Document ID: EPA-HQ-OPP-2012-0418-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-22T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Jessica Rogala (703) 347-0263
Syngenta Crop Protection, LLC
PP 2F8009

EPA has received a pesticide petition (PP 2F8009) from Syngenta Crop Protection LLC  P.O. Box 18300; Greensboro, NC  27419 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 amending the tolerances 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 cotton, delinted seed and cotton, gin by-products from 0.005 parts per million (ppm) to 0.015 parts per million (ppm) and strawberry from 0.02  parts per million (ppm) to 0.06  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 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. Cotton: 
In 2009 nine magnitude of residue (MOR) studies in cotton were conducted with the SC formulation of abamectin.  One trial was located in Virginia, 2 trials in Arkansas, 4 in Texas, and 2 in California.  
      
      In 2010, 3 additional trials in cotton with this formulation were conducted to complete the number of geographical locations that the EPA requires for magnitude of residue studies,  One trial was located in Louisiana, 1 in Texas, and 1 in California.  

The SC formulation of abamectin was applied foliarly to cotton 2 times at a rate of 0.019 lb ai/A with a 21-day interval between applications.  Cotton was sampled 20 days after the last application.  In addition to the proposed target interval, undelinted cottonseed and cotton gin trash were harvested in the decline trials.  In the processing study, undelinted seed was processed into cotton hulls, cotton meal, and refined cottonseed oil.  

Samples were analyzed for abamectin (a mixture containing 80% parent B1a (NOA422601) and 20% B1b (NOA421704) and its delta-8,9 isomer (8,9-Z-isomer of parent B1a.  The maximum residues of abamectin in undelinted cotton seed were 0.01 ppm for avermectin B1a and <0.002 ppm for B1b.  For  cotton gin by-products, the maximum residues of abamectin were 0.68 ppm for B1a and 0.005 for B1b. In the cotton processing study, there was no concentration of abamectin residues in the processed fractions (hulls, meal, refined oil).  
  
In the cotton MOR study (9 trials) conducted in 2009 with the SC formulation, there were some abamectin residues in undelinted seed (TX) and in cotton, gin by-producs (CA) that exceeded the established abamectin tolerance for undelinted seed (0.005 ppm) and the established tolerance for abamectin in cotton gin by-products (0.15 pm).  

In the cotton MOR trials with the SC formulation which were conducted in 2010 (3 trials), there were no abamectin residues in cotton, undelinted seed that exceeded the established abamectin tolerance and no abamectin residues in cotton, gin by-products that exceeded the established abamectin tolerance (0.15 ppm), however in one trial (TX) the level of abamectin residue in gin by-products was at the tolerance level of 0.15 ppm.  .  
          
In the cotton processing study, there was no concentration of abamectin residues in  cotton, processed fractions (hulls, meal, refined oil).  
 
Results of these MOR studies in cotton with the SC formulation of abamectin, indicate the established tolerances for abamectin in cotton, undelinted seed and in cotton, gin by-products, need to be increased. There is no need for a tolerance in cotton processed fractions.  
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Two  magnitude of residue (MOR) trials with the SC formulation of abamectin in strawberries were conducted. One trial was located in North Carolina and the other trial was located in California The SC formulation of abamectin was applied to strawberries 4 times at a rate of 0.19 lb. ai/A per application.  There was a 7-day interval between the first and second applications, a 21-day interval between the second and third applications, and a 7-day interval between the third and fourth applications.  Strawberries were sampled 3 days after the last application.  

Samples from all of the studies (12 total) were analyzed for abamectin (a mixture containing 80% parent B1a (NOA422601) and 20% B1b (NOA421704) and its delta-8,9 isomer (8,9-Z-isomer of parent B1a. The maximum residues of abamectin in strawberries were 0.04 ppm for avermectin B1a and 0.04 ppm for B1b
          
Results of these MOR studies for strawberries with the SC formulation of abamectin as the test material, indicate the established tolerance for abamectin in strawberry (0.02 ppm) needs to be increased.  

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 LD50 of 13.6 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 LC50 of 0.21 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 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 followup 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 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 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.  Acute and chronic Tier III dietary exposure evaluations were made for abamectin using the Dietary Exposure Evaluation Model (DEEM-FCID[TM], version 2.03) from Exponent.  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 Supplemental CSFII children's survey (1998) consumption database.  These Tier III assessments included all currently registered Section 3 foliar crop uses including:  apples, avocado, celeriac, chives, citrus fruit (Crop Group 10), cotton, cucurbits (Crop Group 9), dry beans (seed), dry bulb onions, fruiting vegetables (Crop Group 8), grapes, herbs (crop subgroup 19A, except chives), hops, leafy vegetables except Brassica (Crop Group 4), mint (peppermint and spearmint), pears, pistachios, stone fruit (Crop Group 12), strawberries, tree nuts (Crop Group 14), and tuberous and corm vegetables (Crop Group 1C) .Abamectin is currently registered for seed treatment (ST) uses on corn, cotton, cucurbits, tomatoes, and soybean. Abamectin is also registered for use in food handling establishments), and for cattle ear-tag use.  Established tolerances for abamectin in or on cotton and strawberry are based on residue studies with the EC formulation.  This petition to amend these tolerances applies to the proposed use of the SC formulation of abamectin on these crops.  For these exposure assessments, residue data were taken from cotton and strawberry field trials in which the SC formulation of 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.  All consumption data for these assessments were taken from the USDA'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.  

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 671 (14.9% 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 371 (26.9% of the aRfD).  Since the benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the current 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 2,324 (12.9% 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 672 (44.7% of the chronic RfD).  Since the benchmark MOE for this assessment was 300 and since the EPA generally has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the current 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:  Another potential source of abamectin exposure to the general population is from residues in drinking water.  Estimated Drinking Water Concentrations (EDWCs) are made by reliance on simulation or modeling taking into account data on the physical characteristics and environmental fate of abamectin.  For this assessment, the uses of abamectin were evaluated by Syngenta using the Tier II model, PRZM/EXAMS Shell (PE5), for surface water and the Tier I model SCI-GROW (v 2.3) for groundwater.

For surface water the highest EDWCs resulted from the use for dry beans.  PRZM/EXAMS calculated a surface water acute EDWC of 0.993 ppb and a chronic EDWC of 0.358 ppb.  For groundwater, the currently registered use for strawberry provided the maximum EDWC (acute and chronic) of 0.00229 ppb.  Since the surface water EDWCs exceed the ground water EDWC, the surface water values should be used for comparison purposes and are considered protective for any ground water concentration concerns.

Acute Exposure from Drinking Water.  The acute EDWC of 0.993 ppb was used to calculate the acute drinking water exposure values for the U.S. Population and population subgroups.  Acute drinking water exposure to the U.S. population resulted in a MOE of 13,514 (0.7% of the aRfD of 0.005 mg/kg/day, Benchmark MOE = 100).  The most sensitive sub-population was children (1 - 2 years old) with a MOE of 16,667 (0.6% of the aRfD of 0.005 mg/kg/day, Benchmark MOE = 100).  Since the Benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and proposed uses for abamectin.

Chronic Exposure from Drinking Water.  The chronic EDWC of 0.358 ppb was used to calculate the chronic drinking water exposure values for the U.S. Population and population subgroups.  Chronic drinking water exposure to the U.S. Population resulted in a MOE of 15,903 (Benchmark MOE = 300; 1.9% of the cRfD of 0.0004 mg/kg/day).  The most sensitive sub-population was infants (<1 year old) with a MOE of 4,851 (6.2% of the cRfD of 0.0004 mg/kg/day, Benchmark MOE = 300).  Since the Benchmark MOE for this assessment is 300 and since EPA generally has no concern for exposures below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (drinking water) exposure to residues arising from the current and proposed uses for abamectin.

2.  Non-Dietary Exposure:  A residential exposure and risk assessment was performed for abamectin using the endpoints and uncertainty factors established by the EPA in a recent assessment (March 11, 2009).  Residential exposure and risk assessments were performed for granular abamectin baits used to treat fire ants on lawns.  As such, residential assessments included handler exposure for adults and post-application exposure risks for adults and children.  The highest predicted exposure for adults mixing, loading and applying product by belly grinder application to turf resulted in a combined (dermal plus inhalation) short-term margin of exposure (MOE) of 112,658.  The post-application dermal exposure to adults following use of granules on lawns is MOE = 402,379.  Children's post-application dermal plus non-dietary oral aggregate exposure to abamectin from lawn products had a short-term MOE of 48,209.  Incidental ingestion of granules on treated lawns by children was compared to the acute dietary NOAEL and had a MOE of 65,478.  

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 registered, and proposed abamectin crop uses result in a MOE of 639 (15.6% of the aRfD, Benchmark MOE = 100) for the general U.S. population.  The chronic dietary exposure analysis (food plus drinking water) showed that exposure from all registered and proposed abamectin crop uses result in a MOE of 2,028 (15.0% 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 from aggregate exposure to residues arising from all current, and proposed abamectin uses, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.  

	2. Infants and children.  The acute dietary exposure analysis (food plus drinking water) showed that exposure from all registered and proposed abamectin uses results in a MOE of 363 (27.5% of the aRfD) for children one to years old (the most sensitive population subgroup).  For the short-term aggregate assessments, the children 1-6 years old had an aggregate MOE of 757 (Benchmark MOE = 100).The chronic dietary exposure analysis (food plus drinking water) showed that exposure from all registered and proposed abamectin uses result in a MOE of 632 (47.5% of the cRfD) for children one to years old (the most sensitive population subgroup).  Since all aggregate MOEs were above the Benchmark MOEs and because the EPA has no concern for exposures resulting in a MOE above the Benchmark MOE, Syngenta believes that there is a reasonable certainty that no harm will result to any population subgroup from aggregate exposure to residues arising from all current, and proposed abamectin uses, including anticipated dietary exposure from food, drinking water and all other types of non-occupational exposures.
     

F.  International Tolerances
   
	Codex has established an abamectin Maximum Residue Level (MRL) of 0.02 ppm for peppers.  The fruiting vegetable tolerance of 0.02 ppm for abamectin is harmonized with Codex.  International MRLs for abamectin have been established for various agricultural commodities in a number of countries including Argentina, Australia, Belgium, Brazil, Canada, Czech Republic, Estonia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea (South), Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Russia, , Serbia and Montenegro, Slovak Republic, South Africa, Spain, Switzerland, Taiwan, and the United States.