***** FINAL May 1, 2013 ***** 1 

## Significant New Alternatives Policy Program Solvent Cleaning Sector Risk Screen on Substitute for CFC
- 113, M ethyl C hloroform , and HCFC
- 225cc/cb for Electronics , Precision , and M etals Cleaning Substitute: T rans - 1
- chloro
- 3,3,3
- trifluoroprop
- 1
- ene ( SolsticeTM 1233zd(E))

This risk screen does not contain Clean Air Act (CAA) Confidential Business Information (CBI) and, therefore, may 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 (CAA A). 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 o n assessment of their health and environmental impacts. EPA’s decision on the acceptability of a substitute is based on the findings of a screening assessment of potential human health and environmental risks posed by the substitute in specific applicati ons. 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 sector (EPA 1994) (hereina fter referred to as the Background Document). This risk screen evaluates the potential use of trans

- 1

- chloro

- 3,3,3

- trifluoroprop

- 1

- ene (hereafter referred to as SolsticeTM 1233zd(E) ) as a substitute for CFC

- 113, methyl chloroform (commonly also referred to as 1,1,1

- trichloroethane, TCA, or MCF), and HCFC

- 225ca/cb , as a solvent for electronics , precision cleaning and metals cleaning (e.g., vapor degreasing and defluxing and flushing) end

- uses
. Table 1 presents information on the proposed substitute. Table 1 . Composition of SolsticeTM 1233zd(E)
Constituent Chemical Formula CAS Number Percent of Total (by weight) a tra n s

- 1

-

Chloro

- 3,3,3

- trifluoroprop

- 1

-

ene C 3 H 2 ClF 3 102687

- 65

- 0 >99% Potential Impurities (maximum concentration)***** FINAL May 1, 2013 ***** 2 The potential risks associ ated with use of substitutes as solvents 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 sc reen addresses flammability risk, and an occupational exposure assessment was performed to ensure that manufacture and disposal of the proposed substitute in the solvent end

- use do es not pose unacceptable risk to workers. Modeling was performed at the end

- use to examine potential exposures for those using SolsticeTM 1233zd(E) for the intended application. Lastly, a general population exposure assessment was performed to ensure that the proposed substitute would not pose an unacceptable risk to the populatio n at large. Section 2 of this report summarizes the results of the risk screen for the proposed substitute. The remainder of the report is organized into the following sections:

• Section 3 : Atmospheric Assessment

• Section 4 : Flammability Assessment

• Secti on 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 SolsticeTM 1233zd(E) is re co mmended for SNAP approval as a solvent in the electronics , precision , and metals cleaning end

- uses
. EPA's risk screen indicates that the use of the proposed substitute will be less harmful to the atmosph ere than the continued use of CFC

- 113, MCF, and HCFC

- 225ca/cb. Given that proper training will be given to personnel ; appropriate personal protective equipment (PPE) ( e.g., respiratory protection, goggles, impervious gloves, chemical

- resistant clothing and boots) according to Section VIII of the Occupational Safety & Health Administration ( OSHA ) Technical Manual (OSHA 1994) are available; and proper procedures according to the MSDS (including provisions of adequate ventilation) will be used during manufacturing, end

- use, and disposal , no significant toxicity risk to workers, end

- users, or the general population is anticipated. In addition, based on characterist ics of the proposed substitute and precautions listed in the MSDS for SolsticeTM 1233zd(E), the proposed substitute is not expected to present a significant flammability concern during manufacture or end

- use. 

### 3. ATMOSPHERIC ASSESSMENT This section presents an assessment of the potential risks to atmospheric integrity posed by the use of SolsticeTM 1233zd(E) in the solvent sector. The ozone depletion potential (ODP), global warming potential (GWP), and atmospheric lifetime (ALT) of the proposed substitute ar e presented in Table 2 . As compared to CFC

- 11 3 , MCF, and HCFC

- 225ca/cb , SolsticeTM 1233zd(E) is substantially less harmful to the ozone layer, has less climate impact, and a shorter atmospheric lifetime. SolsticeTM 1233zd(E) does however, have a non

- zero ODP, but at 0.00024 to 0.00034 , this value is very small when conside ring continued used of HC FC

- 225ca/cb

. A recent report by Wang et al. (2011) modeled the potential of SolsticeTM 1233zd(E) to affect the amount of ozone in the global atmosphere. This report found that the release of all SolsticeTM 1233zd(E) , assuming it were substituted for all comp ounds it might replace and that the entire amount used were released, would have a statistically zero impact on global atmospheric ozone (less than 0.01% change in total column ozone). Thus, EPA believes that use of SolsticeTM 1233zd(E) would result in subs tantially less harm to the climate and ozone layer than the continued use of ozone
- depleting substances.***** FINAL May 1, 2013 ***** 3 Table 2 . Atmospheric Impacts of SolsticeTM 1233zd(E) Compared to Other S olvents Refrigerant ODP GWP ALT SolsticeTM 1233zd(E) 0.00024

- 0.00034 a ,c 4.7

- 7 a, b 26 days c CFC

- 11 3 0.85 d 6,130 e 85 years d HCFC

- 225ca 0. 02 d 122 e 1.9 years d HCFC

- 225cb 0. 03 d 595 e 5.9 years d Methyl Chloroform 0.16 d 146 e 5 years d

a Assuming emissions occur in the major regions of the world where blowing agents that SolsticeTM 1233zd(E) might replace are significantly used. Wang et al. (undated). b Wang et. al. (2011)
c SolsticeTM 1233zd(E) SNAP Submission ( Anonymous Submitter 2011b ) d WMO (2011)
e IPCC 4 th Assessment Report (Forster et al. 2007)


### 4. FLAMMABILITY ASSESSMENT SolsticeTM 1233zd(E) is not flammable at ambient temperatures and atmospheric pressure, but can ignite when mixed with air under pressure and exposed to strong ignition sources ( Anonymous Submitter 2011b). In accordance with the MSDS, SolsticeTM 1233zd(E) is to be kept away fr om all sources of ignition and high heat. Because proper precautions specified by the proposed substitute’s MSDS are followed, SolsticeTM 1233zd(E) does not pose a significant flammability risk. 

### 5
. POTENTIAL HEALTH EFFECTS To assess potential health risks from exposure to this proposed substitute, the submitter developed an acceptable exposure limit (AEL) of 300 ppm 1 for SolsticeTM 1233zd(E) ( Anonymous Submitter 2012). The AEL represents the maximum 8

- hour time weighted average (TWA) at which a worker can be exposed regularly without adverse effects. EPA also developed a short

- term exposure limit (STEL) of 9 00 ppm over a 15

- minute period, based on the submitter’s 300 ppm AEL value. 2 According to the MSDS, exposure to SolsticeTM 1233zd(E) may be harmful by ocular or dermal absorption, inhalation, or ingestion. Exposures of SolsticeTM 1233zd(E) to the eyes will cause serious eye irritation and may cause frostbite. In case of ocular exposure, the MSDS for SolsticeTM 1233zd(E) recommends that person(s) should immediately flush the eyes, including under the eyelids, with water for 15 minutes; should frostbite occur, the water should be lukewarm, not hot. Medical attention should be sought if irritation develops or persists. Exposures of SolsticeTM 1233zd(E) to the skin may cause irritation or frostbite. In the case of dermal exposure, the MSDS for SolsticeTM 1233zd(E) recommends that person(s) should immediately wash the aff ected area with water and remove all contaminated clothing; should frostbite occur, person(s) should bathe (not rub) the affected area with lukewarm, not hot, water. If water is not available, cover the affected area with a clean, soft cloth. Medical atten tion should be sought if irritation develops or persists. SolsticeTM 1233zd(E) vapors are heavier than air and can cause suffocation by reducing oxygen available for breathing, causing asphyxiation at high concentrations. If person(s) are exposed to high c oncentrations, the person(s) will likely not realize that he/she is suffocating, but may experience central nervous system effects, such as drowsiness and dizziness. If SolsticeTM 1233zd(E) is inhaled, person(s) should be immediately removed and exposed to fresh air. The MSDS recommends that if breathing is difficult, person(s) should be given oxygen, provided a qualified

1 An AEL of 1,000 ppm was independently developed for SolsticeTM 1233zd(E) based on review of available toxicity studies (see Appendix A). However, as the AEL value of 300 ppm determined by the submitter is more conservative, for purposes of this risk screen, 300 ppm was used to evaluate the potential exposures. 2 STEL was estimated as three to five times the AEL, which is an established method of estimating a short

- term exposu re by the American Conference of Governmental Industrial Hygienists . [STEL] = [AEL] x 3 = 300 ppm x 3 = 9 00 ppm.***** FINAL May 1, 2013 ***** 4 operator is present, and medical attention be sought. SolsticeTM 1233zd(E) is not likely to be hazardous by ingestion; however, in case of ingestion, the MSDS recommends providing the person(s) with a cup of water, if fully conscious, consulting a physician immediately, and to not induce vomiting without medical advice. EPA’s review of the human health impacts of this proposed substitute is contained in the public docket for this decision.
When good industrial hygiene practices and the PPE and engineering control (e.g., ventilation) recommendations outlined in the MSDS for SolsticeTM 1233zd(E) , as summarized in Sections 6 and 7 of this risk screen , are followed, these potential health effects are unlikely to occur. 

### 6. OCCUPATIONAL EXPOSURE ASSESSMENT AT MANUFACTURE Occupational exposure to SolsticeTM 1233zd(E) may occur during manufacture of the proposed substitute as a solvent

. For electronics and precision cleaning, SolsticeTM 1233zd(E) will be used primarily for degreasing carried out in an enclosed vapor degreaser. For metals cleaning, SolsticeTM 1233zd(E) is expected to be used as a flushing agent , and may also be used for degreasing

. Flush ing solvent can be dispensed from a self

- contained unit (e.g., an aerosol can), pressurized cylinder, or tank. As indicated by the submitter, occupational exposure will vary depending on the type of equipment being used, nature of the operation, and other factors such as the degree of ventilation

. For use of SolsticeTM1233zd(E) as a degreas ing solvent in enclosed vapor degreasing units, occupational exposure during manufacture is not expected, as filling occurs at the end

- use, as summarized in Section 7.
T he submitter indicates that aerosol can filling operations , including those for use of SolsticeTM 1233zd(E) as a flushing agent , are highly automated and involve little or no direct contact with the components charged in to the can. Actual monitoring data for manufacture of SolsticeTM 1233zd(E) aerosol cans are not available; however, the submitter measured the loss rate of SolsticeTM 1233zd(E) from an open (i.e., uncapped) aerosol can at room temperature to be 0.5 grams per minute and that a medium

- speed aerosol line fills between 150 to 250 cans per minute.
C oncentrations are expected to be well below the AEL (300 ppm) for SolsticeTM 1233zd(E ) , and the manufactur ing process is highly automated with minimal emissions anticipated . Thus , exposure during the manufacture of aerosol cans for flushing is not expected to present a significant toxicity concern to workers. See the risk screen for Solsti ceTM 1233zd(E) in aerosol solvents for more detailed information (document EPA

- HQ

- OAR

- 2003

- 0118

- 0316). For engineering control and PPE recommendations, the proposed substitute’s MSDS and OSHA guidelines (OSHA 1994) should be referenced

. Adequate ventilatio n should always be established during any handling, or storage of SolsticeTM 1233zd(E) . Engineering controls should include vapor

- in air detection systems and local exhaust ventilation during use of SolsticeTM 1233zd(E) , and filling operations for vapor degr easing units are to occur only at stations with exhaust ventilation facilities. In addition, an eye wash and safety shower should be near the manufacturing facility and ready for use. In general, use of PPE is recommended, such as respiratory protection (a NIOSH

- approved positive

- pressure supplied

- air respirator is recommended where there is insufficient ventilation; self

- contained breathing apparatuses should be used for rescue and maintenance work in storage tanks), chemical splash goggles or face shield, impervious gloves, and chemical

- resistant boots and clothin g consistent with OSHA guidelines ( Anonymous Submitter 2011b, OSHA 1994). Contaminated clothing is not to leave the workplace and must be cleaned before reuse ( Anonymous Submitter 2011b). Because these PPE and ventilation requirements are followed, the risk of exposure to SolsticeTM 1233zd(E) is unlikely to pose a risk to workers during manufacture.***** FINAL May 1, 2013 ***** 5 In addition, there is a risk of generation of toxic decomposition products such as hydrogen fluoride , hydrogen chloride, carbonyl halides, carbon monoxide, and carbon dioxide when SolsticeTM 1233zd(E) is exposed to fire. Containers of SolsticeTM 1233zd(E) should not be allowed to contact open flames, glowing metal surfaces, or electrical heating elements. Because proper handling and disposal guidelines are followed in accordance with good industrial hygiene and manufacturing practices and the MSDS for SolsticeTM 1233zd(E) , there is no significant risk to workers during the manufacture of SolsticeTM 1233zd(E)

. 

### 7. END
- USE EXPOSURE ASSESSMENT SolsticeTM 1233zd(E) is proposed for use as a solvent for electronics , precision, and metals cleaning end

uses; SolsticeTM 1233zd(E) is not intended to be used for residential or direct consumer use. For electronics and precision cleaning, SolsticeTM 1233zd(E) will be used for degreasing , which will typically be performed in an enclosed vapor degreaser , rather than an open

- top vapor deg reaser . A degreaser is a rectangular unit containing one or more sumps which are filled with solvent. One of the sumps is heated to boil the solvent and generate a layer of solvent vapor above the liquid. Degreasers are fitted with cooling coils around the upper perimeter of the sidewalls to condense solvent vapors, maintain the vapor zone, and minimize emissions. Dirty parts are immersed in the liquid sumps and then raised into the vapor zone where solvent vapors give a final rinse before the parts are rem oved from the unit. In flushing applications for metals and precision cleaning , solvent is forced through a part or device to remove contaminants. SolsticeTM 1233zd(E) will be most likely be used to flush refrigeration systems and gauges, lines, and regulat ors of oxygen

- handling equipment. For use of SolsticeTM 1233zd(E) as a degreasing solvent in enclosed vapor degreasing units, occupational exposure during manufacture will be limited to the filling of containers of solvent and filling of degreasing equipm ent by the end user. The submitter anticipates that there will be very low emissions from these operations. In addition, the submitter and a major degreaser manufacturer have developed a system for transferring solvent directly into the solvent cleaning eq uipment that keeps the solvent enclosed by using hoses and a valve to control transfer of the solvent from the storage container. This will minimize emissions, compared to opening the solvent container.

Note that this substitute boils at 19 °C and at room temperature. Therefore, EPA recommends using this substitute in equipment designed to minimize solvent losses, emissions and worker exposure. Examples of such equipment include containers with connected hoses and valves that allow for direct transfer of t he solvent to cleaning equipment without open ing of the storage container, and enclosed or low

- emission cleaning equipment.
A surrogate compound, HFC

- 245fa , was used to assess the potential end

- use exposures to SolsticeTM 1233zd(E) . Air concentrations found during the air monitoring studies with HFC

- 245fa (described below in sections 7.1 and 7.2) are a reasonable estimate of potential air concentrations of SolsticeTM 1233zd(E) , due to similar boiling points of the two compounds and t he lower vapor pressure of SolsticeTM 1233zd(E) .Therefore, EPA believes that this is a reasonable surrogate compound to use for this assessment that will result in protective estimates of exposure

. Table 3 . Boiling Point and Vapor Pressure for SolsticeTM 1233zd(E) and HFC
- 245fa Analog
Parameter SolsticeTM 1233zd(E) Proposed Substitute HFC

- 245fa Analog Boiling Point 19 ° C (66 ° F) 15.3 ° C (59.5 ° F) Vapor Pressure 205 kPa (at 54 ° C) 245 kPa (at 54 ° C) Source: Anonymous Submitter 2011a, Anonymous Submitter 2011c***** FINAL May 1, 2013 ***** 6 7.1 Degreasing For this degreasing exposure analysis, EPA reviewed the submitter’s exposure assessment, which monitored the loss of solvent from a low

- emission open
- top vapor degreaser containing HFC

- 245fa run continuously for ten days. The loss rate was estimated to be 342 mL of HFC

- 245fa per 24

- hour day , which is equivalent to approximately 147 grams of HFC

- 245fa, released every 8 hour s (equivalent to one worker’s shift ) . Vapor degreasers are often run on a continu al basis to minimize emissions in facilities that frequently use degreasers . The submitter assumed the same loss rate (147 grams of SolsticeTM 1233zd(E) every 8

- hours) , which is equivalent to an exposure of less than 8 ppm on an 8

- hr TWA , assuming the degreasing takes place in a 2000 ft 3 workshop (20x10x10 feet) with a ventilation rate of 6 ACH. 3 As t his exposure concentration is substantially lower than the submitter’s AEL value of 300 ppm , use of SolsticeTM 1233 zd(E) in electronics and precision cleaning does not pose a significant risk to end

users. 

### 7.2 Flushing For flushing operations, the submitter administered two separate monitoring tests using HFC

- 245fa as a flushing agent. In the first assessment , a service technician flushed an automobile refrigerant condenser with 2 pounds of HFC

- 245fa . The process was repeated 4 times over a period of 80 minutes. Ventilation in the 20x30x8 f oot laboratory was limited to the normal building air supply (i.e., no additional ventilation was provided 4 ). The submitter assumed that the losses of HFC

- 245fa are equivalent to the anticipated emissions for SolsticeTM 1233zd(E) , so u nder this first exposure assessment , the time

weighted average exposure level for SolsticeTM 1233zd(E) was estimated to be approximately 84 ppm over 80 minutes, or 1 4 ppm on an 8

- hr TWA

. In the second monitoring test , two operators flushed 10 automobile air conditioning units over the course of 5 hours with 2 pounds each of HFC

- 245fa . Ventilatio n in the 50x100x20 feet garage was limited to the normal automobile garage air supply (i.e., no additional ventilation was provided 5 ). Under this second assessment , the t ime

- weighted average exposure levels for SolsticeTM 1233zd(E) were estimated to range fr om 80 to 97 ppm over 5 hours, or 50 to 61 ppm on an 8

- hr TWA , assuming the same loss es as with HFC

- 245fa

. Based on the two HFC

- 245fa monitoring test result s, the anticipated occupational exposure levels for SolsticeTM 1233zd(E) would be significantly lower than its 300 ppm AEL. Because these exposures are under the AEL, and end

- users of SolsticeTM 1233zd(E) are subject to follow ing certain guidelines

including training to properly use and handle the proposed substitute , that employee work habits are conducted in accordance with goo d industrial hygiene practices , and that the solvent is only used in areas with adequate ventilation or local exhaust ventilation , EPA believe s that SolsticeTM 1233zd(E) does not pose a significant concern to worke rs at end

- use. 

### 8. GENERAL POPULATION EXPOSURE ASSESSMENT This section screens potential risks to the general population from exposure to releases of SolsticeTM 1233zd(E) to ambient air, surface water, and solid waste. SolsticeTM 1233zd(E) is not expected to cause significant risks to the environment and human health in the general population when manufactured or used for solvent cleaning end

- use s
.

3 Air change rates for factories vary, but recommended levels range from 6

- 15 ACH (Anonymous Submitter 2011a). 4 According to ASHRAE 62: Ventil ation for Acceptable Indoor Air Quality, laboratories must have a mi nimum ventilation rate of 0.18 c ubic feet per minute (cfm) per square f ee t of space. For a 2 0x 3 0x 8 foot lab , the ventilation rate should be at least 1.4 ACH 5 According to ASHRAE 62 , automobile service garages must have a mi nimum ventilation rate of 1.5 cfm/ft 2 . For a 50x100x20 foot garage, the ventilation rate should be approximately 90 ACH.***** FINAL May 1, 2013 ***** 7 8 .1 Ambient Air Electronic s , precision , and metals cleaning are emissive end

- use s . As such, it is important to minimize emissions to ambient air when possible. However, significant releases to air are not expected, because accidental release measures, handling and storage, engineering controls, and waste disposal are followed per the p roposed substitute’s MSDS. Other releases to the air during electronics , precision , and metals cleaning end

- uses are expected to 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 As indicated by the su bmitter, SolsticeTM 1233zd(E) has only slight solubility in water (1 .9 g/l) and use of SolsticeTM 1233zd(E) as a solvent is not anticipated to result in releases to surface water. At manufacture, the solvent wil l be handled indoors with waste or accidental spills collected with a non

- combustible absorbent material, such as sand or vermiculite

. Vapor degreasers are fitted with water separators so that water and Sols ticeTM 1233zd(E) can be separated after the solvent is condensed. The volume of SolsticeTM 1233zd(E) remaining in the water after separation is low

. In addition, disposal of SolsticeTM 1233zd(E) is subject to local, state, and federal regulations , whic h ensure that releases of SolsticeTM 1233zd(E) and water contaminated with SolsticeTM 1233zd(E) are not be dumped into sewers, on the ground, or into any body of water , but rather taken to a wastewater treatment facility or disposed of properly.
8 .3 Solid Wa ste Industrial sites using SolsticeTM 1233zd(E) as a solvent in electronics , precision , and metals cleaning can collect spent solvent for disposal or reclaim the spent solvent through distillation. To minimize waste, EPA recommends that reclamation of the p roposed 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 co nsidered to be a RCRA hazardous waste (40 CFR Part 261.31). Although the constituents of SolsticeTM 1233zd(E) are not listed as RCRA hazardous wastes, applications of SolsticeTM 1233zd(E) may generate hazardous wastes. Solvents used for electronics, precisi on, and metals cleaning end

- uses 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 di splaying 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, the SolsticeTM 1233zd(E) MSDS recommends that solid materials used during end

- use or clean

- up procedures that may be absorbed with SolsticeTM 1233zd(E) (e. g. , rags, paper towels, non
- combustible absorbent material ) are disposed of in accordance with federal, state, and local environmental regulations. 

### 9
. VOLATILE ORGANIC COMPOUND (VOC) A SSESSMENT EPA has proposed to exempt Solsti ceTM 1233zd(E) as a volatile organic compound (VOC) under the CAA (40 CFR 

### 51.100(s)) , but this determination is not yet final. Thus , emissions of SolsticeTM 1233zd(E) should be controlled. SolsticeTM 1233zd(E) continues to be regulated as a VOC for purposes of regulations in state implementation plans for local air quality unless and until EPA issues a final rule exempting it. An assessment was performed to compare the annual VOC emissions from use of SolsticeTM 1233zd(E) in the solvent cleaning end

- use s in one year to other anthropogenic sources of VOC emissions. Because a breakdown of production by end

- use was not provided by the submitter, thi s assessment assumes that 163 MT of SolsticeTM 1233zd(E) , the maximum production for all solvent end

- uses (i.e., aer osol solvent;***** FINAL May 1, 2013 ***** 8 metals, electronics and precision cleaning; and adhesives, coatings, and inks) is released. This quantity is approximately equal to 7.0 x 10 - 3 percent of the VOC emissions from the solvent sector in the United States, 6 or approximately 1.3 x 10 - 3 percent of all anthropogenic VOC emissions in the U.S. 7
For solvent cleaning applications that take place in less

- controlled e nvironments , such as a fume hood or other ventilated areas which would vent the s olvent to the atmosphere, an emissions rat e of 74% 8 was applied to the entire intended U.S. annual production of SolsticeTM 1233zd(E) for solvent use in order to estimate the maximum impact on VOC emissions across this end

- use. Assuming 74% of the submitter’s intended annual production is entirely released, approximately 121 MT of VOCs would be emitted, which is approximately equal to 5.2 x 10 - 3 percent of the VOC emissions from the solvent sector in the United States, or only approximately 9.9 x 10 - 4 percent of all anthropogenic VOC emissions in the U.S. Although these VOC emissions for the metals, electronics and precision cleaning end

- use s are already several orders of magnitude lower than other anthropogenic emissions , it is likely that emissions would be even lower than estimated here, as this assessment uses very conservative assumptions. First, the amount of SolsticeTM 1233zd(E) produced encompasses the production for other end

- uses, included adhesives, coatings and ae rosol solvents . Secondly, it assumes that all applications of SolsticeTM 1233zd(E) in the metals, electronics and precision cleaning end

- use s occur in a less

- controlled environment , where 74% of production would be emitted to the atmosphere . However, much o f the use of SolsticeTM 1233zd(E) is anticipated to occur indoors, where emissions would be less than 10%. Further, these emissions could be further reduced, and in some facilities may already be so reduced. For example, capture and destruction technologie s for fugitive emissions are employed in larger facilities, and hence emissions during use of SolsticeTM 1233zd(E) may be even less than 10%

. In addition, the majority of solvent use of ODS substitutes (approximately 69%) , including aerosol solvents , adhesives and coatings, and solvent clean ing , is made up of solvents that are considered to be VOCs, such as trichloroethylene and a number of other non
- halogenated organic solvents (ICF 2012 b ). Because SolsticeTM 1233zd(E) has a small intended production f or solvent uses compared to the size of all solvent uses , emissions from SolsticeTM 1233zd(E) for its intended end

- uses would not have a significant impact on VOC emissions compared to other alternatives and compared to VOC emissions. Further, emissions fr om SolsticeTM 1233zd(E) for its intended end

- uses would not have a significant impact on total VOC emissions from all solvent s , including solvent cleaning

.

6 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 non
industrial surface coating. 7 Based on the 2010 annual total VOC emissions for the U.S . (EPA 2011). 8 Leak rate for non

- medical aerosols from EPA’s Vintaging Model (VM IO file_v4.4_11.17.11).***** FINAL May 1, 2013 ***** 9 

### 10
. REFERENCES American Society of Heating, Refrigeration, and Air

- Conditioning Engineers, Inc. (ASHRAE). 2007. Standard 62.1

- 2007: Ventilation for Acceptable Indoor Air Quality. Anonymous Submitter . 2012. SolsticeTM 1233zd(E) Material Safety Data Sheet. February 28, 2012. Anonymous Submitter . 2011a. Response to Incomplete SNAP Submission for Solstic eTM 1233zd(E)

. October 20, 2011. Anonymous Submitter . 2011b. SNAP Submission to EPA for SolsticeTM 1233zd(E) . May 13, 2011. Anonymous Submitter . 2011c. Next Generation (LGWP) of Blowing Agents for Spray Foam Applications. EPA 2011. National Emissions Inven tory 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 1994. Significant New Alternatives Policy Technical Background Document: Risk Screen on th e Use of Substitutes for Class I Ozone

- depleting Substances: Refrigeration and Air Conditioning. 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 t he 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. ICF International. 2012a. Determ ination of an Acceptable Exposure Limit (AEL) for SolsticeTM 1233zd(E) . Prepared for U.S. Environmental Protection Agency. January 23, 2012. ICF International. 2012b. Solvent Sector VOC Analysis for ODS Substitutes. Prepared for EPA’s Stratospheric Ozone Protection Division. March 9, 2012 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 Wang D., Olsen S., Wue bbles D. Undated. “Three

- Dimensional Model Evaluation of the Global Warming Potentials for tCFP.” Department of Atmospheric Sciences. University of Illinois, Urbana, IL. Draft Report. Wang D., Olsen S., Wuebbles D. 2011. “Preliminary Report: Analyses of tCFP’s Potential Impact on Atmospheric Ozone.” Department of Atmospheric Sciences. University of Illinois, Urbana, IL. September 26, 2011. 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 May 1, 2013 ***** 10 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. Wuebbles, D.J., and K.O. Patten, Three

- dimensional mod eling of HCFC

- 12 3 in the atmosphere: Assessing its potential environmental impacts and rationale for continued use, Environ. Sci. Technol ., 43 (9), 3208

- 3213, doi: 10.1021/es802308m, 2009.***** FINAL May 1, 2013 ***** 11 

## Appendix A: Determination of an Acceptable Exposure Limit (AEL) for T rans - 1
- c hloro
- 3,3,3
- trifluoropro
- 1
- ene
Recommended AEL: 1,000 ppm (8

- hour time

- weighted average) Basis and Endpoints: NOAEC: 4,000 ppm (no significant cardiac histopathology observed at this concentration) Critical Study: 90

- day inhalation toxicity study in the rat ( TNO , 2011 b )
Protocol: Whole

- body inhalation, 6 hours/day, 5 days/week for 13 weeks
Concentrations: 0; 4,000; 10,000; 15,000 ppm
NOAEC 9 : 4,000 ppm (identified by independent pathologist’s report [ Experimental Pathology Laboratories , 2011]) NOAEC [HEC 10 ]: 4,000 ppm x 6 hr/8 hr = 3,000 ppm Uncertainty Factors: 3

– animal to human extrapolation

I. Introduction
T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene has been proposed as a replacement for PFCs, HCFCs, HFCs and other halogenated compounds. It is intended for several end

- uses, including as a foam blowing agent, a refrigerant in chillers, a solvent for cleaning in equipment and aerosol cans, and a carrier solvent in adhesives, coatings, and inks. Several studies assessing the potential toxicity of trans

- 1

- chloro

- 3,3,3,

- trifluoroprop

- 1

- ene have been conducted and include the following: 14

- day, 28

- day, and 90

- day inhalation study in rats , developmental inhalation studies in rats and rabbits, a cardiac sensitization assay in beagle dogs, and genotoxicity studies in bacteria and mammalian cells in culture. The results of these studies are discussed in the following sections to inform an as sessment of the potential health risks from human exposure to the study compound in the intended end use.
II. Summary of Toxicity Studies The toxicological studies reviewed for the determination of acceptable exposure limit for trans

- 1

- c hloro

3,3,3

- trifluoropro

- 1

- ene are summarized below in Table 1. Subclinical effects in the heart (monocyte infiltration) associated with inhalation exposure to trans

- 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene were considered to be the most sensitive human health effects for derivation of an AEL; therefore inhalation studies are described and discussed in detail. The remaining studies are considered supporting studies.

9 No Observable Adverse Effect Concentration (NOAEC) 10 Human Equivalent Concentration (HEC)***** FINAL May 1, 2013 ***** 12 Table 1. Tr ans - 1
- c hloro
- 3,3,3
- trifluoropro
- 1
- ene Toxicological Studies Inhalation Studies Doses NOAEL/ NOAEC a Effects
4

- hour acute (nose

- only, rat) 96,000, 156,000 and 120,000 ppm LC 50 , 120,000 ppm (combined sexes) Mortality at ≥ 96,000 ppm for some animals. Tremors at all exposures. 14

- day (whole body, rat) 0, 2,000, 7,500, and 20,000 ppm 2,000 ppm (study rpt.) 7,500 (peer review) b Min. focal mononuclear cell infiltrate (heart)
28

- day with 14

- day recovery (nose

- only, rat) 0, 2,000, 4,500, 7,500, and 10,000 ppm 4,500 ppm c (study report) 10,000 ppm (peer review) Increased serum K+ in 7,500

- ppm males; reversible changes in hematology/clinical chemistry parameters 90

- day study (nose

only, rat) 0, 4,000, 10,000 and 15,000 ppm <4,000 (study rpt.) 4,000 ppm (peer review) Min. focal mononuclear cell infiltrate (heart) Rat fetotoxicity 0, 4,000, 10,000, and 15,000 ppm 10,000 ppm Dilated urinary bladders in the fetuses Rabbit fetotoxicity 0, 2,500, 10,000, and 15,000 ppm 15,000 ppm No adverse effects noted Cardiac sensitization, dog 25,000, 35,000, and 50,000 ppm Negative at 25,000 ppm Tremors present during exposure ≥ 35,000 ppm Supporting Studies Doses NOAEL/ NOAEC a Effects In vitro bacterial reverse mutation assay Max concentration of 905,000 ppm NA Negative In vivo unscheduled DNA synthesis 0, 7,500, and 10,000 ppm NA Negative In vitro chromosomal aberration assay 469, 783, or 1,305 μg/mL NA Negative In vivo micronucleus test (rats) 0, 2,000, 4,500, 7,500, and 10,000 ppm NA Negative In vivo micronucleus test (mice) 0, 50,000 ppm NA Negative

a All values NOAEL/NOAEC unless otherwise reported; NA

- not applicable b NOAEC values were revised in a pathology peer review report ( Experimental Pathology Laboratories , 2011)
c NOAEC identified in study report based on clinical chemistry, not histopathology res ults 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 T rans - 1
- c hloro
- 3,3,3
- trifluoropro
- 1
- ene Several repeated dose inhalation studies assessing the toxic potential of trans

- 1

- chloro

- 3,3,3

- trifluoropro

1

- ene were available for development of an AEL. The NOAEC of 4,000 ppm from the 90

- day inhalation study was chosen as the point of departure for derivation of an AEL for trans

- 1

- chloro

- 3,3,3

- trifluoropro

1

- ene as this was the study with the longest exposure duration with an identifiable NOAEC.
The AEL was calculated in the following manner: 4000 ppm x (6/8) ÷ 3 = 1000 ppm***** FINAL May 1, 2013 ***** 13 A human equivalent concentration (HEC) was determined by adjusting the NOAEC of 4,000 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 full uncertainty factor (UF) of 3 for pharmacokinetic differences between rats as the animal model of study and humans (a UF of 3 for pha rmacodynamic [PD] differences between the two species has been applied). Because subchronic studies are typically used to develop AEL values, an additional UF was not added to account for study duration. Similarly, the database is considered comprehensive, and no additional UF was added to account for database limitations.
IV. Inhalation Studies for T rans - 1
- c hloro
- 3,3,3
- trifluoropro
- 1
- ene Four
- Hour Acute Inhalation Study In an acute 4

- hour nose

- only inhalation study, male and female Crl:SD (outbred) rats (5 /sex) were exposed to three different concentrations of trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (purity 99.99%) and observed for 14 days post

- exposure (when possible) ( TNO , 2009 b ). In the first group (Group A), animals were exposed to 100,000 ppm trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene. Because of the low toxicity observed, a second group (Group B) of 5/sex were exposed to a target concentration of 125,000 ppm, that actually reached 156,000 ppm due to technical difficulties; all animals died during exposu re. A third group (Group C) of 5 animals/sex were then exposed to a target concentration of 120,000 ppm in an effort to provide more data to identify the LC 50 . One female from Group A died on the first day of the recovery period. Other animals, male a nd female, showed clinical signs during recovery, but did not die prematurely. Necropsy did reveal gray discolored lungs in these animals, which was coincident with petechiae in some cases. Three males and two females of Group C died during exposure. Necropsy of these animals revealed reddish lung, with some also being enlarged. In two female animals of group B, red spots were also found on the thymus. In animals sacrificed on schedule fol lowing recovery, no other abnormalities were found. The combined

- sex LC 50 was reported as 120,000 ppm.
Fourteen
- Day Inhalation Study In a dose

- range
- finding inhalation study, Crl:CD (SD) rats (5/sex/group) were exposed via whole body inhalation to 0, 2,000, 7,500, or 20,000 ppm trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.9% pure) ( TNO , 2008). Exposures were for 6 hr/day, 5 days/week, in a 2

- week period (10 total exposure days). Clin ical signs, body weights and food consumption data were collected. Blood samples were drawn at the end of each week for hematology and clinical chemistry analyses. Gross necropsies were performed on all animals following the last exposure, and organs were collected and weighed; select organs, including the respiratory tract, were processed and analyzed histologically. The only clinical sign reported during exposure was restlessness, particularly in the highest concentration; the effect resolved after 15 minutes of exposure. Test

- compound exposure did not induce changes in body weights or food consumption. Regarding changes in hematology, the study author noted an increase in prothrombin time in females at 20,000 ppm, and an increase in absolute and rel ative numbers of monocytes and absolute number of neutrophils in males at 20,000 ppm. Increases in serum liver enzymes (ALAT 11 and ASAT in males at 20,000 ppm) were not confirmed by any changes in liver histopathology, and were thus considered not toxicolo gically relevant. Histology revealed multifocal mononuclear cell infiltrates, identified by the study laboratory in animals at 7,500 and 20,000 ppm. However, following an independent pathological review of the histology slides of the heart tissues ( Exper imental Pathology Laboratories , 2011), many of the lesions originally identified by the study laboratory as ‘very slight’ or ‘slight focal myocardial mononuclear cell infiltrate’ were downgraded to being ‘not remarkable’ or were

11 ALAT, alanine transaminase; ASAT, aspartate transaminase***** FINAL May 1, 2013 ***** 14 noted to be located only in the apex of the heart. According to the reviewing pathologist, lesions in the apex and/or adjacent portions of the right and left ventricles and interventricular septum of the heart in rats with such lesions are “typical of rodent spontaneous cardiomyopa thy”. Given the revised heart data, the reviewing pathologist increased the NOAEC to 7,500 ppm from the original NOAEC of 2,000 ppm identified by the study laboratory. ICF accepts the revised value as reasonable, given the expertise of the reviewing path ologist.
Four
- Week Inhalation Study In a longer

- term, nose

- only, multi

- exposure study, five groups of Sprague

- Dawley rats were exposed 6 hrs/day, 5 days/week in a 28

- day period (e.g., 20

- 21 exposure days) to the following nominal concentrations of trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.9% pure): 0, 2,000, 4,500, 7,500, and 10,000 ppm ( TNO , 2009 c ). Additional groups of 5/sex were exposed to either 0 or 10,000 ppm in an identical fashion, followed by a 14

- day recovery period. The following parameters w ere measured in accordance with harmonized guidelines for this repeat

- exposure study: clinical signs and mortality, food consumption and body weights, hematology and clinical chemistry, gross necropsy, organ weights, and histopathology of select organs.
T he study compound did not induce any changes in clinical signs or mortality, food consumption, body weights, urinalysis parameters, gross necropsy, or organ weights. In contrast to the histopathological findings from the 14

- day study, no mononuclear cell infiltration was noted in cardiac tissue or any other selected organ. An increase in the relative number of basophils was observed in males at 10,000 ppm, which resolved in the 14

- day recovery period. Changes in clinical chemistry parameters were limited to decreased creatinine in males at 10,000 ppm, which also was resolved at the end of the recovery period; and an increase in serum potassium in males at both 7,500 and 10,000 ppm, which were still slightly elevated after recovery, although not statistica lly significant. The study authors identified a NOAEC of 4,500 ppm, arguing that the increased potassium levels at exposure concentrations of 7,500 and 10,000 ppm were related to treatment. The pathologist who performed the peer review of the cardiac hist opathology slides for this study identified a NOAEC of 10,000 ppm, based on the confirmed absence of compound

- induced subcellular damage to cardiac tissue. ICF concurs with the reviewing pathologist, and would add that although the increased potassium lev el observed at ≥7,500 ppm may be indicative of subclinical cardiotoxicity, it cannot be attributed to the test compound alone, and may also be attributed to spontaneous cardiomyopathy. The NOAEC for this study is set, therefore, at 10,000 ppm. Ninety
- Day Inhalation Study In a 90

- day inhalation study, male and female Sprague

- Dawley (Crl:CD[SD]) rats (10/sex/concentration) were exposed to trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.9% purity) via nose

- only exposure at nominal vapor concentrations of 0, 4,00 0, 10,000, or 15,000 ppm for 6 hrs/day for 5 days/week for 13 weeks, for a total of 65 exposure days ( TNO , 2011 b ). Rats were observed twice daily for clinical signs of toxicity, morbidity, and mortality. Body weights and mean food consumption were recorde d weekly. Ophthalmoscopic examinations were conducted at study initiation and during the last week of exposure. Blood samples and urine samples were taken just prior to or the last day prior to sacrifice at the end of the exposure period and were analyzed for hematology, clinical chemistry and urinalysis parameters consistent with harmonized guidelines. Gross necropsies were performed on all surviving animals after the scheduled exposure period, and select organs were removed, weighed, and prepared for his topathology. Mortality, Clinical Effects, Eye Effects, Food Consumption, Body Weights Exposure to the study compound did not induce early mortality or any observed clinical abnormalities. In addition, exposure did not affect body weight gain, food consumption, or changes in eye condition.***** FINAL May 1, 2013 ***** 15 Hematology/Clinical Chemistry Effects on hematological parameters were limited. For example, exposure to the study compound had no effect on red blood cell parameters and affected white blood cells only by decre asing the relative number of lymphocytes in males at 15,000 ppm. Clinical chemistry effects were inconsistent between the sexes. Plasma of ASAT and ALAT were increased at statistically significant levels in males at 15,000 ppm, but not in females, while glucose and urea were increased in females at 10,000 and 15,000 ppm, but not in males. High

- concentration females also exhibited significantly increased potassium and decreased triglyceride levels. No other changes in measured analytes were noted. Organ Weights A treatment

- related decrease in absolute and relative heart weights was noted in male rats, which reached statistical significance at the highest concentration (15,000 ppm). In addition, relative liver weights in the males were significantly incr eased at the highest concentration, whereas by contrast, the relative liver weights of high

- concentration females were significantly decreased. No other changes in organ weights were noted. Macroscopic and Microscopic Findings Exposure to trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene did not induce any changes in the appearance of organs or tissues in the bodies of rats evaluated following gross necropsy. In general, no compound

induced effects were noted upon analyses of histopathology findings, with the exce ption of minimal multifocal mononuclear cell infiltrate in the heart. The study authors also identified inflammation occurring coincident with the infiltrates in some animals. The report of the peer review pathologist indicated that the vast majority of these findings were downgraded to categories of ‘not remarkable’ or were localized to the apex, the lower left ventricle, or the atrium. Again, because of the downgrading of incidences of infiltration reported in the original study, and the identification of some mononuclear infiltration as ‘spontaneous cardiomyopathy,’ the NOAEC was identified as the lowest exposure concentration of 4,000 ppm (the study authors reported the NOAEC as less than 4,000 ppm). ICF concurs, and as such, the NOAEC used in the de termination of an AEL for trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene is 4,000 ppm. Developmental Toxicity T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene was evaluated in two developmental toxicity studies, one in rats and one in rabbits.
Rat Prenatal Developmental Study In the prenatal developmental study in rats ( TNO , 2011 a ), groups of 24 mated female Wistar (Crl:WI[WU]) rats were exposed 6 hrs/day to concentrations of 0, 4,000, 10,000 or 15,000 ppm trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.9% pure) from gd 6 to gd 19. Health parameters measured during the in

- life phase of the study included mortality, clinical signs, maternal body weight, and food consumption. A Caesarean section was performed following the gestation period, and females and fetuses were evaluated via gross necropsy, and for standard reproductive toxicity endpoints (e.g., gestation index, fecundity index, fetus sex ratio, number of corpora lutea, implantation sites, pre

- and post

- implantat ion loss, live and dead fetuses, and resorptions). Fetuses, placentas and reproductive organs were weighed, and fetuses were processed for soft tissue and skeletal abnormalities and malformations. Exposure to the study compound did not affect any of the measured parameters with the exception of the following: a statistically significant increase in the incidence of dilated urinary bladders was observed in the fetuses of the highest concentration group (15,000 ppm). Because the incidence of this anomaly i ncreased with higher concentrations, it is considered treatment

- related. No signs of maternal toxicity were noted at any concentration. The NOAEC for developmental effects is established at 10,000 ppm; the NOAEC for maternal toxicity is established at 15 ,000 ppm.***** FINAL May 1, 2013 ***** 16 Rabbit Prenatal Developmental Study T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene was further evaluated in a developmental study in the New Zealand white rabbit. Huntingdon (2010) exposed 22 pregnant dams/group during organogenesis (gd 6 to gd 28) to trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (~100% purity) via whole

- body inhalation for 6 hrs/day at concentrations of 0, 2,500, 10,000 or 15,000 ppm. During the in

- life phase of the study, the rabbits were observed for mortality, clinical signs, body weigh ts, and food consumption. Following euthanasia of the dams at gd 29, the following parameters were measured: gross necropsy, number of corpora lutea and implantation sites, uterine and placental weights, fetus number (live), fetal weights (live only), sex ratio, external defects, soft tissue abnormalities, and skeletal abnormalities and state of ossification. Exposure to the test compound did not affect any changes in any of the measured parameters of the exposed dams or the fetuses. Therefore, the NOA EC for both maternal and fetal toxicity is established at 15,000 ppm in this rabbit developmental assay. Cardiac Sensitization In a muzzle

- only, acute exposure study in young beagle dogs ( WIL Laboratories , 2011), 6 male dogs were exposed successively to 2 5,000 ppm (2.5%), 35,000 ppm (3.5%) and 50,000 ppm (5%) trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.978% pure) up to a maximum period of 33 minutes, with 48 hours of rest occurring in between exposure periods. Control (air) exposures occurred in the same dogs. For the cardiac sensitization, epinephrine challenge (bolus) injections, ranging from 2 to 8 μg/kg, were started approximately 5 minutes following the initiation of exposure and continued until termination of exposure. Only 2 of the 6 dogs were expo sed to the highest trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene concentration, because behavioral responses (vocalization, injected sclera, excessive salivation, tremors, convulsions and/or reddened gums) prompted the termination of exposure; only one of the do gs at this concentration was given an epinephrine challenge.
No test

- related deaths occurred in the study. Clinical findings similar to those at 50,000 ppm were noted after exposure to 35,000 ppm (tremors, injected sclera, reddened ears and excessive sal ivation). No signs of cardiac sensitization were noted at 25,000 or 35,000 ppm; however, the presence of ECG noise in two animals exposed to 35,000 ppm precluded the complete characterization of cardiac sensitization at this concentration. As noted previo usly, exposure was terminated at the highest concentration and assessment of cardiac sensitization was not possible at this level. Therefore, the results indicate that the study compound does not cause cardiac sensitization at 25,000 ppm.***** FINAL May 1, 2013 ***** 17 V. Supporting Geno toxicity Studies for T rans - 1
- c hloro
- 3,3,3
- trifluoropro
- 1
- ene Reverse Mutation Assay T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene was tested in an Ames bacterial reversion assay in Salmonella typhimurium ( S. typhimurium ) strains TA98, TA100, TA1535, TA1537, and E. coli strain WP2 uvrA ( BioReliance , 2011). This assay measures the ability of the compound to induce either base pair or frame shift mutations in DNA in the presence or absence of S9 fraction from induced rat l ivers (metabolizing enzymes including mixed function oxidases). The study compound was analyzed for mutagenicity twice at concentrations ranging from 73,400 to 905,000 ppm at 25°C for either 24 or 48 hours. Appropriate negative and positive controls were analyzed in the same assays. Mutagenicity was not induced in any strain, but toxicity was seen in all strains at the top two concentrations of 513,000 and 905,000 ppm. A confirmatory assay was performed using slightly reduced exposure concentrations of 17,200; 24,500; 73,400; 147,000; 196,000; 269,000; 513,000 and 905,000 ppm at 25°C. Cytotoxicity was observed at the top two concentrations, as in the previous assays. No positive responses were observed with strains TA98 and TA1537 in the absence of S9 activation and with strains TA98 and WP2uvrA in the presence of S9 activation. The compound is categorized as negative in this genotoxicity assay. Unscheduled DNA Synthesis T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene was tested for the ability to induce unscheduled DNA synthesis in liver hepatocytes isolated from male rats exposed to 7,500 and 10,000 ppm of the study compound in a 28

- day study ( TNO , 2009 c ). The control group was the same one used in the 28

- day study and positive control animals were dosed with standard toxicants per harmonized guidelines. T rans - 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene did not induce unscheduled DNA synthesis under the conditions used in the 28

- day study, and is categorized as negative for this genotoxicity assay.
Micronuclei Two studies were performed to assess the ability of trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene to include micronuclei in bone marrow, as described below. Micronuclei Rat Study T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- enewas tested for the ability to induce micronuclei in bone marrow cells isolated from male rats exposed to 0, 2,000, 4,500, 7,500 and 10,000 ppm of the study compound in a 28

- day study ( TNO , 2009 c ). Appropriate positive control animals were dosed with standard toxicants per harmonized guidelines. The test compound did not induce chromosomal damage or induce micronuclei in the bone marrow under the conditions used in this study (the maximum concentration administered, 10,000 ppm is equivalent to >12,000 mg/kg, much higher than the 1,000 mg/kg limit dose recommended by EPA) and is judged negative for this genotoxicity assay. Micronuclei Mice Study T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- enewas tested in an independent assay for its a bility to induce micronuclei in the bone marrow of male mice ( TNO , 2009 a ). Two groups of 10 male, albino mice (CD

- 1 strain, Charles River) were exposed for a single, nose

- only, 4

- hour exposure to trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.99% pure) at co ncentrations of 0, or 50,000 ppm. Five male mice were injected intraperitoneally with 0.75 mg/kg

- bw of mitomycin C as a positive control for comparison. Bone marrow cells were isolated from half the exposure group at 24 hours and the remainder at 48 hour s post

- exposure; bone marrow smears were prepared and analyzed for the presence of polychromatic and normochromatic erythrocytes and micronuclei in a manner consistent with established guidelines. The test compound did not induce micronuclei or any other form of chromosomal damage and was thus judged negative in this genotoxicity assay.***** FINAL May 1, 2013 ***** 18 Chromosomal Aberration T

rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene (99.98% pure) was tested in a chromosomal aberration assay with human lymphocytes cultured in vitro ( Hunt ingdon , 2011). Human lymphocytes, isolated from whole blood samples provided by volunteers, were treated with t rans - 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene for either 3 or 21 hours at doses of 469, 783, or 1,305 μg/mL in the presence or absence of metabolic act ivation (S9 from the livers of chemically

- induced rats). T rans - 1

- c hloro

- 3,3,3

- trifluoropro

- 1

- ene was determined to be negative in this genotoxicity assay, as the cells treated with trans

- 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene in all experiments did not cause an increase in the frequency of cells exhibiting structural chromosomal aberrations compared with negative controls at any concentration tested.
References
BioReliance 2008. 1233zd(E) bacterial reverse mutation assay using gas

- phase exposure. Amended Final Report. BioReliance, Rockville, MD, performed for Anonymous Submitter . 27 April 2011. Experimental Pathology Laboratories . 2011. Peer review of hearts from inhalation toxicity studies with various fluorocarbons. Experimental Pathology Laboratories, Inc. 19 October 2011. Huntingdon 2010. 1233zd(E): Embryo

- fetal toxicity study in rabbits via whole

- body inhalation exposure (GLP). Huntingdon Life Sciences, New Jersey, for Anonymous Submitter . 2 September 2010. Huntingdon 2011. 1233zd in vitro mammalian chromosome aberration test in human lymphocytes. Amended Final Report. Huntingdon Life Sciences UK for Anonymous Submitter , 31 March 2011.
TNO 2008. Sub

- acute (14

- day) inhalation toxicity study with 1233zd(E) in rats. TNO Quality of Life, The Netherlands, performed for Anonymous Submitter , USA, 15 December 2008.
TNO . 2009 a . Micronucleus test in bone marrow cells of mice treated with 1233zd(E), administered by inhalation. TNO Quality of Life, The Netherlands, performed for Anonymous Submitter , 10 February 2009.
TNO 2009 b . Acute (4

- hour) inhalation toxicity study with 1233zd(E) in rats. TNO Quality of Life, The Netherlands, performed for Anonymous Submitter , USA, 17 February 2009.
TNO 2009 c . A sub

- acute (4

- week) inhalation toxicity study, including unsche duled DNA synthesis and micronucleus test, with 1233zd(E) in rats. TNO Quality of Life, The Netherlands, performed for Anonymous Submitter , USA, 27 May 2009.
TNO 2011 a . A prenatal developmental inhalation toxicity study with 1233zd(E) in rats. TNO Triske lion, The Netherlands, for Anonymous Submitter , 28 January 2011.
TNO 2011 b . Sub

- chronic (13

- week) inhalation toxicity study with 1233zd(E) in rats. TNO Quality of Life, The Netherlands, performed for Anonymous Submitter , 3 May 2011.
U.S. EPA 1994. Methods for Derivation of Inhalation Reference Concentrations (RfCs) and Application of Inhalation Dosimetry. U.S. Environmental Protection Agency, Office of Research and Development, Office of Health and Environmental Assessment, Washington, DC, EPA/600/ 8

- 90/066F.
WIL Laboratories 2011. Acute cardiac sensitization study of 1233zd in beagle dogs. WIL Research Laboratories, LLC, Ashland, OH, performed for Anonymous Submitter . 21 April 2011.