Document ID: EPA-HQ-OPP-2021-0729-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2021-11-23T05:00Z

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

EPA Registration Division contact: Shaja Joyner, (703) 308-3194; PM 20

Syngenta Crop Protection, LLC

PP#1E8946

	EPA has received a pesticide petition (PP#1E8946) from Syngenta Crop Protection, LLC, 410 Swing Road, Greensboro, NC  27409 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 180.507.

   	1. by establishing import tolerances for residues of
	azoxystrobin: (methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate) and the Z isomer of azoxystrobin, (methyl (Z)-2-{2-[6-(2- cyanophenoxy)pyrimidin-4-yloxy]pheny1}-3-methoxyacrylate) in or on the raw agricultural commodity 
	
	Mango at 8 ppm; Papaya at 6 ppm; Palm, Oil at 0.06 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 azoxystrobin is adequately understood for the purpose of the proposed tolerances.  
      
2. Analytical method. An adequate analytical method, gas chromatography with nitrogen-phosphorus detection (GC-NPD) or in mobile phase by high performance liquid chromatography with ultra-violet detection (HPLC-UV), is available for enforcement purposes with a limit of detection that allows monitoring of food with residues at or above the levels set in these tolerances. The Analytical Chemistry section of the EPA concluded that the method(s) are adequate for enforcement. Analytical methods are also available for analyzing meat, milk, poultry and eggs which also underwent successful independent laboratory validations.   

3. Magnitude of residues. Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequately supported. In support of the requested tolerances, Syngenta has conducted the necessary trials in accordance with the requirements of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of azoxystrobin in or on requested commodities. 
            
B. Toxicological Profile

EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk.  EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.  Specific information on the studies received and the nature of the toxic effects caused by azoxystrobin as well as the no-observed-adverse-effect-level (NOAEL) from the toxicity studies can be found in the document titled "Azoxystrobin  - Revised Human Health Draft Risk Assessment for Registration Review'' in Docket ID Number EPA-HQ-OPP-2009-0835 at the following website: http://regulations.gov. A summary of  the toxicological endpoints for Azoxystrobin used for human risk assessment is discussed in Section III, Subsection A of the final interim decision for registration review published in the Federal Register (Docket ID Number EPA-HQ-OPP-2009-0835-0040).

      1. Acute toxicity.  See above

	2. Genotoxicty. See above

	3. Reproductive and developmental toxicity. See above

	4. Subchronic toxicity. See above

	5. Chronic toxicity. See above

	6. Animal metabolism. See above

	7. Metabolite toxicology. See above

	8. Endocrine disruption. See above

C. Aggregate Exposure

1. Dietary exposure.  Tier I acute and Tier III short-term and chronic dietary exposure evaluations were performed for azoxystrobin using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID, version 4.02) and CARES NG Food Model (Creme Global, Version 1.2.0).  Consumption data from the USDA NHANES "What We Eat in America" survey, 2005-2010 was used for both models.  Side-by-side comparison of the two dietary models resulted in effectively no differences for acute and chronic exposures. These exposure assessments included all currently registered uses of azoxystrobin plus proposed import tolerances on mango, palm oil, and papaya.  Residue data was taken from field trials where azoxystrobin was applied at the maximum intended use rate and samples were harvested at the minimum pre-harvest interval (PHI) to obtain maximum residue values.  Proposed tolerances were calculated from the residue values.  Calculated and projected percent crop treated (%CT) values were incorporated in the chronic and short-term assessments, while the acute assessments incorporate 100% crop treated. Anticipated residues in meat and milk were calculated by constructing theoretical nutritionally balanced diets.  Drinking water estimates were included directly into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.

i. Food.  Acute exposure.  The azoxystrobin acute dietary (food only) risk assessment was performed for all population subgroups using an acute reference dose (aRfD) of 0.67 mg/kg/day based an acute neurotoxicity study in rats with a Lowest Observed Adverse Effect Level (LOAEL) of 200 mg/kg/day and an uncertainty factor of 300X (100X for intra- and inter-species variability and 3X for absence of a no observed adverse effect level (NOAEL)).  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 LOAEL by the exposure for each population subgroup.  In addition, exposure was expressed as a percent of the acute reference dose (%aRfD).  At the 95[th] percentile, acute dietary (food only) exposure to the U.S. population resulted in a MOE of 1,902 (15.8% of the aRfD of 0.67 mg/kg/day).  The most sensitive subpopulation was children (1-2 years old) with a MOE of 832 (36.0% of the aRfD of 0.67 mg/kg/day).  Since the benchmark MOE for this assessment is 300 and since EPA generally has no concern for exposures above the benchmark MOE or below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from all current and proposed uses for azoxystrobin.

Chronic exposure.  The azoxystrobin chronic dietary (food only) risk assessment was performed for all population subgroups using a chronic reference dose (cRfD) of 0.18 mg/kg/day based on a combined chronic toxicity/carcinogenicity study in rats with a No Observed Adverse Effect Level (NOAEL) of 18 mg/kg/day and an uncertainty factor of 100X (for combined intra- and inter-species variability).  No additional FQPA safety factor was applied.  For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of 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 dietary (food only) exposure to the U.S. population resulted in a MOE of 2,575 (3.9% of the cRfD of 0.18 mg/kg/day).  The most sensitive subpopulation was children (1-2 years old) with a MOE of 1,301 (7.7% of the cRfD of 0.18 mg/kg/day).  Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures above the benchmark MOE or below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food) exposure to residues arising from all current and proposed uses for azoxystrobin.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) were determined based on Tier I groundwater and Tiers I and II surface water model simulations for all current and proposed uses. Tier I models Screening Concentration in Ground Water (SCI-GROW) and Pesticide in Water Calculator (PWC, v2.001) groundwater module were used to predict groundwater EDWCs. Tier II models Surface Water Concentration Calculator (SWCC) and PWC surface water module were used to predict surface water EDWCs from terrestrial uses. Tier I Rice Model and Tier II Pesticide in Flooded Applications Model (PFAM, v.2.0) were used to predict surface water EDWCs from aquatic uses. Based on the SCI-GROW modeling, the highest ground water EDWC for azoxystrobin is 3.1 ug/L (acute and chronic) based on the currently registered use on turf.  Based on the SWCC modeling, the registered turf use provided the highest surface water EDWCs of 70.2 ug/L for acute and 48.5 ug/L for chronic. 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 70.2 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 108,932 (0.3% of the acute RfD of 0.67 mg/kg-bw/day).  The most exposed sub-population was all infants (<1 year old) with a MOE of 28,906 (1.0% of the aRfD of 0.67 mg/kg/day).  Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the acute RfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and proposed uses for azoxystrobin.

Chronic Exposure from Drinking Water:  The chronic surface water EDWC of 48.5 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 18,367 (0.5% of the chronic RfD of 0.18 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in a MOE of 4,918 (2.0% of the chronic RfD of 0.18 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the chronic RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from the current and proposed uses for azoxystrobin.

Cancer.  Azoxystrobin has been classified as "not likely to be a human carcinogen" based on the revised Cancer Guidelines.  Therefore, no cancer risk assessment was performed for azoxystrobin.
      	
2. Non-dietary exposure.  Risk assessments were conducted for non-dietary uses of azoxystrobin since it is currently registered for residential use outdoors on turf and ornamentals formulated as wettable granules, granules, and liquid products such as Heritage, Heritage Action, Mural, Headway G, Banner Heritage Maxx, and Azoxystrobin H&G. A short-term handler risk assessment was required for adults because there is a residential handler inhalation exposure scenario.  Both short- and intermediate-term risk assessments were required for children based on the potential for hand-to-mouth, object-to mouth, soil, and granule ingestion exposure from treated turf.  For incidental non-dietary oral exposures to azoxystrobin, a NOAEL of 35 mg/kg/day was used for short- and intermediate-term exposure and a NOAEL of 3.8 ug/L (HED of 0.02 mg/kg/day) was used for short- and intermediate-term inhalation exposure.  No dermal assessment is required as no dermal endpoint has been selected.  

For inhalation exposure scenarios, the MOE for adults (U.S. population) making applications to turf is 47 for short-term exposure.  For post-application exposure to treated turf, the non-dietary oral MOE for children 1-6 years is 2,322 for short- and intermediate-term exposure. Since the EPA's benchmark MOE for azoxystrobin is 30 for inhalation exposures and 100 for incidental oral exposures, the residential exposures for both adults and children do not exceed EPA's level of concern.

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".  Azoxystrobin is related to the naturally occurring strobilurins.  Syngenta has concluded that further consideration of a common mechanism of toxicity is not appropriate at this time since there is no data to establish whether a common mechanism exists with any other substances.

E. Safety Determination

1. U.S. population. The acute dietary exposure analysis (food plus water) showed that exposure from all registered and proposed azoxystrobin crop uses would result in a MOE of 1,870 (16.0% of the aRfD) for the general U.S. population, which exceeds the benchmark MOE of 300.  The chronic dietary exposure analysis (food plus water) showed that exposure from all registered, pending and proposed azoxystrobin crop uses resulted in a MOE of 2,258 (4.4% of the cRfD) which exceeds the benchmark MOE of 100.  Based on the completeness and reliability of the toxicity data supporting these petitions, The EPA regulates short-term exposures for azoxystrobin using the "aggregate risk index" (ARI) approach rather than the more common Margin of Exposure (MOE) approach, because the levels of concern for short-term oral (LOC = 100) and short-term inhalation (LOC = 30) are dissimilar. For short-term exposures, the dietary (food and water) exposure was aggregated with residential exposure (inhalation MOE of 47) resulting in a short-term aggregate risk index of 1.5 for the most sensitive subpopulation, adults 50-99. Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.

2. Infants and children. The acute dietary exposure analysis (food plus drinking water) showed that exposure from all registered and proposed azoxystrobin crop uses would result in a MOE of 825 (36.3% of the aRfD) for the most sensitive subpopulation, children 1-2 years old, which exceeds the benchmark MOE of 300.  The chronic aggregate dietary (food and water) exposure analysis showed that exposure from all registered and proposed azoxystrobin crop uses would result in a MOE of 1,186 (8.4% of the cRfD) for the most sensitive subpopulation, children 1-2 years old, which exceeds the benchmark MOE of 100. For short-term exposures, the dietary (food and water) exposure was aggregated with the residential exposure (incidental oral MOE of 2,322) resulting in a short-term aggregate risk index of 11.6 for the most sensitive subpopulation, children 1-2 years old.  The EPA has determined that there is reliable data support using the standard MOE and uncertainty factor (100X for chronic and 300X for acute) for azoxystrobin and that an additional safety factor of 10 is not necessary to be protective of infants and children.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to residues arising from all registered and proposed azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.

F. International Tolerances

Maximum Residue Levels (MRLs) for azoxystrobin have been established in a number of countries including Argentina, Australia, Brazil, Canada, Chile, France, Germany, Italy, Korea and Spain. There are Codex MRLs on almond hulls, bananas, berries, asparagus, celery, ginseng, milk, poultry, eggs, cotton, fruiting vegetables, coffee beans, bulb vegetables, and many other commodities.