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 Team 20 Registration 

Division

EPA has received a pesticide petition 1F7891 from Syngenta 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-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 

commodities in or on the raw agricultural commodity sugarcane 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 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 tolerances have been 

submitted. The requested tolerances are adequately supported.

In support of the requested tolerance, 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 the requested commodities. 
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. Genotoxicty. 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 a proposed 

use on sugarcane. 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 99.9th percentile, acute 

dietary (food only) exposure to the U.S. population resulted in a MOE of 4,467 (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 2,130-(14.0% 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 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 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 9,605 (1.0% of the cRfD of 0.18 mg/kg/day). The most sensitive subpopulation was children (1-2 years old) with a MOE of 3,683 (2.7% 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 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.
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.

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 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 23,156 (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 7868 (3.8% 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 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 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 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 and proposed uses for azoxystrobin.

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.

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.

D. Safety Determination

US. 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 3,744 (7.97% 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 and 

proposed azoxystrobin crop uses resulted in a MOE of 7,005 (1.4% 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 and proposed 

azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other 

types of non-occupational exposures.

1. Infants and Children 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 

1,676 (17.8% 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 and proposed azoxystrobin crop uses 

would result in a MOE of 3,040 (3.3% 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 815 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 863 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 and proposed 

azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other 

types of non-occupational exposures.

F. International Tolerances There are no Codex, Canadian, or Mexican MRLs for azoxystrobin in 

or on the proposed commodities. Therefore harmonization of tolerances is not an issue.