### Page 1 of 45 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### MEMORANDUM

Date : August 20 , 201 3

SUBJECT: Flonicamid

- Human Health Risk Assessment for a Section 3 Registration of

N ew U ses on Alfalfa and Clover Grown for Seed, Mint , Greenhouse Grown Tomatoes, and Tree Nuts

.

PC Code: 1280 16 DP Barcode s : D 408549, D408772, D408773, D408738, D408739
Decision No s .: 473586, 470098, 470100, 470101,

470102 Registration No s

. : 71512

- 9, 71512

- 10

Petition No s .: 2F8088, 2E8137 Regulatory Action: Section 3 Registration
Risk A ss essment Typ e : Single Chemical/Aggregate Case No.: NA

T XR No.: NA CAS No.: 1 5 8 062

- 67

- 0

MRID No.: NA 40 CFR: 180. 613



### FROM: Barry O’Keefe

, Senior Biologist Myron Ottley

, Senior Biol ogist Nancy Dodd , Chemist Cassi Walls, Senior Biologist

Risk Assessment Branch III (RAB III) Health Effects Division (7509P)

THROUGH: Christin e Olinger , Branch Chief Risk Assessment Branch III (RAB III) Health Effects Division (7509P)

TO: Carmen Rodia , Risk Manager

Insect icide Branch Registration Division (7505P)

and Andrew Ertman, Risk Manager Risk Integration, Minor Use and Emergency Response Branch Registration Division (7505P)

This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of flonicam id

. The toxicology reevaluation was performed by Myron Ottley , the drinking water assessment was conducted by James Het rick (EPA Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data an d dietary exposure assessment w ere conducted by Nancy Dodd

, the occupational and residential

### Page 2 of 45 exposure assessment was conducted by Cassi Walls , and the hum an health risk assessment w as conducted by Barry O’Keefe

.

### Page 3 of 45 Table of Contents

1.0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Data D eficiencies

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

2.2.1 Enforcement Analytical Method

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

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

- For Tolerances

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

2.2.4 International Harmonization

................................ ................................ ....................... 11
3.0 Introduction

................................ ................................ ................................ ........................... 12
3.1 Chemical Identity

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

3.2 Physic al/Chemical Characteristics

................................ ................................ ................. 13
3.3 Pesticide Use Pattern

................................ ................................ ................................ ......... 13
3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Toxicology Studies Available for Analysis

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

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

................................ 18
4.3 Summary of Toxicological Effects

................................ ................................ .................. 19

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

................................ . 20

4.4.1 Completeness of the Toxicology Database

................................ ................................ . 20

4.4.2 Evidence of Neurotoxicity

................................ ................................ ............................ 20
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... 21

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5.1 Dose

- Response Assessment

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

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

....... 21

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

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

5.0 Diet ary Exposure and Risk Assessment

................................ ................................ ............ 2 3

5.1 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.3 Water Residue Profile

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

5.4 Di etary Risk Assessment

................................ ................................ ................................ .. 26

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ...... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................. 26
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................... 26

5.4.4 Chronic Dietary Risk Assessments

................................ ................................ ............. 26

5.4.5 Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Bystander Post

- application Inhalation Exposure

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

6.2 Spray Drift

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

7.0 Aggregate Exposure/Risk Characterization

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Short

- /Intermediate

- Term Handler Risk

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

### Page 4 of 45 9.2 Short

- and Intermediate

- Term Post

- Application Risk

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

9.2.1 Dermal Post

- Application Risk

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

9.2.2 Inhalation Post

- Application Risk

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

10.0 References

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

................................ ..................... 32

A.1 Toxicology Data Requirements

................................ ................................ ....................... 32
A.2 Toxicity Profiles

................................ ................................ ................................ ................. 33 Appendix B. Nomenclature and Physicochemical Properties of Flonicamid.

........................ 39 Appendix C. Review of Human Research

................................ ................................ .................... 40 Appendix D. Summaries of Field Residue Data

................................ ................................ .......... 41 Appendix E. Summaries of Occupational Handler Exposure and Risk Estimates

............... 42 Appendix F. International Residue Limits Status Sheet

................................ ........................... 44

### Page 5 of 45 1.0 Executive Summary

Introduction Flonicamid is a systemic insecticide that immediately suppresses the feeding of sucking insects on plants

. Based on its chemical structure ( a nicotinic acid derivative )

, it would be expected to

exhibit the same mode of acti on as similarly structured neo

- nicotinoid pesticides. However,

flonicamid has not been found to activate a cetylcholine esterase (like organophosphate s and carbamates), or nicotinic acetylcholin e receptors (like neo

- nicotinoids).

Flonicamid is registered for use on a variety of agricultural crops, including: cotton, cucurbits, fruiting vegetables, greenhouse grown cucumbers , hops, leafy Brassica g reen s (subgroup 5B), leafy vegetables, low growing berry subgroup 13

- 07G, okra, pome f ruits, potatoes, rapeseed subgroup 20A, root vegetables (except sugar beet; subgroup 1B), stone fruits, tuberous and corm vegetables (subgroup 1C), and turnip greens. Flonicamid is also registered for use on commercial ornamentals, interiorscapes, and nur series; but these labels do not allow use in home gardens

, greenhouses

, or in any residential settings.

Use Profile The proposed actions f or flonicamid are as follows: 1) The Interregional Research Project No. 4 (IR

- 4) is proposing new agricultural uses ( PP# 2 E 8 137 ) on alfalfa and clover grown for seed, mint, and greenhouse grown tomatoes ; 2) ISK Biosciences Corporation (ISK) is proposing a new

use on tree nuts (PP#2F8088) ; 3) IR

- 4 is requesting an increased application rate and a crop

group update for fru iting vegetables ; and 4) IR

- 4 is requesting crop group updates for pome

fruits and stone fruits.

The proposed agricultural labels require occupational handlers to wear the following personal protective equipment (PPE): long

- sleeved shirt and long pants, shoes plus socks ̧ protective eyewear, and chemical resistant gloves . The 12 hour restricted entry interval (REI) listed on the labels is appropriate.

Exposure Profile The proposed agricultural uses of flonicamid would result in new exposures from both food and drinking water. There are no existing or proposed residential uses, and therefore, there are no

non

- occupational exposures expected. However, t he proposed agricultural uses w ill result in occupational exposure s from handl er and post

- application activities. Exposures are expected to

o ccur for short

- and intermediate

- term durations

.

Hazard Assessment

The f lonicamid toxicity/hazard database is nearly complete , with the exception of a subchronic inhalation toxicity study . The kidney and liver are the target organs for flonicamid toxicity via

the oral route in rats and dogs. Increased kidney weight and hyaline droplet deposition as well as liver centrilobular hypertrophy were observed in the 28

- day rat oral range

- finding study

, and in

the 90

- day rat oral, developmental

, and reproductive studies. The 90

- day dog study showed kidney tubular vacuolation, as well as increased adrenal weights, increased reticulocytes and decreased thymus weights. Increased reticulocyte count was noted in both the subchronic and

### Page 6 of 45 chronic dog s tudies. In the 28

- day dermal study , with flonicamid technical

, no dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day).

In rats, d evelopmental effects (increased incidence of cervical ribs) were observed only at doses

that caused liver and kidney effects in maternal animals. In rabbits, d evelopmental effects were not observed at any dose level including maternally toxic doses. Because effects were seen only at maternally toxic doses in rats

, there is no concern for increased susceptib ility of developing

young for flonicamid.

There are no concerns for neurotoxicity or immunotoxicity . Mutagenicity studies with flonicamid were negative, and flonicamid is classified by the Cancer Assessment Review Committee as “suggestive evidence of c arcinogenicity, but not sufficient to assess human carcinogenic potential”, based on increased incidences of lung tumors in CD

- 1 mice. These tumors are species and strain specific and do not correlate well with tumors in humans.

Based on the toxicity da ta, HED recommend s the Food Quality Protection Act ( FQPA ) safety factor (SF) be reduced to 1X because there are no residual uncertainties with regard to pre

- and postnatal susceptibility . However, a 10X database uncertainty factor has be en applied to asse ss risks for inhalation exposure scenarios because a route specific inhalation study is not available and the use of an oral point of departure (POD) does not provide margins of exposure ( MOEs ) >1000 for the current and proposed uses of flonicamid

.

Dietary Exposure The residue chemistry and environmental fate data are adequate to assess human dietary

exposure

. The assessments are based on reliable data and will not underestimate exposure or

risk.

The drinking water assessment was conducted by EFE D using a parent only and total toxic residue (TTR) approach. The predicted concentrations of flonicamid TTRs for the proposed uses are lower than estimated drinking water concentrations (EDWC s ) in previous drinking water

assessments . An EDWC of 1.9 μg/L (ppb) was used in the chronic dietary assessment. The

EDWC w as incorporated directly into the chronic dietary exposure assessment.

There was no acute endpoint identified in the toxicity studies; therefore, no acute dietary

assessment is needed. An unre fined chronic dietary assessment was conducted using 100% crop treated (%CT) estimates, tolerance

- level residues for all commodities

, and empirical or Dietary Exposure Evaluation Model

– Food Commodity Intake Database (DEEM

- FCIDTM) default processing factors. The results of the chronic dietary analysis for food and drinking water assessment show that the chronic dietary risk estimates are below the Agency’s level of concern (LOC) (<100% of the chronic population adjusted dose (cPAD)) for all population subgro ups and utilized 12 % of the c PAD for the general U.S. population and 30 % of the c PAD for the most highly exposed population subgroup (children 1

- 2 years old). Flonicamid is classified as “suggestive evidence of carcinogenicity, but not sufficient to asses s human carcinogenic potential”, therefore, a cancer dietary ris k assessment was not performed.

### Page 7 of 45 Residential Exposure Flonicamid is not currently registered for use in residential settings and n o new residential uses were requested in th e submitted petition s

.

Aggregate Exposure

Neither a short

- nor intermediate

- term aggregate risk assessment was conducted because residential exposure is not expected from the use pattern proposed in this registration request, or from any registered uses. There are no expected long

- term residential exposures. Because drinking water estimates have been combined with dietary exposures, the dietary assessment serves as the chronic aggregate exposure and risk assessment for flonicamid.

Occupational Exposure

Based on t he proposed use pattern of flonicamid, there is a potential for short

- and intermediate

term occupational exposure during handling (mixing, loading, and applying) and post

- application

activities. No dermal hazard was identified for flonicamid; therefore, only a quantitative inhalation exposure assessment was performed for handlers

. A Margin of Exposure (MOE) greater than 1

, 00 0 for the inhalation route is deemed adequate to pr otect occupational handlers of

flonicamid

. Except for one scenario, all exposures result in short

- and intermedia te

- term MOEs that range from 1,000

- 6,300,000 and are not of concern to HED (i.e. an MOE > 1

, 000) with

baseline attire. M ix ing / L oad ing / A ppl ying flonicamid to tomatoes in greenhouses using a mechanically pressurized h andgun resulted in an MOE of 600 at baseline attire, which is below

HED’s LOC . This MOE was no longer a concern when assessed with the addition of a PF5 respirator (MOE = 3,000 ) . Therefore, the proposed labels need to be revised to include the use

of a P F5 respirator for the greenhouse tomato use.

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

- cancer occupational post

- application inhalation exposure assessment was not performed for flonicamid at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for flonicamid

. HED assumes that post

application inhalation exposures are minimal following applications of an active ingredie nt (ai) with low vapor pressure. Since flonicamid has low acute inhalation toxicity (Toxicity Category

I V ) and a low vapor pressure (1.91 x 10 - 8 

### mm Hg at 25 o 

### C) , post

- application inhalation exposures and risks were not quantitatively assessed. Although a quantitative occupational post

application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. Handler exposure resulting from application of pesticides 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.

The 12 hour restricted entry interval (REI) listed on the labels is appropriate.

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 data, which include studies fr om the Pesticide Handlers Exposure Database

, Version 1.1 (PHED 1.1), and the Agricultural Handler Exposu re Task Force (AHETF) database are subject to ethics review pursuant to 40

### Page 8 of 45 CFR 26, have received that review, and are compliant with applicable ethics r equirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

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

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

.

2.0 HED Recommendations

HED has examined the toxicology and residue chemistry databases for flonicamid. Pending

submission of a revised Section F, there are no toxicology or residue chemistry issues that would preclude granting the requested Section 3 registration and establishi ng the recommended tolerances for flonicamid on spearmint, peppermint, tree nuts, and on alfalfa grown for seed west of the Rocky Mountains only. HED also recommends for the crop group conversions for fruiting vegetable group 8

- 10, pome fruit group 11

- 10, and stone fruit group 12

- 12 to add additional crops. HED also recommends for the conversion of existing tolerances for cucumber and

v egetable, cucurbit, group 9, except cucumber to v egetable, cucurbit, group 9. HED also recommends for the new use on gre enhouse tomatoes and the slightly revised use pattern for

field

- grown tomatoes under the fruiting vegetable group 8

- 10 tolerance.

HED recommends against the proposed use on clover since additional field trials are

needed on clover. Two additional field t rials would be needed on clover to support use in the Pacific Northwest only.

Additional data are needed, as outlined below in Section 2.1. The specific tolerance

recommendations are discussed in section 2. 2 and label modifications are discussed in Section

2.3.

2.1 Data Deficiencies

Data gap that needs to be addressed prior to a tolerance being established/registration

allowed

860.1550 Proposed Tolerances

• The petitioner s should submit revised Section F s to propose tolerances in plant and livestock commodities at levels shown in Tables 2.2.2.1 and 2.2.2.2, respectively.

### Page 9 of 45 Previously Required/Outstanding Data Gap

870.3465 28

- Day Inhalation Study

• In 2007, the Agency revised 40 CFR Part 158.500 Toxicology data requirements to

include a 28

- day inhalation toxicity study. The HED Hazard and Science Policy Council (HASPOC) reassessed the need for a subchronic inhalation toxicity study . Based upon a

we ight of evidence approach

, the HASPOC concluded that a subchronic 28

- day inhalation study is required at this time.

Data gap for future use on clover

860.1500 Clover Field Trials

• Additional field trials are needed to support registration on clover. Fo r use in the Pacific Northwest only, two additional field trials would be needed on clover.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plants : F MC Method No. P

- 3561M , a liquid chromatography/tandem mass spectrometry ( LC/MS/MS ) method , is an acceptable enforcement method for flonicamid and its metabolites in plant commodities

. The method determine s residues of flonicamid and its metabolites TFNA

AM, TFNA, and TFNG

. The method has been sufficiently validated in five diverse cro ps. Depending on the matrix, the limit of quantitation ( LOQ ) is 0.01 or 0.02 ppm. The limit of detection ( LOD ) can be estimated as one

- third the LOQ.

Livestock : Three enforcement methods are used for livestock commodities: (1) an LC/MS/MS

method RCC No . 844743 for determination of residues in eggs, poultry tissues, and fat of cattle, goat, hog, horse, and sheep; (2) LC/MS method RCC No. 842993 for determination of residues in milk; and (3) LC/MS/MS method FMC No. P

- 3580, which includes an acid hydrolysi s step, for determination of residues in meat and meat products (kidney and liver) of cattle, goat, hog, horse, and sheep. All three methods determine flonicamid and the metabolites OH

- TFNA

- AM,

TFNA

- AM, TFNG, and TFNA. The LOQs for each analyte in each m atrix (based on the lowest level of method validation) are 0.01 ppm for Methods RCC No. 844743 and RCC No. 842993,

and 0.025 for FMC No. P

- 3580. The LODs are all 0.005 ppm.

2.2. 2 Recommended Tolerances

IR

- 4 and ISK Biosciences Corporation proposed tole rances for residues of the insecticide flonicamid, including its metabolites and degradates.

No revision is needed to the proposed tolerance expression or to the tolerance expression in the

40 CFR. The commodity expressions are correct as proposed.

### Page 10 of 45 Pl ant tolerances should be revised in 40 CFR §180.613(a)(1) as follows:

Table 2.2.2

. 1. Plant Tolerance Summary for Flonicamid

. Commodity Proposed Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments * ( correct commodity definition ) Alfalfa, forage 7.0 10.0 Alfalfa, hay 0.20 1.0
Alfalfa, seed 1.5 1.5

Clover, forage 7.0 none Only one field trial (i.e., 2 considered by HED to be 1) was

conducted on clover . Additional

field trials are needed. Clover, hay 4.0 none

Fruit, pome, group 11

- 10 0.20 0.20 Delete Fruit, pome, group 11 Fruit, stone, group 12

- 12 0.60 0.60 Delete Fruit, stone, group 12 Peppermint, tops 7.0 7.0 Spearmint, tops 7.0 7.0 Vegetable, fruiting, group

8

- 10 0.40 0.40 Delete Vegetable, fruiting, group

8 Vegetable, cucurbit, group 9 1.5 1.5 Delete Cucumber Delete Vegetable, cucurbit, group 9, except cucumber
Almond, hulls 10.0 9.0 Nut, tree, group 14

- 12 0.09 0.15 * Three crop groups are being updated to add additional crops. Also, Crop Group 9 is being revised to include cucumber. The tolerance for Crop Group 9 is being raised from 0.4 ppm to the cucumber level of 1.5 ppm. Upon establishment of the crop groups under the new names, tolerances under the old crop group names and under the

name cucumber should be deleted. N o additional residue data were submitted or required to update the crop groups to add additional crops.



### Livestock tolerance levels should be revised in 40 CFR §180.613(a)(2) as follows:

Table 2.2.2

. 2. Livestock Tolerance Summary for Flonicamid

. Commodity Established Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments * ( correct commodity definition ) Cattle, fat 0.03 0.0 3
Cattle, meat 0.08 0.08 Cattle, meat byproducts 0.08 0.08 Egg 0.04 0.0 4
Goat, fat 0.03 0.0 3
Goat, meat 0.08 0.08 Goat, meat byproducts 0.08 0.08 Hog, fat none 0.03 Hog, meat none 0.03 Hog, meat byproducts none 0.03
Horse, fat 0.03 0.0 3
Horse, meat 0.08 0.08 Horse, meat byproducts 0.08 0.08

Milk 0.03 0.05 Poultry, fat 0.03 0.0 3 Poultry, meat 0.03 0.0 3

### Page 11 of 45 Table 2.2.2

. 2. Livestock Tolerance Summary for Flonicamid

. Commodity Established Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments * ( correct commodity definition ) Poultry, meat byproducts 0.03 0.0 3 Sheep, fat 0.03 0.0 3 Sheep, meat 0.08 0.08 Sheep, meat byproducts 0.08 0.08



### 2.2. 3 Revisions to Petitioned

- For Tolerances

HED

- recommended tolerances in Table 2.2.2.1 are higher for alfalfa forage and hay as compared to the proposed tolerances

. HED is increasing the established tolerance on milk

. HED is proposing new tolerances for hog commodities. HED is not recommending for tolerances on

clover commodities. The remaining tolerance levels recommended by HED in Table 2.2.2.1 are the same as proposed/established.

For alfalfa forage, the tolerance was calculated using 5x the mean of the field trial data was used

to calculate the recommended tolerance of 10.0 ppm , i nstead of the Organization for Economic Cooperation and Development (OECD) calculator because there are only two field trials. For alfalfa hay, the LOQ was used since all residues were <LOQ ; therefore, HED recommends a tolerance of 1.0 ppm . For clover fo rage and hay, the OECD tolerance calculation procedures were used, but the data were considered to represent one field trial with four samples. However, at this time HED is not recommending for tolerances on clover commodities.

The HED

- recommended tolera nces in Table 2.2.2.1 are lower for almond hulls and slightly higher for tree nuts as compared to the proposed tolerances. The HED

- recommended tolerances for almond hulls and tree nuts were calculated using the OECD tolerance calculation procedures

includ ing using average field trial residues.

The remaining tolerance levels recommended by HED in Table 2.2.2.1 are the same as proposed/established.

HED is recommending revision of the livestock tolerances as shown in Table 2.2.2.2. The

recommended livestoc k tolerances are based on the maximum reasonably balanced diets (MRBD), calculated using Table 1 Feedstuffs (June 2008), and additional livestock feed items associated with the proposed uses in both PP#’s 2E8137 and 2F8088.

2.2. 4 International Harmonizati on

There are no Codex maximum residue limits (MRLs) established on any commodity. There are

no Canadian MRLs /tolerances on alfalfa, clover, peppermint, or spearmint. Canada has

individual crop tolerances for commodities within the fruiting vegetable, cu curbit, pome, and stone fruit crop groups whereas the US has crop group tolerances with one tolerance for each of the crop group s ; the tolerance levels are the same in the US and Canada except for cucurbits (0.4 ppm for individual cucurbits in Canada and 1 .5 ppm for the cucurbits crop group in the US).

Canada has the same livestock tolerances as the US for fat, meat and meat byproducts of cattle, goat, horse and sheep: however, Canada has not set tolerances on egg, hogs, or poultry. The

### Page 12 of 45 tolerance expressi ons in the US and Canada are the same. The International Residue Limits (IRL) status table is attached (Appendix F ).

Concurrently, Canada is doing work

- share review with the US on greenhouse tomatoes and mint. Canada has tentatively proposed 7.0 ppm for peppermint and spearmint tops and 0.4 ppm for tomatoes. These tolerance levels are harmonized with the US recommendations for peppermint and spearmint tops and for the fruiting vegetable crop group.

2.3 Label Recommendations

Clover should be removed fr om the proposed Beleaf TM 50SG Insecticide ( EPA Reg. No. 71512

- 10) and Flonicamid 50WG (EPA Reg. No. 71512

- 9) labels since HED is recommending against

the use on clover.

The heading for alfalfa on the proposed labels (i.e., “Alfalfa and Clover Grown for Seed in the Following States: AZ, CA, CO, ID, MT, MN, NV, OR, UT, WA, and WY”) should be changed

to “ Alfalfa Grown for Seed West of the Rocky Mountains.” The residue data for alfalfa are from WA, ID , and southern CA.

The single application rate of 0.089 lb ai/A times 2 applications equals 0.178 lb ai/A/season , not
0.175 lb ai/A/season. HED recommends the maximum application rate be revised to 0.18 lb

ai/A/season

, instead of 0.175 lb ai/A/season

.

Mixing/Loading/Applying flonicamid to greenhouse tomatoes using mechanically pressurized handgun equipment resulted in an MOE of 600 at baseline attire, which is below HED’s level of concern. This MOE was no longer a concern when assessed with the addition of a PF5 respirator (MOE = 3,000 ) . Therefore, the prop osed Beleaf TM 50SG Insecticide ( EPA Reg. No. 71512

- 10)

and Flonicamid 50WG (EPA Reg. No. 71512

- 9) labels need to be revised to include the use of a PF5 respirator for the greenhouse tomato use.

3.0 In troduction

Flonicamid is a systemic insecticide that im mediately suppresses the feeding of sucking insects on plants . From its chemical structure ( a nicotinic acid derivative )

, it would be expected to exhibit the same mode of action as similarly structured neo

- nicotinoid pesticides. However,

flonicamid has not been found to activate a cetylcholine esterase (like organophosphate s and carbamates), or nicotinic acetylcholin e recept ors (like neo

- nicotinoids).

Flonicamid is registered for use on a variety of agricultural crops, including: cotton, cucurbits, fruiting vegetables, greenhouse grown cucumbers , hops, leafy Brassica g reen vegetables (subgroup 5B), leafy vegetables, low grow ing berry subgroup 13

- 07G, okra, pome fruits,
potatoes, rapeseed subgroup 20A, root vegetables (except sugar beet; subgroup 1B), stone fruits, tuberous and corm vegetables (subgroup 1C), and turnip greens. Flonicamid is also registered

for use on commerci al ornamentals, interiorscapes, and nurseries; but these labels do not allow use in home gardens

, greenhouses or in any residential settings.

### Page 13 of 45 The IR

- 4 has requested flonicamid be registered for use on alfalfa and clover grown for seed, peppermint, spearmi nt, and greenhouse

- grown tomatoes (PP# 2E8137) . Additionally, ISK Biosciences Corporation has requested flonicamid be registered for use on tree nuts (PP# 2F8088)

.

3.1 Chemical Identity

The chemical structure and nomenclature of flonicamid and its metab olites TFNA, TFNA

- AM, and TFNG are presented in Appendix B , Table B

- 1

.

3.2 Physical/Chemical Characteristics

Flonicamid has a log octanol/water partition coefficient (log P
ow 

### ) of 0.3 and is considered very soluble in water (5 g/L at 20 o 

### C), and is therefore highly mobile with a very low persistence in

soil. Flonicamid is considered to be not very volatile, with a vapor pressure of 1.91 x 10 - 8 

### mm Hg at 2 5 o 

### C and a Henry’s Law Constant of 4.2 x 10 - 8 

### Pa m 3 

### /mol at 25 o 

### C. With a molecular weight of 229. 2 g/mol , the potential to cross biological barriers is somewhat limited

. The physicochemical properties of flonicamid are summarized in Appendix B , Table B

- 2

.

3.3 Pesticide Use Pattern

IR

- 4 , on behalf of the Agricultural Experiment Stations of AZ, CA, CO, FL, ID, MN, OR, PA, Puerto Rico, TN, TX, UT, and WA, has submitted a petition ( PP# 2E8137) amended labels for

Beleaf TM 50SG Insecticide ( EPA Reg. No. 71512

- 10) and Flonicamid 50WG (EPA Reg. No.

71512

- 9) to add new uses on alfalfa and clover grown for seed, peppermint, spearmint, and greenhouse

- grown tomatoes, and to revise the established use rate on fruiting vegetables. Additionally, ISK Biosciences Corporation has submitted a petition ( PP# 2F8088 ) amended

labels for Beleaf TM 50SG Insecticide ( EPA Reg. No. 71512

- 10) and Flonicamid 50WG (EPA Reg. No. 71512

- 9) to add new uses on tree nuts. Beleaf TM 50SG Insecticide is a SG formulation.

Flon icamid 50WG is a water dispersible granular (WG/WDG ) formulation. Both formulations contain 50% (w/w) of flonicamid active ingredient (ai). The products are to be used to control aphids and other plant bugs.

Additionally, IR

- 4 is requesting an increased application rate and a crop group update for fruit ing vegetables. While there are no proposed changes to the established use pa t terns on cucurbits, stone fruit, and pome fruit, IR

- 4 has requested that the tolerances be revised to match the updates crop groups. The following crop groups have been updated regarding the name and members of the crop group without revision of the established use rates. Also, IR

- 4 is requesting crop group updates for pome fruits and stone fruits.

Table 3.3. 1 . Revisions to Crop Groups Cucurbit Vegetables 1
Balsam apple, balsam pear, bitter melon, Chayote, Chinese cucumber, Chinese waxgourd (Chinese preserving melon), Citron melon; Cucumber, Gherkin, Gourd, edible (includes: hyotan, cucuzza, hechima and Chinese okra), Muskmelon (includes: true cantaloupe, ca ntaloupe, casaba, crenshaw 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, zucchini), Watermelon, Winter Squash (includes butternut squash, calabaza, hubbard squash, acorn squash, spaghetti squash)

### Page 14 of 45 Table 3.3. 1 . Revisions to Crop Groups
Pome Fruit Crop Group 11

- 10 Apple; azarole; crabapple; loquat; mayhaw; medlar; pear; pear, Asian; quince; quinc e, Chinese; quince, Japanese; tejocote; cultivars, varieties, and/or hybrids of these Stone Fruit Crop Group 12

- 12 Apricot; apricot, Japanese; capulin; cherry, black; cherry, Nanking; cherry, sweet; cherry, tart; Jujube, Chinese; nectarine; peach; plum; plum, American; plum, beach; plum Canada; plum, cherry; plum, Chickasaw; plum, Damson; plum, Japanese; plum, Kiamath; plum, prune; plumcot; sloe; cultivars, varieties, and/or hybrids of these

1 A tolerance for Vegetable, cucurbit group 9 is proposed in lie u of existing tolerances on Cucumber and Vegetable, cucurbit group 9, except cucumber

.



### A summary of the proposed use patterns is detailed in Table 3.3 .2

.

### Page 15 of 45 Table 3.3 .2

. Summary of Proposed Directions for Use of Flonicamid.

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 (days) Use Directions and Limitations

Alfalfa

Postemergence; Foliar spray; Ground, aerial, or chemigation equipment BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.089 2 1 0.175 14 (seed)

14 (forage)

62 (hay) Regional registration for use on alfalfa grown for seed in AZ, CA, CO, ID, MT, NM, NV, OR, UT, WA, and WY. Spray to cover plant foliage thoroughly to control aphids and plant bugs. Apply in water, in a minimum of 20 gal/A by ground or 10 gal/A by air. Begin applications before populations begin to build and before damage is evide nt. Retreat as necessary to maintain populations below damaging levels. Allow a minimum of 7 days between applications. Do not use liquid fertilizer as a carrier. Do not use in home gardens. Crop rotation restrictions are 0 days for crops listed on th e label and 30 days for all other crops.

Clover

Postemergence; Foliar spray; Ground, aerial, or chemigation equipment BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.089 2 1 0.175 14 (seed)

34 (forage and hay) Regional registration for use on clover grown for seed in AZ, CA, CO, ID, MT, NM, NV, OR, UT, WA, and WY. Spray to cover plant foliage thoroughly to control aphids and plant bugs. Apply in water, in a minimum of 20 gal/A by ground or 10 gal/A by air. Begin applications before populations beg in to build and before damage is evident. Retreat as necessary to maintain populations below damaging levels. Allow a minimum of 7 days between applications. Do not use liquid fertilizer as a carrier. Do not use in home gardens. Crop rotation restrict ions are 0 days for crops listed on the label and 30 days for all other crops. Fruiting Vegetables (Crop Group 8

- 10) African eggplant; bush tomato; bell pepper; cocona; currant tomato; eggplant; garden huckleberry; gojiberry; groundcherry; ma rtynia; naranjilla; okra; pea eggplant; pepino; nonbell pepper; roselle; scarlet eggplant; sunberry; tomatillo; tomato; tree tomato; cultivars, varieties, and/or hybrids of these

Postemergence; Foliar spray;
Ground equipment BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.089

- 0.133 2 3 0.266 0 Spray to cover plant foliage thoroughly to control aphids, greenhouse whitefly, and other plant bugs. Apply in water, in a minimum of 10 gal/A (0.25 gal/1000 sq ft). For aphids and plant bugs, begin applications before populations begin to build and before damage is evident. For greenhouse whitefly, apply when adult whiteflies first appear. Retreat as necessary to maintain populations below damaging levels. Allow a minimum of 7 days between applications. Do no t use liquid fertilizer as a carrier. Do not use in home gardens. Crop rotation restrictions are 0 days for crops listed on the label and 30 days for all other crops.

### Page 16 of 45 Table 3.3 .2

. Summary of Proposed Directions for Use of Flonicamid.

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 (days) Use Directions and Limitations

Greenhouse Tomatoes

Foliar application BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.0875

- 0.1 34

[2.8

- 4.8 oz/A or

0.065

- 0.1 oz /1000 sq ft or

1.85

- 2.85 g / 1000 sq ft] 2 4 0.268

[9.6 oz/A or

0.2 oz / 1000 sq ft] 0 Apply when adult whiteflies first appear. For aphids and other plant bugs, begin applications before populations begin to build and before damage is evident. Spray to cover thoroughly in a minimum of 10 gallons per acre (0.25 gallons per 1000 sq ft). Allow a minimum of 7 days between application s.

Mint (Peppermint and Spearmint)

Postemergence; Foliar spray; Ground, aerial, or chemigation equipment BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.062

- 0.089 3 2 0.267 7 Spray to cover plant foliage thoroughly to control aphids. Apply

in water, in a minimum of 20 gal/A by ground or 10 gal/A by air. Begin applications before populations begin to build and before damage is evident. Retreat as necessary to maintain populations below damaging levels. Allow a minimum of 14 days between appli cations. Do not use liquid fertilizer as a carrier. Do not use in home gardens. Crop rotation restrictions are 0 days for crops listed on the label and 30 days for all other crops.

Tree Nuts 6
(African nut

- tree; Almond; Beechnut; Brazil nut; Brazilian pine; Bunya; Bur oak; Butternut; Cajou nut; Candlenut; Cashew; Chestnut; Chinquapin; Coconut; Coquito nut; Dika nut;

Ginkgo; Guiana chestnut; Hazelnut; Heartnut; Hickory nut; Japanese horse

- chestnut; Macadamia nut; Mongongo nut; Monkey

- pot; Monkey puzzle n ut; Okari nut; Pachira nut; Peach palm nut; Pecan; Pequi; Pill nut; Pine nut; Pistachio; Sapucala nut; Tropical almond; Walnut, black; Walnut, English; Y ellowhorn)

Postemergence; Foliar spray;

Ground (preferably air

blast) or aerial equipment BeleafTM

50SG [71512

- 10]

Flonicamid

50WG [71512

- 9] 0.062

- 0.089 3 5 0.267 40 Begin applications before aphid populations begin to build and when other plant bugs first appear. Spray to cover plant foliage thoroughly. Apply in water in a minimum of 50 gals per acre by ground or 10 gal/A by air. Repeat as necessary to maintain populations below damaging levels. The minimum retreatment interval is 7 days. Do not use liquid fertilizer as a carrier. Do not use in greenhouses. Do not use in home gardens.

1 Do not apply more than 2 applications per season at the rate of 0.089 lb ai/A/application.

2 Do not apply more than 3 applications per season at the rate of 0.089 lb ai/A/application.

3 Do not apply more than 2 applications per crop season at the rate of 0.133 lb ai/A/application.

4 Do not apply more than 2 applications per crop season at the rate of 0.15 lb ai/A/application.

5 Do not apply more than 3 applications per season at the rate of 0.089 lb ai/A/application.

6 Tree nuts are not ro t ated. For crops which are rotated, crop rotation restrictions are 0 days for crops listed on the label and 3 0 days for all other crops.

### Page 17 of 45 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health r isk to support proposed

new use s of flonicam id on the following crops : alfalfa and clover grown for seed, peppermint, spearmint, tree nuts, and greenhouse

- grown tomatoes

. Humans may be exposed to flonicam id in food and drinking water, since flonicam id may be applied directly to growing crops and application may result in flonicami d reaching surface and ground water drinking water sources

. In occupational settings, applicators may be exposed while handling flonicamid . There is also a potential for post

- ap plication exposure for workers re

- entering treated fields.

Risk assessments have been completed for proposed and existing uses of flonicamid . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new

uses of flonicamid , but also considers existing uses of flonicamid , particularly in the dietary
exposure assessment.

3.5 Consideration of Environmental Justice

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

h uman health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

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

- established procedures. In line with OPP policy, HED estimates risks to populatio n 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 compi led by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and catego rized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

A detailed hazard characterization with a list of available toxicity studies for flonicamid is presented in a previous flonicamid risk assessment (DP347805

, S. Piper, 12/21/2007). The

submitted studies are sufficient to deter mine whether flonicamid poses a human health hazard.

### Page 18 of 45 In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunotoxicity study and a subchronic inhalation toxicity study were required for flonicamid

. An immunotoxicity st udy (MRID 48870201) has been submitted and reviewed

. Previously, the registrant, ISK Biosciences Corporation, submitted waiver requests for the 28

- day and 90

- day subchronic inhalation toxicity studies, which HED granted (DP290408, J. Arthur, 5/9/05 and

DP 297602, J. Arthur, 5/9/05). The waivers were granted based on flonicamid’s low acute inhalation toxicity (Toxicity Category IV) and inhalation MOE s extrapolated from oral points of departure (PODs) that e xceed ed the target inhalation MOE of 1

, 000. Howeve r, based on current requirements (based on anticipated exposure) for inhalation toxicity data, the need for a subchronic inhalation study was reassessed by the HED Hazard and Science Policy Council (HASPOC). Based upon a weight of evidence approach the HA SPOC concluded that a

subchronic 28

- day inhalation study is required at this time (TXR No. 0056400, K. Rury,

0 7/30/ 20 12). In the absence of a route specific inhalation study, a 10X database uncertainty

factor has be en applied to the occupational inhalation exposure assessment

.

4.1 Toxicolog y Studies Available for Analysis

The database of available studies includes subchronic oral studies in the rat, mouse

, and dog, a subchronic dermal study in the rat, chronic studies in the rat and dog, an imm unotoxicity study in the mouse, carcinogenicity studies in the rat and mouse, developmental toxicity studies in the rat and rabbit, a multi

- generation reproduction study in the rat, a battery of mutagenicity studies, and

a battery of neurotoxicity studies (acute and subchronic). Also available are metabolism and pharmacokinetics studies in the rat, and a battery of acute toxicity studies.

4. 2 Absorption, Distribution, Metabolism and Excretion (ADME)

Flonicamid was rapidly absorbed with no apparent gender or dose differences. The apparent plasma half

- life (T1⁄2) was 4.8

- 6.0 hours. The time of maximum plasma concentration (Tmax) for individual animals ranged from 0.25 to 1 hour after treatment (with a mean for each group of

0.3

- 0.6 hours).

Tissue distribution was generally similar between sexes of each dose group, and was proportional between low and high dose groups. The highest concentrations of initial radioactivity in all groups and both sexes were found in the adrenals, thyroid, liver, kidney, spleen

, and ovaries.

Parent and nine metabolites accounted for 80

- 94% of the dose for all groups. The primary

metabolite was 4

- trifluoromethylnicotinamide (TFNA

- AM), 18

- 27% dose in all dose groups, along with minor amounts of TFNA

- AM N

- oxide (1

- 4% dose). Other metabolites in urine and

fece s were detected at less than or equal to 2.5% of the dose. Flonicamid was excreted primarily unchanged in the urine, but biotransformation of flonicamid in rats included nitrile hydrolysis,

N

- oxidation, hydroxylation of the pyridine ring

, an d amide hydrol ysis.

Flonicamid was rapidly excreted with 93% of administered dose eliminated in 48 hours . The elimination followed first order kinetics. The primary route of excretion was the urine which

account ed for 90% of the dose; the feces of treated rats account ed for ~5% of the administered

### Page 19 of 45 dose, with no significant amounts of radiolabel detected in expired air of either sex. Dose

differences were not observed.

4.3 Summary of Toxicological Effects

The oral studies in rats and dogs indicate the kidney and live r are the target organs for flonicamid toxicity. Increased kidney weight and hyaline droplet deposition and liver centrilobular hypertrophy were seen in the rat 28

- day oral range

- finding study, 90

- day oral study, developmental study

, and reproductive stud y. The 90

- day dog study showed kidney tubular vacuolation, as well as increased adrenal weights, increased reticulocytes and decreased thymus weights. Increased reticulocyte counts were noted in both the subchronic and chronic dog

studies. In the 28

- day dermal study

, no dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day) for flonicamid technical.

Developmental effects (increased incidence of cervical ribs) were only observed at maternally toxic doses (liver and kidney gross and histo pathological effects). No developmental effects were seen in rabbit fetuses. Offspring effects (decreased body weight and delayed sexual maturation) in the multi

- generation study were seen only in the presence of parental toxicity (kidney effects in male s, blood effects in females). Thus, there is no concern for increased susceptibility of developing young for flonicamid.

In an acute neurotoxicity study, signs of toxicity such as decreased motor activity, tremors, impaired gait

, and impaired respirati on were observed at lethal dose levels (1000 mg/kg). In a subchronic study, decreased body weight, body weight gain , foot splay, food consumption, and motor activity were seen in males at doses greater than 67 mg/kg/day, and in females at 722 mg/kg/day.

A n immunotoxicity study showed that flonicamid is not an immuno

- suppressant, either structurally or functionally

, at dose levels up to and exceeding the l imit d ose.

Mutagenicity studies were negative for flonicamid and its metabolites TFNA, TFNA

- AM, TFNG, TFNG

- AM, and TFNA

- OH. Flonicamid is carcinogenic in CD

- 1 mice, based on an increased incidence of lung tumors associated with Clara cell activation. This tumor typ e, however, is associated with species and strain sensitivity and is not directly correlated with cancer risks in humans. Nasal cavity tumors in male Wistar rats were linked to incisor

inflammation and were not sufficient to make a similar determination i n female rats. These nasolacrimal duct tumor findings for males were confounded by the lack of a dose

- response, and the biological significance is questionable. The Cancer Assessment Review Committee (CARC)

did not consider the nasolacrimal duct tumors i n rats to be treatment related. The determination of carcinogenicity potential for flonicamid was made by the CARC on January 5, 2005 b ased on the weight of the evidence approach and resulted in the classification “ suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential” (TXR# 0052013, J. Kidwell, 0 2/24/ 20 05). The RAB3 risk assessment team determined that quantification of risk using a non

- linear approach (i.e., using a chronic reference dose ) adequately account s for all chronic toxicity, including carcinogenicity that could result from exposure to fl onicamid

. Therefore, the cRfD is considered protective for carcinogenic effects

. As a result, separate

### Page 20 of 45 cancer risk assessments were not conducted. The cRfD was base d on an endpoint of toxicity from a two generation reproduction study in rats. The No Observable Adverse Effect Level ( NOAEL ) in this study was 3.7 mg/kg/day; the Lowest Observable Adverse Effect Level ( LOAEL ) of 22.3 mg/kg/day is based on increased kidne y weights, kidney hyaline deposition,

and increased blood serum luteinizing hormone in F 1 

### females

.

Flonicamid has a low acute toxicity via the oral (Tox Category III) , dermal (Tox Category IV),

and inhalation (Tox Category IV) routes of exposure. It is not an eye or skin irritant and is not a

skin or dermal sensitizer. Flonicamid metabolites TFNA, TFNA

- AM, TFNG, TFNG

- AM, and

TFNA

- OH likewise are classified as Category III for acute oral toxicity. The acute toxicity
category a nd toxicology profile of technical flonicamid are presented in the appendix (A1.0 and A 2.0).

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

HED has determined that reliable data show it would be safe for infants and children to reduce the FQPA safety factor to 1X because:

• the toxicity data base is complete with the exception of a subchronic inhalation study, and in the absence of this study a 10x database uncertainty factor has been applied to occupational inhalation exposure scenari os;

• there are no concerns for neurotoxicity based on the results of the acute and subchronic neurotoxicity studied;

• t he degree of concern for pre and/or post

- natal susceptibility is low due to the lack of evidence of qualitative and quantitative susceptibi lity in the developmental and reproductive toxicity studies; and

• t here are no residual uncertainties in the flonicamid exposure database

.

4. 4

. 1 Completeness of the Toxicology Database

The toxicity database for flonicamid is complete except for a subchronic inhalation study

. Changes to 40 CFR § 158 make a subchronic inhalation study conditionally required for pesticide registration based on anticipated exposure scenarios.

As explained above in Section 4.0, a subchronic 28

- day inhalation study is r equired at this time (TXR No. 0056400, K. Rury, 7/30/12). In the absence of a route specific inhalation study, the HASPOC recommended that a 10X database uncertainty factor be applied to assess inhalation

exposure risks.

4.4.2 Evidence of Neurotoxicity

The current data base includes acute and subchronic neurotoxicity studies. The clinical effects seen in these studies, while suggestive of an adverse effect on nervous tissue and/or function, did

not occur in the absence of other effects. In the acute st udy, the increase in mortality suggests the animals were in an extreme condition. In the subchronic study, food consumption and body weight measurements suggest the animals were otherwise compromised and in a state of general

### Page 21 of 45 malaise. Also, these types o f effects were not observed in the other subchronic or chronic studies in mice, rats or dogs. Thus, there is not clear evidence of neurotoxicity. Lastly, clear NOAELs and LOAELs were defined for these effects, which are above the levels currently used fo r risk
assessment purposes . T he current risk assessment is protective of these effects, and a developmental neurotoxicity study is not required.

4. 4 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There was no evidence for qua ntitative or qualitative susceptibility following oral exposures to

rats or rabbits in utero . Following oral exposures to rats, developmental effects (cervical ribs) were seen only in the presence of liver and kidney effects seen in maternal animals. No developmental effects were seen in rabbits. In the multi

- generation reproduction study, developmental delays in the offspring (decreased body weights, delayed sexual maturation) were seen only in the presence of parental toxicity (kidney and blood effects ). Also, there are clear NOAELs and LOAELs for all effects. The degree of concern for pre

- and/or post

- natal susceptibility is, therefore, low due to the lack of evidence of qualitative and quantitative susceptibility.

4. 4 .4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the flonicamid exposure database. An unrefined

, conservative chronic dietary exposure assessment for food and drinking water was conducted, assuming tolerance

- level residues for all existing and proposed commodities and that 100% of registered and proposed crops treated. The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protective, high

- end estimates of water concentrations which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the potential exposure for infants, children, or wom en of child bearing

age.

4. 5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

The endpoints and points of departure for this risk assessment have not changed since the previous risk assessment. The rationales for each selection, along with a detailed description of the toxicity studies used for various exposure scenarios are presented in that document ( D 397277, B. O’Keefe, 10/02/2012 ).

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. Short

- and intermediate

- term exposures are not aggregated because there are no potential residential exposures anticipated.

### Page 22 of 45 4.5.3 Cancer Classification and Risk Assessment Recommendation

The Cancer Assessment Review Committee (CARC) classified flonicamid as, “ Suggestive Evidence of Carcinogenicity, but Not Sufficien t to Assess Human Carcinogenic Potential ”. The quantification of hu m an cancer risk was not reco mm ended. (TXR 0052013, J. Kidwell, 02/24/2005)

.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in Dietary and Non

- Occupational Human Health Risk Assessments.

Exposure Scenario Point of Departure Uncertainty/FQ PA Safety

Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological
Effects

Acute Dietary None NA aPAD = NA No toxicological effects seen in a single dose study.

Chronic Dietary NOAEL = 3.7 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD = 0.04 mg/kg/day

cPAD = 0.04

mg/kg/day 2

- Gen Reproduction rat
Parental LOAEL = 22 mg/kg/day based on increased kidney weights, kidney hyaline deposition, increased blood serum LH (F1 females).

Cancer Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic

Potential

Point of Departure (POD) = A data point or estimated point that is derived from observed dose

- related data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = databa se uncertainty factor. FQPA SF = FQPA safety factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. NA = Not Applicable.



### Table 4.5.4.2. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in Occupational Human Health Risk Assessments.

Exposure Scenario Point of Departure Uncertainty

Factors Level of Concern
for Risk

Assessment Study and Toxicological Effects

Short

- Term (1 to 30 days) & Intermediate

Term Dermal (1 to 6 months) None NA Occupational

LOC for MOE =

NA No hazard was indentified, since

the 28

- day dermal study did not show any dermal or systemic

effects at the limit dose of 1000 mg/kg/day.

Short

- Term (1 to 30 days) & Intermediate

Term Inhalation (1 to 6 months) Oral NOAEL =

12 mg/kg/day UF A = 10X

UF H = 10X

UF DB = 10X Occupational

LOC for MOE =

1000 90

- Day oral rat

LOAEL = 60 mg/kg/day based on kidney hyaline deposition.

Cancer Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic

Potential

### Page 23 of 45 Point of Departure (POD) = A data point or estimated point that is derived from observed dose

- related data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in

sensitivit y among members of the human population (intraspecies). UF DB = database uncertainty factor. MOE = margin of exposure. LOC = level of concern. NA = Not Applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants and livestock is adequately understood for the purposes of risk

assessment and tolerance evaluation

. Based on the metabolism studies conducted in plants, the major metabolic pathway of flonicamid in plants involves hy drolysis of the cyano (

- CN) and amide (

- CONH) functional groups and ring hydroxylation. The residues of concern in plants for tolerances and risk assessment are flonicamid and its metabolites TFNA, TFNA

- AM, and TFNG. In livestock commodities, HED has det ermined that the residues of concern for the tolerances and risk assessment are flonicamid, TFNA and TFNA

- AM. A more detailed description of the plant and animal metabolism studies is presented in a previous risk assessment (DP347805, S. Piper, 12/21/ 20 07 ).

A summary of the metabolites and degradates of flonicamid for human health risk assessment is

summarized in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates included in the Flonicamid Risk Assessment and Tolerance Expression

Matrix Residues included in

Risk Assessment Residues included in
Tolerance Expression

Plants Primary Crop Flonicamid, TFNA, TFNA

- AM and
TFNG Flonicamid, TFNA, TFNA

- AM and
TFNG

Rotational Crop Flonicamid, TFNA, TFNA

- AM and

TFNG Flonicamid, TFNA, TFNA

- AM and

TFNG

Livestock Ruminant Flonicamid, TFNA and TFNA

- AM Flonicamid, TFNA and TFNA

- AM

Poultry Flonicamid, TFNA and TFNA

- AM Flonicamid, TFNA and TFNA

- AM

Drinking Water Flonicamid, TFNA, TFNG

- AM, TFNG, TFNA

- OH, TFNA

- AM Not Applicable



### 5 .2 Food Residue Profile

Field trial data on a lfalfa (MRID 4 902620 1)

, clover (MRID 49 026201 )

, mint (MRID 4026203)

tomatoes (field and greenhouse) (MRID 4 9026202 ) , and almonds and pecans (MRID 48935301) have been submitted to support the proposed tolerances. The se data ar e adequate to support dietary risk assessment as well as the proposed tolerances of flonicamid on alfalfa, mint, tomatoes, and tree nuts (almonds and pecans)

. Additionally, for alfalfa, mint, tomatoes, and tree nuts (almonds and pecans) t he number and geo graphic distribution of the field trials are adequate. However, the submitted field trials are not adequate for clover, there are two few trials, and too few geographic regions represented by the data . For use of flonicamid on clover

### Page 24 of 45 in the Pacific Northwest only, two additional field trials would be needed. For clover in the

Pacific Northwest , the ChemSAC recommended that three field trials be conducted in Region 11; the petitioner submitted two field trials (considered by HED to be one field trial) in Region 12 (OR). Summaries of the residue data from the crop field trials are presented in Appendix D,

Table D

- 1 through D

- 3.

Processed Food and Feed The processed commodities associated with the newly proposed crops are spearmint oil and peppermint oil. The processed commodities associated with the proposed revised use on fruiting vegetables are tomato paste and tomato puree. There are no processed commodities for alfalfa

, clover

, or tree nuts

.

The submitted mint processing study is acceptable. An acceptable method was used for residue quantitation, and a dequate data were submitted to support sample storage intervals and

conditions. The processing data indicate that combined residues of flonicamid, TFNA, TFNA

AM, and TFNG do not co ncentrate in oil (average processing factor <0.063x).

F lonicamid, TFNA

- AM, TFNA, and TFNG were shown to concentrate in tomato paste and puree. Because the concentration factors determined in the available tomato processing study were higher than the theo retical concentration factors

. T he theoretical concentration factors ( 5.5x for paste and 1.4x for puree ) applied to the HAFT (0.263 ppm from D290386 or 0.224 ppm from the current petition) were used to determine tolerances for tomato paste and puree. The established tolerance levels on the fruiting vegetable group 8 at 0.40 ppm, tomato paste at 2.0 ppm, and tomato puree at 0.50 ppm are adequate.

Livestock Adequate ruminant and poultry feeding studies are available. The maximum reasonably

balanced diets (MRBD), calculated using the Table 1 Feedstuffs (June 2008), are 1.3 ppm in beef cattle, 3. 4 ppm in dairy cattle, 0. 13 ppm in swine, and 0. 16 ppm in poultry

. The established tolerances of 0.03 ppm in the fat of cattle, goat, horse, and sheep, 0.03 ppm in poultry meat, fat, and meat byproducts, 0.04 ppm in eggs, and 0.08 ppm in meat and meat byproducts of cattle, goat, horse and sheep are adequate. The following additional/revised tolerances are

recommended : 0. 05 ppm in milk and 0.03 ppm in mea t, fat, and meat byproducts of swine

.

Rotational Crops A confined rotational crop study was conducted o n the rotational crops carrot, lettuce, and wheat.

The radiolabeled test substance

, [pyridyl

14 

### C] flonicamid

, was applied twice to bare loamy sand in planting containers at 0.089 lb ai/A/application for a total rate of 0.179 lb ai/A

. Total radioactive residues (TRR) were present at ≥0.01 ppm in some rotated crops planted 30, 120, and 361 days following soil appl ications. As in treated plants, the main pathway of metabolism in rotational crops involves hydrolysis of the cyano (

- CN) and amide (

- CONH

- ) functional groups

in the molecule. Flonicamid and metabolites TFNG, TFNA, TFNG

- AM, TFNA

- AM, and

TFNA

- OH were iden tified in rotational crops. Based on the results of the confined study, a limited field rotational crop study was conducted.

### Page 25 of 45 The limited field rotational crop study conducted on the representative crops turnip and wheat is adequate. Leafy vegetables wer e not included in the study because low residues (<0.01 ppm) were observed in lettuce from the confined rotational crop study. T he studies reflect the

maximum proposed use rate of 0.267 lb ai/A/season. T he residue data are supported by the

available stor age stability data. The a nalytical method , FMC No. P

- 3561M, is adequate for the analysis of the residues of concern

. The residues of concern in rotational crops are flonicamid

and its metabolites TFNA

- AM, TFNA, and TFNG. The results of the limited field rotational crop studies indicate that rotational crop tolerances are not required. The available rotational crop data indicate that a 30

- day plantback interval is appropriate for all crops not listed on the

label.

5.3 Water Residue Profile

The drinki ng water residues used in the dietary risk assessment were provided by EFED (D40 8552

, J. Hetrick , 0 6/24 / 20 13) and incorporated directly into th e dietary assessment. Water residues were incorporated in the DEEM

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

The drinking water assessment considered new uses on alfalfa and clover grown for seed, mint, and tree nuts, the expansion to the full crop group for pome fruits and stone fruits, and the

increase d application rate on fruiting vegetables. All existing uses were also considered. The drinking water assessment was conducted using both a parent only exposure, and a total toxic residue approach, which considers the parent compound and its major degradates of concern.

Total toxic residues include 4

- trifluoromethylnicotinic acid ( TFNA), 4

- trifluoromethylnictinamide (TFNA

- AM), 6

- hydro

- 4

- trifluoromethyln icotinic acid (TFNA

- OH),

N

- (4

- trifluoromethylnicotinoyl)glycine (TFNG), and N

- (4

- trifluoromethylnicotinoyl )glycinamide (TFNG

- AM). The predicted concentrations of flonicamid total toxic residues for the proposed

uses are lower than EDWC s in previous drinki ng water assessments

.

EDWCs from PRZM

- GW ( P esticide R oot Z one M odel

- Ground Water , version 1.0, August 31,

2012 ) were used

. The concentration of total toxic residues of flonicamid (flonicamid TTR) in ground water is predicted to not exceed 15.9 μg/L for the daily peak and 9.92 μg/L for the 30

- year annual average. These concentrations are associated with the proposed increase d application rate of 0.133 lb ai/A on fruiting vegetables. The EFED models and their descriptions

are available at the EPA in ternet site : http://www.epa.gov/oppefed1/models/water/

. See Table

5.3.1

.

Table 5.3.1

. EDWCs B ased on Flonicam id U se. 1

Source of Drinking Water Acute (μg/L) 30

- Year Annual Average (μg/L)

Surface water

- cranberry 94.93 285.44

Sur f ace water

– uses other than cranberry 9.031 0.94

Ground water (PRZM

- GW) 15.9 9.92

1 These are the highest EDWCs for the proposed and previously evaluated use scenarios . The Tier 1 rice model for cranberry is
not used in th is risk assessment because it is considered to be overly conservative

.

### Page 26 of 45 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The dietary exposure analysis incorporates all current and proposed tolerances for residue s of

flonicamid , including its metabolites and degradates. The f lonicamid c hronic dietary exposure assessment was conducted using the DEEM

- FCID, Version 3.16, which incorporates 2003

- 2008 consumption data from USDA’s NHANES/WWEIA. A n un refined chronic dietary analysis was

conducted

. The residue levels used in the chronic assessment were the tolerance levels for plant commodities established under 40 CFR §180.613 and the HED recommended tolerance levels based on the crop field trials for the proposed cr ops. The livestock commodity tolerances are changed from the previous assessment. Estimated concentrations of flonicamid in drinking

water from the proposed use s w ere provided by EFED and incorporated directl y into the chronic assessment (i.e., EDWC of 9 .92 μg/L calculated with PRZM

- GW and based on a fruiting vegetable scenario for ground water )

. Separate tolerances were established for dried potatoes, tomato paste, and tomato puree based on processing studies. The processing factor was set to 1.0

for t hese commodities. DEEM default processing factors were used for the other processed commodities for which default processing factors are available.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure analysis used 100% crop treated.

5.4.3 Acute Dietary Risk Assessment

S ince no observed effects could be attributed to a single dose, an acute endpoint was not established. Therefore, a n acute dietary exposure assessment was not conducted

.

5.4.4 Chronic Dietary Risk Asses sment s

The chronic dietary exposure assessment was a conservative assessment

, conducted using

tolerance

- level residues and 100% crop treated . Estimated concentrations of flonicamid in drinking water from the proposed uses were provided by EFED and incorp orated directly into the

chronic assessments.

The chronic dietary (food and drinking water) exposure to flonicamid is below HED’s level of concern for the general U.S. population and all population subgroups. The chronic dietary exposure estimates util ized 1 2 % of the cPAD for the general U.S. population and 3 0 % of the

cPAD for children 1

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

### Page 27 of 45 5.4. 5 Summary Table

Table 5.4.1

. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Flonicamid 1

Population Subgroup cPAD (mg/kg/day) Exposure
(mg/kg/day) % cPAD

General U.S. Population

0.04 0.0047 20 12
All Infants (< 1 year old) 0.0067 18 17

Children 1

- 2 years old 0.011 869 30

Children 3

- 5 years old 0.008 864 22

Children 6

- 12 years old 0.0053 36 13

Youth 13

- 19 years old 0.0034 02 8. 5

Adults 20

- 49 years old 0.0041 00 10

Females 13

- 49 years old 0.004 197 10

Adults 50

- 99 years old 0.0045 01 11
1 The population with the highest exposure is in bold



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

R esidential exposure is not expected. There are registered labels with use on commercial ornamentals, interiorscapes, and nurseries; but these labels do n ot allow use in home gardens

, greenhouses

, or in any residential settings. Therefore, residential handler scenarios are not expected and need not be assessed. Additionally, because no dermal toxicity endpoint was identified for flonicamid, a post

- applica tion residential exposure/risk assessment is not

necessary.

6. 1 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for flonicamid at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 1.91 x 10 - 8 

### mm Hg at 2 5 0 

### C ), and the low proposed use rates ( 0.089 to 0.134 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 Scientif ic Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 

### . 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 Agency may revisit the need for a quantitative post

- application inhalation e xposure assessment
for flonicam id

.

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Page 28 of 45 6. 2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for flonicam id . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Dr ift website for more information 2 

### ). The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce

off

- target d rift with specific products with significant risk estimates 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 f ields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a

wors t case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalat ion exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with 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 bot h the route and duration of exposure. There were no observed effects attributable to a single dose and an acute dietary endpoint was not established. A cancer dietary assessment was not conducted as flonicamid has been determined to be “Suggestive Eviden ce of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenicity Potential”. For flonicam id

, only potential chronic exposures from food and drinking water were aggregated. There are no expected long

- term residential exposures. Because drinking water estimates have been combined with dietary exposures, the dietary assessment described earlier (see Section 5. 4 ) serves as the aggregate exposure and risk assessment for flonicamid. Because aggregated food and drinking water exposures from this conse rvative assessment for the most highly exposed population subgroup (Children 1

- 2 years old) only amount to 30% of the cPAD, exposure to flonicamid from all registered/proposed uses do not exceed HED’s level of concern.

8.0 Cumulative Exposure/Risk Characteriz ation

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

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

### Page 29 of 45 to flonicamid and any other substances and flonicamid does not appear t o produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

EPA has not assumed that flonicamid has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/R isk Characterization

Flonicam id is proposed for new occupational uses on alfalfa, clover, mint ̧ tree nuts, and greenhouse grown tomatoes. Application methods, maximum application rates, and use sites are

summarized in Section 3.3 and Table 3.3 .2 . Based on the proposed use pattern s , there is a potential for short

- and intermediate

- term occupational exposure to flonicam id during handling (mixing, loading, and applying) and post

- application activities. Flonicamid uses are propos ed for multiple applications

, with the retreatment intervals rang ing from 7 to 14 days. The proposed labels require occupational handlers to wear the following PPE: long

- sleeved shirt and long
pants, shoes plus socks ̧ protective eyewear, and chemical resistant gloves. The 12 hour R EI listed on the labels is appropriate.

9.1 Short

- /Intermediate

- Term Handler Risk

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

Based on the anticipated use patterns from the proposed label s , types of equipment and techniques that can potentially be used, occupational handler exposure is expecte d from the proposed uses. HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for variability among species and a 10X factor to account for variability within species. For inhalation exposures, an additional 10X uncertainty factor is added because of the lack of an available subchronic inhalation toxicity study. Therefore, the total uncertainty factor that has been applied to the inhalation assessments

of flonicam id is 1000X for residential handler exposure. Occupational inhalation exposure and risk resulting in MOEs greater than or equal to 1000 will not be of concern to HED (LOC = 1000).

Summaries of the short

- and intermediate

- term risk estimate s for occupational handlers applying

flonicamid are provided in Appendix E

, Table E

- 1. Based on the proposed use pattern of flonicamid, there is a potential for short

- and intermediate

- term occupational exposure during handling (mixing, loading, and applying) and post

- appli cation activities. For PPE, the proposed labels require occupational handlers to wear long

- sleeved shirt and long pants, shoes plus socks ̧

### Page 30 of 45 protective eyewear, and chemical resistant gloves. Since no hazard was identified for the dermal route of exposure, dermal handler risks were not assessed ; therefore, only a quantitative inhalation exposure assessment was performed for handlers

. HED used data presented in the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (3/2012) to assess

han dler exposures. Except for one scenario, all exposures result in short

- and intermedia te

- term MOEs that range from 1,000

- 6,300,000 and are not of concern to HED (i.e. an MOE > 1

, 000)

with baseline attire. M ix ing / L oad ing / A ppl ying flonicamid to greenhouse t omatoes using mechanically pressurized handgun equipment resulted in an MOE of 600 at baseline attire, which is below HED’s level of concern. This MOE was no longer a concern when assessed with the

addition of a PF5 respirator (MOE = 3,000 ) . Therefore, t he proposed labels need to be revised to include the use of a PF5 respirator for the greenhouse tomato use.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

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

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s deg radation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- Application Risk

Based on the proposed use patterns, short

- and in termediate

- term post

- application dermal exposures to workers re

- entering treated areas is possible. However, s ince no hazard was identified for the dermal route of exposure, dermal post

- application risks were not assessed.

Restricted Entry Interval: For all ac tivities and crops, the REI of 12 hours on the proposed

label s is adequate to protect workers. In addition to systemic hazard, the WPS for Agricultural

Pesticides sets a R EI based on the acute toxicity of chemicals. Technical flonicamid is classified as toxicity category IV for acute dermal toxicity

, primary ey e
, and skin irritation. Under the

WPS , active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12

- hour REI. Therefore, the REI of 12

- hours is adequate to protect agricultural workers from post

- application exposures to flonicamid.

9.2.2 Inhalation Post

- Application Risk

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

- application inhalation exposure

assessment was not performed for flonicam id at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 1.91 x 10 - 8 

### mm Hg at 2 5 o 

### C ) an d the low proposed use rate s (0. 089 to 0. 1 3 4 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 resuspen sion of dusts and/or particulates that contain pesticides. The Agency sought expert

### Page 31 of 45 advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 

### . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and proce dures, to identify the need for and, subsequently, the way to incorporate occupational 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 quantit ative occupational post

- application inhalation exposu re assessment
for flonicam id

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/com mercial handlers. Handler exposure resulting from application of pesticides 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.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

10.0 References

Flonicamid

. Petition for the Establishment of Permanent Tolerances and Registration for New

Use s on Alfalfa, Clover, Spearmint, Pepper mint ; Inclusion of Cucumber in Cucurbit Group 9 ; and Crop Group Conversions for Fruiting Vegetable Group 8

- 10, Pome Fruit Group 11

- 10, and Stone Fruit Group 12

- 12. Summary of Analytical Chemistry and Residue Data. DP413404, N. Dodd, 8/ 14 /13

.

Flonicamid

. Petition for the Establishment of Permanent Tolerances and Registration for Use on

Tree Nuts

. Summary of Analytical Chemistry and Residue Data. DP413407, N. Dodd, 8/ 14 /13

.

F lonicamid : Occupational and Residential Exposure/Risk Assessment for Use on Alfalfa, Clover, Mint, Greenhouse Tomatoes, and Tree Nuts

. DP408 738 , C. Walls, 8/ 5 /13

.

Flonicamid : Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Actions on Tree Nuts, Alfalfa, Clover, Spearmint, Peppermint, and Cucurbit Group 9, and Crop Group Conversions for Fruiting Vegetable Group

8

- 10, Pome Fruit Group 11

- 10, and Stone Fruit Group 12

- 12. DP413405, N. Dodd, 8/ 14 /13

.

Drinking Water Assessment to Assess Flonicamid Use on Alfalfa and Clover Grown for Seed, Fruiting Vegetables, Mint, Tree Nuts, and the Expansion to the Full Crop Group f or Pome Fruit and Stone Fruit. DP408552, J. Hetrick, 6/24/13.

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Page 32 of 45 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for non

- food use for flonicamid are in Table A. 1. Use of the

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Toxicology Data Requirements for Flonicamid.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

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

- Day Dermal

................................ .............................. 870.3465 28

- Day Inhalation

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

yes

yes

no

yes yes

yes

yes

-

no

870.3700a Developmental Toxicity (rodent)

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

............................. 870.3800 Reproduction

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes*

yes yes*

yes no* yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5385 Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

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

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ .................. no

no

yes

yes

no -

- yes

yes

no

870.7485 General Metabolism

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

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

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

no

yes yes

-

yes

Special Studies for Ocular Effects Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. -

-

- -

-

- 

### * The requirements for 870.4100a and 870.4200a are satisfied by 870.4300

### Page 33 of 45 A.2 Toxicity Profile s Table A.2.1. Acute Toxicity of Flonicam id

Table A.2.1. Acute Toxicity Data on Technical Flonicamid and Flonicamid Degradates and Metabolites

. Guideline

No. Study Type MRID

No. Results Toxicity Category

870.1100 Acute Oral

- Rat 45656707 LD 50 = 884 mg/kg (Males),

LD 50 = 1768 mg/kg (Females) III

870.1200 Acute Dermal

- Rat 45656708 LD 50 > 5000 mg/kg IV

870.1300 Acute Inhalation

- Rat 45656709 LC 50 > 4.9 m/L IV

870.2400 Primary Eye Irritation

- Rabbit 45656710 None or very low effects. IV

870.2500 Primary Skin Irritation

- Rabbit 45656711 Erythema & edema scores were zero. IV

870.2600 Dermal Sensitization

- Guinea Pig 45656712 Not a sensitizer. NA

870.1100 Acute Oral

– Rat
Flonicamid metabolite TFNA 45854605 LD 50 ≥ 2000 mg/kg III

870.1100 Acute Oral

– Rat
Flonicamid metabolite TFNA

- AM 45854606 LD 50 ≥ 2000 mg/kg III

870.1100 Acute Oral

– Rat
Flonicamid metabolite TFNG 45854607 LD 50 ≥ 2000 mg/kg III

870.1100 Acute Oral

– Rat
Flonicamid metabolite TFNG

- AM 45854608 LD 50 ≥ 2000 mg/kg III

870.1100 Acute Oral

– Rat
Flonicamid metabolite TFNA

- OH 45854609 LD 50 ≥ 2000 mg/kg III



### Table A.2.2. Non

- acute Toxicity Profile for Flonicami d

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.3100 a 90

- Day oral toxicity in rats 45656721 (2002)

acceptable

- guideline/ 0, 50 , 200, 1000, 2000 (males), or 5000 (females) ppm 0, 3.08, 12.11, 60.0, or 119.4 mg/kg/day ( males ) 0, 14.52, 72.3, or 340.1 mg/kg/day ( females)

28

- day range

- finding: 45656720 (2002)/ acceptable (non

- guideline)/ 0, 50 (males), 500, 1000, 5000 or 10000 (females) ppm ( 3.61, 7.47, 36.45, 73.8, or 353.4 mg/kg/day, males & 8.36, 41.24, 81.9, 372.6, or 642 mg/kg/day, females) NOAEL = 200 ppm (12.11 mg/kg/day , males ) ; 1000 ppm (72.3 mg/kg/day , females )

LOAELs = 1000 ppm (60.0 mg/kg/day , males ) based on hyaline deposition in the kidney; 5000 ppm (340 mg/kg/day , females ) based on h yaline deposition in the kidney and centrilobular hypertrophy in the liver.

28

- day range

- finding:

NOAEL = 100 ppm (7.47 mg/kg/day , males ) ; 1000 ppm (81.9 mg/kg/day , females )

LOAELs = 500 ppm (36.45 mg/kg/day , males ) ; based on hyaline deposition in the kidney; 5000 ppm (372.6 mg/kg/day , females ) based on hyaline deposition in the kidney , centrilobular hypertrophy in

the liver , anemia and increased cholesterol.

### Page 34 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.3100b

90

- Day oral toxicity rodents (mice) 45656719 (2001)

acceptable (non

- guideline)/ 0, 100, 1000 or 7,000 ppm
0, 15.25, 153.9 or 1069 mg/kg bw/day in males,
0, 20.10, 191.5, or 1248 mg/kg bw/day in females NOAEL is 100 ppm (males: 15.25 mg/kg bw/day, females: 20.10 mg/kg bw/day) LOAEL is 1000 ppm (males: 153.9 mg/kg bw/day;
females: 19 1.5 mg/kg bw/day) based on extramedullary hematopoiesis of the spleen.

Many of the tissues/organs recommended by Guideline 870.3100 were not histologically examined in any dose group, but this study is not required and serves as a range

- finding study for the mouse carcinogenicity study. Therefore, it is classified as acceptable, non

- guideline study.

870.3150

90

- Day oral toxicity in dogs 45646722 (2001)

acceptable

– guideline

0, 3, 8, 20, or 50 (females) mg/kg bw/day NOAEL is 8 mg/kg/day in males and 20 mg/kg/day for females. LOAEL is 20 mg/kg/day in males and 50 mg/kg/day in females, based on acute clinical signs in males and females (vomiting, first observed on Day 1 and last observed on Day 90), clinical pathology a t 7 weeks (increased total protein levels in males, lower red blood cells and higher reticulocytes counts in females), increased adrenal weights in males, decreased thymus gland weights in males, and increased kidney tubular vacuolation in females at study termination.

870.3200

21

- Day dermal toxicity in rats 45656723 (2001)
acceptable

– guideline
0, 20, 150, or 1000 mg/kg/day NOAEL is 1000 mg/kg/day LOAEL is >1000 mg/kg/day.

870.3700a

Prenatal developmental in

rats 45656724 (2002)
acceptable

– guideline
0, 20, 100 or 500 mg/kg bw/day Maternal NOAEL is 100 mg/kg bw/day LOAEL is 500 mg/kg bw/day, based on increased liver weight, and liver and kidney pathological changes (hypertrophy of centrilobular hepatocytes in liver and vacuolation of proximal tubular cell in kidneys).

Developmental NOAEL is 100 mg/kg bw/day

LOAEL is 500 mg/kg bw/day, based on the

increased incidence of cervical rib.

870.3700b

Prenatal developmental in

rabbits 45854611

, 45854610 (2002) acceptable

– guideline
0, 2.5, 7.5, 25 mg/kg/day Maternal NOAEL is 7.5 mg/kg/day LOAEL is 25 mg/kg/day, based on decreased body weights, body weight gains, and food consumption.

Developmental

NOAEL is ≥ 25 mg/kg/day
LOAEL is not established.

### Page 35 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.3800 Reproduction and fertility effects in

rats 45854613

, 45854612 (2002)
acceptable

– guideline
0, 50, 300, 1800 ppm

(0/0, 3.7/4.4, 22.3/26.5, 132.9/153.4 mg/kg bw/day [M/F]) Parental NOAEL is 50 ppm (equivalent to 3.7/4.4 mg/kg/day [M/F]). LOAEL is 300 ppm (equivalent to 22.3/26.5 mg/kg/day [M/F]) based on increased relative kidney weight and hyaline droplet deposition in the proximal tubules of the kidneys in the males and
increased blood serum LH levels in the F1 females.

Offspring

NOAEL is 300 ppm (equivalent to 22.3/26.5 mg/kg/day [M/F]). LOAEL is 1800 ppm (equivalent to 132.9/153.4 mg/kg/day [M/F]) based on decreased absolute and relative to body uterus weights and delayed sexual maturation in the F1 females.

Reproductive Perfor m ance NOAEL is 1800 ppm (equivalent to 132.9/153.4 mg/kg/day [M/F]). LOAEL for reproductive performance was not

observed.

870.4100 b Chronic toxicity in dogs 45854614 (2003) acceptable

- guideline 0, 3, 8, or 20 mg/kg/day NOAEL is 8 mg/kg/day. LOAEL is 20 mg/kg/day, based on acute clinical signs (vomiting, mostly within the first week), clinical pathology at 12 months (higher reticulocytes counts) in males and females.

870.4200 b Carcinogenicity in

mice 45854615

, 45854616 (2003) acceptable

– guideline
0, 250, 750, 2250 ppm

(0/0, 29/38, 88/112, 261/334 mg/kg/day [M/F]) NOAEL was not established. LOAEL is 250 ppm (equivalent to 29/38 mg/kg/day [M/F]), based on minimal to moderate centrilobular hepatocellular hypertrophy, minimal to severe

ext ramedullary hematopoiesis, minimal to moderate pigment deposition in the sternal bone marrow, and

increased incidence of tissue masses/nodules in the lungs in the males, and minimal to moderate decreased cellularity in the femoral bone marrow and hyperplas ia/hypertrophy of the epithelial cells of the

terminal bronchioles of the females.

At the doses tested, the carcinogenic potential of IKI

220 is positive at 250 ppm in males and females

based on the increased incidence of alveolar/bronchiolar adenomas, c arcinomas, and combined adenomas/carcinomas. Dosing was considered adequate based on increased incidence of tissue masses/nodules in the lungs and microscopic findings in the liver, spleen, bone marrow, and lungs. However, data were provided suggesting t his effect is specific to sensitive strains of mice.

Carcinogenic in mice.

### Page 36 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.4200 b Carcinogenicity in

mice 46205801 (2004)
acceptable

– guideline
0, 10, 25, 80, 250 ppm

males: 0, 1.20, 3.14, 10.0, 30.3 mg/kg/day;

females: 0, 1.42, 3.67, 11.8, 36.3 mg/kg/day NOAEL is 80 ppm (equivalent to 10/12 mg/kg/day in males/females). LOAEL is 250 ppm (equivalent to 30/36 mg/kg/day in males/females) based on lung masses and terminal bronchiole epithelial cell hyperplasia/hypertrophy in

both sexes.

At the dose s tested, the carcinogenic potential of IKI

220 is positive in males and females based on the incidences of alveolar/bronchiolar adenomas, carcinomas, and combined adenomas and/or carcinomas. Dosing was considered adequate based on lung masses and termina l bronchiole epithelial cell hyperplasia/hypertrophy in both sexes.

Carcinogenic in mice.

870.4300

Combined Chronic toxicity/ Carcinogenicity in

rats 45863801 (2002)
acceptable

– guideline

0, 50, 100 , 200, 1000, or 5000 (females) ppm

0/0, 1.84, 3.68, 7.32/8.92, 36.5/44.1, 219 mg/kg/day [M/F] NOAEL is 200 ppm (equivalent to 7.32/8.92 mg/kg/day in males/females). LOAEL is 1000 ppm (equivalent to 36.5/44.1 mg/kg/day in males/females) based on decreased body weights and body weight gains, and increased
i ncidences of keratitis in males and striated muscle fiber atrophy in females.

At the high dose there was an incidence (12%) of nasolacrimal duct squamous cell carcinomas slightly outside the historical control range (0

- 10%) in male

rats. A correlation between the incidence of inflammation and the fluctuating incidence of nasal tumors was made across dose groups. The CARC

did not consider the nasolacrimal duct tumors to be

treatment

- related.

Female rats had a significant increasing trend in

nasolacrima l duct squamous cell carcinomas at p<0.05, and at the high dose was slightly above the historical control mean (0.8%) and range (0

- 4%).

The CARC considered the nasolacrimal duct squamous cell carcinomas to be possibly treatment related, but that a clear a ssociation with treatment

could not be made.

870.5100

Bacterial reverse gene mutation 45656725 (2002)
acceptable

– guideline
61.7 to 5000 μg/plate +/

- S9 Negative

870.5100

Bacterial reverse gene mutation 45854617 (2002)
acceptable

– guideline

33 to 5000 u g/plate +/

- S9 Negative for metabolite TFNA

870.5100

Bacterial reverse gene mutation 45854618 (2002)
acceptable

– guideline

33 to 5000 u g/plate +/

- S9 Negative for metabolite TFNA

- AM

### Page 37 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.5100

Bacterial reverse gene mutation 45854619 (2002)
acceptable

– guideline

33 to 5000 u g/plate +/

- S9 Negative for metabolite TFNG

- AM

870.5100

Bacterial reverse gene mutation 45854620 (2002)
acceptable

– guideline

33 to 5000 u g/plate +/

- S9 Negative for metabolite TFNA

- OH

870.5100

Bacterial reverse gene mutation 45854621 (2002)
acceptable

– guideline

5 to 5000 u g/plate +/

- S9 Negative for metabolite TFNG

870.5300

In vitro

mammalian cell gene mutation 45656726 (2002)
acceptable

– guideline
28.3 to 2290 μg/mL initial test, and 143 to 2290 μg/mL repeat. Negative

870.5375

In vitro Cytogenetics 45656727 (2002)
acceptable

– guideline
573, 1145 and 2290 μg/mL Negative

870.5395

In vivo cytogenetic (micronucleus)

test in mice 45656728 (2002)
acceptable

– guideline

250, 500

, 1000 mg/kg/day for males

125 , 250, 500 mg/kg/day for

females Negative

Non

- guideline

Other genotoxicity, in vivo Comet assay 45854622 (2002)
unacceptable (non

- guideline)
single doses of 375, 750

, 1500 mg/kg Was not positive for nuclear migration up to 1500 mg/kg

Non

- guideline

Unscheduled DNA synthesis 45854623 (2002)
acceptable (non

- guideline)
once orally at 600 and 2000 mg/kg Is not genotoxic in hepatocytes from treated rats

870.6200a

Acute neurotoxicity screening battery (rats) 45854624 (2002)
unacceptable

– guideline

0, 100, 300, 600 (males), 1000 mg/kg/day NOAEL is 600 mg/kg in males and 300 mg/kg in

females. LOAEL is 1000 mg/kg based on mortality and signs of toxicity (decreased motor activity, tremors, impaired respiration, and impaired gait) in males.

This acute neurotoxicity s tudy is unacceptable because interval motor activity data were not provided as specified according to guidelines, FOB handling and open

- field observations were incomplete, and positive data provided were from a lab other than the performing lab for this st udy.

### Page 38 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

870.6200b

Subchronic neurotoxicity screening battery (rats) 45854702 (2003)
acceptable

– guideline
0, 200, 1000, 10,000 ppm

(0/0, 13/16, 67/81, or 625/722 mg/kg/day [M/F]) NOAEL is 200/1000 ppm (equivalent to 13/81 mg/kg/day [M/F]). LOAEL is 1000/10,000 ppm (equivalent to 67/722 mg/kg/day [M/F]) based on decreased motor activity, rearing, and foot splay in males, decreased body weights, body weight gains, and food consumption in

males and females.

870.7485

Metabolism and pharmacokin etics (rats) 45656729 (2001)
acceptable

– guideline
pilot excre tion study, single oral

dose 0.85 or 21 mg/kg and pilot pharmacokinetic study, single oral

dose of 2 or 50 mg/kg IKI

- 220 was rapidly absorbed and excreted with no apparent differences between the sexes. By 48 hours after treatment, ~93% of the administered dose had been eliminated and by 168 hours ~96% was eliminated. The primary route of elimination was the urine, accounting for ~90% of the dose. The feces of
treated rats accounted for ~5% of the administered dose, with no significant amounts of radiolabel detected in expired air of either sex. After 168 hours of a single high or low dose of the test material, <3% of the radioactivity was recovered in the carcass and <0.05% in the blood, i rrespective of dose or sex.

The pharmacokinetic parameters were also similar between the dose levels (2 and 50 mg/kg) and sexes. The radiolabel was rapidly absorbed and excreted. The apparent plasma half

- life (T1⁄2) was 4.8

- 6.0

hours and the elimination f ollowed first order kinetics. The time of maximum plasma concentration (Tmax) for individual animals ranged from 0.25 to 1 hour after treatment (with a mean for each group of 0.3

- 0.6 hours).

870.7485

Metabolism and pharmacokinetics (rats) 45863802 to

- 5, 45854703 (2002)
acceptable

– guideline
2 or 400 mg/kg Appears that the overall recovery of radioactive dose from all group was 94

- 99% by 168 hours post

- dose. Absorption was rapid and extensive, detected in plasma within 10 minutes of dosing, with maxi mum plasma concentrations within 24

- 54 minutes. By 168 hours post

- dose, total urinary excretion was 72

- 78%, cage rinse was 10

- 21%, and fecal excretion was 4

- 7% dose. Parent (IKI

- 220) and 9 metabolites

accounted for 80

- 94% of the dose for all groups.

Par ent was detected primarily in the urine, 46

- 73% of the dose in excreta in all groups. The primary

metabolite was 4

- trifluoromethylnicotinamide (TFNA

- AM), 18

- 27% dose in all dose groups, along

with minor amounts of TFNA

- AM N

- oxide (1

- 4% dose). Other metabo lites in urine and feces were detected at less than or equal to 2.5% of the dose.

IKI

- 220 was excreted primarily unchanged in the urine, but biotransformation of IKI

- 220 in rats included nitrile hydrolysis, N

- oxidation, hydroxylation of the pyridine ring an amide hydrolysis.

870.7800 Immunotoxicity 48870201 (2012) NOAEL = 1540.2 mg/kg/day

### Page 39 of 45 Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

(mouse)
Acceptable

– guideline

0, 100, 600, 6000 ppm
0, 23.2, 141.8, 1540.2 mg/kg/day) LOAEL not established



### Appendix B. Nomenclature and Physicochemical Properties of Flonicam id

.

TABLE B

- 1. Flonicamid Nomenclature.
Compound

Common name Flonicamid
Company experimental name IKI

- 220

IUPAC name N

- cyanomethyl

- 4

- (trifluoromethyl)nicotinamide

CAS name N

- (cyanomethyl)

- 4

- (trifluoromethyl)

- 3

- pyridinecarboxamide

CAS # 158062

- 67

- 0

End

- use product (EP) BeleafTM 50 SG (EPA Reg. No. 71512

- 10) and Flonicamid 50 WG (EPA Reg.

No. 71512

- 9)

Compound

Common name TFNA

Chemical name 4

- trifluoromethylnicotinic acid

Compound

Common name TFNA

- AM

Chemical name 4

- trifluoromethylnicotinamide

Compound

Common name TFNG

Chemical name N

- (4

- trifluoromethylnicotinoyl)glycine

N C F 3

N H O

C N

N C F 3

O H O

N C F 3

N H 2 O

N C F 3

N H O

O H

O

### Page 40 of 45 TABLE B

- 2

. Physicochemical Properties of Technical Grade Flonicamid.

Parameter Value Reference 1

Molecular weight (g/mole) 229.16
Melting point 157.5 ° C MRID 45854601

pH 4.5 (25 ° C)

Relative Density 1.531 (20 ° C)

Water solubility 5.2 g/L (20 ° C)

Solvent solubility Solvent g/100 mL (20 ° C)

acetone 17.32

acetonitrile 12.04

dichloromethane 0.40 ethyl acetate 3.57

hexane 0.00003 isopropyl alcohol 1.46

methanol 9.76

n

- octanol 0.26

toluene 0.03 MRID 45656705

Vapor pressure 9.43 x 10 - 7 Pa (20 ° C) or 7.07 x 10 - 9 mm Hg

2.55 x 10
- 6 Pa (25 ° C) or 1.91 x 10 - 8 mm Hg MRID 45854601

Dissociation constant, pK

a 11.60 ± 0.03 (20 ± 1 ° C) MRID 45656705

Octanol/water partition coefficient, Log(K OW ) 1.9 (Log P OW = 0.3) (29.8 ° C) MRID 45854601

UV/visible absorption spectrum Acidic and neutral aqueous solutions exhibited similar spectra with an absorption maximum near 265 nm and a molar absorptivity of 3,900 L/cm mol. A basic solution exhibited two absorption peaks. The peak observed in acidic and neutral solutions was present at

a s lightly longer wavelength, 270 nm, with an absorptivity of 4,200 L/cm mol. The second peak had an absorption maxima at 204 nm with an absorptivity of 13,200 L/cm mol.

1 RD Memo, DP# 285457, 9/30/2003, S. Mathur



### Appendix C

. Review of Human Research

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Electronic Database. Task Force Members: Health Canada, U.S. EPA, and the National Agricultural Chemicals Associations, released February 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. EPA. Released June 21, 2011.

Data from the Outdoor Residential Exposure Task Force (ORETF).

HED Residential Standard Operating Procedures (20 12).

### Page 41 of 45 Appendix D. Summaries of Field Residue Data

TABLE D

- 1. Summary of Residue Data from Alfalfa
, Clover , and Tomato Field Trials with Flonicamid.
Commodity Analyte Total

Rate (lb ai/A) PHI (days) Residue Levels (ppm flonicamid equivalents) 1 , 7, 8,9

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Alfalfa Proposed Use = 0.175 lb ai/A/season, 14

- day PHI for seed and forage;62

- day PHI for hay

Alfalfa Forage Combined

Residues 3 0.179

- 0.182 11

- 14 4 2 <0.792 3.574 <0.830 3.065 1.948 1.948 1.580

62

- 65 5 2 <0.078 <0.096 < 0.079 <0.092 0.086 0.086 0.009

0.178

- 0.181 265

- 293 6 2 <0.08 <0.088 <0.08 <0.084 0.082 0.082 0.003

Alfalfa Hay 0.179

- 0.182 62

- 65 2 <0.640 <0.640 <0.640 <0.640 0.640 0.640 <0.001

0.178

- 0.181 282

- 293 2 <0.640 <0.640 <0.640 <0.640 0.640 0.640 <0.001

Alfalfa Seed 0.178

- 0.182 11

- 14 4 <0.08 <0.633 <0.08 <0.625 0.333 0.343 0.243

Clover Proposed Use = 0.175 lb ai/A/season; 14

- day PHI for seed; 34

- day PHI for forage and hay

Clover Forage Combined

Residues 3 0.185

- 0.194 27

- 30 1 <0.275 <0.453 <0.377 <0.377 0.377 0.377 N/A 10

Clover Hay 0.185

- 0.194 34

- 39 1 <1.843 <2.270 <2.045 <2.045 2.045 2.045 N/A

Mint (Peppermint and Spearmint) Proposed Use = 0.267 lb ai/A/season; 7day PHI

Mint Combined
Residues 3 0.268

- 0.273 [301

- 306] 6

- 8 5

-- -- 0.92 3.00 2.67 2.32 0.819

10 0.92 3.07

-- -- 2.65 2.32 0.773

Tomato Frui t Proposed Use = 0.266 lb ai/A/season (field)/0.30 lb ai/A/season (greenhouse); 0

- day PHI

Field Trials Combined

Residues 3 0.265

- 0.287 [297

- 322 0 18

-- -- <0.04 <0.224 < 0.110 < 0.123 0.047

36 < 0.04 <0.227

-- -- <0.113 <0.123 0.046

Green

- house
Trials 0.268

- 0.269 [300

- 302] 3

-- -- <0.080 <0.088 < 0.081 < 0.083 0.004

6 <0.077 <0.090

-- -- <0.082 <0.083 0.005

All Tr ials 0.265

- 0.287 [297

- 322 21

-- -- <0.04 <0.224 < 0.104 < 0.117 0.045

42 <0.04 <0.227

-- -- <0.04 <0.227 0.045

1 Data reflect conversion of quantifiable residues of TFNA, TFNA

- AM and TFNG to parent equivalents by the study reviewer.

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

3 Combined residues of flonicamid, TFNA, TFNA

- AM, and TFNG, calculated as parent equivalents.

4 First cutting of alfalfa forage at the CA sites

5 Second cutting of alfalfa forage at the CA sites

6 First cutting of alfalfa forage at the Pacific Northwest sites

7 For alfalfa and clover: Except for sample min/max, values reflect per trial averages; n = no. of field trials

. 8 For mint: Where n=5, statistics were calculated with trial averages, where n=10, statistics were calculated with individual trial samples.

9 For tomatoes: Where n=18, 3, and 21, statistics were calculated with trial averages, where n=36, 6, and 42, statistics were calculated with individual trial samples.

10 N/A = Not A pplicable.

### Page 42 of 45 TABLE D

- 2. Summary of Residue Data from Tree N ut Field Trials with Flonicamid.

C rop Matrix Analyte Total Application

Rate (lb ai/A) PHI (days) Residue Levels (ppm flonicamid equivalents ) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std

. Dev.

Almonds and Pecans Proposed Use = 0.267 lb ai/acre/season, 40

- day PHI

Almond Hulls Combined

Residues 3 0.268

- 0.274 39

- 42 5 0.869 4.942 0.915 4.826 1.629 2.045 1.591

Almond

Nutmeat 0.268

- 0.274 39

- 42 5 <0.04 <0.074 <0.04 <0.072 0.045 0.051 0.014

Pecan

Nutmeat 0.269

- 0.273 20

- 40 5 <0.04 <0.043 <0.04 <0.043 0.040 0.041 0.001

1 Except for sample min/max, values reflect per trial averages; n = no

. of field trials . N/A = Not applicable. Data reflect conversion of quantifiable residues of TFNA, TFNA

- AM and TFNG to parent equivalents by the study reviewer.

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

3 Combined residues of flonicamid, TFNA, TFNA

- AM, and TFNG.



### Appendix E. Summaries of Occupational Handler Exposure and Risk Estimates

Table E

- 1. Short

- & Intermediate

- Term Agricultural Handler Inhalation Exposure & Risk for Flonicamid

Exposure
Scenario Crop App Rate (lb ai/A) a Amount Treated Daily b Inhalation Unit Exposure c (μg/lb ai) Inhalation Dose (mg/kg/Day) 4 Inhalation

MOEs d

Mixer/Loader

M/L WDG to Support Aerial

Application Clover,

Tree nuts 0.089 350 acres 8.96 0.0035 3,400

Alfalfa,

Mint 0.089 1200 acres 8.96 0.012 1,000

M/L WDG to Support Chemigation Alfalfa, Clover, Mint,

Tree nuts 0.089 350 acres 8.96 0.0035 3,400

Greenhouse

Tomatoes 0.134 60 acres 8.96 0.00090 13,000

M/L WDG to Support
Groundboom Clover,

Tree nuts 0.089 80 acres 8.96 0.00080 15,000

Alfalfa,

Mint 0.089 200 acres 8.96 0.0020 6,000

Greenhouse

Tomatoes 0.134 60 acres 8.96 0.00090 13,000

M/L WDG to Support Airblast

Application Tree nuts 0.089 40 acres 8.96 0.00040 30,000

Applicator

Applying Sprays

via Aerial Equipment Clover,

Tree nuts 0.089 350 acres 0.0049 0.0000019 6,300,000

Alfalfa,

Mint 0.089 1,200 acres 0.0049 0.0000065 1,800,000

Applying Sprays

via Groundboom Clover,

Tree nuts 0.089 80 acres 0.34 0.000030 400,000

### Page 43 of 45 Table E

- 1. Short

- & Intermediate

- Term Agricultural Handler Inhalation Exposure & Risk for Flonicamid

Exposure
Scenario Crop App Rate (lb ai/A) a Amount Treated Daily b Inhalation Unit Exposure c (μg/lb ai) Inhalation Dose (mg/kg/Day) 4 Inhalation
MOEs d

Alfalfa,

Mint 0.089 200 acres 0.34 0.000076 160,000

Greenhouse

Tomatoes 0.134 60 acres 0.34 0.000034 350,000

Applying Sprays

via Airblast Equipment Tree nuts 0.089 40 acres 4.71 0.00021 57,000

Flagger

Flagging for Aerial Sprays Alfalfa, Clover, Mint,

Tree nuts 0.089 350 acres 0.35 0.00014 88,0 00

Mixer/Loader/Applicator

Mechanically

Pressurized Handgun WDG Tree nuts 0.0018 e 1000 gallons 3.9 0.000088 140,000

Clover 0.0045 e 1000 gallons 3.9 0.00022 55,000

Greenhouse

Tomatoes 0.0134 e 1000 gallons 120 0.020 600

0.0134 1000 gallons 24 (PH5) 0.0040 3,000

Manually

Pressurized

Handwand Greenhouse

Tomatoes 0.0134 40 gallons 140 0.00094 13,000

Backpack Greenhouse

Tomatoes 0.0134 40 gallons 30 0.00020 60,000

a Application rates are the maximum application rates determined from p roposed labels for flonicamid

. b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,”

c Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013). Baseline Inhalation: no respirator. Baseline; Eng control for aerial applications (enclosed cockpits)

d Inhalation ST/IT MOE = NOAEL (12 mg/kg/day) / inhalation daily dose (mg/ kg/ day), where inhalation dose = daily unit exposure (μg/ lb ai) x 0. 001 mg/1 μg x applicatio n rate (lb ai/A) x area treated (A/day) / body weight (8 0 kg adult).

LOC = 1

, 00 0

e Application rate for tree nuts 0.0018 lb ai/gal = 0.089 lb ai/A x A/50 gal Application rate for clover 0.0045 lb ai/gal = 0.089 lb ai/A x A/20 g al Application rate for greenhouse tomatoes 0.0134 lb ai/gal = 0.0134 lb ai/A x A/10 gal

### Page 44 of 45 Appendix F . International Residue Limits Status Sheet



## Fl onicamid ( 128016 ; 0 5/03/ 20 13 )
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 40 CFR §180.613(a)(1) Plants: the sum of flonicamid, N

- (cyanomethyl)

- 4

- (trifluoromethyl)

- 3

- pyridinecarboxamide, and its metabolites, TFNA (4

- trifluoromethylnicotinic acid),

TFNA

- AM (4

- trifluoromethylnicotinamide), and TFNG, N

- (4

- trifluoromethylnicotinoyl)glycine, calculated as the stoichiometric equivalent of flonicamid Plants:N

- (cyanomethyl)

- 4

- (trifluoromethyl)

- 3

- pyridinecarboxamide, including the

metabolites 4

- trifluoromethylnicotinic acid,

N

- (4

- trifluoromethylnicotinoyl)glycine and 4

- trifluoromethylnicotinamide None



### Commodity 1 

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

US Canada Mexico 2 

### Codex Alfalfa, forage 10.0 Alfalfa, hay 1.0 Alfalfa, seed 1.5 Peppermint, tops 7.0 Spearmint, tops 7.0

Vegetable, fruiting, group 8

- 10 0.40 0.4 African eggplants, bell peppers, bush

tomatoes, coconas, currant tomatoes,

eggplants, ground cherries, garden huckleberries, goji berries, groundcherries, martynias, naranjillas, nonbell peppers, okras, pea eggplants, pepinos, roselles, scarlet eggplants

, sunberries, tomatillos, tomatoes,

tree tomatoes

2 tomato paste 0.5 tomato puree

Vegetable, cucurbit, group 9 1.5 0.4 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, cucumbers, edible gourds, muskmelons (other than those listed in this item) pumpkins, summer squash, watermelons, west Indian gherkins, winter squash

Fruit, pome, group 11

- 10 0.20 0.2 apples, Asian pears, azaroles, Chinese quinces, crabapples, Japanese quinces, loquats, mayhaws, medlars, pears, quinces, tejocotes

Fruit, stone, group 12

- 12 0.60 0.6 American plums, Apricots, beach plums, black cherries, Canada plums, capulins, cherry plums, chicksaw plums, damson plums, fresh

prune plums, Japanese apricots, Japanese plums, klamath plums, nanking cherries, nectarines, peaches, plumcots, plums, sloes, sweet cherries, tart cherries
Almond, hulls 9.0 Nut, tree, group 14

- 12 0.15

### Page 45 of 45 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex Completed: M. Negussie; 05/09/2013

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.



## Fl onicamid ( 128016 ; 0 6/25/ 20 13 )
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 40 CFR §180.613(a)(2) Livestock: the sum of flonicamid, N

- (cyanomethyl)

- 4

- (trifluoromethyl)

- 3

- pyridinecarboxamide, and its metabolites, TFNA (4

- trifluoromethylnicotinic acid),

and TFNA

- AM (4

- trifluoromethylnicotinamide), calculated as the Stoichiometric equivalent of flonicami d Livestock: N

- (cyanomethyl)

- 4

- (trifluoromethyl)

- 3

- pyridinecarboxamide, including

the metabolites 4

- trifluoromethylnicotinic acid and

4

- trifluoromethylnicotinamide None



### Commodity 1 

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

US Canada Mexico 2 

### Codex
Cattle, fat 0.0 3 0.03 Cattle, meat 0. 08 0.08 Cattle, meat byproducts 0 .08 0.08 Egg 0.0 4 Goat, fat 0.0 3 0.03
Goat, meat 0. 08 0.08 Goat, meat byproducts 0. 08 0.08 Hog, fat 0.03 Hog, meat 0.03 Hog, meat byproducts 0.03
Horse, fat 0.0 3 0.03
Horse, meat 0. 08 0.08 Horse, meat byproducts 0. 08 0.08

Milk 0.05 0.03 Poultry, fat 0.0 3 Poultry, meat 0.0 3 Poultry, meat byproducts 0.0 3 Sheep, fat 0.0 3 0.03 Sheep, meat 0. 08 0.08 Sheep, meat byproducts 0. 08 0.08 Completed: M. Negussie; 06/27/2013

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.