### EMAME CT IN B ENZ OATE Human Heal th Risk Assessment DP No . D 393837



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D.C

. 2 046 0

OFFICE OFCHEM I CAL SAF E TY A N D
POLLUTION PREVE N TION



### MEMORANDUM

Date: 1 / 9 /13



### SUBJECT: Em amectin Benzoate. Revised Human Health Risk Assessment fo r Proposed

Uses on Cucurbits and O u tdoor -G rown Plants in Co mm e r cial Nursery Production.

PC Co de: 1 22806

Dec i sion No.: 452138

Petition No

. : NA DP Barcode: 0393837 Registrat i on Nos.: 100-904, 100 -R U RR

R eg ulat o r y Action: Sect ion 3 Registration

Case No. : NA Risk Assessment Ty p e: Single ChemicaVAggregate

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

40 CF R: 180 .505 MRID No.: NA



### FROM : Nancy Dodd, Chemist and

### ~~..A~**'li;...:** 

# rJ::--;rA-·e-tG/
Nancy T saur, Chemist i

. 

# N U**~** 

# /

Whang Phang

, T oxico l og i st ../

....

## ~~ Ri sk Assessment Branch III (RAB3) 0

Health Effec t s D ivision ( HED ; 7509P )



### THROUGH: J eff Dawson

, Acti ng Bran ch Chief

RAB3/HED (750 9P)



### TO: Barbara Madden/Andrew Ert man
, RM #S



### Risk Integration, Minor Use, and E m ergency Response Branch Registration Di visi on (RD; 7505P)

Th e H ealt h Effects Division (HED) ofthe Office of Pe s ticide Programs (O PP ) is charged with estimating the ri sk to human health from exposure to pesticides. The Registration Division (RD)

ofOPP has requested that HED e val uate hazard and exposure data and conduct die tary, occupational

, residentia l

, and aggregate exposure assessme nt s, as ne eded, to estimate the risk to
human health th at wi ll result from the propos ed uses of emamectin benzoate (a benzoate salt

m i xture of a minim u m of90% 4'

- e pi-me thylamino-4'-deoxyavermectin B 1 a 

### and a maximum of

10% 4 '-e pi-m e th ylamino-4'- d e oxyavermectin B 1 b) 

### and its isomers / metabolites / degradates. The

In terregiona l Research Projec t No.4 ( IR-4 ) ha s p r oposed to register the us e and estab li s h a toleranc e on cucu rbi t vegetab l es (Crop Group 9). Syngenta has a l so proposed to register use on outdoor-grown ornamental plants in commercial nur se ry production, including field

- and container-grown ornamentals. This re vised memo incorporate s re sul ts using the Dietary Exposure Eva luation Model softw are wit h the Food Commodity Intak e Database ( D EEM

Page 1 of62

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

FCID), Version 3.16.

A summary of the findings and an assessment of human risk resulting from the registered and proposed uses for emamectin benzoate are pro vided in this document. The residue chemistry

rev i ew, dietary assessment, and overall risk assessment were performed b y Nancy Dodd. The occupational/residential assessmen t was performed by Nancy Tsaur. The toxicology assessment

was performed by Whang Phang. The drinking water exposure assessment was performed by Tiffany Dowen of the Environmental Fate & 

### Effec ts Di vision (EFED).

Page 2 of62

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 3 of 62 TABLE OF CONTENTS

1.0 Executive Summary

................................ ................................ ................................ ............ 5

2.0 HED Recommendations

................................ ................................ ................................ ..... 8

2.1 Data Deficiencies

................................ ................................ ................................ .......... 8

2.2 Tolerance Considerations

................................ ................................ .......................... 10

2.2.1 Enforcement Analytical Method

................................ ................................ ............... 10

2.2.2 International Harmonization

................................ ................................ .................... 10

2.2.3 Recommended Tolerances

................................ ................................ ......................... 10

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 11

2.3 Label Recommendations

................................ ................................ ............................ 11

2.3.1 Recommendations from Residue Reviews

................................ ............................... 11

2.3.2 Recommendations from Occupational Assessment

................................ ................ 11

2.3.3 Recommendations from Residential Assessment

................................ .................... 13

3.0 Introduc tion

................................ ................................ ................................ ....................... 13

3.1 Chemical Identity

................................ ................................ ................................ ....... 13

3.2 Physical/Chemical Characteristics

................................ ................................ ........... 14

3.3 Pesticide Use Patterns

................................ ................................ ................................ 15

3.4 Anticipated Exposure Pathways

................................ ................................ ............... 17

3.5 Consideration of Environmental Justice

................................ ................................ .. 17

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ........... 18

4.1 Summary of Toxicological Effects

................................ ................................ ............ 18

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

.............................. 21

4.2.1 Completeness of the Toxicology Database

................................ ............................... 21

4.2.2 Evidence of Neurotoxicity

................................ ................................ .......................... 22

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

......... 22

4.2.4 Residual Uncertainty in the Exposure Databas e

................................ ..................... 22

4.3 Toxicity Endpoint and Point of Departure Selections

................................ ............ 23

5.0 Dietary Exposure and Risk Assessment

................................ ................................ .......... 25

5.1 Residues of Concern Summary and Rationale

................................ ........................ 25

5.2 Food Residue Profile

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

5.3 Water Residue Profile

................................ ................................ ................................ 28

5.4 Dietary Risk Assessment

................................ ................................ ............................ 29

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ...... 29

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 30

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 30

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ............. 31

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ .............. 31

5.4.6 Summary Tables

................................ ................................ ................................ ......... 31

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

.............................. 33

6.1 Residential Handler Exposure

................................ ................................ .................. 33

6.2 Post

- Application Exposure

................................ ................................ ........................ 33

6.3 Residential Bystander Post

- application Inhalation Exposure

............................... 33

6.4 Spray Drift

................................ ................................ ................................ .................. 34

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 4 of 62 7.0 Aggregate Exposure/R isk Characterization

................................ ................................ ... 34

7.1 Acute Aggregate Risk

................................ ................................ ................................ . 34

7.2 Short

- /Intermediate

- Term Aggregate Risk

................................ ............................. 34

7.3 Chronic Aggregate Risk

................................ ................................ ............................ 35

7.4 Cancer Aggregate Risk

................................ ................................ .............................. 35

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ 35

9.0 Occupational Exposure/Risk Characterization

................................ ............................. 36

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ . 36

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................. 39

9.2.1 Dermal Post

- Application Risk

................................ ................................ ................... 39

9.2.2 Occupational Post

- Application Inhalation Exposure

................................ ............. 39

10.0 References

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

................................ .................. 42

A.1 Toxicology Data Requirements

................................ ................................ ................. 42

A.2 Toxicity Profiles

................................ ................................ ................................ .......... 43 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 51 Appendix C. Review of Human Research

................................ ................................ ................ 52 Appendix D. Occupational Exposure/Risk Summary Tables

................................ ................ 53 Appendix E. International Tolerances

................................ ................................ ..................... 60 Appendix F. Toxicology Literature References

................................ ................................ ...... 61

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 5 of 62 1.0 Executive Summary

Use Profile : Emamectin benzoate will be applied as a 5% soluble granule ( SG ) formulation (Proclaim® Insecticide; EPA Reg. No. 100

- 904) to cucurbits for control of armyworms, cabbage looper, corn earworm, melon worm, rindworms, tobacco budworm, pickleworm, and Lirioyza

leaf miners

. Proclaim® Insecticide may be applied as a foliar spray via aircraft (except in New York State) or groundboom. Chemigation is prohibite d. For high pest infestations, the maximum single application rate is 4.8 oz/A (0.015 lb ai/A). Applications may be repeated at a

7

- day interval to maintain control, up to a maximum seasonal application rate of 28.8 oz/A (0.090 lb ai/A/season). The preharvest interval (PHI) is 6 days. The proposed restricted entry

interval (REI) is 12 hours.

Emamectin benzoate is also proposed for use on outdoor

- grown plants in commercial nursery production to control lepidopterous larvae (worms/caterpillars) and to suppress leaf miners and spider mites

. Enfold TM Insecticide (EPA Reg. No. 100

- RURR), a 5% SG formulation, may be applied as a foliar spray via groundboom, airblast, or aircraft (except in New York State). Chemigation is prohibited. For high pest infe stations, the maximum single application rate is 4.8 oz/A (0.015 lb ai/A). Applications may be repeated at a 7

- to 14

- day interval to maintain control, up to a maximum seasonal application rate of 28.8 oz/A (0.090 lb ai/A/season). The proposed REI is 12 hours.

Human Health Risk Assessment :

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 sacrif ice 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 l ikely 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

somew h at refin ed 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 new and registered crops, DEEM

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 6 of 62 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 u sed for apples since apple juice contributed significantly to the exposure. The 10X FQPA safety factor was retained

for chronic assessments and reduced to 3X for acute assessments.

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/EXA MS 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 at the 99.9 th 

### percentile of exposure for all population subgroups ( 36 % of the acute population adjusted dose [ aPAD ] for the general U.S. population and 60 % of the aPAD for children 1

- 2 years old , the population with the highest

exposure )

.

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 ( 7. 5 %

of the ch ronic population adjusted dose [ cPAD ] for the general U.S. population and 16 % 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 exp ected.

E mamectin 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. Proclaim®

Insecticide is an RUP which is proposed for use on cucurbits

. Enfold TM Insecticide is an RUP

which is proposed for use on outdoor

- grown plants in commercial nursery production

. 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.

Aggregate Risk: The acute aggregate risk assessment takes in to 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 or p roposed uses.

The long

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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 7 of 62 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:

Occupational Handlers There is potential for short

- and intermediate

- term occupational exposure to emamectin benzoate during handling activities (e.g. mixing, loading, application) for the proposed uses (cucurbit vegetables and outdoor

- grown ornamentals). However, intermediate

- term exposure is less likely due to resistance management, and short

- term sc enarios are more realistic. Emamectin is a Group 6 insecticide that has inherent risks of resistance development. It is strongly advised to be used in a sound resistance management program. Due to changes in unit exposure values and body weight assumptio ns, a ll of the occupational handler exposure and risk estimate tables have been updated in this document since the two occupational and residential exposure (ORE) risk assessments previously conducted by Nancy Tsaur (DP390778, 12/07/2011; and DP393839,

03/ 01/2012)

.

Based on the personal protective equipment ( PPE ) required on the label s , there are some risks of concern. Table 9.1 shows the PPE proposed on both labels (EPA Reg. No. 100

- 904 and EPA Reg. No. 100

- RURR) along with mitigation recommendations bas ed on short

- and intermediate

term risk estimates. In order to achieve risk estimates that do not exceed HED’s level of concern ( LOC ; Aggregate Risk Indexes [ ARIs ] > 1.0), the recommendations based on intermediate

- term exposure are more stringent. Howeve r, when considering resistance management, the short

- term risk estimates are more representative of realistic exposure potential.

Occupational Post

- Application There is a potential for short

- and intermediate

- term occupational exposure during post

applica tion activities. However, intermediate

- term exposure is less likely due to resistance management, and short

- term scenarios are more realistic. HED recommends utilizing the results

from the short

- term quantitative risk assessment because the intermediate

- term results are highly conservative and unlikely. For short

- term exposure duration, a ll scenarios resulted in margins of exposure ( MOEs ) greater than the short

- term LOC of 3 00 (ranging from 520 to 11,000) on day 0 (12 hours after application) and

, therefore

, are not of concern to HED

.

Restricted Entry Interval Typically, under the W orker Protection S tandard ( WPS ) for Agricultural Pesticides , a ctive ingredients classified as acute T oxici ty Category III or IV for acute dermal, eye ir r itation, and

pr imary s kin i rritation are assigned a 12

- hour REI

.

Environmental Justice Considerations :

Environmental j ustice concerns were considered in th is assessment. Refer to Section 3.5.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 8 of 62 Review of Human Research:

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. The se studies (listed in Appendix C ) have been determined to require a review of their ethical conduct, and have received that review.

Additional Data Needs:

Provided a revised Section F and some analytical reference standards are s ubmitted before registration, t he dietary

- exposure database will be adequate to support the proposed registration

on cucurbits. T here is sufficient information available to assess occupational handler exposure to

emamectin benzoate. The toxicology database for emamectin benzoate is largely complete.
However, a n immunotoxicity study (OPPTS Guideline Number 870.7800) is now required for conventional pesticide registration (4 0 CFR Part 158). Additionally, a subchronic (28

- day) inhalation toxicity study (OPPTS GLN 870.3465) is needed for a more accurate assessment of toxicity via the inhalation route, and for inhalation risk assessments for exposures associated

with the existi ng and proposed use pattern s

.

2.0 HED Recommendations

Provided a revised Section F and analytical reference standards are submitted, HED can recommend for a registration and tolerance for the use of emamectin benzoate on cucurbit vegetables and for registration of the use on outdoor

- grown ornamental plants in commercial nursery production. Additional data are needed as outlined in S ection 2.1 below. The specific

tolerance recommendations are discussed in Section 2.2, and label modification s are discussed in

S ection 2.3

.

2.1 Data Deficiencies

Data that needs to submitted prior to establishing a tolerance or allowing a registration:

Residue Chemistry

OPP TS 860.1550 Proposed Tolerance

A revised Section F must be submitted proposing a tolerance for Vegetable, cuc u rbit, group 9 at 0.02 ppm.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 9 of 62 OPPTS 860.1650 Submittal of Analytical Reference Standards

The standard for the 8,9

- Z isomer of B 1 a 

### (NOA 438376) expired on 3/31/2012. An updated certificate of analysis or a new analytical reference standard must be provided to the EPA National Pesticide Standards Repository.

Analytical reference standards for MFB 1a 

### (NOA415692) and 8,9

- Z B 1b 

### are currently unavailable at the Repository. A nalytical reference standards must be provided.

Toxicology

870.3465 Subchronic Inhalation

A subchronic inhalation study is needed. HED determined there was a data gap for a

28

- day inhalation study. This study should be performed using the CF

- 1 mouse.

870.7800 Immunotoxicity

An immunotoxicity study is needed

.

Occupational Exposure

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DF R stud ies are required when a pesticide has residential or occupational

uses t hat could result in post

- application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR 

### ).

This default value is 25 % and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessments. Of the analyzed DF R studies, the maximum F AR 

### value seen was

89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided

th at a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE >

400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council ). A DF R study is required for emamectin benzoate at this time since the dermal MOE is less than 4 times the LOC based on default values for the fraction of application rate available for transfer after a foliar application.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 10 of 62 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 the 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

Codex ( Report of the Codex Alimentarius Commission , Rome, 2012) has a proposed tolerance on cucurbits at 0.007 ppm for residues of emamectin B1a benzoate, expressed as emam ectin (free base). EPA is recommending a tolerance of 0.02 ppm for the use of emamectin benzoate

on cucurbits ; the tolerance is to be expressed as the combined residues of emamectin (free base)

as described in section 2.2.3 below

. T here are no e stablished or proposed Canadian or Mexican

M RLs for residues of emamectin benzoate on cucurbits (Appendix E ).

2.2.3 Recommended Tolerances

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

.

The tolerance expr ession proposed by the petitioner is appropriate, but should be revised by RD

a ccording to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) as follows:

Under 40 CFR § 180.505(a)(1) for plant commodities : “Tolerances are es tablished for emamectin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below 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 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 

### (FAB 1a 

### ), calculated as the stoichiometric equivalent of emamectin.”

Under 40 CFR § 180.505(a)(2) for livestock commodities : “Tolerances are established for emamectin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 11 of 62 measuring only the sum of emamectin (MAB 1a 

### + M AB 1b 

### isomers) and the associated 8,9

- Z isomers (8,9

- ZB 1a 

### and 8,9

- ZB 1b 

### ).”

Table 2.2.3

. Tolerance Summary for Emamectin

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Vegetable, cucurbit, group 9 0.03 0.02



### 2.2.4 Revisions to Petitioned

- For Tolerances

HED attributes the difference between the recommended tolerance and the proposed tolerance (as shown in Table 2.2.3) to the difference in the way the petitioner reported combined residues

in the cucumber submissions. The petitioner reported the combined L OQ in the cucumber study as 0.025 ppm, reflecting the sum of MAB 1a 

### /8,9

- ZB 1a 

### + MAB 1b 

### /8,9

- ZB 1b 

### + AB 1a 

### + MFB 1a 

### +
FAB 1a 

### ; however, the analytical method determine s residues of MFB 1a 

### and FAB 1a 

### as a single

component ; therefore, the combined LOQ should have been 0.02 ppm.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DF R stud ies are required when a pesticide has residential or occupational

uses t hat could result in post

- application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pestic ide Exposure Assessment , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR 

### ).

This default value is 25 % and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessments. Of the analyzed DF R studies, the maximum F AR 

### value seen was

89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE >

400 if the LOC = 100) using the default dislodged residue values would provide an adequate margi n of safety for any potentially higher residues seen in a chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council ). A DF R study is required for emamectin benzoate at this time since the dermal MOE is less than 4 times the LOC based on default values for the fraction of application rate available for transfer after a foliar application.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 12 of 62 Occupational Handler s

– Cucurbits (Proclaim® Insecticide)

There is potential for short

- and intermediate

- term occupational exposure to emamectin benzoate during handling activities (e.g. mixing, loading, application).

All the values in the tables have been updated s ince the ORE review (N. Tsaur, DP Number

D 393839, 03/01/2012) to reflect policy changes (i.e.

, inhalation toxicity uncertainty factors).

Based on the PPE required on the label (see Table 9.1) , there are risks of concern. To achieve
MOEs that do not exceed HED’s LOC (ARIs > 1.0), the following mitigation should be required in addition to the current label requirements for the following scenarios :

For short

- term exposure, mixing/loading dry flowables for groundboom application requires double layer clothing + gloves and PF10 respirators. Mixing/loading dry flowables for aerial application requires engineering controls of water soluble packaging.

For intermediate

- term exposure, mixing/loading dry flowables for groundboom application and flagging for aerial application requir e double layer clothing + gloves and PF10 respirators. Mixing/loading dry flowables for aerial application requires engineering controls of water soluble packaging.

Occupational Handlers

– Ornamentals (EnfoldTM Insecticide)

There is potential for short

- and intermediate

- term occupational exposure to emamectin benzoate during handling activities (e.g. mixing, loading, application).

All the values in th e table s have been updated since the ORE review (N. Tsaur, DP Number

D 390788, 12/07/2011) to reflect poli cy changes (i.e.

, body weight assumptions and inhalation toxicity uncertainty factors)

.

Based on the PPE required on the label (see Table 9.1) , there are risks of concern. To achieve
MOEs that do not exceed HED’s LOC (ARIs > 1.0), the following mitigatio n should be required:

For short

- term exposure, mixing/loading dry flowables for groundboom and airblast application require double layer clothing + gloves and PF10 respirators. Mixing/loading dry flowables for aerial application requires engineering cont rols of water soluble packaging. Open cab airblast is acceptable with PF10 respirators. Handheld equipment is acceptable if gloves are required.

For intermediate

- term exposure, mixing/loading dry flowables for groundboom and airblast application require double layer clothing + gloves and PF10 respirators. Mixing/loading dry flowables for aerial application requires engineering controls of water

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 13 of 62 soluble packaging. The high exposures expected from open cab airblast applications are best mitigated by requ iring an enclosed cab system. Handheld equipment is not of concern if PF5 respirators are required.

Label Recommendation (EnfoldTM Insecticide)

The label must indicate the required PPE for handheld applications as listed in Table 9.1 (i.e.

, applications via backpack sprayers or manually pressurized handwands).

2.3.3 Recommendations f rom Residential Assessment

R esidential 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). T here are

no proposed/

registered products that would lead to residential handler or post

- application

ex posure. 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.

3.0 In troduction

3.1 Chemi cal Identity

Emamectin benzoate i s a semi

- synthetic avermectin, consisting of 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. D393837

Page 14 of 62 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

- hexapyranosyl)

- 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 ,2 1 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/EP Proclaim® Insectic ide; EPA Reg. No. 100

- 904; 5% S G formulation

Enfold TM Insecticide; EPA Reg. No. 100

- RURR; 5% WG formulation

Chemical Class Avermectin insecticide

Known Impurities of Concern None



### 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 Human Health Risk Assessment DP No. D393837

Page 15 of 62 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 Physico chemical Properties in Appendix B.

3.3 Pesticide Use Pattern s

Cucurbits

IR

- 4 is proposing use of Proclaim® Insecticide (EPA Reg. No. 100

- 904) , a 5% water

- soluble granule ( S G ) formulation of emamectin benzoate

, on the cucurbit vegetable group for the control

of armyworms, cabbage looper, corn earworm, melon worm, rindworms, tobacco budworm, pickleworm, and Lirioyza leaf miners.

Proclaim® Insecticide may be applied as a foliar spray via aircraft (except in New York State) or groundboom. Chem igation is prohibited. For high pest infestations, the maximum single application rate is 4.8 oz/A (0.015 lb ai/A). Applications may be repeated at a 7

- day interval to maintain control, up to a maximum seasonal application rate of 28.8 oz/A (0.090 lb ai/ A/season).

The preharvest interval (PHI) is 6 days. The REI on the proposed label is 12 hours.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 16 of 62 Table 3 .3

. 1

. Summary of Directions for Use of Emamectin Benzoate on Cucurbits

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg.
No.] Applic.

Rate (lb ai/A) Max. No.

Applic.

per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI 1

(days) Use Directions and Limitations

Vegetable, Cucurbit, Group 9: Chayote (fruit); Chinese waxgourd (Chinese preserving melon); citron melon; cucumber; gherkin; gourd, edible (includes hyotan, cucuzza); hechima ; Chinese okra; Momordica spp. (includes balsam apple, balsam pear, bitter melon, Chinese cucumber); muskmelon (hybrids and/or cultivars of Cucumis

melo

- includes true cantaloupe, cantaloupe, casaba, Cre nshaw melon, golden pershaw melon, honeydew melon, honey balls, mango melon, Persian melon, pineapple melon, Santa Claus melon, and snake melon); pumpkin; squash, summer (includes crookneck squash, scallop squash, straightneck squash, vegetable marrow, zuc chini); squash, winter (includes butternut squash, calabaza, hubbard squash, acorn squash, spaghetti squash); watermelon (includes hybrids and/or varieties of Citrullus lanatus ).

Postemergence, Broadcast, Foliar,

G round or aerial equipment Proclaim®

Insecticide

5% SG [100

- 904] 0.009 4

-

0.015 NS 2 0.090 6 Begin applications when larvae are first observed; repeat applications at a minimum RTI 3

of 7 days.

Apply in a minimum of 10

g al l o ns of water/A when using

either ground or aerial equipment.

U se of a penetrating type of spray adjuvant is recommended; use of a sticker/binder type adjuvant is prohibited.

1 PHI = preharvest interval.

2 NS = not stated.

3 RTI = retreatment interval.



### The following restrictions appear on the accepted Proclaim® Insecticide label (dated 1/26/10): (1) application through any type of irrigation system is prohibited; (2) for applications to vegetables, make no more than two sequential applications

, then rotate to another insecticide with a different mode of action; (3) for appl ications to vegetables, do not use Proclaim in greenhouses, nurseries, in plant propagation houses, or on any plants grown for use as transplants; (4) do not apply with aircraft in NY state; and (5) there are no rotational crop plant

back restrictions for emamectin benzoate.

Outdoor

- Grown Ornamental Plants in Commercial Nursery Production

Syngenta is proposing use of EndfoldTM Insecticide (EPA Reg. No. 100

- RURR) , a 5% water

dispersible granule formulation of emamectin benzoate, on outdoor

- grown ornamental plants in commercial nursery production for the control of the larval stages (worms/caterpillars) of several lepidopteran species and suppression of Liriomuza leafminer, Tetranychid mites, and pear psylla.

It is a selective insecticide for use on herbaceo us and woody ornamental plants grown outdoors (in containers or in the ground) in commercial nursery production. Woody ornamentals include

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 17 of 62 (but are not limited to) shrubs, non

- bearing fruit and nut trees, Christmas trees, forest seedlings,

and shade trees

.

EnfoldTM Insecticide may be applied as a foliar spray via groundboom, airblast, or aircraft (except in New York State). Chemigation is prohibited. For high pest infestations, the maximum single application rate is 4.8 oz/A (0.015 lb ai/A). Applicati ons may be repeated at a

7

- to 14

- day interval to maintain control, up to a maximum seasonal application rate of 28.8 oz/A (0.090 lb ai/A/season). The REI on the proposed label is 12 hours.

Table 3

. 3.2

. Use Profile for Proposed Emamectin Benzoate Use on Outdoor

- Grown Ornamental s.

Enfold TM Insecticide

EPA Reg. No. 100

- RURR water dispersible granule (WG), 5.0 % ai by weight

Use Site Application Equipment Single Maximum Application Rate

oz/A lb ai/A

Outdoor Ornamentals (Ground or Container) Groundboom, Airblast, Aerial 2.4

- 4.8 0.00075

- 0.015



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use s of emamectin benzoate on cucurbit vegetables and on outdoor

- grown ornamental plants in commercial nursery production . 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 ben zo 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. In an occupational sett ing, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for workers re

- entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of emamectin benzoate, but also considers the existing uses as well, particularly for the dietary exposure assessment.

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 Population s," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf )

.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 18 of 62 As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- esta blished 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 a ssessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, speci alized 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 by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Reference: E

MAMECTIN

- 3 rd Report of the Hazard Identification Assessment Review Committe e

- (Memo, HED TXR. No. 0051605, 03/5/2003).



### 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 s ummaries 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 (Po ng 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 h ave the potential to influence GABA

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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 19 of 62 compound (abamectin) has been shown to have widespread binding but particularly abundant in the cerebellum (Wang and P ong, 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 m ultiple 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 vi vo
, 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 active transport (Marzolini et al., 2004). P

- gp is found in the canallicular su rface 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 whic h 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 sensitiv e to the neurotoxicity of

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 hunche d 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 nota bly 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 develo pmental 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, whole 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 

### parental 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

- l imb extension,

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 20 of 62 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 uni que 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 le sions 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 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 m otor activity on PND 17) and no other offspring toxicity was seen

at the LOAEL.

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

humans.” 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 s ensitizer

. 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. Detailed information has been submitted which confirms the appropriateness of the REI reduction.

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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 21 of 62 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 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.

4.2.1 Completeness o f the Toxicology Database

The toxicology database used to assess pre

- and post

- natal exposure to emamectin is considered adequate. However, under the current data requirement guidelines, an immunotoxicity study and

an inhalation toxicity study are required.

Immunotoxicity study

The risk assessm ent 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 wit h 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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 22 of 62 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, database uncertainty factor is not necessary to account for the lack of an immunotoxicity study at this

time.

Inhalation toxicity study Since no inhalation studies are available, the Agency selected an ora l NOAEL of 0.075 mg/kg/day established in the 15

- day neurotoxicity study in mice for inhalation risk assessments. Therefore, a 28

- day subchronic inhalation study is required for the reasons that the inhalation study (1) may provide route specific effects (route of entry effects) and (2) may result in changes to the endpoints and how the risks are quantified. In addition, the acute inhalation toxicity category for emamectin is II, and in a 5

- day preliminary inhalation study, histopathological changes were found in the respiratory tract at all dose levels (1 μg/L to 125 μg/L). The study should be performed using the CF

- 1 mouse. In 2006, the registrant and the Agency held several meetings to discuss the conduct of the 28

- day inhalation toxicity study (spec ifically the strain of test animal to be used). At this time, the Agency still maintains that this study should be conducted in the most sensitive strain of mice (CF

- 1 mice). A 10x uncertainty factor i s recommended for lack of an inhalation toxicity stud y.

4.2.2 Evidence of N eurotoxicity

Following emamectin exposure, neurotoxicity has been seen in multiple studies with several species of test animals.

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 Uncertainty 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 cro p 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 die tary exposure. Therefore, 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

.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 23 of 62 R esidential exposure is not expected from the established and proposed uses. Residential exposures from commercial nursery production are expected to be negligible because the emamectin is expected to dissipate by the time the plant mo ves from a nursery, through a retail store, to the consumer.

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 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 Die tary and

Non

- Occupational Human Health Risk Assessments 1,2

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 increases in two adequ ate 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.

2 Dermal absorption of 1.8% is assumed.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 24 of 62 Table 4. 3 .2 Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for Use in Occupational

Human Health Risk Assessments 1,2

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) NOAEL =

0.075 mg/kg/day (dermal absorption rate =1.8%) UF A = 10x

UF H = 10x FQPA = 3x Occupational LOC

for MOE = 300 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. Dermal

Intermediate

Term (1

- 6 months) NOAEL =

0.075 mg/kg/day (dermal absorption rate = 1.8%) UF A = 10x

UF H = 10x FQPA = 10x Occupational LOC

for MOE = 1000 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. Inhalation

Short

- Term (1

- 30 days) NOAEL =

0.075 mg/kg/day (assumed equivalent

to oral absorption) UF A = 10x

UF H = 10x

UF

m = 3 0 x Occupational LOC

for MOE = 300 0 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. Inhalation

Intermediate

T erm (1

- 6 months) NOAEL =

0.075 mg/kg/day (assumed equiv alent

to oral absorption) UF A = 10x

UF H = 10x

UF

m = 30 x Occupational LOC

for MOE = 3 000 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 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). UF

m = modifying factor : the 30X consisted of

3X to account fo r the steep ness of the dose

- response curve, severity of effects at the LOAEL (death and neuropathology) and 10 x for lack of an inhalation toxicity study. MOE = margin of expo sure. LOC = level of

concern.

2 Dermal absorption of 1.8% is assumed.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 25 of 62 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies includ e acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including ef fects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studie s that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), emamectin benzoate i s subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the est rogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine whic h, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. Emamectin

benzoate is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future

EDSP orders/data call

- ins, requiring the s ubmission of EDSP screening assays for emamectin

benzoate

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

websi te: http://www.epa.gov/endo/

.

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]e mamectin B 1a 

### (MAB 1a 

### ) was the parent MAB 1a 

### . The isomer 8,9

- ZB 1a 

### and the

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 26 of 62 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 structures, nearly all

co ntributing only a small amount to the total residue; these initial degradates undergo further degradation to yield a very complex residue. These degradations are probably a result of photolysis, and after this photolytic process, these degradates can be f ragmented and incorporated into natural plant constituents.

Ruminants: The parent compounds, emamectin (MAB 1a 

### + MAB 1b 

### ), are the only major residue 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 as sumed 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 t he 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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 27 of 62 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)



### .

5 .2 Food Residue Profile

Crop Field Trials : IR

- 4 submitted crop field trial data on cucumber, squash, and cantaloupe in

support of the proposed use of the 5% SG formulation of emamectin benzoate on cucurbit vegetables

. T he residue data are summarized in Table 5 .2 below

. All residues are <0.02 ppm.

Table 5 .2

. Summary of Residue Data from Crop Field Trials with Emamectin Benzoate (SG Formulation).

Commodity Total App.

Rate (lb ai/A) PHI

(days) Combined Residue s (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Ve getable, Cucurbit, Group 9 (proposed use = 0.09 lb ai/A total application rate, 7

- day PHI)

Cucumber 0.077

- 0.092 6

- 8 8 <0.02 <0.02 0.02 0.02 0.02 0.02 NA

Summer Squash 0.090

- 0.093 6

- 8 8 <0.02 <0.02 0.02 0.02 0.02 0.02 NA

Cantaloupe 0.089

- 0.092 6

- 8 10 < 0.006 <0.0081 0.006 0.00 8 0.006 0.006 0.001

1 Combined residues include total emamectin (MAB 1a and MAB 1b ), its 8,9

- Z isomers (8,9

- ZB 1a and 8,9

- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a , and FAB 1a

. Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.02 ppm for cucumber and squash and 0.006 ppm for cantaloupe) was used for any results reported as <L OQ. NA = Not applicable.

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



### The submitted cucumber, summer squash, and cantaloupe crop field trial data are adequate and fulfill the field trial requirements for the cucurbit vegetable group 9. The studies reflect the maximum proposed use pattern for cucurbit vegetables, and the number and locations of the field trials are in accordance with OCSPP 860.1500 for each crop. An acceptable method was used for residue quantitation, and the data are supported by adequate storage stability data.

T he available residue data are sufficient for establishing a tolerance of 0. 02 ppm for vegetable, cucurbit, group 9 in association with the requested registration of the 5% SG formulation on cucurbit vegetables.

Processing Studies : There are no regulated processed commodities associated with cucurbit vegetables.

Storage Stability : Adequate storage stability data are available to support the cucurbit vegetable field trial studies. No corrections for residue decline during storage are needed.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 28 of 62 Meat, Milk, Poultry, and Eggs : There are no livestock feedstuffs associated with use on cuc urbit vegetables.

R otational Crops : Total radioactive residues in a confined rotational crop study after application of [ 14 

### C]MAB 1a 

### were <0.01 ppm in/on immature and mature head lettuce, carrots, and barley from all plantback intervals (30, 120/141, and 36 5 days); only barley straw had residues at >0.01 ppm (0.016 and 0.030 ppm) at the 30

- and 141

- day plantback interval s

. E mamectin and its

metabolites were not identified in 30

- and 141

- DAT (days after treatment) barley straw. T here is

no indication that e mamectin residues of concern would be present in rotational crops at levels ≥0.01 ppm

, and no plantback restrictions are need ed on the labels.

5.3 Water Residue Profile

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” (Tiffany Dowen, 5/30/ 12 , DP#402307 ) and incorporated directly into this dietary assessme nt. Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”

EFED provided EDWCs for the proposed/registered uses of emamectin benzoate including the proposed uses on o utdoor ornamentals (EPA Reg. No. 100

- RURR) and cucurbit vegetables (EPA Reg. No. 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

average (Table 5 .3 ).

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 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 e nvironmental 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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 29 of 62 Pesticides Total Toxic Residues (TTR) , dated May 20 , 2009.

Table 5.3 Summary of Estimated Surface Water and Ground w ater Concentrations for Emamectin

Benzoate. a

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 - 3

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 i somer, 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 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) and cottonseed oil. 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 (% CT) data and percent crop treated data for new crops ( PCTn ) provided by the Biological and Economic Analysis Division (BEAD) in 2012 wer e 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 . Tolerance

- level residues were used for tree nuts (including pistachios)

and cottonseed oil. DEEM default processing factors were used except for commodities with

chemical

- specific processing studies. P ercent crop treated data and PCTn data provided by

BEAD in 2012 were used. The EDWC of 0.1 50 μg/L (ppb) for the chronic exposure was based

on PRZM/EXAMS modeling of the u se on ornamentals, which resulted in the highest chronic EDWC considering all proposed/registered uses.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 30 of 62 5.4.2 Percent Crop Treated Used in Dietary Assessment

The following 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 b enzoate: 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%.

The following maximum percent crop treated estimates from the SLUA date d 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 %; peppers, 5%; spinach, 5 %; and tomatoes, 1 0%.

The following percent crop treated estimates for new crops (PCTn) (D 403689 , Jihad Alsadek,

8/ 21 /12) were used in th e acute dietary risk assessment: cantaloupe, 51 %; cucumber, 26%; squash, 46%; and watermelon, 21%.

The following PCTn estimates (D403689, Jihad Alsadek, 8/21/12) w ere used in the chronic dietary risk assessment: cantaloupe, 40%; cucumber, 14%; squash, 29%; and watermelon, 19%.

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 ad ults 50+ years old.

As shown in Table 5.4.6.1, t he most highly exposed subgroup was children 1

- 2 years old, with exposure of 60 % 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 for some new and registered crops. Monitoring data were used for apples in t he acute

assessment since apple juice had a significant impact on exposure. The use 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.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 31 of 62 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), c hildren 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+ 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 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 for some new and registered crops. The use 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.

5.4.5 Cancer Di etary 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 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

be low HED’s level of concern at the 99.9 th 

### percentile of exposure for the general U.S. population

and a ll population subgroups ( 36 % of the aPAD for the general U.S. population and 60 % of the

aPAD for children 1

- 2 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) 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 0.000019 7. 4 0.00003 8 1 5 0.000 091 36

All Infants (< 1 year old) 0.00003 7 15 0.00007 0 28 0.0001 38 55

Children 1

- 2 years old 0.00003 8 1 5 0.00007 4 29 0.000 151 60

Children 3

- 5 years old 0.00002 8 1 1 0.0000 59 23 0.000 135 54

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 32 of 62 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

Children 6

- 12 years old 0.00001 8 7. 3 0.00004 2 1 7 0.000 082 33

Youth 13

- 19 years old 0.00001 2 4.8 0.0000 25 10 0.000 084 33

Adults 20

- 49 years old 0.000016 6. 5 0.000032 13 0.00007 7 3 1

Adults 50+ years old 0.00001 8 7. 3 0.00003 5 1 4 0.000 093 37

Females 13

- 49 years old 0.00001 6 6. 5 0.00003 3 13 0.00007 6 3 0



### 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 7.5 % of the cPAD for the ge neral U.S. population and 16 % of the cPAD for all infants (<1 year old) , the most highly exposed population subgroup

.

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 0.000091 36 0.000006 7.5

All Infants (<1 year old)* 0.000138 55 0.000012 16

Children 1

- 2 years old* 0.000151 60 0.000011 15

Children 3

- 5 years old 0.000135 54 0.000009 12

Children 6

- 12 years old 0.000082 33 0.000006 7.4

Youth 13

- 19 years old 0.000084 33 0.000004 5.2

Adults 20

- 49 years old 0.000077 31 0.000005 6.9

Adults 50

- 99 years old 0.000093 37 0.000006 7.7

Females 13

- 49 years old 0.000076 30 0.000005 6.8

*The subpopulations with the highest risk estimates are bolded.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 33 of 62 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 cockroac h 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. Proclaim® Insecticide is an RUP which is proposed for use on cucurbits

. Enfold TM Insecticide is an RUP which is proposed for use on

outdoor

- grown plants in commercial nursery production

.

6.1 Residential Handler Exposure

R esidential exposure is not expected from the registered/proposed products since they are agricultural uses rather than residential uses, restricted use products (r estricted to use by certified applicators only), or limited to non

- residential areas (commercial and industrial areas). Neither the proposed uses nor currently registered products would lead to residential handler exposure.

6.2 Post

- Application Exposur e

For reasons stated in Section 6.1 above, neither the proposed uses nor 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.

6 .3 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- applicatio n 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 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

Scientifi c 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 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 quantitative post

- application inhalation exposure assessm e nt for emamectin benzoate.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 34 of 62 6. 4 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying o perations. 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 T ask 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 evaluati on 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 a ir, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for 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 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 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

O nly food and drinking water are included in the acute aggregate assessment, as the Agency do es 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

- /Intermedi ate

- Term Aggregate Risk

Short

- and intermediate

- term aggregate risk assessments were not conducted because existing and proposed uses are not expected to result in residential exposure.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 35 of 62 7.3 Chronic Aggregate Risk

Chronic or long

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

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

does not routinely assess any long

- term residential expo sures. 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.

OPP’s Guidance For Id entifying 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 guidanc e 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 c rucial 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 cause s 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 t wo 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 sam e, 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 wi th the glutamate

- gated chloride channels and GABA A 

### 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 ap pear to be mediated via interaction with GABA A 

### and possibly glycine gated chloride 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 C asida,

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 36 of 62 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), a s 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 ac tions are lacking. In addition

, specific data demonstrating

GABA A 

### 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 experime ntally. 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 al., 1987).

In conclusion, although GABA A 

### receptor mediated neurotoxicity is a strong hypothesis as a common mechanism endpoint for the macrocyclic lactone pesticides, data demon strating 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 ultim ately 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 CM T cann ot be established.

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 Oc cupational Exposure/Risk Characterization

Based on application rate and label information, exposure from uses on cucurbits and

ornamentals is expected to occur for short

- and intermediate

- term durations. However,

intermediate

- term exposure is less likely due to resistance management, and short

- term scenarios

are more realistic. Chronic exposure is not expected for the proposed use patterns.

9.1 Short

- /Inter mediate

- Term Handler Risk

Occupational handler exposure to emamectin benzoate is expected for indi viduals involved in foliar applications to cucurbit vegetables (mixing, loading, flagging, and applying) and outdoor ornamentals (mixing, loading, and applying)

.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 37 of 62 T he toxicological effects for the dermal and inhalation routes were the same ; however, sinc e the levels of concern are not identical, the 1/ARI (aggregate risk index) approach was used. The risk

estimates were calculated using the following formula s :

MOE = NOAEL/ Dose

ARI = MOE / LOC Combined ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)).



### All of the occupational handler exposure and risk estimate tables have been updated in this

document since the two occupational and residential exposure (ORE) risk assessments previously conducted by Nancy Tsaur (DP390778, 12/07/2011; and DP393839, 03/01/2012).

Summaries of the short

- and intermediate

- term risk estimate s for occupational handlers from t he

uses on cucurbits and ornamentals are included in Appendix D, Tables D.1 through D. 6

. The maximum application rate for each exposure scenario is presented as the worst case scenario.

The values in Tables D.1 through D. 6 reflect current policies (i.e. changes to unit exposures, inhalation toxicity uncertainty factors, and body weights).

Based on the PPE required on the label, there are some risks of concern. Table 9.1 shows the PPE proposed on both labels (EPA Reg. No. 100

- 904 and EPA Reg. No. 100

- RUR R) along with mitigation recommendations based on short

- and intermediate

- term risk estimates. In order to

achieve risk estimates that do not exceed HED’s LOC (ARIs > 1.0), the recommendations based

on intermediate

- term exposure are more stringent. Howev er, when considering resistance management, the short

- term risk estimates are more representative of realistic exposure potential.

Table 9.1

. Occupational Exposure Mitigation Recommendations.

Proposed PPE on the Registered and Proposed Labels (EPA Reg.

No. 100

- 904 and 100

- RURR) Recommended Mitigation

Based on Short

- Term Risk

Estimates Recommended Mitigation

Based on Intermediate

- Term

Risk Estimates Ground Application (except airblast sprayers)

Mixers, Loaders,

Other

Handlers Long

- sleeved shirt and long pants.

Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber. Shoes plus socks. Option 1: Add a PF5 respirator

for ornamentals. Add a PF10 respirator for cucurbit vegetables.

Option 2: Requi re engineering control of closed packaging. Option 1: Add a PF5 respirator

for ornamentals. Add a PF10 respirator for cucurbit vegetables.

Option 2: Require engineering control of closed packaging.

Applicators Long

- sleeved shirt and long pants.

Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber. Shoes plus socks. Adequate. Adequate.

Handheld Application

Applicators, Mixers, Loaders,

Other

Handlers Not explicitly listed. May be assumed to be

equivalent to “Ground Application.” Adequate if assumed to be equivalent to “Ground Application.” Add a PF5 respirator specifically

for backpack sprayer application

to ornamentals.

Airblast Application

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 38 of 62 Table 9.1

. Occupational Exposure Mitigation Recommendations.

Mixers, Loaders,

Other

Handlers Long

- s leeved shirt and long pants.

Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber. Shoes plus socks. Option 1: Add a PF5 respirator

for ornamentals.

Option 2: Require engineering

control of closed packaging. Option 1: Add a PF5 respirator

for ornamentals.

Option 2: Require engineering control of closed packaging.

Applicators Using OPEN

CAB Coveralls over long

- sleeved shirt and long pants.

Chemical

- resistant gloves made of any waterproof

mat erial such as polyvinyl chloride, nitrile rubber or butyl rubber. Shoes plus socks. Option 1: Add a PF5 respirator.

Option 2: Prohibit OPEN CAB equipment. Prohibit OPEN CAB equipment.

Applicators Using

ENCLOSED

CAB While inside the

cockpit must wear: Long

- sleeved shirt and long pants. Shoes plus socks. When entering or leaving the cockpit must also

wear: Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl

rubber. Adequate. Adequate.

Aerial Appl ication

Mixers, Loaders,

Other

Handlers Coveralls over long

- sleeved shirt and long pants

.

Shoes plus socks

. Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber

. Dust/Mist

- filtering respirator or a NIOSH

approved respirator with any N, R, P, or HE filter

. Adequate for ornamentals.

Require engineering control of closed packaging for cucurbit vegetables. Adequate for ornamentals.

Require engineering control of closed packaging for cuc urbit vegetables.

Applicators (ENCLOSED Cockpit)

NOTE : Once

inside the cockpit, applicator

must remove gloves and

store them in a

chemical

resistant

container such as a plastic bag. While inside the

cockpit must wear: Long

- sleeved shirt and long pants

. Sh oes plus socks

. When entering or leaving the cockpit must also

wear: Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl

rubber. Adequate. Adequate.

Flaggers Long

- sleeved shirt and long pants

.

Shoes plus socks

. Chemical

- resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber. Adequate. Adequate for ornamentals.

Add a PF5 respirator for cucurbit vegetables.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 39 of 62 9.2 Short

- /Intermediate

- Term Post

- Application Risk

Agricultural workers performing typical post

- application activities with cucurbits and

ornamentals such as scouting, irrigation, and harvesting are likely to receive exposure to

emamectin benzoate residues based on the repeated use pattern to maintain control of pests

.

9.2.1 Dermal Post

- A pplication Risk

There is a potential for short

- and intermediate

- term occupational exposure during post

application activities. However, intermediate

- term exposure is le ss likely due to resistance management, and short

- te rm scenarios are more realistic. HED recommends utilizing the results

from the short

- term quantitative risk assessment because the intermediate

- term results are highly conservative and unlikely due to th e following reasons:

1. Due to resistance management of a Group 6 insecticide that has inherent risks of

resistan c e development, the frequency of chemical application is expected to be limited

to short

- term use.
2. The intermediate

- term day 0 assumptions are ove rly conservative and should be amortized if further refined (i.e.

, the likelihood of assuming day 0 residues every day for 90 days is not realistic).

The dermal post

- application exposure s associated with ornamentals and cucurbits are summarized in Append ix D, Table D.7

. For short

- term exposure, a ll scenarios resulted in MOEs greater than the short

- term LOC of 3 00 (ranging from 520 to 11, 00 0 ) on day 0 (12 hours after application) and

, therefore

, are not of concern to HED. For intermediate

- term exposure, risk

estimate MOEs are less than the intermediate

- term LOC of 1000 and are of concern on day 0 (12 hours after application).

Restricted Entry Interval Typically, under WPS for Agricultural Pesticides , a ctive ingredients classified as acute T oxici ty Category III or IV for acute dermal, eye irritation, and primary skin i rritation are assigned a 12

- hour REI

.

9 .2.2 Occupational Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitative oc cupational 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 2 1 oC ) and is applied at a low rate (0.015 lb ai/A) . However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of d usts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. T he Agency received the SAP’s final report on March 2, 2010

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 40 of 62 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occu pational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative o ccupational post

- application inhalation exposure assessment for emamect in

benzoate.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pest icides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios.

10. 0 References

Dodd, N., O’Rourke, K., and Phang, W., 7/31/08 , DP Number D345943, Emamectin Benzoate. Human Health Risk Assessment for Proposed Uses on Tree Nuts and Pistachios, and as an Injection Treatment for Ornamental/Nonbearing Trees.
Dodd, N., Phang, W., and Tsaur, N., 6/16/11, DP Number D385990 , Emamectin Benzoate. Human Health Assessment Scoping Document in Support of Registration

Review.
Dodd, N., 8/6/12 , DP Number D392510, Emamectin Benzoate. Petition for the Establishment of a Permanent T olerance on Vegetable, Cucu rbit, Group 9. Summary of

Anal y ti cal Chemistry and Residue Data.
Dodd, N., 12/19/12, DP Number 393838, Emamectin Benzoate: Revised Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for t he Section 3 Registration Action on Cucurbits and Outdoor

- Grown Plants in Commercial Nursery Production.
Tsaur, N., 12/7/11, DP Number D390788, Emamectin Benzoate. Occupational Exposure Assessment for a Proposed Use on Outdoor

- Grown Plants in Commercial N ursery Production.
Tsaur, N., 3/1/12 , DP Number D39 3839

, Emamectin Benzoate. Occupational Exposure Assessment for a Proposed Use on Cucurbit Vegetables (Crop Group 9).
Dowen, T., 5/30/12, DP Number 402307, Amended Drinking Water Asses s ment for the Propose d Use of Emamectin Benzoate on Outdoor Ornamentals and Group 9 Cucurbit Vegetables

. Alsadek, J., Ph.D., 8/21/12, DP Number 403689, 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 401786 , Emamectin Benzoate (122806) Screening Level Usage Analysis (SLUA)

.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 41 of 62 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.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 42 of 62 A ppendix A

. Toxicology Profile and Executive Summaries

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

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Nonrodents

............................. 870.3200 21/28

- Day Dermal Toxicity

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

- Day Dermal Toxicity

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

- Day Inhalation Toxicity

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

yes

yes

-

yes yes

yes

yes

-

no 870.3700a Prenatal Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes

yes

yes

yes yes

yes

yes

yes

yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

.......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. 870.5385 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes

yes yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

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

yes

CR yes

yes

- 870.7485 Metabolism and Pharmacokinetics

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

................................ ........................ 870.7800 Immunotoxicity

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

yes

yes yes

yes

no

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 43 of 62 A.2 Toxicity Profile s

Table A.2 .1. Acute Toxicity Profile

– Emamectin Benzoate Technical (EPA Reg. No.

100

- 902)

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral

- Rats 42851519 LD 50 for L

- 656,748

- 038 = 53 mg/kg II

870.1200 Acute dermal

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

870.1300 Acute inhalation

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

870.2400 Acute eye irritation

- Rabbits 42743615 Severe irritation I

870.2500 Acute dermal irritation

- Rabbits 42743616 No dermal irritation IV

870.2600 Skin sensitization

- Guinea pigs 42743617 Not a dermal sensitizer

-



### Table A.2 .2. Acute Toxicity Profile

– Emamectin Benzoate Technical II (EPA Reg. No.

100

- 1270)

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral

- Rats 47002104 LD 50 for L

- 656,748

- 038 = 53 mg/kg II

870.1200 Acute dermal

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

870.1300 Acute inhalation

- Rats 47002107 LC 50 0.10 mg/L II

870.2400 Acute eye irritation

- Rabbits 47002108 Severe irritation III

870.2500 Acute dermal irritation

- Rabbits 47002109 No dermal irritation IV

870.2600 Skin sensitization

- Guinea pigs 47002110 Not a dermal sensitizer Negative

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 44 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

Acute dermal toxicity study (Not a LD 50 study)

Acute dermal tox.

- rabbits

MK

- 0243 0.16 EC

formulation 42743611 (1991)

Acceptable 0, 0.5, 1.0, & 2.0 mg/kg (2 groups: 4 hr exposure & 24 hr exposure) with

collar on the test

animals. 4 hr. exposure NOAEL= 2.0 mg/kg/day (HDT)

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

Acute dermal tox.

– rabbits (24 hrs exposure with collar on all test animals) 43850111 (1995)

Acceptable 0, 10.4, 21.0, or 42.1 mg/kg MK

- 0244 0.16

EC NOAEL = 42.1 mg/kg. No treatment

- related systemic toxicity was seen in any dosed animals.

The acute dermal LD 50 > 2000 mg/kg for MK

0244

Subchronic toxicity studies

870.3100 13

- Wk oral

- CD rats 42794201 (1992) Acceptable 0, 0.5, 2.5, and 12.5 mg/kg/day. 12.5 mg/kg/day was reduced to 8 mg/kg/day at wk 3 then to 5.0 mg/kg/day at

wk 9. Systemic Toxicity NOAEL=2.5 mg/kg/day; Systemic Toxicity LOAEL=5 mg/kg/day based

on moribundity, tremors, hindlimb splaying, urogenital staining, histologica l changes in brain and spinal cord, sciatic and optic nerves and skeletal muscles in males, emaciation, reduced body weight and reduced food consumption in

both sexes.

13

- Wk oral

- CD

- 1

mice 42743621 (1992)

Acceptable 0, 0.5, 4.5, & 15.0 mg/kg/day. An additional group received a time weighted dose 5.4 mg/kg/day NOAEL = 5.4 mg/kg/day LOAEL = 15.0 mg/kg/day based on mean body weight decrease and decreased in cumulative body weight gain.

870.3150 90

- Day oral

– dogs

(gavage) 42743623 (1992)

Acceptable 0, 1.0, or 1.5 mg/kg/day

for the first 2 wks then reduced to 0.25, 0.5, or

1.0 for the rest of the study. NOAEL = 0.25 mg/kg/day LOAEL = 0.50 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

14

- Wk oral

- dogs (gavage) 43868103 (1994)

Acceptable 0.5, 1.0, or 1.5 mg/kg/day for 2 wks for mid and high dose groups and for 3 wks NOAEL = 0.29 mg/kg/day LOAEL = 0.58 mg/kg/day based on microscopic lesions in the brain (multifocal white matter degeneration), atrophy of skeletal muscle, and spinal cord lesions.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 45 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

for low dose, then they were reduced to 0.25, 0.5, or 2.0 mg/kg/day. The time weighted doses

were 0.29. 0.58, or 0.1.08 mg/kg/day.

870.3200 21

- Day dermal tox

rabbits

MK

- 0244 0.16 EC

formulation 42743625 (1992

Acceptable 0, 50, 100, or 250 mg/kg/day (6 hrs/day) Systemic tox. NOAEL = 100 mg/kg/day LOAEL = 250 mg/kg/day based on axonal degeneration of the sciatic nerve.

Application site irritation was seen in all treated

rabbits.

22

- Day dermal tox.

– rabbits

MK

- 0244 0.16 EC

formulation 44007902 (1996)

Acceptable 0, 250, 500, or 1000 mg/kg/day (6 hrs/day) NOAEL = 1000 mg/kg/day (highest dose tested [HDT]). No systemic toxicity was seen in any dose groups. Note: The test animals were collared to prevent

oral ingestion of the test material.

Chronic toxicity studies

870

. 4100 1

- Year oral tox.

–

dogs (gavage) 42763624 (1992)

Acceptable 0, 0.25, 0.5, 0.75, or 1.0 mg/kg/day (4 dogs/sex/dose) NOAEL= 0.25 mg/kg/day LOAEL=0.5 mg/kg/day based on axonal degeneration in the pons, medulla

, and peripheral nerves (sciatic, sural, and tibial) ; whole body tremors ; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration

.

Chronic oral tox.

– rats (dietary) ( 1 year) 42868902 (1992)

Acceptable 0, 0.1, 1.0, 2.5 mg/kg (initially females received 5.0 mg/kg then reduced to 2.5 mg/kg at

wk 18 due to excessive toxicity ) NOAEL=1.0 mg/kg/day LOAEL=2.5 mg/kg/day , based on increased incidence of neuronal degeneration in the brain and spinal cord, decreased rearing, and an

increased incidence of animals with low arousal.

870.4200 Carcinogenicity

study

- mice (CD

- 1) (dietary) 4386805 (1994)

Acceptable 0, 0.5, 2.5, or 12.5 mg/kg/day (The highest

dose was reduced to 7.5 and 5.0 mg/kg/day for

males at wk 9 and females at wk 3, respectively) NOAEL=2.5 mg/kg/day

. LOAEL=5.0 mg/kg/day for males and 7.5 mg/kg/day for females based on increased mortality, decreased weight gain, tremors, sciatic nerve degeneration , and increase d incidence of severity of infections.

No treatment

- related increase in tumor incidence

was seen.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 46 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

Combined Chronic / Carcinogenicity

- Rat 43868104 (1994)

Acceptable 0, 0.25, 1.0, 2.5/5.0 mg/kg (Initially, high

dose level was 5.0 mg/kg; it was reduced to 2.5 mg/kg on wk 6 for

males and wk 10 for

females due to tremors seen in another study at 5 mg/kg). NOAEL=1.0 mg/kg/day LOAEL=2.5/5.0 mg/kg /day 1 based on marked

neu ral degeneration in the brain and spinal cord of both sexes, brain white matter degeneration in males, and on decreased body weight, body weight gain, and food efficiency in males.

No treatment

- related increase in tumor incidence

was seen.

Developmental and Reproduction Studies

870.3700 Developmental tox.

– rat 42743632 (1992)

Acceptable 0, 2, 4, or 8 mg/kg/day

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

Developmental Toxicity NOAEL=4 mg/kg/day, Developmental Toxicity LOAEL=8 mg/kg/day based on altered growth and an increased incidence of supernumerary

rib.

Developmental tox.

- rabbits 42743636 (1992)

Acceptable 0, 1.5, 3, or 6 mg/kg/day

42743635 (Range finding study) Maternal Tox

. NOAEL= 3 mg/kg/day,

Maternal Tox

. LOAEL= 6 mg/kg/day based on a significant trend towards decreased body weight gain during do sing period and increased clinical signs (mydriasis and decreased pupillary reaction).

Developmental Tox . NOAEL=6 mg/kg/day (HDT)

870.3800 2

- Gen. reproduction

study

- rats 42851511 (1993)

Acceptable

0, 0.1, 0.6, or 3.8/1.8 mg/kg/day (F 0 & F 1a females initially received 3.8 mg/kg, but

it was reduced to 1.8 mg/kg/day on GD 0 following the second

cohabitation of F 0 females). Parental NOAEL = 0.6 mg/kg/day.

Parental LOAEL = 1.8 mg/kg/day based on decreased body weight gain and neuronal degeneration in the brain and spinal cord in both sexes and generations.

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

.

Offspring NOAEL = 0.6 mg/kg/day

Offspring LOAEL = 1.8 mg/kg/day based on

tremors and hind limb extension in the offspring

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 47 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

of both generations, neuronal degeneration in the brain and spinal cord.

Mutagenicity Studies

870.5100 870.5100

Gene Mutation

- Salmonella

MK

- 0243 and L

660,599; L

- 657,831;

L

- 695,638; L

930,905 (photometabolites of

MK

- 0244) 42743637

42851514

42851515

42851516

42851517 Negative for the induction of reverse gene

mutation

.

870.5300 Gene Mutation in

Cultured V

- 79

Chinese Hamster Lung Cells

MK

- 0243 42743638 Negative for the induction of forward gene mutations in Chinese hamster lung fibroblast cells up to a severely cytotoxic nonactivated

dose of 0.01 mM or a severely cytotoxic S9

- activated dose of 0.04 mM.

870.5385 Structural

Chromosome

Aberration

- in vivo

mouse bone marrow

MK

- 0244 42851513 Negative for the induction of chromosome

aberrations in the bone marrow cells of male

CD

- 1 mice.

Neurotoxicity Studies

870.6200 Acute neurotox.

study

- rats (gavage) 42743618 (1992)

Acceptable

0, 27.4, 54.8 or 82.2 mg/kg (range finding study) NOAEL was not established . LOAEL= 27.4 mg/kg/day (LDT); clinical signs (tremors, ataxia, loss of righting reflex, and reduced activities) and as histological lesions in the brain, spinal cord and sciatic nerve occurred at

all doses tested

.

Acute neurotox. study

- rats (gavage) 42743619 (1992)

Supplementary 0, 0.5, 2.5, 5.0, 10.0, or 25.0 mg/kg/day NOAEL = 5.0 LOAEL = 10 mg/kg/day based on tremors irritability. At 25 mg/kg, all rats had tremor and neuronal lesions (white matter degeneration of the brain, degeneration of the spinal cord and

sciatic nerve.

Subchronic

neurotox.

– SD rats (dietary) (14 day) 42743628 (1992)

Acceptable 0, 0.25, 1.0, or 5.0 mg/kg/day NOAEL=1.0 mg/kg/day LOAEL=5.0 mg/kg/day based on tremors, posture, rearing, excessive salivation, fur appearance, gait, strength, mobility and righting

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 48 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

reflex. Neuronal vacuolation in brain and spinal cord; degeneration of nerve fiber in spinal cord

and sciatic nerves. Skele tal muscle atrophy. Male rats appeared to be more affected than

females.

Comparative

neurotox.

– dogs (gavage) (14 days) 42743626 (1992)

Acceptable 2 dogs/sex/compound were given 1.5 mg/kg/day of testing compound. The following effects were seen with different compounds:

Tremors Mydriasis

MK

- 0243 a 2/4 0/4

L

- 682,901 0/4 0/4

L

- 653,648 0/4 4/4

L

- 653,649 2/4 3/4

L

- 655. 372 3/4 0/4 Histopathology findings were not seen in L

- 682,

901 and L

- 653,648 treated dogs. Neuronal degeneration of the brain, spinal cord, and sciatic nerves were seen in dogs treated with

MK

- 0234, L

- 653, 649, and L

- 655,372.

15

- Day neurotox.

– CD

- 1 mice (dietary) 42743629 (1992)

Acceptable 0, 0.6, 1.2, & 2.0 mg/kg/day NOAEL=2.0 mg/kg/day ( HDT) . No

characteristic neuronal lesions in the brain, spinal cord or sciatic nerve in mice of high dose

group

. 15

- Day neurotox.

- CF

- 1 mice (dietary) (L

- 660,599: 4”

- epi

- ( N

- formyl

- N

methyl)

- amino4”

- deoxy

- avermectin

B1 42851503 (1993)

Acceptable 0, 0

. 05, 0

. 075, 0.10, or 0.30 mg/kg/day NOAEL=0.075 mg/kg/day LOAEL=0.10 mg/kg/day based on tremors observed beginning on day 3, ptosis, hunched
posture, decreases in body weight and food consumption as well as degeneration of the

sciatic nerve. At 0.3 mg/kg, tremors were seen on day 2 and fo llowed by hunched posture and ptosis, ataxia, and labored breathing.

15

- Day neurotox.

– CF

- 1 mice (dietary) (L695

- 638: 4”

- deoxy

- 4”

- epi

methylamino

avermectin B1a

delta

- 8,9

- isomer); photoproduct of

MK

- 0244 b 42851504 (1993)

Acceptable 0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day NOAEL = 0.30 mg/kg/day (HDT)

No treatment

- related effects were seen in any dose groups.

15

- Day neurotox.

– 42851 505(1993) NOAEL = 0.243 (HDT). The targeted dose was

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 49 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

CF

- 1 mice (dietary) (L695

- 638: 4”

- deoxy

- 4”

- epi

methylamino

avermectin B1a

delta

- 8,9

- isomer); photoproduct of

MK

- 0244 Acceptable

0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day 0.30 mg/kg/day. No treatment

- related effects were seen in any dose groups.

Female mice only to repeat the exposure dose

levels of MRID 42851504 because female mice received 15% less than the targeted dose in that study.

15

- Day neurotox.

- CF

- 1 mice (dietary) (L

- 660,599; formyl methylamino plant

metabolite of MK

0244 ) 42851506 (1993)

Acceptable 0, 0.10, 0.30, 0.90 mg/kg/day L OAEL <0.1 mg/kg/d ay LDT) based on tremors, hunched posture and piloerection

. However no treatment

- related findings in histopathology were present.

15

- Day neurotox.

- CF

- 1 mice (gavage)

L

- 930,905; a com

plex mixture of polar MK

- 244 photodegradates) 42851507 (1993)

Acc eptable 0, 3, 6, 12, or 18 mg/kg/day NOAEL = 18 mg/kg/day (HDT)

No treatment

- related effects were found.

16

- Day neurotox.

- CF

- 1 mice (dietary)

MK

- 0243 42743630 (1992)

Acceptable 0, 0.05, 0.10, 0.30, or 0.90 mg/kg/day NOAEL = 0.1 mg/kg/day LOAEL = 0.30 mg/kg/day based on tremors, decreased activity, and moribund sacrifice starting on day 2. However, no histopathology findings were present.

15

- Day neurotox.

- CF

- 1 mice (dietary) Formyl amino

derivative of MK

0244 42868901 (1991)

Acceptable 0, 0.050, 0.075, 0.100, & 0.300 mg/kg/day NOAEL = 0.07 mg/kg/day LOAEL = 0.23 mg/kg/day based on decreased body weight gain.

870.6300 Develop. Neurotox.

-

rats (SD) (gavage

for maternal animals; no direct dosing for neonates)

MK

- 0244 4285150 8 (1993)

Acceptable 0, 0.1, 0.6, 3.6/2.5 mg/kg/day (3.6 mg/kg

was reduced to 2.5 mg/kg between GD 17 and 20) Maternal NOAEL=3.6/2.5 mg/kg/day (highest dose tested)

Develo

. Neurotox

. NOAEL=0.10 mg/kg/day

Develo

. Neurotox

. LOAEL = 0.60 mg/kg/day

based on the dose

- related decrease in open field motor activity in females at postnatal day 17.

870.7485 Metabolism

– rats

[ 14 C] 4”

- deoxy

- 4’

- epi

- methylamino

avermectin B1a benzoate, (MAB1a) 42851523 & 42852524

(1993) Acceptable Radio labeled MAB1a benzoate is rapidly absorbed, distributed and excreted following

oral and i.v. administration. The feces was the major route of excretion in oral and i.v. groups,

while <1% of the administered dose was recovered in the urine 7 days post dosin g.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 50 of 62 Table A. 2 . 3

. Repeated D osing and Other Studies on Emamectin

Guideline

No Study Type MRID No. (Year)/

Classification/Doses Results

Tissue distribution and bioaccumulation appeared minimal. The metabolism of MAB1 a benzoate appears to involve primarily N

demethylation to AB1a. AB1a was the only

metabolite detected in the feces while unmetabolized parent compound represented a

lar ge amount of the radioactivity.

Bioequivalence

- Dog

MK

- 0243

solvate vs. monohy

drate 42743641 (1992)

Supplemental The study demonstrated that MK

- 0243 benzoate

MTBE solvate and MK

- 0243 benzoate monohydrate were bioequivalent in male dogs following oral administration as indicated by similar plasma levels for the two compounds.

Bioequivalence

- Dog

MK

- 0243 benzoate

vs. HCL salts 42743640 (1992)

Supplemental The study demonstrated that benzoate and HCl salts are bioequivalent after oral administration

in male beagle dogs.

870.7600 Dermal Absorption

Rhesus Monkey 43850113 (1994) Dermal Absorption was approximated at 1.79%

of the administered dose.

870.7800 Immunotoxicity

study Not available

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 51 of 62 Appendix B

. Physical/Chemical Properties

Table B. Physicochemical Properties of Emamectin Benzoate Technical II.



### Parameter Value Reference

Molecular Weight emamectin benzoate B 1a : 1008.26

emamectin benzoate B 1b : 994.23 DP# 335159, Indira Gairola, 8/7/07
Melting point/range 141

- 146°C MRID # 47002103

pH (at 25°C) 6

- 7

Density 1.20 g/ cm 3

Water solubility (21°C) (average of emamectin B 1a + emamectin B 1b ) 105 mg/L at pure water 101 mg/L at pH 5.0 93 mg/L at pH 7.0

No peaks were observed at pH 9.0. Solvent solubility (25°C) Toluene 20.8 mg/mL Cyclohexane 0.23 mg/mL NMP 576 mg/mL

Acetone 140 g/L Dichloromethane >500 g/L Ethyl acetate 81 g/L

Hexane 77 g/L

Methanol 270 g/L

Octanol 48 g/L

Toluene 26 g/L
Vapor pressure (2 1 °C) 3.0 x 10 - 8 torr or 3.0 x 10 - 8 mmHg

Dissociation constant, pKa 4.2 ( benzoic a cid )

7.6 ( methyl

- amino ) Octanol/water partition coefficient Shake Flask Method

Log P ow = 5 .7 (emamectin B 1a )

Log P ow = 5.2 (emamectin B 1b ) UV/visible absorption (molar absorption coefficients at the absorbance maxima) Neutral: 37,367 l/mol•cm at 245 nm 22,584 l/mol•cm at 245 nm

Acidic: 36,841 l/mol•cm at 245 nm

22,131 l/mol•cm at 245 nm

Basic: 28,952 l/mol•cm at 245 nm

No further abso rption maximum

between 280 and 750 nm was observed.

A erobic soil metabolism half

- life 90 th P ercentile on the mean: 107.5 days; Mean of all of the values (used in SCI

GROW): 79 days.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 52 of 62 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED) and the Agricultural Handler Exposure Task Force (AHETF), have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethical.

Studies reviewed for ethical conduct:

No MRID

- PHED Surrogate Exposure Guide , Agricultural Handler Exposure Task Force

Studies reviewed by the Human Studies Review Board:

None

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 53 of 62 Appendix D. Occupational Exposure/Risk Summary Tables

Table D.1. Short

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate at Baseline PPE (single layer, no gloves, no respirator)

.

Exposure Scenario Crop or Target Dermal

Unit Exposure a Inhalation

Unit Exposure a Maximum

Application

Rate b Area Treated

or Amount

Handled Daily c ST Dermal ST Inhalation

Combined

ST ARI

h Dose d MOE e Dose f MOE g

μg/lb ai lb ai/A acres mg/kg/day LOC = 300 mg/kg/day LOC = 3000 LOC = 1

Mixer/Loader at Baseline PPE (single layer, no gloves, no respirator)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

227 8.96 0.015 80 0.0000612 1,200 0.000135 560 0.1 8 Ornamentals (Nursery) 60 0.0000459 1,600 0.000101 740 0.2 4 Ornamentals (Field

- Grown) 40 0.0000306 2,500 0.0000673 1,100 0.3 5 Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 350 0.000268 280 0.000588 130 0.0 41 Ornamentals (Nursery) 60 0.0000459 1,600 0.000101 740 0.2 4 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.0000153 4,900 0.0000336 2,200 0. 70

Applicator at Baseline PPE * (single layer, no gloves, no respirator)

Applying Sprays via Groundboom Equipment Cucurbit Vegetables

78.6 0.34

0.015 80 0.0000212 3,500 0.00000510 15,000 3.5 Ornamentals (Nursery) 60 0.0000159 4,700 0.00000383 20,000 4.7 Ornamentals (Field

- Grown) 40 0.0000106 7,100 0.00000255 29,000 6.9 Applying Sprays via Aerial Equipment * Cucurbit Vegetables 5 0.068 350 0.00000592 13 ,000 0.00000446 17,000 5.0 Ornamentals (Nursery) 5 0.068 60 0.00000101 74 ,000 0.000000765 98,000 29 Applying Sprays via Airblast Equipment Ornamentals (Nursery) 1770 4.71 20 0.000119 630 0.0000176 4,300 0.85

Flagger at Baseline PPE (single layer, no gloves, no respirator) Flagging for Aerial Application Cucurbit Vegetables 11 0.35 0.015 350 0.000013 5,800 0.0000230 3,300 1.0 Ornamentals (Nursery) 60 0.00000223 34,000 0.0000000394 19,000 6.0

Mixer/Loader/Applicator at Baseline PPE (single layer, no gloves, no respirator)

M/L/A for Backpack Sprayer Ornamentals (Nursery) 13200 140

0.00030 lb ai/gal 40

gallons 0.0000356 2,100 0.0000210 3,600 1.0

8260 2.58 0.0000223 3,400 0.000000388 190,000 9.6

M/ L/A for Manually

- Pressurized Handwand Ornamentals (Nursery) 100000 30 0.00027 280 0.00000450 17,000 0. 8

M/L/A for Mechanically

- Pressurized Handgun Ornamentals (Nursery) 1300 3.9 1000 gallons 0.0000878 850 0.0000146 5,100 1.1

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

. * Baseline aircraft = engineering controls.

b Based on registered and proposed label (Reg. No. 100

- 904 EnfoldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

c Based on Exposure Science Advisory Council Policy No. 9.1.

d Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Dermal absorption factor = 1.8%.

e Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). ST Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 3 00.

f Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount H andled Daily (A or gal/day) ÷ BW ( 80 kg). No inhalation absorption factor (inhalation is equivalent to oral).

g Inhalation MOE = I nhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). S T Inhalation NOAEL = 0.075 mg/kg/day. Inhalation level of concern = 3000.

h ST ARI = MOE / LOC. Combined ST ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 54 of 62 Table D.2. Short

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate with PPE Required on Labels

. a

Exposure Scenario Crop or Target Dermal

Unit Exposure b Inhalation

Unit Exposure b Maximum

Application

Rate c Area Treated

or Amount

H andled Daily d ST Dermal ST Inhalation

Combined

ST ARI

i Dose e MOE f Dose g MOE h

μg/lb ai lb ai/A acres mg/kg/day LOC = 300 mg/kg/day LOC = 3000 LOC = 1 Ground Equipment Mixer/Loader with Label

- Required PPE (single layer, gloves, no respirator)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

51.6 8.96 0.015 80 0.0000139 5,400 0. 0 000135 560 0.1 8 Ornamentals (Nursery) 60 0.0000104 7,200 0.000101 740 0.2 4 Ornamentals (Field

- Grown) 40 0.00000698 11,000 0.0000673 1,100 0.3 6 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.00000349 21,000 0.0000336 2,200 0. 73

Aerial Equipment Mixer/Loader with Label

- Required PPE (double layer, gloves, PF5) Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 41.2 1.792 0.015 350 0.0000486 1,5 00 0.000118 640 0.20 Ornamentals (Nursery) 60 0.00000835 9,000 0.0000201 3,700 1.2

Applicator with Label

- Required PPE (single layer, gloves, no respirator)

Applying Sprays via Groundboom Equipment Cucurbit Vegetables

16.1 0.34

0.015 80 0.00000434 17,000 0.00000510 15,000 4.6 Ornamentals (Nursery) 60 0.00000326 23,000 0.00000383 20,000 6.1 Ornamentals (Field

- Grown) 40 0.00000217 35,000 0.00000255 29,000 8.9 Applying Sprays via Aerial Equipment * Cucurbit Vegetables 5 0.068 350 0.00000592 74,000 0.00000446 17,000 5.0 Ornamentals (Nursery) 60 0.00000101 13,000 0.000000765 98,000 29

Applicator with Label

- Required PPE (double layer, gloves, no respirator) Applying Sprays via Open Cab Airblast Equipment Ornamentals (Nursery) 1480 4.71 0.015 20 0.0000999 750 0.0000176 4,300 0. 91

Flagger at Baseline PPE (single layer, gloves, no respirator) Flagging for Aerial Application Cucurbit Vegetables 12 0.35 0.015 350 0.0000142 5,300 0.0000230 3,300 1.0 Ornamentals (Nursery) 60 0.00000243 31,000 0.00000394 19,000 6.0

Handheld Equipment with Label

- Required PPE (single layer, gloves, no respirator)

M/L/A for Backpack Sprayer Ornamentals (Nursery) 13200 140

0.00030 lb ai/gal 40

gallons 0.0000302 2,500 0.0000210 3,600 1.0

8260 2.58 0.0000223 3,400 0.000000388 190,000 9.6

M/ L/A for Manually

- Pressurized Handwand Ornamentals (Nursery) 430 30 0.00000116 65,000 0.00000450 17,000 5.5

M/L/A for Mechanically

- Pressurized Handgun Ornamentals (Nursery) 390 3.9 1000 gallons 0.0000263 2,90 0 0.0000146 5,100 1.4

a PPE = Personal Protective Equipment. PPE based on registered and proposed labels. See Table D.7.

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

. * Baseline aircraft = engineering controls.

c Based on registered and proposed label s (Reg. No. 100

- 904 EnfoldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

d Based on Exposure Science Advisory Council Policy No. 9.1.

e Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Dermal absorption factor = 1.8%.

f Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). ST Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 3 00.

g Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or g al) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg). No inhalation absorption factor (inhalation is equivalent to oral).

h Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). S T Inhalation NOAEL = 0.075 mg/kg/da y. Inhalation level of concern = 3000.

i ST ARI = MOE / LOC

. Combined ST ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 55 of 62 Table D.3. Short

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate with PPE Required on Labels and Additional Mitigation

. a

Exposure Scenario Crop or Target Dermal

Unit Exposure b Inhalation

Unit Exposure b Maximum

Application

Rate c Area Treated

or Amount

Handled Daily d ST Dermal ST Inhalation

Combined

ST ARI

i Dose e MOE f Dose g MOE h

μg/lb ai lb ai/A acres mg/kg/day LOC = 300 mg/kg/day LOC = 3000 LOC = 1 GROUND EQUIPMENT M/L OPTION 1: Mixer/Loader with Label

- Required PPE + PF5 Respirator (single layer, gloves, PF5 respirator) Mixing/Loading Dry Flowables for Groundboom Application Ornamentals (Nursery)

51.6 1.792 0.015 60 0.0000104 7,200 0.0000201 3,700 1.2 Ornamentals (Field

- Grown) 40 0.00000698 11,000 0.0000135 5,6 00 1.8 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.00000349 21,000 0.00000673 11,000 3.5

GROUND EQUIPMENT M/L OPTION 1: Mixer/Loader with Label

- Required PPE + PF10 Respirator (single layer, gloves, PF10 respirator) Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables 51.6 0.896 0.015 80 0.0000139 5,400 0.0000135 5,600 1.7

GROUND EQUIPMENT M/L OPTION 2: Mixer/Loader with EC (engineering control of closed packaging)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

9.8 0.24 0.015 80 0.00000266 28,000 0.00000360 21,0 00 6.5 Ornamentals (Nursery) 60 0.00000198 38,000 0.00000270 28,0 00 8.7 Ornamentals (Field

- Grown) 40 0.00000132 57,000 0.00000180 42,0 00 13 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.000000662 110,000 0.000000900 83 ,000 26

AERIAL EQUIPMENT M/L ONLY OPTION: Mixer/Loader with EC ( engineering control of closed packaging ) Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 9.8 0.24 0.015 350 0.0000116 6,5 00 0.0000158 4,700 1.5

AIRBLAST APP OPTION 1: Applicator with Label

- Required PPE + PF5 Respirator (double layer, gloves, PF5 respirator) Applying Sprays via Open Cab Airblast Equipment Ornamentals (Nursery) 1480 0.942 0.015 20 0.0000999 750 0.00000354 21,000 1.8

AIRBLAST APP OPTION 2: Applicator with EC (engineering control of closed cab equipment) Applying Sprays via

Closed Cab Airblast Equipment Ornamentals (Nursery) 14.6 0.068 0.015 20 0.000000986 76,000 0.000000255 29 0 ,000 70

a PPE = Personal Protective Equipment. PPE based on registered and proposed labels. See Table d.7.

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

.

c Based on registered and proposed label s (Reg. No. 100

- 904 En foldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

d Based on Exposure Science Advisory Council Policy No. 9.1.

e Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Dermal absorption factor = 1.8%.

f Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). ST Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 3 00.

g Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount H andled Daily (A or gal/day) ÷ BW ( 80 kg). N o inhalation absorption factor (inhalation is equivalent to oral).

h Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). S T Inhalation NOAEL = 0.075 mg/kg/day. Inhalation level of concern = 3000.

i ST ARI = MOE / LOC

. Combined ST ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 56 of 62 Table D.4. Intermediate

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate at Baseline PPE (single layer, no gloves, no respirator)

.

Exposure Scenario Crop or Target Dermal

Unit Exposure a Inhalation

Unit Exposure a Maximum

Application

Rate b Area Treated

or Amount

Handled Daily c IT Dermal IT Inhalation

Combined

IT ARI

h Dose d MOE e Dose f MOE g

μg/lb ai lb ai/A acres mg/kg/day LOC = 1000 mg/kg/day LOC = 3000 LOC = 1

Mixer/Loader at Baseline PPE (single layer, no gloves, no respirator)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

227 8.96 0.015 80 0.0000612 1,200 0.000135 560 0.1 6 Ornamentals (Nursery) 60 0.0000459 1,600 0.000101 740 0.2 1 Ornamentals (Field

- Grown) 40 0.0000306 2,500 0.0000673 1,100 0.3 2 Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 350 0.000268 280 0.000588 130 0.0 38 Ornamentals (Nursery) 60 0.0000459 1,600 0.000101 740 0.2 1 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.0000153 4,900 0.0000336 2,200 0. 64

Applicator at Baseline PPE * (single layer, no gloves, no respirator)

Applying Sprays via Groundboom Equipment Cucurbit Vegetables

78.6 0.34

0.015 80 0.0000212 3,500 0.00000510 15,000 2.1 Ornamentals (Nursery) 60 0.0000159 4,700 0.00000383 20,000 2.8 Ornamentals (Field

- Grown) 40 0.0000106 7,100 0.00000255 29,000 4.1 Applying Sprays via Aerial Equipment * Cucurbit Vegetables 5 0.068 350 0.00000592 74,000 0.00000446 17,000 3.9 Ornamentals (Nursery) 5 0.068 60 0.00000101 13,000 0.000000765 98,000 23 Applying Sprays via Airblast Equipment Ornamentals (Nursery) 1770 4.71 20 0.000119 630 0.0000176 4,300 0.44

Flagger at Baseline PPE (single layer, no gloves, no respirator) Flagging for Aerial Application Cucurbit Vegetables 11 0.35 0.015 350 0.000013 5,800 0.0000230 3,300 0.9 2 Ornamentals (Nursery) 60 0.00000223 34,000 0.0000000394 19,000 5.3

Mixer/Loader/Applicator at Baseline PPE (single layer, no gloves, no respirator)

M/L/A for Backpack Sprayer Ornamentals (Nursery) 13200 140

0.00030 lb ai/gal 40

gallons 0.0000356 2,100 0.0000210 3,600 0. 76

8260 2.58 0.0000223 3,400 0.000000388 190,000 3.2

M/ L/A for Manually

- Pressurized Handwand Ornamentals (Nursery) 100000 30 0.00027 280 0.00000450 17,000 0.27

M/L/A for Mechanically

- Pressurized Handgun Ornamentals (Nursery) 1300 3.9 1000 gallons 0.0000878 850 0.0000146 5,100 0.57

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

. * Baseline aircraft = engineering controls.

b Based on registered and proposed label (Reg. No. 100

- 904 EnfoldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

c Based on Exposure Science Advisory Council Policy No. 9.1.

d Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Fac tor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Der mal absorption factor = 1.8%.

e Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg /kg/day). IT Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 10 00.

f Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handle d Daily (A or gal/day) ÷ BW ( 80 kg). No inhalation absorption factor (inhalation is equivalent to oral).

g Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). I T Inhalation NOAEL = 0.075 mg/kg/day. Inhalation level of concern = 3000.

h IT ARI = MOE / LOC. Combined ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 57 of 62 Table D.5. Intermediate

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate with PPE Required on Labels

. a

Exposure Scenario Crop or Target Dermal

Unit Exposure b Inhalation

Unit Exposure b Maximum

Application

Rate c Area Treated

or Amount

Handled Daily d IT Dermal IT Inhalation

Combined

IT ARI

i Dose e MOE f Dose g MOE h

μg/lb ai lb ai/A acres mg/kg/day LOC = 1000 mg/kg/day LOC = 3000 LOC = 1 Ground Equipment Mixer/Loader with Label

- Required PPE (single layer, gloves, no respirator)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

51.6 8.96 0.015 80 0.0000139 5,400 0.000135 560 0.18 Ornamentals (Nursery) 60 0.0000104 7,200 0.000101 740 0.24 Ornamentals (Field

- Grown) 40 0.00000698 11,000 0.0000673 1,100 0.3 5 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.00000349 21,000 0.0000336 2,200 0.71

Aerial Equipment Mixer/Loader with Label

- Required PPE (double layer, gloves, PF5) Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 41.2 1.792 0.015 350 0.0000486 1,5 00 0.000118 640 0.19 Ornamentals (Nursery) 60 0.00000835 9,000 0.0000201 3,700 1.1

Applicator with Label

- Required PPE (single layer, gloves, no respirator)

Applying Sprays via Groundboom Equipment Cucurbit Vegetables

16.1 0.34

0.015 80 0.00000434 17,000 0.00000510 15,000 3.9 Ornamentals (Nursery) 60 0.00000326 23,000 0.00000383 20,000 5.2 Ornamentals (Field

- Grown) 40 0.00000217 35,000 0.00000255 29,000 7.6 Applying Sprays via Aerial Equipment * Cucurbit Vegetables 5 0.068 350 0.00000592 13 ,000 0.00000446 17,000 3.9 Ornamentals (Nursery) 60 0.00000101 74 ,000 0.000000765 98,000 23

Applicator with Label

- Required PPE (double layer, gloves, no respirator) Applying Sprays via Open Cab Airblast Equipment Ornamentals (Nursery) 1480 4.71 0.015 20 0.0000999 750 0.0000176 4,300 0. 49

Flagger at Label

- Required PPE (single layer, gloves, no respirator) Flagging for Aerial Application Cucurbit Vegetables 12 0.35 0.015 350 0.0000142 5,300 0.0000230 3,300 0.91 Ornamentals (Nursery) 60 0.00000243 31,000 0.00000394 19,000 5.3

Handheld Equipment with Label

- Required PPE (single layer, gloves, no respirator)

M/L/A for Backpack Sprayer Ornamentals (Nursery) 11200 140

0.00030 lb ai/gal 40

gallons 0.0000302 2,500 0.0000210 3,600 0.81

8260 2.58 0.0000223 3,400 0.000000388 190,000 3.2

M/ L/A for Manually

- Pressurized Handwand Ornamentals (Nursery) 430 30 0.00000116 65,000 0.00000450 17,000 5.2

M/L/A for Mechanically

- Pressurized Handgun Ornamentals (Nursery) 390 3.9 1000 gallons 0.0000263 2,90 0 0.0000146 5,100 1.1

a PPE = Personal Protective Equipment. PPE based on registered and proposed labels. See Table D.7.

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

. * Baseline aircraft = engineering controls.

c Based on registered and proposed label s (Reg. No. 100

- 904 EnfoldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

d Based on Exposure Science Advisory Council Policy No. 9.1.

e Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Dermal absorption factor = 1.8%.

f Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). ST Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 3 00.

g Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or g al) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg). No inhalation absorption factor (inhalation is equivalent to oral).

h Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). S T Inhalation NOAEL = 0.075 mg/kg/da y. Inhalation level of concern = 3000.

i I T ARI = MOE / LOC

. Combined ST ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 58 of 62 Table D.6. Intermediate

- Term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Emamectin Benzoate with PPE Required on Labels and Recommended Mitigation

. a

Exposure Scenario Crop or Target Dermal

Unit Exposure b Inhalation

Unit Exposure b Maximum

Application

Rate c Area Treated

or Amount

Handled Daily d IT Dermal IT Inhalation

Combined

IT ARI

i Dose e MOE f Dose g MOE h

μg/lb ai lb ai/A acres mg/kg/day LOC = 1000 mg/kg/day LOC = 3000 LOC = 1 GROUND EQUIPMENT M/L OPTION 1: Mixer/Loader with Label

- Required PPE + PF5 Respirator (single layer, gloves, PF5 respirator) Mixing/Loading Dry Flowables for Groundboom Application Ornamentals (Nursery)

51.6 1.792 0.015 60 0.0000104 7,200 0.0000201 3,700 1.1 Ornamentals (Field

- Grown) 40 0.00000698 11,000 0.0000135 5,6 00 1.6 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.00000349 21,000 0.00000673 11,000 3.1

GROUND EQUIPMENT M/L OPTION 1: Mixer/Loader with Label

- Required PPE + PF10 Respirator (single layer, gloves, PF10 respirator) Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables 51.6 0.896 0.015 80 0.0000139 5,400 0.0000135 5,600 1.4

GROUND EQUIPMENT M/L OPTION 2: Mixer/Loader with EC (engineering control of closed packaging)

Mixing/Loading Dry Flowables for Groundboom Application Cucurbit Vegetables

9.8 0.24 0.015 80 0.00000266 28,000 0.00000360 21,0 00 5.6 Ornamentals (Nursery) 60 0.00000198 38,000 0.00000270 28,0 00 7.5 Ornamentals (Field

- Grown) 40 0.00000132 57,000 0.00000180 42,0 00 11 Mixing/Loading Dry Flowables for Airblast Application Ornamentals (Nursery) 20 0.000000662 110,000 0.000000900 83 ,000 22

AERIAL EQUIPMENT M/L ONLY OPTION: Mixer/Loader with EC ( engineering control of closed packaging ) Mixing/Loading Dry Flowables for Aerial Application Cucurbit Vegetables 9.8 0.24 0.015 350 0.0000116 6,5 00 0.0000158 4,700 1 .3

AIRBLAST APP ONLY OPTION: Applicator with EC (engineering control of closed cab equipment) Applying Sprays via

Closed Cab Airblast Equipment Ornamentals (Nursery) 14.6 0.068 0.015 20 0.000000986 76,000 0.000000255 29 0 ,000 43

FLAGGER at Label

- Required PPE + PF5 Respirator (single layer, gloves, PF5 respirator) Flagging for Aerial Application Cucurbit Vegetables 12 0.07 0.015 350 0.0000142 5,300 0.00000460 16,000 2.7

HANDHELD EQUIPMENT with Label

- Required PPE + PF5 Respirator (single layer, gloves, PF5 respirator)

M/L/A for Backpack Sprayer Ornamentals (Nursery) 11200 28 0.00030 lb ai/gal 40

gallons 0.0000302 2,500 0.00000420 18,000 1.8

a PPE = Personal Protective Equipment. PPE based on registered and proposed labels. See Table.

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 )

.

c Based on registered and proposed label s (Reg. No. 100

- 904 EnfoldTM Insect icide for cucurbit vegetables and 100

- RURR Proclaim® Insecticide for ornamentals ).

d Based on Exposure Science Advisory Council Policy No. 9.1.

e Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or g al) × Area Treated or Amount Handled Daily (A or gal/day) × D ermal

A bsorption F actor (%) ÷ B ody Weight ( 80 kg). Dermal absorption factor = 1.8%.

f Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). ST Dermal NOAEL = 0.075 mg/kg/day. Dermal level of concern = 3 00.

g Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount H andled Daily (A or gal/day) ÷ BW ( 80 kg). No inhalation absorption fa ctor (inhalation is equivalent to oral).

h Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). S T Inhalation NOAEL = 0.075 mg/kg/day. Inhalation level of concern = 3000.

i I T ARI = MOE / LOC

. Combined ST ARI = 1 ÷ ((1/Dermal ARI) + (1/Inhalation ARI)). ARI level of concern = 1.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 59 of 62 Table D. 7

. Short

- and Intermediate

- Term Post

- Application Exposures and Risk Estimates for Em amectin

Benzoate for Commercially Grown Outdoor Ornamentals (Field

- and Container

- Grown) a and Cucurbit Vegetables (Crop Group 9).

Activity Transfer

Coefficient Days After

Treatment DFR b Daily Dermal

Dose c Dermal

MOE d

μg/cm 2 mg/kg/day ST LOC = 3 00

IT LOC = 1000

irrigation (hand set) [ornamentals and CG9] 1,900 0 (12 hours) 0.0421 0.000144 520

1 0.0378 0.000129 580

2 0.0341 0.000116 640

3 0.0307 0.000105 720

4 0.0276 0.000094 790

5 0.0248 0.000085 880

6 0.0223 0.000076 980

7 0.0201 0.000069 1,100

harvesting [ornamentals] 1,400 0 (12 hours) 0.0421 0.000106 710

1 0.0378 0.000095 790

2 0.0341 0.000086 870

3 0.0307 0.000077 970

4 0.0276 0.000070 1,100 scouting, shaping [ornamentals] 580 0 (12 hours) 0.0421 0.000044 1,700

hand harvesting, turning, training, mechanical harvesting [CG9] 550 0 (12 hours) 0.0421 0.000042 1,800

hand harvesting, hand pruning, scouting, container moving, hand weeding, transplanting, grafting, propagating, pinching, tying/training [ornamentals] 230 0 (12 hours) 0.0421 0.000017 4,300

transplanting [CG9] 230 0 (12 hours) 0.0421 0.000017 4,300

hand weeding, grading/tagging [ornamentals] 100 0 (12 hours) 0.0421 0.0000076 9,900

scouting, hand weeding, hand pruning,

thinning fruit [CG9] 90 0 (12 hours) 0.0421 0.0000068 11,000

a These values in this table have been updated since the ORE (N. Tsaur, DP390788, 12/07/2011) to reflect policy changes in body weight and day 0 residue assumptions.

b DFR (μg/cm 2 ) = application rate ( 0.015 lb ai/acre) x fraction of application rate dislodgeable on day 0 (2 5 %) x (1

- fraction of residue that dissipates daily 10%) t x 4.54E8 μg/lb x 2.47E

- 8 acre/cm 2

.

c Short

- / Intermediate

- Term Daily Dermal Dose = [DFR (μg/cm 2 ) x Transfer Coefficient x 0.001 mg/μg x 8 hrs/day x dermal absorption 1 .8 %] body weight (8 0 kg adult).

d Short

- /Intermediate

- Term MOE = NOAEL (mg/kg/day) /Daily Dermal Dose (mg/kg/day) . ST/IT NOAEL = 0. 075 mg/kg/day

. Short

- term level of concern = 300. Intermediate

- term level of concern = 1000.

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 60 of 62 A ppendix E. International Tolerances



## Emamectin Benzoate ( 122806 ; 08/06/2012 )

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

### Codex 3



### 40 CFR 180.505:

Plant: Combined residues 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 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 

### (FAB 1a 

### ).

Livestock: Com

bined residues of emamectin (MAB 1a 

### + MAB 1b 

### isomers) and the associated 8,9

- Z isomers (8,9

- ZB 1a 

### + 8,9

- ZB 1b 

### ). None P lants: emamectin B1a benzoate, expressed as emamectin (free base).

animal commodities:

emamectin B1a benzoate, expressed as emamectin (free

base ).

The residue is not fat

soluble.



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 

### Codex 3



### Vegetable, cucurbit, group 9 0.0 2 0. 007 fruiting vegetables, cucurbits (proposed)



### Completed: M. Negussie; 08/20/2012

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

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

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

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 61 of 62 Appendix F

. Toxicology Literature References

Dawson GR, Wafford KA, Smith A, Marshall GR, Bayley PJ, Schaeffer JM, Meinke PT, McKernan RM. (2000) Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gama

- aminobutyric acid (A) receptor. J. Pharmacol. Exp. Ther.

295: 1051

- 1060.

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

### binds to high

- and low

- affinity sites with dual effects on the gama

- aminobutyric acid

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

- 266.

Ke rb R (2006) Implication of genetic polymorphism in drug transporters for pharmacotherapy.

Cancer Lett. 234: 4

- 33.

Kerr DI and Ong J. (1986) Gama

- aminobutyric acid

- dependent motility induced by avermectin

B 1a 

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

- 10.

Lankas GR, Cartwright ME, and Umbenhauer D (1997) P

- Glycoprotein deficiency in a subpopulation of CF

- 1 mice enhances avermectin

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

- 365.

Marzolini C, Paus E, Buclin T, and Kim RB (2004) Polymorphism I human MDR1 (P

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

75: 13

- 33.

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

- 271.

Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G. (2001) Neurotransmitters as early signals for central nervous system development. Cell

Tissue Res. 305: 187

- 202.

Niles, AT an d Keppler, D (2007) The apical conjugate efflux pump ABCC2 (MRP2). Pfluger

Arch

- Eur J Physiol (2007) 453: 643

- 659.

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

### and other modulators of the gama

- aminobutyric receptor

- chlor ide ion channel complex. J.

Neurosci. 2: 966

- 971.

Represa A, Ben

- Ari Y.(2005) Trophic actions of GABA on neuronal development. Trends

Neurosci. 28: 278

- 283.

Habashi, SL (2006) Dubin

- Johnson Syndrome. http://www.emedicine.com/med/topic 588.htm

### EMAMECTIN BENZOATE Human Health Risk Assessment DP No. D393837

Page 62 of 62 Wang CC, Pong SS. (1982) Actions of avermectin B 1a 

### on GABA nerves. Prog. Clin. Biol. Res.

97: 373

- 395.