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Appendix A. Toxicology Profile and Executive Summaries .................................................. 27

A.1 Toxicology Data Requirements................................................................................... 27

A.2 Toxicity Profiles............................................................................................................ 28

 Appendix B. Physical/Chemical Properties 33

Appendix C. Review of Human Research................................................................................ 34

Appendix D. International Residue Limit Status....................................................37
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1.0 Executive Summary

Flubendiamide is a phthalic acid diamide and is in a class of insecticides which acts through a 

biochemical mode of action in lepidopterous insect pests. It is currently registered on alfalfa, 

corn (field corn, pop corn, sweet corn, and corn grown for seed), cotton, globe artichokes, 

tobacco, vine crops (including grapes), pome fruit, stone fruit, tree nut crops, vegetable crops 

(including cucurbit vegetables, fruiting vegetables, legume vegetables, leafy vegetables, and 

okra, turnip greens), the low growing berry subgroup (except cranberry), peanut, pistachio, the 

small fruit vine climbing subgroup except fuzzy kiwifruit, safflower, sorghum, sugarcane, and 

sunflower. Flubendiamide is also registered for use on Christmas trees. A Section 3 registration 

(Petition #0F7685) is being requested by Bayer CropScience, on behalf of Nichino America, 

Inc., to increase the pome fruit group tolerance from 0.7 to 1.5 ppm and to increase the wet apple 

pomace tolerance from 2 to 5 ppm (L. Cheng, D402067, 09/01/2012)

Use Profile

There are no changes in the use profile. The 4 lb/gal EC formulation is approved for foliar 

application to pome fruit (crop group 11) at a maximum single application rate of 0.156 lb 

ai/acre with a total of 3 applications per year. The minimum retreatment interval (RTI) is 7 days 

and the preharvest interval (PHI) is 14 days.

Toxicity/Hazard

Flubendiamide has low acute toxicity: it is classified as Category III via the oral and dermal 

routes, is only a slight eye irritant and is not a dermal irritant or skin sensitizer. For acute 

inhalation, the LC50 of flubendiamide is > 0.0685 mg/L (the maximum attainable concentration

due to flubendiamide’s physical/chemical properties) and, therefore, is no worse than Category II

via the inhalation route.

In the repeated dose studies, the primary target organs of flubendiamide toxicity identified were 

the liver, thyroid, kidney, and eyes. Liver effects reported in rats, mice, and/or dogs include 

organ weight increase, periportal fatty change, hypertrophy, and minimal foci of cellular 

alteration. Thyroid effects include organ weight increase, follicular cell hypertrophy and slight 

perturbations of triiodothyronine (T3) and thyroid stimulating hormone (TSH) in the rat and 

mouse. Kidney effects include increases in absolute and/or relative to body kidney weights and 

chronic nephropathy in the rat. Eye effects include eye enlargement, opacity, and exophthalmus 

with hemorrhage and appear only in rat pups. Adverse adrenal effects of increased weight and 

cortical cell hypertrophy were also observed in dogs.

The hazard assessment indicated potential toxicity resulting from exposure to flubendiamide via 

different routes over different durations. The observed eye effects were selected as a critical 

effect for the acute dietary exposure scenario, whereas liver and thyroid effects were determined 

to be critical for the chronic dietary exposure scenario. Short- and intermediate-term dermal 

risks were also based on liver and thyroid effects, as well as blood effects. Short- and 

intermediate-term inhalation risks are based on liver toxicity, as well as adrenal weight increase 

and increase in adrenal cortical cell hypertrophy.
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There was no evidence of carcinogenicity in rats and mice up to the limit dose at 24 and 18 months, 

respectively. Flubendiamide was determined to be non-mutagenic in bacteria, negative in an in vivo

mammalian cytogenetics assay, and did not cause unscheduled DNA synthesis (repair of DNA 

damage) in mammalian cells in vitro. Overall, there was no evidence that flubendiamide was either 

mutagenic or clastogenic in either in vivo or in vitro assays. The cancer classification is “not likely to 

be carcinogenic to humans;” therefore, there is no concern for cancer risk to humans.

The flubendiamide risk assessment team evaluated the quality of the toxicity and exposure data 

and, based on these data, recommended that the FQPA Safety Factor be reduced to 1X 

(DP329593, S. Winfield, 4/3/08). 

Drinking Water

Flubendiamide is persistent and potentially mobile in terrestrial and aquatic environments.

These fate properties suggest that it has a potential to move into surface water and ground water.

The Environmental Fate and Effects Division (EFED) completed in 2010 a drinking water 

assessment for flubendiamide using screening level water exposure models. No new or modified 

uses have been added since that assessment. Based on the modeling analysis, the estimated 

drinking water concentration (EDWC) for the 1 in 10 year peak (for acute dietary assessment)

was 24.57 μg/L (approx. 25 μg/L), the highest Tier 2 PRZM/EXAMS estimated surface water 

concentration for flubendiamide, based on application to corn. For the 1 in 10 year annual 

average (for chronic dietary assessment), the highest PRZM/EXAMS EDWC was 11.46 μg/L 

(approx. 12 μg/L) also based on application to corn.

Dietary Exposure (food and drinking water)

Acute and chronic dietary (food and drinking water) exposure assessments were conducted (using the 

dietary model DEEM-FCID) Version 3.16, which uses food consumption data from the U.S. 

Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. For the acute 

assessment, the modeled exposure estimates are based on tolerance level residues, assuming 100% of 

crops were treated, and include the highest modeled EDWC relevant to the scenario. In addition, 

default processing or flubendiamide experimental processing factors were used. The resulting acute 

risk estimates were 3.1% of the acute population adjusted dose (aPAD) for the general US population 

and 5.5% of the aPAD for children 1-2 years old, the highest exposed subpopulation. 

For the chronic assessment, estimates are based on assumptions that registered crops contain residues 

at the average residue levels found in the crop field trials or that the registered crops and livestock 

commodities contain tolerance level residues. In addition, experimental processing factors were used 

where available. In addition to the assumption that 100% of the crops were treated, the highest 

modeled EDWC relevant to the scenario was included. The resulting chronic risk estimates were 20% 

of the chronic PAD (cPAD) for the general US population and 66% of the cPAD for children 1-2 years 

old, the highest exposed subpopulation. 

As all dietary risk estimates were less than 100% of the a/cPAD, no risks of concern were identified.
Flubendiamide Human Health Risk Assessment DP No. 400797

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Residential Exposure

This document only presents the assessment of the proposed increased tolerances for flubendiamide 

on pome fruits and apple pomace. No residential uses are being requested at this time. There are no 

existing residential uses. Therefore, no residential risk assessment has been conducted.

Aggregate Risk

As there are no existing or proposed residential uses, and subsequently no expected residential 

exposure, aggregate risk is considered in the dietary (food and drinking water) exposure and risk 

assessment.

Occupational Exposure and Risk

There have been no changes in the use profile and occupational exposure since the previous risk 

assessment (D376459, B.O’Keefe et al, 11/30/2010). Margins of exposure (MOEs) have 

changed minimally as a result of updated unit exposures and body weight (bw) assumptions. 

Occupational exposures related to applications to fruit trees, including pome fruit, were 

considered in 2008 (D329593, S. Winfield, 04/03/2008). As registered uses have not changed, 

no significant changes are anticipated in the occupational exposure and risk, and MOEs have not 

been recalculated. Previous evaluations indicated MOEs much in excess of 100 and therefore not 

of concern.

Handlers: Occupational short-term (1 - 30 days) and intermediate-term (1 – 6 months) dermal 

and inhalation exposures are expected from flubendiamide handler activities. HED used data 

from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in PHED 

Surrogate Exposure Guide (8/98) to assess handler exposures (HED Science Advisory Council 

for Exposure Standard Operating Procedure (SOP) No. 7, dated 1/28/99). Dermal and inhalation 

risks for short- and intermediate-term exposures were combined in this assessment, since the 

toxicological effects for the dermal and inhalation routes were the same. A Margin of Exposure

(MOE) greater than 100 for dermal and inhalation routes is deemed adequate to protect 

occupational flubendiamide handlers. All handler scenarios resulted in MOEs greater than the 

level of concern (LOC) (i.e., MOEs ≥ 100) for dermal, inhalation, and combined dermal and 

inhalation exposures when wearing labeled personal protective equipment (PPE) (e.g., longsleeve shirt, long pants, shoes, socks, and chemical resistant gloves) an no respirator and,

therefore, are not of concern. The PPE-G baseline dermal plus baseline inhalation MOE for 

pome fruit ranged from 1880 to16000.

Postapplication Workers: Occupational short- and intermediate-term dermal exposures are 

expected from postapplication activities. Chemical-specific data relevant to postapplication 

exposure (i.e., dislodgeable foliar residue [DFR] data) were previously submitted and determined 

to be acceptable; therefore, postapplication exposure estimates were previously calculated using 

results from the DFR studies, as well as standard HED Exposure SAC assumptions (body weight 

and exposure duration) and transfer coefficients (SOP # 003.1). Using crop-specific DFR data, 

risks are not a concern for any postapplication occupational scenario on day 0 (12 hours 
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following application). The occupational postapplication MOE for pome fruit ranged from 440 

to1600 .

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

labels is adequate to protect workers. In addition to systemic hazard, the Worker Protection 

Standard (WPS) sets a REI based on the acute toxicity of chemicals. Technical flubendiamide is 

classified as toxicity category III for acute dermal toxicity and category IV for primary eye and 

skin irritation. Under the WPS for Agricultural Pesticides, active ingredients classified as acute 

toxicity categories III or IV for these routes are assigned a 12-hour REI.

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.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix C) have 

been determined to require a review of their ethical conduct, and have received that review.

2.0 HED Recommendations

HED recommends for an increase in the tolerances for the pome fruit group and wet apple 

pomace, based on new field trial data. No additional data are needed. No label modifications are 

needed. 

2.1 Data Deficiencies

No additional data or information must be provided prior to tolerances being established or 

registration allowed. No additional data are required as a condition of registration.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, Method 

00816/M002, was previously submitted for the determination of residues of in/on samples of 

plant commodities. It is the original proposed enforcement method, but with only one mass ion 

transition. The registrant subsequently submitted supplementary data for this proposed 

enforcement method. The supplemental data demonstrated that the LC/MS/MS method may be 

used for confirmatory analysis by monitoring a second mass ion transition for each analyte. The 

validated limit of quantitation (LOQ) is 0.01 ppm for each analyte in each matrix.

An LC/MS/MS method, Method 00912, was submitted for the determination of residues of 

flubendiamide and metabolite A-14 (see Table 5.1) in livestock commodities. Method 00912 
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was used for data collection and is also the proposed enforcement method for animals. Method 

00912, with a validated LOQ of 0.01 ppm for each analyte in each matrix, was adequately 

validated using samples of muscle, liver, kidney, fat, milk, and poultry egg. 

Methods 00816/M002 and 00912 are suitable as enforcement methods for plant and animal 

commodities, respectively. The provided methods have successfully passed petition method 

validations (PMV) by the Analytical Chemistry Branch/Biological and Economics Analysis 

Division (ACB/BEAD) (DP347049, 02/06/2008, C. Stafford).

2.2.2 Recommended Tolerances

In accordance with HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the 

tolerance expression for flubendiamide in 40 CFR §180.639 (a)(1) and in 40 CFR §180.639 (d) 

should be revised to state:

“Tolerances are established for residues of flubendiamide, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only flubendiamide, N

2

-[1,1-dimethyl-2-

(methylsulfonyl)ethyl]-3-iodo-N

1

-[2-methyl-4-[1,2,2,2-tetrafluoro-1-

(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide), in or on the commodity.”

Table 2.2.3. Tolerance Summary for Flubendiamide

Commodity Established Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Apple, wet pomace 2.0 5.0 Apple, wet pomace

Fruit, pome, group 11 0.70 1.5 Fruit, pome, group 11

2.2.3 Revisions to Petitioned-For Tolerances

The recommended tolerance levels are the same values as in the petition. The Organization of 

Economic Coordination and Development (OECD) calculation procedure was utilized to derive 

the tolerance estimate for pome fruit based on all apple field trial data and all pear field trial data 

(D386262, S. Funk, 04/01/2011). The new apple pomace tolerance is derived from the highest 

average apple field trial result (1.21 ppm) and the processing factor for conversion of apples to 

apple pomace (3.6X) from a previously reviewed study. The proposed increases in tolerances for 

pome fruit and wet apple pomace have no effect on the dietary burdens of livestock. Therefore, 

the established tolerances for meat, milk, poultry, and eggs are adequate. 

2.2.4 International Harmonization

There are no Canadian or Mexican maximum residue limits (MRLs) established for residues of 

flubendiamide in crop or livestock commodities. Codex established flubendiamide MRLs for 

numerous commodities in 2011. Residue definitions are harmonized. MRL values are 

harmonized for soybean hay and the cucurbit vegetable group. Codex established lower MRLs 

for head lettuce and leaf lettuce compared to the US tolerance for the leafy vegetables (except 

Brassica) . Codex also established lower tolerances for field corn grain and the pome fruit 

group. These tolerances cannot be lowered, as they represent the appropriate levels from US 

field trials and establishing lower values might result in tolerance violations from use according 
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to label directions. Codex established higher MRLs than the corresponding US tolerances for 

almond hulls, sweet corn, cotton seed, Brassica head and stem vegetables, the stone fruit group, 

the tree nut group, pulses (compared to pea and bean dry shelled subgroup 6C), legume 

vegetables (compared to legume vegetables, edible podded, subgroup 6A), grapes (compared to 

small vine climbing fruit, subgroup 13-07F0, tomato and pepper (compared to fruiting vegetable 

group 8), mammalian fat (compared to cattle, goat, horse, and sheep fat), mammalian offal 

(compared to cattle, goat, horse, and sheep meat- byproducts), and milk fat. 

For crop commodities, most of the higher Codex values are the results of rounding upwards. For 

example, for almond hulls the data are from US field trials and the statistically calculated value 

is 8.3 ppm. The US rounded to 9 ppm; Codex rounded to 10 ppm. For sweet corn, the data are 

from US field trials. The US adopted 0.01 ppm based on all data <0.01 ppm. Codex rounded up 

to 0.02 ppm. For cotton seed, the data are from US field trials. Statistical calculation yields 0.90 

ppm, which the US used as the tolerance. Codex rounded up to 1.5 ppm. For stone fruit, all data 

(cherry, plum, peach) are from US field trials. The US adopted 1.6 ppm based on statistical 

calculation with the commodity of highest residues (cherry), whereas Codex rounded up to 2 

ppm using the same cherry data. For tree nuts, Codex utilized US crop field trial data for 

almonds and pecans. The US tolerance is based on a statistical analysis of the data, yielding 0.06 

ppm. Codex rounded up to 0.1 ppm. For dry shelled peas and beans (Codex pulses), Codex 

utilized US field trial data, but rounded to 1 ppm (versus US 0.60 ppm). For small vine climbing 

fruit (grapes), Codex used US field trial data for grapes and rounded the US statistically 

determined value of 1.4 ppm to 2 ppm. 

In some cases, the higher Codex MRLs result from the use on non-US data. This is the situation 

for Brassica head and stem vegetables (Australian field trials) and fruiting vegetables (Australian 

field trials). 

The US tolerances for ruminant commodities are lower than the Codex counterparts because of 

differing feed items and because of divergent approaches to the calculation of ruminant dietary 

burden from those feed items. Codex uses a worst case approach, whereas the US uses a 

reasonably balanced diet approach which takes into account the nutritional requirements of the 

livestock.

An International Residue Limit (IRL) form is appended to this document as Appendix D.

2.3 Label Recommendations

As a condition of the waiver of the subchronic inhalation toxicity study requirement, dry 

flowable formulations of flubendiamide (Synapse WG, EPA Reg. No. 264-1026) must be 

canceled, and the uses may be transferred to the liquid formulation (Belt SC, EPA Reg. No 

25654-1025).

3.0 Introduction

Bayer CropScience, on behalf of Nichino America, Inc., has petitioned to increase the pome fruit 

group tolerance from 0.7 to 1.5 ppm and to increase the wet apple pomace tolerance from 2 to 5 
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ppm. This request resulted from the results additional side-by-side apple field trials with and 

without an adjuvant conducted under the existing label conditions. Residues in excess of the 

existing tolerance for pome fruit were found in several trials.

3.1 Chemical Identity

Table 3.1. Flubendiamide Nomenclature.

Chemical structure

Empirical Formula C23H22F7IN2O4S

Common name Flubendiamide

Company experimental name NNI-0001

IUPAC name 3-Iodo-N’-(2-mesyl-1,1-dimethylethyl-N-{4-[1,2,2,2-tetrafluoro-1-

(trifluoromethyl)ethyl]-o-tolyl}phthalamide (from Compendium of Pesticide 

Common Names)

CAS name N

2

-[1,1-Dimethyl-2-(methylsulfonyl)ethyl-3-iodo-N

1

-[2-methyl-4-[1,2,2,2-

tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide

CAS registry number 272451-65-7

End-use products (EPs) BeltTM SC Insecticide (EPA Reg. No. 264-1025)

SynapseTM WG Insecticide (EPA Reg. No. 264-1026)

Chemical Class Phthalic acid diamide insecticide

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

The physicochemical properties of flubendiamide are reported in Appendix B. Flubendiamide 

has a low water solubility and a high log octanol/water partition coefficient. This suggests that 

the pesticide has some potential for bioaccumulation (in fatty tissue and milk). Codex has

classified flubendiamide as fat soluble. A relatively low vapor pressure indicates less concern for 

inhalation. Flubendiamide is slightly to hardly mobile in soils and is stable in both soil and 

water. It is persistent and degrades slowly.

3.3 Pesticide Use Pattern

No changes have been proposed for the existing uses, and no modifications to the existing labels 

are needed to accommodate the use patterns. The 4 lb/gal EC formulation is approved for foliar 

application to pome fruit (crop group 11) at a maximum single application rate of 0.156 lb 

I

N

H

H3C CH3

O

O

HN

H3C

F

CF3

CF3

SO2CH3
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ai/acre with a total of 3 applications per year. The minimum retreatment interval is 7 days and 

the PHI is 14 days.

3.4 Anticipated Exposure Pathways

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

proposed increased tolerance for flubendiamide on pome fruit and apple pomace. Humans may 

be exposed to flubendiamide in food and drinking water, since flubendiamide may be applied 

directly as a foliar spray to growing crops and application may result in flubendiamide reaching 

surface and ground water sources of drinking water. There are no residential uses of 

flubendiamide, so there is not likely to be exposure in residential or non-occupational settings. 

In an occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is a potential for post-application exposure for 

workers re-entering treated fields. 

Risk assessments have been conducted previously for flubendiamide, and no new toxicity data 

have been received since the previous risk assessment. A detailed description of the toxicity data 

and metabolism information may be found in the risk assessment dated 11/30/2010 (D376459, B. 

O’Keefe). The current assessment considers the aforementioned exposure pathways based on 

the increased tolerances for pome fruit and apple pomace and the other existing uses.

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). This dietary survey was conducted from 2003 to 2008. These data are 

analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

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

assessment includes summaries of prior assessments. A comprehensive assessment may be found 

in the assessment for flubendiamide as a new active ingredient (D329593, S. Winfield, 

04/03/2008). The most recent assessment was in 2010 (D376459, B. O’Keefe, 11/30/2010). A 

waiver request for subchronic neurotoxicity was submitted by the registrant and was granted by 

OPP’s Hazard and Science Policy Council (HASPOC) on 03/05/2012 (TXR 0054070). A waiver 

request for subchronic inhalation toxicity was submitted by the registrant and was granted by 

OPP’s Hazard and Science Policy Council (HASPOC) on 10/11/2012. 

4.1 Summary of Toxicological Effects

Flubendiamide represents a chemical family of substituted phthalic acid diamides with 

insecticidal activity. Phthalic acid diamides have been shown to allosterically activate ryanodine 

receptors (RyR), a class of intracellular calcium channels which mediate release of calcium from 

the sarcoplasmic reticulum of skeletal muscle. Flubendiamide stabilizes RyR in the open state 

causing uncontrolled calcium release which leads to muscle paralysis and eventual death. This 

mode of action is described in insects, but not mammals; flubendiamide modulates insect but not 

mammalian ryanodine receptors1. 

The toxicological effects reported in the submitted studies do not reflect the MOA for the 

targeted pests. In the mammalian toxicology database, the primary target organ of 

flubendiamide exposure is the liver (hepatotoxicity), with secondary effects reported in the 

thyroid and kidney at equivalent or higher doses; NOAELs established to protect for liver 

toxicity are protective of effects seen in the thyroid and kidney. Adverse adrenal effects were 

also noted in the dog.

Buphthalmia (eye enlargement), opacity, and exophthalmus with hemorrhage appearing only in 

infancy, were observed in rat offspring in the reproductive and development neurotoxicity

(DNT) studies (D329593, S.Winfield, 04/03/08). There was no clear dose-response relationship 

for this effect but ocular toxicity was noted in three rat studies and accompanied by 

histopathological findings of synechia, hemorrhage, keratitis, iritis, and cataracts. Therefore, 

bupthalmos is considered an effect of treatment. It is pertinent to note that ocular toxicity was 

not observed in mice or dogs. Bupthalmia appears to be specific to the rat but does have human 

relevance and is considered in the human health risk assessment. 

Rat metabolism studies at low and high doses report fairly rapid absorption, with peak blood and 

plasma levels reached at approximately 6-12 hours post dosing followed by a continuous decline. 

Flubendiamide was fairly well distributed among blood and most of the organs and tissues, with 

 

1 Ebbinghaus-Kintscher, U., et. al. (2006). Phthalic acid diamides activate ryanodine-sensitive Ca2+ release channels 

in insects. Cell Calcium, 39, pp 21-33.

2 A-14, see Table 5.1
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some preference to the liver, adrenal glands, and fat. Generally, the liver and kidneys contained 

the greatest percentage of the administered dose. Excretion of residues was rapid (majority of 

radioactivity recovered at the first 24 hour collection point), with feces being the predominant 

route of excretion. Renal excretion accounted for only 2% and <1% of the dose in male and 

female rats, respectively. Parent, NNI-0001-benzylalcohol (A-16), and NNI-0001-benzoic acid 

(A-18) were the major residues identified in the feces2. Additionally, metabolite A-14 was 

identified in the fat of female rats at 1% of the administered dose.

In vitro metabolism and toxicokinetic studies in multiple mammalian species appear to confirm 

the findings reported in the in vivo rat metabolism study, that female rats appear to metabolize 

the parent compound differently from male rats and other species. Female rats do not show an 

ability to convert the parent compound to the NNI-0001 benzyl alcohol metabolite2due to the 

lack of β-NADPH that is required for metabolism, indicating there was no abiotic degradation of 

the test compound in the test systems. The lack of abiotic degradation, resulting in longer 

terminal elimination half-life of the parent compound in the female rats differentiates them from 

other test animals and may be the cause of ocular toxicity seen in rat pups of treated mothers.

The short- and intermediate-term dermal risk scenarios are assessed using the NOAEL of 100 

mg/kg/day from the 30-day dermal toxicity study; and the short- and intermediate-term 

inhalation risk scenarios are assessed using the NOAEL of 2.6 mg/kg/day from the 90-day oral 

toxicity study in the dog. A dermal absorption factor was not applied because the selected 

dermal endpoint was from a route specific study. A default inhalation absorption factor of 100% 

was applied to the inhalation exposure estimates because the endpoint was selected from a study 

that was not route specific (i.e., it was an oral study). 

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

The flubendiamide risk assessment team evaluated the quality of the toxicity and exposure data 

and, based on these data, recommended that the FQPA Safety Factor be reduced to 1X 

(DP329593, S. Winfield, 4/3/08). 

4.2.1 Completeness of the Toxicology Database

The toxicology database for flubendiamide is considered adequate for risk assessment in support 

of the current registration action under FIFRA Section 3 for food use. A brief summary of the 

toxicological findings is discussed above in Section 4.1

The subchronic neurotoxicity study (SCN, OPPTS 870.6200b) is now a data requirement for 

registration of a pesticide (food and non-food uses) under 40 CFR Part 158. The Hazard and 

Science Policy Council (HASPOC) granted a waiver from the requirement (D398683, D.Smegal, 

03/05/2012) based on the following:

The HASPOC concluded that a subchronic neurotoxicity study (SNC) study is not needed

(D398683, D. Smegal, 03/05/2012). The database contains an acute neurotoxicity study where no 

evidence of neurotoxicity was seen at the Limit Dose. In the DNT, adverse effects of treatment 
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were limited to ocular lesions and delayed sexual maturation. In the conventional subchronic and 

chronic toxicity studies with rats, motor activity and behavioral measures, as well as brain weight 

and neuropathology were evaluated; there was no treatment-related findings in those parameters. 

Consequently, based on these weights of evidence considerations, the HASPOC recommended 

that the Registrant’s request be granted for the waiver of the subchronic neurotoxicity study in 

rats.

The 90-day inhalation study (OPPTS 870.3465) is now a data requirement for registration of a 

pesticide (food and non-food uses). However, the HASPOC (10/11/2012, TXR pending)

concluded that the inhalation study is not needed provided the all dry flowable formulation uses 

are canceled (EPA Reg. No. 2564-1026). A subchronic inhalation study is not needed for the 

remaining registered uses (EPA Reg. No. 2564-1025, Belt EC). The decision is based on the 

available hazard and exposure information for flubendiamide, including (1) the 

physical/chemical properties of flubendiamide, including low volatility; (2) the use pattern and

exposure profile; (3) all relevant hazard information, including the low acute inhalation toxicity 

and toxicological profile; and (4) the use of an oral POD which results in MOEs ranging from 

4,800 to 150,000 for risk via the inhalation route resulting from anticipated occupational 

exposure.

4.2.2 Evidence of Neurotoxicity

Flubendiamide is not a neurotoxic chemical based on neurotoxicity assessments conducted 

acutely, developmentally, and incorporated within the chronic rat study. In several short-term 

studies in rats (subacute and subchronic feeding, plaque-forming cell assay, one-generation pilot, 

developmental toxicity), no neurobehavioral signs were observed at doses up to and exceeding 

the limit dose. The only consistent effect related to neurotoxicity was noted in the rat eye. In a 

developmental neurotoxicity study (DNT), adverse effects of treatment were limited to ocular 

lesions and delayed sexual maturation. The points of departure used for risk assessment are 

protective of all eye effects observed in several rat studies. It is pertinent to note that bupthalmia 

was only observed in rats exposed only perinatally to flubendiamide. 

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

No effect on embryo/fetal development was observed in either rat or rabbit and there was no 

evidence to suggest that flubendiamide possessed any potential for developmental toxicity up to 

the limit dose of 1000 mg/kg/day.

Based on the available data, there is a concern for pre- and/or postnatal toxicity from exposure to 

flubendiamide. The DNT study reported that premating exposures are not required to elicit the 

eye effect in pups but developmental biology does indicate that the sensitive period of 

organogenesis for eye development spans between GD 11-15 and that the iris continues to 

differentiate until PND 20. The selected PODs (which are based on clear NOAELs) are 

protective of these effects.
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In addition to the reported eye effects in the DNT study, there was also balanopreputial 

separation (separation of the prepuce (foreskin) from the glans penis (balanus)) delay. While 

these effects are considered adverse, they are not assumed to be developmental effects from in 

utero exposure, but rather considered secondary to reduced postnatal pup body weight. Even 

though the delay in balanopreputial separation may be a result of post-natal exposure, and the 

effect is adverse, it was resolved within the appropriate age range of puberty and no effects on 

reproductive function were observed in the multigeneration study in rats. Delayed 

balanopreputial separation was seen only in the presence of maternal toxicity and is not more 

severe than the maternal effects of hepatotoxicity seen at the common lowest observable adverse 

effect level (LOAEL) of the DNT study. Delayed balanopreputial separation does not cause 

concern for increased sensitivity to the young. Even though the delay in balanopreputial 

separation may be a result of post-natal exposure (sensitivity of the young), and the effect is 

adverse, it is considered reversible and not an indication of perinatal sensitivity/susceptibility.

While both the rat and rabbit developmental studies did not identify teratogenic effects and 

neither showed evidence of increased prenatal susceptibility, the adverse eye effects noted in rat 

pups in multiple studies suggest increased susceptibility that is relevant to the human health risk 

assessment.

Although there is concern for increased susceptibility to offspring following pre- and postnatal 

exposure to rats based on evidence of eye lesions in rat pups post PND 14, the perinatal ocular 

effects occur in the presence of maternal toxicity and have clear NOAELs that are well defined 

and used as points of departure for risk assessment. Furthermore, the points of departure

selected for all exposure scenarios are protective. Therefore, there are no residual concerns for 

pre-/postnatal toxicity.

4.2.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. The exposure is not understated in the 

assessment. There are no exposure data gaps relevant to the FQPA factor for infants and 

children. 

4.3 Toxicity Endpoint and Point of Departure Selections

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

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

Table 4.3.1 for a summary of endpoints and points of departure for dietary and non-occupational

human health risk assessments. See Table 4.3.2 for a summary of endpoints and points of 

departure for use in occupational human health risk assessments.
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Table 4.3.1 Summary of Toxicological Doses and Endpoints for Flubendiamide for use in Dietary and 

Non-Occupational Human Health Risk Assessments1

Exposure 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

general 

population, 

including infants 

and children

NOAEL = 99.5 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x 

aRfD = 0.995 

mg/kg/day

aPAD = 0.995 

mg/kg/day

Two-generation reproduction, one-generation reproduction 

and DNT studies as three co-critical studies (using 1200 ppm 

[99.5 mg/kg/day] from the DNT study as the highest 

NOAEL for eye effects and a LOAEL from the 1-generation 

reproduction study of 127 mg/kg/day), based on

buphthalmia (enlargement of eyes), ocular opacity, retinal 

degeneration, hemorrhage, cataract, atrophy of the optic 

nerve. 

Acute Dietary –

females 13-49 

years old

Chronic Dietary 

– general 

population, 

including infants 

and children

NOAEL = 2.4 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x 

cRfD = 0.024 

mg/kg/day

cPAD = 0.024 

mg/kg/day

2-year rat cancer study, 1-year chronic dog study and 1-year 

chronic rat study as three co-critical studies, using the 

chronic rat study NOAEL of 50 ppm (2.4 mg/kg/day) with 

LOAEL from the 2-year cancer rat study of 33.9 mg/kg/day

Liver toxicity, fatty change, hypertrophy, ↑liver weight and 

↑GGT. 

Short-term (1-30 

days) Incidental 

Oral

NOAEL = 9.9 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x 

LOC =

MOE ≤ 100

Developmental neurotoxicity (DNT) study in rats

LOAEL = 99.5 mg/kg/day based on delayed balanopreputial 

separations.

Intermediate 

Term (1-6 

months) 

Incidental Oral

NOAEL = 2.6 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x (based on 

no quantitative 

susceptibility)

LOC =

MOE ≤ 100

90-day oral toxicity study in the dog

LOAEL = 53 mg/kg/day based on liver toxicity and adrenal 

weight increase and increase in adrenal cortical cell 

hypertrophy in females.

Short-term (1-30 

days) Dermal

NOAEL = 100 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x (based on 

no quantitative 

susceptibility) 

LOC = 

MOE ≤ 100

28/29-day dermal toxicity study in the rat

LOAEL of 1000 mg/kg/day based on liver toxicity, 

increased liver weight periportal fatty change, increased 

thyroid weight and thyroid follicular cell hypertrophy in 

females.

(low dermal absorption = 0.02%)

Intermediate term 

(1-6 months) 

Dermal

Short term (1-30 

days) Inhalation

NOAEL = 2.6 

mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA = 1x 

LOC = 

MOE ≤ 100

90-day oral toxicity study in the dog

LOAEL = 53 mg/kg/day based on liver toxicity and adrenal 

weight increase and increase in adrenal cortical cell 

hypertrophy in females.

Intermediate term 

(1-6 months) 

Inhalation

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans based on negative genotoxicity and carcinogenicity in long term cancer 

studies in rats and mice.
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1

It is important to note, that for this action, the only residential exposure scenario is via the dietary route, since no 

residential uses have been established or proposed. Additional exposure scenarios are retained here for future 

reference in the event a residential use is requested.

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

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

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

Table 4.3.2. Summary of Toxicological Doses and Endpoints for Flubendiamide 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-

30 days) 

Dermal

NOAEL 

=100 

mg/kg/day

UFA = 10x 

UFH = 10x 

LOC = 

MOE ≤ 100

28/29-day dermal toxicity study in the rat

LOAEL of 1000 mg/kg/day based on liver 

toxicity, increased liver weight periportal 

fatty change, increased thyroid weight and 

thyroid follicular cell hypertrophy in 

females.

(low dermal absorption = 0.02%)

Intermediate 

term (1-6 

months) 

Dermal

Short term (1-

30 days) 

Inhalation

NOAEL = 

2.6 

mg/kg/day

UFA = 10x 

UFH = 10x 

LOC = 

MOE ≤ 100

90-day oral toxicity study in the dog

LOAEL = 53 mg/kg/day based on liver 

toxicity and adrenal weight increase and 

increase in adrenal cortical cell 

hypertrophy in females.

Intermediate 

term (1-6 

months) 

Inhalation

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans based on negative genotoxicity and 

carcinogenicity in long term cancer studies in rat and mice.

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The parent compound was the major residue found in all the plant metabolism studies (apple, 

cabbage, corn, tomato) as well as in the confined rotational crop study. The major residue in the 

ruminant and poultry studies was the parent compound. NNI-0001-iodophthalimide (A-14) was 
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found at greater than 10% of the total radioactive residue (TRR) in fat and milk. A-14 is included 

in the risk assessment for ruminants (in addition to parent), due to the similarity in structure to 

the parent compound Flubendiamide is persistent and potentially mobile in terrestrial and aquatic 

environments. In 2008, the risk assessment team brought the residue of concern issue to the 

Residues of Concern Knowledgebase Subcommittee (ROCKS), the outcome of that meeting is 

captured in the following memo: Flubendiamide. Report of the Residues of Concern 

Knowledgebase Subcommittee. PC Code: 027602. DP No.: D351083, 4/3/2008. The 

conclusions are summarized in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Flubendiamide Flubendiamide

Rotational Crop Flubendiamide Flubendiamide

Livestock Ruminant Flubendiamide and its NNI-0001-

iodophthalimide (A-14) metabolite1

Flubendiamide

Poultry Flubendiamide Flubendiamide

Drinking Water Flubendiamide Not Applicable

1 A-14

5.2 Food Residue Profile

The only change from the prior assessment is the addition of additional field trials for apples and 

pears (pome fruits). Side-by-side trials were conducted to demonstrate the effect of adjuvants. 

In both the trials with and without adjuvant residues in some trials exceeded the established 

tolerance. Residue chemistry aspects pertinent to the new field trials and the risk assessment are

detailed below. 

Crop Field Trials

Bayer CropScience submitted field trial data for flubendiamide on apples from 3 trials conducted 

in the United States during the 2009 growing season. The apple trials were performed in Zones 1 

(NY), 5 (MI), and 11 (ID). Each test site included a control plot and two treated plots, one 

without adjuvant in the formulation and one with adjuvant (non-ionic surfactant, NIS, 0.25% 

v/v). The treated plots received three foliar applications of a suspension concentrate (SC) 

formulation of flubendiamide at a target rate of 0.156 lb ai/A/application (0.175 kg 

ai/ha/application) and actual rates of 0.157-0.159 lb ai/A/application, with 7- to 10-day 

retreatment intervals, for a total target rate of 0.468 lb ai/A (0.502 kg ai/ha) and actual rate of 

0.471 to 0.476 lb ai/A. Samples of mature apples were harvested 14 days after the final 

application.
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Results are summarized in Table 5.2.

Table 5.2 Summary of Residue Data from Apple Field Trials with Flubendiamide

Commodity Total Applic. 

Rate

(lb ai/A) Plot2

Residue Levels (flubendiamide; ppm)1

N Min. Max. HAFT3 Median

(STMdR)

Mean

(STMR)

Std. Dev.

Apple fruit 0.471 – 0.476 TRTDI 6 0.164 0.85 0.76340.221 0.384 0.30

TRTD 6 0.185 1.24 1.2140.252 0.553 0.51

1

 Residue of concern for tolerance setting and risk assessment is parent flubendiamide only. 

2 TRTDI refers to trials with a non-ionic surfactant (NIS) adjuvant, and TRTD refers to trials with no adjuvant.

3

 HAFT = Highest Average Field Trial.

4 HAFT exceeds the existing tolerance of 0.7 ppm for pome fruit. This situation was reported previously (Minutes Chem SAC 

Meeting, 08/11/2010). 

Meat, Milk, Poultry, and Eggs

Apple pomace is a dairy cattle feed item, but not a feed item for beef cattle or poultry. The dairy 

cattle dietary burden was recalculated and considered the increased apple pomace residues. The 

revised burden is 28.5 ppm, compared to a former burden of 27.9 ppm. This has no effect on the 

tolerance recommendations for cattle commodities (D384436, L. Cheng, 11/05/2010; D386262, 

S. Funk, 04/01/2011).

Processed Food and Feed

No new processing study was submitted. However, the additional apple field trials submitted 

reveal a maximum HAFT of 1.21 ppm, greater than the 0.467 ppm previously found (D366875, 

J. Stokes, 03/28/2008). In the previously reviewed study, residues of flubendiamide 

concentrated in wet pomace (3.6x) but not in juice (0.07x) following processing of the raw 

agricultural commodity (RAC, whole apples) with quantifiable residues. The maximum 

expected residue of flubendiamide in wet pomace, resulting from the approved use, is 4.36 ppm. 

This value was calculated by multiplying the concentration factor of 3.6x by the new HAFT 

residue of 1.21 ppm

Confined Accumulation in Rotational Crops

Two confined rotational crop studies were previously submitted and reviewed in PP#6F7065

(DP329598, J. Stokes, 3/28/08). The studies were deemed adequate to satisfy data requirements 

pending submission of confirmatory storage stability information and/or data. For both studies 

(MRIDs 46817133 and 46817134), the petitioner was required to submit extraction and analysis 

dates confirming that samples were extracted and analyzed within the stated intervals (or within 

6 months of harvest); otherwise, additional storage stability data may be required. Additional 

information submitted for the confined rotational studies indicate that the crop samples were 

analyzed within a month, and hence no storage stability data are needed (D398374, L Cheng, 

08/15/2012).

Field Accumulation in Rotational Crops
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Adequate limited and extensive field rotational crop data are available to support the rotational 

crop restrictions listed on the product label for BeltTM SC Insecticide and the established 

flubendiamide rotational crop tolerances under 40 CFR §180.639(d) (DP329598, J. Stokes, 

3/28/08).

5.3 Water Residue Profile

The water residue profile is identical to that of the last risk assessment (D376459, B. O’Keefe, 

11/30/2010). Flubendiamide is persistent and potentially mobile in terrestrial and aquatic 

environments. These fate properties suggest that it has a potential to move into surface water 

and ground water. 

A Tier 2 PRZM/EXAMS assessment based on a number of different crops was used to estimate 

drinking water concentrations derived from surface water sources. For the 1 in 10 year peak, the 

highest PRZM/EXAMS estimated drinking water concentration (EDWC) for flubendiamide was 

24.57 μg/L based on application to corn in Texas. For the 1 in 10 year annual average, the 

highest PRZM/EXAMS EDWC was 11.46 μg/L, based on application to corn in North Dakota. 

In lieu of sufficient ground water monitoring data for flubendiamide, the Tier 1 ground water 

screening model SCI-GROW was used to estimate concentration of flubendiamide in ground

water sources. Apples, which represent the highest registered annual use rate (0.468 lbs 

ai/A/year) was used for the modeling, and resulted in a ground water EDWC of 0.094 μg/L.

Water residues are summarized in Table 5.3.

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations 

Duration Flubendiamide

Surface Water 

Conc., μg/La

Groundwater Conc., ppb b

Acute (1 in 10 year peak) 24.57 0.094

Chronic (non-cancer; 1 in 10 year 

annual average)

11.46

a

From the Tier II PRZM-EXAMS – Index Reservoir model. Input parameters are based on the Texas corn scenario, 

with a default percent cropped area (PCA) of 0.87, and application rate of 0.376 lb ai/A/year

b

From the SCI-GROW model assuming a maximum seasonal use rate of 0.468 lb ai/A/year (apples, 3X 0.156 lb 

ai/A), a Koc of 1596 ml/g, and a half-life of 1,000,000 days (soil aerobic metabolism).

5.4 Dietary Risk Assessment

Reference: D402068, S. Funk, Flubendiamide: Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for the Increased Tolerance on Pome 

Fruit, 09/11//2012.

5.4.1 Description of Residue Data Used in Dietary Assessment

Field trial data only were used in the assessment. Tolerance values (point estimates) and 100% 

crop treated were used for the acute dietary risk assessment. Tolerance values or highest average 
Flubendiamide Human Health Risk Assessment DP No. 400797

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field trial (HAFT) residue values and 100% crop treated were used in the chronic dietary risk 

assessment. Experimental processing factors specific to flubendiamide or generic default 

processing factors were used. Tolerance values were used for livestock commodities. The only 

changes from the previous dietary risk assessment were increases in the tolerance and HAFTs for 

pome fruit (apple, pear).

5.4.2 Acute Dietary Risk Assessment

Flubendiamide acute dietary exposure assessments were conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database DEEM-FCID, Version 

3.16, which incorporates consumption data from USDA’s NHANES/WWEIA. This dietary 

survey was conducted from 2003 to 2008. 

At the 95th percentile of exposure, all acute analyses yielded risk estimates well below the 100% 

of the aPAD threshold level of concern for each population subgroup. For the general US 

population subgroup, acute aggregate dietary risk was calculated at 3.1% of the aPAD with an 

exposure level of 0.031 mg/kg/day. For the subgroup with the highest calculated exposure,

children 1-2 years old, acute aggregate dietary risk occupied 5.5% of the aPAD with an exposure 

of 0.055 mg/kg/day. An overview summarizing the results of the acute dietary assessments with 

the population subgroup having the highest exposure noted in bold is presented in Table 5.4.5.

5.4.3 Chronic Dietary Risk Assessment

Flubendiamide chronic dietary exposure assessments were conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database DEEM-FCID, Version 

3.16, which incorporates consumption data from USDA’s NHANES/WWEIA. This dietary 

survey was conducted from 2003 to 2008. 

All chronic analyses yielded risk estimates well below the 100% of the cPAD threshold level of 

concern for each population subgroup. For the general US population, chronic aggregate dietary 

risk was calculated at 20% of the cPAD with an exposure level of 0.0047 mg/kg/day. For the 

subgroup with the highest calculated exposure, children 1-2 years old, chronic aggregate dietary 

risk occupied 66% of the cPAD with an exposure of 0.016 mg/kg/day. Comparison of the food 

only results to the food + water results demonstrates that the additional risk added by water 

consumption is small. An overview summarizing the results of the chronic dietary assessment

with the population subgroup having the highest exposure noted in bold is presented in Table 

5.4.5.

5.4.4 Cancer Dietary Risk Assessment

A determination of cancer risk was not performed with DEEM-FCID as part of the present 

assessment, since this chemical was classified as “Not likely to be Carcinogenic to Humans” 

based on negative genotoxicity and carcinogenicity in long term cancer studies in rats and mice.

5.4.5 Summary Table
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Table 5.4.5. Result of Acute and Chronic Dietary Exposure and Risk Estimates for 

Flubendiamide.

Population Subgroup PAD, 

mg/kg/day

DEEM-FCID (food 

only)

DEEM-FCID (food and 

water)

Exposure, 

mg/kg/day % PAD Exposure, mg/kg/day %PAD

Acute Dietary Estimates (95th Percentile of Exposure)

U.S. Population

0.995

0.029874 3.0 0.030494 3.1

All infants (< 1 yr) 0.034380 3.5 0.034819 3.5

Children 1-2 yrs 0.053594 5.4 0.054454 5.5

Children 3-5 yrs 0.047414 4.8 0.048568 4.9

Children 6-12 yrs 0.029805 3.0 0.030870 3.1

Youth 13-19 yrs 0.022083 2.3 0.022451 2.3

Adults 20-49 yrs 0.026699 2.7 0.027355 2.8

Adults 50-99 yrs 0.028515 2.8 0.028040 2.9

Females 13-49 yrs 0.028179 2.9 0.028929 3.0

Chronic Dietary Estimates

U.S. Population

0.024

0.004434 19 0.004664 20

All infants (< 1 yr) 0.005607 24 0.006201 26

Children 1-2 yrs 0.015457 65 0.015790 66

Children 3-5 yrs 0.010344 44 0.010623 44

Children 6-12 yrs 0.006068 26 0.006270 27

Youth 13-19 yrs 0.0033551 15 0.003523 15

Adults 20-49 yrs 0.003390 15 0.003620 16

Adults 50-99 yrs 0.003836 16 0.004063 17

Females 13-49 yrs 0.003422 15 0.003661 16

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

This document addresses the proposed increased tolerances for the pome fruit group and apple 

pomace. No residential uses are being requested at this time, and no residential uses currently 

exist; therefore, no residential exposure is expected, and subsequently, no risk assessment has 

been conducted.

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

This is particularly the case with aerial application (a method employed for flubendiamide), but, 

to a lesser extent, could also be a potential source of exposure from the ground application 

method also employed for flubendiamide. 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. On a chemical by chemical basis,

the Agency is now requiring interim mitigation measures for aerial applications that must be 
Flubendiamide Human Health Risk Assessment DP No. 400797

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

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

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

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

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

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

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

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

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

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

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

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

duration of exposure.

For this action, there is potential exposure to flubendiamide from food and drinking water, but 

not from residential use sites (as there are no proposed, or existing, residential uses for 

flubendiamide). Since hazard was identified via the oral route over both the acute and chronic 

duration, the aggregate risk assessments consider exposures from food and drinking water 

consumed over the acute and chronic durations. Refer to Section 5.4 for further information.

7.1 Acute Aggregate Risk

Refer to Section 5.4.2, which discusses acute dietary exposure (food and water) in detail. The 

dietary route alone is relevant for acute exposure and risk assessment. The acute dietary 

exposure and risk assessment conducted for flubendiamide is screening-level (i.e., the 

assessment assigns tolerance level residue values to all food commodities proposed to be treated 

with flubendiamide and assigns modeled residue values to all drinking water).

7.2 Chronic Aggregate Risk

Refer to Section 5.4.3, which discusses chronic dietary exposure (food and water) in detail. The 

dietary route alone is relevant for long-term/chronic exposure and risk assessment. The chronic 

dietary exposure and risk assessment conducted for flubendiamide is health protective (the 

assessment assigns tolerance values or average field trial/livestock commodity residue values to 

all food commodities proposed to be treated with flubendiamide and assigns modeled residue 

values to all drinking water).

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 mammalian mechanism of 

toxicity finding as to flubendiamide and any other substances and flubendiamide does not appear 

to produce a toxic metabolite produced by other substances. For the purposes of this tolerance 
Flubendiamide Human Health Risk Assessment DP No. 400797

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action, therefore, EPA has not assumed that flubendiamide has a common mammalian

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

The occupational exposure and risk assessment was reviewed previously by the Exposure 

Science Advisory Council and summarized in the 2010 risk assessment (D376459, B. O’Keefe, 

11/30/2010). Occupational exposures related to applications to fruit trees, including pome fruit, 

were considered in 2008 (D329593, S. Winfield, 04/03/2008). As registered uses have not 

changed, no changes are anticipated in the occupational exposure and risk.

Occupational exposures are expected to occur from the existing flubendiamide uses on numerous 

agricultural crops, including pome fruits. Short- (1-30 consecutive days) and intermediate-term 

(1-6 consecutive months) dermal and inhalation exposures are expected from handler activities;

short- and intermediate-term dermal exposures are expected from post application activities.

Previous evaluations indicated MOEs in excess of 100. Generally body weights of 70 kg were 

used in the exposure assessments. Effective 01/17/2012, it was determined that a body weight of 

80 kg should be used as the basis of calculations. Unit exposures have also been amended. 

However, the risk estimates with these new parameters continue to results in MOEs greatly 

exceeding an MOE of 100 and therefore are not a risk of concern. The conclusions from 2008 

(D329593, S. Winfield, 04/03/2008) on personal protective equipment are not altered.

Although the inhalation and dermal risk estimates are based on different toxicological points of 

departure, the endpoints are equivalent (liver toxicity), which is how this was addressed 

previously (D376459, B. O’Keefe, 11/30/2010). Therefore, the respective risk estimates were

combined via the total MOE approach, resulting in a total MOE that reflects risk resulting from 

exposure via the inhalation and dermal routes, for both short- and intermediate-term exposure 

durations. The LOC is an MOE less than 100. Occupational risks resulting in MOEs greater than 

or equal to 100 do not exceed HED’s LOC. All MOEs were >100. The PPE-G baseline dermal 

plus baseline inhalation MOE for pome fruit ranged from 1880 to 16000 for handlers. . The 

occupational post application MOE for pome fruit ranged from 440 to 1600 (D329593, S. 

Winfield, 04/03/2008).

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

labels is adequate to protect workers. The REI is based on the acute toxicity of flubendiamide

technical material. Flubendiamide is classified in acute toxicity category III for acute dermal 

toxicity and category IV for primary eye irritation and primary skin irritation. It is not a dermal 

sensitizer. 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 for all activities and 

crops is appropriate and meets the requirements of the WPS for Agricultural Pesticides. 
Flubendiamide Human Health Risk Assessment DP No. 400797

25

9.1 Inhalation Post application Risk

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

exposure assessment was not performed for flubendiamide at this time. Based on the Agency's 

current practices, a quantitative post-application inhalation exposure assessment was not 

performed for flubendiamide at this time primarily because of the low acute inhalation toxicity 

(Toxicity Category III and IV), low vapor pressure (10-4Pa or 7.5 x 10-7 mm Hg), and the low 

use rate (0.47 lb ai/A/year). 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 re-suspension of dusts 

and/or particulates that contain pesticides. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report as well as available post-application 

inhalation exposure data generated by the Agricultural Reentry Task Force 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 

flubendiamide.

10.0 References

S. Winfield et al, 04/03/2008, D329593, D331553, Flubendiamide: Human Health Risk 

Assessment for Proposed Uses on Corn, Cotton, Tobacco, Tree fruit, Tree nuts, Vine crops and 

Vegetable crops.

D. Smegal, 03/05/2012, D398683, TXR 0054070, Flubendiamide: Summary of Hazard and 

Science Policy Council (HASPOC) Meeting of March 1, 2012: Evaluation of a waiver request 

for a subchronic neurotoxicity study.

S. Funk, 09/07/2012. D402068, Flubendiamide: Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for the Increased Tolerance on Pome Fruit

B.O’Keefe et al, 11/30/2010, D376459, Flubendiamide: Human Health Risk Assessment for 

Proposed Uses on Alfalfa, Globe Artichokes, the Low Growing Berry Subgroup 13-07G (except 

Cranberry), Peanuts, Pistachios, the Small Fruit Vine Climbing (except Fuzzy Kiwifruit) 

Subgroup 13-07F, Safflower, Sorghum, Sugarcane, Sunflower, and Turnip Greens, and an 

Increased Application Rate for Brassica (Cole) Leafy Vegetables.

L. Cheng, 08/15/2012, D402067, Flubendiamide: Amendment to Tolerances in/on Pome Fruit 

and Apple Wet Pomace. 

L. Cheng, 08/15/2012, D398374, D398375, Flubendiamide: Conditional Registration FollowUp: A New Poultry Feeding Study. Analysis Dates for the Confined Rotational Crop Study.

Summary of Analytical Chemistry and Residue Data
Flubendiamide Human Health Risk Assessment DP No. 400797

26

S. Funk, 04/01/2011, D386262, D386263, D386289, Flubendiamide: Bridging Residue Studies 

Conducted with an Adjuvant (Non-Ionic Surfactant or Crop Oil Concentrate) in Support of 

Proposed Use on Multiple Crops. Reevaluation of the Tolerance for Pome Fruit.

S. Wente, 10/12/2010, D376457, Drinking Water Assessment.
Flubendiamide Human Health Risk Assessment DP No. 400797

27

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses for flubendiamide are in Table 1. Use of the 

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

Test 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 (28/29-day) ..........................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

-

*

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

no

yes

yes

no

yes

yes

yes

yes

-

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5395 Mutagenicity—Other Genotoxic Effects.......................

Yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) .....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

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

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

No

no

yes

yes

no

-

-

yes

**

yes

870.7485 General Metabolism ......................................................

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

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

yes

yes

yes

yes

yes

yes

* This requirement was considered by the HASPOC, and the Committee recommended not to require the study 

(TXR Pending, HASPOC, 10/11/2012).

** This requirement was considered by the HASPOC, and the Committee recommended not to require the study 

(TXR 0054070, HASPOC, 03/05/2012).
Flubendiamide Human Health Risk Assessment DP No. 400797

28

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Flubendiamide

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral – rat 46817142 LD50 >2000 mg/kg III

870.1200 Acute dermal- rat 46817145 LD50 >2000 mg/kg III

870.1300 Acute inhalation – rat 46817148 LC50 >0.0685 mg/LaII

870.2400 Acute eye irritation –rabbit 46817201 Irritating (slight) IV

870.2500 Acute dermal irritation – rabbit 46817204 Non-irritating IV

870.2600 Skin sensitization – guinea pig 46817207 Negative N/A

a

The acute LC50 of flubendiamide (TGAI) is greater than 0.0685 mg/L, the maximum attainable concentration; it 

cannot be further classified due to its physical/chemical properties which limit its aerosolization. Results of 

MRID 46817149 demonstrate that a formulation containing 39% flubendiamide has an LC50 > 2.564 mg/L which 

can be extrapolated to an LC50 of 1.01 mg/L for TGAI, category III.

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

46817210 (2003)/

Acceptable/guideline

ppm:

0 – 20 – 50 – 200 – 2000 

– 20000

mg/kg/day:

M: 0 – 1.15 – 2.85 – 11.4 

– 116 – 1192

F: 0 – 1.30 – 3.29 – 13.1 –

128 – 1320

NOAEL (F) = 13.1 mg/kg/day

LOAEL (F) = 128 mg/kg/day based on: slight 

hepatotoxicity (↑(f) – periportal fatty change,

hepatocellular hypertrophy, ↑wt [abs/rel(f)], 

↑GGT

870.3150 90-Day oral 

toxicity (mouse)

46817211 (2002)/

Acceptable/guideline

ppm:

0 – 50 – 100 – 1000 –

10000

mg/kg/day:

M: 0 – 6.01 – 11.9 – 123 –

1214

F: 0 – 7.13 – 14.7 – 145 –

1424

NOAEL (M/F) = 11.9 / 14.7 mg/kg/day

LOAEL (M/F) = 123 / 145 mg/kg/day based on 

slight hepatotoxicity: (↑fatty change, 

hepatocellular hypertrophy, ↑ abs/rel wt [f])

870.3150 90-Day oral 

toxicity (dog)

46817212 and 46817242

(2003)/ 

Acceptable/guideline

ppm:

0 – 100 – 2000 – 40000

mg/kg/day:

M: 0 – 2.58 – 52.7 – 1076

F: 0 – 2.82 – 59.7 – 1135

NOAEL (M/F) = 2.58 / 2.82 mg/kg/day

LOAEL (M/F) = 52.7 / 59.7 mg/kg/day based 

on clinical signs of toxicity (loose stool), 

shortened APTT, increased ALP and 

triglycerides, increased adrenal weights, and 

microscopic effects on the adrenal glands in 

females:

adrenal: ↑(f) – cortical hypertrophy; ↑(f) – wt

↓(m/f) – APTT

↑ – [ALP(m/f), Triglycerides(f)]
Flubendiamide Human Health Risk Assessment DP No. 400797

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3200 28/29-Day dermal 

toxicity (rat)

46817213 (2004)/

Acceptable/guideline

mg/kg/day:

0 – 10 – 100 – 1000

NOAEL = 100 mg/kg/day (systemic); 1000 

mg/kg/day (local skin)

LOAEL = 1000 mg/kg/day based on: 

liver: ↑(m/f)–periportal fatty change + ↑wt 

[abs/rel]; thyroid: ↑(f)–follicular cell 

hypertrophy

↓(f) –[Hct + MCV + MCH]

↓(f) – AST

870.3700a Prenatal 

developmental in 

(rat)

46817215 and 46817241

(2003)/

Acceptable/guideline

mg/kg/day:

0 – 10 – 100 – 1000

Maternal: NOAEL = 10 mg/kg/day; 

LOAEL = 100mg/kg/day based on: liver: 

↑wt[abs/rel].

Developmental: NOAEL >1000 mg/kg/day; 

LOAEL was not observed (>1000 mg/kg/day).

870.3700b Prenatal 

developmental in 

(rabbit)

46817214 and 46817240 

(2002)/

Acceptable/guideline

mg/kg/day:

0 – 10 – 100 – 1000

Maternal: NOAEL = 100 mg/kg/day; LOAEL 

= 1000 mg/kg/day based on: food consumption 

decrease on last day of treatment (GD27-28) 

and loose stool

Developmental: NOAEL >1000 mg/kg/day; 

LOAEL not observed (>1000 mg/kg/day)

870.3800 Two-generation 

Reproduction and 

fertility effects

(rat)

46817216 (2004)/

Acceptable/guideline

ppm:

0 – 20 – 50 – 2000 –

20000

mg/kg/day (premating 

doses):

Pm: 0 – 1.30 – 3.30 – 131 

– 1307

Pf: 0 – 1.59 – 3.95 – 159 –

1577

F1m: 0 – 1.64 – 4.05 –

162 – 1636

F1f : 0 – 1.84 – 4.59 – 176 

– 1808

Parental/Systemic: NOAEL (M/F) = 3.30 / 

3.95 mg/kg/day; LOAEL (M/F) = 131/159 

mg/kg bw/day based on: liver: ↑P/F1m–[brown 

pigment deposition + wt (rel)]; ↑Pf /F1f –

[enlarged/dark-colored livers + hepatocyte

hypertrophy + periportal fatty change + brown 

pigment deposition + wt]; thyroid: ↑P/F1 –

[follicular cell hypertrophy]; ↑wt (abs Pm); 

kidney: ↑Pf –[tubular basophilic change + 

urinary casts]; ↑Pf /F1f –wt; ovary: ↑Pf –

interstitial cell vacuolation; uterus: ↑wt (Pf );

pituitary: ↓wt (F1); spleen: ↓wt (Pf /F1f )

Reproductive: No effect of treatment on: 

precoital interval; mating, fertility, or gestation 

indices; or gestation duration in either 

generation. Furthermore, the numbers of 

primordial ovarian follicles in the 20,000 ppm 

F1 dams were comparable to controls. No 

effects were noted on estrous cycle duration or 

sperm parameters. The NOAEL is 20,000 ppm 

(1307/1577 mg/kg/day males/females, 

respectively). The LOAEL for reproductive 

toxicity was not observed.

Offspring: NOAEL = 3.30 mg/kg/day; 

LOAEL = 131 mg/kg/day based on: liver: ↑–

[hepatocyte hypertrophy, diffuse fatty change, 

brown pigment deposition, proliferation bile 

ducts; wt]; thyroid: ↑follicular cell hypertrophy; 

spleen + thymus: ↓wt; ↑eyeball enlargement
Flubendiamide Human Health Risk Assessment DP No. 400797

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

One-generation 

reproduction study 

in rat

46817239 

(2004)/Acceptable/nongui

deline

ppm:

0-50-200-2000-20,000

mg/kg/day:

Pm: 0-3.25-12.91-127.2-

1287

Pf: 0-3.84-14.97-148.9-

1490

Parental: LOAEL is 2000 ppm (127.2/148.9 

mg/kg/day in males/females, respectively) 

based on effects on the liver, thyroid, and 

kidneys. The NOAEL is 200 ppm (12.91/14.97 

mg/kg/day in males/females, respectively).

Reproductive: The LOAEL was not observed 

and the NOAEL is 20,000 ppm (1287/1490 

mg/kg/day in males/females, respectively).

Offspring: The LOAEL is 2000 ppm 

(127.2/148.9 mg/kg/day in males/females, 

respectively) based on effects on the eyes and 

liver; and on increased anogenital distance and 

delayed sexual maturation in the males. The 

NOAEL is 200 ppm (12.91/14.97 mg/kg/day in 

males/females, respectively).

Histopathology of 

the Eyes of 

Weanlings in a 

One-generation 

Reproduction 

Study in Rats

46817238/Acceptable/non

-guideline

ppm:

0-50-200-2000-20,000

mg/kg/day:

Pm: 0-3.25-12.91-127.2-

1287

Pf: 0-3.84-14.97-148.9-

1490

Offspring: The LOAEL for offspring toxicity 

is 2000 ppm (127.2/148.9 mg/kg/day in 

males/females, respectively) based on 

confirmed microscopic effects on the eyes in 

both sexes. The NOAEL is 200 ppm 

(12.91/14.97 mg/kg/day in males/females, 

respectively).

Perinatal Ocular 

Toxicity Study in 

CD-1 Mice 

following exposure 

via diet

46817236/ non-guideline

approx. 1000 mg/kg/day 

from day 6 post 

conception until lactation 

day 21

Eye lesions of viable pups were noted neither 

during the lactation period nor during the 

follow-up period lasting from PND 22-42.

Offspring: The LOAEL for offspring toxicity is 

4500/2000 ppm (equivalent to 1052.3 mg/kg/day) 

based on decreased pup body weights and body 

weight gains. The NOAEL was not established.

870.4100a Chronic toxicity

(rat)

46817217 (2004)/

Acceptable/guideline

ppm:

0 – 20 – 50 – 2000 –

20000

mg/kg/day:

M: 0 – 0.8 – 2.0 – 79.3 –

822

F: 0 – 1.0 – 2.4 – 97.5 –

998

NOAEL (F) = 2.4 mg/kg/day.

LOAEL (F) = 97.5 mg/kg/day based on:

hepatotoxicity (periportal fatty change, 

hepatocyte hypertrophy, ↑wt [abs/rel] and 

↑GGT

870.4100b Chronic toxicity 

(dog)

46817218 

Acceptable/guideline

ppm:

0 – 100 – 1500 – 20000

mg/kg/day:

M: 0 – 2.21 – 35.2 – 484

F: 0 – 2.51 – 37.9 – 533

NOAEL (M/F) = 2.21 / 2.51 mg/kg/day.

LOAEL (M/F) = 35.2 / 37.9 mg/kg/day based 

on: liver: ↑wt [abs m+f, rel(m)]

↓(m) – BWG and BW

↓ –[APTT(m/f),

↑(m/f) – ALP
Flubendiamide Human Health Risk Assessment DP No. 400797

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200a Carcinogenicity

(rat)

46817219 (2004)/

Acceptable/guideline

ppm:

0 – 50 – 1000 – 20000

mg/kg/day:

M: 0 – 1.70 – 33.9 – 705

F: 0 – 2.15 – 43.7 – 912

NOAEL (M/F) = 1.70 / 2.15 mg/kg/day.

LOAEL (M/F) = 33.9 / 43.7 mg/kg/day based 

on: liver: ↑(m/f)– [periportal fatty change, 

hypertophy] ;↑wt [abs/rel(m/f)]; kidney: 

↑(m/f)– chronic nephropathy; ↑wt [rel(f)]

No evidence of carcinogenicity

870.4200b Carcinogenicity

(mouse)

46817220 (2004)/

Acceptable/guideline

ppm:

0 – 50 – 1000 – 10000 

mg/kg/day:

M: 0 – 4.85 – 94 – 988

F: 0 – 4.44 – 93 – 937

NOAEL (M/F) = 4.85 / 4.44 mg/kg/day.

LOAEL (M/F) = 94 / 93 mg/kg/day based on: 

hepatotoxicity (periportal fatty changes, 

hypertophy); thyroid changes (↑follicular cell 

hypertrophy with hydropic change, ↑large sized 

follicles)

No evidence of carcinogenicity

870.5100 Gene mutation

(in vitro bacteria)

46817221

Acceptable/guideline

0 – 3.86 – 11.6 – 34.7 –

104 – 313

μg/plate (w/o activation)

0 – 61.7 – 185 – 556 –

1,670 – 5,000

μg/plate (+ activation)

Negative

870.5100 Gene mutation

(in vitro bacteria)

46817222 

Unacceptable/guideline

0 – 16 – 50 – 158 – 500 –

1581 – 5000 μg /plate (+/-

S9 activation)

(conducted w/ NNI-0001 

SC)

Negative 

870.5300 Gene Mutation

(in vitro

mammalian V79)

46817224 

Acceptable/guideline

0 – 7.5 – 15 – 30 – 60 -

120 – 240

μg/ml (+/ – activation)

Negative

870.5375 Mammalian

Cytogenetics (in 

vitro CHL)

Acceptable/guideline

0 – 550 – 1100 – 2200 

μg/ml (+ activation)

0 – (125-550) – (250-

1100) – (500-2200)

μg/ml; 6, 20, or 40 hrs 

exp. (w/o activation)

Negative

870.5395 Mammalian

Cytogenetics

(micronucleus

mouse)

46817226

Acceptable/guideline

0 – 1000 – 2000 – 4000 

mg/kg

Negative

870.5395 Mammalian 

Cytogenetics 

(micronucleus 

mouse)

46817225 

Acceptable/guideline

0 – 500 – 1000 – 2000 

mg/kg

Negative
Flubendiamide Human Health Risk Assessment DP No. 400797

32

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a Acute neurotoxicity 

screening battery

46817227 

Acceptable/guideline

mg/kg/day:

0 – 209 – 731 – 2213

(analytically determined)

NOAEL = 2213 mg/kg/day

LOAEL = Not observed (>2213 mg/kg/day)

870.6300 Developmental 

neurotoxicity

46817228 

Acceptable/non-guideline

ppm:

0 – 120 – 1200 – 12000

ppm

mg/kg/day (based on last 

2 wks of gestation

and 3 wks of lactation):

0 – 9.9 – 99.5 – 979.6

Maternal: NOAEL = 9.9 mg/kg/day

LOAEL = 99.5 mg/kg/day based on: liver: 

↑wt[abs/rel].

Offspring: NOAEL = 9.9 mg/kg/day

LOAEL = 99.5 mg/kg/day based on

↑balanopreputial separation time: this LOAEL 

is also protective of adverse eye effects 

reported at 979.6 mg/kg/day (eye – [enlarged 

eyeball + exophthalamus + general ocular

opacity(m)])

870.7485 Metabolism and 

pharmacokinetics

- rat

46817229, 46817230 and 

46817231 

Acceptable/guideline

Oral absorption = 23.5/34.1% in m/f, 

respectively (average = 29%); see Section 3.2 

Appendix A.2 for more information

870.7600 Dermal penetration

(monkey)

46817234 

Acceptable/non-guideline

Intravenous injection of [14C]NNI0001resulted in excretion of a large fraction of 

the dosed radioactivity in feces. Total

recoveries through 360 hours post-dose were 

80.91% in feces, 7.78% in urine, and 4.11% in 

cage debris/rinse samples. Dermal application 

of [14C]NNI-0001 resulted in a negligible 

absorption of 0.02% at 8 hrs post-dose. The

overall mean total recovery of radioactivity 

from excreta and from the application site was 

105.15%, the majority of which was associated 

with the radioactivity recovered from the 

application site.

870.7800 4-week

Immunotoxicity

(plaque-forming

assay in rat)

46817243

Acceptable/guideline

ppm:

0 – 40 – 400 – 4000

mg/kg/day:

M: 0 – 3.34 – 33.6 – 336.3

F: 0 – 4.0 – 38.4 – 358.8

NOAEL (M/F) = 336/358.8 mg/kg/day.

No evidence of primary immunotoxicity

Effects on Thyroid 

Hormones and 

Liver Enzymes in 

Female Rats

46817235 

Acceptable/non-guideline

ppm:

0-1000-10,000

mg/kg/day:

0-83-812

Study generally support this indirect effect on 

the thyroid via induction of enzymes in the 

liver. Direct effects on the liver included 

increases in organ weights, cytochrome P450, 

UDP-GT and EROD activities, and incidences 

of hepatocyte hypertrophy and vacuolation.

In vitro

Metabolism in rat, 

mouse, dog and 

human microsomes

46817232 

Acceptable/Non-guideline

see Appendix A.3 in DP329593, S. Winfield, 

4/3/08 for more information

Toxicokinetic study 

in rats and mouse

46817233 

Acceptable/Non-guideline

see Appendix A.3 in DP329593, S. Winfield, 

4/3/08 for more information
Flubendiamide Human Health Risk Assessment DP No. 400797

33

Appendix B. Physical/Chemical Properties

Table C.2 Physicochemical Properties of Flubendiamide.

Parameter Value Reference

Molecular weight 682.39 g/mol MRID 46816901

Melting point/range 217.5-220.7 °C BCS Document No. 

MO-04-005115

MRID 46816902

pH 6.05 (20 °C) BCS Document No. 

PA-04/062

MRID 46816902

Density 1.659 g/mL (20 °C) BCS Document No. 

MO-04-005118

MRID 46816902

Water solubility 29.90 μg/mL (20 °C) BCS Document No. 

MO-03-012755

MRID 46816902

Solvent solubility Solvent

p-xylene

n-heptane

methanol

1,2-dichloroethane

acetone

ethyl acetate

Solubility (g/L)

0.488

0.000835

26.0

8.12

102

29.4

BCS Document No. 

MO-04-005121

MRID 46816902

Vapor pressure 10-4Pa (25°C) BCS Document No. 

MO-04-005120

MRID 46816902

Dissociation constant, pKa Does not dissociate BCS Document No. 

MO-04-006915

Octanol/water partition 

coefficient, Log(KOW)

4.2 (pH 5.9, 25°C) BCS Document No. 

MO-03-012727

UV/visible absorption 

spectrum

204.4 nm (neutral methanol) BCS Document No. 

MO-03-012753

MRID 46816902
Flubendiamide Human Health Risk Assessment DP No. 400797

34

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies (which compose PHED, 

listed below) were determined to require a review of their ethical conduct, have received that 

review and have been determined to be ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force 

members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals 

Association, released February, 1995.
Flubendiamide Human Health Risk Assessment DP No. 400797

35

Appendix D: International Residue Limit Status

Flubendiamide (PC Code 027602)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.639:

Plant/Livestock: flubendiamide, N2-[1,1-

Dimethyl-2-(methylsulfonyl)ethyl-3-iodo-N

1

-

[2-methyl-4-[1,2,2,2-tetrafluoro-1-

(trifluoromethyl)ethyl]phenyl]-1,2-

benzenedicarboxamide

None Flubendiamide. 

Residue is fat 

soluble.

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

US Canada Mexico2 Codex

Alfalfa, forage 25

Alfalfa, hay 65

Almond, hulls 9.0 10

Apple, wet pomace 5.0

Artichoke, globe 1.6

Berry, low growing, subgroup 13-

07G, except cranberry 1.5

Brassica, head and stem subgroup 

(5A) 3.0 4

Brassica, leafy greens subgroup 

(5B) 25

Corn,field,forage 8.0

Corn, field, grain 0.03 0.02

Corn, field,stover 15

Corn, pop, grain 0.03

Corn, pop, stover 15

Corn, sweet, forage 9.0

Corn, sweet, kernel plus cob with 

husks removed 0.01 0.02

Corn, sweet, stover 25

Cotton gin byproducts 60

Cotton, undelinted seed 0.90 1.5

Fruit, pome, group 11 1.5 0.8

Fruit, stone, group 12 1.6 2

Grain, aspirated grain fractions 153

Nut, tree, group 14 0.06 0.1

Okra 0.30

Pea and bean, dried shelled, except 

soybean, subgroup 6X 0.60 1(pulses)

Peas and bean, succulent shelled, 

subgroup 6B 0.05

Peanut, hay 60

Peanut, meal 0.03
Flubendiamide Human Health Risk Assessment DP No. 400797

36

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Peanut, nutmeat 0.02

Peanut, oil 0.03

Pistachio 0.06 0.1

(tree nuts)

Fruit, small vine climbing, except 

fuzzy kiwifruit, sub-group 13-07F 1.4 2(grapes)

Rice, grain 0.50

Safflower, seed 5.0

Sorghum, grain, forage 12

Sorghum, grain, grain 5.0

Sorghum, grain, stover 14

Soybean, forage 18

Soybean, hay 60 60

(fodder)

Soybean, hulls 0.80

Soybean, seed 0.25

Sugarcane, cane 0.30

Sunflower, seed 5.0

Turnip, greens 25

Vegetable, cucurbit, group 9 0.20 0.2

Vegetable, fruiting, group 8 0.60 2 tomato

0.7 pepper

Vegetable, legume, edible podded, 

subgroup 6A 0.50 2

Vegetable, leafy, except Brassica, 

group 4 11

5 head lettuce

7 leaf lettuce

5 celery

Vegetable, foliage of legume, except 

soybean, subgroup 7A 35 40 (pea hay or fodder)

Vegetable, foliage of legume, edible 

podded, subgroup 6A 0.50

Cattle, fat

Goat, fat

Horse, fat

Sheep, fat

0.70

2

Hog, fat 0.15

Cattle, meat

Goat, meat

Horse, meat

Sheep, meat

0.08

Hog, meat 0.03

Cattle, meat byproducts

Goat, meat byproducts

Horse, meat byproducts

Sheep, meat byproducts

0.60

1 (edible offal, 

mammalian)

Hog, meat byproducts 0.15

Egg 0.40
Flubendiamide Human Health Risk Assessment DP No. 400797

37

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Milk 0.15

Milk, fat 1.0 5

Poultry, fat 3.0

Poultry, liver 0.60

Poultry, meat 0.10

Completed: M. Negussie; 08/17/10; Revised: L. Cheng, 11/02/10. Revised S. Funk, 09/06/2012

1

. Tolerance values are those established in 40 CFR § 180.639

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.