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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., 

“Honeywell International, Inc.,” with the information specific to your action.

TEMPLATE:

Honeywell International, Inc.

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from Honeywell 

International, Inc., 101 Columbia Road, Morristown, NJ 047962-1053 requesting, 

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-chloro-3,3,3-trifluoropropene (CAS No. 102687-

65-0) 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 

FDDCA; 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 requirements of a tolerance.

3. Magnitude of residues. Trans-1-chloro-3,3,3-trifluoropropene is gaseous at 

ambient temperature with a boiling point of 19o C (66.2o F) 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 Trans-1-chloro-3,3,3-trifluoropropene is a gas at ambient 

temperature and therefore exposure and absorption via the oral route is not likely. Trans1-chloro-3,3,3-trifluoropropene has a molecular weight of 130.5 g/mole and is soluble to 

1.90 g/L at 20o C at a pH of 7.5-7.6 and has an estimated log Kow of 2.2. Data show that 

trans-1-chloro-3,3,3-trifluoropropene evaporates from water at 20o C within 21 hours and 

the compound contains no readily hydrolysable functional groups, such as esters or 

amides in its molecular structure. Trans-1-chloro-3,3,3-trifluoropropene is not expected 

to undergo wet or dry deposition or photolysis to an appreciable extend. Resulting 

chlorine atoms are not present in the atmosphere in sufficient quantities to have a 

significant influence on the lifetime of. trans-1-chloro-3,3,3-trifluoropropene. Trans-1-

chloro-3,3,3-trifluoropropene did not biodegrade in a 28- day study utilizing Japanese 

sludge. The major route of exposure is inhalation. In a 4-hour acute study in rats, the 

LC50 was calculated to be 118,200 ppm and 121,700 ppm for males and females, 

respectfully. 

Historically, fluorohydrocarbons have demonstrated low dermal toxicity in test animals 

and are not known to be skin sensitizers. No significant dermal clinical effects were 

observed in whole body inhalation studies rats, rabbits and dogs carried out with 

trans-1-chloro-3,3,3-trifluoropropene. Skin irritation and skin sensitization studies with 

trans-1-chloro-3,3,3-trifluoropropene are being carried out.

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

of 25,000, 35,000, and 50,000 ppm of. A total of three exposures were conducted, with at 

least a two-day separation between exposures. The dogs were then exposed to the test 

compound and given a series of injections of adrenalin of increasing does (2 μg/kg, 4 

μg/kg, 6 μg/kg , and 8 μg/kg) with a minimum separation of 3 minutes, for a total of up 

to 12 minutes, while being exposed to the test material. No arrhythmias were observed 

but there were clinical signs such as vocalization, reddened gums, convulsions, tremors, 

and excessive salivation. These signs prevented evaluation of the exposures at 35,000 

and 50,000 ppm for signs of cardiac sensitization to the adrenalin injections. It was 

concluded there was no evidence or cardiac sensitization at 25, 000 ppm. 

1. Genotoxicty. A 28-day inhalation toxicity study was conducted using groups of 

5 male and 5 female rats, exposed to 0 (control), 2000, 4500, 7500, or 10,000 ppm of 

trans-1-chloro-3,3,3-trifluoropropene. Exposures were for 6 hours/day, 5 days/week. An 

additional 5 rats/sex were included as recovery groups in the control and high level 

exposure groups. In addition, the potential for the test substance to induce Unscheduled 

DNS Synthesis (males exposed to 0, 7500 and 10000 ppm) or micronuclei was evaluated 

(males exposed to 0, 2000, 4500, 7500, 10000 ppm) . The test material did not induce 

damage to the chromosomes and/or mitotic spindle apparatus (micronuclei) in the bone 

marrow target cells of the male rats, nor did the test material induce unscheduled DNA 

Synthesis.

An In-Vitro Mammalian Chromosome Aberration Test in Human Lymphocytes was 

carried out to assess the potential of trans-1-chloro-3,3,3-trifluoropropene to induce 
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chromosome aberrations. Cultures were grown both in the absence (3-hour treatment 

with 18-hour recovery or 21-hour treatment) and presence (2% or 5% S-9 3-hour 

treatments with 18-hour recovery) of rat S-9 metabolic activation. All positive controls 

preformed as expected demonstrating that the test system and metabolic activation were 

viable. Trans-1-chloro-3,3,3-trifluoropropene did not cause a positive response either in 

the absence or presence of S-9 metabolic activation. It was concluded by the laboratory 

that trans-1-chloro-3,3,3-trifluoropropene showed no evidence of causing an increase in 

the frequency of structural chromosome aberrations under the condition of the study.

An Bacterial Reverse Mutation Test Carried out with trans-1-chloro-3,3,3-

trifluoropropene. The study involved exposure of bacterial cells TA 1535, TA1537, TA 

98, TA 100, and WP2 uvrA both with and without S-9 metabolic activation. Exposure 

levels of up to 905,000 ppm were used. Toxicity was seen with some strains at 267, 000 

ppm and above confirming that the material did reach the cells in culture. Under the 

conditions of this study, trans-1-chloro-3,3,3-trifluoropropene did not induce mutations in 

any culture either in the presence or absence of S-9 metabolic activation.

In a Micronucleus Test in bone marrow cells of Mice, a group of 10 male mice were 

exposed to a level of 50,000 ppm of trans-1-chloro-3,3,3-trifluoropropene for 4 hours. 

Both positive and negative controls were included. At 24 and 48 hours after the 

exposure, bone marrow was collected from the femurs of 5 mice and evaluated for the 

presence of micronucleated polychromatic erythrocytes. It was concluded that the test 

material did not induce chromosomal damage or damage to the mitotic spindle apparatus 

(micronuclei) in the target bone marrow cells. Thus it was concluded that trans-1-chloro3,3,3-trifluoropropene was not active in this assay. This exposure is approximately 

equivalent to an oral dose of 65,000 mg/kg which is much higher than the typical limit 

dose of 2000 mg/kg.

3. Reproductive and developmental toxicity

Maternal and/or embryo-fetal toxicity of trans-1-chloro-3,3,3-trifluoropropene was 

assessed in the rat, following nose-only inhalation exposure from gestation day 6 to 

gestation day 19, inclusively.

Ninety-six presumed pregnant Wistar outbred Crl:WI(WU) rats were distributed into 4 

groups (1 control and 3 treatment groups) of 24 dams/group. These animals received via 

nose-only inhalation exposures 6 hour/day 7 days/week with clean air (air control) or 

with trans-1-chloro-3,3,3-trifluoropropene at exposure concentrations of 0 (control), 

4000, 10, 000, or 15, 000 ppm from gestation day 6 to gestation day 19 (gestation day 0 

equaled day of mating confirmation). There were no effects of exposures on survival, 

clinical signs, body weights, food consumption or maternal or pup findings at sacrifice 

with the exception of a statistically significant increase in the number of dilated urinary 

bladders seen in pups from dams exposed to 15,000 ppm of trans-1-chloro-3,3,3-

trifluoropropene. The clinical significance of this observation is unknown. Therefore, 

the no-observed-effect level (NOEL) for adult pregnant female rats for systemic and 

reproductive and developmental toxicity was 10,000 ppm of trans-1-chloro-3,3,3-

trifluoropropene.
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The definitive Embryo-Fetal Toxicity Study in Rabbits via Whole-Body Inhalation 

Exposure was carried on with trans-1-chloro-3,3,3-trifluoropropene. With Eighty-eight 

time-mated female New Zealand White rabbits distributed into 4 groups (1 control and 3 

treatment groups) of 22 does/group. These animals received whole-body inhalation 

exposures 6-hour/day 7 days/week with clean air (air control) or with trans-1-chloro3,3,3-trifluoropropene at exposure concentrations if 2,513, 9,945, or 14,942 ppm from 

gestation day 6 to gestation day 28 (gestation day 0 was the day of mating confirmation).

All animals were euthanized and necropsied on gestation day 29. There were no effects 

of exposures on survival, clinical signs, body weights, food consumption or maternal or 

pup findings at sacrifice. Therefore, the no-observed-effect level (NOEL) for adult 

pregnant females rabbits for systemic and reproductive and developmental toxicity was 

15, 000 ppm of trans-1-chloro-3,3,3-trifluoropropene.

4. Subchronic toxicity.

A 14-day pilot inhalation toxicity study was conducted with of trans-1-chloro-3,3,3-

trifluoropropene in rats. In this study, groups of 5 male and 5 female rats were exposed 

to vapors of trans-1-chloro-3,3,3-trifluoropropene 6 hours/day, 5- day/week for two 

weeks. The exposure levels were 0 (control), 2000, 7,500, and 20, 000 ppm. There were 

no mortality, nor effects on body weight, body weight change or food consumption. A 

few differences were seen in hematology parameters such as an increase in prothrombin 

time (high level females) and the number of neutrophils and monocytes (high level 

males). These do not indicate a direct effect from the exposures. A significant increase 

was seen in the serum levels of two liver enzymes, ALAT and ASAT (high level males) 

along with a slight increase in ASAT (high level females). Females in the medium and 

high level groups showed an increase in glucose concentrations. Both males and females 

in the high level group showed increases in urea levels. While histopathological 

examination of the kidney and liver did not show evidence for treatment related effects, 

these observations could be suggestive of the beginning of effects on these organs. It 

should be noted that the livers in the high level females did show increases in 

hepatocellular vacuolation. A decrease in the spleen weight was seen in the high level 

males, but not the females. This finding would not appear to be significant. 

Histopathological changes in the heart were seen in the high level males and females and 

the mid level males. These finds were described as multifocal mononuclear cell 

infiltrates and were slight to moderate in the high level males, very slight to slight in the 

high level females and a very slight in the mid level males. Based on the results from this 

study, the high exposure level in the 4-week inhalation toxicity study will be 10,000 ppm.

5. Chronic toxicity. N/A

6. Animal metabolism. See 7. Metabolite Toxicology
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7. Metabolite toxicology. 

The metabolism of trans-1-chloro-3,3,3-trifluoropropene was determined in male Sprague 

Dawley rats, female New Zealand White rabbits and in vitro. Animals were exposed by 

inhalation to 2,000, 5, 000, and 10,000 ppm trans-1-chloro-3,3,3-trifluoropropene for 6 

hours and urine was collected for 48 hours after the end of the exposure. Microsomes 

were incubated with trans-1-chloro-3,3,3-trifluoro-propene at 37o C for 20 hours. Urine 

samples and microsomal incubation supernatants were analyzed for metabolites using 

19F-NMR and LC/MS-MS. A predominant in vitro biotransformation product, S-(3,3,3-

trifluro-trans-propenyl)glutathione was identified in rat, rabbit and human microsomal 

experiments (77% in rat, 81% in rabbit, 86% in human –of total metabolites by 19F NMR 

signal intensities). On the other hand, the oxidative metabolites 3,3,3-trifluorolactic acid 

(TFLA) and N-acetyl-(3,3,3-trifluoro-trans-propenyl)-L-cysteine (MA) were observed as 

the major in vivo metabolites, 32% for TFLA and 40% for MA (rat) and 46% MA 

(rabbit) of the total metabolites by 19F NMR signal intensities in urine sample obtained 

within 6 hours after the exposure. TFLA was not found with rabbits. Quantification by 

LC/MS-MS showed rapid excretions of both metabolites, with half times of less than 6 

hours in both species. Based on metabolite recovery in urine and estimations of inhaled 

trans-1-chloro-3,3,3-trifluoropropene suggest trans-1-chloro-3,3,3-trifluoropropene, 

biotransformation extent was determined to be 0.01% of received dose in rabbits and 

0.0002% in rats. The metabolite structures suggest trans-1-chloro-3,3,3-trifluoropropene 

undergoes both oxidative biotransformation by CYP and direct glutathione conjugation. 

8. Endocrine disruption. N/A

C. Aggregate Exposure 

1. Dietary exposure.

i. Food. Trans-1-chloro-3,3,3-trifluoropropene has a boiling point of 19o C (66.2o 

F). At ambient temperature, trans-1-chloro-3,3,3-trifluoropropene is a gas. 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.

ii. Drinking water. N/A

2. Non-dietary exposure Occupational Exposure to trans-1-chloro-3,3,3-

trifluoropropene at Aerosol Can-Filling: There is the potential for worker exposure to 

trans-1-chloro-3,3,3-trifluoropropene during aerosol can-filling operations. In the 

Background Document (EPA 1994), potential exposures to a surrogate aerosol during 

can-filling were estimated to be approximately 285 ppm (as a 30-minute time-weighted 

average) and 39.3 ppm (as an 8-hour time-weighted average, without local exhaust 

ventilation). These values are more than 10 fold lower than the exposure level shown to 

cause toxicity in animals. No Acceptable Exposure Level (AEL) has been established for 

trans-1-chloro-3,3,3-trifluoropropene.
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D. Cumulative Effects

N/A

E. Safety Determination

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

trans-1-chloro-3,3,3-trifluoropropene is not expected.

2. Infants and children. N/A 

F. International Tolerances

N/A