***** FINAL

— May 1, 20 13 ***** 1 

## Significant New Alternatives Policy Program A d hesives, Coatings, and Inks Sector Risk Screen on Substitutes for CFC - 113, M ethyl C hloroform , and HCFC - 141b as Carrier Solvents in A dhesives and Coatings 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 adhesives, coatings, and inks sect or (EPA 1994) (hereinafter 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 (comm only also referred to as 1,1,1

- trichloroethane, TCA, or MCF), and HCFC

- 141b as a carrier solvent in adhesives and coating s . 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 trans

- 1

-

Chloro

- 3,3,3

- trifluoroprop

- 1

-

ene C 3 H 2 ClF 3 102687

- 65

- 0 >99% Potential Impurities (maximum concentration)

The potential risks associated with use of substitutes in adhesives , coatings , and inks have been examined at length in the Background Document. The reader is referred to this reference for a detailed discussion***** FINAL

— May 1, 20 13 ***** 2 of the methodologies used to conduct this risk screen. This risk screen addresses flammability risk, and an o ccupational exposure assessment was performed to ensure that manufacture and disposal of the proposed substitute in the aerosols solvent end

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

- use to examine potential exposur es 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 population at large. Section 2 of this r eport 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
• Section 5 : Potential Health Effects
• Se ction 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 commended for SNAP approval as a carrier solvent in the adhesives end

- use and coatings end

- use . 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

- 14 1b. Given that appropriate personal protective equipment (PPE) (e.g., respiratory protection, goggles, impervious gloves, chemical

- resistant clothing and boots) according to OSHA guidelines are available, and engineering controls (e.g., exhaust ventilation , vapor - in

- air detection systems) (see Section 6) will be used, n o significant toxicity risks to workers , end

- users, or the general population are expected

. In addition, based on characteristics 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 (see Section 4). 

### 3. ATMOSPHERIC ASSESSMENT This section presents an assessment of the potential risks to atmosphe ric integrity posed by the use of SolsticeTM 1233zd(E) in the adhesives, coatings and inks sector. 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

- 11 3 , MCF, and HCFC

- 141b , SolsticeTM 1233zd(E) is substantially less harmful to the ozone layer, and has less climate impact, a nd a shorter atmospheric lifetime. SolsticeTM 1233zd(E) does however, also have a non

- zero ODP, but at 0.00024

- 0.00034 , this value is very small when conside ring continued used of HCFC

- 141b. A recent report by Wang et al. (2011) modeled the potential of Sol sticeTM 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 compounds it might replace and that the entire amount used were released, would hav e 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 substantially less harm to the climate and ozone layer than the continued use of oz one - depleting substances.***** FINAL

— May 1, 20 13 ***** 3 Table 2 . Atmospheric Impacts of SolsticeTM 1233zd(E) Compared to Other Carrier Solvents for Adhesives and Coatings Refrigerant ODP GWP ALT SolsticeTM 1233zd(E) 0.00024

- 0.00034 a,c 4.7

- 7 b,a 26 days c CFC

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

- 141b 0.12 d 725 e 9.3 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 kep t away from 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 avera ge (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 Solstic eTM 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) recom mends 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 affected area with water and remove all contaminated clothing; shou ld 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 attention should be sought if irritation develops or persists. Sols ticeTM 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 concentrations, the person(s) will likely not realize that he/s he 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

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 occupational exposures. 2 STEL was estimated as three to five times the AEL, which is an established method of estimating a short

- term exposure by the American Conference of Governmental Industrial Hygienists . [STEL] = [AEL] x 3 = 300 ppm x 3 = 9 00 ppm.***** FINAL

— May 1, 20 13 ***** 4 difficult, person(s) should be given oxygen, provided a qualified 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. The potential health effects of SolsticeTM 1233zd(E) are unlikely to occur when following good industrial hygiene practices and the PPE and engineering control (e.g., ventilation) recommendations outlined in the MSDS for SolsticeTM 1233zd(E) and Sections 6 a nd 7 of this risk screen. 

### 6. OCCUPATIONAL EXPOSURE ASSESSMENT AT MANUFACTURE Occupational exposure to SolsticeTM 1233zd(E) may occur during manufacture of adhesive and coating products . Adhesive and coating products typically contain solid components suspended in a carrier solvent. The adhesive/coating is sprayed on a surface via an aerosol can or spray gun , and then the carrier solvent evaporates, leaving the adhesive or coating spread and bonded to the surface. As indicated by the submitter, exposure may occur during blending of the aerosol product, which typically contains a carrier solvent ( e.g., SolsticeTM 1233zd(E) ), one or more propellants, and solid components, such as adhesive solids or pigments . However, as indicated by the submitter, aerosol can filling operations are highly automated and involve little or no direct contact with the components charged into the can. Actual monitoring data for manufacture of SolsticeTM 1233zd(E) aerosol cans are n ot 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. In addition, the submitter indicated that SolsticeTM 1233zd(E) can be charged into the top of an aerosol can just before sealing the can, or through the aerosol valve after the can has been sealed; both processes are not anticipated to result in significant e missions, and the former process is typically performed in an isolated gassing room, further reducing emissions. Further, as summarized in Chapter 5 of the Background Document, exposure to carrier solvent constituents are generally below 10 ppm and do not exceed 15.5 ppm. The maximum 8

- hour time weighted average concentration obtained by one site visit recorded a maximum exposure of 67 ppm. As these concentrations are well below the SolsticeTM 1233zd(E) AEL (300 ppm), and the manufacture process is highly automated with minimal emissions anticipated, exposure during the manufacture of aerosol cans is not expected to present a significant toxicity concern to workers. During manufacture of SolsticeTM 1233zd(E) , a dequate ventilation should always be established during any handling, or storage of the substitute and e ngineering controls should be in place, includ ing vapor - in air detection systems and local exhaust ventilation . F illing operations are to occur only at stations with exhaust ventilation fa cilities. 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 recommend ed 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 consiste nt 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). In addition, there is a risk of generation of toxic decomposition products su ch as hydrogen fluoride, hydrogen chloride, carbonyl halides, carbon monoxide, and carbon dioxide when SolsticeTM 1233zd(E) is exposed to fire. In accordance with the MSDS, c ontainers of SolsticeTM 1233zd(E) should not be allowed***** FINAL

— May 1, 20 13 ***** 5 to contact open flames, glow ing 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 SolsticeTM 1233zd(E) , there is no sign ificant risk to workers during the manufacture of SolsticeTM 1233zd(E)

. 

### 7. END - USE EXPOSURE ASSESSMENT SolsticeTM 1233zd(E) is proposed for use as a carrier solvent for a dhesives and c oatings in industrial and consumer applications ( e.g ., l aminate adhesives, metal to rubber adhesives, flexible foam adhesives, and aerospace coatings for metals )

. The submitter estimates that use of SolsticeTM 1233zd(E) in the adhesive end

- use will be approximately for 10% consumer applications and 90% industrial applications ; uses in the coatings end

- use will be only for industrial applications

. In both industrial and consumer setting s , use of these cans is expected to take place in small, intermittent amounts. SolsticeTM 1233zd(E) boils at 19 °C and a t room temperature, which may require some adjustments when switching to this substitute. At this time, it appears to be particularly suitable for spray adhesive applications and dip coatings. The submitter indicated that typical use of adhesives and coat ings aerosol cans in an industrial setting is anticipated to range between one and three cans a day. Assuming three 454

- gram aerosol cans containing 75% SolsticeTM 1233zd(E) (340 grams) each are released in a 20 x 10 x 10 ft work space in one work day with a ventilation rate of 6 air changes per hour ( ACH ) , the submitter estimates that the maximum concentration reached is 65 ppm. This modeled exposure is well below the 300 ppm 8

- hour AEL. In addition, this exposure concentration was calculated using con servative assumptions . In particular, t he assumed space is relatively small for a shop or commercial facility , the recommended air exchange rate for a factory ranges from 6 to 15 ACH ( Anonymous Submitter 2011 b ) , and the most common rate of usage is 1 aerosol can or less per day , so it is likely that typical exposures will be even lower

. As a second approach for assessing end

- use exposure, EPA modeled the use of aerosol can use over a short period of time, which is representative of typical exposures experienced by both industrial and consumer end

- users. The analysis is based on a simple box

- model approach that draws assumptions from spray tests performed by aerosol manufacturing companies. In this case, the box

- model approach examines an area surroun ding the face of the exposed worker or consumer and determines exposure based on the velocity of ventilation present. As the velocity varies, the volume of moving air surrounding the worker or consumer also changes, which in turn changes the level of expo sure estimated by the box model. The modeling was based upon the assumptions described below in Table 3 , regarding usage, area of exposure, ventilation, and the constituents of the solvent formulation.
Table 3 . Summary of Assumptions for Adhesives and Coatings Carrier Solvent End - Use Exposure Box - Model***** FINAL

— May 1, 20 13 ***** 6 Parameter Assumption

Usage Entire aerosol can (454 grams) sprayed in 3, back

- to

- back 10

- minute periods, or 30

- minutes total a Solvent Formulation 25% propellant and solids , 75% solvent ( SolsticeTM 1233zd(E) ) b Area of Exposure 18 in

. in equidistant directions around end

- user ’s (i.e., worker or consumer) face (3 ft x 3 ft = 9 ft 2 area around the face of end

- user ) 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 be intermittent and of short duration, and use one to three cans per day ( Anonymous Submitter 2011) b Anonymous Submitter 2011 c EPA 1994 The exposure point concentration for occupati onal inhalation exposure is determined by calculating the workplace air chemical concentration. The indoor air concentration for SolsticeTM 1233zd(E) was estimated using Equation 1 (EPA 199 4 ): Equation 1: Workplace Air Concentration

C a = Y v x 1000 m g
x 24.45 G AT x k MW Where:

C a = Concentration of the chemical in air (ppm) Y

v = 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 SolsticeTM 1233zd(E) , 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. 189 g/s of SolsticeTM 1233zd(E) [4 54 gram aerosol can containing 75 % Solsti ceTM 1233zd(E) dispensed over 30

- minutes]. Table 4 shows the results of this analysis. Table 4 . SolsticeTM 1233zd(E) Adhesives and Coatings Carrier Solvent End - Use Exposure (Calculated Using Box Model) Sampling Location Maximum Short

- Term Concentration o ver 15

- min (ppm) 15

- minute STEL (ppm) Area around Worker /Consumer ’s Face During Aerosol Spray Application 167 9 00***** FINAL

— May 1, 20 13 ***** 7 Based on the results of this modeling, even with conservative assumptions about ventilation the short

term concentration is unlikely to reach the STEL

. Although Equation 1 is designed to determine workplace exposure, this equation also adequately models ex pected exposure concentrations for those using adhesive products in a consumer setting. Further, under good industrial hygiene practices and proper handling of the proposed substitute in accordance with the MSDS, it is unlikely that these levels of long

- term and short

- term exposure would occur. EPA recommends all end

- users of SolsticeTM 1233zd(E) follow certain guidelines, including training to properly use and handle the proposed substitute , to ensure that employee work habits are conducted in accord ance with goo d industrial hygiene practices and that aerosol solvent products be labeled to ensure that the products are used in areas with adequate ventilation or local exhaust ventilation. Because use of SolsticeTM 1233zd(E) in aerosol cans is not expecte d to result in significant emissions, EPA does not believe that it presents a significant toxicity concern to workers at end

- use. 

### 8. GENERAL POPULATION EXPOSURE ASSESSMENT This section screens potential risks to the general population from exposure to re leases of SolsticeTM 1233zd(E) to ambient air, surface water, and solid waste. W hen the proper safety and disposal precautions, as listed in the remainder of this section, are followed, 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 the adhesives end

- use and coatings end

- use . 8 .1 Ambient Air Aerosol applications of adhesives and coatings are highly emissive end

- use s . As such, it is important to minimize emissions to ambient air when possible. When SolsticeTM 1233zd(E) is used indoors, it is important to use good manufacturing practices, such as employment of capture and destruction technologies. Overall, the adhesives, coatings, and inks sector is relatively small compared to other ODS sectors, and use of SolsticeTM 1233zd(E) is not expected to present a significant concern 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 carrier solvent in adhesives and coatings is not anticipated to result in releases to surface water. At manufacture, the adhesives and coatings product s wil l be handled indoors with waste o r accidental spills collected with a non

- combustible absorbent material, such as sand or vermiculite . EPA r e commends that releases of SolsticeTM 1233zd(E) and water contaminated with SolsticeTM 1233zd(E) not be dumped into sewers, on the ground, or into any body of water. 8 .3 Solid Waste SolsticeTM 1233zd(E) as a carrier solvent in adhesives and coatings is not expected to generate solid waste, as SolsticeTM 1233zd(E) will evaporate upon application of the adhesive or coating. EPA recommends that adhesives and coatings aerosol cans containing SolsticeTM 1233zd(E) are properly disposed of in accordance with the MSDS for SolsticeTM 1233zd(E)

. In addition, EPA recommends th at solid materials used during end

- use or clean

- up procedures that may have absorbed SolsticeTM 1233zd(E) (e. g. , rags, paper towels, trays) are disposed of in accordance with the federal, state, and local environmental regulations

. 

### 9 . VOLATILE ORGANIC COMP OUND (VOC) A SSESSMENT EPA has proposed to exempt SolsticeTM 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 12 33zd(E) continues to be regulated as a VOC for purposes***** FINAL

— May 1, 20 13 ***** 8 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 adhesives end

- use and coatings end

- use 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., aerosol solvent; 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 f rom the solvent sector in the United States, 3 or approximately 1.3 x 10 - 3 percent of all anthropogenic VOC emissions in the U.S. 4 For adhesives and coatings applications that take place in less

- controlled e nvironments , such as a fume hood or other ventilated areas which would vent the solvent to the atmosphere, an emissions rate of 74% 5 was applied to the entire intended U.S. annual production of SolsticeTM 1233zd(E) for solvent use in order to estimate the maximum impa ct 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 adhesives and coatings end

- use s are already several orders of magnitude lower than other ant hropogenic 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 solv ent cleaning and aerosol solvents . Secondly, it assumes that all applications of SolsticeTM 1233zd(E) in the adhesives and coatings end

- use s occur in a less

- controlled environment , where 74% of production would be emitted to the atmosphere . However, much of 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 destru ction technologies 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 the solvent sector s , including aerosol solvents as well as solvent cleaners, utilizing ODS substitutes (approximately 69%) is made up of solvents that are considered to be VOCs, such as trichloroethylene and non - halogenated organic solvents (ICF 2012 b ). Because SolsticeTM 1233zd(E) has a small intended production for adhes ives and coatings 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 from all solvent s , including adhesives and coatings

.

3 Based on the 2010 annual V OC 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 coatin g. 4 Based on the 2010 annual total VOC emissions for the U.S. (EPA 2011). 5 Leak rate for non

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

— May 1, 20 13 ***** 9 

### 10 . REFERENCES Anonymous Submitter. 2012. SolsticeTM 1233zd(E) Material Safety Data Sheet. February 28, 2012. Anonymous Submitter.2011a. Response to Incomplete SNAP Submission for SolsticeTM 1233zd(E). October 20, 2011. Anonymous Submitter. 2011b. SNAP Submission to EPA for Solstice TM 1233zd(E). May 13, 2011. 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 1994. Significant New Alternatives Policy Technical Background Document: Risk Screen on the Use of Substitutes for Class I Ozone

- depleting Substances: Refrigeration and Air Conditioning. Stratospheric Protection Division. March, 1994. Forster, P., V. Ramas wamy, 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 Physi cal 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 P ress, Cambridge, United Kingdom and New York, NY, USA. ICF International. 2012a. Determination of an Acceptable Exposure Limit (AEL) for SolsticeTM 1233zd(E). Prepared for U.S. Environmental Protection Agency. January 23, 2012. ICF International. 2012b. So lvent 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., Wuebbles D. Undated. “Three

- Dimensional Model Evaluation of the Global Warming Potentials for tCFP.” Department of Atmospheric Scienc es. 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 2 6, 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. WMO (World Meteorological Organization), 2007. Scientific Assessment of Ozone Depletion: 2006 , Global Ozone Research and Monitoring Proje ct

— Report No. 50, 572 pp., Geneva, Switzerland, 2007.***** FINAL

— May 1, 20 13 ***** 10 

## 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 6 : 4,000 ppm (identified by independent pathologist’s report [ Experimental Pathology Laboratories , 2011]) NOAEC [HEC 7 ]: 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

- trifluoro pro - 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.

6 No Observable Adverse Effect Concentration (NOAEC) 7 Human Equivalent Concentration (HEC)***** FINAL

— May 1, 20 13 ***** 11 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, 20 13 ***** 12 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. Nec ropsy 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 following 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). Clinical signs, body weights and food consumption data were collected. Blood samples were drawn at the end of each week for hematology and c linical 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 hematolog y, the study author noted an increase in prothrombin time in females at 20,000 ppm, and an increase in absolute and relative numbers of monocytes and absolute number of neutrophils in males at 20,000 ppm. Increases in serum liver enzymes (ALAT 8 and ASAT i n males at 20,000 ppm) were not confirmed by any changes in liver histopathology, and were thus considered not toxicologically 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 ( Experimental Pathology Laboratories , 2011), many of the lesions originally identified by the study laboratory as ‘very slight’ or ‘slight foca l myocardial mononuclear cell infiltrate’ were downgraded to being ‘not remarkable’ or were

8 ALAT, alanine transaminase; ASAT, aspartate transaminase***** FINAL

— May 1, 20 13 ***** 13 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 ventr icles and interventricular septum of the heart in rats with such lesions are “typical of rodent spontaneous cardiomyopathy”. Given the revised heart data, the reviewing pathologist increased the NOAEC to 7,500 ppm from the original NOAEC of 2,000 ppm iden tified by the study laboratory. ICF accepts the revised value as reasonable, given the expertise of the reviewing pathologist. 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 expo sed to either 0 or 10,000 ppm in an identical fashion, followed by a 14

- day recovery period. The following parameters were 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. The 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 ma les 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 pota ssium in males at both 7,500 and 10,000 ppm, which were still slightly elevated after recovery, although not statistically significant. The study authors identified a NOAEC of 4,500 ppm, arguing that the increased potassium levels at exposure concentratio ns of 7,500 and 10,000 ppm were related to treatment. The pathologist who performed the peer review of the cardiac histopathology 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 level observed at ≥7,500 ppm may be indicative of subclinical cardiotoxicity, it cannot be attributed to the test compound alone, and may al so 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 t rans - 1

- chloro

- 3,3,3

- trifluoropro

- 1

- ene (99.9% purity) via nose

- only exposure at nominal vapor concentrations of 0, 4,000, 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 tw ice daily for clinical signs of toxicity, morbidity, and mortality. Body weights and mean food consumption were recorded weekly. Ophthalmoscopic examinations were conducted at study initiation and during the last week of exposure. Blood samples and urine s amples 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 a ll surviving animals after the scheduled exposure period, and select organs were removed, weighed, and prepared for histopathology. 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, 20 13 ***** 14 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 decreasing 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 n ot 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 weigh ts 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 increased at the highest concentration, whereas by contrast, the relative live r 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 o rgans 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 exception 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 l ocalized 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 NOA EC 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 determination 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 o f 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

- implantation loss, live and dead fetuses, and resorptions). Fetuses, placentas and reproductive organs were weighed, and fetuse s 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 dilat ed urinary bladders was observed in the fetuses of the highest concentration group (15,000 ppm). Because the incidence of this anomaly increased with higher concentrations, it is considered treatment

- related. No signs of maternal toxicity were noted at a ny 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, 20 13 ***** 15 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

- b ody 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 weights, and food consumption. Following euthanasia of the dams at gd 2 9, 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 a bnormalities 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 NOAEC for both maternal and fetal toxicity is established at 15,000 pp m 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 25,000 ppm (2.5%), 35,000 ppm (3.5%) and 50,000 ppm (5%) trans
- 1

- chl oro - 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 exposed to the highest trans
- 1

- chloro

- 3,3,3

- trifluoropro

- 1

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

- 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 salivation). 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 previously, exposure was terminated at the highest concentration and asse ssment 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, 20 13 ***** 16 V. Supporting Genotoxicity Studies for T rans - 1 - c hloro - 3,3,3 - trifluoropro - 1 - ene Rever se 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 livers (metabolizing enzymes including mixed function oxidases). The study comp ound 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 2 5°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 guide lines. 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 abilit y 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 da mage 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 ability 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 concentrations of 0, or 50,000 ppm. Five male mice were injected intraper itoneally 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 hours post

- exposure; bone marrow smears were prepared and analyzed for the p resence 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 genotoxi city assay.***** FINAL

— May 1, 20 13 ***** 17 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 ( Huntingdon , 2011). Human lymphocytes, isolated from whole blood samples pro vided 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 activation (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 ab errations 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 lymphocyt es. 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 De cember 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 unscheduled DNA synthe sis 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 Triskelion, The Nether lands, 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 Laborator ies 2011. Acute cardiac sensitization study of 1233zd in beagle dogs. WIL Research Laboratories, LLC, Ashland, OH, performed for Anonymous Submitter . 21 April 2011.