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Significant New Alternatives Policy Program 

Refrigeration and Air Conditioning Sector

Risk Screen on Substitutes for CFC-11 and HCFC-123 in Centrifugal Chillers

Substitute: Trans-1-chloro-3,3,3-trifluoropro-1-ene (SolsticeTM 1233zd(E))

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

and, therefore, can be disclosed to the public.

1. INTRODUCTION

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

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

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

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

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

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

EPA’s decision on the acceptability of a substitute is based 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 refrigeration and air 

conditioning 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 (also know as (E) 1-chloro-3,3,3-

trifluoroprop-1-ene and hereinafter referred to as SolsticeTM 1233zd(E)) as a substitute for CFC-11 and 

HCFC-123 in low-pressure centrifugal chillers. 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 chillers 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, installation, servicing, and 

disposal of the proposed substitute in the centrifugal chiller end-use does not pose unacceptable risk to 
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workers. Lastly, general population exposure modeling was performed to ensure that the proposed 

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

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

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

 Section 3: Atmospheric Assessment

 Section 4: Flammability Assessment

 Section 5: Potential Health Effects

 Section 6: Occupational Exposure Assessment

 Section 7: General Population Exposure Assessment

 Section 8: Volatile Organic Compound Assessment

 Section 9: References

2. SUMMARY OF RESULTS

SolsticeTM 1233zd(E) is recommended for SNAP approval for the centrifugal chiller 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-11 and HCFC-123. Given that appropriate safety and 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 installation, maintenance, and disposal activities, no 

significant toxicity risks to workers or the general population are expected. In addition, based on the 

characteristics of the proposed substitute and the proper 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 atmospheric integrity posed by the use of 

SolsticeTM 1233zd(E) in the refrigeration and air-conditioning 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 and HCFC-123, 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. SolsticeTM 1233zd(E) does 

however, also have a non-zero ODP, but at 0.00024, this value is very small. 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, 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 ODS. 
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Table 2. Atmospheric Impacts of SolsticeTM 1233zd(E) Compared to CFC-11 and HCFC-123

Refrigerant ODP GWP ALT 

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

b,a 26 daysa

CFC-11 1.0d 4750e 45 yearsd

HCFC-123 0.01f 77e 1.3d

a 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)

fWuebbles and Patten (2009) 

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). 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 

1,000 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. 

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, 

 

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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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 the exposure 

guidelines and the ventilation and PPE recommendations outlined in the MSDS for SolsticeTM 1233zd(E)

and this risk screen. 

6. OCCUPATIONAL EXPOSURE ASSESSMENT

To ensure that use of the proposed substitute in chillers does not pose an unacceptable risk to workers 

during manufacturing, installation, servicing, and disposal, occupational exposure modeling at installation

was performed for the proposed substitute. Although modeling is only performed for installation, it is 

assumed that exposure during servicing and disposal would not exceed exposure during installation. All 

installation, maintenance, and disposal activities for SolsticeTM 1233zd(E) chillers are anticipated to occur 

on-site. Servicing of the chiller is assumed to not exceed exposures during installation and disposal. 

Installation and disposal are anticipated to have similar exposures, since both require the connection of 

pipes to transfer the refrigerant; as it is likely that less refrigerant remains in the unit at disposal, it is 

assumed that installation of a chiller would require transfer of a greater amount of refrigerant, and thus 

result in greater worker exposure. Thus, occupational exposure was conservatively modeled based on 

installation.

 

Installation of chillers is expected to occur with limited frequency (up to approximately one event per 

day) and with limited duration of exposure to the refrigerant charge. Potential exposures to the refrigerant 

are expected to occur during activities related to charging the refrigerant from the storage tanks into the 

chiller (e.g., connecting of pipes). Such activities and related exposure is anticipated to occur within 15-

30 minutes (per event/day). To evaluate the risk of exposure at installation, the maximum modeled 

exposure concentration was compared to 900 ppm, the SolsticeTM 1233zd(E) STEL developed by EPA 

based on the submitter’s 300 ppm AEL value.

The methodology used for this screening assessment is described in Chapter 5 of the Background 

Document. A box-model approach was used to evaluate potential worker exposure to alternative 

refrigerants. This approach has been widely used for many years to estimate probable exposures of 

workers to hazardous airborne materials, and has been described in detail by the National Institute for 

Occupational Safety and Health (NIOSH). This model takes into consideration the duration and 

magnitude of the resulting exposure which is influenced by 1) duration and intensity of the release, 2) rate 

at which contaminated air is diluted with uncontaminated air, 3) proximity of the worker to the source of 

the release, and 4) the length of time the worker remains in the affected space. 

The release per event was conservatively assumed to be 1 percent of the equipment charge during 

installation3and then was multiplied by the number of installations estimated to occur over a workday. 

One installation per workday was assumed based on data obtained from the Vintaging Model.4 The 

 

3One percent release rate at installation was conservatively assumed based on a range of industry estimates. Further, it is assumed 

that installation will be conducted according to best practices, including the use of release-minimizing transfer apparatus, and 

only by trained personnel.

4

ICF International maintains the Vintaging Model for EPA in order to simulate the aggregate impacts of the ODS phaseout on 

the use and emissions of various fluorocarbons and their substitutes over a period of several years across more than 60 different 

end-uses. The model tracks the use and emissions of various compounds for the annual vintages of new equipment that enter 

service in each end-use. The vintage of each type of equipment determines such factors as leak rate, charge size, number of units 

in operation, and the initial ODS substance that the equipment contained. 
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analysis models a refrigerant charge size of 6,000 lbs (2,722 kgs), the maximum charge size indicated by 

the submitter (Anonymous Submitter 2011a). 

Based on the assumptions described above, the modeling indicates that short-term (15-minute) worker 

exposure concentrations could reach 917 ppm during installation of SolsticeTM 1233zd(E), which is 

slightly above the STEL (900 ppm). However, the 15-minute estimated exposure was derived using 

conservative assumptions, and represents a worst-case scenario with a low probability of occurrence. 

These types of systems are typically installed, maintained, and disposed by trained personnel using proper 

industrial hygiene techniques. When installing, servicing, or disposing of large chillers, these techniques 

should be strictly followed. Adherence to the proposed substitute’s MSDS and use of proper engineering 

controls and PPE make it unlikely that exposure to SolsticeTM 1233zd(E) would occur. Adequate 

ventilation should always be established during any use, handling, or storage of Solstice

TM 1233zd(E). 

Engineering controls should include vapor-in air detection systems and local exhaust ventilation during 

use of SolsticeTM 1233zd(E); 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 chemical splash goggles or face shield, impervious gloves, and chemical-resistant boots and 

clothing (Anonymous Submitter 2011b, OSHA 1994). 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, Contaminated clothing is not to leave 

the workplace and must be cleaned before reuse (Anonymous Submitter 2011b). Because use of exposure 

controls and adherence to the appropriate occupational safety guidelines would be followed under good 

manufacturing practices, as mentioned above, EPA believes that SolsticeTM 1233zd(E) does not pose a 

significant risk to workers during installation, maintenance, and disposal activities.

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

hydrogen chloride, carbonyl halides, carbon monoxide, and carbon dioxide when SolsticeTM 1233zd(E) is 

exposed to fire. Containers of SolsticeTM 1233zd(E) should not be allowed to contact open flames, 

glowing metal surfaces, or electrical heating elements. EPA believes that if 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. GENERAL POPULATION EXPOSURE ASSESSMENT

SolsticeTM 1233zd(E) is not expected to cause a significant impact on human health in the general 

population when used as a refrigerant in centrifugal chillers. The compound is proposed for use in closed 

systems that are operated near atmospheric pressure. General population exposures to ambient air and 

surface water releases are not expected from this end use. 

8. VOLATILE ORGANIC COMPOUND (VOC) ASSESSMENT

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

CFR 51.000), 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 

centrifugal chillers in one year to other anthropogenic sources of VOC emissions. Assuming the 

submitter’s maximum annual production of SolsticeTM 1233zd(E) for all refrigeration and air-conditioning 
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sector end-uses (i.e., centrifugal chillers, organic rankine cycle systems, and heat transfer) is entirely 

released, approximately 45 MT of VOCs would be emitted. This is approximately equal to 5.6 x10-1

percent of the VOC emissions caused by the generation of electricity for all refrigeration and air 

conditioning applications in the United States, or approximately 3.7x10-4percent of all anthropogenic 

VOC emissions in the U.S.5 

While these emissions may be significant, release of total production for all refrigeration and airconditioning end- uses is extremely unlikely to occur. Thus, a secondary analysis was made to determine 

likely annual VOC emissions from use of SolsticeTM 1233zd(E) in low-pressure centrifugal chillers. 

Using leak estimates from the Vintaging Model, the annual release rate (including operating, servicing, 

and disposal leak rates) was calculated to be approximately 1.0% of the refrigerant charge size.6 Using 

these anticipated releases of SolsticeTM 1233zd(E) from centrifugal chillers, and assuming that the entire 

production for all refrigeration and air-conditioning end-uses was charged in centrifugal chillers, only 0.5 

MT of VOCs would be expected to be released into the atmosphere. This amount is approximately 

5.8x10-3percent of the VOC emissions caused by the generation of electricity for all refrigeration and air 

conditioning applications in the United States, or approximately only 3.9x10-5percent of all 

anthropogenic VOC emissions in the U.S. Further, VOC emissions from manufacture are controlled 

through standard industry practices, and as such, emissions from the manufacture of the proposed 

substitute for centrifugal chillers are likely to be further minimized. As VOC emissions from anticipated 

releases of SolsticeTM 1233zd(E) are orders of magnitude lower than other anthropogenic sources, the 

environmental impacts of these VOCs are not considered to be a significant concern.

 

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

6 The average annual leak rate (0.4%), annual service rate (0.6%) and EOL disposal rate (1%) for centrifugal chillers was 

approximated using data from the Vintaging Model (v4.4_3.23.11) and industry estimates. Using an average lifetime of 25 years 

for centrifugal chillers, a total annual release rate of 1.0% was determined.
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9. 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.

EIA 2011. Annual Energy Outlook 2011 with Projections to 2035. Independent Statistics & Analysis 

Table Browser. Accessed September 2011. Available online at

<http://www.eia.gov/oiaf/aeo/tablebrowser/>.

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. 2012. Determination of an Acceptable Exposure Limit (AEL) for HBA-2. Prepared for 

U.S. Environmental Protection Agency. January 23, 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.

Wuebbles, D.J., and K.O. Patten, Three-dimensional modeling of HCFC-123 in the atmosphere: 

Assessing its potential environmental impacts and rationale for continued use, Environ. Sci. 

Technol., 43 (9), 3208-3213, doi: 10.1021/es802308m, 2009.
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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

NOAEC7: 4,000 ppm (identified by independent pathologist’s report 

[Engelhardt, 2011])

NOAEC [HEC8]: 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 HBA-2 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.

 

7 No Observable Adverse Effect Concentration (NOAEC)

8 Human Equivalent Concentration (HEC)
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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
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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 

(ALAT9and 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 

 

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

11

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. 

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 - August 3, 2012 *****

12

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.

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

13

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 *****

14

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-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 (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-enewas 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 *****

15

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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