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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Thomas C. Harris, harris.thomas@epa.gov, (703) 308-9423

Syn genta Crop Protection, LLC

PP 2E8018

EPA has received a pesticide petition ( PP 2E8018 ) fr om Syn genta Crop Protection . LLC

, P.O. Box 18300, Greensboro, NC 27419 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

by establishing a tolerance for residues of

emamectin benzoate, 4'-epi-methylamino- 4' -deoxyavermectin B 1 benzoate (a mixture of a minimum of 90% 4'-epi-methylamino- 4'

- deoxyavermectin B 1a and a maximum of 10% 4'-epi-methlyamino-4'deoxyavermectin B 1b benzoate), and its metabolites 8,9

isomer of the B 1a and B 1b component of the parent insecticide in or on the processed agricultural commodity imported wine at 0.0 0 5 parts per million (ppm ). EPA has determined that the petition contains data or information regarding the elements set forth in section 408 ( d)(2) of 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 emamectin benzoate in plants has been

studie d and the nature of the residue has been determined in lettuce, cabbage, and

sweet cor n . The major portion of the residue is parent compound and its delta 8,9- photoisomer. The metabolism of emamectin has also been investigated in goats and poultry to characterize the fate of residues that may be present in animal feed

items

2. Analytical method. Adequate analytical methods (HPLC-fluorescence methods)

are available for enforcement purposes.

3. Magnitude of residues. Sixteen residue trials, in which emamectin benzoate

was app lied to wine grapes, were conducted in Europe and were designed to comply with the EU residue chemistry data requirements. Specifically, the trials

were designed to quantify emamectin benzoate and metabolite residues in grapes based upon the worst case (maximum residue) use pattern in Europe. This worst2

case use pattern included a maximum of 4 applications per season at a rate of 14.25 g AI/ha/application. The maximum season al rate is 57 g AI/ha/season. The minimum retreatment interval is 14 days, and the minimum pre-harvest interval is

7 da ys. Grapes were analyzed using the LC- LC -MS/MS method RAM 465/01 with an LOQ of 0.001 ppm. For the normalized total residues of concern in or on

g rapes, the average value was 0.009 mg/kg and the maximum value was 0.031

mg /kg.

Trials in Australia and New Zealand were conducted to facilitate selection of a local use pattern for which the residues in grapes are less than the limit of quantification. The registered directions for use are:

1. In Australia, a maximum of 2 applications with a maximum rate of 6.6 g

A I/ha/season and a minimum pre-harvest interval of 56 days.

2. In New Zealand, a maximum of 2 applications at a maximum rate of 4.0 g AI/ha/season with applications no later than the pre-bunch closure growth

stage.

The trial most relevant to the registered directions for use in Australia was

conducted with two applications at 6.6 g AI/ha/application for a total of 13.2 g

A I/ha/ season. This trial was conducted at 2x the registered application rate, and

the measured

residues are reported to be non-detectable (LOD = 0.005 mg/kg).

The trial most relevant to the registered label in New Zealand was conducted with two applications; the first application at 80% cap fall and a second application at pre-bunch closure, both at 80 g ai /ha. Total emamectin residue (B1a/8,9-Z + B1b) was measured as 0.0012 mg/kg. The application rate for this use of 80 g ai /ha is

40 -fold greater than the registered directions for use. It is strongly believed, if the applications had been made according to the current ly label ed directions for use, the total measured residues in grapes would have been well below the limit of detection (<0.005 mg/kg).

Two trials were conducted in Italy to determine emamectin residues in grapes and wine at different pre-harvest intervals. In both of the Italian studies, residues were <0.001 ppm in the grapes harvested at 7 and 21 days after application and in the corresponding wine samples. In one of the two studies, residues were 0.004 ppm in g rapes harvested 0-days after the application and <0.001 ppm in the corresponding wine sample. In the second of the two studies, residues in the 0- day PHI grape sample and corresponding wine sample were 0.024 and 0.002 ppm, respectively. These data demonstrate that emamectin benzoate does not concentrate

in wine.

Two trials were conducted in South Australia and Victoria in red and white grape

varieties to determine the sum of residues of emamectin B 1a plus emamectin B 1b in grapes, grape juice and wine. Two applications of emamectinbenzoate were applied at 150 or 300 g ai/ha at 7 day intervals to bunch closure (BBCH 77). The3

product was applied at dilute (~1000 l/ha) and concentrate (~250 l/ha) water

volumes. The residue data include only one quantifiable residue. Grapes from one of the two sites receiving two low volume treatments at a rate of 13.2 g AI/ha/application for a total of 26.4 g AI/ha/season with a 98 -day PHI were determined to have a residue of 0.0009 mg/kg emamectin B 1a (at the limit of quantification) in a single replicate. The measured emamectin B 1a residues in juice and wine from the same trials were determined to be less than the limit of quantification. Residues of emamectin B1b in all trials were, without exception,

de termined to be less than the limit of quantification. These data suggest that

re sidues of emamectin B 1a do not concentrate in grape juice or wine and calculation of a residue processing factor for grape juice or wine is not needed

.

B. Toxicological Profile A full description of the studies regarding the toxicity, animal

meta bolism, and metabolite toxicology, of emamectin benzoate can be found in EPA’s

memor andum, “Emamectin Benzoate. Human Health Risk Assessment Scoping Document in Support of Registration Reviews ,” PC Code: 122806, Decision No.: 444324, DP Barcode: D385990, dated June 16, 2011.

C. Aggregate Exposure

1. Dietary exposure. Tier III acute and chronic dietary exposure evaluations were made for emamectin benzoate using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCIDTM, version 2.16) from Exponent. Empirically derived processing factors for apple juice (0.05X), apple pomace (4.3X), cottonseed oil (0.39X), and wine (0.088X) were used in these assessments. All other processing factors used DEEM TM Version 7.87 default values. All consumption data for these assessments were taken from

the U SDA’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 current and pending uses for emamectin benzoate plus this proposed new tolerance for

re sidues of emamectin benzoate in imported wine. Use of emamectin benzoate on grapes grown for wine is approved in Europe, Australia, and New Zealand. Directions for use that are on the approved labels for emamectin-based end-use products specify up to 4 applications at a rate of up to 15 g a.i./ha per application

for a maximum of 60 g ai/ha per season. A minimum of 7 days between the last application and harvest is the (PHI) These assessments assumed a tol erance of 0.0035 ppm for residues of emamectin benzoate in imported wine. This value was

based on an (estimated 0.04 ppm tolerance in wine grape s ( OECD) multiplied by a 0.088X grape- to -wine processing factor). A percent crop treated value of 100%

%CT was assumed for wine and sherry. Note, it is not necessary to consider secondary residues in meat, milk and eggs since wine is not a livestock feed item. However, secondary residues in meat, milk, and eggs were estimated by constructing “maximum reasonably balanced diets” using the OPPTS 860.1000Table 1 feedstuffs (June 2008 revision) and transfer information taken from multilevel feeding studies (beef, dairy, and swine) or from metabolism studies (poultry4

i

. Food.

Acute Exposure

. The acute dietary risk assessment for emamectin benzoate was performed for all population subgroups using an acute reference dose of 0.00025mg/kg-bw/day from a 15 day neurotoxicity study in mice (LOAEL of 0.1 mg/kgbw/day), based on tremors observed beginning on day 3 of dosing, using an

e ndpoint of 0.075 mg/kg-bw/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, exposure values were expressed in terms of margin of exposure (MOE), calculated by dividing the 0.075 mg/kg-bw/day endpoint by the exposure for each population subgroup. In addition, exposures were expressed 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 555 (54.0% of the aRfD of 0.00025 mg/kg-bw/day). The most sensitive population sub-group waschildren 1-2 years old, with a MOE of 326 (91.9% of the aRfD of 0.00025 mg/kgbw/da y). 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 reference dose, Syngenta believes that there is a reasonable certainty that no

ha rm will result from acute food exposures food exposure to residues arising from all current, pending, and proposed uses for emamectin benzoate.

Chronic Exposure. The chronic dietary risk assessment for emamectin benzoate was performed for all population subgroups based on a chronic reference dose of 0.000075 mg/kg-bw/day from a 15 -day neurotoxicity study in mice (LOAEL of 0.1 mg /kg-bw/day), (LOAEL was based on moribund sacrifices, clinical signs of neurotoxicity, decreases in body weight and food consumption and

hist opathological lesions in the sciatic nerve,) The risk assessment was performed by using an endpoint of 0.075 mg/kg-bw/day and an uncertainty factor of 1000X (100X for intra- and inter-species variability and an additional 10X for absence of

a NOAEL). No additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, exposure values were expressed in terms of margin of exposure (MOE), calculated by dividing the 0.075 mg/kg-bw/day endpoint by

th e exposure for each population subgroup. In addition, exposures were expressed as a percent of the chronic reference dose (%cRfD). Chronic food exposure to the U.S. population resulted in a MOE of 12,744 (7.8% of the cRfD of 0.000075 mg/kg-bw/day). The most sensitive population sub-group was children 1-2 years old, with a MOE of 6,005 (16.7% of the cRfD of 0.000075 mg/kg-bw/day). Since the Benchmark MOE for this assessment is 1,000 and since EPA generally has no concern for exposures above the benchmark or below

100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic food exposures to residues arising from all current, pending, and proposed uses for emamectin benzoate.

Cancer Risk. No cancer risk assessment was performed for emamectin benzoate, which has been classified as a “not likely” human carcinogen based on the lack of evidence of carcinogenicity in male and female rats or male and female mice at5

doses that were judged to be adequate to assess the carcinogenic potential of the

chemical.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of emamectin benzoate (expressed as combined total residues of parent plus 8,9- Z

isom er, AB, MAB, and FAB) were determined using Tier l SCI-GROW which estimates pesticide concentration in ground water and Tier II PRZM/EXAMS which estimates pesticide concentration in surface water. EDWCs for emamectin from the currently registered and pending use on cucurbits and on outdoor nursery

g rown herbaceous and woody ornamentals were determined. Based on the SCIGROW modeling, the groundwater EDWC for emamectin is 5.40E-04 ppb (acute and chronic). Based on Tier II PRZM/EXAMS modeling for surface water, the pending use on outdoor nursery grown herbaceous and woody ornamentals provided an acute EDWC of 1.096 ppb (no Percent Cropped Area (PCA) adjustment) and the currently registered tomato use provided a chronic EDWC of 0.347 ppb (corrected for 0.87 PCA). Since the surface water EDWCs exceed ed 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 : Syngenta utilized the Monte-Carlo probabilistic technique for this exposure assessment, using the nursery standard PRZM scenario. The complete distribution of estimated drinking water concentrations for the period from January 1, 1961 to January 1, 1991 (n = 10,958) were extracted from the EDWC prediction database and were utilized in the DEEM-FCIDTM software as residue distribution files (RDF) for “water, direct and indirect, all sources.” Predicted EDWC results were not adjusted for PCA.

Dr inking water exposures at the 99.9 th percentile were determined by taking the difference between the aggregate exposures (food + drinking water) and food exposures (food only) for each population subgroup. Acute drinking water exposure to the U.S. population resulted in a MOE of 7,500 (4.0% of the aRfD of 0.00025 mg /kg-bw/day). The most sensitive sub-population was children 3-5 years old, with a MOE of 5,357 (5.6% of the aRfD of 0.00025 mg/kg-bw/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 reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposures to residues arising from all current, pending, and proposed uses for emamectin benzoate..

C hronic Exposure from Drinking Water : The chronic surface water EDWC of

0.347 ppb was input directly into the DEEM-FCIDTM software as “water, direct and indirect, all sources” to model the chronic drinking water exposures. Chronic

d rinking water exposure to the U.S. population resulted in a MOE of 10,254 (9.8% of the cRfD of 0.000075 mg/kg-bw/day). Chronic drinking water exposure to the most exposed sub-population (infants <1 year old) resulted in a MOE of 3,128 (32.0% of the cRfD of 0.000075 mg/kg-bw/day). Since the Benchmark6

MOE for this assessment is 1,000 and since EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposures to residues arising from all current, pending, and proposed uses for emamectin benzoate.

2. Non-dietary exposure

. There are no current uses or uses pending EPA approval that result or will result in residential exposures.

D. Cumulat ive 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”. Syngenta did not perform a cumulative risk assessment as part of this tolerance action for emamectin because HED has not yet determined that there are any other chemical substances that have a mechanism of toxicity common with that of emamectin. For purposes of this tolerance action, EPA has assumed that emamectin does not have a common mechanism of toxicity with other substances.

E. Safety Determination

1

. U.S. population. The acute dietary exposure analysis (food plus water) showed

that dietary exposure associated with all of the approved and pending uses of emamectin benzoate as well the proposed tolerance for emamectin benzoate in imported wine would result in an acceptable MOE of 518 (57.9% of the aRfD) for the U.S. population, because it is higher than the Benchmark MOE of 300. The chronic dietary exposure analysis (food plus drinking water) showed that chronic exposure associated with all of the approved and pending uses of emamectin

be nzoate chronic exposure associated with the proposed tolerance for emamectin

benzoate in wine resulted in an acceptable MOE of 5,769 (17.3% of the cRfD) because it exceeds the Benchmark MOE of 1,000. 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 the general U. S. population from aggregate exposure to potential residues arising from all of the approved and

pending uses for emamectin benzoate plus residues of emamectin

be nzoate that may be present in imported wine.

2. Infants and children

. The acute dietary exposure analysis (food plus drinking water) showed that exposure to emamectin benzoate associated with the approved and pending uses and exposure associated with this proposed import tolerance

would r esult in an MOE of 309 (96.9% of the aRfD) for the most sensitive population subgroup, children 1-2 years old, which is acceptable because it exceeds the Benchmark MOE of 300. The chronic aggregate dietary (food and7

drinking water) exposure analysis showed that exposure associated with the approved and pending uses of emamectin benzoate as well as the exposure associated with the proposed tolerance for emamectin benzoate in wine an MOE

of 2,344 (42.7% of the cRfD) for the most sensitive population subgroup, all infants <1 year old, which is acceptable since it exceeds the Benchmark MOE of 1,000. 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 current, pending, and proposed uses for emamectin benzoate.

F. International Tolerances

There are no Codex maximum residue limits (MRLs) established for emamectin benzoate in wine, so harmonization of international tolerances is not an issue.