EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OFCHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 4/ 12/13 

SUBJECT: Emamectin Benzoate. Human Health Risk Assessment for a Proposed 

Tolerance on Imported Wine Grapes. 

PC Code: 122806 

Decision No.: 463856 

Petition No.: NA 

DP Barcode: D402151 

Registration No.: NA 

Regulatory Action: Tolerance with no Section 3 

Risk Assessment Type: Single Chemical/Aggregate Case No.: NA 

TXRNo.:NA CAS No.: 155569-91-8 

MRIDNo.:NA 40 CFR: 180.505 

FROM: Nancy 

Whang 

Dodd, 

Phang, 

Chemist 

Senior Toxicologist 

and Risk Assess~ .-IN~~ ~ ~ 

Risk Assessment Branch III (RAB3) 

Health Effects Division (HED; 7509P) 

THROUGH: Christine Olinger, Branch Chief ;J I t &} 

RAB3/HED (7509P) [k-f ~--~ 

TO: John Hebert/Thomas Harris, RM#7 

Insecticide-Rodenticide Branch 

Registration Division (RD; 7505P) 

The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with 

estimating the risk to human health from exposure to pesticides. The Registration Division (RD) 

of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, 

occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to 

human health that will result from the proposed tolerance for emamectin benzoate (a benzoate 

salt mixture of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin B1a and a maximum 

of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b) and its isomers/metabolites/degradates. 

Syngenta Crop Protection, LLC has proposed establishment of a tolerance on imported wine 

grapes. 

A summary of the findings and an assessment of human risk resulting from the registered uses 

and proposed tolerance for emamectin benzoate are provided in this document. The residue 

chemistry review, dietary assessment, and overall risk assessment were performed by Nancy 

Dodd. The toxicology assessment was performed by Whang Phang. The drinking water 

exposure assessment was performed by Tiffany Dowen of the Environmental Fate & Effects 

Division (EFED). 

Page 1 of 41 
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151 

TABLE OF CONTENTS 

1.0 Executive Summary ............................................................................................................ 4 

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

2.1 Data Deficiencies ............................................................................•............................. 6 

2.2 Tolerance Considerations ..............................................................•............................. 6 

2.2.1 Enforcement Analytical Method ...................................................•............................. 6 

2.2.2 International Harmonization ...................................................................................... 6 

2.2.3 Recommended Tolerances ........................................................................................... 7 

2.2.4 Revisions to Petitioned-For Tolerances ...................................................................... 7 

3.0 Introduction ......................................................................................................................... 7 

3.1 Chemical ldentit'y ......................................................................................................... 7 

3.2 Physical/Chemical Characteristics ...............................................•............................. 9 

3.3 Pesticide Use Patterns ....................................................................•............................. 9 

3.4 Anticipated Exposure Pathways ............................................................................... 11 

3.5 Consideration of Environmental Justice ......................................•........................... 11 

4.0 Hazard Characterization and Dose-Response Assessment ...............•........................... 12 

4.1 Summary of Toxicological Effects ................................................•........................... 12 

4.2 Safet'y Factor for Infants and Children (FQPA Safet'y Factor) ............................. 14 

4.2.1 Completeness of the Toxicology Database ............................................................... 15 

4.2.2 Evidence of N eurotoxicit'y ..............................................................•........................... 15 

4.2.3 Evidence of Sensitivit'y/Susceptibilit'y in the Developing or Young Animal ......... 15 

4.2.4 Residual Uncertaint'y in the Exposure Database ..................................................... 15 

4.3 Toxicit'y Endpoint and Point of Departure Selections ............................................ 16 

5.0 Dietary Exposure and Risk Assessment .......................................................................... 16 

5.1 Residues of Concern Summary and Rationale ............................•........................... 16 

5.2 Food Residue Profile .................................................................................................. 18 

5.3 Water Residue Profile ................................................................................................ 19 

5.4 Dietary Risk Assessment ............................................................................................ 20 

5.4.1 Description of Residue Data Used in Dietary Assessment ...................................... 20 

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 20 

5.4.3 Acute Dietary Risk Assessment .....................................................•........................... 21 

5.4.4 Chronic Dietary Risk Assessment ............................................................................. 21 

5.4.5 Cancer Dietary Risk Assessment .............................................................................. 22 

5.4.6 Summary Tables ......................................................................................................... 22 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .............................. 23 

6.1 Residential Handler Exposure .................................................................................. 23 

6.2 Post-Application Exposure ........................................................................................ 24 

6.3 Residential Bystander Post-application Inhalation Exposure ............................... 24 

6.4 Spray Drift .................................................................................................................. 24 

7.0 Aggregate Exposure/Risk Characterization ................................................................... 25 

7.1 Acute Aggregate Risk ................................................................................................. 25 

7.2 Short-/Intermediate-Term Aggregate Risk ............................................................. 25 

7.3 Chronic Aggregate Risk ............................................................................................ 25 

7.4 Cancer Aggregate Risk ..................................................................•........................... 25 

8.0 Cumulative Exposure/Risk Characterization ................................................................ 25 

9.0 Occupational Exposure/Risk Characterization ............................................................. 27 

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EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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10.0 References.......................................................................................................................... 27

Appendix A. Toxicology Profile and Executive Summaries .................................................. 28

A.1 Toxicology Data Requirements................................................................................. 28

A.2 Toxicity Profiles.......................................................................................................... 29

Appendix B. Physical/Chemical Properties............................................................................. 36

Appendix C. International Tolerances..................................................................................... 37

Appendix D. Toxicology Literature References...................................................................... 38

Appendix E. Crop Field Trials ................................................................................................. 40
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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1.0 Executive Summary

Use Profile: Syngenta is proposing a tolerance without registration on imported wine from use 

of water-soluble granule (SG) formulations on grapes in various countries other than the US. 

Label information has been submitted for France, Italy, Spain, Portugal, Greece, Australia, and 

New Zealand. The maximum label rates for the various countries range from 4-57 g 

ai/ha/season. The minimum preharvest interval is 7 days.

Toxicity/Hazard: Emamectin has moderate acute toxicity by the oral route and low acute 

toxicity by the dermal route. It is not irritating to the skin, nor is it a dermal sensitizer, but it is a 

severe eye irritant. The main target tissue is the nervous system, with neuropathology detected 

in many studies and several species. The dose-response curve was very steep in several studies 

(most notably with CF-1 mice and dogs), with severe effects (morbid sacrifice and 

neuropathology) sometimes seen at the lowest observable adverse effect levels (LOAELs). 

Although no increased sensitivity was seen in developmental toxicity studies in rats and rabbits, 

increased qualitative and/or quantitative sensitivity of rat pups was seen in the reproductive 

toxicity study and in the developmental neurotoxicity study. Review of acceptable oncogenicity 

and mutagenicity studies provide no indication that emamectin is carcinogenic or mutagenic. 

Emamectin is classified as “not likely to be carcinogenic to humans.”

Dietary Exposure (food/drinking water): Acute and chronic dietary (food and drinking water) 

exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model 

software with the Food Commodity Intake Database (DEEM-FCID), Version 3.16. The acute 

dietary exposure assessment was a probabilistic assessment for food and drinking water using 

anticipated residues based on field trial data. The chronic dietary exposure assessment was a 

somewhat refined assessment for food and drinking water using single point estimates (averages)

of anticipated residues based on field trials. Refinements for both the acute and chronic 

assessments included using percent crop treated for some registered crops, DEEM default 

processing factors where appropriate, chemical-specific processing factors where available, and 

anticipated residues based on field trial data for most crops. For the acute assessment, Pesticide 

Monitoring Program (PDP) monitoring data were used for apples since apple juice contributed 

significantly to the exposure. The 10X FQPA safety factor was retained for the chronic dietary 

assessment and reduced to 3X for the acute dietary assessment.

The estimated drinking water concentrations (EDWCs) of emamectin benzoate were provided by

EFED. A drinking water residue distribution based on the Pesticide Root Zone Model/Exposure 

Analysis Modeling System (PRZM/EXAMS) modeling of the use on ornamentals was used in 

the acute assessment. An EDWC based on the PRZM/EXAMS modeling of the use on 

ornamentals was used for the chronic assessment. 

The acute dietary exposure estimates for food and drinking water using the ornamentals scenario 

for drinking water are below HED’s level of concern (LOC) at the 99.9th percentile of exposure 

for all population subgroups (67% of the acute population adjusted dose [aPAD] for the general 

U.S. population and 91% of the aPAD for females 13-49 years old, the population subgroup with 

the highest exposure).
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The chronic dietary exposure estimates for food and drinking water using the ornamentals 

scenario for drinking water are below HED’s level of concern for all population subgroups (11% 

of the chronic population adjusted dose [cPAD] for the general U.S. population and16% of the 

cPAD for all infants less than 1 year old, the population with the highest exposure).

Residential Exposure: There are no existing or proposed residential use sites; therefore, 

residential handler exposure and residential post-application exposure are not expected.

 

Aggregate Exposure/Risk: The acute aggregate risk assessment takes into account exposure 

estimates from dietary (food and drinking water) consumption of emamectin as discussed above. 

Short- and intermediate-term aggregate risk assessments were not conducted because residential 

exposure is not expected from existing uses and there is no proposed US registration associated 

with the proposed tolerance on imported wine.

The long-term aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of emamectin benzoate (food and drinking water) and residential uses. 

However, residential exposures are not expected; therefore, the chronic aggregate risk 

assessment will consider only exposure from food and drinking water, which is discussed above.

Occupational Exposure/Risk: There is no occupational exposure/risk to US workers from 

importation of wine produced from grapes treated with emamectin benzoate.

Environmental Justice Considerations: Environmental justice concerns were considered in 

this assessment. Refer to Section 3.5.

Review of Human Research: This risk assessment did not rely on studies in which human 

subjects were intentionally exposed to a pesticide or other chemical.

Additional Data Needs:

Provided that a revised Section F is submitted before registration, the dietary-exposure database 

will be adequate to support the proposed tolerance on grape, wine. The toxicology database for 

emamectin benzoate is largely complete. An immunotoxicity study (OPPTS Guideline Number 

870.7800) is now required for conventional pesticide registration (40 CFR Part 158); the study

was submitted on 10/24/12 to RD and turned over to the Pesticide Re-evaluation Division (PRD) 

for tracking/review under Registration Review. 

2.0 HED Recommendations

Provided that a revised Section F is submitted, HED can recommend for a tolerance for 

emamectin benzoate on grape, wine. Additional data are needed as outlined in Section 2.1 

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

modifications since there are no US labels for this action.
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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2.1 Data Deficiencies

Data that needs to submitted prior to establishing a tolerance:

Residue Chemistry

OPPTS 860.1550 Proposed Tolerances

A revised Section F must be submitted to propose a tolerance for emamectin, including its 

metabolites and degradates, on grape, wine at 0.05 ppm. Compliance with the tolerance level is 

to be determined by measuring only the sum of emamectin (a mixture of a minimum of 90% 4'-

epi-methylamino-4'-deoxyavermectin B1a and maximum of 10% 4'-epi-methylamino-4'-

deoxyavermectin B1b) and its metabolites 8,9-isomer of the B1a and B1b component of the parent 

(8,9-ZMA), or 4'-deoxy-4'-epi-amino-avermectin B1a and 4'-deoxy-4'-epi-amino-avermectin B1b; 

4'-deoxy-4'-epi-amino avermectin B1a (AB1a); 4'-deoxy-4'-epi-(N-formyl-N-methyl)aminoavermectin (MFB1a); and 4'-deoxy-4'-epi-(N-formyl)amino-avermectin B1a (FAB1a), calculated 

as the stoichiometric equivalent of emamectin. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods (Method 244-92-3 and Method 244-92-3, Revision 1) are available for the 

enforcement of tolerances on plants. The methods determine residues of emamectin (the free 

base) and its regulated isomers and degradates/metabolites using high performance liquid 

chromatography with fluorescence detection (HPLC/FLD). The methods determine residues of 

emamectin in the following analyte combinations: MAB1a + 8,9-ZB1a, MAB1b + 8,9-ZB1b, AB1a, 

and MFB1a + FAB1a, with a limit of quantitation (LOQ) of 0.005 ppm for each analyte or analyte 

combination, for a combined LOQ of 0.02 ppm. 

2.2.2 International Harmonization

As shown in Appendix C, harmonization issues regarding both the tolerance level and tolerance 

expression are associated with this petition. There is a Codex maximum residue limit (MRL) for 

grapes of 0.03 ppm. The Codex residue definition for the MRL and for the risk assessment is 

emamectin B1a benzoate. The recommended US tolerance is 0.05 ppm and includes additional 

analytes. Emamectin benzoate is not registered in Canada.
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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2.2.3 Recommended Tolerances

The proposed and recommended tolerances for wine are presented in Table 2.2.3. 

The petitioner has proposed establishment of a tolerance for the residues of emamectin

benzoate (a benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'-

deoxyavermectin B1a and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b) 

resulting from the application of emamectin benzoate in or on wine at 0.005 ppm.

Tolerances for emamectin are established under 40 CFR §180.505 for the combined residues of 

emamectin (MAB1a and MAB1b), the 8,9-Z isomers of parent, and the metabolites/degradates

AB1a, MFB1a and FAB1a. 

The tolerance expression proposed by the petitioner is not appropriate. A revised Section F must 

be submitted to propose a tolerance for emamectin, including its metabolites and degradates. 

Compliance with the tolerance level is to be determined by measuring only the sum of 

emamectin (a mixture of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin B1a and 

maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b) and its metabolites 8,9-isomer of 

the B1a and B1b component of the parent (8,9-ZMA), or 4'-deoxy-4'-epi-amino-avermectin B1a

and 4'-deoxy-4'-epi-amino-avermectin B1b; 4'-deoxy-4'-epi-amino avermectin B1a (AB1a); 4'-

deoxy-4'-epi-(N-formyl-N-methyl)amino-avermectin (MFB1a); and 4'-deoxy-4'-epi-(Nformyl)amino-avermectin B1a (FAB1a), calculated as the stoichiometric equivalent of emamectin. 

Table 2.2.3. Tolerance Summary for Emamectin 

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Wine 0.005 0.05 Grape, wine

2.2.4 Revisions to Petitioned-For Tolerances

HED attributes the difference between the recommended tolerance of 0.05 ppm and the proposed 

tolerance of 0.005 ppm to OECD tolerance calculation procedures and to the fact that HED did 

not reduce the residue in grapes by the concentration factor to determine the residue in wine, but 

used the residue determined by the OECD tolerance calculation procedures for grapes to set the 

tolerance for grape, wine.

3.0 Introduction

3.1 Chemical Identity

Emamectin benzoate is a semi-synthetic avermectin, consisting of two active homologous 

compounds (a benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'-

deoxyavermectin B1a and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b). 
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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Table 3.1. Test Compound Nomenclature

Chemical Structure

Empirical Formula

emamectin benzoate B1a: C49H75NO13 •C7H6O2

emamectin benzoate B1b: C48H73NO13 •C7H6O2

Common Name emamectin benzoate

Company experimental name MK244

IUPAC name

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

sec-butyl]-21,24-dihydroxy-5',11,13,22-tetramethyl-2-oxo-(3,7,19-

trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-

dihydro-2'H-pyran)-12-yl 2,6-dideoxy-3-O-methyl-4-O-(2,4,6-trideoxy-3-Omethyl-4-methylamino-α-L-lyxo-hexapyranosyl)-α-L-arabino-hexapyranoside 

benzoate and (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-21,24-

dihydroxy-6'-isopropyl-5',11,13,22-tetramethyl-2-oxo-(3,7,19-

trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-

dihydro-2'H-pyran)-12-yl 2,6-dideoxy-3-O-methyl-4-O-(2,4,6-trideoxy-3-Omethyl-4-methylamino-α-L-lyxo-hexapyranosyl)-α-L-arabino-hexapyranoside 

benzoate

CAS Name (4''R)-4''-deoxy-4''-(methylamino)avermectin B1 benzoate (salt)

CAS Registry Number 155569-91-8 (formerly 137512-74-4)

End-use products/EPs

SG and WG1formulations: Affirm (0.95% ai), Affirm (8.55 g/kg), Proclaim (44 

g/kg), and Proclaim (50 g/kg).

Chemical Class Avermectin insecticide

Known Impurities of Concern None

1WG formulations are water dispersible granular formulations.

COO

-

OCH3

O O

O

O

CH3

OH

H3C

O

CH3

CH3

R1

O

O

H3CO

O

H C O 3 CH3

OH

CH3

H3CH2N

+

B1a Component: R1 = CH2CH3

B1b Component: R1 = CH3
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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3.2 Physical/Chemical Characteristics

Emamectin benzoate is a solid at room temperature with a low vapor pressure (3.0 x 10-8 mm Hg

at 21°C); thus, any losses due to volatilization/sublimation are expected to be minimal. 

Emamectin benzoate, the 8,9-Z isomer, AB, MFB, and FAB are expected to be persistent and 

relatively immobile in the environment due to a high degree of sorption to soil particles (KOC

from 25,363 to 730,000). Based upon fate data, significant concentrations of parent or formed 

degradates of toxicological concern are not expected to leach into groundwater.

Refer to a Table of Physicochemical Properties in Appendix B.

3.3 Pesticide Use Patterns

Syngenta is proposing a tolerance on wine from use of emamectin benzoate on grapes in various 

countries other than the US. Registration for use on grapes in the US is not requested. Use 

directions have been submitted for France, Italy, Spain, Portugal, Greece, Australia, and New 

Zealand. The use directions along with the submitted residue data from France, Italy, Spain, 

Australia, and New Zealand are adequate to determine a tolerance level for grape, wine from use 

of emamectin benzoate on grapes. 

A draft Proclaim® Insecticide label from New Zealand has been provided and is summarized in 

Table 3.3.1. Proclaim® is to be used to control leafrollers on grapes. Two foliar spray 

applications will be made per season. High volume sprays are to wet the crop without run-off. 

For high volume sprays, apply 4 g Proclaim Insecticide/100 liters water (0.2 g ai/100 liters;

0.0017 lb/gal); apply in sufficient water to ensure that 40 g Proclaim Insecticide per ha (2 g 

ai/ha) are applied. Concentrate sprays may also be made by adjusting the dilution rate 

accordingly. The label requires the use of a non-ionic surfactant at label rates. Apply any time 

from post flowering to pre bunch closure. The label indicates that applications are not to be 

made to grapes after bunch closure.
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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Table 3.3.1. Summary of Directions for Use of Emamectin Benzoate.

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate

lb ai/gal

(g ai/ha)

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

lb ai/gal

(g ai/ha)

PHI

(days)

Use Directions and Limitations

GRAPES (New Zealand)

Foliar sprays;

Apply any time 

from post 

flowering to pre 

bunch closure.

0.05% SG10.0017 lb 

ai/gal 

(2 g ai/ha)

2 0.0018 lb 

ai/A

(4 g ai/ha)

NS Apply in concentrate or high 

volume sprays. 

High volume sprays are to wet 

the crop without run-off. For 

high volume sprays, apply 4 g 

Proclaim Insecticide/100 liters 

water (0.2 g ai/100 liters); apply 

in sufficient water to ensure that 

40 g Proclaim Insecticide per ha 

(2 g ai/ha) are applied. 

Use a non-ionic surfactant at 

label rates.

Do not apply to grapes after 

bunch closure. 

1 PROCLAIM® INSECTICIDE, containing 50 g/kg ai in the form of a water-soluble granule.

2 NS = not stated.

The directions for use of emamectin benzoate on wine grapes grown in representative countries

of Europe and in Australia and New Zealand are summarized in Table 3.3.2. 

Table 3.3.2. Summary of Directions for Use of Emamectin Benzoate on Wine Grapes

Country % US imports 

for US 

Consumptiona

ai

Conc.h

Max 

apps/ 

season

Maximum Application Rate PHI 

(days)

Min. 

Retreatment 

Interval

(days)

On label kg 

EP/ha 

per 

app.

g ai/ha 

per app.

g ai/ha 

per 

season

France 28.62 0.95% 3 1.5 kg/ha 1.5 14.25b42.75 7 14

Italy 28.402 0.95% 3 1.5 kg/ha 1.5 14.25b42.75 14 14

Spain 6.031 8.55 g/kg

(0.855%)

1 1.5 kg/ha 1.5 12.825c12.825 7 Not

applicable

Portugal 1.484 0.85% 4 1.5 kg/ha 1.5 12.825c51.3 7 10

Greece 0.213 0.95%

w/w

4 150 

g/1000 

m

2

1.5d14.25d57 7 14

Australi

a

15.913 44 g/kg

(4.4%)

2 75 g/ha 0.075 3.3e6.6 56 7

New 

Zealand

3.323 50 g/kg

(5.0%)

2 40 g/ha 0.040f2.0f4

g g

a. USDA Foreign Agriculture Service. http://www.fas.usda.gov/gats/default.aspx

b. (1.5 kg EP/ha/application) x (1000 g EP/kg EP) x (0.95 g ai/100 g EP) = 14.25 g ai/ha/application 
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c. (1.5 kg EP/ha/application) x (8.55 g ai/kg EP) = 12.825 g ai/ha/application

d. (150 g EP/1000 m

2

/application) x (10,000 m2/ha) = 1500 g EP/ha/application

 (1500 g EP/ha/application) x 1 kg EP/1000 g EP) = 1.5 kg EP/ha/application

 (1500 g EP/ha/application) x (0.95 g ai/100 g EP) = 14.25 g ai/ha

e. (75 g EP/ha/application) x (1 kg EP/1000g EP) = 0.075 kg EP/ha/application

 (0.075 kg EP/ha/application) x (44 g ai/kg EP) = 3.3 g ai/ha/application

f. (40 g EP/ha/application) x (1 kg EP/1000 g EP) = 0.040 kg EP/ha/application

 (0.040 kg EP/ha/application) x (50 g ai/kg EP) = 2.0 g ai/ha/application

g. Applications can be made at any time from post-flowering to pre-bunch closure.

h. Formulations used on grapes include Affirm (0.95% ai), Affirm (8.55 g/kg), Proclaim (44 g/kg), and Proclaim (50 

g/kg).

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed tolerance for emamectin benzoate on imported wine. This risk assessment considers 

human exposures from residues in imported wine and from exposure pathways based on the 

registered uses of emamectin benzoate. From registered uses, humans may be exposed to 

emamectin benzoate in food and drinking water, since emamectin benzoate may be applied 

directly to growing crops and application may result in emamectin benzoate reaching surface and 

ground water sources of drinking water. There are no residential uses of emamectin benzoate as 

explained in Section 6.0, so there is not likely to be exposure in residential or non-occupational 

settings. There is no occupational exposure associated with imported wine.

 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the US Department of Agriculture (USDA) under the 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 and 

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 conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based 

on home use of pesticide products and associated risks for adult applicators and for toddlers, 

youths, and adults entering or 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 
EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

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workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been reviewed since the last risk assessment. This 

assessment includes summaries of prior assessments.

Details of the toxicology of emamectin, including executive summaries of the toxicity studies, 

are available in the HED memo, EPA ID#: 000618-RNI: Application for Establishment of 

Permanent Tolerance for the Use of Emamectin on Cole Crops and Leafy Vegetables, G. Reddy, 

06/30/98. A summary of the toxicology profile for emamectin is presented in Appendix A.

4.1 Summary of Toxicological Effects

Emamectin is a member of the naturally derived complex of 16-membered macrocyclic lactones, 

which include abamectin, avermectin, and ivermectin. On the cellular level, a member of this 

group of compounds has been shown to act 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, 

1997; and Dawson et al., 2000). GABA plays a critical role in nervous system development 

through both non-synaptic (Represa and Ben-Ari, 2005) and synaptic (Nguyen et al., 2001) 

mechanisms. Consequently, emamectin may have the potential to influence GABA-mediated 

events important to brain development. Within the mammalian brain, a member of this class of 

compound (abamectin) has been shown to have widespread binding but particularly abundant in 

the cerebellum (Wang and Pong, 1982). Through action on the enteric nervous system and 

induction of longitudinal rhythmic contractions in the isolated ileum, emamectin, like abamectin,

may therefore influence GABA-mediated regulation of metabolism, food intake and body weight 

at multiple sites (Kerr and Ong, 1986, Meister, 2007). Although GABA receptor mediated 

neurotoxicity is a solid hypothesis, data in mammalian preparations linking alterations in GABA 

receptor function to disruptions in neuronal excitability in vitro and in vivo, and ultimately 

adverse outcome are currently lacking.

Integral to its mechanism of action in mammals, this class of compounds is also a substrate for Pglycoprotein (P-gp). P-glycoprotein is a member of the ATP binding cassette transporter 

proteins, which reside in the plasma membrane and function as a transmembrane efflux pump, 

moving xenobiotics from the intracellular to the extracellular domain against a steep 

concentration gradient with ATP-hydrolysis providing the energy for active transport (Marzolini 

et al, 2004). 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), placenta, ovaries, and the testes. As an efflux 

transporter, P-gp acts as a protective barrier to keep xenobiotics out of the body by excreting 

them into bile, urine, and intestinal lumen and prevents accumulation of these compounds in the 

brain and gonads, as well as the fetus. Therefore, some test animals, in which genetic 

polymorphisms compromise P-gp expression, are particularly susceptible to abamectin or 

emamectin-induced neurotoxicity (Lankas et al., 1997). An example is the CF-1 mouse. Some 

CF-1 mice are deficient in P-gp and are found to be highly sensitive to the neurotoxicity of 
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abamectin. A very small population of humans is also found to be deficient of ATP binding 

cassette (ABC) transporter proteins due to polymorphism in the gene encoding ABC transporter 

proteins (Dubin-Johnson Syndrome) (S. Habashi, 2006, A.T. Niles, 2007). In addition, collie 

dogs have been known to be deficient in P-gp (R. Kerb, 2005).

Consistent with the mode of action, the main target organ for emamectin is the nervous system; 

clinical signs (tremors, ptosis, ataxia, and hunched posture) and neuropathology (neuronal

degeneration in the brain and in peripheral nerves, muscle fiber degeneration) were found in 

most of the emamectin studies in rats, dogs and mice. The dose-response curve was very steep 

in several studies (most notably with CF-1 mice and dogs), with severe effects (morbid sacrifice 

and neuropathology) sometimes seen at the LOAELs (0.1 mg/kg/day with a no observable 

adverse effect level (NOAEL) of 0.075 mg/kg/day). Although no increased sensitivity was seen 

in developmental toxicity studies in rats and rabbits, increased qualitative and/or quantitative 

sensitivity of rat pups was seen in the reproductive toxicity and in the developmental 

neurotoxicity studies. In the reproduction study, whole body tremors, hind limb extension, and 

hind limb splay were seen in the F1 and F2 pups while these clinical signs were not seen in F0 

parental animals at similar dose levels. In addition, a greater incidence of decreased fertility was 

seen in the F1 parental females than in the F0 females. In the developmental neurotoxicity study, 

no maternal effect was seen at the highest dose tested whereas dose-related decrease in openfield motor activity was seen in the mid-dose on PND 17. Body tremors, hind-limb extension, 

and auditory startle were also found in the high dose pups. 

A degree-of-concern analysis was conducted to determine whether or not an additional safety 

factor is needed to account for the increased susceptibility in pups; it was concluded that the 

degree-of-concern was low for both 2-generation reproduction and developmental neurotoxicity 

studies. The reasons are as follows: 

∙ For the 2-generation reproduction study, (1) there was a clear NOAEL for the offspring 

toxicity, (2) effects unique to offspring (decreased fertility in F1 adults, and clinical signs 

[tremors and hind limb extensions during and following lactation]) were seen at the same 

dose that caused parental systemic toxicity (decreased body weight gain and 

histopathological lesions in the brain and spinal cord), and (3) the decreased fertility seen in 

F1 adults might have been due to histopathological lesions in the brain and central nervous 

system (seen in both F0 and F1 generations), rather than due to a direct effect on the 

reproductive system. 

∙ For the developmental neurotoxicity study, (1) although multiple offspring effects (including 

decreased pup body weight, head and body tremors, hindlimb extension and splay, changes 

in motor activity and auditory startle) were seen at the highest dose (3.6 mg/kg/day), and no 

maternal effects were seen at any dose, there was a clear NOAEL for offspring toxicity at the 

low dose, and (2) the offspring LOAEL (at the mid dose) is based on a single effect seen on 

only one day (decreased motor activity on PND 17) and no other offspring toxicity was seen 

at the LOAEL.
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The carcinogenicity and mutagenicity studies provide no indication that emamectin is 

carcinogenic or mutagenic. Emamectin is classified as “not likely to be carcinogenic to 

humans.” A toxicity profile for emamectin is presented in Appendix A.

The acute toxicity studies indicate that emamectin has low to moderate acute toxicity by the oral, 

dermal and inhalation routes. It is not irritating to the skin, nor is it a dermal sensitizer. 

However, depending on the technical test substance, abamectin has been shown to be a severe 

eye irritant. A recent (as of 2008) submission of acute toxicity six-pack tests performed on a 

new technical product (Emamectin Benzoate Technical II, EPA Reg. No. 100-1270) resulted in 

new toxicity category assignments. Specifically, the toxicity category for inhalation changed 

from Category IV to Category II. Relevant to the REI, the eye irritation study changed from 

Category I to Category III. HED had concern for the possibility that a change in manufacturers 

and technical registrations could result in a different acute toxicity outcome, while the technical 

compound itself had not changed. 

The most recent toxicity endpoints and points of departure for risk assessment were determined 

by HED in 2003. The available emamectin data show that there is a difference in species 

sensitivity, and the data suggest the following order: rat NOAELs/LOAELs > dog 

NOAELs/LOAELs > mouse NOAELs/LOAELs. The toxicity endpoints and points of departure 

for risk were selected from the results of the 15-day CF-1 mouse oral toxicity study. No new 

toxicity studies have been submitted since 2003, and these selections are still valid.

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

Based on currently available data, HED recommends that the 10X FQPA safety factor be 

retained for chronic assessments and that a 3X FQPA safety factor is adequate for acute 

assessments. For inhalation exposure assessment, additional uncertainty factors of 10X for lack 

of an inhalation toxicity study and of 3X for the steepness of the dose-response curve are to be 

applied; these are combined with the normal 100X safety factor resulting in the application of a 

maximal uncertainty factor of 3000X.

The 10X FQPA safety factor has been retained for chronic/long-term and intermediate-term 

assessments for oral and dermal exposure due to the steepness of the dose-response curve, 

severity of effects at the LOAEL (death and neuropathology), and the use of a short-term study 

for long-term risk assessment. (HED did not use a chronic study for the point of departure 

because the chronic studies were conducted in rats, dogs, and CD-1 mice. The 15-day study 

employed the CF-1 mice, which do not have the glycoprotein. As a result, the point of departure 

is protective of all population subgroups.) The steepness of the dose-response curve and the 

severity of the effects at the LOAEL also are the basis for HED retaining a 3X FQPA safety 

factor for acute assessments. A 3X FQPA safety factor was judged to be adequate (as opposed to 

a 10X) for the following reasons: (1) A NOAEL was established in the 15-day neurotoxicity CF1 mouse study used to determine the acute toxicity endpoint for risk assessment; (2) Although 

the effects of concern are seen after repeated dosing, the NOAEL here is used for a single 

exposure risk assessment; and (3) The most sensitive endpoint in the most sensitive species is 

selected.
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4.2.1 Completeness of the Toxicology Database

The toxicology database used to assess pre- and post-natal exposure to emamectin is considered 

adequate. Although an inhalation study has not been submitted, it is not relevant to this petition 

for a tolerance on an imported commodity with no registration in the US. An immunotoxicity 

study (OPPTS 870.7800), which is required under current guidelines, was submitted on 10/24/12 

to RD and turned over to PRD for tracking/review under Registration Review. 

Immunotoxicity study

The risk assessment team evaluated subchronic, chronic, carcinogenicity, developmental and 

reproduction studies as well as acute and subchronic neurotoxicity studies for any effects which 

might indicate that emamectin induced changes in the organs generally associated with 

immunological toxicity. In the studies evaluated, only the 14-week oral toxicity study in dogs 

showed an increase in the incidence of thymus atrophy at 1 mg/kg/day. In the 1-year feeding 

study in the dog, thymus atrophy was not reported at similar dose levels tested. Currently, the 

point of departure for risk assessment is 0.075 mg/kg/day, which is more than 10x less than the 

dose where thymus atrophy had been reported. At this time, the acute and chronic reference 

doses (RfD's) are 0.00025 mg/kg/day and 0.000075 mg/kg/day, respectively; therefore, a 

database uncertainty factor is not necessary pending review of the submitted immunotoxicity 

study. 

4.2.2 Evidence of Neurotoxicity

Following emamectin exposure, neurotoxicity has been seen in multiple studies with several 

species of test animals. An adequate developmental neurotoxicity study has been submitted.

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

Although no increased sensitivity was seen in developmental toxicity studies in rats and rabbits, 

increased qualitative and/or quantitative sensitivity of rat pups was seen in the reproductive 

toxicity study and in the developmental neurotoxicity study (see details in Section 4.1: Summary 

of Toxicological Effects). 

4.2.4 Residual Uncertainty in the Exposure Database

The assessment for food incorporates somewhat refined anticipated residue estimates for most 

commodities that were derived from field trial data and percent crop treated (% CT) data. 

Monitoring data were used for apples in the acute assessment. The availability and use of more 

monitoring data and of food preparation-reduction factors for washing, cooking, etc. may have 

resulted in a more refined estimate of dietary exposure. Despite the use of some refinements, 

exposures to residues in food are not expected to be underestimated.

The dietary drinking water assessment utilizes water concentration values generated by model 

and associated modeling parameters which are designed to provide conservative, health 

protective, high-end estimates of water concentrations which will not likely be underestimated.
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4.3 Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior dose-response assessment. There have been no changes 

to the prior recommendations for combining routes of exposure and/or cancer classification.

The points of departure, uncertainty factors, and toxicity endpoints are presented in Tables 4.3.1 

and 4.3.2.

Table 4.3.1 Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for Use in Dietary and 

Non-Occupational Human Health Risk Assessments1

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

NOAEL = 

0.075 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 3x

Acute RfD = 

0.00025 

mg/kg/day

aPAD 

=0.00025 

mg/kg/day

15-day mouse

LOAEL = 0.1 mg/kg/day based on 

tremors on day 3 of dosing. At the next 

higher dose (0.3 mg/kg/day), tremors 

were seen at day 2 of treatment.

Chronic 

Dietary (All 

Populations)

NOAEL = 

0.075 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

Chronic RfD 

= 0.000075

mg/kg/day

cPAD = 

0.000075 

mg/kg/day

15-day mouse

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve.

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.

1

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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. (The 10X 

FQPA safety factor for chronic/long-term and intermediate-term assessments is to account for the steepness of the 

dose-response curve, severity of effects at the LOAEL (death and neuropathology), and the use of a short-term study 

for intermediate-term risk assessment. The 3X FQPA safety factor for acute assessments is to account for steepness 

of the dose-response curve and the severity of the effects at the LOAEL.) PAD = population adjusted dose (a = 

acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

Plants: The major metabolite identified in lettuce, cabbage, and sweet corn treated with 

[

14C]emamectin B1a (MAB1a) was the parent MAB1a. The isomer 8,9-ZB1a and the 

metabolites/degradates AB1a, MFB1a, and FAB1a were identified at <5% of the TRR. MAB1a

initially degrades rapidly to a large number of residues of MAB1a-like structures, nearly all 

contributing only a small amount to the total residue; these initial degradates undergo further 
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degradation to yield a very complex residue. These degradations are probably a result of 

photolysis, and after this photolytic process, these degradates can be fragmented and 

incorporated into natural plant constituents. 

Ruminants: The parent compounds, emamectin (MAB1a + MAB1b), are the only major residues

found in goat milk, fat, meat and meat byproducts. However, the analytical method for the 

determination of residues of emamectin and its metabolites in livestock commodities cannot 

distinguish between the parent compounds and its metabolites, 8,9-ZMA (8,9-ZB1a + 8,9-ZB1b). 

In the absence of toxicity data, the metabolites 8,9-ZMA (8,9-ZB1a + 8,9-ZB1b) are assumed to 

be of comparable toxicity to the parent.

Drinking water: Parent and degradates (refer to Table 5.1) were included in the drinking water 

assessment for emamectin benzoate. The degradates are assumed to be of equal or lesser toxicity 

to that of the parent compound.

The residues of concern for the dietary risk assessment and the tolerance expression are 

summarized in Table 5.1. 

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

Plants1Primary Crops emamectin (MAB1a + 

MAB1b), the associated 8,9-Z 

isomers (8,9-ZB1a + 8,9-

ZB1b), and 

metabolites/degradates AB1a, 

MFB1a and FAB1a

emamectin (MAB1a + 

MAB1b), the associated 8,9-Z 

isomers (8,9-ZB1a + 8,9-

ZB1b), and 

metabolites/degradates AB1a, 

MFB1a and FAB1a

Rotational Crops Same as for primary crops Same as for primary crops

Livestock1 Ruminant emamectin (MAB1a + MAB1b) 

and its 8,9-Z isomers (8,9-

ZB1a and 8,9-ZB1b)

emamectin (MAB1a + MAB1b) 

and its 8,9-Z isomers (8,9-

ZB1a and 8,9-ZB1b)

Poultry Not applicable Not applicable

Drinking Water2emamectin (MAB1a + 

MAB1b), the associated 8,9-Z 

isomers (8,9-ZB1a + 8,9-

ZB1b), and 

metabolites/degradates 

Not Applicable

1 TXR#0050315, Manying Xue, 1/28/02

2 TXR#0050315 (Manying Xue, 1/28/02) indicated that drinking water residues should be emamectin (MAB1a + 

MAB1b), the associated 8,9-Z isomers (8,9-ZB1a + 8,9-ZB1b), and the metabolites/degradates AB1a, MF B1a, and 

FAB1a. DP#402307 (T. Dowen, 5/30/12) indicated that the drinking water analytes included emamectin and the 

following four degradates: (8,9-Z)-4"-epimethylamino-4"-deoxy avermectin B1 (8,9 ZMA isomer); 4"-epiamino-4"-

deoxyavermectin B1 (AB); avermectin B1 monosaccharide; and 4"-epi-(N-formyl)-4"-deoxyavermectin B1 (FAB).
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5.2 Food Residue Profile

DER References: 48758306.der, 48758307.der, 4875308.de1, 48758310.de1 (Crop Field Trials)

48758308.de2, 48758310.de2 (Processing Studies)

48758304.der (Storage Stability)

Grape Field Trials: Syngenta submitted crop field trial data from use of SG formulations on 

grapes in support of the proposed tolerance on imported wine. The residue data are summarized 

in Appendix E. Residue data were submitted from France, Italy, Spain, Australia, and New 

Zealand. The petitioner submitted label information for use of emamectin benzoate on grapes in

France, Italy, Spain, Australia, New Zealand, Portugal, and Greece. 

The submitted grape field trial data are adequate to reflect the maximum submitted use pattern 

for grapes, and the number and locations of the field trials are adequate. An acceptable method 

was used for residue quantitation, and the data are supported by adequate storage stability data. 

The available label information and residue data are adequate to establish a tolerance of 0.05 

ppm on grape, wine. 

 

Processing Studies: Adequate processing data are available for determining a processing factor 

for wine. Following one foliar broadcast application of emamectin benzoate at 0.013 lb ai/A 

(14.08-14.46 g ai/ha), residues of MAB1a + MAB1b, expressed as MAB1a, were 0.004-0.024 ppm 

in/on grape bunches (RAC) and <0.002-0.002 ppm in/on wine from grapes harvested at a 0-day 

PHI. The processing data are adequate to indicate that the residues do not concentrate in wine 

(average processing factor of 0.29x). The processing factor is less than the theoretical 

concentration factor of 1.2x for juice (based separation of components; OPPTS 860.1520, Table 

3).

Storage Stability: The storage stability data demonstrate that residues of MAB1a, MAB1b, 8,9-

ZB1a, and metabolites/degradates AB1a, FAB1a and MFB1a are stable in/on tomato, potato and 

green beans stored frozen (≤-18 C) for up to 26 months (793-804 days), and in tomato paste 

stored frozen (≤-18 C) for up to 13 months (388 days). Residue decline was <30%, except for 

MFB1a in tomato paste, in which the average corrected recovery was 67%. An acceptable 

method was used for quantitation of residues. 

The available storage stability data are adequate to conclude that the residues in grapes and 

processed commodities are stable in frozen storage for the durations of the field trial studies. 

Grapes and processed commodities were stored frozen for ≤7.9 months. The frozen storage 

interval for tomatoes covers the interval of frozen storage for grapes and processed commodities. 

Since grapes and tomatoes are both acidic commodities, the available data for tomatoes can be 

translated to grapes and processed commodities. No corrections for residue decline during 

storage are needed.

Meat, Milk, Poultry, and Eggs: There are no livestock feedstuffs associated with use on imported 

wine.

Rotational Crops: There are no rotational crop issues associated with imported wine.
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5.3 Water Residue Profile

Since the current request for a tolerance on imported wine does not impact drinking water, the 

EFED memo previously provided for the petition on outdoor ornamentals and cucurbit 

vegetables was used. The drinking water residues used in the dietary risk assessment were 

provided by EFED in the following memorandum: “Amended Drinking Water Assessment for 

the Proposed Use of Emamectin Benzoate on Outdoor Ornamentals and Group 9 Cucurbit 

Vegetables” (Tiffany Dowen, 5/30/12, DP#402307) and incorporated directly into this dietary 

assessment. Water residues were incorporated in the DEEM-FCID into the food categories 

“water, direct, all sources” and “water, indirect, all sources.” 

In DP#402307, EFED provided EDWCs for the then proposed/registered uses of emamectin 

benzoate including the uses on outdoor ornamentals (EPA 100-RURR) and cucurbit vegetables 

(EPA 100-904). EDWCs from use on outdoor-grown ornamentals are the highest. Emamectin 

benzoate residues (parent + degradation products), based on applications made to ornamentals 

and group 9 cucurbits, are not expected to exceed 0.465 μg/L for the 1 in 10 year daily peak, 

0.150 μg/L for the 1 in 10 year annual average, and 0.112 μg/L for the 30 year annual average 

(Table 3). A distribution of drinking water numbers using the ornamentals scenario was used in 

the acute assessment. The EDWC of 0.150 μg/L was used in the chronic assessment.

The Agency identified four degradates of concern based on structural similarity to emamectin 

benzoate that are formed via photolysis (MARC memo references: D238206, Sept 2, 1997; 

D255357, Aug 20, 2001; D277085, Aug 20, 2001): 

(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"-deoxyavermectin B1 (FAB). 

These degradates were included in the drinking water assessment for emamectin benzoate and 

are assumed to be of equal or lesser toxicity to that of the parent compound. The total toxic 

residues approach is used for determining the environmental fate data parameters for modeling 

using the Guidance for Selecting Input Parameters in Modeling the Environmental Fate and 

Transport of Pesticides, Version 2.1, October 22, 2009, and the draft Guidance for Modeling 

Pesticides Total Toxic Residues (TTR), dated May 20, 2009.

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

Benzoate.a, d

Scenario Surface Water Conc., ppb b Groundwater Conc., ppb c

Acute 0.465 0.54 x 10-3

Chronic (non-cancer) 0.150 0.54 x 10-3

Chronic (cancer) 0.112 0.54 x 10-3
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Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Emamectin 

Benzoate.a, d

Scenario Surface Water Conc., ppb b Groundwater Conc., ppb c

a Degradates of concern included in the calculation of EDWCs: (8,9-Z)-4"-epimethylamino-4"-deoxy avermectin 

B1, 4"-epiamino-4"-deoxyavermectin B1, avermectin B1 monosaccharide, and 4"-epi-(N-formyl)-4"-

deoxyavermectin B1 (the 8,9 ZMA isomer, AB, MAB, and FAB, respectively). 

b

From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on the use on 

ornamentals. Typically, the values generated by the models for drinking water are multiplied by a percent crop 

area factor (PCA). The PCA accounts for the fact that is it unlikely for any basin to be completely planted to 

agricultural crops. The PCA adjustment factor is assumed to be 0.87 for the group 9 cucurbit vegetables and 1.0 

for the outdoor ornamentals crops as per the PCA guidance. 

c From the SCI-GROW model. Input parameters are based on the use on ornamentals/group 9 cucurbit vegetables.

d “Amended Drinking Water Assessment for the Proposed Use of Emamectin Benzoate on Outdoor Ornamentals 

and Group 9 Cucurbit Vegetables” (Tiffany Dowen, 5/30/12, DP#402307)

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute assessment: A probabilistic acute dietary exposure assessment was conducted. The 

anticipated residue estimates, used for most crops, were based on field trial data. Tolerance-level 

residues were used for tree nuts (including pistachios), cottonseed oil, and wine. Pesticide Data 

Program (PDP) monitoring data for years 2009 and 2010 were used for apples since apple juice

had a significant impact on exposure. DEEM default processing factors were used except for 

commodities with chemical-specific processing studies. Percent crop treated data provided by 

the Biological and Economic Analysis Division (BEAD) in 2012 were used. The EDWCs of 

emamectin benzoate were provided by EFED. A drinking water residue distribution based on 

the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) 

modeling of the use on ornamentals was used in the acute assessment.

Chronic assessment: A somewhat refined chronic dietary exposure assessment was conducted. 

The anticipated residue estimates, used for most crops, were single point estimates (averages) 

based on field trial data. Established/recommended tolerance-level residues were used for tree 

nuts (including pistachios), cottonseed oil, and wine. DEEM default processing factors were 

used except for commodities with chemical-specific processing studies. Percent crop treated 

data provided by BEAD in 2012 were used. The EDWC of 0.150 μg/L (ppb) for the chronic 

exposure was based on PRZM/EXAMS modeling of the use on ornamentals; it results in the 

highest chronic EDWC considering all registered uses.

 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates [D401786, Jihad Alsadek, 5/29/12; 

Screening Level Usage Analysis (SLUA) dated 5/29/12] were used in the acute dietary risk 

assessment for the following crops that are currently registered for emamectin benzoate: 

almonds, 2.5%; apples, 20%; broccoli, 20%; cabbage, 25%; cauliflower, 20%; celery, 40%; 

cotton, 2.5%; lettuce, 20%; pears, 20%; peppers, 15%; spinach, 10%; and tomatoes, 20%.
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The following average percent crop treated estimates from the SLUA dated 5/29/12 were used in 

the chronic dietary risk assessment for the following crops that are currently registered for 

emamectin benzoate: almonds, 1%; apples, 10%; broccoli, 5%; cabbage, 10%; cauliflower, 10%; 

celery, 25%; cotton, 1%; lettuce, 10%; pears, 5%; peppers, 5%; spinach, 5%; and tomatoes, 10%.

The following percent crop treated estimates, which were provided for the cucurbit petition in 

2012 (D403689, Jihad Alsadek, 8/21/12), were used in the acute dietary risk assessment: 

cantaloupe, 51%; cucumber, 26%; squash, 46%; and watermelon, 21%.

The following percent crop treated estimates, which were provided for the cucurbit petition in 

2012 (D403689, Jihad Alsadek, 8/21/12), were used in the chronic dietary risk assessment: 

cantaloupe, 40%; cucumber, 14%; squash, 29%; and watermelon, 19%.

For both acute and chronic dietary assessments, 100% crop treated was assumed for wine.

5.4.3 Acute Dietary Risk Assessment

The general U.S. population and the following population 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 5.4.6.1, the most highly exposed subgroup was females 13-49 years old, with 

exposure of 91% of the aPAD. The risk estimates for all populations assessed were below the 

level of concern.

The acute assessment is a probabilistic assessment which incorporates anticipated residue 

estimates for most commodities that were derived from field trial data. Percent crop treated data 

were used. Monitoring data were used for apples in the acute assessment since apple juice had a 

significant impact on exposure. The use of more monitoring data and of food preparationreduction factors for washing, cooking, etc. may have resulted in more refined estimates of 

dietary exposure. More highly refined analyses are not needed at this time since the risk 

estimates are below HED’s level of concern.

5.4.4 Chronic Dietary Risk Assessment

The general U.S. population and the following population 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 5.4.6.2, the most highly exposed subgroup was all infants less than one year 

old, with exposure of 16% of the cPAD. The risk estimates for all populations assessed were 

below HED’s level of concern.

The chronic assessment for food is a somewhat refined assessment which incorporates 

anticipated residue estimates for most commodities that were derived from field trial data. 

Percent crop treated data were used. The use of more monitoring data and of food preparation-
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reduction factors for washing, cooking, etc. may have resulted in more refined estimates of 

dietary exposure. More highly refined analyses are not needed at this time since the risk 

estimates are below HED’s level of concern.

5.4.5 Cancer Dietary Risk Assessment

Emamectin benzoate is classified as “not likely to be carcinogenic to humans” based on the 

absence of significant tumor increases in two adequate rodent carcinogenicity studies.

5.4.6 Summary Tables

The results of the acute dietary (food + drinking water) exposure analysis at the 95th, 99th, and 

99.9th percentiles of exposure are reported in Table 5.4.6.1 below. The acute dietary exposure 

estimates for food and drinking water using the ornamentals scenario for drinking water are 

below HED’s level of concern at the 99.9th percentile of exposure for the general U.S. population 

and all population subgroups (67% of the aPAD for the general U.S. population and 91% of the 

aPAD for females 13-49 years old, the most highly exposed population subgroup). 

Table 5.4.6.1. Results of Acute Dietary (Food and Drinking Water) Exposure Analysis Using DEEM 

FCID 

Population Subgroup aPAD 

(mg/kg/

day)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

General U.S. Population 0.00025 0.000031 12 0.000082 33 0.000168 67

All Infants (< 1 year old) 0.000037 15 0.000070 28 0.000138 55

Children 1-2 years old 0.000038 15 0.000074 30 0.000151 60

Children 3-5 years old 0.000028 11 0.000059 23 0.000135 54

Children 6-12 years old 0.000019 7.4 0.000042 17 0.000090 36

Youth 13-19 years old 0.000013 5.1 0.000030 12 0.000132 53

Adults 20-49 years old 0.000032 13 0.000095 38 0.000187 75

Adults 50+ years old 0.000039 16 0.000086 35 0.000175 70

Females 13-49 years old 0.000033 13 0.000097 39 0.000227 91

The results of the chronic dietary (food and drinking water) exposure analysis are reported in 

Table 5.4.6.2 below. The emamectin benzoate chronic dietary risk estimates for food and 

drinking water using the ornamental scenario for drinking water are below HED’s level of 

concern for the general U.S. population and all population subgroups, at 11% of the cPAD for 

the general U.S. population and 16% of the cPAD for all infants (<1 year old), the most highly 

exposed population subgroup.
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Table 5.4.6.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for 

Emamectin Benzoate

Population Subgroup

Acute Dietary

(99.9 Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

General U.S. Population 0.000168 67 0.000008 11

All Infants (<1 year 

old)*

0.000138 55 0.000012 16

Children 1-2 years old* 0.000151 60 0.000012 15

Children 3-5 years old 0.000135 54 0.000009 12

Children 6-12 years old 0.000090 36 0.000006 7.5

Youth 13-19 years old 0.000132 53 0.000004 5.7

Adults 20-49 years old 0.000187 75 0.000008 11

Adults 50-99 years old 0.000175 70 0.000009 12

Females 13-49 years old*

0.000227 91 .0000008 11

*The subpopulations with the highest risk estimates are bolded. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no existing or proposed residential use sites; therefore, residential handler exposure 

and residential post-application exposure are not expected. 

Emamectin benzoate is registered for agricultural uses, as a tree injection use, and as a cockroach 

bait. Except for OptigardTM Cockroach Bait (EPA Reg. No. 100-1290), all registered emamectin 

benzoate end-use products are restricted use products (RUPs; restricted to use by professional 

certified operators [PCOs] only). OptigardTM Cockroach Bait is not a restricted use product but 

EPA has indicated that it is to be used only in commercial and industrial areas. 

Residential exposure is not expected from the registered/proposed products since they are 

agricultural uses rather than residential uses, restricted use products (restricted to use by certified 

applicators only), or limited to non-residential areas (commercial and industrial areas). There are 

no proposed/registered products that would lead to residential handler or post-application 

exposure. Residential exposures from commercial nursery production are expected to be 

negligible because the emamectin is expected to dissipate by the time the plant moves from a 

nursery, through a retail store, to the consumer.

6.1 Residential Handler Exposure

Residential exposure is not expected from the registered products since they are agricultural uses 

rather than residential uses, restricted use products (restricted to use by certified applicators 
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only), or limited to non-residential areas (commercial and industrial areas). Currently registered 

products would not lead to residential handler exposure. There are no proposed uses within the 

US.

6.2 Post-Application Exposure

For reasons stated in Section 6.1 above, no currently registered products would lead to residential 

post-application exposure. Residential exposures from commercial nursery production are 

expected to be negligible because the emamectin is expected to dissipate by the time the plant 

moves from a nursery, through a retail store, to the consumer. There are no proposed uses within 

the US.

6.3 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for emamectin benzoate at this time because the chemical has low 

vapor pressure (3.0 × 10-8 mm Hg at 21 oC) and is applied at a low rate (0.015 lb ai/A). 

However, 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.epa.gov/scipoly/sap/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are developed, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for emamectin benzoate.

6.4 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for emamectin 

benzoate. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.
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Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for occupational flaggers. This exposure scenario is 

representative of a worse case inhalation (drift) exposure and may be considered protective of 

most outdoor agricultural and commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

7.1 Acute Aggregate Risk

Only food and drinking water are included in the acute aggregate assessment, as the Agency does

not routinely assess any one-day residential exposures. Refer to section 5.4.3 for a detailed 

discussion of the acute dietary assessment. 

7.2 Short-/Intermediate-Term Aggregate Risk

Short- and intermediate-term aggregate risk assessments were not conducted because existing 

uses are not expected to result in residential exposure and there are no proposed uses within the 

US.

7.3 Chronic Aggregate Risk

Chronic or long-term aggregate assessments include exposures that will exceed six months. 

Only food and drinking water are included in the chronic aggregate assessment, as the Agency 

does not routinely assess any long-term residential exposures. Refer to section 5.4.4 for a 

detailed discussion of the chronic dietary assessment.

7.4 Cancer Aggregate Risk

Emamectin benzoate is classified as “not likely to be carcinogenic to humans.”

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity (CMT), EPA has not made a common mechanism of toxicity 

finding as to emamectin benzoate and any other substances and emamectin benzoate does not 

appear to produce a toxic metabolite produced by other substances. For the purposes of this 

tolerance action, therefore, EPA has not assumed that emamectin benzoate has a common 

mechanism of toxicity with other substances.
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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 toxicity. This 

guidance defines mechanism of toxicity as the major steps leading to a toxic effect following 

interaction of a pesticide 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 required in order to describe a mechanism of toxicity. For example, a 

mechanism of toxicity may be described by knowing the following: a chemical binds to a given 

biological target in vitro, and causes the receptor-related molecular response; in vivo it also leads 

to the molecular response and causes a number of intervening biological and morphological steps 

that result in an adverse effect. In this context a common 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, sequence of major biochemical events. Hence, the 

underlying basis of the toxicity is the same, or essentially the same, for each chemical. In the 

case of the macrocyclic lactone pesticides (e.g., abamectin, emamectin, and avermectin), 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 GABAA gated 

chloride channels. This is presumed to be the insecticidal mechanism of action of emamectin 

and abamectin as well. Mammals lack glutamate-gated chloride channels; the toxic actions of 

avermectin appear to be mediated via interaction with GABAA and possibly glycine gated 

chloride channels (Kamijima M, Casida JE, 2000). There is evidence that avermectin B1a binds 

to GABAA receptors and activates Clflux 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 associated with adverse outcomes. Thus, while the downstream steps leading 

to toxicity via disruption of GABAA receptor function for avermectin can be postulated, 

experimental data supporting these actions are lacking. In addition, specific data demonstrating 

GABAA receptor interaction in mammalian preparations are lacking for abamectin and 

emamectin. Moreover, the specificity of such interaction on the adverse outcome would need to 

be shown experimentally. GABAA 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 affinity at the [3H]ivermectin site. The authors hypothesized that these findings may be 

related to differential affinity or efficacy at subtypes of the GABAA receptor. Other reports have 

indicated species differences in abamectin effects on GABAA receptor function in the mouse as 

compared to the rat (Soderlund et al., 1987).

In conclusion, although GABAA receptor mediated neurotoxicity is an hypothesis as a common 

mechanism endpoint for the macrocyclic lactone pesticides, data demonstrating the interactions 

of emamectin and abamectin with mammalian GABAA receptors are not available, and data in 

mammalian preparations linking alterations in GABAA receptor function to disruptions in 

neuronal excitability in vitro and in vivo, and ultimately adverse outcome, are also currently 

lacking for this class of compounds. In the absence of such data, the key biological steps leading 

to the adverse outcome (i.e., the mammalian mechanism of action) cannot be established and by 

extension a CMT cannot be established.
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For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

There is no occupational exposure/risk to US workers from importation of wine.

10.0 References

Alsadek, J., Ph.D., 8/21/12, DP Number D403689, Percent Crop Treated for Emamectin 

Benzoate on Proposed New Uses for Cantaloupe, Cucumber, Squash, and Watermelons.

Alsadek, J., Ph.D., 5/29/12, DP Number D401786, Emamectin Benzoate (122806) 

Screening Level Usage Analysis (SLUA).

Dodd, N., 1/19/13, DP Number D393837, Emamectin Benzoate. Revised Human Health 

Risk Assessment for Proposed Uses on Cucurbits and Outdoor-Grown Plants in 

Commercial Nursery Production.

Dodd, N., 2/20/13, DP Number D402152, Emamectin Benzoate: Acute and Chronic 

Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for a 

Tolerance on Imported Wine.

Dodd, N., 4/3/13, DP Number D401837, Emamectin Benzoate. Petition for the 

Establishment of a Permanent Tolerance on Imported Wine. Summary of Analytical 

Chemistry and Residue Data.

Dowen, T., 5/30/12, DP Number D402307, Amended Drinking Water Assessment for the 

Proposed Use of Emamectin Benzoate on Outdoor Ornamentals and Group 9 Cucurbit 

Vegetables.

Raffaele, K., 3/5/03, TXR No. 0051605, EMAMECTIN - 3

rd Report of the Hazard 

Identification Assessment Review Committee.

Xue, M., 1/28/02, TXR#050315, Emamectin. Conclusions of the 12/4/2001 Meeting of 

the HED Metabolism Assessment Review Committee (MARC) Meeting on Livestock 

Metabolism Studies.
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48753807.der: MAB1a/8,9-Z isomer (one peak) and MAB1b. LOQ = 0.01 ppm for each analyte or analyte 

combination for a total method LOQ of 0.02 ppm.

48758308.de1: MAB1a and MAB1b, expressed as MAB1a. The LOQ is 0.001 ppm for each analyte.

48758310.de1: MAB1a/ 8,9-ZB1a (one peak) and MAB1b/ 8,9-ZB1b (one peak). The LOQ is 0.001 ppm for each 

combination of analytes, for a method LOQ of 0.002 ppm.

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 was used for any results reported as <LOQ. NA = not applicable.

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

4

Six field trials in Spain (1 study), France (3 studies), and Switzerland (2 studies); one sample per trial.

5 Three field trials in Italy; one sample per trial.

6 Ten field trials in Spain (2 studies), France (3 studies), Italy (the same 3 studies), and Switzerland (2 studies); one 

sample per trial.

7 One trial in Italy; one sample per trial.