Draft External Peer Review Charge Questions for the Draft IRIS Toxicological Review of
Perfluorononanoic Acid [PFNA, CASRN 375-95-1] and Related Salts

March 2024

INTRODUCTION

The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of the draft IRIS
Toxicological Review of Perfluorononanoic Acid (PFNA) and Related Salts. IRIS assessments are
prepared by EPA's Center for Public Health and Environmental Assessment within the Office of
Research and Development IRIS assessments contain information about chemicals that
encompasses hazard identification and dose-response assessment, two of the four steps in the
human health risk assessment process. When used by risk managers in combination with
information on human exposure and other considerations, IRIS assessments support the Agency's
regulatory activities and decisions to protect public health.

There is no existing IRIS assessment for PFNA. The draft Toxicological Review of PFNA is based on
a comprehensive review of the available scientific literature on the noncancer and cancer health
effects in humans and experimental animals exposed to PFNA or salts of PFNA. The systematic
review protocol for PFNA and appendices for dose-response modeling, mechanistic evaluations,
and pharmacokinetic information and other supporting materials are provided as Supplemental
Information (see Appendices A to F) to the draft Toxicological Review.

REVIEW MATERIALS PROVIDED

•	Draft PFNA Toxicological Assessment

•	Supplemental Material (PFNA Appendices)

CHARGE QUESTIONS

In response to the numbered charge questions below, organized by topic area (italicized headers),
the advice provided as part of this peer review would be most useful when prioritized to indicate its
relative importance as follows:

•	Tier 1: Necessary Revisions - Use this category for any revisions you believe are necessary
to adequately support and substantiate the analyses or scientific basis for the assessment
conclusions.

•	Tier 2: Suggested Revisions - Use this category for any revisions you encourage EPA to
implement to strengthen the analyses or scientific basis for the assessment conclusions or
to improve the clarity of the presentation in the PFNA Toxicological Review.

•	Tier 3: Future Considerations - Use this category for any advice you have for scientific
exploration that might inform future work. While these recommendations are generally
outside the immediate scope or needs of the PFNA Toxicological Review, they could inform
future reviews or research efforts.

Literature Search Methods and Documentation

1. The Toxicological Review for PFNA describes and applies a systematic review protocol for
identifying and screening pertinent studies. The protocol is described in brief detail in
Section 1.2.1 (Literature Searching and Screening) and in full detail in Appendix A
[Systematic Review Protocol for the PFAS IRIS Assessments). Please:

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a.	Comment on whether the literature search strategy and screening criteria for PFNA
are appropriate and clearly described.

b.	Identify additional peer-reviewed studies of PFNA that EPA should consider
incorporating prior to finalizing the assessment.

i. EPA fully synthesized the literature published through April 2022 in the external
review draft and has been monitoring newly identified studies (i.e., studies
identified by EPA or the public that meet the PECO (population, exposure,
comparator, and outcome) criteria or otherwise inform key assessment
conclusions but that were not addressed in the external review draft—for
example, due to publication after April 2022). EPA characterizes these studies in
a tabular format in Appendix B.2. The characterization focuses on EPA's
judgment of whether the studies would have a material impact on the
conclusions (i.e., identified hazards or toxicity values) in the external review
draft. Studies that were classified as having a possible material impact on the
conclusions (e.g., epidemiological studies of hepatic effects and breastfeeding
duration; absorption, distribution, metabolism, and excretion/pharmacokinetic
[ADME/PK] studies that informed clearance values or otherwise were helpful in
the interpretation of the available ADME/PK data) were incorporated into the
evidence synthesis. Please review EPA's characterizations and provide tiered
recommendations regarding which additional studies, if any, would have a
material impact on the draft's conclusions and should be incorporated into the
assessment before finalizing, as well as your interpretation of the impact of those
studies to be incorporated.

Noncancer Hazard Identification

2. For each health effect considered in the assessment and outlined below, please comment on
whether the available data have been clearly and appropriately synthesized to describe the
strengths and limitations, including whether the presentation and analysis of study results
are clear, appropriate, and effective to allow for scientifically supported syntheses of the
findings across sets of studies. Please comment on whether the study confidence conclusions
for the PFNA studies are scientifically justified, giving appropriate consideration to important
methodological features of the assessed outcomes.1 Please specify any study confidence
conclusions that are not justified and explain any alternative study evaluation decisions. For
each, please also comment on whether the weight-of-evidence decisions for hazard
identification have been clearly described and scientifically justified. Note that the data from
studies considered informative to the assessment are synthesized in the relevant health
effect-specific sections and are available in the Health Assessment Workspace Collaborative
(HAWC).

a. For developmental effects, the Toxicological Review concludes that the available

evidence demonstrates that PFNA exposure causes developmental effects in humans
given sufficient exposure conditions, based primarily on growth impairments
observed in epidemiological studies. It was determined that there was robust evidence

1The Toxicological Review provides an overview of individual study evaluations within each evidence synthesis section, and the
results of those outcome-specific evaluations are made available in the Health Assessment Workplace Collaborative. Note that
a "HAWC FAQ for assessment readers" document, linked here (scroll to the bottom of the page, and the document is available
for download under "Attachments"), is intended to help the reviewer navigate this online resource.

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of decreased birth weight in studies of exposed humans, with support from generally
coherent epidemiological findings for other fetal and postnatal growth restriction
endpoints (e.g., birth length, postnatal weight and height). In further support, cross-
stream coherence is provided by moderate animal evidence for PFNA-induced
developmental effects in gestationally exposed rodent offspring that included reduced
postnatal survival and body weights, and delays in attaining developmental
milestones.

i. The evidence synthesis and integration for potential PFNA-induced

developmental effects included a meta-analysis (see Appendix C.l) conducted
by EPA (Wright et al., 2023) that considered the findings of birth weight deficit
to be statistically robust across all sampling periods and study confidence
levels, indicating there are demonstrated birth weight deficits as PFNA
exposure levels increase. Although the epidemiological data were ultimately
judged as robust, there is residual uncertainty regarding some potential for
confounding by other per- and polyfluoroalkyl substances (PFAS) and sample
timing; however, these factors were not interpreted by EPA to substantially
reduce confidence in the evidence base. Please comment on whether the
determination that the epidemiological evidence is robust is scientifically
justified.

b. For liver effects, the Toxicological Review concludes that the available evidence
indicates PFNA exposure is likely to cause liver effects in humans given sufficient
exposure conditions, based on consistent and coherent evidence from human, animal,
and mechanistic studies. There is moderate evidence in human studies that PFNA is
associated with liver injury based on increased ALT, AST GGT, and bilirubin. In
animals, there was robust evidence from a series of short-term studies in rats and mice
demonstrating consistent and coherent effects on liver weight, clinical pathology, and
histopathology that included hepatocellular necrosis, cholestasis, and triglyceride
accumulation. The liver findings for PFNA were similar to those for other structurally
related long-chain PFAS and were determined to be adverse.

i.	The judgment that there is moderate evidence in human studies was
based primarily on cross-sectional studies in general population adults.
For nearly all epidemiological studies of PFNA exposure, there is potential
that exposure to other highly correlated PFAS could contribute to the
observed effects. The evidence synthesis for potential PFNA-induced
hepatic effects included evaluation of the adequacy of studies with
exposure and outcome measured concurrently as well as the likelihood of
confounding across PFAS. It was concluded that these sources of
uncertainty were unlikely to explain the observed effects. Please
comment on whether these conclusions are scientifically justified.

ii.	Additional considerations influenced the liver effects hazard
identification decisions. Appendix A (Systematic Review Protocol for the
PFAS IRIS Assessments) outlines the human relevance of hepatic effects in
animals that involve peroxisome proliferator-activated receptor alpha
(PPARa) receptors as a key science issue. For PFNA, there is evidence of
both PPARa-dependent and -independent (e.g., CAR/PXR) pathways

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contributing to hepatotoxic effects, consistent with the judgment drawn
for several other PFAS. The Toxicological Review evaluates the evidence
relevant to the potential involvement of PPARa and non-PPARa pathways
with respect to the reported liver effects. The Toxicological Review
ultimately concludes that evidence from in vivo and in vitro studies
supports a potential role for multiple pathways operant in the induction
of hepatic effects from PFNA exposure and that the effects are potentially
relevant to humans. Detailed information is provided in the Mechanistic
and Supplemental Information of Section 3.2.4, Hepatic Effects. Please
comment on the basis for the judgment of human relevance of the liver
effects and whether it is scientifically justified.

iii. In judging that the animal evidence for hepatic effects is robust, the
Toxicological Review concludes that the hepatic effects in animals were
adverse (vs. adaptive), based in part on consideration of criteria from Hall
et al. (2012). The liver enlargement from short-term testing in rats and
mice was accompanied by histopathological lesions, including adverse
lesions such as necrosis. However, the lack of longer-duration exposures
was a substantial source of uncertainty. Therefore, although the linkage
between liver hypertrophy and histological evidence of necrotic changes
was found to support adversity, the short-term data were further
evaluated based on additional criteria set forth in Hall et al. (2012) that
considers dose-dependent and biologically significant changes in at least
two clinical pathology parameters (see Hall etal., 2012) as confirmatory
indicators of hepatocellular damage. The PFNA database was found to
meet at least two of the additional criteria set forth by Hall etal. (2012),
including large increases in ALT and AST in mice (effects in rats were
mild); large increases in bile acids and bilirubin in male rats considered
by the National Toxicology Program (NTP) to be indicators of intrahepatic
cholestasis; in addition to reductions in blood proteins, increasing
triglyceride accumulations and disrupted lipid homeostasis. Please
comment on the basis for determination under the criteria set forth in
Hall etal. (2012) and others (e.g., U.S. EPA, 2002; EMEA, 2008; Thoolen et
al., 2010; Boone et al., 2005) that the hepatoxic effects observed in
rodents are considered adverse.

c.	For male reproductive effects, the Toxicological Review concludes that the available
evidence indicates PFNA exposure is likely to cause male reproductive effects in
humans given sufficient exposure conditions. This conclusion is based primarily on a
high confidence 28-day oral toxicity study in adult rats that reported a consistent and
coherent pattern of adverse male reproductive effects, with additional support from
medium confidence, short-term studies in adult rats and prepubertal mice observing
effects at similar doses.

d.	For immune effects, the Toxicological Review concludes that the available evidence
suggests, but is not sufficient to infer, that PFNA exposure has the potential to cause
immunosuppression in humans. This conclusion is primarily based on epidemiological
studies (see Table 3-22) providing evidence of reduced antibody response with PFNA

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exposure, and possible evidence for effects on asthma and asthma-related outcomes,
but with concerns regarding imprecision and potential residual confounding by other
PFAS. The human evidence was considered slight and the animal evidence
indeterminate.

i. The evidence for immune effects for PFNA differs from that of other long-chain
PFAS (e.g., perfluorodecanoic acid [PFDA] and perfluorohexanesulfonic acid
[PFHxS]), which found stronger evidence of immunosuppression. Please
comment specifically on whether the weight-of-evidence decisions for
immunosuppression have been clearly described and are scientifically justified.

e.	For thyroid effects, the Toxicological Review concludes that the available evidence
suggests, but is not sufficient to infer, that PFNA exposure may have the potential to
cause effects on the thyroid in humans. This was a complex evidence base to interpret,
and the judgment was based primarily on moderate animal evidence from a high
confidence 28-day study in adult rats that showed large, dose-dependent reductions in
serum free and total T4 in females and in serum free T4 in males. Although this study
provided evidence of effects on T4 homeostasis, there were uncertainties surrounding
the reliability of methods used for measuring free T4 in both sexes. There were also
body weight losses in males at higher doses that challenged interpretation of the T4
reductions, as well as additional responses in males that were difficult to decipher (i.e.,
decrease in thyroid-stimulating hormone [TSH], including at doses absent substantial
body weight loss). The epidemiological database was slight and did not demonstrate
coherence with the animal evidence, with the strongest evidence showing positive
associations with T4 in children/adolescents, although effect sizes were small.
However, there was considerable uncertainty in the human evidence because of
inconsistent directions of association and concerns related to study sensitivity.

f.	For cardiometabolic effects, the Toxicological Review concludes that the available
evidence suggests, but is not sufficient to infer, that PFNA exposure may have the
potential to cause cardiometabolic effects in humans. This conclusion was based on
studies in humans that showed generally increased serum lipids and some potentially
supportive but mixed results for other increased risk factors for cardiovascular
disease. However, the evidence has unexplained inconsistencies within and across
studies and concerns for imprecision, which add considerable uncertainty. Evidence in
experimental animals was indeterminate.

g.	For neurodevelopmental effects, the Toxicological Review concludes that the available
evidence suggests, but is not sufficient to infer, that PFNA exposure may have the
potential to cause neurobehavioral effects in humans, based on associations between
PFNA and outcomes related to attention and behavior in epidemiological studies.
However, there is considerable uncertainty in this association, including imprecision
in all the estimates from the three studies evaluating attention-deficit/hyperactivity
disorder (ADHD) diagnosis, the most specific outcome, and some unexplained
inconsistency. There was no relevant evidence in experimental animals to inform this
outcome.

h.	For female reproductive, urinary, adrenal, and other noncancer effects fi.e..
hematological, respiratory, digestive, dermal, and musculoskeletal), the Toxicological
Review concludes there is inadequate evidence to determine whether PFNA
exposure has the potential to cause these effects in humans based on the sparsity

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and/or uncertainties of available evidence.

Noncancer Toxicity Value Data Selection and Modeling

3. For PFNA, no reference concentration (RfC) was derived for inhalation exposures. A
reference dose (RfD) was derived based on the epidemiological study by Sagiv et al.
(2018) examining reduced birth weight in humans. Note that the selected RfD
based on developmental effects is further supported by the lifetime oral hepatic
organ-specific (os) RfD, based on Kim et al. (2023).

a. Is the selection of the study for developmental effects for use in deriving the RfD values
(both lifetime and subchronic) for PFNA scientifically justified? If so, please provide an
explanation. If not, please provide an alternative study(ies) or effect(s) that should be
used to support the derivation of the RfD and detail the rationale for use of such an
alternative.

i.	As part of the recommendations in "a" above, please comment on whether the
effects selected are appropriate for use in deriving the lifetime RfD, including
considerations regarding adversity (or appropriateness in representing an
adverse change) and the scientific support for their selection. Please also see
charge questions 2a and 2a(i).

ii.	EPA used benchmark dose (BMD) modeling (U.S. EPA, 2012) to identify points
of departure (PODs) for PFNA-induced developmental effects. In addition, a
meta-analysis was performed for the relationship between PFNA and mean
birth weight differences in humans. Are the modeling and meta-analysis for
decreased birth weight approaches appropriate? Are the selection and
justification of benchmark response levels, selection of the BMD models used
to identify each POD for toxicity value derivation, and the POD selected for
deriving the candidate value for developmental effects scientifically justified
and clearly described?

b.	For liver effects, an (os) RfD was derived based on the epidemiological study by Kim et
al. (2023) examining biomarkers of liver functions in humans. Are the modeling
approaches for the liver effects, selection of cutoff for abnormal, selection and
justification of benchmark response levels, selection of the BMD models used to
identify each POD for toxicity value derivation, and the POD selected for deriving the
candidate value for hepatic effects scientifically justified and clearly described?

c.	For male reproductive effects, quantitative information was limited to studies in
animals exposed to PFNA for 28 days, and little to no information was available to
evaluate the effects of chronic exposure on these health hazards. Therefore, the
derivation of lifetime os RfD values was not attempted for male reproductive
effects. However, this endpoint was considered for the derivation of a subchronic
(os) RfD (see Question 4). Please comment on whether the provided scientific
rationale supports the decision to consider only these effects for the subchronic
RfD? Are the selection and justification of benchmark response levels, selection of
the BMD models used to identify each POD for toxicity value derivation, and the
POD selected for deriving the candidate value for male reproductive effects
scientifically justified and clearly described?

d.	For immune and thyroid effects, no reference values were derived given

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uncertainties in the databases that were judged to indicate suggestive evidence of
effects. However, while a dose-response assessment is typically not conducted for
health effect judgments of "evidence suggests," when the database includes at least
one well-conducted study, quantitative analysis may still be useful for some
purposes, such as providing a sense of the magnitude and uncertainty of estimates
for health effects of concern, informing responses in potentially susceptible
populations, or setting research priorities (U.S. EPA, 2005; U.S. EPA, 2020). For this
assessment, immunosuppression in children and reduced serum T4 in adult female
rats were advanced for dose-response modeling to facilitate comparisons with
other PODs and to inform uncertainty factor (UF) selection given that effects have
been observed for several other PFAS.

i.	For immune effects, the BMD modeling of the selected medium confidence
epidemiological studies by Grandjean etal. (2012) using untransformed PFNA
concentrations by Budtz-J0rgensen et al. (2018) was null and did not show
effects of PFNA on antibody concentrations in children aged five and seven
years in both the single-PFAS model and in the multi-PFAS model of PFNA
controlling for PFOS and PFOA. Thus, BMDs and BMDLs (benchmark dose
[lower confidence limits]) for the effects of PFNA on childhood antibody
concentrations to diphtheria and tetanus are provided to compare to other
PODs but are not advanced further for RfD derivations. Are the modeling
approaches for immune endpoints appropriate and scientifically justified, and
is the decision to not advance the modeling for derivation of reference values
supported?

ii.	For thyroid effects, with emphasis on results observed in females (results in
males were uncertain), the 28-day study in adult rats indicates reductions in
serum T4 that are suggestive of an effect but were found insufficient to infer a
hazard (see Question 2e). Despite the uncertainties, there is concern for effects
given that the T4 reductions in rats from a high confidence study were large in
magnitude, and there are concerns for downstream effects on neurodevelopment,
which is generally a data gap for this chemical. These concerns were further
informed by delays in eye opening observed in developmental toxicity studies in
two strains of mice, which is a well-characterized effect of T4 insufficiency
although thyroid effects were not evaluated in these studies. Given these results
and observations of thyroid effects for other PFAS, PODs were derived for total T4
in adult females for comparative purposes and to inform uncertainty. Is the
approach taken for thyroid effects appropriate and scientifically justified, and is
the decision to not advance the reductions in serum total T4 in female rats for
derivation of a subchronic reference value supported?

e. Given the lack of studies on inhalation exposure to PFNA, no RfC is derived. Please
comment on this decision.

4. In addition, for PFNA, an RfD for less-than-lifetime ("subchronic") exposures is derived. No
subchronic RfC was derived. The same studies and outcomes were chosen for use in
deriving the lifetime and subchronic RfDs.

a. Please comment on whether the selection of these studies and these effects for the

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derivation of the subchronic RfD for PFNA is scientificallyjustified.

b.	If not, please provide an alternative study(ies) or effect(s) that should be used to
support the derivation of the subchronic RfD and detail the rationale for use of such
an alternative.

c.	As part of the recommendations in "a" or "b" above, please comment on whether
the effects selected are appropriate for use in deriving the subchronic RfD,
including considerations regarding adversity (or appropriateness in representing
an adverse change) and the scientific support for their selection.

d.	Please comment on the other subchronic (os) RfDs (i.e., for liver and male
reproductive effects).

e.	Given the lack of studies on inhalation exposure to PFNA, no subchronic RfC is
derived. Please comment on this decision.

Noncancer Toxicity Value Pharmacokinetic Extrapolation and Uncertainty Factors

5. Section 3.1 evaluates and synthesizes the PK data in relevant species and sexes, and among
human lifestages, up to the derivation of key PK parameters used in the subsequent analysis.
Appendix E.l provides a statistical analysis of PK parameters in male and female rats and mice
while differences in clearance between male and female humans as a function of lifestage are
evaluated in Section 3.1.4 (subsection Excretion in Humans). However, the evaluation of
existing physiologically based pharmacokinetic (PBPK) models and a classic PK model
described in Appendix E.4 found that these options were not sufficiently reliable for use.

For PODs derived from laboratory animal studies, given the information available on potential
interspecies differences in PFNA PK and the results of comparing PK model predictions to
bioassay data (E.4.1), EPA concluded that a hybrid approach for extrapolation of POD values in
animals to estimate corresponding human equivalent doses (HEDs) was the best option in the
derivation of the respective RfDs. Specifically, distinct approaches are proposed for estimation
of internal doses in male and female rats from the NTP bioassay vs. estimation for mice
examined in developmental studies:

>	PFDA serum concentrations measured at the end of the NTP bioassay were algebraically
interpolated to estimate internal dose POD (PODmt) values for the applied dose PODs
identified from that study. The interpolation for male rats assumed a linear increase in
serum concentration over the 28-day study, whereas that for female rats assumed the
average concentration is close to the end-of-study value.

>	For endpoints from mouse developmental studies (including results in nonpregnant
females from those studies), the PK model was used to estimate the PODmt values.
Specifically, the average serum concentration calculated from the time of mating until the
day of observation for each endpoint was used to provide metrics consistent with the
dosing regimen (gestation only) and endpoint evaluation at late gestation vs. multiple
postnatal times.

>	The estimated human clearance (CLh) was used to convert the PODmt values from these
animal experiments to PODhed values.

Likewise, for PODmt values that are human serum concentrations identified from
epidemiological analyses, CLh was used to calculate the corresponding PODhed-

a. Are these methods for calculating PODmt values for PFNA for endpoints in rats (adult

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animals) vs. mice (adult females and pups) scientifically justified for conversion of
PODs from animal toxicity studies to HEDs? If not, please provide an explanation and
detail on a more appropriate approach.

b.	Is application of CLh to estimate PODhed values from PODmt values (from animal
or epidemiological studies as summarized above) scientifically justified? If not,
please provide an explanation and detail on a more appropriate approach.

c.	Have the uncertainties in the PODmt estimates for animal studies and CLh been
adequately evaluated and described?

6. EPA has evaluated and applied, where appropriate, UFs to account for intraspecies

variability (UFh), interspecies differences (UFa), database limitations (UFd), duration (UFs),
and LOAEL-to-NOAEL (lowest-observed-adverse-effect level to no-observed-adverse-effect
level) extrapolation (UFl) for PFNA. For a-f below, please comment on whether the
uncertainty in the derivation of the candidate and selected toxicity values is scientifically
justified and clearly described.

a.	Please comment specifically on whether the methods used to derive toxicity values for
PFNA appropriately account for uncertainties in pharmacokinetics, including
accounting for differences between the experimental animal data and humans.

b.	For developmental effects, a UFA of 1 was used since the value was based on human
data. A UFs of 10 was not considered as the developmental period is recognized as a
susceptible lifestage for these types of effects and, therefore, exposure during this
time window can be considered more relevant than exposure in adulthood (U.S. EPA,
1991). Uncertainties with regard to additional susceptible lifestages (e.g., other early-
life developmental stages) are addressed as part of the UFD. Does the provided
scientific rationale support this decision? If not, please explain.

c.	For liver effects and derivation of the lifetime fosl RfD using human studies, a UFa of 1
was applied as the liver effects were reported in epidemiological studies and the value
was based on human adult data. Does the provided scientific rationale support this
decision? If not, please explain.

d.	For liver effects and derivation of the subchronic fosl RfD using animal studies, a
value of 3 is applied to extrapolate between effects in laboratory animals and in
humans during the derivation of the subchronic RfD. Although PPARa dependence
might support a value of UFA = 1 for hepatotoxicity if that were the sole pathway
leading to these effects, evidence for the involvement of non-PPARa pathways is
available in the PFNA database. Thus, uncertainty remains regarding the potential
differences in sensitivity across species because of the involvement of both PPARa-
dependent and PPARa-independent mechanisms. As such, the Toxicological Review
concludes the available data are not adequate to determine whether humans are likely
to be equally or less sensitive compared to laboratory animals with respect to the
observed liver effects and that a value of UFA = 3 is warranted to account for the
residual uncertainty in toxicodynamic differences across species. Please comment on
whether the available animal and mechanistic studies support this conclusion and
whether the analysis presented in the Toxicological Review and Derivation of Toxicity
Values is clearly documented.

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e.	For liver and male reproductive effects, a value of 10 is applied for the UFS when
extrapolating from 28-day animal data to a subchronic exposure. Considering the
potential for some health effects (prolonged diestrus, sperm measures, and increased
liver weight) to worsen with increasing duration and the large uncertainty associated
with the lack of chemical-specific data to evaluate the effects of subchronic exposure
on liver and male reproductive outcomes, the Toxicological Review concludes that
application of a UFs of 10 is supported for the purpose of deriving the subchronic RfD
from the 28-day toxicity data. Does the provided scientific rationale support this
decision? If not, please explain.

f.	Are the provided rationales for the remaining UFs (UFL, UFD, UFH) scientifically
justified and clearly described (to inform the UFH, the assessment evaluates and
considers the available evidence on potential susceptibility to PFNA within different
populations or lifestages, including any potential impacts from early-life exposure to
PFNA on lifelong health, although few studies on susceptibility were available)? If not,
please explain.

Carcinogenicity Hazard Identification and Toxicity Value Derivation

7.	The Toxicological Review concludes there is inadequate information to assess carcinogenic
potential for PFNA and that this descriptor applies to oral and inhalation routes of human
exposure. Please comment on whether the available human, animal, and mechanistic studies,
as well as the analysis presented in the Toxicological Review, are scientifically justified and
clearly described.

8.	Given the conclusion there was inadequate information to assess carcinogenic potential for
PFNA, the Toxicological Review does not derive quantitative estimates for cancer effects for
oral or inhalation exposures. Is this decision scientifically justified and clearly described?

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