Interregional Research Project Number 4 (IR-4)

PP# 4E8319

EPA has received a pesticide petition (4E8319) from Interregional Research Project 

Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ 08540 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 180.507 as follows:

By establishing tolerancesfor 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 raw agricultural commodities Ti palm, leaves at 50 part per million 

(ppm); Ti palm, roots at 0.5 ppm; Fruit, stone, group 12-12 at 2.0 ppm; and Nut, tree, group 14-12 at 

0.02 ppm.

Upon the approval of the aforementioned tolerances, to remove established tolerances 

for 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 raw agricultural 

commodities Fruit, stone, group 12 at 1.5 ppm; Nut, tree, group 14 at 0.02 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. ChemSAC agreed that for ti palm roots a tolerance of 0.50 ppm 

that covers the representative crops in crop subgroup 1A (Vegetable, root, subgroup), should 

adequately cover ti palm root residues when ti palm is treated with the same use pattern as 

other crop subgroup 1A crops. They also agreed that for ti palm leaves, a tolerance of 50 

ppm can be translated from the tolerance for the Leaves of root and tuber vegetable crop 

group 2 and should adequately cover ti palm leaves when it is treated with the same use 

pattern as other members of the Leaves of root and tuber vegetables crop group 2. 

4. 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. Tier III acute, short-term, intermediate-term, and chronic dietary

exposure evaluations were made for azoxystrobin using the Dietary Exposure Evaluation 

Model with the Food Commodity Intake Database (DEEM-FCID, version 3.16). DEEMFCID software incorporates food consumption data from the National Health and Nutrition 

Examination Survey)/“What We Eat in America” (NHANES/WWEIA) dietary survey

conducted in 2003-2008. These exposure assessments included all currently registered and 

pending uses of azoxystrobin plus proposed import tolerances on tea, coffee, and Asian 

pear and proposed use on ti palm. 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. Proposed 

tolerances were calculated from the 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 Lowest Observed Adverse 

Effect Level (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 no observed adverse effect level 

(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 5,495 (5.4% of the aRfD of 0.67 mg/kg/day). The 

most sensitive subpopulation was children (1-2 years old) with a MOE of 2,706 (11.0% 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 above the benchmark MOE 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 No 

Observed Adverse Effect Level (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 9,870 (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 3,562 (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 MOE 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. 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 were 

determined. The proposed import tolerances on tea, coffee and Asian pear have no impact 

on drinking water. 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 exposure 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 22,254 (1.3% of the 

acute RfD of 0.67 mg/kg-bw/day). The most exposed sub-population was all infants (<1 

year old) with a MOE of 13,686 (2.2% 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 below 100% of the acute RfD, Syngenta believes that there is a reasonable 
certainty that no harm will result from acute drinking water exposure to residues arising 

from the 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 26,050 (0.4% of the chronic RfD of 0.18 mg/kgbw/day). Chronic drinking water exposure to the most exposed sub-population (infants, <1 

year old) resulted in a MOE of 10,103 (1.0% of the chronic RfD 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 chronic RfD, Syngenta believes that there is a 

reasonable certainty that no harm will result from chronic drinking water exposure to 

residues arising from the current 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 turf is 58,182 for short-term exposure. For post-application 

exposure to treated turf, the non-dietary oral MOEs for children 1-6 years are 2,989 for 

short-term exposure and 2,391 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. US. 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 4,407 (6.8% 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 7,158 (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, 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 2,396 (12.5% of the aRfD) for the most sensitive 

subpopulation, children 1-2 years 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 

2,975 (3.4% of the cRfD) for the most sensitive subpopulation, 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 2,989) resulting 

in a short-term aggregate MOE of 1,839 for the most sensitive subpopulation, children 1-

6 years old. For intermediate-term exposures, the food plus water exposure was 

aggregated with the residential exposure (MOE 2,391) resulting in an intermediate-term 

aggregate MOE of 1,471 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

Maximum Residue Levels (MRLs) for azoxystrobin have been established in a number of 

countries including Argentina, Australia, Brazil, Canada, Chile, France, Germany, Italy, Korea 

and Spain. Compatibility between U.S. tolerances and Codex MRLs only exist for bananas, 

caneberries, cotton seed, cranberries, peanuts, rice grain, rye grain, soybean seed, strawberries, 

sunflower seed and legume vegetables. Codex MRLs and U.S. tolerances are incompatible for 

the remaining commodities with U.S. tolerances including cereal grains, citrus fruit, meat and 

milk.