) PFOA <LLOQ (1o2r) 211)
|
Preliminary Descriptive Summary of Serum Fluorochemical Levels (ppb) in Children (N = 599)
|
Geom. Cumulative
! Analyte
Mean* Range
Median Mean* 95 th Percentile
| PFOA
56 <LLOQ-56.1 sl 49 102
PFOS
435 6751s
367 375 902
Vales ht rc< LLOQ were ays he midpint betwee ro and the <LLOQ
PFOA LLO=Q (19or2) (238)
ay
i
Fore air sews
wee -- xg
>
ai
won|-- a
|
BinWa
eR
wr
|
| ER ee reel|
wo "wo
a LE
wo
ow
5
|
STE i " ee
rE ow
lr
a5"
Summary
Mammalian Toxicology * Believe that all relevant endpoints have been addressed
Environmental Fate / Distribution Adsorption / desorption study underway
Phys. / chem. properties: validating existing data Non-biodegradable & non-bioaccumulative * Some evidence of PFOA in biota (low incidence,
low levels) -- do not fully understand pathways of exposure Discussion with experts to define more appropriate models of distribution to all
compartments
Environmental Effects Aquatic compartment: completing program to define the hazard(s)
Other compartments (sediment, terrestrial, atmosphere): 1) no effects data available;2) considering whether or not anything data is required
26
