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**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING OF PESTICIDE PETITION**  **EPA Registration Division contact: Sidney Jackson (703) 305 -**  **7610 Interregional Research Project Number 4 (IR** **- 4)**  **Pesticide Petition Number: 2E8117** EPA has received a pesticide petition **(PP # 3E8175)**  from IR - 4, which Sy ngenta Crop Protection LLC supports, 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 by establishing a tolerance for the combined residues of the insecticide avermectin B 1 (a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O demethyl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demeth yl 25 - de(1 - methylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )) and its delta - 8,9 - isomer in or on caneberry

subgroup 13 - 07A to 0.20 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 support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The metabolism of abamectin in plants is adequatel y understood and the residues of concern include the parent insecticide abamectin (also referred to as avermectin B 1 which is a mixture of a minimum of 80% avermectin B 1a and a maximum of 20% avermectin B 1b ) and the delta 8,9 - isomer of the B 1a and of the B 1b components of the parent insecticide. 2. Analytical method. The anal yt ical methods involve homogenization, filtration, partition, and cleanup with anal ys is by high performance liquid chromotography (HPL C) - fluorescence detection. The methods are sufficiently sensitive to detect residues at or above the tolerances proposed. All methods have undergone independent laboratory validation . 3. Magnitude of residues, Caneberry Magnitude of residue data have been collected from seven field trials located in NAFTA Regions. At each trial, three foliar applications of the test substance were made2

6 - 8 day s apart to the treated plots. The application rates ranged from 0.01 73 to 0.0206 pound of active ingredient per acre ( lb ai/A ) per application for a total rate range of 0.0547 to 0.0605 lb ai/A per season. All applications were made using appropriate spray equipment, and the spray volume was sufficient to provide adequate dispersal of the test substance. Sampling started in the untreated control plot and ended in the treated plot. At all the field trials, samples were harvested 7 day s after the last application. Additionally , at the OR03 trial, duplicate samples were collected 0, 3, 7 and 9 day s after the last application. The total residues of abamectin ranged from 0.0062 to 0.1215 ppm in samples taken at 7 day s PHI. The residues declined over time. Data from this study may be used to support a tolerance proposal for abamectin on caneberry subgroup 13 - 07A . B. Toxicological Profile 1. Acute toxicity. The database includes the following studies with Sy ngenta’s technical abamectin products: Abamectin Technical: i. A rat acute oral stud y with a lethal dose ( LD ) 50 of 13.6 milligram per kilogram ( mg/kg ) . ii. A rat acute oral study

with a LD 50 of 214 - 232 mg/kg. iii. A rabbit acute dermal study with a LD 50 of 2000 mg/kg. iv. A rat acute inhalation study with a lethal concentration ( LC ) 50 of 0.21 mg/ liter ( L ) (nose only). v. A primary

ey e irritation study

in rabbits which showed no irritation. vi. A primary

skin irritation study

in rabbits which showed slight irritation. vii. A dermal sensitization study (Buehler) in guinea pigs which was negative. Abamectin Technical II3

i. A rat acute oral stud y with a LD 50 of 372.5 mg/kg ii. A rat acute dermal study with a LD 50 of >200 mg/kg but <2000 mg/kg ii. A rat acute inhalation study with a LC 50 of >0.0518 mg/L (nose onl y) v. A primary

ey e irritation study

in rabbits which showed no irritation. vi. A primary

skin irritation study

in rabbits which showed slight irritation. vii. A dermal sensitization study (Buehler) in guinea pigs with Abamectin Technical supports the registration of this technical.

2. Genotoxicty. The Ames assay s conducted with and without metabolic activation were both negative. The V

– 79 mammalian cell mutagenesis assay s conducted with and without metabolic activation did not produce mutations. In an alkaline elution/rat hepatocy

te assay , abamecti n was found to induce single strand DNA breaks without significant toxicity in rat hepatocy

tes treated in vitro at doses greater than 0.2 millimole per liter (mM). This in vitro dose of 0.2 mM is biologically unobtainable in vivo , due to the toxicity

of th e compound. However, at these potentiall y lethal doses, in vivo treatment did not induce DNA single strand breaks in hepatocy tes. In the mouse bone marrow assay , abamectin was not found to induce chromosomal damage. There are also, many

studies and a great deal of clinical and follow - up experience with regard to ivermectin, a closely

similar human and animal drug. 3. Reproductive and developmental toxicity. In a 2 - generation study in rats , the no observed adverse effect level (NOAEL ) was established at 0.1 2 mg/kg/day in pups based upon retinal folds, decreased body weight (bwt), and mortality . The NOAELs for sy stemic and reproductive toxicity were 0.4 mg/kg/day . In the 1 - generation reproduction study in rats with the delta 8,9 - isomer, the NOAEL was 0.4 mg/k g/day and the lowest observed adverse effect level (LOAEL) was greater than 0.4 mg/kg/day highest dose tested (HDT). In an oral developmental toxicity study in rabbits the maternal NOAEL was 1.0 mg/kg/day

based upon decreased body weights and tremors. The fetal NOAEL was 1.0 mg/kg/day

based upon clubbed feet. In an oral developmental toxicity study in rats the maternal and fetal NOAEL was 1.6 mg/kg/day , the HDT. In an oral developmental toxicity

study the maternal NOAEL in CF - 1 mice that expressed P gl ycopr otein was greater than 1.5 mg/kg/day , the highest and onl y dose tested. No cleft palates were observed in fetuses that expressed normal levels of P - gl ycoprotein, but fetuses with low or no levels of P - gl yc oprotein had increased incidence of cleft palates. In a developmental neurotoxicity study in rats the maternal NOAEL was 0.4 mg/kg/day ,4

the HDT, and the offspring NOAEL was 0.12 mg/kg/day with an offspring L OAEL of 0.2 mg/kg/day

based on slight pup body weight loss. In a second developmental neurotoxicity study

in rats the maternal NOAEL was 0.4 mg/kg/day , the HDT, and the offspring NOAEL was 0.2 mg/kg/day with an offspring LOAEL of 0.4 mg/kg/day based on decreased bod y weight in both sexes. There was no evidence of neurotoxicity in the offspring. 4. Subchronic toxicity. Subchronic toxicity studies included the following: i. A rat 14

–

week oral toxicity

study with a NOAEL of 0.4 mg/kg/day , the HDT. ii. A dog 12

–

week feeding study

with a NOAEL of 0.5 mg/kg/day based upon mydriasis. iii. A dog 18

–

week ora l study

with a NOAEL of 0.25 mg/kg/day based upon mortality . 5. Chronic toxicity. A rat 53

– week carcinogenicity feeding stud y was negative for carcinogenicity , with a NOAEL of 1.5 mg/kg/day based upon tremors. A CD

– 1 mouse 94

– week carcinogenicity feeding study was negative for carcinogenicity , with a NOAEL of 4 mg/kg/day

based upon decreased body weights. A dog 53

–

week chronic feeding study resulted in a NOAELof 0.25 mg/kg/day based upon mydriasis. 6. Animal metabolism. Rats were given oral doses of 0.14 or 1.4 mg/kg bwt/day of abamectin or 1.4 mg/kg bwt/day of the delta 8,9 isomer. Over 7

– day s, the percentages excreted in urine were 0.3

– 1% of the administered dose of abamectin and 0.4% of the dose of the isomer. The animals eliminated 69

– 82% of the dose of abamectin and 94% of the dose of isomer in feces. In rats, goats, and cattle, unchanged parent compound accounted for up to 50% of the total radioactive residues in tissues. The 24 - hydrox ym ethyl derivative of abamectin was found in rats, goats, and catt le treated with the compound and in rats treated with the delta 8,9 isomer, and the 3’’ - O - demethyl derivative was found in rats and cattle administered abamectin and in rats administered the isomer. 7. Metabolite toxicology . There are no metabolites of concern based on a differential metabolism between plants and animals. The potential hazard of the 24 - hydrox ym ethyl or the 3’’ - O - demeth yl animal metabolites was evaluated in toxicology studies with abamectin photoly tic break - down product, the delta 8,9 - iso mer. 8. Endocrine disruption . There is no evidence that abamectin is an endocrine disrupter. Evaluation of the rat multigenerational study demonstrated no effect on the time to mating or on the mating and fertility indices, suggesting no effects on the es trous cycle, on mating behavior, or on male or female fertility at doses up to 0.4 mg/kg/day , the HDT. Furthermore, the range finding study demonstrated no adverse effect on female fertility at doses up to 1.5 mg/kg/day , the HDT. Similarly , chronic and sub chronic5

toxicity studies in mice, rats, and dogs did not demonstrate an y evidence of toxicity to the male or female reproductive tract, or to the th yroid or pituitary (based upon organ weights and gross and histopathologic examination). In the developmenta l studies, the pattern of toxicity

observed does not seem suggestive of an y endocrine effect. Finall y, experience with ivermectin in breeding animals, including sperm evaluations in multiple species, shows no adverse effects suggestive of endocrine disrupt ion. The EPA notified registrants of the EPA’s first group of specified active ingredients and manufacturers of the EPA’s first group of specified inert ingredients that the Agency was initiating the Endocrine Disruptor Screening Program for these comp ounds. In 2010 , the EPA issued Data - Call In s for the endocrine assays required for specified active ingredients including abamectin . The Abamectin EDSP Consortium is generating the required assay s . C. Aggregate Exposure 1. Dietary Exposure. Tier III/IV acute, short - term, and chronic aggregate exposure evaluations were made for abamectin using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCID TM , version 3.14), which 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 assessments included all current foliar, food handling establishment (FHE), and residential uses for abamectin, pendi ng uses on cotton and strawberries, including a request for updated crop group tolerances, and a proposed new IR - 4 use on caneberry subgroup 13 - 07A. For these exposure assessments, residue data were taken from field trial residue studies in which abamecti n was applied at the maximum intended use rate and samples were harvested at the minimum pre - harvest interval (PHI) to obtain maximum residue values. Drinking water estimates were incorporated directl y into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. Percent crop treated values were estimated based upon economic, pest, and competitive pressures. Residue values for milk and livestock commodities were obtained from th e EPA’s July 18, 2011 abamectin dietary risk assessment (D380796). i. Food Acute Exposure. The abamectin acute dietary (food onl y) risk assessment was performed for all population subgroups with an acute reference dose of 0.005 mg/kg bw/day based on a 12 - week dose - range finding study in dogs with a No Observed Adverse Effect Level (NOAEL) of 0.5 mg/kg - bw/day and an uncertaint y factor of 100X. The 100 - fold safet y factor includes intra - and interspecies variations and no additional FQPA safety

factors were included in these acute assessments. For the purpose of the aggregate risk assessment, exposure values were expressed in terms of margin of exposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each6

population subgroup. In a ddition, exposure was also expressed as a percent of the acute reference dose (%aRfD). Acute (food onl y) exposure to the U.S. population resulted in a MOE of 719 (13.9% of the acute RfD of 0.005 mg/kg - bw/day). The most sensitive sub population was childr en (1 - 2 y ears old) with a MOE of 376 (26.6% of the aRfD). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Sy ngenta believes that there is a reasonable certainty that no harm will result from acute food exposure to residues arising from all current, pending, and proposed uses for abamectin. Chronic Exposure. The abamectin chronic dietary (food only) risk assessment was performed for all pop ulation subgroups with a chronic reference dose of 0.0004 mg/kg bw/day based on combined data from three reproduction studies and two developmental neurotoxicity

studies with a No Observed Adverse Effect Level (NOAEL) of 0.12 mg/kg bw/day and an uncertainty factor of 300X. The 300 - fold safet y factor includes intra - and interspecies variations (100X) and the additional FQPA safety factors of 3X for the steepness of the dose - response curve and the severity of effects. For the purpose of the aggregate risk a ssessment, exposure values were expressed in terms of margin of exposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each population subgroup. In addition, exposure was also expressed as a percent of the chronic reference dose (% RfD). Chronic (food only) exposure to the U.S. population resulted in a MOE of 2,936 (10.2% of the chronic RfD of 0.0004 mg/kg - bw/day). The most sensitive sub - population was children (1 - 2 years old) with a MOE of 669 (44.8% of the chronic RfD). Since th e Benchmark MOE for this assessment was 300 and since the EPA generall y has no concern for exposures above the benchmark or below 100% of the reference dose, S yn genta believes that there is a reasonable certaint y that no harm will result from chronic food exposure to residues arising from all current, pending, and proposed uses for abamectin. Cancer . Abamectin is considered “not likel y to be a human carcinogen”. Therefore, no can cer risk assessment was performed for abamectin. ii. Drinking Water: The Estimated Drinking Water Concentrations (EDWCs) of abamectin were determined using Tier 1SCI - GROW which estimates pesticide concentration in ground water and Tier 2 PRZM/EXAMS which estimates pesticide concentration in surface water. EDWCs of abamec tin from the currentl y registered and pending uses as well as a proposed use on caneberries were determined using EPA’s model inputs. Based on the SCI - GROW modeling, the highest ground water EDWC for abamectin is 0.00188 ppb (acute and chronic) based on the currentl y registered/pending use on strawberries. Based on the PRZM/EXAMS modeling, the currentl y registered use7

on dry beans provided the highest surface water EDWCs of 2.35 ppb for acute and 1.39 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 an y ground water exposure concerns. Acute Exposure from Drinking Water. The acute surface water EDWC of 2.35 ppb was incorporat ed directl y into the DEEM software as “water, direct and indirect, all sources” to model the acute drinking water exposures b y taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup at the 99.9% - ile of exposures. Acute drinking water exposure to the U.S. population resulted in a MOE of 4,808 (2.1% of the acute RfD of 0.005 mg/kg bw/day). The most exposed sub - population was all infants (<1 y ear old) with a MOE of 3,106 (3.2% of the aRfD of 0.005 mg/kg/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generall y has no concern for exposures above the benchmark or below 100% of the reference dose, Sy ngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from all current, pending, and proposed uses for abamectin. Chronic Exposure from Drinking Water. The chronic surface water EDWC of 1.39 ppb was input directl y into the DEEM s oftware 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 4,123 (7.3% of the chronic RfD of 0.0004 mg/kg bw/day). Chronic drinking water exposure to the most exposed sub - population (infants, <1 y ear old) resulted in a MOE of 1,599 (18.8% of the chronic RfD of 0.0004 mg/kg bw/day). Since the Benchmark MOE for this assessment was 300 and since the EPA generall y has no concern for exposures above the benchmark or below 100% of the reference dose, S yn genta believes that there is a reasonable certaint y that no harm will result from chronic drinking water exposure to residues arising from all current, pending, and proposed uses for abamectin. 2. Non - Dietary

Exposure: Residential exposure risk assessments were performed for use of abamectin formulated as Varsit y® Fire Ant Bait and Optigard® Fire Ant Bait for residential turf. Residential adult handler/applicator assessments were performed for a ctivities including push spreader, bell y grinder, spoon, cup, hand dispersal, and shaker can. Residential post - application exposure scenarios assessed included adult and child high contact dermal, adult and youth mower, adult and y outh golfer, and child h and - to mouth, object - to - mouth, soil ingestion, and ingestion of granules. The most - exposed adult (19+ years) handler/applicator scenario was for bell y - grinder applications, with a short - term MOE of 899,348 (Benchmark = 300). The most - exposed youth (11 - 16 years) post - application scenario was for the youth golfer, with a short - term MOE of 15,753,170 (Benchmark = 300). The most - exposed youth (6 - 11 y ears) post - application scenario was for the youth golfer, with a short - term MOE of 13,418,308 (Benchmark = 300 ). The8

most - exposed children’s (1 - 6 y ears) post - application scenario was via hand - to - mouth and dermal exposures resulting from play activities on treated turf, with a combined short term MOE of 343,564 (Benchmark = 300). Incidental oral ingestion of granules by children had a short - term MOE of 48,017 (Benchmark = 300; granule ingestion is not aggregated with other exposure scenarios). D. Cumulative Effects Cumulative Exposure to Substances with a Common Mechanism of Toxicity . Section 408(b)(2)(D)(v) r equires 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 tox icity”. If, in the future, EPA obtains new data suggesting that abamectin shares a common mechanism of toxicity with other chemical substances, the Agency will revisit the need for a cumulative risk assessment. For the purposes of this filing, Sy ngenta h as not assumed that abamectin has a common mechanism of toxicity with other substances. E. Safet y Determination 1. U.S. Population . The acute dietary exposure analy sis (food plus drinking water) showed that exposure from all current, pending, and propo sed abamectin crop uses result in a MOE of 625 (16.0% of the aRfD, Benchmark MOE = 100) for the general U.S. population. The short - term exposure analy sis (food plus drinking water plus residential) showed that exposure from all current, pending, and propo sed abamectin uses result in a MOE of 1,711 (Benchmark MOE = 300) for the general U.S. population. The chronic dietary exposure anal ys is (food plus drinking water) showed that exposure from all current, pending, and proposed abamectin crop uses result in a MOE of 1,715 (17.5% of the chronic RfD, Benchmark MOE = 300) for the general U.S. population. Based on the completeness and reliability of the toxicity

data supporting these uses, Sy ngenta believes that there is a reasonable certaint y that no harm will result to the general U.S. population from aggregate exposure to residues arising from all current, pending, and proposed abamectin uses, including anticipated dietary exposure from food, water, and all other ty pes of non - occupational residential exposures . 2. Infants and children. The acute dietary exposure anal ys is (food plus drinking water) showed that exposure from all current, pending, and proposed abamectin uses results in a MOE of 342 (29.2% of the aRfD) for children 1 - 2 y ears old (the most sensit ive population subgroup). For the short - term aggregate assessments, children 1 - 2 y ears old had an aggregate MOE of 542 (Benchmark MOE = 300) for all current, pending, and proposed abamectin uses. The chronic dietary exposure anal ys is (food plus drinking water) showed that exposure from all current, pending, and proposed abamectin uses result in a MOE of 542 (55.3% of the cRfD) for children 1 - 2 y ears old (the most sensitive9

population subgroup). Based on the completeness and reliability of the toxicity

data supporting these uses, Syngenta believes that there is a reasonable certaint y that no harm will result to infants and children from aggregate exposure to residues arising from all current, pending, and proposed abamectin uses, including anticipated diet ary exposure from food, water, and all other ty pes of non - occupational residential exposures. F. International Tolerances Codex has established Maximum Residue L evels (MRL s) for abamectin on a number of commodities including almonds, apples, citrus, cotton, cucumbers, hops, lettuce, meat, milk, and related commodities (beef and goat), melons, pears, peppers, potatoes, squash, strawberries, tomatoes, and walnuts. In addition, country or region - specific international MRL s for abamectin have been establish ed or proposed in a number of countries including: Argentina, Australia, Brazil, Canada, Chile, China, France, Germany , Greece, Hungary , Ital y, Japan, Korea, Mexico, Russia, South Africa, Spain, Switzerland, Taiwan, Turkey , United Kingdom, and the United States.