EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Andrew Ertman , (703) 308-9367

IR-4

PP #1E7851

EPA has received a pesticid e petition (PP #1E7851) from Interregional Project 4 / IR-4, 500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFD CA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 b y establishing a tolerance for residues of azoxystrobin: (methy l (E)-2-{2-[6-(2- cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate) and the Z isomer of azoxystrobin, (methyl (Z)-2-{2-[6-(2- cyanophen oxy)pyrimidin-4-yloxy]pheny1}-3- methoxyacrylate) in or on the following:

Onion, bulb subgroup 3-07A at 1.0 parts per million Onion, green subgroup 3-07B, at 7.5 parts per million Caneberry subgroup 13-07A, at 5.0 parts per million Bushberry subgroup 13-07B, at 3.0 parts per million Small fruit vine climbing subgroup, excep t fuzzy kiwifruit, 13-07F, at 1.0 parts per

million Low growing berry subgroup 13-07G, excep t cranberry, at 10.0 parts per million Vegetable, fruiting, subgroup 8-10A, at 0.2 parts per million Vegetable, fruiting, subgroups 8-10B, at 2.0 parts per million Fruit, citrus, group 10-10, at 10.0 parts per million Rapeseed subgroup 20A, at 1.0 parts per million Sunflower subgroup 20B, at 0.5 parts per million Cottonseed subgroup 20C, at 0.6 parts per million Wasabi, at 50.0 parts per million Dragon Fruit, at 2.0 parts per million

And by amending the tolerance for residues of

Vegetable, tuberous and corm, subgroup 1C

, at 6.0 parts per million

Upon approval of the aforementioned tolerances , it is proposed that 40 CFR 180.507 be amended

to remove the established tolerances for the resi dues of azoxystrobin in or on the raw agricultural

commodities:

Onion, bulb, at 1.0 parts per million Onion, green, at 7.5 parts per million Bushberry subgroup 13B, at 3.0 parts per million Juneberry, at 3.0 parts per million Lingonberry, at 3.0 parts per million Salal, at 3.0 parts per million Grape, at 1.0 parts per millionStrawberry, at 10.0 parts per million Tomato, at 0.2 parts per million Vegetable, fruiting, group 8, except tomato at 2.0 parts per million Fruit, citrus, group 10 at 10.0 parts per million Canola, seed, at 1.0 parts per million Cotton, undelinted seed, at 0.6 part per million Crambe, seed, at 0.5 parts per million Flax, seed at 0.5 parts per million Mustard, field, seed at 0.5 parts per million Mustard, Indian, seed at 0.5 parts per million Mustard, seed at 0.5 parts per million Rapeseed, Indian, at 0.5 parts per million Rapeseed, seed, at 0.5 parts per million Safflower, seed, at 0.5 parts per million Sunflower, seed, at 0.5 parts per million Potato, at 0.03 parts per million

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 be fore 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 understo od for purposes of the tol erances. Plant metabolism has been evaluated in four diverse crops, cotto n, 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 azoxystr obin in plants is co mplex 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 mo bile phase by high performance liquid chromatography with ultra-violet detect ion (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 tolera nces. 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 wh ich also underwent successful independent laboratory validations.

3. Magnitude of residues. Complete residue data to support the requested tolerances have been submitted. The requested tole rances are adequately supported.In support of the requested tolerance, IR -4 has conducted the necessary trials in accordance with the requirements of the EP A Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of azoxys trobin in or on 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 m g /k g /da y 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 fo rward gene mutation in mouse lymphoma cells, but was not mutagenic in the salmonella/mammalian activation gene mutation assay, showed some evidence of conc entration-related induction of chromosomal aberrations over background in the presence of mod erate to severe toxicity in the in vitro mammalian cytogenetics assay in human lymphocy tes, caused no increase in the induction

of micronuclei in the mouse bone marrow mi cronucleus assay, and did not increase the incidence of unscheduled DNA synthesi s 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 usin g 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 indi viduals (CSFII) with the 1994-96 consumption database and the Supplemental CSFII children’s survey (1998) consumption database. These exposure assessments included all curren tly registered uses of azoxystrobin plus a proposed a proposed post-harvest use on potato es. Residue data was taken from field trials where azoxystrobin was applied at the maxi mum intended use rate and samples were harvested at the minimum pre-harvest interval (PHI) to obtain maximum residue values. Calculated and projected percent crop treate d (%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

. Dietary exposure from currently registered and proposed uses are acceptable. The azoxystrobin acute dietary (food on ly) risk assessment was performed for all population subgroups using an acute refere nce 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 LO AEL by the exposure for each population subgroup. In addition, exposure was expresse d 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 4,461 (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 2,111 (14.1% of the aRfD of 0.67 mg/kg/day). Since the benchmark MO E 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 usin g a chronic reference dose (cRfD) of 0.18 mg/kg/day based on a combined chronic toxici ty/carcinogenicity study in rats with a NOAEL of 18 mg/kg/day and an uncertainty fact or of 100X (for combined intra- and interspecies 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 9,610 (1.0% of the cRfD of 0.18 mg/kg/day). The mo st sensitive sub-population was children (1-2 years old) with a MOE of 3,685 (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 forexposures 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 Can cer 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 sc reening models, SCI-GROW which estimates pesticide concentration in ground wat er and FIRST which estimates pesticide concentration in surface water. EDWCs of azoxystrobin from the currently registered uses plus the proposed sugarcane use were determ ined. 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 th e difference between the aggregate (food + drinking water) exposures and the food (alo ne) exposures for each population subgroup. Acute drinking water exposure U.S. populat ion resulted in a MOE of 1,936 (15.4% 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 725 (41.2% 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 aRfD, Syngenta believes th at 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 ex posed sub-population (inf ants <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 conducte d for non-dietary uses of azoxystrobin since it is curren tly registered for residential use outdoors on turf and ornamentals and for use in residentially app lied 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 toornamentals at rates of up to 0.75 lb a.i./acre (n ot to exceed 5 lb a.i./acre per year). The maximum concentration of azoxystrobin in pain t is 1% a.i. (w/w). A short-term handler risk assessment was required for adults beca use there is a residential handler inhalation exposure scenario. Both short- and intermed iate-term risk assessments were required for toddlers based on the potentia l for hand-to-mouth, object-t o mouth, and soil ingestion exposure from treated turf. For incidental no n-dietary oral and inhalation exposures to azoxystrobin, a NOAEL of 25 mg/kg/day was us ed for short-term exposure and a NOAEL of 20 mg/kg/day was used for intermediate-t erm 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 or al MOEs for children 1-6 years are 1,399 for short-term exposure and 1,927 for intermedia te-term exposure. Since the EPA’s benchmark MOE for azoxystrobin is 100, the res idential exposures for both adults and

children do not exceed EPA’s level of concern.

Cumulative Effects. Cumulative Exposure to Substances wi th 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 “availa ble information” concerning the cumulative effects of a particular pesticide’s residue s and “other substances that have a common mechanism of toxicity”. Azoxystrobin is relat ed to the naturally occurring strobilurins. Syngenta has concluded that further consider ation 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 azoxystrob in crop uses would result in a MOE of 1,349 (22.1% of the aRfD) for the general U.S. po pulation, 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 7,007 (1.4% of the cRfD) which exceeds the benchmark MOE of 100. Based on the completeness and reliability of the toxicity data supporting thes e 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 oth er 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 azo xystrobin crop uses would result in a MOE of 539 (55.3% of the aRfD) for the most sensitiv e population subgroup, infants <1 year old, which exceeds the benchmark MOE of 300. The chronic aggregate dietary (food and water) exposure analysis showed that expo sure from all registered and proposed azoxystrobin crop uses would result in a MOE of 3,042 (3.1% 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 aggregateMOE of 815 for the most sensitive populatio n 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 de termined that there is reliable data support using the standard MOE and uncertainty factor (100X for chronic a nd 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 complete ness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonab le 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 type s 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.