{0902.003 / 111 / 00077975.DOC 8}

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 petiti on. 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 c ompany 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 pro posing, 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 - tetrafluoroprop 1 - ene ( CAS No. 29118 - 24 - 9) u nder 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; ho wever, 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.{0902.003 / 111 / 00077975.DOC 8} 2

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 K ow 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 o r 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. Ac cording 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 - tetraf luoroprop - 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 epinephri ne. 2. Genotoxicity
. T rans - 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 chan ges were used to assess the carcinogenic potential of trans 1,3,3,3 - 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 trans 1,3,3,3 - tetrafluoroprop - 1 - ene to both positive (tetrafluoroethylene, 1 - amino - 2,4 - dibromoanthraquinone, and tris (2,3 - dibromopropyl)phosphate) and negative (trichlorofluoromethane, iodo - form, t etrafluoroethane 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 - tetr afluoropropene to be noncarcinogenic in both female mouse liver and male rat kidney. It was noted that treatment with trans - 1,3,3,3 - tetrafluoroprop -{0902.003 / 111 / 00077975.DOC 8} 3

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 obser ved. 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 th e 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 trans 1,3,3,3 - 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 tu mor 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 D NA 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 U DS. 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 p pm; 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, grou ps 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 w as 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, an d 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 -{0902.003 / 111 / 00077975.DOC 8} 4

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 inha lation 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 i n 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 - c hronic (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 week s. 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 a nd 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 conclu ded 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{0902.003 / 111 / 00077975.DOC 8} 5

renal toxins and mutagenic. The lack of renal toxicity and mutagenicity i s 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 biotransformat ion 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 d ated 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 wor ker 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 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). 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 80 0 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 recommen ds 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, R isk 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

- HQ

OAR

- 2003

- 0118.{0902.003 / 111 / 00077975.DOC 8} 6

Exposure to trans - 1,3,3,3 - t etrafluoroprop - 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 trans
1,3,3,3

- tetrafluoroprop

- 1

- ene during commercial or consu mer 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 concentratio n 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 adequat e 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 application s, 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 spr ay 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 ar ea, 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