EMAMECTIN BENZOA TE 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 Import e d Wine Grapes.

PC Code: 122806 Decision No. : 463856 Petition No.: NA DP Barcode: D402151 Re gistration No.: NA Re gulatory Action: Tolerance with no Section 3 Case No.: NA Risk Assessment Type: Single Chemical / Aggregate TXRNo. :NA CAS No.: 155569-91-8 40 CFR : 180.505 MRIDNo.:NA



### FROM: Nancy Dodd, Chemist and Risk

### Assess~**~ ~**  Whang Phang, Senior Toxicologist**.- 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 Di v i sion (HED) of the Office of Pesticide Programs (OPP) is charged with estimating th e 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, re sidentia l

, and aggregate exposure assessments, as needed, to estimate th e risk to human health that will resu l t from the proposed tol erance for emamectin benzoate (a benzoate salt mixture of a minimum of 90% 4'-epi-methy l am i no-4'-deoxyavermectin B 1 a and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B 1 b) and its isomers/metabolites/degradates. Syngenta Crop Protection, LLC has proposed establishmen t 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 benzoa te are provided in this document. The residue chemistry revi ew, die t ary assessment, and overall risk assessment were performed by Na ncy Dodd. The toxico logy assessment was performed by Whang Phang. The drinking water exposure assessment was performed 

### b y Tiffany Dowen of the Environmental Fate & 

### Effects Division (EFED).

Page 

### 1 of 41EMAMECTIN B ENZ OATE Human Health Risk Assessment D P No. D402151

TABLE OF CONTENTS 1.0 Executive Summary

. .. .. . .. ... . . ... ..... .. .. . ... . ... . .. . ... . ... .. ..... . .... . ...... .. .. .. ... . . ... .. .... . .... .. .. . . . ...... .. ... . . 4 2.0 HED R e commendations

. . . .. .. .. ...... . .... . . ........... .. ...... .. ...... .... .... .. . . ...... . . . .•

.. ........................... 5 2.1 Data Deficiencies

. .. . ... ..... .. .. . .. .. . ... . .......... . ... . ... . ................. . . . .... . . .. . . .•

... .. .. . ... ... . ... .. .. ....... 6 2.2 To le rance Considerati ons

.. . ......... .. ...... .. . ... . . ......... . . . . .. .. .. .. . .. ....... . ..•

.. ... . ... . .. ... . . ..... ...... . 6 2.2.1 Enforcement Anal ytical Method

... .. .. . ..... . . ................... . ... . ... .. .. . .. ..•

. ..... .. ....... . ... . ... .. ... . 6 2.2.2 I n ter na t ion a l Ha rmonization

... . . .. ... . .. . .... . .. .. ..... ... .. . .. . ... ... . ... . .... . ..... . . ... . ... . ... .. . ..... . . . .. .. 6 2.2.3 Rec ommended Tol erances

... .. .. ..... .. .. .. .. .. .. . .. ...... . .... . ...... .. . ... .. .. . ... ............... . ... .. ... .. .. . . .. 7 2.2.4 Revis i ons t o Petitioned-Fo r Tolerances

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

. . . ... . ....... .... .. ..... .. . . . .. . . ...... . .... . .. .. . ....... . .. ....... . .. . .... . ......... .. ....... .. .. . .... .. . .... . ... . .... . 7 3. 1 Chemical ldentit'y

. . ...... . ...... . . . ... . ..... ... .. ..... .. .. ... . .. .. .. .. .. .. .. .. .. .. ........ . ....... .. .. .. .. ... . ....... ... .. 7 3.2 Physical/Chem i cal Characteristics

.... . .. .. . ....... . .. ... . . . .. ....... . ......... . .•.

. ... . . ...................... 9 3.3 Pesti cide U se Patterns

.. .. .. .. .. . ...... .. .. .. . ... . ...... . ... . ... . ... . ... .. . . ...... .. .. . .. .•

... .. . ... .. ....... . . . . .. .. ... 9 3. 4 Anticipated Exp osure Pathways

. ..... . . ..... . ... .. .. . ... .. . ....... . .. . ........ .. ... . . . . . . ... . . .. ... . ... .. . . ... 11 3.5 C onsidera tion of Environmental Ju stice

.. . ... . .. .. .. . . .. .. ..... . .. ... .. . ... ..•..

... . ... .. .. ....... .. ... . . 11 4.0 Hazard Characterization and Dose-R espo nse Assessment

. . . ....... . . . .. •.

.. .. .. .. .. .. .. .. ....... ... 12 4 .1 Summary of Toxicological Effects

.. .. .. .. .... . . .... . ... . .. .. . . . ... .. .. ... . .. . ....•..

... . . ..... . . ............. 12 4 .2 Safet'y Factor for Infants and Children (FQ PA Safet'y Fa c tor)

. ... ... . ... ........... . .. .... 14 4.2. 1 Completeness of the Toxi co lo gy Database

.................................. . ... .. .. .. ... . ........ . ...... 15 4.2.2 Eviden ce o f N eurotoxicit'y

. .. .. ... . . . . ... . . .. . .. . ...... .. .. . .... . ......... .. ..... . ... .. . •......

.. .. ... . ... . ..... ... . 1 5 4.2.3 Evidence of Sensitivit'y/Susceptibilit'y in the Developing or Young An ima l

. ... ... . . 15 4.2.4 Residual Un certaint'y in the Exp osure Database

........................ . ... ... . .. . .. .. . ...... .. ..... 15 4.3 Tox ici t'y Endpoint and Point of Departure Selections

... . .... . .. . ........ . ....... .. . .. ... .. ...... 1 6 5.0 Di etary Exposure and Risk Assessment

.. . ... .. . ..... .. . .. ...... .. ... . .. .. .. .. ........... .. . .. ... . ............... 16 5.1 Residues o f Conc e rn Summary and Rationale

.. . .. .. .. .. .......... . .. . .. .•

... .. .. . ....... . .. . ... .. . .. 1 6 5.2 F o od Res id ue Profile

. . ..... ... . . .. ..... .. . .. . . .. .. ... . . .... . . ... ........ ..... .. .. .. .. .. .. ...... . . ... . . .... .... ... . . ... 1 8 5.3 Water Residue Profile

........ . .... . . .. .. ..... . .... . .. . ... .. . ... .. .. . ... . .. .......... .. . . . . .. ... . ... . ... .. .. ... . .. ... . 19 5 .4 Dietary Risk Assessment

. ..... . ..... .. .. .. .. .. ... . ..... ... . .. ... . .. .. ...... . ... .. .. .. . ..... .. ... . .. . . . . .... . ... . . .. . 20 5.4. 1 Description of R es idue Data U sed in Dietary Assessment

.. . .. .. . . . .................... ... . . . . . 20 5

. 4.2 Percent Crop Treated Us e d in Di etary Assessm ent

............ . . ... .. . ... . .... . .. ... . ... ... .. . .... 20 5.4.3 Acute Dietary Risk Assessment

. ............ ..... .. .. .. .. .. .. . . . . .. .. . ... .. .. . .. ... .•

... . ... . .. ... . ... . . .. .. ... . 21 5.4.4 Chronic Dietary Risk A sses s men t .

.... . ... . ...... .. . ... . ... . ... .. . .. ... . ....... .. .. ...... .. . ....... ... .. .. . . . . 21 5

. 4.5 Cancer Dietary Risk Assessment

.. ...... . .. .. .. .. .. . ... .......... . .. ... . ... . .. ... .. . ........ . .. ... . . .. .. ...... 22 5.4.6 Summary Table s .. . .. .. . .. .. ... . .. ...... . .. . ... . .. ...... . ... .. . ... . ... . . ........................... ... . ... .. .. ... .. .. ... . 22 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

.. ... . ............... ......... 23 6.1 Resident i al Handler Expo sure

. . . ... .. .. . ... .. . . . . . .. .. .. ...... .. .......... . . . ... . ... . ... ... . ....... .. .. ... . . ... 23 6

. 2 Post-Application Exposure

....... . .............. . . .... . .. . .... . ..... ... . ... . ... . .. .. . . ... .. ........... .. .. ... . .. .. 24 6.3 Residential Byst a n der Post-applicat ion Inhalation Exp osure

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

. .. .. ... . ....... . ....... . . ... .. . ...... . ... .. . . . ... . .......... .. . .. ... . ... . .... . . .. .... .. ... . .. ....... . ... ... .. .. .. 24 7.0 Agg rega te Exp os ure/Risk Characterization

...... . .. .. .............. ... . .. .. .. . . ... . .............. ............ 25 7

. 1 Acut e Ag g r egate Risk

....... . . . ... .. .. .. . . .. . . . . ..... .. . ... . ... . ... . . . ... . ............... . ...... ... .. ... .. . .. .. . . ... .. 25 7

. 2 Short-/Intermediate- Term Aggregate Risk

.. . ............... . .. .. ... . ... . .. .. ....... ........... .. . ..... 25 7.3 Chronic Agg r egate Risk

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

. . .......... . .. ...... . ... .. .. . ...... ... . .. . ..... .. ...... .. .. . ... .. •

. .. . .. ................. .. .. 25 8.0 Cumulative Exposure/R isk Characterization

............. ................ . ... . .. .................. .......... 25 9 .0 Occupational Ex posure/Risk Characterization

......... .. ...... ... . ............... . . .. ... . . .. ... .... .. ..... 27

Page 2 of 41EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 3 of 41 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 Litera ture References

................................ ................................ ...... 38 Appendix E. Crop Field Trials

................................ ................................ ................................ . 40EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 4 of 41 1.0 Executive Summary

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

- soluble granul e ( SG ) formulations on grapes in various coun tries other than the US. Label information has been submitted for France, Italy, Spain, Portugal, Greece, Australia, and New Zealand. The maximum label rate s for the various countries range from 4

- 5 7 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 toxicit y 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.”

Die tary 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

somew h at refined assessment for food and drinking water using single point estimate s (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 def aul t 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 w ere used for apples since apple juice contributed signi ficantly 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 d rinking 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 ornamental s 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 99.9 th 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 )

.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 5 of 41 The chronic dietar y 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 ch ronic population adjusted dose [ cPAD ] for the general U.S. population and 16 % of t he 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 assessm ents 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 ex posure 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 dri nking 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 j ustice concerns were considered in th is 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, t he dietary

- exposure database will be adequate to support the proposed tolerance on grape, wine

. The toxicology database for emamectin benzoate is largely complete. A n 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 u nder 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 S ection 2.1 below. The specific tolerance recommendations are discussed in Section 2.2 . There are no label modifications since there are no US label s for this action.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 6 of 41 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 B 1a and maximum of 10% 4'

- epi

- methylamino

- 4'

- deoxyavermectin B 1b ) and its metabolites 8,9

- isomer of the B 1a and B 1b component of the pare nt (8,9

- ZMA), or 4'

- deoxy

- 4'

- epi

- amino

- avermectin B 1a and 4'

- deoxy

- 4'

- epi

- amino

- avermectin B 1b ; 4'

- deoxy

- 4'

- epi

- amino avermectin B 1a (AB 1a ); 4'

- deoxy

- 4'

- epi

- ( N

- formyl

- N

- methyl)amino

avermectin (MFB 1a ); and 4'

- deoxy

- 4'

- epi

- ( N

- formyl)amino

- avermectin B 1a (FA B 1a ), calculated as the stoichio metric equivalent of emamectin.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate method s ( 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 method s determine residues of emamectin in t he following analyte combinations: MAB 1a + 8,9

- ZB 1a , MAB 1 b + 8,9

- ZB 1b , AB 1a , and MFB 1a + FAB 1a , 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

A s shown in Appendix C , harmonization issues regarding both the tolerance level and tolerance expression are associated with this petition. T here is a Codex maximum residue limit (MRL) for
grape s 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

Page 7 of 41 2.2.3 Recommended Tolerances

The proposed and recommended tolerance s for wine are presented in Table 2.2.3

.
The petitioner has proposed e st ab l i s h m e n t o f a to l e ra n ce f o r t h e resi d u e s o f e m a me c tin b en z oa t e ( a b en z oa te s a lt m i x t u re o f a m i n i m u m o f 9 0 % 4 '

- e p i

- me t h y la m in o

- 4 '

- deo xy a v e r me ctin B 1 a a n d a ma x i m u m o f 1 0 % 4'

- e p i

- me t h y la m in o

- 4 '

- d eo xy a v e r me c t in B 1 b )

r e s u lting f

r o m t h e app l i c a t i o n o f em am e ctin b en z oa t e i n o r o n wine at 0.005 ppm.

Tolerances for emamectin are established under 40 CFR § 180.505 for the combined residues of emamectin ( MA B 1a and MA B 1b ) , the 8,9

- Z isomer s of parent, and the metabolites /degradates AB 1a , MFB 1a and FAB 1a . The tolerance expression proposed by the petitioner is not appropriate. A revised Section F must be sub mitted 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 B 1a and maximum of 10% 4'

- epi

- methylamino

- 4'

- deoxyavermectin B 1b ) and its metabolites 8,9

- isomer of the B 1a and B 1b component of the parent (8,9

- ZMA), or 4'

- deoxy

- 4'

- epi

- amino

- avermectin B 1a and 4'

- deoxy

- 4'

- epi

- amino

- avermectin B 1b ; 4'

- deoxy

- 4'

- epi

- amino averm ectin B 1a (AB 1a ); 4'

- deoxy

- 4'

- epi

- ( N

- formyl

- N

- methyl)amino

- avermectin (MFB 1a ); and 4'

- deoxy

- 4'

- epi

- ( N

formyl)amino

- avermectin B 1a (FAB 1a ), calculated as the stoichio metric equivalent of emamectin.

Table 2.2.3

. Tolerance Summary for Emamectin Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Wine 0.0 05 0.0 5 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 determ ine 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 In troduction

3.1 Chemical Identity

Emamectin benzoate i s a semi

- synthetic avermectin, consisting o f two active homologous compounds (a benzoate salt mixture of a minimum of 90% 4'

- epi

- methylamino

- 4'

- deoxyavermectin B 1a and a maximum of 10% 4'

- epi

- methylamino

- 4'

- deoxyavermectin B 1b ).EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 8 of 41 Table 3.1

. Test Compound Nomenclature

Chemical Structure

Empirical Formula emamectin benzoate B 1a : C 49 H 75 NO 13 • C 7 H 6 O 2

emamectin benzoate B 1b : C 48 H 73 NO 13 • C 7 H 6 O 2 Common Name emamectin benzoate Company experimental name MK244

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

- 3

- O

- methyl

- 4

- O

- (2,4,6

- trideoxy

- 3

- O

methyl

- 4

- methylamino

- α

- L

- lyxo

- h exapyranosyl)

- α

- L

- arabino

- hexapyranoside benzoate 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 )

- 21,24

- dihydroxy

- 6'

- isopropyl

- 5',11,13,22

- tetramethyl

- 2

- oxo

- (3,7,19

- trioxatetracyclo[15.6.1.1 4,8 .0 20,24 ]pentacosa

- 10,14,16,22

- tetraene)

- 6

- spiro

- 2'

- (5',6'

- dihydro

- 2' H

- pyran)

- 12

- yl 2,6

- dideoxy

- 3

- O

- methyl

- 4

- O

- (2,4,6

- trideoxy

- 3

- O

methyl

- 4

- methylamino

- α

- L

- lyxo

- hexapyranosyl)

- α

- L

- arabino

- hexapyranoside benzoate CAS Name (4''R)

- 4''

- deoxy

- 4''

- (methylamino)avermectin B 1 benzoate (salt) CAS Registry Number 155569

- 91

- 8 (formerly 137512

- 74

- 4)

End

- use product s /EP s SG and WG 1 formulations: 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

1 WG formulations are water dispersible granular formulations.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 9 of 41 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 (K OC 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 Pattern s
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. U se directions have been submitted for France, Italy, Spain, Portugal, G reece, 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 cro p 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 als o 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

Page 10 of 41 T able 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% SG 1 0.0017 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.

Us e 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.

T h e d i r e cti o n s f

o r use o f e m a me c tin b en z oa t e o n w ine g ra pe s g rown in re p r e s en t a ti v e c oun tries

o f E u ro p e an d in A u stralia a n d N e w Ze a la n d a re s u m m a r i z e d in Table 3.3.2

.

Table 3.3.2

. Summary of Directions for Use of Emamectin Benzoate on W i ne Gr a p es
Co un try % US i m

po r t s f o r US Consumption a ai

Conc. h M a x

app s /

se a so n Maximum Application Rate PHI ( da y s ) M in

. Re t r ea t men t I n t e r v a l ( da y s ) O n lab e l kg

EP/ha per app. g ai/ha per app. g ai/ha

per
season

France 28.62 0

. 95 % 3 1 .5 k g / h a 1.5 14.25 b 42.75 7 14 Italy 28.402 0

. 95 % 3 1 .5 k g / h a 1.5 14.25 b 42.75 14 14 Spain 6.031 8

. 5 5 g / k g (0.855%) 1 1 .5 k g / h a 1.5 12.825 c 12.825 7 Not applicable Portugal 1.484 0.85% 4 1 .5 k g / h a 1.5 12.825 c 51.3 7 10 Greece 0

. 21 3 0

. 95 % w/w 4 150

g/1000

m 2 1.5 d 14.25 d 57 7 14

Australi

a 15

. 9 1 3 44 g/kg (4.4%) 2 75 g/ha 0.075 3.3 e 6.6 56 7

New Zealand 3

. 32 3 50 g/kg (5 .0 %) 2 40 g/ha 0.040 f 2.0 f 4 g g

a. US D A Fo r eig n A g r i cu l t u re S e r v ice

. h t t p : / / w w w

. fas

. usd a

. go v / ga t s / de f a ul t

. asp x
b

. ( 1 .5 k g EP/ h a

/ a p pl i ca t ion ) x ( 100 0 g E P / k g EP) x ( 0

. 9 5 g ai /1 0 0 g EP) = 14

. 2 5 g ai /h a / ap p l i ca t i o nEMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 11 of 41 c

. ( 1 .5 k g EP/ h a

/ a p pl i ca t ion ) x ( 8

. 5 5 g ai / k g EP) = 1 2

. 8 2 5 g ai / ha / a p pl i ca t io n
d

. ( 15 0 g E P / 10 0 0 m 2 / a p pl i ca t io n ) x ( 10

, 00 0 m 2 / ha ) = 1 5 0 0 g E P/ ha / a p pl i ca t io n ( 150 0 g EP/ h a

/ ap p l i ca t i on ) x 1 k g EP/ 1 00 0 g EP) = 1 .5 k g E P/ ha / a p pl i ca t io n ( 150 0 g EP/ h a

/ ap p l i ca t i on ) x ( 0

. 9 5 g ai / 1 0 0 g EP) = 1 4

. 2 5 g ai /h a

e

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

ha / a pp l ic a t ion ) x ( 4 4 g ai /kg EP) = 3

. 3 g ai / ha / app l ica t io n

f. ( 4 0 g EP /

ha / a pp l ic a t ion ) x (1 k g EP/ 10 0 0 g EP) = 0

. 04 0 k g E P/ ha / a p pl i ca t io n ( 0

. 04 0 k g E P / ha

/ app l i c a t i o n ) x ( 5 0 g ai /

k g EP) = 2

. 0 g ai / ha

/a ppl i ca t io n

g

. A ppl i ca t i o n s c a n b e m a d e a t a n y tim e fr o m p o s t

- f l o w e r in g to p r e

- bu n c h c l osu r e.
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 e mamectin 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, h umans may be exposed to emamectin benz oate in food and drinking water, since emamectin benzoate may be applied directly to growing crops and application may result in emamectin benzo ate 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 en vironmental 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

- establ ished 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 ass essments 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 po st

- 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 farmEMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 12 of 41 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 w idespread binding but particularly abundant in the cerebellum (Wang and Pong, 1982). Through action on the enteric nervous system and induction of l ongitudinal rhythmic contractions in the isolated ileum , e mamectin

, 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

rec eptor 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 P

glycoprotein (P

- gp). P

- glycoprotein is a member of the ATP binding cassette transporter proteins, which reside in the plasma membrane and function as a trans membrane efflux pump, moving xenobiotics from the intracellular to the extracellular domain against a steep concentration gradient with ATP

- hydrolysis providing the energy for ac tive transport (Marzolini et al , 2004). P

- gp is found in the canallicular sur face 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 ofEMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 13 of 41 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, t he 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 sens itivity was seen in developmental toxicity studies in rats and rabbits, increased qualitative and/or quantitative sensitivity of rat pups was se en in the reproductive toxicity and in the developmental neurotoxicity stud ies

. In the reproduction study, whol e body tremors, hind limb extension, and hind limb splay were seen in the F 1 and F 2 pups while these clinical signs were not seen in F 0 parental animals at similar dose levels. In addition, a greater incidence of decreased fertility was seen in the F 1 par ental females than in the F 0 females. In the developmental neurotoxicity study, no maternal effect was seen at the highest dose tested whereas dose

- related decrease in open

field 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 F 1 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 lesion s in the brain and spinal cord), and (3) the decreased fertility seen in F 1 adults might have been due to histopathological lesions in the brain and central nervous system (seen in both F 0 and F 1 generations), rather than due to a direct effect on the
repr oductive 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.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 14 of 41 The carcino genicity and mutagenicity studies provide no indication that emamectin is carcinogenic or mutagenic. Emamectin is classified as “not likely to be carcinogenic to huma ns.” A toxicity profile for emamectin is presented in Appendix A.

The acute toxicity studies indicate that e mamectin has low to moderate acute toxicity by the oral

, dermal and inhalation route s. It is not irritating to the skin, nor is it a dermal sensi tizer

. 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 inhalati on 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 F actor 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 result ing 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 sho rt

- 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 CF

1 mouse study used to determine the acute toxicity endpoint for risk assessment; (2) Although the ef fects 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.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 15 of 41 4.2.1 Completeness o f the Toxicology Database

The toxicology da tabase 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 i mmunotoxicity study (OPPTS 870.7800) , which is required under current guidelines, was submitted on 10/24/12 to RD and turned over to P RD for tracking/review under Registration Review.

Immunotoxicity study The risk assessment team evaluated subchronic, ch ronic, 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, res pectively; therefore, a database uncertainty factor is not necessary pending review of the submitted immunotoxicity study.

4.2.2 Evidence of N eurotoxicity

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 o f Sensitivity/Su sceptibility in the Developing o r 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 detail s in Section 4.1: Summary of Toxicological Effects).

4.2.4 Residual Uncertain ty in the Exposure Datab ase
The assessment for food incorporate s 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,

e xposures to r esidues 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

.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 16 of 41 4.3 Toxicity Endpoint and Point of D eparture 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 classific ation

. 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 Assessments 1

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 UF A = 10x

UF H = 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 UF A = 10x

UF H = 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 increas es 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 obs erved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor

. ( 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 sho rt

- 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. ) P AD = population adjusted dose (a = acute, c = chro nic). 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 [ 14 C]emamectin B 1a (MAB 1a ) was the parent MAB 1a . The isomer 8,9

- ZB 1a and the metabolites/degradates AB 1a , MFB 1a , and FAB 1a were identified at <5% of the TRR. MAB 1a initially degrades rapidly to a large number of residues of MAB 1a - like struct ures, nearly all contributing only a small amount to the total residue; these initial degradates undergo furtherEMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 17 of 41 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 (MAB 1a + MAB 1b ), are the only major residue s found in goat milk, fat, meat and meat byproducts. However, the analytical method for the determination of residues of emamectin and its metabolit es in livestock commodities can not distinguish between the parent compounds and its metabolites, 8,9

- ZMA (8, 9

- ZB 1a + 8,9

- ZB 1b ). In the absence of toxicity data, the metabolites 8,9

- ZMA (8,9

- ZB 1a + 8,9

- ZB 1b ) 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 a re 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

Plants 1 Primary Crops emamectin (MAB 1a + MAB 1b ), the associated 8,9

- Z isomers (8,9

- ZB 1a + 8,9

- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a and FAB 1a emamectin (MAB 1a + MAB 1b ), the associated 8,9

- Z isomers (8,9

- ZB 1a + 8,9

- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a and FAB 1a Rotational Crops Same as for primary crops Same as for primary crops

Livestock 1 Ruminant emamectin (MAB 1a + MAB 1b ) and its 8,9

- Z isomers (8,9

- ZB 1a and 8,9

- ZB 1b ) emamectin (MAB 1a + MAB 1b ) and its 8,9

- Z isomers (8,9

- ZB 1a and 8,9

- ZB 1b )
Poultry Not applicable Not applicable
Drinking Water 2 emamectin (MAB 1a + MAB 1b ), the associated 8,9

- Z isomers (8,9

- ZB 1a + 8,9

- ZB 1b ), 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 (MAB 1a + MAB 1b ), the associated 8,9

- Z isomers (8,9

- ZB 1a + 8,9

- ZB 1b ), and the metabolites/degradates AB 1a , MF B 1a , and FAB 1a . 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)

.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 18 of 41 5 .2 Food Residue Profile

DER References: 48758306.de r, 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. T he residue data are summarized in Appendix E

. Residue data were submitted from France, Italy, Spa in, 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 re flect the maximum submitted use pattern for grapes, a n d the number and locat ions 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 MAB 1a + MAB 1 b , expressed as MAB 1a , 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 0.29 x ). T he processing factor is less than the theoretical concentration factor of 1.2 x for juice (based separation of components; OPPTS 860.1520, Table 3).

Storage St ability : The storage stability data demonstrate that residues of MAB 1a , MAB 1b , 8,9

- ZB 1a , and metabolites/degradates AB 1a , FAB 1a and MFB 1a 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 MFB 1a in tomato paste, in which the average corrected recovery was 67%. An acceptable method was used for quantitation of residues.

The available s torage 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 froze n 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 c orrections for residue decline during storage are needed.

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

R otational Crops : There are no rotational crop issues associated with imported wine.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 19 of 41 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 E FED in the following memorandum : “ Amended Drinking Water Assessment for the P roposed U

se of Emamectin Benzoate on O utdoor O rnamentals and Group 9 C ucurbit V egetables” (Tiffa ny 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 provid ed 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 fo r 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 a verage (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.

T he 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 asses sment 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 e nvironmental fate data parameters for modeling using the Guidance for Selecting I nput 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 a nd Ground w ater Concentrations for Emamectin

Benzoate. a , d

Scenario Surface Water Conc., ppb b Ground w ater 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 - 3EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 20 of 41 Table 5.3

. Summary of Estimated Surface Water a nd Ground w ater Concentrations for Emamectin

Benzoate. a , d

Scenario Surface Water Conc., ppb b Ground w ater 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 gu idance.

c From the SCI

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

d “ Amended Dri nking Water Assessment for the Proposed Use of Emamectin Benzoate on Outdoor Ornamentals and Group 9 Cucurbit V

egetables” (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. P ercent crop treated data provided by the Biological and Economic Analysis Division (BEAD) in 2012 were use d. 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.

Ch ronic 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 t olerance

- 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 u se on ornamentals ; it result s in the highest chronic EDWC considering all registered uses.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The followin g maximum percent crop treated estimates [ D 401786, 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%.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 21 of 41 The following average p ercent 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, 1 0%; broccoli, 5 %; cabbage, 10 %; cauliflower, 1 0%; celery, 25 %; cotton, 1%; lettuce, 1 0%; pears, 5 %; pepper s, 5%; spinach, 5 %; and tomatoes, 1 0%.

The following percent crop treated estimates

, which were provided for the cucurbit petition in 2012 (D 403689 , Jihad Alsadek, 8/ 21 /12)

, were used in th e acute dietary risk assessment: cantaloupe, 51 %; cucumber, 26%; s quash, 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)

, w ere 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

T he 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, t he most highly exposed subgroup was fema les 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 us e of more monitoring data and of food preparation

reduction factors for washing, cooking, etc. may have re sulted in more refined estimate s 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

T he 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
y ears old , adults 20

- 49 years old , females 13

- 49 years old , and adults 50

- 99 y ears 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 f ood 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

-EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 22 of 41 reduction factors for washing, cooking, etc. may have re sulted in more refined estimate s of dietary exposure. More highly refined analys es 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 increas es in two adequate rodent carcinogenicity studies.

5.4.6 Summary Tabl e s
The results of the acute dietary (food + drinking water) exposure analysis at the 95 th , 99 th , and 99.9 th percentiles of exposure are reported in Table 5.4.6.1 below

. T he acute dietary exposure estimates for food and drinki ng water using the ornamentals scenario for drinking water are below HED’s level of concern at the 99.9 th percentile of exposure for the general U.S. population and a ll population subgroups ( 67 % of the aPAD for the general U.S. population and 91 % of the aPAD for females 13

- 49 ye ars 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) 95 th Percentile 99 th Percentile 99.9 th 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 b elow. 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

.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 23 of 41 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 cockro ach 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 n ot 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, re stricted 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

R esidential 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 applicatorsEMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 24 of 41 only), or limited to non

- residential areas (commercial and i ndustrial areas). C urrently 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, n o currently registered products would le ad 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 c onsumer. 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 benz oate at this time because the chemical has low
vapor pressure ( 3.0 × 10 - 8 mm Hg at 2 1 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, de velop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agen c y may revisit the need for a qu antitative post

- application inhalation exposure assessm e nt 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 appropriate ly 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 practi ces to reduce off

- target drift with specific products with significant risks associated with drift.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 25 of 41 Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treat ed 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 comme rcial p os t

- 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 reside ntial 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 do es not routinely assess any one

- day residential exposures. Refe r 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. O nly food and dri nking 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.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 26 of 41 OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanis m 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 f ollowing 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 des cribe 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 molecu lar 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 e ffect 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), t here 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 chloride channels. T his 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 GABA A and possibly glycine gated chlo ride channels (Kamijima M, Casida JE, 2000). 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 alt erations 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 GABA A receptor function for avermectin can be postulated, experimental data supporting these actions are lacking. In addition

, specific data demonstrating GABA A receptor in teraction 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. GABA A receptors have multiple binding sites which have been proposed to relate to adverse outcomes. For example, Dawson et al (20 00) showed for a group of a vermectin

- 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 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 a l., 1987).

In conclusion, although GABA A receptor mediated neurotoxicity is a n hypothesis as a common mechanism endpoint for the macrocyclic lactone pesticides, data demonstrating the interactions of emamectin 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 lacking for this class of compounds. In t he 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 CM T cannot be established.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 27 of 41 For information regarding EPA’s efforts to determine which chemic als 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.

1 0.0 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 N umber 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 D 402307, Amended Drinking Water Asses s ment for the Proposed Use of Emamectin Benzoate on Outdoor Orna mentals and Group 9 Cucurbit Vegetables

. Raffaele, K., 3/5/03, TXR No. 0051605, E MAMECTIN

- 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 Meta bolism Assessment Review Committee (MARC) Meeting on Livestock Metabolism Studies.EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D402151

Page 41 of 4 1 48753807.der: MAB 1a

/8,9

- Z isomer (one peak) and MAB 1b. LOQ = 0.01 ppm for each analyte or analyte combination for a total method LOQ of 0.02 ppm. 48758308.de1: MAB 1a and MAB 1b, expressed as MAB 1a . The LOQ is 0.001 ppm for each analyte. 48758310.de1: MAB 1a/ 8,9

- ZB 1 a (one peak) and MAB 1b / 8,9

- ZB 1b (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 = n ot 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.