Page 1 of 62 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICA L SA FETY AND POLLUTION PREVENTION Date: 7/18 /11 SUBJECT: Abamectin. Human Health Risk Assessment for Proposed Uses on the Bulb

Onion Subgroup 3 - 07A, Chives, and Dry Beans PC Code: 122804 Decision No.: 436528 Petition No.: 0E7738 Risk Assessment Type: Single Chemical/Aggregate T XR No.: None MRID No.: None DP Barcode: 380523 Registration Nos. : 100 - 898, 100 - 1351, 100 - 1154 Regulatory Action: Section 3 Registration Case No.: None CAS No.: 71751 - 41 - 2 40 CFR: 180.449 FROM: Nancy

Dodd, Chemist/Risk Assessor Nancy Tsaur, Chemist Whang Phang, Toxicologist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P) THROUGH: Paula Deschamp, Branch Chief

RAB3/HED (7509P) TO: Barbara Madden/Laura Nollen, RM#5

Registration Division (7505P) The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed use of abamectin, also known as avermectin B 1 [a mixture of avermectins containing ≥80% avermectin B 1a (5 - O - demeth yl avermectin A 1 ) and ≤20% avermectin B 1b (5 - O - demeth yl - 25 - de (1 - methylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )], and its delta - 8,9 - isomer on the bulb onion subgroup 3 - 07A, chives, and dry beans. HED evaluated the abamectin petition and determined that potential exposure could occur via the dietary (food and drinking water), residential, and occupational pathway s. HED determined that there is reasonable certainty that no harm will result to the general population and to infants and children from aggregate exposure resulting from the uses on the bulb onion subgroup 3 - 07A, chives, and dry

beans.Page 2 of 62

A summary

of the findings and an assessment of human health risk resulting from the registered and proposed uses for abamectin are provided i n this document. The HED team members contributing to this risk assessment include: Nancy Dodd (risk assessment/residue chemistry review/dietary

exposure assessment), Nancy Tsaur (occupational/residential exposure assessment), and Whang Phang (toxicology assessment). Greg Orrick of the Environmental Fate & Effects Division (EFED) provided the drinking water exposure assessment.Page 3 of 62 Table of Contents 1.0 Executive Summary ................................ ................................ .............................. 5 2.0 HED Recommendations ................................ ................................ ....................... 7 2.1 Data Deficiencies/Conditions of Registration ................................ ..................... 8 2.2 Tolerance Considerations ................................ ................................ ..................... 9 2.2.1 Enforcement Analytical Method ................................ ................................ ......... 9 2.2.2 International Harmonization ................................ ................................ ............... 9 2.2.3 Recommended Tolerances ................................ ................................ .................. 10 2.2. 4 Revisions to Petitioned - For Tolerances ................................ ............................ 10 2.3 Label Recommendations ................................ ................................ .................... 10 3.0 Introduction ................................ ................................ ................................ ......... 10 3.1 Chemical Identity ................................ ................................ ................................ 12 3.2 Physical/Chemical Characteristics ................................ ................................ .... 13 3.3 Pesticide Use Pattern ................................ ................................ .......................... 13 3.4 Anticipated Exposure Pathways ................................ ................................ ........ 15 3.5 Consideration of Environmental Justice ................................ .......................... 16 4.0 Hazard Characterization and Dose - Response Assessment ............................. 17 4.1 Adequacy of the Toxicity Database ................................ ................................ ... 17 4.2 Mode of Action ................................ ................................ ................................ .... 17 4.3 Toxicological Effects ................................ ................................ ........................... 18 4.4 FQ PA Considerations ................................ ................................ ......................... 18 4.4.1 Adequacy of the toxicity database for FQPA consideration ........................... 18 4.4.2 Evidence of Neurotoxicity ................................ ................................ .................. 19 4.4.3 Developmental Toxicity ................................ ................................ ...................... 19 4.4.4 Reproductive Toxicity ................................ ................................ ........................ 20 4.4. 5 Additional Information from Literature Sources ................................ ............ 22 4.4.6 Determination of Susceptibility ................................ ................................ ......... 22 4.5 FQ PA Safety Factor for Infants and Children ................................ ................. 23 4.6 Dose - Response Assessment ................................ ................................ ................ 25 4.7 Endocrine Disruption ................................ ................................ ......................... 30 5.0 Diet ary Exposure and Risk Assessment ................................ ............................ 31 5.1 Metabolite/Degradate Residue Profile ................................ .............................. 31 5.1.1 Summary of Plant and Animal Metabolism Studies ................................ ....... 31 5.1.2 Summary of Environmental Degradation ................................ ........................ 32 5.1.3 Comparison of Metabolic Pathways ................................ ................................ .. 33 5.1.4 Residues of Concern Summary and Rationale ................................ ................. 33 5.2 Food Residue Profile ................................ ................................ ........................... 34 5.3 Water Residue Profile ................................ ................................ ......................... 36 5.4 Dietary Risk Assessment ................................ ................................ .................... 37 5.4.1 Description of Residue Data Used in Dietary Assessment .............................. 37 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ ......... 38 5.4.3 Acute Dietary Risk Assessment ................................ ................................ ......... 39 5.4.4 Chronic Dietary Risk Assessment ................................ ................................ ..... 39 5.4.5 Cancer Dietary Risk Assessment ................................ ................................ ....... 39 5.4.6 Summary Table ................................ ................................ ................................ ... 40 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................ 41Page 4 of 62

6.1 Residential Handler Exposure ................................ ................................ ........... 41 6.2 Residential Post - Application Exposure ................................ ............................. 43 6.3 Spray Drift ................................ ................................ ................................ ........... 45 7.0 Aggregate Risk Assessments and Risk Characterization ................................ 45 7.1 Acute Aggregate Risk ................................ ................................ ......................... 45 7.2 Shor t - and Intermediate - Term Aggregate Risk ................................ ............... 46 7.3 Long - Term (Chronic) Aggregate Risk ................................ .............................. 47 7.4 Cancer Risk ................................ ................................ ................................ ......... 47 8.0 Cumulative Risk Characterization/Assessment ................................ ............... 47 9.0 Occupational Exposure/Risk Pathway ................................ .............................. 47 9.1 Short -/Intermediate - Term Handler Risk ................................ ......................... 48 9.2 Occupational Post -Application Exposures and Risks ................................ ..... 51 10.0 References ................................ ................................ ................................ ............ 53 Appendix A: Toxicology Assessment ................................ ................................ ....................... 54 Appendix B: Toxicology Literature References ................................ ................................ ..... 59 Appendix C: Physical/Chemical Properties ................................ ................................ ............ 60 Appendix D: Review of Human Research ................................ ................................ ............... 61 Appendix E: International Residue Limits ................................ ................................ ............. 62Page 5 of 62

1.0 Executive Summary Use Profile : Abamectin is a mixture of 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. Abamectin is a natural ferme ntation product of the soil bacterium Streptomyces avermitilis. Abamectin is an insecticide/miticide used to control mites, leafminers, and other insects in commercially important crops. Abamectin acts as an insecticide by interfering with the nervous sy stem of the insect, causing the insect to become paral yz ed. IR - 4 proposed registration of Agri - Mek® 0.15 EC Miticide/ In secticide (2% ai; EPA Reg . No. 100 - 898), Agri - Mek® SC Miticide/ In secticide (8% ai; EPA Reg No. 100 - 1351), and Epi - Mek® 0.15 EC Miticid e/ In secticide (2% ai; EPA Reg . No. 100 - 1154 ) on the bulb onion subgroup 3 - 07A , chives, and dry

beans . All formulations are currentl y registered for use on a variety of crops. H uman Health Risk Assessment: Toxicity/Hazard: Abamectin has high to moderate acute toxicity by the oral route (depending on the vehicle), high acute toxicity by the inhalation route, and low acute toxicity by the dermal route. It is slightly

irritating to the skin, but is not an ocular irritant or a dermal sensitizer. The mai n target organ is the nervous s ys tem, and the reduced body weight effect is one of the most frequent findings. Neurotoxicity and developmental effects were detected in multiple studies and species of test animals. The dose/response curve is very steep in several studies, with severe effects (including death and morbid sacrifice) seen at dose levels as low as 0.4 mg/kg/day and 0.1 mg/kg/day in rats and mice, respectivel y , following repeated/chronic exposures . (For details, refer to Section 4.5.) In creased susceptibility (qualitative and/or quantitative) was seen in prenatal developmental toxicity studies in mice and rabbits, and an increase in quantitative and qualitative susceptibility

was seen in the rat reproductive toxicity study . Review of a cceptable oncogenicity and mutagenicity studies provides no indication that abamectin is carcinogenic or mutagenic. The RAB3 Risk Assessment Team has evaluated the entire toxicity database of abamectin and determined that an additional 3x FQPA safety factor is needed to address residual concerns as to all risk assessments other than acute dietary . For all risk assessments involving repeat exposures, the selected toxicity

endpoint is based on the decrease in pup body weight seen in the dev elopmental neurotoxicity study (2007) and three reproduction studies in the rat. With respect to acute dietary exposure , the endpoint selected for risk assessment is based on mydriasis observed in dogs. The additional 3x factor applied to chronic and oth er exposure scenarios is not applicable to acute exposure because steepness of the dose /response curve and severity of effects were not seen in the studies where m ydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exp osure scenarios is not a single dose effect.Page 6 of 62

T he immunotoxicity

study (870.7800) is required to fulfill current 40 CFR Part 158 data requirements . However, the RAB3 toxicity team examined the entire database of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . Dietary Exposure (Food/W ater) : T he residue chemistry and environmental fate data are adequate to assess human exposure. Acute and chronic aggregate dietary (food and drinking w ater) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM - FCIDTM, Version 2.03. Although tolerance - level residues and 100% crop treated were used for the proposed crops and okra , the acute and chronic dietary exposure assessments were refined assessments using anticipated or average residues derived from field trial data for most c rops . Default processing factors and percent crop treated (%CT) were used as available. Estimated drinking water concentrations (EDWCs) were provided b y the Environmental Fate and Effects Division (EFED) . T he maximum (acute) concentration of abamectin and its major soil degradate (a mixture of an 8 - alpha - hydrox y and a ring opened aldeh yde derivative) in surface water is not likely to exceed 2.3 ppb. The mean (chronic) estimated surface water concentration is 1.3 ppb. The acute dietary

exposure estimates for food and drinking water are below HED’s level of concern (<100% aPAD) at the 99.9 th percentile of exposure. Abamectin dietary exposure at the 99.9 th percentile for food and drinking water is 16% of the aPAD for the general U.S. population and 30 % of the aPAD for all infants (<1 ye ar old) , the most highly exposed population subgroup. The chronic dietary

exposure estimate s for food and drinking water are below HED’s level of concern (<100% cPAD) for the general U.S. population and all population subgroups. Abamectin dietary

exposure for food and drinking water is 18% of the cPAD for the general U.S. population and 50% of the cPAD for children 1 - 2 years old, the most highly exposed population subgroup. Residential Exposure : Abamectin is currentl y registered for a number of residential insecticidal uses. Because the FQPA requires consideration of aggregate exposure to all likely non occupational uses, this assessment includes contact with abamectin from residential crack and crevice and lawn treatments as the most common and worst - case contributors to such exposures. The Margins of Exposure ( MOEs ) for applicable residential scenarios were calculated using exposure monitoring data and the HED Standard Operating Procedures for Residential Exposure Assessments (Draft, December 18, 1997), along with interim changes presented in HED Science Advisory Council for Exposure SOP No.11 (February 22, 2001). In addition, for the indoor crack and crevice treatment, measured airborne and surface residue data were available to perform an assessment of post - application inhalation, dermal , and incidental oral risks. Combined residential exposures/risks were estimated for adults and for children. Children’s exposure from incidental ingestion of granules on treated lawns was compared to the acute dietary NOAE L of 0.5 mg/kg/day . The exposure/risk from this latter scenario was not combined with other scenarios, nor was it included in the aggregate assessment, because it is considered to be a one - t ime, episodic event, rather than occurring for several day s (or several months). The MOEs for all residential scenarios are greater than the levels of concern ( LOC s) of 300 , and therefore, are not of concern.Page 7 of 62

Aggregate Risk: For the proposed uses, human health aggregate risk assessments have been conducted for acute aggregate exposure (food + drinking water), short - /intermediate - term aggregate exposure (food + residential exposure + drinking water), and chronic aggregate exposure (food + drinking water) scenarios. For short - /intermediate - term aggregate exposure , the residential LOC s are 300 and the MOEs are greater than 300 , and thus are not of risk concern . A cancer aggregate risk assessment was not performed because abamectin is classified as “not lik ely

to be carcinogenic to humans .” All potential exposure pathway s were assessed in the aggregate risk assessment . None of the aggregate exposure and risk estimates exceed HED's level of concern. Occupational Exposure/Risk: Based on the proposed uses , there is a potential for short - and intermediate - term occupational exposure to abamectin during handling activities (e.g. mixing, loading, application). No chemical - specific exposure data were submitted in support of this Section 3 registration. To ass ess handler exposures for regulatory actions when chemical specific monitoring data are not available, HED relies on the most scientifically- reliable surrogate data currentl y available from various sources. The abamectin labels contain specific requirements for personal protective equipment (PPE) for applicators and other handlers. All handler activities result in MOE s >300 with baseline clothing or baseline plus gloves, and , therefore, do not exceed HED’s level of concern since the occupational LOCs are 300. There is a potential for short - and intermediate - term occupational exposure during post application activities. Based on a post - application assessment of common agricultural practices, the proposed 12 - ho ur re - entry interval ( REI ) on all the label s is acceptable . A ll MOEs are >300 on the day

of application, and therefore, are not of concern to HED since the LOC is 300. Environmental Justice Considerations: Potential areas of environmental justice conc erns, to the extent possible, were considered in this human health risk assessment. Dietary and non dietary exposures were considered. Review of Human Research : As discussed in Appendix D , this risk assessment relies on the most scientifically- reliable surrogate data currently available from various sources such as the Pesticide Handler Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF). Some of this data, such as the i ndustry

task force data, is compensatory , subject to the data protection provisions of FIFRA. HED policy

on use of surrogate data is described in more detail on the Agency ’s website (htpp://www.epa.gov/pesticides/science/handler- exposure - data.html). Scen ario - specific surrogate exposure data, including their sourc e s, are presented in the “ Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler - exposure - table.pdf ). 2.0 HED Recommendations Provided revised Sections B ( OPPTS 860.1200 ) and F ( OPPTS 860.1550) are submitted, HED can recommend for a conditional registration of abamectin for use on the bulb onion subgroup 3 - 07A, chives, and dry

beans except cowpea and for permanent tolerances for the proposed uses onPage 8 of 62

the bulb onion subgroup 3 - 07A, chive, and dry bean except cowpea. Additional data are needed as a condition of registration as outline d in S ection 2.1 below. The specific tolerance recommendations are discussed in S ection 2.2, and label modifications are discussed in S ection 2.3 . 2.1 Data Deficiencies/Conditions of Registration The following must be provided prior to a tolerance being established or registration allowed: 860.1200 Directions for Use  Label revisions are required for the EC labels to remove the statement that adjuvants may be used on chives and dry bean s since the submitted crop field trials on chives and dry beans do not reflect the use of an adjuvant.  The labels must be revised to specify a 7 - day PHI for chives and dry

beans since most of the chive and dry

bean data reflect a 7 - day PHI.  The amount (v/v) of the non - ionic surfactant and/or horticultural oil is required to be specified in the Directions for Use for each crop on the SC label and is required to be within the range of the amount (v/v) used in the available SC field trials (D364734, N. Dodd, 1/21/10) .  Cowpea must be removed from the label under dry bean since residue data for cowpea forage and hay

must be submitted to support use on cowpea. 860.1550 Proposed Tolerances  The petitioner should submit a revised Section F reflecting the recommended tolerance levels and correct commodity definitions as presented in Table 2.2.4 . The proposed tolerance level for chives, dried leaves must be lowered from 0.07 ppm to 0.02 ppm. C owpea must be excluded from the dry bean seed tolerance since residue data for cowpea forage and hay

must be submitted before cowpea can be included in the dry bean seed tolerance. The following data are required as condition s of registration: TOXICOLOGY 870.7800 Immunotoxicity

● Under the current data requirement guidelines, the immunotoxicity study is re quired to fulfill current 40 CFR Part 158 data requirements . The registrant has co mmitted to provide this data in 2012.Page 9 of 62

RESIDUE CHEMISTRY 860.1500 Crop Field Trials  The petitioner needs to submit the storage temperature of the dry bean samples from the crop field trial. The following d ata must be submitted for future uses on cowpea: RESIDUE CHEMISTRY 860.1500 Crop Field Trials  Residue data for cowpea forage and hay must be submitted before cowpea can be included in the dry bean seed tolerance. 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method Adequate enforcement methods for abamectin in plant and livestock commodities are available in the Pesticide Analy

tical Manual, Volume II ( PAM II) . The methods have been validated for citrus and processed fractions (Method I), ginned cottonseed (Method IA ), and bovine tissues and milk (Method II ). These methods determine residues in plant and livestock commodities at limits of quantitation (LOQs) of 0.02 ppm for meat and meat b yproducts and ≤0.01 ppm for other plant/livestock commodities. The limit of de tection (LOD) of the methods for plant and livestock commodities is 0.001 ppm for each anal yte, equivalent to 0.002 ppm for two anal y te peaks (i.e., avermectin B 1a and its delta - 8,9 - isomer in one peak and avermectin B 1b and its delta 8,9 - isomer in the othe r peak). The plant methods used for data collection, using high performance liquid chromatography (HPL C) with fluorescence detection, adequatel y m easure the residues of concern. The methods have been validated at 0.002 for each analy te (avermectin B 1a , avermectin B 1b , and 8,9 - Z avermectin B 1a). The Pestrak database indicates that abamectin and its metabolites are not recovered or not likely to be recovered b y FDA multiresidue methods. Therefore, the multiresidue methods can not be used to determine re sidues for dietary exposure assessment and can not be used as the primary enforcement method. 2.2.2 International Harmonization There are currently

no maximum residue limits (MRL s) established b y C odex, Canada, or Mexico for abamectin on the bulb onion s ubgroup 3 - 07A, chive, or dry beans. Therefore, there are no issues regarding international harmonization raised b y this action. An International Residue L imit Status sheet is attached ( Appendix E ).Page 10 of 62

2.2.3 Recommended Tolerances HED recommends for the following tolerances and residue definition: “Tolerances are established for residues of abamectin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be deter mined by measuring only

avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demethyl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demeth yl - 25 - de(1 - methylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer.”

Onion, bulb, subgroup 3 - 07A ................................ .. 0.01 ppm Chive, fresh leaves ................................ ................... 0.01 ppm Chive, dried leaves ................................ ................... 0.02 ppm Bean, dry , seed , except cowpea ............................... 0.01 ppm 2.2.4 Revisions to Petitioned - For Tolerances Table 2.2.4 compares proposed and recommended tolerance levels and tolerance expressions. The recommended tolerance levels are based on the submitted magnitude of the residue data and the chive processing study . EPA is recommending that the proposed tolerance for chive, dried leaves be reduced from 0.07 ppm to 0.02 ppm based on the results of the chive processing study . T he Agency ’s tolerance spreadsheet from the Guidance for Setting Pesticide Tolerances Based on Field Trial Data was not used because all of the treated samples from the field trials bore residues below the LOQ . The correct commodity definitions were obtained from the “Food and Feed Commodity

Vocabulary”, which can be found at http://www.epa.gov/pesticides/foodfeed. Table 2.2.4 . Tolerance Summary for Abam ectin Comm odity Established/Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Onion, bulb, subgroup 3 - 07A 0.01* 0.01 Chive, fresh leaves 0.01 0.01 Chive, dried leaves 0.07 0.02 Bean, dry, seed 0.01 0.01 Bean, dry, seed, except cowpea * An established time - limited tolerance of 0.05 ppm on onion, bulb will expire on 12/31/12. 2.3 Label Recommendations Refer to Section 2.1 above for label recommendations from residue chemistry reviews. 3.0 In troduction Abamectin is a mixture of avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demeth ylavermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer. Avermectins are macrocyclic lactones produced as natural fermentationPage 11 of 62

products of the soil bacterium Streptomyces avermitilis. Abamectin is an insecticide/miticide used to control mites, leafminers, and other ins ects in commerciall y important crops. Abamectin acts as an insecticide b y i nterfering with the nervous sy stem of the insect, causing the insect to become paral yz ed. Available mechanistic data indicate a neurotoxic mechanism of action, related to interference with GABA - mediated neurotransmission. Tolerances have been established in 40 CFR §180.449(a) 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 ave rmectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demeth yl - 25 - de(1 - methylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer in/on various plant and livestock commodities at levels ranging from 0.005 to 0.20 ppm . T ime limited t olerance s are established in 40 CFR §180.449(b) for residues of avermectin B 1 and its delta - 8 , 9 - isomer in/on onion, bulb at 0.005 ppm (to expire on 12/31/12 ) and in/on b ean, lima, seed at 0.005 ppm (set to expire on 12/31/13). The registered formulation types include emulsifiable concentrate, granular, bait, gel, and dust. The registered uses include food, food handling establishments, and residential uses. Clinch® Ant Bait is registered for control of fire ants in citrus, almonds, walnuts, potatoes, around barns and equipment, and around chicken houses. There are registered granular products for the application of abamectin to lawns to control fire ants (e.g., Affirm Fire Ant Insecticide Bait/EPA Reg. No. 100 - 893 and PT 370 Ascend Fire Ant Stopper Bait/EPA Reg. No. 499 - 370). New uses involving three formulations have been proposed for registration: Agri - Mek® 0.15 EC, Agri - Mek® SC, and Epi - Mek® 0.15 EC. Agri - Mek® 0.15 EC and and Epi - Mek® 0.15 EC are emulsifiable concentrate formulations containing 0. 15 lb ai/gal. Agri - Mek® SC is a suspension concentrate containing 0.7 lb ai/gal. The products are to be applied as multiple foliar spray s using ground and aerial (except chive) methods. The maximum seasonal rate is 0.056 lb ai/A for bulb onion, chives, and dry beans. The pre harvest intervals (PHI s ) are 30 day s for bulb onion and 6 day s for chives and dry beans.3.1 Chemical Identity

Table 3.1. Test Compound Nom enclature Chemical Structure

Em pirical Formula C 48 H Common Names abamectin, avermectin B Com pany experimental name MK - 0936 IUPAC name mixture of (10 sec - butyl] trioxatetracyclo[15.6.1.1 ' - dihydro arabino (10E ,14 Page 12 of 62 Table 3.1. Test Compound Nom enclature

H 72 O 14 (B 1a); C 47 H 70 O 14 (B 1b ) abamectin, avermectin B 1 0936 mixture of (10E ,14E ,16E) - (1 R ,4 S,5 ' S,6 S,6 'R ,8 R ,12 S,13 S,20R butyl] - 21,24 - dihydroxy - 5 ',11,13,22 - tetramethyl - 2 - oxo - (3,7,19 trioxatetracyclo[15.6.1.1 4,8 .0 20,24 ]pentacosa - 10,14,16,22 - tetraene) dihydro - 2 'H

- py ran) - 12 - yl 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O arabino - hexopyranosyl) - 3 - O - methyl - α - L - arabino - hexopyranoside and ,14E ,16E) - (1 R ,4 S,5 ' S,6 S,6 'R ,8 R ,12 S,13 S,20R ,21 R ,24 S ) - 21,22 R ,21 R ,24 S

) - 6 ' - [( S ) - (3,7,19 - tetraene) - 6 - spiro - 2 ' - (5 ',6 O - methyl - α - L hexopyranoside and

21,22 - dihydroxy - 6 ' -Page 13 of 62

Table 3.1. Test Compound Nom enclature isopropyl - 5 ',11,13,22 - tetramethyl - 2 - oxo - (3,7,19 - trioxatetracyclo[15.6.1.1 4,8 .0 20,24 ]pentacosa - 10,14,16,22 - tetraene) - 6 - spiro - 2 ' - (5 ',6 ' - dihydro - 2 'H

- py ran) - 12 - yl 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O - methyl - α - L arabino - hexopyranosyl) - 3 - O - methyl - α - L - arabino - hexopyranoside CAS Name Avermectin B 1 CAS Registry Number Avermectin B 1 - 71751 - 41 - 2; Avermectin B 1a - 65195 - 55 - 3; Avermectin B 1b - 65195 - 56 - 4 End - use product/EP Agri - Mek® 0.15 EC, EPA Reg. No. 100 - 898 (contains 0.15 lb ai per gallon); Clinch® Ant Bait, EPA Reg. No. 100 - 894 (contains 0.011% ai); Y - TEX BOVAMECTM Cattle Ear Tags, EPA Reg. No. 39039 - RT (contains 8.0% abamectin and 20.0% piperonyl butoxide technical, w/w) Chemical Class Insecticide/Miticide Known Impurities of Concern None 3.2 Physical/Chemical Characteristics Avermectin is a cry stalline powder with very low vapor pressure. It has very low water solubility but is soluble in organic solvents. Residues do not readil y leach to groundwater due to their affinity for soil particles. Abamectin is stable to abiotic hydrol ys is. Acceptable data are not available to determine stability via other routes. Abamectin is stable to abiotic hydrol ys is; d etermination of stability to photolysis and biodegradation is pending submission of acceptable data. R efer to Appendix C for the table of ph ys ical/chemical properties. 3.3 Pesticide Use Pattern Table 3 . 3. Summ ary of Directions for Use of Abam ectin . Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] Applic .

Rate (lb ai/A) Max. No. Applic. per Season Max. Seasonal Applic. Rate (lb ai/A) PHI 1

(days) Use Directions and Limitations 2

Onion, bulb (Crop Subgroup 3 - 07A) (onion, bulb including daylily, bulb; fritillaria, bulb; garlic, bulb; garlic, great - headed, bulb; garlic, serpent, bulb; lily, bulb; onion, Chinese, bulb; onion, pearl; onion, potato, bulb; shallot, bulb; cultivars, varieties, and/or hybrids of these) Foliar spray (ground or aerial) 4,5 Agri - Mek® 0.15

EC Insecticide/Miticide [ EPA Reg. No. 100 - 8 98] Agri - Mek® SC Insecticide/ Miticide [ EPA Reg . No. 100 - 1351] Epi - Me k® 0.15 EC Insecticide/Miticide 0.019 Not stated 0.056 30 Do not apply in less than 20 gallons of water/A with ground application equipme nt. Do not apply in l ess than 5 gallons of water/A with aircraft. Include a non - ionic surfactant commercially used on dry bulb onions . RTI 3 = 7 days. Adjuvant Requirement SC formulation: To avoid illegal crop residues, the SC formulations must always bePage 14 of 62

Table 3 . 3. Summ ary of Directions for Use of Abam ectin . Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] Applic .

Rate (lb ai/A) Max. No. Applic. per Season Max. Seasonal Applic. Rate (lb ai/A) PHI 1

(days) Use Directions and Limitations 2

[ EPA Reg . No. 100 - 1154 ] mixed wi th a non - ionic activator type wetting, spreading and/or penetrating adjuvant. Do not use binder sticker type adjuvants . ( See Use Information and Use Restrictions . ) EC formulation: Add a non - ionic activator ty pe wetting, spreading and/or penetrating adjuvant approved for use on bulb onion. Do not use binder sticker type adjuvants. Chives Foliar spray (ground) 4 Agri - Mek® 0.15

EC Insecticide/Miticide [ EPA Reg. No. 100 - 898] Agri - Mek® SC Insecticide/ Miticide [ EPA Reg . No. 100 - 1351] Epi - Me k® 0.15 EC Insecticide/Miticide [ EPA Reg . No. 100 - 1154 ] 0.019 Not stated 0.056 6 Apply as a foliar spray in a minimum of 20 gallons of water per acre. Adjuvant Requirement SC formulation: To avoid illegal crop residues, the SC formulations must always be mixed wi th a non - ionic activator type wetting, spreading and/or penetrating adjuvant. Do not use binder sticker type adjuvants . ( See Use Information and Use Restrictions . ) 6 RTI = 7 days. EC formulation: When necessary to improve the wetting of foliage and t o smooth out spray deposits, a nonionic surfactant is recommended . Beans, dry [ Cicer arietinum (chickpea, garbanzo bean); Lupinus spp. (including sweet lupine, white sweet lupine, white lupine, and grain lupine); Phaseolus spp. (including kidney bean, lima bean, mung bean, navy bean, pint o bean, snap bean and waxbean); Vicia faba (broad bean, fava bean); Vigna spp. (including adzuki bean, asparagus bean, blackeyed pea, catjang, Chinese longbean, cow pea, crowder pea, moth be an, mung bean, rice bean, southern pea, urd bean, and yardlong bean) ] Foliar spray (ground or aerial) 4,5 Agri - Mek® 0.15

EC Insecticide/Miticide [ EPA Reg. No. 100 - 898] Agri - Mek® SC Insecticide/ Miticide [ EPA Reg . No. 100 - 1351] Epi - Me k ® 0.15 EC Insecticide/Miticide 0.019 Not stated 0.056 6 Do not apply in less than 1 0 gallons of water/A with ground application equipme nt. Do not apply in less than 5 gallons of water/A with aircraft. Adjuvant Requirement SC formulation: To avoid illegal crop residues, the SC formulations must always be mixed wi th a non - ionic activator type wetting, spreading and/or penetrating adjuvant. Do not use binder sticker type adjuvants . ( See Use Information and Use Restrictions . ) 6Page 15 of 62

Table 3 . 3. Summ ary of Directions for Use of Abam ectin . Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] Applic .

Rate (lb ai/A) Max. No. Applic. per Season Max. Seasonal Applic. Rate (lb ai/A) PHI 1

(days) Use Directions and Limitations 2

[ EPA Reg . No. 100 - 1154 ] RTI = 6 days. EC formulation: A non - ionic activator type wetting, spreading and/or penetrating adjuvant approved for use on dry bean s and peas can be used to help improve control. Do not use binder sticker type adjuvants. 1 PHI = preharvest interval . 2 Onion, bulb - Make 2 consecutive applications then rotate to a chemistry ( pesticide ) with a different mode of action. Make at least 2 applications of a chemistry (pesticide ) with a different mode of action before making additional applications. Do not make more than 2 sequential applications o f any other foliarly applied abamectin containing product. Chive s - Do not m ake more than 2 applications o f any foliarly applied abamectin containing product per single cutting (harvest). Dry beans - Do not make mo re than 2 sequential applications o f any foliarly applied abamectin containing product. 3 RTI =retreatment interval. 4 Do not apply through any type of irrigation system. 5 Aerial applications are not allowed in NY. 6 The use of an adjuvant i s required on the Agri - Mek® SC Insecticide/Miticide label, but is not specified in the Section B use directions for chives and dry beans. Conclusions : The submitted labels for Agri - Mek® 0.15 EC Insecticide/Miticide (EPA Registration No. 100 - 898), Agri - Mek® SC Insecticide/ Miticide (EPA Registration No. 100 - 1351), and Epi - Mek® 0.15 EC Insecticide/Miticide (EPA Registration No. 100 - 1154) are adequate to allow evaluation of the residue data relative to the proposed uses. The ChemSAC determined on 5/18/11 that the available bridging studies for the SC formulation on leafy vegetables, fruiting vegetables, cucurbit vegetables, citrus fruits, and pome fruits (DP#364734, N. Dodd, 1/21/10) can be translated to support use of the SC formulation on the bu lb onion subgroup 3 - 07A, chive s , and dry bean s provided the use directions for the SC formulation alway s require use of a non - ionic surfactant or a horticultural oil in the spray mix and the preharvest intervals are ≥ 7 day s. Refer to Section 2.3 for r ecommended modifications to the proposed label . 3.4 Anticipated Exposure Pathways Humans may

be exposed to abamectin in food and drinking water since abamectin may be applied directl y to growing crops. Although significant residues are not expected to occur in groundwater because of the low water solubility of residues and their affinity to soil particles, residues may

occur in surface water due to runoff, erosion, and spray drift. The proposed uses on the bulb onion subgroup 3 - 07A, chive, and dry bean do not include residential uses; however, there are registered residential uses of abamectin, so there is the possibility of exposure inPage 16 of 62

residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling and a

ppl ying abamectin. There is a potential for post - application exposure for workers re - entering treated fields. 3.5 Consideration of Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http ://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures bas ed on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Although not applicable to a specific environmental justice demographic, this risk assessment gives consideration to genetic poly morphism and the potential for susceptibilities in human populations. CF - 1 mice were the most sensitive strain of test animals due to the lack of P gl ycoprotein. In mammals, P - gl yc oprotein acts as a protective barrier to keep xenobiotics out of the body by excreting them into bile, urine, and intestinal lumen and prevents accumulation of these compounds in the brain and gonads, as well as the fetus. Because abamectin is a substrate for p - gl ycoprotein, this protective mechanism may be less effective , as demonstrated in test animals where genetic poly morphisms compromise P - gl yco protein expression. An example is the CF - 1 mouse, some of which are defici ent in P - gl ycoprotein and highly sensitive to the neurotoxicity

of abamectin. A small population of humans is also found to be deficient in p gl ycoprotein due to polymorphism in the gene encoding P - gl ycoprotein. It was determined that the 10x factor for intraspecies variability adequately

protects the most sensitive population. An additional factor of 3x for the steepness of the dose - response curve and the severity of effects is applied to all risk assessments other than acute dietary .Page 17 of 62

4.0 Hazar d Characterization and Dose - Response Assessment 4.1 Adequacy of the Toxicity Database The toxicology

database for abamectin is sufficient to characterize the hazard to humans, to conduct FQPA assessment, and to select toxicity endpoints for risk assessment. Data quality is acceptable and meets the criteria set in the OPPTS guidelines and 40 CFR §158.500. However, under the current data requirement guidelines, immunotoxicity data (OPPTS 870.7800 ) shall be required as a condition of registration. An immunotoxicity study is specifically

designed to detect any deficit in the ability of the immune sy stem to respond to a challenge (chemical). Refer to Appendix B for toxicology citation s. To address the issue of the immunotoxicity data gap and the associated database uncertainty factor, the RAB3 toxicity team examined the entire database of abamectin and determined that an additional uncertainty

factor is not needed to account for potential immunotoxicity . For abamectin, a complete battery of subchronic, chronic, carcinogenicity, developmental and reproductive studies as well as acute and subchronic neurotoxicity screen ing studies are available for consideration . In addition, two developmental neurotoxicity studies have been conducted on abamectin. At the dose levels tested, abamectin did not induce effects which can be associated with immunotoxicity, and abamectin does not belong to a class of chemicals that would be expected to be immuno toxic. Therefore, based on the above considerations, HED does not believe that conducting a special series 870.7800 immunotoxicity study will result in a NOAEL that is less than any

which is used for point of departure for this risk assessment. An additi onal uncertainty factor (UF DB ) for database uncertainties does not need to be applied at this time . 4.2 Mode of Action In nematodes, abamectin blocks the signal transmission from the central command interneurons to the peripheral motoneurons leading to paral ys is and death. In the mammalian toxicity studies submitted by

the registrant, paral ys is is also a common finding prior to moribund sacrifice. On the cellular level, abamectin acts by binding to g amma - aminob uty ric acid (GABA) gated chloride channels at two different sites, a high affinity binding site that activates the channel and a low affinity site that blocks the channel ( Pong et al., 1982; Huang and Casida , 1997 ; and Dawson et al., 2000). GABA play s a critical role in nervous sy stem development through both non - sy naptic (Represa and Ben - Ari, 2005) and s yn aptic (Nguyen et al., 2001) mechanisms. Consequently , abamectin may have the potential to influence GABA - mediated events important to brain development. Within the mammalian brain , abamectin binding is widespread but particularl y abundant in the cerebellum (Wang and Pong , 1982). Abamectin also act s on GABA receptors in the enteric nervous s ys tem and induce s longitudinal rh ythmic contractions in the is olated ileum (Kerr and Ong , 1986). Abamectin may therefore influence GABA - mediated regulation of metabolism, food intake and body weight at multiple sites (Meister , 2007 ). This is consistent with the results seen in some submitted studies because the body weight effect is a frequent finding and is generall y seen at dose levels lower than those producing a neurological effect in the test animals. Integral to its mechanism of action in mammals, abamectin is also a substrate for P - gl ycoproteinPage 18 of 62

(P - gp). P - gl yc oprotein is a member of the ATP binding cassette transporter proteins , which reside in the plasma membrane and function as a transmembrane efflux pump, moving xenobiotics from intracellular to the extracellular domain against a steep concentration gradient with ATP - hydrol ys is providing the energy for active transport (Marzolini et al., 2004). P - gp is found in the canallicular surface of hepatocy tes, the apical surface of proximal tubular cells in the kidney s, brush border surface of enterocy tes, luminal surface of blood capillaries of the brain (blood brain barrier), placenta, ovaries, and the testes. As an efflux transporter, P - gp acts as a protective barrier to keep xenobiotics out of the body by excreting them into bile, urine, and intestinal lumen an d prevents accumulation of these compounds in the brain and gonads, as well as the fetus. Therefore, some test animals, in which genetic pol ym orphisms compromise P - gp expression, are particularly susceptible to abamectin - induced neurotoxicity (Lankas et al ., 1997). An example is the CF - 1 m ouse. S ome CF - 1 mice are deficient in P - gp and are found to be highl y sensitive to the neurotoxicity of abamectin . A small population of humans is also found to be deficient of p - gl yc oprotein due to poly morphism in the gene encoding P - gp (Dubin Johnson Sy

ndrome) (S. Habashi, 2006). In addition, collie dogs have been known to be deficient in P - gp (R. Kerb, 2005). 4.3 Toxicological Effects Abamectin has high to moderate acute toxicity by the oral route (depending on the vehicle), high acute toxicity

by the inhalation route, and low acute toxicity by the dermal route. It is slightl y irritating to the skin, but is not an ocular irritant or a dermal sensitizer. The acute toxicity of abamectin technical is summarized in Table A.1 of Appendix A. In general, the results of available toxicity studies with single or repeated dosing reflect the mode of action of abamectin discussed in Section 3.2, and they indicate that the main targe t organ is the nervous s ys tem, and that decreased body weight is also one of the most frequent findings . Neurotoxicity

and developmental effects are detected in multiple studies and species of test animals. The dose/response curve is very steep in several studies, with severe effects (including death and morbid sacrifice) seen at dose levels as low as 0.4 mg/kg/day and 0.1 mg/kg/day

in rats and mice, respectively, following repeated exposures. Increased susceptibility (qualitative and/or quantitative) wa s seen in prenatal developmental toxicity studies in mice and rabbits, and an increase in quantitative and qualitative susceptibility was also seen in the rat reproductive toxicity studies. Review of acceptable oncogenicity and mutagenicity studies provid e no indication that abamectin is carcinogenic or mutagenic. The studies, which demonstrated neurotoxicity

as well as other effects, are summarized in Section 3.4.2 and in Tables A.2 & A.3 of the Appendix A. 4 .4 FQ PA Considerations 4.4.1 Adequacy of the toxicity database for FQPA considerationPage 19 of 62

As me ntioned before, the toxicology database is sufficient to conduct an FQPA assessment. Some of the to xicity

studies conducted in the 1980’s do not fully meet the current guideline requirements. However, when considered in conjunction with acceptable guideline studies, they provide adequate information for determining the toxicity of abamectin in adult, f

etal, and young animals. 4. 4.2 Evidence of Neurotoxicity Signs of neurotoxicity

ranging from decrease in foot splay reflex, mydriasis (i.e., excessive dilation of the pupil), curvature of the spine, decreased fo re - and hind - limb grip strength, tip - toe gate, tremors, ataxia, or spastic movements of the limbs are reported in various studies with different duration of abamectin exposure. These neurotoxicity signs are seen singularly or in combination in rats, mice (CD - 1 and CF - 1 mice), or dogs. In dogs, mydriasis was the most common finding at doses as low as 0.5 mg/kg/day after one week of treatment. In CF - 1 mice, tremor was seen prior to death at doses of 0.1 mg/kg/day and above following repeated exposure. In comparison to dogs and CF - 1 mice, neurotoxic signs were seen at higher dose levels (1.0 mg/kg/day

or above) in rats. The studies which reported the neurotoxicity findings are summarized in Appendix B of D362615 (N. Dodd, 3/11/09) . 4.4.3 Developmental Toxicity There are several developmental toxicity studies available indicating that there is a qualitative and quantitative increase in sensitivity and susceptibility

in the developing mouse and rabbit fetuses to the effects of abamectin (MRIDs 44179901 and 00130819) (Tables A.2 and A.3 of Appendix A). Three representative prenatal developmental toxicity studies are summarized below. Prenatal developmental toxicity study in rats (MRID 00130819; 1982): Pregnant Crl: CD rats were dosed with avermectin B 1 (95% pure, sesame oil as vehicle) at dose levels of 0.4, 0.8, and 1.6 mg/kg/day

on gestation day

6 through 19. No treatment related maternal or developmental toxicity was seen in the study . Both maternal and developm ental toxicity NOAELs were considered to be at the highest - dose tested (1.6 mg/kg/day). A range finding study was performed; the results indicated that at 2.0 mg/kg/day, one dam had tremors and lost weight and was sacrificed after 12 doses. The results o f the dose - range - finding study indicated that the highest dose employed in the final study was approaching the level which would lead to severe toxicity . Prenatal developmental toxicity in rabbits (MRID 00130819; 1982): Pregnant New Zealand White rabbits were administered abamectin (94% pure) at dose levels of 0.5, 1.0, and 2.0 mg/kg/day

on gestation day s 6 through 16. At 2.0 mg/kg/day , decreases in body weights and food/water consumptions were seen. Developmental toxicity was reported in fetuses of the 2 mg/kg/day

group; the findings were cleft palate, clubbed foot, increased pup deaths at birth, and delayed ossification of sternebrae, metacarpals, and phalanges. No effects were seen in dose levels of 1.0 and 0.5 mg/kg/day . The maternal LOAEL was 2.0 m g/kg/day ; the maternal NOAEL was 1.0 mg/kg/day . The developmental toxicity L OAEL was 2.0 mg/kg/day and the NOAEL was 1.0 mg/kg/day .Page 20 of 62

Prenatal developmental toxicity study in CD - 1 mice (MRID 44179901 ; 1996 ): Pregnant CD - 1 mice were administered abamectin at doses of 0, 0.75, 1.5, and 3.0 mg/kg/day from gestation day s 6 through 15. At 3.0 gm/kg/day , maternal toxicity was reported as limb splay . This dose was considered to be the maternal LOAEL, and the NOAEL was 1.5 mg/kg/day . Hindlimb extension was found in 2 fetuses from 2 litters each for 0.75, 1.5, & 3.0 mg/kg/day groups. Therefore, the developmental LOAEL was 0.75 mg/kg/day , and a NOAEL could not be established. In addition, the data indicate that the most sensitive effect of abamectin on the fetuses is the increase in the incidence of cleft palates in mice and rabbits in the presence of no or minimal maternal toxicity . This effect is particularl y apparent in CF - 1 mice (Table A.3, Appendix A). In CF - 1 mice, cleft palate was seen at doses as low as 0.1 mg/kg/day in developmental toxicity studies; but no effect was seen at 0.06 mg/kg/day or below (Table A.3 of Appendix A). In CD - 1 mice and rabbits, cleft palate wa s found at slightly higher dose levels, 0.75 mg/kg/day and 2.0 mg/kg/day , respectivel y. In general, most of the maternal effects were found at 2 mg/kg/day or above in CD - 1 mice or rabbits. It should be noted that the CF - 1 mouse developmental toxicity studies were thoroughly

reviewed by the Developmental and Reproductive Toxicity Peer Review group in 1993 (Memorandum: R. Gardner to G. LaRocca, July 8, 1993). Subsequently , additional data were submitted by the registrant demonstrating that the sensitivity of some CF - 1 mice to abamectin was correlated with a deficiency

in P - gp. In consideration of this information, a decision was made in 1998 by the Hazard Identification and Assessment Review Committee (HIARC) not to employ the results from the CF - 1 mice s tudies for establishing toxicity endpoints (HIARC Report, Sept. 15, 1998). Currently , HED establishes a point of departure of 0.12 mg/kg/day for risk assessment of chronic, short, and intermediate terms of exposure based on the combined data from three rep roduction studies and two developmental neurotoxicity studies. With the intraspecies safety factor of 10x, the effects seen in the most sensitive subpopulation (CF - 1 mice) are protected. (Details are presented in Section 4 .5). 4.4.4 Reproductive Toxicity There are three available reproduction studies in rats: two one - generation reproduction studies and a two - generation reproduction study (MRIDs 00096450, 00096451, and 00164151) (Table A.2, Appendix A). The result s of all three studies show the effects (decreased pup body weights and/or survival) in the pups at lower dose levels (0.4 mg/kg/day) than the LOAELs of the parental animals (>0.4 mg/kg/day or 1.5/2.0 mg/kg/day). A similar lower offspring LOAEL, based on decreased pup body weight, than that of the maternal animals was also found in the developmental neurotoxicity study (offspring LOAEL=0.2 mg/kg/day ; maternal LOAEL >0.4 mg/kg/day). Two - generation reproduction study in rats (MRID 00164151 ; 198 4 ): Groups of 30 SD rats/sex/dose were administered abamectin b y gavage at dose levels of 0, 0.05, 0.12, and 0.4 mg/kg/day . F0 males were dosed for a total of 259 day s while F0 females were treated for a minimum of 177 day s. For F0 animals, mating and fertili ty indexes and body

weights werePage 21 of 62

comparable among all dose groups. For the pups, F1a and F1b pups had decreases in viability and lactation indexes and a decrease in body weights at 0.4 mg/kg/day . Similar decreases were also seen in F2a and F2b groups. In the F2b weanlings, there was a treatment - related increase in the incidence of retinal rosettes. The parental NOAELwas 0.4 mg/kg/day (highest dose tested). The reproductive NOAEL was also 0.4 mg/kg/day. The offspring NOAEL was 0.12 mg/kg/day , while th e LOAEL was 0.4 mg/kg/day based on increased incidence of retinal rosettes in F2b pups, increased dead pups at birth (decrease d viability index), decreased lactation index, and reduced pup body weights. Developmental neurotoxicity study in rats (MRID 47116201 ; 2007 ): Abamectin (96.2% a.i. on dry basis; Batch No.: VS094KO) in sesame oil was administered via gavage (10 mL/kg) to pregnant Alpk:AP f

SD rats (30/dose) from gestation day (GD) 7 through lactation day (LD) 22 at doses of 0, 0.12, 0.20, or 0.40 mg/kg/ day . The pups were not directly dosed. Maternal toxicity : There were no effects of treatment on mortality , clinical signs, functional observational battery parameters, body weights, body weight gains, food consumption, reproductive performance, or gestation length. The maternal LOAEL was not observed. The maternal NOAEL was 0.4 mg/kg/day . Offspring toxicity : At 0.40 mg/kg/day , pup death was seen. The pups were generall y small and presented with deh ydration and tremors. Additionally , at this d ose, pup body weights were decreased (p ≤ 0.05 ) b y 1 0 - 3 5 % compared to controls from post - natal day (PND) 8 to 36 for males and females. There were no surviving pups at this dose level after PND 38. Since these deaths left an insufficient number of pups to complete all of the study objectives, all dams and pups at this dose were removed from the study during PND 15 - 38. At 0.12 and 0.20 mg/kg/day , n o treatment - related effects were observed on litter parameters (number born live, number born dead, sex ratio ( % male), mean litter size, live birth index, and viability index ) , clinical signs , FOB parameters, motor activity , auditory startle reflex, learning and memory , sexual maturation, brain weight, or gross or microscopic pathology . D ecreases (p ≤0.05) in post - weaning body weight were observed in the 0.12 and 0.20 mg/kg/day males throughout the post - weaning interval (PND 36 - 63). The individual pup body weight data were re - evaluated using Mixed Model Analy sis of Body Weight Data from the Developmental Neurotoxi city

Study . The results indicated that there was a statisticall y significant difference for mid - and low - dose males from the corresponding controls, and for females no statistically significant difference existed at either the low - or mid - dose level. How ever, the body weight decrease in low - dose males was approximately 3% relative to the controls, and it was determined not to be toxicologically

significant. The offspring LOAEL for this effect is established at 0.2 mg/kg/day

based on statistically

and bio logicall y significant body weight reductions (6%). The NOAEL for this effect is established at 0.12 mg/kg/day . Because the dose - response to abamectin is body weight loss (detected at the low dose) leading to moribundity at the high dose, an additional 3X uncertainty factor, for steepness of the dose - response curve, is included in the reference dose and Level of Concern calculations. This additional 3X safety factor yields a de facto NOAEL of 0.04 mg/kg/day which is protective of the slight body weight de crease seen in low - dose males (p<0.01 using Mixed Model Analy sis).Page 22 of 62

Developmenta l neurotoxicity study in rats ( MRIDs 46727403, 46727402, and 46727401 ; all 2005 ): Abamectin (96.2% a.i. on dry basis; Batch No.: VS094KO) in sesame oil was administered via gavage (10 mL/kg) to pregnant Alpk:AP f SD rats (30/dose) from gestation day (GD) 7 through lactation day (LD) 22 at doses of 0, 0.12, 0.20, or 0.40 mg/kg/day . The pups were not directl y dosed. Dams were allowed to deliver naturall y and were killed at weaning on LD 29. On post - natal day (PND) 5 , litters were standardized to 8 pups/litter; the remaining offspring and dams were sacrificed and not examined further. Subsequently, 1 pup/sex/litter/group (at least 10 pups/sex/dose when available) were allocated to the following subsets: Subset 1: functional observational battery (FOB) on PND 5, 12, 22, 36, 46, and 61; motor activity

on PND 14, 18, 22, and 60; and brain weight and neuropathology on PND 63. Subset 2: FOB on PND 5, 12, 22, 36, 46, and 61; water maze on PND 24 and 27; and brain weight and neuropathology on PND 63. Subset 3: FOB on PND 5 and 12; auditory startle on PND 23 and 61 (for animals not sacrificed on PND 12); and brain weight and neuropathology on PND 12. Subset 4: FOB on PND 5, 12, 22, 36, 46, and 61; water maze on PND 59 and 62. Maternal toxicity : There were no effects of treatment on mortality , clinical signs, functional observational battery

parameters, body

weights, body

weight gains, food consumption, reproductive performance, or gestation length. The maternal LOAEL wa s not observed. The maternal NOAEL is 0.4 mg/kg/day (HDT) . Offspring toxicity : No treatment - related effects were observed on litter parameters (number born live, number born dead, sex ratio (% male), mean litter size, live birth index, and viability ind ex ) , clinical signs , FOB parameters, motor activity , auditory startle reflex, learning and memory , sexual maturation, brain weight, or gross or microscopic pathology . On the day

of weaning (PND 29), minor decreases (p ≤ 0.05) in pup body weights of 5 - 7% were observed at 0.40 mg/kg/day . Pup body weights continued to be decreased (p<=0.01) by 5 - 6% in the males and b y 8 - 10% in the females throughout the post - weaning interval (PND 36 - 63). The offspring LOAEL is 0.4 mg/kg/day , due to decreased body weights in b oth sexes. The NOAEL is 0.2 mg/kg/day . There was no evidence of neurotoxicity in the offspring. 4 .4.5 Additional Information from Literature Sources No additional information relevant to potential susceptibility in the developing young was found in open literature sources. 4 .4. 6 Determination of Susceptibility In creased susceptibility

was demonstrated in the fetuses of CD - 1 and CF - 1 mice and rabbits in the developmental toxicity studies both quantitatively and qualitatively

as discussed in Section 4 .4.3. Quantitative increase in susceptibility was also shown in reproductive toxicity and developmental neurotoxicity studies in rats where the L OAELs were substantially lower in the pups than those in the parental animals.Page 23 of 62

4.5 FQ PA Safety Factor for Infants and Children In previous abamectin risk assessments, the 10X FQPA safety factor was retained as a database uncertainty factor for the lack of a developmental neurotoxicity study . Two developmental neurotoxicity

studies have now been submitted and reviewed and the findings in these studies were considered in the identification of toxicological points of departure and uncertainty/ safety factors. With the addition of the developmental neurotoxicity (DNT) studies, the toxicity database for abamectin is complete , except for immunotoxicity studies. EPA began requiring functional immunotoxicity

testing of all food and non - food use pesticides on December 26, 2007. To address the issue of an immunotoxicity data gap and the associated database uncertainty factor, RAB3 examined the entire database of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . Abamectin has not been found to induce effects associated with immunotoxicity and abamectin does not belong to a class of chemicals that wou ld be expected to be immunotoxic. Therefore, based on the above considerations, HED does not believe that conducting a special series 870.7800 immunotoxicity study will result in a NOAELless than the NOAEL s of 0.5 and 0.12 mg/kg/day already s et for abame ctin acute and repeated exposures, respectively . An additional uncertainty factor (UF DB ) for database uncertainties associated with immunotoxicity does not need to be applied at this time . The RAB3 Risk Assessment Team has evaluated the entire toxicity database of abamectin and determined that an additional 3x FQPA safety factor is needed to address residual concerns as to all risk assessments other than acute dietary . For all risk assessments involving repeat exposures , the selected toxicity

endpoint is based on the decrease in pup body weight seen in the developmental neurotoxicity study (2007) and three reproduction studies in the rat . Although the study identified a NOAEL for the effects observed in the pups, the dat a clearly indicate that the decrease in pup body weight seen at 0.2 mg/kg/day rapidly progresses to death at the next higher tested dose level (0.4 mg/kg/day) in both reproduction and developmental neurotoxicity studies . As shown in Figure 1, the combine d data from several reproduction toxicity and developmental neurotoxicity

studies have documented a very narrow dose range from NOAEL(0.12 mg/kg/day) to adverse effect (0.2 mg/kg/day) to severe adverse effect (0.4 mg/kg/day). Dose spacing is commonly

gre ater than the <2x between NOAEL and LOAEL here, and the 3x difference between the NOAEL and the dose that induced mortality in the pups in the developmental neurotoxicity study provides little margin of safety for such a severe effect. Retaining an additi onal 3x FQPA safety factor effectivel y provides a 10x margin between the dose which causes death (0.4 mg/kg/day) and the NOAEL adjusted by the additional safety factor (0.12 mg/kg/day

/3x = 0.04 mg/kg/day). A dose spacing of 10x between a NOAEL and LOAEL is as broad, if not broader, than the dose spacing generall y used in animal testing and thus removes the residual concern with the steepness of the dose response curve and the severe effects seen here. Additionally , this adjusted point of departure (0.04 mg/kg/day) would also address the concerns for the increased susceptibility seen at higher doses in the two - generation reproduction study in rats (LOAEL = 0.4 mg/kg/day), prenatal developmental study in CD - 1 mice (LOAEL = 0.75 mg/kg/day), the prenatal deve lopmental toxicity study in rabbits (LOAEL = 2 mg/kg/day), and the one - generation reproduction study (LOAE L = 0.2 mg/kg/day). The 10xPage 24 of 62

intraspecies factor is protective of the effects seen in CF - 1 mice which were found to be the most sensitive strain of te st animals due to the lack of P - gl ycoprotein. The data on CF - 1 mice show that most of the effects are seen at doses above 0.06 mg/kg/day (Table A.3 of Appendix A.) Therefore, the additional 3x factor for the steepness of the dose - response curve and severity of effects is adequate. With respect to acute dietary exposure, the endpoint selected for risk assessment is based on mydriasis observed in dogs. The additional 3x factor applied to chronic and other exposure scenarios is not applicable to acute expo sure because steepness of the dose and severity of effects were not seen in the studies where mydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exposure scenarios is not a single dose effect.

Figure 1. Dose res ponse for pup body weight decrease and pup mortality seen in developmental neurotoxicity

study in rats (MRID 47116201). There are no residual concerns with respect to the exposure databases. The chronic and acute dietary food exposure assessment utilizes conservative assumptions including anticipated residues, default processing factors, and percent crop treated. The dietary drinking water assessment utilized modeling results which included conservative assumptions for the parent and all degradates of con cern. Conservative assumptions were used in the water models. Therefore, the water exposure assessment will not underestimate the potential risks for infant s and children . Likewise, the use of maximum application rates and central - to - high end inputs res ults in calculated residential exposures that should not underestimate the risks to infants and children from these requested uses. Ab am ectin D ose Response

0 5 10 15 20 25 30 35

0. 12 0. 2 0. 4

Do se (mg/ kg/day)% Body Wt Decrease

0 20 40 60 80 100 120Mortality % Body W t D ec re as e Mo rta lityPage 25 of 62

4.6 Dose - Response Assessment On June 19, 2008, the ToxSAC evaluated the previous toxicity endpoints and points of departures based on the current toxicity database with newly

added studies, such as a second developmental neurotoxicity study , and acute and subchronic neurotoxicity studies on abamectin. The Committee recommended new toxicity endpoints and points of departures for risk assessment. On September 25, 2008, the ToxSAC met a second time to discuss the decrease in pup body weight seen in the 2007 developmental neurotoxicity study . Subsequent to the ToxS AC consultation, the RAB3 Risk Assessment Team determined the toxicity endpoints presented in Table 4 .6.2 to be most protective and appropriate for risk assessment. The rationale for the endpoint selection is summarized below, and the toxicity endpoints and the points of departure for risk assessment for various exposure scenarios are presented in Table 4 .6.2. Acute Dietary Endpoint: Previously , the acute toxicity endpoint was based on mydriasis seen in a 53 - week study

in dogs (HIARC report, Sept. 1998), and the selected point of departure for risk assessment was a NOAEL of 0.25 mg/kg/day based on mydriasis as a likely single - dose effect. As mentioned before, at that time, acute neurotoxicity and developmental neurotoxicity studies were not available. On June 19, 2008, the ToxSAC evaluated all the toxicity studies relevant to establishing an acute oral toxi city endpoint and focused on the m ydriasis seen in the toxicity studies in the dog and other effects demonstrated in the acute neurotoxicity study in the rat. The results of the mydriasis seen in the dog studies are compiled and presented in Table 4 .6.1. The dog toxicity

studies were conducted in the 1980’s, and significant mydriasis was reported. The data show that mydriasis was not reported in treated dogs at dose levels equal to or less than 0.5 mg/kg/day

with a single dose administration. However, at 0.25 mg/kg/day, mydriasis was noted only after at least 9 weeks of treatment, and at 0.5 mg/kg/day , m ydriasis was seen at treatment day 7. As treatment time progressed, the incidence of this effect was increased as indicated by the finding that at treatment week 6, 5/12 dogs showed signs of mydriasis. With increasing dose levels, the time for m ydriasis to occur was shortened. At 8 mg/kg/day, mydriasis was seen within 24 hrs of treatment. In dogs treated with 1 mg/kg/day , m ydriasis was noted from 1 to 5 times during the first week of treatment. It was entirely possible that after a single dose at 1 mg/kg, mydriasis was present. Therefore, the LOAELfor m ydriasis resulting from a single dose is 1 mg/kg and the NOAELis 0.5 mg/kg. The point of departure for acute oral exposure assessment is 0.5 mg/kg/day , and the toxicity endpoint is mydriasis seen in the 12 - week dose range - finding toxicity

study . This point of departure for risk assessment is also supported by the results of the acute neurotoxicity study in rats (MRID 46959202 ). This study showed the reduced splay

reflex in males and females at 1 .5 mg/kg/day ( LOAE L) . At the next high er dose level , decreased motor activity , reduced splay reflex, and tip toe gait were seen. All the data considered together, the 12 - week range - finding study in dogs and the acute neurotoxicity study in rats are considered as critical studies in establishing the acute dietary endpoint. For acute dietary

exposure, the FQPA safety factor may be reduced to 1x, based on m ydria sis in dogs. The additional 3x factor for chronic and other exposure scenarios is not applicable to acute exposure because steepness of the dose and severity of effects were not seen in the studies where mydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exposure scenarios is not a single dose effect. B ased on the safety factor of 100x (10x forPage 26 of 62

interspecies difference and 10x for intraspecies variability), the acute RfD is 0.005 mg/kg/day . Table 4 .6.1. Mydriasis seen in all the available toxicity studies in dogs Study Dose Levels (mg/kg/day)

0.25 0.5 1 2 4 8 12 - Week dose range finding study (feeding) (1984) (0.25, 0.5, 1, 4/2 mg/kg/day) (2M/2F) Mydriasis

wa s never noted. Mydriasis was

never noted. Mydriasis wa s

noted from 1 to 5 times/ week, beginning on week 1. Mydriasis was

noted. Food consumption wa s markedly reduced. 4 mg/kg was

reduced to 2 mg/kg due to marked reduction in FC. Mydriasis wa s noted. Tremor, rapid respiration, & weakness were seen. 18 - Week toxicity study (gavage) (1982) (0.5, 2, & 8 mg/kg/day) (3M/3F) On treatment day 7, mydriasis was seen in 1 dog. On week 2, mydriasis was seen in 4/6 dogs. Whole body tremor, ataxia, & ptyalism was seen in one dog at week 2 and persisted until the end of the study. Mydriasis, ataxia, ptyalism, and anorexia were seen in all dogs by day 3 of dosing. After the third day of dosing , 1 dog died with signs of convulsion prior to death. Mydrasis wa s reported 24 hrs after dosing. 4/6 dogs had tremor, ataxia, ptyalism within 3 to 6 hour s after dosing, & 2/6 dogs died within 4 hrs.

53 - Week toxicity study feeding (1987) (0.25, 0.5, & 1.0 mg/kg/day) (6M/6F) On week

10, 1 dog wa s noted to have mydria sis, and none before that time. On week 1, one

dog was reported to have mydriasis. By w eek 6, 5 dogs had mydriasis. On w eek 1,

one dog had mydriasis . By week 3, 4 dogs had mydriasis. By week 33, 3 males died. Chronic Dietary Endpoint: Considering all the available toxicity data, it was determined that the decrease in pup body weights in the three reproduction studies and the recent developmental neurotoxicity

study (2007; MRID 47116201) was found to be the most sensitive effect and to occur in young animals which were exposed to abamectin pre - and post - natally . [ The pup body weight data are summarized in Tables C.2 (2005 DNT study) and C.3 (2007 DNT study) of Appendix C of D362615 (N. Dodd, 3/11/09).] Inthe 2007 developmental neurotoxicity study , a decrease in pup body weight was demonstrated in the pups at 0.12 and 0.2 mg/kg/day starting on PND 36 to the end of the study (PND 63 ) (Table C.3 of Appendix C of D362615 . In addition, inPage 27 of 62

the high - dose group, the pup body weight decrease was present s tarting on PND 8 and the percent decrease relative to the controls was progressive (from 11% on PND 8 and reaching greater than 30% on PND 36). By PND 38, there were no surviving pups at this dose level. The pup body weight data of this study were anal yz ed using a statistical Mixed Model Anal ys is of Body Weight Data. This model takes into account the correlations of animals in the same litter and of measures of the same animal, can select the best covariance, uses all information available from the data , and is more appropriate for DNT body weight data structure than the ANOVA or Repeated Measures ANOVA. The model provides a measurement of the rate of body weight changes with time among the test groups. The anal ys is showed that there was a statisticall y significant decrease in male pup body

weights in 0.12 and 0.2 mg/kg dose groups relative to the controls (p<0.0001 for 0.2 mg/kg males and p<0.002 for 0.12 mg/kg males) (Table C.4 of Appendix C of D362615 ). The decrease was 6% and 3.3 % in 0.2 and 0.12 mg/kg males, respectively. The decrease in mid - and low - dose females was not statistically significant (0.12 mg/kg: 3.2 % with p<0.141; 0.2 mg/kg: 4.3% with p<0.053). To further evaluate the pup body weight reduction affected by abamectin, RAB3 conducted a comparative evaluation of all the pup body weight changes from PND 7 to 21 in all the available reproduction studies with abamectin. The results are summarized in Table C.1 of Appendix C of D362615 . The two one - generation studies appeared to be dose - range finding studies because one study (MRID 00096450, 1982) employed dose levels which were too high (0.5, 1.00 and 1.5 mg/kg/day). In this study , decreased body weight was seen at all dose levels and death occurred in the high dose group at PND 14. The other one generation study (MRID 00096451, 1982) employed dose levels of 0.10, 0.2, and 0.4 mg/kg/day, which were less than the lowest dose of the first study . The mean pup body weights were decreased from PND 7 to 21 by as much as 16% at the highest dos e tested (0.4 mg/kg/day). No pup body weight decrease was seen in the 0.2 and 0.1 dose groups. The two - generation studies used dose levels of 0.05, 0.12 and 0.40 mg/kg/day . Decreased pup body weights were consistently

seen in F 1a , F 1b , F 2a , and F 2b pups at 0.4 mg/kg/day . The above data and discussion were presented to the ToxSAC on Sept. 25, 2008, to request the Committee’s opinion on determining the offspring L OAEL based on the pup body weight data for offspring toxicity . The ToxSAC recommended three scenarios for choosing the NOAEL/LOAEL for the DNT study which were then thoroughly considered by

the RAB3 Risk Assessment Team. The RAB3 Risk Assessment Team concluded that the decrease in male pup body weight at the 0.2 mg/kg/day dose in the 2007 d evelopmental neurotoxicity study was statistically

and biologically

significant, while decreased body weight at the 0.12 mg/kg/day dose was not biologicall y significant. The 0.2 mg/kg/day dose is considered to be statistically and biologicall y significant for the following reasons: 1) At 0.2 mg/kg/day , other effects such as spastic movement and delayed incisor eruption were also seen in the pups; and 2) The body weight decrease was 6%, whereas an approximately 5% decrease in body weight in pups is generall y considered to be biologically significant. Therefore, the NOAEL was established at 0.12 mg/kg/day

and the LOAEL was established at 0.2 mg/kg/day based on decreased pup body weight seen in the developmental neurotoxicity study . Therefore, the decrease i n male pup body weight at the 0.2 mg/kg/day dose in the developmental neurotoxicity study is established as the toxicity endpoint, and the NOAEL of 0.12 mg/kg/day is the point of departure for risk assessment. As discussed in the FQPA Safety Factor Sectio n, the 10x intraspecies factor isPage 28 of 62

protective of the most sensitive subpopulation as represented b y CF - 1 mice. An additional 3x factor for the steepness of the dose - response curve and the severity of effects is applied. With that 3x factor and the standard safety factor of 100x (10x for intraspecies and 10x for interspecies differences), the chronic RfD is 0.0004 mg/kg/day. Carcinogenicity : Abamectin is characterized as “not likely to be carcinogenic to humans” based on the absence of significant increase in tumor incidence in two adequate (rat and mouse) carcinogenicity

studies. Incidental Oral, Dermal

, and Inhalation Endpoints (all durations) : The endpoints for these routes of exposure were decreased pup body weight seen at the LOAEL of 0.2 mg/kg/d ay from combined results of three reproduction studies and two developmental neurotoxicity studies in the rat. The details for selecting this endpoint and safety factor are discussed in the Chronic Dietary Endpoint Section . This endpoint was selected be cause it best represented the exposure scenario time frames (appropriate duration), was relevant due to evidence of increased susceptibility

to the offspring following pre - and postnatal exposure to abamectin, and adequatel y reflected all the populations at risk. Because an oral study was selected for all durations of dermal and inhalation exposure, a 1% dermal absorption factor and a 100% inhalation absorption factor will be used in the route - to - route extrapolation. Dermal Absorption : According to the H IARC report dated September 15, 1998 (HED document No. 012845), a dermal penetration factor of 1% should be used for risk assessment purposes. This value was based on the results from a dermal absorption study in monkey s which demonstrated that <1% of an applied dose is absorbed. Because of the phy sical - chemical properties, and known pharmacokinetics and excretion pattern of avermectin B 1a , the monkey is considered to be an appropriate model to use in determining dermal absorption for this chemical. Level of Concern (LOC) for Residential Risk Assessment : For residential exposure risk assessments, the uncertainty factor is 300 (10x for interspecies extrapolation, 10x for intraspecies variations, and a 3x factor for the steepness of the dose/response curve in several studies and the severity of effects [death] seen at the slightly higher dose level). Level of Concern (LOC) for Occupational Risk Assessment : For occupational exposure risk assessments, the uncertainty factor is 300 (10x for interspecies extrapolation, 10x for intraspecies variations, and an additional factor of 3x for the steepness of the dose - response curve and the severity of effects).Page 29 of 62

Table 4.6.2. 1. Summary of Toxicological Doses and Endpoints for Abam ectin for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenarios Point of

Departure Uncertainty/

FQPA Safety Factor RFD, PAD,

Level of Concern (LOC) Study and Toxicological Effects

Ac ute Dietary (General population, including infants and children) NOAEL =

0.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=1x aRfD = 0.005

mg/kg/day 12 - Week dose - range finding study in dogs

LOAEL = 1.0 mg/kg/day based on mydriasis seen 1 - 5 times during the first week of treatment. Acute neurotoxicity st udy in rats LOAEL= 1.5 mg/kg/day based on increased incidence of foot splay. Chronic Dietary (All populations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* cPAD =

0.0004 mg/kg/day Combined data fromthree reproduction

studies and two developm ental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint) LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups at 0.2 mg/kg/day. Short - Term

and Intermediate Term Incidental Oral NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 Combined data fromthree reproduction

studies and two developm ental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint) LOAEL = 0.2 mg/kg/day based on decreased pup body w eight. Dermal (All Durations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 Combined data fromthree reproduction

studies and two developm ental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint) LOAEL = 0.2 mg/kg/day based on decreased pup body weight. Inhalation (All durations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 Combined data fromthree reproduction

studies and two developm ental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint) LOAEL = 0.2 mg/kg/day based on decreased pup body weight. Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans based on the absence of significant

increase in tumor incidence in two adequate rodent carcinogenicity studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. * The additional FQPA safety factor of 3x is for the steepness of the dose - response curve and the severity of effects.Page 30 of 62

Table 4.6.2.2. Summ ary of Toxicol ogical Doses and Endpoints for Abam ectin for Use in Occupational Hum an Health Risk Assessments Exposure/ Scenarios Point of Departure Uncertainty/

Safety Factor RFD, PAD,

LOC* Study and Toxicological Effects

Dermal (Short - Term and Intermediate Term) NOAEL = 0.12 mg/kg/day 1% Dermal Absorption Factor UF A = 10X

UF H = 10X SF = 3X LOC: MOE = 300 Combined data fromthree reproduction studies and two developmental neurotoxicity studies. LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups. Inhalation (Short Term and Intermediate - Term) NOAEL = 0.12 mg/kg/day UF A = 10X

UF H = 10X SF = 3X LOC: MOE = 300 Combined data fromthree reproduction studies and tw o developmental neurotoxicity studies. LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups. Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to human based on the absence of significant

increase in tumor incidence in two adequate rodent carcinogenicity studies. Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. N OAEL = no observed adverse effect level. L OAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sens itivity among members of the human population (intraspecies). SF = Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). Rf D = reference dose. M OE = margin of exposure. L OC = level of c oncern. N/A = not applicable. * Level of Conce rn (LOC): F or occupational exposure risk assessments, the uncertainty factor is 300X (10X for interspecies extrapolation; 10X for intraspecies variations; and 3X for the steepness of the dose - response curve in several studies and the severity of effects [ death] seen at the slightly higher dose level). Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity

endpoints selected for these routes of exposure may be aggregated as follows: the oral, dermal, and inhalation routes of exposure can be combined to assess aggregate risks because of the selecti on of a common toxicity endpoint for all routes and durations of exposure. 4.7 Endocrine Disruption As required b y FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemi cals. Collectively, these studies include acute, subchronic and chronic toxicity , including assessments of carcinogenicity , neurotoxicity , developmental, reproductive, and general or sy stemic toxicity . These studies include endpoints which may be suscept ible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual maturation, fertility , pregnancy rates, reproductive loss,Page 31 of 62

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for re levant risk assessment scenarios from the existing hazard database. However, as required b y FFDCA section 408(p), abamectin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to dete rmine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designat e.” The EDSP employs a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine - related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p ), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Abamectin was inc luded on that list and has been issued an order to conduct the Tier 1 testing. Once all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk ass essment performed if necessary . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/ . 5.0 Dietary Exposure and Risk Assessment 5.1 Metabolite/Degradate Residue Profile 5.1.1 Summary of Plant and Animal Metabolism Studies Metabolism in Primary

Crops : No new plant metabolism data were submitted with this registration request. The qualitative nature of the abamectin residues in the bulb onion subgroup 3 - 07A, chives, and dry

beans is adequatel y understood based on metabolism studies on cotton, citrus, and celery

(PP#'s 5G3500, 5G3287, and 8F3649, respectivel y), as well as a report titled "Comparative Degradation of Avermectin B 1 a in Cotton Leaf, Citrus Fruit, Celery , and In Vitro " (PP#9F3703, S. Willett, 12/15/89). The available studies indicate that the metabolism of abamectin in plants results in a complex mixture of residues. The majority of the terminal residue is composed of several unidentified polar degradates. The parent compound, its delta - 8,9 - isomer, and the alpha 8 - OH degradate have been ide ntified in plants, with only the parent and its delta - 8,9 - isomer each accounting for at least 10% of the total residue. The polar degradates generated on citrus (7 - day PHI) and in vitro (30 hour sample) have been tested for toxicityPage 32 of 62

(in the developmental t oxicity study in CF - 1 mice) and were found to be of no toxicological significance at the levels tested (TOX memos 7080 and 7081, W. Dykstra, 3/15/89; PP#8F3592, F. Boyd, 6/21/89; D203373, G. J. Herndon, 3/29/95). As stated in The Pesticide Manual , Eleventh Edition, British Crop Protection Council (1997), abamectin has limited plant sy stemic activity , but does exhibit some translaminar movement. For the tolerance expression and risk assessment, the residues of concern in these crops are the parent compound s (avermectin B 1a and B 1b ) and their delta - 8,9 - isomers (also known as 8,9 - Z avermectin B 1a and 8,9 - Z avermectin B 1b ). Metabolism in Rotational Crops: No rotational crop studies were submitted with this registration request. Review of the results of the confined rotational crop study indicated that avermectin residues accumulated in some rotational crops at levels up to 10 - 12 ppb. However, the radioactivity

was due to polar degradates that were of little toxicological concern as compared to the parent compound avermectin B 1 and/or the delta - 8,9 - isomer (Memo, P. Mastradone, 4/24/88). Therefore, field rotational crop studies are not required (PP#7F3500 , PP#8F3592, and PP#5E4566, DP#s 230333, 230352, and 230880, G. Herndon, 1/10/97). Metabolism in L ivestock : No new livestock metabolism data were submitted with this registration request. The qualitative nature of abamectin residues in ruminants as a result of application to crops is adequatel y understood based on a goat metabolism study which was previously

submitted (PP#7G3468, L . Cheng, 2/11/87; PP#9F3703, S. Willett, 12/15/89). The residues of concern in rumin ants for the tolerance expression and risk assessment are the parent compounds (avermectin B 1a and B 1b ) and their delta - 8,9 - isomers. An additional metabolite (24 - hydrox ym ethyl avermectin B 1a) was identified and is potentially of toxicological significance , but was not included in the tolerance expression because of its presence at low levels (PP#8F3592, F. Bo yd, 6/21/89; DP#203373, G. J. Herndon, 3/29/95). If the tolerances for residues in meat and milk need to be raised at some future time due to registration of abamectin on additional feed items, the 24 - hydroxy methyl metabolite may

need to be included in the tolerance expression and appropriate enforcement methods developed. No poultry

metabolism study

has been submitted. Since no significant poultry f eed items are associated with the proposed uses, as indicated in Table 1 Feedstuffs (June 2008) , no poultry metabolism study

is required. Metabolism in Rats : Avermectin B 1a does not bioaccumulate in rat tissues. Avermectin B 1a in rats is metabolized to 24 - hydroxy- methyl B 1a (i.e., 24 - OH - Me - B 1a), which accounts for most of the radiolabeled residues. 5.1.2 Summary of Environmental Degradation Abamectin is stable to abiotic hydrol ys is; determination of stability to photoly sis and biodegradation is pending submission of acceptable data. Abamectin has very low water solubility but i s soluble in organic solvents. Abamectin is not expected to leach since it is not soluble in w ater and binds to soil. Abamectin is degraded b y soil microorganisms.Page 33 of 62

The previous screening assessment of estimated drinking water concentrations (EDWCs) included abamectin and its major soil degradate (a mixture of an 8 - α - hydroxy and a ring opened aldeh yde derivative). T he delta - 8,9 - isomers (also known as 8,9 - Z isomers) were not included in the drinking water assessment because they were not identified in the fate studies. This current drinking water exposure assessment conservativel y models only parent abamectin based on an assumption of stability until acceptable environmental fate data are submitted (D380524, G. Orrick, 1/31/11). 5.1.3 Comparison of Metabolic Pathways Avermectin B 1a does not bioaccumulate in rat tissues. Avermectin B 1a in rats is metabolized to 24 - hydroxy- methyl B 1a (i.e., 24 - OH - Me - B 1a), which accounts for most of the radiolabeled residues. Metabolism of abamectin in ruminants (goats) appears to be similar to its metabolism in rats in that the 24 - hydroxy- methyl metabolite is formed, although it is a minor metabolite in ruminants . Based on the goat metabolism study, the residues of concern in ruminants for the tolerance expression and risk assessment are the parent compounds (averme ctin B 1a and B 1b ) and their delta - 8,9 - isomers. A poultry metabolism study

has not been conducted . Since no significant poultry feed items, as indicated in Table 1 Feedstuffs (June 2008), are associated with the proposed uses, no poultry metabolism study is required. Metabolism studies on cottonseed , citrus, and celery indicate that the metabolism of abamectin in plants results in a complex mixture of residues. The majority of the terminal residue is composed of several unidentified polar degradates. The parent compound, its delta - 8,9 - isomer, and the alpha 8 - OH degradate have been identified in plants, with only the parent and its delta 8,9 - isomer each accounting for at least 10% of the total residue. In citrus, the majority of the residue remained in the peel but a small amount translocated into the pulp. For the tolerance assessment and risk assessment, the residues of concern in these crops are the parent compounds (avermectin B 1a and B 1b ) and their delta - 8,9 - isomers (also known as 8,9 - Z isomers). The results of a confined rotational crop study indicated that avermectin residues accumulated in some rotational crops at levels up to 10 - 12 ppb; however, the radioactivity was due to polar degradates that were of little toxicological concern as compared to the parent compound avermectin B 1 and/or the delta - 8,9 - isomer. It is not likely that residues of concern will occur in rotational crops. 5.1.4 Residues of Concern Summary and Rationale The metabolism studies on cotton, citrus, and celery indicate that the metabolism of abamectin in plants results in a complex mixture of residues, with the majority of the terminal residue composed of several unidentified polar degradates. The parent compound, its delta - 8,9 - isomer,Page 34 of 62

and the alpha 8 - OH degradate have been identified in plants, with only the parent and its delta 8,9 - isomer each accounting for at least 10% of the total residue. The polar degradates generated on citrus (7 - day PHI) and in vitro (30 hour sample) have been tested for toxicity (in the develop mental toxicity study in CF - 1 mice) and were found to be of no toxicological significance at the levels tested (TOX memos 7080 and 7081, W. Dykstra, 3/15/89; PP#8F3592, F. Boyd, 6/21/89; D203373, G. J. Herndon, 3/29/95). Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Rotational Crop Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers)** Livestock Ruminant* Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Poultry Not applicable Not applicable Drinking Water Parent (avermectin B 1a and B 1b ) *** Not applicable * Residues of concern in ruminants include both use on crops and use in cattle ear tags. ** No rotational crop tolerances have been established. *** T he delta - 8,9 - isomers (also known as 8,9 - Z isomers) are not included in the drinking water assessment because they we re not identified in the fate studies . The major soil degradate included in the previous assessment ( a mixture of an 8 - alpha - hydroxy and a ring opened aldehyde derivative ) was not included in the current assessment based on an assumption of stability of parent until acceptable environmental fate data are submitted (D380524, G. Orrick, 1/31/11). 5 .2 Food Residue Profile Reference s : Abamectin . Petition for Tolerances/Section 3 Registration on the Bulb Onion Subgroup 3 - 07A,

Chives, and Dry Beans. Summary of Analytical Chemistry and Residue Data , DP#380795, N. Dodd, 5/18/11. DER References: 48135001.der (onion, bulb), 48135002.der (chives, fresh), 48135003.der (beans, dry) As stated in The Pesticide Manual , Eleventh Edition, British Crop Protection Council (1997), abamectin has limited plant sy stemic activity , but does exhibit some translaminar movement. In the citrus metabolism study , the majority of the residues remained in the peel but a small amount translocated into the pulp. Residues from application to dry bulb onion, chive (fresh), and dry bean are reported in Table 5. 2 bel ow. The number and geographic representation of the field trials are adequate.Page 35 of 62

The field trials were conducted using the emulsifiable concentrate (EC) formulation. The ChemSAC determined on 5/18/11 that the available bridging studies for the suspension concentrate (SC) formulation on leafy vegetables, fruiting vegetables, cucurbit vegetables, citrus fruits, and pome fruits (DP#364734, N. Dodd, 1/21/10) can be translated to support use of the SC formulation on the bulb onion subgroup 3 - 07A, chive, and dry bean provided the use directions for the SC formulation alway s require use of a non - ionic surfactant or a horticultural oil in the spray mix and the preharvest intervals are ≥ 7 days. T he dry bulb onion field trials reflect the proposed use pattern, including the use of an adjuvant in all trials. The fresh chive field trials reflect the proposed use pattern, including application rate and PHI. An adjuvant was not used in the field trials. Label revisions are required for the EC labels to remove the statement that adjuvants may be used on chives since the submitted c hive field trials do not reflect the use of an adjuvant. Also, the labels must be revised to specify a 7 - day PHI for chives since most of the chive data reflect a 7 - day PHI . The dry bean field trials reflect the proposed use pattern, including application rate and PHI. An adjuvant was not used in the field trials. The EC label indicates than an adjuvant can be used with the applications, but is not required . Label revisions are required for the EC labels to remove the statement that adjuvants may be used on dry

beans since the submitted dry bean field trials do not reflect the use of an adjuvant. The labels must be revised to specify a 7 - day PHI for dry bean s since most of the dry bean data reflect a 7 - day PHI. The petitioner should also submit the storage temperature of the dry bean samples. Residue data for cowpea forage and hay must be submitted before cowpea can be included in the dry bean seed tolerance. The residue data for fresh chive, dry bulb onion , and dry bean were not entered into the tolerance spreadsheet since >15% of treated samples bore residues below the LOQ. For the purpose of setting tolerances, HED will rely on the maximum residues observed in the field trials (i.e., 0.004 6 ppm for dry

bulb onion; 0.0045 ppm for fresh chives; and 0.006 ppm for dry bean). B ased on these data, HED recommends tolerance s of 0.01 ppm for dry bulb onion, chive, and dry bean. T able 5. 2. Summary of Residue Data from Crop Field Trials with an Abamectin Formulation

(EC form ulation). Commodity Total

Applic. Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT Median Mean Std. Dev.

Total Combined Residues Bean, dry (proposed use = 0.056 lb ai/A total application rate, 6 - day PHI) Bean, dry 0.054 -

0.061 5 - 7 24 <0.004 0.006 0.005 0.004 0.0041 0.0

Chive (proposed use = 0.056 lb ai/A total application rate, 6 - day PHI) Chive, fresh leaves 0.057 - 0.059 5 - 7 6 <0.004 0.004 5 0.0042 0.004 0.0041 0.0

Onion, d ry bulb (proposed use = 0.056 lb ai/A total application rate, 30 - day PHI)Page 36 of 62

T able 5. 2. Summary of Residue Data from Crop Field Trials with an Abamectin Formulation

(EC form ulation). Commodity Total

Applic. Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT Median Mean Std. Dev. Onion, dry bulb 0.0567 -

0.0767 29 - 31 16 <0.004 0.0046 0.0043 0.004 0.0040 0.0002 5.3 Water Residue Profile Reference : Abamectin: Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3 - 07A, D P#380524, G. Orrick, 1/31/11. Estimated drinking water concentrations (EDWCs) were provided for parent abamectin. The aquatic photodegradatio n products, which are polar and of low molecular weight, appear to be sugars with low toxicity

relative to the parent. T he delta - 8,9 - isomers (also known as 8,9 - Z isomers) are not included in the drinking water assessment because they were not identified i n the fate studies. The previously included major soil degradate (a mixture of an 8 - α - hydrox y and a ring opened aldeh yde derivative) was not included in the current assessment based on an assumption of stability

of parent until acceptable environmental fate data are submitted . Groundwater and surface water monitoring data are not available for abamectin at this time. Therefore, screening models were used to determine estimated concentrations for abamectin in groundwater and surface water for the prop osed uses. The estimated residues in surface water were derived using the Tier II model PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analy sis Modeling S ys tem). The Tier I SCI - GROW (Screening Concentration in Ground Water) model was used to derive the e stimated concentration in ground water. The modeled values used in this assessment for drinking water were based on residues in surface water from the use of abamectin on dry beans in Michigan. The surface water residue estimates were adjusted for the national default percent cropped area (PCA) adjustment factor of 87%. The estimated residues in ground water were lower than those in surface water. Results from the PRZM/EXAMS screening model predict that the maximum acute (1 - in - 10 year peak) concentration of parent abamectin in surface water is not expected to exceed 2.3 ug/L (ppb), based on the current maximum seasonal use rate of 0.056 lb ai/A/year on dry beans in MI. The maximum chronic (1 - in - 10 year annual mean) concentration of parent abamectin in surface water is not expected to exceed 1.3 ug/L (ppb), based on the one - in - 10 year annual mean and the current maximum seasonal use rate in the M I dry bean scenario. Results from the SCI - GROW screening model predict that the maximum acute and chronic concentration of parent abamectin in shallow ground water is not expected to exceed 1.6 x 10 - 3 ug/L (ppb) based on the current maximum seasonal us e rate on tomatoes and cucurbits of 0.18 lb ai/A/year.Page 37 of 62

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Abam ectin

and its Major Soil Degradates. c Abamectin Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute 2.3 1.6 x 10 - 3 Chronic (non - cancer) 1.3 1.6 x 10 - 3 Chronic (cancer) 0.94 Not applicable a From the Tier II PRZM - EXAMS model. Input parameters for acute and chronic are based on the MI dry bean scenario of 0.056 lb ai/A/year with the percent cropped area adjustment factor of 87%. b From the SCI - GROW model based on the tomato and cucurbits scenario of 0.18 lb ai/A/year. c Data source: D380524, G. Orrick, 1/31/11. 5.4 Dietary Risk Assessment 5.4.1 Description of Residue Data Used in Dietary Assessment Reference s : A bamectin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 on Bulb Onions, Chives, and Dry Beans, DP# 380796, N. Dodd, 6/13/11 . Abamectin : Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3 - 07A , D P# 380524, G. Orrick, 1/31/11 . Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were c onducted using the Dietary Exposure Evaluation Model DEEM - FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. These analy ses were performed to support Section 3 requests for use on the bulb onion subgroup 3 - 07A, chives, and dry bean. Tolerance - level residues and 100% crop treated were used for the proposed crops. No monitoring data were used. Anticipated residues based on field trial data were used. Empirical/default processing factors and percent crop treated (%CT) data were also used . Also, for the chronic dietary

assessment, residues o f abamectin in foods exposed in a food - handling establishment w ere assumed t o be 1⁄2 LOD (0.0002 ppm) (D P# 283668, J. Morales, 20 -NOV 2003). As shown in Section 5.3 above, drinking water values were 2.3 ppb for the acute assessment and 1.3 ppb for the chronic assessment.Page 38 of 62

5.4.2 Percent Crop Treated Used in Dietary Assessment Reference: Usage Report Package in Support of Registration f or the Insecticide Abamectin (122804) , DP#3 82732 , Arthur H. Grube, 10/21 / 10 . A S creening L evel U sage Anal ys is (SLUA) was provided by BEAD based on data years 200 1 - 200 8 ; the SLUA as provided by BEAD is included in the dietary exposure assessment memo (DP#380796, N. Dodd, 6/13/ 11 ). The estimated maximum percent crop treated was used for the acute dietary

risk assessment ; the estimated weighted average percent crop treated was used for the chronic dietary

risk assessment. The percent crop treated data, as used in the acute and chronic food residue input files in the D EEM, are summarized in Table 5.4 .2 below. For other crops , 100% CT was assumed. Table 5.4.2. Screening Level Estimates of Agricul tural Uses of Abamectin dated October 6, 2010 1,2 Crop Percent Crop Treated Average Maximum Almonds 50 75 Apples 5 10 Apricots 5 5 Avocados 40 60 Cantaloupes 15 30 Celery 40 65 Cherries <1 <2.5 Cotton 5 20 Cucumbers 5 10 Grapefruit 60 80 Grapes 10 25 Honeydew 20 35 Lemons 35 55 Lettuce 10 20 Oranges 25 45 Peaches <1 <2.5 Pears 70 80 Pecans <1 <2.5 Peppers 10 25 Potatoes <1 <2.5 Prunes <2.5 10 Pum pkins <2.5 10 Spinach 20 45 Squash 5 10 Straw berries 30 45 Tangerines 60 65 Tomatoes 10 20 Walnuts 10 20 Watermelons 5 10 1 SLUA data sources include the USDA -NASS (United States Department of Agriculture’s National Agricultural Statistics Service); Private Pesticide Market Research; and California DPR (Department of Pesticide Regulation). 2 For chronic, the % CT was used in calculations; if the food handling establishment (FHE) value of 0.0002 ppm wa s greater than the product of residue level x processing factor x % crop treated, then the FHE value was used .Page 39 of 62

5.4.3 Acute Dietary Risk Assessment A refined acute dietary

(food and drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin. Tolerance level residues were used for the proposed crops and okra . Acute anticipated residues for the remaining commodities were derived from field trial data. Empirical and default processing factors and percent crop treated (%CT) were used as available. Estimated drinking water concentrations (EDWCs) from the Environmental Fate and Effe cts Division (EFED) were also included. Surface drinking water concentrations were estimated using the Tier II PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analy sis Modeling Sy stem) computer model and percent c ropped area (PCA) of 87%. The model predic ts that the maximum concentration of total residues of abamectin in surface water (the 1 - in - 10 - ye ar peak exposure) is not likely to exceed 2.3 ppb from the use of aerial/ground application to dry beans in Michigan. As shown in Table 5.4.6, the acute die tary exposure estimates for food and drinking water are below HED’s level of concern (<100% aPAD) at the 99.9 th percentile of exposure for the general U.S. population and all population subgroups . Abamectin dietary exposure at the 99.9 th percentile for fo od and drinking water is 16% of the aPAD for the general U.S. population and 30 % of the aPAD for all infants (<1 ye ar old) , the most highly exposed population subgroup . 5.4.4 Chronic Dietary Risk Assessment A refined chronic dietary (food and drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin. Tolerance level residues were used for the proposed crops and okra . Average residues from field trials were use d for the remaining crops. Empirical and default processing factors and %CT were used as available. Drinking water was represented b y a single point estimate of average abam e ctin residues (the 1 - in - 10 - year annual mean) . The estimated surface water conce ntration of 1.3 ppb was based on the a pplication to dry beans in Michigan. As shown in Table 5.4.6, the chronic dietary exposure estimates for food and drinking water are below HED’s level of concern (<100% cPAD) for the general U.S. population and all po pulation subgroups. Abamectin dietary exposure for food and drinking water is 18% of the cPAD for the general U.S. population and 50% of the cPAD for children 1 - 2 y rs old, the most highly

exposed population subgroup . 5.4.5 Cancer Dietary Risk Assessment The HED RfD/Peer Review Committee classified abamectin as “not likely to be carcinogenic to humans ” based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies.Page 40 of 62

5.4.6 Summary Table Table 5. 4.6 . Results of Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Estim ates for Abamectin. Population Subgroup PAD, mg/kg/day DEEM - FCID

Exposure, mg/kg/day % PAD Acute Dietary Estim ates (99.9 th Percentile of Exposure) U.S. Population 0.005 0.00077 7 16 All infants (< 1 yr) 0.005 0.001 501 30 Children 1 - 2 y

rs 0.005 0.0012 30 25 Children 3 - 5 y

rs 0.005 0.0009 76 20 Children 6 - 12 y

rs 0.005 0.000 599 12 Youth 13 - 19 y

rs 0.005 0.0005 54 1 1 Adults 20 - 49 y

rs 0.005 0.0004 64 9 Adults 50+ yrs 0.005 0.0003 55 7 Females 13 - 49 y

rs 0.005 0.0004 67 9

Chronic Dietary Estimates U.S. Population 0.0004 0.000070 18 All infants (< 1 yr) 0.0004 0.00015 1 38 Children 1 - 2 yrs 0.0004 0.000 199 50 Children 3 - 5 y

rs 0.0004 0.00015 2 38 Children 6 - 12 y

rs 0.0004 0.00009 8 2 4 Youth 13 - 19 y

rs 0.0004 0.000059 15 Adults 20 - 49 y

rs 0.0004 0.000056 14 Adults 50+ yrs 0.0004 0.00005 4 13 Females 13 - 49 y

rs 0.0004 0.000054 13

Cancer Dietary Estim ate U.S. Population Classification: “Not likely to be carcinogenic to humans” based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies.Page 41 of 62

6.0 Residential (Non - Occupational) Exposure/Risk Characterization References: Abamectin . Occupational and Residential Exposure Assessment for Proposed IR - 4 Foliar Uses

on Bulb Onions (Subgroup 3 - 07A), Chives, and Dry Beans, N. Tsaur, DP#380797, 3/29/11 . Abamectin: Occupational and Residential Risk Assessment to Support Section 3 Request for Uses on Various Food Crops and Food -Handling Establishments, J. Arthur, DP#306906, 10/29/04 6.1 Residential Handler Exposure While no residential uses are proposed in the current petition, there are residential uses currently registered fo r abamectin. Short - to intermediate - term exposures may occur to adults from handling the pesticide. Residential handler exposures are assessed below for two uses which are considered to represent the reasonable high - end residential exposure potential: 1) granular baits used to treat lawns; and 2) indoor crack and crevice dust products. The critical exposure (worst case scenario) of all residential uses are accounted for in the aggregate. Lawn Applications Short - /Intermediate - term total MOEs (dermal + inhalation exposures) for residential handlers range from 110,000 to 17,000,000 which are greater than the LOC of 300 , and are not of concern. Exposure and risk assessment inputs and results for residential lawn applicators are summarized in Table 6.1.1 . Crack and Crevice Applications T he short - and intermediate - term MOEs for dermal and inhalation exposure are each 5,000,000. The combined dermal and inhalation MOE is 2,500,000, which is greater than the LOC of 300 and is not of concern. Exposure and risk inputs and estimates are summarized in Table 6.1.2 .Page 42 of 62 Table 6.1. 1. Exposure and Risk Estimate for Residential Lawn Applicators PHED Scenario Exposure Scenario Personal

Protective Equipment Exposure

Route Application

Rate (lb ai/acre) Acres

Treated (acres/ day) Unit

Exposure (m g/lb ai) Data

Confidence Absorption

Factor Body

Weight (k g) Daily Dose 1 (m g/k g/day) Short- and

Intermediate Term NOAEL (m g/k g/day) Short- and

Intermediate Term MOE 2 Granular Bait Dispersed by Hand short sleeves

short pants no gloves Dermal 1.1E - 4 0.023 430 Medium 0.01 60 1.8.0E - 7 0.12 6.7E+5

Inhalation 1.1E - 4 0.023 0.47 Medium 1.0 60 2.0E - 8 0.12 6.0E+6 Total 2.0E - 7 0.12 6.0E+5 Belly Grinder Granular Open Pour (Mix, Load, and Apply) short sleeves

short pants no gloves Dermal 1.1E - 4 0.5 110 Medium 0.01 60 1.0E - 6 0.12 1.2E+5

Inhalation 1.1E - 4 0.5 0.062 High 1.0 60 5.7E - 8 0.12 2.2E+6 Total 1.1E - 6 0.12 1.1E+5 Push Type Granular (Mix, Load, and Apply) short sleeves

short pants no gloves Dermal 1.1E - 4 0.5 0.68 Note 1. 0.01 60 6.0E - 9 0.12 2.0E+7

Inhalation 1.1E - 4 0.5 9.1E - 4 Note 1. 1.0 60 1.0E - 9 0.12 1.2E+8 Total 7.0E - 9 0.12 1.7E+7 1 Daily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x Unit Exposure (mg/lb ai handled) x Absorption Factor]/Body Weight 2 Short - and I

ntermediate - Term MOE = Short - and I ntermediate - Term NOAEL/Daily Dose Note 1. Unit exposure values taken from ORETF study (OMA003) and are consid ered to be more reliable and applicable than PHED values for this scenario. Table 6.1.2. Exposure and Risk Estimate for Residential Application of 0.05% Crack & Crevice Powder PHED Scenario Selected from Draft SOP for Residential Exposure Assessments Clothing Exposure Route Application

Rate 1 (lb ai/day) PHED

Unit Exposure (m g/lb ai) PHED

Data Confidence Absorption

Factor Body

Weight (kg) Daily Dose 2

(m g/kg/day) Short - and

Intermediate Term NOAEL (m g/kg/day) Short - and

Intermediate Term MOE 3 Wettable powder, open mi xing and loading short sleeves short pants no gloves Dermal 3.3 E - 5 4.4 Low 0.01 60 2.4E - 8 0.12 5.0E+6

Inhalation 3.3 E - 5 0.043 Medium 1.0 60 2.4E - 8 0.12 5.0E+6 Total: 4.8E - 8 0.12 2.5E+6 1 Application rate = 5.0E - 4 (0.05% ai) x 30 g/day (weight of 1 package) x 2.2E - 3 lb/g = 3.3E - 5 lb ai/day 2 Daily Dose =[Application rate (lb ai handled/day) x PHED Unit Exposure (mg/lb ai handled) x Absorption Factor]/Body Weight (B W) 3 Short - & Intermediate - Term Dermal or Inhalation MOE = Short - & Intermediate - Term Dermal or Inhalation NOAEL/Daily DosePage 43 of 62

6.2 Residential Post - Application Exposure Since residential uses of a bamectin are currentl y registered, short - to intermediate - term exposures may

occur to both adults and children from contact with treated areas following application. Residential post - application exposures are assessed below for two uses which are considered to represent the reasonable high - end residential exposure potential: 1) granular baits used to treat lawns; and 2) indoor crack and crevice dust products. Recreational exposures to turf are expected to be similar to, or less than, those evaluated in this section. Treated Lawns The only post - application scenario applicable to the granular abamectin formulations used on lawns is ingestion of granules by toddlers. The maximum rate for all registered lawn uses and representative high end exposures w ere used to calculate the margin of exposure. C hildren’s exposure and risk from incidental ingestion of granules from treated lawns is summarized in Table 6.2.1. The acute ingestion MOE for children is 68,000 . Since this MOE is above 300, the risk presented by children’s incidental ingestion of granules is not of concern to HED . Table 6.2.1. Incidental Ingestion of Granules Exposure and Risk for Children fromTreated Lawns Fraction Available Ingestion Rate

(g/day) Body Weight

(kg) Daily Dose 1

(m g/kg/day) NOAEL

(m g/kg/day) MOE 2 0.00011 0.001* 15 0.0000073 0.5 68,000 1 Daily Dose = [Fraction available x Ingestion rate (g/day) x 1000 mg/g] / [Body Weight (kg)] 2 MOE = Acute Dietary NOAEL/Daily Dose. * It should be noted that HED’s Draft Residential SOPs give a standard value of 0.3 g product/day for the ingestion rate (IgR). This value is based on the application of 300 lbs of product distributed evenly over an acr e, which results in approximately 3 grams of product per ft2 . An assumption that a child will ingest one - tenth of what is available in one ft2 of la wn leads to the IgR value of 0.3 g product/day. Because the abamectin lawn product application rate is onl y 1 pound of product per acre, it is appropriate to scale down the standard IgR value, proportionately. Using the SOP methodology, one pound of product, spread evenly over an acre results in 0.01 g/ft2 . One tenth of this gives an ingestion rate of 0.001 g/day. Crack and Crevice Post - application exposure from the use of Avert Prescription Treatment 310 for crack and crevice applications was estimated for adults (dermal and inhalation routes) and children (dermal, inhalation, and incidental oral routes). Children's combined post - application exposure (dermal, incidental oral, and inhalation) and risk, and adults combined post - application exposure (dermal and inhalation) and risk are summarized in Table 6.2.2. Since short - /intermediate - term MOEs from all exposure scenarios are above 300 , the risk from combined adult and combined children’s post - application exposure to crack and crevice products containing abamectin are not of concern.Page 44 of 62 Table 6.2.2. Combined Exposure and Risk fromCrack & Crevice Tre atm ent Exposure Route Data Source 1 Daily Dose (m g/kg/day) Short - and

Intermediate - Term NOAEL (m g/kg/day) Short - and Intermediate Term MOE Children's Combined Dermal, Oral and Inhalation Post - A pplication Exposure and Risk Dermal 1990 Study 2.2E - 7 0.12 5.5E+5 1995 Study 4.4E - 8 2.5E+6 Oral Hand - to - Mouth 1990 Study 7.5E - 7 0.12 1.6E+5 1995 Study 1.6E - 7 7.5E+5 Oral Object - to - Mouth 1990 Study 4.7E - 8 0.12 2.6E+6 1995 Study 1.0E - 8 1.2E+7 Inhalation 1990 Study 1.3E - 4 0.12 920 1995 Study 4.7E - 5 2,600 Total: 1990 Study 1.3E - 4 0.12 920 1995 Study 4.7E - 5 2,600 Adult Combined Handler and Post - Application Dermal and Inhalation Exposure and Risk Handler Dermal PHED 2.4E - 8 0.12 5.0E+6 Handler Inhalation PHED 2.4E - 8 0.12 5.0E+6 Post - application Dermal 1990 Study 1.6E - 7 0.12 7.5E+5 1995 Study 2.9E - 8 4.1E+6 Post - application Inhalation 1990 Study 8.4E - 5 0.12 1,400 1995 Study 3.0E - 5 4,000 Total: PHED & 1990 Study 8.4E - 5 0.12 1,400 PHED & 1995 Study 3.0E - 5 4,000 1 1990 Study: Evaluation of Avert Prescription Treatment 310 Residual Study in Air, Food and on Surfaces , November 8,

1990 (MRID No. 44665901) 1995 Study: Evaluation of Indoor Exposure to a Crack and Crevice Application of Whitmire Avert Crack and Crevice

Prescription Treatment 310 and Prescription TC 93A Bait , October 27, 1995 (MRID No. 44147801)Page 45 of 62

6.3 Spray Drift Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground a pplication method employed for abamectin. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the A gency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product lab els/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast , and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios . So metimes the risk presented from direct application of lawn treatment products can supersede potential risk concerns from agricultural spray drift. However, in the case of abamectin, agricultural use rates are higher than those for residential lawn treatment, and the assessment of post - application risks for abamectin lawn products did not include a dermal exposure component. 7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure

. 7.1 Acute Aggregate Risk The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of abamectin (food and drinking water). The acute aggregate food and drinking water assessment results are presented in Section 5.2 above. The most highly exposed subgroup is all infants (<1 year old) at 30 % of the aPAD , which is below the level of concern.Page 46 of 62

7.2 Short - and Intermediate - Term Aggregate Risk The short - /intermediate - term aggregate risk assessment estimates risks likely to result from exposure to abamectin residues from food, drinking water, and residential pesticide uses. High end estimates of residential exposure are used, while average values ar e used for food and drinking water exposure. A short - /intermediate - term risk assessment is required for adults because there are potential residential handler and post - application exposures from the crack and crevice use. In addition, a short - /intermediate - term risk assessment is required for infants and children because there is a residential post - application exposure scenario for crack and crevice treatment. The ingestion of granules (from the lawn treatment for fire ants) is not included in the aggreg ate assessment because it is considered to be a one - time, episodic event, rather than occurring for several day s (or several months). The results of the short - /intermediate - term aggregate assessments are presented in Table 7.2. HED is generally

not conce rned if the MOEs remain above the LOC, which for this assessment is 300. The MOEs for all scenarios are greater than 300, and therefore, are not of concern. Table 7.2. Short - Termand/or Interm ediate - Term Aggregate Risk Calculations

(Inhalation/Oral/Dermal Endpoints and NOAELs are the Same.) Population Short - or Intermediate - Term Scenario

NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average

Food & Water Exposure mg/kg/day Residential

Exposure 3 mg/kg/day Aggregate MOE

(food and residential) 4 U.S. Population 0.12 300 0.0004 0.000070 0.000030 1200 Children (1 - 2 years old) 0.12 300 0.0004 0.000200 0.000047 500 1 The LOC includes the standard inter- and intra - species uncertainty factors (UF A and UF

H , respectively) totaling 100, a nd an additional factor of 3x for the steepness of the dose - response curve and the severity of effects. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalati on exposure] . Refer to Table 6.2.2 for residential exposure values used in the aggregate assessment. 4 Aggregate MOE = [NOAEL  (Avg Food &W ater Exposure + Residential Exposure)]Page 47 of 62

7.3 Long - Term (Chronic) Aggregate Risk The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of abamectin (food and drinking water) and residential uses. However, due to the use patterns, no chronic residential e xposures are expected. Therefore, the chronic aggregate risk assessment will consider exposure from food and drinking water onl y. The chronic aggregate food and drinking water assessment results are presented in Section 5.2 above. The most highly

expose d subgroup is children 1 - 2 years old at 50% of the cPAD, which is below the level of concern. 7.4 Cancer Risk Abamectin is classified as “not likely to be carcinogenic to humans ” based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies. 8.0 Cumulative Risk Characterization/Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach base d 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 b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that abamectin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effe cts of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway Reference : Abamectin . Occupational and Residential Exposure Assessment for Proposed IR - 4 Foliar Uses

on Bulb Onions (Subgroup 3 - 07A), Chives, and Dry Beans , D380797, N. Tsaur, 3/29/11. Occupational handler exposure to abamectin is expected for individuals involved in foliar applications to bulb onions (subgroup 3 - 07A), chives, and dry beans (mixing, loading, and applying) . Handler exposure is expected to be short - or intermediate - term based on information provided on the proposed label. Agricultural workers performing typical post - application activities (e.g. scouting, irrigation, transplanting/harvesting, etc.) may receive short - and intermediate - term exposure to abamectin residues.Page 48 of 62

9.1 Short -/Intermediate - Term Handler Risk Handler’s exposure and risk were estimated for the following scenarios: mixer/loaders (mixing/ loading liquid to support groundboom or aerial applications ) ; flaggers (flagging to support aerial application); applicators (applying spray s with groundboom or aerial equipment with enclosed cockpit). The minimum level of PPE for handlers is based on acute t oxicity for the end - use product. All three labels state that all handlers must wear the proper PPE: coveralls worn over a short - sleeved shirt with short pants, chemical resistant gloves, chemical - resistant footwear with socks, protective eyewear, chemical - resistant headgear for overhead exposure, and a chemical resistant apron when cleaning equipment, mixing, or loading. The Registration Division (RD) is responsible for ensuring that PPE listed on the label is in compliance with the Worker Protection Standard (WPS). No chemical - specific handler exposure data were submitted in support of this Section 3 registration. In accordance with HED’s Exposure Scie nce Advisory Council (SAC) policy , exposure data from the Pesticide Handlers Exposure Database (PHED) , Version 1.1, as presented in PHED Surrogate Exposure Guide (8/98), were used with other HED standard values for acres treated per day , body weight, and the level of personal protective equipment to assess handler exposures. Exposure/risk assessments were performed using applicable toxicity endpoints. Daily

dermal and inhalation exposures were calculated separately , appl yi ng a dermal absorption factor of 1%, and an inhalation absorption factor of 100%. T he dermal and inhalation exposures were added together and compared to the common NOAEL of 0.12 mg/kg/day (from c ombined data from three reproduction studies and two development al neurotoxicity studies where the LOAEL = 0.2 mg/kg/day

based on decreased pup body weight) to determine the handler risk (from total dermal and inhalation exposure) for short - and intermediate - term exposures. The total MOEs (when gloves are added to the mixing/loading scenarios) range from 750 (fo r open mixing/loading of liquid to support aerial application with PPE including gloves ) to 91 00 (for appl yi ng sprays via aerial equipment (en closed cockpit) . These MOEs do not exceed HED’s level of concern of 300 (when gloves are added to the m ixing/loading scenario s ). Assumptions and estimates for occupational handler exposure are summarized in Tables 9.1.1 and 9.1.2.Page 49 of 62

Table 9.1.1. Abam ectin Short - and Interm ediate - Term Agricultural Occupational Exposures and Risks (Baseline: single layer, no gloves, no respirator). Exposure Scenario Application Rate a Area

Treated Daily b Dermal

UE c Inhalation

UE c Dermal

Dose d Dermal

MOE e Inhalation

Dose f Inhalation

MOE g Com

bined Dose h ST/IT

Com bined MOE i lb ai/A acres mg/lb ai mg/lb ai mg/kg/day LOC = 300 mg/kg/day LOC = 300 mg/kg/day LOC = 300 Mixer/Loader Mixing/Loading Liquid for Groundboom Applications 0.0191 80 2.9 0.0012 0.00074 160 0.000031 3900 0.00077 160 Mixing/Loading Liquid for Aerial Applications 0.0191 350 2.9 0.0012 0.0032 37 0.00013 900 0.0034 36 Flagger Flagging for Aerial Application 0.0191 350 0.011 0.00035 0.000012 9800 0.000039 3100 0.000051 2300 Applicator Applying Sprays via Groundboom Equipment 0.0191 80 0.014 0.00074 0.0000036 34,000 0.000019 6000 0.000022 5300 Applying Sprays via Aerial Equipment j 0.0191 350 0.0050 0.00007 0.0000056 21,000 0.0000076 16,000 0.000013 9100 a Application Rates based on maximum proposed use rate s for abamectin labels: EPA Reg. No. 100 - 898, EPA Reg. No. 100 - 1351 , EPA Reg. No. 100 - 1154 . b Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1. c UE = Unit Exposures based on PHED Version 1.1 data. Baseline = single layer, no gloves, no respirator. d Dermal Dose (mg/kg/day) = application rate ( lb ai/acre ) x amount handled /day ( acres/day) x daily unit exposure (mg/lb ai) x absorptio n factor (1%) / body weight (60 kg). e Dermal M argin of Exposure = NOAEL (mg/kg/day) / Dermal Dose ( mg/kg/day). Level of concern = 3 00. Short - and Intermediate - Term NOAEL = 0.12 mg/kg/day. f Inhalation Dose (mg/kg/day) = application rate ( lb ai/acre ) x amount handled /day ( acres/day) x daily unit exposure (mg/lb ai) x absorptio n factor (100%) / body weight (60 kg). g Inhalation M argin of Exposure = NOAEL (mg/kg/day) / Inhalation Dose ( mg/kg/day). Level of concern = 3 00. Short - and Intermediate - Term NOAEL = 0.12 mg/kg/day. h Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day). i Short - and Intermediate - Term Combined Margin of Exposure = NOAEL (mg/kg/day) / Combined Dose ( mg/kg/day). Level of concern = 3 00. ST/IT NOAEL = 0.12 mg/kg/day. j Only engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircraft (enclosed ca b, no gloves, no respirator) .Page 50 of 62

Table 9.1.2. Abam ectin Short - and Interm ediate - Term Agricultural Occupational Exposures and Risks (PPE: single layer, gloves, no respirator). Exposure Scenario Application Rate a Area

Treated Daily b Dermal

UEs c Inhalation

UEs c Dermal

Dose d Dermal

MOE e Inhalation

Dose f Inhalation

MOE g Com

bined Dose h ST/IT

Com bined MOE i lb ai/A acres mg/lb ai mg/lb ai mg/kg/day LOC = 300 mg/kg/day LOC = 300 mg/kg/day LOC = 300 Mixer/Loader Mixing/Loading Liquid for Groundboom Applications 0.0191 80 0.023 0.0012 0.0000059 20,000 0.000031 3900 0.000036 3300 Mixing/Loading Liquid for Aerial Applications 0.0191 350 0.023 0.0012 0.000026 4700 0.00013 900 0.00016 750 a Application Rates based on maximum proposed use rate s for abamectin labels: EPA Reg. No. 100 - 898, EPA Reg. No. 100 - 1351, EPA Reg. No. 100 - 1154 . b Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1. c UE = Unit Exposures based on PHED Version 1.1 data. PPE = single layer, gloves, no respirator. d Dermal Dose (mg/kg/day) = application rate ( lb ai/acre ) x amount handled /day ( acres/day) x daily unit exposure (mg/lb ai) x absorptio n factor (1%) / body weight (60 kg). e Dermal M argin of Exposure = NOAEL (mg/kg/day) / Dermal Dose ( mg/kg/day). Level of concern = 3 00. Short - and Intermediate - Term NOAEL = 0.12 mg/kg/day. f Inhalation Dose (mg/kg/day) = application rate ( lb ai/acre ) x amount handled /day ( acres/day) x daily unit exposure (mg/lb ai) x absorptio n factor (100%) / body weight (60 kg). g Inhalation Margin of Exposure = NOAEL (mg/kg/day) / Inhalation Dose ( mg/kg/day). Level of concern = 3 00. Short - and Intermediate - Term NOAEL = 0.12 mg/kg/day. h Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day). i Short - and Intermediate - Term Co mbined Margin of Exposure = NOAEL (mg/kg/day) / Combined Dose ( mg/kg/day). Level of concern = 3 00. ST/IT NOAEL = 0.12 mg/kg/day.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 51 of 62 9 .2 Occupational Post -Application Exposures and Risks Short -/Intermediate -/Long - Term Post - Application Risk There is a potential for post - application exposure to scouts, harvesters and other field workers following foliar application to agricultural crops. Chemical - specific post - application exposure data were not provided. The transfer coefficients used in this assessment are from the transfer coefficient standard operating procedure (SOP) developed b y HED’s Science Advis ory Council (SAC) for Exposure (Exposure SAC Policy No. 3.1, “Agricultural Transfer Coefficients,” August 2000) using proprietary data from the Agricultural Re - entry Task Force (ARTF) database). Also, this assessment uses HED’s default assumption that 20% of the application rate is available for transfer on the day of treatment, and that th e residue dissipates at a rate of 10% per day thereafter. The short - and intermediate - term MOEs for post - application exposure on day 0 (12 hours after application) ran ge from 840 to 21 ,000. Since these calculated MOEs are greater than 300 on the day of application, they do not exceed HED’s level of concern . A summary of the post application exposure and risk as sessment is presented in Table 9.2 . HED’s post - application exposure estimates are based on surrogate data. The transfer coefficients are considered to be central tendency . Maximum application rates were used in this assessment. Overall, the post - application risks are characterized as being central t o high - end estimates. The post - application exposure associated with agricultural crops is summarized in Table 9.2 . All scenarios resul ted in MOEs greater than 3 00 (ranging from 840 to 21,000) on day 0 (12 hours after application) and , therefore , are not of concern to HED.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 52 of 62 Table 9.2. Short - and Intermediate - Term Post - Application Exposures and Risk for Abamectin. Crop Grouping/Crop Activity Transfer Coefficient Day s After

Treatment DFR a Daily Dermal Dose b Dermal

MOE c μg/cm 2 mg/kg/day LOC = 3 00 Bulb Onions (Subgroup 3 - 07A) irrigation, scouting,

thinning, hand weeding 300 0 (12 hours) 0.0429 0.000017 7,000

Chives hand harvesting, thinning 2500 0 (12 hours) 0.0429 0.000143 840 irrigation, scouting 1500 0 (12 hours) 0.0429 0.000086 1,400 hand weeding 500 0 (12 hours) 0.0429 0.000029 4,200 Dry Beans hand harvesting 2500 0 (12 hours) 0.0429 0.000143 840 irrigation, scouting 1500 0 (12 hours) 0.0429 0.000086 1,400 hand weeding 100 0 (12 hours) 0.0429 0.0000057 21,000 a DFR (μg/cm2 ) = application rate (lb ai/acre) x fraction of application rate dislodgeable on day 0 (20%) x (1 - fraction of residue that dissipates daily 10%) t x 4.54E8 μg/lb x 2.47E - 8 acre/cm2

. b Short -/Intermediate - Term Daily Dermal Dose = [DFR (μg/cm2 ) x Transfer Coefficient x 0.001 mg/μg x 8 hrs/day x dermal absorption 1%]  body weight (60 kg adult). c Short -/Intermediate - Term MOE = NOAEL (mg/kg/day) /Daily Dermal Dose (mg/kg/day) . ST/IT NOAEL = 0.12 mg/kg/day . Restricted Entry

Interval Since both sh ort - and intermediate - term post - application risks were not a concern on day 0 (12 hours following application), the REI is based on the acute toxicity of abamectin technical material. Under WPS for Agricultural Pesticides , a ctive ingredients classified as acute T oxici ty Category III or IV for Acute Dermal, Eye Irritation, and Primary Skin Irritation are assigned a 12 - hour REI. Thus, the 12 - hour REI on the proposed labels are acceptable. Occupational Post - Application Inhalation Exposure Based on the Agenc y's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for abamectin at this time. However, there are multiple potential sources of post - application inhalation exposure to individuals performin g post application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force. The Agency may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put i nto place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for abamectin.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 53 of 62 10.0 References N. Dodd, 5/18/11, DP#380795, Abamectin . Petition for Tolerances/Section 3 Registration on the Bulb Onion Subgroup 3 - 07A, Chives, and Dry Beans. Summary of Analytical Chemistry and Residue Data . N. Dodd, 6/13/11, DP#380796, Abamectin . Acute and Chronic Aggregate Dietary (Food and Drinking W

ater) Exposure and Risk Assessments for the Section 3 on Bulb Onions, Chives, and Dry Beans . A. Grube, 10/21/10 , DP#382732, Usage Report Package in Support of Registration for the Insecticide Abamectin (122804) . N. Tsaur, 3/29/11, D P# 380797, Abamectin . Occupational and Residential Exposure Assessment for Proposed IR - 4 Foliar Uses on Bulb Onions (Subgroup 3 - 07A), Chives, and Dry Beans . J. Arthur, 10/29/04 , DP#306906 , Abamectin : Occupational and Residential Risk Assessment to Support Section 3 Request for Uses on Various Food Crops and Food -Handling Establishments . G. Orrick, 1/31/11, D P# 380524, Abamectin : Drinking W ater E xposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3 - 07A . N. Dodd et al., 3/11/09, DP#362615, Abamectin . Revised Human Health Risk Assessment for Proposed Uses on Pasture and Rangeland Grass, Stone Fruit Crop Group 12, Tree Nut Crop Group 14, Pistachio, Tuberous and Corm Vegetables Subgroup 1C and Request for Cattle Ear Tag Use.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 54 of 62 Appendix A: Toxicology Assessment Table A.1. Acute Toxicity of Abam ectin Technical Guideline No. Study Type MRID # Results Toxicity Category 870.1100 Ac ute Oral - rat

(sesame oil vehicle) 006894 LD 50 = 13.6 mg/kg I 870.1100 Ac ute Oral - rat

(methyl cellulose vehicle) 45607202 LD 50 =214 - 232 mg/kg II 870.1200 Ac ute Dermal - rabbit 00255978 LD 50 = 2000 mg/kg III 870.1300 Ac ute Inhalation - rat 45623501 LC 50 =< 0.21 mg/L (nose only) I 870.2400 Primary Eye Irritation 45063501 not an irritant IV 870.2500 Primary Skin Irritation 41123904 slight irritation III 870.2600 Dermal Sensitization 00139564 negative in Buehler Negative 870.6200a Ac ute Neurotoxicity none none none Table A.2. Toxicity Profile of Abam ectin Technical for Repeated Dosing and Genotoxicity Studies Guideline No./ Study Type MRID No. / Classification /Doses Results 870.3100 Subchronic feeding study - rats 00131081 (1982)

Unacceptable/Non guideline 0, 0.10, 0.20, 0.40 mg/kg/day NOAEL > 0.40 mg/kg/day LOAEL = not established

870.3150 Subchronic toxicity Dogs (18 week gavage study) 00131082 (1982)

Acceptable/Guideline 0, 0.25, 0.5, 2.0, 8.0 mg/kg/day NOAEL = 0.25 mg/kg/day LOAEL = 0.50 mg/kg/day based on body tremors, one death, liver pathology, decreased body weight. Mydriasis was seen during week one in one dog. 870.3150 12 - Week dose range finding study - dogs (feeding) 00164152 (1982)

0.25, 0.50, 1.0, and 4.0/2.0 mg/kg/day (during week 4, 4.0 mg/kg/day wa s reduced to 2.0 mg/kg/day due to tremor, weakness, incoordination, and disorientation) The report stated that mydriasis wa s seen in 1.0 and 4.0 mg/kg/day dogs during week 1.The effect was not seen at each examination day for any dog, but it was generally noted from 1 to 5 times a week. However, mydriasis was never noted at 0.5 and 0.25 mg/kg/day.

870.3200 21/28 - Day dermal toxicity Study not available. Study not available.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 55 of 62 Table A.2. Toxicity Profile of Abam ectin Technical for Repeated Dosing and Genotoxicity Studies Guideline No./ Study Type MRID No. / Classification /Doses Results 870.4300a Com bined Chronic toxicity/carcinogenici ty - rats 40069601, 40375511,

40517801 (1985) Acceptable/Guideline 0, 0.75, 1.5, 2.0 mg/kg/day NOAEL = 1.5 mg/kg/day LOAEL = 2.0 mg/kg/day based on tremors No evidence of carcinogenicity 870.4100b Chronic toxicity dogs 40375510 (1987)

Acceptable/Guideline 0, 0.25, 0.5, 1.0 mg/kg/day NOAEL = 0.25 mg/kg/day LOAEL = 0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day 870.4300b Com bined Chronic toxicity/Carcinogenic ity - mice 40069602, 40375512,

40517801 (1985) Acceptable/Guideline 0, 2, 4, 8 mg/kg/day NOAEL = 4.0 mg/kg/day LOAEL = 8.0 mg/kg/day based on increased mortality in males, tremors, body weight decreases in females, dermatitis in males, extramedullary hematopoiesis in spleen of males No evidence of carcinogenicity 870.3700a Prenatal developmental in rodents - rats Accession: 00130819

(1982) Acceptable/guideline 0, 0.4, 0.8, 1.6 mg/kg/day Maternal NOAEL > 1.6 mg/kg/day Maternal LOAEL = not established Developm ental NOAEL > 1.6 mg/kg/day LOAEL = not established 870.3700a Prenatal developmental in rodents - CD - 1 mouse 44179901 (1999)

Acceptable/Non - Guideline 0, 0.75, 1.5, 3.0 mg/kg/day Maternal NOAEL = 1.5 mg/kg/day Maternal LOAEL = 3.0 mg/kg/day based on hind limb splay Developm ental NOAEL < 0.75 mg/kg/day Developm ental LOAEL = 0.75 mg/kg/day based on hind limb extension 870.3700b Prenatal developmental in nonrodents - rabbits Accession: 00130819

(1982) Acceptable./Guideline 0, 0.5, 1.0, 2.0 mg/kg/day Maternal NOAEL = 1.0 mg/kg/day Maternal LOAEL = 2.0 mg/kg/day based on decreased body weight, food consumption and water consumption Developm ental NOAEL = 1.0 mg/kg/day LOAEL = 2.0 mg/kg/day based on cleft palate, clubbed foot, delayed ossification of sternebrae, metacarpals, phalanges 870.3800a 2 - Generation Reproduction and fertility effects - rat 00164151 (1984)

Acceptable/Guideline 0, 0.05, 0.12, 0.40 mg/kg/day Parental/Systemic NOAEL = 0.40 mg/kg/day LOAEL =not established Reproductive NOAEL = 0.40 mg/kg/day LOAEL = not established Offspring NOAEL = 0.12 mg/kg/day LOAEL = 0.40 mg/kg/day based on increased retinal folds, increased dead pups at birth, decreased viability and lactation indices, decreased pup body weight 870.3800b 1 - Generation Reproduction and fertility effects - rat 00096450

Unacceptable/Non Guideline 0, 0.5, 1.0, 1.5/2.0 mg/kg/day Parental/Systemic NOAEL = 1.0 mg/kg/day. LOAEL=1.5/2.0 based on whole body tremors, ataxia, ptyalis, ocular/nasal discharges and mortality Reproductive NOAEL = 3.0 mg/kg/day Offspring NOAEL < 0.5 mg/kg/day LOAEL = 0.5 mg/kg/day based on decreased pup survival and body weight between days 1 - 21 and delay in opening of eyesDRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 56 of 62 Table A.2. Toxicity Profile of Abam ectin Technical for Repeated Dosing and Genotoxicity Studies Guideline No./ Study Type MRID No. / Classification /Doses Results 870.3800c 1 - Generation Reproduction and fertility effects - rat 00096451

Unacceptable/Non guideline 0, 0.1, 0.2, 0.4 mg/kg/day Parental/Systemic NOAEL = 0.4 mg/kg/day LOAEL = not established Reproductive NOAEL = 0.4 mg/kg/day Offspring NOAEL =0.1 mg/kg/day LOAEL = 0.2 mg/kg/day based on spastic movements and, delayed incisor eruption 870.3800c 1 - Generation Reproduction and fertility effects - rat 40713404 (1988)

Acceptable/Non - guideline 0, 0.1, 0.2, 0.4 mg/kg/day with delta - 8,9 isom er 0, 0.06, 0.12, 0.40 mg/kg/day Parental/Systemic NOAEL = 0.4 mg/kg/day LOAEL = not established Reproductive NOAEL = 0.4 mg/kg/day Offspring NOAEL =0.4 mg/kg/day LOAEL = not established Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay Accession: 246894,

265568, 265569 (1986) Acceptable/Guideline Three studies: (1) 0, 3, 10, 30, 100, 1000 ug/plate, (2) 0, 100, 300, 1000, 3000, 10,000 ug/plate both with and without S - 9, (3) doses not specified. negative both with and without S - 9

870 - 6100 Ac ute neurotoxicity in rats (gavage) 46959202 (2006)

Acceptable/guideline 0.5, 1.5, and 6.0 mg/kg NOAEL = 0.5 mg/kg/day LOAEL = 1.5 mg/kg/day based on reduced splay reflex in males and females. At high dose, decreased motor activity, reduced splay reflex, & tip toe gait were seen. No death or histopathological changes in nervous system were found. 870 - 6200 Subchronic neurotoxicity in rats (gavage) 46959201 (2006)

Acceptable/guideline 0.4, 1.6, and 4.0 mg/kg/day NOAEL = 1.6 mg/kg/day LOAEL = 4.0 mg/kg/day based on upward curvature of the spine, tip - toe gate, decreased fore - and hind - limb grip strength. Decreased body was also seen. This dose group was terminated prematurely at week 7. 870 - 630 Developmental neurotoxicity study in rats 46727403, 46727402,

46727401 (2005) Acceptable/nonguideline 0.12, 0.20, and 0.40 mg/kg/day. Pups were not directly dose. Maternal NOAEL = 0.4 mg/kg/day (HDT) Offspring NOAEL = 0.2 mg/kg/day. Offspring LOAEL= 0.4 mg/kg/day based on decreased body weight in males and females.. 870 - 6200 Developmental neurotoxicity study in rats 47116201 (2007)

Acceptable/nonguideline 0.12, 0.20, and 0.40 mg/kg/day. Pups were not directly dosed. Maternal NOAEL = 0.4 mg/kg/day (HDT) Offspring NOAEL =0.12 mg/kg/day. Offspring LOAEL = 0.2 mg/kg/day based on slight but statistically significant decrease in pup body weight.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 57 of 62 Table A.2. Toxicity Profile of Abam ectin Technical for Repeated Dosing and Genotoxicity Studies Guideline No./ Study Type MRID No. / Classification /Doses Results Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay 40713402 (1988)

Acceptable/Guideline doses not specified up to 3000 ug/plate both with and without S - 9 using delta - 8,9 isomer negative both with and without S - 9 up to 3000 ug/plate

Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay 40713405 (1988)

Acceptable/Guideline doses up to 10,000 ug/plate both with and without S - 9 using polar degradates negative both with and without S - 9

Gene Mutation 870.5300 CHO/HGPRT Forward Mutation Assay 265570 (1986)

Acceptable/Guideline both with and without S - 9 Negative

Gene Mutation 870.5300 Mammalian cells in culture in V79 cells MRID Unavailable

1983 Acceptable/Guideline Not mutagenic for V79 cells in absence of S - 9, but in the presence of S - 9 appeared to have a mutagenic potential, provided the test cells had an appropriate level of sensitivity Cy togenetics 870.5395 in vivo micronucleus assay - male mice MRID Unavailable

Acceptable/non - Guideline 0, 1.2, 12.0 mg/kg i.p. No chromosomal aberrations in male mice, but females not tested

Other Effects 870.5550 MRID Unavailable

(1983) 0.3 and 0.6 mM single strand DNA breaks at 0.3 and 0.6 mM in rat hepatocytes in vitro, but negative when hepatocytes from rat at LD50 dose level wa s used Metabolism Accession: 252114

Unacceptable/Non Guideline 69 - 82% of label is excreted in feces by day 7; T 1⁄2 =1.2 days. The reliability of these data is questionable. Metabolism No MRID

(1985) Nonguideline Avermectin B 1a did not bioaccumulate in rat tissues. Half - life slightly longer in females than in males for several tissues. Metabolism No MRID

(1985) Nonguideline The metabolism of avermectin B 1 in rats results in the formation of 24 - OH - Me - B 1a and accounts for most of the radiolabeled residues. Avermectin B 1a does not bioaccumulate. 870.7600 Dermal penetration Accession: 265590 (1986)

Acceptable/ Nonguideline in Monkeys Dermal penetration is 1%.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 58 of 62 Table A.3. Toxicity Profile of Abam ectin Technical - for CF1 Mice Guideline No./ Study Type MRID No. / Classification /Doses Results 870.3700a Prenatal developmental in rodents - CF1 mouse 44160501 (1996)

Acceptable/Non - Guideline 0, 1.5 mg/kg/day on gestation days (GD) 6 - 15 to females which were heterozygous (+/ - ) and homozygous ( - / - , +/+) for p - glycoprotein and then mated to heterozygous and homozygous males Maternal NOAEL = 1.5 mg/kg/day Maternal LOAEL = not established 97% of ( - , - ) fetuses, 40% of (+, - ) fetuses, and 0% of (+,+) fetuses had cleft palate. It was determined that the observed increase in cleft palate in CF - 1 mice following treatment appears to be a consequence of fetal P glycoprotein genoty

pe. 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1986)

Acceptable/Guideline 0, 1.5, 3.0, 6.25, 12.5, 25, 50 mg/kg/day with delta - 8,9 isomer Maternal NOAEL < 1.5 mg/kg/day Maternal LOAEL = 1.5 mg/kg/day (mortality) Developm ental NOAEL < 1.5 mg/kg/day LOAEL = 1.5 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1986)

Acceptable/Guideline 0, 0.03, 0.1, 0.5 mg/kg/day with delta - 8,9 isomer Maternal NOAEL = 0.1 mg/kg/day Maternal LOAEL = 0.5 mg/kg/day (mortality) Developm ental NOAEL = 0.03 mg/kg/day LOAEL = 0.1 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1985)

Acceptable/Guideline 0, 0.05, 0.1, 0.5, 1.0 mg/kg/day with deta - 8,9 isomer Maternal NOAEL = 0.1 mg/kg/day Maternal LOAEL = 0.5 mg/kg/day (mortality) Developm ental NOAEL = 0.05 mg/kg/day LOAEL = 0.1 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 40912701 (1988)

Acceptable/Guideline 0, 0.25, 0.50, 1.0 mg/kg/day with citrus derived polar degradates Maternal NOAEL > 1.0 mg/kg/day Maternal LOAEL = not established Developm ental NOAEL > 1.0 mg/kg/d ay LOAEL =not established 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 073759, 073761 (1984)

Acceptable/Non - Guideline 0, 0.1, 0.3, 0.6 mg/kg/day Maternal NOAEL = 0.1 mg/kg/day Maternal LOAEL = 0.3 mg/kg/day (mortality, tremors) 870.3700a Prenatal developmental in rodents - CF1 mouse 00096446 (1986)

Acceptable/Guideline 0, 0.1, 0.2, 0.4, 0.8 mg/kg/day Maternal NOAEL < 0.1 mg/kg/day Maternal LOAEL = 0.1 mg/kg/day (mortality) Developm ental NOAEL = 0.2 mg/kg/day LOAEL = 0.4 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1985)

Acceptable/Guideline 0, 0.01, 0.03, 0.06 mg/kg/day with delta - 8,9 isomer Maternal NOAEL > 0.06 mg/kg/day Maternal LOAEL = not established Developm ental NOAEL > 0.06 mg/kg/day LOAEL = not established 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 40713406 (1986)

Acceptable/Guideline 0, 0.25, 0.50, 1.0 mg/kg/day with polar degradates of abamectin Maternal NOAEL > 1.0 mg/kg/day Maternal LOAEL = not established Developm ental NOAEL > 1.0 mg/kg/day LOAEL = not establishedDRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 59 of 62 Appendix B : Toxicology Literature References Dawson GR, Wafford KA, Smith A, Marshall GR, Bayley PJ, Schaeffer JM, Meinke PT, McKernan RM. (2000) Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gama - aminobutyric acid (A) receptor. J . Pharmacol . Exp . Ther. 295: 1051 - 10 60. Huang J, Casida JE. (1997) Avermectin B 1 a binds to high - and low - affinity sites with dual effects on the gama - aminobuty ric acid - gated chloride channel of cultured cerebellar granule neurons. J. Pharmacol. Exp. Ther. 281: 261 - 266. Kerb R (2006) Implication of genetic pol ym orphism in drug transporters for pharmacotherap y. Cancer Lett. 234: 4 - 33. Kerr D I and Ong J. (1986) Gama - aminobuty ric acid - dependent motility induced by

avermectin B 1a in the isolated intestine of the guinea pigs . Neurosci . Lett. 65: 7 - 10. Lankas GR, Cartwright ME, and Umbenhauer D (1997) P - Gl ycoprotein deficiency in a subpopulation of CF - 1 mice enhances avermectin - induced neurotoxicity . Toxicol. and Appl. Pharmacol. 143: 357 - 365. Marzolini C, Paus E, Buclin T , and Kim RB (2004) Poly morphism I human MDR1 (P gl ycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther. 75: 13 - 33. Meister B. (2007) Neurotransmitters in key neurons of the hy

pothalamus that regulate feeding behavior and bo dy

weight. Physiol . Behav. 92: 263 - 2 71. Nguye n L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G. (2001) Neurotransmitters as earl y signals for central nervous s ys tem development. Cell Tissue Res . 305: 187 - 202. Pong SS, DeHaven R, Wang CC. (1982) A comparative study of avermectin B 1a and other modulators of the gama - aminobuty ric receptor - chloride ion channel complex. J . Neurosci. 2: 966 - 9 71 . Represa A, Ben - Ari Y. (2005) Trophic actions of GABA on neuronal development. Trends Neurosci. 28: 278 - 2 83. Habashi, SL(2006) Dubin - Johnson Sy ndrome. http://www.emedicine.com/med/topic 588.htm Wang CC, Pong SS. (1982) Actions of avermectin B 1a on GABA nerves. Prog . Clin . Biol . Res. 97: 373 - 3 95.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 60 of 62 Appendix C : Physical/Chemical Properties Table C. Physiochemical Properties Parameter Value Reference 1 Molecular Weight 873.11 Melting point/range 155 - 157°C Accession No. 260785 pH Not available Density 1.16 g/cm3 at 21°C Accession No. 260785 Water solubility (20°C) < 0.01 mg/mL in distilled water < 0.001 mg/mL in tap water < 0.001 mg/mL in buffer system pH 6, 7.4 & 9.0 < 0.001 mg/mL in 0.9% NaCl Accession No. 260785

Solvent solubility (20°C to 25°C) > 3 mg/mL in ethanol; >2 mg/mL in isopropyl myristate, chloroform, dimethylacetamide, dimethylformamide, glycerol formal & polyethylene glycol 400. Accession No. 260785 Vapor pressure (25°C) 1.5 x 10 - 9 hPa Accession No. 260785 Dissociation constant, pKa Not available Octanol/water partition coefficient, Log(KOW) 9.9 x 10 - 3 Accession No. 260785 UV/visible absorption spectrum Not available 1 Product Chemistry data were reviewed by Leung Cheng (Accession No. 260785, RCB No. 388, 5/1/1986).DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 61 of 62 Appendix D : Review of Human Research T his risk assessment relies in part on data from Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) database in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies have been reviewed for ethical conduct and have been determined to be ethical. The two studies used to estimate residential post - application exposure from abamectin crack and crevice products [ref: “Evaluation of Avert Prescription Treatment 310 Residual Study in Air, Food and on Surfaces,” dated November 8, 1990 (MRID No. 44665901), and “Ev aluation of Indoor Exposure to a Crack and Crevice Application of Whitmire Avert Crack and Crevice Prescription Treatment 310 and Prescription TC 93A Bait,” dated October 27, 1995 (MRID No. 44147801)] measured only ambient concentrations of abamectin in treated areas and did not involve collection of data for estimation of direct human exposure from the application activity . Therefore, the requirements for ethical review or for review b y the Human Studies Review Board are not applicable to these studies.DRAFT INTERNAL CONFIDENTIAL AND DELIBERATIVE

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Page 62 of 62 Appendix E : International Residue Limit s Abamectin (PC Code 122804 ; 03/31/2011) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico Codex 40 CFR 180.449: Plant/Livestock: sum of 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 - demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )) and its delta - 8,9 - isomer avermectin B 1 (a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demethyl avermectin A 1a) and less than or equal to 20% avermectin B 1b (5 - O demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1a) and its delta - 8,9 - i somer) Plants: sum of avermectin B1a, avermectin B1b, 8,9 - Z - av ermectin B1a an d 8,9 - Z avermectin B1b. Animal commodities: sum of avermectin B1a and 8, 9 - Z avermectin B1a. Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico Codex Onion, bulb, subgroup 3 - 07A 0.01 Chive, fresh leaves 0.01 Chive, dried leaves 0.02 Bean, dry, seed , except cowpea 0.01

Completed: M. Negussie; 03/31/2011