Document ID: EPA-HQ-OPP-2013-0428-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-09-12T04:00Z

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 Syngenta 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 B1 (a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5-O- demethyl avermectin A1) and less than or equal to 20% avermectin B1b (5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1)) 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 adequately understood and the residues of concern include the parent insecticide abamectin (also referred to as avermectin B1 which is a mixture of a minimum of 80% avermectin B1a and a maximum of 20% avermectin B1b) and the delta 8,9-isomer of the B1a and of the B1b components of the parent insecticide.
	2. Analytical method. The analytical methods involve homogenization, filtration, partition, and cleanup with analysis by high performance liquid chromotography (HPLC)-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 made 6-8 days apart to the treated plots.  The application rates ranged from 0.0173 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 days after the last application.  Additionally, at the OR03 trial, duplicate samples were collected 0, 3, 7 and 9 days after the last application.
	The total residues of abamectin ranged from 0.0062 to 0.1215 ppm in samples taken at 7 days 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 Syngenta's technical abamectin products:

Abamectin Technical:  
i. A rat acute oral study with a lethal dose (LD)50 of 13.6 milligram per kilogram (mg/kg).
ii. A rat acute oral study with a LD50 of 214-232 mg/kg.
iii. A rabbit acute dermal study with a LD50 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 eye 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 II

i. A rat acute oral study with a LD50 of 372.5  mg/kg
ii. A rat acute dermal study with a LD50 of >200 mg/kg but <2000 mg/kg 
ii. A rat acute inhalation study with a LC50 of >0.0518 mg/L (nose only)
v. A primary eye 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 assays conducted with and without metabolic activation were both negative. The V - 79 mammalian cell mutagenesis assays conducted with and without metabolic activation did not produce mutations. In an alkaline elution/rat hepatocyte assay, abamectin was found to induce single strand DNA breaks without significant toxicity in rat hepatocytes 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 the compound. However, at these potentially lethal doses, in vivo treatment did not induce DNA single strand breaks in hepatocytes. 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 0.12 mg/kg/day in pups based upon retinal folds, decreased body weight (bwt), and mortality. The NOAELs for systemic 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/kg/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-glycoprotein was greater than 1.5 mg/kg/day, the highest and only dose tested. No cleft palates were observed in fetuses that expressed normal levels of P-glycoprotein, but fetuses with low or no levels of P-glycoprotein had increased incidence of cleft palates. In a developmental neurotoxicity study in rats the maternal NOAEL was 0.4 mg/kg/day, the HDT, and the offspring NOAEL was 0.12 mg/kg/day with an offspring LOAEL 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 body 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 oral study with a NOAEL of 0.25 mg/kg/day based upon mortality.
	5. Chronic toxicity. A rat 53 - week carcinogenicity feeding study 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 NOAEL of 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 - days, 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-hydroxymethyl derivative of abamectin was found in rats, goats, and cattle 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-hydroxymethyl or the 3''-O-demethyl animal metabolites was evaluated in toxicology studies with abamectin photolytic break-down product, the delta 8,9-isomer.
	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 estrous 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 subchronic toxicity studies in mice, rats, and dogs did not demonstrate any evidence of toxicity to the male or female reproductive tract, or to the thyroid or pituitary (based upon organ weights and gross and histopathologic examination). In the developmental studies, the pattern of toxicity observed does not seem suggestive of any endocrine effect. Finally, experience with ivermectin in breeding animals, including sperm evaluations in multiple species, shows no adverse effects suggestive of endocrine disruption.  
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 compounds. In 2010, the EPA issued Data-Call Ins for the endocrine assays required for specified active ingredients including abamectin.  The Abamectin EDSP Consortium is generating the required assays. 
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-FCIDTM , 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, pending 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 abamectin 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 directly 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 the EPA's July 18, 2011 abamectin dietary risk assessment (D380796).  
i.  Food   Acute Exposure.  The abamectin acute dietary (food only) 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 uncertainty factor of 100X.  The 100-fold safety 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 by dividing the NOAEL by the exposure for each population subgroup.  In addition, exposure was also expressed as a percent of the acute reference dose (%aRfD).  Acute (food only) 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 children (1-2 years 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, Syngenta 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 population 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 safety 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 assessment, exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by 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 the Benchmark MOE for this assessment was 300 and since the 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 exposure to residues arising from all current, pending, and proposed uses for abamectin.

Cancer.  Abamectin is considered "not likely to be a human carcinogen".  Therefore, no cancer 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 abamectin from the currently 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 currently registered/pending use on strawberries.  Based on the PRZM/EXAMS modeling, the currently registered use 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 any ground water exposure concerns.  
Acute Exposure from Drinking Water.  The acute surface water EDWC of 2.35 ppb was incorporated directly into the DEEM software as "water, direct and indirect, all sources" to model the acute drinking water exposures by 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 year 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 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 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 directly into the DEEM 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 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 year 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 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 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 Varsity(R) Fire Ant Bait and Optigard(R) Fire Ant Bait for residential turf.  Residential adult handler/applicator assessments were performed for activities including push spreader, belly 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 youth golfer, and child hand-to-mouth, object-to-mouth, soil ingestion, and ingestion of granules.  The most-exposed adult (19+ years) handler/applicator scenario was for belly-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 years) post-application scenario was for the youth golfer, with a short-term MOE of 13,418,308 (Benchmark = 300).  The most-exposed children's (1-6 years) 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) 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".  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, Syngenta has not assumed that abamectin has a common mechanism of toxicity with other substances. 
E.  Safety Determination
1.  U.S. Population.  The acute dietary exposure analysis (food plus drinking water) showed that exposure from all current, pending, and proposed 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 analysis (food plus drinking water plus residential) showed that exposure from all current, pending, and proposed abamectin uses result in a MOE of 1,711 (Benchmark MOE = 300) for the general U.S. population.  The chronic dietary exposure analysis (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, Syngenta believes that there is a reasonable certainty 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 types of non-occupational residential exposures.  
2. Infants and children.  The acute dietary exposure analysis (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 years old (the most sensitive population subgroup).  For the short-term aggregate assessments, children 1-2 years old had an aggregate MOE of 542 (Benchmark MOE = 300) for all current, pending, and proposed abamectin uses.  The chronic dietary exposure analysis (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 years old (the most sensitive population subgroup).  Based on the completeness and reliability of the toxicity data supporting these uses, 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 abamectin uses, including anticipated dietary exposure from food, water, and all other types of non-occupational residential exposures.  
F.  International Tolerances
Codex has established Maximum Residue Levels (MRLs) 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 MRLs for abamectin have been established or proposed in a number of countries including:  Argentina, Australia, Brazil, Canada, Chile, China, France, Germany, Greece, Hungary, Italy, Japan, Korea, Mexico, Russia, South Africa, Spain, Switzerland, Taiwan, Turkey, United Kingdom, and the United States.