Environ. Sci. Technol. 2002, 36, 4761-4769
Predicted Distribution and
Ecological Risk Assessment of a
“Segregated” Hydrofluoroether in
the Japanese Environment
JOHN L. NEWSTED,† JUNKO NAKANISHI,‡
IAN COUSINS,§ KURT WERNER,| AND
J O H N P . G I E S Y * ,⊥
ENTRIX, Inc., 4295 Okemos Road, Suite 101,
Okemos, Michigan 48864;
Graduate School of Environment and Information Services,
Yokohama National University; 3M Center, DABT,
Building 236-1B-10, St. Paul, Minnesota 55144;
Trent University, Peterborough, Ontario K9J7B8; and
National Food Safety and Toxicology Center,
Institute of Environmental Toxicology, Department of Zoology,
Michigan State University, Lansing Michigan 48824
An assessment of HFE-7500, a “segregated” hydrofluoroether, was conducted to evaluate the potential for
exposure to and subsequent effects on humans and
wildlife in Japan. The segregated hydrofluoroethers belong
to a class of fluorochemicals currently being proposed
as replacements for traditional fluorochemicals (CFCs and
PFCs) that are currently being used in several industries,
in particular, the semiconductor industry. These traditional
compounds have been implicated as ozone-depleting or
potent “greenhouse gases”. The segregated hydrofluoroethers
have useful physical and chemical properties, but do not
contribute to ozone depletion and have lower “global warming
potential” (GWP) indices. Although the physical properties
of these materials (low H2O solubility and high vapor
pressure) suggest there would be a very low level of risk
to aquatic systems, a thorough analysis had not been
previously performed. Predicted environmental concentrations
(PECs) of HFE-7500 in Japan were determined with the
Higashino model, a Gausian puff and plume model that used
an approximation of environmental releases to the
atmosphere as input to the model. Allowable concentrations
to protect aquatic life, wildlife, and humans from noncancer
effects were determined as detailed in USEPA’s Final
Water Quality Guidance for the Great Lakes Systems.
Potential risk to ecological receptors and humans was
determined by calculating hazard quotients and margins
of safety. The results of the risk assessment indicate that
HFE-7500 poses no significant risk to either aquatic or
terrestrial wildlife species or humans living in the Japanese
environment. The least margin of safety for any ecological
receptor was 100 000, and a margin of safety greater
than 100 000 000 for most receptors indicated that
HFE-7500 poses no threat to human health. Because of a
* Corresponding author phone: (517) 353-2000; fax: (517) 4321984; e-mail: JGIESY@AOL.COM.
† ENTRIX, Inc.
‡ Yokohama National University.
§ Trent University.
| 3M DABT.
⊥ Michigan State University.
10.1021/es0257321 CCC: $22.00
Published on Web 10/19/2002
 2002 American Chemical Society
scarcity of toxicity and exposure data, the risk assessment
was based on very conservative assumptions. Therefore,
the actual margins of safety for both humans and wildlife
could have been 100- to 1000-fold greater if additional
data were available such that less stringent uncertainty
factors could be applied. These results suggest that the
environmental impact of HFE-7500 should be inconsequential
based on the marked improvement in its atmospheric
properties relative to the traditional compounds currently
in use. Given the short atmospheric lifetime and low global
warming potential of this material, its replacement of
CFCs and PFCs would result in a net improvement of
environmental health and safety.
Introduction
Currently, perfluorocarbons (PFCs) are used in the semiconductor manufacturing industry as heat-transfer liquids
to maintain process temperature. The industrial processes
that use these liquids include ion implanters, dry etchers,
deposition tools, steppers, automated test equipment (ATE),
and other machines. In addition, PFCs are used to cool
sensitive electronics, fuel cells, and lasers, etc. (1). However,
these applications can result in losses of PFCs to the
atmosphere, and as a result, PFCs have come under increased
regulatory scrutiny due to their long atmospheric lifetimes
and to their relatively great global warming potential (GWP).
Therefore, under the U.S. Environmental Protection Agency’s
(USEPA’s) significant new alternatives policy (SNAP), PFC
liquids are allowed as heat transfer media only in those
applications for which no alternatives are currently feasible.
As gaseous emissions from plasma-aided processes are
reduced, the percentage of the net PFC emissions attributable
to PFC heat transfer will increase. National, industry, and
individual company efforts to reduce emissions of compounds with significant GWP (greenhouse gases) have
prompted development of replacements such as segregated
hydrofluoroethers (HFEs). These compounds have shorter
atmospheric lifetimes and less GWPs but share many of the
desirable properties of PFCs needed for industrial application
as heat-transfer liquids.
Segregated hydrofluoroethers are compounds that contain
hydrogen and fluorine atoms on a backbone consisting only
of carbon and oxygen atoms. They are termed “segregated”
because these chemicals possess a perfluorocarbon segment
that is separated or “segregated” from the fully hydrogenated
portion of the molecule by an ether linkage (Figure 1).
Reliable, quantitative structure-activity relationships (QSARs)
capable of predicting environmentally relevant ecotoxicological data or physical chemical properties of HFEs, based
on their structure, do not yet exist. One HFE compound,
currently registered for use in the United States, Europe,
Korea, and most other nations is 3-ethoxyperfluoro (2methylhexane), which is marketed by 3M as Novec Engineered Fluid HFE-7500. Physical and chemical properties of
HFE-7500 (Table 1) were measured in support of its registration for commercial applications in several countries. The
atmospheric lifetimes of HFEs are approximately 100 times
less than PFCs and, therefore, HFEs have GWPs that are much
less than those of PFCs. For instance, the GWP of HFE-7500
is 210 (100-yr time horizon) vs 5000 to 11 000 for PFCs (19).
Additionally, HFEs are inherently nonozone depleting (ODP)
because neither the HFEs nor their degradation products
catalyze ozone depletion (19). Currently, HFE-7500 is under
consideration as a replacement for PFCs in several applicaVOL. 36, NO. 22, 2002 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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4761
TABLE 2. Parameters Used in the Higashino Model for
HFE-7500
parameter
dissipation rate to upper mixing
(1/sec)
photochemical degradation ratea
(1/sec)
dry deposition
soil (cm/sec)
water (cm/sec)
Henry’s law constant (unitless)b
wet deposition ratec
FIGURE 1. Structure of HFE-7500.
TABLE 1. Physical and Chemical Properties of HFE-7500a
chemical name
structure
CAS number
molecular weight (g/mol)
boiling point (°C)
pour point (°C)
vapor pressure (Pa) @ 20 °C
water solubility (µg/L) @ 22 °C
Henry’s law constant (Pa m3/mol)b
Log Kow
Log Koc
BCF (laboratory value)
HFE-7500
C7F15OC2H5
297730-93-9
414
128
-100
1000
13.3
3.1 × 107
4.9
4.9
8544
a HFE-7500 samples used for analyses were from 3M and were >
99% pure. b Calculated by dividing vapor pressure (Pa) by water
solubility (mol/m3).
tions in Japan. However, the environmental fate and potential
risks of inadvertent release of HFE-7500 to the Japanese
environment have not been evaluated. The objectives of this
study were the following: (1) to determine whether there are
sufficient data to conduct an environmental risk assessment
for HFE-7500; (2) conduct an environmental risk assessment
using USEPA methodology; and (3) to identify areas of
uncertainty.
Materials and Methods
Approach. The methodology used to evaluate the toxicity
and environmental fate of HFE-7500 was based on guidance
outlined in the U.S. Environmental Protection Agency (EPA)
document entitled “ Final Water Quality Guidance for the
Great Lakes Systems” (2). This methodology provides the
framework for conducting both human and environmental
risk assessments of organic and inorganic chemicals. Specifically, the Great Lakes Water Quality Initiative (GLI) provides
specific procedures and methodologies that use environmental fate and toxicity data to derive water quality values
that are protective of aquatic organisms, upper trophic level
wildlife, and humans. This approach was selected because
it is one of the most comprehensive assessment strategies
currently being used by regulatory agencies. Potential
environmental concentrations (PECs) of HFE-7500 in Japanese surface freshwaters were determined on the basis of
estimated environmental releases from industrial applications and a Gausian puff and plume model that has been
validated in Japan (3). Toxicant reference values (TRVs) for
wildlife (TRVw) and human health (TRVH) values were
determined for each receptor from mammalian toxicity data
by use of appropriate safety factors to account for data
extrapolations. Species-specific bioaccumulation factors,
water and diet consumption rates, and dietary compositions
were based on parameters taken from the GLI guidance. This
approach assumes that the primary route of exposure of
wildlife and humans is from water through species-specific
food chains. Because site-specific data were not available,
the default values given in the GLI guidance were not adjusted
for regional differences that may exist between the North
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ENVIRONMENTAL SCIENCE & TECHNOLOGY / VOL. 36, NO. 22, 2002
reference
10-6
16
1.28 × 10-8
19
0.2
0.2
1.26 × 104
7.93 × 10-5
17
17
5.00 ×
a Converted from the reported atmospheric half-life (1.5 × 104 hours)
The H value from Table 1 converted as H′ ) H/RT at 20 °C. c Calculated
by dividing 1 by Henry’s law constant or H′ (unitless).
b
American Great Lakes and Japan. Potential risks posed by
HFE-7500 to selected wildlife and humans were determined
by calculating hazard quotients (HQ) and margins of safety
(MOS) (Equations 1 and 2).
HQ )
PEC
PNEC
(1)
1
HQ
(2)
MOS )
The HQ is the quotient of the predicted environmental
concentration (PEC) divided by the TRV expressed as the
predicted no-effect concentration (PNEC). Finally, an uncertainty analysis was conducted to evaluate data gaps and
other questions that are pertinent to the risk assessment.
Higashino Model. The Higashino model was developed
to simulate long-term concentrations of chemicals in the
atmosphere of Japan (3). The model is formulated for the
entire Kanto plain, which includes metropolitan Tokyo and
six surrounding prefectures. This area has more than 30
million inhabitants and is the most industrialized area in
Japan. The analytical domain, with a scale of 276 × 224 km,
has 40 × 60 grids, each equal to a 5-km square. This model
was developed with the spatial resolution of 5 km2 and with
the time resolution of one month. The atmospheric concentration of HFE-7500 was calculated in 4-h increments
and averaged over one month. Data for wind velocity and
direction, and precipitation from an automated meteorological data acquisition system (AMeDAS) collected in 1997
were used as meteorological input data in the simulation.
The input parameters used in the Higashino model simulation are compiled in Table 2. The primary strength of the
Higashino model in this analysis is that it has been calibrated
to reflect the use patterns of other chemical products for
which HFE-7500 has been proposed as a replacement
compound. Specifically, this model has been validated for
fate and distribution of trichloroethylene (TCE) and tetrachloroethylene (PCE). Thus, results from the Higashino model
would reflect a “realistic” case study of the fate and
distribution of HFE-7500 in the Kanto plain based on historic
uses of chemicals that have similar use patterns and
environmental behaviors. A copy of the model is available
from the authors.
Sources and Emissions. On the basis of its chemical
properties, HFE-7500 is suited as a low- and mediumtemperature fluid for semiconductor applications such as
etching, plasma vapor deposition (PVD), and ion implant
and testing. Using the assumption that the sole uses of HFE7500 would be in the above-mentioned applications, a
preliminary assessment suggested that release of HFE-7500
to the environment would occur primarily through volatilization during storage and use. Furthermore, since manu-
FIGURE 2. Concentration map of HFE-7500 in the Kanto region as predicted by the Higashino Model. Each color represents a different
atmospheric concentration of HFE-7500 in units of ng/m3.
facturing and packaging of HFE-7500 would occur outside
of Japan (4), these activities would not be a source of HFE7500 in Japan. Finally, releases of HFE-7500 “down the drain”
to water treatment systems or directly to aquatic or terrestrial
environments are not expected under normal use patterns,
therefore, this route was not included in estimates of
environmental releases. On the basis of the above assumptions and scenarios, and for purposes of this assessment, the
estimated total releases of HFE-7500 to the Japanese environment would be 100 000 kg/yr in Japan (4).
Based on the estimated total annual release of HFE-7500
to the Japanese environment, an allotment of the total
emission to each prefecture was made by using the proportion
of TCE as a surrogate for HFE-7500 emissions. These values
reflect the historic emissions of TCE to the atmosphere in
this region as reported in the Ministry of Economics, Trade
and Industry (METI) extensive national emissions inventory
of TCE (data not available to the public). Assuming that the
pattern of emissions of HFE-7500 would mimic that of TCE,
the Kanto plain accounted for 42% of total atmospheric
emissions of HFE-7500 expected in Japan. Emissions of HFE7500 in the Kanto plain were allotted to each 5 km square
grid in proportion to the monetary value of production in
the electronic and electric industry for that grid.
Results
Higashino Model Simulations. The maximum annually
averaged concentration of HFE-7500 in air for any grid in the
TABLE 3. Maximum, Mean, and Minimum Atmospheric Levels
of HFE-7500 for All Grids in the Kanto Plain, Japan (ng/m3)
month
maximum
mean
minimum
January
February
March
April
May
June
July
August
September
October
November
December
1.63 ×
1.37 × 101
1.43 × 101
1.59 × 101
1.68 × 101
1.73 × 101
1.74 × 101
1.87 × 101
1.78 × 101
1.77 × 101
1.60 × 101
1.68 × 101
1.74 ×
1.58 × 100
1.57 × 100
1.62 × 100
1.54 × 100
1.58 × 100
1.57 × 100
1.62 × 100
1.58 × 100
1.74 × 100
1.61 × 100
1.72 × 100
1.90 × 10-4
1.48 × 10-4
2.69 × 10-3
2.36 × 10-3
6.83 × 10-3
1.35 × 10-2
5.85 × 10-3
1.86 × 10-3
1.85 × 10-3
4.07 × 10-4
5.76 × 10-4
1.70 × 10-4
101
100
conceptualization of the Kanto plain was 16.4 ng/m3 (Figure
2). The estimated maximum, mean, and minimum monthly
averaged concentrations for all grids in the model and the
results indicated that the concentration of HFE-7500 varied
slightly between summer and winter months (Table 3). The
Higashino model was validated by comparing predicted
atmospheric concentrations of TCE with measured atmospheric concentrations of the compounds in the Kanto plain
(3). The predicted concentrations of TCE from the Higashino
model (Figure 3) emphasize that the model is capable of
estimating the long-term average distribution of chemicals
VOL. 36, NO. 22, 2002 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 3. Predicted atmospheric trichoroethylene (TCE) concentrations by the Higashino model in the Kanto plain located in Japan. Each
color represents atmospheric TCE emission rate in units of µg/m3.
FIGURE 4. Comparison of observed and predicted values of
atmospheric trichoroethylene concentrations in summer (subscript
“s”) and in winter (subscript “w”) for various locations in the Kanto
region. Each capital letter indicates an individual station measured
or estimated in either summer or winter.
over a wide flat area. The validation step of the model is
important in that HFE-7500 is not currently not being used
in Japan, and consequently, no measurable concentrations
would be expected to be found in the Japanese environment
at this time. Predicted atmospheric concentrations of TCE
(Figure 4) were in agreement with atmospheric TCE concentrations measured in the Kanto plain (3). Thus, the
Higashino model predicted the concentration of a highly
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volatile compound in the Japanese atmosphere with a
reasonable degree of accuracy. Based on the model, the
predicted atmospheric concentrations of HFE-7500 for the
Kanto plain would be less than 5 ng/m3 (Figure 3). Furthermore, less than 1.7% of the entire Kanto plain would be
expected to have atmospheric concentrations greater than
10 ng/m3.
Surface water concentrations of HFE-7500 were estimated
with a surface-water-to-air ratio derived from the results of
simulations with the ChemCan model (5). Using an average
air concentration of 16.4 ng/m3 and a water-to-air ratio of
3.13 × 10-4, the average surface water concentration of HFE7500 was estimated to be 5.13 × 10-6 ng/L. However,
environmental models are subject to uncertainty that affects
their ability to predict accurately the concentration of
chemicals in environmental media. This is due, in part, to
the simplification of complex processes in the model that
can alter the spatial and temporal distribution of the chemical
in an environment. Therefore, to account for this uncertainty
and variability in the Higashino model predictions, uncertainty factors were applied to the results to ensure that actual
environmental concentrations are not underestimated. Depending on how well a chemical’s properties and its
environmental behavior are understood, safety factors can
range from 10 to 1000. For this assessment, an uncertainty
factor of 100 was applied to the predicted surface water
concentration that resulted in a final water concentration of
5.13 × 10-4 ng/L.
Mammalian Toxicity Evaluation. Results from acute
toxicity tests conducted with HFE-7500 indicate that this
compound exhibits relatively low toxicity. Rat LD50 values
for dermal, inhalation, and oral (5 d) exposure were >2000
mg/kg, 10 000 mg/L, and >2 000 mg/kg, respectively. HFE-
7500 was negative in the Ames mutagenicity test and exhibited
no clastogenic effects in the Chinese hamster chromosomal
aberration bioassay. On the basis of these results, HFE-7500
has a toxicity profile that would not elicit a concern for
carcinogenicity and is an unlikely candidate for investigation
in a 2-y cancer assay. Therefore, noncancer endpoints were
used to calculate TRVs. TRVs were based on a 28-d repeateddose study with rats dosed daily via gavage with 0, 40, 200,
or 1000 mg/kg HFE-7500 (6). No changes in survival, clinical
pathology, blood chemistry, body weight, food consumption,
or behavior were observed in individuals at any dose group
during the exposure or recovery phase of the study. Histological examination revealed that rats of both sexes had
centrilobullar acidophilic changes in liver hepatocytes when
dosed with HFE-7500 at 1000 mg/kg, but that these changes
were not observed at the end of the recovery period.
Therefore, the no-observed-effect level (NOEL) was estimated
to be 200 mg/kg, and the lowest-observed-effect level (LOEL)
was estimated as 1000 mg/kg. The selection of NOEL or LOEL
values are a function of the experimental design and may
not reflect the specific point in the dose response relationship
where organisms are protected from adverse effects. The
NOEL is likely to underestimate the maximum dose that could
cause impairment, while the LOEL is likely to overestimate
the minimum dose that will cause adverse effects in
susceptible species. The minimum dose where adverse effects
to species are likely to occur is therefore between the NOEL
and the LOEL. For this analysis, both the NOEL and LOEL
were used as toxic doses (TD) to provide a range of the
potential risk of HFE-7500 to wildlife and humans in the
Japanese environment. Ideally, a TD can be estimated from
dietary toxicity studies where bioavailability and absorption
of the chemical from food across the gastrointestinal tract
is accounted for in the study design. Uptake of most chemicals
is greater in oral gavage studies than that observed in dietary
studies because of the effect of food proteins and fats that
alter the absorption of chemicals from the GI tract (7). For
this risk assessment, absorption of HFE-7500 from a dietary
source was assumed to be 100 percent. Based on this
conservative assumption, the NOEL and LOEL from the rat
28-d oral gavage study were used, instead of no-observedadverse-effect level (NOAEL) and lowest-observed-adverseeffect level (LOAEL) values, in the calculation of human and
wildlife TRVs.
Aquatic Toxicity Evaluation. Two studies with HFE-7500
have been conducted with fish (8). In a 48-h acute toxicity
study with Japanese Medaka (Oryzias latipes), no mortality
was observed for fish exposed to 25 mg/L or 50 mg/L. The
lethal concentration to kill 50% of the population (LC50) was
determined to be >50 mg/L. In a bioconcentration study
conducted with carp (Cyprinus carpio), no mortality or
adverse effects were observed in fish exposed to 0.5 mg/L for
6 wk. Based on the above results and the data quality criteria
outlined in the GLI for deriving water quality criteria, an LC50
of 50 mg/L was assumed to be the threshold value. It is
noteworthy that this value is approximately 3760 times that
of the water solubility limit for this material.
Aquatic Life Criteria. The GLI guidance provides a twotiered procedure to derive chemical-based water quality
(WQC) for the protection of aquatic life. These WQCs are
intended to protect aquatic organisms from continuous
exposure to chemicals. These methods are very similar to
those used in current guidelines for developing National WQC
(section 304(a) of the U.S. Clean Water Act). Tier I values are
derived using methodologies where there are sufficient data
from acute and chronic studies with aquatic organisms which
can be adopted as numeric criteria into a water quality
standard. The Tier II methodology is used when there are
fewer toxicity data than that needed to compute a Tier I
value. The Tier II methodology generally produces more
stringent values than the Tier I methodology to reflect the
greater uncertainty in the absence of additional toxicity data.
As more data become available, the derived Tier II values
tend to become less conservative. That is, they more closely
resemble Tier I numeric criteria.
As there is a lack of acute and chronic toxicity data for
aquatic species, a Tier II secondary acute value (SAV) was
calculated. Because the SAV incorporates less information,
safety factors are applied such that a conservative safe
concentration can be determined. To calculate a SAV, the
lowest acute toxicity result (LC50 or EC50) was divided by the
secondary acute factor (SAF). The SAF is an adjustment factor
specified in the water quality guidelines (2) that depends on
the number of data requirements that have been satisfied
for a Tier I criterion. For HFE-7500, the SAF was set at 21.9
because there was only one acute toxicity value available
(Japanese Medaka LC50 ) 50 000 µg/L). A Tier II SAV of 2283
µg/L was calculated by dividing the LC50 by the SAF. Because
no chronic aquatic studies have been conducted with HFE7500, a secondary chronic value (SCV) was calculated instead
of a final chronic value (FCV). The GLI recommends an acuteto-chronic ratio (ACR) of 18. A SCV of 127 µg/L was calculated
by dividing the SAV by the ACR. A Tier II water quality analysis
results in WQC. The first is a secondary maximum concentration (SMC), which is equal to one-half the SAV, and the
second is a secondary continuous concentration (SCC) which
is equal to the SCV. For HFE-7500, the SMC and SCC are
1142 and 127 µg/L, respectively. Thus, aquatic organisms
would not be unacceptably affected if the four-day average
concentration of HFE-7500 does not exceed 1142 µg/L
(approximately 86-times H2O solubility) more than once every
three years on average. Nor would they be unacceptably
affected if the 1-h average concentration does not exceed
127 µg/L more than once every three years on the average.
Terrestrial Life Criteria. Japan has a flora and fauna that
shares similar types of species with those found in the North
American Great Lakes. Therefore, it was considered appropriate to conduct the exposure analysis with species used
in the Great Lakes Water Quality Initiative that have been
used to establish water quality criteria for persistent, lipophilic
chemicals. Species included in the environmental risk
analysis were mink, river otter, kingfisher, herring gull, and
the bald eagle. These species represent organisms that inhabit
upper trophic levels of aquatic food chains and are among
the animals most sensitive to many classes of persistent,
organic compounds. Furthermore, they can serve as surrogates for several Japanese threatened or endangered species
including the Japanese river otter, Japanese ermine, the redcrown crane, the red-faced cormorant, and the Hodgson
Hawk Eagle (18).
HFE-7500 bioaccumulation factors (BAFs) for trophic level
3 and 4 organisms were derived using procedures outlined
in the GLI guidance. The baseline BAF was calculated using
a laboratory-measured bioconcentration factor (BCF) for
carp. This study met the basic requirements outlined in the
GLI guidance document and provided an experimental value
that was more accurate than one derived from a structure
activity model. Baseline BAFs for trophic level 3 (TL3) and
trophic level 4 (TL4) fish were calculated (eq 3) as follows:
Baseline BAF ) (FCM)
[
][ ]
Measured BCFtT 1
ffd
f1
(3)
where BCFtT is the bioconcentration factor (BCF ) 8544) (8);
fl is the fraction of the tissue that is lipid (fraction ) 0.041);
ffd is the fraction of the total chemical in the water that is
freely dissolved; and FCM is the food chain multiplier for
trophic levels 3 and 4.
The lipid fraction of fish was taken from experimental
results from the carp bioconcentration study. The freely
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TABLE 4. HFE-7500 Specific Bioaccumulation Factors (BAF) Derived for Human and Wildlife Species
receptor
trophic level
standardized fraction
lipid valuea
food chain multiplierb
baseline BAF
trophic level BAF
wildlife
TL3
TL4
TL3
TL4
0.0648
0.1031
0.0182
0.0310
2.780
2.193
NA
NA
613 612
483 802
613 612
483 802
37 421
47 112
10 543
14 166
human
a
Standard lipid values taken from GLI for human and wildlife.
b
FCM values were taken from Table B-1 of the GLI, based on log Kow of 4.9.
TABLE 5. Assignment of Uncertainty Factors (UF) for the Calculation of Wildlife Values (WV) for HFE-7500
uncertainty factor
*intertaxon extrapolation
*exposure duration
*toxicological endpoint
*modifying factors
threatened species
relevance of endpoint
lab to field extrapolation
co-contaminants
endpoint unclear
study species sensitivity
organ ratios
intraspecies variability
*overall UF
notes
The laboratory study that provided the threshold dose used rat as the test organism.
All other species used in this report belong to the same class, but different orders,
so Amammal ) 5.
Because avian species belong to the same phylum, but different class, Aavian ) 10.
The rat study used in this report was a 28-d oral gavage subacute study, so B ) 5.
The 28-d rat study determined a NOAEL based on histological changes in the liver.
The effects were reversible and classified as mild, so C ) 2.
Japanese river otters are listed, so d1 ) 1.5.
Liver histological changes in liver was the endpoint, so d2 ) 1.5.
The oral gavage study duration was short, not dietary, and does not represent actual
year-round intake rates of most mammals, so d3 ) 1.5.
No co-contaminants were evaluated, so d4 ) 2.
Liver lesions are not mechanistically clear relative ecological impact on natural populations,
so d5 ) 1.5.
No comparative data exist, so d6 )1.
Tissue ratios were not used, so d7 ) 0.
Only adult rats have been tested, no data have been collected on other life stages, so d8 ) 2.
UFmammal ) (5 × 5 × 2 × (1.5 + 1.5 + 1.5 + 2 + 1.5 + 1.0 + 0 + 2) ) 550.
UFavian ) (10 × 5 × 2 × (1.5 + 1.5 + 1.5 + 2 + 1.5 + 1 + 0 + 2) ) 1100.
dissolved HFE-7500 fraction (ffd) in water as outlined in the
GLI (eq 4) is as follows:
ffd )
1
(DOC)(Kow)
+ (POC)(Kow)
1+
10
(4)
where DOC is concentration of dissolved organic carbon
(0.0000002 kg DOC/L); POC is concentration of particulate
organic carbon (0.00000004 kg POC/L); and Kow ) octanolwater partitioning coefficient of HFE-7500 (Kow ) 79 432).
The food chain multiplier (FCM) represents the ratio of
a BAF to an appropriate BCF. The FCM is used in the
calculation of trophic level specific baseline BAFs when there
are no available field-measured BAFs or biota-sediment
accumulation factors (BSAF). Based on the log Kow for HFE7500 (4.9), the FCM for trophic level 3 was 2.78, whereas the
FCM for trophic level 4 was 2.193 (taken from Table B-1 of
GLI). Human and wildlife TL3 and TL4 bioaccumulation
factors for trophic levels 3 and 4 were calculated as follows
(eq. 5) and are reported in Table 4:
Human or Wildlife BAFTLx )
[(baseline BAFtlx)(Std lipid value) + 1](ffd) (5)
Uncertainty related to the interpretation of toxicity test
data among different species, use of different laboratory
endpoints, and differences in experimental design are
addressed by applying uncertainty factors (UFs). There are
several methods that exist to estimate UFs based on different
regulatory programs and their requirements (9). One method
developed by USEPA Region 8 for the Rocky Mountain Arsenal
(RMA; 10), uses rigorous study-selection criteria and a 4-step
“balanced” uncertainty factor protocol to calculate TRVs.
The RMA procedure uses four categories of uncertainty
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factors: (1) intertaxon variability extrapolation, (2) exposure
duration extrapolation, (3) toxicologic endpoint extrapolation, and (4) modifying factors. The overall uncertainty factor
is calculated as the product of all four categories. The selection
and rationale for calculating mammalian and avian uncertainty using the RMA protocol are given in Table 5. Wildlife
values (WV) for each ecological receptor were estimated with
eq 6:
TRVW )
TD or NOAEL
× BW
Oveall UF
WC +
∑(FC
TLi
× BAFWL
TLi)
(6)
where TRVw is the wildlife value (mg/L), TD is the test dose
or threshold dose for the test species (mg/kg/day), BW is the
average weight (kg) for the representative species, FCTLi is a
species-specific average daily amount of food consumed (kg/
day), and WC is a species-specific average daily amount of
water consumed (L/day).
Ideally, concentrations for the protection of wildlife are
derived from chronic toxicity studies in which an ecologically
relevant endpoint has been assessed in the species of concern
or in a closely related species. Although TRVws can be
expressed or defined as NOAELs, the use of LOAELs is
generally preferred because, by definition, NOAELs incorporate greater uncertainty than LOAELs. In the 28-d oral rat
study, only a NOAEL was determined. In addition, the study
duration was short, less than 10% of the lifetime of the test
organism, and did not include reproductive or developmental
endpoints. Because of the lack of a definitive chronic study,
wildlife values were calculated using both NOEL and LOEL
as determined in the 28-d rat study. Exposure parameters,
including body weights (BW), feeding rates (FCTli), drinking
rates (WC), and trophic level dietary composition (as food
ingestion rate and food item percent in diet, for humans and
TABLE 6. Exposure Parameters for Human and Five Surrogate Wildlife Species Evaluated for the Japanese Environment
receptor
adult BW
(kg)
human (adult)
mammals
mink
otter
birds
kingfisher
herring gull
bald eagle
food ingestion rate of each prey
in each trophic level
(kg/day)b
water ingestion rate
(L/day)
trophic level of prey
(% diet)
2.0a
TL3: 0.0336; TL4: 0.0114
not applicable
0.80
7.4
0.081
0.600
TL3: 0.159; other: 0.0177
TL3: 0.977; TL4: 0.244
TL3: 90; other: 10
TL3: 80; TL4: 20
0.15
1.1
4.6
0.017
0.063
0.160
TL3: 0.0672
TL3: 0.192; TL4: 0.0480; other: 0.0267
TL3: 0.371; TL4: 0.0929 PB: 0.0283;
other: 0.0121
TL3; 100
fish: TL3: 80; TL4: 20; other: 10
fish (92): TL3: 80; TL4: 20;
birds (8): PB: 70; other: 30
70
a Mean water consumption including both drinking and incidental ingestion. b TL3 or TL4 ) trophic level 3 or 4 fish; PB) piscivorous birds;
other ) nonaquatic birds and mammals.
TABLE 7. Wildlife Values for Mammalian and Avian Species
Based on NOEL and LOEL for HFE-7500
species
mammalian species
mink
otter
geometric mean
avian species
kingfisher
herring gull
bald eagle
geometric mean
NOEL-TRVw (ng/L)
LOEL-TRVw (ng/L)
44
56
49
220
280
247
11
19
42
21
54
96
211
103
wildlife are given in Table 6. Wildlife values for both
mammalian and avian species evaluated in this study are
given in Table 7.
Criteria Based on Noncancer Human Health. A human
health criterion for HFE-7500 was derived to establish an
ambient WQC that would be protective of humans who
consumed fish that had accumulated HFE-7500. This criterion, if not exceeded, will protect individuals from adverse
health impacts from that chemical due to consumption of
contaminated fish and drinking water, or through the
ingestion of water because of participation in water-oriented
recreational activities. Noncancer endpoints were used to
derive the maximum ambient water concentration of HFE7500 at which no adverse effects are likely to occur in human
populations from lifetime exposures. Depending on the
availability of suitable data, Tier I or Tier II human noncancer
criterion (HNC) can be calculated. The minimum data
requirements for calculating Tier I values include at least
one well-conducted epidemiology study or a well-conducted
chronic study with test animals. The animal studies should
demonstrate a dose-response relationship involving one or
more critical effects that are biologically relevant to humans.
In addition, the duration of the study should span multiple
generations of the exposed population or at least a major
portion of its life span. For shorter studies, the study should
be at least 90 d for rodents or 10% of the life span of other
appropriate species. The minimum data requirements for
Tier II values include at least one repeated dose study of 28
d (in rodents) with a dose-response relationship that includes
endpoints that are relevant to humans. A review of the
relevant toxicity data for HFE-7500 indicates that there is
not sufficient data for the derivation of a Tier I TRCHNC value.
Therefore, a TRVHNV was calculated as a conservative and
interim level of protection for human life (eq 7):
TRVHNV (mg/L) )
ADE × BW × RSC
(7)
HH
WC + [(FCTL3 × BAFHH
TL3) + (FC × BAFTL4)]
where ADE is the acceptable daily exposure (mg/kg/day);
BW is the weight of average human (kg); RSC is the relative
source contribution factor for contaminant from aquatic
sources (0.8); WC is total per capita water consumption
including drinking water and incidental daily consumption
(L/day); FCTLi is mean consumption of trophic level i fish by
regional consumers of locally caught fish (kg/day); and
HH
BAFTli
is the human bioaccumulation factor for edible
portion of trophic level i fish.
Bioaccumulation factors used in the human health
criterion (eq 5) were calculated using the baseline BAF that
was calculated to estimate wildlife values. The acceptable
daily exposure (ADE) estimates were based on the NOEL
and LOEL from the 28-d rat study. To account for the
uncertainties in predicting acceptable dose levels for the
general human population based on test animal data,
uncertainty factors (UF) were selected on the basis of quantity
and quality of the data. The selection of uncertainty factors
was based on criteria outlined in the GLI document. Because
the duration of the 28-d rat study was less than 10% of a rat’s
normal life cycle, an uncertainty factor of 3000 was used in
the analysis. This factor not only accounted for the uncertainty in the animal to human extrapolation, but also
considered the uncertainty in subacute to chronic extrapolation. Furthermore, an additional uncertainty factor of 3.0
was included to account for the lack of reproductive or
developmental endpoint evaluation during the rat study. This
resulted in an overall uncertainty factor of 9000. The high
Henry’s constant and apparent lack of biological activity also
suggest the magnitude of uncertainty due to chronic toxicity
or across species extrapolation has been overestimated.
Dividing the NOEL or LOEL by the overall uncertainty factor
resulted in an ADENOEL and ADELOEL of 0.022 and 0.111 mg/
kg/day, respectively. Noncancer human health values were
estimated (eq 7) and are reported in Table 8.
Risk Characterization. Hazard quotients (HQ) and margins of safety (MOS) were calculated to evaluate potential
risks of HFE-7500 to humans and wildlife. Hazard quotients
are ratios of predicted environmental concentrations to
threshold concentration to which an organism can be
exposed continuously for their entire life without suffering.
If a predicted environmental concentration is equal to a TRV
then the HQ would be 1.0. Thus, for HQ values greater than
1.0, some potential for injury can be inferred. HQ values less
than 1.0 indicates that the potential for injury is low. Because
very conservative (protective) assumptions are used in the
calculations, HQ values less than 1.0 are associated with safe
conditions. Margins of safety (MOS) are the inverse of the
HQ and represent the magnitude of the difference between
predicted environmental concentrations and no-effect concentrations.
Aquatic Organisms. Based on the Tier II WQC, the release
of HFE-7500 to the Japanese environment poses little risk to
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TABLE 8. Hazard Quotients (HQ) and Margins of Safety (MOS)
for Humans, Avian, and Mammalian Species Exposed to
HFE-7500
organism
avian
NOEL
LOEL
mammal
NOEL
LOEL
human
NOEL
LOEL
predicted
water conc.
(ng/L)
critical
health value
(ng/L)
HQ
MOS
5.13 × 10-4
5.13 × 10-4
21
103
2.5 × 10-5
5.0 × 10-6
4.0 × 104
2.0 × 105
5.13 × 10-4
5.13 × 10-4
49
247
1.0 × 10-5
2.1 × 10-6
9.7 × 104
4.8 × 105
5.13 × 10-4
5.13 × 10-4
6177
30 887
8.3 × 10-8
1.7 × 10-8
1.2 × 107
6.0 × 107
aquatic organisms. Under the assumptions used in this risk
analysis, the HQ value was 4.0 × 10-9 with a MOS of 2.5 ×
108.
Mammal and Avian Organisms. The geometric mean of
the mammalian and avian wildlife values were used as “safe
values” and compared to predicted water concentrations
taken from the Higashino model. The results (Table 8) show
that HFE-7500 poses no risk to either mammalian or avian
species. For either group, the margin of safety was greater
than 50 000. The margin of safety is probably even greater
because of the conservative application of 100 in safety factors
to the predicted water concentration
Noncancer Human Health Evaluation. Noncancer human health values were used in the risk assessment of HFE7500 rather than a cancer-based assessment because of the
lack of whole organism carcinogenicity data. Furthermore,
two in vitro tests, a mutagenicity and clastogenesis bioassay,
indicated that HFE-7500 was not genotoxic. Results of the
risk calculations are given in Table 8. Using a predicted water
concentration of 5.13 × 10-4 ng/L, the noncancer HQ was
3.7 × 10-8 and the MOS was 2.7 × 107.
Discussion
On the basis of the results of the environmental fate modeling
and toxicological evaluation of HFE-7500, it can be concluded
that this chemical does not pose any risk to aquatic or
terrestrial organisms in Japan. For the receptors evaluated
in the study, all HQ values were significantly less than 1 with
margins of safety greater than 200 000. In addition, these
risk calculations were based on water concentrations that
included a safety factor of 100 to account for the uncertainty
in model predictions for surface water concentrations. Safety
factors were also included in the calculation of wildlife values
and human health values to take into account the lack of
relevant toxicity data for both aquatic and terrestrial species.
Thus, the predictions of risk were extremely conservative
and may have overestimated the actual risk that HFE-7500
could pose to biota and humans in Japan.
Evaluation of Uncertainty. The evaluation of uncertainty
involves identifying sources of uncertainty associated with
the ERA process that may potentially affect the conclusions
of the assessment. According to the U.S. EPA (11), an
uncertainty analysis increases the credibility of an environmental risk assessment by explicitly describing the magnitude
and direction of uncertainties. This analysis also provides
the basis for efficient data collection and application of refined
methods to evaluate further the risk assessment’s assumptions and conclusions. Specifically, uncertainty associated
with measurement endpoint results translates into uncertainty associated with the conclusions regarding HFE-7500
releases to the Japanese environment. To reduce the potential
for uncertainty resulting in underestimates of actual risks of
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HFE-7500 to humans and wildlife in Japan, conservative
methods and procedures were used throughout the assessment.
One source of uncertainty in the analysis was the lack of
subchronic and chronic toxicity data that included an
evaluation of potential effects of HFE-7500 on reproductive
and developmental processes in traditional laboratory species. Furthermore, no studies exist that evaluate the effect
of HFE-7500 on wildlife, including semi-aquatic or terrestrial
mammals, or avian species. Because of the lack of toxicity
data, the calculation of wildlife values from test species data
incorporated additional uncertainty factors to account for
toxicity endpoint and interspecies extrapolations. A 100-fold
safety factor was also used to account for the uncertainty in
model predictions for surface water concentrations. Overall,
because of the lack of toxicity studies to relevant species, the
risk analysis used very conservative assumptions that resulted
in risk quotients that were between 100- and 1000-fold larger
than they might be if additional data were available. Again,
the high Henry’s constant and apparent lack of biological
activity also suggests the magnitude of uncertainty due to
chronic toxicity or among-species variation has been overestimated.
Another possible source of uncertainty was the lack of
environmental fate properties for inclusion in the fate and
distribution models. In particular, the lack of media-specific
half-lives added significantly to the final uncertainty incorporated into this analysis. For instance, the only reactive
loss value accounted for in the Higashino model was
atmospheric degradation that proceeds through photochemical mechanisms. However, although the model did
not directly address advective losses from the atmosphere,
processes such as washout by precipitation would not be
significant. This is because, due to the low water solubility
of HFE-7500, partitioning of HFE-7500 from air into atmospheric water droplets would not be a significant loss process
when compared to its reactive losses. The atmospheric
lifetime of a compound is the time it takes for a compound
to decrease to approximately 37% of its original concentration. To estimate the lifetime due to rainout is based on the
assumption that rainout is the only mechanism contributing
to atmospheric loss and that it is mostly dependent on Henry’s
law constant (H). Thus, the concentration of a HFE-7500 in
cloud-water droplets would be in equilibrium with the
concentration of HFE-7500 in the surrounding air. The
atmospheric lifetime due to rainout can then be estimated
as a function of it’s Henry law constant (for compounds with
H < 104 M/atm, eq 7 can be used)(20):
tRainout ) 105/H (days)
(7)
The Henry’s law constant for HFE-7500 was 3.1 × 107 Pa
m3/mol and is equivalent to an H of 3.27 × 10-6 M/atm. This
results in an estimated atmospheric lifetime of 3.06 × 1010
days. Thus, rainout would be a minor process in the removal
of HFE-7500 from the atmosphere, where expected to be
removed from the atmosphere in rainwater, since H indicates
it would partition almost entirely into the gas phase. Finally,
there was no accounting for advective or reactive losses of
HFE-7500 from surface waters. Again, due to its low water
solubility and relatively great vapor pressure, it would not be
expected to remain in water for any significant duration.
However, the significance or uncertainty associated with
these processes does not affect the overall conclusions of
this study. This is because of the very large margins of safety
used in our analyses. Thus, even if the total release of HFE7500 to the environment, the accumulation, and toxicity to
receptors were underestimated, there would be essentially
no chance of adverse effects.
A third area of uncertainty in the risk assessment concerns
the formation and accumulation of HFE-7500 breakdown
products and their effect on environmental systems. Although
the photodegradation pathway of HFE-7500 has not been
fully characterized, an evaluation of this pathway provides
valuable insight to potential breakdown products that could
be found in ecological systems (12). A hydroxyl radical
reaction rate measurement indicates that it would have an
atmospheric lifetime of about 2.5 yrs (19). Based on analogous
HFEs, as well as other related fluorochemicals, one can make
reasonable predictions about the degradation products (2123). The predominant degradation intermediates of a related
product, ethyl iso-perfluorobutyl ether (CF3CF(CF3)CF2OCH2CH3), are the acetate and the formate forms where the acetate
predominates. For HFE-7500, the acetate and formate would
have the structures C3F7CF(OC(dO)CH3)CF(CF3)2 and C3F7CF(OCH(dO))CF(CF3)2. By analogy to other HFEs, these two
components are likely to be removed from the atmosphere
by wet or dry deposition. Once out of the atmosphere, the
acetate and formate are likely to react with water and lose
an HF to form a perfluoroketone, C3F7C(O)CF(CF3)2. This
hydrolytic reaction could also occur in water droplets within
the atmosphere. If this ketone reenters the atmosphere, it
would likely photodegrade further within days or weeks,
breaking at the keto group to form two perfluororadicals,
e.g., C3F7C(O) and CF(CF3)2. The straight chain perfluororadical would go through a series of photochemical reactions
and fully degrade to HF and CO2. The branched chain
perfluororadical would degrade to form HF, CO2, and
trifluoroacetic acid. If deposition of the acetate and formate
predominates, HFE-7500 would produce one mole of trifluoroacetic acid per mole of HFE-7500 and the remainder
would degrade to HF and CO2. Perfluorobutyric acid and
iso-perfluorobutyric acid are additional potential photochemical degradation products that could form in the
atmosphere. Like trifluoroacetic acid, these water-soluble
compounds would washout of the atmosphere and would
be present in the environment as acetate salts.
Hydrofluorocarbon breakdown products, such as trifluoroacetic acid (TFA), are not expected to cause adverse
effects in ecological systems. Numerous studies have been
conducted that evaluate the environmental properties and
toxicity of trifluoroacetic acid (TFA) to algae, aquatic macrophytes, terrestrial plants, fish, animals, and humans (13).
TFA is an organic acid with a pKa of 0.23. TFA exists in water
in a completely dissociated state and is miscible in water
(solubility over 1000 g/L). Its low octanol/water partition
coefficient (Kow)0.008) indicates no potential to bioaccumulate. Toxicity tests on fish and aquatic invertebrates show
no adverse effects at large concentrations (up to 1 g of TFA/
L). However, the NOEC for the algal species, Selenastrum
capricornutum, was approximately 0.1 mg TFA/L. Toxicological data with mammals also show TFA hsd low toxicity
(NOAEL ) 150 mg/kg/day). While TFA is a ubiquitous
contaminant in the hydrosphere, concentrations of in rain
and water are expected to be low (14, 15). Therefore, based
on its low toxicity, the expectation that all its emissions will
be to the atmosphere, and its low propensity to partition
into water, the potential risk of HFE-7500 to wildlife and
humans is very small. In addition, HFE-7500 has a relatively
short environmental half-life, is not a contributor to pho-
tochemical smog, and has a very low GWP. Therefore, HFE7500 would make a much smaller contribution to global
warming relative to the materials it would replace and the
substitution of HFE-7500 for currently used products would
likely result in a net improvement in the environmental health
and safety.
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Received for review April 19, 2002. Revised manuscript received August 21, 2002. Accepted August 26, 2002.
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