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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING EPA Registration Division contact: Laura Nollen , (703) 305 - 7390 Interregional Research Project Number 4 (IR- 4) Petition Number 0E7738 EPA has received a pes ticide petition , PP 0E7738, from IR
- 4 , 500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 b y establishing tolerance s 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
- methylpropyl)
- 25
- (1
- methylethyl) avermectin A 1 )) and its delta
- 8,9
- isomer in or o n the raw agricultural commodities onion, bulb, subgroup 3
- 07A at 0.01 parts per million (ppm); chive , fresh leaves at 0.01 ppm; chive, dried leaves at 0.07 ppm ; and bean, dry , seed at 0.01 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 granti ng 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 th e 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. Ana lytical 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 as required b y PR Notice 96

– 1. 3. Magnitude of residues. Bulb Onions : Eight residue field trials were conducted in California, Colorado, New Mexico, New York, Ohio, O regon, Texas, and Washington. Three foliar applications totaling approximately 0.057 lb ai/A of abamectin were applied to the treated plots (except in one California trial, where four foliar applications totaling 0.076 lb ai/A was applied. . Commerciall y mature dry bulb onions were collected approximately

30 day s after the last application. The maximum combined avermectin B 1a2

and 8,9
- Z avermectin B 1a residue from dry bulb onions was 0.0026 ppm in the New York trial. In all other samples the residues were below the lowest limit of method validation (LLMV). There were no residues of avermectin B 1b greater than the LLMV. Chives : Three residue field trials were conducted in New Jersey , Washington, and Maryland. Three foliar applications totaling approximate ly 0.057 lb abamectin /A was applied to the treated plots. . Commercially mature fresh chive leaves were collected approximately

6 (±1) days after the last application. At the Washington site, one treated and one untreated fresh chive sample was collecte d 7 day s after the final application and dried in a drying cabinet for 2 day s before collection. An additional fresh chive harvest was conducted at the Washington site approximately 13 day s after the final application to support the possibility

of adding c hive to the existing tolerance for the Herb crop subgroup (except chives).. The maximum combined avermectin B 1a and 8,9
- Z avermectin B 1a residue found in the Maryland trial at a 6 ±1 day PHIin fresh chives leaves was 0.00247 ppm,. Another sample, found in the Washington fresh chives trial, contained a combined avermectin B 1a and 8,9
- Z avermectin B 1a residue of 0.00216 ppm. The maximum combined avermectin B 1a and 8,9
- Z avermectin B 1a residue from dried chives leaves was 0.0101 ppm, found in the Washington trial. In all other samples fresh and dry , the residues were below the LL MV. There were no residues of avermectin B 1b greater than the LL MV. Dry Beans : Twelve field trials were conducted with dry beans in California, I daho, Washington, Ohio, North Dakota, Wisconsin, and New Jersey . A total of approximately 0.057 lb ai/A of abamectin was applied to the treated plots in three foliar applications. Commercially

mature dry

beans were collected approximately 6 (±1) day s after the final application. The maximum c ombined avermectin B 1a and 8,9
- Z avermectin B 1a residue in dry beans ,found in a California trial, was 0.004 ppm,. In all other samples the residues were below the LLMV. There were no residues of avermectin B 1b greater than the LLMV. 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 an LD 50 of 13.6 mg/kg. ii. A rat acute oral study

with an LD 50 of 214
- 232 mg/kg. iii. A rabbit acute dermal study with an LD 50 of 2000 mg/kg. iv. A rat acute inhalation study with an LC 50 of 0.21 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 whi ch showed slight irritation. vii. A dermal sensitization study (Buehler) in guinea pigs which was negative. Abamectin Technical II i. A rat acute oral stud y with an LD 50 of 372.5 mg/kg3

ii. A rat acute dermal study with an LD 50 of >200 mg/kg but <2000 mg/kg ii. A rat acute inhalation study with an 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 stu dy (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 , abamectin 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 the 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 followup experience with regard to ivermectin, a closely

similar human and animal drug. 3. Reproductive and deve lopmental toxicity. Ina 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 s ys temic and reproductive toxicity were 0.4 mg/kg/day . In the 1
- ge neration 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 bod y 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 ycoprotein 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
- gl yc oprotein, but fetus es with low or no levels of P
gl ycoprotein 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 wei ght 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 feedin g stud y with a NOAEL of 0.5 mg/kg/day based upon my driasis. 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 stud y was negative for4

carcinogenicity , with a NOA EL of 1.5 mg/kg/day based upon tremors. A CD

– 1 mouse 94

– week carcinogenicity feeding stud y 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/k g/day based upon my driasis. 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
- hy drox ym ethyl 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
- hy drox 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
- 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 cy cle, 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 an y evidence of toxicity to the male or female reproductive tract, or to the th yroid or pituit ary (based upon organ weights and gross and histopathologic examination). In the developmental studies, the pattern of toxicity

observed does not seem suggestive of an y endocrine effect. Finall y, experience with ivermectin in breeding animals, including sp erm evaluations in multiple species, shows no adverse effects suggestive of endocrine disruption. C. Aggregate Exposure 1. Dietary Exposure. Acute and chronic Tier III dietary exposure evaluations were made for abamectin using the Dietary Exposure Ev aluation 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 childre n’s survey (1998) consumption database. These Tier III assessments included all currently registered Section 3 foliar crop uses including: apples, avocado, celeriac, citrus fruit (Crop Group 10), cotton, cucurbits (Crop Group 9), fruiting vegetables (Cro p 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 (Crop5

Group 1C). Section 18 registered uses include bean (lima, seed) and dry bulb onions. Abamectin is currently

registered for seed treatment (ST) uses on corn, cotton, cucurbits, and tomatoes, as a food handling establishment use (Whitmire), a cattle ear
- tag use; a seed treatment use on soy beans is pending. Proposed uses include an I R
- 4 foliar uses on chives, dry

beans (seed), and dry

bulb onions. Percent of crop treated values were conservativel y estimated to be 100% for the proposed use on dry beans. For these exposure assessments, residue data were taken from field trial data where abamectin was applied at the maximum intended use rate and samples were harvested at the minimum pre - harvest interval (PHI) to obtain maximum residue va lues. 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 fro m the USDA’s Continuing Survey of Food Intake b y 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 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 1 00X. 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 margi n 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 acute reference dose (%aRfD). Acute (food onl y) exposure to the U.S. population res ulted in a MOE of 660 (15.1% of the acute RfD of 0.005 mg/kg
- bw/day). The most sensitive sub
population was children (1
- 2 y ears old) with a MOE of 367 (27.2% of the aRfD). Since the benchmark MOE for this assessment was 100 and since the EPA generally ha s 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 onl y) exposure to residues arising from the current and proposed uses for abamectin. Chronic Exposure. T he 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 safet y factor includes intra
- and interspecies variations (100X) and the additional FQPA safety factors of 3X for the steepness of the dose
- re sponse 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 b y dividing the NOAEL b y the exposure for each population subgroup. In a ddition, 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 2,344 (12.8% of the chronic RfD of 0.0004 mg/kg
- bw/day). The most sensitive sub
- population wa s children (1
- 2 years old) with a MOE of 677 (44.3% of the chronic RfD). Since the benchmark MOE for this assessment was 300 and since the6

EPA generall y has no concern for exposures below 100% of the RfD, S yn genta believes that there is a reasonable certa int y 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 likel y to be a human carcinogen”. Therefore, no cancer risk assessment was perform ed for abamectin. ii. Drinking W

ater. Another potential source of abamectin exposure to the general population is from residues in drinking water. Estimated Drinking Water Concentrations (EDWCs) are made b y reliance on simulation or modeling taking int o account data on the phy sical characteristics and environmental fate of abamectin. For this assessment the proposed uses of abamectin on bulb onion, beans (dry) and chives, as well as all existing uses were evaluated using the Tier 2 Model, PRZM/EXAMS Sh ell (PE5) for surface water and the Tier 1 model SCI
- GROW (v 2.3) for groundwater. For surface water the highest EDWCs resulted from the proposed 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 ground water the currently registered use for cucurbits provided higher EDWCs than the proposed uses. For the groundwater model, the cucurbits application parameters consisted of one seed treatment at 0.066 lb a.i./A (adjusted for 6% desorption from seed) followed by three aerial applications at 0.019 lb a.i./A with application intervals of 7 day s. This provided an EDWC (acute and chronic) of 0.00184 ppb. Since the surface water EDWCs exceed the ground water EDWC, the surface water values shou ld 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. Popu lation and population subgroups. Acute drinking water exposure to the U.S. population resulted in a MOE of 25,000 (0.4% of the aRfD of 0.005 mg/kg/day , Benchmark MOE = 100). The most sensitive sub
- population was children (3
- 5 y ears old) with a MOE of 2 0,833 (0.5% 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, S yn genta believes that there is a reasonable certaint y that n o 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 valu es for the U.S. Population and population subgroups. Chronic drinking water exposure to the U.S. Population resulted in a MOE of 15,000 (Benchmark MOE = 300; 2.0% of the cRfD of 0.0004 mg/kg/day). The most sensitive sub
- population was infants (<1 y ear ol d) with a MOE of 5,000 (6.0% of the cRfD of 0.0004 mg/kg/day , Benchmark MOE = 300). Since the Benchmark MOE for this assessment is 300 and since EPA generall y has no concern for exposures below7

100% of the cRfD, S yn genta believes that there is a reasonabl e certaint y 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 usi ng the endpoints and uncertaint y factors established b y the EPA in a recent assessment (March 11, 2009). Residential exposure and risk assessments were performed for granular abamectin baits used to treat lawns and for indoor abamectin
- based crack and cre vice products. 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 appl yi ng product by belly grinder application to turf resulted in a combined (dermal plus inhalation) short
- term margin of exposure (MOE) of 60,550. 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 48,192. Incidental ingestion of granules on treated lawns by children was compared to the acute dietary

NOAEL and had a MOE of 65,563. The highest predicted exposure for adu lts applying dust to crack and crevices resulted in a combined (dermal plus inhalation) short
- term MOE of 1,976,285. The post
- application dermal exposure to adults following use of a dust formulation had a MOE of 1,796,407. Post
- application dermal plus n on dietary oral exposure from abamectin use in dust products are acceptable (short
- term aggregate MOE = 288,462, intermediate
- term aggregate MOE = 483,871) for children re
entering indoor carpeted areas following crack and crevice treatments. Other formul ations for similar crack and crevice products are expected to have less migration from the treated area and thus, to result in lower risk from dermal, oral, and inhalation post application exposure. The MOEs for all residential scenarios for children do n ot exceed the EPA’s level of concern (Benchmark MOE of 300) and there is a reasonable certaint y that no harm will result from the residential uses of abamectin. 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 hav e 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, Sy ngenta 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 analy sis (food plus drinking water) showed that exposure from all registered and proposed abamectin crop uses result8

in a MOE of 643 (15.5% of the aRfD, Benchmark MOE = 100) for the general U.S. population. The chronic dietary exposure anal ys is (food plus drinking water) showed that exposure from all registered and proposed abamectin crop uses result in a MOE of 2,043 (14.7% 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 petitions, Sy

ngenta believes that there is a reasonable certaint y that no harm will result from aggregate exposure to residues arising from all current and proposed abamectin uses, including anticipated dietary expos ure from food, water, and all other ty pes of non
- occupational exposures . 2. Infants and children. The acute dietary exposure anal ys is (food plus drinking water) showed that exposure from all registered and proposed abamectin uses result in a MOE of 36 3 (27.5% of the aRfD) for children one to y ears old (the most sensitive population subgroup). The chronic dietary exposure anal ys is (food plus drinking water) showed that exposure from all registered and proposed abamectin uses result in a MOE of 637 (47. 1% of the cRfD) for children one to y ears 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, Sy ngenta 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 ty

pes 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. Internatio nal 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, German y, Greece, Hungary , Is rael, Italy , Japan, Korea (South), Malay sia, Mexico, Netherlands, New Zealand, Poland, Portugal, Russia, , Serbia and Montenegro, Slovak Republic, South Africa, Spain, Switzerland, Taiwan, and the United States.