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)

[a]Note 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 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.

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
                                    540[b]
                                    7.1[c]
                                    CFC-113
                                    0.85[e]
                                    6130[d]
                                     85[e]
                                      MCF
                                    0.16[e]
                                    146[d]
                                     5[e]
                                   HCFC-141b
                                   0.12 [e]
                                    725[d]
                                    9.2[e]
                                  HCFC-225ca
                                    0.02[f]
                                    122[d]
                                    1.9[e]
                                  HCFC-225cb
                                    0.03[f]
                                    595[d]
                                    5.9[e]
[a] HFE-347pcf2 SNAP Submission (AGC Chemicals Americas, Inc.,  2005)
b IPCC/TEAP (2005)
cTokuhashi et al (2000)
[d] IPCC (2007)
[e]WMO (2011)
[f] WMO (2007)

4.	FLAMMABILITY ASSESSMENT

HFE-347pcf2 was tested for flammability according to the ASTM E681 method and was found to be non-flammable (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 ppm, 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.
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 end-use; 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.

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
         [a]An 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.

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 total[a]
                              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 ft[2] area around the face of worker)
                           Ventilation/Air Flow Rate
No mechanical ventilation present; Air flow rate is equal to 450 ft[3]/min or 12.7 m[3]/min (50 ft/min over 9 ft[2] 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
                                     24.45

                                       g

                                    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 (m[3]/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 HFE-347pcf2 [454 gram aerosol can containing 90% HFE-347pcf2 dispensed over 30-minutes].Table 7 shows the results of this analysis.

            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, 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 HFE-347pcf2/100g water at 25C), 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 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 HFE-347pcf2 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%, is expected to escape from the control technologies (freeboard and 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 HFE-347pcf2 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[-][4] percent of the VOC emissions from the solvent sector in the United States would be released, or only approximately 3.7x10[-][5] percent of all anthropogenic VOC emissions in the U.S.

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% 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[-][3] percent of the VOC emissions from the solvent sector in the United States would be emitted, or only approximately 2.8x10[-][4] percent 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.

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 HCFC-225 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.

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.

                                 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
NOAEC:
1000 ppm
NOAEC [HEC]:
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

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 HFE-347pcf2.

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.

Table 1: Summary of Toxicological Studies for HFE-347pcf2
Inhalation Studies
                                     Doses
                                NOAEL/ NOAEC[a]
                                    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 treatment-related 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 treatment-related effects reported.
In vitro bacterial reverse mutation assay
                     Max concentration of 10,000 ug/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 ul  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)

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-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.  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

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 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 tissues 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.

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 tissues 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 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).

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 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 high-concentration 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 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. 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 tissues 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 ug/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
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 [3]H-thymidine incorporation at any concentration tested and was therefore not considered a potential dermal sensitizer.

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. D-3365. 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.


[Federal Register: February 9, 2006 (Volume 71, Number 27)]
[Notices]
[Page 6797]
[DOCID:fr09fe06-85]

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SECURITIES AND EXCHANGE COMMISSION

Submission for OMB Review; Comment Request

Upon Written Request, Copies Available From: Securities and Exchange
Commission, Office of Filings and Information Services, Washington, DC
20549.

Extension:
    Form N-54A; SEC File No. 270-182; OMB Control No. 3235-0237.

    Notice is hereby given that, pursuant to the Paperwork Reduction
Act of 1995 [44 U.S.C. 3501 et seq.] (the ``PRA''), the Securities and
Exchange Commission (``Commission'') has submitted to the Office of
Management and Budget (``OMB'') a request for extension of the
previously approved collection of information discussed below.
     Form N-54A under the Investment Company Act of 1940;
Notification of Election to be Subject to Sections 55 through 65 of the
Investment Company Act of 1940 Filed Pursuant to Section 54(a) of the
Act.
    Form N-54A [17 CFR 274.53] is the notification to the Commission of
election to be regulated as a business development company. A company
making such an election only has to file a Form N-54A once.
    It is estimated that approximately 46 respondents per year file
with the Commission a Form N-54A. Form N-54A requires approximately 0.5
burden hours per response resulting from creating and filing the
information required by the Form. The total burden hours for Form N-54A
would be 23.0 hours per year in the aggregate. The estimated annual
burden of 23.0 hours represents an increase of 21.0 hours over the
prior estimate of 2.0 hours. The increase in burden hours is
attributable to an increase in the number of respondents from 4 to 46.
    The estimate of average burden hours for Form N-54A is made solely
for the purposes of the PRA and is not derived from a comprehensive or
even representative survey or study of the cost of Commission rules and
forms.
    The collection of information under Form N-54A is mandatory. The
information provided by the Form is not kept confidential. An agency
may not conduct or sponsor, and a person is not required to respond to,
a collection of information unless it displays a currently valid
control number.
    General comments regarding the above information should be directed
to the following persons: (i) Desk Officer for the Securities and
Exchange Commission, Office of Information and Regulatory Affairs,
Office of Management and Budget, Room 10102, New Executive Office
Building, Washington, DC 20503, or e-mail to:
<EMAIL_ADDRESS>and (ii) R. Corey Booth, Director/Chief

Information Officer, Office of Information Technology, Securities and
Exchange Commission, 100 F Street, NE., Washington, DC 20549. Comments
must be submitted to OMB within 30 days of this notice.

     January 30, 2006.
Nancy M. Morris,
Secretary.
 [FR Doc. E6-1781 Filed 2-8-06; 8:45 am]

BILLING CODE 8010-01-P


[Federal Register Volume 78, Number 52 (Monday, March 18, 2013)]
[Notices]
[Pages 16676-16678]
[FR Doc No: 2013-06128]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-D-0194]

Agency Information Collection Activities; Proposed Collection;
Comment Request; Draft Guidance for Industry and FDA Staff; Total
Product Life Cycle: Infusion Pump--Premarket Notification [510(k)]
Submissions

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the Agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal Agencies are required to publish notice in the
Federal Register concerning each proposed collection of information and
to allow 60 days for public comment in response to the notice. This
notice solicits comments on ``Guidance for Industry and FDA Staff;
Total Product Life Cycle: Infusion Pump--Premarket Notification
[510(k)] Submissions.''

DATES: Submit either electronic or written comments on the collection
of information by May 17, 2013.

ADDRESSES: Submit electronic comments on the collection of information
to http://www.regulations.gov. Submit written comments on the
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. All comments should be identified with the docket
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Daniel Gittleson, Office of
Information Management, Food and Drug Administration, 1350 Piccard Dr.,
PI50-400B, Rockville, MD 20850,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
Agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.

``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal Agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information before
submitting the collection to OMB for approval. To comply with this
requirement, FDA is publishing notice of the proposed collection of
information set forth in this document.
    With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.

Draft Guidance for Industry and FDA Staff; Total Product Life Cycle:
Infusion Pump--Premarket Notification [510(k)] Submissions--0910-NEW

    This draft guidance is intended to assist industry in preparing
premarket notification submissions for infusion pumps and to identify
device features that manufactures should address throughout the total
product life cycle. The draft guidance is available at (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm206153.htm).
    In the Federal Register of March 26, 2010 (75 FR 21632), FDA
published a notice seeking comment on the proposed information
collection activity. Given the lapse in time since its publication, FDA
is reissuing this notice, responding to a single comment and providing
the public and additional opportunity to comment on this proposed
information collection activity, prior to the issuance of the final
guidance document.
    In the March 26, 2010, notice, the FDA estimated ``it will receive
31 infusion pump submissions annually. The Agency reached this estimate
by averaging the number of premarket notifications for infusion pumps
submitted to FDA over the past 5 years. The draft guidance identifies
56 potential hazards FDA recommends addressing if applicable to a
particular device. Although there may be additional hazards identified
by a manufacturer, the Agency believes these hazards may offset FDA
identified hazards not applicable to a particular device. FDA estimates
it will take infusion pump manufactures approximately 56 hours
(approximately 1 hour per hazard) to complete the case assurance report
described in section 6 of the draft guidance. FDA reached this estimate
based on its expectation of the amount of information that will be
contained in the report.''
    However, based on a single public comment provided to FDA, related
to the FDA burden estimate, we are adjusting the burden associated with
this collection. The public comment is summarized as follows: It will
take significantly longer than one hour to conduct assurance case
reports for each of the 56 potential hazards identified * * * . For
instance, due to the iterative nature of the assurance case report
process, each of the applicable hazards will need to be re-evaluated at
multiple stages of the development process. In addition, it will be
difficult to estimate the time required to conduct an assurance case
report without specific guidance on the assurance case reports.
    While the commenter believes the reporting burden is greater than 1
hour, and FDA agrees, it is also important to note that the burden
associated with this new recommendation to present data is the time and
effort necessary to comply with submitting a new 510(k) or 510(k)
supplements for legally marketed infusion pumps for which no assurance
case exists. The Agency has revised the burden estimate, by averaging
the number of premarket notifications for infusion pumps submitted to
FDA over the past 5 years. The draft guidance identifies 56 potential
hazards FDA recommends addressing if applicable to a particular device.
Although there may be additional hazards identified by a manufacturer,
the Agency believes the reporting of these hazards may be offset by FDA
identified hazards not applicable to a particular device. FDA has
revised the estimate of time it will take infusion pump manufactures
from approximately 56 hours to 112 hours (approximately 2 hours per
hazard) to submit the case assurance report described in section 6 of
the draft guidance. FDA reached this estimate based on its expectation
of the amount of information that will be contained in the report and
the public comment received.
    The respondents to this collection of information are infusion pump
manufacturers subject to FDA's laws and regulations.
    The Agency estimates the burden of this collection of information
as follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
   Guidance title: Infusion pumps--premarket notification 510(k)        Number of      responses per     Total annual   Average  burden    Total hours
                            submissions                                respondents       respondent       responses      per  response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Guidance Section 6--Assurance Case Report..........................              31                1               31              112            3,472
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    The premarket notification procedures discussed in the draft
guidance (21 CFR 807, subpart E) have been approved under OMB control
number 0910-0120. The proposed information collection seeks to add
clinical or scientific data demonstrating that new or changed infusion
pumps are as safe and effective as those legally marketed and do not
raise different questions of safety and effectiveness than predicate
devices in this generic device type. In this way manufacturers of
infusion pumps may demonstrate substantial equivalence and receive
premarket clearance for their devices.
    This draft guidance also refers to previously approved information
collections found in FDA regulations. The collections of information in
21 CFR part 803 are approved under OMB control number 0910-0437; the
collections of information in 21 CFR part 801 are approved under OMB
control number 0910-0485; the collections of information in 21 CFR part
812 are approved under OMB control number 0910-0078; the collections of
information in 21 CFR part 814, subparts B and E are approved

under OMB control number 0910-0231; the collections of information in
21 CFR part 820 are approved under OMB control number 0910-0073; the
collections of information in 21 CFR part 822 are under OMB control
number 0910-0449; and the collections of information in 21 CFR 56.115
are approved under OMB control number 0910-0130.

    Dated: March 12, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-06128 Filed 3-15-13; 8:45 am]
BILLING CODE 4160-01-P