Document ID: EPA-HQ-OPP-2014-0788-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-11T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2014-0788

EPA Registration Division Contact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 
Pesticide Petition Number: 4E8321
EPA has received a pesticide petition, PP# 4E8321, from  Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201W,  Princeton, NJ 08540  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 by  establishing tolerances for residues 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 the stoichiometric equivalent of propiconazole, in or on the raw agricultural commodities: Dill, fresh at 30 parts per million (ppm);  Dill, dried at 80 ppm; Dill, seed at 15 ppm; Leafy brassica greens, subgroup 5B at 20 ppm; Radish, tops at 0.2 ppm; Radish, roots at 0.04 ppm; Ti palm, leaves at 10 ppm; Ti palm, roots at 0.3 ppm, Watercress at 6 ppm, Fruit, stone, group 12-12, except plum at 4.0 ppm and Nut, tree, group 14-12 at 0.1 ppm. Upon approval of proposed tolerances, the petitioner requests removal of the established tolerances under 40 CFR 180.434 in or on Fruit, stone, group 12 except plum at 4.0 ppm, and Nut, tree, group 14 at 0.1 ppm that are superseded by this action.  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 support granting of the petition. Additional data may be needed before EPA rules on the petition.
      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 metabolic 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 the 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 analyzed to date.  Analytical methods AG-626 and AG-454A were developed for the determination of residues of propiconazole and its metabolites containing the DCBA moiety.   Analytical method AG-626 has been accepted and published by EPA as the tolerance enforcement 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 on dill, leafy brassica greens, radish and watercress. These residue trials satisfy the requested tolerance on these crops.  
EPA's Chemistry Science Advisory Council (ChemSAC) agreed that for Ti palm roots, A tolerance of 0.3 ppm covers the representative crops in crop sub-group 1B and a garden beet root tolerance and therefore, should adequately cover Ti palm root residue when Ti palm is treated with the same use pattern as other 1B crops.  
ChemSAC also agreed that for Ti palm leaves: A tolerance of 10 ppm can be translated from the sugar beet tops established tolerance of 10 ppm, and should adequately cover Ti palm leaves when it is treated with the same use pattern as leaves of root and tuber vegetables.
B. Toxicological Profile
      1. Acute toxicity. Propiconazole exhibits low toxicity.  Available data indicated the following:  a rat acute oral lethal dose (LD)50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a rat inhalation lethal concentration (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 LD50 of 1,517 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 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 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 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 maximum tolerated dose (MTD) was exceeded at 2,500 ppm in males based on decreased survival and body weight. Increased incidence of liver tumor 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 toxicity 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 compound 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 MTD.  Dosage levels in the rat study were appropriate for identifying a cancer risk.  The EPA 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 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 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 chronic 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 is 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 (DEEM-FCID(TM) 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, 13-07B, 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); turf grass, and wild rice.  A use on canola is pending.  IR4 minor uses on dill, Ti palm, radish, watercress, and leafy Brassica (Crop Group 5B) are proposed.  Existing 40 CFR 180.434 or proposed tolerances were used for all commodities.  Experimental processing factors were used for canola meal (1.48X), canola oil (0.03X), orange juice (0.011X), pineapple juice (0.11X), 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).  DEEM[TM] 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) 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 factor 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 749 or 13.4% 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 281 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% 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 values 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 819 or 12.2% 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 284 or 35.2% 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 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:  The 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) and the Modified Tier 1 Rice Model which estimate pesticide concentration in surface water for terrestrial and aquatic uses, respectively.  This drinking water assessment was conducted to assess all currently registered uses, pending uses on canola as well as the proposed uses on dill, watercress and leafy brassica greens, crop subgroup 5B.  For groundwater, the currently registered use on turf provided the highest EDWC of 0.725 ppb (acute and chronic).  For surface water, the proposed use on watercress provided an acute EDWC of 272 ppb and a chronic EDWC of 174 ppb.  No Percent Cropped Area (PCA) adjustments were made for surface water 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 acute surface water EDWC of 272 ppb was input directly into the DEEM-FCID(TM) 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 the 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 3,627 (2.8% of the aRfD of 0.30 mg/kg-body weight (bw)/day).  The most exposed sub-population was infants <1 year old, with a MOE of 1,216 (8.2% 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 174 ppb was input directly into the DEEM-FCID(TM) 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 MOE of 2,745 (3.6% of the cRfD of 0.10 mg/kg-bw/day).  The most exposed sub-population was infants <1 year old, with a MOE of 1,064 (9.4% 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 propiconazole
2. Non-dietary exposure.  Short-term exposure assessments were conducted to assess exposures resulting from non-dietary residential uses of propiconazole arising from uses on golf course and residential turf.  Activity scenarios for adults (19+ years old) included mixer/loader/applicator, high contact dermal events, mower, and golfer.  Activity scenarios for 11-16 year old youths included mower and golfer.  Activity scenarios for 6-11 year old youths included golfer.  Activity scenarios for children 1-6 years included re-entry and various activities on treated turf.  A dermal absorption value of 40% was used.  For all turf and ornamental scenarios, the scenario producing the highest short-term exposure for each population subgroup selected.  For adults 19+, the worst-case short-term MOE was 1,639 (adult high contact turf).  For youths 11-16, the worst-case short-term MOE was 19,910 (youth golfer).  For youths 6-11, the worst-case short-term MOE was 1,639 (youth golfer).  For children 1-6, the worst-case short-term MOE was 764 (combined dermal + hand-to-mouth).  Exposure risks were also assessed for children's accidental ingestion of lawn granules (MOE = 147) and were found to be acceptable (Benchmark MOE = 100); the ingestion of lawn granules by children is considered to be episodic in nature and is not aggregated with dietary or other residential exposures.  Since the Benchmark 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 have 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 pesticidal 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 following 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 878 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 of 631 for the U.S. population.  Since the worst case aggregate MOE of 621 (short-term risk) exceeds the Benchmark MOE of 100, Syngenta 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 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 256 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 377 for children 1-2 years old.  The chronic aggregate exposure analysis (food and water) showed that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of 247 for children 1-2 years old.  Since the worst case aggregate MOE of 247 (chronic risk) exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable 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 (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).  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 Codex, Canadian and Mexican MRLs; however, differences in use patterns and the supporting residue data have precluded reducing many tolerances.