UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

September 22, 20 15 

MEMORANDUM 

SUBJECT: PC Code: 711358; Trans-1-3, 3, 3-tetrafluoropropene; Human Health Risk 

Assessment and Ecological Effects Assessment to Support Proposed 

Exemption from the Requirement of a Tolerance When Used as Inert 

Ingredients in Pesticide Fonnulations. 

All PC Code: 71 1358 

Decision No.: N/A 

DP Barcode: N/A 

Regulatory Action: Inert 

Tolerance Exemption; 40 

CFR 180.910, 180.930 

and 180.940(a) 

Petition No: IN-10753 All CAS Reg. No: 29118-

24-9 

Inert Tracking No: N/A 

FROM: 

Through: 

TO: 

Lisa Austin, Ph.D., Toxicologist 

Mark Dow, Ph.D., Biologist 

Chemistry, Inert and Toxicrtlogy Assessment Branch (CITAB) 

Registration Division (750 ) J 

C

Kerry 

hemi

L

stry

eif

, 

e

I

r

nert 

, Tean1 

and 

Leader 

Toxico:rJ.~ ~Jy A~esessment ..._ ~ Branch (CITAB) 

Registration Division (7505P) 

PV Shah, Chief 

Chemistry, Inert and Toxicology Assessment Branch (CITAB) 

Registration Division (7505P) 
EXECUTIVE SUMMARY 

EPA received a petition (PP# 1 E7938) from The Acta Group, L.L.C., 2000 Pennsylvania 

Avenue, N.W., Suite IOOW Washington, D.C. 20037, on behalfofHoneywell Specialty 

Materials NIC4, I 01 Columbia Road, Morristown, NJ 07962-1053 requesting an exemption from 

the requirement of a tolerance for the use of trans 1-3, 3, 3-tetrafluoropropene (CAS Reg. No. 

29118-24-9) as an inert ingredient (propellant) up to 30% in pesticide products on all pre- and 

post-harvest food commodities under 40 CFR part 180.910; in pesticide products applied to 

animals under 40 CFR part 180.930; and in pesticide products used for food-contact surface 

sanitizing solutions under 40 CFR part 180.940(a). EPA published the notice of filing (NO F) for 

this petition in the Federal Register on April 4, 2012 (77 FR 43566). No comments were 

received in response to this notice. Currently, trans 1-3, 3, 3-tetrafluoropropene is recommended 

for approval as an aerosol propell ant under the Significant New Alternatives Policy (SNAP) as 

an alternative for ozone-depleting substances. 

Toxicity summaries oftrans 1-3, 3, 3-tetrafluoropropene were reproduced from data 

submitted by The Acta Group, L.L.C., on behalf of Honeywell Specialty Materials NIC4. Trans 

1-3, 3, 3-tetrafluoropropene was administered via the inhalation route of exposure only in these 

studies. Some of the studies contained the incorrect chemical name but contained the correct 

alternate CAS# 1645-83-6. Therefore, in the some of the fo llowing studies, trans 1-3, 3, 3-

tetrafluoropropene was identified by the alternate CAS # 1645-83-6 when the incorrect name 

was used. 

Acute inhalation toxicity was low for CAS # 1645-83-6. Acute inhalation LDsos were 2: 

I 01,850 parts per million (ppm) (approximately 713 milligrams/kilogram (mg/kg)) in rats and 

mice. CAS# 1645-83-6 was not a dermal irritant in rabbits. 

Two subchronic toxicity studies via the inhalation route of exposure were available for CAS# 

1645-83-6 in rodents. Toxicity was not observed in rats or mice at doses as high as 5000 ppm 

(approximately equi valent to 7800 mg/kg/day human equivalent dose) following 13 weeks and 

90 days of exposure, respectively. The 90 day inhalation toxicity study in mice also evaluated 

the carcinogenic potential of CAS# 1645-83-6 by conducting a toxicogenomic assessment. 

CAS# 1645-83-6 was classified as non-carcinogenic by the toxicogenomic assessment at I 0,000 

ppm (approximately equivalent to 15600 mglkg/day human equivalent dose), the highest dose 

tested. 

Developmental toxicity studies via the inhalation route were available in rats and rabbits. 

Neither maternal nor developmental toxicity was observed in either study up to 15000 ppm 

(approximately equivalent to 23400 mg/kg/day human equivalent dose), the highest dose tested. 

Two Ames Tests via gas exposure were available for review with CAS# 1645-83-6. The 

mouse micronucleus assay was performed via inhalation exposure. These tests were negative. 

A chronic study with CAS# 1645-83-6 was not available for review. A chronic study with 

trans-1 ,3,3,3-tetrafluoropropene is not available for review. Although a chronic toxicity study is 

not available, there is no concern for the lack of it because toxicity is not seen following up to 13 

weeks of exposure to trans-1.3.3,3-tetrafluoroprop-1-ene at excessive doses (7800 and 15,600 

2 
mg/kg/day). Also, toxicity is not seen in the developmental study at an excessive dose of23,400 

mg/kg/day. Therefore, the likelihood that chronic exposure to doses below the limit dose will 

result in toxic effects is highly unlikely and the Agency has no concerned with regard to it. 

Neurotoxicity studies were not available for review. However, evidence of neurotoxicity was 

not observed in the submitted inhalation studies. 

Immunotoxicity studies were not available for review. However, very slight mononuclear 

cell infiltrates in the heart were observed in only females (3/5) at the LOAEL of 5000 ppm 

(approximately equivalent to 7800 mg/kg/day human equivalent dose lowest dose tested) 

following 10 days of exposure via inhalation in Sprague Dawley rats. This effect was not dose 

dependent with regard to either incidence or severity. Similar effects along with increased 

monocyte count were observed in the heart at 15,000 ppm (approximately equivalent to 23400 

mg/kg/day human equivalent dose; highest dose tested) in a 13 week study via inhalation in 

Sprague Dawley rats. The NOAEL was 5000 ppm (equivalent to 7800 mg/kg/day human 

equivalent dose). This study included more rats, was conducted in the same species ofrats that 

underwent the same route of exposure and was of longer duration (13 weeks vs I 0 days). 

Mononuclear cell infiltrates in the heart were not observed at 5000 ppm (equivalent to 7800 

mg/kg/day human equivalent dose) in either the male or female rat as was observed in the I 0 day 

study. Therefore, since the incidence and severity of these effects were not dose-dependent in 

the 10 day study, the 13 week study was considered more reflective of toxicity resulting from 

exposure to CAS# 1645-83-6. However, the Agency is not concern about these effects since 

they occur well above the limit dose and exposure beyond that is highly unlikely and unrealistic. 

Two studies were available for CAS# 1645-83-6 on male rodent metabolism and 

pharmacokinetics. In rodents, CAS# 1645-83-6 via the inhalation route of exposure was rapidly 

absorbed, metabolized and excreted. The urine was the major route of excretion. In rats, the 

major metabolite was S-(333-trifluoro-trans-propenyl)-mercaptolactic acid. In mice, the major 

metabolite was a presumed amino acid conjugate of 3, 3, 3-trifluoropropionic acid. Other 

identified metabolites were S-(3.3,3-trifluoro-transpropenyl)- L-cysteine, N-acetyl-S-(3,3,3-

trifluoro-trans-propenyl)-L-cysteine and 3,3,3-trifluoropropionic acid. 

An endpoint of concern was not identified in the toxicity database for trans 1-3, 3, 3-

tetrafluoropropene. No adverse effects were observed at doses as high as 5000 ppm 

(approximately 7800 mg/kg/day human equivalent dose). Therefore, a qualitative risk 

assessment for trans 1-3, 3, 3-tetrafluoropropene was conducted for all pathways of human 

exposure for acute and chronic dietary exposure assessment and short and intermediate dermal 

and inhalation exposures. 

Trans 1-3, 3, 3-tetrafluoropropene is expected to persist in soil and sediment. Bioconcentration in aquatic organisms is moderate to high. It is not expected to be toxic to aquatic 

organisms. Trans l-3, 3, 3-tetrafluoropropene is not biodegraded by microorganisms in sludge. 

Potential areas of environmental justice concerns, to the extent possible. were considered in 

this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 

3 
Taking into consideration all available information on trans 1-3, 3, 3-tetrafluoropropene, 

EPA concludes that there is a reasonable certainty that no harm will result to the general 

population or to infants and children from aggregate exposure to trans 1-3, 3, 3-

tetrafluoropropene. Therefore, the establishment of an exemption from tolerance under 40 CFR 

180.910, 180.930 and l80.940(a) for residues of trans 1-3, 3, 3-tetrafluoropropene when used as 

an inert ingredient (propellant) at no more than 30% by weight in the end-product formulation 

can be considered safe under section 408 of the FFOCA. 

1. BACKGROUND 

On November 3, 20 11 The Acta Group, L.L.C., 2000 Pennsylvania Avenue, N.W., Suite 

I OOW Washington, D.C. 20037, on behalf of Honeywell Specialty Materials NIC4 101 

Columbia Road, Morristown, NJ 07962-1053, submitted a petition (PP# I E7938) requesting an 

amendment to 40 CFR 180.910, 180.930 and 180.940 by establishing an exemption from the 

requirement of a tolerance for residues of trans 1-3, 3, 3-tetrafluoropropene (CAS Reg. No. 

291 I 8-24-9), when used as an inert ingredient as a propellant in pesticide formulations. EPA 

published the Notice of Filing for this petition in the Federal Register on April 4, 20 12 (77 FR 

43566). No comments were received in response to this notice. 

Currently, trans 1-3, 3, 3-tetrafluoropropene was recommended for approval as an aerosol 

propellant under the Significant New Altematives Policy (SNAP) as an altemative for ozonedepleting substances. In the risk screen document for HFO 1234ze (trans l-3, 3, 3-

tetrafluoropropene) ICF recommended an acceptable exposure limit of I ,000 ppm for long-term 

occupational exposures based on the 13-week inhalation study in rats. Intermittent consumer 

exposure was not to exceed 420 ppm based on the 4-week inhalation study in rats (EPA, 20 I 0). 

This document provides an assessment of the risk to human health and the environment for 

trans 1-3, 3, 3-tetrafluoropropene when used as an inert ingredient (propellant) in pesticide 

formulations. Study reports submitted to the Agency were reproduced and referenced in this 

assessment. 

2. Inert Ingredient Profile 

Some ofthe physical and chemical characteristics oftrans 1-, 3, 3, 3-tetrafluoropropene 

along with its structure and nomenclature, are found in Table I. 

Table 1. Physical and Chemical Properties of Trans 1-3, 3, 3-tetrafluoropropene 

Parameter Value Source 

4 
Structure 

CAS# 

Molecular Weight (g/mol) 

Common Names 

Physical State 

Melting Point (°C) 

Boiling Point (°C) 

Density (g/cm3) 

Vapor Pressure (hPa) 

Partition Coefficient (Log P) 

Water Solubility 

Log Kow 

Specific Gravity 

3. Hazard Assessment 

F, l 

C H I '\, I 

F c-;:;C, 

I F 

H 

291 18-24-9; 1645-83-6 

114 

!-Propene, 1 ,3,3,3-tetrafluoro-, 

(I E)-, HF0-1 234ze, (E)-

1.3,3,3-tetrafluoroprop- 1-ene 

Clear colorless liquified gas 

Not Available 

-1 9 

Not Available 

4 192 

1.6 

373 mg/L 

2.0 1 

Not Available 

Y ounis (2006) 

Spruit et.al. (2006) 

Hori (2008) 

MRID 48649503 

Spruit et.al. (2006) 

Kayashima (2008) 

MRID 48649504 

Spruit et.al. (2006) 

Hori (2008) 

MRID 48649503 

Spruit et.al. (2006) 

Spruit et.al. (2006) 

The following toxi city studies for trans 1-3, 3, 3-tetrafluoropropene were reproduced from 

the data package submitted by The Acta Group, L.L.C., on behalf of Honeywell Specialty 

Materials NIC4. In some of the studies the chemical name was incorrect but was correctly 

identified by the alternate CAS # 1645-83-6. Therefore, in the following studies. trans 1-3, 3, 3-

tetrafluoropropene was identified by the alternate CAS # 1645-83-6 when the incorrect name 

was used. 

Acute Toxicitv Studies 

Table 2. Acute Toxicity Profile of CAS Reg. No.# 1645-83-6 

Study Type Reference Results 

Acute Dermal DiDonato, 2010 Not an irritant 

Irritation- rabbit 

5 
Table 2. Acute Toxicity Proftle of CAS Reg. No.# 1645-83-6 

Study Type Reference Results 

Acute Inhalation- Hoffman, 2004 LCso> 10 1,850 

mous mg/L;(approximately 713 e 

mg/kg/day) 

Acute Inhalation- LCso > I 03,300 mg/L; 

rat (approximately 723 mg/kg/day) 

Acute Inhalation- Hoffman, 2010 Negative for micronucleus assay 

Micronucleus 

Assay-mouse 

Dermal Irritation: 

In an acute dermal toxicity study, 3 rabbits (I male; 2 females) were dosed with 0.4 ml of 

trans 1-3, 3, 3-tetrafluoropropene onto a hilltop chamber for a 4 hour exposure. The male animal 

was dosed on Site #2 and the two female animals were dosed on Site #3. Erythema and edema 

were scored at 60 minutes, and at 24, 48 and 72 hours following patch removal. Animals were 

observed for toxicological and pharmacological effects at each dermal observation period and 

observed for mo11ality daily. Body weights of all animals were recorded pretest and tem1ination. 

Neither Erythema nor edema was observed at any time point following the 4 hour exposure. 

There were no abnormal physical signs and body weight changes were normal. CAS# 1645-83-6 

was not a dermal irritant (MRJD 486495 I 0). 

Inhalation: 

An acute inhalation toxicity range-fi nding study was conducted in CD-I mice (2/sex) at 

20,000 or 100,000 ppm (approximately 140 or 700 mg/kg/day) of CAS# 1645-83-6. The test 

substance was administered via whole-body exposure for 4 hours. Exposure levels were 

determined using a MlRAN® Ambient Air Analyzer. 

Observations for signs of toxicity were conducted on all animals at fifteen-minute intervals 

during the first hour of exposure and hourly for the remainder of the exposure. Detailed physical 

observations were performed on all animals just pri or to exposure and immediately upon 

removal from the chamber and once daily thereafter. Body weight measurements were obtained 

just prior to exposure and at termination. After a 7-day post-exposure observation period, all 

animals were sacrificed. Complete macroscopic postmortem examinations were performed on all 

animals. 

6 
There were no mortalities or treatment related effects on body weight. At 20,000 ppm 

(approximately 140 mg/kg/day), labored breathing was observed during the last 2 hours of 

exposure in 2/8 animals. At I 00,000 ppm (approximately 700 mglkg/day), 4/8 animals displayed 

labored breathing during the last 2 hours of exposure. The LCso was greater than I 0 I ,850 ppm 

((approximately 713 mg/kg/day) based on the average analytical concentration) (MRlD 

48649512). 

Acute Inhalation and Micronucleus Assay: 

Five male and 5 female Sprague Dawley rats were exposed (nose only) to 0 (control), 

100,000 or 207,000 ppm (approximately 700 or I449 mglkg/day) of CAS# 1645-83-6 for 4-

hours and held for a 14-day post-exposure observation period. All rats survived and there were 

no toxicologically significant findings. Additionally, groups of I 0 male and 10 female CD-I 

mice were exposed to the same levels. Mice were held for 1 or 2 days following exposure and 

then euthanized and bone marrow san1pled for micronucleus evaluation. There were no 

toxicologically significant signs reported and there was no increase in the frequency of 

micronuclei. 

There were no mortalities in the mouse study. The LCso was greater than 103,300 ppm 

(approximately 721 rng/kg/day). 

Micronucleus evaluation: 

No statistically significant increases in the frequency of rnicronucleated polychromatic 

erythrocytes and no substantial decreases in the proportion of polychromatic erythrocytes were 

observed in mice exposed to CAS# 1645-83-6 and killed 24 or 48 hours later, compared to 

concurrent negative control values (P>O.O I in each case). The positive control compound, 

cyclophosphamide, produced highly significant increases in the frequency of micronucleated 

polychromatic erythrocytes at 24 and 48 hours after dosing (P<O.OO I). A statistically signi ftc ant 

decrease in the proportion of polychromatic erythrocytes was observed at the 48 hour sampling 

time only (P>O.O 1 ). lt was concluded that CAS# 1645-83-6 did not show any evidence of 

causing an increase in micronuclei or bone marrow cell toxicity when administered to CD-I mice 

for a single 4-hour nose-only inhalation exposure in this in vivo test procedure (MRID 

48649516). 

Repeated Dose Studies via Inhalation: 

In the following studies, the doses in the parentheses represent the approximate human 

equivalent dose in mg/kg/day that was calculated by the reviewer. The formula used to derive 

these values can be found in the appendix. 

2-week toxicity -Rat: 

Groups of 5 male and 5 female Sprague Dawley rats were exposed nose-only to target 

concentrations of 0 (control), 5,000, 20,000, or 50,000 ppm (7800, 31200. or 780000 mg/kg/day) 

7 
CAS# I 645-83-6 for 6 hours a day, 5 days a week during a 2-week period, with a total number of 

10 exposure days. 

Data on clinical observations, body weight gain, food consumption, food conversion 

efficiency, hematology and clinical chemistry were determined. In addition, animals were 

examined grossly at necropsy, organs were weighed, and a selection of organs and tissues 

(including the complete respiratory tract and nasal passages) was examined microscopically. 

The mean actual concentrations(± standard deviation) of CAS# 1645-83-6 in the test 

atmospheres, based on total carbon analysis, were 4,961 (±52), 20,904 (±833) and 51,770 

(±1778) ppm (7739, 32610, or 80761 mg/kg/day) for the low-, mid- and high-concentration 

levels. Corresponding nominal concentrations as calculated from the ratio of the flow of test 

material and the total flow were 4,895, 20,462 and 49,186 ppm (7636, 31921 and 76730 

mg/kg/day). 

Daily observation of the animals did not reveal any exposure-related clinical abnormalities. 

No treatment-related differences in body weight gain, food consumption and food conversion 

efficiency were seen. 

The concentration of red blood cells (5%) and thrombocytes (12%) were increased and the 

mean corpuscular hemoglobin concentration was decreased (2%) in males of the high 

concentration group. Prothrombin time was increased in female animals of the mid- (22%) and 

high (24%) concentration groups. Monocyte count was increased (100%) in the male animals of 

the high concentration group. 

The levels in plasma of glucose (52%), alanine aminotransferase (45%), aspartate 

aminotransferase (115%), albumin (7%) and urea (53%) were increased and the levels of 

cholesterol (53%) and phospholipids (28%) and sodium (2%) were decreased in male animals of 

the high-concentration group. The levels of aspartate aminotransferase (56%) and urea (26%) 

were also increased in the male animals of the mid concentration group. In female animals of the 

high concentration group, the levels of alkaline phosphatase (39%), alanine aminotransferase 

(50%) and urea (53%) were increased and cholesterol was decreased (53%). In the female 

animals of the mid concentration group the level of cholesterol ( 17%) was also decreased and the 

level of aspartate aminotransferase was increased (50%). Although the latter was also higher 

(31 %) in female animals of the high concentration group, it did not reach statistical significance. 

Absolute (13%) and relative lung (9%) weights were decreased in male animals of the high 

concentration group. Absolute (9 and 13%) and relative ( 13 %) liver weights were increased in 

male and female animals of the high-concentration group, though statistical significance was not 

reached for the absolute liver weight ( 13%) in the female animals. 

Macroscopic examination at necropsy revealed an exposure-related pale appearance (4/5 vs 0 

in control animals) of the li vers of almost all animals of the high-concentration group. 

Microscopic examination revealed exposure-related histopathological changes in the liver of 

the mid- and high concentration male (mononuclear cell aggregates/necrotic hepatocytes and 

8 
hepatocellular vacuolation) and high concentration femal e (increased severity of hepatocellular 

vacuolation) animals, in the nasal passages (decreased goblet cell expression in the septum) of 

the high-concentration male and female animals, and in the heart (very slight mononuclear cell 

infiltrates) of the mid- and high-concentration male and female animals. The NOAEL was not 

established. The LOAEL was 5,000 ppm (approximately 7800 mg/kg/day) based on 

mononuclear cell infiltrates in the heart of female animals (MRID 48649515). 

13-week toxicity - Rat: 

Groups of I 0 male and I 0 female Sprague Dawley rats were exposed nose-only to target 

concentrations of 0 (control) 1500, 5,000 ppm or 15,000 ppm (mean actual concentrations(± 

standard deviation, based on total carbon analysis, were 1504 (± 4), 4999 (± 18), and 15,002 (± 

57) ppm (approximately 2340. 7800 and 31200 mg/kg/day) CAS# 1645-83-6 (gas) for 6 hours a 

day, 5 days a week during a 13-week period, with a total number of 63-64 exposure days. 

Clinical signs, body weight gain, food consumption, food conversion efficiency, 

ophthalmoscopy, hematology and clinical chemistry were evaluated. In addition, animals were 

examined grossly at necropsy, organs were weighed, and a selection of organs and tissues 

(including the complete respiratory tract and nasal passages) was examined microscopically. 

One female control animal was found dead on the 75th day of the study. Otherwise, there 

were no mortalities. There were no treatment-related find ings regarding clinical abnormalities, 

body weight gain, food consumption. food conversion efficiency. or ophthalmoscopic 

examination. 

There were significant differences seen in hematology parameters, i.e. increases in 

thrombocytes (14%) and monocytes ( 100%) in male animals of the high concentration group and 

increases in hemoglobin concentration (4%), and packed cell volume (6%), and to a slight extent 

also monocytes (92%) in females of the high concentration group may be related to the 

treatment. 

Similarly, there were significant increases seen in clinical chemistry parameters, i.e. in ASA T 

(129%) and urea (14%) in plasma ofthe male animals of the high concentration group, and in 

glucose (18%), urea (22%), inorganic phosphate (20%), and potassium (II %) in female animals 

of the high concentration group. 

The absolute and relative weight of the uterus was decreased in female animals of the high 

concentration group. This finding was considered due to uterus weight variations related to the 

oestrous cycle rather than related to the exposure. No other changes in absolute or relative organ 

weights were detected. 

Macroscopic examination did not show exposure-related gross pathology. 

Microscopic examination revealed that CAS# 1645-83-6 induced multifocal mononuclear 

cell infiltrates in the heart of the high-concentration males (9/ 1 0) and females (5/1 0) versus 0/ 10 

in control animals. Fibrosis was not observed. 

9 
The NOAEL was 5000 ppm (7800 mg/kg/day). The LOAEL was 15000 ppm (23400 

mglkg/day) based on increased monocytes, potassium and increased incidence of multi focal 

mononuclear cell infiltrates in the heart of the high-concentration males and females (MRJD 

48649517). 

Developmental/Reproduction Toxicity Studies: 

Range Finding- rabbit 

Four groups oftime-mated female New Zealand White rabbits (6/group) were exposed to 

either clean filtered air or vapor atmospheres of test article, CAS# 1645-83-6, for 6 hours daily in 

whole body inhalation chambers during gestation days 6-28. Target test article concentrations 

were 0, 1500, 5000 and 15000 ppm (2340, 7800 and 23400 mglkg/day). Overall mean measured 

exposure concentrations were 0, 1502, 5026 and 15040 ppm (approximately 2340, 7800 and 

23400 mg/kg/day) for the same respective target exposures. All animals were observed twice 

daily for mortality and moribundity. Clinical observations, body weights and food consumption 

were recorded at appropriate intervals. On gestation day 29, a laparohysterectomy was 

performed on each female. The uteri, placentae and ovaries were examined. and the numbers of 

fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid 

uterine weights were recorded, and net body weights and net body weight changes were 

calculated. The fetuses were weighed and examined for external malformations and 

developmental variations. 

All animals survived to the scheduled necropsy on gestation day 29. No clinical observations 

or macroscopic findings were attributed to test article exposure. Mean maternal body weights, 

body weight gains, net body weights. net body weight gains, gravid uterine weights and food 

consumption were unaffected by test article exposure at all exposure levels. 

Intrauterine growth and survival were unaffected by maternal test article exposure at 1500, 

5000 and 15000 ppm (2340, 7800 and 23400 mg/kg/day). 

No external fetal malformations were attributed to maternal test article exposure; no external 

developmental variations were noted for fetuses at any exposure level. 

The maternal and developmental NOAEL was 15000 ppm (23400 mg/kg/day) (MRID 

48649514). 

In another study, 88 (22 does/dose) time-mated female New Zealand White rabbits received 

whole-body inhalation exposures with clean air (air control) or with CAS# 1645-83-6 at 

exposure concentrations of 4,000, 10,000 or 15,000 ppm (6240, 15600 and 23400 mglkg/day) 

from GD 6 to GD 28 (GO 0 =day of mating confirmation). The exposure durations were 6 

hours per day for 7 consecutive days per week. 

All animals were euthanized and necropsied on GO 29. Viability, clinical observations, body 

weights and feed consumption were evaluated. A macroscopic postmortem evaluation was 

performed on GO 29, during which corpora lutea, implantation data and uterine weights were 

10 
recorded. The fetuses were removed, weighed (live and recently dead fetuses), sexed and 

examined externally for defects. All fetuses were examined for soft tissue abnormalities, skeletal 

abnormalities and ossification state. Placentas were examined and weighed. 

There were no effects of exposures on survival, clinical signs, body weights, food 

consumption or maternal or fetal findings at sacrifice. The maternal and developmental noobserved-adverse- effect levels (NOAELs) were 15,000 ppm (23400 mg/kg/day) the highest dose 

tested (MRID 48649519). 

Twenty-four mated female Wistar rats were exposed (nose only) to CAS# 1645-83-6 at 

concentrations of I ,500; 5,000 and 15,000 ppm (mean actual daily concentrations as measured 

by total carbon analysis, were 1,504 (± 3); 5,003 (±10) and 14,997 (± 15) ppm (equivalent to 

2340, 7800 and 23400 mg/kg/day), respectively. The control group of twenty-four mated 

females was exposed to clean air. At Caesarean section females and fetuses of all groups were 

macroscopically examined. Fetuses, placentas and reproductive organs were weighed. Fetuses 

were further processed for fetopathological examination. 

There were no mortalities or treatment related clinical observations. No effect was seen on 

the mean maternal body weight and on food consumption. No statistically significant differences 

were observed in the female fecundity index, gestation index, number of corpora lutea, the 

number of implantation sites, number of live fetuses, post-implantation loss and the sex ratio. 

No effect was seen on the weight of gravid uterus, empty uterus and ovaries. Macroscopic 

findings at necropsy did not reveal any remarkable or treatment related findings among the 

dosing and control groups. 

No statistically significant differences in the incidences of fetal external observations and/or 

placental findings were observed. Fetal and placental weights were not affected. No treatmentrelated effects were observed at visceral and skeletal examination. 

The maternal and developmental NOAELs were 15,000 ppm (23400 mglkg/day), the highest 

dose tested (MRTD 48649518). 

Dern1al Toxicity and Dermal Absorption Studies: 

Dermal toxicity and dermal absorption studies were not available for review. However, based on 

the physical properties of CAS# 1645-83-6 dennal exposure is expected to be negligible. 

Neurotoxicity Studies: 

Neurotoxicity studies were not available for review. However, evidence of neurotoxicity was 

not observed in the submitted studies. 

lmmunotoxicity Study-Rat: 

11 
lmmunotoxicity studies were not available for review. However, very slight mononuclear 

cell infiltrates in the heart were observed in only females (3/5) at the LOAEL of>5000 ppm 

(7800 mg/kg/day; lowest dose tested) following I 0 days of exposure via inhalation in Sprague 

Dawley rats. This effect was not dose dependent with regard to either incidence or severity. 

Monocyte count was increased and multifocal mononuclear cell infiltrates were also observed in 

the heart at 15,000 ppm (23400 mg/kg/day; highest dose tested) in a 13 week study via inhalation 

in Sprague Dawley rats. The NOAEL was 5000 ppm (equivalent to 7800 mg/kg/day). This 

study included more rats, was conducted in the same species of rats that underwent the same 

route of exposure and was of longer duration (13 weeks vs 10 days). Mononuclear cell infiltrates 

in the heart were not observed at 5000 ppm (7800 mg/kg/day) in either the male or female rat. 

Since the incidence and severity of mononuclear cell infiltrates in the heart were not dosedependent in the 10 day study, the 13 week study was considered more reflective of toxicity 

resulting from exposure to CAS# 1645-83-6. However, the Agency is not concern about these 

effects since they occur well above the limit dose and exposure beyond that is highly unlikely 

and unrealistic. 

Mutagenicity: 

Ames Test 

Trans 1-3, 3, 3-tetrafluoropropene was tested at 50000 ppm (78000 mg/kg/day) in Salmonella 

typhimurium strains TA98, TA I 00, TA 1535 and/or TA 1537 in an Ames Test. No substantial 

increases in revertant colony numbers of any of the tester strains were observed following 

treatment with CAS# 29118-24-9 at 50000 ppm (78000 mg/kg/day), in the presence or absence 

of S-9 mix, in either mutation test. The concurrent positive controls demonstrated the sensitivity 

of the assay and the metabolizing activity of the liver preparations. It appeared that the dose 

level of ethylene oxide was slightly too high in the first mutation test as toxicity was observed. 

However the toxicity and positive response observed with WP2 vwrA in the presence of S-9 mix 

demonstrated that the bacteria on the seeded plates were exposed to the gas in the desiccator. A 

satisfactory positive response was obtained with ethyl ene oxide in the second mutation test. The 

study was negative for mutagenicity (MRID 48649521). 

The mutagenicity of CAS # 1645-83-6 in bacteria using Salmonella typhimurium (S. 

typhimurium) TA98, TA I 00, TA 1535, TA1537. and Escherichia coli (E. coli) 

WP2uvrA/pKMI012

), by the gas exposure method with (+S9mix) or without (-S9mix) metabolic 

activation. The test was performed with 0, 1%, 2%, 2, 5%, 10%, 20% and 50% (approximately 

0, I 0000, 20000, 25000, 100000, 200000, and 500000 ppm) of CAS # 1645-83-6. The test 

substance did not increase in number of revertant colonies more than twice of that of the negative 

control in any strain with or without metabolic activation, and did not inhibit bacterial growth in 

any condition of the test. The numbers of revertant colonies for the negative and positive 

controls were within the range of standard values derived from historical control data. Based on 

the above results, CAS # 1645-83-6 was assessed to be non-mutagenic (negative) in the reverse 

mutation test in bacteria (MRID 48649522). 

Chronic/Carcinogenicity - Rat: 

12 
(90-day study evaluated for carcinogenic potential using gene expression) 

Female B6C3F l/Crl mice and male F344/CrlBR rats (10/dose) were exposed for 13 weeks to 

HF0-1234ze. Known carcinogens were included in the study as positive controls. 

Tetrafluoroethylene, 1-Amino-2, 4-dibromoanthraquinone, Tris (2,3-dibromopropyl)phosphate I, 

5- are known mouse liver and rat kidney carcinogens. Only the kidney and liver were evaluated 

based on the sensitivity of each species to the formation of tumors in these organs. The animals 

were exposed to 0, 2000 or 10,000 ppm (3 120 and 15600 mg/kg/day) ofCAS# 1645-83-6 six 

hour/day/5 days/week for 13 weeks in single whole body chambers. Following a subchroni c 

exposure, changes in gene expression biomarkers were used to assess the carcinogenic potential 

of CAS# 1645-83-6. A predictive set of genes were identified and along with the support vector 

machine (SVM) model was used to predict the carcinogenic potential of CAS# 1645-83-6. 

There were no treatment-related mortalities in either study. In rats, bodyweight, kidney and liver 

absolute and relative weights were comparable to controls, there were no treatment related 

histopathological lesions. Based on gene expression changes and statistical classification 

models, CAS# 1645-83-6 was predicted to be non-carcinogenic in the male rat kidney and 

female mouse liver (MRTD 48649520). 

Metabolism-Rat: 

Male Sprague-Dawley rats were exposed to air containing 2,000; I 0,000; or 50,000 ppm 

(3 120, 15600 and 78000 mg/kg/day) (n = 5/concentration) HF0-1 234ze. Male B6C3F l mice 

were only exposed to 50,000 ppm (78000 mg/kg/day) HF0-1234ze. All inhalation exposures 

were conducted for 6 h in a dynamic exposure chamber. In urine samples of rats exposed to 

50,000 ppm (78000 mg/kg/day) HF0-1234ze, the predominant metabolite was S-(333-trifluorotrans-propenyl)-mercaptolactic acid and accounted for 66% of all integrated 19F-NMR signals in 

urines. No 19F-NMR signals were found in spectra of rat urine san1ples collected after inhalation 

exposure to 2000 or I 0,000 ppm (3 120 or 15600 mg/kg/day) HF0-1234ze likely due to 

insufficient sensitivity. S-(3,3,3-Trifluoro-transpropenyl)- L-cysteine, N-acctyl-S-(3,3,3-

tritluoro-trans-propenyl)-L-cysteine and 3,3,3-trifluoropropionic acid were also present as 

metabolites in urine samples of rats and mice. A presumed amino acid conjugate of 3,3,3-

trifluoropropionic acid was the major metabolite ofHF0-1234ze in urine samples of mice 

exposed to 50,000 ppm (78000 mg/kg/day) and related to 18% of total integrated 19F-NMR 

signals. Quantification of three metabolites in urines ofrats and mice was performed, using 

LC/MS-MS and GC/MS. The quantified amounts of the metabolites excreted with urine in both 

mice and rats, suggest only a low extent (<1% of dose received) of biotransfonnation ofHF0-

1234ze and 95% of all metabolites were excreted within 18 h after the end ofthe exposures 

(MRID 48649524). 

Acute Cardiac sensitization Study-Special Study- Dog: 

HF0-1234ze was administered to 6 male dogs via muzzle-only inhalation exposure (vapor) 

as acute exposures at concentrations of2.0%. 6.0% and 12% (20,000, 60,000 and 120,000 ppm; 

and equivalent to 31200, 93600 and 187200 mg/kg/day). Each dog served as its own control. 

Animals were administered a pre-exposure dose of epinephrine as a bolus injection via a cephalic 

13 
vein approximately 5 minutes prior to exposure to the test article. Five minutes after exposure to 

the test article began, the animals were administered a challenge dose of epinephrine. Following 

the final exposure, all dogs were returned to stock. All animals were observed twice daily for 

mortality and moribundity. Clinical examinations were performed prior to initiation of each 

exposure, continually during the exposure and immediately following each exposure period. 

Detailed physical examinations were performed and body weights were collected on the day 

prior to the first day of exposures and at the completion of all exposures. Electrocardiographic 

data were recorded continuously throughout the pre-exposure epinephrine dosing, exposure to 

the test gas and for 5 minutes following administration of the challenge epinephrine dose (total 

of approximately 17 minutes). 

All animals survived to study termination. There were no test article-related clinical 

observations. Body weights were unaffected by test article administration. There was no 

indication of cardiac sensitization noted in any dogs at 20,000, 60,000 or 120,000 ppm (3 1200, 

93600 and 187200 mglkg/day) HF0-1234ze when fol lowed by the administration of 

epinephrine. The no-observed-effect level (NOEL) for HF0-1234ze was 120,000 ppm 

(approximately 187200 mglkg/day human equivalent dose), the highest dose tested for cardiac 

sensitization (MRID 48649523). 

Table 3. Toxicology Proftle for Trans-1, 1, 1, 3-tetrafluoropropene 

Study Type Doses Results 

2 week-I nhalation 

Tox 0, 5,000; 20,000; or 50.000 NOAEL was not established. icity-Rat ppm (equivalent to 7800, 

31200,or780000 LOAEL = 5000 ppm (7800 mglkglday) was based on 

mglkglday) mononuclear cell infiltrates in the heart of female animals. 

13 week-Toxicity StudyInhalation- Sprague- 0. 1500. 5000 or 15.000 NOAEL= 5000 ppm (equivalent to 7800 mglkglday). 

Daw ppm (equivalent to 2340, ley Rat 7800 and 31200 mglkglday) LOAEL= 15000 ppm (equivalent to 31200 mglkglday) 

based on increased monocytes. potassium and increased 

incidence of multi focal mononuclear cell in filtrates in the 

heart. 

90-Day Toxicity Study 

with toxicogenomic 0, 2000 and I 0000 ppm NOAEL = I 0000 ppm {approximately 15600 mglkglday 

(equivalent to 3120 and human equivalent dose). assessment of cancer 

potential- B6C3 F I fema le 

15600 mglkglday). LOAEL was not established. 

mice and F344 male rat- Classified as non-carcinogenic. Inhalation 

Developmental toxicityWistar ra 0, 1500, 5000 and 15000 Maternal NOAEL = 15000 ppm (equivalent to 23400 t -Inhalation 

ppm (equivalent to 2340. mg/kglday). 

7800 and 23400 

mglkglday). Maternal LOAEL was not established. 

Developmental NOAEL =15000 ppm (equivalent to 23400 

mglkglday). 

Developmental LOAEL \vas not established. 

14 
Table 3. Toxicology Profile for Trans-1, 1, 1, 3-tetrafluoropropene 

Study Type Doses Results 

Developmental toxicity 

(range-finding study) 0, 1500, 5000 and 15000 Maternal NOAEL = 15000 ppm (equivalent to 31200 -New 

ppm (equivalent to 2340, mglkg/day). Zealand White rabbit -

lnJ1alation 

7800 and 23400 

m Maternal LOAEL was not established. g/kg/day). Developmental OAEL = I 5000 ppm (equivalent to 31200 

mglkg/day). 

Developmental LOAEL was not established. 

Developmental toxicityNew Zealand White rabbit 4,000, I 0000 or 15000 Maternal and Developmental NOAELs = 15000 ppm 

-Inhalation ppm( equivalent to 6240. (equivalent to 23400 mg/kg/day). 

15600 and 23400 

mglkg/day Maternal and Developmental LOAELs were not ) established. 

Ames Test-Gas exposure 0 or 50000 ppm with and Negative 

without S9 (approximately 

7800 mg/kglday). 

Ames Test- Gas exposure 0, I%, 2%, 2. 5%, I 0%. Negative 

20% and 50% 

(approximately 0. 10000, 

20000,25000, 100000, 

200000, and 500000 ppm) 

with and without S9 

Metabolism-Male Sprague- 0 or 2,000; I 0,000; or HF0-1234ze (CAS# 1645-83-6) administered via inhalation 

Dawley Rat-Inhalation 50.000 ppm (approximately 

to male rats is rapidly absorbed. metabolized and excreted 

equivalent to 3120, 15600 (the majority within 18 hrs). The urine was the major route 

and 78000 mg/kg/day). of excretion. The major metabolite was S-(333-tritluorotrans-propenyl)-mercaptolactic acid. Other identified 

metabolites were S-(3 .3,3-tritluoro-transpropenyf)- Lcysteine, N-acetyl-S-(3 ,3 .3-tritl uoro-trans-propenyl)-Lcysteine and 3,3.3-tritluoropropionic acid. 

Metabolism- Male B6C3 F 1 

mice 0 or 50,000 ppm HFO- I 234ze (CAS# 1645-83-6) administered via -Inhalation (approximately equivalent inhalation to male rats is rapidly absorbed, metabolized and 

to 78000 mg/kg/day). excreted (the majority within 18 hrs). The urine was the 

major route of excretion. The major metabolite was a 

presumed amino acid conjugate of3,3,3-tritluoropropionic 

acid. Other identified metabolites were S-(3.3,3-tritluorotranspropenyl)- L-cysteine, N-acetyl-S-(3.3,3-tritluorotrans-propenyl)-L-cysteine and 3,3,3-tritluoropropionic 

acid. 

Acute Cardiac 0, 20,000, 60,000 or NOAEL= 120,000 ppm (approximately 187,200 

Sensitization-Dog 120.000 ppm mglkg/day). 

(approximately equivalent LOAEL was not established. 

to 3 1200, 93600 and 

187200 mglkglday). 

15 
4. Toxicity Endpoint Selection 

The available toxicity studies indicate that trans- I , I, l , 3-tetrafluoropropene has a very low 

overall toxicity. The lowest NOAEL in the database was 5000 ppm (approximately 7800 

mg/kg/day human equivalent dose) observed in a 13 week toxicity study in rats via the inhalation 

route of exposure. Since signs of toxicity were not observed at well above the limit dose an 

endpoint of concern for risk assessment purposes was not identified. Therefore, since no 

endpoint of concern was identified for the acute and chronic dietary exposure assessment and 

short and intermediate dermal and inhalation exposure, a qualitative risk assessment for trans-I, 

l, I, 3-tetrafluoropropene was conducted. 

5. Special Considerations for Infants and Children 

As part of its qualitative assessment, the Agency did not use safety factors for assessing risk. 

and no additional safety factor is needed for assessing risk to infants and children. Based on the 

lack of toxicity of trans l-3, 3, 3-tetrafluoropropene in the available studies, EPA has concluded 

that there are no toxicological endpoints of concern for the U.S. population, including infants and 

children. 

6. Exposure Assessment 

Dietary Exposure: 

In evaluating dietary exposure to trans 1-3, 3, 3-tetrafluoropropene, EPA considered 

exposure under the petitioned for exemptions from the requirement of a tolerance. Since no 

endpoint of concern was identified for the acute and chronic dietary exposure assessment and 

short and intermediate dermal and inhalation exposure, a quantitative risk assessment for trans 1-

3, 3, 3-tetratluoropropene is not necessary. 

Cancer. Trans 1-3, 3, 3-tetrafluoropropene is not expected to be carcinogenic based on its lack 

of toxicity and the negative response for mutagenicity. Therefore, a cancer dietary exposure 

assessment was not performed. 

Residential (Non-Occupational) and Occupational Exposure: 

The tenn " residential exposure" is used in this document to refer to non-occupational. nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and 

flea and tick control on pets). Trans 1-3, 3, 3-tetratluoropropene may be used in inert ingredients 

in products that are registered for specific uses that may result in residential exposure. However. 

since an endpoint of concern was not identified, a qualitative assessment was conducted. 

7. Occupational Exposure/Risk Pathway 

16 
Occupational exposure was qualitatively assessed since an endpoint of concern was not 

identified for trans 1-3, 3, 3-tetrafluoropropene. · 

8. Cumulative Exposure: 

Section 408(b )(2)(D)(v) of FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the EPA consider "available information" concerning the 

cumulative effects of a particular pesticide's residues and "other substances that have a common 

mechanism of toxicity." Unlike other pesticides for which EPA has followed a cumulative risk 

approach based on a common mechanism of toxicity, EPA has not made a common mechanism 

of toxicity finding as to trans 1-3, 3, 3-tetrafluoropropene and any other substances and, this 

material does not appear to produce a toxic metabolite produced by other substances. For the 

purposes ofthis tolerance action, therefore, EPA has not assumed that trans 1-3, 3. 3-

tetrafluoropropene have a common mechanism of toxicity with other substances. For 

information regarding EPA's efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA's Office of Pesticide Programs concerning common mechanism detenninations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA's website at http://www.epa.gov/pesticides/cumulative/. 

9. Environmental Fate 

Environmental fate data were reproduced from toxicity studies submitted by The Acta 

Group, L.L.C., on behalf of Honeywell Specialty Materials N lC4. 

The biodegradability of trans 1-3, 3, 3-tetrafluoropropene by microorganisms was evaluated 

according to the Closed Bottle Test. Trans 1-3, 3, 3-tetrafluoropropene (2. 73 mg theoretical 

oxygen demand (ThO.I- 1

)) was cultivated with mineral medium inoculated with sludge filtrate 

(for 28 days (sealed and standing) in darkness. DO was calculated on days 7, 14, 2 1 and 28; and 

BOD was calculated on days 7 and 28. Trans 1-3, 3, 3-tetrafluoropropene was inhibitory to the 

inoculum at 2.8 mg/1·

1

• The authors concluded that trans 1-3, 3, 3-tetratluoropropene was not 

biodegraded by microorganisms under the conditions of the study (MRJD 48649506). 

In a second study, the biodegradability of trans 1-3, 3, 3-tetratluoropropene by 

microorganisms was evaluated according to the Closed Bottle Test. Trans 1-3, 3, 3-

tetrafluoropropene (7.39 mg/L) was cultivated with mineral medium inoculated with sludge 

filtrate (for 28 days (sealed and standing) in darkness. Dissolved oxygen (DO) and biochemical 

oxygen demand (BOD) were calculated on days 7, 14,21 and 28. Trans 1-3, 3, 3-

tetratluoropropene was not biodegraded by microorganisms under the conditions of this study 

(MRJD 48649504). 

l 0. Ecotoxicity 

17 
These data were reproduced from toxicity studies submitted by The Acta Group, L.L.C., on 

behalf of Honeywell Specialty Materials NIC4. 

Aquatic Effects 

Acute Toxicity to invertebrates (Daphnia magna): Test media was exposed to CAS# 1645-

83-6 for 4, 7.5, 15,30 and 60 minutes. The test consisted of four airtight closed vessels per 

concentration each vessel containing 5 daphnids. Samples for analysis of actual exposure 

concentrations were taken at the start and the end of the 48-hour test. Chemical analysis showed 

initial concentrations of90, 200 and 400 mg/1 in the solutions exposed to trans 1-3, 3, 3-

tetratluoropropene for 15, 30 and 60 minutes, respectively. The geometric mean concentrations 

were 50, 160 and 350 mg/ 1, respectively. No more than I 0% immobilization was recorded at 

measured concentrations of up to 160 mg/1, while 45 % was recorded at the highest 

concentration of 350 mg/ I after 48 hours of exposure. The study met the acceptability criteria 

prescribed by the protocol and was considered valid. The 48h-ECso for Daphnia magna exposed 

to CAS# 1645-83-6 was > 160 mg/1, the no observed effect concentration CAS#1645-83-6 can 

be classified as not harmful for crustaceans (Bogers, 2006; MRID 48649507). 

Acute Toxicity to algae: Exponentially growing algal cultures were exposed to solutions with 

an initial concentration of 480 mg/1 of CAS# 1645-83-6 for 72 hours under continuous 

illumination. Each test group consisted of 6 replicates, i.e. in airtight closed vessels with a screwcap holding a septum. The volume ratio of solution and vessel was 3:4 and the initial cell density 

was I x 104 cells/mi. Samples for analysis were taken from all test concentrations and the control 

at the start and at the end of the test. 

At the end of the 72-hour test period, the concentrations of CAS# 1645-83-6 varied markedly 

among the different replicates (41 to 111 mg/1). Based on these results. the overall average 

exposure concentration was 170 mg/1 , while the maximum average concentration was 230 mg/1. 

Based on the area under the growth curves, total cell growth was inhibited by > I 0% but < 

50 %. A significant lower mean growth rate was recorded for the treatment control compared 

with the blank-control for the 0-24h interval. Compared with the treatment control, the 

CAS# 1645-83-6 treated solutions reduced the growth rate by less than 10 %. 

The NOEC of CAS# 1645-83-6 for total cell growth of fresh water algae was 

< 170 mg/1 (NOEsC), while for growth rate it was 170 mg/1 (NOERC). 

The ECso of CAS# 1645-83-6 > 170 mg/1 for both total cell growth and growth rate, and 

CAS# 1645-83-6 can be classified as not harmful to fresh water algae (Bogers. 2006; MRID 

48649509). 

11. Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in 

this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

18 
Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo l2898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup's food and water consumption, and activities in and around the home that involve 

pesticide use in a residenti al setting. Extensive data on food consumption pattems are compiled 

by the USDA under the Continuing Survey of Food intake by Individuals (CSFIJ) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths. and adults entering or playing on treated areas 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

pattems among specific subgroups. 

12. Risk Characterization 

EPA received a petition (PP# lE7938) from The Acta Group, L.L.C., 2000 Pennsylvania 

Avenue, N.W., Suite lOOW Washington, D.C. 20037, on behalf of Honeywe ll Specialty 

Materials NIC4, 101 Columbia Road, Morristown, NJ 07962-1053 requesting an exemption from 

the requirement of a tolerance for the use of trans 1-3, 3, 3-tetratluoropropene (CAS Reg. No. 

29118-24-9) as an inert ingredient (propellant) up to 30% in pesticide products on all pre- and 

post-harvest food commodities under 40 CFR part 180.91 0; in pesticide products applied to 

animals, 40 CFR part 180.930; and in pesticide products used for food-contact surface sanitizing 

solutions, 40 CFR part 180.940(a). EPA published the notice of fi ling (NOF) for this petition in 

the Federal Register on April 4, 2012 (77 FR 43566). No comments were received in response 

to this notice. Currently. trans 1-3, 3, 3-tetrafluoropropene is recommended for approval as an 

aerosol propellant under the Significant New Alternatives Policy (SNAP) as an alternative for 

ozone-depleting substances. 

This risk assessment evaluated the potential human health associated with the inhalation 

exposure scenario resulting from the use of trans 1-3, 3, 3-tetrafluoropropene. In some of the 

studies the chemical name was incorrect but was correctly identified by the alternate CAS # 

1645-83-6. Therefore, in the following studies, trans 1-3, 3, 3-tetratluoropropene was identified 

by the alternate CAS # 1645-83-6 when the incorrect name was used. 

Toxicity summaries of trans l-3, 3, 3-tetrafluoropropene were reproduced from data 

submitted by The Acta Group, L.L.C., on behalf of Honeywell Specialty Materi als NIC4. Trans 

1-3, 3, 3-tetrafluoropropene was administered via the inhalation route of exposure only in these 

studies. 

19 
Acute inhalation toxicity was low for CAS # 1645-83-6 in rats and mice. It was not a dennal 

irritant in rabbits. Trans 1-3, 3, 3-tetratluoropropene did not cause any effects at doses up to 

5000 ppm (approximately 7800 mg/kg/day human equivalent dose) in rats and rabbits via the 

inhalation route of exposure. It does not exhibit the potential for teratogenicity, neurotoxicity, 

immunotoxicity, mutagenicity or carcinogenicity. Metabolism studies showed that it was rapidly 

absorbed, metaboli zed and excreted. Urine was the major route of excretion. In rats, the major 

metabolite was S-(333-trifluoro-trans-propenyl)-mercaptolactic acid. In mice, the major 

metabolite was a presumed amino acid conjugate of 3,3,3-tritluoropropionic acid. Other 

identified metabolites were S-(3 ,3 ,3-tritl uoro-transpropenyl )- L-cysteine, N -acetyl-S-(3 ,3 ,3-

trifluoro-trans-propenyl)-L-cysteine and 3,3,3-trifluoropropionic acid. 

Dietary, non-dietary and occupational exposures were qualitatively assessed since and 

endpoint of concern was not identified. 

Trans 1-3, 3, 3-tetrafluoropropene is expected to persist in soil and sediment. Bioconcentration in aquatic organisms is moderate to high. It is not expected to be toxic to aquatic 

organisms. Trans 1-3, 3, 3-tetratluoropropene is not biodegraded by microorganisms in sludge. 

Potential areas of environmental justice concerns, to the extent possible, were considered in 

this hwnan health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo l2898.pdf. 

Taking into consideration all available information on trans l-3, 3, 3-tetrafluoropropene. 

EPA concludes that there is a reasonable certainty that no harm will result to the general 

population or to infants and children from aggregate exposure to trans 1-3, 3, 3-

tetrafluoropropene. Therefore, the establishment of an exemption from tolerance under 40 CFR 

180.910, 180.930 and 180.940(a) for residues of trans 1-3, 3, 3-tetrafluoropropene when used as 

an inert ingredient (propellant) at no more than 30% by weight in the end-product formulation 

can be considered safe under section 408 of the FFDCA. 

20 
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Weinberg, J. (2004) Acute Cardiac Sensitization Study of HF0-1234ze and HFO 1234yf in 

Dogs: Final Report. Project Number: 447008. Unpublished study prepared by WIL Research 

Laboratories, fnc. 105p. MRlD 48649523. 

23 
Appendix. 

The toxicological endpoint or point of departure was identified from an inhalation exposure 

study. The endpoint was identified as being 5000 ppm/day. In order for the Agency to complete 

a risk assessment, that endpoint must be converted to a dose in mg/kg bw/day for use in risk 

calculation. The following convention is utilized by the Health Effects Division, Office of 

Pesticide ProgramsfUSEPA to convert endpoints expressed in parts per million to an expression 

in mglkg bw/day in humans based on 24 hour exposure. 

Parts per million (ppm) conversion: 

Trans 1-3, 3, 3-tetrafluoropro-1-ene molecular weight = 114 g/mol 

Conversion factor for gases and vapors: ppm to mg/m3 at 25°C is 24.25 

ppm x MW/24.45=23,300 mg/m3 

5000 ml/m3 x 114 /24,45 

Human Equivalent Dose: 

mg/kg bw/day = mg/m3 x respiratory volume during exposure /exposure timex body weight (kg 

bw) 

Thus, 

mglkg bw/day = 23,300 mg/m3

_x 20m3/day x 1/60 kg bw= 7800 mg/kg bw/day 

24