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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact:

The Tea Association ofthe USA. PP#

EPA has received a pesticide petition PP#_ from The Tea Association ofthe U.S.A., Inc., 362 5th Avenue, Suite 801, NewYork, NewYork 10001, proposing, pursuantto section 408(d) ofthe Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.434.



### 1. by establishing tolerance for residue of Propiconazole, 1-[[2-(2,4-dichlorophenyl)-4- propyl-1 ,3-dioxolan-2-yl] methyl]-lH-1,2,4-triazole in or on the raw agricultural commodity [Tea] at4.0 parts per million (ppm). EPA has determined thatthe petition contains data or information regarding the elements set forth in section 408 (d)(2) ofthe FDDCA; however, EPA has notfully evaluated the sufficiency of the submitted data at thistime orwhetherthe data supports granting ofthe petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry . Trials to measure the magnitude of residues of propiconazole in tea were conducted in India and Sri Lanka to support the requested tolerance of propiconazo1e '" tea. These residue trials satisfy the requested tolerance on tea.


### 1. Plantmetabolism. The metabolism of propiconazole as well as the nature ofthe residues is adequately understood for purposes ofthe tolerances. Plant metabolism has 'leer evaluated in five diverse crops, wheat, grapes, celery, peanuts and carrots which should serve to define the similar metabolism of propiconazole in a wide range ofcrops. The plant metabolism pathwayfor propiconazole is well understood. Parent metabolite CGA-64250 isthe major compound found in crops. Comparison ofthe metabolism of propiconazole in different plant species shows that the differences between the respective metabolic pathways to be quantitative in nature.

2.

### Analyticalmethod. Propiconazole parent has been reported to be detected by numerous multi-residue methods used in compliance and enforcement. US FDA Pesticide Analytical Method (PAM) 1 also indicatesthe abilityto determine residues of propiconazole parent in a wide range of plant products. Consequently, US Government compliance and enforcement methods are available to supportthe proposed importtolerance and residue definition.

3. 

### Magnitude ofresidues.. Residue studies were performed in India and Sri Lanka to supportthe setting of a Codex CXL. These studies have been submitted under OPPTS 860.1500 to support the requested importtolerance for propiconazole in/on tea. The maximum residue of propiconazole on tea was 1.8 ppm. These residue trials satisfy the proposed tolerance for tea of4.0 ppm for parent propiconazole.


### 8. Toxicological Profile

1.

### Acutetoxicity. Propiconazole exhibits lowtoxicity. Data indicated the following: a rat acute oral LD50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a rat inhalation LC50 >5.8 mg/liter air; minimal skin and slight eye irritation; and no sensitization.

2. 

### Genotoxicity. Propiconazole exhibits no mutagenic potential based on the following data: In vitro gene mutation test (Ames assay, rat hepatocyte DNA repair test, (human fibroblast DNA repair test), In vitro chromosome test, (human lymphocyte cytogenetic test), ~n vivo mutagenicitytest, (Chinese hamster bone marrow cell nucleus anomalytest, Chinese hamster bone marrow cell micronucleus test, mouse dominant lethal test), and other mutagenicity test (BALB/3T3 cell transformation assay).

3. 

### Reproductive anddevelopmental toxicity. In an oral teratology study in the rabbit, a maternal no observed adverse effect level (NOAH) of 30 mg/kg was based on reduced fo:d intake but without any fetotoxicity even atthe top dose of 180 mg/kg. In an oral teratologystudy in the rabbit, a maternal NOAEL of 100 mg/kg was based on reductions in body weight gain and food consumption and a fetal NOAEL of 250 mg/kg was based on increased skeletal variations at 400 mg/kg. In an oral teratology study in the rat, a maternal and fetal NOAEL of 100 mg/kg was based on decreased survival, body weight gain, and food consumption in the dams and delayed ossification in the fetuses at 300 mg/kg. In a second teratology study in the rat, a maternal and fetal NOAEL of 30 mg/kg was based on reductions in body weight gain and food consumption in the dams and delayed development in the fetuses at 90 and 360/300 mg/kg. A supplemental teratology study in the rat involving eight times as many animals per group as usually required showed no teratogenic potential for the compound. A 2-generation reproduction study in the rat showed excessive toxicity at 5,000 ppm without any teratogenic effects. A 2-generation reproduction study in the rat showed no effects on reproductive or fetal parameters at any dose level. Postnatal growth and survival were affected at the top dose of 2,500 ppm, and parental toxicity was also evident. The NOAEL for development toxicity is 500 ppm.
4. 

### Subchronic toxicity. In a 21-day dermal study in the rabbit, a NOAEL of 200 mg/kg was based on clinical signs ofsystemic toxicity. In a 28-day oral toxicity study in the rat, a NOAEL of 50 mg/kg was based on increased liver weight. In a subchronic feeding study in the mouse, a NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 13 week feeding study in the male mouse, a NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 90 day feeding study in rats, the NOAEL was 240 ppm (24 mg/kg) based on a reduction in body weight gain. In a 90 day feeding study in dogs, the NOAEL was 250 ppm (6.25 mg/kg) based on reduced food intake and stomach histologic changes.]

5. 

### Chronic toxicity. In a 12-monthfeeding study in the dog, a NOAEL of 50 ppm (1.25 mg/kg) was based on stomach histologic changes. In a 24 month oncogenicity feeding study in the mouse, the NOAEL was 100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males based on decreased survival and body weight. Increased incidence of livertumor was seen in these males but no evidence of carcinogenicity was seen atthe next lower dose of 500 ppm in either sex. In a 24 month chronic feeding/oncogenicity study in the rat, a NOAEL o~ 100 ppm (5 mg/kg) was based on body weight and blood chemistry. The MTD was 2,500 ppl\1 based on reduction in body weight gain and no evidence of oncogenicity was seen . Based or. the available chronic toxicity data, the Reference dose (RfD) for propiconazole is believed tc be 0.0125 mg/kg/day. This RfD is based on a 1 year feeding study in dogs with a NOAEL 

### cf 1.25 mg/kg/day (50 ppm) and an uncertainly factor of 100. No additional modifying factor for the nature of effects was judged to be necessary as stomach mucous hyperemia was the 'l'lost sensitive indicator oftoxicity in that study.

### Using the Guidelines for Carcinogenic Risk Assessment published on September 24, 1986 {51 FR 33992), the USEPA has classified propiconazole in group Cfor carcinogenicity (evidence of possible carcinogenicity for humans). The compound was tested in 24 month studies with both rats and mice. The only evidence ofcarcinogenicity was an increase in livertumor incidence in male mice at a dose level that exceeded the maximum tolerated dose (MTD). Dosage levels in the rat study were appropriate for identifying a cancer risk. The Cancer Peer Review Committee recommended the RfD approach for quantitation of human risk. Therefore, the RfD is deemed protective ofall chronic human health effects, including cancer.]
6. Animalmetabolism. 

### Metabolism in animals is similar to plant metabolism. In animals both the rat and the goat rapidly metabolize and excrete propiconazole. Neither animal retains significant amounts of propiconazole or its metabolites in tissues. Significant quantities of parent or metabolites do not appear in goat's milk. Similar metabolites are produced by both species, and unconjugated (phase I) metabolites are similar in plants and animals. The metabolism profile supports the use ofan analytical enforcement method that accounts for combined residues of propiconazole and its metabolites that contain the 2,4- dichlorobenzoic acid (DCBA) moiety. 7. Metabolite toxicology. 

### There are no metabolites ofconcerned based on a differential metabolism between plants and animals.
8. Endocrine disruption. 

### Developmental toxicity studies in rats and rabbits and reproduction studies in rats gave no indication that propiconazole might have any effects on endocrine function related to development and reproduction. The sub-chronic and chronic studies also showed no evidence ofa long- term effect related tothe endocrine system. Further, due to the moderate rate ofdegradation ofthe product, there is no risk that propiconazole may accumulate in the environment. In animals, propiconazole is quickly excreted and has no tendency for accumulation in the body. Based on these results, it is 

### ,,~ry likelythat propiconazole has no potential to interfere specifically with the endocrine systern.


### C. Aggregate Exposure



### 1. Dietary exposure. 

### Tier I acute, short-term, and chronic aggregate exposure assessments were performed for propiconazole using the Dietary Exposure Evaluation Mod:?I (DEEM-FCIDTM Version 3.16) from Exponent and consumption data from the USDA NHANES"What We Eat in America" survey, 2003-2008. Propiconazole is currently registered for uses on alfalfa; avocados; banana; beans (dry and succulent); beets (garden); beets (sugar); berries (Crop Groups 13-07A, 13-078, 13-07G); bulb vegetables (Crop Group 3); carrots; cilantro (leaves); citrus fruits (Crop Group 10); corn (field, pop, sweet); cranberries; grasses; leaf petioles (Crop Group 4B); mushrooms; nectarines; ornamentals; parsley (fresh, dried); peaches; peanuts; peppermint; pineapple; pistachio; rice; small cereal grains (barley, oats, rye, wheat); sorghum; soybean; spearmint; stone fruit (Crop Group 12}; strawberries; sugarcane; tomatoes; tree nuts (Crop Group 14}; turfgrass, and wild rice. A use on canola is pending. IR4 minor uses on dill, Ti palm, radish, watercress, and leafy Brassica (Crop Group SB) are proposed. A use on imported tea is also proposed byTea association of USA. Existing (40CFR180.434} or proposed tolerances were used for all commodities. Experimental processing factors were used for canola meal (1.48X}, canola oil (0.03X}, orangejuice (O.OllX}, pineapplejuice (O.llX}, pineapple process residue (1.49X}, soybean oil (0.08x}, sugarcane sugar (0.02X}, sugarcane molasses (0.49X}, wheat bran (2.4x}, wheat flour (0.2x}. DEEMTM Version 7.87 default processing factors were used for all other commodities. No adjustments were made for "percent crop treated, " i.e., 100%CT was assumed. For livestock commodities, established tolerances were used. Drinking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. 

### i. Food Acute Food Risk: : The acute dietary (food only) risk assessment was performed for all population subgroups with an acute reference dose (aRfD) of0.3 mg/kg-bw/day based on an acute no observed adverse effect level (NOAEL) of30 mg/kg-bw/dayfrom an acute neurotoxicitystudy in rats and an uncertainlyfactor of lOOX. The lOOX safety factor included intra- and inter-species variations. No additional FQPA safety factor was applied. For the purpose ofthe aggregate risk assessment, the exposure value was expressed in terms of margin of exposure (MOE), which was calculated by dividingthe NOAH bythe exposure for each sub-population . In addition, exposure was expressed as a percent ofthe acute reference dose (%aRfD). Atthe 95th percentile, acute exposure to the U.S. population resulted in a MOE of748 or 13.4% ofthe aRfD (Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Acute exposur~ t\J the most sensitive subpopulation (children 1-2 years old} resulted in a MOE of280 or 35.6% of the aRfD (Benchmark = 100; aRfD = 0.3 mg/kg-bw/day). Since the Benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures above the benchmark or below 100% ofthe reference dose, Syngenta believes thatthere is a reasonable certainty that no harm will result from acute dietary (food) exposure to residues arising from all current, pending, and proposed uses for propiconazole.

### Chronic Food Risk: : The chronic dietary (food only) risk assessment was performed for all population subgroups with a chronic reference dose (cRfD) of0.1 mg/kg-bw/day based on a 24-month oncogenicity study in mice with a NOAH of 10 mg/kg-bw/day and an uncertainly factor of

### lOOX. The 

### lOOX safety factor included intra- and interspecies variations. No additional FQPA safetyfactor was applied. For the purpose ofthe aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAH bythe exposure for each sub-population . In addition, exposure was expressed as a percent ofthe chronic reference dose (%cRfD). Chronic exposure to the U.S. population resulted in a MOE of817 or 12.2% ofthe cRfD (Benchmark= 100; cRfD = 0.1 mg/kg-bw/day). Chronic exposure to the most exposed sub-population (children 1 -2 years old) resulted in a MOE of 284 or 35.2% ofthe cRfD (Benchmark = 100; cRfD = 0.1 mg/kg-bw/day) . Since the Benchmark MOE forthis assessment is 100 and since EPA generally has no concern for exposures above the benchmark or below 100% ofthe reference dose, Syngenta believes that there is a reasonable certaintythat no harm will result from chronic dietary (food) exposure to residues arising from all current, pending, and proposed uses for propiconazole. Cancer Risk: A quantitative risk assessment using a cancer endpoint was not performed. The chronic risk assessment is adequately protective for cancer risk as well as other chronic effects. ii. Drinking Water . 

### Notapplicable tothis importtolerance petition . Acute Exposure from Drinking Water. Not applicable to this importtolerance petition.
Chronic Exposure from Drinking Water. Not applicable to this importtolerance petition.

2. Non-dietary exposure. 

### Not applicable to this importtolerance petition. D. Cumulative Effects 

### Cumulative Exposure to Substances with a Common Mechanism ofToxicity. Section 408(b)(2)(D)(v) requires that, when considering whetherto establish, modify, or revoke a tolerance, the Agency consider "available information" conc erning the cumulative effect!: '.J~ 3 

### particular pesticide's residues and "other substances that have a common mechanism of

### toxicity". Propiconazole is a member ofthe triazole-containing class of pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between this pesticidal activity and their mechanism oftoxicity in mammals. Structural similarities do not constitute a common mechanism oftoxicity. There is currently no evidence to indicate that conazoles share common mechanisms oftoxicity and the EPA is not following a cumulative risk approach based on a common mechanism oftoxicity for the conazoles.
E. 

### SafetyDetermination

1. 

### U.S. population. . Using the conservative assumptions described above, and based on the completeness and reliability ofthe toxicity data, the acute aggregate (food plus water) exposure calculation for all current, pending, and proposed uses of propiconazole provided a MOE of620forthe U.S. population. For short-term exposures, chronic dietary (food and water) exposures were aggregated with residential exposures, resulting in aworst-case shortterm aggregate MOE of878 for the U.S. population . The chronic aggregate exposure analysis (food and water) showed that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of630 for the U.S. population. Since the worst case aggregate MOE of620 (short-term risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certaintythat no harm will occur to the U.S. population from aggregate exposures arising from all current, pending, and proposed uses for propiconazole.

2. 

### Infants andchildren. Using the conservative assumptions described above, and based on the completeness and reliability ofthe toxicity data, the acute aggregate (food plus water) exposure calculation for all current, pending, and proposed uses of propiconazole provided a MOE of256 for children 1 -2 years old. For short-term exposures, chronic dietary (food and water) exposures were aggregated with residential exposures resulting in a short term aggregate MOE of376 for children 1 -2years old. The chronic aggregate exposure analysis (food and water) showed that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of247 for children 1 -2years old. Since the worst case aggregate MOE of247 (chronic risk) exceeds the Benchmark MOE of 100, Syngenta believ~s that there is a reasonable certaintythat no harm will occurto infants and children from aggregate exposures arisingfrom all current, pending, and proposed uses for propiconazole.F. International Tolerances The Codex Alimentarius Commission has established several maximum residue limits (MRLs) for propiconazole in or on various raw agricultural commodities (banana; barley; coffee beans; cranberry; maize; pecan; pineapple; popcorn; rape seed; rye; soya; sugar beet; sugar cane; sweet corn; triticale; wheat; and meat, milk, and eggs) but not tea. The Codex MRLs are expressed in terms of propiconazole per se. In addition, both Canada and Mexico have established MRLs/tolerances on several commodities which also have U.S. tolerances. The U.S. tolerance expression includes all metabolites determined as 2,4-dichloro-benzoic acid. In conjunction with the reregistration process EPA intends to revise the tolerance expression to propiconazole per se. To the extent possible, for the present petitions, U.S. tolerances have been numerically harmonized with Canadian MRL in tea.