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Talking Points, August 10, 2017, GenX Discussion
DuPont describes the "GenX technology" fluoropolymer manufacturing process as including the mixing of
the "precursor", C6HF11O3, "PFPrOPrA" or "GenX" (CASN 13252-13-6; 2,3,3,3-tetrafluoro-2-
heptafluoropropoxy)-propanoic acid) with an ammonium hydroxide solution, producing the ammonium
salt "processing aid", C6HF11O3•H3N (CASN 62037-80-3; ammonium 2,3,3,3-tetrafluoro-2-
(heptafluoro propoxy)-pro panoate). Documentation supplied by Chemours to the Netherlands public
health agency (2016) indicates that GenX and the processing aid (ammonium salt) are released to the
wastewater stream, and GenX and a process byproduct, "E1" (CASN 3330-15-2; C5HF11O,
heptafluoropropyl 1,2,2,2-tetrafluoroethyl ether) are released to the air. (Beekam et al. 2016)
Cape Fear River Studies, EPA studies, NCSU studies -
1. EPA NERL RTP researchers publish a journal art cl, Nakayan
water surveys collected in 2006 and analyzed fox a, -.,suite of 1
The work was part of the LCMSMS PFAS analytic#
samples from 80 locations in the mainstem and tri
Greensboro to the coast. They found PFAS in all th
target PFAS were C4-C12 chain -lengths, and includ
GenX. They did analyze for an un-related straight-
Different PFAS profiles were observed at each 6ic
reported was 329 ng/L for C7 perfluoro Wanoic
detected in a Haw River sample above tie confluei
In 2015, a journal article was
others (Stry-nar et al. 2015).1
sulfonic acids i;n surface wat
Sample locations -were thos
was to use specialalytical
detected unidentified PFAS.
that differed .)
the CFR Basin.'
degradation -re
JPFAS at a soui
shorter (50)1
C6HF11O3 (CASN
Nafion, a them
ed that re
b samples collet
in C6, perF#uorohexanoic acid (PFHxA).
n. The hii?hestindividual PFAS concentration
} }-(pFHpA). The, ni , est JPFAS was 942 ng/L
ce wi#ft the Deep River.
!d wo,rkbyscientists from EPA NERL, ORNL and
novel pj irflooroalkyl ether carboxylic and
CFR and its tributaries in 2012.
re PFAS had bee de#eted previously. The objective of the study
sits to confirm the identification and sources of the previously
They id>
-CF2 ory
ad that t
ed two homologous series of perfluoroalkyl ether PFAS
). This work identified GenX as one of the novel PFECAs in
ed. They reported more
logous series were manufacturing products and not
n 2-orders of magnitude increased concentrations of
with evidence of significant shift in dominant chain -length from longer (>_C8) to
!y noted significarrt levels of non -covalent dimers of the perfluoroalkyl ether,
3252-13-6, later identified as "GenX"). They also report finding evidence of
lreported,to be produced at the facility located upstream of the GenX and
perfluoroalkyl ether homci(ogous series detections.
3. Sun et al. (2016) paper published by NCSU, and EPA NERL (National Exposure Research Laboratory)
RTP provided analytical. Results of the paper were presented in NC in May -June 2017. The authors
reported the discovery of 7-novel perfluoroalkyl ether carboxylic acids (PFECA) in surface waters at
the intakes of 3 WTPs collected from the Cape Fear River Basin in 2013. GenX was one of the novel
PFECAs identified at the intake location of one WTP.
4. Sun et al. (2016) identifies GenX as "PFPrOPrA", perfluoro-2-propoxypropanoic acid (CASN 13525-
13-6), which is identified in DuPont documents as a C6 alternative to PFOS. The GenX was detected
in the raw water of a WTP downstream of a "PFAS manufacturer" at 631 ng/L (mean).
5. In grab WTP samples collected in 2014, Sun et al. (2016) reported that GenX, and other PFAS, were
not effectively removed in the drinking water treatment processes. The published data for this
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plant indicates a slight elevation of the GenX concentration in the finished water, relative to the
raw intake water. The WTP was not utilizing an activated carbon treatment.
6. Sun et al. (2016) also reported on batch reactor GAC adsorption studies utilizing grab CFR surface
waters collected in 2014 downstream of a PFAS manufacturing facility. The water samples included
C4-C10 PFCA, C4-C8 PFSA, and C3-C8 mono- and poly -ether PFECA PFAS. Carbon removal
efficiencies increased with increasing chain -length and increasing individual PFAS concentration.
PFSA were more effectively removed that PFCA of the same chain -length. The authors reported
that the overall removal efficiencies of the PFECAs present at the highest concentrations was
minimal (-5 - <15%).
7. In addition to GenX, the Sun et al. (2016) study reported other novel and legacy PFAS detected in
the CFRB waters & 3 WTPs, including C4-C10 PFCA and PFSA PFAS, and C8 PFOS and its
degradation product PFOA. Not all detected PFAS could be .quantified. due to a lack of calibration
standards source. Some of the PFAS that could not be quantified had peak areas <_15 times that of
GenX, indicating they were likely present at much higher concentrations.
GenX Toxicology Studies -
1. PFAS compounds of all types are indicated to be q,4ic-kly (_within minutes) and efficiemt (100%)
adsorbed on oral exposure, including by humans. PFAS bioaccumulate by bindingt4 proteins,
predominantly in the blood and other protein-1 0 organs (liver, kidneys). This means of
bioaccumulation is atypical of most envfrat}tTreta( contaminants that accumulate in lipids, and for
which the KoW partitioning coefficient can be used to estimate bioaccurnulation potential and food
chain magnification. KoW values cannot be used to predict the bioaccurnu{otion potential of PFAS.
2. The rate of uptake and elimination:of some classes of PFAS, re _highly variable across test species,
includingcomparisons between rats and mice, non-humanprirnates, and humans. This
complicates.the ability to extra olate animal d4ta to humans, to estimate body burden and
bioaccumulation,parameters 41Humans, and decisions on appropriate uncertainty factors - all
considerations important when identifying the critical -effect dose for development of toxicity
values.
3. The single, available carcinogenicity study,Prat 2-yr chronic exposure study) performed by
Chemours and DuPont scientists used rats. ,(A a et al, 2015). Other studies that have compared
PFAS effects.to rats and mice hue indicated that mice are more sensitive to some PFAS. The rat 2-
year carcinogenicity study reported a dose -related increase in liver tumor incidence in females,
and tumors ofthe'pancreas and<testes in males.
4. The Rae et al. (20I5)2-year rat study data also indicated histopathological cellular and sub -cellular
changes in the liver and kidneys that are responses known to be indicative of tumor promotion,
including cellular necrosis and lipid accumulation. These observations strengthen the causation
relationship of GenX exposure and tumor incidence.
5. Other non -cancer -related effects seen in the rat 2-year chronic exposure study (Rae et al, 2015)
included changes to red blood cells mass and function, and hemoglobin and protein levels.
Biomarkers of liver damage and observations of generalized cellular damage were reported,
including liver cell enlargement and increased liver mass. Again, these adverse effects and tumor
responses were reported in rats which have shown decreased levels of adverse biological response
to some PFAS relative to other test species.
6. The Gannon et al. (2016) study by Chemours/DuPont scientists exposed rats to a single dose of
GenX to track elimination kinetics over a 7-day study period. The exposure concentrations were
orders of magnitude (-6) higher than environmentally -relevant concentrations (10 and 30 mg/kg).
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Based on recovery concentrations in urine, the authors proposed that GenX was completely
eliminated within the 7-day period. There is concern that the elevated exposure concentrations
likely saturated tissue and cellular uptake mechanisms, and re -adsorption mechanisms in the
kidneys, resulting in urine elimination concentrations that prevented detection of exposure and
elimination concentration differences and potential tissue uptake. The authors did not perform
tissue analyses to confirm that GenX was not taken into tissues or organs. Because of the study
design including a single exposure regime, extreme exposure concentrations relative to likely
environmental exposure concentrations, and no confirmatory tissue data, this study does not
adequately address GenX tissue uptake. Additionally, kinetics based on a single dose may not be
representative of typical human environmental exposure regimes that are characterized by
multiple sources of exposure to multiple classes of PFAS, contributing to cumulative chronic
exposures. Chronic cumulative exposures uptake kinetics may not be reflected by a single dose
exposure.
7. A 2017 article reports (Wang et al. 2017) onday oral expasure5to mice. They identified many
DNA expression changes in liver cells, as welt neralized�tiv6t,.4.rtlargement and biomarkers of
liver damage, liver cell necrosis, liver cell enlargOthent and inducti ' ofJnflammatory responses.
Much of the gene expression alterations were ce►iuiai functions associated with cancer pathway
induction (alterations to lipid metabolism, liver cell necrosis and inflammatory responses),
providing further support for the potential carcinogeM611, y at..GenX. The medb6Ais1Jc p4thways
observed in the liver responses support a non-PPAR relate�ay for tumor- f0uctton, which
has been observed in other PFAS cancer studfes and has been pr©posed as a cancer pathway of
questionable relevance to human cancer inducttori. Additional studies are needed to confirm
tumor response and define the cancer. mode of action The authorsnoted that the response levels
observed in their mouse subjects were more senshe same responses observed for PFOA
in other studies.
8. Chemourstas provided
published papers. It is currently
9. In 2017, the Netherlands public;
grass and leaves at,S locations n
GenX and PF.4Are;taicerl-up by
were extracted (i.e., not.as urfac
meters from -the facility. Tho.#
lag/kg to 4.3. (ag/kg GenX and 'I
directly correlate with distant
both. Background locations di
stated that the data "represe
the raw toxicity study data o,r Gannon et al., and Rae et al.
er internal review.
�alth agency analyzed the' concentrations of GenX and PFOA in
Ir a GenX-production facility. The limited study indicated that
lants. The brief notes on methodology noted that the samples
wipe or rinse). The sampling locations ranged from 50-3000
!s had higher concentration than the grass, ranging from 86
a 28 lag/kg1,1PFOA. The PFOA and GenX concentrations did not
it the highest concentrations were at the 50 m locations for
t from the facility (85 km) were non -detect. The PH agency
a warning signal for consumers of locally grown food". The PH
agency also studiedthe upta:ke.of PFOA from soil to edible plants and identified that PFOA was
taken up from soil and distributed to the ingested portions of crops, with the ratio of uptake
varying by crop and identified as "1% for tuber crops to 3.5% for other crops. There is no data
from this study for the uptake of GenX from soils to plants. (RIVM 2017)
10. In a study published DuPont and Chemours scientists, Hoke et al. (2016) report on 28-day GenX
bioconcentration studies on common carp. They exposed the carp to 2.Oe04 and 2.Oe05 ng/L
dissolved GenX. No GenX was detected in the fish tissue at the end of the study, but the tissue
reporting limits were elevated (5.5e05 ng/kg). They also reported a reproductive -effect LOEC = 8.1
mg/L GenX in a Daphnia magna 21-day reproduction test, a NOEC >107 mg/L for a 72-hr static
green algae (Pseudokirchneriella subcapitata) growth test, and >8.9 mg/L NOEC and EC50 for a
rainbow trout 90-day early life -stage test, evaluated as hatching success, mobility and growth
parameters. While the fish tissue bioconcentration test did not provide useful data due to the
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elevated reporting limits, the suite of aquatic toxicity tests for the other standard aquatic toxicity
testing organisms did not indicate that GenX is acutely or chronically toxic at the selected test
concentrations to these organisms.
General PFAS, PFOS/PFOA Toxicology -
1. PFAS compounds are rapidly absorbed (minutes) and accumulate by binding to proteins in the
blood and other protein -rich tissues (liver, kidneys). PFAS can cross the placenta and accumulate in
breast milk.
2. Most of the health -effect studies for PFAS have focused on PFOS and PFOA, which are being
phased out in favor of shorter -chain PFAS that are suggested to be less toxic, less bioaccumulative
and more rapidly eliminated. Commonly reported epidemiological (human) health effects of
PFOS/PFOA exposure include: increased serum lipid levels, increased uric acid levels (an indication
of deficits in kidney function), indicators of liver damage, increased incidence of thyroid disease
(with possible implications of endocrine effects). HBP during *grtattcy, and ulcerative colitis.
Decreased birth weight and decreased fertility have b_ eert reported in some studies. While
increased incidences of kidney, testicular and prostate cancers have be--en-re ported associated with
human exposures, the evidence of carcinogenicity of PFAS is considered "inconclusive". There is
some evidence that PFAS compounds may have endocrine 41sruptor ("hormonally acfve"
toxicants) effects in humans, but that has not been confirmed.
3. The most sensitive effects of PFOS/PF(JA exposure reported in animal studies are developmental
effects and liver damage. Development effects re parted, include behavioral and neurological
changes, skeletal effects, delayed onset>of puberty:arhd delayed attamtnent of developmental
milestones. Animal tests indicate perfluoroalkyl mppounds affect the regulation of genes involved
in a broa6range of complex ical responsesassociated Wirthlipid metabolism, glucose and
lipid regulation, cholestet'olsyrithesis, regulation of signal trnsduction pathways and nervous
system funcns, fatty-acid_xetebolism, hormone reulatior} and immune and inflammation
responses. Suppression of genes involved in criticalsysterris influencing the regulation of cellular
communication, cell adhesion, growth and apoptosis (controlled cell death) have also been
reported. These pathways are all imol#sated in controlling cellular perturbations involved in the
control anct;progression-oftumor deve#e}ment. Biological membrane function may also be
affected.
slm/Chemours/Talking Points_
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Abbreviations:
CFRB = Cape Fear River Basin
EC50 = concentration at which there is a statistically significant non -lethal effect to 50% of the test
organisms as compared to the control response level
LCMSMS = Liquid chromatography tandem mass spectrometer analytical instrument system
LOEC = lowest observed (statistically significant) effect concentration
NERL = EPA's National Exposure Research Laboratory, RTP
NOEC = no observed (statistically significant) effect concentration
ORNL = Oak Ridge National Laboratory, TN
PFAS = polyfluoroalkyl and perfluoroalkyl substances
PFAA = perfluoroalkyl acids
PFCA = perfluoroalkyl carboxylic acid, PFAAs
PFSA = perfluoroalkyl sulfonic acid, PFAAs
PFOS = perfluorooctane sulfonic acid, C8 PFSA
PFOA = perfluorooctanoic acid, C8 PFCA
References:
Beekam et al. 2016. Evaluation of subst
RIVM, National Institute for Public
Gannon et al., 2016. Toxicology 340(2C
Hoke et al., 2016. Chemosphere 149 (2(
Nakayama et al.,,2C►(37. Environs Sci. Tec
Rae et al, 2015. Toxicology Reports 2,(2
Strynar et al., 2015: Envfron. SEi. Techni
sed in d
and the
W,
Sun et al (2016). Environ. Sci. Technol. Lett. 2016, 3, 415-419.
Wang et al. 2017. J. Appl. Toxicol. 2017; 37: 436-444.
hnology fiy,Chemours, Dordrecht.
nt, the Netherlands.
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