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

EPA Registration Division contact: Ms. Erin Malone, (703) 347-0253; PM Team 20 Fungicide Branch

Syngenta Crop Protection, LLC

1E7945

      EPA has received a pesticide petition (1E7945) 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 an import tolerance 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 agricultural commodity ginseng extract (red ginseng extract and ginseng extract) at 0.5 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

     Plant metabolism. The metabolism of azoxystrobin as well as the nature of the residues is adequately understood for purposes of the tolerances. Plant metabolism has been evaluated in four diverse crops, cotton, grapes, wheat and peanuts which should serve to define the similar metabolism of azoxystrobin a wide range of crops. Parent azoxystrobin is the major component found in crops. Azoxystrobin does not accumulate in crop seeds or fruits. Metabolism of azoxystrobin in plants is complex with more than 15 metabolites identified. These metabolites are present at low levels, typically much less than 5% of the TRR.

     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.

     Magnitude of residues. Complete residue data to support the requested tolerance has been submitted. The requested tolerance is adequately supported.  In support of the requested tolerance, Syngenta has submitted studies conducted by the Korea Food and Drug Administration (KFDA) which include 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 the requested commodity.

  A. Toxicological Profile
   
     1.  Acute toxicity. 
         
                                                                 Acute toxicity
 NOAEL = < 200 mg/kg/day UF = 300
 Acute RfD = 0.67 mg/kg/day FQPA SF = 1X
aPAD = Acute RfD + FQPA
SF = 0.67 mg/kg/day
Acute neurotoxicity study in rates LOAEL = 200 mg/kg/day based on
diarrhea and 2- hours post dose at all dose levels up to and including 20 mg/kg/day (the LOAEL)







         2.  Genotoxicity. Azoxystrobin was positive for forward gene mutation in mouse lymphoma cells, but was not mutagenic in the salmonella/mammalian activation gene mutation assay, showed some evidence of concentration-related induction of chromosomal aberrations over background in the presence of moderate to severe toxicity in the in vitro mammalian cytogenetics assay in human lymphocytes, caused no increase in the induction of micronuclei in the mouse bone marrow micronucleus assay, and did not increase the incidence of unscheduled DNA synthesis in rat hepatocytes/mammalian cells.

         3.  Reproductive and developmental toxicity
         
Reproductive and Developmental toxicity)
NOAEL = 25 mg/kg/day 
UF = 100
FQPA  SF = 1.X
 Prenatal developmental oral toxicity 
 study in rates
LOA.EL = 100 mg/kg/day based on
 increased maternal diarrhea, urinary incontinence,: and salivation.



 
      4.  Subchronic toxicity
     
Subchronic Toxicity
NOAEL = 20 mg/kg/day 
 UF = 100
FQPA  SF = 1.X
 90-Day feeding study in rats
LOA.EL = 211/223 mg/kg/day in males/females based on decreased body weight gain in both sexes and clinical signs indicative of reduced nutrition.



            
      5.  Chronic Toxicity
      
Chronic Toxicity
NOAEL = 18 mg/kg/day 
UF = 100
Chronic RfD = 0.18 mg/kg/day
FQPA  SF = 1.X
cPAD = chronic RfD + FQPA
SF = 0.18 mg/kg/day
 Combined chronic toxicity
 carcinogenicity feeding study in rates LOAEL = 34/117 mg/kg/day in males/females based on reduced body weights in both sexes and bile duct lesions in males.
 
 Azoxystrobin is classified "as not likely to be carcinogenic in humans"
 

 
 
 
 
 



     6.  Animal metabolism. The metabolism of azoxystrobin as well as the nature of the residues is adequately understood.

     7.  Metabolite toxicology. There are no metabolites of concern based on a differential metabolism between plants and animals.
     
     8.  Endocrine disruption. There is no evidence that azoxystrobin is an endocrine disrupter.

  B. Aggregate Exposure
   
     1.  Dietary exposure. Acute (Tier III) and chronic (Tier III) dietary exposure evaluations were made for azoxystrobin using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), version 2.16) from Exponent.  All consumption data for these assessments were taken from the USDA's Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption database and the Supplemental CSFII children's survey (1998) consumption database.  These exposure assessments included all currently registered and pending uses of azoxystrobin plus proposed uses on sugarcane and imported ginseng extracts.  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.  Calculated and projected percent crop treated (%CT) values were incorporated in these assessments.  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 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 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 99.9[th] percentile, acute dietary (food only) exposure to the U.S. population resulted in a MOE of 4,445 (6.7% of the aRfD of 0.67 mg/kg/day).  The most sensitive sub-population was infants (<1 year old) with a MOE of 2,025 (14.7% 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 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, pending 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 NOAEL of 18.2 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 9,518 (1.1% of the cRfD of 0.18 mg/kg/day).  The most sensitive sub-population was children (1-2 years old) with a MOE of 3,618 (2.8% 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 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, pending and proposed uses for azoxystrobin.
     
     Cancer Risk.  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.

     ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of azoxystrobin were determined using Tier l screening models, SCI-GROW which estimates pesticide concentration in ground water and FIRST which estimates pesticide concentration in surface water.  EDWCs of azoxystrobin from the currently registered and pending uses plus the proposed sugarcane use were determined.  Based on the SCI-GROW modeling, the highest groundwater EDWC for azoxystrobin is 3.1 ppb (acute and chronic) based on the currently registered use on turf.  Based on the FIRST modeling, the turf use provided the highest surface water EDWCs of 173 ppb for acute and 33 ppb 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 concentration concerns.
     
     Acute Exposure from Drinking Water:  The acute surface water EDWC of 173 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 99.9%-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 23,699 (1.3% of the aRfD of 0.67 mg/kg-bw/day).  The most exposed sub-population was all infants (<1 year old) with a MOE of 9,509 (3.2% 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 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 azoxystrobin.

     Chronic Exposure from Drinking Water:  The chronic surface water EDWC of 33 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 25,878 (0.4% of the cRfD 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 7,893 (1.3% of the cRfD 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 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 all current, pending and proposed uses 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 and for use in residentially applied paint.  Azoxystrobin may be applied to turf at rates of up to 1.19 lb a.i./acre (not to exceed 5 lb a.i./acre per year) and to ornamentals at rates of up to 0.75 lb a.i./acre (not to exceed 5 lb a.i./acre per year).  The maximum concentration of azoxystrobin in paint is 1% a.i. (w/w).  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 toddlers based on the potential for hand-to-mouth, object-to mouth, and soil ingestion exposure from treated turf.  For incidental non-dietary oral and inhalation exposures to azoxystrobin, a NOAEL of 25 mg/kg/day was used for short-term exposure and a NOAEL of 20 mg/kg/day was used for intermediate-term exposure.  No dermal assessment is required.  
                                          
     For inhalation exposure scenarios, the MOE for adults (U.S. population) making applications of treated paint is 1,406 for short-term exposure.  For post-application exposure to treated turf, the non-dietary oral MOEs for children 1-6 years are 1,399 for short-term exposure and 1,927 for intermediate-term exposure.  Since the EPA's benchmark MOE for azoxystrobin is 100, 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, pending and proposed azoxystrobin crop uses would result in a MOE of 3,743 (8.0% 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 6,959 (1.5% of the cRfD) which exceeds the benchmark MOE of 100.  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 from aggregate exposure to residues arising from all current, pending 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, pending and proposed azoxystrobin crop uses would result in a MOE of 1,669 (17.9% of the aRfD) for the most sensitive population subgroup, infants <1 year old, which exceeds the benchmark MOE of 300.  The chronic aggregate dietary (food and water) exposure analysis showed that exposure from all registered, pending and proposed azoxystrobin crop uses would result in a MOE of 2,996 (3.4% of the cRfD) for the most sensitive population subgroup, 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 (MOE 1,399) resulting in a short-term aggregate MOE of 1,081 for the most sensitive population subgroup, children 1-6 years old.  For intermediate-term exposures, the food plus water exposure was aggregated with the residential exposure (MOE 1,927) resulting in an intermediate-term aggregate MOE of 1,279 for children 1-6 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, pending and proposed azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.
      
F. International Tolerances 

     According to the results of the 2011 Joint FAO/WHO Meeting on Pesticide Residues (JPMR) summary report, issued October 2011, the recommended Codex MRL for azoxystrobin on ginseng, processed products, is 0.5 ppm, equivalent to the proposed import tolerance.
      
