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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: August 20, 2013

SUBJECT: Flonicamid - Human Health Risk Assessment for a Section 3 Registration of 

New Uses on Alfalfa and Clover Grown for Seed, Mint, Greenhouse Grown 

Tomatoes, and Tree Nuts.

PC Code: 128016 DP Barcodes: D408549, D408772, D408773, 

D408738, D408739

Decision Nos.: 473586, 470098, 470100, 470101, 

470102

Registration Nos.: 71512-9, 71512-10

Petition Nos.: 2F8088, 2E8137 Regulatory Action: Section 3 Registration

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

TXR No.: NA CAS No.: 158062-67-0

MRID No.: NA 40 CFR: 180.613

FROM: Barry O’Keefe, Senior Biologist

Myron Ottley, Senior Biologist

Nancy Dodd, Chemist

Cassi Walls, Senior Biologist

Risk Assessment Branch III (RAB III)

Health Effects Division (7509P)

THROUGH: Christine Olinger, Branch Chief

Risk Assessment Branch III (RAB III) 

Health Effects Division (7509P)

TO: Carmen Rodia, Risk Manager

Insecticide 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 flonicamid. The toxicology reevaluation was performed by 

Myron Ottley, the drinking water assessment was conducted by James Hetrick (EPA 

Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data and

dietary exposure assessment were conducted by Nancy Dodd, the occupational and residential 
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exposure assessment was conducted by Cassi Walls, and the human health risk assessment was

conducted by Barry O’Keefe. 
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Table of Contents

1.0 Executive Summary ................................................................................................................5

2.0 HED Recommendations.........................................................................................................8

2.1 Data Deficiencies..................................................................................................................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 Physical/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 Dietary Exposure and Risk Assessment ............................................................................23

5.1 Residues of Concern Summary and Rationale .............................................................23

5.2 Food Residue Profile .........................................................................................................23

5.3 Water Residue Profile.......................................................................................................25

5.4 Dietary 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
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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
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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 action as similarly structured neo-nicotinoid pesticides. However, 

flonicamid has not been found to activate acetylcholine esterase (like organophosphates and 

carbamates), or nicotinic acetylcholine 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 greens (subgroup 5B), 

leafy vegetables, low growing 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 

commercial ornamentals, interiorscapes, and nurseries; but these labels do not allow use in home 

gardens, greenhouses, or in any residential settings.

Use Profile

The proposed actions for flonicamid are as follows: 1) The Interregional Research Project No. 4 

(IR-4) is proposing new agricultural uses (PP# 2E8137) 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 fruiting 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, the proposed agricultural uses will result in 

occupational exposures from handler and post-application activities. Exposures are expected to 

occur for short- and intermediate-term durations.

Hazard Assessment 

The flonicamid 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 
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chronic dog studies. 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, developmental effects (increased incidence of cervical ribs) were observed only at doses 

that caused liver and kidney effects in maternal animals. In rabbits, developmental 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 susceptibility 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 carcinogenicity, 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 data, HED recommends 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 been applied to assess 

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 EFED 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 (EDWCs) in previous drinking water 

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

EDWC was 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 unrefined 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 subgroups 

and utilized 12% of the cPAD for the general U.S. population and 30% of the cPAD for the most 

highly exposed population subgroup (children 1-2 years old). Flonicamid is classified as 

“suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential”, therefore, a cancer dietary risk assessment was not performed.
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Residential Exposure

Flonicamid is not currently registered for use in residential settings and no new residential uses 

were requested in the submitted petitions.

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 the proposed use pattern of flonicamid, there is a potential for short- and intermediateterm 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 1,000 for the inhalation route is deemed adequate to protect occupational handlers of 

flonicamid. Except for one scenario, all exposures result in short- and intermediate-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. Mixing/Loading/Applying flonicamid to tomatoes in greenhouses using a 

mechanically pressurized handgun 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 PF5 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 postapplication inhalation exposures are minimal following applications of an active ingredient (ai) 

with low vapor pressure. Since flonicamid has low acute inhalation toxicity (Toxicity Category 

IV) and a low vapor pressure (1.91 x 10-8 mm Hg at 25o C), post-application inhalation 

exposures and risks were not quantitatively assessed. Although a quantitative occupational postapplication 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 from 

the Pesticide Handlers Exposure Database, Version 1.1 (PHED 1.1), and the Agricultural 

Handler Exposure Task Force (AHETF) database are subject to ethics review pursuant to 40 
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CFR 26, have received that review, and are compliant with applicable ethics requirements. 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 Considerations

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

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

to Address Environmental Justice in Minority Populations and 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 establishing 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 

vegetable, cucurbit, group 9, except cucumber to vegetable, cucurbit, group 9. HED also 

recommends for the new use on greenhouse 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 trials 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 petitioners should submit revised Section Fs to propose tolerances in plant and 

livestock commodities at levels shown in Tables 2.2.2.1 and 2.2.2.2, respectively.
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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 

weight 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. For 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: FMC 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 determines residues of flonicamid and its metabolites TFNAAM, TFNA, and TFNG. The method has been sufficiently validated in five diverse crops. 

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 hydrolysis 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 matrix (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 tolerances 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.
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Plant 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. No 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 0.03

Cattle, meat 0.08 0.08

Cattle, meat byproducts 0.08 0.08

Egg 0.04 0.04

Goat, fat 0.03 0.03

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 0.03

Horse, meat 0.08 0.08

Horse, meat byproducts 0.08 0.08

Milk 0.03 0.05

Poultry, fat 0.03 0.03

Poultry, meat 0.03 0.03
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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 0.03

Sheep, fat 0.03 0.03

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, instead 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 forage 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 tolerances 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 

including 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 livestock 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 Harmonization

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, cucurbit, pome, and 

stone fruit crop groups whereas the US has crop group tolerances with one tolerance for each of 

the crop groups; 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 
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tolerance expressions 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 from the proposed BeleafTM 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 proposed BeleafTM 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 Introduction

Flonicamid is a systemic insecticide that immediately 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 acetylcholine esterase (like organophosphates and 

carbamates), or nicotinic acetylcholine 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 green vegetables 

(subgroup 5B), leafy vegetables, low growing 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 commercial ornamentals, interiorscapes, and nurseries; but these labels do not allow 

use in home gardens, greenhouses or in any residential settings.
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The IR-4 has requested flonicamid be registered for use on alfalfa and clover grown for seed, 

peppermint, spearmint, 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 metabolites 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 Pow) 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 25o C and a Henry’s Law Constant of 4.2 x 10-8 Pa m3

/mol at 25oC. 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 

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

Reg. No. 71512-9) to add new uses on tree nuts. BeleafTM 50SG Insecticide is a SG formulation. 

Flonicamid 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 fruiting 

vegetables. While there are no proposed changes to the established use patterns 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 Vegetables1

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, cantaloupe, 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; quince, 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 lieu 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 21 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 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 restrictions are 0 

days for crops listed on the 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 21 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 begin 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 restrictions 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; martynia; 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 23 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 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.
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]

0.0875-0.134

[2.8-4.8 oz/A or

0.065-0.1 oz/1000 sq ft or

1.85-2.85 g/1000 sq ft]

24

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 applications. 

Mint (Peppermint and Spearmint)

Postemergence;

Foliar spray; 

Ground, aerial, or 

chemigation 

equipment

BeleafTM 

50SG

[71512-10]

Flonicamid 

50WG

[71512-9]

0.062-0.089 32 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 

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 the label and 30 days for all other crops.

Tree Nuts6

(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 nut; Okari nut; Pachira nut; 

Peach palm nut; Pecan; Pequi; Pill nut; Pine nut; Pistachio; Sapucala nut; Tropical almond; Walnut, black; Walnut, English; Yellowhorn)

Postemergence; 

Foliar spray; 

Ground 

(preferably airblast) or aerial 

equipment

BeleafTM 

50SG

[71512-10]

Flonicamid 

50WG

[71512-9]

0.062-0.089 35 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 rotated. For crops which are rotated, crop rotation restrictions are 0 days for crops listed on the label and 30 days for all other crops. 
Page 17 of 45

3.4 Anticipated Exposure Pathways

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

new uses of flonicamid on the following crops: alfalfa and clover grown for seed, peppermint, 

spearmint, tree nuts, and greenhouse-grown tomatoes. Humans may be exposed to flonicamid in 

food and drinking water, since flonicamid may be applied directly to growing crops and 

application may result in flonicamid 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-application 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 

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the 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 categorized by subgroups based on age and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm 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 determine 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 study (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 

DP297602, J. Arthur, 5/9/05). The waivers were granted based on flonicamid’s low acute 

inhalation toxicity (Toxicity Category IV) and inhalation MOEs extrapolated from oral points of 

departure (PODs) that exceeded the target inhalation MOE of 1,000. However, 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 HASPOC concluded that a 

subchronic 28-day inhalation study is required at this time (TXR No. 0056400, K. Rury, 

07/30/2012). In the absence of a route specific inhalation study, a 10X database uncertainty 

factor has been applied to the occupational inhalation exposure assessment.

4.1 Toxicology 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 immunotoxicity 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 

feces 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, and amide hydrolysis.

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 

accounted for 90% of the dose; the feces of treated rats accounted 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 liver 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 study. 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 histopathological 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 males, 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 respiration 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.

An immunotoxicity study showed that flonicamid is not an immuno-suppressant, either 

structurally or functionally, at dose levels up to and exceeding the limit dose. 

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 type, 

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 in 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 in rats to be treatment related. The determination 

of carcinogenicity potential for flonicamid was made by the CARC on January 5, 2005 based 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, 02/24/2005). The RAB3 risk assessment team determined that quantification of risk 

using a non-linear approach (i.e., using a chronic reference dose) adequately accounts for all 

chronic toxicity, including carcinogenicity that could result from exposure to flonicamid. 

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 based 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 kidney weights, kidney hyaline deposition, 

and increased blood serum luteinizing hormone in F1 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 and 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 scenarios;

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

neurotoxicity studied;

• the degree of concern for pre and/or post-natal susceptibility is low due to the lack of 

evidence of qualitative and quantitative susceptibility in the developmental and 

reproductive toxicity studies; and

• there 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 required 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 study, 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 of 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 for risk 

assessment purposes. The current risk assessment is protective of these effects, and a 

developmental neurotoxicity study is not required.

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

There was no evidence for quantitative 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 Database

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 women of child bearing 

age.

4.5 Toxicity Endpoint and Point of Departure 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

(D397277, 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 Sufficient to Assess Human Carcinogenic Potential”. The

quantification of human cancer risk was not recommended. (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

UFA = 10X

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

sensitivity among members of the human population (intraspecies). UFDB = database 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) & IntermediateTerm 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) & IntermediateTerm Inhalation (1 to 

6 months)

Oral NOAEL = 

12 mg/kg/day

UFA = 10X

UFH = 10X 

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

sensitivity among members of the human population (intraspecies). UFDB = 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 hydrolysis 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 determined 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, 12/21/2007).

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 alfalfa (MRID 49026201), clover (MRID 49026201), mint (MRID 4026203) 

tomatoes (field and greenhouse) (MRID 49026202), and almonds and pecans (MRID 48935301)

have been submitted to support the proposed tolerances. These data are 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) the number and geographic 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 adequate data were submitted to support sample storage intervals and 

conditions. The processing data indicate that combined residues of flonicamid, TFNA, TFNAAM, and TFNG do not concentrate in oil (average processing factor <0.063x).

Flonicamid, 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 theoretical concentration factors. The 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 meat, fat, and meat byproducts of swine.

Rotational Crops

A confined rotational crop study was conducted on the rotational crops carrot, lettuce, and wheat. 

The radiolabeled test substance, [pyridyl14C] 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 applications. 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 identified 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 were not included in the study because low residues (<0.01 ppm) 

were observed in lettuce from the confined rotational crop study. The studies reflect the 

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

available storage stability data. The analytical 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 drinking water residues used in the dietary risk assessment were provided by EFED 

(D408552, J. Hetrick, 06/24/2013) and incorporated directly into the 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

increased 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-trifluoromethylnicotinic 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 EDWCs in previous drinking water assessments. 

EDWCs from PRZM-GW (Pesticide Root Zone Model-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 increased

application rate of 0.133 lb ai/A on fruiting vegetables. The EFED models and their descriptions 

are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. See Table 

5.3.1.

Table 5.3.1. EDWCs Based on Flonicamid Use.1

Source of Drinking Water Acute

(μg/L)

30-Year Annual Average 

(μg/L)

Surface water -cranberry 94.93 285.44

Surface 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 this 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 residues of 

flonicamid, including its metabolites and degradates. The flonicamid chronic dietary exposure 

assessment was conducted using the DEEM-FCID, Version 3.16, which incorporates 2003-2008 

consumption data from USDA’s NHANES/WWEIA. An unrefined 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 crops. The livestock commodity tolerances are 

changed from the previous assessment. Estimated concentrations of flonicamid in drinking 

water from the proposed uses were provided by EFED and incorporated directly 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 these 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

Since no observed effects could be attributed to a single dose, an acute endpoint was not 

established. Therefore, an acute dietary exposure assessment was not conducted.

5.4.4 Chronic Dietary Risk Assessments

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 incorporated 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 utilized 12% of the cPAD for the general U.S. population and 30% 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 Flonicamid1

Population Subgroup cPAD 

(mg/kg/day)

Exposure 

(mg/kg/day) % cPAD

General U.S. Population

0.04

0.004720 12

All Infants (< 1 year old) 0.006718 17

Children 1-2 years old 0.011869 30

Children 3-5 years old 0.008864 22

Children 6-12 years old 0.005336 13

Youth 13-19 years old 0.003402 8.5

Adults 20-49 years old 0.004100 10

Females 13-49 years old 0.004197 10

Adults 50-99 years old 0.004501 11

1 The population with the highest exposure is in bold

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposure is not expected. There are registered labels with use on commercial 

ornamentals, interiorscapes, and nurseries; but these labels do not 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-application 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 250 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 Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 20101

. 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 exposure assessment 

for flonicamid.

 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 method employed for flonicamid. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

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

management practices (see the Agency’s Spray Drift website for more information2

). The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant 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 fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worst case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

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

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

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

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

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

duration of exposure. 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 Evidence of Carcinogenicity, but Not 

Sufficient to Assess Human Carcinogenicity Potential”. For flonicamid, 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 conservative 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 Characterization

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 to 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/Risk Characterization

Flonicamid 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 patterns, there is a 

potential for short- and intermediate-term occupational exposure to flonicamid during handling 

(mixing, loading, and applying) and post-application activities. Flonicamid uses are proposed 

for multiple applications, with the retreatment intervals ranging 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 REI 

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 tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns from the proposed labels, types of equipment and 

techniques that can potentially be used, occupational handler exposure is expected 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 flonicamid 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 estimates 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-application 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 

handler exposures. Except for one scenario, all exposures result in short- and intermediate-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. 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 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 reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, 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 degradation 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 intermediate-term post-application dermal 

exposures to workers re-entering treated areas is possible. However, since no hazard was 

identified for the dermal route of exposure, dermal post-application risks were not assessed.

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

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

Pesticides sets a REI based on the acute toxicity of chemicals. Technical flonicamid is classified 

as toxicity category IV for acute dermal toxicity, primary eye, 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 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 25o C) and 

the low proposed use rates (0.089 to 0.134 lb ai/A). However, there are multiple potential 

sources of post-application inhalation exposure to individuals performing post-application 

activities in previously treated fields. These potential sources include volatilization of pesticides 

and resuspension of 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, 20103

. 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 procedures, 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 quantitative occupational post-application inhalation exposure assessment 

for flonicamid.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of 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 

Uses on Alfalfa, Clover, Spearmint, Peppermint; 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.

Flonicamid: Occupational and Residential Exposure/Risk Assessment for Use on Alfalfa, Clover, 

Mint, Greenhouse Tomatoes, and Tree Nuts. DP408738, 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 for 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

Appendix 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 Profiles

Table A.2.1. Acute Toxicity of Flonicamid

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 LD50 = 884 mg/kg (Males), 

LD50 = 1768 mg/kg (Females) III

870.1200 Acute Dermal - Rat 45656708 LD50 > 5000 mg/kg IV

870.1300 Acute Inhalation - Rat 45656709 LC50 > 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 LD50 ≥ 2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNA-AM

45854606 LD50 ≥ 2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNG

45854607 LD50 ≥ 2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNG-AM

45854608 LD50 ≥ 2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNA-OH

45854609 LD50 ≥ 2000 mg/kg III

Table A.2.2. Non-acute Toxicity Profile for Flonicamid

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

870.3100a

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 hyaline 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: 191.5 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 at 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 Performance

NOAEL is 1800 ppm (equivalent to 132.9/153.4 

mg/kg/day [M/F]). 

LOAEL for reproductive performance was not 

observed. 

870.4100b

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. 

870.4200b

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 

extramedullary 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 

hyperplasia/hypertrophy of the epithelial cells of the 

terminal bronchioles of the females. 

At the doses tested, the carcinogenic potential of IKI220 is positive at 250 ppm in males and females 

based on the increased incidence of 

alveolar/bronchiolar adenomas, carcinomas, 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 this 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

870.4200b

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 doses tested, the carcinogenic potential of IKI220 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 terminal 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 

incidences 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 

nasolacrimal 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 association 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 ug/plate +/- S9

Negative for metabolite TFNA

870.5100

Bacterial reverse 

gene mutation

45854618 (2002)

acceptable – guideline

33 to 5000 ug/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 ug/plate +/- S9

Negative for metabolite TFNG-AM 

870.5100

Bacterial reverse 

gene mutation

45854620 (2002)

acceptable – guideline

33 to 5000 ug/plate +/- S9

Negative for metabolite TFNA-OH

870.5100

Bacterial reverse 

gene mutation

45854621 (2002)

acceptable – guideline

5 to 5000 ug/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 study 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 study. 
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 

pharmacokinetics 

(rats)

45656729 (2001)

acceptable – guideline

pilot excretion 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, irrespective 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 followed 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 maximum 

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. 

Parent 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 metabolites 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 Flonicamid.

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

CF3

N

H

O

CN

N

CF3

OH

O

N

CF3

NH2

O

N

CF3

N

H

O

OH

O
Page 40 of 45

TABLE B-2. Physicochemical Properties of Technical Grade Flonicamid.

Parameter Value Reference1

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, pKa 11.60 ± 0.03 (20 ± 1 °C) MRID 45656705

Octanol/water partition coefficient, 

Log(KOW)

1.9 (Log POW = 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 slightly 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 (2012). 
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.

LAFT2 HAFT2 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 

Residues3

0.179-0.182 11-144 2 <0.792 3.574 <0.830 3.065 1.948 1.948 1.580

62-655 2 <0.078 <0.096 <0.079 <0.092 0.086 0.086 0.009

0.178-0.181 265-

2936

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 

Residues3

0.185-0.194 27-30 1 <0.275 <0.453 <0.377 <0.377 0.377 0.377 N/A10

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 

Residues3

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 Fruit

Proposed Use = 0.266 lb ai/A/season (field)/0.30 lb ai/A/season (greenhouse); 0-day PHI 

Field Trials Combined 

Residues3

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 Trials 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 Applicable. 
Page 42 of 45

TABLE D-2. Summary of Residue Data from Tree Nut Field Trials with Flonicamid.

Crop Matrix Analyte Total

Application

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm flonicamid equivalents)

1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Almonds and Pecans

Proposed Use = 0.267 lb ai/acre/season, 40-day PHI

Almond Hulls Combined 

Residues3

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 

Dailyb

Inhalation Unit 

Exposurec

(μg/lb ai)

Inhalation Dose 

(mg/kg/Day)4

Inhalation 

MOEsd

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 

Dailyb

Inhalation Unit 

Exposurec

(μg/lb ai)

Inhalation Dose 

(mg/kg/Day)4

Inhalation 

MOEsd

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 88,000

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 proposed 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 application rate (lb ai/A) x area treated (A/day) / body weight (80 kg adult). 

LOC = 1,000

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 gal

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

Flonicamid (128016; 05/03/2013)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 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

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 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 Mexico2 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.

Flonicamid (128016; 06/25/2013)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 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 flonicamid

Livestock: N-(cyanomethyl)-4-

(trifluoromethyl)-3-

pyridinecarboxamide, including 

the metabolites 4-

trifluoromethylnicotinic acid and 

4-trifluoromethylnicotinamide

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Cattle, fat 0.03 0.03

Cattle, meat 0.08 0.08

Cattle, meat byproducts 0.08 0.08

Egg 0.04

Goat, fat 0.03 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 0.03 0.03

Horse, meat 0.08 0.08

Horse, meat byproducts 0.08 0.08

Milk 0.05 0.03

Poultry, fat 0.03

Poultry, meat 0.03

Poultry, meat byproducts 0.03

Sheep, fat 0.03 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.