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EPA / SPI FMG Meeting
January 30, 2002
Agenda
Introduction
Toxicology/PK Program Studies underway Progress Time line
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Environmental Effects/Fate Testing program Environmental distribution
Summary
I
PROJECT SUMMARY REF: APFO - 2
SPONSOR
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni)
CHEMICAL
Ammonium Perfluoro-octanoate (APFO - FC143)
STUDY
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 toxicity of APFO in a sub-human primate. In particular, to study the effects on the liver, on pancreatic function, on hormone levels and to understand the relationship between administered dose and APFO levels in body fluids (eg plasma) and tissues.
CONTRACTING LABORATORY
Covance Laboratories Inc, Madison, Wisconsin.
STATUS
REPORTING DEADLINE
Study completed. Reports issued and delivered to EPA in January 02 Poster presented at US SoT meeting, March 01
Text of publication in external literature now finalised.
Dec 1999 (COVANCE): Q1 2000 - interim report.
VERSION 1
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DATE 18.01.02.
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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.
Signs of toxicity, 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
SPONSOR
PROJECT SUMMARY REF: APFO-9
3M
CHEMICAL
Ammonium perfluoro-octanoate (APFO - FC143)
STUDY
Two generation reproductive toxicity study in the rat Test run to comply with US EPA Health Effects Test Guidelines.
PURPOSE
To study the effect of APFO on male and female fertility and on neo natal development and survival in the rat
CONTRACTING LABORATORY
Argus Research, Pennsylvania.
STATUS
REPORTING DEADLINE
Project initiated in November 2000. Project to be reported - February 2002.
VERSION 1
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DATE 25.01.02.
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.
GEN.
Results
NOAEL, Male
NOAEL, Female
P
< 1 mg/kg/day (liver &
10 mg/kg/day (decreased
kidney weight ratio
kidney weight @ 30
increases @ 1 mg/kg/day) mg/kg/day)
FI < 1 mg/kg/day (decreased lOmg/kg/day (increased BW/BWG and organ weight post-weaning mortality & changes at 1 mg/kg/dayO decreased post-weaning BWG & feed consumption, delayed sexual maturation, increased estrous cycling @ 30 mg/kg/day)
F2 > 30 mg/kg/day
> 3:0 mg/kg/day
Study Reproductive NOAEL > 30 mg/kg/day
r
SPONSOR
PROJECT SUMMARY REF: APFO-8
DuPont
CHEMICAL STUDY
PURPOSE CONTRACTING LABORATORY
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.
STATUS
REPORTING DEADLINE
Project initiated in September 2001 Project reported - December 2001..
VERSION 1
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i
PROJECT SUMMARY REF: APFO-1
SPONSOR
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Ausimont, Daikin, Solvay, AtoFina, 3M, Miteni)
CHEMICAL
Ammonium Perfluoro-octanoate (APFO -F C 143)
STUDY
Mechanistic studies in rat and human hepatocytes and pancreatic acinar cells.
PURPOSE
CONTRACTING LABORATORY
To understand the mechanisms o f APFO-induced pancreatic cancer in rats and its relevance to human health risk assessment.
University o f Dundee Biomedical Research Centre (Facility inspection by DGF - August 98)
(Dr CR Elcombe)
STATUS
REPORTING DEADLINE
Work commenced - May 1998. Phase II proposal focusing on PPARy received.
18 months from commencement.
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DATE 18.01.02.
7
SPONSOR CHEMICAL STUDY
PURPOSE
CONTRACTING LABORATORY
PROJECT SUMMARY
REF: APFO-3
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni)
Ammonium perfluoro-octanoate (APFO - FC143)
Toxicokinetic Studies
1. ADME mass balance in rats. 2. Protein binding studies in rats and humans 3. PBPK modelling in rats and humans
1. To determine APFO absorption, distribution, metabolism and elimination in rats following single and repeated administration. Will form a scientifically defensible basis for the development and validation of the PBPK model.
2. To determine the extent and nature of APFO binding to protein in rats and humans in order to make qualitative and quantitative comparisons.
3. To develop PBPK models for APFO in the rat and human. To relate external dose to internal dose of APFO in rats and to be able to quantitatively extrapolate to humans.
DuPont Haskell Laboratory, Delaware.
STATUS
REPORTING DEADLINE
Project initiated in Q2 2001 Targeted reporting date - Q4 2002..
VERSION 1
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DATE 19.01.02. %
Ammonium Perfluoro-octanoate (APFO)
CF,(CF2)fiCOO- N H / (acid - PFOA)
Solid - sublimes at 130C
Solubility in water - >100 g/1
Vapour pressure - 9.2 x 10"5 HPa
APFO - Aquatic Toxicity
Daphnia:
48 hour EC 50- 632 mg/1 chronic study ongoing.
Algae:
14 day EC 50- 73 mg/1
Fish:
96 hour LC so- > 100 mg/1 (biuegili sunfish, fathead minnows
orange-red killifish). Chronic study ongoing (early life stage).
10
SPONSOR
CHEMICAL STUDY PURPOSE
CONTRACTING LABORATORY
PROJECT SUMMARY REF: APFO-5
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni)
Ammonium perfluoro-octanoate (APFO - FC143)
Reproduction study in D a p h n ia m agn a To assess the toxicity of APFO on the reproductive efficacy of Daphnia magna in a 21-day semi-static test in compliance with
OECD Test Guideline No 211 Preliminary acute toxicity study (non GLP)
CIT, Evreux, France.
STATUS
REPORTING DEADLINE
Project initiated in December 2001
Targeted reporting dates: Acute toxicity study - January 2002
Reproduction study - May 2002.
VERSION 1
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DATE 19.01.02.
II
SPONSOR
PROJECT SUMMARY
REF: APFO-6
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni)
CHEMICAL
Ammonium perfluoro-octanoate (APFO - FC143)
STUDY
Early-life stage toxicity test in the Rainbow Trout
PURPOSE
To assess the lethal and sub-lethal effects of APFO on hatchling and early-life stages (embryo, larvae and juveniles) of Oncorhynchus 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.
STATUS
REPORTING DEADLINE
VERSION 1
apfoe-6.doc
Project initiated in December 2001
Targeted reporting dates: Acute toxicity study - January 2002.. Early-life stage study October 2002.
DATE 19.01.02.
SPONSOR
CHEMICAL STUDY PURPOSE
CONTRACTING LABORATORY
PROJECT SUMMARY REF: APFO-7
APME PTFE Committee Members and APFO Suppliers (Asahi Glass, DuPont, Dyneon, Daikin, Ausimont, Solvay, AtoFina
3M, Miteni)
Ammonium perfluoro-octanoate (APFO - FC143)
Algal Growth Inhibition test in Selenastrum capricornutum
To assess acute toxic effects of APFO in algae using OECD Test Guideline No 201.
CIT, Evreux, France (?).
STATUS
REPORTING DEADLINE
Project to be initiated in Q2 2002 Targeted reporting dates: Q2 2002
VERSION 1
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DATE 25.01.02.
13
APFO - Environmental Fate
Biodegradation: no evidence of biodegradation (not readily biodegradable - OECD)
Adsorption/Desorption: sediment/sludge -study recently initiated
SPONSOR CHEMICAL STUDY
PURPOSE
CONTRACTING LABORATORY
PROJECT SUMMARY
REF: APFO-4
APME PTFE Committee Members and APFO Suppliers (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. To study the sorption behaviour of APFO in soils, sediments and sludges with varying characteristics.
2. To provide data for determining the leaching and runoff 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.
STATUS
REPORTING DEADLINE
Project to be initiated in Q1 2002 Targeted reporting date - December 2002..
VERSION 1
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DATE 19.01.02.
APFO - Bioconcentration Factor
Bioconcentration Factor: 3M Study in minnow: BCF 1.8 Japanese Study in carp: BCF <9.4 Studies judged to be adequate.
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 et al.).
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 w t) and detection frequencies (%) (Geisy & Kannan)
Species
PFOS
PFOA
Marine mammals
1520(77%) 41(4%)
Mink & Otter
4900(100%) 110(11%)
Birds
2570(60%) 440(3%)
Fish 1000(38%) 46(2%)
Concentrations are in ppb Detection limits varied from 3 to 75 ppb
Fish and mink where PFOA was found
Species Mink Fish Species:
Source Mass.
T issu e
n
Sam ples
ng/g w et
wt
or ml
(+)
LOQ ng/g wet wt or ml
Liver 31
18 1 8 .4 -1 0 8
18.8
(m = 32)
(dry wt)
(dry wt)
Fish Various species
Fish Various species
Belgium
M uscle
26
8
< 7 .5 -4 6
(m=17)
Michigan Inland Lakes
Eggs*
19
1
13.7
M uscle
103
3
Detected,
not
quantified
7.5
8.03 20.1
8.03 20.1
Marine mammalian species where PFOA was found.
California Sea Lion
Grey Seal
California Baltic Sea
Liv. 6 1 Bid 26 1
41 6.79
Bottlenose Dolphin
Italian Coast Bid
Ringed Seal
Baltic Sea
Bid
43 18 1
2, 3, 4 7
Ser. 10 3 8.3, 14.6, 17.1
Liv. 81 2 29.1,39.5
C aspian Seal
Caspian Sea,
Bid
8
3
7,11,23
Russia
Stenella clymene
Gulf of Mexico
Liv.
31
20
35.9 4.98 mL 6.22 6.22 18.8 5.99 7.5
0
Fish-eating water birds where PFOA was found
Species
C orm orant
Source
M editerranean Sea
Tissue
n
L iv er
12
Sam ples (+)
12
ng/g w et wt or mL
29 - 444 m = 94)
LOQ ng/g w et w t
or mL
N one reported
Laysan albatross
Sand Island, M idw ay A toll
L iv er
3
1
182
180
D ouble crested corm orant
Lake W innipeg
Y olk
4
2
192, 245
180
St. M artin Island, Great Lakes
B lood
2
1
4 8 .9
2 9 .9
B lack b illed gull
Sulphur Island, Great Lakes
Y olk
3
2
196, 197
wet wt
S ea Eagle
K ite
B lack H eaded G ull
Japan Japan Japan
B lood
27*
2
4 .5 , 6.2
L iver
2
1 D etected, not q u a n tifie d
L iver
i
1 D etected, not q u a n tifie d
3 .3 5 18.8 N ot stated
Summary of species in which PFOA was not detected above the Limit of Quantitation (LOQ)
Species
M ink & O tter
Source
USA
Tissue n
L iver
51
LOQ ng/g wet
wt
1 8 .8 -3 5 .9
Fresh & salt w ater fish at least 15 d ifferen t sp e c ie s
P acific, M edittrranean, B altic, A ntartica
M ichigan lakes, Poland, C zech R epublic
W hole L iver M uscle T estes Eggs
M arine & m am m alian sp ecies (seals, otters, sea
lions, dolphins, w hale and polar bear)
C alifornia, A laska, M editerranean,R ussia, India, A rctic, A ntarctic,
G u lf o f M exico
L iver B lood B r a in K idney M uscle
F ish -eatin g w ater birds (corm orant, loon, gull, pelican, albatross, heron,
egret, stork, ibis)
G reat L akes, C alifornia, C arolinas, Florida,
M ontana, T exas, M idw ay A to ll, Japan, India, K orea
L iver B lood/plasm a/
serum K idney
9 109 83
5 5
126 124
2 3 3
88 73
7
3 7 .4 -7 1 .9 7 .5 -7 1 .9 7 .5 -3 5 .9 8 .0 -2 0 .1 1 8 .0 -3 5 .9
7 .5 -7 1 .8 2 .4 -9 .6
3 5 .9 3 5 .9 3 7 .5
1 8 .7 -1 8 0 .0 2 .5 -3 5 .9
1 8 0 .0
Market Basket Survey
In over 230 samples of foodstuffs, PFOA was detected in only 6 samples above a limit of detection of 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
Preliminary Descriptive Summary of Serum Fluorochemical Levels (ppb) in Adult American Red Cross Blood Donors (N = 652)
Geom. Cumulative
Analvte
Mean* Range
Median Mean* 95 th Percentile
PFOA
5.6 <LLOQ-52.3 4.7 4.6 12.9
PFOS
43.7 cLLOQ-1656
35.8 35.1
Values that are < LLOQ were analyzed as the midpoint between zero and the <LLOQ
PFOS < LLOQ = (4.27) PFOA <LLOQ = (1.92) or (2.11).
90.5
Preliminary Descriptive Summary of Serum Fluorochemical Levels (ppb) in Children (N = 599)
Geom. Cumulative
Analvte
Mean* Range
Median Mean* 95 th Percentile
PFOA
5.6 <LLOQ-56.1 5.1 4.9 10.2
PFOS
43.5 6.7-515
36.7 37.5
Values that are < LLOQ were analyzed as the midpoint between zero and the <LLOQ
PFOA <LLOQ = (1.92) or (2.88)
90.2
Multi-City Study Data from Table 4 of Executive Summary
Sam ple
Decatur, AL
C leveland, TN
M obil, AL
C olum bus, GA
Pensacola, FL
POTW Effluent
2.14 ,2 .4 2
0.655, 0.674
0.067, 0.088
0.139, 0.147
ug/L
POTW Sludge,
1 0 1 ,2 4 4
3.11 ,2 .8 2
NQ
16.5, 16.3
Dry ug/K g
D rinking Water,
ND
ND
N D 0.026, N Q
Intake ug/L
Drinking Water,
ND
ND
N D 0.025, 0.029
Treated ug/L
Drinking Water,
ND
ND
N D 0.026, NQ
Tap 1 ug/L
Drinking W ater,
NA
ND
ND 0.026, NQ
Tap 2 ug/L
D rinking Water,
NA
ND
N D 0.025, N Q
Tap 3 ug/L
Landfill Leachate ug/L
4 8 .1 ,4 6 .8
NC
N D N Q , 0.028
Surface W ater 1
NQ, ND
NQ, ND
0.026, 0.027
0.026, 0.026
ug/L
Surface W ater 2
ND, NQ
ND
0.054, 0.060
0.026, 0.027
ug/L
Surface W ater 3
ND
N D 0.083, 0.083 N Q
ug/L
Sedim ent, Dry 1
ND, NQ
ND
NQ
ND
ug/K g
Sedim ent, Dry 2
NQ
NQ
ND
ND
ug/K g
Sedim ent, Dry 3
NQ
ND
NQ
ND
ug/K g
Q uiet W ater ug/L
0.057, 0.063
NC
N Q , 0.027
ND
ND = Not detec ted; NQ = Not quantifiable; NC = Not collected; NA = Not analyzed
0.084, 0.090 2 .5 1 ,2 .4 0 ND ND ND ND ND ND ND ND ND ND NQ, ND ND ND
Port St. Lucie, FL (1999)
0 .0 4 1 ,0 .0 4 4 NQ ND ND ND ND ND
0.953, 0.939 ND NQ ND
0 .3 7 0 ,0 .3 2 6 0.316, 0.294
1.68, 1.75 0.737, 0.760
Port St. L ucie, FL (2000)
0.043, 0.040 ND ND ND ND ND ND
1.03, 1.02 ND ND ND ND ND ND
0.097, 0.097
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
