**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS**

**PUBLISHED IN THE FEDERAL REGISTER EPA**  **Registration Division contact:**  **Erin Malone ,**  **703 -**  **3 47**  **- 0253** 

**Syngenta Crop Protection LLC. PP# 2F8135** 

**EPA has received a pesticide petition**  **PP# 2F8135**  **from Syngenta Crop Protection LLC.,**  **P.O. Box 18300, Greensboro, NC 27419 -**  **8300 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**  **.434 .**  1. **by establishing tolerance**  **for residue of Propiconazole, 1**  **- [[2**  **- (2,4** **- dichlorophenyl)**  **- 4**  **- propyl**  **- 1,3**  **- dioxolan**  **- 2**  **- yl] methyl]**  **- 1H**  **- 1,2,4** **- triazole and its**  **metabolites determined as 2,4, -**  **dichlorobenzoic acid and expressed as parent compound**  **in or on the raw agricultura**  **l commodity R**  **apeseed subgroup 20A**  **at 0.**  **3 parts per million (ppm).**  **EPA has determined that the petition contains data or**  **information regarding the elements set forth in section 408 (d)(2) of the 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

. **Syngenta conducted complete**  **magnitude of residue trials on canola in Canada to support the requested use of**  **propiconaozle . These residue trials**  **satisfy the requested tolerance on rapeseed.** 1. **Plant metabolism. The metabolism of propiconazole as well as the nature of**  **the residues is adequately understood for purposes of the tolerances. Plant**  **metabolism has been 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 of crops. The plant metabolism pathway for propiconazole is well** 

**understood. Parent metabolite CGA -**  **64250 is the major compound found in crops. Comparison of the metabolism of propiconazole in different plant species shows that**  **the differences between the respective m etabolic pathways to be quantitative in**  **nature .**  **2. Analytical method.**  **The metabolism data in plants and animals suggest that analytical methods to detect either the phenyl or the triazole ring would be**  **appropriate for the measurement of residues. However, because of the natural occurrence of compounds that interfere with th**  **e measurement of triazoles, methods designed to detect this moiety have been proven unreliable and unacceptable.**  **Conversely, conversion of phenyl moiety to 2,4 -**  **dichlorobenzoic acid (DCBA) has proven to be satisfactory for all agricultural products analyze**  **d to date. Analyti cal**  **methods AG -**  **626 and AG -**  **454A were developed for the determination of residues of**  **propiconazole and its metabolites containing the DCBA moi**  **ety. Analytical method AG**  **- 626**  **has been accepted and published by EPA as the tolerance enforceme nt**  **method for crops. The limit of quantitation (LOQ) for the method is 0.05 ppm ]**  **. 3.**  **Magnitude of residues .**  **. [IR**  **- 4 conducted magnitude of residue trials on**  **several crops under OPPTS 860.1500 to support the requested use**  **of propiconaozle**  **in/on rapeseed subgroup 20A**  **. The maximum residue of propiconaozle on canola was**  **0.22 ppm. These residue trials satisfy the proposed tolerances for these crops. ]**  **B. Toxicological Profile**  **1. Acute toxicity.**  **Propiconazole exhibits low toxicity. Data indicated the following: a rat acute oral LD**  **50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute**  **dermal LD 50**  **>6,000 mg/kg; a rat inhalation LC 50**  **>5.8 mg/liter air; minimal skin and slight eye irritation; and nonsensitization**  **. 2.**  **Genotoxicty. Propiconazole exhibits**  **low toxicity. Data indicated the following: a rat acute oral LD**  **50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute**  **dermal LD 50**  **>6,000 mg/kg; a rat inhalation LC 50**  **>5.8 mg/liter air; minimal skin and slight eye irritation; and nonsensitization.** 

**3. Reproductive and developmental toxicity.**  **In an oral teratology study in the rabbit, a maternal no observed adverse effect level (NOAEL) of 30 mg/kg was based on**  **reduced food intake but without any fetotoxicity even at the top dose of 180 mg/kg. In an oral**  **teratology study 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 feta**  **l 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 of systemic 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**  **- month feeding 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 liver tum or was seen in these males but no evidence of**  **carcinogenicity was seen at the next lower dose of 500 ppm in either sex. In a 24 month chronic feeding/oncogenicity study in the rat, a NOAEL of 100 ppm (5 mg/kg)**  **was based on body weight and blood chemistry. The MTD was 2,500 ppm based on**  **reduction in body weight gain and no evidence of oncogenicity was seen. Based on the available chronic toxicity data, Syngenta believes the Reference dose (RfD) for**  **propiconazole is 0.0125 mg/kg/day. This RfD is based on a 1 year feeding study in**  **dogs with a NOAEL of 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 most sensitive indicator of to xicity 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 C for carcinogenicity (evidence of possible carcinogenicity for humans). The compoun**  **d was tested in 24 month studies with both rats and mice. The only evidence of**  **carcinogenicity was an increase in liver tumor incidence in male mice at a dose level that exceeded the maximum tolerated dose (MTD). Dosage levels in the rat study**  **were appro priate 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 of all chronic human health effects, including cancer.**  **] 6.**  **Animal metabolism. 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 of an analytical enforcement method tha t**  **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 of concerned 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**  **subchronic and chro nic studies also showed no evidence of a long** **– term effect related**  **to the endocrine system. Further, due to the moderate rate of degradation of the product, there is no risk that propiconazole may accumulate in the environment. In**  **animals, propiconazole i s quickly excreted and has no tendency for accumulation in**  **the body. Based on these results, it is very likely that propiconazole has no potential to interfere specifically with the endocrine system.**  **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 Model software with**  **the Food Commodity Intake Database (DEEM -**  **FCID TM**  **, version 2.16) from Exponent. Propiconazole is current**  **ly registered for use on alfalfa (indirect), avocado (Section 18), bananas, barley, berries (Crop Groups 13**  **- 07A, 13**  **- 07B, and 13**  **- 07G), carrots, cilantro, corn** 

**(field, sweet, and popcorn), cranberries (regional), garden beets, grasses, leaf petioles (Crop Su**  **bgroup 4B), mushrooms, nectarines and peaches (Section 18, expires 31 -**  **Dec -**  **2013), oats, onions (bulb and green), parsley, peanuts, peppermint, pineapples (seed piece treatment),**  **pistachios, rice, rye, sorghum, soybeans, spearmint, stone fruits (Crop Group 1 2),**  **strawberries, sugar beets, tree nuts (Crop Group 14), wheat, wild rice (regional), and turf and ornamental uses** **, a revised use on mint (7**  **- day PHI), revised use patterns for Propi**  **- ShieldTM**  **brand paint and stain additive products, IR -**  **4 foliar uses on succ ulent and dried legumes (Crop**  **Group 6), post -**  **harvest uses on citrus fruit (Crop Group 10 -**  **10), stone fruit (Crop Group 12), and tomatoes (Crop subgroup 8** **– 10A)**  **. Pending uses include a foliar use on sugarcane**  **and foliar**  **use on small cereal grains including b arley, oats, rye, and wheat. Existing (40CFR180.434) or**  **estimated tolerances were used for all commodities. DEEMTM (version 7.87) default processing factors were used for all processed commodities except citrus oil (185X), orange juice**  **(0.011X), pineapple juice (0.11X), pineapple process residue (1.49X), sugarcane sugar (0.02X),**  **and sugarcane molasses (0.49X). No adjustments were made for “percent crop treated,” i.e., 100%CT was assumed. For livestock commodities, established tolerances were used where**  **a vailable for beef and dairy, however for livestock commodities that do not already have**  **established tolerances (i.e., pork meat, fat, and all poultry commodities), anticipated residues were calculated by constructing theoretical “maximum reasonably balance**  **d diet” (MRBD) livestock diets. Drinking water estimates were selected using the higher of the estimated**  **drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments were taken from the USDA’s Continuing**  **Survey of Food Intake by individuals (CSFII) with the 1994**  **- 1996 consumption database and the Supplemental CSFII**  **children’s survey (1998) consumption database.** i **. Food**  **Acute Food Risk: The acute dietary (food only) risk assessment was performed for all**  **population subgroups with an acute reference dose (aRfD) of 0.3 mg/kg -**  **bw/day based on an acute no observed adverse effect level (NOAEL) of 30 mg/kg**  **- bw/day from an acute**  **neurotoxicity study in rats and an uncertainly factor of 100X. The 100X safety fac tor included**  **intra -**  **and inter -**  **species variations. No additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of**  **margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for**  **each sub -**  **population. In addition, exposure was expressed as a percent of the acute reference dose (%aRfD). At the 95th percentile, acute exposure to the U.S. population resulted in a MOE**  **of 667 or 15.0%**  **of the aRfD (Benchmark = 100; aRfD = 0.3**  **mg/kg -**  **bw/day) . Acute exposure to**  **the most sensitive subpopulation (children 1 -**  **2 years old) resulted in a MOE of 277 or 36.0% of the**  **aRfD (Benchmark = 100; aRfD = 0.3 mg/kg**  **- bw/day)**  **. Since the Benchmark MOE for this assessment is 100 and si**  **nce EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there 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) of 0.1 mg/kg** **- bw/day**  **based on a 24 -**  **month oncogenicity study in mice with a NOAEL of 10 mg/kg** **- bw/day**  **and an uncertainly factor of 100X. The 100X safety factor included intra -**  **and interspecies variations. No additional FQPA safety factor was applied. For the**  **purpose of the aggregate risk assessment, the exposure v alues were expressed in**  **terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each sub**  **- population. In addition, exposure was expressed as a**  **percent of the chronic reference dose (%cRfD). Chronic exposure to the U.S.**  **population resulted in a MOE of 720 or 13.9%**  **of the 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 273 or 36.6%**  **of the cRfD (Benchmark = 100; cRfD = 0.1**  **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% of the reference dose, Syngenta believes that there is a reasonable certainty that no**  **harm will re sult 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 adequate ly protective for cancer risk as**  **well as other chronic effects .**  **ii. Drinking Water** 

**. The Estimated Drinking Water Concentrations (EDWCs) of**  **propiconazole were determined using Tier l SCI -**  **GROW (version 2.3) which estimates pesticide concentration in ground water and Tier II PRZM/EXAMS (PE version 5.0)**  **which estimates pesticide concentration in surface water. This drinking water**  **assessment was conducted to assess all currently registered uses, the pending change to the use pattern for mint, and the proposed use on legume vegetables (succulent**  **and dried) as well as proposed post -**  **harvest uses on citrus, stone fruit, and tomatoes.**  **The post -**  **harvest uses have no impact on drinking water because post -**  **harvest treatment is an indoor use posing negligible impact to drinking water concentrations.**  **For groundwater, the currently registered use on turf provided the highest EDWC of**  **0.725 ppb (acute and chronic). For surface water, the currently registered use on turf provided an acute EDWC of 101.826 ppb and a chronic EDWC of 52.438 ppb. No**  **Percent Cropped Area (PCA) adjustments were made for surface wa ter EDWCs.**  **Since the surface water EDWCs exceed the ground water EDWC, the surface water values** **were used for risk assessment purposes and will be considered protective for any**

**ground water exposure concerns. Acute Exposure from Drinking Water**  **. The ac**  **ute surface water EDWC of 101.826 ppb was input directly into the DEEM**  **- FCIDTM software as “water, direct and indirect, all**  **sources” to model the acute drinking water exposures. Exposure contributions at the 95%**  **- ile of exposures were determined by taking th**  **e difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each sub**  **** **population. Acute drinking water exposure U.S. population resulted in a MOE of 3,467 (0.9% of the aRfD of 0.30 mg/kg** **- bw/day). The most expose**  **d sub -**  **population was children 1**  **- 2 years old, with a MOE of 2,227 (1.3% of the aRfD of 0.30 mg/kg/day).**  **Since the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures above the benchmark or below 100% of the aRfD,**  **Syngenta believes that there is a reasonable certainty that no harm will result from acute**  **drinking water exposure to residues arising from all current, pending, and proposed uses for propiconazole.**  **Chronic Exposure from Drinking Water .**  **The chronic surface water EDWC of 52.438 ppb was input directly into the DEEM**  **- FCIDTM software as “water, direct and indirect, all sources” to**  **model the chronic drinking water exposures. Chronic drinking water exposure to the U.S.**  **population resulted in a M OE of 9,048 (1.1% of the cRfD of 0.10 mg/kg**  **- bw/day). The most**  **exposed sub -**  **population was infants <1 year old, with a MOE of 2,760 (3.6% of the cRfD of 0.10 mg/kg**  **- bw/day). Since the Benchmark MOE for this assessment was 100 and since EPA**  **generally has no concern for exposures above the benchmark or below 100% of the cRfD,**  **Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from the current, pending, and proposed uses for**  **p ropiconazole.**  **2. Non**  **- dietary exposure**  **. Short**  **- term exposure assessments were conducted to**  **assess exposures resulting from non -**  **dietary uses of propiconazole arising from**  **registered turf and ornamental uses and from Propi -**  **ShieldTM brand paint and stain additi**  **ve products containing propiconazole. Adult turf and ornamental handler scenarios assessed included low**  **- pressure hand wand sprayer, garden hose**  **- end**  **sprayer, granular push spreader, hand held belly grinder spreader, and spreading granular formulation by ha**  **nd. Adult and youth post -**  **application exposure scenarios included high contact activities (lawns) and golf. For children, re**  **- entry to treated**  **turfgrass areas resulted in dermal and non -**  **dietary oral exposures via hand -** **to -**  **mouth, object**  **- to**  **- mouth, and ingesti**  **on of treated soil. A dermal absorption value of 40% was used to calculate exposure for turf and ornamental uses. For Propi**  **- ShieldTM brand**  **paint additive products, adult applicator scenarios assessed included paintbrush and roller applications of in**  **- can t**  **reated paint and stain, airless sprayer application of in -** **can treated paint and stain, and low -**  **pressure hand wand sprayer application of wood**

**preservative stains. Dermal absorption values of 1.0% and 26.6% for consumers applying paint or stain, respective**  **ly, were taken from a recent EPA assessment (DP# D364956, Nov. 2009). For all turf and ornamental scenarios assessed, the worst**  **- case**  **combined short -** **term MOE was 181 (Benchmark = 100) for children 1 -**  **6 years old for combined dermal and non**  **- dietary oral expo**  **sures resulting from post -**  **application exposures to propiconazole treated turfgrass. Post**  **- application exposure to**  **ornamental plants is negligible; and was, therefore, not assessed. For all paint and stain scenarios assessed, the worst**  **- case combined short**  **- term MOE was 160**  **(Benchmark = 100) for all adults 20+ years old applying in -**  **can treated stain with an airless sprayer. Exposure risks were also assessed for children’s accidental ingestion**  **of lawn granules (MOE = 331) and paint chips (MOE = 4,500) contain ing propiconazole**  **and were found to be acceptable (Benchmark MOE = 100); the ingestion of lawn granules and paint chips by children is considered to be episodic in nature and is not**  **aggregated with dietary or other residential exposures. Since the Benchma**  **rk MOE for this assessment was 100 and since the EPA generally has no concern for exposures**  **above the benchmark, Syngenta believes that there is a reasonable certainty that no harm will result from short**  **- term non**  **- dietary exposures arising from all**  **current, pending, and proposed uses**  **for propiconazole. D. Cumulative Effects**  **Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section**  **408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the**  **cumulative effects of a particular pesticide’s residues and “other substances that hav e**  **a common mechanism of toxicity”. Propiconazole is a member of the triazole**   ** containing class of pesticides. Although conazoles act similarly in plants (fungi) by** **inhibiting ergosterol biosynthesis, there is not necessarily a relationship between this pe**  **sticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. There is currently no evidence to**  **indicate that conazoles share common mechanisms of toxicity and the EPA is not follo**  **wing a cumulative risk approach based on a common mechanism of toxicity for the conazoles.**  **E. Safety Determination 1.**  **U.S. population. Using the conservative assumptions described above, and**  **based on the completeness and reliability of the toxicity data , the acute aggregate**  **(food plus water) exposure calculation for all current, pending, and proposed uses of propiconazole provided a MOE of**  **621 for the U.S. population. For short**  **- term**  **exposures, chronic dietary (food and water) exposures were aggregated with residential exposures, resulting in a worst**  **- case short**  **- term aggregate MOE of 148 for** **the U.S. population. The chronic aggregate exposure a nalysis (food and water)** 

**showed that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of 649 for the U.S. population. Since the worst case aggregate MOE**  **of 148 (short**  **- term risk)**  **exceeds the Benchmark MOE of 100, Synge nta believes that**  **there is a reasonable certainty that no harm will occur to the U.S. population from aggregate exposures arising from all current, pending, and proposed uses for**  **propiconazole. 2.**  **Infants and children .**  **Using the conservative assumption s described above,**  **and based on the completeness and reliability of the toxicity data, the acute aggregate (food plus water) exposure calculation for all current, pending, and proposed uses of**  **propiconazole provided a MOE of 267 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 of 150 for children 1 -**  **6 years old. The chronic aggregate exposure analysis (food and water) showed th**  **at exposures from all current, pending, and proposed propiconazole uses resulted in a**  **MOE of 262 for children 1 -**  **2 years old. Since the worst case aggregate MOE of 150 (short**  **- term risk)**  **exceeds the Benchmark MOE of 100, Syngenta believes that there is a re**  **asonable certainty that no harm will occur to infants and children from aggregate exposures arising from 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. The**  **Codex MRLs are expressed in terms of propiconazole per se**  **. In addition, both Canada and Mexico have established MRLs/to**  **lerances 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 Codex, Canadian and Mexican MRLs; however, differences in use patterns and the supporting residue data have precluded reduci**  **ng many tolerances. A summary of Codex MRLs, Canadian MRLs and Mexican tolerances and the**  **corresponding U.S. tolerances for propiconazole is discusses at www.regulations.gov**  **Docket No. EPA -**  **HQ -**  **OPP -**  **2006 -**  **0347 -**  **0004; pages 53**  **- 54**