### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 1 of 78 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Date: DRAFT June 30, 2015

SUBJECT: Abamectin. Human Health Risk Assessment for Uses on the Caneberry Subgroup 13-07A, Soybeans, Sweet Corn, Ear Tags for Lactating Dairy Cattle, and Golf Course Turf.

PC Code: 122804 Decision No.: 480177 Petition Nos.: 3E8175, 3F8184 Risk Assessment Type: Single Chemical/Aggregate TXR No.: NA MRID No.: NA DP Barcode: D426599 Registration Nos.: 100-898, 100-1154, 100-1350, 100-1351, 100-1408, 100-1439, 100-RLNO, 100- RLRN, 39039-17 Regulatory Action: Section 3 Registration Case No.: NA CAS No.: 71751-41-2 40 CFR: 180.449



### FROM: Nancy Dodd, Chemist/Risk Assessor Whang Phang, Senior Toxicologist Nancy Keller, Chemist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P)

THROUGH: Christine Olinger, Branch Chief Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P)

TO: Mark Suarez/Jessica Rogala, PM#7 Invertebrate and Vertebrate Branch 3 Registration Division (7505P) and Barbara Madden/Sidney Jackson, PM#5 Minor Use and Emergency Response Branch Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (O PP) has requested the Health Effects Division (HED) to conduct dietar y, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed uses of abamectin, also known as avermectin B 1 

### [a mixture of avermectins containing ≥ 80% avermectin B 1a 

### (5- O -demethyl avermectin A 1 

### ) and ≤ 20% avermectin B 1b 

### (5- O -demethyl25-de (1-methylpropyl)-25-(1-m ethylethyl) avermectin A 1 

### )], and its delta-8,9-isomer on the

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 2 of 78 caneberry subgroup 13-07A, soybeans, sweet corn, ear tags for lactating dairy cattle, and golf course turf.

HED evaluated the abamectin petition and determined that potential exposure could occur via the dietary (food and drinking wate r), residential, and occupati onal exposure pathways. HED determined that there is reasonable certainty that no harm will result to the general population and to infants and children from aggregate e xposure resulting from the proposed uses of abamectin on caneberries, soybeans, sweet corn, dair y cattle ear tags, and gol f course turf. Also, HED has conducted a screening level cumulative assessment which indicates 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 combin ed proposed/registered uses of abamectin and the registered uses of emamectin. The Agency expects that the screening level cumulative residues overestimate actua l cumulative residues.

The HED team members contributing to this risk assessment incl ude: Nancy Dodd (risk assessment/residue chemistry review/dieta ry exposure assessment), Nancy Keller (occupational/residential exposure assessment) , and Whang Phang (toxicology assessment). Greg Orrick of the Environmental Fate & Eff ects Division (EFED) provided the drinking water exposure assessment.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 3 of 78 TABLE OF CONTENTS 1.0 Executive Summary ........................................................................................................... 5 2.0 HED Recommendations .................................................................................................... 8 2.1 Data Deficiencies ............................................................................................................ 8 2.2 Tolerance Considerations .............................................................................................. 8 2.2.1 Enforcement Analytical Method ............................................................................... 8 2.2.2 Recommended Tolerances ......................................................................................... 8 2.2.3 Revisions to Petitioned-For Tolerances .................................................................... 9 2.2.4 International Harmonization................................................................................... 10 3.0 Introduction .................................................................................................................. .... 10 3.1 Chemical Identity ......................................................................................................... 11 3.2 Physical/Chemical Characteristics ............................................................................. 12 3.3 Pesticide Use Pattern .................................................................................................... 12 3.4 Anticipated Exposure Pathways ................................................................................. 16 3.5 Consideration of Environmental Justice .................................................................... 17 4.0 Hazard Characterization and Dose-Response Assessment .......................................... 17 4.1 Toxicological Studies Available for Analysis ............................................................. 19 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............................. 19 4.2.1 Dermal Absorption ................................................................................................... 20 4.3 Toxicological Effects .................................................................................................... 20 4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 21 4.4.1 Completeness of the Toxicology Database .............................................................. 21 4.4.2 Evidence of Neurotoxicity ........................................................................................ 21 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........ 21 4.4.4 Residual Uncertainty in the Exposure Database ................................................... 22 4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 23 5.0 Dietary Exposure and Risk Assessment ......................................................................... 26 5.1 Residues of Concern Summary and Rationale .......................................................... 26 5.2 Food Residue Profile .................................................................................................... 26 5.3 Water Residue Profile .................................................................................................. 27 5.4.1 Description of Residue Data Us ed in Dietary Assessment .................................... 28 5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 28 5.4.3 Acute Dietary Risk Assessment ............................................................................... 29 5.4.4 Background Dietary Exposure ................................................................................ 29 5.4.5 Cancer Dietary Risk Assessment............................................................................. 30 5.4.6 Summary Table......................................................................................................... 30 6.0 Residential (Non-Occupational) Expo sure/Risk Characterization ............................. 30 6.1 Residential Handler Exposure ........................................................................................ 31 6.2 Residential Post-Application Ex posure and Risk Estimates .................................... 32 6.3 Residential Bystander Post-Application Inhalation Exposure ................................ 33 6.4 Spray Drift ................................................................................................................... . 33 7.0 Aggregate Exposure/Risk Characterization .................................................................. 34 7.1 Acute Aggregate Risk ................................................................................................... 34 7.2 Short- and Intermediate-Term Aggregate Risk ........................................................ 34 7.3 Chronic Aggregate Risk ............................................................................................... 35 7.4 Cancer Aggregate Risk ................................................................................................ 35

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 4 of 78 8.0 Cumulative Exposure/Risk Characterization ............................................................... 35 9.0 Occupational Exposure/Risk Characterization ............................................................ 36 9.1 Short-/Intermediate-Term Handler Risk ................................................................... 36 9.2 Short-/Intermediate-Term Post-App lication Exposures and Risks ......................... 37 10.0 References .................................................................................................................... ..... 38 Appendix A. Abamectin Toxicology Pr ofile and Executive Summaries ............................... 40 A.1 Toxicology Data Requirements ................................................................................... 40 A.2 Data Demonstrating the Sensitivity of Beagl e Dogs to the Effects of Abamectin and Emamectin ..................................................................................................................... .......... 41 Appendix B. Toxicology Literature References ...................................................................... 48 Appendix C. Abamectin Phys ical/Chemical Properties ......................................................... 50 Appendix D. Review of Huma n Research for Abamectin ...................................................... 51 Appendix E. International Residue Limits Table for Abamectin ......................................... 52 Appendix F. Abamectin Field Trial Tables ............................................................................. 54 Appendix G. Abamectin Occupational and Residential Exposure Tables ........................... 55 Appendix H. Abamectin and Emamectin Cumulative Screening Assessment ..................... 58 Appendix I. Emamectin Toxicity Profiles ................................................................................ 70

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 5 of 78 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 -demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A 1 

### )] and its delta-8,9-isomer. Abamectin is a natural fermentation product of the soil bacterium Streptomyces avermitilis. Abamectin is an insecticide/miticide used to control mites, leaf miners, and other insects in commercially im portant crops. Abamectin acts as an insecticide by interfering with the nervous sy stem of the insect, causing the insect to become paralyzed. Abamectin is a member of a sub-class of m acrocyclic lactone pes ticides known as the avermectins. Currently only abamectin and em amectin are members of this group with active registrations of pesticides.

The Interregional Research Project No. 4 (IR-4), on behalf of the Agri cultural Experiment Stations of CA, SC, AR , NC, WA, and DE, has submitted a petition to propose use of abamectin to control mites on caneberries and to establish a tolerance fo r the caneberry subgroup 13-07A. The petitioner proposed addition of the use on caneberries to the Agri-Mek 0.15 EC and EpiMek 0.15 EC labels. IR-4 proposed a tolerance for residues of abamectin in/on the caneberry subgroup 13-07A.

Syngenta Crop Protection LLC (Syngenta) has su bmitted a petition to propose use of abamectin on soybeans and sweet corn. The petitioner proposes addition of the uses on soybeans and sweet corn to the labels for Agri-Flex® Miticide/Inse cticide, Agri-Mek® SC Miticide/Insecticide, EpiMekTM SC Miticide/Insecticide, and Epi-MekTM SC L Miticide/Insecticide. Syngenta proposed tolerances for sweet corn commodities (forage, kernel plus cob with husk removed, and stover) and soybean commodities (forage, hay, and seed).

Syngenta has also proposed use of two new end-us e products (EPs) on golf course greens, tees, and fairways. The new EPs are AgadorTM 0.17 SC Nematicide (EPA Reg. No. 100-RLNO), and DivanemTM 0.15EC Nematicide (EPA Reg. No. 100-RLRN).

Y-TEX Corporation has requested registration of an ear tag containing abamectin and piperonyl butoxide for use on lactating dairy cattle. An ear tag use has been registered on beef cattle and non-lactating dairy cattle. Tolerances for abamec tin on fat, meat, and meat byproducts of cattle were previously increased to reflect that use. This review concerns residues in milk. No tolerance on milk was proposed. This review concerns only ab amectin; piperonyl butoxide has been under separate review.

Toxicity/Hazard: The most recent risk assessment for abamectin was conducted in 2012 (DP# D402677. Since then, the Agency has re-evalu ated the entire abamectin and emamectin toxicological database along with additional stud ies published in the open literature. The points of departures (PODs), uncertainty factors (UFs ) and safety factor (SFs) for abamectin and emamectin have been altered based on this re-eva luation. In addition, the toxicity of the two structurally related chemicals (abamectin and emamectin) have been compared for consistency, and all the toxicity data were c onsidered together in a cumulativ e screen using similar endpoints.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 6 of 78 In general, available toxicity data showed that , with single dose or repeated dose administration, the primary target organ was the nervous system, and that decreased body we ight was also one of the most frequent findings. The toxicity endpo ints and PODs for all exposure scenarios were recently reevaluated and are selected from the subc hronic and chronic oral toxicity studies in the dogs. The PODs selected from the dog studies ar e based on clear NOAELs and protective of all the adverse effects seen in the studies conducte d in rats, CD-1 mice, and rabbits. There are no residual uncertainties of pre and/ or post-natal toxicity to infants and children. Therefore, the default 10X Food Quality Protection Act (FQPA) safety factor has been reduced to 1X.

Dietary Exposure (Food/Water) : The residue chemistry and environmental fate data are adequate to assess human exposure. Acute a nd chronic aggregate di etary (food and drinking water) exposure and risk assessments were c onducted using the Dietary Exposure Evaluation Model software with the Food Commodity Inta ke Database (DEEM-FCI D), Version 3.16. The acute and chronic dietary exposur e assessments were refined assessments using anticipated or average residues derived from field trial data. Empirical and default processing factors and percent crop treated (%CT) estimates were us ed as available. Estimated drinking water concentrations (EDWCs) were provided by th e Environmental Fate and Effects Division (EFED).

The acute dietary exposure estimates for food and drinking water are below HED’s LOC [<100% of the acute population adjusted dose (aPAD)] at the 99.9 th 

### percentile of exposure. Abamectin dietary exposure at the 99.9 th 

### percentile for food and drinking water is 50% of the aPAD for the general U.S. population and 90% of the aPAD fo r children 1-2 years old, the most highly exposed population subgroup.

The chronic dietary exposure estimates for food and drinking water are below HED’s LOC [<100% of the chronic population adjusted dose (cPAD)] for the general U.S. population and all population subgroups. Abamectin di etary exposure for food and drinking water is 3.3% of the cPAD for the general U.S. population and 16% of th e cPAD for children 1-2 years old, the most highly exposed population subgroup.

Residential Exposure : The level of concern (LOC) risk from residential exposure is a margin of exposure (MOE) of 100. Residentia l exposure estimates from the proposed golf course turf use are not of concern for adults a nd children 11-16 years old; the s hort-term post-application MOEs range from 9,000 to 12,000. Furthermore, all ex isting residential exposures have been reassessed, and there are no regist ered products that would lead to residential handler or postapplication risk estimates of concern. Short- term combined (dermal + inhalation) residential handler MOEs range from 860,000 to 2,700,000,000. Po st-application exposures from existing uses are not expected, and thus do not need to be updated.

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 + resi dential exposure + drinking wa ter), and chronic aggregate exposure (food + drinking water) scenarios. Fo r short-/intermediate-term aggregate exposure, the MOEs are greater than the LOC a nd thus there are no risks of concern. All potential exposure pathways were assessed in the aggregat e risk assessment. None of the aggregate

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 7 of 78 exposure and risk estimates exceed HED's level of concern. An aggregate risk assessment for cancer is not required since abamectin is classified as “not likely to be carci nogenic to humans.”

Occupational Exposure/Risk: The level of concern (LOC) risk from occupational exposure is a margin of exposure (MOE) of 100. Based on all of the proposed uses, occupational exposures to abamectin are expected for short- and inte rmediate-term durations when conducting handling and post-application activities. Potential routes of exposure incl ude both dermal and inhalation for occupational workers. The results of the occupational handler expos ure and risk assessment indicate that short- and intermediate-term combin ed (dermal + inhalation) risk estimates are not of concern at baseline mitigation without pers onal protective equipment (PPE). Short- and intermediate-term MOEs range from 360 to 25,000. Note that only engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircraft.

The results of the quantitative occupational pos t-application exposure and risk assessment indicate that short- and intermediate-term dermal risk estimates are not of concern at baseline mitigation without PPE. Short- and intermed iate-term MOEs range from 3,700 to 5,400. Based on the Agency's current practices, a quantit ative non-cancer occupati onal post-application inhalation exposure assessment wa s not performed for abamectin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation expos ure assessment for abamectin.

Screening Cumulative Assessment of Abamectin and Emamectin : As discussed in Appendix H, HED has determined based on screening guidance ( Pesticide Cumulative Risk Assessment: Framework for Screening Analysis , EPA draft memo dated 6/ 23/15) that abamectin and emamectin share a similar toxicological profile an d a testable hypothesis can be identified. Thus, HED has developed a screening level cumulative analysis using highly conservative exposure assumptions. Specifically, dietary and residential exposures were assessed to determine whether there would be any potential cumu lative concern. This screen ing assessment indicated that aggregate dietary and residential exposures for abamectin and emamectin are below the Agency’s levels of concern.

Environmental Justice Considerations: Potential areas of environm ental justice concerns, to the extent possible, were considered in this human health risk assessment. Dietary and nondietary exposures were considered.

Review of Human Research: This risk assessment relies in pa rt on data from studies in which adult human subjects were intent ionally exposed to a pesticide or other chemical. As indicated in Appendix D, these studies have been determined to require a review of their ethical conduct, and have received that review.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 8 of 78 2.0 HED Recommendations

Provided that the requested analy tical reference standard is provi ded and a revised Section F is submitted, there are no residue chemistry consid erations that would preclude granting the requested registrations and establishing the re commended tolerance for abamectin on sweet corn, soybeans, and the canebe rry subgroup 13-07A.

Provided that a tolerance of 0.015 ppm is proposed for abamectin in milk and the requested analytical reference standard is submitted, ther e are no residue chemistry considerations that would preclude granting the requeste d registration for use of the ear ta g on lactating dairy cattle.

The specific tolerance recommendations are discussed in Section 2.2. There are no recommended label modifications.

2.1 Data Deficiencies

The registrants must submit five grams of the analytical reference standard for 8,9- Z avermectin B 1a 

### (NOA427011) to the EPA National Pesticide Standards Repository.

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 Analytical Manua l, Volume II (PAM II). The methods have been validated for citrus and processed fractions (Method I), gi nned 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 byproducts and ≤ 0.01 ppm for other plant/livestock commodities. The limit of detection (LOD) of the methods for plant and livestock commodities is 0.001 ppm for each analyt e, equivalent to 0.002 ppm for two analyte peaks (i.e., avermectin B 1a 

### and its delta-8,9-isomer in one peak and avermectin B 1b 

### and its delta8,9-isomer in the other peak).

2.2.2 Recommended Tolerances

Syngenta must propose a tolerance of 0.40 ppm for grain, aspirated grain fractions and increase some of the established livestock tolera nces, as indicated in Table 2.2.2 below.

Table 2.2.2. Toleranc e Summary for Abamectin.

Commodity Established Tolerance

(ppm) Proposed Tolerance

(ppm) HEDRecommended Tolerance

(ppm)* Comments ( correct commodity definition )

Caneberry subgroup 13-07A None 0.20 0.20 Cattle, fat 0.03 none 0.05 Cattle, meat 0.02 none 0.02 Cattle, meat byproduc ts 0.06 none 0.09 Corn, sweet, forage none 0.2 0.20

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 9 of 78 Table 2.2.2. Toleranc e Summary for Abamectin.

Commodity Established Tolerance

(ppm) Proposed Tolerance

(ppm) HEDRecommended Tolerance

(ppm)* Comments ( correct commodity definition )

Corn, sweet, kernel plus cob with husk removed none 0.01 0.01

Corn, sweet, stover none 0.5 0.50 Goat, fat 0.01 none 0.03 Goat, meat 0.02 none 0.02 Goat, meat byproducts 0.02 none 0.04 Grain, aspirated grain fractions none none 0.40

Hog, fat 0.01 none 0.01 Hog, meat 0.02 none 0.02 Hog, meat byproducts 0.02 none 0.02 Horse, fat 0.01 none 0.03 Horse, meat 0.02 none 0.02 Horse, meat byproducts 0.02 none 0.04 Milk 0.005 none 0.015 Poultry, meat 0.02 none 0.02 Poultry, meat byproducts 0.02 none 0.02 Sheep, fat 0.01 none 0.03 Sheep, meat 0.02 none 0.02 Sheep, meat byproducts 0.02 none 0.04 Soybean, forage none 0.3 0.30 Soybean, hay none 1 1.0 Soybean, seed none 0.01 0.01 * Changes from established/proposed tolerances are bolded.



### 2.2.3 Revisions to Petitioned-For Tolerances

As shown in Table 2.2.2 above, HED is r ecommending a tolerance of 0.40 ppm for grain, aspirated grain fractions since aspirated grain fractions are associated with soybeans ( Table 1 Feedstuffs , June 2008; in that document, refer to Part V, Table A under aspirated grain fractions and to Attachment 1, Table 1 under grain ). The recommended to lerance of 0.40 ppm for grain, aspirated grain fractions is based on residues of <0.006 ppm in soybean seed and a concentration factor of 59X in aspirated grain fractions.

HED is recommending that some of the establishe d livestock tolerances be increased based on a new dietary burden calculation which includes the proposed uses on soybeans, sweet corn, and ear tags for lactating dairy cattle. (There ar e no livestock feed items associated with the proposed use on the caneberry subgroup 13-07A.) Because of these calculations, HED is recommending increasing the established tolerances on cattle fat from 0.03 to 0.05 ppm; cattle meat byproducts from 0.06 to 0.09 ppm; fat of goat, horse and sheep from 0.01 to 0.03 ppm; meat byproducts of goat, horse, and sheep from 0.02 to 0.04 ppm; and milk from 0.005 to 0.015 ppm. The higher tolerances on cattle fat and me at byproducts as compared to goat, horse and sheep fat and meat byproducts are due to th e proposed use of ear tags on cattle.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 10 of 78 2.2.4 International Harmonization

The plant tolerance definitions are essentially the same for the US, Codex, and Canada, all including avermectin B 1a 

### , avermectin B 1b 

### , and the 8,9-Z isomers. There are no Codex or Canadian maximum residue limits (MRLs) for abamectin on sweet corn or soybean commodities. There are no Codex MRLs for abamectin on caneberries. Canada and the US are concurrently establishing the new tolerance on the caneberry subgroup 13 -07A at 0.20 ppm. Therefore, there are no harmonization issues at this time for plant commodities.

The livestock residue definitions are essentially the same for the US and Canada; the Codex residue definition includes only avermectin B 1a 

### and its 8,9-Z isomer, whereas the US and Canada include both avermectin B 1a 

### and avermectin B 1b 

### and their 8,9-Z isomers. There are no Canadian tolerances set on livestock commodities. There are some Codex MRLs on livestock commodities, but fewer than US tolerances. None of the Codex MRLs are set at the same level as the US recommended tolerance levels. The US cannot harmonize with the Codex MRLs on livestock commodities since they reflect different uses (i.e., different dietary burdens) as compared to the US.

An International Residue Limit Stat us sheet is attached (Appendix E).

3.0 Introduction

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 -demethyl-25-de(1-methylpropyl)-25 -(1-methylethyl) avermectin A 1 

### )] and its delta-8,9-isomer. Avermectins are macrocyc lic lactones produced as natural fermentation products of the soil bacterium Streptomyces avermitilis. Currently abamectin and emamectin are the only members of this group with active pesticide registrations. Abamectin is an insecticide/miticide used to control mites, l eaf miners, and other insects in commercially important crops. Abamectin acts as an insecticid e by interfering with the nervous system of the insect, causing the insect to become paralyzed. Av ailable mechanistic data indicate a neurotoxic mechanism of action, related to interference with GABA- mediated neurotransmission.

Tolerances are established under 40 CFR §180.449 for residues of abamectin (avermectin), including its metabolites and degradates, in or on various crop and livestock commodities at levels ranging from 0.002 ppm to 0.20 ppm. Compliance with the tolerance levels is to be determined by measuring only avermectin B 1 

### and its delta-8,9-isomer.

The registered formulation types include emulsi fiable concentrate (EC), suspension concentrate (SC), granular, bait, gel, and dust. The registered uses include food, food handling establishments, and residential uses.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 11 of 78 3.1 Chemical Identity

Table 3.1. Abamect in Nomenclature Chemical Structure

Empirical formula C 48 H 72 O 14 (B 1a ); C 47 H 70 O 14 (B 1b ) Common Names abamectin, avermectin B 1 Company experimental name MK-0936

IUPAC name mixture of (10 E ,14 E ,16 E )-(1 R ,4 S ,5 ' S ,6 S ,6 ' R ,8 R ,12 S ,13 S ,20 R ,21 R ,24 S )-6 '-[( S )-

sec -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)-6-spiro-2 '-(5 ',6 '-dihydro-2 ' H -pyran)-12-yl 2,6-dideoxy-4- O -(2,6-dideoxy-3- O -methyl- α -Larabino -hexopyranosyl)-3- O -methyl- α -L- arabino -hexopyranoside and (10 E ,14 E ,16 E )-(1 R ,4 S ,5 ' S ,6 S ,6 ' R ,8 R ,12 S ,13 S ,20 R ,21 R ,24 S )-21,22-dihydroxy-6 '-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 -pyran)-12-yl 2,6-dideoxy-4- O -(2,6-dideoxy-3- O -methyl- α -Larabino -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

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 12 of 78 Table 3.1. Abamect in Nomenclature

End-use products/EPs 1 AgadorTM 0.17 SC Nematicide, EPA Reg. No. 100-RLNO (contains 0.170 lb ai/gallon; 13.7% abamectin); Agri-Flex® Miticide/Insecticide, EPA Reg. No. 100-1350 (contains 0.277 lb abamectin and 1.27 lb thiamethoxam per gallon; 3.0% abamectin and 13.9% thiamethoxam); Agri-Mek® 0.15 EC Miticide/Insecticide, EPA Reg. No. 100-898 (contains 0.15 lb ai per gallon; 2.0% abamectin); Agri-Mek® SC Miticide/Insecticide, EPA Reg. No. 100-1351 (contains 0.7 lb ai per gallon; 8.0% abamectin); DivanemTM 0.15EC Nematicide, EPA Reg. No. 100-RLRN (contains 0.150 lb ai/gallon; 2.0% abamectin); Epi-MekTM 0.15 EC Miticide/Insecticide, EPA Reg. No. 100-1154 (contains 0.15 lb ai per gallon; 2.0% abamectin); Epi-MekTM SC Miticide/Insecticide, EPA Re g. No. 100-1408 (contains 0.7 lb ai per gallon; 8.0% abamectin); Epi-MekTM SCL Miticide/Insecticide, EPA Reg. No. 100-1439 (contains 0.35 lb ai per gallon; 4.2% abamectin); Y-TEX® XP 820TM Insecticide Cattle Ear Tags, EPA Reg. No. 39039-17 (have an average weight of 9 grams per tag and contain a formulation of 8% abamectin, 20% piperonyl butoxide, and 72% inerts). Chemical class Macrocyclic lactone; Insecticide/Miticide Known impurities of concern None

1 EC = emulsifiable concentrate; SC = suspension concentrate; SCL= suspension concentrate.



### 3.2 Physical/Chemical Characteristics

Abamectin is a crystalline powder w ith very low vapor pressure. It has very low water solubility but is soluble in organic solvents. Abamectin is stable to hydrolysis. Abamectin has low dermal absorption ( ≤ 1% of the applied dose). Refer to A ppendix C for the table of physical/chemical properties.

3.3 Pesticide Use Pattern

The labels are adequate to allow evaluation of the residue and exposur e data relative to the proposed uses. A summary of the use pr ofile is provided in Table 3.3 below.

Table 3.3. Summary of Proposed Directions for Use of Abamectin on Caneberry, Cattle Ear Tags, Sweet Corn, Soybeans, and Golf Course Turf

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations 2

Caneberry (Crop Subgroup 13-07A) (Blackberry, loganberry, raspberry ( bl ack and red), wild raspberry and cultiv ars/varieties, and/or hybrids of these) Postemergence; Broadcast foliar spray; Ground or aerial equipment Agri-Mek® 0.15 EC [100-898] 0.0094- 0.019 not stated 0.056 7 Restricted Use Pesticide Apply when spider mites are first observed and repeat as needed.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 13 of 78 Table 3.3. Summary of Proposed Directions for Use of Abamectin on Caneberry, Cattle Ear Tags, Sweet Corn, Soybeans, and Golf Course Turf

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations 2

Epi-Mek® 0.15 EC [100-1154] Do not apply with aircraft in NY state. Apply in a minimum of 10 gals. water by ground or 5 gal water by air. The retreatment interval is 7 days. The maximum number of applications at the maximum rate is 3. Do not make more than 2 sequential applications of an abamectin- containing product. A nonionic activator type wetting, spreading, and/or penetrating adjuvant can be used. Do not use binder sticker type adjuvants. Cattle Ear Tags 1 or 2 ear tags per animal for 2- 5 months per
treatment depending on the target pest Y-TEX® XP 820TM Insecticide Cattle Ear Tags [39039-17] NA NA NA Not stated Use on beef and dairy (including lactating) cattle. Reapply as necessary with up to two treatments per year. Remove tags before slaughter. Corn (Sweet) Postemergence; Broadcast foliar
spray; Ground or aerial equipment Agri-Flex® Miticide/ Insecticide [100-1350] 0.012 – 0.018 not stated 0.037 7 (forage or ears)

14 (stover) Apply to thoroughly cover the crop to control spider mites and insects. Apply when spider mites first appear. Repeat as needed to maintain control. Do not apply more than 0.018 lb ai/A of Agri-Flex® or more than 0.019 lb ai/A of any other foliar applied abamectin containing product or more than 0.086 lb ai/A of any other foliar applied thiamethoxam containing product per application. Do not apply more than 0.037 lb ai/A of Agri-Flex® or more than 0.038 lb ai/A of any other foliar applied abamectin containing

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Page 14 of 78 Table 3.3. Summary of Proposed Directions for Use of Abamectin on Caneberry, Cattle Ear Tags, Sweet Corn, Soybeans, and Golf Course Turf

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations 2

product or more than 0.172 lb ai/A of any other foliar applied thiamethoxam containing product per

season. Postemergence; Broadcast foliar
spray; Ground or aerial equipment Agri-Mek® SC Miticide/ Insecticide [100-1351]

Epi-MekTM SC Miticide/ Insecticide [100-1408]

Epi-MekTM SCL Miticide/ Insecticide [100-1439] 0.0096- 0.019 not stated 0.038 7 (forage,
ears, or stover) Apply to thoroughly cover the crop to control spider mites. Apply when spider mites first appear. Repeat as needed to maintain control. Do not apply more than0.019 lb ai/A of AgriMek® SC/Epi-MekTM SC/Epi-MekTM SCL or any other foliarly applied abamectin- containing product per application. Do not apply more than0.038 lb ai/A of AgriMek® SC/ Epi-MekTM SC/Epi-MekTM SCL or any other foliarly applied abamectin-containing product in a growing

season. Soybeans
Postemergence; Broadcast foliar
spray; Ground or aerial equipment Agri-Flex® Miticide/ Insecticide [100-1350] 0.011- 0.014 not stated 0.028 28 Apply to thoroughly cover the crop to control spider mites and insects. Apply when spider mites first appear. Repeat as needed to maintain control. Do not apply more than 0.014 lb ai/A of Agri-Flex® or more than 0.019 lb ai/A of any other foliar applied abamectin containing product or more than 0.063 lb ai/A of any other foliar applied thiamethoxam containing product per application. Do not apply more than 0.028 lb ai/A of Agri-Flex® or more than 0.038 lb ai/A of any other foliar applied

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Page 15 of 78 Table 3.3. Summary of Proposed Directions for Use of Abamectin on Caneberry, Cattle Ear Tags, Sweet Corn, Soybeans, and Golf Course Turf

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations 2

abamectin containing product or more than 0.125 lb ai/A of any other foliar applied thiamethoxam containing product per

season. Do not allow livestock to graze in treated areas or harvest treated soybean forage, straw or hay as feed for meat or dairy animals. Do not feed treated soybean fodder or silage to meat or dairy animals. Postemergence; Broadcast foliar
spray; Ground or aerial equipment Agri-Mek® SC Miticide/ Insecticide [100-1351]

Epi-MekTM SC Miticide/ Insecticide [100-1408]

Epi-MekTM SCL Miticide/ Insecticide [100-1439] 0.0096- 0.019 not stated 0.038 7 (forage or hay)

28 (seed) Apply to thoroughly cover the crop to control spider mites. Apply when spider mites first appear. Repeat as needed to maintain control. Do not apply more than0.019 lb ai/A of AgriMek® SC/Epi-MekTM SC/ Epi-MekTM SCL or any other foliarly applied abamectin- containing product per application. Do not apply more than0.038 lb ai/A of AgriMek® SC/Epi-MekTM SC/ Epi-MekTM SCL or any other foliarly applied abamectin-containing product in a growing

season. Turfgrass (including Golf Course Greens, Tees, and Fairways only)

Broadcast (ground only) AgadorTM 0.17 SC Nematicide [100-RLNO] 0.069 lb ai/A

0.00080 3 lb ai/gal 4 0.276 NA Multiple applications may be required before improvements in turf quality are observed. For best results, irrigate before the

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Page 16 of 78 Table 3.3. Summary of Proposed Directions for Use of Abamectin on Caneberry, Cattle Ear Tags, Sweet Corn, Soybeans, and Golf Course Turf

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] Applic. Rate (lb ai/A) Max. No. Applic.

per Season Max. Seasonal Applic.

Rate (lb ai/A) PHI (days) Use Directions and Limitations 2

DivanemTM 0.15EC Nematicide [100-RLRN] 0.067 lb ai/A

0.00080 3 lb ai/gal 0.267 NA spray droplets have dried on the turf. Do not apply to golf course roughs. Do not apply to residential turf, sports fields, or commercial turf. Do not use aerial application. Do not apply this product through any ty p e of irrigation system or ultra-low volume spray. Apply in 2 gallons of water per 1,000 square feet of turf.

1 Formulation code: EC = emulsifiable concentrate, SC = suspension concentrate; SCL = suspension concentrate.

2 Restrictions that apply to sweet corn and soybean labels: Restricted Use Pesticide To avoid illegal residues, Agri-Flex®/Agri-Mek® SC/ Epi-MekTM SC/Epi-MekTM SC must be mixed with a nonionic activator type wetting, spreading and/or penetratin g spray adjuvant. Do not use binder or sticker type adjuvants. Do not apply with aircraft in NY state. Do not apply in less than 10 gal water /A by ground or 5 gal water/A by air. The retreatment interval is 7 days. For resistance management, do not make more than 2 se quential applications of Agri-Flex®/Agri-Mek® SC/ EpiMekTM SC/ Epi-MekTM SCL or any other foliar applied abamectin containing product. Unless specifically restricted in the individual Crop Use Directions on the Agri-Mek® SC, Agri-Flex®, Epi-MekTM SC, or Epi-MekTM SCL labels, those products may be used in the same year abamectin is used as an atplant seed treatment. Abamectin is registered as a seed treatment on the Avicta® 500 FS label (EPA Reg. No. 100- 1204) at rates of 0.20-0.25 mg ai/seed for corn and 0.10-0.15 mg ai/seed for soybean.

3 Application rate is based on use direction to “apply in 2 gallons of water per 1,000 square feet of turf.”



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assess ment of human health risk to support the proposed new uses of abamectin on the caneberry subgroup 13-07A, sweet corn, soybeans, beef/dairy cattle ear tags, and turf (golf course greens, tees, and fairways). Humans may be exposed to abamectin in food and drinking water since abamectin may be applied directly to growing crops. Although significan t residues are not expected to occur in ground water because of the low water solubility of residues and their a ffinity to soil particle s, residues may occur in surface water due to runoff, erosion, and spray drift.

Based on all of the proposed uses, occupational e xposures to abamectin are expected for shortand intermediate-term durations when conducti ng handling and post-application activities. Potential routes of exposure include both derm al and inhalation for occupational workers. Furthermore, the proposed golf course use results in a potential for residential short-term dermal post-application exposures for adults and child ren (11 to 16 years old) conducting recreational

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Page 17 of 78 golfing activities. There are proposed and registered residential uses of abamectin, so there is the possibility of exposure in reside ntial or non-occupational settings.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-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 c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption, and activities in and around the home that involve pesticide us e in a residential setting.

Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) using 2003-2008 food consumpti on data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food us es of a pesticide. Thes e data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized s ubgroups and exposure assessments are performed when conditions or circumstances warrant. When ever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or pl aying on treated areas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

As mentioned in Section 3.0, abamectin consists of two components, B 1a 

### and B 1b, 

### which have very similar biological and t oxicological properties. Emam ectin is a structurally and toxicologically related chemical which is a derivative of abamectin. The only difference between abamectin and emamectin is that abamectin has a hydroxyl moiety at the 4” position of the tetrahydropyrane ring whereas, in emamectin, the hydroxyl group is replaced by a methylamine (circled groups in the following figures).

Since the last risk assessm ent (D402677 & D405843, N. Dodd, 12/ 20/2012), the Agency has reevaluated the entire abamectin and emamectin toxicological database along with studies published in the open literature. Due to the similarity of the two chemicals the Agency has reevaluated the toxicity of both abamectin and emamectin to ensure consistency of approach. The evaluation of abamectin is presented in this sec tion, since this risk asse ssment has been prepared to address new uses of abamectin. The revise d toxicity profile tabl es for emamectin are presented in Appendix I. While no common mechanism group has been established for macrocyclic lactone pesticides (i.e., key events leading from the molecular initiating event to apical neurotoxicity cannot be causally determined ), the Agency has presented a screening level cumulative evaluation (Appendix H) based on screening guidance ( Pesticide Cumulative Risk

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 18 of 78 Assessment: Framework for Screening Analysis , EPA draft memo dated 6/23/15) to assess the potential for cumulative risk and the extent to wh ich additional toxicity information is needed to determine the key events for a common mechanism grouping.

Abamectin

Emamectin

Mode of Action : In nematodes, abamectin blocks signal transm ission from the central command interneurons to the peripheral motoneurons, leading to paralysis and death. In the mamm alian toxicity studies submitted by the registrant, paralysis is also a common finding prior to mo ribund sacrifice. The in vitro data derived from a primary culture of rat cerebellar granular neurons show that, on the cellular level, abamectin acts by binding to gamma-aminobutyric 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 Ca sida, 1997; and Dawson et al., 2000). GABA plays a critical role in nervous system development through both non-synaptic (Represa and Ben-Ari, 2005) and synaptic (Nguyen et al., 2001) m echanisms. The literature data show that within the mammalian brain abamectin binding to GABA receptors is widespread but particularly abundant in the cerebellum (Wang and Pong, 1982). Abamectin also has been suggested to act on GABA receptors in the ente ric nervous system and induces longitudinal rhythmic contractions in the isolated ileum (Kerr and Ong, 1986). Abamectin may therefore influence GABA-mediated regulation of metabo lism, food intake and body weight at multiple sites (Meister, 2007). Although GABA receptor mediated neurotoxicity is a solid hypothesis, as described in detail in Appendix H, data in ma mmalian preparations link ing alterations in GABA

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Page 19 of 78 receptor function to disrupti ons in neuronal excitability in vitro and in vivo, and ultimately adverse outcomes, ar e currently lacking.

4.1 Toxicological Studies Available for Analysis

The toxicology database is complete excep t for subchronic dermal toxicity and an immunotoxicity studies. HED’ s HASPOC, however, based on a weight of evidence consideration has granted wa ivers to these studies (HASPOC Reports: TXR Numbers 0056687 and 0056509). The toxicology database include the following studies:

 subchronic oral toxicity studies in rats and dogs,

 combined chronic toxicity/c arcinogenicity study in rats,

 chronic toxicity study in dogs,

 carcinogenicity study in mice,

 developmental toxicity studies in rats, rabbits, and CD-1 mice,

 reproduction study in rats,

 acute and subchronic neurot oxicity studies in rats,

 subchronic inhalation study in rats,

 developmental neurotoxicity (DNT) studies in rats,

 mutagenicity studies

 metabolism study in rats, and

 dermal absorption study in monkeys.

The toxicity profile table with a brief summa ry of all studies submitted may be found in Appendix A. Several literature studies were used for characterizati on and are cited throughout this document.

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

The metabolism study was performed with avermectin B 1a 

### . With oral dosing, the test material in the gastrointestinal trac t of the rat was almost completely absorbed and distri buted throughout all major tissues and organs, with the highest residu es found in fat. Maximum concentrations in blood were achieved within 4-8 hours after admini stration. The absorbed abamectin was rapidly eliminated from the body, almost exclusively in the feces, and did not accumulate in the body after repeated exposure. The major biot ransformation pathways of avermectin B 1a 

### in the rat were demethylation, hydroxylation, cleavage of the olea ndrosyl ring, and oxidation reactions. There were 11 isolated metabolites. In the rat, avermectin B 1a 

### was metabolized to 24-hydroxy-methyl B 1a 

### (i.e., 24-OH-Me-B 1a 

### ), which accounts for most of the radiolabeled residues. However, the [8, 9- Z ]-isomer of avermectin B 1a 

### was not found in the rat meta bolism studies. Avermectin B 1a 

### did not bioaccumulate in rat tissues.

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Page 20 of 78 4.2.1 Dermal Absorption

A dermal absorption study was conduc ted with rhesus monkey using 3 

### H-avermectin B 1a 

### . The maximal dermal absorption of avermectin B 1a 

### is 1% of the app lied dose (HIARC report, 9/15/1998).

4.3 Toxicological Effects

The toxicological effects observe d in the test animals are cons istent to the proposed MOA as described in the Section 4.0 ( Mode of Action). In general, available toxicity data showed that, with single dose or repeated dos e administration, the primary target organ was the nervous system, and that decreased body weight was al so one of the most frequent findings. Neurotoxicity (including tremors, mydriasis, ataxia, and death) wa s seen in mice, dogs, and rats. Developmental effects such as cleft palate were reported in rabbits. GABA also plays a role in development; cleft palate findings may reflec t the interaction of abamectin on the GABA receptor. Generally the finding of cleft palate was seen at higher dose levels that those for neurotoxicity.

Integral to the dose response assessment in mammals for this class of compounds is Pglycoprotein (P-gp). P-gp is a member of adenosine triphosphate (ATP) binding cassette transporter proteins, which resi de in the plasma membrane a nd function as a transmembrane efflux pump, moving xenobiot ics from the intracellu lar to the extracellu lar domain. P-gp is found in the canallicular surface of hepatocytes, the apical surface of proxima l tubular cells in the kidneys, brush border surface of enterocytes, lu minal surface of blood capillaries of the brain (blood brain barrier), placenta, ova ries, and the testes. As an e fflux transporter, P-gp acts as a protective barrier to keep xenobi otics 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 in the fetus. Therefore, test animals w ith genetic polymorphisms that compromise P-gp expression, are particularly suscep tible to abamectin induced neur otoxicity (Lankas et al., 1997). The neonatal rat is also particularly sensitive to abamectin and emamectin. P-gp is undetectable in the neonatal rat brain; the first detection of P-gp is on post-natal day (PND) 7 and does not reach adult levels until approximately PND 28 (M atsuoka, 1998). As shown in the reproductive and DNT studies, neonatal rats are sensitive to the effects of abamectin induced pup body weight reductions and death. In contrast, in the deve loping human fetus, P-gp was found as early as 22 weeks of gestation (Daood, 2008; van Kalken, et al., 1991). Based on the difference in the ontogeny of P-gp in neonatal ra ts and human newborns, the Ag ency, at this time, does not believe that the early post-nata l findings in the rat are releva nt to human newborns or young children.

The CF-1 mouse is also uniquely sensitive to ab amectin and emamectin. Some CF-1 mice have a polymorphism for the gene encoding P-gp a nd are either devoid (homozygous) or have diminished (heterozygous) levels of P-gp. These mice are found to be uniquely sensitive to the neurotoxic effects of abamectin and its derivative, emamectin.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 21 of 78 Many studies on human multidrug resistance ( MDR-1 ) gene encoding P-gp and polymorphism of MDR-1 gene are available. The data are inconclusi ve with respect to th e functional significance of the genetic variance in P-gp in human. At the present, the re ported cases of polymorphism of the MDR-1 gene in human populations have not been shown to result in a loss of P-gp function similar to that found in CF-1 mice (Macdonald & Gledhill, 2007). Give n the ontogeny of P-gp and the lack of convincing evidence from the literature on human polymorphism of MDR-1 gene resulting in diminished P-gp function, the Agency considers the results of the studies with CF-1 mice not relevant for human health risk assessment. Therefore, the Agency is using results from toxicological studies conducted in the species that do not have diminished P-gp function for selecting toxicity endpoints and poi nts of departure for risk assessment. Among the test animals with fully functional P-gp, th e beagle dog is the most sensitive species (Appendix A).

Abamectin is classified as a Group E chemical (Evidence of Non-carcinogenicity for Humans) based on the lack of evidence for carcinogenicity in mice or rats and no concern for mutagenicity (TXR No 0011983).

Abamectin has high to moderate ac ute toxicity by the oral route (depending on the vehicle), high acute toxicity by the inhalation rout e, and low acute toxicity by the dermal route. It is slightly irritating to the skin, but is not an ocul ar irritant or a dermal sensitizer.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The PODs and the toxicity endpoints of concern selected from the subc hronic and chronic oral toxicity studies in the dogs are protective of all the a dverse effects seen in the studies conducted with rats, CD-1 mice, a nd rabbits. There are no residual uncerta inties for pre and/or post-natal toxicity to infants and children. Therefore, the 10X FQPA safety factor is reduced to 1x. The detailed rationale are presented in 4.4.1 to 4.4.4.

4.4.1 Completeness of the Toxicology Database

The toxicology database for abamectin is comple te for human health risk assessment. As mentioned in Section 4.1 waivers have been gr anted for immunotoxicity and subchronic dermal toxicity studies (HASPOC Reports: TXR 0056687; 1/07/2013 and TX R 0056509; 1/30/2013). No additional toxicology studies are required at this time.

4.4.2 Evidence of Neurotoxicity

The proposed MOA is interaction with GABA recep tors leading to neurotoxicity. The findings of neurotoxic signs observed in the abamectin data base are consistent with the proposed MOA. Signs of neurotoxicity ranging fr om decreases in foot splay re flex, mydriasis (i.e., excessive dilation of the pupil), curvature of the spine, decreased fore- and hind-limb gr ip strength, tip-toe gate, tremors, ataxia, or spastic movements of the limbs are reported in various studies with different durations of abamectin exposure. In dogs, mydriasis was the most common finding at doses as low as 0.5 mg/kg/day at one week of treatment.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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Page 22 of 78 There was no evidence of increased susceptibity following in utero exposure to CD-1 mice or Sprague-Dawley rats for following pre/post-na tal exposure to rats in a one-generation reproduction study

In the developmental toxicity with rabbits, there was evidence for qualitative susceptibility where decreases in body weight and food consum ption were seen in maternal animals at 2.0 mg/kg/day. In contrast, the feta l effects at this dose (2.0 mg/ kg/day) were much more severe, consisting of cleft palate, clubbed foot, and death. The degree of concern is low for the observed susceptibility since the developmental effects were seen at a dose (2.0 mg/kg/day) that was 10- fold higher than the POD (0.25 mg/kg/day) used for overall risk assessment. (i.e, the POD is protective of developmental effect s seen in the rabbit fetuses).

The rat reproduction toxicity and developmen tal neurotoxicity studies with abamectin demonstrated both qualitative and quantitative su sceptibility in the pups to the effects of abamectin (observed as decreased pup weights a nd increased postnatal pu p mortality). This observation is consistent with the finding that P-gp is not fully developed in rat pups until postnatal day 28. Therefore, during the period from birth to postnatal day 28, the rat pups are substantially more susceptible to the effects of abamectin than adult rats. However, in humans, P-gp has been detected in the fetus at 22 week s of pregnancy, and the human newborns have functioning P-gp. Therefore, huma n infants and children are not expected to have enhanced sensitivity as seen in rat pups.

The 10x FQPA safety factor for infants and ch ildren is reduced to 1x based on the following weight of evidence considerations: 1) there was no evidence of increased susceptibility following in utero exposure to mice and rats: 2) there was no evidence of increased susceptibity following pre and post-natal exposure in th e one-generation study; 3) the findings in the DNT and the rat two-generation reproduction study are attributable to the rat pups being more susceptible since the P-gp is not fully developed and therefore are not relevant for human infants; 4) the developmental effects in the rabbit developmen tal study was seen a much higher dose than the POD used for overall risk assessment; and 5) ther e are no residual uncertainties for pre-and/or postnatal toxicity or in the exposure database.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual concerns w ith respect to the exposure data bases. The chronic and acute dietary food exposure assessment utilizes cons ervative assumptions including anticipated residues, default processing factors, and per cent crop treated. The dietary drinking water assessment utilized conservative modeling inpu ts which included conservative assumptions for the parent and all degradates of concern. Th erefore, the water exposure assessment will not underestimate the potential risks for infants and children. Likewise, the use of maximum application rates and central-to -high end inputs results in ca lculated residential exposure assessments will not underestimate the risks to infants and children from the requested uses.

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Page 23 of 78 4.5 Toxicity Endpoint and Point of Departure Selections

The toxicity studies in rats, CD-1 mice, and beag le dogs demonstrated that the beagle dog is the most appropriate species to assess the risk of abamectin. The toxicity endpoints and points of departure for human health risk assessme nt are presented in Tables 4.5.1 and 4.5.2.

Dietary Exposure and Incidental Oral Endpoint (all durations) For all oral exposure scenarios, clinical signs (tremors and mydr iasis) of neurotoxicity were observed in the subchronic (12- and 18-weeks) and chronic oral t oxicity studies in dogs at the lowest observed adverse effect level (LOAEL) of 0.5 mg/kg were selected. The point of departure (no observed adverse effect leve l; NOAEL) is 0.25 mg/kg (Tables 4.5.1 and 4.5.2). Tremors and mydriasis were observed as early as the first week of exposure. After extended exposure in the chronic toxicity study, adverse eff ects were observed at similar dose levels as the shorter-term studies. The Agency assumes that th ese clinical signs could result from a single dose.

There are three lines of eviden ce which support the use of the 0.25 mg/kg for all oral exposure scenarios and durations: (1) kinetic data supports rapid ab sorption/excretion, (2) acute neurotoxicity was observed in rats, and (3) th e neurotoxic effects produced by abamectin in beagle dogs did not progress with time.

Kinetic data : Given the rapid absorption and elimin ation of abamectin, the Agency has concluded that some of the neurotoxic effect s seen in the subchronic and chronic toxicity studies in dogs could be elicite d by a single dose. As describe d previously, the kinetic data of abamectin show a pattern of rapid absorpti on and elimination. With oral dosing in rats and mice, abamectin was absorbed rapidl y, and maximum concentration in blood was achieved within 4-8 hours after administration. It was rapidly eliminated from the body, almost exclusively in the feces, and did not accu mulate in the body after repeated exposure.

Acute neurotoxicity study in rats : The use of the subchronic and chronic dog studies is supported by the acute neurotoxicity study in rat (range finding and main studies). The ACN shows that clinical signs of ne urotoxicity such as reduced foot splay reflex, ataxia, tremors, and mydriasis (decreased pupillary light response) were observed from a single dose Most of the effects observed in the rat ACN were cons istent with those seen in the subchronic and chronic dog studies.

Effects seen in the subchronic and chronic dog studies: The effects seen in the subchronic (gavage) and chronic dog studies were sim ilar despite repeated dosing, suggesting the response could be due to each individual exposure rather than to accumulation of abamectin in tissues. Clinical signs such as ataxia a nd or whole body tremors were reported within 3 hours of the first dose at higher dose levels.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 24 of 78 Dermal and Inhalation Exposur e Endpoints (all durations) For short-term dermal, and inhalation exposures, or al subchronic and chroni c toxicity studies in dog were chosen as co-critical st udies to establish the toxicity endpoint and point of departure. The dermal absorption factor is 1%, which repr esents maximal dermal absorption seen in the dermal absorption study. The adverse effects fo r establishing the toxici ty endpoints are tremors and mydriasis, and the POD is 0.25 mg/kg/day. There is no repeat dose dermal toxicity study available. For inhalation, a 30-day inhalation stu dy in rats is available, but the results show no toxicity at the highest tested concentrati on (2.5 μg/L, approximately equivalent to 0.568 mg/kg/day). The use of the results from the dog st udies in establishing th e toxicity endpoint and point of departure (0.25 mg/kg/da y) inhalation route is appropri ate and protective for these exposure scenarios.

For residential exposure risk assessments, the LO C is a MOE of 100 based on a total uncertainty factor of 100x (10 for interspecies extrapol ation, 10x for intrasp ecies variations).

For occupational exposure risk assessments, the LOC is a MOE of 100 based on a total uncertainty factor of 100x (10x for interspecies ex trapolation, 10x for intras pecies variations).

Carcinogenicity: Abamectin is classified as a Group E Chemical; Evidence for Noncarcinogenicity in Humans based on lack of evid ence for carcinogenicity in mice and rats and no concern for mutagenicity (TXR No. 0011983).

Combined routes of exposure: Oral, dermal and inhalation routes of exposure could be combined since the toxicity endpoints were similar.

Table 4.5.1 and 4.5.2 summarize the toxicity endpoi nts and points of departure for risk assessment for abamectin.

Table 4.5.1. Summary of Toxicolo gical Doses and Endpoints for Aba mectin for Use in Dietary and NonOccupational Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

Dietary (all durations) (General Population, including Infants and Children) & Incidental Oral NOAEL=0.25 mg/kg/day UF A = 10x UF H = 10x FQPA SF =1x Acute RfD = aPAD = 0.0025 mg/kg/day Subchronic & chronic oral toxicity studies in dogs Chronic 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 Subchronic LOAEL=0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day. Dermal (Short-Term andIntermediateTerm) NOAEL = 0.25 mg/kg/day

Dermal Absorption = 1% UF A = 10x UF H = 10x FQPA SF =1x LOC: MOE = 100

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Page 25 of 78 Table 4.5.1. Summary of Toxicolo gical Doses and Endpoints for Aba mectin for Use in Dietary and NonOccupational Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

Inhalation (Short-Term andIntermediateTerm) NOAEL = 0.25 mg/kg/day

Toxicity via the inhalation route assumed to be equivalent to oral
route. UF A = 10x UF H =10x FQPA SF =1x LOC: MOE = 100

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate r odent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 (intra species). 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.

Table 4.5.2. Summary of Toxicolo gical Doses and Endpoints for Abamect in for Use in Occupational Human Health Risk Assessments

Exposure/ Scenarios Point of Departure Uncertainty/ Safety Factor LOC Study and Toxicological Effects

Dermal (Short-Term and Intermediate-Term) NOAEL = 0.25 mg/kg/day

Dermal Absorption = 1% UF A = 10x UF H = 10x LOC: MOE = 100 Subchronic & Chronic oral Toxicity studies in Dogs Chronic 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 Subchronic LOAEL=0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day.

Inhalation (Short-Term and Intermediate-Term) NOAEL = 0.25 mg/kg/day

Toxicity via the inhalation route assumed to be equivalent to oral
route. UF A = 10x UF H =10x LOC: MOE = 100

Cancer (oral, dermal, inhalation) Classification: Group E Chemical based on the abse nce of evidence for carcinogenicity in 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 en vironmentally relevant human exposures. NOAEL = no observed 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

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 26 of 78 sensitivity among members of the human population (intraspeci es). SF = Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

A detailed discussion of the residues of concern for primary crops, rotational crops, and livestock is presented in the previous risk a ssessment (N. Dodd, D402677, D405843, 12/20/2012). Residues of concern for the risk assessment a nd tolerance expression are summarized in Table 5.1 below.

Table 5.1 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 ), NOA 448111, NOA 448112, NOA 426289, NOA 445495, NOA 457464, and NOA 457465 Not applicable

* Residues of concern in ruminants include both use on crops used as animal feed and use in cattle ear tags. ** No rotational crop tolerances have been established.



### 5.2 Food Residue Profile

Plant Commodities Adequate field trials were submitted for abamectin on caneberries, sweet corn, and soybeans. The field trials for caneberries, sweet corn a nd soybeans adequately re flect the proposed use pattern. The number of field trials and the geographic repres entation are adequate. Decline studies show decreasing residues with increasing PHI. Adequate stor age stability data are available to support the field trials . Adequate data collection methods were used. The field trials on caneberries, sweet corn, and soybeans are summa rized below and tabulated in Table F.1 in Appendix F. A processing study on soybeans indicat ed that combined residues of avermectin

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 27 of 78 B 1a 

### , avermectin B 1b 

### , and 8,9-Z avermectin B 1a 

### may concentrate significan tly in/on aspirated grain fractions (average processing f actor of 59x), and slightly in meal (1.1x), and hulls (1.2x). Residues in rotational crops are not expected from the proposed uses.

Livestock Commodities Abamectin is currently registered for use in cattle ear tags applied to beef cattle and non-lactating dairy cattle. Y-TEX Corporation submitted a stu dy to determine residues of abamectin in milk from use of the ear tag on lactating dairy catt le. Although some of sa mples analyzed showed minimal transfer of residues to milk, there was one sample with residues close to the existing tolerance that is based on secondary residues from cattle consuming treated feed. Therefore, the tolerance for milk needs to be increased to acco mmodate this use. Syngenta has proposed use of abamectin on sweet corn and soybeans, which are both livestock feed items. The Agency has reevaluated the Maximum Reasonable Dietary Burd en (MRDB) for livestock considering the proposed uses, and additional modifications to milk, meat by products, an d fat tolerances are required. Note that the Agency generally set tolerances for the edible commodities of sheep, goats, and horses at the same level of cattle. However, since the ear tags containing abamectin are registered for use only on cattle, tolerances on cattle commodities are based on potential resides from ear tags and feed items, while the residues in the remaining types of livestock can only be as a result of secondary residue from consuming treated feed. Further details on the reassessment of the livestock di etary burden may be found in the chemistry assessment of the proposed uses (D410993, N. Dodd, 5/14/14;D4 14022, N. Dodd, 5/15/14; D416280, N. Dodd, 5/15/14).

No poultry feeding studies have been submitted or required. Based on dietary burden calculations using Table 1 Feedstuffs (June 2008), no secondary residues are expected to occur in poultry commodities; therefore, no pou ltry feeding studies are required.

5.3 Water Residue Profile

EDWCs were provided by EFED for abamectin. The abamectin residues of concern include the parent compound mixture and the structur ally similar degradates: NOA 448111, NOA 448112, NOA 426289, NOA 445495, NOA 457464, and NOA 457465. In absence of toxicity data on these degradates, they are assumed to have toxic ity profiles similar to that of abamectin on the basis of the structural similarities.

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 proposed uses.

The Tier I Pesticide Root Zone Model - Ground Water (PRZM-GW) and Tier I Screening Concentration in Ground Water (S CI-GROW) models were used to assess residues in ground water. Surface drinking water concentrations were estimated using the Tier II surface water concentration calculator (SWCC) computer model. The EDWCs used in the acute and chronic assessments are the residues in surface water since the residues in ground water are lower. Considering all registered/proposed uses, the proposed use on soybeans in MS at 0.037 lb ai/A/year results in the highest acute drinking water exposure and the registered use on beans in

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 28 of 78 MI at 0.056 lb ai/A/year results in the highest chroni c drinking water exposure. The acute EDWC is 0.76 ppb, the 1-in-10 year annual maximu m concentration in surface water, as shown in Table 5.3 below; however, for the acute di etary assessment, a drinking water residue distribution file provided by EFED was used. For the background (chronic) dietary assessment, the annual mean concentration of 0.30 ppb in surface water was used.

Table 5.3. Screening-Level EDWCs for Proposed Uses of Abamectin 1

Source (Tier: Model) Use Site (Max. Annual App. Rate) Acute EDWC ( μ g/L) Chronic EDWC ( μ g/L)
Surface water (Tier II: SWCC) Soybeans (0.037 lbs ai/A)/ Beans (0.056 lbs ai/A) 0.76 (soybeans) 0.30 (beans) Ground water (Tier I: PRZM-GW) Golf courses (0.27 lbs ai/A) 0.074 N/A Ground water (Tier I: SCI-GROW) Golf courses (0.27 lbs ai/A) ≤ 0.0031

1 Maximum values in bold. Values include parent compound and several structurally similar degradates.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute assessment: A refined acute dietary (food and dr inking water) exposure assessment was conducted for all proposed and esta blished food uses of abamectin. Acute anticipated residues derived from field trial data we re used. Empirical and default processing fact ors and percent crop treated (% CT) estimates were used, as availa ble. No monitoring data were used. Drinking water residues were represented by a residue distribution file based on the application to soybeans.

Background Dietary assessment: A refined background (chroni c) dietary (food and drinking water) exposure assessment was conducted for all proposed and estab lished food uses of abamectin. Average residues from field trials were used. Residues from use in food handling establishments were included. Empirical and default processing factors and % CT estimates were used, as available. Drinking water was represented by a single point estimate of average abamectin residues (the 1-in-ten-year annual mean ). The estimated surface water concentration of 0.30 ppb was based on the application to beans.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates for abamectin provided by BEAD (D415573, Sepehr Haddad, 11/6/13 and D420218, Don Atwood, Ph.D., 7/23/14) were used in the acute dietary risk assessment for the follo wing crops: almonds: 80%; apples: 20%; apricots: 40%; avocados: 60%; blackberries: 55%; cantaloupe s: 40%; celery: 70%; cherries: 15%; corn, sweet, kernel plus cob with husk removed: 44%; cotton: 25%; cucumbers: 10%; grapefruit: 85%; grapes: 25%; hazelnuts: 2.5%; honeydew: 35%; lemons: 55%; lettuce: 40%; nectarines: 20%; oranges: 60%; peaches: 20%; pears: 85%; pecans: 2.5%; pepper s: 30%; pistachios: 2.5%; potatoes: 20%; prunes: 30%; pumpkins: 10%; ra spberries: 55%; soybean s: 11%; spinach: 45%; squash: 15%; strawberries: 45%; tangerines: 55%; tomatoes: 25%; walnuts: 55%; and watermelons: 15%. For livestock commodities ot her than poultry and swine commodities, 85%

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 29 of 78 crop treated based on the feed item dried citr us pulp was used. For poultry and swine commodities, 25% crop treated base d on cotton meal was used.

The following average percent crop treated estimates for abamectin provided by BEAD (D415573, Sepehr Haddad, 11/6/13 and D420218, Don Atwood, Ph.D., 7/23/14) were used in the chronic dietary risk assessment for th e following crops: almonds: 65%; apples: 10%; apricots: 15%; avocados: 35%; bl ackberries: 48%; cantaloupes: 20%; celery: 45%; cherries: 5%; corn, sweet, kernel plus cob with husk removed: 38%; cotton: 15%; cucumb ers: 5%; grapefruit: 70%; grapes: 15%; hazelnuts: 2.5%; honeydew: 20% ; lemons: 40%; lettuce: 20 %; nectarines: 20%; oranges: 40%; peaches: 5% ; pears: 75%; pecans: 1%; pe ppers: 15%; pistachios:1%; potatoes: 5%; prunes: 5%; pumpkins: 5%; rasp berries: 48%; soybeans: 8%; spinach: 30%; squash: 5%; strawberries: 35% ; tangerines: 35%; tomatoes : 15%; walnuts: 25%; and watermelons: 10%. For livestock commodities ot her than poultry and swine commodities, 70% crop treated based on dried citrus pulp was use d. For poultry and swine commodities, 15% crop treated based on cotton meal was used.

All commodities included for f ood handling residues were assigne d the value of 5% CT (DP# 413125, J. Becker, 10/7/2014).

5.4.3 Acute Dietary Risk Assessment

The general U.S. population and the following popul ation subgroups were assessed: all infants (<1 year old), children 1-2 years old, children 3-5 years old, children 6- 12 years old, youth 13-19 years old, adults 20-49 years old, females 13- 49 years old, and adults 50-99 years old.

As shown in Table 5.4.6, the acu te 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 for the general U.S. population and all population subgroups. Abamectin dietary exposure at the 99.9 th 

### percentile for food and drinking water is 50% of the aPAD for the general U.S. population and 90% of the aPAD for children 1-2 years old, the most highly exposed population subgroup

. Although this assessment was refined to the extent possible with the data available, it could be further refined with monitoring da ta. Limited Pesticide Data Pr ogram (PDP) monitoring data are available for abamectin, but the data that are avai lable indicate that gene rally actual residues are lower than those found in the crop field trials. Therefore, these risk estimates could be considerably lower if monitoring data were av ailable to better assess actual exposure. A sensitivity analysis of the acute dietary risk a ssessment found that the commodity leading to the greatest contribution to abamectin risk estimates was milk. Since this assessment involves new uses monitoring data could not be used for mil k, but many of the assumptions in this exposure estimates (deterministic value, high percent crop treated value), will overestimate exposure to abamectin in milk and therefore, represents a conservative repr esentation of risk.

5.4.4 Background Dietary Exposure

Table 5.4.6 shows the background dietary exposure estimates for food and drinking water. A chronic dietary risk assessment was not conducte d because the endpoints are acute in nature.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 30 of 78 The general U.S. population and the following popul ation subgroups were assessed: all infants (<1 year old), children 1-2 years old, children 3-5 years old, children 6- 12 years old, youth 13-19 years old, adults 20-49 years old, females 13- 49 years old, and adults 50-99 years old.

Although this assessment was refined to the extent possible with the data available, it could be further refined with monitoring da ta. Limited Pesticide Data Pr ogram (PDP) monitoring data are available for abamectin, but the data that are avai lable indicate that gene rally actual residues are lower than those found in the crop field trials. Therefore, these exposure estimates could be considerably lower if monitoring data were available to better assess actual exposure.

5.4.5 Cancer Dietary Risk Assessment

Since abamectin is classified as “not likely to be carcinogenic to hum ans,” a cancer dietary exposure assessment is not required.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Abamectin

Population Subgroup Acute Dietary (99.9 th Percentile) Background Dietary Exposure Dietary Exposure (mg/kg/day) % aPAD* (mg/kg/day)

General U.S. Population 0.001249 50 0.000082

All Infants (< 1 year old) 0.001683 67 0.000128

Children 1-2 years old* 0.002243 90 0.000393

Children 3-5 years old 0.001295 52 0.000239

Children 6-12 years old 0.000824 33 0.000137

Youth 13-19 years old 0.000549 22 0.000069

Adults 20-49 years old 0.000448 18 0.000056

Adults 50-99 years old 0.000357 14 0.000051

Females 13-49 years old 0.000416 17 0.000054

* The subpopulation with the highest risk estimates is bolded.



### 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

At this time, there are proposed residential use si tes that may lead to handler and post-application exposures. Furthermore, recent revisions to th e toxicity endpoints and PODs for abamectin require a reassessment of all currently registered re sidential uses with all current policies. These revisions of residential exposures will impact the human health aggregate risk assessment.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 31 of 78 The proposed end-use products (for control of turf-parasitic nematodes on golf course greens, tees, and fairways) that may lead to these pos t-application exposures include the following: 1. AgadorTM 0.17 SC (EPA Reg. No. 100-RLNO), and 2. DivanemTM 0.15EC (EPA Reg. No. 100-RLRN).

The products already registered for residentia l use sites include several formulations of homeowner bait and bait station products regist ered under multiple companies. These products include an outdoor granular ba it (GB) formulation for use on fi re ant mounds, and several indoor ready-to-use baits (RBs) of both dust and gel form ulations. For this assessment, the exposures and risk estimates for applying outdoor granul ar baits are assessed us ing the 2012 Residential SOPs 1 

### and exposure from indoor ready-to-use gel ba its is considered neg ligible. In addition, exposure data for hand dispersal of granular bait is chosen as a surroga te to calculate risk estimates from indoor RBs.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task as was described above for occupational handlers. Residential handlers ar e addressed somewhat differently by HED as homeowners are assumed to complete all elem ents of an application without use of any protective equipment.

The quantitative exposure/risk a ssessment developed for reside ntial handlers is based on the following scenarios: l oading/applying GB outdoor via (1) push -type spreaders, (2 ) belly grinders, (3) spoons, (4) hand, and (5) cup or shaker; and (6) applying granular bait indoor by hand (as a surrogate for a ready- to-use dust bait).

There are no registered products that would lead to any residen tial handler risk estimates of concern. Short-term combined (dermal + inha lation) residential handl er MOEs range from 860,000 to 2,700,000,000.

Table 6.1. Residential Hand ler Non-Cancer Exposu re and Risk Estimates for Abamectin.

Exposure Scenario Dermal Unit Exposure Inhalation Unit Exposure Maximum Application Rate Area Treated or Amount

Handled Daily b Dermal Inhalation Total

Dose c MOE d Dose e MOE f MOE g mg/lb ai mg/kg/day LOC = 100 mg/kg/day LOC = 100 Mixer/Loader/Applicator for Outdoor Bait Application Push-Type Spreaders 0.81 0.0026 0.000231 lb ai/A 0.5 acres 1.20×10 -8 21,000,000 3.8E-09 66,000,000 16,000,000 Belly Grinders 360 0.039

5.31×10 -9 lb ai/sq ft 1200 sq ft 2.90×10 -7 870,000 3.1E-09 80,000,000 860,000 Spoon 6.2 0.087
100 sq ft 4.10×10 -10 610,000,000 5.8E-10 430,000,000 250,000,000 Cup 0.11 0.013 7.30×10 -12 34,000,000,000 8.6E-11 2,900,000,000 2,700,000,000 Hand Dispersal 160 0.38 1.10×10 -8 24,000,000 2.5E-09 99,000,000 19,000,000

Shaker Can 0.11 0.013 7.30×10 -12 34,000,000,000 8.6E-11 2,900,000,000 2,700,000,000 Mixer/Loader/Applicator for Indoor Bait Application Bait (granular; 160 0.38 0.0000132 2.60 ×10 -7 940,000 6.30 ×10 -8 4,000,000 760,000

1 Available: http://www.epa.gov/pesticides/scien ce/residential-exposure-sop.html

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 32 of 78 Table 6.1. Residential Hand ler Non-Cancer Exposu re and Risk Estimates for Abamectin.

Exposure Scenario Dermal Unit Exposure Inhalation Unit Exposure Maximum Application Rate Area Treated or Amount

Handled Daily b Dermal Inhalation Total

Dose c MOE d Dose e MOE f MOE g mg/lb ai mg/kg/day LOC = 100 mg/kg/day LOC = 100 hand dispersal) lb ai/package/day a Based on registered labels: EPA Reg. Nos. 100-893, 100-1029, 100-1452 (50 mg ai/lb product): Apply 7 tbsp/mound (1 tbsp ≈ 0.4 oz). Do not treat more

than 12 ant mounds per acre (i.e. 12 mounds/A × 7 tbsp product/mound × 0.4 oz product/tbsp product × 0.0625 lb product/oz product × 50 mg ai/lb product × 2.20462×10 -6 lb ai/mg ai = 0.00023 lb ai/A). 0.00023 lb ai/A × (1 A/43560 ft 2 ) = 5.31×10 -9 ft 2

. EPA Reg. No. 499-383 (0.05% ai bait dus t): Package contains 100 bait placements (12 gram s of product). The label

recommends up to 30 bait placements in an average sized kitche n (i.e. assuming one package can be used in one day, 12 g product/day × 0.05% ai/product × 0.00220462 lb ai/g ai = 0.000013 lb ai/day). b Exposure Science Advisory Council Policy #9.1. Based on HED’s SOPs: Lawn s/Turf (January 2012). c Dermal Dose = Dermal Unit Ex posure (mg/lb ai) × Applic ation Rate (lb ai/acre or gal) × Ar ea Treated or Am ount Handled (A or gallons/day) × DAF (1%) ÷ BW (80 kg). d Dermal MOE = Dermal NOAEL (m g/kg/day) / Dermal Dose (mg/kg/day). ST/I T Dermal NOAEL = 0.25 mg /kg/day. Level of

concern = 100. e Inhalation Dose = Inhalation Unit Exposur e (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount

Handled (A or gallons/day) ÷ BW (80 kg). f Inhalation MOE = Inhalation NOAEL (m g/kg/day) ÷ Inhalation Dose (mg/kg/da y). ST/IT Inhalation NOAEL = 0.25 mg/kg/day. Level of concern = 100. g Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhala tion Dose). ST/IT Combined Dermal/Inhalation NOAEL = 0.25

mg/kg/day. Level of concern = 100.



### 6.2 Residential Post-Application Ex posure and Risk Estimates

Post-application exposure for adults and children (1 to <2) is unlikely for the currently registered uses of abamectin. For currently registered outdoor treatments, adults and children are not expected to directly contact fi re ant mounds. For currently regi stered indoor pest control, bait placements are intended to be placed in cracks and crevices where direct contact by adults and children (1 to <2) is unlikely.

However, residential post-applica tion exposure for adults and children (6 to <11 and 11 to <16) is possible for the newly proposed use of abamectin on golf courses. Adults and children (6 to <11 and 11 to <16) performing physical post-ap plication activities on golf course turf may receive dermal exposure to abamectin residues. Th e scenarios, lifestages, and routes of exposure include: golfing for adults (dermal), children 11 to < 16 years old (dermal), and children 6 to < 11 years old (dermal). Table 6.2 presents the pos t-application dermal MOEs calculated after applications of abamectin to golf course turf (g reens, tees, and fairways only). Post-application risk estimates for all scenarios are greater than the LOC of 100 and theref ore are not of concern (MOEs range from 9,000 to 12,000).

Table 6.2. Short-Term Residential Post-Application Ex posure and Risk Estimates for Abamectin on Turf
Lifestage Post-Application Exposure Activity Scenario Dose a MOE b mg/kg/day Liquid Formulation on Turf (Golf Cour se Greens, Tees, and Fairways) max single application rate: 0.34 lb ai/A Adult Dermal Exposure Golfing 0.0000203 12,000 Child 11 to < 16 years old Golfing 0.0000237 11,000 Child 6 to < 11 years old Golfing 0.0000278 9,000

a Dermal Dose = TTR/DFR (μg/cm 2 ) × CF1 (0.001 mg/μg) × TC (cm 2 /hr) × Exposure Time (hrs) ÷ body weight (kg). TCs for

golfing: 300 cm 2 /hr for adults, 4,400 cm 2 /hr for children 11 to < 16 years old, and 2,900 cm 2 /hr for children 6 to < 11 years

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 33 of 78 old. Exposure time for golfing: 4 hrs. Body weight for adult: 80 kg. Body weight for children 11 to < 16 years old: 57 kg. Body weight for children 6 to < 11 years old: 32 kg. b MOE = NOAEL ÷ Daily Dose (mg/kg/day). Dermal NOAEL= 0.25 mg/kg/day. Level of concern = 100.



### Guideline 875.2100 - Turf Trans ferable Residues (TTR): Since the estimated residential turf post-application exposure for residentia l golf course using default TTR values for abamectin is minimal in comparison to the LOC (i.e. the calculated MOE is greater than 10 times higher than the LOC ( MOE = 9,000 compared to the LOC of 100); EPA is waiving the 40 CFR TTR data requirement. In this instance, it is unlikely that chemicalspecific TTR data would be needed to furthe r refine exposure assessments or would add appreciably to our general unders tanding of the availability of turf transferable pesticide residues.

6.3 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pes ticides may be a source of post-ap plication inhala tion exposure to individuals nearby pesticide app lications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insec ticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (S AP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/ SAP/meetings/2009/120109meeting.html). The Agency has evaluated the SAP report and has de veloped a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docke tDetail;D=EPA-HQ-OPP-2014-0219). During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for abamectin.

6.4 Spray Drift

Spray drift is a potential source of exposure to those nearby pest icide applications. This is particularly the case with aerial application, but, to a lesser exte nt, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for abamectin. The Agency has been working with the Spray Drift Task Force (a task force composed of various regist rants which was developed as a result of a Data Call-In issued by EPA), EPA Regi onal Offices, and State Lead Ag encies for pesticide regulation and other parties to develop the best spray drif t management practices (see the Agency’s Spray Drift website for more information). 2 

### The Agency has also developed a policy on how to appropriately consider spray drif t as a potential source of expo sure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses fo r that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Resi dential Exposure Asse ssment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non-occupati onal exposure to drift.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 34 of 78 7.0 Aggregate Exposure/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and resi dential exposures when considering tolerance petitions. The aggregate risk assessment must consider exposures from oral, dermal and inhalation exposures. The toxicity endpoints se lected for these routes of exposure may be aggregated together due to their common toxi city endpoint and effect s for all routes and durations of exposure.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment considers ex posure estimates from dietary consumption of abamectin (food and drinking water). The acute aggregate food and drinking water assessment results are presented in Section 5.4 above. The most highly exposed subgroup is children 1-2 years old at 90% of the aPAD, whic h is below the level of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

The short-/intermediate-term aggregate risk as sessment estimates risks likely to result from exposure to abamectin residues from food, drinking water, and residential pesticide uses. Highend estimates of residential exposure are use d, while average values are used for food and drinking water exposure.

For the purpose of this human health risk asse ssment, a summary of the worst-case residential exposure estimates are provided in Table 7.2.1. The recommended residential exposure for use in the adult and youth aggregate assessments re flect dermal exposure from golfing activities following applications to golf course turf.

Table 7.2.1. Scenarios Recommended for Aggregate Risk Assess ment of Abamectin (Short-Term Only)

Scenario Daily Dose 1 MOE 2 mg/kg/day LOC = 100 Adults Post-Application: Dermal Only Exposure (Liquid Application to Golf Course Turf) 0.0000203 12,000
Children 11 to < 16 years old Post-Application: Dermal Only Exposure (Liquid Application to Golf Course Turf) 0.0000237 11,000

Children 6 to < 11 years old Post-Application: Dermal Only Exposure (Liquid Application to Golf Course Turf) 0.0000278 9,000

1 Daily Dose = See Table 5.2 for all adult and childre n golfing scenarios (dermal dose + inhalation dose).

2 MOE = NOAEL/Daily Dose (mg/kg/day). ST Derm al = NOAEL = 0.25 mg/kg/day. LOC = 100.



### Short-term aggregate risk is calculated in Ta ble 7.2.2 below. All short-term aggregate exposure estimates resulted in MOEs greater than 100, and were not of concern.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 35 of 78 Table 7.2.2 Short-Term Aggregate Risk Calculations

Population Short-Term Scenario

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

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food, water, and residential) 5

Adults 0.25 100 0.0025 0.000082 0.0000203 0.0001023 2400 Children 11 to <16 years old 0.25 100 0.0025 0.000137 0.0000237 0.0001607 1600

Children 6 to <11 years old 0.25 100 0.0025 0.000137 0.0000278 0.0001648 1500

1 The LOC includes the standard inter- an d intra-species uncertainty factors (UF A and UF H , respectively) totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] from Tables 6.2 and 7.2.1.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure).

5 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)].



### 7.3 Chronic Aggregate Risk

The chronic aggregate risk assessment consider s average exposure estimates from dietary consumption of abamectin (food and drinking water) and residential uses. However, due to the use patterns, no chronic residen tial exposures are expected. As noted in Section 4.5 the same point of departure can be used for all exposure durations, so the acute ag gregate risk assessment will be protective of the chronic assessment as well.

7.4 Cancer Aggregate Risk

Abamectin is classified as “not likely to be carcinogenic to humans” ba sed on the absence of a significant increase in tumor in cidence in two adequate rode nt carcinogenicity studies.

8.0 Cumulative Exposure/Risk Characterization

EPA’s Office of Pesticide Programs has deve loped a draft guidance document dated 2/23/15, entitled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis . This draft document provides guidance on how to screen gr oups of pesticides for cumulative evaluation using a two-step approach beginning with the ev aluation of available toxicological information and, if necessary, followed by a risk-based screening approach. This framework supplements the existing guidance documents for establis hing common mechanism groups (CMGs) ( Guidance for Identifying Pesticide Chem icals and Other Substances That Have a Common Mechanism of Toxicity , dated 1/29/99) and conducting cumula tive risk assessments (CRAs) ( Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity , dated 1/14/02).

The Agency has utilized this sc reening framework for abamectin. and determined that abamectin along with emamectin form a candidate CMG. Alt hough there is not adequate data at this time for establishing key events in a pathway as described in 1999 CMG guidance (e.g., lack of dose

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 36 of 78 or temporal concordance of proposed key events ), there are sufficient toxicological data to suggest a common pathway; therefore, EPA has determined that these pesticides form a candidate CMG because they share characteristic s to support a testable hypothesis for a common mechanism of action. Consistent with the guida nce described in the cumulative screening framework, the Agency has conducted a screening- level cumulative exposure assessment. This screening assessment, included as Appendix H to this assessment, indicates that cumulative aggregate dietary and residential exposures for abamectin and emamectin are below the Agency’s levels of concern.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are invo lved in the pesticide application process. HED believe s that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a ha ndler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and curr ent labeling, types of equipment and techniques that can potentially be used, occupational handl er exposure is expected from the proposed agricultural uses. The quantita tive exposure/risk assessment de veloped for occupational handlers is based on several scenarios which include mixi ng/loading/applying the liquid formulations of abamectin. The use sites are summarized in Sect ion 3.3. Methods of app lication include aerial, chemigation, groundboom, and handheld equipment. Fl agging for aerial use is also a potential source of worker exposure. Refer to Table G.1 in Appendix G for a detailed list of each scenario.

The results of the occupational handler exposure and risk assessment indicate that short- and intermediate-term inhalation risk estima tes are not of concern (i.e. all MOEs ≥ 100) at baseline mitigation (no PPE). Since the short- and intermediate-term PODs are the same, the combined MOEs are also the same, ranging 360 to 25,000. No te that only engineer ing control (enclosed cockpit) data are available to assess ri sks to handlers operating aircrafts.

The Agency matches quantitative occupatio nal exposure assessment with appropriate characterization of exposure poten tial. While HED presents quantitative risk estimates for human flaggers where appropriate , agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation A ssociation (NAAA) survey of their membership, the use of G PS for swath guidance in agricultu ral aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potenti al for human flaggers in agricultural aerial applications.

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Page 37 of 78 HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Ther efore, risks to pilots are assessed using the engineering control (enclosed coc kpits) and baseline attire (long- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations fo r engineering controls, pilots are not required to wear protective gloves for the dura tion of the application. With this level of protection, there are no risk es timates of concern for applicators.

9.2 Short-/Intermediate-Term Post-A pplication Exposures and Risks

Based on the proposed use patterns, post-appli cation exposure to abamectin is possible. Agricultural workers and golf course maintena nce workers performing typical post-application activities may receive dermal e xposure to abamectin residues.

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pe sticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including ac tivities related to crop producti on, such as scouting for pests or harvesting. Post-application e xposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was trea ted, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

The short- and intermediate-ter m post-application exposure scenar ios associated with the newly proposed uses are summarized in Table G.2 in Appe ndix G. All risk estimates are not of concern (MOEs range from 530 to 67,000) on day 0 (12 hours afte r application).

Guideline 875.2100 - Dislodgeable Foliar Residue (DFR): Since the highest estimated occupational post- application exposure using default DFR values for abamectin is minimal in comparison to the LOC (i .e. the calculated MOE is greater than 2 times higher than the LOC, MOE = 530 compared to the LOC of 100; EPA is waiving the 40 CFR DFR data requirement. In this instance, it is unl ikely that chemical-specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pestic ide residues for abamectin.

Guideline 875.2100 - Turf Trans ferable Residues (TTR): Since the estimated occupationa l post-application exposure for golf courses using default TTR values for abamectin is minimal in comparison to the LOC (i.e. the calculated MOE is greater than 10 times higher than the LOC ( MOE = 8,700 compared to the LOC of 100); EPA is waiving the 40 CFR TTR data requirement. In this inst ance, it is unlikely that chemical-specific TTR data would be needed to further refine expos ure assessments or woul d add appreciably to our general understanding of the availability of turf transferable pesticide residues.

Occupational Post-Application Inha lation Exposure/Risk Estimates There are multiple potential sources of post-app lication inhalation exposure to individuals performing post-applicati on activities in previously treated fields. These potential sources

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 38 of 78 include volatilization of pesticides and resuspension of dusts and/or particulat es that contain pesticides. The Agency sought expert advice an d input on issues relate d to volatilization of pesticides from its Federal Insecticide, Fungicide , and Rodenticide Act Scie ntific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html). The Agency has evaluated the SAP report and has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/ #!docketDetail;D=EPA-HQOPP-2014-0219 ). During Registration Review, the Agency will utilize this an alysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for abamectin.

In addition, the Agency is continuing to eval uate the available post- application inhalation exposure data generated by the Ag ricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation expos ure into the Agency's risk assessments.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

Restricted Entry Interval: Abamectin is classified as Toxicity Category III via the dermal route, IV for eye irritation, III for skin irritation, and it is not a sensitiz er. Typically, the REI specified on the proposed label is based on the acute toxi city of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingred ients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irri tation are assigned a minimum of 12 hours for the REI. Thus, the 12-hour REI on the proposed label is adequate to protect workers.

10.0 References

(Refer to Appendix B for toxi cology literature references.)

D. Atwood, 7/23/14, DP Nos. 420312 and 420218, Percent Crop Treated for Abamectin (122804) on IR4 Proposed New Use on Caneberrie s and New Foliar Use on Soybeans and Sweet Corn.

G. Orrick, 5/15/14, DP No. D412861, Abamectin : Drinking Water Exposure Assessment for Proposed New Uses on Soybeans, Sweet Corn, Caneberries (Crop Group 13-07A), and Golf Course Tees, Greens, and Fairways.

J. Becker, 10/7/14, D413125, Upper Bound Estimate of the Likelihood of Insecticide Residues on Food Resulting from Treatment in Food Handling Establishments.

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Page 39 of 78 N. Dodd, 4/15/15, DP No. 426800, Emamectin Benzoate : Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments using Revised Toxicology Endpoints.

N. Dodd, 5/15/14, DP No. D410993, Abamectin . Review of a Secti on 3 Registration Request for Ear Tag Use on Lactating Dairy Cattle. Summary of Analytical Chemistry and Residue Data.

N. Dodd, 5/15/14, DP No. D412860, Abamectin . Petition for the Establishment of a Permanent Tolerance and Registration for Use on the Cane berry Subgroup 13-07A. Summary of Analytical Chemistry and Residue Data.

N. Dodd, 5/15/14, DP No. D414022, Abamectin . Petition for the Establishment of Permanent Tolerances and Registration for Use on Sweet Co rn and Soybeans. Summary of Analytical Chemistry and Residue Data.

N. Dodd, 10/28/14, DP No. D421348, Abamectin Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessme nts for the Section 3 Registration Actions for Uses on Caneberries, Sweet Corn, So ybeans, and Dairy Cattle Ear Tags.

N. Dodd, 2/20/13, DP No. D402152, Emamectin Benzoate : Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Ri sk Assessments for a Tolerance on Imported Wine.

N. Dodd, 4/12/13, DP No. D402151, Emamectin Benzoate. Human Health Risk Assessment for a Proposed Tolerance on Imported Wine Grapes.

N. Dodd, 12/20/12, DP No. D402677, Abamectin . Human Health Risk Assessment for Uses of the SC Formulation on Cotton and Strawberry.

N. Keller, 12/18/14, DP No. D412860, Abamectin . Occupational Exposure and Risk Assessment for the Proposed Agricultural Uses on Caneberries (Crop Subgroup 13-07A), Corn, and Soybeans; and Turf Use on Golf C ourses (Greens, Tees, and Fairways).

S. Haddad, 11/6/13, DP No. 415573, Usage Report P ackage in Support of Abamectin (PC Code 122804).

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Page 40 of 78 Appendix A. Abamectin Toxicolo gy Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for abamectin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical
Required Satisfied 870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................
870.1300 Acute In halation Toxicity ..............................................
870.2400 Acut e Eye Irr itation

....................................................... 870.2500 Acute Dermal Irritation ................................................. 870.2600 Skin Sensitiza tion .......................................................... yes
yes
yes
yes
yes
yes yes
yes
yes
yes
yes
yes 870.3100 90-Day Oral Toxicity in Rodents .................................. 870.3150 90-Day Oral Toxicity in Nonrodents ............................. 870.3200 21/28-Da y Dermal Toxicity .......................................... 870.3250 90-Day Dermal Toxicity ............................................... 870.3465 90-Day Inhalation To xicity ........................................... yes
yes
yes CR
CR yes
yes waived a

- yes 870.3700a Prenatal Developm ental Toxicity (rodent) .................... 870.3700b Prenatal Developmen tal Toxicity (nonrodent) .............. 870.3800 Reproductio n and Fertility Effects ................................ yes
yes
yes yes
yes
yes 870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Carcinog enicity (rat) ...................................................... 870.4200b Carcinoge nicity (mouse) ............................................... 870.4300 Combined Chroni c Toxicity/Carci nogenicity ............... yes

no
yes
yes
yes yes
yes
yes
yes
yes 870.5100 Mutagenicity—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test .. 870.5xxx Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5xxx Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes
yes yes
yes
yes
yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 870.6300 Developm ental Neurot oxicity ....................................... yes
yes
yes yes
yes
yes 870.7485 Metabolism and Pharmacokinetics ................................
870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes CR
Yes yes
yes waived b

a HASPOC Report: TXR 0056509, 01/30/2013.

b HASPOC Report: : TXR 0056687, 01/07/2013

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Page 41 of 78 A.2 Data Demonstrating the Sensitivity of Be agle Dogs to the Effects of Abamectin and Emamectin

To illustrate the order of sensitivity to the eff ects of abamectin and emamectin in test animals that have fully functioning P-gp, the results of th e subchronic (90-day) oral toxicity studies on emamectin with rats, CD-1 mice, and dogs were used for comparison. The data indicate that the effects produced in the dogs are qualitatively more seve re and have a substantially lower LOAEL relative to those produced in the rats and CD-1 mice, as shown in the table below. Similar data on abamectin also demonstrate this order of sensitivity.

Comparison of the results of subchronic (90-day) oral toxicity studies on emamectin Test species NOAEL (mg/kg/day) LOAEL Effects seen at LOAEL

Beagle dogs 0.25 0.50 Skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males. Rats 2.5 5 Tremors, hindlimb splaying, urogenital staining, histological changes in brain and spinal cord, sciatic and optic nerves and skeletal muscles in males, emaciation, reduced body weight and reduced food consumption in both sexes, and moribundity. CD-1 mice 5.4 15.0 Mean body weight decrease

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Page 42 of 78 A.3 Toxicity Profiles

Table A.3.1. Acute Toxicity Profile of Abamectin Technical

Guideline No. Study Type MRID # Results Toxicity Category

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

870.1100 Acute Oral - rat (methyl cellulose vehicle) 45607202 LD 50 =214-232 mg/kg II

870.1200 Acute Dermal - rabbit 00255978 LD 50 = 2000 mg/kg III

870.1300 Acute 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 Acute Neurotoxicity none none none

Table A.3.2. Toxicity Profile of Abamectin Tec hnical for Repeated Dosing and Genotoxicity Studies

Guideline No./

Study Type MRID No. (year)/ Classification /Doses Results

870.3100 Subchronic feeding study-rats 00131081 (1982) Acceptable/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 was reduced to 2.0 mg/kg/day due to tremor, weakness, incoordination, and disorientation) The report stated that mydriasis was 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.

870-3465 30-Day inhalation toxicity -rats 46921502 (2006) 0, 0.0001, 0.0005, and 0.0025 mg/L 46921501 (5 day preliminary study; 2006) No effect was found at the highest concentration tested.

NOAEL ≥ 0.0025 mg/L (Equivalent to 0.568 mg/kg)

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Page 43 of 78 Table A.3.2. Toxicity Profile of Abamectin Tec hnical for Repeated Dosing and Genotoxicity Studies

Guideline No./

Study Type MRID No. (year)/ Classification /Doses Results

870.3200 21/28-Day dermal toxicity Study not available. Study requirement was waived due to very low dermal absorption (<1%) (HASPOC Report: TXR 0056509, 01/30/2013).

870.3465 30-Day inhalation
tox.-rats 46921502 (2006) Acceptable/Guideline NOAEL = >2.5 μ g/L (0.0025 mg/L) (HDT) ( ≈ 0.68 mg/kg/day)

870.4300a Combined 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 (dietary) 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 Combined 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 Developmental 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

Developmental NOAEL > 3.0 mg/kg/day. No adverse developmental effects were seen at the doses tested.

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 Developmental 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

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Page 44 of 78 Table A.3.2. Toxicity Profile of Abamectin Tec hnical for Repeated Dosing and Genotoxicity Studies

Guideline No./

Study Type MRID No. (year)/ Classification /Doses Results

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 isomer 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 LOAEL = not established 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 Acute 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. Th is dose group was terminated prematurely at week 7.

870-630 Developmental neurotoxicity study in
rats 46727403, 46727402, 46727401 (2005) Acceptable/non-guideline 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.

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

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Page 45 of 78 Table A.3.2. Toxicity Profile of Abamectin Tec hnical for Repeated Dosing and Genotoxicity Studies

Guideline No./

Study Type MRID No. (year)/ Classification /Doses Results

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 00139572 (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

Cytogenetics 870.5395 in vivo micronucleus assay -male mice MRID 00139574 (1983) 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 00139573 (1983) Acceptable

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 was used

Metabolism –CF 1 mice Wild type for P-gp (+/+) and mutant (-/-) 49009003 (2008) ( 14 C- abamectin) 0.1 & 0.2 mg/kg in sesame oil Abamectin was rapidly absorbed; T max was approximately 4 hours for blood and plasma. Within 48 hours after administration greater than 90% of the administ ered dose was eliminated via fecal route (primarily route).

Metabolism Accession: 252114Unacceptable/NonGuideline 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 MRID 00145888 (1985) Non-guideline Avermectin B 1a did not bioaccumulate in rat tissues. Half-life slightly longer in females than in males for several tissues.

Metabolism MRID 00145907 (1985) Non-guideline 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/ Non-guideline in Monkeys The result showed the dermal absorption to be <1% of the applied dose. For risk assessment, a dermal penetration factor of 1% was recommended.

870.7800 Immunotoxicity This study is waived (HASPOC Report: TXR 0056687, 01/07/2013)

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Page 46 of 78 Table A.3.3 Toxicity Profile of Abamectin Technica l - 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 followingtreatment appears to be a consequence of fetal Pglycoprotein genotype.

870.3700a Prenatal developmental
in rodents-CF1 mouse 00096446 (1985) 0, 0.025, 0.050, 0.075, 0.10 mg/kg/day (GD 6-15) Dose range finding study (Study #: TT 77-17-1) Maternal NOAEL = 0.05 Maternal LOAEL = = 0.075 Based on one mouse was sacrificed in comatose state after 4 dosing. After 3 dosing, one mouse was dead at 0.1 mg/kg/day group. Before death or moribund sacrifice, tremors and coma were observed.

870.3700a Prenatal developmental
in rodents-CF1 mouse 00164020 (1985) (Main study) 0, 0.025, 0.050, 0.075, 0.10 mg/kg/day (GD 6-15) ( Study #: TT 84-721-0) Maternal NOAEL = 0.05 mg/kg/day Maternal LOAEL = 0.075 mg/kg/day Based on 2 deaths (one occurred on day 11 and the other on day 12). Before death, tremors occurred. Developmental NOAEL = 0.1 mg/kg/day (HDT)

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) Developmental 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) Developmental 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) Developmental 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 Developmental NOAEL > 1.0 mg/kg/day 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) Developmental NOAEL = 0.2 mg/kg/day LOAEL = 0.4 mg/kg/day based on increased cleft palate

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Page 47 of 78 Table A.3.3 Toxicity Profile of Abamectin Technica l - for CF1 Mice
Guideline No./ Study Type MRID No. / Classification /Doses Results

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 Developmental 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 Developmental NOAEL > 1.0 mg/kg/day LOAEL = not established

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 48 of 78 Appendix B. Toxicology Literature References Daood., MJ, Tsai, C., Ahdab-Barmada, M., and Watchko, JF (2008). ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing Human CNS. Neuropediatrics . 2008 August ; 39(4) : 211.

Dawson, GR, Wafford, KA, Smith, A, Marshall, GR, Bayley, PJ, Schaeffer, JM, Meinke, PT, and McKernan, RM. (2000) Anticon vulsant and adverse effects of avermectin analogs in mice are mediated through the gama-aminobutyric acid (A) receptor. J. Pharmacol. Exp. Ther. 295: 1051-1060.

Huang, J, Casida, JE. (1997) Avermectin B 1a 

### binds to high- and low-a ffinity sites with dual effects on the gama-aminobutyric acid-gated chloride channel of cultured cer ebellar granule neurons. J. Pharmacol. Exp. Ther. 281: 261-266.

Kerr, DI and Ong, J. (1986) Gama-aminobutyric acid-dependent motility induced by avermectin B 1a 

### in the isolated intestine of the gu inea pigs. Neurosci. Lett. 65: 7-10.

Lankas, GR, Cartwright, ME, a nd Umbenhauer, D. (1997) P-Glyc oprotein deficiency in a subpopulation of CF-1 mice enhances averm ectin-induced neurotoxicity. Toxicol. and Appl. Pharmacol. 143: 357-365.

Marzolini, C., Paus, E., Buclin, T., and Kim, RB (2004) Polymorphism In human MDR1 (P- glycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther. 75: 13-33.

Macdonald, N. and Gledhill, A. (2007). Pote ntial impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in human. Arch Toxicol (2007) 81:553-563.

Matsukoa, Y., Okazaki, M., Kitamura, Y., and Ta niguchi, T. (1999). Developmental expression of P-glycoprotein (multidrug resistan ce gene product) in the rat brain. Journal of Neurobiology, 39(3), 383-392.

Meister, B. (2007) Neurotransmitters in key ne urons of the hypothalamus that regulate feeding behavior and body weight. P hysiol. Behav. 92: 263-271.

Nguyen, L., Rigo, JM, Rocher, V., Belachew, S., Malgra nge, B., Rogister, B., Leprince, P., and Moonen G. (2001) Neurotransmitters as ear ly signals for central nervous system development. Cell Tissue Res. 305: 187-202.

Pong, SS, DeHaven, R., and Wang, CC. (1982) A comparative study of avermectin B 1a 

### and other modulators of the gama-aminobutyric recepto r- chloride ion channel complex. J. Neurosci. 2: 966-971.

Represa, A. and Ben-Ari, Y. (2005) Trophic acti ons of GABA on neuronal development. Trends Neurosci. 28: 278-283.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 49 of 78 van Kalken, CK, Giaccone, G., van der Valk, P ., Kuiper, CM, Hadisaput ro, MMN, Bosma, SAA, Scheper, RJ, Meijer, CJLM, and Pinedo, HM (1992). Multidrug resistance gene (Pglycoprotein) expression in the human fetus. American Journal of Pathology , vol 141 No.5, November 1992.

Wang, CC and Pong, SS. (1982) Actions of avermectin B 1a 

### on GABA nerves. Prog. Clin. Biol. Res. 97: 373-395.

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Page 50 of 78 Appendix C. Abamectin Ph ysical/Chemical Properties

Table C. Physicochemical Properties of the Technical Grade of Abamectin
Parameter Value Reference 1 Molecular weight (g/mole) 873.11 Melting point/range (°C) 155-157°C Accession No. 260785 pH Not available Density (g/cm 3 ) 1.16 g/cm 3 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(K O W ) 9.9 x 10 -3 Accession No. 260785

Aerobic soil metabolism half-life Not available DP No. D380524, G. Orrick, 1/31/11

1 Product Chemistry data were reviewed by Leung Cheng (Accession No. 260785, RCB No. 388, 5/1/1986).

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Page 51 of 78 Appendix D. Review of Hu man Research for Abamectin

This abamectin risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or ot her chemical. These data, which include studies from the Pesticide Handlers Exposure Databa se Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database , the Outdoor Residential Exposure Task Force (ORETF) database, the Agricultural Reentry Task Force (ARTF) database; and the Residential Standard Operating Procedures (SOPs: Lawns/Turf ) are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data s ources, as well as guidanc e on their use, can be found at the Agency website 3



### .

3 http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html

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Page 52 of 78 Appendix E. International Resi due Limits Table for Abamectin



## Abamectin (122804; 11/01/12 and 9/19/13) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 3 

### 40 CFR §180.449: 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-Odemethyl avermectin A 1a 

### ) and less than or equal to 20% avermectin B 1b 

### (5-Odemethyl-25-de(1- methylpropyl)-25-(1- methylethyl) avermectin A 1a 

### ) and its delta-8,9- isomer) Plants: sum of avermectin B1a, avermectin B1b, 8,9-Z-avermectinB1a and 8,9-Zavermectin B1b. Animal commodities: sum of avermectinB1a and 8,9-Zavermectin B1a..

Animals: sum of avermectinB1a and 8,9-Zavermectin B1a..


### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex 3 Caneberry subgroup 13-07A 0.20 0.20 (pending) Cattle, fat 0.05 0.1 4 Cattle, meat 0.02 0.01 (*)
Cattle, meat byproducts 0.09 0.05 4 cattle kidney 0.1 4 cattle liver Corn, sweet, forage 0.20 Corn, sweet, kernel plus cob with husks removed 0.01
Corn, sweet, stover 0.50 Goat, meat 0.02 0.01 (*)
Goat, meat byproducts 0.04 0.1 goat edible offal Grain, aspirated grain fractions 0.40 Hog, fat 0.01 Hog, meat 0.02 Hog, meat byproducts 0.02 Horse, fat 0.03 Horse, meat 0.02 Horse, meat byproducts 0.04

Milk 0.015 0.005 cattle milk 0.005 goat milk Poultry, meat 0.02 Poultry, meat byproducts 0.02 Sheep, fat 0.03 Sheep, meat 0.02 Sheep, meat byproducts 0.04

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Page 53 of 78 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 3 Soybean, forage 0.30 Soybean, hay 1.0 Soybean, seed 0.01 Completed: M. Negussie; 11/01/12 and 9/19/13

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated co mmodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

4 The MRL accommodates external animal treatment.

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Page 54 of 78 Appendix F. Abamectin Field Trial Tables

Table F.1. Summary of Residue Data from Caneberry, Soybean, and Sweet Corn Field Trials with Abamectin Commodity Total Applic.

Rate, (lb ai/A) PHI (days) Residue Levels 1,2 (ppm)

n Sample Min. Sample Max. LAFT 3 HAFT 3 Median Mean Std. Dev. CANEBERRY Proposed Use = 0.05 6 lb ai/acre/season, 7-day PHI Blackberry 0.056- 0.059 7 4 <0.0164 0.0632 <0.0171 0.0535 <0.0233 <0.029 0.017

Raspberry 0.055- 0.061 7 3 <0.0062 0.1215 <0.0067 0.1184 0.0084 0.045 0.064

Blackberry and Raspberry 0.055- 0.061 7 7 <0.0062 0.1215 <0.0067 0.1184 <0.0204 <0.0358 0.040

SOYBEAN Proposed Use = 0.038 lb ai/acre/season; 7-day PHI for forage and hay; 28-day PHI for seed Soybean, forage 0.0776- 0.127 6-8 20 <0.0120 0.165 <0.0138 <0.158 0.037 0.059 0.047

Soybean, hay 0.0776- 0.127 6-8 20 <0.0420 0.741 <0.0448 0.607 0.200 0.240 0.174

Soybean, seed 0.0770- 0.127 27-29 20 <0.006 <0.006 <0.006 <0.006 <0.006 <0.006 N/A

SWEET CORN Proposed Use = 0.03 8 lb ai/acre/season, 7-day PHI Sweet corn, forage 0.0504- 0.0795 6-7 12 <0.0129 <0.115 <0.0146 <0.102 0.063 0.056 0.029

Sweet corn, K+CWHR 0.0504- 0.0795 6-7 12 <0.006 <0.006 <0.006 <0.006 0.006 0.006 N/A

Sweet corn,
stover 0.0504- 0.0795 6-7 12 <0.0158 0.363 <0.0221 0.329 0.065 0.101 0.094

1 Combined residues of avermectin B 1a , 8,9-Z avermectin B 1a , and avermectin B 1b were reported.

2 Except for sample min/max, values reflect per trial aver ages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.002 ppm for each analyte in each matrix) was used for any results reported as <LOQ. N/A = Not applicable.

3 LAFT = lowest average field trial; HAFT = highest average field trial.

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Page 55 of 78 Appendix G. Abamectin Occupational and Residential Exposure Tables

Table G.1. Occupational Handler Exposure and Risk Estimates for Proposed Abamectin Uses

Exposure Scenario Crop or Target a Unit Exposure b Max App Rate c Area Treated or Amount Handled Daily d Dose e MOE f

Dermal Inhalation Dermal Inhalation Dermal Inhalation Total

μ

g/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100
Mixer/Loader

Mixing/Loading

Liquids for

Aerial Application Orchard

220 0.219 0.019 350 0.000183 0.0000183 1,400 14,000 1,300 Typical Field CropsHighAcreage Field Crops 1200 0.000628 0.0000624 400 4,000 360

Mixing/Loading

Liquids for

Airblast Application Orchard 40 0.0000209 0.00000208 12,000 120,000 11,000

Mixing/Loading

Liquids for Chemigation Application Orchard

350 0.000183 0.0000183 1,400 14,000 1,300 Typical Field CropsHighAcreage Field Crops

Mixing/Loading

Liquids for Groundboom Application Golf Courses (fairways, tees, and greens) 0.069 40 0.0000759 0.00000755 3,300 33,000 3,000

Typical Field Crops 0.019 80 0.0000418 0.00000416 6,000 60,000 5,500
HighAcreage Field Crops 200 0.000105 0.0000104 2,400 24,000 2,200

Applicator

Applying Sprays for Aerial Application Orchard

5 0.068

0.019 350 0.00000416 0.00000565 60,000 44,000 25,000 Typical Field CropsHighAcreage Field Crops 1200 0.0000143 0.0000194 17,000 13,000 7,400

Applying Sprays

for Airblast Application Orchard 1770 4.71 40 0.00000139 0.000000646 180,000 5,600 1,200

Applying Sprays for Groundboom

Application Golf Courses (fairways, tees, and greens) 78.6 0.34 0.069 40 0.0000271 0.0000117 21,000 9,200 6,400

Typical Field Crops 0.019 80 0.0000149 0.00000646 39,000 17,000 12,000
HighAcreage Field Crops 200 0.0000374 0.0000161 16,000 6,700 4,700

Flagger Orchard 11 0.35 0.019 350 0.00000915 0.0000291 27,000 8,600 6,500

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Page 56 of 78 Table G.1. Occupational Handler Exposure and Risk Estimates for Proposed Abamectin Uses

Exposure Scenario Crop or Target a Unit Exposure b Max App Rate c Area Treated or Amount Handled Daily d Dose e MOE f

Dermal Inhalation Dermal Inhalation Dermal Inhalation Total

μ

g/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100

Flagging for Aerial Application Typical Field CropsHighAcreage Field Crops Mixer/Loader/Applicator

M/L/A Liquids forMechanicallyPressurized

Handgun Sprayers Golf Courses (fairways, tees, and greens) 1,140 1.9 0.069 5

acres 0.0000491 0.00000820 5,100 30,000 4,400

Orchard 1,300 3.9 0.0019 1000 gallons 0.000309 0.0000926 810 2,700 620 Typical Field Crops a “Orchard” includes caneberries (crop subgroup 13-07A). “Typical Field Crops” include sweet corn. “High-Acreage Field Crops” include corn and soybeans. b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Bas eline except for aerial applicator whic h includes engineering controls. c Based on the maximum application rates on the proposed labels (Reg. Nos. 100-898, -1154, -1350, -1351, -1408, -1439, RLNO, an d -RLRN). d Exposure Science Advisory Council Policy #9.1. e Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or

Amount Handled Daily (A or gal/day) × DAF (1%) ÷ BW (80 kg). Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or

Amount Handled Daily (A or gal/day) ÷ BW (80 kg). f Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Do se (mg/kg/day). ST/IT Dermal NOAEL = 0.25 mg/kg/day. Inhalation MOE = Inhalation NOAEL (mg/kg/ day) ÷ Inhalation Dose (mg/kg/day). ST /IT Inhalation NOAEL = 0.25 mg/kg/day. Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose). ST/IT Combined Derma l/Inhalation NOAEL = 0.25 mg/kg/day.

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Page 57 of 78 Table G.2. Short-Term Post-Application Expo sures and Risk Estimates for Abamectin

Activity Transfer Coefficient Days After Treatment DFR a Daily Dermal Dose b Dermal MOE c μg/cm 2 mg/kg/day LOC = 100 Caneberries (Crop Subgroup 13-07A): Vine/Trellis irrigation (hand set) 1,900

0 (12 hours) 0.053 0.000101 2,500 hand harvesting,

tying/training 1,400 0.0000746 3,400
scouting, hand pruning, hand weeding, tying/training 640 0.0000341 7,300

transplanting 230 0.0000123 20,000 Corn: Field/Row Crop, Tall hand detasseling, hand harvesting d 8,800

0 (12 hours) 0.053 0.000469 530

irrigation (hand set) 1,900 0.000101 2,500
scouting 1,100 0.0000586 4,300
scouting 210 0.0000112 22,000
hand weeding 70 0.00000373 67,000 Soybean: Field/Row Crop, Low/Medium scouting 1,100 0 (12 hours) 0.053 0.0000586 4,300

hand weeding 70 0.00000373 67,000

Golf Course: Turf/Sod
maintenance 3,700 0 (12 hours) 0.0077 0.0000286 8,700
maintenance, greens only 2,500 0.0000194 13,000
a DFR (μg/cm 2 ) = application rate (0.019 or 0.069 lb ai/acre) × fraction of application ra te dislodgeable on day 0 (25%) × (1 - fraction of residue that dissipates daily 10%) t × 4.54×10 8 μg/lb × 2.47× -8 acre/cm 2

. b Short-Term Daily Derm al Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day  body weight (80 kg). c Short-Term MOE = NOAEL (mg/ kg/day) ÷ Daily Dermal Dose (mg/kg/day) . ST NOAEL = 0.25 mg/kg/day. LOC = 100.

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Page 58 of 78 Appendix H. Abamectin and Emamect in Cumulative Screening Assessment

H.1.0 Introduction

EPA’s Office of Pesticide Programs has develope d to a draft guidance document dated 6/23/15, entitled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis . This document provides guidance on how to screen gr oups of pesticides for cumulative evaluation using a two-step approach beginning with the ev aluation of available toxicological information and, if necessary, followed by a risk-based screening approach. This framework supplements the existing guidance documents for establ ishing common mechanism groups (CMGs) 4 

### and conducting cumulative risk assessments (CRA) 5 

### . Abamectin and emamectin share a common toxicological profile and a te stable hypothesis has been id entified (Section H.2.0 below).

Consistent with the framework, a screening-level cumulative assessment was conducted for the candidate CMG of avermectin macrocyclic lacton es, which contains the insecticides abamectin and emamectin. This screen, which adds exposures of abamectin and emamectin, is expected to be an overestimate of exposure and risk (i.e., th is screen assumes co-o ccurrence of residues in water and some crops from both abamectin and emamectin).

Abamectin is registered for use on various food a nd feed crops, as well as some residential use sites including fire ant mounds and indoor sites. Additional food and residential uses are proposed.

Emamectin is registered for use on various raw agricultural commodities, including cotton, turnip greens, pome fruit, tree nuts, Brassica a nd other leafy vegetables , cucurbits, fruiting vegetables, tobacco, and wine grapes . It is also regist ered as a cockroach bait and tree injection. Currently there are no proposed or regist ered residential uses of emamectin.

Both insecticides are registered for use on the fo llowing crops: cotton, tree nuts, apples, pears, fruiting vegetables, cucurbits, and leafy vegetabl es, except Brassicas. Tolerances are also established for both chemicals for livestock commodities and grapes (the tolerance for emamectin applies to imported wine grapes only). Furthermore, since there is an “all foods” tolerance that applies to the use of abamectin in food handlin g establishments (FHE), there could be co-occurrence of residues in almost any f ood that bears residues of emamectin. The “all foods tolerance” is lower than tolerances based on agricultura l uses, so the FHE uses are expected to be minor contri butors to the exposure.

Based on the use patterns for abamectin and emam ectin, the potential routes and durations of exposure for cumulative consideration include ac ute exposure (dietary only) and short-term exposure (including dietary and residential, with residential exposure from abamectin only since there are no residential uses from emamectin).

4 

### Guidance For Identifying Pes ticide Chemicals and Other Subs tances that have a Common Mechanism of Toxicity (USEPA, 1999)

5 

### Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USEPA, 2002)

### ABAMECTIN Human Health Risk Assessment DP No. 426599

Page 59 of 78 H.2.0 Toxicological Considerations in Determining a Candidate CMG

H. 2.1 Chemical Structural Similarity

Emamectin is a derivative of abamectin, and they ar e structurally and toxico logically related. No other pesticides were identified with sufficient structural similarity for consideration in the candidate CMG. The only difference between abamectin and emamectin is that abamectin has a hydroxyl moiety at the 4” position of the te trahydropyrane ring whereas, in emamectin, the hydroxyl group is replaced by a methylamine (c ircled groups in the following figures).

Abamectin Emamectin

H. 2.2 Hazard Profile Comparison for Candidate CMG

Abamectin and emamectin share a common toxi cological profile as summarized below:

 Both abamectin and emamectin share a comm on toxicity profile consistent with GABA receptor interaction (Appendixes A and I).

 Both pesticides elicit similar clinical signs of neurotoxicity such as tremors, mydriasis, and abnormal gaits in dogs, rats, and mice.

 The dog is the most sensitive and human-relevant species for studying the effects of abamectin and emamectin. In dogs treated with these two pesticides, a set of common clinical signs indicativ e of neurotoxicity occurred at the same LOAEL or above with a common NOAEL (0.25 mg/kg/day) for establ ishing the point of departure for risk assessment (POD). Although the dog studies on these two pesticides did not employ the same dose levels, the effects demonstrated a similar dose-response relationship for the two chemicals.

 Both abamectin and emamectin have similarly low dermal absorption (i.e., 1% for abamectin and 1.8% for emamectin).

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 60 of 78 H. 2.3 Toxicological evaluation to determine a CMG

OPP’s Guidance For Identifying Pesticide Chemic als and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) describes the weig ht of the evidence approach for determining whether or not a group of pesticides share a common mechanism of toxicity. This guidance defines a mechanism of toxicity as the major steps leading to a toxic effect following interaction of a pesticide with biol ogical targets. All steps leading to an effect do not need to be specifically understood. Rather, it is the identification of the crucial events following chemical interaction that are required in order to describe a mechanism of toxicity. For example, a mechanism of toxicity may be described by knowing the following: a chemical binds to a given biological target in vitro, and causes the receptor-related molecular response; in vivo it also leads to the molecular response and causes a number of intervening biological and morphological steps that result in an adverse effect . In this context a common mechan ism of toxicity pertains to two or more pesticide chemicals or other substanc es that cause a common toxic effect to human health by the same, or essentially the same, seque nce of major biochemical events. Hence, the underlying basis of the toxicity is the same, or essentially the same, for each chemical.

In the case of the macrocyclic lactones of the avermectin class (e.g., abamectin and emamectin), there is a wealth of data on the insecticidal m echanism of action for aver mectin: its insecticidal actions are mediated by inter action with the glutamate-gate d chloride channels and GABA A 

### gated chloride channels. This is presumed to be the insecticidal mechanism of action of emamectin and abamectin as well. There is evidence that avermectin B 1a 

### binds to GABA A 

### receptors and activates Cl

- 

### flux into neurons (Abalis et al ., 1986; Huang and Casida, 1997). However, there is a paucity of da ta regarding the resultant alterati ons in cellular excitability of mammalian neurons and neural networks (i.e., ch anges in cellular excitability and altered network function as documented wi th pyrethroids), as well as in vivo measurements of altered excitability associated with adverse outcomes . Thus, while the downstream steps leading to toxicity via disruption of GABA A 

### receptor function for avermectin can be postulated, experimental data supporting these actions are la cking. In addition, specific data demonstrating GABA A 

### receptor interaction in mammalian prep arations are lacking for abamectin and emamectin. Moreover, the specificity of such in teraction on the adverse outcome would need to be shown experimentally. GABA A 

### receptors have multiple binding sites which have been proposed to relate to adverse outcomes. For ex ample, Dawson et al (2000) showed for a group of avermectin-like compounds that rank order for anticonvulsant activity di d not parallel the rank order for affinity at the [3H]ivermectin site. Th e authors hypothesized that these findings may be related to differential affinity or efficacy at subtypes of the GABA A 

### receptor. Other reports have indicated species differences in abamectin effects on GABA A 

### receptor function in the mouse as compared to the rat (Soderlund et al., 1987).

Although GABA A 

### receptor mediated neurotoxicity is a strong hypothesis as a common mechanism endpoint for the macrocyclic lactone pe sticides, data demonstr ating the interactions of emamectin and abamectin with mammalian GABA A 

### receptors are not available, and data in mammalian preparations li nking alterations in GABA A 

### receptor function to disruptions in neuronal excitability in vitro and in vivo , and ultimately adverse outcome, are also currently lacking for this class of compounds. there is not currently adequate da ta for establishing key events in a pathway as described in the mode of action/adverse outcome pathway (MOA/AOP)

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 61 of 78 framework 6,7,8,9 

### (e.g., lack of dose or temporal concorda nce of proposed key events). In the absence of such data, the key biological st eps leading to the adverse outcome (i.e., the mammalian mechanism of action) cannot be es tablished and by extens ion a science policy document establishing a common mechanism group in accordance with EPA’s 1999 CMG guidance cannot be developed.

Nevertheless, the Agency has determined that abamectin and emamectin should be considered a candidate CMG due to their structural similarity, the fact that they share characteristics to support a testable hypothesis fo r a common mechanism of action, and that there is sufficient toxicological data to suggest a common pathway.

H.3.0 Dose Response Assessment

H.3.1 Selection of Points of Departu re for Screening Cumulative Assessment

As discussed in Section 4.0, the Agency has re-evaluated the en tire toxicity databases for abamectin and emamectin and the available lite rature information on the polymorphism in the human gene encoding P-gp. The toxic effects obs erved in the CF-1 mouse and rat juvenile pup studies are not considered representative of ab amectin and emamectin effects in humans and will not be considered for toxicity endpoints and points of departure selections.

The Agency considered results from abamectin and emamectin toxicological studies conducted in the species which do not have diminished P-gp function for selecting PODs for risk assessment. The toxicity studies in rats, CD-1 mice, and beag le dogs demonstrated that the beagle dog is the most appropriate species to as sess the risk of abamectin and emamectin. The cumulative screen relies on toxi city studies conducted in the dog, with neurotoxic effects for both abamectin and emamectin. The points of depart ure used in the screen are also those used for single chemical assessment of the individual chemicals and represent the most sensitive points of departure that are rele vant to humans. The point of departure used for both chemicals is the NOAEL of 0.25 mg/kg/day; the adverse effect s noted at the LOAEL consist of mydriasis, tremors, and neuropathology. Mydriasis and trem ors are produced by both chemicals at similar dose levels, while neuropathology is seen with emamectin. The points of departure selected from the dog studies are based on clear NOAELs a nd are protective of a ll the adverse effects seen in the studies conducted in human relevant studies with rats, CD-1 mice, and rabbits.

6 

### USEPA (2005), Guidelines for Carcinogen Risk Assessment , Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register 70(66):17765-17817; http://www.epa.gov/raf.

7 

### Boobis, A.R. et al . (2008), IPCS Framework for Analyzing the Relevance of a Noncancer Mode of Action for Humans , Crit Rev Toxicol 38:87-96.

8 

### Seed, J. et al . (2005), Overview: Using Mode of Action and L ife Stage Informa tion to Evaluate the Human Relevance of Animal Toxicity Data , Crit Rev Toxicol 35(8-9): 664-672.

9 

### Sonich-Mullin, C. et al. (2001), IPCS Conceptual Framework for Evaluating a Mode of Action for Chemical Carcinogenesis , Regul Toxicol Pharmacol 34:146-152.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 62 of 78 Therefore, the extrapolation factor of 100x ( 10x for interspecies extrapolation and 10x for intraspecies difference) was applied for both chemicals.

Finally, the toxicity endpoints and points of departure for the rele vant exposure scenarios are the same for abamectin and emamectin; consequently , identification of an index chemical for developing screening level relative potency factor (RPF) is not needed for purposes of screening analysis. For dermal exposure assessment, th e dermal absorption for both abamectin and emamectin is quite similar with rather low dermal absorption factors, 1% for abamectin and 1.8% for emamectin.

The toxicity endpoints and points of departure of the two chemi cals are compared in Table H.3.1 below. The Toxicology Profile Tables and summ aries of toxicity endpoints and points of departure for human health risk assessment are presented in Appendix A (abamectin) and Appendix I (emamectin).

Table H.3.1. Comparison of Toxicological Doses an d Endpoints for Abamectin and Emamectin for Use in Dietary and Non-Occupational Hu man Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty/ FQPA Safety Factors RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects of Abamectin Study and Toxicological Effects of Emamectin Acute Dietary (General Population, including Infants and Children) NOAEL= 0.25 mg/kg/day UF A = 10x UF H = 10x FQPA SF = 1x Acute RfD = aPAD = 0.0025 mg/kg/day Subchronic & chronic oral toxicity studies in dogs Chronic 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 Subchronic LOAEL=0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day. Subchronic and chronic oral toxicity studies in dogs Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males. Chronic LOAEL=0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial) ; whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration. Incidental Oral Short- andIntermediateTerm NOAEL= 0.25 mg/kg/day UF A = 10x UF H = 10x Residential LOC for MOE = 100

Dermal Short- andIntermediateTerm NOAEL= 0.25 mg/kg/day UF A = 10x UF H = 10x Residential LOC for MOE = 100

Inhalation Short- andIntermediateTerm NOAEL= 0.25 mg/kg/day UF A = 10x UF H = 10x Residential LOC for MOE = 100

Cancer (oral, dermal, inhalation) Classification for abamectin and emamectin: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 (intra species). 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.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 63 of 78 H.3.2 FQPA Safety Factor for Prot ection of Infants and Children

For both abamectin and emamectin, the toxicity e ndpoint and point of depa rture for all exposure scenarios are selected from the s ubchronic and chronic oral toxici ty studies in the dogs, whose sensitivity to the effects of the abamectin is next to CF-1 mice. The points of departure selected from the dog studies are based on clear NOAELs a nd are protective of a ll the adverse effects seen in the studies conducted in human relevant studies with rats, CD-1 mice, and rabbits. Therefore, the FQPA safety f actor could be reduced to 1x.

H.3.3 Incorporation of Uncertainty Factors/ Extrapolation Factors and the Level of Concern MOE.

The level of concern MOE is 100 for the cumulative screening analysis.

H.4.0 Dietary Cumulative Exposure and Risk Assessment/Characterization

H.4.1 Food Exposure Pathway

Abamectin is used on various raw agricultural commodities. Tolerance levels from 40 CFR §180.449 are shown in Table H.4.1 below. Abamectin is an 80/20 mixture of avermectin B 1a 

### /avermectin B 1b 

### . For crops and livestock commodities, compliance with the tolerance is determined by measuring avermectin B 1a 

### , avermectin B 1b 

### , and the 8,9-Z isomers.

Emamectin is used on various raw agricultural commodities. Tolerance levels from 40 CFR §180.505 are shown in Table H.4.1 below. Emamectin is a 90/10 mixture of emamectin B 1a 

### /emamectin B 1b 

### . For crops, compliance with the to lerance is determined by measuring emamectin B 1a 

### , emamectin B 1b 

### , the 8,9-Z isomers, and additional metabolites: AB 1a 

### , MFB 1a 

### , and FAB 1a 

### . For livestock commodities, compliance with the tolerance is determined by measuring emamectin B 1a 

### , emamectin B 1b 

### , and the 8,9-Z isomers.

Table H.4.1. Abamectin and Emamectin Established and Recommended Tolerances 1 Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm) Almond, hulls 0.10 0.20 Apple 0.020 --- Apple, wet pomace 0.10 0.075 Avocado 0.020 --- Bean, dry, seed 0.01 --- Caneberry subgroup 13-07A 0.20 --- Cattle, fat 0.05 0.010 Cattle, liver --- 0.050 Cattle, meat 0.02 0.003 Cattle, meat byproducts 0.09 --- Cattle, meat byproducts, except liver --- 0.020 Celeriac, roots 0.05 --- Celeriac, tops 0.05 --- Chive, dried leaves 0.02 --- Chive, fresh leaves 0.01 --- Citrus, dried pulp 0.10 --- Citrus, oil 0.10 ---

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 64 of 78 Table H.4.1. Abamectin and Emamectin Established and Recommended Tolerances 1 Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm) Citrus 0.02 --- Corn, sweet, forage 0.20 Corn, sweet, kernel plus cob with husk removed 0.01 ---

Corn, sweet, stover 0.50 Cotton, gin byproducts 1.0 0.050 Cotton, undelinted seed (entered in DEEM as oil) 0.02 0.025

Food products in Food Handling Establishments 0.01 ---

Fruit, pome, group 11 --- 0.025 Fruit, stone, group 12 0.09 --- Goat, fat 0.03 0.010 Goat, liver --- 0.050 Goat, meat 0.02 0.003 Goat, meat byproducts 0.04 --- Goat, meat byproducts, except liver --- 0.020 Grain, aspirated grain fractions 0.40 --- Grape 0.02 --- Grape, wine 1 --- 0.03 Herb subgroup 19A, except chive 0.030 --- Hog, fat 0.01 0.003 Hog, liver --- 0.020 Hog, meat 0.02 0.002 Hog, meat byproducts 0.02 --- Hog, meat byproducts, except liver --- 0.005 Hop, dried cones 0.20 --- Horse, fat 0.03 0.010 Horse, liver --- 0.050 Horse, meat 0.02 0.003 Horse, meat byproducts 0.04 --- Horse, meat byproducts, except liver --- 0.020 Milk 0.015 0.003 Nut, tree, group 14 0.01 0.02 Onion, bulb, subgroup 3-07A 0.01 --- Pear 0.02 --- Peppermint, tops (entered as peppermint and peppermint oil) 0.010 ---

Pistachio 0.01 0.02 Plum, prune, dried 0.025 --- Poultry, meat 0.02 --- Poultry, meat byproducts 0.02 --- Sheep, fat 0.03 0.010 Sheep, liver --- 0.050 Sheep, meat 0.02 0.003 Sheep, meat byproducts 0.04 --- Sheep, meat byproducts, except liver --- 0.020 Soybean, forage 0.30 --- Soybean, hay 1.0 --- Soybean, seed 0.01 ---

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 65 of 78 Table H.4.1. Abamectin and Emamectin Established and Recommended Tolerances 1 Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm) Spearmint, tops (entered as spearmint and spearmint top) 0.010 ---

Strawberry 0.05 --- Tomato, paste --- 0.150 Turnip, greens --- 0.050 Vegetable, Brassica, leafy, group 5 --- 0.050 Vegetable, cucurbit, group 9 0.005 0.02 Vegetable, fruiting, group 8 0.020 0.020 Vegetable, leafy, except brassica, group 4 0.10 0.100

Vegetable, tuberous and corm, subgroup 01C 0.01 ---

1 Imported only; no US registrations.



### H.4.2 Drinking Water Pathway

Residues of abamectin and emamectin were incl uded in the dietary exposure assessments as residue distribution files rather than as point estimates.

Abamectin : As discussed in Section 5.3, residues of abamectin may occur in ground and surface water, with higher residues in surface water (0.76 μg/L or ppb for acute exposure; 0.30 ppb for chronic exposure). The abamectin resi dues of concern include avermectin B 1a 

### , avermectin B 1b 

### , and the structurally similar degradates: NOA 448111, NOA 448112, NOA 426289, NOA 445495, NOA 457464, and NOA 457465. In absence of toxi city data on these degradates, they are assumed to have toxicity profiles similar to that of abamectin on the basis of the structural similarities.

Table H.4.2.1. Screening-Level EDWC s for Proposed Uses of Abamectin 1

Source (Tier: Model) 2 Use Site (Max. Annual App. Rate) Acute EDWC ( μ g/L) Chronic EDWC ( μ g/L)
Surface water (Tier II: SWCC) Soybeans (0.037 lbs ai/A)/ Beans (0.056 lbs ai/A) 0.76 (soybeans) 0.30 (beans) Ground water (Tier I: PRZM-GW) Golf courses (0.27 lbs ai/A) 0.074 N/A Ground water (Tier I: SCI-GROW) Golf courses (0.27 lbs ai/A) ≤ 0.0031

1 Maximum values are in bold. Values include parent compound and degradates.

2 SWCC = Surface Water Concentration Calculator; PRZM-G W = Pesticide Root Zone Model – Ground Water; SCI-GROW = Screening Concentration in Ground Water.



### Emamectin : Residues of emamectin in drinking wate r were assessed in connection with an import tolerance on wine grapes (D402151, N. Dodd, 4/12/13; D402152, N Dodd, 2/20/13). Residues of emamectin may occur in ground and su rface water, with higher residues in surface water (0.465 ppb for acute exposure; 0.150 ppb for chronic exposure). The emamectin residues of concern include emamectin B 1a 

### , emamectin B 1b 

### , and four metabolites, which are assumed to be of equal or lesser toxicity to that of the parent compound:

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 66 of 78  (8,9-Z)-4"-epimethylamino-4"-deoxy av ermectin B1 (8,9 ZMA isomer);

 4"-epiamino-4"-deoxyavermectin B1 (AB);

 avermectin B1 monosaccharide (MAB); and

 4"-epi-( N

-formyl)-4"-deoxyavermectin B1 (FAB).

Table H.4.2.2. EDWCs for Ema mectin Residues from Use on Ou tdoor Ornamentals and Group 9 Cucurbit Vegetables 1

Use Model 2 1 in 10 year 30 year Annual Average Peak Annual Mean μg/L
Surface Water

Ornamentals PRZM/EXAMS 3 0.465 0.150 0.112

Ground Water
Ornamentals/Group 9 Cucurbit Vegetables SCI-GROW 0.54 x 10 -3 0.54 x 10 -3 0.54 x 10 -3

1 Maximum values are in bold. Valu es include parent and degradates.

2 PRZM-EXAMS = Pesticide Root Zone Model and Expo sure Analysis Modeling System; SCI-GROW = Screening Concentration in Ground Water.

3 Typically, the values generated by the models for drinking water are multiplied by a percent crop area factor (PCA). The PCA accounts for the fact that is it unlikely for any basin to be completely planted to agricultural crops. The PCA adjustment factor is assumed to be 0.87 for the group 9 cucurbit vegetables and 1.0 for the outdoor ornamentals crops as per the PCA guidance.



### H.4.3 Dietary (Food and Drinking Water) Assessment

Acute : The screening-level cumula tive acute dietary exposures from combined residues of abamectin and emamectin are calculated in Tabl e H.4.3.1 below. The combined residues of 57% of the aPAD for the general U.S. population and 96% of the aPAD for children 1-2 years old, the most highly exposed subgroup, are belo w HED’s level of concern of 100%.

Table H.4.3.1. Summary of Acute Dietary Exposure and Risk Assessment for Combined Abamectin and Emamectin

Abamectin Exposure Emamectin Exposure Combined Exposure aPAD Combined % aPAD Ratio Aba:EMA General U.S. Population 0.001249 0.000168 0.001417 0.0025 57 7.4 All Infants (<1 year old) 0.001683 0.000138 0.001821 0.0025 73 12.2 Children 1-2 years old* 0.002243 0.00015 0.002393 0.0025 96 15.0 Children 3-5 years old 0.001295 0.000136 0.001431 0.0025 57 9.5 Children 6-12 years old 0.000824 0.000089 0.000913 0.0025 37 9.3 Youth 13-19 years old 0.000549 0.000132 0.000681 0.0025 27 4.2 Adults 20-49 years old 0.000448 0.000188 0.000636 0.0025 25 2.4 Adults 50-99 years old 0.000357 0.000175 0.000532 0.0025 21 2.0 Females 13-49 years old* 0.000416 0.000226 0.000642 0.0025 26 1.8

 The subpopulation with the highest combined risk estimate is bolded.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 67 of 78 Background Dietary Exposure: The screening-level cumulative background dietary exposures from combined residues of abamectin and em amectin are calculated in Table H.4.3.2 below.

Table H.4.3.2. Aggregate Chronic Dietary Ex posure and Risk Assessment fo r Combined Abamectin and Emamectin

Abamectin Exposure Emamectin Exposure Combined Exposure Ratio Aba:EMA General U.S. Population 0.000082 0.000008 0.000090 10.2 All Infants (<1 year old) 0.000128 0.000012 0.000140 10.7 Children 1-2 years old* 0.000393 0.000012 0.000405 32.8 Children 3-5 years old 0.000239 0.000009 0.000248 26.6 Children 6-12 years old 0.000137 0.000006 0.000143 22.8 Youth 13-19 years old 0.000069 0.000004 0.000073 17.2 Adults 20-49 years old 0.000056 0.000008 0.000064 7.0 Adults 50-99 years old 0.000051 0.000009 0.000060 5.7 Females 13-49 years old* 0.000054 0.000008 0.000062 6.8

 The subpopulation with the highest combine risk estimate is bolded.



### H.5.0 Residential Pathway

Abamectin : As discussed in detail in Section 6.0 above, there are pr oposed residential use sites that may lead to handler and post-application exposures

. The proposed end-use products (for control of turf-parasitic nemat odes on golf course greens, tees, a nd fairways) that may lead to these post-application exposur es include the following:

1. AgadorTM 0.17 SC (EPA Reg. No. 100-RLNO), and 2. DivanemTM 0.15EC (EPA Reg. No. 100-RLRN).

The products already registered for residentia l use sites include several formulations of homeowner bait and bait station products regist ered under multiple companies. These products include an outdoor granular ba it (GB) formulation for use on fi re ant mounds, and several indoor ready-to-use baits (RBs) of both dust and gel form ulations. For this assessment, the exposures and risk estimates for applying outdoor granul ar baits are assessed us ing the 2012 Residential SOPs 10 

### and exposure from indoor ready-to-use gel ba its is considered neg ligible. In addition, exposure data for hand dispersal of granular bait is chosen as a surroga te to calculate risk estimates from indoor RBs.

Emamectin : There are no existing or propos ed residential use sites; th erefore, residential handler exposure and residential post-applica tion exposure are not expected.

10 Available: http://www.epa.gov/pesticides/scien ce/residential-exposure-sop.html

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 68 of 78 H.6.0 Combined Screening Level Diet ary + Residential Cumulative

Short- and Intermediate-Term: The screening-level short-term a ggregate risk is calculated in Table H.6.0 below. All short-term aggregate expo sure estimates resulted in MOEs greater than 100; therefore, they are not of concern.

Table H.6.0. Short-Term Aggregate Risk Calc ulations for Combined Abamectin and Emamectin

Population Short-Term Scenario

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

Water Exposure mg/kg/day (abamectin + emamectin) Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food, water, and residential) 5

Adults 0.25 100 0.0025 0.000082 + 0.000008 =

0.000090 0.0000203 0.00011 2300

Children 11 to <16 years old 0.25 100 0.0025 0.000137 + 0.000006 =

0.000143 0.0000237 0.00017 1500

Children 6 to <11 years old 0.25 100 0.0025 0.000137 + 0.000010 =

0.000147 0.0000278 0.00017 1500

1 The LOC includes the standard inter- an d intra-species uncertainty factors (UF A and UF H , respectively) totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] from Tables 6.2 and 7.2.1. Residential exposure is from abamectin only; there is no residential exposure from emamectin. The abamectin residential exposure scenario is a liquid formulation on turf (golf courses, greens, tees, and fairways) at the maximum single application rate of 0.34 lb ai/A.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure).

5 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)].



### H.7.0 Characterizing the Screenin g-Level Cumulative Estimates

HED screened combined aggregate abamectin a nd emamectin dietary and residential exposures to determine whether there would be any potenti al cumulative concern for the candidate common mechanism group. This screening assessment uses c onservative assumptions that are expected to overestimate exposures. It is unlik ely that both chemicals would be used on the same crop at the maximum use rate; however, by adding exposures for food and water for both chemicals from field trial data this assessment implicitly assumes co-occurrence of residues at these levels reflecting the maximum use rate. For both chemical s, this assessment is based primarily on field trial data for food exposures (and monitoring data for emamectin in apples), percent crop treated data, and conservative water modeling for dr inking water exposures based on maximum use rates. Although the acute dietary assessment is somewhat refined with the use of percent crop treated information and residue distribution files, the residue data used is based on crop field trials that reflect use patterns on product labels leading to the highest residues. The screening residential assessment is also conservative since high-end estimates of residential exposure are used, while average values are used for food and drinking water exposure.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 69 of 78 The assessment could be more refined by using m onitoring data that would reflect actual use patterns and weathering of resi dues during distribution and by modifying the screening level default assumption that crops (wit h registered uses of both chem icals) would be treated with abamectin and emamectin at the maximum use ra te, resulting in co-occ urrence of residues.

HED believes that a more refined cumulative ex posure assessment would continue to provide exposure estimates that are below HED’s level of concern since much of the high simulated exposures for abamectin are directly attribut ed to conservative inputs for milk. For the population with the highest exposure (children 1-2 y ears old), the main cont ributor to the dietary exposure is abamectin in milk. The relative inputs for this residue driver for abamectin is 0.011 ppm with a percent crop treate d of 85% based on dried citrus pulp, and the residue value for emamectin is 0.0003 ppm with a percent crop tr eated of 20% based on wet apple pomace. The residue distribution file for milk assumed that 85% of all milk contained a residue of 0.011 ppm, based on the magnitude of residue data and assumptions; hence, the DEEM CEC report indicates that most of the outco mes at and above the per capita 99.9 th 

### percentile are attributed to a few children who drank considerable amounts of milk (e.g., 88% of the aPAD or 0.0022 mg ai/kg bw: 2L milk x 0.011 mg ai/L milk / 10 kg bw). If milk is removed from the acute dietary exposure assessment, then aggregate exposure at the per capita 99.9 th 

### percentile would fall from 90% of the aPAD to about 35% of th e aPAD for children 1-2 years old.

H.8.0 Conclusion

This conservative screening assessment indicates th at combined aggregate dietary and residential risk estimates for abamectin and emamectin are below the Agency’s levels of concern; therefore, the Agency has no concern for the cumulative e xposure to the existing and proposed uses of abamectin and emamectin at this time. The Ag ency expects that the screening-level residues overestimate actual cumulative residues since co-o ccurrence is assumed in this assessment. Risk estimates in this screening assessment are belo w HED’s level of concer n, so no additional data are required at this time. However, additional to xicological or exposure data may be required for any additional uses requested in the futu re that change the current conclusions.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 70 of 78 Appendix I. Emamectin Toxicity Profiles

I.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for emamectin are in Table I.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical
Required Satisfied 870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................
870.1300 Acute In halation Toxicity ..............................................
870.2400 Acut e Eye Irr itation

....................................................... 870.2500 Acute Dermal Irritation ................................................. 870.2600 Skin Sensitiza tion .......................................................... 

### yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 90-Day Oral Toxicity in Rodents .................................. 870.3150 90-Day Oral Toxicity in Nonrodents ............................. 870.3200 21/28-Da y Dermal Toxicity .......................................... 870.3250 90-Day Dermal Toxicity ............................................... 870.3465 90-Day Inhalation Toxicity (5-Day study in rats) ... yes
yes
yes

- yes yes
yes
yes

- Waived a 870.3700a Prenatal Developm ental Toxicity (rodent) .................... 870.3700b Prenatal Developmen tal Toxicity (nonrodent) .............. 870.3800 Reproductio n and Fertility Effects ................................ yes
yes
yes yes
yes
yes 870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Carcinog enicity (rat) ...................................................... 870.4200b Carcinoge nicity (mouse) ............................................... 870.4300 Combined Chroni c Toxicity/Carci nogenicity ............... yes
yes
yes
yes
yes yes
yes
yes
yes
yes 870.5100 Mutagenicity—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test .. 870.5385 Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5xxx Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes yes
yes
yes

870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 870.6300 Developm ental Neurot oxicity ....................................... yes
yes CR yes
yes

- 870.7485 Metabolism and Pharmacokinetics ................................
870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes
yes
yes yes
yes
yes

a HASPOC Report: TXR 0051377, 03/12/2015.

### ABAMECTIN Human Health Ri sk Assessment DP No. 426599

Page 71 of 78 I.2 Toxicity Profiles

Table H.2.1. Acute Toxicity Profile – Emamectin Benzoate T echnical (EPA Reg. No. 100-902)

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral - Rats 42851519 LD 50 for L-656,748- 038 = 53 mg/kg II

870.1200 Acute dermal - Rabbits (EC) 43850111 LD 50 > 2.0 g/kg III

870.1300 Acute inhalation - Rats 43868101 0.44 mg/L <LC 50 <2.12 mg/L III

870.2400 Acute eye irritation - Rabbits 42743615 Severe irritation I

870.2500 Acute dermal irritation - Rabbits 42743616 No dermal irritation IV

870.2600 Skin sensitization - Guinea pigs 42743617 Not a dermal sensitizer -

Table I.2.2. Acute Toxicity Profile – Emamectin Be nzoate Technical II (E PA Reg. No. 100-1270)

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral - Rats 47002104 LD 50 for L-656,748- 038 = 53 mg/kg II

870.1200 Acute dermal - Rabbits (EC) 47002106 LD 50 > 2.0 g/kg III

870.1300 Acute inhalation - Rats 47002107 LC 50 0.10 mg/L II

870.2400 Acute eye irritation - Rabbits 47002108 Severe irritation III

870.2500 Acute dermal irritation - Rabbits 47002109 No dermal irritation IV

870.2600 Skin sensitization - Guinea pigs 47002110 Not a dermal sensitizer Negative

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

Acute dermal tox.- rabbits MK-0243 0.16 EC formulation 42743611 (1991) Acceptable 0, 0.5, 1.0, & 2.0 mg/kg (2 groups: 4 hr exposure & 24 hr exposure) with collar on the test animals. 4 hr. exposure NOAEL= 2.0 mg/kg/day (HDT)

24 hr. exposure NOAEL = 0.5 mg/kg/day LOAEL = 1.0 mg/kg/day one rabbit had neuron lesion occurred in cerebellar peduncle.

Acute dermal tox. – rabbits (24 hrs exposure with collar on all test animals) 43850111 (1995) Acceptable 0, 10.4, 21.0, or 42.1 mg/kg MK-0244 0.16 EC NOAEL = 42.1 mg/kg. No treatment-related systemic toxicity was seen in any dosed animals. The acute dermal LD 50 > 2000 mg/kg for MK0244 870.3100 13-Wk oral-CD rats 42794201 (1992) Acceptable 0, 0.5, 2.5, and 12.5 mg/kg/day. 12.5 mg/kg/day was reduced to 8 mg/kg/day at wk 3 then to 5.0 mg/kg/day at wk 9. Systemic Toxicity NOAEL=2.5 mg/kg/day; Systemic Toxicity LOAEL=5 mg/kg/day based on moribundity, tremors, hindlimb splaying, urogenital staining, histological changes in brain and spinal cord, sciatic and optic nerves and skeletal muscles in males, emaciation, reduced body weight and reduced food consumption in both sexes. 13-Wk oral-CD-1 mice 42743621 (1992) Acceptable 0, 0.5, 4.5, & 15.0 mg/kg/day. An additional group received a time weighted dose 5.4 mg/kg/day NOAEL = 5.4 mg/kg/day LOAEL = 15.0 mg/kg/day based on mean body weight decrease and decreased in cumulative body weight gain.

870.3150 90-Day oral – dogs (gavage) 42743623 (1992) Acceptable 0, 1.0, or 1.5 mg/kg/day for the first 2 wks then reduced to 0.25, 0.5, or 1.0 for the rest of the study. NOAEL = 0.25 mg/kg/day LOAEL = 0.50 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

14-Wk oral-dogs (gavage) 43868103 (1994) Acceptable 0.5, 1.0, or 1.5 mg/kg/day for 2 wks for mid and high dose groups and for 3 wks for low dose, then they were reduced to 0.25, 0.5, or 2.0 mg/kg/day. The time weighted doses were 0.29. 0.58, or 0.1.08 mg/kg/day. NOAEL = 0.29 mg/kg/day LOAEL = 0.58 mg/kg/day based on microscopic lesions in the brain (multifocal white matter degeneration), atrophy of skeletal muscle, and spinal cord lesions.

870.3200 21-Day dermal toxrabbits MK-0244 0.16 EC formulation 42743625 (1992 Acceptable 0, 50, 100, or 250 mg/kg/day (6 hrs/day) Systemic tox. NOAEL = 100 mg/kg/day LOAEL = 250 mg/kg/day based on axonal degeneration of the sciatic nerve.

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

Application site irritation was seen in all treated rabbits. 22-Day dermal tox. – rabbits MK-0244 0.16 EC formulation 44007902 (1996) Acceptable 0, 250, 500, or 1000 mg/kg/day (6 hrs/day) NOAEL = 1000 mg/kg/day (highest dose tested [HDT]). No systemic toxicity was seen in any dose groups. Note: The test animals were collared to prevent oral ingestion of the test material. 870.3465 Subchronic inhalation - 5-day inhalation tox.-rats (emamectin benzoate) 49395601 (2014)Acceptable/nonguideline 0, 1, 3, 10, and 30 μg/L 0, 0.26, 0.74, 2.4, and 7.4 mg/kg/day Systemic tox: NOAEL = 0.74 mg/kg/day LOAEL = 2.4 mg/kg/day based on tremors, abnormal gaits, and vocalization (at day 5 or day 6) Portal of entry tox: NOAEL = 0.5 mg/kg/day LOAEL = 0.74 mg/kg/day based on borderline effects of metaplasia along with inflammation in the larynx. 870.4100 1-Year oral tox. – dogs (gavage) 42763624 (1992) Acceptable 0, 0.25, 0.5, 0.75, or 1.0 mg/kg/day (4 dogs/sex/dose) NOAEL= 0.25 mg/kg/day LOAEL=0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration. Chronic oral tox. – rats (dietary) (1 year) 42868902 (1992) Acceptable 0, 0.1, 1.0, 2.5 mg/kg (initially females received 5.0 mg/kg then reduced to 2.5 mg/kg at wk 18 due to excessive toxicity ) NOAEL=1.0 mg/kg/day LOAEL=2.5 mg/kg/day , based on increased incidence of neuronal degeneration in the brain and spinal cord, decreased rearing, and an increased incidence of animals with low arousal.

870.4200 Carcinogenicity study-mice (CD-1) (dietary) 4386805 (1994) Acceptable 0, 0.5, 2.5, or 12.5 mg/kg/day (The highest dose was reduced to 7.5 and 5.0 mg/kg/day for males at wk 9 and females at wk 3, respectively) NOAEL=2.5 mg/kg/day. LOAEL=5.0 mg/kg/day for males and 7.5 mg/kg/day for females based on increased mortality, decreased weight gain, tremors, sciatic nerve degeneration , and increased incidence of severity of infections.

No treatment-related increase in tumor incidence was seen. Combined Chronic/ Carcinogenicity-Rat 43868104 (1994) Acceptable 0, 0.25, 1.0, 2.5/5.0 mg/kg (Initially, high dose level was 5.0 mg/kg; it was reduced to 2.5 mg/kg on wk 6 for males and wk 10 for females due to tremors seen in another study at 5 mg/kg). NOAEL=1.0 mg/kg/day LOAEL=2.5/5.0 mg/kg/day 1 based on marked neural degeneration in the brain and spinal cord of both sexes, brain white matter degeneration in males, and on decreased body weight, body weight gain, and food efficiency in males.

No treatment-related increase in tumor incidence was seen.

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

870.3700 Developmental tox.
–rat 42743632 (1992) Acceptable 0, 2, 4, or 8 mg/kg/day

42743631 (range finding study) Maternal Toxicity NOAEL=2 mg/kg/day, Maternal Toxicity LOAEL=4 mg/kg/day based on a significant trend towards decreased body weight gain during the dosing period.

Developmental Toxicity NOAEL=4 mg/kg/day, Developmental Toxicity LOAEL=8 mg/kg/day based on altered growth and an increased incidence of supernumerary rib. Developmental tox.- rabbits 42743636 (1992) Acceptable 0, 1.5, 3, or 6 mg/kg/day

42743635 (Range finding study) Maternal Tox. NOAEL= 3 mg/kg/day, Maternal Tox. LOAEL= 6 mg/kg/day based on a significant trend towards decreased body weight gain during dosing period and increased clinical signs (mydriasis and decreased pupillary reaction).

Developmental Tox. NOAEL=6 mg/kg/day (HDT) 870.3800 2-Gen. reproduction study - rats 42851511 (1993) Acceptable 0, 0.1, 0.6, or 3.8/1.8 mg/kg/day (F 0 & F 1a females initially received 3.8 mg/kg, but it was reduced to 1.8 mg/kg/day on GD 0 following the second cohabitation of F 0 females). Parental NOAEL = 0.6 mg/kg/day. Parental LOAEL = 1.8 mg/kg/day based on decreased body weight gain and neuronal degeneration in the brain and spinal cord in both sexes and generations.

Reproductive NOAEL=0.6 mg/kg/day Reproductive LOAEL=1.8 mg/kg/day based on decreased fecundity and fertility indices.

Offspring NOAEL = 0.6 mg/kg/day Offspring LOAEL = 1.8 mg/kg/day based on tremors and hind limb extension in the offspring of both generations, neuronal degeneration in the brain and spinal cord.
870.5100 870.5100 Gene Mutation - SalmonellaMK-0243 and L660,599; L-657,831;L-695,638; L930,905 (photometabolites of MK-0244) 42743637 42851514 42851515 42851516 42851517 Negative for the induction of reverse gene mutation.

870.5300 Gene Mutation in Cultured V-79 Chinese Hamster Lung Cells MK-0243 42743638 Negative for the induction of forward gene mutations in Chinese hamster lung fibroblast cells up to a severely cytotoxic nonactivated dose of 0.01 mM or a severely cytotoxic S9- activated dose of 0.04 mM.
870.5385 Structural Chromosome 42851513 Negative for the induction of chromosome aberrations in the bone marrow cells of male CD-1 mice.

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

Aberration- in vivo mouse bone marrow MK-0244
870.6200 Acute neurotox. study-rats (gavage) 42743618 (1992) Acceptable 0, 27.4, 54.8 or 82.2 mg/kg (range finding study) NOAEL was not established. LOAEL= 27.4 mg/kg/day (LDT); clin ical signs (tremors, ataxia, loss of righting reflex, and reduced activities) and as histological lesions in the brain, spinal cord and sciatic nerve occurred at all doses tested.

Acute neurotox. study- rats (gavage) 42743619 (1992) Supplementary 0, 0.5, 2.5, 5.0, 10.0, or 25.0 mg/kg/day NOAEL = 5.0 LOAEL = 10 mg/kg/day based on tremors irritability. At 25 mg/kg, all rats had tremor and neuronal lesions (white matter degeneration of the brain, degeneration of the spinal cord and sciatic nerve. Subchronic neurotox. –SD rats (dietary) (14 day) 42743628 (1992) Acceptable 0, 0.25, 1.0, or 5.0 mg/kg/day NOAEL=1.0 mg/kg/day LOAEL=5.0 mg/kg/day based on tremors, posture, rearing, excessive salivation, fur appearance, gait, strength, mobility and righting reflex. Neuronal vacuolation in brain and spinal cord; degeneration of nerve fiber in spinal cord and sciatic nerves. Skeletal muscle atrophy. Male rats appeared to be more affected than females. Comparative neurotox. – dogs (gavage) (14 days) 42743626 (1992) Acceptable 2 dogs/sex/compound were given 1.5 mg/kg/day of testing compound. The following effects were seen with different compounds: Tremors Mydriasis MK-0243 a 2/4 0/4 L-682,901 0/4 0/4 L-653,648 0/4 4/4 L-653,649 2/4 3/4 L-655. 372 3/4 0/4Histopathology findings were not seen in L682, 901 and L-653,648 treated dogs. Neuronal degeneration of the brain, spinal cord, and sciatic nerves were seen in dogstreated with MK-0234, L-653, 649, and L655,372. 15-Day neurotox. – CD-1 mice (dietary) 42743629 (1992) Acceptable 0, 0.6, 1.2, & 2.0 mg/kg/day NOAEL=2.0 mg/kg/day (HDT). No characteristic neuronal lesions in the brain, spinal cord or sciatic nerve in mice of high dose group. 15-Day neurotox.- CF-1 mice (dietary) (L-660,599: 4”-epi- ( N

-formyl- N

methyl)- amino4”- deoxy-avermectin B1 42851503 (1993) Acceptable 0, 0.05, 0.075, 0.10, or 0.30 mg/kg/day NOAEL=0.075 mg/kg/day LOAEL=0.10 mg/kg/day based on tremors observed beginning on day 3, ptosis, hunched posture, decreases in body weight and food consumption as well as degeneration of the sciatic nerve. At 0.3 mg/kg, tremors were seen on day 2 and followed by hunched posture and ptosis, ataxia, and labored breathing.

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

15-Day neurotox. – CF-1 mice (dietary) (L695-638: 4”-deoxy-4”-epimethylaminoavermectin B1adelta-8,9-isomer); photoproduct of MK-0244 b 42851504 (1993) Acceptable 0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day NOAEL = 0.30 mg/kg/day (HDT) No treatment-related effects were seen in any dose groups.

15-Day neurotox. – CF-1 mice (dietary) (L695-638: 4”-deoxy-4”-epimethylaminoavermectin B1adelta-8,9-isomer); photoproduct of MK-0244 42851505(1993) Acceptable 0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day NOAEL = 0.243 (HDT). The targeted dose was 0.30 mg/kg/day. No treatment-related effects were seen in any dose groups.

Female mice only to repeat the exposure dose levels of MRID 4285 1504 because female mice received 15% less than the targeted dose in that study.

15-Day neurotox.- CF-1 mice (dietary) (L-660,599; formyl methylamino plantmetabolite of MK0244 ) 42851506 (1993) Acceptable 0, 0.10, 0.30, 0.90 mg/kg/day LOAEL <0.1 mg/kg/day LDT) based on tremors, hunched post ure and piloerection. However no treatment-related findings in histopathology were present.

15-Day neurotox.- CF-1 mice (gavage)L-930,905; a complex mixture of polar MK-244 photodegradates) 42851507 (1993) Acceptable 0, 3, 6, 12, or 18 mg/kg/day NOAEL = 18 mg/kg/day (HDT) No treatment-related effects were found.

16-Day neurotox.- CF-1 mice (dietary) MK-0243 42743630 (1992) Acceptable 0, 0.05, 0.10, 0.30, or 0.90 mg/kg/day NOAEL = 0.1 mg/kg/day LOAEL = 0.30 mg/kg/day based on tremors, decreased activity, and moribund sacrifice starting on day 2. However, no histopathology findings were present.

15-Day neurotox.- CF-1 mice (dietary) Formyl aminoderivative of MK0244 42868901 (1991) Acceptable 0, 0.050, 0.075, 0.100, & 0.300 mg/kg/day NOAEL = 0.07 mg/kg/day LOAEL = 0.23 mg/kg/day based on decreased body weight gain.

870.6300 Develop. Neurotox.- rats (SD) (gavage for maternal animals; no direct dosing for neonates) MK-0244 42851508 (1993) Acceptable 0, 0.1, 0.6, 3.6/2.5 mg/kg/day (3.6 mg/kg was reduced to 2.5 mg/kg between GD 17 and 20) Maternal NOAEL=3.6/2.5 mg/kg/day (highest dose tested) Develo. Neurotox. NOAEL=0.10 mg/kg/day Develo. Neurotox. LOAEL = 0.60 mg/kg/day based on the dose-related decrease in open field motor activity in females at postnatal day 17. 870.7485 Metabolism –rats [ 14 C] 4”-deoxy-4’- epi-methylamino 42851523 & 42852524 (1993) Acceptable Radiolabeled MAB1a benzoate is rapidly absorbed, distributed an d excreted following oral and i.v. administration. The feces was the

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Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

avermectin B1a benzoate, (MAB1a) major route of excretion in oral and i.v. groups, while <1% of the administered dose was recovered in the urine 7 days post dosing. Tissue distribution and bioaccumulation appeared minimal. The metabolism of MAB1a benzoate appears to involve primarily Ndemethylation to AB1a. AB1a was the only metabolite detected in the feces while unmetabolized parent compound represented a large amount of the radioactivity. Bioequivalence -Dog MK-0243solvate vs. monohydrate 42743641(1992) Supplemental The study demonstrated that MK-0243 benzoate MTBE solvate and MK-0243 benzoate monohydrate were bioequivalent in male dogs following oral administration as indicated by similar plasma levels for the two compounds. Bioequivalence-Dog MK-0243 benzoate vs. HCL salts 42743640 (1992) Supplemental The study demonstrated that benzoate and HCl salts are bioequivalent af ter oral administration in male beagle dogs.870.7600 Dermal AbsorptionRhesus Monkey 43850113 (1994) Dermal Absorption was approximated at 1.79% of the administered dose. 870.7800 Immunotoxicity study (female CD-1 mice) 48980301 (2012) Acceptable/guideline 0, 10, 30, 60 ppm 1.7, 4.8, 10.6 mg/kg/day (free base) 1.9, 5.5, 12.1 mg/kg/day (benzoate sat) No systemic toxicity was seen. No evidence of a serum T-cell dependent antibody (IgM) response to sRBC.

Table I.2.4. Summary of Toxicological Doses and Endpoints for Emamectin for Use in Dietary and NonOccupational Human Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty/ FQPA Safety Factors RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

Dietary (all durations) (General Population, including Infants and Children) & Incidental Oral NOAEL= 0.25 mg/kg/day UF A = 10x UF H = 10x FQPA SF = 1x Acute RfD = 0.0025 mg/kg/day

aPAD = 0.0025 mg/kg/day Subchronic and chronic oral toxicity studies in dogs Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males. Chronic LOAEL=0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration. Dermal Short- and Intermediate Term NOAEL= 0.25 mg/kg/day

Dermal Absorption = 1.8 % UF A = 10x UF H = 10x FQPA SF= 1x Residential LOC for MOE = 100

Inhalation Short- andIntermediateTerm NOAEL= 0.25 mg/kg/day

Toxicity via the inhalation route UF A = 10x UF H = 10x FQPA SF= 1x Residential LOC for MOE = 100

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assumed to be equivalent to the oral route Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 (intra species). 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.

Table I.2.5. Summary of Toxicolo gical Doses and Endpoints for Emamect in for Use in Occupational Human Health Risk Assessments

Exposure/ Scenarios Point of Departure Uncertainty/ Safety Factor RFD, PAD, LOC Study and Toxicological Effects

Dermal (Short-Term andIntermediateTerm) NOAEL= 0.25 mg/kg/day

Dermal Absorption = 1.8 % UF A = 10x UF H = 10x LOC: MOE =100 Subchronic and chronic oral toxicity studies in dogs Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males. Chronic LOAEL=0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration. Inhalation (Short-Term andIntermediateTerm) NOAEL= 0.25 mg/kg/day

Toxicity via the inhalation route assumed to be equivalent to the oral route UF A = 10x UF H = 10x LOC: MOE = 100

Cancer (oral, dermal, inhalation) Classification: Not likely to be car cinogenic 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. NOAEL = no observed 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). SF = Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = marg in of exposure. LOC = level of concern. .