Document ID: EPA-HQ-OPP-2009-1009-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-19T04:00Z

EPA Registration Division contact: Andrew Ertman, (703) 308-9367

  December 7, 2009
Interregional Research Project Number 4 (IR-4)
PP #9E7659
	EPA has received a pesticide petition (PP #9E7659) 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 (1) increasing tolerance on peppermint, tops and spearmint, tops from 3.5 parts per million (ppm) to 10 parts per million (ppm); by (2) establishing tolerance for : Onion, bulb, subgroup 3-07A at 0.2  parts per million (ppm); Onion, green, subgroup 3-07B at 9.0 parts per million (ppm); Caneberry subgroup 13-07A at 1.0 parts per million (ppm); Bushberry subgroup 13-07B at 1.0 parts per million (ppm); Low growing berry subgroup 13-07G, except cranberry at 1.3 parts per million (ppm) and by (3) removing tolerances for Berry group 13 at 1.0 parts per million (ppm); Onion, bulb at 0.2 parts per million (ppm), Onion, green at 9.0 parts per million (ppm) and strawberry at 1.3 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
      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. The limit of quantitation of (LOQ) for the method in all matrices were 0.05 ppm.

	 Mint.  Five mint trials (5) were conducted during the 2005 growing seasons, two each in Washington (EPA region 5) and Wisconsin (EPA region 5) and one in Idaho (Region 11).  The number of trials and geographic representation are in accordance with OPPTS Guideline 860.1500.
 In each trial, four applications of Tilt 3.6 EC at a rate of approximately 0.1125 lb ai/A each were made, for a total of approximately 0.3375 lb ai/A.  No adjuvants were used in these applications.  Applications were made 6 to 8 days apart and timed so that commercially mature mint tops (leaves and stems) could be collected  6 to 7 days after the final application.
Sample analysis for total residues of propiconazole was conducted by the Food and Environmental Quality Laboratory (FEQL), Richland, WA.  The procedure used was the FEQL method "Working Analytical Method for the Determination of Propiconazole in Mint Leaves as 2,4-Dichlorobenzoic Methyl Ester Using Gas Chromatography with Electron Capture Detector".  This method was adapted from "Determination of Total Residues of Propiconazole in Crops as 2,4-Dichlorobenzoic Acid by Capillary Gas Chromatography".  The maximum storage interval for field-treated samples in this study was 294 days.  
Maximum propiconazole equivalent residues in mint were 5.453 ppm.

B. Toxicological Profile
      1. Acute toxicity. Propiconazole exhibits low toxicity.  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 nonsensitization.

      2. Genotoxicty. Propiconazole exhibits low toxicity.  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 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 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 completed 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), bananas, barley, berries (Crop Group 13), carrots, cilantro, corn (field, sweet, and popcorn), cranberries (regional), garden beets, grasses, leaf petioles (Crop Subgroup 4B), mushrooms, nectarines (expires 31-Dec-2010), oats, onions (bulb and green), parsley, peaches (expires 31-Dec-2010), 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, and wild rice (regional).  Propiconazole is proposed for a revised use on spearmint and peppermint harvested at a reduced pre-harvest interval (PHI) of 7 days.  The 2007 revisions to the EPA crop groupings and use patterns for caneberries (Crop subgroup 13-07A), bushberries (Crop subgroup 13-07B), low growing berries except cranberries (Crop subgroup 13-07G), and bulb vegetables (Crop Group 3-07) have been incorporated into these assessments as appropriate.  Percent of crop treated values were conservatively set at 100% for all uses and default processing factors from DEEM(TM) (version 7.87) were used for processed commodities.

Food. Acute Risk.  The acute dietary (food only) risk assessment was performed for all population subgroups with an acute reference dose of 0.3 mg/kg-bw/day based on an acute no observable 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 1,524 (6.6% of the acute RfD of 0.3 mg/kg-bw/day).  Acute exposure to the most sensitive subpopulation (children 1-2 years old) resulted in a MOE of 615 (16.2% of the aRfD of 0.3 mg/kg-bw/day).  Since the benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food) exposure to residues arising from the current and proposed uses for propiconazole.

Chronic Risk.  The chronic dietary (food only) risk assessment was performed for all population subgroups with a chronic reference dose 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 1,626 (6.1% of the cRfD of 0.1 mg/kg-bw/day).  Chronic exposure to the most exposed sub-population (children 1-2 years old) resulted in a MOE of 586 (17.1% of the cRfD of 0.1 mg/kg-bw/day).  Since the benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (food only) 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. Estimated Drinking Water Concentrations (EDWCs) for propiconazole were determined using Tier l SCI-GROW (version 2.3), which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS (version PE5) which estimates pesticide concentrations in surface water.  This drinking water assessment was conducted to assess the proposed rate and pre-harvest interval (PHI) changes to the currently registered mint use (currently registered at 0.113 lb a.i./A x 2 applications at 14 day intervals and a 30 day PHI).  The proposed mint use is based on 0.113 lb a.i./A x 3 applications at 14 day intervals and a 7 day PHI.  The modeling was conducted using environmental fate parameters from a 2006 EPA drinking water assessment and the EDWCs were compared against Syngenta's baseline EDWCs based on the currently registered use on turf.  These proposed changes to mint have no impact on the current drinking water assessment.  For ground water, the currently registered use on turf at a rate of 1.79 lb a.i./A  x 4 applications at 14 day intervals (7.16 lbs a.i./A/year) provided the highest EDWC of 7.25E-01 ppb (acute and chronic).  For surface water, the currently registered turf use based on the same rate noted above was still considered to be the crop driver.  Employing the Pennsylvania turf standard PRZM scenario, the PRZM/EXAMS output provided an acute EDWC of 101.8 ppb and a chronic EDWC of 52.4 ppb.  No Percent Cropped Area (PCA) adjustments were made for surface water EDWCs.  

Acute Exposure from Drinking Water.  The acute EDWC of 101.8 ppb (0.1018 ppm) for surface water was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources."  Drinking water exposures were determined by taking the difference between the aggregate exposures (food + drinking water) and food exposures alone (food only) for each population subgroup.  At the 95th percentile, acute drinking water exposure to the U.S. population resulted in a MOE of 2,844 (1.1% of the aRfD of 0.3 mg/kg-bw/day).  The most exposed sub-population was all infants <1 year old, with a MOE of 942 (3.2% of the aRfD of 0.3 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the 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 exposure to drinking water residues arising from all current and proposed uses for propiconazole.

Chronic Exposure from Drinking Water.  The chronic EDWC of 52.4 ppb (0.0524 ppm) for surface water was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources."  Chronic drinking water exposures to the U.S. population resulted in a MOE of 9,054 (1.1% of the chronic RfD of 0.1 mg/kg/day).  The most exposed sub-population was all infants <1 year old, with a MOE of 2,762 (3.6% of the cRfD of 0.1 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the 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 exposure to drinking water residues arising from all current 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.  Although propiconazole is registered for use in products including paints and stains, exposures resulting from those uses were not included in these assessments since paint products containing propiconazole (Propi-Shield(TM)) are not currently sold for consumer use.  Adult handler scenarios assessed included low-pressure handwand sprayer, hose-end sprayer, and trigger-pump sprayer.  Adult post-application exposure scenarios included high contact activities and playing golf.  Children's' post-application non-dietary oral exposure scenarios included exposures resulting from hand-to-mouth, object-to-mouth, and ingestion of treated soil.  The worst-case combined short-term MOE was 487 for children 1 to 6 years old resulting from dermal and non-dietary oral 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 and proposed residential 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 and proposed uses of propiconazole provided a MOE of 1,313 for the U.S. population.  For short-term exposures, chronic dietary (food and water) exposures were aggregated with residential exposures resulting in a short-term aggregate MOE of 471 for the U.S. population.  The chronic aggregate exposure analysis (food and water) showed that exposures from all current and proposed propiconazole uses resulted in a MOE of 1,379 for the U.S. population.  Since the worst case aggregate MOE of 471 (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 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 and proposed uses of propiconazole provided a MOE of 579 for all infants <1 year old.  For short-term exposures, chronic dietary (food and water) exposures were aggregated with residential exposures resulting in a short-term aggregate MOE of 386 for children 1 to 6 years old.  The chronic aggregate exposure analysis (food and water) showed that exposures from all current and proposed propiconazole uses resulted in a MOE of 535 for children 1-2 years old.  Since the worst case aggregate MOE of 386 (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 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.