Document ID: EPA-HQ-OPP-2013-0428-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-11T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2013-0428

EPA Registration Division Contact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 
Pesticide Petition Number: 4E8309
	EPA has received a pesticide petition PP# 4E8309 from the Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters,  Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450  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 180.449 by establishing a tolerance for the residues of the insecticide avermectin (abamectin), including its metabolites and degradates, determined by measuring only avermectin B1 a mixture of avermectins containing greater than or equal to 80% avermectin B1 a (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 the raw agricultural commodities: Fruit, stone, group 12 - 12 at 0.09 parts per million (ppm), Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13  -  07F at 0.02 ppm, Nut, tree, group 14-12 at 0.01 ppm, Vegetable, fruiting, group 8-10 at 0.07 ppm, Fruit, citrus, group 10-10 at 0.02 ppm, Berry, low growing, subgroup 13-07G at 0.05 ppm, Fruit, pome, group 11-10 at 0.02 ppm, Papaya at 0.40 ppm, Star apple at 0.40 ppm, Black sapote at 0.40 ppm, Sapodilla at 0.40 ppm, Canistel at 0.40 ppm, Mamey sapote at 0.40 ppm, Guava at 0.015 ppm, Feijoa at 0.015 ppm, Jaboticaba at 0.015 ppm, Wax jambu at 0.015 ppm, Starfruit at 0.015 ppm, Passionfruit at 0.015 ppm, Acerola at 0.015 ppm, Lychee 0.01 ppm, Longan at 0.01 ppm, Spanish lime at 0.01 ppm, Rambutan at 0.01 ppm, Pulasan at 0.01 ppm, Pineapple at 0.015 ppm, Bean at 0.015 ppm, and Onion, green, subgroup 3-07B at 0.08 ppm. Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180.449 be amended to remove the established tolerances for the residues of avermectin B1 in or on the raw agricultural commodity: : Bean, dry, seed at 0.01 ppm, Pear at 0.02 ppm, Apple at 0.02 ppm, Citrus at 0.02 ppm, Fruit, stone, group 12 at 0.09 ppm, Nut, tree, group 14 at 0.01 ppm, Pistachio at 0.01 ppm, Grape at 0.02 ppm, Strawberry at 0.05 ppm and Vegetable, fruiting group, 8 at 0.02 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 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.
      1. Analytical method. The analytical methods involve homogenization, filtration, partition, and cleanup with analysis by high performance liquid chromatography (HPLC)-fluorescence detection. The methods are sufficiently sensitive to detect residues at or above the tolerances proposed. All methods have undergone independent laboratory validation. 
      2. Magnitude of residues. Complete residue data to support the requested tolerances have been submitted.  The requested tolerances are adequately supported.  
In support of the requested tolerances, IR-4 has conducted the necessary trials in accordance with the requirements of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of avermectin B1 in or on requested commodities.
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 an lethal dose (LD)50 of 13.6 milligram per kilogram (mg/kg).
ii. A rat acute oral study with an LD50 of 214-232 mg/kg.
iii. A rabbit acute dermal study with an LD50 of 2000 mg/kg.
iv. A rat acute inhalation study with an 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 an LD50 of 372.5  mg/kg
ii. A rat acute dermal study with an LD50 of >200 mg/kg but <2000 mg/kg 
ii. A rat acute inhalation study with an 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 (EDSP) for these compounds. In 2010 the EPA issued Data-Call In's 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 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 3.18), 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 and pending foliar, seed treatment, food handling establishment (FHE), and residential uses for abamectin, as well as a number of revised crop groupings and proposed new IR-4 uses on green onion (subgroup 3-07B), fruiting vegetables (Crop Group 8-10), citrus fruit (Crop Group 10-10), small vine-climbing fruit except fuzzy kiwifruit (subgroup 13-07F), low growing berries (subgroup 13-07G, except cranberry), stone fruit (Crop Group 12-12), pome fruit (Crop Group 11-10), tree nuts (Crop Group 14-12), papaya, star apple, black sapote, sapodilla, canistel, mamey sapote, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, acerola, lychee, longan, Spanish lime, rambutan, pulasan, pineapple, and bean.  For these exposure assessments, residue data were obtained either from the EPA Health Effects Division's July 18, 2011 dietary exposure assessment (DP Barcode: D380796) or 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.  Empirical processing factors were used for cottonseed oil (0.48x), grape juice (0.23x), grapefruit juice (0.85x), orange juice (0.25x), orange peel (2.5x), dried prune (3.9x), raisins (0.75x), tomato paste (0.84x), tomato puree (0.4x), and field corn flour (1.96x).  Percent crop treated values were estimated based upon economic, pest, and competitive pressures.  Residue values for milk and livestock commodities were also obtained from the EPAs July 18, 2011 dietary risk assessment.  
	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 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 percentage of the acute reference dose (% aRfD).  Acute (food only) exposure to the U.S. population resulted in a MOE of 601 (16.6% 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 262 (38.2% 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 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 2,512 (11.9% 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 577 (52.0% 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 1 Screening Concentration in Ground Water (SCI-GROW) and PRZM-GW 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, pending and proposed uses (green onion, guava, lima bean, lychee, papaya, pineapple, snap bean, and greenhouse tomato) were determined.  Based on the currently registered/proposed use on golf course turf, SCI-GROW modeling provided the highest groundwater EDWC of  0.00833 parts per billion (ppb) (acute and chronic) and PRZM/EXAMS modeling provided the highest surface water EDWCs of 1.25 ppb for acute and 0.416 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 1.25 ppb was input directly into the DEEM-FCID(TM) 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 the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup.  Acute drinking water exposure to the U.S. population resulted in a MOE of 11,905  (0.8% 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 2,841 (3.5% 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 0.416 ppb was input directly into the DEEM-FCID(TM) 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 13,776 (2.2% 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 5,343 (5.6% 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 Optigard Fire Ant Bait for use on turf, lawns, and landscapes; Abamectin-chelate A12115F for use on golf course fairways, tees and greens; and for off-site drift of agricultural products.  Abamectin-chelate A12115F is labeled for professional use only; therefore no residential handler exposure assessments are required for this product.  Application of Optigard Fire Ant Bait by residents is allowed; therefore residential handler exposure assessments are required.  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, adult and child spray drift, and child hand-to-mouth, object-to-mouth, soil ingestion, and ingestion of granules.  The most-exposed adult (19+ years) scenario was for post-application spray drift, with a short-term MOE of 4,588 (Benchmark = 300).  The most-exposed youth (11-16 years) post-application scenario was for the youth golfer, with a short-term MOE of 5,219 (Benchmark = 300).  The most-exposed youth (6-11 years) post-application scenario was for the youth golfer, with a short-term MOE of 4,445 (Benchmark = 300).  The most-exposed children's (1-2 years) scenario was via post-application spray drift, with a combined short-term MOE of 881 (Benchmark = 300).  
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".  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to abamectin and any other substances and abamectin does not appear to produce a toxic metabolite produced by other substances.  Therefore, 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 572 (17.5% 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 621 (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 2,125 (14.1% 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 257 (38.9% 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 336 (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 544 (55.1% 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.