**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 Sy ngenta Crop Protection, LLC 1E7945 EPA has received a pesticide petition ( 1E7945 ) from Sy ngenta Crop Protection , LLC, P.O. Box 18300, Greensboro, NC 27419
- 8300 request ing, 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

n import 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 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 1. Plant metabolism. The metabolism of azox ys trobin 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 def ine the similar metabolism of azoxy

strobin a wide range of crops. Parent azox ystrobin is the major component found in crops. Azox

ystrobin does not accumulate in crop seeds or fruits. Metabolism of azoxy strobin in plants is complex with more than 15 metabol ites identified. These metabolites are present at low levels, t

ypi cally 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 l iquid 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 Anal yt ical Chemistry section of the EPA concluded that the method(s) are adequate for enforcement. Analy tical methods are also available for anal yz ing meat, milk, poultry and eggs which also underwent successful independent laboratory

validations. 3. Magnitude of residues. Complete residue data to support the requested tolerance ha s been submitt ed. The requested tolerance is adequatel y s upported. In support of the requestedtolerance, Sy ngenta 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 azox ys trobin in or on the requested commodity
. 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. Genotoxic i ty. 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 background in the pre sence of moderate to severe toxicity in the in vitro mammalian cy togenetics assay

in human l ymphocy

tes, caused no increase in the induction of micronuclei in the mouse bone marrow micronucleus assay , and did not increase the incidence of unscheduled DNA s y nthesis 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 Toxicit

y 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 azox ys trobin 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 Exposure 1. 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

I ntake Database (DEEM
- FCI DTM, 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 currentl y registered and pending uses of azox ys trobin plus proposed uses on sugarcane and import ed ginseng extracts. Residue data was taken from field trials where azox ys trobin 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 directl y into the dietary

exp osure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. i. Food. Acute exposure : The azoxy strobin 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 fo r intra
- and inter
- species variability and 3× 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 calcul ated b y dividing the LOAEL b y 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 ye ar 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 generall y has no concern for exposures above the benchmark or below 100% of the aRfD, Sy ngenta believes that there is a reasonable certaint y that no harm will result from dietary (food onl y) exposure to residues arising from all current, pending and proposed uses for azox ys trobin. 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 0.18mg/kg/day based on a combined chronic toxicity /carcinogenicity

study in rats with a NOAEL of 18.2 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 ter ms of MOE, which was calculated b y dividing the NOAEL 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 result ed 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 y ears 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 generall y has no concern for exposures above the benchmark or below 100% of the cRfD, S yn genta 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 azoxy strobin. Cancer Risk
. 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 FI RST which estimates pesticide concentration in surface water. EDWCs o f azox ys trobin 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 azoxy strobin is 3.1 ppb (acute and chronic) based on the currentl y registered u se 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 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 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 ye ar old) with a MOE of 9,509 (3.2% of the aRfD of 0.67 mg/kg/day). Since th e benchmark MOE for this assessment was 100 and since EPA generall y has no concern for exposures above the benchmark or below 100% of the aRfD, Sy ngenta 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 azox ys trobin. 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 theU.S. population resulted in a MOE o f 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 above the benchmark or below 100% of the cRfD, S yn genta believes that there is a reasonable certaint y that no harm will result from chronic drinking water exposure to residues arising from all curre nt, pending and proposed uses for azoxy strobin. 2. 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 and ornamentals and for use in residential ly 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 ye ar). 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 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 azoxy strobin, 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 exposur e 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 azoxy strobin is 100, the residential exposures for both adults and children d o 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”. 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. E. Safety Determination 1. U
. S. population

. The acute dietary exposure analy sis (food plus water) showed that exposure from all registered, pending and proposed azoxy strobin 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 anal ys is (food plus water) showedthat exposure from all registered, pending and proposed az oxy strobin 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, Sy ngenta believes that there is a reasonable certaint y th at no harm will result from aggregate exposure to residues arising from all current, pending and proposed azoxy strobin crop uses, including anticipated dietary exposure from food, water, and all other t ypes of non
occupational exposures. 2. Infants and c hildren

. The acute dietary exposure anal ys is (food plus drinking water) showed that exposure from all registered, pending and proposed azox ys trobin crop uses would result in a MOE of 1,669 (17.9% of the aRfD) for the most sensitive population subgroup, inf

ants <1 ye ar old, which exceeds the benchmark MOE of 300. The chronic aggregate dietary

(food and water) exposure anal ysis showed that exposure from all registered, pending and proposed azox ys trobin crop uses would result in a MOE of 2,996 (3.4% of the cR fD) 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 1,081 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 aggre gate MOE of 1,279 for children 1
- 6 y ears old. The EPA has determined that there is reliable data support using the standard MOE and uncertaint y factor (100X for chronic and 300X for acute) for azoxy strobin and that an additional safet y 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 to infants and children from ag gregate exposure to residues arising from all registered, pending and proposed azox ys trobin crop uses, including anticipated dietary exposure from food, water, and all other t ypes of non
occupational exposures. F. International Tolerances According to the results of the 2011 J oint FAO/WHO M eeting on Pesticide Residues ( JPMR) summary

report , issued October 2011 , the recommended Codex MR L for azoxy strobin on ginseng, processed products , is 0.5 ppm , equivalent to the proposed import toleranc e .