Document ID: EPA-HQ-OPP-2011-0772-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-11-09T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Ms. Shaja Joyner, (703) 308-3194, PM Team 20: Fungicide Branch

Syngenta Crop Protection, LLC

1F7892

	EPA has received a pesticide petition (1F7892) from Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300 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

   by establishing a tolerance for residues of

	propiconazole:  1H-1,2,4-Triazole, 1-{[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl}-, and its metabolites determined as 2,4-dichlorobenzoic acid and expressed as parent compound in or on the raw agricultural commodity sugarcane at 1.0 (ppm).  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. The metabolism of propiconazole as well as the nature of the residues is adequately understood for purposes of the tolerance.  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 the differences between the respective metabolic pathways to be quantitative in nature.

      2. Analytical method. Analytical methods adequate to determine parent propiconazole, total propiconazole as 2,4-dichlorobenzoic acid, and the triazole metabolites (1,2,4-Triazole, Triazole Alanine, and Triazole Acetic Acid) are available for enforcement purposes with limits of detection that allow monitoring of food with residues at or above the levels set in this tolerance.

      3. Magnitude of residues. In the appropriate growing areas of the US, eight residue trials were conducted on sugarcane.  Propiconazole, formulated as a 3.6 lb a.i./gallon emulsifiable concentrate (EC), was applied four times at a rate of approximately 0.169 lb a.i./A (1X rate).  Sugarcane stalks (cane) were sampled ca. 30 days after the last application (DALA).  Residue decline samples were also collected at 16, 23, 44, and 51 DALA at one trial site.  In addition, at two sites, sugarcane was treated four times at a rate of approximately 0.845 lb a.i./A (5X rate).  Sugarcane stalks from the untreated control and 5X rate treated plots were processed to produce refined sugar and molasses.

      Samples were analyzed for propiconazole (parent), propiconazole (total residue as 2,4-dichlorobenzoic acid (2,4-DCBA)), and the triazole metabolites (1,2,4-Triazole (T), Triazole Alanine (TA), and Triazole Acetic Acid (TAA)).  The maximum residues of propiconazole, propiconazole as 2,4-DCBA, and the triazole metabolites (T, TA, and TAA), obtained from the analyses of 1X rate treated sugarcane samples were 0.216, 0.337, not detected, 0.012, and <0.01 ppm, respectively.  Analytical results from the residue decline samples do not indicate a pattern of residue increase over time for any of the analytes.  Separate tolerances for processed commodities are not being requested.  

B. Toxicological Profile

      1. Acute toxicity.  Propiconazole has low to moderate toxicity in experimental animals.  Data indicated the following:  a rat acute oral LD50 of 1,517 milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 of >4,000 mg/kg; a rat inhalation LC50 of >5.84 mg/liter air, and is a minimal skin and slight eye irritant.  It is a dermal sensitizer.  Propiconazole is readily absorbed by the rat skin with absorption within 10 hours of application.  

      2. Genotoxicity. Propiconazole was negative for mutagenicity in the in vitro BALB/ C 3T3 cell transformation assay, bacterial reverse mutation assay, Chinese hamster bone marrow chromosomal aberration assay, unscheduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, mitotic gene conversion assay and the dominant lethal assay in mice.  Hepatocellular proliferation studies in mice suggest that propiconazole induces cell proliferation followed by treatment-related hypertrophy in a manner similar to the known hypertrophic agent phenobarbital.
      
      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 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 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 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 software with the Food Commodity Intake Database (DEEM-FCID[TM], version 2.16) from Exponent.  Propiconazole is currently 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 Subgroup 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 12), strawberries, sugar beets, tree nuts (Crop Group 14), wheat, wild rice (regional), and turf and ornamental uses.  Pending uses include a revised use on mint (7-day PHI), revised use patterns for Propi-Shield(TM) brand paint and stain additive products, IR-4 foliar uses on succulent and dried legumes (Crop Group 6), and post-harvest uses on citrus fruit (Crop Group 10-10), stone fruit (Crop Group 12), and tomatoes (Crop subgroup 8 - 10A).  Existing (40CFR180.434) or estimated tolerances were used for all commodities.  DEEM(TM) (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.  Anticipated residues in meat, milk, and egg (MME) commodities were calculated by constructing a theoretical "maximum reasonably balanced diet" (MRBD) livestock diet using the June 2008 revisions to the OPPTS 860.1000 Table 1 feedstuffs.  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 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 population subgroup.  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 671 or 14.9% 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 283 or 35.3% 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 population subgroup.  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 724 or 13.8% 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 282 or 35.5% 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 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 uses on the mint (revised use pattern), legumes, and post-harvest citrus, stone fruit, and tomatoes as well as the proposed use on sugarcane.  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 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 101.826 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 population subgroup.  Acute drinking water exposure U.S. population resulted in a MOE of 3,553 (0.8% of the aRfD of 0.30 mg/kg-bw/day).  The most exposed sub-population was children 1-2 years old with a MOE of 2,354 (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-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 9,048 (1.1% of the cRfD of 0.10 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in 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 propiconazole.

      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-Shield(TM) brand paint and stain additive 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 hand.  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 ingestion of treated soil.  A dermal absorption value of 40% was used to calculate exposure for turf and ornamental uses.  For Propi-Shield(TM) brand paint additive products, adult applicator scenarios assessed included paintbrush and roller applications of in-can treated 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, respectively, 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 exposures 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) containing 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 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 635 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 analysis (food and water) showed that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of 671 for the U.S. population.  Since the worst case aggregate MOE of 148 (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 273 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 that exposures from all current, pending, and proposed propiconazole uses resulted in a MOE of 269 for children 1-2 years old.  Since the worst case aggregate MOE of 149 (short-term 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.  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.  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.