### Flubendiamide Human Health Risk Assessment DP No. 400797

3 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

4 1.0 Executive Summary

Flubendiamide is a phtha lic 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 co rn, 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 vegetab les, legume vegetables, leafy vegetables, and okra, turnip greens), the low growing berry subgroup (except cranberry), peanu t, 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 Baye r 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 pr ofile. 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 C ategory III via the oral and dermal

route s , is only a slight eye irritant and is not a dermal irritant or skin sensitizer. For acute inhalation, t he LC 50 

### 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 , t he prim ary 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 mini mal foci of cellular

alteratio n. T hyroid 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 bo dy kidney weights and

chronic nephropathy in the rat. Eye effects include e ye 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, wher eas 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 inhalat ion risks are based on liver toxicity , as well as adrenal weight increase and increase in adrenal cortical cell hypertrophy.

### Flubendiamide Human Health Risk Assessment DP No. 400797

5 There was no evidence of carcinogenicity in rats and mice up to the limit dose at 24 and 18 months, respectively. Flubendiamide w as 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 like ly to be carcinogenic to humans; ” therefore

, there is no concern for cancer risk to humans.

The flubendiamide risk assessment team evaluated the q uality 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 e nvironments

. These fate properties suggest that it has a potential to move into s urface 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 ba sed 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

assessm ent, 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 factor s were used. The resulting acute

risk estimate s 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 sub population.

For the chronic assessment, estimate s 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 fa ctors were used

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

modeled EDWC relevant to the scenario was included . The resulting chronic risk estimate s 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

6 Residential Exposure
This document only presents the as sessment of the proposed increased tolerances for flubendiamide on pome fruits and apple pomace . No residential uses a re being requested at this time. There are no existing residential uses. T herefore, 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). A s registered uses have not changed,

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

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

of concern.

Handler s: Occupational short

- term (1

- 30 days) and intermediate

- term (1

– 6 months) dermal

and inhalation ex posures are expected from flubendiamide handler activities

. HED use d 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 effect s for the dermal an d 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 tha n the level of concern (L OC) (i.e., MOEs ≥ 1 00) for dermal, inhalation, and combined dermal and inhalation exposures when wearing labeled personal protective equipment (PPE) ( e.g

. , long

sleeve shirt, long pants, shoes, socks, and chemical resistant gloves) an no respirator and

, th erefore

, a re not of concern

. The PPE

- G baseline dermal plus baseline inhalation MOE for pome fruit ranged from 1880 to 16000.

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 occu pational scenario on day 0 (12 hours

### Flubendiamide Human Health Risk Assessment DP No. 400797

7 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 adequ ate 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 environ mental 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 H

uman 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 recommend s for a n 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 esta blished 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 ) meth od, Method

00 816/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 suppleme ntary 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.

A n 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

8 was used for data collection and is als o the proposed enforcement method for animals. Method 00912, with a validated LOQ of 0.01 ppm for each analyte in each matrix

, w as 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 An alysis Division (AC B /BEAD) ( DP347049 , 02/06/ 20 08, C. Stafford).

2.2. 2 Recommended Tolerances

In a ccord ance 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) an d in 40 CFR §180.639 (d)

should be revised to state:

“Tolerances are established for residues of flubendiamide, including i t s 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 f ruit 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 compa red 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 violation s from use according

### Flubendiamide Human Health Risk Assessment DP No. 400797

9 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 (co mpared 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 almon d 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 tria ls. 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 fi eld trial data, but rounded to 1 ppm (versus US 0.60 ppm). For small vine cli mbing 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 cal culation 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.

A n International Residue Limit (I RL) 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

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

25654

- 1025).

3.0 In troduction

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

### Flubendiamide Human Health Risk Assessment DP No. 400797

10 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 C 23 H 22 F 7 IN 2 O 4 S

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

- D imethyl

- 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) Belt TM SC Insecticide (EPA Reg. No. 264

- 1025 ) Synapse TM 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 suggest s that the pesticide has some potential for bioaccumulation (i n 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 prop osed 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

11 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 i ncreased 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 flubendiam ide 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 whi le 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 toxic ity 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’Keef e )

. The current assessment considers the aforem entioned 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 consider ed 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 pat terns 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 Healt h 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 dev elopment 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

12 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 flubendiamid e as a new active ingredient (D 329 593, S. Winfield

, 04/03/2008 ). The most recent assessment was in 2010 (D376459, B. O’Keefe, 11/30/201 0). A waiver request for subchronic neurotoxicity was submitted by the registrant and was granted by OPP’s Hazard and Science Policy Council (HASPOC) on 0 3/05/2012 (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 represe nts 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; flu bendiamide modulates insect but not mammalian ryanodine receptors 1



### .

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

. In the mammalian toxicology database, t he primary target organ of

flubendiam ide 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 (e ye enlargement ) , opacity, and exophthalmus with hemorrhage appear ing only in infancy, were observed in rat offspring in the reproductive and development neurotoxicity ( DNT ) studies (D329593, S.Winfield, 0 4/03/08) . 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 c onsidered an effect of treatment. I t 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 metab olism 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 o rgans and tissues, with

1 Ebbinghaus

- Kintscher, U., et. al. (2006). Phthalic acid diamides activate ryanodine

- sensitive Ca 2+ release channels

in insects

. Cell Calcium

, 39 , pp 21

- 33.

2 A

- 14, see Table 5.1

### Flubendiamide Human Health Risk Assessment DP No. 400797

13 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 feces 2 

### . 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 metabol ite 2 

### due 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 compou nd 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.

T he short

- and i ntermediate

- 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 inter mediate

- 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 wa s not applied because the selected

derm al 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 S afety F actor 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. Winf

ield, 4/3/08).

4.2.1 Completeness o f 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, 03/05/2 012)

. 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

14 were limited to ocular lesions and delayed sexual maturation. In the conventional subchronic an d 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 considera tions, 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, t he 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

- 102 6 ). 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 fr om anticipated occupational

exposure

.

4.2.2 Evidence of N eurotoxicity

Flubendiamide is not a neurotoxic chemical based on neurotoxicity assessments conducted acutely

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

- ter m studies in rats (subacute and subchronic feeding, plaque

- forming cell a ssay, 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 neurotox icity 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 ob served 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 o f Sensitivity/Su sceptibility in the Developing o r 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, ther e 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

organo genesis 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.

### Flubendiamide Human Health Risk Assessment DP No. 400797

15 In addition to the reported eye effects in the DNT study, t here 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 considere d 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 reproduc tive 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 t he 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 t here is concern for increased susceptibility to of fspring fol lowing pre

- and post natal 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 ris k 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 Datab ase

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 D eparture Selections

There have been no changes to the prior dose

- response assessment. There have been no changes to the prior recommendations for combining routes of exposure and/or cancer classification. See

Table 4 .3.1 for a summary of endpoints and points of departure for dietary and non

- o ccupational

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.

### Flubendiamide Human Health Risk Assessment DP No. 400797

16 T able 4. 3.1 Summary of Toxicological Doses and Endpoints for Flubendiamide for use in Dietary and

Non

- Occupational Human Health Risk Assessments 1

Exposure

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary general population, including infants

and children NOAEL = 99.5

mg/kg/day UF A = 10x

UF H = 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

b uphthalmia (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 UF A = 10x

UF H = 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 UF A = 10x

UF H = 10x FQPA = 1x LOC =
MOE ≤ 100 D evelopmental 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 UF A = 10x

UF H = 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 UF A = 10x

UF H = 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 follicul ar 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 UF A = 10x

UF H = 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.

### Flubendiamide Human Health Risk Assessment DP No. 400797

17 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 relevan t human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). 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 UF A = 10x

UF H = 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 UF A = 10x

UF H = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). 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

### Flubendiamide Human Health Risk Assessment DP No. 400797

18 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 Subc ommittee . PC Code: 027602. DP No.: D351083, 4/3/ 20 08 . The

conclusion s 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) metabolite 1 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 aspect s pertinent to the new field trials and the risk assessment are

detailed below.

Crop Field Trials

Bayer C ropScience submitted field trial data for flubendiamide on apple s 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 (I D). 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. S amples of mature apples were harvested 14 days after the final application.

### Flubendiamide Human Health Risk Assessment DP No. 400797

19 R esults are summarized in Table 5.2

.

T able 5.2 Summary of Residue Data from Apple Field Trials with Flubendiamide

Commodity Total Applic.

Rate (lb ai/A) Plot 2 Residue Levels ( flubendiamide; ppm) 1

N Min. Max. HAFT 3 Median (STMdR) Mean

(STMR) Std. Dev.

Apple fruit 0.47 1

– 0.476 TRTDI 6 0.164 0.85 0.763 4 0.221 0.384 0.30

TRTD 6 0.185 1.24 1.21 4 0.252 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 comm odities (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 quant ifiable 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 Accumulat

ion 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 stab ility 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 harve st); 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,

08/15/201 2 ).

Field Accumulation in Rotational Crops

### Flubendiamide Human Health Risk Assessment DP No. 400797

20 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

flube ndiamide 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 persiste nt and potentially mobile in terrestrial and aquatic

environments

. These fate properties suggest that it has a potential to move into s urface 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) fo r flubendiamide was

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

h ighest 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 estima te 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 result ed 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/L a 

### 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 K

oc 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, Flu bendiamide: 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 use d 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

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

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 t he 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

- FCI D, Version 3.16, which incorporates consumption data from USDA’s NHANES/WWEIA. This dietary survey was conducted from 2003 to 2008.

At the 95 th 

### percentile of exposure, all acute analys e s yielded risk estimates well below the 100%

of the aPA D threshold l evel of concern for each population subgroup. For the general US

p opulation 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,

c hildr en 1

- 2 years old

, acute aggregate dietary risk occupied 5.5 % of the aPA D with an exposure

of 0.0 55 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 pr esented 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 conduct ed from 2003 to 2008.

All chronic analys e s yielded risk estimates well below the 100% of the c PA D threshold level of concern for each population subgroup. For the general US p opulation, chronic aggregate dietary

risk was calculated at 20% of the cPAD w ith an exposure level of 0.0047 mg/kg/day. For the subgroup with the highest calculated exposure, c hildren 1

- 2 years old , chronic aggregate dietary

risk occupied 66 % of the c PA D with an exposure of 0.0 1 6 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 h aving the highest exposure noted in bold is presented i n 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 genot oxicity and carcinogenicity in long term cancer studies in rats and mice.

5.4.5 Summary Table

### Flubendiamide Human Health Risk Assessment DP No. 400797

22 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 (95 th 

### 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 t he proposed increased tolerances for the pom e 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 t o 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

23 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. pest icide 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 Age ncy 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 an d 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 consi der 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

asse ssment 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 toleran ce 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

24 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 Ex posure 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, includ ing 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.

Occupati onal 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 expec ted from handler activities;

short

- and intermediate

- term dermal exposures are expected from post application activities.

Previous evaluations indicated MOEs in excess of 100. Ge nerally 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 200 8 (D329593, S. Winfield, 04/03/2008) on personal protective equipment are not altered.

Although th e inhalation and dermal risk estimates are based on different toxicological points of departure

, t he endpoints are equivalent (liver toxicity) , which is how th is 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, f or both short

- and intermediate

- term exposure
dur ations. The LOC is an MOE less than 100. Occupational risk s resulting in MOEs greater than or equal to 1 00 do not exceed HED ’s LOC

. All MOEs were >100. The PPE

- G baseline dermal plus baseline inhalation M OE 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 ac tivities and crops, the REI of 12 hours on the existing

label s 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. There fore, the REI of 12 hours for all activities an d

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 expos ure 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 - 4 

### Pa or 7.5 x 10 - 7 

### mm Hg ), and the low use rate (0. 47 lb ai/A /year ). However, th ere 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 p articulates 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 rec eived 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 Agri cultural 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 , 201 2 : Evaluation of a waiver request

for a subchronic neurotoxicity stud y

.

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 Fru it

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 Fuzz y 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 Follow

Up: 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 A ppendix 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

................................ ...................... y es

yes

yes

yes

yes

yes y es

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

................................ .......................... y es

yes

yes

no

yes y es

yes

yes

-

*

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . Y es

yes

yes y es

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

................................ .................... Y es

no

yes

yes

no y es

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

....................... Y es

yes

yes

yes y es

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

................................ .............................. N o

no

yes

yes

no -

- yes

**

yes

870.7485 General Metabolism

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

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

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

yes

yes y es

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 Profile s

Table A.2.1. Acute Toxicity Profile

– Flubendiamide

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

– rat 4681714 2 LD50 > 2000 mg/kg III

870.1200 Acute dermal

- rat 4681714 5 LD50 >2000 mg/kg III

870.1300 Acute inhalation

– rat 468171 48 LC50 >0.0685 mg/L a II

870.2400 Acute eye irritation

– rabbit 4681720 1 Irritating (slight) IV

870.2500 Acute dermal irritation

– rabbit 4681720 4 Non

- irritating IV

870.2600 Skin sensitization

– guinea pig 4681720 7 Negative N/A

a The acute LC 50 of flu bendiamide (TGAI) is greater tha n 0.0685 mg/L, the maximum attainable concentration; it

cannot be further classified due to its physical/chem ical propertie s which limit its aerosolization . Results of MRID 46817149 demonstrate that a formulation containing 39% flubendiamide has an LC 50 > 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 gland s in

females : adrenal: ↑(f)

– cortical hypertrophy; ↑(f)

– wt ↓(m/f)

– APTT ↑

– [ALP(m/f), Trig lycerides (f)]

### Flubendiamide Human Health Risk Assessment DP No. 400797

29 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

Devel opmental: 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

g eneration. 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,

r espectively). 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

30 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 a nogenital 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

- gu ideline

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, hep atocyte hypert r ophy, ↑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

31 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

vitr o 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 separ ation 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 Append ix A.2 for more information

870.7600 Dermal penetration

(monkey) 46817234

Acceptable/non

- guideline Intravenous injection of [14 C]NNI

0001resulted 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 (2 0 °C) BCS Document No.

PA

- 04/062

MRID 46816902

Density 1.659 g/mL (2 0 °C) BCS Document No.

MO

- 04

- 005118

MRID 46816902

Water solubility 29.90 μ g/ m L (2 0 °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 - 4 Pa (25°C) BCS Document No.

MO

- 04

- 005120

MRID 46816902

Dissociation constant, pK

a Does not dissociate BCS Document No.

MO

- 04

- 006915

Octanol/water partition coefficient, Log(K OW ) 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 Mexico 2 

### Codex 3



### 40 CFR 180. 639:

Plant/Livestock : 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 

### None Flubendiamide.

Residue is fat

soluble.



### Commodity 1 

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

US Canada Mexico 2 

### 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 Mexico 2 

### Codex 3

Peanut, nutmeat 0.02

Peanut, oil 0.03

Pistachio 0.06 0.1 (tree nuts)

F ruit , 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 Mexico 2 

### Codex 3

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 fina lized by the CCPR and the CAC.