Interregional Research P roject N umber 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 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 .507 as follows:

B y establishing tolerance s for residue s of azoxystrobin: (methyl (E)

- 2

- {2

- [ 6

- (2

- cyanop henoxy)pyrimidin

- 4

- yloxy]phenyl}

- 3

- methoxyacrylat e) and the Z isomer of azoxystrobin, (methyl (Z)

- 2

- {2

- [ 6

- ( 2

- cyanophenoxy)pyrimidin

- 4

- y loxy]pheny1}

- 3

- methoxyacrylate) in or o n the raw agricultural commodities Ti palm, le aves at 50 part per million (ppm ) ; Ti palm, roots at 0.5 ppm ; F ruit , stone, group 12

- 12 at 2.0 p pm ; Nut, tree , group 14

- 12 at 0.02

ppm ; and Quinoa, grain at 3.0 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
commodit ies 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 gran ting 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 nitrogen

phosphorus 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. Analytic al 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, subgro up), 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 gr oup 2

.

4. 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 = Acu t 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. Genoto xic i ty. 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 backgroun d 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 unsche duled DNA synthesis in rat hepatocytes/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 t oxicity

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

yChronic 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.

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. 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 t hat 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). DEEM

FCID software incorporat es 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 azoxystrobi n 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 in terval (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 cal culated 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 Adve rse 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

r eference dose (%aRfD). At the 99.9 th 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 andsince 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 n o 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 subgrou ps 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

- s pecies 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 c hildren (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 o f 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 (ac ute 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, th e 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 s oftware 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 13,6 86 (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 reasonablecertainty 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 a nd 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/kg

bw/day). Chronic drinking water exposure to the most expose d 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, Syn genta 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

- di etary 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./a cre 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 i ntermediate

- 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 effec ts 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 Determination1. US. populati on

. 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 o f 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 comple teness 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 use s, including anticipated dietary exposure from food, water, and all other types of non

- occupational exposures.

2. Infants and c hildren

. 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 chil dren 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 protectiv e 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 residu es arising from all registered, pending and proposed azoxystrobin crop uses, including anticipated dietary exposure from food, water, and all other types of non

occupational exposures.

F. International Tolerances

Maximum Residue Levels (MRLs) for azoxy strobin 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, c ranberries, 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 an d
milk.