DEQ-CFW_00000382

Initial Calculation of a Provisional Health Screening Level for GenX in drinking water from the Cape
Fear River.
Upon learning of the media reports of GenX occurring in drinking water, DHHS responded to urgent
inquiries about health effect data for this compound. To bring context to the concentrations of GenX
reported to be in drinking water in 2013 and 2014, DHHS initially calculated a provisional drinking water
level that corresponded to a Derived No Effect Level for humans for oral exposure published by the
European Chemical Agency (ECHA). The initial response process is outlined below.
1) In the absence of health guidance values published by organizations in the U.S., we used
documentation from Europe. A Derived No Effect Level (DNEL) for humans for oral exposure was
taken from the European Chemical Agency (ECHA) website (CAS62037-80-3).
https•//echa.europa.eu/registration-dossier/-/registered-dossier/2679/7/1
2) DNEL for humans was calculated by,&eFl_A_: ► )Upocv�- clan(,{ ne, p r+Zci
a. NOAEL= 1.0 mg/kg bw/day (2-year chronic tox & cancer study)
b. Total uncertainty factor of 100
i. Interspecies variability=10
ii. Intraspecies variability=.10
c. DNEL=(1.0 mg/kg bw/day)/100= 0.01mg/kg/day
3) DHHS applied ex
concentration th
C
e6' 0' '
C� IIQP
DXLY
v
lam PIZ.'
n=
isure factors using ATSDR e
corresponds to ECHA's DN
se*Body Weight/Intake. TI
the large amount of water
'here was an assumption;ti
The ATSDR g
in relation to
i. Dose
iv.
line accounts for t
it low bodvweishi
Body We
Intake=l.
4) We used 71,000 ng/L a .(-
on appropriate revisions.
Moving forward:
osure dose guidelines. A drinking water
was determined based on the calculation of
values used for body weight and drinking water
at bottle-fed infants consume in relation to their
100% of the dose was coming from water.
rge amount of water bottle-fed infants consume
L mg/kg bw/day
;ht=7.8 kg OC4rakiq Pulolisheci CIS
L L/day 70) qo -1 )J91 L
ition=(0.01 mg/kg/day)*7.8kg/(1.1L/day)=71,000 ng/L
x '71µSI4j,= 0.071(V\.3IL
provisional health screening value, and now we are seeking guidance
After calculating this initial value, DHHS identified specific information about GenX that requires
modifications and special considerations for risk assessment. These considerations are described in
the remainder of this document.
(P.1)
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000382

DHHS is currently reviewing our provisional health screening level of 71,000 ng/L and seeking input
from the ATSDR and EPA.
Four risk assessment considerations are listed below for GenX. EPA has already provided feedback in
agreement of using the POD of 0.1 mg/kg/day. Input is still required on the remaining three
considerations.
Animal toxicity studies and the point of departure (POD): Sufficient data was available to lower
the POD NOAEL to 0.1 mg/kg/day (subchronic toxicity test OECD 407 with mice).(An uncertainty
factor of 10 will be applied for subchronic to chronic extrapolation) i:PA 8;8 No-ir voice
2) Routes of exposure and the relative source connlri
through routes other than drinking water. The #
r
organic chemicals is 0.2, and this is the value used
PFOS drinking water ealth advisories. We regwesl
use of an RSC of 0.2.
-'1-yPically
3)
PFos
Pr-OA
kiue�c 1n+0
WAS &oat .
4)
tEaue
(RSQ: People may be exposed to GenX
used for RSC in risk assessment of
the EPA for their evaluation of PFOA and
iidance from the EPA and ATSDR on the
Risk assessment method and interspecies uncertainty fact
variability of 10 is likely to underestimate the toxicity of Gei
method used to extrapolate a human equivalent dose (HED
document. Interspecies uncertainty modeling for PFOA and
140 to 71OX for kinetics differences and an additions! 3Xm
across species. The total uncertainty accounted for across s
was calculated by DHHS and the maximum was 2,100X. We
and ATSDR on an appropriate interspecies uncertainty fac,
X-dld E(�R use O.2 ane�
ch►1c1 � o r was � +- o . 2
and ?ma�-ecna"
or: The default value for interspecies
iX to humans. We present the EPA
for PFOA and PFOS in this
PFOS yielded a calculated factor of
is allocated for other variability
pecies by EPA for PFOA and PFOS
also request euida cn a from the EPA
Drinking water concentration guidance for other PFECAs: The Sun et al 2016 publication
identified not only GenX, but also other perfluoroalkyl ether carboxylic acids (PFECAs) present in
the Cape Fear River and local drinking water in 2013 and 2014. Quanfication of the
concentrations of other PFECAs was not possible due to the lack of analytical chemistry
standards, however some PFECAs may have been present at concentrations 15 times higher
than GenX. Presumed high concentrations are prompting questions about drinking water safety,
however no toxicity data is available for these PFECAs. We request guidance from the EPA and
? basis?
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
a
DEQ-CFW 00000383

OECD-- Orrnisa�"gym -fo economy ..c, (2o-ai)er N 6(ld
zeuetopm*-A4
ECWF�: IJelst�k,�> �i�la�cQ
1) Test animal toxicity data and the point of departure (POD)
Since the initial assessment, DHHS reviewed the available toxicity studies on GenX to determine an
appropriate POD (Table 1). Review of the NOAELs is also helpful for demonstrating the interspecies
variability referenced in the next section.
Methods in data collection:
OECD standardized studies were submitted during chemical registration in Europe and
summaries of the findings are published on the European ChemicatAgency (ECHA) Website.
Studies on the ECHA website were included in our review if the exposure duration was sub -
chronic or chronic. ECHA also reports extra studies provided to them. However these extra
studies lacked method details and were not included in our review.
We also looked for other peer reviewed studies and Gi* found four on toxicity. Two articles
restate chemical registration studies shown on ECHA and so were not added to the table below
(Gannon et al 2016 Toxicology, Rae et al 2015 Toxicology Reports). One study was an ecological
risk assessment so was not included (Hoke et al 2016 Chemosphere). Rushing et al 2017
Evaluation of the Immunomodulatory Effects of (GenX) in C57BL/6 Mice was a new study and so
was included in our evaluation.
Table 1: Subchronic and chronic toxicity studies with GenX
Method Lowest NOAEL in Study NOAELs
Studies
Repeated dose toxicity
Oral
OECD 407: 28-Da y Ora I Tox i n Rode nts Rats
30mg/kg bw/da
30 mg/kg bw/day (male)
300m /k bw/da female
OECD 407: 2 8-Da y Oral Tox in Rodents Mice
0.1 m /k bw/da
0.1 mg/kg bw/day (male)
3 m /k bw/da female
OECD 408: 90-Da y Ora I Tox i n Rode nts Rats
10m k bw/day
10 mg/kg bw/da y (m a le)
100 m/k bw/da female
OECD 408: 90-Day Oral Tox in Rodents Mice
0.5 mg/kg bw/day
0.5 mg/kg bw/da M&F
OECD 453:2- r Combined Chronic Toxicity & Carcinogenicity Rats
1mg/kg bw/da y
1 mg/kg bw/day (ma le)
50mg/kg bw/da female
Carcinogenicity
"Findings are from same experimental trial as reported on for OECD 453 above.
OECD 453:2- r Combined Chonic Toxicity &Carcino enicit (Rats)
1mg/kg bw/day
1 mg/kg bw/day (ma le)
50mg/kg bw/da (female)
Toxicity to reproduction
Toxicitityto reproduction
OECD 421: Re roduction/Develo mental Tox Screen (Mice)
0.1 mg/kg bw/da
0.1 mg/kg w ay (FO ma e
0.5 mg/kg bw/day (FOfema le)
0.5 mg/kg bw/day (Offspring)
5 m /k bw/da (Reproductive Toxicity)
Developmental toxi city/te ra toge ni city
OECD414: Prenatal Developmental Tox Rats
10 mg/kg bw day
10 mg/kg bw/day (Materna 1)
10 mg/kg bw/da Offs rin
Additional peer -reviewed studies
Rushinget al 2017. Evaluation ofimmunomodulatoryeffects of GenX in mice.
Toxicol.Sci.156(1):179-189
1 1mg/kg/day
1 mg/kg/day (M&F)
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000384

Comparison of NOAELs, including interspecies variability and sex -specific differences
The 28-day study's lowest NOAEL for mice was two orders of magnitude lower than that for rats,
Zaps and NOAELs for males were one order of magnitude lower than those for females. Similar trends
are seen in the 90-day studies, where mice were more sensitive than rats (by one to two orders of
magnitude) and male rats were more sensitive than female rats (by one order of magnitude).
Effects on the liver were the primary endpoints noted in these subchronic studies, and the lowest
NOAELs were 0.5 andl0.1 mg/kg/day)in the mice studies.
4 lowest ®f -mac "loU"
2 The 2-year chronic toxicity and carcinogenicity study used rats, and both carcinogenic and liver
endpoints had NOAELs of 1.0 mg/kg/day. A 2-year chronic mouse study was not conducted. Two
studies were conducted on reproduction and development. OECD 421 used mice, while OECD 414
used rats. Once again we see two orders of magnitude between the species' NOAELs with the
lowest mouse NOAEL at 0.1 mg/kg/day. It is of interest to note that the lowest NOAEL for offspring
(with dosing occurring to the parental generation only) was 0.5 mg/kg/day for system toxicity to
both males and females in the F1 generation. One additional study was found in the peer reviewed
literature that used mice to study immunological effects. The lowest NOAELs were 1.0 mg/kg/day.
Caveats for old POD: There are caveats regarding the cancer and chronic study because the most
sensitive rodent was not tested. The reported NOAEL of 1.0 mg/kg/day is likely to underestimate
chronic and carcinogenic toxicity compared to the subchronic tests submitted, and therefore is not
the most protective POD. Three of the seven subchronic studies for GenX have NOAELS in the range of
0.1-0.5 mg/kg bw/day. These studies are subchronic and would therefore be subject to modification
by an uncertainty factor of 10
X 10 ici( bvbehro"k- +0 6vr0r0tcr
w ��k selection of new POD: We find sufficient supao t to lower our initial POD of 1.0 mg/kg/day. The
jJ�`� revised POD will be a NOAEL of 0.1 mg/kg/day for subchronic toxicity to mice (OECD 407). The same
POD was selected by both RIVM and EPA when reviewing these GenX toxicity studies (RIVM 2016,
EPA 2008).
X \�'
` Caveat for cancer risk assessment: The chronic toxicity and carcinogenicity study has caveats
` because the most sensitive species (mice) was not tested. Closer review of the study also reveals
that control animals had high background levels of interstitial cell adenomas and hyperplasia (data
summarized in table A4 of RIVM Letter 2016). These observations raise questions about QA/QC and
test data validity. In addition, we currently lack sufficient data to calculate a slope factor for GenX
and are unable to conduct a cancer risk assessment. Requests for additional cancer testing with
GenX may be warranted and mice would be a more appropriate test species for observing sensitive
endpoints.
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000385

Observation of high interspecies variability in reponse to GenX: It is also important to notice the
trend that these limited test results are showing for interspecies variability and sex -specific
differences. GenX is a perfluorinated alkyl substance, as are more well studied chemicals
perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). PFOS and PFOA are known to
have high interspecies variability and sex -specific differences for chemical clearance rates and
toxicity endpoints (EPA 2016a, 2016b). High interspecies variability is an important consideration in
the risk assessment process, as will be further discussed in the next section.
l4e c's ci e s uc.ab►lci,.V
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000386

3) An interspecies uncertainty factor for GenX
Rationale for using high interspecies variability uncertainty factor for GenX
GenX is a member of a chemical group called per- and polyfluorinated alkyl substances (PFASs).
Perfluorooctanoic Acid (PFOA) and perfluorooctane sulfonate (PFOS) are among the better studied
PFASs. The US EPA has established a non -regulatory drinking water health advisory (HA) for the
total concentration of PFOA and PFOS of 70 ng/L (EPA 2016a, 2016b)). There is a wealth of peer
reviewed environmental and human health data available for PFOA and PFOS, including animal
studies and epidemiological studies with humans. The availability of a risk assessment from an
authoritative agency provides a relevant model to evaluate for considerations specific to this class
of chemicals.
High interspecies variability is a major consideration in the EPA risk assessment of PFOA and PFOS.
High interspecies variability (up to 300X) is seen in the limited rodent studies available on GenX.
Similar interspecies and sex -specific toxicity trends can been seen in GenX and other PFASs. Taken
together, this warrants departure from the default of 10X for interspecies uncertainty in the risk
assessment of GenX. ( depacivr<Z, LieS, possis reoso(\a61C
Kaukng already 6\0ss en Poo as "nnos+ iensii Az 1
J
gh interspecies variability approach used for PFOA & PFOS
9- L
® ` Risk assessments often default to using a value of 10 for assessing interspecies variability in
toxicokinetics and toxicodynamics (Rhomberg & Lewandowski 2004). Toxicokinetics are the affect
r �
of the body on the chemical, such as adsorption, distribution, metabolism, and excretion.
Toxicodynamics are the affect of the chemical on the body, such as impacts on a target molecule or
organ.
Animals used for laboratory testing have been shown to remove PFOA and PFOS from their bodies
at a rate that is faster than humans do. For example, humans in two epidemiological studies were
found to have PFOA half lives of 2.8 and 3.8 years on average (EPA 2016b). In contrast, PFOA half
lives measured in monkeys, rats, and mice ranged from 3.4 hours to 30 days (EPA 2016b). The
mechanisms for these differences are complex and the reader is refe{o to the PFQA and PFOS
drinking water HA documents for details. Q H
The EPA HA risk assessments for PFOA and PFOS address kinetic differences by modeling a human
equivalent dose (HED) via modeled animal blood serum concentrations. The EPA's modeling yielded
HED values that were between 140 and 710 times smaller than the NOAELs from the test animals
(Table 2). The HEDs accounted for he majority of the Interspecles variability, and an additional
interspecies variability uncertainty factor of 3 was multiplied by the HED to account for remaining
differences. The total interspecies variability accounted for ranged from 420 to 2,100 (Table 3). For
comparison see the 2016 RIVM report letter, in which interspecies variability is broken down into
66 for kinetics and 1.8 for other (Table 5).
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000387

0
Table 2: Magnitude of Difference Between NOAELs and Modeled HED Values for PFOA and
PFOS Drinicing Water Health Advisories
References for NOAELs and LOAELs for PFOS and PFOA
NOAEL
HED
*Calculated
NOAEL/HED
PFOS
Seacat et al 2003
0.34
0.0013
260
Luebker et al 2005b
0.1
0.00051
200
Luebker et al 2005a
0.4
0.0016
250
Butenhoff et al 2009
0.3
0.00084
360
Lau et al 2003
1.0
0.0014
710
PFOA
Palazzolo et al 1993 & Perkins et al 2004
0.64
0.0044
140
DeWitt et al 2008
1.88
0.0053
360
NOAEL: No Observed Adverse Effect Level; HED: Human Equivalent Dose.
NOAEL and HED values came from EPA PFOA and PFOS drinking water health advisory development documents.
*Calculated NOAEL/HED values were calculated by DHHS.
While NOAEL values were sometimes provided with one significant digit, EPA calculations consistently provided
HEDs with two significant digits. Our calculations of NOAEL/HED are also reported in two significant digits.
Selection of an interspecies uncertainty factor for GenX V0 '1" 0 2 I 0 0 (-�Q- C � O IN�
NC DHHS does not have the expertise to determine how large the interspecies uncertainty factor
should be for GenX. However, we can calculate drinking water levels for GenX using different
potential uncertainty factors in order to gain insight on the possible range of values that should be
considered. DHHS compared drinking water concentrations calculated with a default interspecies
variability (10) and the maximum calculated PFOA and PFOS interspecies variability value (2,100)
(Table 4). This provides a range of theoretical health protective GenX drinking water concentrations
between 140 and 0.7 ng/L. These theoretical health protective drinking water concentrations are
lower than the average concentrations of GenX (631ng/L) found in the Cape Fear River in 2013 and
2014 (Sun et al 2016). DHHS is seeking guidance from EPA and ATSDR on the selection and/or
development of an appropriate interspecies uncertainty factor for GenX.
0.7 N5 I L -fio
ea Ali.
..�O�14�yl�.,
No+e, : 70)1cD0148) L —7 0.7N9 I L
* 10®, 00C) #Id low-c 2.,
C�.
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000388

21
Table 5: Comparison of PODs and UFs used by other agencies to obtain a reference dose tqfebohumans
EPA PFOA & PFOS
Health Advisories
ECHA
RIVM
EPA 2008 Consent
Order
WV DEP Consent
Order
PFOA & PFOS
(mg/kg/day)
UFs
GenX
(mg/kg/day)
UFs
GenX
(mg/kg/day)
UFs
GenX
(mg/kg/day)
UFs
GenX
(mg/kg/day)
UFs
PODS
NOAEL
0.1-1.88
1.0
0.1
0.1
0.1
Uncertainty
Factors
Interspecies
Variability (Total)
*420-
2,100
10
*120
10
10
(UFs)
Intraspecies
Variability
10
10
10
10
-
LOAEL to NOAEL
Extrapolation
**10
-
-
-
-
Subchronic to
Chronic Extrapolation
**10
-
-
-
10
Total Uncertainty
Factor
A
100
1200
100
100
Final reference dose
for humans
0.00002
0.01
-
0.001
0.001
Values used by the EPAApfor PFOA and PFOS are shown in ranges because a variety of calculations were compared y the EPA before selecting the most protective value.
*Interspecies variability (total) was calculated by DHHS from multiple types of uncertainty provided in EPA (PFOA), E A (PFOS) and RIVM (GenX) documents.
**LOAEL to NOAEL & subchronic to c�ronic extrapolations were applied to some PODs but not all. EPA evaluated se ral potential PODs and these two uncertainty factors
applied to some studies but not all.
RIVM does not offer a reference dose in these units because they assessed occupational exposure via inhalation.
It E5
,jC�G`�
G
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17

0
0
6
n
I
0
0
0
0
0
w
0
�5 P X\
NC
lio Cj
0
Table 3: Uncertainty Factors Accounted for in PFOA nd PFOS DrinkingWater qealth Advisories
References for NOAELs and
LOAELs for PFOS and PFOA
NOAEL
Interspecies Variability
Intra ;;
species
Variability
Subchronic
to Chronic
*Total OF
*Calculated
NOAEL HED
Other
*Total
PFOS
Seacat et al 2003
0.34
260
3
780
10
7,800
Luebker et al 2005b
0.1
200
3
600
10
6,000
Luebker et al 2005a
0.4
250
3
750
10
7,500
Butenhoff et al 2009
0.3
360
3
1'100
10
11,000
Lau et al 2003
1.0
710
1 3
2100
10
21,000
PFOA
Palazzolo et al 1993 & Perkins et al 2004
0.64
140
3
420
10
4,200
DeWitt et al 2008
1.88
360
3
1,100
10
10
11,000
NOAEL: No Observed Adverse Effect Level; HED: Human Equivalent Dose; UF:Uncertainty Factor.
NOAEL and HED values came from EPA PFOA and PFOS drinking water health advisory development documents.
- - - - - -- -- - -- _..— _- . ---.. __ _ .� _ �_._ . -- -1-1-1-1 --
*Values calculated by DHHS based on using NOAEL/HED for an additional interspecies uncertainty factor.
While NOAEL values were sometimes provided with one significant digit, EPA calculations consistently provided HEDs with two
significant digits. DHHS calculations are also reported in two significant digits.
Table 4: Use of PFOA & PFOS Interspecies Uncertaint to. Calculate Possible Health Protective Drinking Water Concentrations
Uncertainty Factors (UFs)
Drinking Drinking
NOAEL *Possible Intra RfD DWEL Water Water
Inter Subchronic
(mg/kg/day) species Total OF (mg/kg/day) (mg/L) Concentration Concentration
species to Chronic
Variability, Variability (mg/L) (ng/L)
OECD 407 Subchronic Mice O.I 10 10 10 1,000 0.0001000 0.00071 0.00014 140
with GenX 0.1 2,100 10 10 210,000 0.0000005 0.000003 0.0000007 0.7
Possible Interspecies Variability=Coml*rson of defaut value of 10 with maximum PFOA and PFOS calculated interspecies uncertainty factor from Table 3 (2,100).
Reference Dose=RfD=NOAEL/Total OF
Drinking Water Equivalent Level=DWEL=RfD*BW/DWI. Bodyweight=BW. Drinking water intake=DWI. BW=7.8kg and DWI=1.1L/day for infants per ATSDR guidelines
Drinking Water Concentration-DWEL RSC. Relative Source Contribution=RSC=20 /o
f 3 Nsi ivt %using �n�ra�spzca.�,s �c4�'�Id bo�� 1 i��w1�Ge ���C
specteg 10
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17

Clarification on risk assessment methods for GenX requiring further guidance from EPA and ATSDR
Relative Source Contribution (RSC): RSCs are important in risk assessment because they recognize that
people are exposed to chemicals through drinking water, but they are also exposed through food, dust,
soil, and air. For specific examples, the RIVM report shows significant emissions in one manufacturing
scenario and shows that inhalation can be a relevant exposure route for members of a community near
a GenX manufacturing plant. The EPA HAs for PFOA and PFOS consider the ubiquitous presence of these
chemicals and use an RSC of 20% to allow for multiple exposure routes. GenX is a replacement for PFOA
and the volume of GenX use and extent of potential widespread GenX occurrence is unknown. The RSC
value commonly applied to organic chemicals is 20%, and that is the value we propose adopting for
assessment of GenX. ( io r act A S 7�
Uncertainty Factor for Interspecies Variability: Interspecies variability in GenX toxicity is likely to be
underestimated by the default value of 10. Mice and rat studies with GenX that were submitted for
chemical registration and manufacturing were up to 300X different in rats and mice using the same test
method. EPA's PFOA and PFOS drinking water health advisories used interspecies variability calculated
up to a maximum of 2,100X (Table 3). Methods are needed to account for the high interspecies
variability in GenX and more research is needed to provide an appropriate uncertainty factor value that
is more specific to GenX.
Residents in this comm
PFECA chemicals that v
performed to determine what cony
data available for these chemicals a
available. Would it be appropriate t
research data can be collected and
sting guidance on interpreting concentrations of GenX and other
their drinking water in 2013 and 2014. Additional testing is being
ations are in their drinking water at this time. There is no health
t is expected that it could take years until more data will become
>e the PFOA + PFOS health advisory of 70 ng/L until more
ore specific guidance can be offered?
I�1aS�,5
7SbNE proute�et'� ?
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000391

Appendix:
EPA PFOA and PFOS drinking water health advisory calculations
Summary of risk assessment methods EPA used when developing drinking water health advisory
levels for PFOA and PFOS (EPA 2016a, 2016b).
1) Animal studies with NOAELs and LOAELs were selected to use as points of departure (POD).
2) PODs were modeled to get human equivalent doses (HEDs). ,S��k
a. Part of the inter`species variability was accounted for in this step. .�h� •�k �s
b. Example PODS and corresponding HEDs are shown below in table 5-1 from the PFOA
document.
3) HEDs were adjusted by uncertainty factors (UFs) to get reference doses (RfDs) and the most
conservative RfD was selected for moving on to the next step.
a. Values for UFs were multiplied to obtain UFTotai
i. UFH: Intraspecies variability=10
ii. UFA: Interspecies variability=3 `t4 ���
iii. UFO: LOAEL to NOAEL extra polation=10'-• "3e �
iv. UFs: Subchronic to Chronic extrapolation=10
v. UFD: Database uncertainty did not apply
b. RfD = HED/UFTotal
c. Example HEDs and corresponding RfDs are shown below in table 5-2 from the PFOA
document.
4) Exposure to the RfD was calculated and reported as a drinking water equivalent level
(DWEL).
a. DWEL=[RfD x bw]/DWI
i. Where bw=body weight and DWI=drinking water egtOvafei:�t
ii. DWI/bw=0.054L/kg/day ? ; 6 +K% 5 ?
5) DWEL was adjusted for the relative source contribution (RSC) from water in order to get a
lifetime HA level.
a. Lifetime HA = DWEL x RSC
b. RSC used for both PFOA and PFOS was 20%
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
DEQ-CFW 00000392

Table 5-1. Human Equivalent Doses Derived from the Modeled Animal
Average Serum Values
Study
Dosing
NOAEL
NOAEL
HIED
LOAEL
LOAEL
HED
duration
mg/kg/d
Av serum
mg/kg/d
mg/kg/d
(Av serum)
mg/kgfd
days
mg/L
ra IL
DeWitt et al. (2008):
15
1.88
38.2
0.0053
3.75
61.9
0.0087
mice; I IgM response
to SRBC
Lau et al. (2006): nice
17
None
-
-
1
38.0
0.0053
decreased I pup
ossification (nL f),
accelerated nnale
puberty
Palazzolo et al. (1993):
91
0.64
31.6
0.0044
1.94
77.4
0.0108
Perkins et al. (2004):
rats: f liver
weight`necrosis
Wolf et al. (2007):
17
None
-
-
3
77.9
0.0109
nrice: GD 1-17
Pup body weight
Wolf et al. (2007):
11
None
-
-
5
87.9
0.0123
niice: GD 7-17
jPup body weights
Butenhoff et al.
84
None
-
-
1
45.9
0.0064
(2004a): I relative
body wetghtT relative
kidney «eight and
Tkickiey: brain weight
ratio in FO and F 1 at
sacrifice
Notes:
Significance p < 0.05 or p = 0.01
m = wale; f = female; SRBC = sheep red blood cell; IgM = immunoglobulin M; GD = gestation day
n serum from pups on PND 22
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Table 5-2. Candidate RfDs Derived from the HEDs k2m, the Pharmacokinetic Model
'Average Serum Values ^
HED POD
Candidate RfD
POD
mglkWday
UFH
UFA
UFL
UFs
UFn
OF
mg/kg/day
PK-HEDNoAm Palazzolo
0.0044
10
3
-
-
-
30
0.00015
et al. (1993)1Peakins et al.
(2004)
rats. Tlivet
weight/necrosis
PK-HEDLoaEL Wolf et al.
0.0109
10
3
10
-
-
300
0.00004
(2007) GD1-17 mice;
jPup body weight
PK-HEDLOAM Wolf et al.
0.0123
10
3
10
-
-
300
OA0004
(2007) GD 7-17 nice;
I Pup body weight (serum
from pups on PND 22)
PK-HEDxoAmDeWitt et
0.0053
10
3
-
10
-
300
0.00002
al_ (2008)
mice; 1 IgN-1 response to
SRBC
PK-HEDLOAM Lau et al_
0.0053
10
3
10
-
-
300
0.00002
(200+6)
mice decreased 1 pup
ossification (m, f),
accelerated male puberty
PK-HEDLoAm Butenhoff
0.0064
10
3
10
-
-
300
0.00002
et al_ (2004a)
relative body weight,/T
relative kidney weight
and -Tkidney: brain weight
ratio in FO and Fl at
sacrifice
Notes:
PK-BED = phannacol inetic human equivalent dose; NT OAEL = no observed adverse effect level;. LO.4EL = lowest observed
adverse effect level; GD = gestation day; IgM = immnmoglobulin M; m = male; f = female; SRBC = sheep red blood cell; UFx =
intraindiv7dual uncertainty factor; UFA = interspecies rmcertairAy factor UFs = subchronic to chronic uncertainty factor, UFL =
LOAEL to NOAEL uncertainty factor; UFn = incomplete database uncertainty factor; UFtwg = total (multiplied) uncertainty
factor
Table 5-2 from EPA Drinking Water Health Advisory for PFOA
� v �
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DEQ-CFW 00000394

F
�--oS
Table 5-1. Human Equivalent Doses Derived from the liodeled Annnal Average
serum a� lues
Dosing
NO.AEEL
LO EL
duration
NO.AEL
Av serum
BED
L©AEL
A`• serum
BED
Studs
days
mglkgId
p tImL
mglkgld
rngikg1d
µg/mL
mjWd
Seacat et al. (2003):
98
0.34
1&5
0.0013
1.33
6C6
0.0052
shale rat TALT.
TBUN
Luebker et al.
84
0.1
6.26
0.00051
0.4
25
0.002
2005b): 1 rat pup
bode weight
Luebker et al.
63
None
None
None
0.4
19.9
0.0016
(2005a):1 rat pup
body weight
Luebker et al.
63
0.4
19.9
0.0016
0.8
39.7
0.0032
(2005a): rat j
maternal body
weight, gestation
length, and pup
Survival
Butenhoff et al.
41
0.3
10.4
0.00084
1.0
34.6
0.0028
(2009): rat DINT
(Tmotor activity;
,habituation)
Lau et al. (2003):
19
1.0
17.6
0.0014
2..0
35.1
0.0028
Irat pup sunrival;
Iniaternal and pup
body weight
Notes:
ALT = alaniae Iran sanminase; BUN = blood urea nitrogen; DNT = developmental neurotgaicity; N©AEL. = no observed adverse
effect level; LOAEL = lowest obsen-ed arhww effect leve$ BED = hiunan equivalent dose
Water Health Advisory for PFOS
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DEQ-CFW 00000395

PPS
Table 5-2. Candidate RfDs Derived from HEDs from the Pharmacoldnetic Model Average
Serum Values
Candidate
HED POD
RED
POD
mglkWday
UYE
17FA
UFL
UF's
ITFn
UFtow
mg1&g1day
(Seacat et al. 2003): male
0.0013
10
3
1
1
1
30
0.00004
rat NOAEL for TALI,
TBUN
PK-HED (Lau et al.
0.0014
10
3
1
1
1
30
0.00005
2003): rat, NOAEL for 1
pup survival and body
weight
PK-HED (Buteuhoffet al.
0.00084
10
3
1
1
1
30
0,00003
2009): rat, NOAEL for
Tmotor activity
lhabituatiou
FK-HED (Luebker et al.
0.00051
10
3
1
1
1
30
0.00002
2005b): rat. NOAEL for
jpup body weight
PK-HED (Luebker et al.
0.0016
10
3
1
1
1
30
0.000U5
2005a): rat. NOAEL for
J,pup survival
PK-HED LOAEL
0.0016
10
3
3
1
1
100
0.00002
(Luebker et al. 2005a): rat,
LOAEL for Jpup body
weigbt
Mates.
PK H D = phanwcokinetic human ec U-mlent dose; NOAEL — no observed adverse effect leael; LOAEL = lo%mt observed
adverse effect level; UFH = irnra-individual uncertainty factor; UFA = intersperies unceatai * factor. UF% = subchmnic to chronic
uncertainty factor, UFs = LOAEL to NOAEL uncertainty factor; L'F© = incomplete database uncertainty factor; UF,m.i = total
(multiplied) uncertainty factor
?A Drinking Water Health Advisory for PFOS
OF s 100
baksed K modlQIk( cC�
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Resources
A collection of tests using OECD and EPA standardized methods were submitted for product registration
in the EU and US*a T hese studies are discussed by many grou s in diff, Pent wags. ustn9 ar ►/1
-5.o assAss?�.ev
1) f(aw data can be acquired tl} h Chemours by requesting from Shawn �`^e�kO&.S
Gannon. __ ��
2) Summaries on the European Chemical Agency (ECHA) Website. Navigate the test types on the
left side of the webpage and use the pull -down button at the top of the page to move through
studies 001, 002, etc. https://echa.europa.eu/registration-dossier/-/registered-dossier/2679/1
3) RIVM letter 2016 is an assessment from a European group focused on risk to a community in
proximity to a GenX manufacturing facility from inhalation exposure. An interspecies uncertainty
factor of 66 is applied for kinetics alone. ; k(Nes a iwhala a� ?
4) EPA 2008 Consent order contains a point of departure selected at that time.
5) WV DEP Consent order contains a point of departure selected at that time.
6) Peer reviewed literature by Caverly Rae et al 2015 covers OECD 453._,
7) Peer reviewed literature Gannon et al 2016, covers kinetics and metabolism studies also on the
ECHA website.
References
Caverly Rae, J. M., L. Craig, T. W. Slone, SO'
chronic toxicity and carcinogenicity of am
Dawley rats. Toxicol. Reports. (2),:939-949
EPA 2008. Consent 0
EPA 2016a. Drinking
EPA 20
ns
Ith Advisory for Pe
L. W. Buxton, and G. L. Kennedy. 2015. Evaluation of
3,3,37-tetrafluor6propoxy)-propanoate in Sprague-
r for P-08-508 and P-08-509.
to Sulfonate (PFOS). EPA 822-R-16-004
noic Acid (PFOA). EPA 822-R-16-005
Gannon, S. A., W. J. Fasano, M. P. Mawn, D. L. Nabb, R. C. Buck, W. Buxton, G. W. Jepson, and S. R.
Frame. 2016. Adsorption, distribution; metabolism, excretion, and kinetics of 2,3,3,3-tetrafluoro-2-
(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and
cynomolgus monkey. Toxicology (340) 1-9
Hoke, R. A., B. D. Ferrell, T. L. Sloman R. C. Buck, and L. W. Buxton. 2016. Aquatic hazard,
bioaccumulation and screening risk assessment for ammonium 2,3,3,3-tetrafluoro-2-
(heptafluoropropoxy)-propanoate. Chemosphere (149) 336-342
Rhomberg, L. R and T. A. Lewandowski. 2004. Methods for identifying a default cross -species scaling
factor. Prepared by Gradient Corporation for US EPA.
RIVM letter report 2016-0174. Evaluation of substances used in the GenX technology by Chemours,
Dordrecht. http://www.rivm.nl/bibliotheek/rapporten/2016-0174.pdf
Rushing, B. R., Q. Hu, J. N. Franklin, R. L. McMahen, S. Dagnino, C. P. Higgins, M. J. Strynar, and J. C.
DeWitt. 2017. Evaluation of the Immunomodulatory Effects of 2,3,3,3-Tetrafluoro-2-
(Heptafluoropropoxy)-Propanoate in C57BL/6 Mice. Toxicol. Sci. 156 (1):179-189
Working document to assess knowledge gaps in GenX risk. Wednesday 7/05/17
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