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

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 analytical method, gas chromatography with nitrogenphosphorus 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 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.

B. 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.

C. 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-FCIDTM, 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 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 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 99.9th 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-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 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-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 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 nonoccupational 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 nonoccupational 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.