***** Final - August 3, 2012 *****

1

Significant New Alternatives Policy Program 

Aerosols Sector

Risk Screen on Substitutes for CFC-113, Methyl Chloroform, HCFC-141b, HCFC225ca, and HCFC-225cb in Aerosol Solvents

Substitute: Trans-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 (CAAA). The U.S. Environmental Protection 

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

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

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

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

potential human health and environmental risks posed by the substitute in specific applications. EPA has 

already screened a large number of substitutes in many end-uses within all of the major ODS-using 

sectors, including refrigeration and air conditioning, solvent cleaning, foam blowing, aerosols, fire 

suppression, adhesives, coatings and inks, and sterilization. The results of these risk screens are presented 

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

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

(EPA 1994) (hereinafter referred to as the Background Document). This risk screen evaluates the 

potential use of trans-1-chloro-3,3,3-trifluoropro-1-ene (as also know as (E) 1-chloro-3,3,3-trifluoroprop1-ene and hereinafter 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), HCFC-141b, HCFC-225ca, and 

HCFC-225cb in the aerosol solvent end-use. 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 C3H2ClF3 102687-65-0 >99%

Potential Impurities (maximum concentration)

The potential risks associated with use of substitutes in aerosol solvent end-uses have been examined at 

length in the Background Document. The reader is referred to this reference for a detailed discussion of 

the methodologies used to conduct this risk screen. This risk screen addresses flammability risk, and an 

occupational exposure assessment was performed to ensure that manufacture and disposal of the proposed 

substitute in the aerosols solvent end-use does 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 
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2

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 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

 Section 5: Potential Health Effects

 Section 6: Occupational Exposure Assessment at Manufacture

 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 recommended for SNAP approval for the aerosol solvent 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, HCFC-141b, HCFC-225ca, and HCFC-225cb. Given that appropriate 

personal protective equipment (PPE) (OSHA Category C or higher) and engineering controls (e.g., 

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

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

expected. In addition based on characteristics of the proposed substitute and precautions lististed 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 atmospheric integrity posed by the use of 

SolsticeTM 1233zd(E) in the aerosol 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-113 and HCFC-141b, and HCFC-225ca/cb, SolsticeTM 1233zd(E) is substantially less 

harmful to the ozone layer, has less climate impact, and a shorter atmospheric lifetime. In addition, 

SolsticeTM 1233zd(E) also has lower climate impact and a shorter atmospheric lifetime than those 

predicted for other substitutes examined in the Background Document, as well as a more recent substitute, 

HFC-43-10mee. SolsticeTM 1233zd(E) does however, also have a non-zero ODP, but at 0.00024, this 

value is very small when considering continued used of HCFC-141b or HCFC-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 compounds 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 substantially less harm to the 

climate and ozone layer than the continued use of ozone-depleting substances. 
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Table 2. Atmospheric Impacts of SolsticeTM 1233zd(E) Compared to Other Aerosol Solvents

Refrigerant ODP GWP ALT

SolsticeTM 1233zd(E) 0.00024-0.00034a,c 4.7-7

b,a 26 daysa

CFC-113 0.85d 6,130e 85 yearsd

HCFC-141b 0.12d 725e 9.3 yearsd

Methyl Chloroform 0.16d 146e 5 yearsd

HCFC-141b 0.12d 725e 9.2 yearsd

HCFC-225ca 0.02f 122e 1.9 yearsd

HCFC-225cb 0.03f 595e 5.9 yearsd

HFC-43-10mee 0 1,640e 15.9 yearse

a Assuming emissions occur in the major regions of the world where blowing agents that HBA-2 might replace are significantly used. Wang et. 

al. (undated).

b Wang et. al. (2011)

c SolsticeTM 1233zd(E) SNAP Submission (Anonymous Submitter 2011b)

dWMO (2011)

e

IPCC 4th 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, EPA recommends that SolsticeTM 1233zd(E) be kept away from 

all sources of ignition and high heat. By keeping SolsticeTM 1233zd(E) away from all sources of ignition 

and high heat and adhering to the other precautions listed in the proposed substitute’s MSDS, 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 ppm1for 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 

900 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 affected 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 attention should 

be sought if irritation develops or persists. 

 

1An 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 = 900 ppm.
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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

concentrations, 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 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 and 7 of this risk screen.

6. OCCUPATIONAL EXPOSURE ASSESSMENT AT MANUFACTURE

Occupational exposure to SolsticeTM 1233zd(E) may occur during manufacture of products containing 

SolsticeTM 1233zd(E) in aerosol cans. As indicated by the submitter, exposure may occur during blending 

of the aerosol product, which typically contains one or more solvents (i.e., SolsticeTM 1233zd(E)), one or 

more propellants, and an active ingredient such as a lubricant or release agent. 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 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. 

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 emissions, 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 aerosol 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), adequate ventilation should always be established during 

any handling or storage of the substitute and engineering controls should be in place, including vapor-in 

air detection systems and local exhaust ventilation. Filling operations 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 OSHA Category C or higher 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 clothing (Anonymous Submitter 2011b, OSHA 

1994). Contaminated clothing is not to leave the workplace and must be cleaned before reuse 

(Anonymous Submitter 2011b).
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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. In accordance with the MSDS, containers of SolsticeTM 1233zd(E) should not be allowed 

to contact open flames, glowing metal surfaces, or electrical heating elements. EPA believes that because

proper handling and disposal guidelines are followed in accordance with good industrial hygiene and 

manufacturing practices and the MSDS for 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 the aerosol solvent end-use in commercial applications (e.g., as 

contact cleaners, mold release agents, spray lubricants, and insecticides). In an occupational setting, use 

of these cans is expected to be intermittent, although the aerosol may be regularly used throughout the 

day. Based on suppliers of aerosol mold release agents and electronic aerosol cleaners, typical use of 

aerosol cans 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 space with a 

ventilation rate of 1 ACH, the submitter estimates that the maximum concentration reached is 400 ppm.

While this modeled exposure is above the 300 ppm 8-hour AEL, it was calculated based on conservative 

assumptions: the 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 2011b), and the most 

common rate of usage is 1 aerosol can or less per day. Assuming a 6 ACH ventilation rate and the use of 

1 can in a day, the submitter estimates that the maximum concentration reached is 65 ppm, significantly 

lower than the 8-hour AEL.

As a second approach to assessing risks of short-term exposure, EPA modeled the use of an aerosol 

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

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

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

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

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

The modeling was based upon the following assumptions, described below in Table 3, regarding usage, 

area of exposure, ventilation, and the constituents of the solvent formulation.

Table 3. Summary of Assumptions for Aerosol Solvent End-Use Exposure Box-Model

Parameter Assumption

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

or 30-minutes totala

Solvent Formulation 25% propellant, 75% solvent (SolsticeTM 1233zd(E))

b

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

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

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

/min or 12.7 

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

a The submitter indicated that use of the aerosol solvent would typically be intermittent and of short duration, and use one 

to three cans per day (Anonymous Submitter 2011)

b Anonymous Submitter 2011

c EPA 1994
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The exposure point concentration for occupational 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 1994):

Equation 1: Workplace Air Concentration

Ca =

Yv x 1000

mg

x

G 24.45

AT x k MW

Where:

Ca = Concentration of the chemical in air (ppm)

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

AT = Air flow rate (m3/s)

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

24.45 = Factor used to convert from mg/m

3

to ppm

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

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

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

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

contains the same concentration of 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) (454 gram aerosol can containing 75% SolsticeTM 1233zd(E) dispensed over 

30-minutes). Table 4 shows the results of this analysis.

Table 4. SolsticeTM 1233zd(E) Aerosol Solvent End-Use Exposure 

(Calculated Using Box Model)

Sampling Location Maximum Short-Term 

Concentration (ppm) 15-minute STEL (ppm)

Area around Worker’s 

Face During Aerosol 

Spray Application

167 900

Based on the results of this modeling, even with conservative assumptions about ventilation the shortterm concentration is unlikely to reach the STEL.

Further, under good manufacturing practices, it is unlikely that these levels of 8-hour and short-term 

exposure would occur, as the proposed substitute will be used for industrial applications; where those 

applications occur indoors, robust mechanisms for containing the aerosol spray and/or for better 

ventilation, such as a fume hood, will likely be used, and aerosol solvent products will 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 expected to result in significant emissions and because 

end-users of SolsticeTM 1233zd(E) will follow certain guidelines (including training to properly use and 

handle the proposed substitute) to ensure that employee work habits are conducted in accordance with 

good industrial hygiene practices, EPA does not believe that it presents a significant toxicity concern to 

workers at end-use.
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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. Because the proper safety and disposal 

precautions in accordance with the MSDS and as part of good industrial hygiene practices, are followed, 

SolsticeTM 1233zd(E) is not expected to cause a significant threat to the environment and human health in 

the general population when manufactured or used for the aerosol solvent end-use.

8.1 Ambient Air

Aerosol solvents are a highly emissive end-use. 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 aerosol sector is 

relatively small compared to other ODS sectors, and use of SolsticeTM 1233zd(E) in replacement of other, 

more toxic alternatives, is not expected to present a significant concern to the general population. 

8.2 Surface Water

As indicated by the submitter, SolsticeTM 1233zd(E) has only slight solubility in water (1.9 g/l) and use of 

SolsticeTM 1233zd(E) in the aerosol solvent end-use is not anticipated to result in releases to surface 

water. At manufacture, the aerosol solvent product will be handled indoors with waste or accidental spills

collected with a non-combustible absorbent material, such as sand or vermiculite. EPA recommends 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

Depending upon the application for which SolsticeTM 1233zd(E) aerosol solvent is used, the spent solvent 

may be considered 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, other components of the aerosol solvent 

product or chemical compounds picked up during use of the aerosol solvent may cause the spent solvent 

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

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

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

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

EPA believes are sufficient to control human health and environmental risks. Because solid materials 

used during end-use or clean-up procedures that may be absorbed with SolsticeTM 1233zd(E) (i.e., rags, 

paper towels, trays) are disposed of in accordance with the local and federal regulations, EPA does not 

expect general population exposure to SolsticeTM 1233zd(E) through solid waste .

9. VOLATILE ORGANIC COMPOUND (VOC) ASSESSMENT

SolsticeTM 1233zd(E) has not been exempted as a volatile organic compound (VOC) under the CAA (40 

CFR 51.100(s)), and as such, emissions of SolsticeTM 1233zd(E) should be controlled. EPA has received 

a petition to exempt this compound from the definition of VOC for purposes of regulations in state 

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

insignificant impacts on ground-level ozone; however, SolsticeTM 1233zd(E) continues to be regulated as 

a VOC for that purpose 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 aerosol solvent 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, this assessment assumes that 163

MT of SolsticeTM 1233zd(E), the maximum production for all solvent end-uses (i.e., aerosol solvent; 

solvent cleaning; and adhesives, coatings, and inks) is released. This quantity is approximately equal to 
***** Final - August 3, 2012 *****

8

7.0 x 10-3percent of the VOC emissions from the solvent sector in the United States,3or approximately 

1.3 x 10-3 percent of all anthropogenic VOC emissions in the U.S.4

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

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

74%5 was applied to the entire intended U.S. annual production of SolsticeTM 1233zd(E) for aerosol 

solvent in order to estimate the maximum impact on VOC emissions across this end-uses. 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 10-3percent of the VOC emissions from the solvent 

sector in the United States, or only approximately 9.9 x 10-4percent of all anthropogenic VOC emissions 

in the U.S.

Although these VOC emissions for the aerosol solvent end-use are already several orders of magnitude 

lower than other anthropogenic emissions, it is likely that these emissions are 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 solvent cleaning and adhesives, 

coatings, and inks. Secondly, it assumes that all applications of SolsticeTM 1233zd(E) in the aerosol 

solvent end-use 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 destruction 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, 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 organic solvents (ICF 2012b). Because SolsticeTM 1233zd(E) has a small 

intended production 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 solvents, including 

aerosol solvents.

 

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

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

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 - August 3, 2012 *****

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

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

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

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

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

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

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

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. 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., Wuebbles 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.

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.
***** Final - August 3, 2012 *****

10

Appendix A:

Determination of an Acceptable Exposure Limit (AEL) 

for Trans-1-chloro-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 (Muijser H., 2011)

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

Concentrations: 0; 4,000; 10,000; 15,000 ppm

NOAEC6: 4,000 ppm (identified by independent pathologist’s report 

[Engelhardt, 2011])

NOAEC [HEC7]: 4,000 ppm x 6 hr/8 hr = 3,000 ppm

Uncertainty Factors: 3 – animal to human extrapolation

I. Introduction

Trans-1-chloro-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 1233zd(E) 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 assessment 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-chloro3,3,3-trifluoropro-1-ene are summarized below in Table 1. Subclinical effects in the heart (monocyte 

infiltration) associated with inhalation exposure to trans-1-chloro-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)
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11

Table 1. Trans-1-chloro-3,3,3-trifluoropro-1-ene Toxicological Studies 

Inhalation Studies Doses NOAEL/ NOAECa Effects

4-hour acute (nose-only, 

rat)

96,000, 156,000

and 120,000 ppm

LC50, 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 ppmc(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 (noseonly, 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/ NOAECa 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

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

bNOAEC values were revised in a pathology peer review report (Engelhardt, 2011)

cNOAEC identified in study report based on clinical chemistry, not histopathology results

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 Trans-1-chloro-3,3,3-trifluoropro-1-ene

Several repeated dose inhalation studies assessing the toxic potential of trans-1-chloro-3,3,3-trifluoropro1-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-trifluoropro1-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 - August 3, 2012 *****

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 pharmacodynamic [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 Trans-1-chloro-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) (van Triel, 2009). 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 exposure. 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 LC50. 

One female from Group A died on the first day of the recovery period. Other animals, male and 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 following recovery, no other abnormalities were found. The combined-sex LC50

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) (Staal, 

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 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 relative numbers of 

monocytes and absolute number of neutrophils in males at 20,000 ppm. Increases in serum liver enzymes 

(ALAT8and ASAT in 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 (Engelhardt, 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 noted to be located only 

 

8 ALAT, alanine transaminase; ASAT, aspartate transaminase
***** Final - August 3, 2012 *****

13

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 cardiomyopathy”. 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 

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 (Staal, 2009). 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 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 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 statistically 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 

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 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, 4,000, 10,000, or 15,000 ppm for 6 hrs/day for 5 days/week for 13 

weeks, for a total of 65 exposure days (Muijser, 2011). Rats were observed twice 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 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 

histopathology. 
***** Final - August 3, 2012 *****

14

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.

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 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 increased 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 compoundinduced 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 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 determination of an AEL for trans-1-chloro-3,3,3-

trifluoropro-1-ene is 4,000 ppm.

Developmental Toxicity

Trans-1-chloro-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 (Waalkens-Berendsen and van den Hoven, 2011), 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-implantation 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.
***** Final - August 3, 2012 *****

15

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 

increased 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.

Rabbit Prenatal Developmental Study

Trans-1-chloro-3,3,3-trifluoropro-1-ene was further evaluated in a developmental study in the New 

Zealand white rabbit. Hoffman (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 weights, 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 NOAEC 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 (Atterson, 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-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 exposed 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 dogs 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 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 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 - August 3, 2012 *****

16

V. Supporting Genotoxicity Studies for Trans-1-chloro-3,3,3-trifluoropro-1-ene

Reverse Mutation Assay

Trans-1-chloro-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

(Wagner et al., 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 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

Trans-1-chloro-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 (Staal, 2009). 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. Trans-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

Trans-1-chloro-3,3,3-trifluoropro-1-ene was 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 (Staal, 2009). 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

Trans-1-chloro-3,3,3-trifluoropro-1-ene was tested in an independent assay for its ability to induce 

micronuclei in the bone marrow of male mice (de Vogel, 2009). 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-chloro3,3,3-trifluoropro-1-ene (99.99% pure) at concentrations 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 hours postexposure; 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 - August 3, 2012 *****

17

Chromosomal Aberration

Trans-1-chloro-3,3,3-trifluoropro-1-ene (99.98% pure) was tested in a chromosomal aberration assay with 

human lymphocytes cultured in vitro (Pritchard and Damant, 2011). Human lymphocytes, isolated from 

whole blood samples provided by volunteers, were treated with trans-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). Trans-1-chloro-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.

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