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

Interregional Research Project Number 4 (IR-4)

PP No. 1E7904

EPA has received a pesticide petition (PP No. 1E7904) from Interregional Research Project No. 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 (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establis hing a tolerance for

residues of emamectin benzoate, 4'-epi-methylamino- 4'-deoxyavermectin B 1 benzoate (a

mixture of a minimum of 90% 4'-e pi-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 raw agricultural commodity crop group, vegetable, cucurbit, group 9 at 0.03 parts per million (ppm). EPA has determined that th e petition contains data or information regarding the elements set fo rth 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 da ta may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of emamectin benzoate in plants has been

studied and the nature of the residue has been determined in lettuce, cabbage, and sweet corn. The major portion of the residue is parent compo und and its delta 8,9- photoisomer. The metabolism of emamectin has also been inve stigated in goats and poultry to characterize the fate of resi dues 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

. In the appropriate growing areas of the US, IR-4 conducted magnitude of residue studies in cucumber (pickling and slicing varieties), cantaloupe, and squash, the representative commodities for crops in the

crop group, vegetable, cucurbit, group 9 . A total of approximately 0.090 lb ai/A was applied in six foliar applications of Proclaim 5SG at a rate of approximately 0.015 lbs ai/A. Raw agricultural commodities (RAC) samples were harvested 6-8 days after the last treatment. In addi tion, IR-4 also conducted residue decline trials in 4 locations (3 cucumber and 1 squash). In these decline trials, crop samples were collected at 0, 3, 10, 13, and/or 14 days PHI.

There were no detectable residues of any of the six emamectin benzoate analytes in the cucumber and squash RAC samples harvested at 6-8 days PHI. For the cantaloupe RAC samples harvested at 6-8 days PHI, one of the six analytes,2

NOA-426007 (emamectin B1a), was present in amounts above the lowest limit of method validation (LLMV). All other anal ytes were below the LLMV. In the decline trials, squash taken at 0 days PHI showed combined emamectin B1a + 8,9Z residues above the LLMV (all other analytes were below the LLMV) and declined to below the LLMV for all analytes at the subsequent sampling events.

B. Toxicological Profile A full description of the studies describing the toxicity, animal metabolism, metabolite toxicology, and endocri ne disruption of emamectin benzoate can be found in the final rule published in th e Federal Register of July 9, 2003 (68 FR 40791)

C. Aggregate Exposure

1. Dietary exposure. Tier III acute and chronic diet ary exposure evaluations were made for emamectin benzoate using the Dietary Exposure Evaluation Model software with the Food Commodity In take Database (DEEM-FCIDTM, version 2.16) from Exponent. Empirically derive d processing factors for apple juice (0.05X), apple pomace (4.3X), and cottons eed oil (0.39X) were used in these assessments. All other processing factors used DEEM TM Version 7.87 default values. All consumption data for these assessments was taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption database and the Supplemen tal CSFII children’s survey (1998) consumption database. These exposure a ssessments included a ll current uses for emamectin benzoate, a pending use on outdoor nursery ornamentals, and a proposed new use on cucurbit vegetables (Crop Group 9). The intended use pattern includes up to six applications at a rate of up to 0.015 lbs. a.i./A (maximum seasonal rate = 0.09 lbs. a.i./A) with a pre-harvest in terval (PHI) of 7 days. Percent crop treated (%CT) valu es were estimated based upon economic, pest, and competitive pressures. Secondary residues in meat, milk, and eggs were estimated by constructing “maximum r easonably balanced diets” using the OPPTS 860.1000 Table 1 feedstuffs (June 2008 revision) and transfer information taken from multi-level feeding studies (beef, dairy, and swine) or from metabolism studies (poultry).

i . Food.

Acute Exposure

. The emamectin benzoate acute food risk assessment was performed for all population subgroups using an acute reference dose of 0.00025 mg/kg-bw/day from a 15 day neurotox icity study in mice (LOAEL of 0.1 mg/kgbw/day), based on tremors observed be ginning on day 3 of dosing, using an endpoint of 0.075 mg/kg-bw/day and an un certainty factor of 300X (100X for intra- and inter-species variability and 3X for absence of a NOAEL). No additional FQPA safety factor was applie d. For the purpose of the aggregate risk assessment, exposure values were expre ssed 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 (food3

only) exposure to the U.S. population resu lted in a MOE of 557 (53.8% of the aRfD of 0.00025 mg/kg-bw/day). The most sensitive population sub-group was children 1-2 years old, with a MOE of 326 (91.9% of the aRfD of 0.00025 mg/kgbw/day). Since the Benchmark MOE for this assessment is 300 and since EPA generally has no concern for exposures a bove the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute food exposures to residues arising from all current, pending, and proposed uses for emamectin benzoate.

Chronic Exposure. The emamectin benzoate chronic food risk assessment was performed for all population subgroups using a chronic reference dose of 0.000075 mg/kg-bw/day from a 15 day neur otoxicity study in mice (LOAEL of 0.1 mg/kg-bw/day), based on moribund sacrifi ces, clinical signs of neurotoxicity, decreases in body weight and food consum ption and histopathol ogical lesions in the sciatic nerve, using an endpoint of 0.075 mg/kg-bw/day and an uncertainty factor of 1000X (100X for intra- and inte r-species variability and an additional 10X for absence of a NOAEL). No additi onal FQPA safety factor was applied. For the purpose of the aggregate risk a ssessment, exposure values were expressed in terms of margin of exposure (MOE ), calculated by dividing the 0.075 mg/kgbw/day endpoint by the 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. populat ion resulted in a MOE of 13,801 (7.2% of the cRfD of 0.000075 mg/kg-bw/day). The most sensitive population subgroup was children 1-2 years old, with a MOE of 6,010 (16.6% of the cRfD of 0.000075 mg/kg-bw/day). Since the Benc hmark MOE for this assessment is 1,000 and since EPA generally has no concern for exposures above the

benchmark or below 100% of the referen ce dose, Syngenta believes that there is a reasonable certainty that no harm will re sult from chronic food exposures to residues arising from all current, pend ing, and proposed uses for emamectin

benzoate.

Cancer Risk No cancer risk assessment was performed for emamectin benzoate,

which has been classified as a “not li kely” human carcinogen based on the lack of evidence of carcinogenicity in male and fema le rats or male and female mice at 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 isomer, AB, MAB, and FAB) were dete rmined using Tier l SCI-GROW which estimates pesticide conc entration in ground water and Tier II PRZM/EXAMS which estimates pesticide concentration in surface water. EDWCs for emamectin from the currently registered and pending uses plus the proposed use on cucurbits

were determined. Based on the SC I-GROW modeling, the groundwater EDWC for emamectin is 5.40E-04 ppb (acute a nd chronic) based on the current and pending/proposed uses on Brassica head and stem vegetables, Brassica leafy vegetables, fruiting vegetables, leaf y vegetables, outdoor nursery grown4

herbaceous and woody ornamentals, a nd cucurbits. Based on Tier II PRZM/EXAMS modeling for surface water, the pending use on outdoor nursery grown herbaceous and woody ornamental s 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 the ground water EDWC, the surface water values were used for risk assessment purposes a nd will be considered protective for any ground water exposure concerns.

Acute Exposure from Drinking Water : Syngenta utilized the Monte-Carlo probabilistic technique for th is exposure assessment, us ing the nursery standard PRZM scenario. The complete dist ribution of estimated drinking water concentrations for the period from January 1, 1961 to January 1, 1991 (n = 10,958) were extracted from the EDWC pred iction database and were utilized in

the DEEM-FCIDTM software as residue dist ribution files (RDF) for “water, direct and indirect, all sources.” Predicted EDWC results were not adjusted for PCA. Drinking water exposures at the 99.9 th percentile were de termined by taking the difference between the aggregate exposur es (food + drinki ng water) and food exposures (food only) for each populati on 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 sens itive sub-population was children 3-5 years old, with a MOE of 5,769 (5.2% 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 th e 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 e xposures to residues arising from all current, pending, and proposed uses for emamectin benzoate.

Chronic 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 ch ronic drinking water exposures. Chronic drinking 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/d ay). 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 Benchmark MOE for this assessment is 1,000 and since EPA generally has no concern for exposures above the benchmark or belo w 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 that result in residential exposures. All proposed and pending uses , including professionally applied tree injection and professionally applied cockroach gel bait, are not expected to result in residential exposures for any population subgroup.5

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 408(b)(2)(D)(v) requi res that, when considering whether to establish, modify, or revoke a tolera nce, the Agency consider “available information” concerning the cumulative effects of a part icular pesticide’s residues and “other

substances that have a common mechanis m of toxicity”. Syngenta did not perform a cumulative risk assessment as part of this tolerance action for emamectin because HED has not yet determin ed that there are any other chemical

substances that have a mechanism of t oxicity 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 analys is (food plus water) showed that exposure from all established and proposed emamectin benzoate uses would result in a MOE of 519 (57.8% of th e aRfD) for the U.S. population, which

exceeds the Benchmark MOE of 300. Th e chronic dietary exposure analysis (food plus water) showed that exposu re from all established and proposed

emamectin benzoate tolerances resulte d in a MOE of 6,250 (16.0% of the cRfD)

which exceeds the Benchmark MOE of 1,000. Based on the completeness and reliability of the toxicity data supporti ng 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 resi dues arising from all current, pending, and proposed uses for emamectin benzoate.

2. Infants and children

. The acute dietary exposure an alysis (food plus water) showed that exposure from all establishe d and proposed emamectin benzoate uses would result in a MOE of 311 (96.4% of the aRfD) for the most sensitive population subgroup, children 1-2 years old, which exceeds the Benchmark MOE of 300. The chronic aggregate dietary (f ood and water) exposure analysis showed that exposure from all established and proposed emamectin benzoate uses would result in a MOE of 2,344 (42.7% of the cRfD) for the most sensitive population subgroup, all infants <1 year old, whic h exceeds the Benchmark MOE of 1,000. Based on the completeness and reliability of the toxicity da ta supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggreg ate exposure to residues arising from all current, pending, and proposed uses for emamectin benzoate.

F. International Tolerances

There are no Codex maximum residue limits (M RLs) established for emamectin benzoate in or on any commodities, so harmonization of international tolerances is not an issue.6