Health Based Guidance for Water
Health Risk Assessment Unit, Environmental Health Division
651-201-4899

Web Publication Date: April 2019

Toxicological Summary for: Perfluorohexane sulfonate

CAS: 108427-53-8 (anion)
355-46-4 (acid)
3871-99-6 (potassium salt)
Synonyms: PFHxS; perfluorohexanesulfonic acid; 1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexane-1sulfonate
Short-term, Subchronic and Chronic* Non-Cancer Health Based Value (nHBV) = 0.047 µg/L**

*Due to the highly bioaccumulative nature of PFHxS within the human body, serum concentrations are the most
appropriate dose metric and the standard equation to derive the HBV is not appropriate. Short-term exposures have the
potential to stay in the body for an extended period of time. In addition, accumulated maternal PFHxS is transferred to
offspring (i.e., placental and breastmilk transfer). A single HBV has therefore been recommended for short-term,
subchronic, and chronic durations. The 2019 HBV was derived using a toxicokinetic (TK) model previously developed by
MDH (Goeden 2019). Model details and results are presented below.
**Relative Source Contribution (RSC): Using the most recent published biomonitoring results (CDC 2018, 2019) and USEPA’s
Exposure Decision Tree (USEPA 2000) as outlined in MDH 2008, Section IV.E.1., an RSC of 0.5 (50%) was selected.
Intake Rate: In keeping with MDH’s peer-reviewed and promulgated methodology, 95th percentile water intake rates (Table
3-1 and 3-3, USEPA 2011) or upper percentile breastmilk intake rates (Table 15-1, USEPA 2011) were used. Breastmilk
concentrations were calculated by multiplying the maternal serum concentration by a PFHxS breastmilk transfer factor of
1.4%. For the breast-fed infant exposure scenario, a period of exclusive breastfeeding for one year was used as
representative of a reasonable maximum exposure scenario. [Note: “exclusively breast-fed” intake rates refers to infants
whose sole source of milk comes from human breastmilk, with no other milk substitutes (USEPA 2011, page 15-2).]
A simple equation is typically used to calculate HBVs at the part per billion level with results rounded to one significant digit.
However, the toxicokinetic model used to derive the HBV for PFHxS showed that serum concentrations are impacted by
changes in water concentrations at the part per trillion level. As a result, the 2019 HBV contains two digits.

Reference Dose/Concentration: HED/Total UF = 0.00292/300 = 0.0000097 mg/kg-d (or 9.7
ng/kg-d) (adult Sprague Dawley rats). [The corresponding
serum concentration is 32.4/300 = 0.108 µg/mL. Note: this
serum concentration is inappropriate to use for individual
or clinical assessment.***]
Source of toxicity value: Determined by MDH in 2019
Point of Departure (POD): 32.4 µg/mL (or mg/L) serum concentration (male rats NTP 2018, MDH modeled BMDL20%)
Dose Adjustment Factor (DAF): Toxicokinetic Adjustment based on Chemical-Specific
Clearance Rate = Volume of Distribution (L/kg) x (Ln2/Half-

PFHxS - 1

 Human Equivalent Dose (HED):
Total uncertainty factor (UF):
Uncertainty factor allocation:

Critical effect(s):
Co-critical effect(s):
Additivity endpoint(s):

life, days) = 0.25 L/kg x (0.693/1935 days) = 0.000090 L/kgday. (Half-life from Li et al 2018)
POD x DAF = 32.4 mg/L x 0.000090 L/kg-d = 0.00292
mg/kg-d
300
3 for interspecies differences (for toxicodynamics), 10 for
intraspecies variability, and 10 for database uncertainty to
address concerns regarding early life sensitivity to
decreased thyroxine (T4) levels as well as lack of 2
generation or immunotoxicity studies.
decreased free T4
decreased free and total T4, triiodothyronine (T3), and
changes in cholesterol levels and increased hepatic focal
necrosis
Hepatic (Liver) System and Thyroid (E)

***The serum concentration is useful for informing public health policy and interpreting population-based exposure
potential. This value is based on population-based parameters and should not be used for clinical assessment or for
interpreting serum levels in individuals.

Toxicokinetic Model Description (Goeden 2019):
PFHxS is well absorbed and is not metabolized. Serum concentrations can be calculated from the dose
and clearance rate using the following equation.

Where:

𝑺𝑺𝒎𝒎
𝑫𝑫𝑪𝑪𝑫𝑫𝑺𝑺 �
�
𝑺𝑺𝒎𝒎
𝒌𝒌𝒎𝒎 ∙ 𝒅𝒅𝑪𝑪𝒅𝒅
𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺 𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑺𝑺𝑪𝑪𝑪𝑪𝑺𝑺𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪 �
�=
𝑳𝑳
𝑳𝑳
𝑪𝑪𝑪𝑪𝑺𝑺𝑪𝑪𝑺𝑺𝑪𝑪𝑪𝑪𝑪𝑪𝑺𝑺 𝑹𝑹𝑪𝑪𝑪𝑪𝑺𝑺 �
�
𝒌𝒌𝒎𝒎 ∙ 𝒅𝒅𝑪𝑪𝒅𝒅

Dose (mg/kg-day) = Water or Breastmilk Intake (L/kg-day) x Water or Breastmilk Concentration (mg/L)
and
Clearance (L/kg-day) = Volume of distribution (L/kg) x (Ln 2/human half-life, days)

Two exposure scenarios were evaluated: 1) an infant fed formula reconstituted with contaminated
water starting at birth and continuing ingestion of contaminated water through life; and 2) an infant
exclusively breast-fed for 12 months, followed by drinking contaminated water. In both scenarios the
simulated individuals began life with a pre-existing body burden through placental transfer of PFHxS
(maternal serum concentration x 70%) based on median cord to maternal serum concentration ratios
reported in the literature. The serum concentration of the mother at delivery was assumed to be at
steady-state and was calculated by using the equation above with a time-weighted 95th percentile
intake from birth to 30 years of age (0.047 L/kg-d). During lactation a 95th percentile water intake rate
of 55 mL/kg-d and a body weight of 65.2 kg ((USEPA 2011), Table 3-3) was used to calculate daily
maternal serum concentrations.
PFHxS - 2

 Consistent with MDH methodology, 95th percentile water intake and upper percentile breastmilk
intake rates were used to simulate a reasonable maximum exposed individual. A PFHxS breastmilk
transfer factor of 1.4%, based on average breastmilk to maternal serum concentration ratios reported
in the literature, was used to calculate breastmilk concentration. According to the 2016 Breastfeeding
Report Card (CDC, 2016), nearly 66 percent of mothers in Minnesota report breastfeeding at six
months, dropping to 41% at twelve months. MDH chose to use the breastmilk intake rates for
exclusively breastfed infants, as reported in USEPA 2011, for one year for the breast-fed infant
scenario.
Daily post-elimination serum concentration was calculated as:
𝑆𝑆𝑚𝑚
𝑆𝑆𝑚𝑚
𝑇𝑇𝐶𝐶𝑑𝑑𝑑𝑑𝑑𝑑 ′ 𝑠𝑠 𝐼𝐼𝐶𝐶𝐼𝐼𝑑𝑑𝐼𝐼𝑆𝑆(𝑆𝑆𝑚𝑚)
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶. � � = �𝑃𝑃𝑆𝑆𝑆𝑆𝑃𝑃. 𝑑𝑑𝑑𝑑𝑑𝑑 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶. � � +
� × 𝑆𝑆 −𝑘𝑘
𝐿𝐿
𝐿𝐿
𝐿𝐿
𝑉𝑉𝑑𝑑 � � × 𝐵𝐵𝐵𝐵(𝐼𝐼𝑚𝑚)
𝐼𝐼𝑚𝑚

To maintain mass balance, daily maternal serum concentrations and loss-of-chemical via transfer to
the infant as well as excretion represented by the clearance rate, were calculated.
Summary of Reasonable Maximum Exposure (RME) Scenario Model Parameters
Model Parameter

Value Used

Volume of distribution (Vd)

0.25 L/kg (average of male (0.287) and female (0.213) nonhuman
primate Vd, Sundstrom, 2012)

Vd Age Adjustment Factor

2.1 age 1-30 days decreasing to 1.2 age 5-10 years and 1.0 after age 10
years (Friis-Hansen 1961)

Half-life

1935 days (mean value for all ages, Li et al 2018)
(5th to 95th percentile range: 1095 – 3358 days)

Elimination rate constant (k)

Calculated from Ln 2/half-life

Placental transfer factor
(% of maternal serum level)

70% (mean of median paired maternal:cord blood ratios reported in the
literature. Range of mean values 43 – 95%.)

Breastmilk transfer factor
(% of maternal serum level)

1.4% (mean of mean paired maternal serum:breastmilk ratios reported
in the literature. Range of mean values 0.8 – 2%.)

Water Intake Rate (L/kg-d)

95th percentile consumers only (default values, MDH 2008) (Table 3-1 &
3-3, USEPA 2011)

Breastmilk Intake Rate (L-kg-d)

Upper percentile exclusively breast-fed infants (Table 15-1, USEPA 2011)

Body weight (kg)

Calculated from water intake and breastmilk intake rate tables

(Mean 95th percentile value 110%, range 69 – 168%.)

(No 95th percentile values reported in literature.)

A relative source contribution factor (RSC) is incorporated into the derivation of a health-based water
guidance value to account for non-water exposures. MDH utilizes the Exposure Decision Tree process
presented in USEPA 2000 to derive appropriate RSCs. Determination of an appropriate RSC must
recognize the long elimination half-life of PFHxS, such that a person’s serum concentration at any given

PFHxS - 3

 age is not only the result of his or her current or recent exposures within the duration of concern, but
also from exposure from years past.
Human biomonitoring data provide a quantitative description of the ongoing widespread exposure, but
the serum data are not informative as to the specific pathways and exposure routes. The most recently
reported 95th percentile serum concentrations from CDC (2019) range from 1.62 µg/L serum for young
children to nearly 5 µg/L serum for older children and adults. This suggests that ‘background’
exposures, when compared to the ‘reference’ serum concentration (108 µg/L serum) would not
represent significant sources of exposure. Using the most recent published biomonitoring results and
USEPA’s Exposure Decision Tree (USEPA 2000) as outlined in MDH 2008, an RSC of 0.5 (50%) was
selected.
As mentioned above, two exposure scenarios were examined: 1) an infant fed formula reconstituted
with PFHxS-contaminated water starting at birth and continuing ingestion of contaminated water
throughout life; and 2) an infant exclusively breast-fed for 12 months, followed by drinking PFHxScontaminated water throughout life. For the first scenario, the formula-fed infant, the water
concentration that maintains a serum concentration attributable to drinking water at or below an RSC
of 50% is 0.108 µg/L (Figure 1).
Figure 1. Exclusively formula-fed infant scenario serum concentrations over a lifetime, based on MDH’s
RME and an RSC of 50%.

Applying this water concentration (0.108 µg/L) in the context of the breast-fed infant resulted in
serum PFHxS concentrations exceeding the ‘reference’ serum concentration for nearly 2 years, and the
50% RSC threshold for nearly 17 years. See Figure 2.

PFHxS - 4

 Figure 2. Breast-fed infant scenario serum concentrations over a lifetime, based on MDH’s RME and a
water concentration of 0.108 µg/L.

In order to maintain serum concentrations at or below an RSC of 50% for breast-fed infants, the water
concentration should not exceed 0.047 µg/L; see Figure 3. This water concentration also produces
steady state serum concentrations at approximately 20% of the ‘reference’ serum concentration.
Figure 3. Exclusively breast-fed infant scenario serum concentrations over a lifetime, based on MDH’s
RME, and a water concentration of 0.047 µg/L.

To ensure protection of all segments of the population, the final health-based value for PFHxS is set
at 0.047 µg/L.

PFHxS - 5

 Cancer Health Based Value (cHBV) = Not Applicable
Cancer classification:
Slope factor (SF):
Source of cancer slope factor (SF):
Tumor site(s):
Volatile:

Not Classified
Not Applicable
Not Applicable
Not Applicable

Yes (moderate)

Summary of Guidance Value History:
MDH first reviewed PFHxS in 2009 and determined that there was insufficient data to derive a value. In
2013, MDH’s Site Assessment and Consultation Unit began using the guidance value for PFOS as a
surrogate to assess potential risks from exposure to PFHxS, in the absence of adequate chemical
specific data. In 2018 additional toxicokinetic and toxicity information became available. In 2019, MDH
derived a noncancer HBV (applicable to short-term, subchronic, and chronic durations) of 0.047 µg/L.
Summary of toxicity testing for health effects identified in the Health Standards Statute (144.0751):

Even if testing for a specific health effect was not conducted for this chemical, information about that effect might be
available from studies conducted for other purposes. MDH has considered the following information in developing health
protective guidance.

Tested for
specific effect?
Effects
observed?

Endocrine

Immunotoxicity

Development

Reproductive

Neurotoxicity

Yes

No

Yes

Yes

Yes

Yes1

-2

No3

Yes4

No5

Comments on extent of testing or effects:
1 Several human epidemiological studies have evaluated the possible association between serum
PFHxS and alterations in thyroid hormone levels. Two studies found an association in women
between serum PFHxS and thyroid hormone levels, however, other studies did not find this
association. Two general population epidemiology studies have evaluated associations between
PFHxS and reproductive hormones, finding no association.
Based on studies in laboratory animals, alterations in serum thyroid hormone levels, in particular
thyroxine (T4), appear to be a sensitive effect. The POD is based on decreased serum T4 levels in
adult male rats however, decreased serum T4 levels have also been reported in pregnant and
lactating rats and pups. Unfortunately, serum PFHxS levels were not measured in pregnant or
lactating rats or pups at the NOAEL and LOAEL dose levels, however, study results suggest that pups
may be more sensitive than adult nonpregnant animals. A database uncertainty factor (DB UF) has
been incorporated into the RfD derivation, in part, due to concerns that early life stages may be more
sensitive.

PFHxS - 6

 Androgenic effects have also been evaluated in laboratory animals to a limited extent. No changes in
adult male reproductive organ weights or sperm parameters were observed at serum levels up to
~600-fold higher than the ‘reference’ serum concentration. Androgenic activity was also evaluated in
pups exposed in utero and through lactation. No significant effects were observed on anogenital
distance, nipple retention, or reproductive organ weights at serum levels ~1300-fold higher than the
‘reference’ serum concentration.
2

Several epidemiology studies have examined the potential association between PFHxS and
suppression of the immune system. Inverse or no associations were observed in these studies. In
general, available studies have not found an association between PFHxS and infectious disease
resistance or with hypersensitivity outcomes.
Immunotoxicity has not been studied in laboratory animals. A DB UF has been incorporated into the
RfD derivation, in part, to address this data gap.

3

General population epidemiology studies have evaluated potential associations between maternal
PFHxS and a variety of birth outcomes. A couple of studies have reported associations with birth
weight or neurobehavioral outcome but others found no association.
Reproductive/developmental screening studies in rats and mice have not found treatment related
changes in development outcome, including neurobehavioral effects, at serum levels > ~900-fold
higher than the ‘reference’ serum concentration. Neurobehavioral outcomes were also evaluated in
a study using a single oral exposure to neonatal mice on postnatal day 10. No serum levels were
measured and therefore, the results could not be quantitatively incorporated into MDH’s
assessment. No 2-generation study has been conducted. A DB UF has been incorporated into the RfD
derivation, in part, to address this data gap.

4

In general, epidemiology studies evaluating potential associations between PFHxS and reproductive
measures have not found any associations. A small number of studies have reported associations
with earlier menopause or time to pregnancy. However, since menstruation, childbirth, and lactation
are potential elimination routes for women this could confound the associations.
Laboratory studies in rats did not find changes in reproductive parameters at serum levels > ~1600fold higher than the ‘reference’ serum concentration. A decrease in the number of pups per litter has
been reported in mice, however the dose-response curve was flat and there was no difference in the
number of pups born to the implant ratio. The ‘reference’ serum concentration is ~500-fold lower
than the serum concentrations at which this effect occurs in mice, therefore the RfD is protective for
this potential effect.

5

Two epidemiology studies have evaluated association between PFHxS serum levels and self-reported
memory loss or periods of confusion. One study reported a decrease in risk at the fifth quintile
whereas the second study found no association.

PFHxS - 7

 Laboratory animal studies have evaluated neurotoxicity using the functional observation battery
(FOB) and motor activity assessment. No effects were observed on adult rats and mice at serum
concentrations >~600-fold higher than the ‘reference’ serum concentration. Potential neurological
effects have also been evaluated in rat pups using these same evaluation tools. No effects were
observed at serum concentrations up to ~800-fold higher than the ‘reference’ serum concentration.
A neurotoxicity evaluation following a single oral dose to neonatal animals has also been conducted.
See footnote #3 above.

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