### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 1 of 98 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### MEMORANDUM

Date : April 18 , 2016

SUBJECT: Abamectin. Human Health Risk Assessment for Uses on Caneberr y Subgroup
13

- 07A ; Soybean ; Sweet Corn ; Ear Tags for Lactating Dairy Cattle ; Golf Course
Turf ; Bean ; Onion, Green, Subgroup 3

- 07B; Fruit, Pome, Group 11

- 10; Fruit, Small Vine Climbing, E xcept Fuzzy Kiwifruit, Subgroup 13

- 07F; Berry, Low Growing, Subgroup 13

- 07G; Vegetable, Fruiting, Group 8

- 10 ; Greenhouse Tomato; Fruit, Citrus, Group 10

- 10; Fruit, Stone, Group 12

- 12; and Nut, Tree, Group 14

- 12; and Various Tropical Fruits

.

PC Code: 122804
Decision No s .: 480177 , 495169, 495170, 478520,
476238
Petition Nos.: 3E8175, 3F8184 , 4E83 09 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: Laura Nollen, Biologist, Risk Assessor Kristin Rickard, Biologist Whang Phang, Senior Toxicologist Nancy Dodd, Chemist Nancy Keller, Chemist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P)

THROUGH: Christine Olinger, Branch Chief

, RAB3 Health Effects Division (HED) (7509P)

TO: Barbara Madden/ Andrew Ertman , PM#5 Minor Use and Emergency Response Branch Registration Division (7505P)
and
Mark Suarez /Jessica Rogala, P M#7

In vertebrate and Vertebrate Branch 3 Registration Division (7505P)

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 2 of 98 The Registration Division (RD) requested that the Health Effects Division (HED) conduct a risk assessment for the active ingredient (ai) abamectin. A summary of the findings and an

assessme nt of human health risks resulting from the proposed and registered uses of abamectin are provided in this document.

The HED team members contributing to this risk assessment are Laura Nollen (occupational/residential exposure assessment and risk assessment), Kristin Rickard (dietary exposure assessment), Whang Phang (toxicology assessment), Nancy Dodd (dietary exposure assessment, residue chemistry and risk assessment) and Nancy Keller (occupational/residential exposure assessment)

. Greg Orr ick of the Environmental Fate & Effects Division (EFED) provided the drinking water exposure assessment.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 3 of 98 1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Recommendations

................................ ................................ ................................ .... 9
2.1 Data Deficiencies

................................ ................................ ................................ ............ 9
2.2 Tolerance Considerations

................................ ................................ .............................. 9
2.2.1 Enforcement Analytical Method

................................ ................................ ............... 9
2.2.2 Recommended Tolerances

................................ ................................ ......................... 9
2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .. 11
2.2.4 International Harmonization

................................ ................................ ................... 12
2.3 Label Recommendations

................................ ................................ .............................. 13
2.3.1 Label Recommendations from Residue Reviews

................................ ................... 13
3.0 Introduction

................................ ................................ ................................ ...................... 13
3.1 Chemical Identity

................................ ................................ ................................ ......... 14
3.2 Physical/Chemical Characteristics

................................ ................................ ............. 15
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 15
3.4 Anticipated Exposure Pathways

................................ ................................ ................. 25
3.5 Consideration of Environmental Justice

................................ ................................ .... 25
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 25
4.1 Toxicological Studies Available for Analysis

................................ ............................. 27
4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

............................. 28
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 28
4.3 Toxicological Effects

................................ ................................ ................................ .... 28
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 29
4.4.1 Completeness of the Toxicology Database

................................ .............................. 30
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 30
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 30
4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 30
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 31
4.5.1 Combined Routes of Exposure

................................ ................................ ................ 32
4.5.2 Carcinogenicity:

................................ ................................ ................................ ........ 32
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 34
5.1 Residues of Concern Summary and Rationale

................................ .......................... 34
5.2 Food Residue Profile

................................ ................................ ................................ .... 35
5.3 Water Residue Profile

................................ ................................ ................................ .. 36
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 37
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 37
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 38
5.4.4 Chronic Dietary Exposure

................................ ................................ ....................... 38
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 39
5.4.6 Summary Table

................................ ................................ ................................ ......... 39
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 40 6.1 Residential Handler Exposure

................................ ................................ ........................ 40
6.2 Residential Post

- Application Exposure and Risk Estimates

................................ ........ 41
6.3 Residential Bystander Post

- Application Inhalation Exposure

................................ 42
6.4 Non

- Occupational Spray Drift Exposure and Risk Estimates

................................ . 42
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 43
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 43

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 4 of 98 7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 43
7.3 Chronic Aggregate Risk

................................ ................................ .............................. 44
7. 4 Cancer Aggregate Risk

................................ ................................ ................................ 45
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 45
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 46
9.1 Short

- /Intermediate

- Term Occupational Handler Risk

................................ ........... 46
9.2 Short

- /Intermediate

- Term Post

- Application Exposures and Risks

........................ 47
9.2.1 Short

- /Intermediate

- Term Post

- Application Dermal Exposures and Risks

....... 47
9.2.2 Short

- /Intermediate

- Term Post

- Application Inhalation Exposures and Risks

.. 48
10.0 References

................................ ................................ ................................ ......................... 49 Appendix A. Abamectin Toxicology Profile and Executive Summaries

............................... 52
A.1 Toxicology Data Requirements

................................ ................................ ................... 52
A.2 Data Demonstrating the Sensitivity of Beagle Dogs to the Effects of Abamectin and
Emamectin

................................ ................................ ................................ ............................... 53 Appendix B. Toxicology Literature References

................................ ................................ ...... 60 Appendix C

. Abamectin Physical/Chemical Properties

................................ ......................... 62 Appendix D . Review of Human Research for Abamectin

................................ ...................... 63 Appendix E. International Residue Limits Table for Abamectin

................................ ......... 64 Appendix F. Abamectin Field Trial Tables

................................ ................................ ............. 66 Appendix G. Abamectin Occupational Exposure Tables

................................ ....................... 68 Appendix H. Avermectin Macrocyclic Lactones Cumulative Screening Assessment

......... 75
H.1.0 Executive Summary

................................ ................................ ................................ .. 75
H. 2.0 Introduction

................................ ................................ ................................ .............. 75
H. 3.0 Toxicological Considerations in Determining a Candidate CMG

....................... 76
H. 4.0 Dose Response Assessment

................................ ................................ ...................... 79
H. 5.0 Dietary Cumulative Exposure and Risk Assessment/Characterization

.............. 81
H. 6.0 Residential Pathway

................................ ................................ ................................ . 87
H. 7.0 Combined Screening

- Level Cumulative Assessment (Dietary + Residential)

.... 88
H. 8.0 Characterizing the Screening

- Level Cumulative Estimates

................................ . 88
H. 9.0 Conclusion

................................ ................................ ................................ ................. 89 Appendix I. Emamectin Toxicity Profiles

................................ ................................ ................ 90

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 5 of 98 1.0 Executive Summary

The Health Effects Division (HED) has prepared a human health risk assessment in response to
several re quests for new uses of the insecticide abamectin. This document also includes a screening

- level cumulative exposure and risk analysis for abamectin and a similar insecticide,
emamectin benzoate.

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. Aba mectin is a natural fermentation product of the soil bacterium Streptomyces avermitilis and is an insecticide/miticide used to control mites, leaf miners, and
other insects in commercially important crops. Abamectin acts as an insecticide by interfering
wi th the nervous system of the insect, causing the insect to become paralyzed. Abamectin is a
member of a sub

- class of macrocyclic lactone pesticides known as the aver mectins. Currently

, only abamectin and emamectin are members of this group with active regi strations of pesticides.

The Interregional Research Project No. 4 (IR

- 4), on behalf of the Agricultural Experiment Stations of CA, SC, AR, NC, WA, and DE, has submitted pesticide petition (PP# ) 3E8175 to request the establishment of a permanent tolerance for residues of abamectin on C aneberry subgroup 13

- 07A. In conjunction with this petition, section 3 registration requests were
submitted for the end

- use products (EPs) Agri

- Mek ® 0.15 EC (EPA Reg. No. 100

- 898) and Epi

Mek ® 0.15 EC Miticide/Insecticide (EPA Reg. No. 100

- 1154)

.

IR

- 4, on behalf of the Agricultural Experiment Stations of CA, HI, OR, SC, TN, FL, DE, and PR, additionally submitted PP# 4E8309 to request the establishment of permanent tolerances for
residues of abamectin on bean ; papaya ; star app le ; black sapote ; sapodilla ; canistel ; mamey sapote ; guava ; feijoa ; jaboticaba ; wax jambu ; starfruit ; passionfruit ; acerola ; lychee ; longan ; Spanish lime ; rambutan; pulasan; pineapple; Onion, green, subgroup 3

- 07B; Fruit, pome, group
11

- 10; F ruit, small vi ne climbing, except fuzz y kiwifruit, subgroup 13

- 07F; B erry, low growing, subgroup 13

- 07G; V egetable, fruiting, group 8

- 10 ; Fruit, citrus, group 10

- 10; Fruit, stone, group
12

- 12; and N ut, tree, group 14

- 12. These uses are associated with one or more of four EPs : Epi

Mek® 0.15 EC Miticide/Insecticide (EPA Reg. No. 100

- 1154), Agr i

- Mek® SC Miticide/Insecticide (EPA Reg. No. 100

- 1351), Epi

- Mek TM 

### SC Miticide/Insecticide (EPA Reg.
No. 100

- 1408), and Epi

- Mek TM 

### SCL Miticide/Insecticide (EPA Reg. No. 100

- 1439).

Syngenta Crop Protection LLC (Syngenta) has submitted PP# 3F8184 to request the establishment of permanent tolerances for residues of abamectin on sweet corn commodities (forage, kernel plus cob with husk rem oved, and stover) and soybean commodities (forage, hay, and seed). The petitioner has propose d the addition of sweet corn and soybean to the following

EPs: Agri

- Flex® Miticide/Insecticide (EPA Reg. No. 100

- 1350) , Agri

- Mek® SC
Miticide/Insecticide (EPA Reg. No. 100

- 1351) , Epi

- MekTM SC Miticide/Insecticide (EPA Reg.
No. 100

- 1408) , and Epi

- MekTM SCL Miticide/Insecticide (EPA Reg. No. 100

- 1439)

. Syngenta

prop osed tolerances for sweet corn commodities (forage, kernel plus cob with husk removed, and stover) and soybean commodities (forage, hay, and seed).

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 6 of 98 Syngenta has also proposed use of two new EPs on golf course greens, tees, and fai rways. The new EPs are AgadorTM 0.17 SC Nemat icide (EPA Reg. No. 100

- RLNO), and DivanemTM 0.15EC Nematicide (EPA Reg. No. 100

- RLRN)

.

Finally, Y

- TEX Corporation has requested registration of an ear tag containing abamectin and piperonyl butoxide for use on lactating dairy cattle to the EP, Y

- TEX® XP 8 20TM Insecticide Cattle Ear Tags (EPA Reg. No. 39039

- 17)

. In association with this request, Y

- TEX Corporation submitted PP# 3F8200 in order to request an amended tolerance in milk at 0.01 ppm. An ear tag
use has previously been registered on beef cattle a nd non

- lactating dairy cattle. Tolerances for abamectin on fat, meat, and meat byproducts of cattle were previously increased to reflect that

use. This review concerns only abamectin; piperonyl butoxide has been considered under a separate review.

Toxicity/ Hazard: Since the last risk assessment, the Agency has re

- evaluated the entire abamectin and emamectin toxicological database s , along with additional literat ure information

on the sensitivity of laboratory animals and the human population to the toxicity of abamectin
and ema mectin. The points of departure (PODs) and uncertainty factors (UFs) for abamectin and
emamectin have been changed based on th is re

- evaluation. Th e updated h azard c haracterization represents a more refined analysis of the h azard for abamectin. In addition, the hazard characterizations of abamectin and emamectin have been evaluated and compared for consistency , and all the toxicity data were considered together in a cumulative screen using similar endpoints.

In general, available toxicity data showed that with a single dose or repeated dose administration, the primary target organ was the nervous system and that decreased body weight was also one of the most frequent findings. The toxicity endpoint s and POD s f or all exposure scenarios were recently reevaluated and selected from the subchronic and chronic oral toxicity studies in the dogs

. The PODs selected from the dog studies are based on clear no observed adverse effect
level s ( NOAELs ) that are protective of all the adverse effects seen in the studies conducted in rats, CD

- 1 mice, and rabbits. Therefore, the Food Quality Protection Act ( FQPA ) safety factor has been reduced to 1X, and the level of concern (LOC) is a margin of exposure (MOE) of 100 for all exposure scenarios

.

Dietary Exposure (Food/Water) and Risk Estimates : The residue chemistry and environmental fate data are adequate to assess human exposure. Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessm ents were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID), Version 3.16. T he acute and chronic dietary exposure assessments were refined assessments using anticipated or average residues de rived from field trial data. Empirical and
d efault processing factors and percent crop treated ( P CT) estimates were used as available. Estimated drinking water concentrations (EDWCs) were provided by the 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 drinki ng water is 4 5 % of the aPAD for the

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 7 of 98 general U.S. population and 8 8 % of the aPAD for children 1

- 2 years old, the most highly exposed population subgroup.

Although the acute and chronic dietary PODs are the same for both durations, a chronic dietary
exposure assessment was conducted for abamectin for the purposes of aggregate risk assessment and to incorporate residues/exposures from the registered food handling establishment (FHE)

uses as per HED policy

. The chronic dietary exposure estimates for food and drinking wate r ar e below HED’s LOC [ <100% of the chronic population adjusted dose ( cPAD) ] for the general U.S. population and all population subgroups. Abamectin dietary exposure f or food and drinking
water is 2. 2 % of the cPAD for th e general U.S. population and 11 % of the cPAD for children 1

- 2 years old, the most highly exposed population subgroup.

Residential Exposure and Risk Estimates : For the proposed golf course turf use, residential handler exposure is not expected. Dermal p ost

- application r esidential exposure estimates from the proposed turf use are not of concern for adults and children 6 to < 16 years old; the short

term post

- application MOEs range from 9,000 to 12,000. Furthermore, all existing residential exposures have been reassessed, and there are no registered products that would lead to residential handler or post

- applicat ion risk estimates of concern. Short

- term combined (dermal + inhalation) residential handler MOEs range from 8 60,000 to 2,700,000,000. Post

- application exposures fr om existing uses are not expected.

A ggregate Exposure Risk Estimates : For the proposed uses, human health aggregate risk assessments have been conducted for acute aggregate exposure (food + drinking water), short

term aggregate exposure (food + residentia l exposure + drinking water), and chronic aggregate exposure (foo d + drinking water) scenarios. For short

- term aggregate exposure, the residential level of concern ( LOCs ) is 1 00 and the MOEs are greater than 1 00, and thus are not of risk

concern. A cancer aggregate risk assessment was not performed beca use abamectin is classified

as not likely to b e carcinogenic to humans. All potential exposure pathways were assessed in the aggregate risk assessment. None of the aggregate exposure and risk estimates exceed HED's
level of concern.

Occupational Handler and Post

- Application Exposures and Risk Estimates : Based on all proposed uses, occupational exposures to abamectin are expected for short

- and intermediate

term durations when handling abamectin or from post

- application activities. Potential routes of exposure include both dermal and inhalation for occupational workers.

The results of the occupational handler exposure and risk assessment associated with PP#s
3E8175 and 3F8184 indicate that short

- / interm ediate

- term combined (dermal + inhalation) risk
estimates are not of concern at baseline mitigation without personal protective equipment (PPE) ; MOEs range from 360 to 25,000. The results of the occupational handler assessment associated
with PP# 4E8309 in dicate that short

- /intermediate

- term combined risk estimates are not of concern with a single layer of clothing, no respirator, and the PPE of gloves, which are required for all occupational handlers ; MOEs ranged from 150 to 97,000. Note that only engineering
control s (enclosed cockpit) data are available to assess risks to handlers operating aircraft.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 8 of 98 Q uantitative occupational post

- application exposure and risk assessment s indicate that short

- and
intermediate

- term dermal risk estimates are not of concern at baseline mitigation without PPE on Day 0 (12 hours following application) for all proposed uses (LOC = 100)

. MOEs range d from 3,700 to 5,400 for the uses associated with PP#s 3E8175 and 3F8184 ; MOEs ranged from 240 to 67,000 for PP# 4E8309

. Bas ed on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for abamectin
at this time.

Screening

- Level Cumulative Assessment of the Avermectin Macrocyclic Lactones : HED has developed cumulative screening framework entitled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose (USEPA, 2016 ) . U tilizing this framework , HED has
determined that abamectin and emamectin form a candidate common mechanism group (CMG)

. Therefore

, HED has conducted a screening

- level cumulative exposure analysis for the avermectin macrocyclic lactones, which contain the insecticides abamectin and emamectin. Thi s assessment indicated that aggregate dietary and residential expos ures for abamectin and
emamectin are below the Agency’s levels of concern. Additional information regarding this cumulative exposure and risk assessment may be found in Appendix H

.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally 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 Risk Assessment DP No. D426599



### Page 9 of 98 2.0 HED Recommendations

P rovided that revised Section s B and F are submitted , there are no residue chemistry

con siderations that would preclude granting the requested registrations and establishing the
recommended tolerance s for abamectin on sweet cor n; soybeans ; C aneberry subgroup 13

- 07A ; bean, papaya, star apple, black sapote, sapodilla, canistel, mamey sapote, gu ava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, acerola, lychee, longan, Spanish lime, rambutan, pulasan, pineapple, Onion, green, subgroup 3

- 07B; Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; Berry, low growing, subgrou p 13

- 07G; Fruit, pome, group 11

- 10; Vegetable, fruiting, group 8

- 10 (including greenhouse tomato); Fruit, citrus, group 10

- 10; Fruit, stone, group 12

- 12; Nut, tree, group 14

- 12 ; and milk (associated with the registration request for
ear tag s on lactating dairy cattle)

.

For all proposed uses, t he specific tolerance recommendations are discussed in Section 2.2, and
the recommended label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

There are no data deficiencies at this t ime.

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 Manual, Volume II ( PAM II)

. The methods have been validated for citrus and processed fractions (Method I), ginned cottonseed (Method IA), and bovine tissues and milk (Method II ). These methods determine residues in plant and livestock commodities at limits of quantitation (LOQs) of 0.02 ppm for meat and meat byproduct s and ≤0.01 ppm for other plant/livestock c ommodities. The limit of detection (LOD) of the methods for plant and livestock commodities is 0.001 ppm for each analyte, equivalent to 0.002 ppm for two analyte peaks (i.e., avermectin B 1a 

### and its delta

- 8,9

- isom er in one peak and avermectin B 1b 

### and its delta

8,9

- isomer in the other peak).

2.2. 2 Recommended Tolerances

The currently established tolerance expression for abamectin is adequate, and includes coverage and compliance statements for enforcement purposes. HED recommends that 40 CFR § 180.449 be amended by establishing , revising or removing the tolerances as liste d in Table s 2.2.2 .1 and 2.2.2.2, below.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 10 of 98 Table 2.2.2

. 1. Tolerance Summary for Abamectin

.

Commodity Established
Tolerance

(ppm) Proposed
Tolerance

(ppm) HED

Recommended

Tolerance

(ppm) 1 Comments ( correct commodity definition )

Caneberry subgroup 13

- 07A n one 0.20 0.20 Cattle, fat 0.03 none 0.05 Cattle, meat 0.02 none 0.02 Cattle, meat byproducts 0.06 none 0.09 Corn, sweet, forage none 0.2 0.20 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 0.01 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 Vegetable, fruiting, group 8

- 10 0.07 0.07 Includes greenhouse

- grown

tomatoes.

Fruit, citrus, group 10

- 10 0.02 0.02 Retain established tolerances of 0.10 ppm on citrus, dried pulp and citrus, oil. Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F none 0.02 0.02 (Fruit, small vine climbing, except fuzzy kiwifruit, subgroup
13

- 07F) Berry, low growing, subgroup 13

- 07G none 0.05 0.05

Fruit, stone, group 12

- 12 none 0.09 0.09 Fruit, pome, group 11

- 10 none 0.02 0.02

Nut, tree, group 14

- 12 none 0.01 0.01 Retain tolerance on almond

, hulls at 0.10 ppm. Papaya none 0.40 0.40 Star apple none 0.40 0.40 Black sapote none 0.40 0.40 Sapodilla none 0.40 0.40

Canistel none 0.40 0.40

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 11 of 98 Table 2.2.2

. 1. Tolerance Summary for Abamectin

.

Commodity Established
Tolerance

(ppm) Proposed
Tolerance

(ppm) HED

Recommended

Tolerance

(ppm) 1 Comments ( correct commodity definition )

Mamey sapote none 0.40 0.40

Guava none 0.015 0.015 Feijoa none 0.015 0.015

Jaboticaba none 0.015 0.015 Wax jambu none 0.015 0.015

Starfruit none 0.015 0.015

Passionfruit none 0.015 0.015

Acerola none 0.015 0.015 Lychee none 0.01 0.01 Longan none 0.01 0.01 Spanish lime none 0.01 0.01

Rambutan none 0.01 0.01

Pulasan none 0.01 0.01 Pineapple none 0.015 0.015

Bean none 0.015 0.015 Onion, green, subgroup 3

- 07B none 0.08 0.08

1 Changes from established/proposed tolerances are bolded.

Table 2.2.2.2. Established Tolerances to be Removed upon Establishment of Tolerances in Table 2.2.2.1. Commodity Established Tolerance (ppm ) Recommended Tolerance (ppm) Comments

Bean, dry, seed 0.01 Revoke Covered by Bean tolerance
Citrus 0.02 Revoke Covered by Fruit , citrus, g roup 10

- 10
tolerance Apple 0.02 Revoke Covered by Fruit , pome, g roup 11

- 10
tolerance Pear 0.02 Revoke Fruit, stone, group
12 0.09 Revoke Covered by Fruit, stone, group 12

- 12
tolerance Nut, tree, group 14 0.01 Revoke Covered by Nut, tree, group 14

- 12 tolerance

Pistachio 0.01 Revoke Grape 0.02 Revoke Covered by Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F
tolerance Strawberry 0

. 05 Revoke Covered by Berry, low growing, subgroup
13

- 07G tolerance Vegetable, fruiting, group 8 0.020 Revoke Covered by Vegetable, fruiting, group 8

- 10
tolerance



### 2.2. 3 Revisions to Petitioned

- For Tolerances

As shown in Table 2.2.2 .1 above, HED is recommending a tolerance of 0.40 ppm for grain, aspirated grain fractions

, since aspirated grain fractions are associated with soybean s ( 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 tolerance 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.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 12 of 98 HED is also recommending that some of the established livestock tolerances be increased based

on a new dietary burden calculation

, which includes the proposed uses on soybeans, sweet corn,
and ear ta gs for lactating dairy cattle. 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

. The higher tolerances on catt le fat and meat byproducts as compared to goat, horse and sheep fat and meat byproducts are due to the proposed use of ear tags on lactating dairy cattle. Additionally, the amended tolerance for milk, proposed at 0.01 ppm, is recommended to be established at 0.015 ppm. There are no livestock feed items associated with the proposed use on Caneberry subgroup 13

- 07A. Further, because of limited feed items associated with PP# 4E8309, the established livestock tolerances were not reassessed for those proposed us es.

Finally , t he commodity definition should be revised to reflect the correct nomenclature for Subgroup 13

- 07F.

2.2.4 International Harmonization

The plant tolerance definitions are essentially the same for the U

. S

. , Codex, and Canada, all including a vermectin B 1a 

### , avermectin B 1b 

### , and the 8,9

- Z isomers. There are no Codex or Canadian maximum residue limits (MRLs) established for abamectin for the following
commodities: sweet corn, soybean, papaya, star apple, black sapote, sapodilla, canistel, mamey

sa pote, guava, feijoa, jaboticaba, wax jambu, starfruit, passionfruit, acerola, lychee, longan, Spanish lime, rambutan, pulasan

, pineapple , bean or green onion commodities

. Additionally,

t here are no Codex MRLs for abamectin on the commodities in Caneberry subgroup 13

- 07A; Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; or Fruit, stone, group 12

- 12

.

The following recommended U.S. tolerance s are harmonized with established, related Codex

MRLs: Fruit, pome, group 11

- 10; and Nu t, tree, group 14

- 12

. The recommended U.S. tolerances
for C aneberr y subgroup 13

- 07A at 0.20 ppm ; Fruit, citrus, group 10

- 10 at 0.02 ppm; Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; and Fruit, pome, group 11

- 10 are harmonized with t he proposed or established related Canadian MRLs

.

The Codex MRL on citrus is not harmonized with the U.S. tolerance on Fruit, citrus, group 10

- 10. The e stablished Canadian MRLs on tree nut commodities are not harmonized with the U.S.
tolerance recommenda tion for Nut, tree, group 14

- 12. Finally, the established Codex and Canadian MRL on strawberry is not harmonized with the recommended U.S. tolerance on Berry,
low

- growing, subgroup 13

- 07G. Residue data underlying the se recommende d U.S. tolerances
resulted in tolerance recommendations that are higher than the established Codex or Canadian

MR Ls on these related commodities

.

Codex and Canadian MRLs for abamectin on fruiting vegetable commodities are not harmonized
with the recommend ed U.S. tolerance on Vegetable, fruiting, group 8

- 10 . The residue data underlying the recommended U.S. fruiting vegetable tolerance resulted in a tolerance recommendation that is higher than the established Codex MRL on sweet peppers and the

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 13 of 98 Canadian MRLs on pepper and tomato. Codex has also established a separate tolerance on dried chili pepper that is higher than the recommended U.S. fruiting vegetable tolerance.

The livestock residue definitions are essentially the same for the U

. S

. and Canada; the Cod ex 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 M RLs on livestock commodities, but fewer than US tolerances. None of the Codex MRLs are set at the same level
as the U

. S

. 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 Status sheet may be found in Appendix E.

2.3 Label Recommendations

2.3.1 Label Recommendations from Residue Reviews

860.1200 Directions for Use The petitioner needs to resolve the following inconsistencies: On the Epi

- Mek TM 

### SCL label for greenhouse

- grown tomatoes, the maximum rate is given as 3.5 fl oz/A. Because Epi

- Mek TM 

### SCL contains only 0.35 lb ai/gal, 3.5 fl oz is 0.0096 lb ai/A, not 0.019 lb ai/A as stated unde r Use Restrictions on page 29. Other greenhouse

- grown tomato labels have the maximum single application rate of 0. 0 19 lb ai/A

. Additionally, the u se r estrictions on pages 28

- 29 refer to Epi

Mek TM 

### SC rather than Epi

- Mek TM 

### SCL.

3.0 In tr oduction

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 del ta

- 8,9

- isomer. Avermectins are macrocyclic lactones produced as natural fermentation products of the soil bacterium Streptomyces avermitilis. Currently abamectin and emamectin ar e the only members of this group with active pesticide registrations. Abamectin is an insecticide/miticide used to control mites, leaf miners, and other insects in commercially important crops. A bamectin acts as an insecticide by interfering with the nervo us system of the insect, causing t he insect to become paralyzed. Available mechanistic data indicate a neurotoxic mechanism of action, related to interference with GABA

- mediated neurotransmission.

Tolerances are established under 40 CFR §180.449 for resid ues of abamectin (avermectin), including its metabolites and degradates, in or on various crop and livestock commodities at levels ranging from 0.00 2 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.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 14 of 98 The registered formulation types include emulsifiable concentrate (EC)

, suspension concentrate (SC), granular, bait, gel, dust , and impregnated materials (e.g., ear tags)

. The registered uses include food, food handling establish ments, and residential uses.

3.1 Chemical Identity

Table 3.1. Abamectin 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

- L

arabino

- 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

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 15 of 98 Table 3.1. Abamectin Nomenclature
',6 '

- dihydro

- 2 ' H

- pyran)

- 12

- yl 2,6

- dideoxy

- 4

- O

- (2,6

- dideoxy

- 3

- O

- methyl

- α

- L

arabino

- hexopyranosyl)

- 3

- O

- methyl

- α

- L

- arabino

- hexopyranoside

CAS name Avermectin B 1

CAS Registry Number Avermectin B 1 - 71751

- 41

- 2; Avermectin B 1a - 65195

- 55

- 3; Avermectin B 1b - 65195

- 56

- 4

End

- use product s /EP s 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 0.15 lb ai/gallon; 2.0% abamectin); Epi

- MekTM 0.15 EC Miticide/Insecticide, EPA Reg. No. 100

- 1154 (c ontains 0.15
lb ai per gallon ; 2.0% abamectin ); Epi

- MekTM SC Miticide/Insecticide, EPA Reg. 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

a i per gallon; 4.2% abamecti n) ; 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

A bamectin is a crystalline powder with very low vapor pressure (1.5x10

- 9 

### hPa)

. It has very low water solubility (<0.001 to 0.01 mg/ml); but

, i s soluble in organic solvents. Abamectin is stabl e to hydrolysis. Abamectin has low dermal absorpti on (≤ 1% of the applied dose). Refer to Appendix C for the table of physical/chemical properties.

3.3 Pe sticide Use Pattern

The labels are adequate to allow evaluation of the residue and exposure data relative to the proposed use s . A summary of the use profile is provided in Table 3.3 below.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 16 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

Caneberry Subgroup 13

- 07A

Postemergence;
Broadcast foliar spray; Ground or aerial equipment Agri

- Mek® 0.15 EC [100

- 898]

Epi

- Mek® 0.15 EC [100

- 1154] 0.0094

- 0.019 NS 4 0.056 7 Apply when spider mites are first observed and repeat as
needed. Do not apply with aircraft in NY state. Apply in a minimum of 10 gals. water by ground or 5 gal water by air.
RTI is 7 days. The maximum number of applications at the
maximum rate is 3. Do not make more than 2 sequential ap plications of an
abamectin.
Cattle Ear Tag
1 or 2 ear tags per
animal for 2

- 5 months per treatment 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 NS 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 c ontaining 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 product or more than 0.172 lb ai/A of any other foliar applied thiamethoxam containing product

per season.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 17 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

Postemergence;
Broadcast foliar

spray; Ground or aerial equipment Agri

- Mek® SC
Miticide/Insecticide [100

- 1351]

Epi

- MekTM SC
Miticide/Insecticide [100

- 14 08]

Epi

- MekTM SCL
Miticide/Insecticide [100

- 1439] 0.0096

- 0.019 NS 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 than 0.019 lb ai/A of Agri

- Mek® SC/Epi

- MekTM SC/Epi

- MekTM SCL or any other foliarly applied abamectin per application. Do not apply more than 0.038 lb ai/A of Agri

- Mek® SC/ Epi

- MekTM SC/Epi

- MekTM SCL or any other foliarly applied abamectin

- containing product i n a growing season.

Soybean

Postemergence;
Broadcast foliar

spray; Ground or aerial equipment Agri

- Flex® Miticide/
Insecticide [100

- 1350] 0.011

- 0.014 NS 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. RTI = 7 days. 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 ap plied 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 abamectin containing product or more than 0.125 lb ai/A of any other foliar applied thiamethoxa m 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; Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] 0.0096

- 0.019 NS 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. RTI = 7 days

.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 18 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

Ground or aerial equipment Epi

- MekTM SC
Miticide/Insecticide [100

- 1408]

Epi

- MekTM SCL
Miticide/nsecticide [100

- 1439] Do not apply more than 0.019 lb ai/A of Agri

- Mek® SC/Epi

- MekTM SC/ Epi

- MekTM SCL or any other foliarly applied abamec tin

- containing product per application. Do not apply more than 0.038 lb ai/A of Agri

- Mek® SC/Epi

- MekTM SC/ Epi

- MekTM SCL or any other foliarly applied abamectin

- containing product in a growing season.

Turf (Golf Course Greens, Tees, and Fairways)

Broadcast (ground only) AgadorTM 0.17 SC
Nematicide [100

- R LNO] 0.069
lb ai/A

0.00080 5 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 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

a pply this product through any ty pe of irrigation system or
ultra

- low volume spray. Apply in 2 gallons of water per 1,000 square feet of turf. DivanemTM 0.15EC
Nematicide [100

- RLRN] 0.067
lb ai/A

0.00080 5 lb ai/gal 0.267 NA

Green Onion Subgroup 3

- 07B

Ground, Aerial 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.019 2 sequential 0.0 5 6 7 Apply with a minimum of 20 gal/A for ground applications. RTI is 7 days

.

Fruiting Vegetable Group 8

- 10

Ground, Aerial 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal) 0.019 2 sequential 0.056 7 Apply with a minimum of 20 gal/A for ground applications. RTI is 7 days

.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 19 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Greenhouse Tomato

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal)

0.019 lb ai/A 2 sequential 0.056 1 Apply with a minimum of 20 gal/A. RTI is 7 days. 8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Citrus Fruit Group 10

- 10

Ground, Aerial 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal) 0.023 lb ai/A 3 0.047 1 Apply with a minimum of 150 gal/A for ground applications. RTI is 30 days

.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 20 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Pome Fruit Group 11

- 10

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal)

0.023 2 0.047 28 Apply with a minimum of 40 gal/A for ground applications. RTI is 21 days

. 8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Stone Fruit Group 12

- 12

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal) 0.023 2 0.047 21 Apply with a minimum of 40 gal/A for ground applications. RTI is 21 days

.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 21 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Small Fruit, Vine Climbing, Subgroup 13

- 07F

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal)

0.019 2 0.038 28 Apply with a minimum of 50 gal/A for ground applications;

as low 5 gal/A may be used for an electro

- static sprayer. RTI is 21 days

. 8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Low

- growing Berry Subgroup 13

- 07G

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 22 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal)

0.019 NS 0.075 3 Apply with a minimum of 50 gal/A for ground applications; as low 10 gal/A may be used for an electro

- static sprayer. RTI is 7 days

. 8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

4.2% SC Epi

- MekTM SCL
Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Tree Nut Group 14

- 12

Ground 8% SC Agri

- Mek® SC
Miticide/Insecticide [100

- 1351] (0.7 lb ai/gal)

0.023 2 0.047 21 Apply with a minimum of 40 gal/A for ground applications. RTI is 21 days

. 8% SC Epi

- Mek® SC Miticide/Insecticide [100

- 1408] (0.7 lb ai/gal)

2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal)

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 23 of 98 Table 3.3. Summary of Proposed Directions for Use of Abamectin

Applic. Timing, Type, and Equip. Formulation 1 [EPA Reg. No.] App. Rate (lb ai/A) Max. No. App. per Season Max.
Seasonal App. Rate (lb ai/A) PHI 2 (days) Use Directions and Limitations 3

4.2% SC Epi

- MekTM SCL Miticide/Insecticide [100

- 1439] (0.35 lb ai/gal)

Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Acerola

Ground 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.023 0.07 3 7 Apply with a minimum of 50 gal/A for ground applications; as low 5 gal/A may be used for an electro

- static sprayer. RTI
is 14 days

.

Lychee, Longan, Spanish Lime, Rambutan

Ground 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.023 0.04 5 2 14 Apply with a minimum of 50 gal/A for ground applications; as low 5 gal/A may be used for an electro

- static sprayer. RTI is 30 days

.

Papaya, Star Apple, Black Sapote, Sapodilla, Canistel, Mamey Sapote

Ground 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.023 3 0.07 3 Apply with a minimum of 50 gal/A for ground applications;
as low 5 gal/A may be used for an electro

- static sprayer. RTI is 3 days

.

Bean

Ground, Aerial 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.019 2 0.056 7 Apply with a minimum of 10 gal/A for ground applications. RTI is 6 days

.

Pineapple

Ground 2% EC Epi

- Mek® 0.15 EC
Miticide/Insecticide [100

- 1154] (0.15 lb ai/gal) 0.023 2 0.046 112 Apply with a minimum of 50 gal/A for ground applications; as low 5 gal/A may be used for an electro

- static sprayer. RTI is 7 days

.

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

.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 24 of 98 2 PHI = Pre

- harvest interval

3 Restrictions that apply to proposed labels: All end

- use products are classified as Restricted Use Pesticide. The following apply to EPs other than the Cattle Ear Tag: To avoid illegal residues, end

- use products must be mixed with a non

- ionic activator type wetting, spreading and/or penetrating spray adjuvant. Do not use binder or sticker type adjuvants. Do not apply with aircraft in NY (for commodities that allow aerial applications)

. RTI = Re

- treatment interval For resistance management, do not make more than 2 sequential applications of Agri

- Flex®/ Agri

- Mek® SC/ Epi

- MekTM 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 at

- plant 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.

4 NS = Not specified

5 Turf a pplication rate is based on use direction to “apply in 2 gallons of water per 1,000 square feet of turf.”

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### Page 25 of 98 3.4 Anticipated Exposure Pathways

Abamectin has been proposed for use on multiple agricultural commodities , in cattle ear tags, and on golf course turf. Based on the proposed and registered uses of abamectin, h umans may be exposed to abamectin in food and drinking water since abamectin may be applied directly to growing crops. Although significant residues are not expected to occur in ground water because of the low water solubility of residues and their affinity to soil particles, residues may occur in surface water due to runoff, erosion, and spray drift.

Based on all of the proposed uses, occupational exp osures to abamectin are expected for short

and intermediate

- term durations when conducting handling and post

- application activities. Potential routes of exposure include both dermal and inhalation for occupational workers. Furthermore, the proposed golf c ourse use results in a potential for residential short

- term dermal
post

- application exposures for adults and children ( 6 to 16 years old) resulting from recreational golfing activities. Finally, t he registered residential uses of abamectin result in the possibility of exposure in residential or non

- occupational settings.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordanc e with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/e o12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according t o well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are b ased on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.

Extensive data on food consumption patterns are c ompiled by the U.S. Department of Agriculture (US DA) using 2003

- 2008 food consumption 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 uses of a pesticide. These data are analyzed a nd categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed
when condit ions or circumstances warrant. Whenever appropriate, non

- die tary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are 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 traditional dietary patterns among specific subgroups.

4 .0 Hazard Characterization and Dose

- Response Assessment

As mention ed in Section 3.0, abamectin consist s of two components , B 1a 

### and B 1b

, 

### which have very similar biological and toxicological properties. Emamectin is a structurally and

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### Page 26 of 98 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 tetrahydropyran ring whereas

, in emamectin

, the hyd roxyl group is replaced by a methylamine (circled groups in the following figures).

Since the last risk assessment (D402677 and D405843, N. Dodd, 12/20/2012), the Agency has

re

- evaluated the abamectin and emamectin toxicological database s along with curr ently available
literature information to ensure consistent hazard evaluation for these st ructurally related pesticides. This hazard characterization and dose

- response assessment represents a more refined analysis than previous assessments, using the liter ature data to enhance the characterization of
the studies submitted to the A gency. Due to the similarity of the two chemicals the Agency has

re

- evaluated the toxicity of both abamectin and emamectin to ensure consis tency of approach.
The evaluation of abam ectin is presented in this section, since this risk assessment has been prepared to address new uses of abamectin. The revised toxicity profile tables for emamectin are presented in Appendix I

. While no common mechanism group has been established for the

a vermectin macrocyclic lactone s, abamectin and emamectin ( i.e., key events leading from the
molecular in i tiating 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 Assessment: Framework for Screening Analysis Purpose

, US E PA
2016 ) to assess the potential for cumulative risk and the extent to which additional toxicity information is needed to determine the key even ts for a common mechanism grouping.

Abamectin

Emamectin

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### Page 27 of 98 Mode of Action :
In nematodes, abamectin blocks signal transmission from the central command interneurons to the peripheral motoneurons, leading to paralys is and death. In the mammalian toxicity studies submitted by the registrant, paralysis is also a common findin g prior to moribund 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 Casida, 1 997; and Dawson et

. al., 2000). GABA plays a critical role in nervous system through both non

- synaptic (Represa and

Ben

- Ari, 2005) and synaptic (Nguyen et

. al., 2001) mechanisms. The literature data show that
within the mammalian brain abamectin binding to GABA receptors is widespread but particularly abundant in the cer ebellum (Wang and Pong, 1982). Abamectin also has been suggested to act on GABA receptors in the enteric nervous system and induces longitudinal rhythmic contractions in the isolat ed ileum (Kerr and Ong, 1986 ). Abamectin may therefore
influence GABA

- mediated regulation of metabolism, food intake and body weight at m ultiple sites (Meister, 2007). Although GABA receptor mediated neurotoxicity is a solid hypothesis, as described in detail in Appendix H

, data in m ammalian preparations linking alterations in GABA receptor function to disruptions in neuronal excitability in vitro and in vivo, and ultimately
adverse outcome s , are currently lacking.

4.1 Toxicological Studies Available for Analysis

Most of the required toxicity stud ies on abamectin are available. The requirements for subchronic dermal toxicity and immunotoxicity studies have been waived (TXR 0056687

, U. Habiba, 0 1/07/2013 and TXR 0056509

, K. Rury, 0 1/30/2013)

. T he studies currently available for
abamectin are:

• subchronic oral toxicity studies in rats and dogs

,

• combined chronic toxicity/carcinogenicity 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 neurotoxicity 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 summary of all studies submitted may be found in Appendix A

. Several literature studies were used for characterization and are cited throughout
this document

.

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### Page 28 of 98 4.2 Absorption, Distribution, Metabolism, and Excretio n (ADME)

The metabolism study was performed with avermectin B 1a 

### . With oral dosing, the test material in the gastrointestinal tract of the rat was almost completely absorbed and distributed throughout all major tissues and organs, with the highest residues found in fat. Maximum concentrations in
blood were achieved within 4

- 8 hours after administration. The absorbed avermectin was rapidly eliminated from the body, almost exclusively in the feces, and did not accumulate in the body after repeated exposure. The parent compound represented 46

- 56% of the total radioactivity found in the fecal samples of the low dose groups. The major biotransformation pathways of
avermectin B 1a 

### in the rat were demethylation, hydroxylation, cleavage of the oleandrosyl ring,
and oxidation reactions. There were 11 isolated metabolites. In the rat, a vermectin 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 no t found in the rat
metabolism studies. Avermectin B 1a 

### did not bioaccumulate in rat tissues.

4.2.1 Dermal Absorption

A dermal absorption study was conducted with rhesus monkey using 3 

### H

- avermectin B 1a 

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

### was 1% of the applied dose ( J. Rowland, TXR 0012854, 9/15/1998).

4.3 Toxicological Effects

The toxicological effects observed in the test animals are consistent to the proposed MOA a s described in the section 4.0, Mode of Action

. 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 weight was also one of the most frequent findings. Neurotoxicity (including tremors, mydriasis, ataxia, and death) was seen in mice, dogs, and rats. Developmental effects such as cleft pa late were reported in rabbits. GABA also plays a role in development ; cleft palate findings may reflect the interaction of abamectin on the GABA
receptor . Generally

, the finding of cleft palate was seen at higher dose levels tha n those for neurotoxicity.

Integral to the dose response assessment in mammals for this class of compo unds is the role of P

glycoprotein (P

- gp) in target tissues . P

- gp is a member of adenosine tripho sphate ( ATP ) binding cassette transporter proteins, which reside in the plasma membrane and function as a transmembrane efflux pump, moving xenobiotics from the intracellular to the extracellular
domain. P

- gp is found in the canallicular surface of hepatocytes, the apical surface of proximal tubular cells in the kidneys, brush border surface of enterocytes, luminal surface of blood capillaries of the brain (blood brain barrier), plac enta, ovaries, and the testes. As an efflux transporter, P

- gp acts as a protective barrier to keep xenobiotics out of the body by excreting them into bile, urine, and intestinal lumen and prevents accumulation of these compounds in the brain and go nads, as well as in the fetus. Therefore, tes t animals with genetic polymorphisms that compromise P

- gp expression are particularly susceptible to abamectin induced neurotoxicity (Lankas et al., 1997).

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### Page 29 of 98 In this connection, t he CF

- 1 strain of mouse is also uniquely sensitive to abamectin and
emamectin . Some CF

- 1 mice have a polymorphism for the gene encoding P

- gp and 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, em amectin.

In addition, t he 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 approximatel y PND 28 ( Matsuoka, 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 developing human fetus, the presence of 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 rat s and human newborn s , the Agency does not believe that the early post

- natal findings in the rat are rel evant to human newborns or young
children at this time

.

T he human multidrug resistance ( MDR

- 1 ) gene encoding P

- gp and polymorphism of MDR

- 1

gene are well studied

. The literature data are inconclusive with respect to the functional significance of the gene tic variance in P

- gp in human. Currently , the reported 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). Given 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 points of departure (PODs) for risk

assessment. Among th e test animal s with fully functional P

- gp, the beagle dog is the most sensitive species (A ppendix A).

Carcinogenicity studies in rats and mice (CD

- 1) and mutagenicity studies provide no indication
that abamectin is carcinogenic or mutagenic.

Abamectin has high to moderate acute toxicity by the oral route (depending on the vehicle), high acute toxicity by the inhalation route, and low acute toxicity by the dermal route. It is slightly irritating to the skin, but is not an ocular irritant or a dermal sen sitizer.

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

Currently, the toxicity endpoint and point of departure for all exposure scenarios were selected from the subchronic and chronic oral toxicity studies in dogs

. The point s of departure selected from the dog studies are based on clear NOAELs and are protective of all the adverse effects
seen in the available human

- relevant studies with rats, CD

- 1 mice, and rabbits. Therefore, the FQPA safety factor has been reduced to 1x. D e taile d rationale is presented in 4.4.1 to 4.4.4.

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### Page 30 of 98 4.4 .1 Completeness of the Toxicology Database

The toxicology database for abamectin is complete for human health risk assessment. As
mentioned in Section 4.1

, w aivers have been granted for i mmunotoxicity and subchronic dermal toxicity studies (TXR 0056 687

, U. Habiba, 0 1/0 7 /2013 and TXR 0056509; K. Rury,
0 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 database are consistent with the proposed MOA

. Signs of neurotoxicity ranging from decrease s in foot splay reflex, mydriasis (i.e., excessive dilation of the pup il), curvature of the spine, decreased fore

- and hind

- limb grip strength, tip

- toe gate, tremors, ataxia, or spastic movements of the limbs are reported in various studies with
different du rations of abamectin exposure. In dogs, mydriasis was the most commo n 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

A n increase in qualitative susceptibility was seen in the rabbit developmental toxicity study,
where decea ses in body weight and food consumption were seen in maternal animals at 2.0 mg/kg/day. In contrast, the fetal effects were much more severe, consisting of cleft palate, clubbed foot, and death at 2.0 mg/kg/day . The POD (0.25 mg/kg/day) selected from the d og studies is 8 x lower than the dose where rabbit fetal effects were seen. Therefore, it is protective of fetal effects seen in the rabbit developmental toxicity study.

The rat reproduction toxicity and developmental neurotoxicity studies demonstrated both qualitative and quantitative susceptibility in the pups to the effects of abamectin (decrease pup weights and increased postnatal pup mortality). This observation is consistent with the finding
that P

- gp is not fully developed in r at pups until postna tal 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 human s, P

- gp has been detected in the fetus at 22 weeks of pregnancy, and the human newborns have functioning P

- gp. Therefore, human infants and children are not expected to have enhanced s ensitivity as seen in rat pups. The 10x FQPA safety
factor for infants and children is reduced to 1x.



## 4 .4 .4 Residual Uncertainty in the Exposure Database

There are no residual concerns with resp ect to the exposure databases. The acute and chronic dietary food exposure assessment utilizes conservative assumptions including anticipated residues, default processing fact ors, and percent crop treated. The dietary drinking water
assessment utilized conservative modeling inputs which included conservative assumptions for the parent chemicals and all degradates o f concern. Therefore, the water exposure assessment
will not und erestimate the potential risks for infants and children. Likewise, the use of maximum application rates and central

- to

- high end inputs results in calculated residential exposure

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 31 of 98 assessments will not underestimate the risks to infants and children from the requested uses.

4.5 Toxicity Endpoint and Point of Departure Selections

T he toxicity studies in rats, CD

- 1 mice and beagle dogs demonstrated that the beagle dog is the most appropriate species to assess the risk of abamectin

. The toxicity endpoints and PODs for
human health risk assess ment 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 m ydriasis) of neurotoxicity were observed in the subchronic (12

- and 18

- weeks) and chronic oral toxicity studies in dogs at the lowest observed adverse effect level ( LOAEL ) of 0.5 mg/kg

. The POD ( no observed adverse effect level; NOAEL) is 0.25 mg/kg (Table s 4.5.1 and 4.5.2 ). T remors and mydriasis were observed as early as the first week of exposure. After extended exposure in the chronic toxicity study, adverse effects were observed at similar dose level s as the shorter

- term studies. The
A gency assumes that these clinical signs could result from a single dose.

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

Kinetic data : Given the rapid absorption and elimination of abamectin, the Agency has
concluded that some of the neurotoxic effects seen in the subchronic and chronic toxicity
studies in dogs coul d be elicited by a single dose. As described previously, the kinetic data of abamectin show a pattern of rapid absorption and eliminati on. With oral dosing in rats and
mice , abamectin was absorbed rapidly, 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 accumulate 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 (ACN) study in rat (range finding and main studies)

. The ACN shows that clinical signs of neurotoxicity

, such as reduced foot spla y reflex, ataxia, tremors and mydriasis (decreased pupillary light response)

, were observed from a single
dos e

. Most of the effects observed in the rat ACN were consistent with those seen in the subchronic and chronic dog studies

.

S ubchronic and chronic dog studies: The effects seen in the subchronic (gavage) and chronic dog studies were similar despite repeated dosing, suggesting the response may be due to each individual exposure rather than to accumulation of abamectin in tissues. Clinical signs such

a s ataxia and or whole body tremors were reported within 3 hours of the first dose at higher
dose levels.

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### Page 32 of 98 Dermal and Inhalation Exposure Endpoints (all durations) :

For short

- term dermal and inhalation exposures, oral subchronic and chronic toxicity studies in dog were chosen as co

- critical studies to establish the toxicity endpoint and POD

. The dermal absorption factor is 1%, which represents maximal dermal absorptio n seen in the dermal absorption study. The adverse effects for establishing the toxicity 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 study in rats is available, but the results show no toxicity at the highest tested concentration (2.5 μg/L, approximately equivalent to 0. 5 68 mg/kg/day). T he use of the results from the dog studies in establishing the toxicity endpoint and
POD (0.25 mg/kg/day) f or the inhalation route is appropriate and protective for these exposure
scenarios.

T he LOC is 100 for residential exposure risk assessments, based on a total uncertainty factor of 100x (10 for interspecies extrapolation, 10x for intraspecies variations)

.

For occupational exposure risk assessments, the LOC is 100 based on a total uncertainty factor of 100x (10x for interspecies extrapolation, 10x for intraspecies variations).

4.5 .1 C ombined Routes of Exposure

Oral, dermal and inhalation routes of exposure could be combined since the toxicity endpoints
were chosen from the same co

- critical studies.

4.5.2 Carcinogenicity:

Abamectin is characterized as not likely to be carcinogenic to humans based on the absence of significant increase in tumor inc idence in two adequate rodent (rats and mice) carcinogenicity studies. Quantification of cancer risk assessment is not required.

Table s 4.5.1 and 4.5 .2 summarize the toxicity endpoints and PODs for risk assessment for
abamectin.

Table 4.5 .1. Summary of Toxicological Doses and Endpoints for Abamectin for Use in Dietary and Non

Occupational Human Heal th 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.

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### Page 33 of 98 Table 4.5 .1. Summary of Toxicological Doses and Endpoints for Abamectin for Use in Dietary and Non

Occupational Human Heal th Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD,
LOC for

Risk
Assessment Study and Toxicological Effects

Dermal (Short

- Term
and
Intermedia te

Term) NOAEL =
0.25 mg/kg/day

Dermal Absorption =
1% UF A = 10x

UF H = 10x FQPA SF =1x LOC: MOE
= 100

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 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 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 eff ect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (int er species). UF H = potential variation in sensitivity among members of the human population (int ra species). FQPA SF = FQPA Sa fety 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 Toxicological Doses and Endpoints for Abamectin 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 o n 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

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### Page 34 of 98 Table 4.5 .2. Summary of Toxicological Doses and Endpoints for Abamectin for Use in Occupational
Human Health Risk Assessments

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

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to human based on the absence of significant increase in tumor incidence in two adequate rodent carcinogenicity studies.
Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect l evel. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). . MOE = margin of exposure. LOC = level of

concern.



### 5.0 Dietary Exp osure 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 assessment ( D402677 and D405843, N. Dodd, 12/20/2012)

. The

r esidues of concern for the risk assessment and the 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) 2

Livestock Ruminant 1 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

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

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### Page 35 of 98 5 .2 Food Residue Profile

Plant Commodities : Adequate field trials were submitted for abamectin on caneberries (blackberry and raspberry)

, sweet corn

, soybeans , greenhouse

- grown tomato, green onion, guava, lima bean, lychee, papaya, pineapple and snap bean that adequately reflect the proposed use pattern. The number of field trials and the geographic representation are adequate. Decline studies show decreasing residues with increasing PHI. Adequate storage stability data are available to support the field trials

. A dequate data collectio n methods were used. The se field trials are summarized in Table s F.1 and
F.2 in Appendix F

.

There are no processed commodities for caneberries, sweet corn, green onion, guava, lima bean, lychee, papaya, or snap bean. The processe d commodities for soybean are meal, hulls, refined oil, and aspirated grain fractions (AGF). A processing study on soybeans indicated that
combined residues of avermectin B 1a 

### , avermectin B 1b 

### , and 8,9

- Z avermectin B 1a 

### may concentrate significantly in/on aspirated grain fractions (average processing factor of 59x), and slightly in meal (1.1x), and hulls (1.2x). A dditionally, a processing study on tomatoes was previously
reviewed ( N. Dodd, MRID 47702 806; D364734, 1/21/10 ) . Based on the results from the 5x rate field trials, the average processing factors for total abamectin residues were 0.52x in puree and 0.94x in paste. These data indicate that abamectin residues do not concentrate in tomato processed fractions; therefo re, separate tolerances are not required for tomato paste or puree. The processed commodities for pineapple are process residue (also known as wet bran) and juice. No processing stud ies have been submitted for pineapple , however, c rop field trials were con ducted at exaggerated application rates (in addition to the proposed label rate) and residues of abamectin were not detected. Therefore, a processing study for pineapple is not needed , and tolerances for pineapple processed commodities are not required.

R esidues 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 c attle a nd non

- lactating dairy cattle. Y

- TEX Corporation submitted a study to determine residues of abamectin in milk from use of the ear tag on lactating dairy cattle

. Although some of the samples analyzed showed minimal transfer of residues to milk, there was one sample with residues close to the existing
tolerance that is based o n secondary residues from cattle consuming treated feed. Therefore, the
tolerance for milk needs to be increased to accommodate this use

. Syngenta has proposed use of abamectin on sweet corn and soybeans, which are both livestock feed items. The IR

- 4 has

p roposed a tolerance on pineapple, and pineapple process residue, a by

- product of pineapple processing, is a cattle feed item. The Agency has re

- evaluated the Maximum Reasonable Dietary Burden (MRDB) for livestock considering the proposed uses, and addition al modifications to milk, meat byproducts, an d fat tolerances are required. Note that the Agency generally
establishes tolerances for the edible commodities of sheep, goats, and horse s at the same level of
cattle. However, since the ear tags containing aba mectin 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 consu ming t reated feed. Further details on the reassessment of the livestock dietary burden

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 36 of 98 may be found in the chemistry assessment of the proposed uses (D410993, N. Dodd, 03/17/2016 ; D414022

, N. Dodd, 03/17/2016 ; D416280, N. Dodd, 03/17/2016 ; D424008, N. Dodd,
12/2 2/2015 )

.

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

.

5.3 Water Residue Profile

EDWCs were provided by EFED for abamectin. The abamectin residues of concern include the parent compound mixture and the structurally similar degradates: NOA 448111, NOA 448112, NOA 426289, NOA 445495, NOA 457464, and NOA 457465

. In absence of toxicity dat a on these degradates, they are assumed to have toxicity profiles similar to that of abamectin on the
basis of the structural similarities.

Groundwater and surface water monitoring data are not availab le for abamectin at this time. Therefore, screening mo dels 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 (SCI

- GROW) models w ere 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 surfac e water since the resid ues 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
MI at 0.056 lb ai/A/year results in the highest chronic drinking water exposure

. The acute
EDWC is 0.76 ppb, the 1

- in

- 10 year annual maximum concentration in surface water

, as shown
in Table 5.3 below; however, for the acute dietary assessment, a drinking water residue
d istribution file provided by EFED was used. For the chronic dietary assessment, the annual
mean concentration of 0.3 0 ppb in surface water was used.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 37 of 98 Table 5.3. Screening

- Level EDWCs for Proposed Uses of Abamectin 1

Source (Tier: Model) Use Site (Max. Annual App. Rate) Acute EDWC (μg/L) Chronic EDWC (μg/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 drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin

. Acute anticipated residues derived from field
trial data were used

. Empirical and default processing f actors and percent crop treated ( P CT)
esti mates were used, as available. No monitoring data were used. Drinking water residues were represented by a residue distribution file based on the application to soybeans.

Chronic assessment:
A refined chronic dietary (food and drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin

. Average residues from field trials were used. Residues from use in food handling establishments were included. Empirical and defaul t processing factors and P CT estimates were used, as available. Drinking water was represented by a single point estimate of average abamectin residues (t he 1

- in

- ten

- year annual mean). The
estimated su rface 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 ( J. Alsadek, No DP number, 07/01/2015 and D. Atwood, D428074, 08/27/2015) were used in the

acu te dietary risk assessment for the following crops: almond: 80%; apple: 30%; apricot: 30%; avocado: 60%; bean, dry: 2.5%; blackberry: 68%; boysenberry: 68%; cantaloupe: 45%; celery: 70%; cherry: 20%; corn, sweet: 57%; cotton: 30%; cucumber: 10%; grape: 35% ; grapefruit: 90%; hazelnut: 2.5%; honeydew: 35%; lemon: 55%; lettuce: 45%; loganberry: 68%; nectarine: 20%; onion, bulb: 10%; orange: 70%; peach: 25%; pear: 85%; pecan: 2.5%; pepper: 30%; pistachio: 2.5%; plum/prune: 35%; potato: 20%; pumpkin: 10%; raspbe rry: 68%; soybean: 11%; spinach: 45%; squash: 15%; strawberry: 45%; tangerine: 55%; tomato: 25%; walnut: 55%; and
watermelon: 15%.

The percent crop treated values that were used to refine the livestock commodities for the acute
assessment were based on: sweet corn (44%) for beef, goat, horse, and sheep commodities; and the food handling establishment uses (5%) for hog and poultry meat and meat byproducts.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 38 of 98 The following average percent crop treated estimates for abamectin provided by BEAD ( J. Alsadek, No DP number, 07/01/2015 and D. Atwood, D428074, 08/27/2015 ) were used in the chronic dietary risk assessment for the following crops: almond: 70%; apple: 10%; apricot: 15%; avocado: 35%; bean, dry: 2.5%; blackberry: 56%; boysenberry: 56%; cantaloupe: 25%; celery: 45%; cherry: 5%; corn, sweet: 45%; cotton: 20%; cucumber: 5%; grape: 15%; grapefruit: 70%; hazelnut: 2.5%; honeydew: 20%; lemon: 40%; lettuce: 20%; loganberry: 56%; nectarine: 20%; onion, bulb: 2.5%; orange: 40%; peach: 10%; pear: 70%; pecan: 1%; pepper: 15%; pistachio: 2.5%; plum/prune: 10%; potato: 5%; pumpkin: 5%; raspberry: 56%; soybeans: 8%; spinach: 25%; squash: 5%; strawberry: 30%; tangerine: 35%; tomato: 10%; walnuts: 25%; and
watermelons: 5%.

The percent crop treated values that were used to refine the livestock commodities for the
chronic assessment were based on: cotton (30%), soybe an (8%), and sweet corn (38%). The PCT for poultry and hog commodities is based on the food handling establishment (FHE) PCT (%)
since the tolerances for FHE uses result in residues considerably higher than secondary residues from hogs and poultry consuming treated feed.

All commodities included for food handling residues were assigned the value of 5 P CT (D413125, J. Becker, 10/ 0 7/2014).

5.4.3 Acute Dietary Risk Assessment

The general U.S. population and the following popu lation 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, t he acute dietary exposure estimates for food and drinking water are below HED’s level of concern (<100% aPAD) at the 99.9 th 

### percentile of exposure 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 4 5 % of the aPAD for the general U.S. population and
8 8 % of the aPAD for children 1

- 2 years old, the most highly exposed population subgroup

.

Limited P esticide Data Program (P DP ) monitoring data are available and virtually all samples do
not have detectable re sidues of abamectin. Incorporating PDP monitoring data would not lower the risk estimates for abamectin because the limit of detection for PDP monitoring (0.02 ppm) tends to be higher than those used in the abamectin crop field trials (0.002 ppm or 2.0 ppb ). Additionally, there are numerous non

- detects in the crop field trials with abamectin indicating low residues in growing crops

.

5.4.4 Chronic Dietary Exposure

Table 5.4.6 shows the background dietary exposure estimates for food and drinking water. HED notes that the PODs selected for assessing acute and chronic dietary exposure are the same; because of the conservative, nature of the inputs into an acute dietary exposure assessment, usually if the PODs are the same for both acute and chronic durations, only an acute dietary exposure assessment is conducted. However, a chronic dietary exposure assessment has been

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 39 of 98 conducted for abamectin for the purposes of generating a food exposure value for the aggregate assessment and to incorporate residues/exposure from the food hand ling establishment (FHE)

uses. Residues in food resulting from food handling establishment uses are not included in acute dietary exposure assessments because of the conservative nature of the survey data used in the acute dietary exposur e assessmen ts, as per HED policy

. Acute assessments rely on individual food consumption events over two days. If the food handling establishment uses were included in the acute assessment, it would assume that a person ate all meals in a restaurant/food ha ndling establishment for two days and that all food was treated with abamectin a t the established
tolerance

- level; which is considered extremely conservative.

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.

Incorporating PDP monitoring data would not lower the risk estimates for abamectin because the limit of detection for PDP monitoring (0.02 ppm) tends to be higher than those used in the abamectin crop field trials (0.002 ppm or 2.0 ppb). Additionally, there are numerous non

- detects in the crop field trials with abamectin in dicating low residues in growing crops.

5.4 .5 Cancer Dietary Risk Assessment

Since abamectin is classified as “not likely to be carcinogenic to humans,” 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) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population 0.001135 45 0.000056 2.2

All Infants (< 1 year old) 0.001584 63 0.000096 3.9

Children 1

- 2 years old* 0.002192 88 0.000268 11

Children 3

- 5 years old 0.001553 62 0.000160 6.4

Children 6

- 12 years old 0.000729 29 0.000090 3.6

Youth 13

- 19 years old 0.000475 19 0.000045 1.8

Adults 20

- 49 years old 0.000446 18 0.000038 1.5

Adults 50

- 99 years old 0.000345 14 0.000037 1.5

Females 13

- 49 years old 0.000427 17 0.000038 1.5

* The subpopulation with the highest risk estimates is bolded.

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### Page 40 of 98 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

T here are proposed residential use sites that may lead to handler and post

- application exposure s

. Furthermore, recent revisions to the toxicity endpoints and PODs for abamectin require d a reassessment of all currently regist ered residential u ses to be consistent w ith all current policies. These revisions of residential exposures will impact the human health aggregate risk assessment.

The proposed EPs (for control of turf

- parasitic nematodes on golf course greens, tees, and
f

airways) that may lead to post

- application exposures include:
1. AgadorTM 0.17 SC (EPA Reg. No. 100

- RLNO), and
2. DivanemTM 0.15EC (EPA Reg. No. 100

- RLRN )

.

Previously

- registered end

- use products that may result in residential handler or post

- application

exposures include several formulations of homeowner bait and bait station products regist ered under multiple companies. These products include an outdoor granular bait (GB) formulation for use on fire ant mounds, and several indoor ready

- to

- use baits (RBs)

. For thi s assessment, the exposures and risk estimates for applying outdoor granular baits were assessed using the 2012
Residential SOPs 1 

### and exposure from indoor ready

- to

- use gel baits is considered negligible

. In addition, exposure data for hand dispersal of granular bait is chosen as a surrogate 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 p esticide application process. HED believes that ther e are distinct tasks related to applications and that exposures can vary depending on the specifics of each task as was described ab ove for occupational handlers. Residential handlers are addressed somewhat differently by HED

, as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure and risk assessment developed for residential handlers is based on : (1)
l oading/applying GB outdoor s via push

- type spreaders, belly grinders, spoons, hand, and cup or shaker; and ( 2 ) applying granular bait indoor s by hand (as a surrogate for a ready

- to

- use dust bait).

There are no registered products that would lead to any residential hand ler risk estim ates of

concern. Short

- term combined (dermal + inhalation) residential handler MOEs range from 860,000 to 2,700,000,000.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 41 of 98 Table 6.1. Residential Handler Non

- Cancer Exposure and Risk Estimates for Abamectin.

Exposure
Scenario 1 Dermal Unit Exposure Inhalation Unit Exposure Max App

. Rate Area Treated or
Amount Handled Daily 2 Dermal Inhalation Total

Dose 3 MOE 4 Dose 5 MOE 6 MOE 7

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 2

. 3 ×10

- 4

lb ai/A 0.5 acres 1.20×10

- 8 2

. 1 ×10 7 3.8 ×10

- 9 6

. 6 ×10 7 1

. 6 ×10 7

Belly
Grinders 360 0.039

5.31×10

-

9 lb ai/sq
ft 1

. 2 ×10 3 sq ft 2.90×10

- 7 8

. 7 ×10 5 3.1 ×10

- 9 8

. 0 ×10 7 8

. 6 ×10 5

Spoon 6.2 0.087

100 sq ft 4.10×10

-

10 6

. 1 ×10 8 5.8 ×10

- 10 4

. 3 ×10 8 2

. 5 ×10 8

Cup 0.11 0.013 7.30×10

-

12 3

. 4 ×10 11 8.6 ×10

- 11 2

. 9 ×10 9 2

. 7 ×10 9

Hand Dispersal 160 0.38 1.10×10

- 8 2

. 4 ×10 7 2.5 ×10

- 9 9

. 9 ×10 7 1

. 9 ×10 7

Shaker Can 0.11 0.013 7.30×10

-

12 3

. 4 ×10 10 8.6 ×10

- 11 2

. 9 ×10 9 2. 7 ×10 9

Mixer/Loader/Applicator for Indoor Bait Application

Bait (granular; dispersal) 160 0.38 1

. 3 ×10

- 5 lb ai/package/day 2.60 ×10

- 7 9

. 4 ×10 5 6.30 ×10

- 8 4. 0 ×10 6 7

. 6 ×10 5

1 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 dust): Package contains 100 bait placements (12 grams of product). The label recommends up to 30 bait placements in an average sized kitchen (i.e. assuming one package can be used in one day, 12 g produ ct/day × 0.05% ai/product × 0.00220462 lb ai/g ai = 0.000013 lb ai/day).
2 Exposure Science Advisory Council Policy #9.1. Based on HED’s SOPs: Lawns/Turf (January 2012).
3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A

or gallons/day) × DAF (1%) ÷ BW (80 kg).
4 Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). ST/IT Dermal NOAEL = 0.25 mg/kg/day. Level of

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

Handled (A or gallons/day) ÷ BW (80 kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST/IT Inhalation NOAEL = 0.25

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

7 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose). ST/IT Combined Dermal/Inhalation NOAEL = 0.25

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



### 6.2 Residential Post

- Application Exposure and Risk Estimates

Post

- application exposure for adults and children (1 to < 2 years old ) is unlikely for the currently registered uses of abamectin. For currently registered outdoor treatments, adults and children are not expected to dir ectly contact fire ant mounds. For currently registered indoor pest control,
b ait s are intended to be placed in cracks and crevices where direct contact by adults and children (1 to < 2 years old ) is unlikely.

However, r esidential post

- application exposure for adults and children (6 to < 11 and 11 to < 16 years old ) is possible for the newly proposed use of abamectin on golf courses

. Adults and
children ( 6 to < 11 and 11 to < 16 years old ) performing physical post

- application activities on golf course turf may receive dermal exposure to abamectin residues. The 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 post

- application

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 42 of 98 dermal MOEs calculated after applications of abamectin to golf course t urf (greens, tees, and fairways only)

. Post

- application risk estimates for all scenarios are greater than the LOC of 100
and therefore are not of concern (MOEs range from 9,000 to 12,000).

Table 6 .2. Short

- Term Residential Post

- Application Exposure and Risk Estimates for Abamectin on Turf

Lifestage Post

- Application Exposure Activity
Scenario Dose 1 MOE 2 mg/kg/day Liquid Formulation on Turf (Golf Course Greens, Tees, and Fairways) max single application rate: 0.34 lb ai/A

Adult Dermal Exposure Golfing 0.000020 12,000

Child 6 to < 11 years old Golfing 0.000028 9,000

Child 11 to < 16 years old Golfing 0.000024 11,000

1 Dermal Dose = TTR/DFR (μg/cm 2 ) × CF1 (0.001 mg/μg) × TC (cm 2 /hr) × Exposure Time (hr) ÷ 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 old. Exposure time for golfing: 4 hr. 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.
2 MOE = NOAEL ÷ Daily Dose (mg/kg/day). Dermal NOAEL= 0.25 mg/kg/day. Level of concern = 100.



### Guideline 875.2100

- Turf Transferable Residues (TTR): Since the estimated residential turf post

- application exposure for re sidential 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 chemical

specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of turf transferable pesticide
residues.

6 .3 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues
related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;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
inh alation toxicological studies) or further analysis is required for abamectin.

6 .4 Non

- Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, 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 registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices, and State Lead Agencies for pesticide regulation and

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 43 of 98 other parties to develop the best spray drift management practices ( see the A gency’s Spray Drift website for more information). 2 

### The Agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in ri sk assessments for pesticides. The potential for spray drift will be qu antitatively evaluated for each pesticide during
the Registration Review process which ensures that all uses for that pesticide wi ll be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For
Residential Risk Assessment (SOPs)

- Residential Exposure Ass essment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification
of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterizat ion

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures when considering tolerance petitions. The aggregate risk assessment must consider exposure s from oral, de rmal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated together due to their common toxicity endpoint and effects for all routes and durations of exposure.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment considers exposure estimates from dietary consumption of
abamec tin (food and drinking water). The acute aggregate food and drinking water assessment results are presented in Section 5.4 above. The most highly exposed subgro up is children 1

- 2 years old at 8 8 % of the aPAD, which is below the level of concern.

7.2 Short

- Term Aggregate Risk

The short

- term aggregate risk assessment estimates risks likely to result from exposure to abamectin residues from food, drinking water, a nd residential pesticide uses. High

- end estimates of residential exposure are used, while average values are used for food and drinking water

exposure.

For the purpose of this human health risk assessment, 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 reflect dermal exposure from golfing activities following applications to golf course turf. There is no recommended residential risk estimate for children under the age of six for use in the aggregate assessment, because residential risk estimates are expected to be negligible to infants and young children.

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

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 44 of 98 Table 7.2.1. Scenarios Recommended for Aggregate Risk Assessment of Ab amectin (Short

- Term Only)

Scenario Daily Dose 1 MOE 2 mg/kg/day LOC = 100

Adults

Post

- Application: Dermal Exposure (Liquid Application to Golf Course Turf) 0.000020 12,000

Children 6 to < 11 years old

Post

- Application: Dermal Only Exposure (Liquid Application to Golf Course Turf) 0.00002 8 9,000

Children 11 to < 16 years old

Post

- Application: Dermal Exposure (Liquid Application to Golf Course Turf) 0.00002 4 11,000

1 Daily Dose = See Table 5.2 for all adult and children golfing scenarios (dermal dose + inhalation dose).
2 MOE = NOAEL/Daily Dose (mg/kg/day). ST Dermal = NOAEL = 0.25 mg/kg/day. LOC = 100.



### Short

- t erm a ggreg ate r isk is calculated in Table 7.2.2

, below. All short

- term aggregate exposure estimates resulted in MOEs greater than 100, and were not of concern

.

Table 7.2.2 Short

- Term Aggregate Risk Calculations

Population Short

- T erm 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 0.00003 7 0.000020 0.0000 5 7 4, 4 00
Children 6 to <11 years old 0.0000 90 0.000028 0.0001 2 2

, 1 00

Children 11 to <16 years old 0. 000045 0.00002 4 0.00006 9 3

, 6 00

1 The LOC = 100 and includes the standard inter

- and intra

- species uncertainty factors (UF A and UF H , respectively)

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 considers average exposure estimates from dietary consumption of abamectin (food and drinkin g water) and residential uses. However, due to the use patterns, no chronic reside ntial exposures are expected. T herefore, the chronic aggregate risk
assessment will consider exposure from food and drinking water only.

The chronic aggregate food and drinking water assessment resu lts are presented in Section 5.4
above. The result of this assessment is 2.2% of the cPAD for the general U.S. population. The most highly exposed su bgroup is children 1

- 2 years old at 11 % of the cPAD, which is below the
level of concern.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 45 of 98 7.4 Cancer Aggregate Risk

Abamectin is classified as not likely to be carcinogenic to humans based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies.

8.0 Cumulative Exposure/Risk Characterization

Section 408 (b)(2)(D)(v) of the Federal Food, Drug, and Cosmetic Act (FFDCA) requires EPA to consider available evidence concerning the cumulative effects of pesticide residues and other substances that have a common mechanism of toxicity (i.e., a common toxic effect to human health by the same, or essentially the same, sequence of major biochemical events). EPA’s Office of Pesticide Programs (OPP) has previous ly developed guidance documents for establishing common mechanism groups (CMGs) 3 

### and conducting cumulative risk assessments (CRAs) 4 

### . OPP recently developed an additional guidance document, entitled Pesticide Cumulative Risk Assessment: Framework for Scre ening Analysis Purpose (USEPA, 2016 )

. This document builds upon those previous guidance documents in order to provide a tiered approach to screening pesticides for potential common mechanism groupings and conducting screening

level CRAs. Using the f ramework, pesticides are screened for potential cumulative evaluation using a two

- step approach: (1) evaluation and comparison of available toxicological information (e.g., chemical structures, hazard profiles); and, (2) depending upon the results of step 1, a risk

based screening approach.

Using this weight of evidence approach, t he Agency will conclude one of three options as the outcome of the CMG screening analysis: (1) no CMG and no further cumulative analysis; (2)
candidate CMG can be formed and a s creening

- level exposure analysis is conducted; or (3) CMG
can be established and a CRA is conducted.

OPP has utilized this framework for abamectin and has determined that abamectin and
emamectin fo rm a candidate CMG of the avermectin macrocyclic lactones

. A c andidate CMG ( o ption 2) share s characteristics to support a testable hypothesis for a common mechanism of
action and there is sufficient toxicological data to suggest a common pathway . However

, the re

are not adequate data to establish those key events in a pathway as described in the mode of action/adverse outcome pathway (MOA/AOP) framework ( e.g ., lack of dose or temporal concordance of proposed key events). Subsequently, the A gency has conducted a screening

- level cumulative exposure analys is consistent with the guidance described in the cumulative screening
framework. The screening

- level cumulative assessment for the avermectin macrocyclic lactones,
abamectin and emamectin

, indicates that cumulative aggregate dietary and residential exposur es for abamectin and emamectin are below the Agency’s levels of concern.

3 

### Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999)

4 

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

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### Page 46 of 98 Additional information regarding cumulative exposure and risk characterization, in general, as well as the screening assessment for the avermectin macrocyclic lactones , in particular , may be found in Appendix H.

9.0 Occupational Exposure/Risk Characterization

Occupational exposure and risk estimates have been quantified for all proposed uses in two separate assessments: The proposed uses associated with PP#s 3F8184 and 3E8175 (Caneberry subgroup 13

- 07A, corn, soybeans, and proposed golf course turf) were assessed in a memo completed on 12/18/2014 (D41 4874 , N. Keller, 12/18/2014). The proposed uses associated with PP# 4E8309 (Green onion subgroup 3

- 07B; Stone fruit group 12

- 12; Small fruit, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07f; Tree nut group 14

- 12; Fruiting vegetable group 8

- 10; Citrus fruit group 10

- 10; Low growing berry subgroup 13

- 07G; Pome fruit group 11

- 10; bean; and various tropical fruit commodities) wer e assessed in a memo completed on 2/25/2016 (D424010, L. Nollen, 2/25/2016).

9.1 Short

- /Intermediate

- Term Occupational Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believ es 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 handler can cause exposure levels to differ in a manner speci fic to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure s are expected from the proposed

uses. The quantitative exposure/risk assessment developed for occupational handlers is based on several scenarios which include mixing/loading/applying liq uid formulations of abamectin. The

use sites are summarized in Section 3.3. Methods of application include aerial, chemigation,

groun dboom, and /or handheld equipment. Flagging for aerial use is also a potential source of worker exposure. For these uses , both short

- and intermediate

- term exposur es are expected from occupational use. Since the PODs for short

- and intermediate

- term exposure are the same, the assumptions and risk calculations are protective of both durations. Refer to Table s G.1 and G.2
in Appendix G for a detailed list of each scenario.

The results of the occupational handler exposure and risk assessment associated with PP#s
3E8175 and 3F8184 indicate that short

- /intermediate

- term combined (dermal + inhalation) risk
estimates are not of concern at b aseline mitigation without personal protective equipment (PPE).

T he combined MOEs ranged from 360 to 25,000.

The results of the occupational handler assessment associated with PP# 4E8309 indicate that
short

- /intermediate

- term combined risk estimates are not of concern with a single layer of clothing, no respirator, and the PPE of gloves, which are required for all occupational users

. S hort

- / intermediate

- term combined dermal and inhalatio n MOEs ranged from 150 to 97,000.

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### Page 47 of 98 The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. 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 Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural 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 m ost recent (2012) NAAA survey. The Agency will continue to monitor all available information sour ces to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockp its. T herefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are no t required to wear protective gloves for th e duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

9.2 Short

- /Intermediate

- Term Post

- Application Exposures and Risks

9.2.1 Short

- /Intermediate

- Term Post

- Application Dermal Exposures and Risks

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 pesticide (also refe rred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as sco uting for pests or harvesting. Post

- application exposure levels vary over time an d depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application,
and the che mical’s degradation properties. In addition, the timing of pesticide applications,
relative to harvest activit ies, can greatly reduce the potential for post

- application exposure.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational post

- application exposures are expected from the proposed uses . Agricultural workers and golf course maintenance workers performing typical
post

- application activities may have dermal exposure to abamectin residues.

Quantitative occupational post

- application exposure and risk assessments indicate that s hort

- and
intermediate

- term dermal risk estimates are not of concern at baseline mitigation without PPE on Day 0 (12 hours following application) for all proposed uses. Short

- /intermediate

- term post

application dermal MOEs ranged from 3,700 to 5,400 for th e uses associated with PP#s 3E8175 and 3F8184; MOEs ranged from 240 to 67,000 for PP# 4E8309 . Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for abamectin at this time. The short

- and intermediate

- term post

application exposure scenarios associated with the newly proposed uses are summarized in
Table s G. 3 and G .4 in Appendix G

.

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### Page 48 of 98 Guideline 875.2100

- Dislodgeable Foliar Residue (DFR):
In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post

- application exposure to foliage. Chemical

specific DFR studies are currently available for abamectin. Studies have been submitted for citrus, as well as greenhouse and field

- grown ornamentals. These data are currently under review by the Agency; however, the initial review of these studi es show that the default values described above are likely to be more conservative than the values obtained from the submitted studies. Once the Agency has completed the review of each of these DFR studies, results will be
considered in future assessments of post

- application exposure in order to estimate chemical

specific post

- application exposure to foliage treated with abamectin. Therefore, EPA used the
default value of 25%.

Guideline 875.2100

- Turf Transferable Residues (TTR):
Since the estimated occu pational 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

, 7 00 compared to the LOC of 100); EPA is waiving
th e 40 CFR TTR data requirement. In this instance, it is unlikely that chemical

- specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of turf transferable pesticide residues.

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 sensitizer. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irritation are assigned a minimum of 12 hours for the REI. This is the REI listed on the prop osed labels, with the exception of activities associated with grapes (grape girdling, cane turning and tying in grapes), which have a 4

- day REI restriction. These REIs are considered protective of
post

- application exposure to abamectin.

9.2.2 Short

- /Inte rmediate

- Term Post

- Application Inhalation Exposures and Risks

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources
include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Sci entific Advisory Panel (SAP) 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 A genc y has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDe tail;D=EPA

- HQ

OPP

- 2014

- 0219 ). D uring Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for abamectin

.

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### Page 49 of 98 In addition, the Agen cy is continuing to evaluate 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

occu pational post

- applicatio n inhalation exposure into the A gency's risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occ upational/commercial
handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure t han post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be pro tective of most occupational post

- application inhalation exposure scenarios.

10.0 References (Refer to Appendix B for toxicology literature references.)

D. Atwood, 0 7/23/ 20 14, DP Nos. 420312 and 420218, Percent Crop Treated for Abamectin (122804) on IR4 Prop osed New Use on Caneberries and New Foliar Use on Soybeans
and Sweet Corn.

G. Orrick, 0 5/15/ 20 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. Alsadek, 07/01/2015, No DP Number, Updated Screening Level Usage Analysis (SLUA) Report for Abamectin, PC Code (122804)

J. Becker, 10/7/ 20 14, D P No. 413125, Upper Bound Estimate of the Likelihood of Insecticide
Residues on Food Resulting from Treatment in Food Handling Establishments.

K. Rickard, 01/30/2013, TXR0056509, Abamectin : Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 8, 2012: Recommendations on the Requirement of a Subchronic Inhalation Study and Dermal Toxicity Study.

K. Rickard, 0 4/14/2016, D P Nos. 424009 and D421348

, Abamectin: PP# 4E8309
, 3E8175, and
3F8184 Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Registration Actions for Four Separate New Use Actions and Tolerance Petitions: (1) New Uses on Bean, Papaya, Star Apple, Black Sapote, Sapodilla, Canistel , Mamey Sapote, Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Acerola, Lychee, Longan, Spanish Lime, Rambutan, Pulasan, Pineapple; Onion, Green, Subgroup 3

- 07B; Fruit, Pome, Group 11

- 10; Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13

- 07F; Berry, Low Growing, Subgroup 13

- 07G; and Conversion of Existing Crop Groups to Vegetable, Fruiting, Group 8

- 10 (and Addition of
Greenhouse

- grown Tomato); Fruit, Citrus, Group 10

- 10; Fruit, Stone, Group 12

- 12; and Nut, Tree, Group 14

- 12 . (2 ) New Uses on Caneberry Subgroup 13

- 07A. (3) Sweet Corn and Soybeans. And (4) Cattle Ear Tag on Lactating Cattle.

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### Page 50 of 98 L. Nollen, 0 2/25/2016, DP No. 424010, Abamectin. Occupational and Residential Exposure Assessment for a Proposed Use on Green Onion Subgroup 3

- 07B; Stone Fruit Group 12

- 12; Small Fruit, Vine Climbing, Except Fuzzy Kiwifruit, Subgroup 13

- 07F; Tree Nut Group 14

- 12; Fruiting Vegetable Group 8

- 10; Citrus Fruit Group 10

- 10; Low Growing Berry Subgroup 13

- 07G; Pome Fruit Group 11

- 10; Bean; and Variou s Tropical Fruit
Commodities.

N. Dodd, 12/20/ 20 12, DP No. D402677 and D405843

, Abamectin . Human Health Risk Assessment for Uses of the SC Formulation on Cotton and Strawberry.

N. Dodd, 04/12/ 20 13, DP No. D402151, Emamectin Benzoate. Human Health Risk Assessment for a Proposed Tolerance on Imported Wine Grapes.

N. Dodd, 12/23/2015, DP No. D430706, Emamectin Benzoate: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments using Updated
Percent Cro p Treated

.

N. Dodd, 03/17/2016 , DP No. D410993, Abamectin . Review of a Section 3 Registration Request for Ear Tag Use on Lactating Dairy Cattle. Summary of Analytical Chemistry
and Residue Data.

N. Dodd, 03/17/2016 , DP No. D412860, Abamectin . Petitio n for the Establishment of a Permanent Tolerance and Registration for Use on the Caneberry Subgroup 13

- 07A. Summary of Analytical Chemistry and Residue Data.

N. Dodd, 03/17/2016 , DP No. D414022, Abamectin . Petition for the Establishment of
Permanent Tol erances and Registration for Use on Sweet Corn and Soybeans. Summary of Analytical Chemistry and Residue Data.

N. Dodd, 03/17/2016 , DP No. D24008, Abamectin . Petition for the Establishment of Permanent Tolerances and Registration for New Uses on Bean, Various Tropical Fruits, Onion, Green, Subgroup 3

- 07B; Fruit, Pome, Group 11

- 10; Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13

- 07F; Berry, Low Growing, Subgroup 13

- 07G; and Conversion of Existing Crop Groups to Vegetable, Fruiting, Group 8

- 10 (and Addition of
Greenhouse

- grown Tomato); Fruit, Citrus, Group 10

- 10; Fruit, Stone, Group 12

- 12; and Nut, Tree, Group 14

- 12. Summary of Analytical Chemistry and Residue Data.

N. Keller, 12/18/ 20 14, D P No. 41 4874

, 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 Courses (Greens, Tees, and Fairways).

U. Habiba, 08/15/2014, TXR0056775, Abamectin: Immunotoxicity Study (870.7800) Waiv er Decision.

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### Page 51 of 98 USEPA, 2016, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose.

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### Page 52 of 98 A ppendix A

. Abamectin Toxicology 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.

Table A.1. Toxicology Data Requirements for Abamectin

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... 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

- Day Dermal Toxicity

................................ .......... 870.3250 90

- Day Dermal Toxicity

................................ ............... 870.3465 90

- Day Inhalation Toxicity

................................ ........... yes

yes

yes
CR

CR yes

yes
waived a

-
yes
870.3700a Prenatal Developmental Toxicity (rodent)

.................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

.............. 870.3800 Reproduction and Fertility Effects

................................ yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity/Carcinogenicity

............... 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

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other 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 Developmental Neurotoxicity

................................ ....... yes

yes

yes yes

yes

yes
870.7485 Metabolism and Pharmacokinetics

................................ 870.7600 Dermal Penetration

................................ ........................ 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 53 of 98 A.2 Data Demonstrating the Sensitivity of Beagle Dogs to the Effects of Abamectin and
Emamectin

To illustrate the order of sensitivity to the effects of abamec tin and emamectin in test animals that have fully functioning P

- gp, the results of the 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 a re qualitatively more severe 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.

Table A.2. Comparison of the resul ts 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 54 of 98 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. T oxicity Profile of Abamectin Technical 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 effec t 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 55 of 98 Table A.3.2. T oxicity Profile of Abamectin Technical 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 μg/L (0.0025 mg/L) (HDT) (≈0.68 mg/kg/day)

870.4300a
Combined Chronic toxicity/carcinogenicity

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/Carcinogenicity

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 56 of 98 Table A.3.2. T oxicity Profile of Abamectin Technical 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. N egative 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. This 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 57 of 98 Table A.3.2. T oxicity Profile of Abamectin Technical 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 administered dose was eliminated via fecal route (primarily route).

Metabolism Accession: 252114 Unacceptable/Non

Guideline 69

- 82% of label is excreted in feces by day 7; T 1⁄2 =1.2 days. The reliability of these data is questionable.

Metabolism 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.

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### Page 58 of 98 Table A.3.2. T oxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

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

870.7800

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

Table A .3. 3 Toxicity Profile of Abamectin Technical

- for CF1 Mice

Guideline No./ Study Type MRID No. / Classification /Doses Results

870.3700a
Prenatal developmental in
rodents

- CF1 mouse 44160501 (1996) Acceptable/Non

- Guideline 0, 1.5 mg/kg/day on gestation days (GD) 6

- 15 to females which were heterozygous (+/

- ) and homozygous (

- /

- , +/+) for p

- glycoprotein and then mated to heterozygous and homozygous males Maternal NOAEL = 1.5 mg/kg/day
Maternal LOAEL = not established 97% of (

- , - ) fetuses, 40% of (+,

- ) fetuses, and 0% of (+,+) fetuses had cleft palate. It was determined that the observed increase in cleft palate in CF

- 1 mice following treatment appears to be a consequence of fetal P

glycoprotein 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 mg/kg/day
Maternal LOAEL = 0.075 mg/kg/day
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 m g/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

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### Page 59 of 98 Table A .3. 3 Toxicity Profile of Abamectin Technical

- for CF1 Mice

Guideline No./ Study Type MRID No. / Classification /Doses Results

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

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

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### Page 60 of 98 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) Anticonvulsant 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

- affinity sites with dual effects on the gama

- aminobutyric acid

- gated chloride channel of cultured cerebellar granule neurons. J. Pharmacol. Exp. Ther. 281: 261

- 266.

Kerr

, DI and Ong

, J. (1986) Gama

- aminobutyric acid

- dependent mo tility induced by avermectin

B 1a 

### in the isolated intestine of the guinea pigs. Neurosci. Lett. 65: 7

- 10.

Lankas

, GR, Cartwright

, ME, and Umbenhauer

, D

. (1997) P

- Glycoprotein deficiency in a subpopulation of CF

- 1 mice enhances avermectin

- induced neurotoxicity. Toxicol. and Appl. Pharmacol. 143: 357

- 365.

Marzolini

, C

. , Paus

, E

. , Buclin

, T

. , and Kim

, RB (2004) Polymorphism In human MDR1 (P

glycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther.
75: 13

- 33.

Macdonald, N . and Gledhill, A. (2007). Potential impact of ABCB1 (p

- glycoprotein) polymorphisms on avermectin toxicity in human. Arch Toxicol (2007) 81:553

- 563.

Matsukoa, Y., Okazaki, M., Kitamura, Y., and Taniguchi, T. (1999). Developmental expression
of P

- glycoprot ein (multidrug resistance gene product) in the rat brain. Journal of Neurobiology, 39(3), 383

- 392.

Meister

, B. (2007) Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol. Behav. 92: 263

- 271.

Nguye n , L

. , Rigo

, JM, Rocher

, V

. , Belachew

, S

. , Malgrange

, B

. , Rogister

, B

. , Leprince

, P

. , and
Moonen G. (2001) Neurotransmitters as early 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 receptor

- chloride ion channel complex. J.
Neurosci. 2: 966

- 971.

Represa

, A. and Ben

- Ari

, Y. (2005) Trophic actions of GABA on neuronal development. Trends
Neurosci. 28: 278

- 283.

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### Page 61 of 98 van Kalken, CK, Giaccone, G

. , van der Valk, P., Kuiper, CM, Hadisaputro, MMN, Bosma, SAA, Scheper, RJ, Meijer, CJLM, and Pinedo, HM (1992). Multidrug resistance gene (P

glycoprotein) 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 62 of 98 Appendix C

. Abamectin Physical/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,
dimet hylacetamide, 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 OW ) 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 63 of 98 Appendix D

. Review of Human 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 other che mical. These data, which include studies
from the Pesticide Handlers Exposure Database Ve rsion 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; the Residential Standard Operating Procedures ( SOPs : Lawns/Turf ) ; and Registrant

- submitted data, MRID #44339801, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with a pplicable ethics requirements. For certain studies, the ethics review may have in cluded review by t he Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 5



### .

5 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 64 of 98 Appendix E . International Residue Limits Table for Abamectin

Table E.1. 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

- O

- demethyl
avermectin A 1a ) and less than or equal to 20% avermectin

B 1b (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- ( 1

- methylethyl ) avermectin A 1a )
and its delta

- 8,9

- isomer) Plants: sum of avermectin B1a, avermectin B1b, 8,9

- Z

- avermectin B1a and 8,9

- Z

avermectin B1b.
Animal
commodities: sum
of avermectin B1a and 8,9

- Z

avermectin B1a.

.

Animal s: sum of
avermectin B1a and 8,9

- Z

avermectin 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 Soybean, forage 0.30 Soybean, hay 1.0 Soybean, seed 0.01

V e g e t a b l e , f r u i ti n g , g r oup 8

- 10 0.07 0.01 peppers,

tomatoes 0.2 peppers chili,
dried

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 65 of 98 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 quant itation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have no t been finalized by the CCPR and the CAC.

4 The MRL accommodates external animal treatment. 0.02 Peppers, sweet (including pimento or pimiento), tomato

F r u i t

, c i t r u s , g r oup 10

- 10 0.02 0.02 0.01 (*)

F r u i t

, s m a ll

, v i n e c li m b i n g , exce p t f u z zy k i w ifr u i t

, s u bg r oup 13

- 07F 0.02 0.02 grapes

Berry, low growing, subgroup 13

- 07G 0.05 0.02 strawberries 0.02 strawberry

F r u i t

, s t one, g r oup 12

- 12 0.09

F r u i t , po m e, g r oup 11

- 10 0.02 0.02 apples, pears 0.02 apple, pear

N u t

, t r ee, g r o u p 14

- 12 0.01 0.005 almond nuts, black walnuts, English
walnuts 0.01 (*) almonds,
walnuts

Papa y a 0.40

S t ar ap p l e 0.40

B l ack sap o t e 0.40 Sapod i l l a 0.40

C an i s t el 0.40

Ma m ey sapo t e 0.40

G ua va 0.015

Fe i j oa 0.015

J abo t i c aba 0.015

Wax j a m bu 0.015

S t a r fr u i t 0.015

Pa s s i on f r u i t 0.015

A ce r o l a 0.015

L y chee 0.01

L on g an 0.01 Span i s h l i m e 0.01

R a m bu t an 0.01

Pu l a s an 0.01

P i nea p p l e 0.015

B ean 0.015

O n i on, g r een, s ub g r oup 3

- 0 7B 0.08 Completed: M. Negussie; 11/01/ 1 2, 9/19/13 , and 10/302015

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### Page 66 of 98 Appendix F. Abamectin Field Trial Tables

Table F.1. Summary of Residue Data from Soybean and Sweet Corn (PP# 3F8184) and Caneberry (PP# 3E8175) Field Trials wit h Abamectin Commodity Total Applic.

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

n 2 Sample
Min. Sample

Max. LAFT 3 HAFT 3 Median Mean Std.
Dev.

CANEBERR Y Proposed Use = 0.056 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 = 0.038 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 averages; 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 appl icable.

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

Table F.2. Summary of Residue Data from Greenhouse Tomato, Green Onion, Guava, Lima Bean, Lychee, Papaya, Pineapple, and Snap Bean (PP# 4E8309) Trials with Abamectin

Commodity Total Application

Rate (lbs ai/A) PHI (days) n 1 Abamectin Residues 2 (ppm)

Min. 3 Max. 3 LAFT 4 HAFT 4 Median 4 Mean 4 SD 4

GREENHOUSE

- GROWN TOMATO Proposed Use = 0.056 lb ai/acre total application rate, 1

- day PHI Agri

- Mek SC

Tomato fruit 0.0597

- 0.0625 1 4 0.00663 0.02706 0.00684 0.02476 0.01540 0.01560 0.007

3 4 0.00562 0.01971 0.00621 0.01699 0.01306 0.01233 0.004 Agri

- Mek 0.15EC

Tomato fruit 0.0593

- 0.0626 1 4 0.00519 0.04491 0.00587 0.04120 0.01285 0.01819 0.014

3 4 0.00566 0.03372 0.00573 0.03248 0.01088 0.01499 0.010 GREEN ONION Proposed Use = 0.076 lb ai/acre total application rate, 7

- day PHI

Green onion 0.079

– 0.082 6

- 8 5 <0.004 <0.0048 <0.004 <0.0046 <0.004 <0.004 0.00025

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### Page 67 of 98 GUAVA Proposed Use = 0.070 lb ai/acre total application rate, 7

- day PHI

Guava 0.073

- 0.074 8 3 <0.004 <0.0059 <0.004 <0.0050 0.0040 0.0043 0.0005 LIMA BEAN Proposed Use = 0.056 lb ai/acre total application rate, 7

- day PHI

Lima bean 0.0551

- 0.0566 6 6

- 8 7 <0.004 <0.004 <0.004 <0.004 0.004 0.004 N/A 5 LYCHEE Proposed Use = 0.046 lb ai/acre total application rate, 14

- day PHI
Lychee 0.048

- 0.050 8

- 13 3 <0.002 0.0034 <0.002 <0.0027 0.0024 0.0024 0.0004 PAPAYA Proposed Use = 0.070 lb ai/acre total application rate, 3

- day PHI
Papaya 0.074

- 0.082 3

- 5 3 < 0.0047 0.164 <0.005
1 0.131 0.123 0.0863 0.0705

PINEAPPLE Proposed Use = 0.047 lb ai/acre total application rate, 16

- week PHI
Pineapple 0.0465

- 0.0475 78

- 112 8 <0.004 <0.004 <0.004 <0.004 0.004 0.004 N/A 5

0.231

- 0.238 98

- 108 3 <0.004 <0.004 <0.004 <0.004 0.004 0.004 N/A 5 SNAP BEAN Proposed Use = 0.056 lb ai/acre total application rate, 7

- day PHI
Snap bean 0.0378

- 0.0944 7 5

- 7 7 <0.004 <0.004 <0.004 <0.004 0.004 0.004 N/A 5

1 n = number of trials.

2 Combined residues of abamectin:
Greenhouse

- grown tomato, green onion, guava, and pineapple: Combined residues of avermectin B 1a /8,9

- Z avermectin B 1a and
avermectin B 1b Papaya, lima bean and snap bean: Combined residues of avermectin B 1a /8,9

- Z avermectin B 1a , and avermectin B 1b /8,9

- Z
avermectin B 1b

. Lychee: Combined residues of avermectin B 1a /8,9

- Z avermectin B 1a . The B 1b residue component was not monitored in this study.

3 Values based on total number of samples.

4 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest averag e field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ (0.002 ppm for greenhouse

- grown tomatoes and lychee; 0.004 ppm for green onion, guava, lima bean, pa paya, pineapple, and snap bean).

5 N/A = not applicable.

6 The lima bean trials included one SC trial at 0.0751 lb ai/A.

7 The snap bean trials targeted three applications, but the data reflect two to five applications; the number of applications depended on the rate of crop maturation.

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### Page 68 of 98 Appendix G. Abamectin Occupational Exposure Tables

Table G.1. Occupational Handler Exposure and Risk Estimates for Proposed Abamectin Uses Associated
with PP#s 3E8175 and 3F8184

Exposure
Scenario Crop
/ Target 1 Unit Exposure 2 Max App

Rate 3 Area
Treated /
Am ount Handled

Daily 4 Dose 5 MOE 6

Dermal Inhalation Dermal Inhalation Dermal Inhalation Total

μg/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 Crops High

Acreage

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 Crops High

Acreage

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

High

Acreage

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 Crops High

Acreage

Field Crops 1200 0.0000143 0.0000194 17,000 13,000 7,400

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### Page 69 of 98 Table G.1. Occupational Handler Exposure and Risk Estimates for Proposed Abamectin Uses Associated
with PP#s 3E8175 and 3F8184

Exposure
Scenario Crop
/ Target 1 Unit Exposure 2 Max App
Rate 3 Area
Treated /
Am ount Handled

Daily 4 Dose 5 MOE 6

Dermal Inhalation Dermal Inhalation Dermal Inhalation Total

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

High

Acreage

Field Crops 200 0.0000374 0.0000161 16,000 6,700 4,700

Flagger

Flagging for
Aerial Application Orchard

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

Field Crops High

Acreage

Field Crops Mixer/Loader/Applicator

M/L/A Liquids
for Mechanically

Pressurized

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

1 “Orchard” includes caneberries (crop subgroup 13

- 07A).

“Typical Field Crops” include sweet corn. “High

- Acreage Field Crops” include corn and soybeans.
2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Baseline

except for aerial applicator which includes engineering controls.
3 Based on the maximum application rates on the proposed labels (Reg. Nos. 100

- 898,

- 1154,

- 1350,

- 1351,

- 140 8,

- 1439, RLNO, and

- RLRN).
4 Exposure Science Advisory Council Policy #9.1.
5 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or

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

6 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (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 Co mbined Dermal/Inhalation NOAEL = 0.25 mg/kg/day.

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### Page 70 of 98 Table G.2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Abamectin Associated with
PP# 4E8309

Exposure
Scenario Crop or Target 1 LOC Unit Exposure 2

Max App.

Rate 3 Area
Treated
Amount
Handled

Daily 4 Dermal Inhalation

Total
MOE 6 Dermal Inhalation Dose (mg/kg/ day) 5 MOE 6 Dose (mg/kg/

day) 5 MOE 6

(μg/lb ai)

Mixer/Loader

Mixing Loading Liquids for

Aerial Application Orchard/

V ineyard

100 37.6 0.219 0.023 350 0.000038 6600 0.000022 11,000 4100

Field

crop, typical 0.023 350 0.000038 6600 0.000022 11,000 4100

Field

crop, high

acreage 0.019 1200 0.00011 2300 0.000062 4,000 1500

Mixing Loading Liquids for

Airblast Application Orchard/

V ineyard 0.023 40 0.0000043 58,000 0.0000025 100,000 37,000

Mixing Loading Liquids for
Groundboom Application Orchard/ Vineyard 0.023 40 0.0000043 58,000 0.0000025 100,000 37,000

Field

crop, typical 0.023 80 0.0000087 29,000 0.0000050 50,000 18,000

Field

crop, high

acreage 0.019 200 0.000018 14,000 0.000010 24,000 8800

Applicator

Applying Sprays for

Aerial Application Orchard/ Vineyard

100 2.08

0.0049 0.023 350 0.0000021 120,000 0.00000049 510,000 97,000

Field

crop, typical

Field

crop, high

acreage 0.19 0.019 1200 0.0000059 42,000 0.0000014 180,000 34,000

Applying Sprays for

Airblast Application Orchard/ Vineyard 1590 4.71 0.023 40 0.00018 1400 0.000054 4,600 1100

Applying Sprays for
Groundboom Orchard/ Vineyard 16.1 0.34 0.023 40 0.0000019 140,000 0.0000039 64,000 44,000

Field 0.023 80 0.0000037 68,000 0.0000078 32,000 22,000

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### Page 71 of 98 Table G.2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Abamectin Associated with
PP# 4E8309

Exposure
Scenario Crop or Target 1 LOC Unit Exposure 2

Max App.

Rate 3 Area
Treated
Amount
Handled

Daily 4 Dermal Inhalation

Total
MOE 6 Dermal Inhalation Dose (mg/kg/ day) 5 MOE 6 Dose (mg/kg/

day) 5 MOE 6

(μg/lb ai)

Application crop, typical

Field

crop, high

acreage 0.019 200 0.0000077 33,000 0.000016 16,000 11,000

Flagger

Flagging for
Aerial Application Orchard/ Vineyard

100 11 0.35 0.023

350 0.000012 21,000 0.000035 7100 5300

Field

crop, typical 0.023 0.000012 21,000 0.000035 7100 5300

Field

crop, high

acreage 0.019 0.000010 25,000 0.000029 8600 6400

Mixer/Loader/Applicator
M/L/A Liquids
for Mechanically

Pressurized

Handgun Sprayers Orchard/ Vineyard

100 2050 8.68 0.0046 1000 gal 0.0012 210 0.00050 500 150

Field

crop, typical

M/L/A Liquids for Backpack

Sprayers Orchard/ Vineyard 8260 2.58 0.0046 40 gal 0.00019 1300 0.0000059 4200 2400

a Orchard/Vineyard = Citrus Group 10

- 10, Pome Fruit Group 11

- 10, Stone Fruit Group 12

- 12, Tree Nuts Group 14

- 12, Guava,

Feijoa, Jaboticaba, Wax jambu, Starfruit, Passionfruit, Acerola, Lychee, Longan, Spanish lime, Rambutan, Pulasan, Papaya, Star apple, Black sapote, Sapodilla, Canistel, Mamey sapote (Small Fruit, Vine

- Climbing Subgroup 13

- 07F maximum application rate is lower, at 0.019 lb ai/A); Field crop, typical = Fruiting Vegetable Group 8

- 10, Greenhouse tomato, Low Growing Berry Subgr oup 13

- 07G, Green Onion Subgroup 3

- 07B, Pineapple; Field crop, high

- acreage = Beans
b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of

mitigation = Single layer of clothing + gloves and no r espirator, except for aerial applicator, which includes engineering
controls

c Based on the maximum application rates on the proposed labels (Reg. Nos. 100

- 1351,

- 1408,

- 1154,

- 1439).
d Exposure Science Advisory Council Policy #9.1. Units in acres, unless otherwise noted.

e Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × 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 Exposur e (μg/lb ai) × Conversion Factor (0.001 mg/μg) × 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 Dose (mg/kg/day). ST/IT Dermal NOAEL = 0.25 mg/kg/da y.

Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST/IT Inhalation NOAEL = 0.25 mg/kg/day.

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### Page 72 of 98 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose). ST/IT Combined Dermal/Inhalation NOAEL = 0.25 mg/kg/day.

Table G. 3

. Short

- Term Post

- Application Exposures and Risk Estimates for Abamectin Associated with
PP#s 3E8175 and 3F8184

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 rate 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 Dermal 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.

Table G.4. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Abamectin,
Associated with PP# 4E83 09

Crop/Site a Policy Crop Group Category Activities Transfer
Coefficient

(cm 2 /hr) DFR/

TTR b Dermal Dose (mg/kg/day) c MOE d

Short

- /Intermediate

- term e

Almond, Hazelnut, Tree, “nut” Mechanical harvesting (shaking) 190

0.06 0.000012 20,000
Scouting, Hand pruning 580 0.000037 6,700
Transplanting 230 0.000015 17,000

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### Page 73 of 98 Table G.4. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Abamectin,
Associated with PP# 4E83 09

Crop/Site a Policy Crop Group Category Activities Transfer
Coefficient

(cm 2 /hr) DFR/

TTR b Dermal Dose (mg/kg/day) c MOE d

Short

- /Intermediate

- term e

Macadamia

nut, Pecan, Pistachio, English Walnut Orchard maintenance, Poling, Hand weeding 100 0.0000065 39,000

Apple,

Pear Tree, "fruit",
deciduous Hand harvesting 1,400

0.06 0.000090 2,800

Propping, Orchard maintenance, Hand weeding, Propping 100 0.0000065 39,000

Pruning, Hand; Training; Scouting; Hand pruning 580 0.000037 6,700

Thinning Fruit 3,600 0.00023 1,100

Transplanting 230 0.000015 17,000

Apricot Cherry
Nectarine

Peach Tree, "fruit",
deciduous Scouting 580

0.06 0.000037 6,700 Orchard maintenance, Propping,

Bird control, Hand weeding 100 0.0000065 39,000

Thinning Fruit 3,600 0.00023 1,100 Hand harvesting 1,400 0.000090 2,800 Hand pruning, Training 580 0.000037 6,700 Transplanting 230 0.000015 17,000 Bean, dry; Pea, dry Chickpea Bean, snap Field / row crop, low /

medium Irrigation (hand set) 1,900

0.05 0.00010 2,500 Hand weeding 70 0.0000037 67,000

Scouting 1,100 0.000059 4,300

Blueberry,

lowbush Berry, low Hand harvesting; Scouting 1,100

0.05 0.000059 4,300 Hand weeding 70 0.0000037 67,000
Irrigation (hand set) 1,900 0.00010 2,500

Transplanting 230 0.000012 20,000

Pepper, bell Pepper, chili

Eggplant,

Tomato Vegetable, fruiting Hand harvesting, Tying/Training 1,100

0.05 0.000059 4,300 Hand pruning, Hand weeding; Thinning fruit 90 0.0000048 52,000

Irrigation (hand set) 1,900 0.00010 2,500 Scouting 210 0.000011 22,000 Transplanting 230 0.000012 20,000

Grape, table Grape, wine Grape juice Vine / trellis Girdling, Turning 19,300 0.05 0.0010 240

Scouting, Propagating, Hand pruning, Hand weeding, Bird control, Trellis repair 640

0.05 0.000034 7,300

Tying/Training , Hand harvesting, Leaf pulling, 10,100 0.00054 460

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### Page 74 of 98 Table G.4. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Abamectin,
Associated with PP# 4E83 09

Crop/Site a Policy Crop Group Category Activities Transfer
Coefficient

(cm 2 /hr) DFR/

TTR b Dermal Dose (mg/kg/day) c MOE d

Short

- /Intermediate

- term e
Transplanting 230 0.000012 20,000 Irrigation (hand set) 1,900 0.00010 2,500

Grapefruit

Lemon Orange Tree, "fruit",

evergreen Orchard maintenance, Hand weeding, Baiting/Trapping 100

0.06 0.0000065 39,000

Scouting, Hand pruning 580 0.000037 6,700 Transplanting 230 0.000015 17,000
Hand harvesting 1,400 0.000090 2,800

Greenhouse

vegetable (tomato) Unassigned Hand harvesting, Pinching, Pollination, Hand pruning, Scouting, Turning, Tying/Training, Hand weeding, Propagating 1,200

0.03 0.000032 7,800

Transplanting, Irrigation (hand watering) 230 0.0000061 41,000

Onion, green Vegetable,
"root" Hand harvesting, Scouting 1,400

0.05 0.000075 3,400 Irrigation (hand set) 1,900 0.00010 2,500

Thinning plants 330 0.000018 14,000
Hand weeding 4,200 0.00022 1,100

Pineapple Vegetable,
stem / stalk Hand harvesting 1,100

0.06 0.000071 3,500 Scouting 210 0.000014 18,000 Hand weeding 70 0.0000045 55,000

Strawberry Berry, low Harvesting, Hand 1,100

0.05 0.000059 4,300 Transplanting 230 0.000012 20,000 Scouting 210 0.000011 22,000 Hand weeding, Canopy management 70 0.0000037 67,000

a Crop/Site = Proposed crops or representative crops within proposed crop groups or subgroups.
b DFR = Application Rate (varies) × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day

TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.1 and D = 0.10 per day.

c Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (1%)] ÷ BW (80

kg).
d MOE = POD (mg/kg/day) / Daily Dermal Dose.

The MOEs presented for each exposure activity scenario for crop groups represent the lowest available calculated MOEs for any commodity within a crop group for any given scenario.

e Short

- and Intermediate

- term Post

- Application exposures are considered eq uivalent, because the PODs are equal.

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### Page 75 of 98 A ppendix H

. Avermectin Macrocyclic L actones Cumulative Screening Assessment

H.1.0 Executive Summary

Using the cumulative screening framework outlined in the Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose (USEPA, 2016 ) for candidate common mechanism groups ( CMGs ) , the Agency has conducted a screening

- level cumulative exposure analysis for the avermectin macrocyclic lactones, whi ch contain the insecticides abamectin and emamectin. This screening

- level assessment adds exposures of abamectin and emamectin and is designed to be an overestimate of exposure and risk ( i.e. , this screen assumes co

- occurrence of
residues in water and some crops from both abamectin and emamectin).

Abamectin and emamectin are registered for use on a variety of food and feed crops and have
tolerances established for use on: cotton, tree nuts, apples, pears, fruiting vegetables, cucurbits, and leafy vegetables, except Brassicas. Tolerances have been established for both chemicals in livestock commodities and grapes, although the tolerance for emamectin applies to i mported wine grapes. Abamectin is also registered for use in food handling establishments (FHE) ; an all

foods tolerance has been established to support that use pattern. The all

- foods FHE tolerance is
lower than tolerances that have been established based on agricultural uses, so the FHE uses are expected to be minor contributors to the overall exposure to abamectin residues. Finally

,
a bamectin is registered for use in or on fire ant mounds and other indoor sites that could result in
residential handler exp osure and is proposed for use on turf that could result in post

- application residential exposure . T here are currently no registered residential uses of emamectin.

Based on the use patterns for abamectin and emamectin, the potential routes and durations o f exposure for consideration in the screening

- level cumulative analysis include acute dietary

exposure as well as short

- term dietary and residential exposure

.

The screening

- level cumulative assessment for the avermectin macrocyclic lactones, abamectin
and emamectin, indicates that combined aggregate dietary and residential risk estimates are below the Agency’s levels of concern. Given the conservatisms underlying the cumulative assessment ( i.e. , point

- estimate aggregate methodology combined with high

- end dietary and residential exposures while assuming complete co

- exposure for all available exposure scenarios without any related co

- exposure refinements), EPA expects that the screening

- level residues
overestimate actual cumulative residues ; therefore , no ad ditional data are required at this time.

H

. 2 .0 Introduction

Section 408 (b)(2)(D)(v) of the Federal Food, Drug, and Cosmetic Act (FFDCA) requires EPA to consider available evidence concerning the cumulative effects of pesticide residues and other
substa nces that have a common mechanism of toxicity . EPA has developed guidance that defines a common mechanism of toxicity as a common toxic effect to human health by the same, or essentially the same, sequence of major biochemical events. To facilitate complia nce with this provision, EPA’s Office of Pesticide Programs (OPP) has previously developed guidance

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### Page 76 of 98 documents in 1999 for establishing common mechanism groups (CMGs) 6 

### and in 2002 for conducting cumulative risk assessments (CRAs) 7



### . OPP recently developed an additional guidance document, entitled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose (USEPA, 2016 )

. This document builds upon those previous guidance
documents by provid ing a framework for screening pesticides for potential common mechanism groupings

, called candidate CMGs, and conducting screening

- level CRAs.

Using the f ramework, pesticides are screened for potential cumulative evaluation using a two

step approach

. First, OPP evaluat es and compar es available toxi cological information (e.g., chemical structures, hazard profiles) to determine if a candidate CMG can be formed. The Agency will use a weight of evidence approach to evaluate this information and reach one of
three conclusions:

(1) the data do not support establishing a CMG, and no further cumulative analysis is required ; (2) the data support forming a c andidate CMG

, and the Agency will conduct a screening

level exposure analysis consistent with the Framework; or (3) the data support establishing a CMG consistent with the 1999 CMG guidance, and the Agency will conduct a CRA consistent with the 2002 CRA guidance.

OPP has utilized this framework for abamectin and has determined that abamectin and
emamectin form a c andidate CMG (option 2)

. These pesticides form a candidate CMG because they shares characteristics to support a testable hypothesis for a common mechanism of action
and there are sufficient toxicological data to suggest a common pathway. However, the Agen cy does not have adequate data to establish a CMG consistent with the 1999 CMG guidance document. Adequate data are lacking to determine those key events in a pathway as described in the mode of action/adverse outcome pathway (MOA/AOP) framework ( e.g ., lac k of dose or temporal concordance of proposed key events). Further information regarding the common toxicological profile and testable hypothesis identified for abamectin and emamectin may be
found in Section H. 3 .0.

H

. 3 .0 Toxicological Considerations in D etermining a Candidate CMG

Consistent with the Agency’s mixture risk assessment guidance (USEPA 1986; USEPA, 2000), OPP assumes dose additivity in CRA unless data are available to support an alternative approach. Then

, OPP will evaluate the toxicological database for dose response data to identify an index chemical and to develop screening

- level relative potency factors (RPFs) and PODs for purposes of screening exposure analysis. The data and mathematical approach used in the derivation of the screening RP Fs and PODs should be described, including characterization of their refinement (or lack thereof). Screening

- level RPFs and PODs should, to the extent possible, be related to hypothesized MOA/AOP and the common toxic ef fect for the class. However, in

6 

### Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999)

7 

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

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 77 of 98 some analyses, the same POD values may be used for each chemical in the CMG and no RPF would be developed.

H. 3 .1 Chemical Structural Similarity

Similarities in chemical structure may translate to shared toxicophore ( i.e., a feature or group within a chemical structure that is associated with toxic properties) and ultimately to a common mechanism of toxicity. When evaluated in combination with other toxicological considerations, a shared chemical structure may support the f inding of a CMG or candidate CMG.

Emamectin is a derivative of abamectin

, and the two compounds are structurally and toxicologically related. The only structural difference between abamectin and emamectin a hydroxyl moiety at the 4” position of the tetrah ydropyran ring of abamectin; for emamectin, the hydroxyl group is replaced by a methylamine . These differences are shown within the circled groups in the following figures.

Abamectin Emamectin

H. 3 .2 Hazard Profile Comparison for Candidate CMG

Abamectin and emamectin share a common toxicological profile as summarized below:

• Both abamectin and emamectin share a common toxicity profile consistent with GABA receptor interaction (Appendi c es A and I).

• Both pesticides elicit similar clinical signs o f 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 comm on clinical signs indicative of neurotoxicity demonstrated a similar dose

- response relationship for the two chemicals, occurred at similar LOAEL s and yield a common NOAEL (0.25 mg/kg/day) for establishing the POD for risk assessment. .

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

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### Page 78 of 98 H. 3

. 3 Toxicological E valuation to determine a CMG for Abamectin and Emamectin

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) describes the weight of the evidence approach for determining whether or not a group of pesticides share a common mechanism of to xicity. This guidance defines mechanism of toxicity as the major steps leadin g to a toxic effect following interaction of a pest icide with biological 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 requi red in order to des cribe a mechanism of toxicity. For example, a mechanism of toxicity may be descr ibed 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 le ads to the molecular response and causes a number of intervening biological and morphological steps
tha t result in an adverse effect. In this context a common mechanism of toxicity pertains to two or more pesticide chemicals or other substances that cause a common toxic effect to human health by the same, or essentially the same, sequenc e of major biochemical events. Hence, the underlying basis of the toxicity is the same, or essentiall y the same, for each chemical.

In the case of the macrocyclic lactones of the avermectin class ( i.e.

. , abamectin and emamectin),
there is a wealth of data on the insecticidal mechanism of action for avermectin: its insecticidal actions are mediated by interaction with the glutamate

- gated chloride channels and GABA A 

### gated chlo ride channels. This is presumed to be the insecticidal mechanism of action of

em amectin 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 data regarding the resultant alterations in cellular excitability of mammalian neurons and neural networks (i.e., changes in cellular excitability and altered network function as documented with pyrethroids), as well as in vivo measurements of altered excitability ass ociated 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 support ing these actions are lack ing. In addition, specific data demonstrating
GABA A 

### receptor interaction in mammalian preparations are lackin g for abamectin and
emamectin. Moreover, the specificity of such interaction on the adverse outcome would ne ed to be shown experimentally. GABA A 

### receptors have multiple binding sites which have been proposed to relate to adverse outcomes. For example, Dawson et al (2000) showed for a group of
avermectin

- like compounds that rank order for anticonvulsant activity did not parallel the rank
order for affini ty at the [3H]ivermectin site. The 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).

A lthough GABA A 

### receptor mediated neurotoxicity is a strong hypothesis as a common mechanism endpoint for the macrocyclic lactone pesticides, data demonstrating the interactions
of ema mectin and abamectin with mammalian GABA A 

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

### receptor function to disruptions in neuronal excitability in vitro and in vivo , and ultimately adverse outcome, are also currently
lacki ng for this class of compounds. In the absence of such data, the key biological steps leading

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 79 of 98 to the adverse outcome ( i.e., the mammalian mechanism of action) cannot be established and by extension a common mechanism group cannot be establis hed.

The A gency 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 for a common mechanism of action , and that there is sufficient toxicological data to suggest a common pathway . However, there are no t currently adequate data for establishing key events in a pathway as described in the MOA/AOP framework 8

, 9

, 10

, 11



### .

H

. 4 .0 Dose Response Assessment

An important component in cumulative hazard assessment is the derivation of a uniform measure of dose response that accurately represents all members of a CMG. For example, toxicity values may be derived from the PODs from single chemical risk assessments, from NOAELs or
LOAELs fr om specific toxicology studies or possibly benchmark doses (BMDs). In some analyses, the same value may be used for each chemical in the candidate group.

H

. 4 .1 Selection of Points of Departure for Screening Cumulative Assessment

T he Agency has re

- evaluat ed the toxicity databases for abamectin and emamectin, as well as the
available literature information on a polymorphism in the human gene encoding the P glycoprotein ( P

- gp )

. Because of species and life stage differences in the expression of P

- gp, t oxic
effects of macrocyclic lactones observed in the CF

- 1 mouse and the juvenile rat are not considered representative of abamectin and emamectin effects in human s and will not be considered for toxicity endpoints and points of departure selections. The CF

- 1 mouse and rats younger than 28 days have diminished P

- gp function compared to other mammals (including humans)

.

T he Agency considered results from abamectin and emamectin toxicological studies conducted in the species that do not have diminished P

- gp function (adult rats, CD

- 1 mice, rabbits and dogs) for selecting PODs for risk assessment

. Based on that assessment, the dog was determined

to be the most appropriate species to assess the ri sk of abamectin and emamectin. The
cumulative screen relies on toxicity studies conducted in the dog, with neurotoxic effects for
both abamectin and emamectin. The PODs used in the screen are also those used for single chemical assessment of the individual chemicals and represent the most sensitive points of departur e that are relevant to humans. The POD used for both chemicals is the NOAEL of 0.25

8 

### USEPA ( 2005 ), Guidelines for Carcinogen Risk Assessment , Risk Assessment Forum, Washington, DC; EPA/630/P

- 03/001F. Federal Register 70(66):17765

- 17817;
htt p://www.epa.gov/raf.

9 

### 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.

10 

### Seed , J. et al

. (2 005 ), Overview: Using Mode of Action and Life Stage Information to Evalua te the Human Relevance of Animal Toxicity Data , Crit Rev Toxicol 35(8

- 9): 664

- 672.

11 

### Sonich

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

- 152.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 80 of 98 mg/kg/day; the adverse effects noted a t the LOAEL consist of mydriasis , tremors, and neuropathology. Mydriasis and tremors are produced by both chemicals at similar dose lev els

, while neuropat hology is seen with emamectin. The POD selected from the dog studies are based on clear NOAELs and are protective of all the adverse effects seen in the studies conducted in human relevant studies with rats, CD

- 1 mice, and rabbits. There fore, the uncertainty factor of 100x (10x for interspecies extrapolation and 10x for intraspecies variation ) was applied for both
chemicals.

The f ramework describes the use of Relative Potency Factors (RPFs) for higher tier screening
assessments. As noted above, t he toxicity endpoints and PODs for the relevant exposure
scenarios are the same

, so RPF s are not needed for purposes of screening analysis

. For dermal
exposure assessment s , the dermal absorption for bo th abamectin and emamectin is quite similar with rather low dermal absorption factors, 1% for abamectin and 1.8% f or emamectin

.

The toxicity endpoints and PODs of the two c hemicals are compared in Table H

. 4 .1 below. The Toxicology profile t ables and sum maries of toxicity endpoints and points of departure for human health risk assessment are presented in Appendix A (abamectin) and Appendix I (emamectin).

Table H

. 4 .1 . Comparison of Toxicological Doses and Endpoints for Abamectin and Emamectin for Use in Dietary and Non

- Occupational Human 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
Emamecti n 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

Subchronic LOAEL=0.5 mg/kg/day
based on mydriasis during week one, death at 1.0 mg/kg/day.

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 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

- and
Intermediate

Term NOAEL=
0.25 mg/kg/day UF A = 10x

UF H = 10x Residential
LOC for MOE
= 100

Dermal
Short

- and
Intermediate

Term NOAEL=
0.25 mg/kg/day UF A = 10x
UF H = 10x Residential
LOC for MOE
= 100

Inhalation
Short

- and
Intermediate

Term NOAEL=
0.25 mg/kg/day UF A = 10x
UF H = 10x Residential
LOC for MOE
= 100

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### Page 81 of 98 Table H

. 4 .1 . Comparison of Toxicological Doses and Endpoints for Abamectin and Emamectin for Use in Dietary and Non

- Occupational Human 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
Emamecti n 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 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 o bserved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (int e r s pecies). UF H = potential variation in sensitivity among members of the human population (int ra 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.



### H

. 4 .2 FQPA Safety Factor for Protection of Infants and Children

For both abamectin and emamectin, t he toxicity endpoint and POD for all exposure scenarios

was selected from the subchronic and chronic oral toxicity studies in the dogs, whose sensitivity
to the effects of the abamectin is second only to CF

- 1 mice

. The Ag ency does not consider these
more sensitive effects to be representative of abamectin and emamectin effects in humans
because the diminished P

- gp function seen in CF

- 1 mice is not seen in humans

. The POD selected from the dog studies is based on clear NOAE Ls , which are protective of all the adverse
effects seen in the human relevant studies conducted with rats , DC

- 1 mice, and rabbits. Therefore, the FQPA safety factor has been reduced to 1x. The FQPA safety factors for the
cumulative screen ing

- level assessment are the same as the single chemical assessment; further details on all of these considerations may be found in the single chemical discussions.

H

. 4 .3 Incorporation of Uncertainty Factors/Extrapolation Factors and the Level of
Concern MOE.

The level of concern MOE is 100 for the screening

- level cumulative analysis , as described in

s ection H.4.1.

H

. 5 .0 Dietary Cumulative Exposure and Risk Assessment/Characterization

The cumulative screening framework outlined in the Pesticide Cumulative Risk Assessment: Framework for Screening Analysis Purpose (USEPA, 2016 ) presents a tiered approach for the cumulative screening

- level dietary exposure analysis. F our tiers

, with increasing refinements at each tier, allow reviewers to systematically analyze dietary data for the candidate CMG beginning at the first tier ( i.e. , combined food + water exposures from each member in a candidate CMG are extracted and summed and then compared to the POD of the most potent member of the candidat e CMG) and continue until reaching the tier of refinements where the dietary risk does not exceed the level of concern.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 82 of 98 H

. 5 .1 Food Exposure Pathway

EPA conducted a screening

- level cumulative exposure analysis for the avermectin macrocyclic lactones, which contain the insecticides abamectin and emamectin. Humans may be exposed to
abamectin and emamectin residues in food since these two chemicals may be applied directly to growing crops

.

Abamectin : Abamectin is an 80/2 0 mixture of avermectin B 1a 

### /avermectin B 1b 

### that may be applied on various raw agricultural commodities

. 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. Tol erances for abamectin have been established or are being recommended as a part of this action in 40 CFR §180.449 , as presented in Table H. 5 .1, below.

Emamectin : Emamectin is a 90/10 mixture of emamectin B 1a 

### /emamectin B 1b 

### that m ay be applied
on various raw agricultural commodities . For crops, compliance with the tolerance 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.
Tolerances for emamectin have been established in 40 CFR §180.505 , as presented in Table

H

. 5

. 1

, below.

Table H

. 5

. 1. Abam ectin and Emamectin Established and Recommended Toleranc es Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm)

Acerola 0.015 Almond, hulls 0.10 0.20 Apple 0.020 2

--- Apple, wet pomace 0.10 0.075
Avocado 0.020

--- Bean 0.015 Bean, dry, seed 2 0.01

--- Berry, low growing, subgroup 13

- 07G 0.05

Black sapote 0.40 Caneberry subgroup 13

- 07A 0.20

--- Canistel 0.40 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

--- Citrus 0.02 2

--- Corn, sweet, forage 0.20 Corn, sweet, kernel plus cob with
husk removed 0.01

---

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### Page 83 of 98 Table H

. 5

. 1. Abam ectin and Emamectin Established and Recommended Toleranc es Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm) Corn, sweet, stover 0.50 Cotton, gin byproducts 1.0 0.050 Cotton, undelinted seed 3 0.02 0.025 Feijoa 0.015 Food products in Food Handling
Establishments 0.01

---

Fruit, citrus, group 10

- 10 0.02 Fruit, pome, group 11

--- 0.025 Fruit, pome, group 11

- 10 0.02 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 0.02

Fruit, stone, group 12 0.09 2 Fruit, stone, group 12

- 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 2

--- Grape, wine 1

--- 0.03

Guava 0.015 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
Jaboticaba 0.015 Lychee 0.01 Longan 0.01 Mamey sapote 0.40

Milk 0.015 0.003 Nut, tree, group 14 0.01 2 0.02 Nut, tree, group 14

- 12 0.01 Onion, bulb, subgroup 3

- 07A 0.01

--- Onion, green, subgroup 3

- 07B 0.08 Papaya 0.40
Passionfruit 0.015

Pear 0.02 2

--- Peppermint, tops (entered as peppermint and peppermint oil) 0.010

---

Pineapple 0.015

Pistachio 0.01 2 0.02 Plum, prune, dried 0.025

---

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### Page 84 of 98 Table H

. 5

. 1. Abam ectin and Emamectin Established and Recommended Toleranc es Crop Abamectin Tolerances (ppm) Emamectin Tolerances (ppm) Poultry, meat 0.02

--- Poultry, meat byproducts 0.02

--- Pulasan 0.01
Rambutan 0.01 Sapodilla 0.40 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

--- Spanish lime 0.01 Spearmint, tops (entered as spearmint and spearmint top) 0.010

---

Star apple 0.40

Starfruit 0.015 Strawberry 0.05 2

--- 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 2 0.020 Vegetable, fruiting, group 8

- 10 0.07 Vegetable, leafy, except brassica, group 4 0.10 0.100

Vegetable, tuberous and corm, subgroup 01C 0.01

---

Wax jambu 0.015

1 Imported only; no US registrations.

2 These tolerances are proposed for revocation as part of this action, as the tolerances will be superseded by tolerances established by this action.

3 This commodity was entered in DEEM as oil



### H

. 5 .2 Drinking Water Pathway

EPA use d the screening

- level drinking water exposure assessment s from the single chemical
assessments for the screen ing

- level cumulative assessment of the avermectin macrocyclic lactones, which contain the insecticides abamectin and emamectin. Residues of abamectin an d
emamectin resulting from exposure to drinking water were included in the dietary exposure assessments as residue distribution files rather than as point estimates in the acute assessment. Single point estimates were used in the short

- term aggregate, base d on the chronic exposure

assessment.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 85 of 98 Abamectin : R esidues of abamectin in drinking water 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 residues 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 toxicity 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. 5 .2. 1. Screening

- Level EDWCs for Proposed Uses of Abamectin 1

Source (Tier: Model) 2 Use Site (Max. Annual App. Rate) Acute EDWC (μg/L) Chronic
EDWC (μg/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

- GW = Pesticide Root Zone Model

– Ground Water ; SCI

- GROW = Screening Concentration in Ground Water.



### Emamectin : Residues of emamectin in drinking water may occur in ground and surface water. Estimated drinking water concentrations were previously assessed as part of an action requesting

an import tolerance on wine grapes ( D402152, N

. Dodd, 2/20/13 ). Residues of emamectin may occur in ground and surface 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 : (8,9

- Z)

- 4"

- epimethylamino

- 4"

- deoxy avermectin B1 (8,9 ZMA isomer); 4"

- epiamino

- 4"

- deoxyavermectin B1 (AB); avermectin B1 monosaccharide (MAB); and 4"

- epi

- ( N

- formyl)

- 4"

- deoxyaverm ectin B1 (FAB).

Table H. 5 .2.2. EDWCs for Emamectin Residues from Use on Outdoor 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. Values include parent and degradates.

2 PRZM

- EXAMS = Pesticide Root Zone Model and Exposure 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 complet ely 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.

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 86 of 98 H

. 5 .3 Dietary (Food and Drinking Water ) Assessment

The Agency ha s determined to use the Tie r I approach for this cumulative screening

- level dietary exposure assessment. In this, combined dietary (food + water) exposures from each of the most recent single pesticide chemical risk assessment s for abamectin and emamectin have been
extracted and added together

. Tier 1 assessments also call for the exposures of each chemical to
be RPF

- scaled. However, in the case of the avermectin macrocyclic lactones, the POD is the
same for both abamectin and emamectin

, so this was not nec essary

. This tier assumes complete

co

- occurrence of all food and drinking water residues for abamectin and emamectin. The assumptions for the most recent single pesticide chemical dietary assessments for abamectin and
emamectin were refined with field tria l residue data and percent crop treated (PCT) estimates. Further information regarding the dietary assumptions may be found in the single chemical dietary assessments for emamectin and abamectin ( D430736, N. Dodd, 12/ 23/2015 and

D 424009, K. Rickard, 04/14/ 2016 ).

Acute : The screening

- level cumulative acute dietary exposures from combined residues of
abamectin and emamectin are calculated in Table H. 5 .3.1

, below. The combined residues result
in 52 % of the aPAD for the general U.S. population and 9 5 % of the aPAD for children 1

- 2 years old, the most highly exposed subgroup . These acute cumulative dietary exposures are below
HED’s level of concern of 100%.

Table H. 5 .3.1

. Summary of Acute Dietary Exposure and Risk Assessment for Combined Abamectin and
Emamect in

Population subgroup Abamectin Exposure Emamectin Exposure Combined Exposure aPAD Combined
% aPAD Ratio
Aba: Ema

General U.S. Population 0.001135 0.000172 0.001307 0.0025 52 6. 6

All Infants (<1 year old) 0.001584 0.000160 0.001744 0.0025 70 9. 9

Children 1

- 2 years old* 0.002192 0.000187 0.002379 0.0025 95 12

Children 3

- 5 years old 0.001553 0.000205 0.001758 0.0025 70 7. 6

Children 6

- 12 years old 0.000729 0.000101 0.00083 0.0025 33 7.2

Youth 13

- 19 years old 0.000475 0.000132 0.000607 0.0025 24 3. 6

Adults 20

- 49 years old 0.000446 0.000186 0.000632 0.0025 25 2. 4

Adults 50

- 99 years old 0.000345 0.000176 0.000521 0.0025 2 1 2.0

Females 13

- 49 years old 0.000427 0.000226 0.000653 0.0025 26 1.9



### * The subpopulation with the highest combined risk estimate is bolded.



### Chronic Dietary Exposure: The screening

- level cumulative background dietary exposures
from combined residues of abamectin and emamectin are calculated in Table H. 5 .3.2 below.

Table H. 5.3.2. Summary of Chronic Dietary Exposure and Risk Assessment for Combined Abamectin and
Emamectin

Population subgroup Abamectin Exposure Emamectin Exposure Combined Exposure cPAD Combined %
cPAD

General U.S. Population 0.000056 0.000008 0.000064 0.0025 2.6

All Infants (<1 year old) 0.000096 0.000014 0.000110 0.0025 4.4

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 87 of 98 Table H. 5.3.2. Summary of Chronic Dietary Exposure and Risk Assessment for Combined Abamectin and
Emamectin

Population subgroup Abamectin Exposure Emamectin Exposure Combined Exposure cPAD Combined %
cPAD

Children 1

- 2 years old* 0.000268 0.000014 0.000282 0.0025 11

Children 3

- 5 years old 0.000160 0.00001 0.000170 0.0025 6.8

Children 6

- 12 years old 0.000090 0.000007 0.000097 0.0025 3. 9

Youth 13

- 19 years old 0.000045 0.000005 0.000050 0.0025 2.0

Adults 20

- 49 years old 0.000038 0.000008 0.000046 0.0025 1.8

Adults 50

- 99 years old 0.000037 0.000009 0.000046 0.0025 1.8

Females 13

- 49 years old* 0.000038 0.000008 0.000046 0.0025 1.8



### * The subpopulation with the highest combine d risk estimate is bolded.



### H

. 6 .0 Residential Pathway

The cumulative screening framework presents a tiered approach for the cumulative screening

level residential exposure analysis. Each tier provides increasing refinements, which allow s reviewers to systematically analyze CMG residential exposure s and risk data until reaching the
tier of refinements where residential risks do not exceed the level of concern.

It should be noted that m ost residential exposure assessments conducted by OPP include high

end, default assumptions with regard to surface residues (i.e., turf residues). Any refinements used in the cumulative screening

- level residential exposure analysis would be in addition to those already in place in the single pesticide chemic al assessments.

The Agency has determined to use the Tier I, or unrefined, approach for this cumulative screening

- level residential exposure assessment. In this approach, residential exposures from the most recent risk assessment(s) are extracted and add ed together.

Abamectin : As discussed in detail in Section 6.0

, above, t here are proposed and registered use sites that may lead to residential handler and post

- application exposures to abamectin , including

a proposed use for control of turf

- parasitic nematodes on golf course greens, tees, and fairways

. Adults and youth (6 to <16 years old ) may receive dermal exposure from golfing activities following applications of abamectin to golf course turf. This use scenario was use d in the short

term aggregate r isk calculations in the adult and youth aggregate assessment, and therefore the
cumulative assessment

. There is no recommended residential risk estimate for children under the age of six, because residential risk estimates are expected to be negligible to infants and young
children

Emamectin : There are no existing or proposed residential use sites; therefore, there are no residential handler exposure or re sidential post

- application exposure s to be extracted for use in
the cumulative assessment.

Because th ere are no registered uses of emamectin that are expected to result in residential handler or post

- application exposures, residential exposures for use in the cumulative risk

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 88 of 98 assessment are from the proposed liquid formulation on turf (golf courses, greens , tees, and
fai rways)

.

H

. 7 .0 Combined Screening

- Level Cumulative Assessment ( Dietary + Residential )

Short

- Term : The screening

- level s hort

- term aggregate risk is calculated in Table H. 7 .0 below.
All short

- term aggregate exposure estimates resulted in MOEs greater than 100 ; therefore, they

are not of concern

. Intermediate

- term residential exposures are not expected.

Table H. 7 .0. Short

- Term Aggregate Risk Calculations for Combined Abamectin and Emamectin

Population Short

- Term Scenario

NOAEL LOC 1 Max Exposure 2 Abamectin Emamectin Combined
Residential Exposure 3 Total Exposure 4 Aggregate MOE (food,

water + residential) 5 Average Food and Water Exposure

mg/kg/day

Adults

0.25 100 0.0025 0.000037 6 0.0000090 6 0.000046 0.00002 0.000066 3,800
Children 6
to <11 years old 0.000090 7 0.0000050 7 0.000095 0.000028 0.00012 2,000

Children
11 to <16 years old 0.000045 8 0.0000070 8 0.000052 0.000024 0.000076 3,300

1 The LOC includes the standard inter

- and 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)].

6 Adult population subgroup utilized dietary exposure estimates f or Adults 50

- 99 years old.

7 Children 6 to <11 years old population subgroup utilized dietary exposure estimates for Children 6

- 12 years old

8 Children 11 to <16 years old population subgroup utilized dietary exposure estimates for Youth 13

- 19 years old.



### H

. 8 .0 Characterizing the Screening

- Level Cumulative Estimates

HED screened combined aggregate abamectin and emamectin dietary and residential exposures to determine whether there would be any potential cumulative concern for this CMG, the
avermectin macrocyclic lactones

. T his screening

- level assessment use d conservative assumptions that are expected to over estimate exposures , including Tier 1 dietary (food + water) and residential cumulative screening assessment assumptions. The screening

- level dietar y

assessment included the conservatism of complete co

- occurrence of both food and drinking
water residues for abamectin and emamectin.

HED believes that a more refined cumulative exposure assessment is not required at this time
since the exposure estimat es using a T ier 1 approach are below HED’s level s of concern

.

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### Page 89 of 98 H

. 9 .0 Conclusion

The screening

- level cumulative assessment for the candidate CMG of the avermectin macrocyclic lactones

, abamectin and emamectin

, utilized conservative dietary and residential exposure assumptions and indicates that combined aggregate dietary and residential risk estimates are below the Agency’s levels of concern. Therefore, the Agency has no concern for the cumulative exposure to t he existing and proposed uses of abamectin or emamectin at this time. Given the conservatisms underlying the abamectin and emamectin cumulative assessment ( i.e. , point

- estimate aggregate methodology combined with high

- end dietary and residential

exposures while assuming complete co

- exposure for all available exposure scenarios without any
related co

- exposure refinements), EPA expects that the screening

- level residues overestimate
actual cumulative residues.

Although this assessment is an unrefined screeni ng

- level for the purposes of the cumulative screen, the assumptions underlying the single chemical dietary assessments for abamectin and emamectin have been refined. Further information regarding the dietary assumptions may be found in the single chemical dietary assessments for emamectin and abamectin ( D430736, N. Dodd, 12/23/2015 and D424009, K. Rickard

, 04/14/ 2016 ).

Since risk estimates in this cumulative screening

- level assessment are below HED’s level s of concern, no additional data are required at t his time. Should future uses result in risk est imates
above the LOC s , the Agency will review whether additional toxicological or exposure data may be required in order to reevaluate the assumptions and resulting conclusions of the avermectin macrocyclic lactones cumulative assessment.

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### Page 90 of 98 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) g uideline protocols were used.

Table I.1. Toxicology Data Requirements for Emamectin

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... 

### 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

- Day 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

- W aived a 870.3700a Prenatal Developmental Toxicity (rodent)

.................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

.............. 870.3800 Reproduction and Fertility Effects

................................ yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity/Carcinogenicity

............... 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

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other 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 Developmental Neurotoxicity

................................ ....... yes

yes
CR yes

yes

- 870.7485 Metabolism and Pharmacokinetics

................................ 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yes

a HASPOC Report : TXR 0051377

, 0 3/12/ 20 15

.

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### Page 91 of 98 I .2 Toxicity Profiles

Table I .2.1. Acute Toxicity Profile

– Emamectin Benzoate Technical (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 Benzoate Technical II (EPA 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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### Page 92 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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 MK

0244

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

s pinal 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 tox

rabbits

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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### Page 93 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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/non

guideline 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, 5.0/ 2.5 mg/kg /day 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.

Note: F emales dose reduced on w ee k 18 from 5.0 to 2.5 mg/kg /day due to exce ssive toxicity

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 wa s 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

neu ral degeneration in the brain and spinal
cord of both sexe s, brain white matter degeneration in males, and on dec reased body weight, body weight gain, and food efficiency
in males.

No treatment

- related increase in tumor
incidence was seen.

870.3700 Developmental tox.

– rat 42743632 (1992) Acceptable Maternal Toxicity NOAEL=2 mg/kg/day, Maternal Toxicity LOAEL=4 mg/kg/day based

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### Page 94 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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

0, 2, 4, or 8 mg/kg/day

42743631 (range finding study) 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 reacti on).

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, neur onal degeneration in the brain and spinal cord.

870.5100 870.5100
Gene Mutation

- Salmonella

MK

- 0243 and L

660,599; L

- 657,831;

L

- 695,638; L

930,905 (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
Aberration

- in vivo
mouse bone marrow

MK

- 0244 42851513 Negative for the induction of chromosome
aberrations in the bone marrow cells of male
CD

- 1 mice.

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### Page 95 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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

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); clinical 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 tre mors 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 testi ng 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 0/4 Histopathology findings were not seen in L

682, 901 and L

- 653,648 treate d dogs. Neuronal degeneration of the brain, spinal cord, and sciatic nerves were seen in dogs
treated with MK

- 0234, L

- 653, 649, and L

655,372.

15

- Day neurotox.

– CD

- 1 mice (dietary) 42743629 (1992) Acceptable 0, 0.6, 1.2, & 2.0 mg/kg/day NOAEL=2.0 mg/k g/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.

15

- Day neurotox.

– CF

- 1 mice (dietary) 42851504 (1993) Acceptable NOAEL = 0.30 mg/kg/day (HDT)

No treatment

- related effects were seen in any dose groups.

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### Page 96 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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

(L695

- 638: 4”

- deoxy

- 4”

- epi

methylamino

avermectin B1a

delta

- 8,9

- isomer); photoproduct of

MK

- 0244 b 0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day

15

- Day neurotox.

– CF

- 1 mice (dietary) (L695

- 638: 4”

- deoxy

- 4”

- epi

methylamino

avermectin B1a

delta

- 8,9

- is omer); 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 42851504 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 plant
metabolite of MK

0244 ) 42851506 (1993) Acceptable 0, 0.10, 0.30, 0.9 0 mg/kg/day LOAEL <0.1 mg/kg/day LDT) based on tremors, hunched posture and piloerection.

However no treatment

- related findings in histopathology were present.

15

- Day neurotox.

- CF

- 1 mice (gavage)

L

- 930,905; a com

plex mixture of polar

MK

- 244 photodegrad ates) 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 amino
derivative of MK

0244 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
avermectin B1a benzoate, (MAB1a) 42851523 & 42852524 (1993) Acceptable Radio labeled MAB1a benzoate is rapidly absorbed, distributed and excreted following
oral and i.v. administration. The feces was the major route of excretion in oral and i.v. groups,
while <1% of the administered dose was

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### Page 97 of 98 Table I .2.3. Repeated Dosing and Other Studies on Emamectin

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

recovered in the urine 7 days post dosin g. Tissue distribution and bioaccumulation appeared minimal. The metabolism of MAB1 a benzoate appears to involve primarily N

demethylation to AB1a. AB1a was the only
metabolite detected in the feces while unmetabolized parent compound represented a
lar ge amount of the radioactivity. Bioequivalence

- Dog

MK

- 0243

solvate vs. monohy

drate 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 after oral administration
in male beagle dogs.

870.7600 Dermal Absorption

Rhesus 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 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

- and
Intermediate

Term NOAEL= 0.25 mg/kg/day

Toxicity via the
inhalation route
assumed to be UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC
for MOE = 100

### ABAMECTIN Human Health Risk Assessment DP No. D426599



### Page 98 of 98 Table I .2.4. Summary of Toxicological Doses and Endpoints for Emamectin for Use in Dietary Human Health
Risk Assessments Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD, LOC
for Risk
Assessment Study and Toxicological Effects

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 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 o bserved adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populati on 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 Toxicological Doses and Endpoints for Emamectin for Use in Occupational Human
Health R isk Assessments

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

Dermal (Short

- Term
and
Intermediate

Term) 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 m ales.
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
and
Intermediate

Term) 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 carcinogenic to human based on the absence of significant increase in tumor incidence in two adequate rodent carcinogenicity studies.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose

- response data and
used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolatio n 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 = margin of exp osure. LOC = level of concern. .