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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Pv Shah, 703-308-1846]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases 

where the outline element does not apply, please insert “NA-Remove” and maintain the 

outline. Please do not change the margins, font, or format in your pesticide petition. Simply 

replace the instructions that appear in green, i.e., “[insert company name],” with the 

information specific to your action.

TEMPLATE:

Honeywell International, Inc.

[1E7938]

EPA has received a pesticide petition ([1E7938]) from Honeywell International, Inc., 

101 Columbia Road, Morristown, NJ 07962-1053 proposing, pursuant to section 408(d) of the 

Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 

to establish an exemption from the requirement of a tolerance for trans-1,3,3,3-tetrafluoroprop1-ene (CAS No. 29118-24-9) under 40 C.F.R. §§ 180.910, 180.930, and 180.940 when used as 

an inert ingredient (propellant) in pesticide formulations. EPA has determined that the 

petition contains data or information regarding the elements set forth in section 408 (d)(2) of 

FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time 

or whether the data supports granting of the petition. Additional data may be needed before EPA 

rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [N/A]

2. Analytical method. No analytical method is included as this is a petition for 

exemption from the requirement of a tolerance.

3. Magnitude of residues. Trans-1,3,3,3-tetrafluoroprop-1-ene is gaseous at room 

temperature, with a boiling point of -19oC, and not likely to result in any measurable 

residues on raw agricultural commodities or feed/food processes or preparation equipment 

or facilities.
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B. Toxicological Profile

1. Acute toxicity. As trans-1,3,3,3-tetrafluoroprop-1-ene is a gas at ambient 

temperature, exposure and absorption via the oral route is not likely. Trans-1,3,3,3-

tetrafluoroprop-1-ene is a small molecule (MW 114 g/mole), soluble in water, and has an 

estimated log Kow of 2.01. In addition, the substance is not ionized in the aqueous 

environment and has an aliphatic structure. Due to these characteristics, absorption via 

the dermal (and especially via the inhalation) route is possible. Testing in rabbits indicates 

trans-1,3,3,3-tetrafluoroprop-1-ene is not irritating or corrosive to the skin. In an Acute 

Inhalation Toxicity Screen in mice with a four-hour exposure at approximately 10,000 

ppm, there were no deaths or findings of toxic or irritant effects following exposure of mice 

to trans-1,3,3,3-tetrafluoroprop-1-ene.

Trans-1,3,3,3-tetrafluoroprop-1-ene did not cause sensitization by repeated topical 

applications to the skin of humans under controlled patch conditions. Subjects were 

evaluated for irritation at the site of exposure 24-48 hours following treatment. According 

to the testing laboratory, trans-1,3,3,3-tetrafluoroprop-1-ene showed no evidence of 

irritation. 

In an acute cardiac sensitization study, a group of six beagle dogs were exposed to 

levels of 20,000, 40,000, and 120,000 ppm of trans-1,3,3,3-tetrafluoroprop-1-ene. A total of 

six exposures were conducted, with at least a two-day separation between exposures. 

Initially a determination was made for the maximum level of epinephrine that would not 

cause a cardiac arrhythmia. The dogs were then exposed to the test compound for a total 

of ten minutes. After the first five minutes of exposure, each dog received an injection of 

epinephrine at the pre-determined maximum sub-arrhythmia dose. During the next five 

minutes of exposure, the dogs were monitored for the development of a cardiac 

arrhythmia. No arrhythmias, nor other signs of toxicity, were seen in any of these dogs. 

The testing laboratory concluded that exposure of dogs to a level of 120,000 ppm did not 

cause a cardiac sensitization to epinephrine.

2. Genotoxicity. Trans-1,3,3,3-tetrafluoroprop-1-ene appears not to be active in the 

Ames assay carried out with cultures of Salmonella typhimurium TA98, TA100, TA1535, 

and TA1537, as well as Escherichia coli WP2uvrA/pKM101.

Gene expression changes were used to assess the carcinogenic potential of trans1,3,3,3-tetrafluoroprop-1-ene following exposure of female B6C3F1 mice and male F344 

rats to levels of 2,000 and 10,000 ppm six hours/day, five days/week for 13 weeks. The 

assessment was based on the results from a comparison of the responses seen with trans1,3,3,3-tetrafluoroprop-1-ene to both positive (tetrafluoroethylene, 1-amino-2,4-

dibromoanthraquinone, and tris(2,3-dibromopropyl)phosphate) and negative 

(trichlorofluoromethane, iodo- form, tetrafluoroethane and N-(1-naphthyl)ethylenediamine 

dihydrochloride) controls. Vehicle controls were also included. In addition, 

histopathological examination of selected tissues was conducted. Statistical classification 

analysis predicted t-1,1,1,3-tetrafluoropropene to be noncarcinogenic in both female mouse 

liver and male rat kidney. It was noted that treatment with trans-1,3,3,3-tetrafluoroprop-
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1-ene produced large scale gene expression changes in the female mouse liver that were 

related to a variety of basic cellular functions. The majority of the changes were similar 

between the low and high level exposure groups. Large scale changes in gene expression 

were not seen in the male rat kidney. No treatment-related histopathological lesions were 

observed. 

Trans-1,3,3,3-tetrafluoroprop-1-ene had been predicted to be associated with lung 

tumor induction in mice based on statistical analysis of genomic signatures obtained after 

90-day inhalation exposures. In contrast to the >95% correlation seen in the liver and 

kidney findings, however, with the lung, the correlation was only ~75%. Also the number 

of genes that were seen was too small to permit a robust conclusion; therefore, these results 

for the lung tumors are considered inconclusive. Furthermore, the low toxicity of trans1,3,3,3-tetrafluoroprop-1-ene, the absence of lung pathology in rats and mice after 13 weeks 

of inhalation, the low rates of biotransformation, and the absence of genotoxicity in 

mammalian cells do not support a risk for lung tumor induction in humans as a 

consequence of exposure to trans-1,3,3,3-tetrafluoroprop-1-ene.

In a four-week inhalation toxicity study in rats, in addition to the normal toxicology 

assessment, two genetic toxicity assessments were conducted: unscheduled DNA synthesis 

(UDS) and bone marrow micronucleus formation. There were no findings of positive 

genetic response in either of the two assays. The levels tested were 0; 5,000; 10,000; and 

15,000 ppm for micronucleus evaluation and 0; 5,000; and 10,000 ppm UDS.

3. Reproductive and developmental toxicity. A prenatal developmental inhalation 

toxicity study with trans-1,3,3,3-tetrafluoroprop-1-ene in rats was carried out with groups 

of 24 mated female rats exposed nose-only to levels of 0 (control); 1,500 ppm; 5,000 ppm; 

and 15, 000 ppm of trans-1,3,3,3-tetrafluoroprop-1-ene for six hours/day on days six to 19 

of gestation. There was no mortality, no effect on body weight or food consumption, and 

clinical observations for all groups were unremarkable. The testing laboratory concluded 

the no-observed effect level was 15,000 ppm, the highest dose testing.

An Embryo-fetal toxicity study in rabbits via whole-body inhalation exposure was 

carried out with trans-1,3,3,3-tetrafluoroprop-1-ene. In this study, groups of 22 mated 

New Zealand white female rabbits were exposed whole-body to levels of 0 (control); 4,000; 

10,000; and 15,000 ppm of trans-1,3,3,3-tetrafluoroprop-1-ene for six hours/day on days six 

to 28 of gestation. 

There was no mortality. No effect was seen on body weight or food consumption 

and clinical observations for all groups were unremarkable. There were no significant 

differences in fecundity index. The number of corpora lutea, implantation sites, live 

fetuses, the post implantation loss, and the sex ratio of the pups were similar in the test 

groups and the control group. The no-observed effect level for adult pregnant female 

rabbits for systemic and reproductive developmental toxicity appears to be 15,000 ppm, the 

highest dose tested.

4. Subchronic toxicity. A sub-acute (two-week) inhalation toxicity study with trans-
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1,3,3,3-tetrafluoroprop-1-ene in rats was carried out. In this study, groups of rats were 

exposed to levels of 0 (control); 5,000; 20,000; and 50,000 ppm of trans-1,3,3,3-

tetrafluoroprop-1-ene for six hours/day, five days/week for two weeks. There were no 

effects on body weight gain, food consumption, and food utilization. A few hematological 

abnormalities were reported primarily in males in the high-level exposure group. 

Likewise, serum chemistry measurement in the mid- and high- level exposure groups 

showed several differences when compared to control levels. This study was used primarily 

to determine the appropriate dose exposure levels for a subsequent four-week inhalation 

toxicity study. The levels for four-week inhalation were selected to be 0 (control); 1,000; 

5,000; 10,000; and 15,000 ppm.

The subsequent sub-acute (four-week) inhalation toxicity study, in which groups of 

rats were exposed to levels of 1,000; 5,000; 10,000; and 15,000 ppm of trans-1,3,3,3-

tetrafluoroprop-1-ene for six hours/day, five days/week for four weeks, was conducted. 

Beside the normal toxicology assessment, two genetic toxicity assessments were conducted: 

UDS and bone marrow micronucleus formation. There were no findings of positive genetic 

response in either of the two assays. The levels tested were 0; 5,000; 10,000; and 15,000 

ppm for the micronucleus evaluation and 0; 5,000; and 10,000 ppm for the UDS. The only 

note-worthy finding in the toxicology evaluation consisted of exposure-related, very slight 

to moderate inflammation of the heart, found only in the male rats in the 15,000 ppm 

exposure level group. Thus, 10,000 ppm was considered to be the no-observed effect level.

A sub-chronic (13-week) inhalation toxicity study was conducted with trans-1,3,3,3-

tetrafluoroprop-1-ene in rats, in which four groups of ten male and ten female rats were 

exposed to levels of 0; 5,000; and 15,000 ppm for six hours/day, five days/week for 13 

weeks. Exposure at these levels did not induce treatment-related clinical abnormalities, 

including no ophthalmoscopy, or treatment-related changes in body weight gain, food 

consumption or food conversion efficiency. Some changes were seen in the hematology and 

clinical chemistry parameters in the high level exposure group. While several were noted 

in only one sex or were slight, they may be related to treatment. A decreased weight of the 

uterus was also seen in the high level group. Macroscopic examination did not show any 

gross treatment-related findings in any group. Microscopic examination revealed that 

trans-1,3,3,3-tetrafluoroprop-1-ene induced multifocal mononuclear cell infiltrates in the 

heart of the high concentration males and females. Fibrosis was not observed. Therefore, 

5,000 ppm was the no-observed-adverse-effect level in this 13-week inhalation toxicity 

study with trans-1,3,3,3-tetrafluoroprop-1-ene.

5. Chronic toxicity. N/A

6. Animal metabolism. See 7. Metabolite toxicology.

7. Metabolite toxicology. The metabolism of trans-1,3,3,3-tetrafluoroprop-1-ene was 

studied in male Sprague Dawley rats at exposure levels of 2,000; 10,000; and 50,000 ppm 

and in male B6C3F1 mice at an exposure level of 50,000 ppm. The investigators concluded 

that based on the metabolites excreted, the rate of metabolism was very low (<<1% of the 

inhaled dose). Many of the fluorinated alkenes such as tetrafluoroethylene and CTFE are 
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renal toxins and mutagenic. The lack of renal toxicity and mutagenicity is attributed to the 

observation that any cysteine conjugate cannot be cleaved to a thioketone or thionoacyl 

fluoride due to the absence of a halogen atom on the olefinic carbon adjacent to the sulfur. 

This fact, coupled with the low rate of biotransformation of the trans-1,3,3,3-

tetrafluoroprop-1-ene, would appear to explain the absence of systemic toxicity. Likewise, 

the low biotransformation would result in a low rate of production of the epoxide from 

addition across the double bond. This fact, as well as efficient detoxification by 

glutathione, would be responsible for the absence of liver toxicity.

8. Endocrine disruption. N/A

C. Aggregate Exposure

1. Dietary exposure. Trans-1,3,3,3-tetrafluoroprop-1-ene is a gas at room 

temperature. It is not expected that toxicological significant residue will be present in the 

diet or water from the proposed use as an aerosol in pesticide formulations.

i. Food. N/A

ii. Drinking water. N/A

2. Non-dietary exposure. According to EPA’s review of trans-1,3,3,3-tetrafluoroprop-1-

ene under the Significant New Alternative Policy Program dated June 9, 2010,1 EPA concluded 

the following:

Occupational Exposure to trans-1,3,3,3-tetrafluoroprop-1-ene at Aerosol 

Can-Filling: There is the potential for worker exposure to trans-1,3,3,3-

tetrafluoroprop-1-ene during aerosol can-filling operations. In the Background 

Document (EPA 1994), potential exposures to a surrogate aerosol during canfilling were estimated to be approximately 285 ppm (as a 30-minute timeweighted average) and 39.3 ppm (as an 8-hour time-weighted average, without 

local exhaust ventilation). Based on the toxicological data available, these levels 

are 3 to 25 times lower than the recommended AEL for trans-1,3,3,3-

tetrafluoroprop-1-ene of 800 ppm (as an 8-hour time weighted average). 

Therefore, no significant toxicity risks are expected for workers during aerosol 

can-filling operations. To ensure exposures to trans-1,3,3,3-tetrafluoroprop-1-ene

remain below the recommended AEL, ICF recommends that all facilities filling 

cans with trans-1,3,3,3-tetrafluoroprop-1-ene ensure levels of trans-1,3,3,3-

tetrafluoroprop-1-ene do not exceed 800 ppm through adequate ventilation, 

engineering controls and good work practices.

 

1

Significant New Alternatives Policy Program, Aerosols Sector, Risk Screen on 

Substitutes for CFC-11, HCFC-22, and HCFC-142b as Aerosol Propellants, Substitute: 

trans-1,3,3,3-tetrafluoroprop-1-ene available at www.regulations.gov in docket EPA-HQOAR-2003-0118.
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Exposure to trans-1,3,3,3-tetrafluoroprop-1-ene at End-Use: 

There also is the potential for exposure to trans-1,3,3,3-tetrafluoroprop-1-ene at 

the end-use (i.e., when used in aerosol products). Actual exposure data for trans1,3,3,3-tetrafluoroprop-1-ene during commercial or consumer use of aerosol 

products are not available. 

ICF determined the 8-hour time-weighted average (TWA) concentrations for a 

scenario modeled and found that the TWA concentration would be 23 ppm. 

Based on the toxicological data available, this concentration is more than 40 times 

lower than the recommended AEL value of 800 ppm (as an 8-hour TWA). 

Therefore, occupational exposure to trans-1,3,3,3-tetrafluoroprop-1-ene when 

used as an aerosol propellant is not expected to pose a significant toxicity risk. To

further protect against the limited toxicity risks, ICF recommended that all 

facilities using aerosol cans with trans-1,3,3,3-tetrafluoroprop-1-ene as the 

propellant ensure levels of trans-1,3,3,3-tetrafluoroprop-1-ene do not exceed800 

ppm through adequate ventilation, engineering controls and good work practices. 

With proper use, trans-1,3,3,3-tetrafluoroprop-1-ene is not expected to pose an 

occupational health risk.

Further, if trans-1,3,3,3-tetrafluoroprop-1-ene is used in consumer aerosol 

applications, ICF believes potential exposures to the substitute will be intermittent 

and small. While consumers may also use the aerosol in different manners than 

represented in the model, if proper ventilation is in place and the consumer does 

not continuously spray the aerosol, toxicity risks should be minimal. To mitigate 

toxicity risks, all aerosol cans containing trans-1,3,3,3-tetrafluoroprop-1-ene

should list safety instructions for consumers, including that the can should only be 

used in a well-ventilated area, that the aerosol should not be sprayed for more 

than a few seconds at a time and that the can must be stored in such a way as to 

prevent exposures to high temperatures.

D. Cumulative Effects

N/A

E. Safety Determination

1. U.S. population. Chronic general population exposure to ambient air releases of 

trans-1,3,3,3-tetrafluoroprop-1-ene is not expected

2. Infants and children. N/A

F. International Tolerances

N/A