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1

Significant New Alternatives Policy Program 

Aerosols and Solvent Cleaning Sectors

Risk Screen on Substitutes for CFC-113, Methyl Chloroform, and HCFC-141b in

Aerosol Solvent, Electronics Cleaning, and Precision Cleaning

Substitute: HFE-347pcf2 (AE-3000)

This memorandum does not contain Clean Air Act (CAA) Confidential Business Information (CBI) 

and, therefore, can be disclosed to the public.

1. INTRODUCTION

Ozone-depleting substances (ODS) are being phased out of production in response to a series of 

diplomatic and legislative efforts that have taken place over the past two decades, including the Montreal 

Protocol and the Clean Air Act Amendments of 1990 (CAAA). The U.S. Environmental Protection 

Agency (EPA), as authorized by Section 612 of the CAAA, administers the Significant New Alternatives 

Policy (SNAP) Program, which identifies acceptable and unacceptable substitutes for ODS in specific 

end-uses based on assessment of their health and environmental impacts. 

EPA’s decision on the acceptability of a substitute is based largely on the findings of a screening 

assessment of potential human health and environmental risks posed by the substitute in specific 

applications. EPA has already screened a large number of substitutes in many end-uses within all of the 

major ODS-using sectors, including refrigeration and air conditioning, solvent cleaning, foam blowing, 

aerosols, fire suppression, adhesives, coatings and inks, and sterilization. The results of these risk screens 

are presented in a series of Background Documents that are available in EPA's docket.

The purpose of this risk screen is to supplement EPA’s Background Document on the solvent cleaning

sector and aerosols sector (EPA 1994) (hereinafter referred to as the Background Document). This risk 

screen evaluates the potential use of HFE-347pcf2 (also known as AE-3000) as a substitute for CFC-113, 

methyl chloroform (commonly also referred to as 1,1,1-trichloroethane, TCA, or MCF), HCFC-141b, 

HCFC-225ca, and HCFC-225cb in electronics cleaning, precision cleaning, and aerosol solvent end-uses. 

Table 1 presents information on the proposed substitute.

Table 1. Composition of HFE-347pcf2

Constituent Chemical 

Formula CAS Number Percent of Total(by weight)a

2,2,2-Trifluoroethoxy-1,1,2,2-tetrafluoroethane

(HFE-347pcf2)

C4H3F7O 406-78-0 >99.5%

Potential Impurities (maximum concentration)

aNote that less than 0.5 percent of HFE-347pcf2 is composed of impurities. These impurities are reasonably anticipated to be present when the 

proposed substitute is manufactured for commercial purposes; however, these impurities are not thought to be present in quantities sufficient to 

pose a risk to humans or to the environment. 

The potential risks associated with use of substitutes in aerosol solvents, electronics cleaning, and 

precision cleaning end-uses have been examined at length in the Background Document. The reader is 

referred to this reference for a detailed discussion of the methodologies used to conduct this risk screen. 

This risk screen addresses flammability risk, and an occupational exposure assessment was performed to 

ensure that manufacture and disposal of the proposed substitute in the aerosols solvent, electronics 
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cleaning, and precision cleaning end-uses do not pose unacceptable risk to workers. Modeling was 

performed at the end-use to examine potential exposures for those using HFE-347pcf2 for the intended 

applications. Lastly, a general population exposure assessment was performed to ensure that the proposed 

substitute would not pose an unacceptable risk to the population at large. 

Section 2 of this report summarizes the results of the risk screen for the proposed substitute listed in Table 

1. The remainder of the report is organized into the following sections:

 Section 3: Atmospheric Assessment

 Section 4: Flammability Assessment

 Section 5: Potential Health Effects

 Section 6: Occupational Exposure Assessment

 Section 7: End-Use Exposure Assessment

 Section 8: General Population Exposure Assessment

 Section 9: Volatile Organic Compound Assessment 

 Section 10: References

2. SUMMARY OF RESULTS

HFE-347pcf2 is recommended for SNAP approval for aerosol solvent, electronics cleaning, and 

precision cleaning uses. EPA's risk screen indicates that the use of the proposed substitute will be less 

harmful to the atmosphere than the continued use of CFC-113, MCF, and HCFC-141b. Given that 

appropriate personal protective equipment (PPE) (OSHA Category B or higher) and engineering controls 

(e.g., exhaust ventilation, vapor-in-air detection systems) will be used during manufacture, end-use, and 

disposal activities, no significant toxicity risks to workers, end-users, or the general population are 

expected according to occupational, end-use, and general population exposure assessments. In addition, 

the characteristics of the proposed substitute indicate that flammability is not a concern at end-use.

3. ATMOSPHERIC ASSESSMENT

This section presents an assessment of the potential risks to atmospheric integrity posed by the use of 

HFE-347pcf2 in the aerosols and solvent cleaning sectors. The ozone depletion potential (ODP), global 

warming potential (GWP), and atmospheric lifetime (ALT) of the proposed substitute are presented in 

Table 2. As compared to CFC-113, HFE-347pcf2 has a lower climate impact and a shorter ALT.

Although the proposed substitute has comparable climate impact and ALT to HCFC-141b, the proposed 

substitute has zero ODP, and compared to the non-zero ODP values for CFC-113, MCF, and HCFC-141b, 

EPA believes that use of HFE-347pcf2 would result in substantially less harm to the ozone layer than the 

continued use of ODS.
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Table 2. Atmospheric Impacts of HFE-347pcf2 Compared to Ozone Depleting Substances Replaced

Aerosol Solvent /Solvent 

Cleaner ODP GWP ALT (years)

HFE-347pcf2 0

a 540b 7.1c

CFC-113 0.85e 6130d 85e

MCF 0.16

e 146d 5e

HCFC-141b 0.12 e 725d 9.2

e

HCFC-225ca 0.02f 122d 1.9

e

HCFC-225cb 0.03f 595d 5.9

e

a HFE-347pcf2 SNAP Submission (AGC Chemicals Americas, Inc., 2005)

b

IPCC/TEAP (2005)

cTokuhashi et al (2000)

d

IPCC (2007)

eWMO (2011)

fWMO (2007)

4. FLAMMABILITY ASSESSMENT

HFE-347pcf2 was tested for flammability according to the ASTM E681 method and was found to be nonflammable (AGC Chemicals Americas, Inc., 2006). Thus, EPA believes that HFE-347pcf2 does not pose 

a flammability risk. 

5. POTENTIAL HEALTH EFFECTS

To assess potential health risks from exposure to this proposed substitute, EPA compared long-term 

exposures to the manufacturer’s acceptable exposure limit (AEL) of 50 ppm1, and developed a ceiling 

limit of 150 ppm to assess acute exposure. The AEL represents the maximum 8-hour time weighted 

average (TWA) at which a worker can be exposed regularly without adverse effects. 

According to the MSDS, exposure to HFE-347pcf2 may be harmful by inhalation, ingestion, or skin 

absorption. Inhalation may cause coughing, dizziness, dullness, drowsiness, and headache. Higher 

concentrations can produce heart irregularities, central nervous system depression, narcosis, 

unconsciousness, respiratory failure, or death. If high concentrations of HFE-347pcf2 are inhaled, 

person(s) should be immediately removed and exposed to fresh air and kept calm. The MSDS 

recommends that if breathing is difficult, person(s) should be given oxygen, provided a qualified operator 

is present, and medical attention be sought. HFE-347pcf2 is not likely to be hazardous by ingestion; 

however, in case of ingestion, the MSDS recommends consulting a physician and not inducing vomiting, 

as there is a greater hazard associated with aspirating the compound into the lungs than ingesting it. In 

case of direct eye or skin contact, the MSDS for HFE-347pcf2 recommends that person(s) should 

immediately flush the affected area with water for 15 minutes and seek immediate medical attention if 

irritation is present (AGC Chemicals Americas, Inc., 2011). EPA’s review of the environmental and 

human health impacts of this proposed substitute is contained in the public docket for this decision. 

The potential health effects of HFE-347pcf2 are unlikely to occur when following good industrial hygiene 

practices and ventilation and PPE recommendations outlined in the MSDS for HFE-347pcf2 and Sections 

6, 7, and 8 of this risk screen. 

 

1 EPA independently developed an AEL of 75 ppm over an eight-hour time-weighted average (see Appendix A to this risk 

screen). However, since the manufacturer’s AEL of 50 ppm was more protective, EPA used that value in assessing risks. 
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6. OCCUPATIONAL EXPOSURE ASSESSMENT

HFE-347pcf2 is currently manufactured in Japan, and there are currently no plans to manufacture the 

proposed substitute in the United States. Should manufacture occur in the United States, the proposed 

substitute’s MSDS should be referenced and proper engineering controls and PPE used. HFE-347pcf2 is 

not expected to pose a risk to workers during manufacture when the engineering controls and PPE 

recommendations suggested by EPA and referenced in the MSDS for HFE-347pcf2 are followed. 

Engineering controls should include normal ventilation for standard manufacturing procedures; however, 

local exhaust ventilation should be used when large amounts of the proposed substitute are released, and 

mechanical ventilation should be used in the event of a spill to properly ventilate liquid which may pool 

in low-lying areas. In addition, an eye wash and safety shower should be near the manufacturing facility 

and ready for use. In general, use of OSHA Category B or higher PPE is recommended, such as 

respiratory protection (including a self-contained breathing apparatus [SCBA] if a large spill occurs), 

chemical splash goggles, impervious gloves, and impermeable apron and boots (AGC Chemicals 

Americas, Inc., 2011 and OSHA, 1994). 

In addition, there is a risk of generation of toxic degradation products such as hydrogen fluoride, carbonyl 

fluoride, carbon monoxide, and carbon dioxide if containers of HFE-347pcf2 are exposed to high 

temperatures. Containers should not be allowed to contact open flames, glowing metal surfaces, or 

electrical heating elements. EPA believes that because proper handling and disposal guidelines are 

followed in accordance with good industrial hygiene and manufacturing practices and the MSDS for 

HFE-347pcf2, there is no significant risk to workers during the manufacture of HFE-347pcf2.

7. END-USE EXPOSURE ASSESSMENT

HFE-347pcf2 is proposed for the precision and electronics cleaning end-uses and the aerosol solvent enduse; HFE-347pcf2 is not intended to be used for residential or direct consumer use. A surrogate 

compound, AK-225 (a mixture of 45% HCFC-225ca and 55% HCFC-225cb, by mass) was used to assess

the potential end-use exposures during electronics and precision cleaning to HFE-347pcf2. Air 

concentrations found during the air monitoring studies with AK-225 (described below in section 7.1) are a 

reasonable estimate of potential air concentrations of HFE-347pcf2, due to the similar boiling point of the 

two compounds and lower vapor pressure of HFE-347pcf2 (see Table 3) (AGC Chemicals Americas, Inc., 

2011). Therefore, EPA believes that this is a reasonable surrogate compound to use for this assessment. 

Table 3. Boiling Point and Vapor Pressure for HFE-347pcf2 and AK-225 Analog

Parameter HFE-347pcf2 Proposed 

Substitute

AK-225 Analog

Boiling Point 56 C 54 C

Vapor Pressure 31 KPa (at 25 C) 38 KPa (at 25 C)

7.1 Electronics Cleaning and Precision Cleaning

For the electronics cleaning and precision cleaning end-uses exposure analysis, EPA again reviewed the 

submitter’s exposure assessment for AK-225, which analyzed breathing zone air samples representative 

of an employee’s full shift exposure during routine electronics cleaning and precision cleaning at four 

different cleaning installations (AGC Chemicals Americas, Inc., 1995a). Table 4 describes the cleaning 

installation locations. 
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Table 4. Electronics Cleaning and Precision Cleaning Exposure Analysis Sampling Locations

Installation Type Ventilation Solvent Emissions

A (Plausible Worst) Open-Top General Moderate

B (Typical) Open-Top General Plus Local Moderate

C (Best) Closed-Top General/Natural Very Small

D (Best) Closed-Top General/Natural Very Small

Samples were taken from four places within each installation location: personnel air samples (Personal), 

in front of the cleaning equipment (Area 1), near exhaust fan, when provided, (Area 2), and near work 

table at a height of 1.5 meters (Area 3). The 8-hour TWA ranged from less than 1 ppm to 6 ppm for 

personnel while performing standard cleaning operating, which was dependent on installation type and 

ventilation. The highest exposure levels were detected directly in front of the equipment. Because of the 

similar physical and chemical properties between HFE-347pcf2 and AK-225, the exposure concentrations 

for HFE-347pcf2 were approximated from the surrogate AK-225 concentrations using the relative vapor 

pressures of each compound. Table 5 shows the results of the solvent cleaning exposure assessment for 

HFE-347pcf2. 

Table 5. HFE-347pcf2 Electronics Cleaning and Precision Cleaning End-Use Exposure Modeling

Installation Personal TWA 

(ppm)

Area 1 TWA 

(ppm)

Area 2 TWA

(ppm)

Area 3 TWA

(ppm)

A (Plausible Worst) 5.2 11 15 N/A

B (Typical) 3.7 5.3 6.3 1.2

C (Best) 0.4 0.4 a 0.6 0.3

D (Best) 1.0 1.0 a 2.0 1.4

aAn exhaust fan was not present at this installation. This sample was also taken near the work table.

The anticipated exposure concentrations for HFE-347pcf2 are well below the AEL for HFE-347pcf2 (50 

ppm) for all installation types. The submitter demonstrates that worker exposures to AK-225, and 

therefore HFE-347pcf2, can be maintained well below the recommended 8-hour TWA limit of 50 ppm. 

Because use of HFE-347pcf2 as a solvent cleaner is not expected to result in signification emissions, and 

because end-users of HFE-347pcf2 will follow appropriate cleaning equipment guidelines and 

environmental measures, such as mechanical ventilation, EPA does not believe that it presents a 

significant risk to workers at end-use.

7.2 Aerosol Solvent

To assess the short-term exposure risks of short-term exposure during end-use, EPA modeled the use of 

an aerosol solvent. The analysis is based on a simple box-model approach that draws assumptions from 

spray tests performed by aerosol solvent manufacturing companies. In this case, the box-model approach 

examines an area surrounding the face of the exposed worker and determines exposure based on the 

velocity of ventilation present. As the velocity varies, the volume of moving air surrounding the worker 

also changes, which in turn changes the level of exposure estimated by the box model.

The modeling was based upon the following assumptions, described below in Table 6, regarding usage, 

area of exposure, ventilation, and the constituents of the solvent formulation.
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Table 6. Summary of Assumptions for Aerosol Solvent End-Use Exposure Box-Model

Parameter Assumption

Usage Entire aerosol can (454 grams) sprayed in 3, back-to-back 10-minute periods, 

or 30-minutes totala

Solvent Formulation 10% propellant (HFC-134a), 90% solvent (HFE-347pcf2)b

Area of Exposure 18 in in equidistant directions around worker’s face 

(3 ft x 3 ft = 9 ft2 area around the face of worker)

Ventilation/Air Flow Rate No mechanical ventilation present; Air flow rate is equal to 450 ft3

/min or 12.7 

m3/min (50 ft/min over 9 ft2 of area at the face of worker)c

a The submitter indicated that use of the aerosol solvent would typically take place up to three times over the course the day in 10-

minute periods (AGC Chemicals Americas, Inc., 1995b)

b This is a conservative assumption because HFE-347pcf2 is a relatively mild solvent and is likely to be blended with other, more 

aggressive solvents, such as trans-1,2-dichloroethylene.

c EPA 1994

The exposure point concentration for occupational inhalation exposure is determined by calculating the 

workplace air chemical concentration. The indoor air concentration for HFE-347pcf2 was estimated 

using Equation 1 (EPA 1994):

Equation 1: Workplace Air Concentration

Ca =

Yv x 1000

mg

x

g 24.45

AT x k MW

Where:

Ca = Concentration of the chemical in air (ppm)

Yv = Mass emission rate of volatile compound released (g/s)

AT = Air flow rate (m3/s)

k = Dimensionless room ventilation mixing coefficient (assumed as 0.5, EPA 1991)

24.45 = Factor used to convert from mg/m

3

to ppm

The mixing factor, k, accounts for the slow and incomplete mixing of ventilation air with room air (i.e., 

ventilation effectiveness is reduced by poor dispersion characteristics within the room). In this case, a 

small area around the user (the breathing zone) was evaluated, so complete mixing is assumed and a 

default value of one is used. The model assumes that the entire area surrounding the solvent sprayer 

contains the same concentration of HFE-347pcf2, and that the chemicals are completely volatilized into 

the air after release. This assumption is appropriate given the method of application (aerosol canister).

Based on the assumptions above, the short-term mass emission rate of solvent is 0.227 g/s of HFE347pcf2 [454 gram aerosol can containing 90% HFE-347pcf2 dispensed over 30-minutes].Table 7 shows 

the results of this analysis.
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Table 7. HFE-347pcf2 Aerosol Solvent End-Use Exposure 

(Calculated Using Box Model)

Sampling Location Maximum Short-Term 

Concentration (ppm) Ceiling Limit (ppm)

Area around Worker’s 

Face During Aerosol 

Spray Application

130 150

Based on the results of this modeling, even with conservative assumptions regarding ventilation and the 

amount of solvent, the short-term concentration is unlikely to reach the ceiling limit.. 

The submitter also reports that aerosol spray cans containing HFE-347pcf2 (aerosol solvent end-use) may 

be used within manufacturing facilities. End-users will follow certain guidelines, including training and 

review of the MSDS, to ensure that employee work habits are conducted in accordance with good 

industrial hygiene practices. The submitter also recommends that aerosol solvent products be labeled to 

ensure that the products are used in areas with adequate ventilation or local exhaust ventilation. Because

of the results of the exposure assessment and because end-users of HFE-347pcf2 are expected be trained 

to properly use and handle the proposed substitute, EPA does not consider end-use exposure during 

aerosol solvent use to be a concern.

8. GENERAL POPULATION EXPOSURE ASSESSMENT

This section screens potential risks to the general population from exposure to releases of HFE-347pcf2 to 

ambient air, surface water, and solid waste. Because the proper safety and disposal precautions, as listed 

in the remainder of this section, are expected to be followed, HFE-347pcf2 is not expected to cause a 

significant threat to the environment and human health in the general population when manufactured or 

used for aerosol solvent, electronics cleaning, and precision cleaning end-uses.

8.1 Ambient Air

HFE-347pcf2 has a high evaporation rate of 67,

2 meaning that releases of the proposed substitute will 

likely volatilize; however, if the accidental release measures, handling and storage, engineering controls, 

and waste disposal are followed per the proposed substitute’s MSDS, significant releases to air are not 

expected to occur. Other releases to the air during aerosol solvent, electronics cleaning, and precision

cleaning end-uses will occur indoors with good manufacturing practices, such as employment of capture 

and destruction technologies, and therefore not expected to cause exposure to the general population.

8.2 Surface Water

Due to the high relative evaporation rate (67) and near-insolubility of HFE-347pcf2 in water (0.01g HFE347pcf2/100g water at 25C), HFE-347pcf2 is not likely to accumulate in surface water (AGC Chemicals 

Americas, Inc., 2004). For aerosol solvent, electronics cleaning, and metal cleaning end-uses, the product 

will be handled indoors with waste or accidental spills collected as wastewater or taken up with an 

absorbent material, such as sand or a general-purpose binder. Water contaminated with HFE-347pcf2

 

2 A relative evaporation rate is the rate at which a material will vaporize compared to the rate of vaporization of a specific known 

material. Ether, which has a relative evaporation rate of 100, is considered to be highly volatile. HFE-347pcf2, which has a 

relative evaporation rate of 67, would also be considered to have high volatility. 
***** Final - July 30, 2012 *****

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should not be dumped into sewers, on the ground, or into any body of water, in accordance with the 

MSDS.

For facilities which collect the wastewater for treatment, the wastewater must be sent to an industrial 

wastewater treatment facility that employs sufficient controls in order to remove fluorinated materials. 

Domestic (sanitary) wastewater treatment facilities do not meet these requirements. EPA believes that 

treated wastewater which meets the discharge concentration requirements of an industrial treatment 

facility is sufficient to control human health and environmental risks, and thus recommends that all spent 

solvent collected as wastewater is sent to an industrial treatment facility. 

8.3 Solid Waste

Industrial sites using HFE-347pcf2 can collect spent solvent for disposal or reclaim the spent solvent

through distillation. EPA recommends that reclamation of the substitute through distillation be performed 

to the extent feasible. Residuals from the distillation process and spent solvent collected in containers 

(and therefore not collected as wastewater and sent to a wastewater treatment facility) are generally 

considered to be a RCRA hazardous waste (40 CFR Part 261.31). However, not all applications of HFE347pcf2 may generate hazardous wastes. Although the constituents of HFE-347pcf2 are not listed as 

RCRA hazardous wastes, solvents used for electronics and precision cleaning applications generally pick 

up metals and other chemical compounds during the process, which causes the spent solvent to display 

characteristics of hazardous waste (ignitability, corrosivity, reactivity, or toxicity); any solid waste 

displaying these characteristics or having a specific waste code (e.g., F001) is considered to be a 

hazardous waste (40 CFR Part 261). Waste regulated as RCRA hazardous wastes is subject to the 

requirements of the Subtitle C program (including storage, treatment, and disposal requirements), which 

EPA believes are sufficient to control human health and environmental risks. In addition, because solid 

materials used during end-use or clean-up procedures that may be absorbed with HFE-347pcf2 (i.e., rags, 

paper towels, trays) are disposed of in accordance with the HFE-347pcf2 MSDS, EPA does not expect 

general population exposure to HFE-347pcf2 through solid waste to occur. 

9. VOLATILE ORGANIC COMPOUND (VOC) ASSESSMENT

HFE-347pcf2 has not yet been exempted as a volatile organic compound (VOC) under the CAA (40 CFR 

51.100(s)), and as such, emissions of HFE-347pcf2 should be controlled. EPA has received a petition to 

exempt this compound from the definition of VOC for purposes of regulations in state implementation 

plans for local air quality because of low photochemical reactivity that would result in insignificant 

impacts on ground-level ozone; however, HFE-347pcf2 continues to be regulated as a VOC for that 

purpose unless and until EPA issues a final rule exempting it. 

The submitter intends to manufacture HFE-347pcf2 as an aerosol solvent and solvent cleaner for

electronics cleaning and precision cleaning end-uses. The IPCC estimates that 50% of initial solvent 

charge is emitted per year (IPCC/TEAP, 2007); however, this emission factor encompasses all solvent 

cleaning processes, including cold cleaning, which has very high emissions, and more controlled 

equipment, such as vapor degreasing, which is less emissive. 

HFE-347pcf2 is intended to be used indoors within a controlled environment for the aerosol solvent, 

electronics cleaning, and precision cleaning end-uses, in which spent solvent is captured and recovered or 

disposed as sludge throughout its use within a completely contained unit. Only a portion of the solvent, 

assumed to be on the order of 10%,

3

is expected to escape from the control technologies (freeboard and 

 

3 The IPCC estimates that 50% of initial solvent charge is emitted per year (IPCC/TEAP, 2007), including all solvent cleaning 

procedures and equipment. Replacing old degreasing equipment with new equipment providing better containment of solvents 

can reduce emissions in this sector up to 80%, so vapor degreasing units have an approximated emission rate of 10%
***** Final - July 30, 2012 *****

9

condensing coils) employed in a typical vapor degreaser, and subsequently be released to the atmosphere. 

Many larger end-use facilities may employ additional technologies to control and remove solvent from 

workplace air before it is vented from the facility.

An assessment was performed to compare the annual VOC emissions from use of HFE-347pcf2 in the 

aerosol solvent, electronics cleaning, and precision cleaning end-uses in one year to other anthropogenic 

sources of VOC emissions. An emissions estimate of 10% was assumed for use of HFE-347pcf2 in highly 

controlled equipment (i.e., vapor degreasers), which is the maximum annual amount of solvent released 

during end-use for facilities without additional engineering controls on their ventilation systems, such as 

carbon absorption units. Because a breakdown of production by end-use was not provided by the 

submitter, the emissions rate of 10% was applied to the entire intended U.S. annual production of HFE347pcf2 for the aerosol solvents, electronics cleaning, and precision cleaning end-uses in order to estimate 

the maximum impact on VOC emissions across these end-uses. Assuming 10% of the submitter’s 

intended annual production is released, approximately 2.0x10-4percent of the VOC emissions from the 

solvent sector in the United States4 would be released, or only approximately 3.7x10-5percent of all 

anthropogenic VOC emissions in the U.S.5

For aerosol solvent spray applications that take place in less-controlled equipment, such as a fume hood 

or other ventilated areas which would vent the aerosol solvent to the atmosphere, an emissions rate of 

74%6 was applied to the entire intended U.S. annual production of HFE-347pcf2 for aerosol solvent, 

electronics cleaning, and precision cleaning end-uses in order to estimate the maximum impact on VOC 

emissions across these end-uses. Assuming 74% of the submitter’s intended annual production is entirely 

released, approximately 1.5x10-3percent of the VOC emissions from the solvent sector in the United 

States would be emitted, or only approximately 2.8x10-4percent of all anthropogenic VOC emissions in 

the U.S.

Although these VOC emissions for highly controlled aerosol solvents and solvent cleaning applications 

and less controlled applications are several orders of magnitude lower than other anthropogenic 

emissions, it is likely that the estimated VOC emissions estimated here can be further reduced, and in 

some facilities may already be so reduced. For example, capture and destruction technologies for fugitive 

emissions are employed in larger facilities, and hence emissions during use of HFE-347pcf2 may be even 

less than estimated here. In addition, the majority of the solvent sector utilizing ODS substitutes 

(approximately 69%) is made up of solvents that are considered to be VOCs, such as trichloroethylene 

and organic solvents (ICF 2012). Because HFE-347pcf2 is intended for smaller, niche markets (e.g., 

electronics cleaning and precision cleaning) and its small intended production compared to the size of the 

entire solvent sector, emissions from HFE-347pcf2 for its intended end-uses would not have a significant 

impact on VOC emissions from the solvent sector. 

 

(IPCC/TEAP, 1999).

4 Based on the 2010 annual VOC emissions for solvent utilization for the U.S. (EPA 2011). The solvent utilization sector includes 

consumer and commercial solvent use, degreasing, dry cleaning, graphic arts, industrial surface coating and solvent use, and nonindustrial surface coating.

5 Based on the 2010 annual total VOC emissions for the U.S. (EPA 2011).

6 Leak rate for non-medical aerosols from EPA’s Vintaging Model (VM IO file_v4.4_11.17.11).
***** Final - July 30, 2012 *****

10

10. REFERENCES

AGC Chemicals Americas, Inc.. 2011. Material Safety Data Sheet Asahiklin HFE-347pcf2. March 25, 

2009. Revised June 23, 2011.

AGC Chemicals Americas, Inc.. SNAP Submission. 2005. Significant New Alternatives Policy Program 

Submission to the United States Environmental Protection Agency, November 2005. Docket 

Folder Number: EPA-HQ-OAR-2009-0286.

AGC Chemicals Americas, Inc.. 1995a. Exposure Result of Employee Expsure Monitoring for HCFC225 at Cleaning Installations. Submitted to: Office of Atmospheric Programs, United States 

Environmental Protection Agency. March 1995.

AGC Chemicals Americas, Inc.. 1995b. Exposure Assessment to AK225 during Aerosol Spray 

Applications. Submitted to: Stratospheric Protection Division, United States Environmental 

Protection Agency. December 1995.

EPA 2011. National Emissions Inventory Air Pollutant Emissions Trends Data. Accessed 23 December 

2011. Updated October 2011. Available at: 

<http://www.epa.gov/ttn/chief/trends/index.html#tables>

EPA 2008. Acute Exposure Guideline Levels: Definitions. Accessed 27 February 2009. Available at: 

<http://www.epa.gov/opptintr/aegl/pubs/define.htm>.

EPA 1994a. Significant New Alternatives Policy Technical Background Document: Risk Screen on the 

Use of Substitutes for Class I Ozone-depleting Substances: Aerosols. Stratospheric Protection 

Division. March, 1994.

EPA 1994b. Significant New Alternatives Policy Technical Background Document: Risk Screen on the 

Use of Substitutes for Class I Ozone-depleting Substances: Solvent Cleaning. Stratospheric 

Protection Division. March, 1994.

Forster, P., V. Ramaswamy, P. Artaxo, T. Berntsen, R. Betts, D.W. Fahey, J. Haywood, J. Lean, D.C. 

Lowe, G. Myhre, J. Nganga, R. Prinn, G. Raga, M. Schulz and R. Van Dorland. 2007. Changes 

in Atmospheric Constituents and in Radiative Forcing. In: Climate Change 2007:The Physical 

Science Basis. Contribution of Working Group I to the Fourth Assessment Report of the 

Intergovernmental Panel on Climate Change [Solomon, S., D. Qin, M. Manning, Z. Chen, M. 

Marquis, K.B. Averyt, M.Tignor and H.L. Miller (eds.)]. Cambridge University Press, 

Cambridge, United Kingdom and New York, NY, USA.

Campbell, N., J. Hu, P. Lapin, A. McCulloch, A. Merchant, K. Mizuno, J. Owens, P. Rollet. 2007. 

IPCC/TEAP Special Report: Safeguarding the Ozone Layer and the Global Climate System, 

Chapter 10: Non-Medical Aerosols, Solvents, and HFC-23.

ICF International. 2012. Solvent Sector VOC Analysis for ODS Substitutes. Prepared for EPA’s 

Stratospheric Ozone Protection Division. March 9, 2012

IPCC/TEAP. 2005. Safeguarding the Ozone Layer and the Global Climate System. Intergovernmental 

Panel on climate Change Technology and Economic Assessment Panel.

IPCC. 1999. Meeting Report of the Joint IPCC/TEAP Expert Meeting on Options for the Limitation of 

Emissions of HFCs and PFCs. Intergovernmental Panel on climate Change Technology and 

Economic Assessment Panel. 26-28 May 1999.
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OSHA. 1994. General description and discussion of the levels of protection and protective gear. 1910.120 

App B. Last updated August 22, 1994. Available at: 

http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9767

Tokuhashi, Kazukai, Akifumi Takahashi, Masahiro Kaise, Shigeo Kondo, Akira Sekiya, Shiro 

Yamashita, and Haruaki Ito. 2000. Rate Constants for the Reactions of OH Radicals with 

CH3OCF2CHF2, CHF2OCH2CF2CHF2, CHF2OCH2CF2CF3, and CF3CH2OCF2CHF2 over 

the Temperature Range 250-430 K. J. Phys. Chem. A, 104 (6), 1165 -1170.

WMO (World Meteorological Organization), 2007. Scientific Assessment of Ozone Depletion: 2006, 

Global Ozone Research and Monitoring Project—Report No. 50, 572 pp., Geneva, Switzerland, 

2007.

WMO (World Meteorological Organization), 2011. Scientific Assessment of Ozone Depletion: 2010, 

Global Ozone Research and Monitoring Project—Report No. 52, 516 pp., Geneva, Switzerland, 

2011.
***** Final - July 30, 2012 *****

12

Appendix A: 

Recommendation for an Acceptable Exposure Limit (AEL) for HFE-347pcf2

Recommended AEL: 75 ppm (8-hour Time Weighted Average) with a ceiling of 150 

ppm

Basis and Endpoints: Lack of neurotoxicity and systemic toxicity in sub-chronic 

study evaluating inhalation exposure

Study: HFE-347PC-F: 90-day inhalation toxicity study in the rat with 

recovery phase (Central Toxicology Laboratory, 2005)

Protocol: Whole-body inhalation, 6 hours/day, 5 days/week for 13 weeks 

with 14-day recovery period for control and high dose groups

Concentrations: 0; 100; 300; 1000 ppm

NOAEC7: 1000 ppm

NOAEC [HEC8]: 1000 ppm x 6 hr/8 hr = 750 ppm

Uncertainty Factors: 3 – animal to human extrapolation

3 – factor added to adjust for steepness of dose-response curve

Total - 10

 

7 No Observable Adverse Effect Concentration (NOAEC)

8 Human Equivalent Concentration (HEC)
***** Final - July 30, 2012 *****

13

I. Introduction

AGC Chemicals Americas, Inc. Americas, Inc. submitted HFE-347pcf2 (HFE-347pc-f2, 2,2,2-

trifluoroethyl-1,1,2,2- tetrafluorethyl-ether) to the Significant New Alternatives Policy (SNAP) 

Program as a replacement for PFCs, HCFCs, HFCs and other halogenated solvents in November 

2005. It is intended for use as an aerosol solvent cleaner and in electronics and precision 

cleaning. ICF completed an initial review of the available toxicity studies in October 2006, 

including a range-finding (4-hour acute) inhalation study and 28-day and 90-day inhalation 

studies. Although the 90-day study provided a free-standing NOAEC, the acute 4-hour inhalation 

study indicated convulsions at inhalation concentrations slightly higher than those with no 

apparent toxicity. Therefore, an additional short-term repeated dose inhalation toxicity study in 

rats was recommended to more thoroughly investigate the dose-response curve of the compound.

At the joint request of EPA’s SNAP Program and New Chemicals Program, additional data is 

now available for review, allowing for a more complete characterization of the dose-response 

curve. The additional studies include a 28-day inhalation study with neurotoxicity assessment 

and a 5-day inhalation study. Both provide further data points for the dose-response curve, 

expanding the range up to 5000 ppm. This additional information has enabled development of 

both an acceptable exposure limit (AEL) and a ceiling limit for workplace exposures to HFE347pcf2. 

II. Summary List of Toxicity Studies

A standard battery of toxicological studies was conducted for HFE-347pcf2 and is listed in Table 

1. Neurotoxicological effects, including tremors and/or convulsions, associated with inhalation 

exposure to HFE-347pcf2 were considered to be the most critical health effects for derivation of 

an AEL; therefore inhalation studies with HFE-347pcf2 are described and discussed in detail. 

The remaining studies are considered supporting studies.
***** Final - July 30, 2012 *****

14

Table 1: Summary of Toxicological Studies for HFE-347pcf2

Inhalation Studies Doses NOAEL/ 

NOAECa

Effects

4-hour acute 

inhalation study

(1994)

1000 or 3000 ppm LC50 >3000 

ppm

Mortality at 3000 ppm

5-day inhalation 

study (2008)

0, 1250, 1800, 2500, or 5000 

ppm

1800 ppm Mortality reported at 

5000 ppm. Tremors/ 

convulsions at ≥2500 

ppm. 

28-day inhalation 

study with 14-day 

recovery (2000)

0, 24, 120, or 600 ppm 120 ppm Reversible increased 

liver weight reported at 

600 ppm

28-day inhalation 

study with 

neurotoxicity 

assessment (2009)

0, 1000, 1500, 2000, or 2500 

ppm

1500 ppm Mortality at ≥ 2000. 

Tremors/ convulsions at 

≥ 2000.

90-day inhalation 

study with 

neurotoxicity

assessment and 28-

day recovery (2005)

0, 100, 300, or 1000 ppm 1000 ppm No adverse treatmentrelated effects reported.

Supporting Studies

Acute oral toxicity 2000 mg/kg LD50> 2000 

mg/kg

No mortality or adverse 

clinical effects reported

28-day oral study 0,10, 100, or 1000 mg/kg 1000 

mg/kg/day

No adverse treatmentrelated effects reported.

In vitro bacterial 

reverse mutation 

assay

Max concentration of 10,000 

μg/plate

NA Negative

In vitro

chromosomal 

aberration assay

Max concentration of 5 mg/L NA Negative

Skin irritation 0.5 mL NA Negative

Eye irritation 0.1 mL NA Negative

Local lymph node 

assay

25 μl of 25, 50, or 100 % w/v 

in acetone test solutions

NA Negative

a All values NOAEL/NOAEC unless otherwise reported; NA- not applicable

NOAEL = No observed adverse effect level (commonly used for oral or dermal exposures)

NOAEC = No observed adverse effect concentration (commonly used for inhalation exposures)
***** Final - July 30, 2012 *****

15

III. Development of the AEL for HFE-347pcf2

Several repeated dose studies assessing the toxic potential of HFE-347pcf2 were available for 

development of an AEL. A NOAEC from an inhalation study was selected as the point of 

departure rather than a NOAEL from an oral study as inhalation is the more probable and 

relevant route for human exposure. The NOAEC of 1000 ppm from the 90-day inhalation study

was chosen as the point of departure for derivation of an AEL for HFE-347pcf2 since this was a 

well conducted, subchronic duration study and no significant or treatment-related effects were 

reported at the highest concentration tested.

The AEL was calculated in the following manner:

1000 x (6/8) ÷ 10 = 75 ppm

A human equivalent concentration (HEC) was determined by adjusting the NOAEC of 1000 ppm 

by the ratio of rat exposure duration per day to that of an occupational worker (6 hours/8 hours). 

The guidelines for developing Reference Concentration (RfC) values (U.S. EPA, 1994) were 

followed, which obviated the need to apply a UF of 3 for pharmacokinetic differences between 

rats as the animal model of study and humans. We have maintained a UF of 3 for 

pharmacodynamic [PD] differences between the two species. Because the dose-response curve 

for this compound is so steep, and because the adverse effects noted in the inhalation studies are 

severe, we apply an additional UF of 3, thereby giving a total UF of 10. Because sub-chronic 

studies are typically used to develop AEL values for the workplace, an additional UF was not 

added to account for study duration. This compound has not been evaluated in either a 

reproductive or developmental toxicity study; however, there were no indications in the toxicity

studies to date, that reproductive organs would be targeted by this compound, nor that 

developmental effects would be a concern. The current database is considered sufficiently 

comprehensive, and no additional UF was added to account for database limitations. 

In addition to the AEL (8-hour TWA), a Ceiling Limit Value, which is an exposure 

concentration which should not be exceeded for any length of time, is also proposed given the 

seriousness of the neurotoxic effects observed in animals exposed to high vapor concentrations 

of HFE-347pcf2. One of the serious shortcomings of the standard toxicity protocols is that there 

are rarely enough dose levels to fully characterize the shape and steepness of a critical effect 

level, particularly when the effect noted can be sudden and serious such as convulsions and/or 

tremors. The dose-response curve for HFE-347pcf2, with respect to neurotoxicity in the form of 

tremors, convulsions, and death, is quite steep and has been further examined by the addition of 

data points from the 5-day exposure study, with multiple dose levels bracketing those from 

longer-term exposure patterns. This characterization of the dose-response curve better informs 

the risk of suddenly increasing exposure concentrations. 

The toxicity studies with HFE-347pcf2 indicate that neurotoxicity is the most sensitive endpoint.

Although liver effects were noted at a lower concentration in a shorter-term study, these effects 

were mild, were not seen consistently at greater exposure concentrations in all studies, and have 

been shown to be reversible. In the 90-day inhalation study, no neurotoxicity or clinical signs 

were noted at the maximum exposure concentration of 1000 ppm. In the subsequent requested 5-
***** Final - July 30, 2012 *****

16

day exposure study, convulsions and tremors were noted at 2500 ppm and 5000 ppm, resulting in 

a NOAEL of 1800 ppm. In the 28-day inhalation study, no neurotoxicity was noted at 1500 

ppm, but tremors and convulsions (as well as morbidity/mortality) were observed in individual 

animals at 2000 ppm and at 2500 ppm. As mentioned, these data indicate that concentrations 

exceeding 1000 ppm, which can be withstood for at least 90 days, quickly induce severe 

neurological effects when increased to 2000 ppm over the course of 6 hours/day for 5 days (see 

Figure 1). A concentration of 1800 ppm for 5 days appears to result in no observable signs of 

toxicity. Given these data, we propose a Ceiling Limit Value of 150 ppm for human exposure. 

This value is twice the AEL and an order of magnitude lower than the 1500 ppm NOAEC in the

28-day inhalation study.9 This value is believed appropriate as an upper limit given that no 

adverse neurotoxic effects, manifested as tremors or convulsions, were observed in rats 

following exposure to 1500 ppm HFE-347pcf2 for 28 days.

Figure 1: Comparison of inhalation study concentration exposures for HFE-347pcf2

 

9 Currently there are no available guidelines for establishing ceiling limit values. Although no specific calculations 

are cited for OSHA or ACGIH ceiling limit values, such values are generally 2-4 times higher than the AEL (TLV). 

Therefore, the selected factor of 2 for the ceiling limit value for HFE-347pcf2 represents a conservative approach. 

A list of some typical OSHA PELs and corresponding ceiling limit values can be viewed online at: 

http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9993&p_text_version=

FALSE

2000 ppm

150 ppm 0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

4-hour inhalation 

study

5-day inhalation 

study

28-day inhalation 

study (2000)

28-day inhalation 

study (2009)

90- day 

inhalation study

ppm

Study

AE-3000 Exposure Concentrations by Study
***** Final - July 30, 2012 *****

17

IV. Detailed Discussion of Inhalation Studies for HFE-347pcf2

Several studies assessing the potential toxicity of HFE-347pcf2 have been conducted and include 

acute oral and inhalation studies in rats, a 28-day oral study in rats, a 5-day, 28-day, and 90-day

inhalation study in rats, as well as whole animal eye irritation, skin irritation, and dermal 

sensitization assays, and genotoxicity studies in bacteria and mammalian cells in culture. The 

results of these studies are discussed in the following sections to inform an assessment of the 

potential health risks from human exposure in the intended end uses.

Four-hour acute inhalation study (1994)

In an acute 4-hour nose-only inhalation study, male rats (5/dose) were exposed to 1000 or 3000 

ppm HFE-347pcf2 (purity 99.9%) and observed for 14 days post-exposure (Mitsubishi-Kasei 

Institute of Toxicological and Environmental Sciences, 1994). No deaths were reported at 1000 

ppm; however 2/5 males exposed to 3000 ppm HFE-347pcf2 died during the first hour of 

exposure. Necropsy of the animals that died during the study reported reddish lung, dilation of 

the atrium, congestion of cerebellum aperture and moderate congestion and edema of the lung. 

Clinical signs of toxicity, lasting until 1 hour post-exposure, in the 3000-ppm animals included 

struggling, increased urine output and soiled fur. The LC50 was reported as > 3000 ppm.

Five-day inhalation study (2008)

In a dose range-finding inhalation study, Crl:CD(SD) rats (5/sex/group) were exposed via whole 

body inhalation to 0, 1250, 2500, or 5000 ppm of vaporized HFE-347pcf2 (purity 99.99%) for 6 

hours/day for 5 consecutive days (WIL Research Laboratories, 2008). Due to mortality in the 

5000-ppm group early in the study, an additional group of rats was added to the experiment and 

exposed to 1800 ppm HFE-347pcf2 under identical experimental conditions. Rats exposed to 0, 

1250, 1800, or 2500 ppm HFE-347pcf2 were sacrificed at the end of the exposure period and 

subjected to complete necropsy. All surviving rats from the 5000-ppm group were euthanized 

and subjected to complete necropsy after 2 days exposure and 3 days non-exposure. Body

weights were obtained prior to study initiation and then prior to the first, third, and fifth 

exposures; food consumption was recorded on study day 4. Clinical and physical examinations 

were conducted at scheduled intervals during the study. 

One 5000-ppm male rat was found dead on study day 1; no additional deaths were observed for 

any dose group for the remaining duration of the study. Convulsions and /or tremors were 

reported in both 2500- and 5000-ppm male and female rats. Red, yellow, and/or brown staining 

material was noted on various body surfaces in 5000-ppm males and females. Slightly reduced 

food consumption was reported in 2500-ppm males and females from study days 0 through 4. 

No changes in body weights, organ weights, clinical pathology, or macroscopic findings were 

noted in any test group. The NOAEC was reported as 1800 ppm, while the LOAEC was 

identified as 2500 ppm based on neurotoxicity (tremors) in both sexes of rats.

Four-Week Inhalation Studies

Study #1 (2000)

Two sub-chronic 28-day inhalation studies have been conducted with HFE-347pcf2. In the first 

study conducted by the Mitsubishi Chemical Safety Institute Ltd. (2000), Sprague-Dawley rats 

(6/sex/concentration) were exposed to HFE-347pcf2 (purity 100%) via whole-body inhalation at 
***** Final - July 30, 2012 *****

18

nominal vapor concentrations of 0, 0.2, 1, or 5 mg/L (equivalent to approximately 24, 120, or 

600 ppm) for 6 hours/day for 7 days/week for 4 weeks. Actual measured concentrations were 

0.247, 0.99, and 5.10 mg/L (equivalent to 30, 119, or 612 ppm). Control and high-exposure 

animals were maintained and observed for an additional 14-day recovery period.

Clinical observations were made twice daily (before and after exposure) and once per day during 

the recovery period. Body weights and food consumption were recorded weekly. All animals 

were necropsied following scheduled sacrifice on day 29 or 43. Terminal blood samples were 

taken from all animals as were urine samples on study day 24. The brain, lungs, kidneys,

adrenals, thymus, spleen, testes, and ovaries were removed and weighed. Selected tissues (heart, 

liver, spleen, kidneys, adrenals, lungs, trachea, and nasal cavity) from control and high-dose 

animals were examined microscopically.

There were no treatment-related effects noted in clinical observations, body weight, food 

consumption, urinalysis, hematology, blood chemistry, necropsy, or histopathology. Increased 

relative liver weights were seen in high-concentration (600 ppm) females. Increased relative 

liver weights were observed in high-concentration males and increased absolute liver weights in 

both high-concentration male and female rats; however these increases were not statistically

significant. All observed changes in liver weights were reversible during the recovery period. 

The NOEC was identified by the study authors as 0.99 mg/L (approximately 120 ppm).

Study #2 (2009)

In the second study conducted by WIL Research Laboratories (2009), Crl:CD(SD) rats 

(15/sex/concentration) were exposed to HFE-347pcf2 via whole-body inhalation at vapor 

concentrations of 0, 1000, 1500, 2000, or 2500 ppm for 6 hours/day for 5 days/week for 4 weeks. 

Five animals/sex/concentration were evaluated for general toxicity and 10 

animals/sex/concentration were evaluated for potential neurotoxic effects. The rats used for the 

neurotoxicity evaluation received 19-23 exposures because the testing extended over several 

days in contrast to the 20 exposures received by the rats used for the general toxicity segment of 

the study.

Animals were observed twice daily for mortality and moribundity and once daily for clinical 

effects. Physical examinations were performed prior to study initiation and weekly thereafter. 

Body weights and food consumption were recorded weekly. Clinical pathology evaluations and 

complete necropsies were performed on all general toxicity animals. Select organs (adrenal 

glands, brain, kidneys, liver, heart, lungs [prior to inflation with fixative], testes, epididymides,

ovaries with oviducts, spleen, and thyroid with parathyroids) were weighed at terminal sacrifice

for all general toxicity groups. Select tissues10 were examined microscopically in the control 

and 2500-ppm groups. The liver, lungs, kidneys, and all gross lesions were examined for all 

general toxicity groups.

 

10 Select tissues include: adrenals, aorta, bone with marrow, cerebellum cervix, epididymides, eyes with optic 

nerve, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, Harderian glands, heart, kidneys, 

lacrimal gland, larynx, liver, lungs, lymph nodes, nasal cavity, ovaries with oviducts, pancreas, peripheral nerve, 

Peyer’s patches, pharynx, pituitary, prostate, salivary glands, seminal vesicle, skeletal muscle, skin, spinal cord, 

spleen, testes, thymus, thyroid with parathyroids, trachea, urinary bladder, uterus, vagina, and gross lesions.
***** Final - July 30, 2012 *****

19

A functional observational battery (FOB), including home cage observations, handling 

observations, open field observations, sensory observations, neuromuscular observations, 

physiological observations, and locomotor activity, was conducted for the neurotoxicity group 

animals. All surviving animals were sacrificed at study termination. The central and peripheral 

nervous system tissues were dissected and preserved. Select nerve tissues11 were examined 

microscopically from 6 randomly selected animals/sex in the control and 2500-ppm groups.

One 2000-ppm male was found dead on study day 22 and one 2500-ppm female was euthanized 

in extremis on day 25. There were no clinical or macroscopic findings pointing to a cause of 

death for the male rat although his bodyweight was reduced by 65 grams during the last week of 

exposure. Tremors were observed during exposures or 0-1 hour post-exposure for the euthanized 

2500-ppm female rat during the study. Additionally, salivation, lacrimation, clonic convulsions 

(in which the muscles alternately tense and relax), popcorn seizures (seizures in which the 

animal jumps into the air), and hyperactivity were observed during the first hour of exposure in 

the days preceding euthanasia. No other mortalities were reported during the study.

Tremors were observed in ≥ 2000-ppm male and female rats at the midpoint of the daily 6-hour 

exposures or within 0-1 hour post-exposure. Intermittent tremors (defined as moderate, 

intermittent muscle tremors) were reported in 5 males and 4 females in the 2000-ppm group and 

in 11 males and 10 females in the 2500-ppm group. Such tremors were reported early in the 

study (within the first week of exposure) and continued until study termination. Continuous 

tremors (defined as moderate, continuous muscle contractions), seen only in 2500-ppm male and 

female rats, occurred sporadically during the midpoint of exposures beginning the second week 

of the study and continued until scheduled sacrifice. The onset of tremors was seen to occur 

earlier in the exposure time window during weeks 3 and 4 at which time effects were seen within 

1 hour 15 minutes of exposure initiation. One 2000-ppm male, two 2500- ppm males, and one 

2500-ppm female also exhibited clonic convulsions, continuous tremors, or popcorn seizures. 

Mean body weight gain and reduced food consumption (p<0.05) was reported for 2500- ppm 

male rats during study week 0-1. This finding, while statistically significant, was not observed 

during any other week during the study. There were no changes in measured hematological 

parameters, serum chemistry, or macroscopic findings for any exposure group. Relative liver 

weight was higher for 2500-ppm females (p<0.01) compared with controls; absolute and relative 

spleen weights were lower for 2000- and 2500-ppm females but were within the historical 

control data range. There were no test substance-related effects on clinical pathology

parameters, macroscopic observations, organ weights, FOB parameters, locomotor activity, or 

microscopic observations. The NOAEC is 1500 ppm and the LOAEC is 2000 ppm based on 

neurotoxicity in both sexes and mortality in one male. 

Ninety-day inhalation study

In a 90-day inhalation study, Alpk:ApfSD (Wistar–derived) rats (10/sex/concentration) were 

exposed to HFE-347pcf2 (99.9% purity) via whole-body inhalation at nominal vapor 

 

11 Select nerve tissues include: brain, spinal cord, trigenica ganglia/nerves, lumbar dorsal root ganglia at T13-L4, 

lumbar dorsal root fibers at T13-L4, lumbar ventral root fibers at T13-L4, cervical dorsal root ganglia at C3-C7, cervical 

dorsal root fibers at C3-C7, cervical ventral root fibers at C3-C7, sciatic nerves (mid-thigh region), sciatic nerves (at 

sciatic notch), sural nerves, tibial nerves, peroneal nerves, optic nerves, eyes, and skeletal muscle.
***** Final - July 30, 2012 *****

20

concentrations of 0, 100, 300, or 1000 ppm for 6 hours/day for 5 days/week for 4 weeks (Central 

Toxicology Laboratory, 2005). An additional control and 1000-ppm group (10 / 

sex/concentration) were exposed under identical experimental conditions but then maintained for 

an additional 28-day recovery period.

Rats were observed twice daily during the first ninety days of the study for clinical signs of 

toxicity, morbidity, and mortality and once daily during the recovery period. Body weights were 

recorded weekly; mean food consumption was calculated weekly. Ophthalmoscopic 

examinations were conducted at study initiation and during week 13 for the control group and 

1000 ppm group of the main study. A FOB was performed during week 12 of the study and 

included grip strength measurements, time to tail flick, landing foot splay, and motor activity. 

Urine samples, collected during week 13 from the main study animals and during week 17 for 

the recovery group animals, were analyzed for the parameters listed in Table 2. Cardiac blood 

samples were taken at scheduled sacrifice (week 14 and week 18) and analyzed for the 

hematological and clinical chemistry parameters detailed in Tables 3 and 4. Liver samples from 

5 animals/ sex/concentration were analyzed for palmitoyl coenzyme A activity (as a marker for 

peroxisomal activity). 
***** Final - July 30, 2012 *****

21

Table 2. Urinalysis parameters measured for rats in 90-day inhalation study with HFE-347pcf2

x Color x Glucose

x Appearance x Ketones

x Volume x Bilirubin

x Specific gravity / osmolality x Blood 

x pH x Urobilinogen

x Protein

x – measured parameter

Table 3. Hematology parameters measured for rats in 90-day inhalation study with HFE-347pcf2

x Hematocrit (HCT) x Leukocyte differential count

x Hemoglobin (HGB) x Mean corpuscular HGB (MCH)

x Leukocyte count (WBC) x Mean corpusc. HGB conc. (MCHC)

x Erythrocyte count (RBC) x Mean corpusc. volume (MCV)

x Blood clotting measurements x Reticulocyte count

(Activated Partial Thromboplastin time) x Platelet count

(Prothrombin time)

x – measured parameter

Table 4. Clinical Chemistry parameters measured in 90-day inhalation study with HFE-347pcf2

ELECTROLYTES OTHER

x Calcium (Ca) x Albumin 

x Chloride (Cl) x Creatinine

x Phosphorus (P) x Urea

x Potassium (K) x Urea nitrogen 

x Sodium (Na) x Albumin/globulin ratio

x Cholesterol

ENZYMES x Glucose

x Alkaline phosphatase (AP) x Total bilirubin 

x Creatine kinase activity x Total protein (TP)

x Alanine aminotransferase (ALT/also SGPT) x Triglycerides

x Aspartate aminotransferase (AST/also SGOT) x Phospholipids

x Gamma glutamyl transferase (GGT)

x – measured parameter

Select organs (detailed in Table 5) were weighed and/or examined microscopically.

Mortality, Clinical Effects, Eye Effects, Food Consumption, Body Weights

There were no reported mortalities or adverse clinical effects noted during the exposure or 

immediate post-exposure intervals. Ophthalmoscopy revealed no adverse exposure-related 

effects on the eyes of the control or 1000-ppm exposure groups at week 13. 

No exposure-related effects in food consumption were noted throughout the study; any changes 

in food consumption were minor and transient. Differences in body weights between the 
***** Final - July 30, 2012 *****

22

controls and low and mid-concentration males, while statistically significant, were not 

considered treatment-related as a dose-response relationship was absent. Body weights for highconcentration females were statistically lower compared with controls during weeks 5, 6, 12, and 

14 (maximum difference, 5%) and in weeks 4 and 6 of the recovery group (maximum difference, 

6%). However, these effects were small and inconsistent and therefore not considered adverse.

Table 5. Weighed and/or microscopically examined rat organs in 90-day inhalation study with

 HFE-347pcf2

DIGESTIVE SYSTEM CARDIOVASC./HEMAT. NEUROLOGIC

x Oral cavity (store) x Aorta x# Brain (medulla pons, cerebellum 

cortex, and cerebral cortex)

x Salivary glands x# Heart x Sciatic nerve

x Esophagus x Bone (femur including joint) x Spinal cord (3 levels)

x Stomach x Lymph nodes (cervical and 

mesenteric)

x# Pituitary

x Duodenum x Peyer’s patches x Eyes (retina and optic nerve )

x Jejunum x# Spleen GLANDULAR

x Ileum x# Thymus x# Adrenal gland

x Cecum x Lacrimal gland

x Colon UROGENITAL x Parathyroid

x Rectum x# Kidneys x# Thyroid

x# Liver x Urinary bladder x Harderian gland

x Pancreas x# Testes

x# Epididymides OTHER

x Prostate x Bone (sternum with bone marrow) 

RESPIRATORY x Seminal vesicles x Voluntary muscle

x*# Lung x Ovaries x Skin (right flank)

x*# Trachea x# Uterus x* All gross lesions and masses

x Nasopharynx x Mammary gland

x Pharynx x Cervix

x Larynx x Vagina

x- Histological examination for control and high dose groups

*- Histological examination for low and mid-dose groups

#- Weighed for all dose groups

Functional Observational Battery

No treatment-related effects were reported from the FOB. Small differences in the landing foot 

splay of mid-concentration males, motor activity measurements in low- and mid-concentration 

males, and motor activity of high-concentration females compared with controls were observed 

during one to three isolated time intervals; however the differences were not exposure-related 

and not considered biologically relevant.

Hematology/Clinical Chemistry

The study author reported that the neutrophil count was higher in high-concentrations males at 

14 weeks but the mean values were within the historical mean values for the testing laboratory. 

At 14 weeks, reticuloytes and prothrombin time were elevated for high-concentration females 

compared with controls while white blood cells, neutrophils, monocytes, and basophil counts 

were reduced for mid-concentration females. These changes were not considered to be treatment 

related due to the lack of a dose-response. Recovery group high-concentration males had 
***** Final - July 30, 2012 *****

23

increased red blood cells and reduced mean cell volume, neutrophils, white blood cells and 

monocytes compared with controls. There were no statistically significant differences in 

reticulocyte and prothrombin time in recovery group high-concentration females compared with 

controls indicating that changes seen at 14 weeks were reversible by 18 weeks. Mean cell 

hemoglobin and mean cell hemoglobin concentrations were also increased in 1000-ppm recovery

females. The study author stated that none of the effects reported at 18 weeks were of 

hematological or toxicological significance. 

No treatment-related effects were reported in clinical chemistry parameters at week 14. Small 

differences in glucose (mid-concentration females) and cholesterol (mid-concentration males) 

were not dose-related and therefore not considered biologically relevant. Mean reduced plasma 

GGT activity in 1000-ppm males during the recovery period was attributed to the influence of a 

single high value in a control male rat and a single low value in an exposed male rat. Reanalysis 

of the 1000-ppm male GGT results excluding the outlier data still showed lower values; however 

this finding was not statistically significant and not toxicologically relevant. Mean increased 

plasma transaminase activity was seen in 1000-ppm recovery females. Slight changes in reduced 

urine volume and specific gravity in 1000-ppm males in recovery group were small and not 

considered of toxicological significance.

Organ Weights

Spleen weights were lower for 1000-ppm males; this effect was attributed to a single high spleen 

weight for a control animal. Thymus weights were increased in all HFE-347pcf2 treated females; 

however the study author attributed these findings to a low control mean and noted that all 

treatment groups fell within the historical control data range. Absolute weights for adrenal gland, 

kidney and liver were decreased for 1000-ppm females. Absolute thymus weights were reduced 

in 1000-ppm recovery females. Relative organ weights in these females were not affected by 

exposure. 

Macroscopic and Microscopic findings

There were several small lesions observed, none of which were treatment-related. There was a 

minimal increase (3/10 compared with 0/10 in controls) in the incidence of eosinophilic casts in 

the kidneys of males at 1000 ppm in addition to a decreased incidence of tubular basophilia in 

the kidney; the study authors reported that both changes were considered to be unrelated to 

treatment.

V. Detailed Discussion of Supporting Studies for HFE-347pcf2

Acute oral study

Following a single oral gavage dose of 2000 mg/kg bw of HFE-347pcf2 (purity 99.9%) to 

Crj:CD(SD) rats (5M/5F), no mortality or abnormal clinical signs of toxicity were noted within 

14 days of dosing (Hita Research Laboratories,1993(a)). The LD50 was reported as > 2000 

mg/kg bw.

Four-week oral study

HFE-347pcf2 (purity 99.82%) was administered via oral gavage to Crj:CDCSD(IGS) rats at 

doses of 0, 10, 100, or 1000 mg/kg for 28 days (Nippon Experimental Research Institute Co. 
***** Final - July 30, 2012 *****

24

Ltd., 2000). Control group and 1000-mg/kg group animals were then maintained and observed 

for a 14-day recovery period. Ten male and female rats were used for the control and 1000-

mg/kg groups; five male and female rats were used for the 10- and 100-mg/kg dose groups, 

respectively. Clinical observations were made once daily during the study. Body weights were 

recorded prior to study initiation and then weekly thereafter. Food and water consumption were 

calculated weekly. Ophthalmoscopy measurements were made prior to study initiation, during 

week 4 of the exposure period, and during week 2 of the recovery period. Urine samples were 

collected at study termination and recovery period termination. Prior to scheduled necropsy, 

blood samples were obtained from the abdominal aorta while the animals were under anesthesia. 

Selected organs were weighed: brain, liver, kidneys, spleen, adrenals, testes, prostate, ovaries, 

and uterus. Selected tissues12 were examined microscopically.

No mortalities were observed during the study. Salivation was seen sporadically after the first 9 

days of exposure. Significantly decreased activated partial thromboplatin time and decreased 

triglyceride were observed. In the absence of histopathologically related changes in the liver, 

these changes were not considered toxicologically relevant. Decreased reticulocytes and 

increased total cholesterol were not dose-related, and therefore not considered treatment-related. 

A slightly decreased eosinophil ratio was also not considered treatment-related. Significantly 

reduced weight of right adrenal was not dose-dependent and no change in relative weight was 

noted. No changes in body weight, food consumption, water intake, ophthalmoscopy, urinalysis, 

necropsy, or histopathology were observed. The NOAEL was reported as 1000 mg/kg bw.

Genotoxicity 

HFE-347pcf2 was tested in an Ames bacterial reversion assay in Salmonella typhimurium (S. 

typhimurium) strains TA98, TA100, TA1535, TA1537, and E. coli strain WP2 uvrA (measuring 

either base pair or frame shift mutations) in the presence and absence of S9 fraction from 

induced rat livers (metabolizing enzymes including mixed function oxidases) at concentrations 

ranging from 313 to 10,0000 μg/plate (Hita Research Laboratories, 1993(b)). Appropriate 

negative and positive controls were analyzed in the same assays. The number of mutants induced 

by HFE-347pcf2 did not reach the criteria for a positive response in this assay indicating that 

HFE-347pcf2 does not cause either base pair exchange mutations or frame-shift mutations in 

bacterial cells either in the presence or absence of activating enzymes.

HFE-347pcf2 was tested in a chromosomal aberration assay with Chinese hamster lung cells 

(CHL/IU) (BML, Inc., 1999). Cells were treated with HFE-347pcf2 for 6 hours at doses of 1.25, 

2.5, or 5.0 mg/L in the presence and absence of metabolic activation. Longer-term exposures (24 

and 48 hours) were also conducted. In all experiments, cells treated with HFE-347pcf2 did not 

cause an increase in the frequency of cells exhibiting structural chromosomal aberrations 

compared with negative controls at any dose tested.

Skin irritation, eye irritation, and dermal sensitization 

 

12 Selected tissues include: brain, pituitary, thyroid gland and parathyroid gland, thymus, salivary gland, heart, 

trachea and lungs, liver, stomach, duodenum, kidneys, spleen, adrenals, testes, prostate, epididymis, seminal 

vesicles, ovaries, uterus, urinary bladder, bone and bone marrow, eyeballs, Harderian gland and all organs and 

tissues with macroscopic abnormalities.
***** Final - July 30, 2012 *****

25

HFE-347pcf2 was evaluated for skin irritation, eye irritation, and dermal sensitisation potential 

according to harmonized standards. All test results were negative; therefore HFE-347pcf2 is not 

considered to be a dermal irritant, an ocular irritant, or a dermal sensitizer. 

Following administration of 0.5 ml AEL-3000 (purity not reported) to the intact skin of 3 male 

rabbits for four hours via a semi-occluded patch, no evidence of erythema or edema was 

observed within 72 hours of exposure (Safepharm Laboratories Limited, 2003(a)).

Following administration of 0.1 ml HFE-347pcf2 (purity not reported) to one eye of each of 

three male rabbits, moderate conjunctivae was observed in all rabbits 1 hour after treatment. 

Minimal conjunctivae (redness) was reported in one rabbit 24 hours post-treatment with signs of 

redness being resolved in all rabbits by 48 hours. HFE-347pcf2 was classified as a minimal eye 

irritant according to the modified Kay and Calandra rating system (Safepharm Laboratories 

Limited, 2003(b)). 

In a local lymph node assay (an assay which determines dermal sensitisation potential by

measuring the levels of T lymphocyte proliferation in the lymph node draining the site of 

application), 25 ul of HFE-347pcf2 (purity 99.99%) was applied to 4 female mice at doses of 25, 

50 or 100% w/v preparations in acetone (Syngenta Central Toxicology Laboratory, 2005). A 

vehicle control group was similarly treated using acetone alone. HFE-347pcf2 did not produce a 

greater than 3-fold increase in 3H-thymidine incorporation at any concentration tested and was 

therefore not considered a potential dermal sensitizer. 
***** Final - July 30, 2012 *****

26

VI. References

BML, Inc. (Section of Safety Division of Cell Biology) 1999. In vitro chromosome aberration 

test in cultured mammalian cells with 1,1,2,2- tetrafluorethyl-2,2,2-trifluoroethyl. Study number 

6174. January 27, 1999.

Central Toxicology Laboratory 2005. HFE-347PC-F: 90 day inhalation toxicity study in the rat 

with recovery period. Report No.: CTOL/PR1302/Regulatory/Report. January 24, 2005.

EPA 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of 

Inhalation Dosimetry. EPA/600/8-90/066F. Office of Research and Development, Washington, 

DC. October 1994.

Hita Research Laboratories 1993(a). Acute oral toxicity of E347-pc-fm in rats. Report No. D3365. March 22, 1993. 

Hita Research Laboratories 1993(b). Mutagenicity test of E347-pc-fm using microorganisms. 

Report No. T-3349. March 30, 1993.

Mitsubishi Chemical Safety Institute Ltd., 2000. Twenty-eight day repeated inhalation toxicity

study of 1,1,2,2- tetrafluorethyl-1-(2,2,2-trifluoroethoxy)ethane in rats. Study No. 9L939. July

25, 2000.

Mitsubishi-Kasei Institute of Toxicological and Environmental Sciences 1994. A simplified 

acute toxicity study of 1,1,2,2- tetrafluorethyl-2,2,2-trifluoroethyl by nose only inhalation 

exposure in rats. Study No.: 3L316-6. January 4, 1994.

Nippon Experimental Research Institute Co. Ltd. 2000. A 28-day repeated dose toxicity study of 

HFE-347-pc-f in mammals. May 8, 2000.

Safepharm Laboratories Limited 2003(a). 2,2,2- trifluoroethyl-1,1,2,2- tetrafluorethyl-ether 

(CAS 406-78-0) Acute dermal irritation in the rabbit. SPL Project number 1458/013. February

27, 2003.

Safepharm Laboratories Limited 2003(b). 2,2,2- trifluoroethyl-1,1,2,2- tetrafluorethyl-ether 

(CAS 406-78-0) Acute eye irritation in the rabbit. SPL Project number 1458/014.

February 27, 2003.

Syngenta Central Toxicology Laboratory 2005. HFE-347PC-F: Local Lymph Node Assay. 

Report No.: GM7907-REG. October 27, 2005.

WIL Research Laboratories 2008. A 5-day repeated-dose inhalation toxicity study of Asahiklin 

HFE-347pcf2 in Sprague-Dawley rat. Study No. WIL-534011. May 14, 2008.

WIL Research Laboratories 2009. A 28-day inhalation combined toxicity and neurotoxicity

study of Asahiklin HFE-347pcf2 in Sprague-Dawley rats. Study number WIL-534015. 

September 24, 2009.