Document ID: EPA-HQ-OPP-2007-0338-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-02T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF                  

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES        

December 21, 2007

MEMORANDUM

SUBJECT:	Flonicamid: Human Health Risk Assessment for Proposed Uses on
Root Vegetables (Except Sugarbeet; Subgroup 1B), Tuberous and Corm
Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B),
Turnip Greens, Hops and Okra. PC Code: 128016, Petition No: 6E7081, DP
Barcode: D347805.

 

Section 3 Registration Action

Single Chemical Aggregate

FROM:	Sheila Piper, Risk Assessor

Mark Dow, Biologist			

Alternative Risk Integation Assessment Team (ARIA)

Registration Branch (7505P)

Amelia Acierto, Residue Chemist 

Registration Action Branch 3 (RAB3)

Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Chief

Registration Action Branch 3 (RAB3)

Health Effects Division (7509P)

J.R. Tomerlin, PhD., Plant Pathologist

ARIA/Registration Branch (7505P)

TO:		Ann Sibold, PM Team #10

Insecticide Branch

Sidney Jackson, IR-4

Registration Division (7505P)

The Office of Pesticide Programs (OPP) is charged with estimating the
risk to human health from exposure to pesticides.  The Registration
Division of OPP has requested that ARIA evaluate hazard and exposure
data and conduct dietary, occupational, residential and aggregate
exposure assessments, as needed, to estimate the risk to human health
that will result from proposed IR-4 tolerances for root vegetables
(except sugar beets), tuberous and corm vegetables, leafy Brassica
greens, turnip greens, hops, and okra.  A summary of the findings and an
assessment of human-health risk resulting from the proposed tolerances
for flonicamid are provided in this document.  The residue chemistry
data review and dietary exposure assessment were provided by Amelia
Acierto (RAB3), the risk assessment by Sheila Piper (ARIA), the hazard
characterization and endpoint selection by Meta Bonner (RAB 3), and
occupational exposure assessment by Mark Dow (ARIA), and the drinking
water exposure assessment by Lucy Shanaman of the Environmental Fate and
Effects Division (EFED).

NOTE:  HED previously completed a Section 3 human-health risk assessment
for the use of flonicamid on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Stone Fruit, Potatoes, and
Nursery and Landscape Ornamentals (Memo J. Arthur, et al., 5/25/2005,
D289592).  The hazard characterization and endpoint selection from the
previous risk assessments on Flonicamid can be applied directly to this
action.

Table of Contents

 TOC \f 

1.0	Executive Summary	1

2.0	Ingredient Profile	6

2.1	Summary of Registered/Proposed Uses	6

2.2	Structure and Nomenclature	8

2.3	Physical and Chemical Properties	8

3.0  Hazard Characterization/Assessment	11

3.1	Hazard and Dose Response Characterization	11

3.1.1	Adequacy of the Toxicity Data Base	12

3.1.2	Evidence of Neurotoxicity	12

3.1.3	Developmental Toxicity Studies	13

3.1.4	Reproductive Toxicity Studies	14

3.1.5	Additional Information from Literature Sources	16

3.1.6    Pre-and/or Postnatal Toxicity	16

3.1.6.1	Determination of Susceptibility	16

3.1.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility	16

	3.1.7   Recommendation for a Developmental Neurotoxicity Study	17

3.2	Description of Rat Metabolsim	17

3.3	FQPA Safety Factor	18

3.4	Hazard Identification and Toxicity Endpoint Selection	18

3.4.1   Acute Reference Dose (aRfD)	18

3.4.2	Chronic Reference Dose (cRfD)	19

3.4.3	Incidental Oral Exposure (Short and Intermediate Term)	19

3.4.4	Dermal Absorption	20

3.4.5	Dermal Exposure (Short, Intermediate and Long Term)	20

3.4.6	Inhalation Exposure (Short, Intermediate and Long Term)	20

3.4.7	Level of Concern for Margins of Exposure	20

3.4.8	Recommendation for Aggregate Exposure Risk Assessment	21

3.4.9	Classification of Carcinogenic Potential	21

3.5	Endocrine Disruption	23

4.0	Public Health Data	23

4.1	Incident Reports	23

5.0       Dietary Exposure/ Risk Characterization	24

5.1	Pesticide Metabolism and Environmental Degradation	24

5.1.1	Metabolism in Primary Crops	24

5.1.2	Metabolism in Confined and Rotation Crops	25

5.1.3	Metabolism in  Livestock	26

5.1.4	Analytical Methodology	27

5.1.5	Pesticide Metabolism and Environmental Degradation	28

		5.1.6   Toxicity Profile of Major Metabolites and Degradates	28

	5.1.7   Pesticide Metabolites and Degradation of Concern	29



	5.1.8   Drinking Water Residue Profile	29

	5.1.9   Food Residue Profile	31

	5.1.10   International Residue Limits	31

5.2	Dietary Exposure and Risk	31

5.2.1	Acute Dietary Exposure/Risk	32

5.2.2	Chronic Dietary Exposure/Risk	32

5.2.3	Cancer Dietary Exposure/Risk	33

5.3	Anticipated Residues and Percent Crop Treated (%CT) Information	33

6.0      Residential (Non-Occupational) Exposure/Risk Characterization
33

6.1	Home Uses	33

6.2       Spray Drift	33

7.0	Aggregate Risk Assessments and Risk Characterization	34

	7.1       Acute Aggregate Risk	34

7.2	Short-Term Aggregate Risk	34

7.3	Intermediate-Term Aggregate Risk	34

7.4	Long-Term (Chronic) Aggregate Risk	35

7.5	Cancer Risk	35

8.0	Cumulative Risk Characterization/Assessment	35

9.0	Occupational Exposure/Risk Pathway	35

9.1	Short/Intermediate/Long-Term Handler Risk	35

9.2	Short/Intermediate/Long-Term Postapplication Risk	38

9.3	Restricted Entry Interval	38

10.0	Data Needs and Label Requirements	38

10.1	Toxicology	38

10.2	Residue Chemistry	38

10.3	Occupational and Residential Exposure	38

10.0	Tolerance Summary Table	39

        Appendix A1.0  Toxicology Data Requirement	41

        Appendix A2.0  Acute Toxicity of Flonicamid Technical	42

         Appendix A3.0  Flonicamid Technical	43

Appendix A4.0 International Residue Limit Status Sheet	531.0	Executive
Summary tc \l1 "1.0	Executive Summary 

	

ARIA conducted a human health risk assessment for the insecticide,
flonicamid for the purpose of making a tolerance/registration
eligibility decision to establish new uses in or on root vegetables
(except sugar beets), tuberous and corm vegetables, leafy Brassica
greens, turnip greens, hops, and okra as requested by the Interregional
Research Project No. 4 (IR-4).  IR-4 has submitted a request for an
amended registration of the end-use products Flonicamid 50WG (EPA Reg.
No. 71512-9), a water dispersible granule formulation, and the 50% SG
formulation (Beleaf™ 50SG; EPA Reg. No. 71512-10), a soluble granule
formulation each containing 50% flonicamid.  

Use Profile

In addition to chemigation, Flonicamid 50WG will be applied as broadcast
or banded foliar sprays using ground or aerial equipment at 0.036-0.089
lb ai/acre/application with 7-day re-treatment intervals and a maximum
seasonal application rate of 0.267 lb ai/acre.  The proposed pre-harvest
intervals (PHIs) range from 0 days for cucurbit, fruiting vegetables,
leafy vegetables, head and stem brassica vegetables, mustard greens, and
okra; 3 days for root vegetables (except sugar beets); 7 days for
tuberous and corm vegetables; and up to 10 days for hops.

Also, HED assumes that the proposed food-use sites are commercial in
nature, and that applications on landscape ornamentals would only be
made by professional pest control operators (PCOs)  The end-use product,
F1785N, a 50% ai water dispersible granule for use on nusery and
landscape ornamentals, at a maximum rate of 0.134 lb ai/100 gallons.

Hazard Characterization

Flonicamid is a systemic (plant) insecticide that immediately suppresses
the feeding of sucking insects (e.g., flonicamid acts as an antifeedant
and a behavioral modifier on aphids within 30 minutes of exposure
resulting in insect mortality from starvation within 5 to 7 days after
exposure).  Flonicamid’s chemical structure (including the nicotinic
acid structure) suggests the same insecticidal mode of action as
similarly structured neo-nicotinoid pesticides.  However, flonicamid has
not been found to activate acetylcholine esterase (OPs and carbamates),
or nicotinic acetylcholine receptors (neo-nicotinoids).  Flonicamid has
been described as a new chemistry (cyanomethyl trifluoromethyl
nicotinamide) with a novel (but undefined) mode of action, different
from other commercially available products.  For these reasons, it is
unclear how the insecticidal mode of action relates to human health. 
Nonetheless, the available toxicological database provides adequate
information to characterize potential hazards/effects.

Flonicamid has low acute toxicity being classified as Category III for
acute oral toxicity and Category IV for dermal, inhalation, eye and skin
irritation toxicities.  Flonicamid metabolites
4-trifluoromethylnicotinic acid (TFNA), 4-trifluoromethylnicotinic acid
(TFNA-AM), N-(4- trifluoromethylnicotinoyl) glycine (TFNG),
N-(4-trifluoromethylnicotinoyl)-glycinamide (TFNG-AM), and
6-hydroxy-4-trifluoromethylnicotinic acid (TFNA-OH) likewise are
classified as Category III for acute oral toxicity.  Flonicamid is not a
dermal sensitizer.  In the 28-day dermal study no dermal or systemic
toxicity was seen at the limit dose (1000 mg/kg/day) for flonicamid
technical.  

The oral studies in rats and dogs indicate the kidney and liver are the
target organs for flonicamid toxicity.  Kidney weight increases and
kidney hyaline deposition and liver centrilobular hypertrophy effects
were seen in the rat 28-day oral range-finding study, 90-day oral study,
developmental study and reproductive study.  These effects were not
observed in the rabbit developmental study.  The 90-day dog study showed
kidney tubular vacuolation, as well as increased adrenal weights,
increased reticulocytes, and decreased thymus weights.  Increased
reticulocyte was noted in both the subchronic and chronic dog studies.

Developmental effects were only observed in the rat at high doses. 
Furthermore, developmental and reproductive effects only occurred at
maternally toxic doses.  Thus, susceptibility issues are not of concern
for flonicamid.  Further, only high dose effects were noted in the acute
and subchronic neurotoxicity studies and there are no concerns for
neurotoxicity from other studies.

Mutagenicity studies were negative for the parent chemical, flonicamid,
and its metabolites TFNA, TFNA-AM, TFNG, TFNG-AM, and TFNA-OH. 
Flonicamid is carcinogenic in CD-1 mice, based on increased incidences
of lung tumors associated with Clara cell activation; the effects,
however, are associated with species and stain sensitivity.  Nasal
cavity tumors in male Wistar rats were linked to incisor inflammation;
data were not sufficient to make a similar determination in female rats.
 The determination of carcinogenicity potential was made by the Cancer
Assessment Committee on January 5, 2005 for flonicamid based on the
weight of the evidence approach and resulted in the classification
“suggestive evidence of carcinogenicity, but not sufficient to assess
human carcinogenic potential.”

The acute reference dose (aRfD) was not identified because no
appropriate acute endpoint could be determined from the database.  The
2-generation reproduction toxicity rat study was chosen for the chronic
reference dose (cRfD) based on increased kidney weights and hyaline
depositions, and increased blood serum level of LH (F1 females) at a
parental LOAEL of 22 mg/kg/day with a NOAEL of 3.7 mg/kg/day.  This
study is justified because observed effects on the kidney are consistent
with effects seen in other studies (rat 28-day, rat chronic, rat
developmental, and dog 90-Day toxicity studies) demonstrating evidence
of kidney toxicity;  the kidney is considered the target organ. 

No endpoint was chosen for the incidental oral exposure because
incidental oral exposure is not expected based on the use pattern in
this assessment.  No dermal absorption studies are available.No dermal
exposure endpoint was chosen because the 28-day dermal toxicity study
showed no dermal or systemic toxicity at the limit dose of 1000
mg/kg/day.  

Residue Chemistry 

Flonicamid is a Group 9C insecticide (selective feeding blocker)
currently registered for the control of a variety of aphid pests and the
suppression of a variety of non-aphid pests in head and stem Brassica
vegetables, cotton, cucurbit vegetables, fruiting vegetables, leafy
vegetables, potato, pome fruit, and stone fruit.  

Tolerances have been established for residues of flonicamid under 40 CFR
180.613.  Tolerances are currently established under 180.613(a)(1) for
the combined residues of flonicamid, TFNA, TFNA-AM, and TFNG in/on head
and stem Brassica, cotton, cucurbit vegetable, fruiting vegetable, leafy
vegetable, mustard greens, potato, pome fruit, spinach and stone fruit
commodities, at 0.20 to 11 ppm.  Tolerances have also been established
for the combined residues of flonicamid, TFNA, and TFNA-AM in egg, milk,
and the fat, meat, and meat byproducts of cattle, goat, horse, poultry,
and sheep, at 0.02 to 0.08 ppm.  

The nature of the residue has been adequately understood based on
acceptable peach, potato, and wheat metabolism studies.  HED has
determined that the residues of concern in plants are flonicamid and its
metabolites TFNA-AM, TFNA, and TFNG.  The nature of the residue in
livestock is also understood, based on acceptable goat and hen
metabolism studies.  HED has determined that the residues of concern in
livestock are flonicamid and its metabolites TFNA and TFNA-AM.

Adequate analytical method, enforcement methods, storage stability data,
field trial data, processing studies, livestock feeding studies, and
rotational crop data are available to support the proposed root
vegetables (except sugar beet, subgroup 1B), tuberous and corm
vegetables, leafy Brassica greens, turnip greens, hops, and okra.

Dietary Exposure Assessment

 

There is potential for exposure to residues via the dietary (food +
water) pathways.  An unrefined Tier 1 dietary exposure assessment was
conducted (assuming tolerance level residues and 100% crop-treated)
using the Dietary Exposure Evaluation Model software with the Food
Commodity Intake Database (DEEM-FCIDTMversion 2.0) model.  Also, no
surface water, groundwater or drinking water monitoring data are
available; therefore, conservative estimated drinking water
concentrations (EDWCs) were modeled using the Tier 2 surface water model
Pesticide Root Zone Model/Exposure Analysis Modeling System
(PRZM/EXAMS), and the groundwater model Screening Concentration in
Groundwater (SCI-GROW).  

Risk was estimated for chronic exposure only since no acute endpoint
was identified and evidence for carcinogenicity was suggestive and
quantitative risk assessment was not recommended.  The assessment
assumed that all included crops contained tolerance level residues
(i.e., 100 % crop treated).  These assumptions result in highly
conservative estimates of dietary exposure and risk.  Typically, HED has
concerns regarding dietary risk when the exposure estimates exceed 100%
of the cPAD.  Even with the conservative assumptions noted above, the
chronic risk estimates associated with dietary (food + drinking water)
exposure to flonicamid are significantly below HED’s level of concern.
 

Residential Risk

There are no residential handler uses of flonicamid; application of
flonicamide in residential use sites is made only by professional pest
control operators (PCOs).  Therefore, residential handler scenarios are
not expected and need not be assessed.  Flonicamid label language should
preclude use by non-professionals (e.g., homeowners), particularly
regarding landscape ornamentals.  Because no dermal toxicity endpoint
was identified for flonicamid, a postapplication residential
exposure/risk assessment was not necessary.

Aggregate Risk

For flonicamid, potential exposures from food and drinking water were
considered, and aggregated.  Although acute, short- and
intermediate-term and chronic exposures may occur, acute exposures were
not considered because an appropriate quantitative estimate of hazard
(i.e., an adverse effect attributable to a single dose) was not
identified from the toxicological database to which an acute exposure
estimate could be compared. Furthermore, evidence of flonicamid’s
carcinogenicity is only suggestive and not sufficient to assess human
carcinogenic potential, and therefore, an aggregate cancer assessment
was not conducted.  Estimates of long-term (chronic) aggregate risk
associated with the registered and proposed uses of flonicamid do not
exceed HED’s level of concern for the general U.S. population or any
population subgroup.

 

Occupational Risk 

Occupational handlers may be exposed to flonicamid during mixing,
loading and application for all uses subject to this registration action
(i.e., agricultural crops and nursery/landscape ornamentals).  Handlers
are assumed to have potential short-term (1-30 days) and
intermediate-term (31-180 consecutive days) dermal and inhalation
exposure to flonicamid.  Long-term handler exposure is not expected. 
Because no dermal toxicity endpoint was identified for flonicamid, only
inhalation exposures and risks were assessed.

No chemical-specific handler exposure data were submitted in support of
this action.  Handler exposures were estimated using data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
PHED Surrogate Exposure Guide (8/98).  The PHED Surrogate Exposure Guide
does not contain water dispersible granule values; therefore, dry
flowable (open mixing) or liquid (open pour) values were used as
reasonable surrogates for this formulation.  HED standard values were
used for the amount treated per day and body weights.  All handler
scenarios resulted in MOEs (100 with baseline protective equipment and
clothing, and therefore do not exceed HED’s level of concern. 

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,”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . 

The Office of Pesticide Programs (OPP) typically considers the highest
potential exposures from the legal use of a pesticide when conducting
human health risk assessments, including, but not limited to, people who
obtain drinking water from sources near agricultural areas, the
variability of diets within the U.S. (including different ages, regions,
and ethnicities), and people who may be exposed when harvesting crops. 
Should these highest exposures indicate potential risks of concern, OPP
further refines the risk assessments to ensure that the risk estimates
are based on the best available information.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethnical conduct, and have received that review.  The studies in PHED
were considered appropriate (or ethnically conducted) for use in risk
assessments.

Recommendations

Provided a revised Section F is submitted, there are no residue
chemistry issues that would preclude granting a registration for the
requested uses of flonicamid on root vegetables (except sugar beets),
tuberous and corm vegetables, leafy Brassica greens, turnip greens,
hops, and okra, or establishment of tolerances for flonicamid residues
as follows:

Tolerances to be established under 40 CFR 180.613(a)(1):

Brassica, leafy greens, subgroup 5B ……………….16 ppm

Hop, dried cones…………………………………....7.0 ppm

Okra	 ………………………………….…………0.40 ppm

Turnip, greens ………………………………………16 ppm

Vegetable, root, except sugar beet, subgroup 1B	..0.60 ppm

Vegetable, tuberous and corm, subgroup 1C	…..   . 0.20 ppm

Tolerances to be revised under 40 CFR 180.613(a)(2):

Cattle, fat	0.03 ppm

Cattle, meat	0.08 ppm

Egg	0.04 ppm

Goat, fat	0.03 ppm

Goat, meat	0.08 ppm

Horse, fat	0.03 ppm

Horse, meat	0.08 ppm

Milk	0.03 ppm

Poultry, fat	0.03 ppm

Poultry, meat	0.03 ppm

Poultry, meat byproducts	0.03 ppm

Sheep, fat	0.03 ppm

Sheep, meat	0.08 ppm

2.0	Ingredient Profile tc \l1 "2.0	Ingredient Profile 

Flonicamid is a Group 9C insecticide (selective feeding blocker)
registered for the control of a variety of aphid pests and the
suppression of a variety of non-aphid pests in head and stem Brassica
vegetables, cotton, cucurbit vegetables, fruiting vegetables, leafy
vegetables, potato, pome fruit, and stone fruit.  

Summary of Registered and Proposed Uses

The proposed use directions for the 50% WG and 50% SG formulations are
adequate to allow an assessment as to whether the submitted residue data
reflect the maximum residues likely to occur in/on root vegetables
(except sugar beet), tuberous and corm vegetables, leafy Brassica
greens, hops, and okra.  

Table 2.1.		Summary of Proposed Directions for Use of Flonicamid.

Formulation

[EPA Reg. No.]	Application Timing	Application Rate 

(lb ai/A)	Max. No. Applic. per Season	RTI1

(days)	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and other Limitations

Root Vegetables (except sugar beets) including:  garden beet; edible
burdock; carrot; celeriac; turnip-rooted chervil; chicory; ginseng;
horseradish; turnip-rooted parsley; parsnip; radish; oriental radish;
rutabaga; salsify; black salsify; Spanish salsify; skirret; turnip

50% WG

[71512-9]	Postemergence Broadcast	0.036-0.089	3	7	0.267	3	Applications
are to be made in a minimum of 10 gal/A using ground equipment or 3
gal/A using aerial equipment.

50% SG

[71512-10]

	Tuberous and Corm Vegetables including:  arracacha; arrowroot; Chinese
artichoke; Jerusalem artichoke; edible canna; bitter and sweet cassava;
chayote (root); chufa; dasheen (taro); ginger; leren; potato;2 sweet
potato; tanier; turmeric; yam bean; yam (true)

50% WG

[71512-9]	Postemergence Broadcast	0.036-0.089	3	7	0.267	7	Applications
are to be made in a minimum of 10 gal/A using ground equipment or 3
gal/A using aerial equipment.

50% SG

[71512-10]

	Leafy Brassica Greens including:  broccoli raab (rapini); Chinese
cabbage (bok choy); collards; kale; mizuna; mustard greens;3 mustard
spinach; rape greens; turnip greens

50% WG

[71512-9]	Postemergence Broadcast	0.036-0.089	3	7	0.267	0	Applications
are to be made in a minimum of 10 gal/A using ground equipment or 3
gal/A using aerial equipment.

50% SG

[71512-10]

	Hops

50% WG

[71512-9]	Postemergence Broadcast or banded	0.054-0.089	3	7	0.267	10
Applications are to be made in a minimum of 10 gal/A using ground
equipment or 3 gal/A using aerial equipment.

50% SG

[71512-10]

	Okra 4

50% WG

[71512-9]	Postemergence Broadcast	0.036-0.089	3	7	0.267	0	Applications
are to be made in a minimum of 10 gal/A using ground equipment or 3
gal/A using aerial equipment.

50% SG

[71512-10]	Postemergence Broadcast or banded

1  RTI = Retreatment interval

2  Uses on potato have been registered previously.

3  Uses on mustard greens have been registered previously.

4  Uses on okra are included under Fruiting Vegetables on the proposed
labels.

The following rotational crop restrictions are proposed: a 0-day
plantback interval for any registered crop listed on the label; and a
30-day plantback interval for all other crops.

The proposed labels specify that the product may be tank mixed with
products approved for use on the crops listed on the label, with the
instructions that all manufacturer’s label recommendations for the
companion product must be read and followed.  The labels also specify
that the products may not be used with spray adjuvants.

The crop field trial data submitted reflect application of the 50% WG
formulation only.  The basic producer of flonicamid, ISK Biosciences
Corporation, has previously submitted side-by-side crop field trial data
for the 50% WG and 50% SG formulations of flonicamid on tomato and leaf
lettuce.  A previous review of these data (DP# 304829, 1/9/2006, A.
Acierto) concluded that combined residues of flonicamid and its
metabolites TFNA-AM, TFNA and TFNG in/on tomato and leaf lettuce were
comparable whether the 50% WG or 50% SG formulation was applied.  The
review further concluded that previously submitted data for the 50% WG
formulation could be used to support registration of the 50% SG
formulation on the same crops.  Therefore, the data for the 50% WG
formulation submitted with the current petition may be used to support
uses of the 50% SG formulation on the same crops at the same rates.

2.2	Structure and Nomenclature

The PC Code and nomenclature of flonicamid are listed below in Table
2.2.  The physicochemical properties of flonicamid are listed in Table
2.3.  The chemical names and structures of flonicamid and its
transformation products are presented in Table 2.4.

Table 2.2.	Flonicamid Nomenclature

Chemical structure	

Common name	

Flonicamid

PC Code	

128016

Company experimental name	

IKI-220; F-1785

IUPAC name	

N-cyanomethyl-4-(trifluoromethyl)nicotinamide

CAS name	

N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide

CAS registry number	

158062-67-0

End-use product (EP)	

Flonicamid 50WG

2.3	Physical and Chemical Properties

Table 2.3.	Physicochemical Properties of Flonicamid*

Parameter	

Value	

Reference

Melting point/range	

157.5 (C	

MRID 45854601

pH, 1% aqueous suspension	

4.5 (25 (C)	

MRID 45854601

Density	

1.531 (20 (C)	

MRID 45854601

Water solubility	

5.2 g/L (20 (C)	

MRID 45854601

Solvent solubility	

Solvent	g/100 mL (20 (C)

acetone	17.32

acetonitrile	12.04

dichloromethane	0.40

ethyl acetate	3.57

hexane	0.00003

isopropyl alcohol	1.46

methanol	9.76

n-octanol	0.26

toluene	0.03	

MRID 45656705

Vapor pressure	

9.43 x 10-7 Pa (20 (C)

2.55 x 10-6 Pa (25 (C)	

MRID 45854601

Dissociation constant, pKa	

11.60 ± 0.03 (20 ± 1 (C)	

MRID 45656705

Octanol/water partition coefficient	

1.9 (Log POW = 0.3) (29.8 (C)	

MRID 45854601

UV/visible absorption spectrum	

Acidic and neutral aqueous solutions exhibited similar spectra with an
absorption maximum near 265 nm and a molar absorptivity of 3,900 L/cm
mol. A basic solution exhibited two absorption peaks. The peak observed
in acidic and neutral solutions was present at a slightly longer
wavelength, 270 nm, with an absorptivity of 4,200 L/cm mol. The second
peak had an absorption maxima at 204 nm with an absorptivity of 13,200
L/cm mol.	

MRID 45854601

*Reviewed by RD, Dr. Shyam Mathur, D285457, 9/30/2003.

Table 2.4.  Chemical Names and Structures of Flonicamid and its
Transformation Products

Company Name	

Chemical Name	

Structure

Flonicamid	

N-(cyanomethyl)-(4-trifluoromethyl)-3-pyridinecarboxamide	

TFNA	

4-trifluoromethylnicotinic acid	

TFNA-AM	

4-trifluoromethylnicotinamide	

TFNG	

N-(4- trifluoromethylnicotinoyl) glycine	

TFNG-AM	

N-(4-trifluoromethylnicotinoyl)-glycinamide	

N-oxide of flonicamid	

	

N-oxide of TFNG	

	

OH-TFNA-AM	

6-hydroxy-4-trifluoromethylnicotinamide	

TFNA-OH	

6-hydroxy-4-trifluoromethylnicotinic acid	

3.0  	Hazard Characterization/Assessment

3.1 	Hazard and Dose Response Characterization

From its chemical structure (including the nicotinic acid structure) it
would be expected to exhibit the same insecticidal mode of action as
similarly structured neo-nicotinoid pesticides.  However, flonicamid has
not been found to activate acetylcholine esterase (OP's and carbamates),
or nicotinic acetylcholine receptors (neo-nicotinoids).  Flonicamid has
been described as a new chemistry (cyanomethyl trifluoromethyl
nicotinamide) with a novel (but undefined) mode of action, different
from other commercially available products.  For these reasons, it is
unclear how the insecticidal mode of action relates to human health. 
Nonetheless, the available toxicological database provides adequate
information to characterize potential hazards/effects.

Flonicamid has low acute toxicity being classified as Category III for
acute oral toxicity and Category IV for dermal, inhalation, eye and skin
irritation toxicities.  Flonicamid metabolites TFNA, TFNA-AM, TFNG,
TFNG-AM, and TFNA-OH, likewise are classified as Category III for acute
oral toxicity.  Flonicamid is not a dermal sensitizer.  In the 28-day
dermal study no dermal or systemic toxicity was seen at the limit dose
(1000 mg/kg/day) for flonicamid technical.

The oral studies in rats and dogs indicate the kidney and liver are the
target organs for flonicamid toxicity.  Kidney weight increases and
kidney hyaline deposition and liver centrilobular hypertrophy effects
were seen in the rat 28-day oral range-finding study, 90-day oral study,
developmental study and reproductive study.  These effects were not
observed in the rabbit developmental study.  The 90-day dog study showed
kidney tubular vacuolation, as well as increased adrenal weights,
increased reticulocytes and decreased thymus weights.  Increase
reticulocyte was noted in both the subchronic and chronic dog studies.

Developmental effects (increased incidence of cervical ribs in
fetuses/litters) were only observed in the rat at high doses. 
Furthermore, developmental and reproductive effects only occurred at
maternally toxic doses.  Thus, susceptibility issues are not of concern
for flonicamid.  Further, only high dose effects were noted in the acute
and subchronic neurotoxicity studies and there are no concerns for
neurotoxicity from other studies.

Mutagenicity studies were negative for the parent chemical, flonicamid,
and its metabolites TFNA, TFNA-AM, TFNG, TFNG-AM, and TFNA-OH. 
Flonicamid is carcinogenic in CD-1 mice, based on increased incidences
of lung tumors associated with Clara cell activation, the effects,
however, are associated with species and strain sensitivity.  Nasal
cavity tumors in male Wistar rats were linked toincisor inflammation:
data were not sufficient to make a similar determination in female rats.
 The determination of carcinogenicity potential was made by the Cancer
Assessment Review Committee on January 5, 2005 for flonicamid based on
the weight of the evidence approach and resulted in the classification
“suggestive evidence of carcinogenicity, but not sufficient to assess
human carcinogenic potential.”   The acute toxicity and toxicology
profile of technical flonicamid are presented in the appendix (A1.0 and
A2.0).

3.1.1  	Adequacy of the Toxicity Data Base

The database contains acute and subchronic neurotoxicity studies, a
2-generation reproduction study, and developmental toxicity studies in
rats and rabbits.  For registration purposes, the subchronic
neurotoxicity, the 2-generation, and the developmental studies provide
an adequate database. 

3.1.2  	Evidence of Neurotoxicity

For additional information on the neurotoxicity and endpoint selection,
view the previous HED human-health risk assessment for the use of
flonicamid (Flonicamid Human Health Risk Assessment for Proposed Uses on
Cotton, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables, Pome
Fruit, Stone Fruit, Potatoes, and Nursery and Landscape Ornamentals. J.
Arthur, 5/25/2005, DP Barcode: D289592).

Neurotoxicity issues were adequately addressed in the subchronic
neurotoxicity study.  Except where noted below for the acute
neurotoxicty study, definitive neurotoxicity effects were not seen in
the other studies, thus no additional studies are required at this time.
 At high doses, 1000 mg/kg for the acute study and beginning at 625
mg/kg/day for the subchronic study, neurotoxicity was observed in the
form of decreased motor activity in both the acute and subchronic
neurotoxicity studies in rats.  Tremors, impaired respiration, and
impaired gait were also observed in the acute neurotoxicity study at the
high dose.  However, the effects observed in both the acute and
subchronic neurotoxicity studies are of low concern because: 

The effects only occurred in the high doses tested;  

The high doses tested were higher than those levels chosen as endpoints
for regulation;

The highest dose tested for the acute neurotoxicity study was also the
limit dose at which mortality was observed. 

3.1.3  	Developmental Toxicity Studies

In the rat developmental study maternal and development effects were
noted.  No developmental effects were observed in the rabbit study.  

Executive summary of rat developmental study:

Reference: Hojo, H. (2002) IKI-220 Technical: A teratogenicity study in
rats. The Institute of Environmental Toxicology, Uchimoriya-machi 4321,
Misukaido-shi, Ibaraki 303-0043, Japan.  Document No. IET 00-0023,
February 21, 2002.  MRID 45656724.  Unpublished.

EXECUTIVE SUMMARY: 	In a developmental toxicity study (MRID 45656724)
IKI-220 technical (98.7% a.i., lot# 9809) was administered to 24
Jcl:Wistar rats/dose by gavage at dose levels of 0, 20, 100 or 500 mg/kg
bw/day from days 6 through 19 of gestation. 

In the 500 mg/kg group, mean food consumption was slightly lower than
that in the control group during gestation days 6-9, although the
decrease was not statistically significant.  In this dose group,
maternal pathological observations also revealed a significant increase
in liver weights, hypertrophy of centrilobular hepatocytes in the liver
and vacuolation of the proximal tubular cell in the kidneys.  The
maternal LOAEL is 500 mg/kg bw/day, based on increased liver weight, and
liver and kidney pathological changes.  The maternal NOAEL is 100 mg/kg
bw/day. 

A variety of malformations were observed in the control and treated
groups.  The incidence of cervical rib was significantly increased in
fetuses/litters in the 500 mg/kg group (60/23) when compared to controls
(10/7).  The developmental LOAEL is 500 mg/kg bw/day, based on the
increased incidence of cervical rib.  The developmental NOAEL is 100
mg/kg bw/day.

The developmental toxicity study in the rat is classified
Acceptable/Guideline; and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

Executive summary of rabbit developmental study:

Reference: Takahashi, K.  (2002) IKI-220 technical:  a teratogenicity
study in rabbits.  The Institute of Environmental Toxicology,
Misukaido-shi, Ibaraki, Japan.  Laboratory Project ID:  IET 00-0025,
February 19, 2002 (amended November 28, 2002).  MRID 45854611. 
Unpublished.

EXECUTIVE SUMMARY: 	In a developmental toxicity study (MRID 45854611),
IKI-220 (Flonicamid; Lot/Batch # 9809, 98.7% a.i.) in 1.0% (w/v) aqueous
sodium carboxymethylcellulose was administered daily by oral gavage. 
The dose volume of 5 mL/kg body weight was administered to 25 female
Japanese White (Kbl:JW) rabbits/group on gestation days (GD) 6 through
27 at dose levels of 0, 2.5, 7.5, or 25 mg/kg.  Animals from all dose
groups were sacrificed on GD 28; their fetuses were removed by cesarean
section and examined.

No effects of treatment were observed on maternal survival, clinical
signs, or gross pathology.

In the 25 mg/kg females, a statistically significant consistent decrease
in body weight gain was observed from GD 6-12 (decrease 405%) that
presented to termination, GD 6-28 (decrease 83%).  Food consumption was
decreased generally throughout treatment, with significant decreases
occurring on GD 9-21 (decrease 19%) to GD 18-21 (26-44%).

The maternal LOAEL is 25 mg/kg, based on decreased body weight gains
(405% at GD 6-12) and food consumption.  The maternal NOAEL is 7.5
mg/kg/day.

No effects of treatment were noted on numbers of litters, live fetuses,
dead fetuses, resorptions (early, late, or complete litter), fetal body
weight, placental weight, sex ratio, or post-implantation loss.

No effects of treatment on external, visceral, or skeletal malformations
were observed.

No effects of treatment on fetal growth were observed.

The developmental LOAEL is not established.  The developmental NOAEL is
greater than or equal to 25 mg/kg/day. 

This study is classified as acceptable/guideline (OPPTS 870.3700b) and
satisfies the requirements for a developmental study in the rabbit.

3.1.4  	Reproductive Toxicity Studies

Parental and offspring toxicity were observed in the two-generation
reproduction study in rats.  The LOAEL for reproductive performance was
not observed. 

Executive summary of rat reproductive study:

Reference: Takahashi, K. (2002) IKI–220 Technical: reproductive
toxicity study in rats.  The Institute of Environmental Toxicology,
Misukaido-shi, Ibaraki, Japan.  Laboratory Document No.: IET 99-0085,
December 12, 2002.  MRID 45854613.  Unpublished.

Takahashi, K. (2002) IKI–220 Technical: reproductive toxicity study in
rats: preliminary study (amended report).  The Institute of
Environmental Toxicology, Misukaido-shi, Ibaraki, Japan.  Laboratory
Document No.: IET 99-0084, February 25, 2002 (final report amended
December 26, 2002).  MRID 45854612.  Unpublished.

EXECUTIVE SUMMARY: 	In a two-generation reproduction toxicity study
(MRIDs 45854613 and 45854612), IKI-220 technical (Flonicamid; 98.7%
a.i.; Lot #9809) was administered continuously in the diet to Jcl:Wistar
rats (24/sex/dose) at nominal dose levels of 0, 50, 300, or 1800 ppm
(equivalent to 0/0, 3.7/4.4, 22.3/26.5, and 132.9/153.4 mg/kg bw/day
[M/F]).  The P animals were given test article diet formulations for 10
weeks prior to mating to produce the F1 litters.  After weaning, F1
animals (24/sex/dose) were selected to become the parents of the F2
generation and were given the same concentration test formulation as
their parents.  F1 animals were given test formulations for 10 weeks
prior to mating to produce the F2 litters.  In addition to the typical
parameters examined in a reproductive toxicity study, serum
concentrations of follicle stimulating hormone (FSH), luteinizing
hormone (LH), testosterone (males), 17β-estradiol, and progesterone
(females) were measured in the F1 parents using a radioimmunoassay
method.  In a supplemental in vitro study (IET 01-8008) reported in MRID
45854613, Flonicamid technical solutions were serially diluted (ranging
from 10-2 M to 10-9 M), and estrogen receptor (ER) binding assays were
conducted in triplicate analyses per concentration.

There were no effects of treatment on parental survival, clinical signs,
body weights, body weight gains, or food consumption.  Treatment-related
findings were restricted to the kidneys.

At ( 300 ppm, relative (to body) kidney weights were increased in the F1
males (incr. 4-20%; p ( 0.05).  Increased (p ( 0.001) incidences of
hyaline droplet deposition were observed in the proximal tubule cells in
the males of both generations (23-24/24 treated vs 0/24 each control
group).  In the F1 parental females, blood serum levels of LH were
increased by 31-50% (p ( 0.05).  

of 17-β estradiol were decreased by 27% (not significant).  No
treatment-related findings were noted at 50 ppm.

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

There were no effects of treatment on offspring body weights, anogenital
distance, gross pathology, or on birth, live birth, viability, or
lactation indices.  Treatment-related findings were restricted to the
kidneys.

At 1800 ppm, the time until vaginal opening was increased (incr. 5%; p (
0.01) in the F1 pups (34.1 days) compared to controls (32.6 days). 
However, there were no effects of treatment on the time to vaginal
opening or the body weight at vaginal opening in the F2 pups.  Absolute
and relative (to body) uterus weights were decreased (decr. 19%; p (
0.05) in the F1 weanlings sacrificed at 25-27 days old.  However, no
macroscopic findings in the F1 or F2 pups or weanlings could be
attributed to treatment, and microscopic examinations were not
performed.

        

No treatment-related findings were noted at 50 or 300 ppm.

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

There were no effects of treatment on: (i) precoital or gestation
intervals; (ii) mating, fertility, or gestation indices; (iii) estrous
cycle duration or cyclicity; (iv) sperm enumeration, motility, or
morphology; or (v) the number of primordial ovarian follicles.

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

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

3.1.5  	Additional Information from Literature Sources

There is no additional information from literature sources.

3.1.6  	Pre-and/or Postnatal Toxicity

3.1.6.1	Determination of Susceptibility

There was no evidence for quantitative or qualitative susceptibility
following oral or dermal exposures to rats in utero or oral exposure to
rabbits in utero.

Following oral exposures to rats, developmental effects were seen only
in the presence of maternal toxicity.  No developmental effects were
seen in rabbits.

3.1.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility

The degree of concern for pre and/or post-natal susceptibility is low
due to the lack of evidence of qualitative and quantitative
susceptibility.  This is because developmental effects were only seen in
one species, only at the maternally toxic dose, and offspring effects
were not more severe maternally toxic effects.  Thus, neither
qualitative nor quantitative susceptibility issues are of concern for
flonicamid.  The database for required developmental and reproductive
studies is complete and there are no residual uncertainties.

The FQPA Safety Factor should be reduced to 1X because the lack of
susceptibility evidence in the developmental studies and reproductive
study.  The effects seen in offspring were mild and occurred only in one
species.

3.1.7 	Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study is not required at this time. In
both the acute and subchronic neurotoxicity studies, neurotoxicity
effects were only seen at the high doses (HDT= 1000 mg/kg in the acute
and 67/722 mg/kg/day (male/female) in the subchronic).  Observed general
overt toxicity was substantiated by mortality in the acute neurotoxicity
study and by decreases in body weight and body weight gain, along with
reduced food consumption in the subchronic neurotoxicity study.  Thus, a
DNT study is not required considering the following:

Neurotoxicity was observed at or near the limit dose;

Mortality was also observed at the limit dose that showed neurotoxicity,
therefore indicating general lethality effects;

There is no concern for susceptibility of developing young indicated
from the 2-generation reproduction rat, and the developmental rat and
rabbit studies’ conclusions;

Systemic toxicity is observed at considerably lower doses compared to
where neurotoxicity signs were observed at high doses; and 

Neurotoxic signs were observed in other studies where toxicity was
observed (note especially, not in the 90-Day rat study that used lower
dosing than the neurotoxicity studies).

3.2	Description of Rat Metabolism

The metabolic profile of flonicamid in rats was determined from the 0-48
hour interval rat urine after single dose administration of [14C]-
pyridyl-flonicamid by oral gavage in male and female Sprague-Dawley rats
at levels of 2 or 400 mg/kg body weight. Flonicamid was the major
component in male and female rats with 52-72% of administered dose (AD)
and the major metabolite is TFNA-AM, with 18-25% of AD.  Minor
metabolites identified were: TFNA-AM N-oxide (3% of AD), Flonicamid
N-oxide (2% of AD), TFNG-AM (1% of AD), TFNA conjugate (0.52% of AD),
OH-TFNA-AM (0.44% of AD), TFNA (0.36% of AD), and TFNA-AM N-Oxide
conjugates (0.30% of AD).  TFNG was not detected in the urine.  Analysis
of flonicamid rat metabolism for repeated dosing gave the following
results: Flonicamid (46-54% of AD) and TFNA-AM (21-27% AD) were the
major components found in rat urine following multiple low doses of
[14C]- pyridyl-flonicamid.  

In liver samples, the major components in male rat liver following 0.5
and 6 hours were flonicamid (51% and 27% total radioactive residues
(TRR), respectively) and TFNG (24% and 8% of TRR, respectively). 
TFNA-AM was 10% of TRR after 0.5 hours and 45% after 6 hours.  In the
rat biliary study, flonicamid was rapidly absorbed and excreted in the
urine within 24 hours.				

As in plants and livestock,  the metabolic pathway of flonicamid in rats
involves hydrolysis of the cyano (-CN) and amide (-CONH2) functional
groups in the flonicamid molecule, although in rats, flonicamid was
further metabolized by several routes, including N-oxidation and
hydroxylation of the pyridine ring, leading to multiple metabolites.

3.3	FQPA Safety Factor 

Based on the hazard data, the Health Effects Division (Flonicamid Human
Health Risk Assessment for Proposed Uses on Cotton, Cucurbit Vegetables,
Fruiting Vegetables, Leafy Vegetables, Pome Fruit, Stone Fruit,
Potatoes, and Nursery and Landscape Ornamentals. J. Arthur, 5/25/2005,
DP Barcode: D289592) recommended the FQPA safety factor (SF) be reduced
to 1x because there are no concerns and no residual uncertainties with
regard to susceptibility with pre- and/or postnatal toxicity.  The
flonicamid risk assessment team evaluated the quality of the exposure
data; and, based on these data, recommended that the FQPA SF be reduced
to 1x.  The recommendation is based on the following:

The dietary food exposure assessment utilizes proposed tolerance level
or higher residues and 100% CT information for all commodities.  By
using these screening-level assessments, chronic exposures/risks will
not be underestimated.	

The dietary drinking water assessment (Tier 1 estimates) utilizes values
generated by model and associated modeling parameters which are designed
to provide conservative, health protective, high-end estimates of water
concentrations.

The potential for residential exposure is negligible.

3.4 	Hazard Identification and Toxicity Endpoint Selection

3.4.1 	Acute Reference Dose (aRfD) - No acute reference dose was
identified for flomicamid.

No acute toxicity endpoint was identified.  There was no endpoint noted
in the database from a single dose exposure suitable for risk
assessment.  Endpoints from the acute neurotoxicity and developmental
toxicity studies, as well as from other short- and long-term studies,
were not appropriate for assessing acute dietary risk.  Body weight
decreases were considered inappropriate for an acute endpoint since in
these studies they occur later than the acute time interval.  The
vomiting observed in the acute and subchronic dog studies occurred
without manifestations of any other acute clinical signs or related
pathology; thus, acute clinical effects seen the in the dog studies were
considered unsuitable for establishing an acute endpoint.  The acute
neurotoxicity study was also appropriate for setting an acute endpoint
for the general population since the effects observed only occurred in
the highest doses tested in the presence of mortality; therefore; the
neurotoxicity signs were probably part of the death response. 
Furthermore, the acute neurotoxicity study did not have all the required
observations.  The effects observed in the developmental studies were
not attributable to an acute response; therefore, the developmental
studies were not used for an acute endpoint for females of reproductive
age.  For all of these reasons, the toxicity database does not support
the selection of an acute dietary endpoint. 

3.4.2 	Chronic Reference Dose (cRfD)

Study Selected: 2-generation reproduction

MRID No.: 45854613

Executive Summary: See Section 3.4.4

Dose and Endpoint for Establishing cRfD: The 2-generation reproduction
toxicity rat study is chosen for the cRfD based on increased kidney
weights and hyaline depositions, and increased blood serum level of LH
(F1 females) at a parental LOAEL of 22 mg/kg/day with a NOAEL of 3.7
mg/kg/day.

Comment about Study/ Endpoint/ Uncertainty Factors: This study is
justified because observations on the kidney are consistent with effects
seen in other studies where there is evidence of kidney toxicity (rat
28-day, rat chronic, rat developmental, and dog 90-Day toxicity
studies); the kidney is considered as the target organ. 

This study is the appropriate route and length for the endpoint.

The Uncertainty Factor (UF) is: 100X (10X for interspecies extrapolation
and 10X for intraspecies variations).

Chronic RfD  =         3.7 mg/kg/day (NOAEL)    = 0.04	 mg/kg/day

			        100 (UF)

3.4.3 	Incidental Oral Exposure

There are no existing or proposed residential uses that would result in
incidental oral exposure; therefore, an endpoint for risk assessment was
not selected. 

3.4.4 	Dermal Absorption

No dermal absorption studies are available.  A dermal absorption factor
of 3.6% was calculated by comparing the LOAEL of 36 mg/kg/day from the
28-day oral range finding study in the rat and an upper bound value of
1000 mg/kg/day from a 28-day dermal toxicity study in the rat.  In the
oral toxicity studies in rats and dogs the LOAELs are based on kidney
toxicity after 28 days/13 weeks.  The kidney appears to be the target
organ for flonicamid.  Evaluation of the kidneys did not reveal any
treatment-related effects following dermal exposure.  Therefore, it is
appropriate to use the NOAEL of 1000 mg/kg/day as the upper bound value
to calculate the dermal absorption factor.

3.4.5	Dermal Exposure (Short- and Intermediate-Term)

No short-term or intermediate-term systemic dermal endpoint was
identified for risk assessment. The 28-day dermal study did not show any
dermal or systemic effects at the limit dose of 1000 mg/kg/day.  There
is not a concern for neurotoxicity, nor any concern for developmental
susceptibility issues.

In a previous risk assessment, long-term exposure was expected from the
use of flonicamid in greenhouses.  However, in the current assessment no
long-term dermal exposure is expected; therefore, an endpoint for
long-term dermal exposure was not selected. 

3.4.6 	Inhalation Exposure (Short- and Intermediate-Term)

The subchronic study in rats (MRID 456567-21) is chosen for short- (1 to
30 days) and intermediate-term (1 to 6 months) inhalation exposure.  No
long-term (> 6 months) inhalation endpoint was selected because
long-term exposure is not expected.  In the absence of a repeated
exposure inhalation study, an oral dose was selected.  Absorption via
inhalation is presumed to be equivalent to oral absorption (inhalation
absorption rate = 100%).  Confidence in the study is high.  The study
covers the appropriate durations and has effects seen in other studies
in the database for flonicamid.

For the executive summary of subchronic rat toxicity study, please
reference:  Flonicamid Human Health Risk Assessment for Proposed Uses on
Cotton, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables, Pome
Fruit, Stone Fruit, Potatoes, and Nursery and Landscape Ornamentals. J.
Arthur, 5/25/2005, DP Barcode: D289592.

3.4.7   Level of Concern for Margin of Exposure

A dermal toxicity endpoint was not identified, and therefore dermal
exposure/risk is not assessed for handlers.

Table 3.4.7.   Summary of Target Margins of Exposure (MOEs) for Risk
Assessment

Route

                                    		

Short-Term

(1-30 Days)	

Intermediate-Term

(1 - 6 Months)	

 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	

-	

-	

-

Inhalation	

100	

100	

-

The MOE is based on the conventional uncertainty factor of 100X (10X for
intraspecies extrapolation and 10X for interspecies variation).

3.4.8 	Recommendation for Aggregate Exposure Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal, and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows: short-, intermediate- and long-term exposures (incidental oral,
dermal, and inhalation exposure) can be aggregated because of the use of
a common endpoint for oral, dermal (oral equivalent) and inhalation
(oral equivalent) routes of exposure.

  

3.4.9	Classification of Carcinogenic Potential

In accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (July 1999), the Cancer Assessment Review Committee (CARC)
classified Flonicamid as “Suggestive Evidence of Carcinogenicity, but
Not Sufficient to Assess Human Carcinogenic Potential,” and
recommended that quantification of human cancer risk not be performed. 
This classification was based on the following weight-of-the-evidence
considerations:	

a)	Flonicamid is not mutagenic.

b)	The treatment-related CD-1 mouse lung tumors (benign and malignant)
which occurred in both sexes were due to an established mitogenic mode
of action that occurred in a susceptible mouse strain with a high
background tumor rate.  A clear species difference was observed between
mice and rats in the incidence of lung tumors and the BrdU Index
studies.  No tumors were seen in the lungs of rats.  The flonicamid
induced increase in the BrdU Index appears to be related to the
different sensitivity of strains of mice, with the CD-1 mice being a
relatively sensitive strain.

c)	The only other tumor response was nasolacrimal duct tumors in female
rats at the high dose which were considered to be possibly
treatment-related, but a clear association with treatment could not be
made.  Unlike male rats, the nasal tumor response in females could not
be clearly associated with spontaneous inflammation due to the low
incidence of both the neoplastic and non-neoplastic lesions.

Table 3.4.9 presents a summary of the toxicological doses and endpoints
chosen for flonicamid.

Table 3.4.9.  Summary of Toxicological Dose and Endpoints for Flonicamid
for Use in Dietary and Non-Occupational Human Health Risk Assessments. 

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary	

None	

FQPA SF = NA

aPAD = NA	

There are no acute dietary toxicity concerns.

Chronic Dietary	

NOAEL = 3.7 mg/kg/day

UF = 100

Chronic RfD = 0.04 mg/kg/day	

FQPA SF = 1

aPAD = chronic RfD

              FQPA SF

= 0.04 mg/kg/day	

2-Gen  Reproduction rat 

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

Incidental Oral (All time intervals)	

None	

Residential LOC for MOE = NA 	

Quantitative risk assessment is not required since incidental oral
exposure is not expected based on use pattern. 

Short-Term Dermal (1 to 30 days)	

None	

Residential LOC for MOE = NA

Occupational LOC for MOE = NA 	

Quantitative risk assessment is not required since the 28-day dermal
study did not show any dermal or systemic effects at the limit dose of
1000 mg/kg/day.

Intermediate-Term

Dermal (1 to 6 months)	

None	

Residential LOC for MOE = NA 

Occupational LOC for MOE = NA 	

Quantitative risk assessment is not required since the 28-day dermal
study did not show any dermal or systemic effects at the limit dose of
1000 mg/kg/day.

Long-Term Dermal (>6 months)

	

None	

Residential LOC for MOE = NA

Occupational LOC for MOE = NA 	

Quantitative risk assessment is not required since no long-term exposure
is expected in this assessment

Short-Term Inhalation (1 to 30 days)

	

Oral NOAEL = 12 mg/kg/day

(inhalation absorption rate = 100%)	

Residential LOC for MOE = NA 

Occupational LOC for MOE = 100 	

90-Day oral rat

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

Intermediate-Term Inhalation (1 to 6 months)

	

Oral NOAEL = 12 mg/kg/day

(inhalation absorption rate = 100%)	

Residential LOC for MOE = NA 

Occupational LOC for MOE = 100 	

90-Day oral rat

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

Long-Term Inhalation (>6 months)	

None	

Residential or  Occupational LOC for MOE = NA 	

Quantitative risk assessment is not required since no long-term exposure
is expected in this assessment

Cancer	

Suggestive Evidence of Carcinogenic Potential

UF = uncertainty factor, FQPA SF =  FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

3.5	Endocrine Disruption tc \l2 "4.6	Endocrine disruption 

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).  When additional
appropriate screening and/or testing protocols being considered under
the Agency’s EDSP have been developed, flonicamid may be subjected to
further screening and/or testing to better characterize effects related
to endocrine disruption.

4.0	Public Health Data

4.1	Incident Reports tc \l2 "5.1	Incident Reports 

There are no incident reports currently for flonicamid.  The flonicamid
registrations for greenhouse ornamentals and interiorscapes were
established in 2003 and for agricultural food crops in 2006.  These uses
were just recently approved.

5.0  	Dietary Exposure/ Risk Characterization 

 tc \l1 "6.0  	Exposure Characterization/Assessment 

5.1 	Pesticide Metabolism and Environmental Degradation

Metabolism in Primary Crops

Reference: PP#6E7081.  Flonicamid. Petition for the Establishment of
Permanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. 
Summary of the Analytical Chemistry and Residue Data. Amelia Acierto. 
11/16/07. D332316, PC Code 128016.

Adequate plant metabolism studies are available reflecting the
application of [14C]- pyridyl-flonicamid as foliar application to
potato, peach and wheat.  The residues of concern in plants for
tolerance and risk assessment are flonicamid and its metabolites
TFNA-AM, TFNA, and TFNG.

The metabolic profile of flonicamid in crops was determined in potato,
peach and wheat using radiolabelled test substance, [14C]-
pyridyl-flonicamid.  In potato, the test substance was applied as two
foliar broadcast sprays to potato plants at a rate equivalent to 0.089
lb ai/A/application (1x) and at 0.446 lb ai/A/application (5x).  Mature
potato tubers and foliage were harvested 14 days following the last
application.  In the low rate treatment, flonicamid (5.6% TRR) was
identified as a minor component, TFNG and TFNA were the major identified
residues accounting for 39.3% TRR and 34.4% TRR, respectively.  In the
high rate treatment, the parent, TFNG and TFNA were the major residues
which accounted for 19.3% TRR, 25.1% TRR, and 33.7% TRR, respectively. 
A similar pattern was observed in potato foliage from the low and high
treatment.  Metabolites TFNG-AM and TFNA were identified as minor
components, each at <1.5% TRR in tubers and <8% TRR in foliage.



In peach, the test substance was also applied as two foliar broadcast
sprays to peach trees at a rate equivalent to 0.091 lb ai/A/application
(1x) and at 0.428 -0.435 lb ai/A/application (5x).  Mature peach fruits
and leaves were harvested 21 days following the last application. In the
low-rate treatment, flonicamid and TFNA were identified in the fruit as
major components (30.1 %TRR and 49.3% TRR, respectively).  In the high
rate treatment, flonicamid accounted for most of the radioactivity
(60.75% TRR) and TFNA accounted for 17.5% TRR.  TFNG, TFNG-AM and
TFNA-AM were identified as minor metabolites in peach fruits, each
present at <5.9% TRR from the low treatment and < 4.3% TRR in the high
treatment rate.  In leaves, from the low rate treatment, flonicamid,
TFNA and TFNG were identified at 32.9% TRR, 15.8% TRR and 19.3% TRR,
respectively.  In the high rate treatment, flonicamid accounted for
64.9% TRR, TFNA and TFNG accounted for 5.3% TRR and 8.5% TRR,
respectively.  TFNG-AM, TFNA-AM were also identified as minor components
in leaves (< 4.1% TRR).  The parent, flonicamid was a major (40- 73%
TRR) component identified in all matrices.

In wheat, the metabolic profile of flonicamid was determined in mature
and immature wheat.  For the mature wheat, the test substance was
applied as a single foliar broadcast spray to wheat plants at the soft
dough stage at 0.089 lb ai/A/application (1x) and 0.446 lb
ai/A/application (5x). The straw, chaff, and grain were harvested 21
days following the application.  In the immature wheat study, the
radiolabeled test substance was applied to the wheat plants at various
growth stages. Immature forage was harvested 14 days following a single
application at 0.089 lb ai/A (made 35 days after planting), immature hay
was harvested 7 days following treatment (made 71 days after planting). 
The parent flonicamid was a major component in straw (50.6% TRR), in
chaff (41.7% TRR) and in grain (29.9% TRR).  TFNG was also a major
residue in straw (20.2% TRR), in chaff (18.7% TRR), and grain (40.1%
TRR). Metabolites TFNA, TFNG-AM, and TFNA-AM were identified as minor
metabolites (< 8.2% TRR each) in straw, chaff and grain.  N-oxide of
TFNA-AM was identified as minor residue in grain only.  N-oxide TFNG was
tentatively identified in wheat grain (3.1% TRR) together with TFNG-AM. 
In the immature wheat, the major components identified were flonicamid
(42.8% TRR in forage, and 21.7% TRR in hay) and TFNG (32.7% TRR in
forage and 52.6% TRR in hay). TFNG-AM was also identified in forage
(11.0% TRR) and hay (13.1% TRR).  TFNA and TFNA-AM were identified as
minor residues, each at <6.5% TRR in forage and hay.  In addition, the
N-oxide of flonicamid and an unstable conjugate of TFNA were tentatively
identified as minor metabolites (<1% TRR) in forage only.

Based on the plant metabolism studies, the major metabolic pathway of
flonicamid in plants involves hydrolysis of the cyano (-CN) and amide
(-CONH2) functional groups in the molecule.    

Metabolism in Confined and Rotational Crops

Reference: PP#6E7081.  Flonicamid. Petition for the Establishment of
Permanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. 
Summary of the Analytical Chemistry and Residue Data. Amelia Acierto. 
11/16/07. D332316, PC Code 128016.

Confined and field rotational crop data indicate that a 30-day plantback
interval is appropriate for all crops not listed on the label.  The
radiolabeled test substance, [pyridyl-14C]flonicamid, was formulated as
a WG formulation and applied twice to bare loamy sand soil in planting
containers at 0.089 lb ai/A/application for a total rate of 0.179 lb
ai/A.  Rotational carrot, lettuce, and wheat were planted at plantback
intervals (PBIs) of 30, 120, and 361 days.  HED has determined that no
residues other than flonicamid and its metabolites TFNA-AM, TFNA, and
TFNG are of concern in rotational crops.  

An adequate limited field rotational crop study was conducted on the
representative crops turnips and wheat; leafy vegetables were not
included in the limited field trial study because low residues (<0.01
ppm) were observed in lettuce from the confined rotational crop study. 
A total of six field rotational crop trials (two turnip and four wheat
trials) were conducted at five field sites in cotton growing regions: AR
(Region 4), CA (Region 10), OK (Region 6), SC (Region 2), and TX (Region
8).  At each trial site, a primary cover crop of cotton received three
broadcast foliar applications of a 50% WG formulation at ~0.089 lb
ai/A/application for total seasonal rates of ~0.267 lb ai/A (1x the
proposed maximum seasonal rate).  Cotton was harvested 29-30 days after
the last application, the soil was disced or cultivated, and rotational
crops (turnips and wheat) were planted 30-32 and 58-63 days after the
last application and grown to maturity.  

Individual residues of flonicamid and its metabolites TFNA-AM, TFNA, and
TFNG were each below the method LOQ (<0.01 ppm for turnip roots and tops
and wheat forage and grain; <0.02 ppm for wheat straw) in all samples of
rotational crop commodities from both PBIs.

Although the harvest and analysis of wheat hay samples was not included
in the limited field rotational crop study, HED concluded that these
data would not be required because residues were not quantifiable in
wheat forage and straw.  The results of the limited field rotational
crop studies indicate that rotational crop tolerances are not required,
and that the proposed 30-day plantback interval, for all crops not
listed on the label, is appropriate.  

Metabolism in Livestock

Reference: PP#6E7081.  Flonicamid. Petition for the Establishment of
Permanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. 
Summary of Analytical Chemistry and Residue Data. Amelia Acierto. 
11/16/07. D332316, PC Code 128016.

The nature of flonicamid residues in livestock is adequately understood
based on an acceptable goat and hen metabolism studies.  The residues of
concern in livestock commodities for the tolerance expression and risk
assessment were determined to be flonicamid, TFNA and TFNA-AM. 

The metabolism of flonicamid was investigated in livestock using
lactating goats and laying hens.  The test substance was [14C]
flonicamid (labeled at the 3 position of the pyridine ring; specific
activity 100,000 dpm/µg).  In goats, the test substance was
administered orally at 10 ppm (4.2x) in the diet for five consecutive
days. Milk was collected twice daily throughout the study, and tissues
(liver, kidney, muscle, and fat) were collected at sacrifice.  In hens,
the test substance was also administered orally at 10 ppm (25x) in the
diet for five consecutive days.  Eggs were collected twice daily
throughout the study, and tissues (liver, muscle, skin, and fat) were
collected at sacrifice.	

The available data indicate that the metabolism of flonicamid is similar
in goats and hens. The majority of the dose was rapidly excreted. 
TFNA-AM (4-trifluoromethylnicotinamide) was the major metabolite (29-92%
TRR) in goats (tissues and milk) and in laying hens (tissues and eggs).
Flonicamid was found in minor quantities in goat and hen matrices, at
<6% TRR.  TFNA-AM was also identified in goat muscle, liver, and kidney
in significant quantities (23-31% TRR) in the acid hydrolysates of
nonextractable residues.  A metabolite determined to be an unstable
conjugate of TFNA was identified in goat kidney at 12% TRR and the
metabolite OH-TFNA-AM was identified in liver acid hydrolysate at 11%
TRR.  The metabolism of flonicamid in livestock shows the main pathway
of metabolism involves hydrolysis of the cyano and amide functional
groups in the molecule, identical to the plant metabolism.

Analytical Methodology

Reference: PP#6E7081.  Flonicamid. Petition for the Establishment of
Permanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. 
Summary of the Analytical Chemistry and Residue Data. Amelia Acierto. 
11/16/07. D332316, PC Code 128016.

Adequate LC/MS/MS methods are available for both collecting and
enforcing tolerances for flonicamid and the major metabolites TFNA-AM,
TFNA, and TFNG in plants (FMC No. P-3561M).   The method has been
adequately validated by an independent laboratory in conjunction with a
previous petition.  A revised version (FMC No. P-3822) has been recently
submitted (DP Nos: 329381 and 379663) in response to the conditional
requirements for the earlier petition (PP#3F6552).  The amended method
includes instructions for the determination of residues of flonicamid,
TFNA, TFNA-AM, and TFNG in/on Brassica leafy vegetables, cotton hulls,
cotton gin byproducts, cotton meal, cotton refined oil, cotton seed,
cucurbits, fruiting vegetables, leafy vegetables, pome fruits, potato
chips, potato flakes, potato tuber, potato wet peel, stone fruits,
turnip roots, turnip tops, wheat forage, wheat germ, wheat grain, wheat
middlings, and wheat straw.  The validated limits of quantitation (LOQs)
for each analyte are 0.025 ppm for Brassica leafy vegetables, 0.02 ppm
for wheat straw and cotton matrices, 0.02 ppm for apple and 0.01 ppm for
all other crop commodities.  

For enforcement of tolerances for livestock commodities, three methods
are available:  LC/MS/MS method (RCC No. 844743) for residues in eggs
and livestock tissues; LC/MS method (RCC No. 842993) for residues in
milk; and LC/MS/MS method (FMC P3580) which includes an acid hydrolysis
step for residues in cattle muscle, kidney, and liver.  The validated
LOQs are 0.01 ppm for methods RCC Nos. 844743 and 842993, and 0.025 ppm
for method FMC P3580.  

The EPA Analytical Chemistry Branch (ACB/BEAD, Fort Meade, MD) reviewed
the LC/MS/MS method.  For method FMC No. P-3822, homogenized samples,
other than samples of oil, are extracted with acetonitrile (ACN) and
water.  The extracts of oily samples (cotton seed, cotton hulls, cotton
meal, potato chips, and wheat germ) are partitioned with hexane,
discarding the hexane phase.  Samples of oil are mixed with hexane and
partitioned with ACN/water.  Concentrated HCl is added to the extracts
(all samples), and the extracts are cleaned up by C-18 solid-phase
extraction (SPE; wheat straw and middlings samples only) and/or ethyl
acetate partitioning (all samples).  The ethyl acetate phases are
concentrated and redissolved in ACN/water for analysis by LC/MS/MS.  The
validated limits of quantitation (LOQs) for each analyte are 0.025 ppm
for Brassica leafy vegetables, 0.02 ppm for wheat straw and cotton
matrices, 0.02 ppm for apple and 0.01 ppm for all other crop
commodities.  

Adequate multiresidue method data for flonicamid and its metabolites
were submitted previously in conjunction with PP#3F6552.  The compounds
were evaluated using the FDA Multi-Residue Method Test guidelines in PAM
Volume I.  Flonicamid and its metabolites were not found to be naturally
fluorescent; therefore, further testing under Protocol A was not
required.  Flonicamid and TFNA-AM were completely recovered using
Protocol D (with no cleanup) but were not recovered using Protocols E
and F.  TFNA and TFNG were not recovered using Protocols B, D, E, and F.

Pesticide Metabolism and Environmental Degradation

 tc \l2 "6.1	Dietary Exposure/Risk Pathway 

Reference: Drinking Water Assessment for the IR-4 New Uses of Flonicamid
on Brassica, Hops, Tubulars , and Okra, Including The Flonicamid
Degradation Products (TFNG, TFNA, TFNA-OH, TFNA-AM, and TFNG-AM), memo
from Lucy Shanaman, Environmental Risk Branch III, EFED (DP
Barcodes:330894, D331070, and D331027, October 29, 2007).

Under normal environmental conditions, flonicamid degrades into three
major (TFNA, TFNG-AM and TFNA-OH) and two minor (TFNG and TFNA-AM)
degradates.  Under aerobic conditions, flonicamid degrades by hydrolytic
cleavage of the cyano and amide side chains to TFNA and TFNG-AM,
respectively.  TFNA degrades rapidly to TFNA-OH.  TFNG-AM degrades
rapidly to TFNG, which, in turn, degrades mainly to TFNA, with some
intermediary transformation into TFNA-AM.  The half-lives of these
transformation products are less than 1 to 3 days, with almost complete
conversion to carbon dioxide and soil-bound residues within 30 days
under aerobic conditions in soil.  

Under anaerobic conditions, flonicamid degrades by hydrolytic cleavage
of the cyano and amide side chains into TFNA.  TFNA is stable under
anaerobic conditions.  Concentrations of TFNA were at a maximum after
flonicamid was allowed to degrade in soil for one year under anaerobic
conditions.

The flonicamid transformation products, TFNA, TFNG, TFNA-OH, TFNA-AM,
and TFNG-AM, are very mobile in soil, with individual partition
coefficient (Kd) values ranging between 0.00 and 0.2, indicating a
potential for leaching and runoff in the open environment.  Average Kd
values for each degradate ranged from 0.01 to 0.12.  Leaching of all
five identified transformation products is likely to be limited to some
degree due to rapid metabolism when exposed to aerobic conditions in
soil.  However, under anaerobic aquatic conditions, flonicamid and the
only reported anaerobic degradate, TFNA, is persistent and may
accumulate.  Data are not available to evaluate the persistence of the
four remaining aerobic transformation products (TFNG, TFNA-OH, TFNA-AM,
and TFNG-AM) under anaerobic conditions.  

Flonicamid was more persistent under terrestrial field conditions than
under aerobic laboratory conditions.  Terrestrial field dissipation
studies were conducted in four soils (sand, sandy loam, silt loam, and
loamy sand), at four test sites (Washington, California, North Dakota,
and North Carolina).  The first-order half-lives calculated from log
transformed data were 3, 5, and 10 days, respectively. 

5.1.6 	Toxicity Profile of Major Metabolites and Degradates 

Flonicamid and the major metabolites from the rat metabolism study are
similar in their chemical structures.  Flonicamid has been classified as
Category III for acute oral toxicity, as have flonicamid metabolites
TFNA, TFNA-AM, TFNG, TFNG-AM, and TFNA-OH.  Mutagenicity studies were
negative for all of these metabolites.  Based on the structures of
TFNA-AM and TFNA-AM N-oxide (the major metabolites found in rats) and
the observed toxicity in the mutatgenicity and acute studies, HED
concluded that these compounds are likely to be toxicologically similar
to the parent and should be included in the risk assessment.  

5.1.7 	Pesticide Metabolites and Degradations of Concern

Table 5.1.7.  Summary of Metabolites and Degradates included in the
Flonicamid Risk Assessment and Tolerance Expression

Matrix	

Residues included in 

Risk Assessment	

Residues included in 

Tolerance Expression

Plants

	

Primary Crop	

Flonicamid, TFNA, TFNA-AM and TFNG	

Flonicamid, TFNA, TFNA-AM and TFNG

	

Rotational Crop	

Flonicamid, TFNA, TFNA-AM and TFNG	

Flonicamid, TFNA, TFNA-AM and TFNG

Livestock

	

Ruminant	

Flonicamid, TFNA and TFNA-AM 	

Flonicamid, TFNA and TFNA-AM 

	

Poultry	

Flonicamid, TFNA and TFNA-AM 	

Flonicamid, TFNA and TFNA-AM 

Drinking Water

	

Flonicamid, TFNA, TFNG-AM, TFNG, TFNA-OH, TFNA-AM	

Not Applicable

Drinking Water Residue Profile

Reference: Drinking Water Assessment for the IR-4 New Uses of Flonicamid
on Brassica, Hops, Tubulars , and Okra, Including The Flonicamid
Degradation Products (TFNG, TFNA, TFNA-OH, TFNA-AM, and TFNG-AM), memo
from Lucy Shanaman, Environmental Risk Branch III, EFED (DP
Barcodes:330894, D331070, and D331027, October 29, 2007).

The estimated drinking water concentrations from surface water sources
were calculated using Tier II PRZM and EXAMS. PRZM is used to simulate
pesticide transport as a result of runoff and erosion from an
agricultural field and EXAMS estimates environmental fate and transport
of pesticides in surface water.  Simulations were done using the Index
Reservoir scenario in EXAMS, which is a surrogate for a drinking water
source drawn from surface water.  Weather and agricultural practices
were simulated over 30 years so that the 1-in-10 year exceedance
probability at the site can be estimated.  The values generated by the
models for drinking water were adjusted by a national crop area factor
(PCA), which accounts for the fact that it is unlikely for any basin to
be completely planted to agricultural crops. 

Concentrations in ground water were estimated using the Tier I SCI-GROW
model.  Both the acute and chronic estimated concentrations of
flonicamid estimated in ground water using the SCI-GROW (version 2.3)
model at 1.32 x 10-3 µg/L (ppb) for the combined residues.  



The model predictions are based on the maximum seasonal application rate
of 0.267 lb ai/acre (i.e., three applications at 0.089 lb ai/acre with a
14-day interval modeled for parent only, and a 7-day interval for the
combined residues).  Aerial spray applications are simulated for all
surface water scenarios to provide the more conservative drinking water
estimates, as drift from aerial applications result in higher exposure
concentrations in surface water than ground applications. 

EFED used the standard crop scenarios: 1 cabbage scenario, 1 lettuce
scenario, 1 hops scenario, 2 potato scenarios, 1 sweet potato scenario,
and 1 carrot scenario. Each of these seven use scenarios were simulated,
then adjusted for national percent crop area factor (PCA factor = 0.87).
Typically, HED uses the higher of the surface or groundwater estimates
for each duration when assessing dietary risk. The Florida carrot use
estimated the highest acute exposure (PCA adjusted) for the combined
toxic residues at 9.8 ppb (µg/L). The California lettuce and Maine
potato scenario estimated the highest mean chronic annual mean
concentration (PCA adjusted) of 1.5 ppb (µg/L). The highest overall
mean (cancer) concentration of 0.97 ppb (µg/L) was predicted by the
Idaho potato scenario.  Relevant surface and groundwater estimates are
presented in Table 5.1.8 below.

Table 5.1.8.  Estimated Drinking Water Concentrations of Combined
Residues of Flonicamid and Degradation Products, from Surface Water
Sources.

State - Agricultural Commodity	

PCA	

Acute Value

(1-in-10 year  Peak)

ppb	

Chronic Value

(1-in-10 year Annual Mean)

ppb	

Cancer Value

(Overall Annual 

Mean Value)

ppb

FL – cabbage	

0.87	4.4	0.78	0.43

CA- lettuce	

0.87	4.4	1.5	0.90

OR – hops	

0.87	2.1	0.60	0.50

ID – potato	

0.87	3.1	1.0	0.97

ME – potato	

0.87	5.0	1.5	0.82

NC – sweet potato	

0.87	5.1	1.2	0.70

FL – carrot	

0.87	9.8	0.94	0.46

Food Residue Profile

Reference: PP#6E7081.  Flonicamid. Petition for the Establishment of
Permanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting
Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. 
Summary of the Analytical Chemistry and Residue Data. Amelia Acierto. 
11/16/07. D332316, PC Code 128016.

Adequate field trial data are available for root vegetables, except
sugar beet, subgroup 1B (carrot and radish), leafy Brassica greens
subgroup 5B (mustard greens), and hops.  An adequate number of
geographically representative field trials were conducted at 1x the
proposed maximum seasonal rate for each crop.  The crop field trial data
are supported by adequate storage stability data.  

The available field trial data indicate that the proposed tolerance for
the root vegetable subgroup is too low; an increased tolerance of 0.60
ppm is needed.  The proposed tolerances for the leafy Brassica greens
subgroup and dried hops cones are appropriate.  When the tolerance for
leafy Brassica greens is established, the existing tolerance for mustard
greens should be removed, as residues in mustard greens will be covered
by the leafy Brassica greens tolerance.   HED has concluded that a
tolerance for radish tops is not needed for a use on subgroup 1B (root
vegetable, except sugar beet).

The available data for mustard greens are adequate to support the
proposed tolerance for turnip greens.  Adequate field trial data have
been submitted previously for potato to support the requested tolerance
for the tuberous and corm vegetables subgroup, and previously submitted
field trial data for tomato are adequate to support the requested
tolerance for okra.  The proposed tolerances for tuberous and corm
vegetables, okra, and turnip greens are adequate.  When the tolerance
for the tuberous and corm vegetables is established, the existing
tolerance for potato should be removed, as residues in potato will be
covered by the tuberous and corm vegetables tolerance.  

HED does not required data for any processed commodities associated with
crop subgroup 1B, crop subgroup 5B, hops and okra.  Data are required
for the processed commodities of potato and were submitted. The
available data indicate that combined residues of flonicamid, TFNA,
TFNA-AM, and TFNG do not concentrate in potato wet peel, but may
concentrate in potato chips and flakes.  It was concluded that no
tolerance was needed for potato chips, but that a tolerance was needed
for potato flakes/granules at 0.40 ppm; this tolerance has since been
established.  

5.1.10	International Residue Limits

There are currently no established Codex, Canadian, or Mexican MRLs for
flonicamid.  See appendix for the International Residue Limit Status
sheet.



Dietary Exposure and Risk

5.2.1	Acute Dietary Exposure/Risk

An acute dietary riskRfD was not established; therefore an acute dieary
risk assessment was not conducted.  No endpoint attributable to a single
oral dose was identified in the toxicity database.

5.2.2	Chronic Dietary Exposure/Risk tc \l3 "6.1.2	Chronic Dietary
Exposure and Risk 

Reference: PP#6E7081. Flonicamid. Chronic Dietary (Food and Drinking
Water) Exposure and Risk Assessements for an IR-4 Section 3 Registration
Action on Root Vegetables (Except Sugar Beet; Subgroup 1B), Tuberous and
Corm Vegetables (Subgroup 1C), Leafy Brassica Leafy Greens (Subgroup
5B), Radish Tops, Turnip Greens, Hops, Dried Cones, and Okra. Amelia
Acierto.  11/08/07. D343466, PC Code 128016.

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID(, version 2.0), which uses food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  In addition to residues
in/on food items, the assessment also addresses potential residues in
drinking water.  In this analysis, the chronic dietary exposure and risk
estimates resulting from food and drinking water intake were determined
for the general U.S. population and various population subgroups.  The
chronic analysis was conducted to evaluate tolerances in conjunction
with a Section 3 registration for flonicamid in/on vegetable, root crop
(except sugar beet, subgroup 1B), radish, tops, tuberous and corm
vegetable subgroup, Brassica, leafy greens (subgroup 5B), turnip
(greens), hop, dried cones, and okra.  

The conservative chronic dietary exposure assessment was conducted for
all supported flonicamid food uses and incorporated EFED’s drinking
water estimated concentration of 1.5 ppb (1.5 x 10-3 ppm) flonicamid in
drinking water from the proposed uses of California lettuce and Maine
potato scenario estimated the highest mean chronic annual mean
concentration. Typically, HED has concerns regarding dietary risk when
the exposure estimates exceed 100% of the cPAD.  Even with the
conservative assumptions noted above, risk estimates associated with
dietary exposure to flonicamid are significantly below HED’s level of
concern.  The U.S. population and all population subgroups have exposure
and risk estimates that are below HED’s level of concern.  The chronic
dietary (food and drinking water) exposure estimates are 10% cPAD for
the general U.S. population, 15% cPAD for all infants (<1 year old), and
23% cPAD for children 1-2 years old, the most highly exposed population
subgroup.

Table 5.2.2.   Summary of Chronic Dietary (Food and Drinking Water)
Exposure and 

Risk Estimates for Flonicamid

Population Subgroup	

cPAD (mg/kg/day)	

Exposure (mg/kg/day)	

% cPAD

DEEM-FCID	

DEEM-FCID

General U.S. Population	

0.04	

0.004095	10

All Infants (< 1 year old)	

0.04	

0.006087	15

Children 1-2 years old	

0.04	

0.009070	23

Children 3-5 years old	

0.04	

0.007205	18

Children 6-12 years old	

0.04	

0.004483	11

Youth 13-19 years old	

0.04	

0.003280	8

Adults 20-49 years old	

0.04	

0.003513	9

Females 13-49 years old	

0.04	

0.003504	9

Adults 50+ years old	

0.04	

0.003978	10

5.2.3	Cancer Dietary Risk

A cancer dietary assessment is not appropriate because evidence of
flonicamid’s carcinogenicity is only suggestive and not sufficient to
assess human carcinogenic potential.

5.3	Anticipated Residues and Percent Crop Treated (%CT) Information

The residue levels used in the chronic assessment were the established
tolerance levels for plant commodities established under 40 CFR 180.613
and the tolerance levels are based on the crop trials for the proposed
crops.  Also, assumes 100% crop treated.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization tc
\l2 "6.3	Residential (Non-Occupational) Exposure/Risk Pathway 

6.1	Home Uses tc \l3 "6.3.1	Home Uses 

Based upon the product label, HED assumes that the proposed food-use
sites are commercial in nature, and that applications on landscape
ornamentals would only be made by professional pest control operators
(PCOs).  Therefore, residential handler scenarios are not expected and
need not be assessed.  Flonicamid label language should preclude use by
non-professionals (e.g., homeowners), particularly regarding landscape
ornamentals.  Because no dermal toxicity endpoint was identified for
flonicamid, a postapplication residential exposure/risk assessment was
not necessary.	

6.2	 tc \l3 "6.3.2	 Spray Drift tc \l3 "Spray Drift 

Spray drift is a potential source of exposure to residents nearby to
spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for flonicamid. 
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  On
a chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling.  The Agency has completed its evaluation of the
new data base 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 Risk Assessments and Risk Characterization

 tc \l1 "7.0  	Aggregate Risk Assessments and 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
flonicamid, potential exposures from food and drinking water were
considered, and aggregated.  Although acute, short- and
intermediate-term and chronic exposures may occur, acute exposures were
not considered because an appropriate quantitative estimate of hazard
(i.e., an adverse effect attributable to a single dose) was not
identified from the toxicological database to which an acute exposure
estimate could be compared.  Furthermore, evidence of flonicamid’s
carcinogenicity is only suggestive and not sufficient to assess human
carcinogenic potential, and therefore, an aggregate cancer assessment
was not conducted.



7.1	Acute Aggregate Risk tc \l2 "7.1	Acute Aggregate Risk 

An acute dietary riskRfD was not established; therefore an acute
aggregate risk assessment was not conducted.  No endpoint attributable
to a single oral dose was identified in the toxicity database.

7.2	Short-Term Aggregate Risk tc \l2 "7.2	Short-Term Aggregate Risk 

This assessment was not conducted because residential exposure is not
expected from the use pattern proposed in this registration request;
furthermore, appropriate toxicity endpoints were not identified.

7.3	Intermediate-Term Aggregate Risk tc \l2 "7.3	Intermediate-Term
Aggregate Risk 

This assessment was not conducted because residential exposure is not
expected from the use pattern proposed in this registration request,
neither were appropriate toxicity endpoints identified.

7.4	Long-Term (Chronic) Aggregate Risk tc \l2 "7.4	Long-Term (Chronic)
Aggregate Risk 

This assessment was conducted for food and drinking water exposures
only.  There are no expected long-term residential exposures.  Because
drinking water estimates have been combined with dietary exposures, the
dietary assessment described earlier (see Section 5.2.2.) serves as the
aggregate exposure and risk assessment for flonicamid.  Because
aggregated food and drinking water exposures from this conservative Tier
I assessment for the most highly exposed population subgroup (Children
1-2 years old) only amount to 23% of the cPAD, exposure to flonicamid
from the uses subject to this registration action do not exceed HED’s
level of concern.

7.5	Cancer Risk tc \l2 "7.5	Cancer Risk 

This assessment was not deemed necessary because evidence of
flonicamid’s carcinogenicity is only suggestive and not sufficient to
assess human carcinogenic potential.



8.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flonicamid and any other
substances and flonicamid does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that flonicamid has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs on EPA’s
website at http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Pathway tc \l1 "9.0	Occupational
Exposure/Risk Pathway 

Reference: FLONICAMID-Occupational Exposure/Risk Assessment for Proposed
Uses of Flonicamid on Root Vegetables (Crop SubGroup 1B) (Except
Sugarbeet), Tuberous and Corm Vegetables (Crop SubGroup 1C), Brassica
Leafy Green Vegetables (Crop SubGroup 5B), Turnip Greens, Hops and Okra.
 Mark Dow. 10/16/2007. D345362. PC Code 128016

9.1	Short-/Intermediate-Term Handler Risk tc \l2 "9.1
Short-/Intermediate-Term Handler Risk 

Occupational handlers may be exposed to flonicamid during mixing,
loading and application.  Handlers are assumed to have potential
short-term (1-30 days) and intermediate-term (31-180 consecutive days)
dermal and inhalation exposure to flonicamid.  Long-term handler
exposure is not expected.  A dermal toxicity endpoint was not
identified, and therefore dermal exposure/risk need not be assessed for
handlers.  Inhalation exposure was compared to the NOAEL of 12 mg/kg/day
from a 90-day oral toxicity study in the rat (based on kidney hyaline
deposition), with an assumed 100% absorption factor to estimate handler
inhalation risks.

No chemical-specific handler exposure data were submitted in support of
this action.  It is the policy of the HED to use data from the Pesticide
Handlers Exposure Database (PHED) Version 1.1 as presented in PHED
Surrogate Exposure Guide (8/98) to assess handler exposures for
regulatory actions when chemical-specific monitoring data are not
available ( HED Science Advisory Council for Exposure Draft Policy # 7,
dated 1/28/99).  Appropriate unit exposure values were found in the
Surrogate Exposure Guide to cover all potential exposure scenarios. 
However, some bridging of data was necessary.  The PHED Surrogate
Exposure Guide does not contain water dispersible granule values for the
proposed application methods.  Therefore, dry flowable (open mixing) or
liquid (open pour) values were used as reasonable surrogates for the WDG
formulation.  HED standard values were used for the amount treated per
day and body weights. 

Based upon the proposed new use patterns, the most highly exposed
occupational pesticide handler scenaruis are:

Mixer/loaders using open pour loading of dry flowables;

Applicators using open-cab ground-boom sprayers;

Applicators using open-cab airblast sprayers;

Aerial applicators; and  

5)	Flaggers.

Maximum application rates were used to assess short-/intermediate-term
exposure for flonicamid handlers; leading to conservative exposure
estimates. 

A summary of the exposure and risk estimates for occupational handlers
is included in Table 9.1.  Inhalation MOEs for all handler scenarios are
greater than 100 with baseline personal protective equipment (PPE) and
clothing, and therefore, do not exceed HED’s level of concern. 

Table 9.1. Short-Intermediate Term Occupational Exposure and Risk
Estimates for Flonicamid

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Short & Intermediate term

Mixer/Loader Open Pour Dry Flowable

Inhal. 0.00077	0.089	350	Inhal.  0.000343	35,000

Applicator Open Cab Ground Boom

Inhal. 0.00074	0.089	200	Inhal.   0.000188	64,000

Applicator Open Cab Airblast

Inhal. 0.0045	0.089	40	Inhal.   0.000229	52,000

Aerial Applicator

Inhal. 0.000068	0.089	350	Inhal.   0.00003 	400,000

Flagger (Liquid formulations)

Inhal  0.00035	0.089	350	Inhal.   0.000156	77,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Inhal. = Inhalation.  Units = mg
a.i./pound of active ingredient handled.  

2.  Applic. Rate = Taken from the Section B of the IR4 submission.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   Science Advisory Council for
Exposure; Revised 5 July 2000; 

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (70 kg).  

5.  NOAEL = No Observable Adverse Effect Level (12 mg a.i./kg bw/day for
short-term and intermediate-term  inhalation)

6.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL)  ( ADD.  

9.2	Short-/Intermediate-Term Postapplication Risk  tc \l2 "9.2
Short-/Intermediate-Term Postapplication Risk   

Postapplication exposure is possible for workers tending treated food
crops and nursery and landscape ornamentals, however, because no dermal
toxicity endpoint was identified for flonicamid, occupational
postapplication exposures were not assessed. 

The proposed flonicamid labels include a 12-hour restricted entry
interval (REI).  The 12-hour REI complies with criteria under the Worker
Protection Standard. 

9.3	Restricted Entry Interval

Flonicamid is classified as Acute Toxicity Category IV for acute dermal
toxicity, acute inhalation toxicity, primary eye irritation, and primary
skin irritation.  It is not a dermal sensitizer.  Therefore, the interim
worker protection standard (WPS) REI of 12 hours is adequate to protect
agricultural workers from post-application exposures to flonicamid.  The
product labels both list a REI of 12 hours.  

10.0	Data Needs and Label Recommendations tc \l1 "10.0	Data Needs and
Label Recommendations 

10.1	Toxicology 

None identified tc \l2 "10.1	Toxicology (None identified) 

10.2	Residue Chemistry tc \l2 "10.2	Residue Chemistry 

Provided a revised Section F is submitted, there are no residue
chemistry issues that would preclude granting a registration for the
requested uses of flonicamid on root vegetables (except sugar beets),
tuberous and corm vegetables, leafy Brassica greens, turnip greens,
hops, and okra.

10.3	Occupational and Residential Exposure

None identified tc \l2 "10.1	Toxicology (None identified) 

11.0  Tolerance Summary Table

A summary of the recommended tolerances for the combined residues of the
insecticide flonicamid and its metabolites TFNA, TFNA-AM, and TFNG in/on
the commodities is presented in Table 11.1 below.  

Table 11.1. 	Tolerance Summary for Flonicamid

Commodity or Subgroup	Proposed Tolerance (ppm)	Established Tolerance
(ppm)	Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances for combined residues of flonicamid and its metabolites TFNA,
TFNA-AM, and TFNG

[40 CFR 180.613(a)(1)]:

Brassica, leafy greens, subgroup 5B	16	--	16

	Hop, dried cones	7.0	--	7.0

	Mustard greens	--	11	16	Residues in/on mustard greens will be covered
by the tolerance for leafy Brassica green, subgroup 5B.

Okra	0.4	--	0.40

	Potato

0.20	None	Residues in/on potato will be covered by the tolerance for
tuberous and corm vegetables, subgroup 1C.

Radish, tops	16	--	None	Residues will be covered by the tolerance for
leafy Brassica green, subgroup 5B.

Turnip, greens	16	--	None

	Vegetable, root, except sugar beet, subgroup 1B	0.45	--	0.60
Recommended tolerance based on crop field trial data

Vegetable, tuberous and corm, subgroup 1C	0.2	--	0.20

	Tolerances for combined residues of flonicamid and its metabolites
TFNA-AM and TFNA in/on livestock commodities [40 CFR 180.613(a)(2)]:

Cattle, fat	--	0.02	0.03	Increased tolerances are needed to reflect
combined limits of quantitation for all regulated residues.

Cattle, meat	--	0.05	0.08

	Egg	--	0.03	0.04	An increased tolerance is needed to account for all
regulated residues.

Goat, fat	--	0.02	0.03	Increased tolerances are needed to reflect
combined limits of quantitation for all regulated residues.

Goat, meat	--	0.05	0.08

	Horse, fat	--	0.02	0.03	Increased tolerances are needed to reflect
combined limits of quantitation for all regulated residues.

Horse, meat	--	0.05	0.08

	Milk	--	0.02	0.03	Increased tolerances are needed to reflect combined
limits of quantitation for all regulated residues.

Poultry, fat	--	0.02	0.03

	Poultry, meat	--	0.02	0.03

	Poultry, meat byproducts	--	0.02	0.03

	Sheep, fat	--	0.02	0.03

	Sheep, meat	--	0.05	0.08

	

References

HED Flonicamid Risk Assessment (D289592, J. Arthur, 5/25/2005)

HED Residue Chemistry Summary Document (D343466, A. Acierto, 11/08/2007)

HED Dietary Exposure & Risk Assessment (D332316, A. Acierto, 11/16/2007)

EFED Estimated Environmental Concentrations (D330894, D331070, and
D331027, L.              Shanaman, 10/29/2007)

HED/ARIA Occupational Exposure Memo (D345362, M. Dow, 10/16/2007)

Appendix A tc \l1 "Appendices 

A1.0	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for flonicamid 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	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		

yes

yes

yes

no

no	

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

yes

-

yes

yes	

yes

yes

-

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5xxx	Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx	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

no

870.7485	General Metabolism	

870.7600	Dermal Penetration		

yes

no	

yes

-

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

-

-

-	

-

-

-

A2.0	Acute Toxicity of Flonicamid Technical

Acute Toxicity of Flonicamid Technical (PC Code 128016) & Selected
Metabolites

Guideline

 No.	

Study Type	

MRID #	

Results	

Toxicity Category

870.1100	

Acute Oral - rat	

45656707	

LD50 = 884 mg/kg (Males), 

LD50 = 1768 mg/kg (Females)	

III

870.1200	

Acute Dermal – rat	

45656708	

LD50  > 5000 mg/kg	

IV

870.1300	

Acute Inhalation - rat	

45656709	

LC50 > 4.9 m/L	

IV

870.2400	

Primary Eye Irritation - rabbit	

45656710	

None or very low effects.	

IV

870.2500	

Primary Skin Irritation - rabbit	

45656711	

Erythema & edema scores were zero.	

IV

870.2600	

Dermal Sensitization - guinea pig	

45656712	

Not a sensitizer.	

NA

870.1100	

Acute oral toxicity / rat 

Flonicamid metabolite -TFNA	

45854605	

LD50 ( 2000 mg/kg 

	

III

870.1100	

Acute oral toxicity / rat 

Flonicamid metabolite -TFNA-AM	

45854606	

LD50 ( 2000 mg/kg 

	

III

870.1100	

Acute oral toxicity / rat 

Flonicamid metabolite -TFNG	

45854607	

LD50 ( 2000 mg/kg 

	

III

870.1100	

Acute oral toxicity / rat 

Flonicamid metabolite -TFNG-AM	

45854608	

LD50 ( 2000 mg/kg 

	

III

870.1100	

Acute oral toxicity / rat 

Flonicamid metabolite -TFNA-OH	

45854609	

LD50 ( 2000 mg/kg 

	

III

A3.0	Flonicamid Technical

Flonicamid Technical (PC Code 128016) Toxicology Profile

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100a

90-Day oral toxicity rodents (rats)

	

45656721 (2002)/ 

acceptable-guideline/ 

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

28-day range-finding: 45656720 (2002)/ acceptable (non-guideline)/ 0, 50
(males), 500, 1000, 5000 or 10000  (females) ppm ( 3.61, 7.47,  36.45, 
73.8, or  353.4 mg/kg/day, males & 8.36, 41.24,  81.9,  372.6, or 642
mg/kg/day, females)	

NOAEL = 200 ppm (12.11 mg/kg/day, males); 1000 ppm (72.3 mg/kg/day,
females) 

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

28-day range-finding: 

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

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

870.3100b

90-Day oral toxicity rodents (mice)	

45656719 (2001)/ 

acceptable (non-guideline)/ 

0, 100, 1000 or 7,000  ppm (0, 15.25, 153.9 or 1069 mg/kg bw/day in
males, and 0, 20.10, 191.5, or 1248 mg/kg bw/day in females)	

NOAEL is 100 ppm (males: 15.25 mg/kg bw/day, females: 20.10 mg/kg
bw/day)

LOAEL is 1000 ppm (males: 153.9 mg/kg bw/day; females: 191.5 mg/kg
bw/day) based on extramedullary hematopoiesis of the spleen. 

Many of the tissues/organs recommended by Guideline 870.3100 were not
histologically examined in any dose group, but this study is not
required and serves as a range-finding study for the mouse
carcinogenicity study. Therefore, it is classified as acceptable,
non-guideline study.

870.3150

90-Day oral toxicity (nonrodents- dogs) 

	

45646722 (2001)/ 

acceptable - guideline/ 

0, 3, 8, 20, or 50 (females) mg/kg bw/day	

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

870.3200

28-Day dermal toxicity

(rats)	

45656723 (2001)/ acceptable - guideline/  0, 20, 150, or 1000  mg/kg/day

NOAEL is 1000 mg/kg/day

LOAEL is >1000 mg/kg/day. 

870.3700a

Prenatal developmental toxicity (rats)	

45656724 (2002)/ acceptable - guideline/ 0, 20, 100 or 500 mg/kg bw/day	

Maternal 

NOAEL is 100 mg/kg bw/day

LOAEL is 500 mg/kg bw/day, based on increased liver weight, and liver
and kidney pathological changes (hypertrophy of centrilobular
hepatocytes in liver and vacuolation of proximal tubular cell in
kidneys). 

Developmental 

NOAEL is 100 mg/kg bw/day 

LOAEL is 500 mg/kg bw/day, based on the increased incidence of cervical
rib. 

870.3700b

Prenatal developmental toxicity (rabbits)

	

45854611 & 45854610 (2002)/ acceptable - guideline/ 0, 2.5, 7.5, or 25
mg/kg/day	

Maternal 

NOAEL is 7.5 mg/kg/day  

LOAEL is 25 mg/kg/day, based on decreased body weights, body weight
gains, and food consumption. 

Developmental 

NOAEL is ( 25 mg/kg/day 

LOAEL is not established.

870.3800

Reproduction and fertility effects (rats)

	

45854613 and 45854612 (2002)/ acceptable - guideline/ 0, 50, 300, or
1800 ppm (0/0, 3.7/4.4, 22.3/26.5, and 132.9/153.4 mg/kg bw/day [M/F])	

Parental

NOAEL is 50 ppm (equivalent to 3.7/4.4 mg/kg/day [M/F]). 

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

Offspring

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

Reproductive Perforance

NOAEL is 1800 ppm (equivalent to 132.9/153.4 mg/kg/day [M/F]). 

LOAEL for reproductive performance was not observed.  

870.4100b

Chronic toxicity (dogs)

	

45854614 (2003)/ 

acceptable - guideline/ 

0, 3, 8, or 20 mg/kg/day	

NOAEL is 8 mg/kg/day. 

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

870.4200b

Carcinogenicity (mice)	

45854615 & 45854616 (2003)/ acceptable - guideline/ 0, 250, 750, or 2250
ppm (0/0, 29/38, 88/112, or 261/334 mg/kg/day [M/F])	

NOAEL was not established. 

LOAEL is 250 ppm (equivalent to 29/38 mg/kg/day [M/F]), based on minimal
to moderate centrilobular hepatocellular hypertrophy, minimal to severe
extramedullary hematopoiesis, minimal to moderate pigment deposition in
the sternal bone marrow, and increased incidence of tissue
masses/nodules in the lungs in the males, and minimal to moderate
decreased cellularity in the femoral bone marrow and
hyperplasia/hypertrophy of the epithelial cells of the terminal
bronchioles of the females. 

At the doses tested, the carcinogenic potential of IKI-220 is positive
at 250 ppm in males and females based on the increased incidence of
alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas.  Dosing was considered adequate based on increased
incidence of tissue masses/nodules in the lungs and microscopic findings
in the liver, spleen, bone marrow, and lungs.  However, data were
provided suggesting this effect is specific to sensitive strains of
mice.

Carcinogenic in mice.

870.4200b

Carcinogenicity (mice)

	

46205801 (2004)/acceptable - guideline/ 0, 10, 25, 80, 250 ppm [males:
0, 1.20, 3.14, 10.0, 30.3 mg/kg/day; females: 0, 1.42, 3.67, 11.8, 36.3
mg/kg/day]	

NOAEL is 80 ppm (equivalent to 10/12 mg/kg/day in males/females). 

LOAEL is 250 ppm (equivalent to 30/36 mg/kg/day in males/females) based
on lung masses and terminal bronchiole epithelial cell
hyperplasia/hypertrophy in both sexes. 

At the doses tested, the carcinogenic potential of IKI-220 is positive
in males and females based on the incidences of alveolar/bronchiolar
adenomas, carcinomas, and combined adenomas and/or carcinomas.  Dosing
was considered adequate based on lung masses and terminal bronchiole
epithelial cell hyperplasia/hypertrophy in both sexes.

Carcinogenic in mice.

870.4300

Combined Chronic/carcinogenicity (rats)

	

45863801 (2002)/ acceptable - guideline/ 0, 50 (males), 100 (males),
200, 1000, or 5000 (females) ppm (0/0, 1.84, 3.68, 7.32/8.92, 36.5/44.1,
and 219 mg/kg/day   [M/F])	

NOAEL is 200 ppm (equivalent to 7.32/8.92 mg/kg/day in males/females).  

LOAEL is 1000 ppm (equivalent to 36.5/44.1 mg/kg/day in males/females)
based on decreased body weights and body weight gains, and increased
incidences of keratitis in males and striated muscle fiber atrophy in
females. 

At the high dose there was an incidence (12%) of nasolacrimal duct
squamous cell carcinomas slightly outside the historical control range
(0-10%) in male rats.  A correlation between the incidence of
inflammation and the fluctuating incidence of nasal tumors was made
across dose groups.  The CARC did not consider the nasolacrimal duct
tumors to be treatment-related.

Female rats had a significant increasing trend in nasolacrimal duct
squamous cell carcinomas at p<0.05, and at the high dose was slightly
above the historical control mean (0.8%) and range (0-4%).  The CARC
considered the nasolacrimal duct squamous cell carcinomas to be possibly
treatment related, but that a clear association with treatment could not
be made.

870.5100

Bacterial reverse mutation	

45656725 (2002)/ acceptable - guideline/ 61.7 to 5000 µg/plate  +/- S9 
	

Negative

870.5100

Bacterial system, mammalian activation gene mutation	

45854617 (2002)/ acceptable - guideline/ 33 to 5000 ug/plate +/- S9	

Negative for metabolite TFNA

870.5100

Bacterial system, mammalian activation gene mutation	

45854618 (2002)/ acceptable - guideline/ 33 to 5000 ug/plate +/- S9	

Negative for metabolite TFNA-AM 

870.5100

Bacterial system, mammalian activation gene mutation	

45854619 (2002)/ acceptable - guideline/ 33 to 5000 ug/plate +/- S9	

Negative for metabolite TFNG-AM 

870.5100

Bacterial system, mammalian activation gene mutation	

45854620 (2002)/ acceptable - guideline/ 33 to 5000 ug/plate +/- S9	

Negative for metabolite TFNA-OH

870.5100

Bacterial system, mammalian activation gene mutation	

45854621 (2002)/ acceptable - guideline/ 5 to 5000 ug/plate +/- S9	

Negative for metabolite TFNG

870.5300

In vitro mammalian cell gene mutation	

45656726 (2002)/ acceptable - guideline/ 28.3 to 2290 µg/mL initial
test, and 143 to 2290 µg/mL repeat.	

Negative

870.5375

In vitro Cytogenetics	

45656727 (2002)/ acceptable - guideline/ 573, 1145 and 2290 µg/mL	

Negative

870.5395

In vivo cytogenetic (micronucleus) test in mice	

45656728 (2002)/ acceptable - guideline/ twice orally by intragastric
gavage at doses of 250, 500 and 1000 mg/kg/day for males and 125, 250
and 500 mg/kg/day for females	

Negative

Non-guideline

Other genotoxicity, in vivo Comet assay	

45854622 (2002)/ unacceptable (non-guideline)/ single doses of 375, 750
and 1500 mg/kg	

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

Non-guideline

Unscheduled DNA synthesis	

45854623 (2002)/ acceptable (non-guideline)/ once orally at 600 and 2000
mg/kg	

Is not genotoxic in hepatocytes from treated rats

870.6200a

Acute neurotoxicity screening battery (rats)	

45854624 (2002)/ unacceptable - guideline/ 0, 100, 300, 600 (males), or
1000 mg/kg/day	

NOAEL is 600 mg/kg in males and 300 mg/kg in females.  

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

This acute neurotoxicity study is unacceptable because interval motor
activity data were not provided as specified according to guidelines,
FOB handling and open-field observations were incomplete, and positive
data provided were from a lab other than the performing lab for this
study.  This study is not required for this risk assessment and
additional information is not required.

870.6200b

Subchronic neurotoxicity screening battery (rats)	

45854702 (2003)/ acceptable - guideline/ 0, 200, 1000, or 10,000 ppm
(0/0, 13/16, 67/81, or 625/722 mg/kg/day [M/F])	

NOAEL is 200/1000 ppm (equivalent to 13/81 mg/kg/day [M/F]).  

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

870.7485

Metabolism and pharmacokinetics (rats)	

45656729 (2001)/ acceptable - guideline/ pilot excretion study, single
oral dose 0.85 or 21 mg/kg and pilot pharmacokinetic study, single oral
dose of 2 or 50 mg/kg 	

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

The pharmacokinetic parameters were also similar between the dose levels
(2 and 50 mg/kg) and sexes.  The radiolabel was rapidly absorbed and
excreted.  The apparent plasma half-life (T½) was 4.8-6.0 hours and the
elimination followed first order kinetics.  The time of maximum plasma
concentration (Tmax) for individual animals ranged from 0.25 to 1 hour
after treatment (with a mean for each group of 0.3-0.6 hours).

870.7485

Metabolism and pharmacokinetics (rats)

	

45863802 to -5, 45854703 (2002)/ acceptable - guideline/  2 or 400 mg/kg

Appears that the overall recovery of radioactive dose from all group was
94-99% by 168 hours post-dose.  Absorption was rapid and extensive,
detected in plasma within 10 minutes of dosing, with maximum plasma
concentrations within 24-54 minutes.  By 168 hours post-dose, total
urinary excretion was 72-78%, cage rinse was 10-21%, and fecal excretion
was 4-7% dose.  Parent (IKI-220) and 9 metabolites accounted for 80-94%
of the dose for all groups.  Parent was detected primarily in the urine,
46-73% of the dose in excreta in all groups.  The primary metabolite was
4-trifluoromethylnicotinamide (TFNA-AM), 18-27% dose in all dose groups,
along with minor amounts of TFNA-AM N-oxide (1-4% dose). Other
metabolites in urine and feces were detected at less than or equal to
2.5% of the dose.  IKI-220 was excreted primarily unchanged in the
urine, but biotransformation of IKI-220 in rats included nitrile
hydrolysis, N-oxidation, hydroxylation of the pyridine ring an amide
hydrolysis.

A4.0	International Residue Limit Status Sheet

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  N-(cyanomethyl)-4-trifluoromethyl)-3-pyridinecarboximide
Common Name:

Flonicamid	X Proposed tolerance

( Reevaluated tolerance

( Other	Date: 4/24/2007

Codex Status (Maximum Residue Limits)	U. S. Tolerances

X No Codex proposal step 6 or above



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摧⤫Øࠀ⁯Codex proposal step 6 or above for the crops requested
Petition Number:  PP#6E7081

DP#:  329381

Other Identifier:  Decision #368509

Residue definition (step 8/CXL):  N/A	Reviewer/Branch:  Amelia Acierto,
RAB3

	Residue definition:  Flonicamid and metabolites TFNA
(4-trifluoromethylnicotinic acid), TFNA-AM
(4-trifluoromethylnicotinamide), and TFNG
[N-(4-trifluoromethylnicotinoyl) glycine]  SEQ CHAPTER \h \r 1   SEQ
CHAPTER \h \r 1 

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Vegetable, root, except sugar beet, subgroup 1B	0.45

Radish, tops	16

Vegetable, tuberous and corm, subgroup 1C	0.2

Brassica, leafy greens, subgroup 5B	16

Turnip, greens	16

Hop, dried cones	7.0

Okra	0.4

	Limits for Canada	Limits for Mexico

X   No Limits

   No Limits for the crops requested	X   No Limits

   No Limits for the crops requested

Residue definition  N/A	Residue definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

	Notes/Special Instructions:  S. funk, 04/25/2007.

	

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