**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE**

**PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact:**  Shaja Joy ner , (703) 30 8 - 3194; PM Team 20 Registration Division EPA has received a pesticide petition 1F7891 from Sy ngenta Crop Protection, LLC 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. 1. by establishing a tolerance for residues of azoxystrobin: (methyl (E) - 2 - {2 - [ 6 - (2 - cyanop henoxy)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 commodities in or on the raw agricultural commodity s ugarcane at 0.2 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 th e 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 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. 2. Analytical method. An adequate anal yt ical method, gas chromatography with nitrogen phosphorus detection (GC - NPD) or in mobile phase by high performance liquid chromatograph y with ultra - violet detection (HPL C - 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 Analy tical Chemistry

section of the EPA concluded that the method(s) are adequate for enforcement. Analy tic al 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 requeste d tolerances are adequately supported. In support of the requested tolerance, Sy ngenta 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 azox ys trobin in or on the requested commodities.B. Toxicological Profile

1. Acute toxicity. Acute toxicity N

OAEL = < 200 mg/kg/

day UF = 300 Acute Rf D = 0.67 mg/kg/

day FQPA SF = 1X aPAD = Acut e 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 dos e at all dose levels up to and including 20 mg/kg/day

(the LOAEL) 2. Genotoxicty. Azoxy strobin was positive for forward gene mutation in mouse ly mphoma cells, but was not mutagenic in the salmonella/mammalian activation gene mutation assay , showed some evidence of concentration - related induction of chromosomal aberrations over backgroun d in the presence of moderate to severe toxicity in the in vitro mammalian cy togenetics assay

in human ly

mphocy tes, caused no increase in the induction of micronuclei in the mouse bone marrow micronucleus assay , and did not increase the incidence of unsche duled DNA s ynthesis in rat hepatocy tes/mammalian cells. 3. Reproductive and developmenta l toxicity Reproductive and Developmental toxicity) NOAEL = 25 mg/kg/ day UF= 100 FQPA SF = 1.X Prenatal developmental oral toxici ty study in rates LOA .EL = 100 mg/kg/day based on increas ed 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 N OAEL = 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. Azoxy strobin is classified “as not likely to be carcinogenic in humans” 6. Animal metabolism. The metabolism of azoxy strobin as well as the nature of the residues is adequatel y understood. 7. M etabolite toxicology. There are no metabolites of concern based on a differential metabolism between plants and animals. 8. Endocrine disruption. There is no evidence that azoxy strobin is an endocrine disrupter. C. Aggregate Exposure1. Dietary exposure. Acute (Tier III) and chronic (Tier III) dietary exposure evaluations were made for azox ys trobin using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM - FCIDTM, version 2.16) from Exponent. All consumption data for these assessments were taken from the USDA’s Continuing Survey of Food Intake b y individuals (CSFII) with the 1994 - 96 consumption database and the Supplemental CSFII children’s survey (1998) consumption database. These exposure assessments included all c urrentl y registered and pending uses of azox ys trobin plus a proposed use on sugarcane. Residue data was taken from field trials where azoxy strobin 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 b y 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 azox ys trobin acute dietary (food onl y) 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 uncertaint y 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 onl y) exposure to the U.S. population resulted in a MOE of 4,46 7 (6.7% of the aRfD of 0.67 mg/kg/day). The most sensitive sub - population was infants (<1 y ear old) with a MOE of 2,1 30 - (14. 0 % of the aRfD of 0.67 mg/kg/day). Since the benchmark MOE for this assessment is 300 and since EPA generall y has no concern for exposures below 100% of the aRfD, Sy ngenta believes that there is a reasonable certaint y that no harm will result from dietary (food only) exposure to residues arising from all current and proposed uses for azoxy strobin. Chronic exposure. The azoxy strobin chronic dietary (food onl y) 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 mg/kg/day and an uncertaint y 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 b y dividing the N OAEL b y 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 9,60 5 (1.0% of the cRfD of 0.18 mg/kg/day). The most sensitive sub population was children (1 - 2 y ears old) with a MOE of 3,68 3 (2.7% of the cRfD of 0.18 mg/kg/day). Since the benchmark MOE for this assessment was 100 and since EPA generall y has no concern for exposures below 100% of the cRfD, Sy ngenta 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 azoxy strobin.Cancer . Azoxy strobin 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 azox ys trobin. ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of azoxy strobin 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 o f azox ystrobin from the currently registered uses plus the proposed sugarcane use were determined. Based on the SCI - GROW modeling, the highest groundwater EDWC for azoxy strobin 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 an d will be considered protective for an y ground water concentration concerns. Acute Exposure from Drinking W ater : The acute surface water EDWC of 173 ppb was input directly into the DEEM - FCIDTM software as “water, direct and indirect, all sources” to mode l the acute drinking water exposures. Exposure contributions at the 99.9% - ile of exposures were determined b y 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 23,156 (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 7 868 ( 3.8 % of the aRfD of 0.67 mg/kg/day). Since the benchmark MOE f or this assessment was 100 and since EPA generall y has no concern for exposures 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 and proposed uses for azoxy strobin. Chronic Exposure from Drinking W ater : The chronic surface water EDWC of 33 ppb was input directly into the DEEM - FCIDTM 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 y ear 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 below 100% of the cRfD, Sy ngenta believes that there is a reasonable certaint y that no harm will result from chronic drinking water exposure to residues arising from all current and proposed uses for azoxy strobin. Non
- dietary exposure. Risk assessments were conducted for non - dietary uses of azoxy strobin since it is currentl y registered for residential use outdoors on turf an d ornamentals and for use in residentially

applied paint. Azox ys trobin 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 ye ar) and to ornamentals at rates of up to 0.75 lb a.i./acre (not to exceed 5 lb a.i./acre per y ear). The maximum concentration of azoxy strobin 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 asse ssments 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 azox ys trobin, a NOAEL of 25 mg/kg/day was used for sho rt - term exposure and a NOAEL of 20 mg/kg/day was used for intermediate - term exposure. No dermalassessment 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 y ears 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. 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”. Azoxy strobin is related to the naturally occurring strobilurins. Sy ngenta 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. D. Safety Determination US. populati on The acute dietary exposure anal ys is (food plus water) showed that exposure from all registered and proposed azoxy strobin crop uses would result in a MOE of 3,744 ( 7.97 % of the aRfD) for the general U.S. population, which exceeds the benchmark MOE of 300. The chronic dietary exposure anal ys is (food plus water) showed that exposure from all registered and proposed azox ys trobin crop uses resulted in a MOE of 7,00 5 (1.4% of the cRfD) which exceeds the benchmark MOE of 100. Based on the completene ss and reliabilit y of the toxicity data supporting these petitions, Sy ngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed azoxy strobin crop uses, including anticipated dietary exposure from food, water, and all other ty pes of non - occupational exposures. 1. Infants and Children The acute dietary exposure analy sis (food plus water) showed that exposure from all registered and proposed azox ys trobin crop uses would result in a MOE of 1,676 ( 1 7. 8 % of the aRfD) for the most sensitive population subgroup, infants <1 y ear old, which exceeds the benchmark MOE of 300. The chronic aggregate dietary (food and water) exposure anal ys is showed that exposure from all registere d and proposed azoxy strobin crop uses would result in a MOE of 3,040 ( 3.3 % of the cRfD) for the most sensitive population subgroup, children (1 - 2 y ears 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 815 for the most sensitive population subgroup, children 1 - 6 y ears 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 863 for children 1 - 6 y ears old. The EPA has determined that there is reliable data support using the standard MOE and uncertainty factor (100X for chronic and 30 0X for acute) for azox ys trobin 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, Sy

ngenta believes that there is a reasonable certaint y that no harm will result toinfants and children from aggregate exposure to residues arising from all registered and proposed

azoxy strobin crop uses, including anticipated dietary exposure from food, water, and all other ty pes of no n - occupational exposures. F. International Tolerances There are no Codex, Canadian, or Mexican MRLs for azoxy strobin in or on the proposed commodities. Therefore harmonization of tolerances is not an issue.