UNITED STATES ENVIRONMENTAL PROTECTION
AGENCY![](media/image1.png){width="0.7541666666666667in"
height="0.7076388888888889in"}

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

**December 21, 2007**

**[MEMORANDUM]{.underline}**

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**

**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**

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 (F~1~ 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-FCID^TM^version 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," <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**

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.

1.  **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.  |        |       |      |   |        |     |                |
| Su    |        |       |      |   |        |     |                |
| mmary |        |       |      |   |        |     |                |
| of    |        |       |      |   |        |     |                |
| Pro   |        |       |      |   |        |     |                |
| posed |        |       |      |   |        |     |                |
| Direc |        |       |      |   |        |     |                |
| tions |        |       |      |   |        |     |                |
| for   |        |       |      |   |        |     |                |
| Use   |        |       |      |   |        |     |                |
| of    |        |       |      |   |        |     |                |
| Flo   |        |       |      |   |        |     |                |
| nicam |        |       |      |   |        |     |                |
| id.** |        |       |      |   |        |     |                |
+=======+========+=======+======+===+========+=====+================+
| F     | Appli  | A     | Max. | R | Max.   | PHI | Use Directions |
| ormul | cation | pplic | No.  | T | Se     |     | and other      |
| ation | Timing | ation | App  | I | asonal | (da | Limitations    |
|       |        | Rate  | lic. | ^ | A      | ys) |                |
| \[EPA |        |       | per  | 1 | pplic. |     |                |
| Reg.  |        | (lb   | Se   | ^ | Rate   |     |                |
| No.\] |        | ai/A) | ason |   |        |     |                |
|       |        |       |      | ( | (lb    |     |                |
|       |        |       |      | d | ai/A)  |     |                |
|       |        |       |      | a |        |     |                |
|       |        |       |      | y |        |     |                |
|       |        |       |      | s |        |     |                |
|       |        |       |      | ) |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| Root  |        |       |      |   |        |     |                |
| Veget |        |       |      |   |        |     |                |
| ables |        |       |      |   |        |     |                |
| (e    |        |       |      |   |        |     |                |
| xcept |        |       |      |   |        |     |                |
| sugar |        |       |      |   |        |     |                |
| b     |        |       |      |   |        |     |                |
| eets) |        |       |      |   |        |     |                |
| inclu |        |       |      |   |        |     |                |
| ding: |        |       |      |   |        |     |                |
| g     |        |       |      |   |        |     |                |
| arden |        |       |      |   |        |     |                |
| beet; |        |       |      |   |        |     |                |
| e     |        |       |      |   |        |     |                |
| dible |        |       |      |   |        |     |                |
| bur   |        |       |      |   |        |     |                |
| dock; |        |       |      |   |        |     |                |
| ca    |        |       |      |   |        |     |                |
| rrot; |        |       |      |   |        |     |                |
| cele  |        |       |      |   |        |     |                |
| riac; |        |       |      |   |        |     |                |
| tur   |        |       |      |   |        |     |                |
| nip-r |        |       |      |   |        |     |                |
| ooted |        |       |      |   |        |     |                |
| che   |        |       |      |   |        |     |                |
| rvil; |        |       |      |   |        |     |                |
| chi   |        |       |      |   |        |     |                |
| cory; |        |       |      |   |        |     |                |
| gin   |        |       |      |   |        |     |                |
| seng; |        |       |      |   |        |     |                |
| ho    |        |       |      |   |        |     |                |
| rsera |        |       |      |   |        |     |                |
| dish; |        |       |      |   |        |     |                |
| tur   |        |       |      |   |        |     |                |
| nip-r |        |       |      |   |        |     |                |
| ooted |        |       |      |   |        |     |                |
| par   |        |       |      |   |        |     |                |
| sley; |        |       |      |   |        |     |                |
| par   |        |       |      |   |        |     |                |
| snip; |        |       |      |   |        |     |                |
| ra    |        |       |      |   |        |     |                |
| dish; |        |       |      |   |        |     |                |
| ori   |        |       |      |   |        |     |                |
| ental |        |       |      |   |        |     |                |
| ra    |        |       |      |   |        |     |                |
| dish; |        |       |      |   |        |     |                |
| ruta  |        |       |      |   |        |     |                |
| baga; |        |       |      |   |        |     |                |
| sal   |        |       |      |   |        |     |                |
| sify; |        |       |      |   |        |     |                |
| black |        |       |      |   |        |     |                |
| sal   |        |       |      |   |        |     |                |
| sify; |        |       |      |   |        |     |                |
| Sp    |        |       |      |   |        |     |                |
| anish |        |       |      |   |        |     |                |
| sal   |        |       |      |   |        |     |                |
| sify; |        |       |      |   |        |     |                |
| ski   |        |       |      |   |        |     |                |
| rret; |        |       |      |   |        |     |                |
| t     |        |       |      |   |        |     |                |
| urnip |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      | 0     | 3    | 7 | 0.267  | 3   | Applications   |
| WG    | osteme | .036- |      |   |        |     | are to be made |
|       | rgence | 0.089 |      |   |        |     | in a minimum   |
| \     | Bro    |       |      |   |        |     | of 10 gal/A    |
| [7151 | adcast |       |      |   |        |     | using ground   |
| 2-9\] |        |       |      |   |        |     | equipment or 3 |
|       |        |       |      |   |        |     | gal/A using    |
|       |        |       |      |   |        |     | aerial         |
|       |        |       |      |   |        |     | equipment.     |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   |        |       |      |   |        |     |                |
| SG    |        |       |      |   |        |     |                |
|       |        |       |      |   |        |     |                |
| \[    |        |       |      |   |        |     |                |
| 71512 |        |       |      |   |        |     |                |
| -10\] |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| Tub   |        |       |      |   |        |     |                |
| erous |        |       |      |   |        |     |                |
| and   |        |       |      |   |        |     |                |
| Corm  |        |       |      |   |        |     |                |
| Veget |        |       |      |   |        |     |                |
| ables |        |       |      |   |        |     |                |
| inclu |        |       |      |   |        |     |                |
| ding: |        |       |      |   |        |     |                |
| arrac |        |       |      |   |        |     |                |
| acha; |        |       |      |   |        |     |                |
| arrow |        |       |      |   |        |     |                |
| root; |        |       |      |   |        |     |                |
| Ch    |        |       |      |   |        |     |                |
| inese |        |       |      |   |        |     |                |
| artic |        |       |      |   |        |     |                |
| hoke; |        |       |      |   |        |     |                |
| Jeru  |        |       |      |   |        |     |                |
| salem |        |       |      |   |        |     |                |
| artic |        |       |      |   |        |     |                |
| hoke; |        |       |      |   |        |     |                |
| e     |        |       |      |   |        |     |                |
| dible |        |       |      |   |        |     |                |
| c     |        |       |      |   |        |     |                |
| anna; |        |       |      |   |        |     |                |
| b     |        |       |      |   |        |     |                |
| itter |        |       |      |   |        |     |                |
| and   |        |       |      |   |        |     |                |
| sweet |        |       |      |   |        |     |                |
| cas   |        |       |      |   |        |     |                |
| sava; |        |       |      |   |        |     |                |
| ch    |        |       |      |   |        |     |                |
| ayote |        |       |      |   |        |     |                |
| (r    |        |       |      |   |        |     |                |
| oot); |        |       |      |   |        |     |                |
| c     |        |       |      |   |        |     |                |
| hufa; |        |       |      |   |        |     |                |
| da    |        |       |      |   |        |     |                |
| sheen |        |       |      |   |        |     |                |
| (t    |        |       |      |   |        |     |                |
| aro); |        |       |      |   |        |     |                |
| gi    |        |       |      |   |        |     |                |
| nger; |        |       |      |   |        |     |                |
| l     |        |       |      |   |        |     |                |
| eren; |        |       |      |   |        |     |                |
| potat |        |       |      |   |        |     |                |
| o;^2^ |        |       |      |   |        |     |                |
| sweet |        |       |      |   |        |     |                |
| po    |        |       |      |   |        |     |                |
| tato; |        |       |      |   |        |     |                |
| ta    |        |       |      |   |        |     |                |
| nier; |        |       |      |   |        |     |                |
| turm  |        |       |      |   |        |     |                |
| eric; |        |       |      |   |        |     |                |
| yam   |        |       |      |   |        |     |                |
| bean; |        |       |      |   |        |     |                |
| yam   |        |       |      |   |        |     |                |
| (     |        |       |      |   |        |     |                |
| true) |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      | 0     | 3    | 7 | 0.267  | 7   | Applications   |
| WG    | osteme | .036- |      |   |        |     | are to be made |
|       | rgence | 0.089 |      |   |        |     | in a minimum   |
| \     | Bro    |       |      |   |        |     | of 10 gal/A    |
| [7151 | adcast |       |      |   |        |     | using ground   |
| 2-9\] |        |       |      |   |        |     | equipment or 3 |
|       |        |       |      |   |        |     | gal/A using    |
|       |        |       |      |   |        |     | aerial         |
|       |        |       |      |   |        |     | equipment.     |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   |        |       |      |   |        |     |                |
| SG    |        |       |      |   |        |     |                |
|       |        |       |      |   |        |     |                |
| \[    |        |       |      |   |        |     |                |
| 71512 |        |       |      |   |        |     |                |
| -10\] |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| Leafy |        |       |      |   |        |     |                |
| *Bras |        |       |      |   |        |     |                |
| sica* |        |       |      |   |        |     |                |
| G     |        |       |      |   |        |     |                |
| reens |        |       |      |   |        |     |                |
| inclu |        |       |      |   |        |     |                |
| ding: |        |       |      |   |        |     |                |
| bro   |        |       |      |   |        |     |                |
| ccoli |        |       |      |   |        |     |                |
| raab  |        |       |      |   |        |     |                |
| (rap  |        |       |      |   |        |     |                |
| ini); |        |       |      |   |        |     |                |
| Ch    |        |       |      |   |        |     |                |
| inese |        |       |      |   |        |     |                |
| ca    |        |       |      |   |        |     |                |
| bbage |        |       |      |   |        |     |                |
| (bok  |        |       |      |   |        |     |                |
| c     |        |       |      |   |        |     |                |
| hoy); |        |       |      |   |        |     |                |
| coll  |        |       |      |   |        |     |                |
| ards; |        |       |      |   |        |     |                |
| kale; |        |       |      |   |        |     |                |
| mi    |        |       |      |   |        |     |                |
| zuna; |        |       |      |   |        |     |                |
| mu    |        |       |      |   |        |     |                |
| stard |        |       |      |   |        |     |                |
| green |        |       |      |   |        |     |                |
| s;^3^ |        |       |      |   |        |     |                |
| mu    |        |       |      |   |        |     |                |
| stard |        |       |      |   |        |     |                |
| spi   |        |       |      |   |        |     |                |
| nach; |        |       |      |   |        |     |                |
| rape  |        |       |      |   |        |     |                |
| gr    |        |       |      |   |        |     |                |
| eens; |        |       |      |   |        |     |                |
| t     |        |       |      |   |        |     |                |
| urnip |        |       |      |   |        |     |                |
| g     |        |       |      |   |        |     |                |
| reens |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      | 0     | 3    | 7 | 0.267  | 0   | Applications   |
| WG    | osteme | .036- |      |   |        |     | are to be made |
|       | rgence | 0.089 |      |   |        |     | in a minimum   |
| \     | Bro    |       |      |   |        |     | of 10 gal/A    |
| [7151 | adcast |       |      |   |        |     | using ground   |
| 2-9\] |        |       |      |   |        |     | equipment or 3 |
|       |        |       |      |   |        |     | gal/A using    |
|       |        |       |      |   |        |     | aerial         |
|       |        |       |      |   |        |     | equipment.     |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   |        |       |      |   |        |     |                |
| SG    |        |       |      |   |        |     |                |
|       |        |       |      |   |        |     |                |
| \[    |        |       |      |   |        |     |                |
| 71512 |        |       |      |   |        |     |                |
| -10\] |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| Hops  |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      | 0     | 3    | 7 | 0.267  | 10  | Applications   |
| WG    | osteme | .054- |      |   |        |     | are to be made |
|       | rgence | 0.089 |      |   |        |     | in a minimum   |
| \     | Bro    |       |      |   |        |     | of 10 gal/A    |
| [7151 | adcast |       |      |   |        |     | using ground   |
| 2-9\] | or     |       |      |   |        |     | equipment or 3 |
|       | banded |       |      |   |        |     | gal/A using    |
|       |        |       |      |   |        |     | aerial         |
|       |        |       |      |   |        |     | equipment.     |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   |        |       |      |   |        |     |                |
| SG    |        |       |      |   |        |     |                |
|       |        |       |      |   |        |     |                |
| \[    |        |       |      |   |        |     |                |
| 71512 |        |       |      |   |        |     |                |
| -10\] |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| Okra  |        |       |      |   |        |     |                |
| ^4^   |        |       |      |   |        |     |                |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      | 0     | 3    | 7 | 0.267  | 0   | Applications   |
| WG    | osteme | .036- |      |   |        |     | are to be made |
|       | rgence | 0.089 |      |   |        |     | in a minimum   |
| \     | Bro    |       |      |   |        |     | of 10 gal/A    |
| [7151 | adcast |       |      |   |        |     | using ground   |
| 2-9\] |        |       |      |   |        |     | equipment or 3 |
|       |        |       |      |   |        |     | gal/A using    |
|       |        |       |      |   |        |     | aerial         |
|       |        |       |      |   |        |     | equipment.     |
+-------+--------+-------+------+---+--------+-----+----------------+
| 50%   | P      |       |      |   |        |     |                |
| SG    | osteme |       |      |   |        |     |                |
|       | rgence |       |      |   |        |     |                |
| \[    | Bro    |       |      |   |        |     |                |
| 71512 | adcast |       |      |   |        |     |                |
| -10\] | 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    ![](media/image2.wmf){width="2.0in"
                        height="1.1152777777777778in"}

  Common name           Flonicamid

  PC Code               128016

  Company experimental  IKI-220; F-1785
  name                  

  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           | 4.5 (25 °C)         | MRID 45854601       |
| suspension               |                     |                     |
+--------------------------+---------------------+---------------------+
| Density                  | 1.531 (20 °C)       | MRID 45854601       |
+--------------------------+---------------------+---------------------+
| Water solubility         | 5.2 g/L (20 °C)     | MRID 45854601       |
+--------------------------+---------------------+---------------------+
| Solvent solubility       | [S                  | MRID 45656705       |
|                          | olvent]{.underline} |                     |
|                          | [g/100 mL (20       |                     |
|                          | °C)]{.underline}    |                     |
|                          |                     |                     |
|                          | 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        |                     |
+--------------------------+---------------------+---------------------+
| Vapor pressure           | 9.43 x 10^-7^ Pa    | MRID 45854601       |
|                          | (20 °C)             |                     |
|                          |                     |                     |
|                          | 2.55 x 10^-6^ Pa    |                     |
|                          | (25 °C)             |                     |
+--------------------------+---------------------+---------------------+
| Dissociation constant,   | 11.60 ± 0.03 (20 ±  | MRID 45656705       |
| pK~a~                    | 1 °C)               |                     |
+--------------------------+---------------------+---------------------+
| Octanol/water partition  | 1.9 (Log P~OW~ =    | MRID 45854601       |
| coefficient              | 0.3) (29.8 °C)      |                     |
+--------------------------+---------------------+---------------------+
| UV/visible absorption    | Acidic and neutral  | MRID 45854601       |
| spectrum                 | 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.    |                     |
+--------------------------+---------------------+---------------------+

\*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   ![](media/image2.wmf){width="2.0in"
                                                                               height="1.1152777777777778in"}

  TFNA             4-trifluoromethylnicotinic acid                             ![](media/image3.wmf){width="1.3333333333333333in"
                                                                               height="1.1152777777777778in"}

  TFNA-AM          4-trifluoromethylnicotinamide                               ![](media/image4.wmf){width="1.3847222222222222in"
                                                                               height="1.1152777777777778in"}

  TFNG             N-(4- trifluoromethylnicotinoyl) glycine                    ![](media/image5.wmf){width="2.0833333333333335in"
                                                                               height="1.0833333333333333in"}

  TFNG-AM          N-(4-trifluoromethylnicotinoyl)-glycinamide                 ![](media/image6.wmf){width="2.0833333333333335in"
                                                                               height="1.051388888888889in"}

  N-oxide of                                                                   ![](media/image7.png){width="2.5840277777777776in"
  flonicamid                                                                   height="1.475in"}

  N-oxide of TFNG                                                              ![](media/image8.png){width="2.584722222222222in"
                                                                               height="1.0729166666666667in"}

  OH-TFNA-AM       6-hydroxy-4-trifluoromethylnicotinamide                     ![](media/image9.png){width="2.5854166666666667in"
                                                                               height="1.3527777777777779in"}

  TFNA-OH          6-hydroxy-4-trifluoromethylnicotinic acid                   ![](media/image10.wmf){width="1.7083333333333333in"
                                                                               height="1.1152777777777778in"}
  ----------------------------------------------------------------------------------------------------------------------------------

**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]{.underline}. 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]{.underline}: 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]{.underline}. 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]{.underline}: 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]{.underline}. 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]{.underline}: 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 F~2~ generation and were given the same concentration
test formulation as their parents. F~1~ animals were given test
formulations for 10 weeks prior to mating to produce the F~2~ 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 F~1~ 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 F~1~ 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 F~1~ parental females, blood serum levels of LH were
increased by 31-50% (p ≤ 0.05).

Additionally, at **1800 ppm**, increases in kidney weights were observed
in the males of both generations (incr. 17%; p ≤ 0.001). Pale kidney was
observed in males in the P (24/24) and F~1~ (10/24) generations compared
to 0/24 in each control group. Increased (p ≤ 0.001) incidences of
tubular basophilic change and granular casts in dilated tubules were
observed in the males of both generations (21-24/24 treated vs 0/24 each
control group). Incidences of vacuolation of the proximal tubule cells
were increased (p ≤ 0.001) in the females of both generations (22-24/24
treated vs 0/24 each control group). Additionally in the F~1~ females,
blood serum levels of FSH were increased by 58% (p ≤0.01), and levels 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 F~1~ 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 F~1~ 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 F~2~ pups. Absolute
and relative (to body) uterus weights were decreased (decr. 19%; p ≤
0.05) in the F~1~ weanlings sacrificed at 25-27 days old. However, no
macroscopic findings in the F~1~ or F~2~ 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 F~1~
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 \[^14^C\]-
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
\[^14^C\]- 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 (-CONH~2~) 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]{.underline}: 2-generation reproduction

[MRID No.]{.underline}: 45854613

[Executive Summary]{.underline}: See Section 3.4.4

[Dose and Endpoint for Establishing cRfD]{.underline}: 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]{.underline}: 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).

**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**            | *             | **Inter        | **          |
|                      | *Short-Term** | mediate-Term** | Long-Term** |
|                      |               |                |             |
|                      | **(1-30       | **(1 - 6       | **(\> 6     |
|                      | Days)**       | Months)**      | 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        |                |               |                        |
| Toxi      |                |               |                        |
| cological |                |               |                        |
| Dose and  |                |               |                        |
| Endpoints |                |               |                        |
| for       |                |               |                        |
| F         |                |               |                        |
| lonicamid |                |               |                        |
| for Use   |                |               |                        |
| in        |                |               |                        |
| Dietary   |                |               |                        |
| and       |                |               |                        |
| Non-Occ   |                |               |                        |
| upational |                |               |                        |
| Human     |                |               |                        |
| Health    |                |               |                        |
| Risk      |                |               |                        |
| Asses     |                |               |                        |
| sments.** |                |               |                        |
+===========+================+===============+========================+
| **E       | **Dose Used in | **FQPA SF and | **Study and            |
| xposure** | Risk           | Level of      | Toxicological          |
|           | Assessment,    | Concern for   | Effects**              |
| **S       | UF**           | Risk          |                        |
| cenario** |                | Assessment**  |                        |
+-----------+----------------+---------------+------------------------+
| Acute     | **None**       | FQPA SF =     | There are no acute     |
| Dietary   |                | **NA**        | dietary toxicity       |
|           |                |               | concerns.              |
|           |                | **aPAD** =    |                        |
|           |                | **NA**        |                        |
+-----------+----------------+---------------+------------------------+
| Chronic   | NOAEL =        | FQPA SF =     | **2-Gen Reproduction   |
| Dietary   | **3.7**        | **1**         | rat**                  |
|           | mg/kg/day      |               |                        |
|           |                | **aPAD** =    | Parental LOAEL =       |
|           | UF = **100**   | [chronic      | **22** mg/kg/day based |
|           |                | RfD           | on increased kidney    |
|           | **Chronic RfD  | ]{.underline} | weights, kidney        |
|           | = 0.04**       |               | hyaline deposition,    |
|           | mg/kg/day      | FQPA SF       | increased blood serum  |
|           |                |               | LH (F1 females).       |
|           |                | = **0.04**    |                        |
|           |                | mg/kg/day     |                        |
+-----------+----------------+---------------+------------------------+
| I         | **None**       | **            | Quantitative risk      |
| ncidental |                | Residential** | assessment is not      |
| Oral (All |                | LOC for MOE = | required since         |
| time      |                | **NA**        | incidental oral        |
| i         |                |               | exposure is not        |
| ntervals) |                |               | expected based on use  |
|           |                |               | pattern.               |
+-----------+----------------+---------------+------------------------+
| S         | **None**       | **            | Quantitative risk      |
| hort-Term |                | Residential** | assessment is not      |
| Dermal (1 |                | LOC for MOE = | required since the     |
| to 30     |                | **NA**        | 28-day dermal study    |
| days)     |                |               | did not show any       |
|           |                | **O           | dermal or systemic     |
|           |                | ccupational** | effects at the limit   |
|           |                | LOC for MOE = | dose of 1000           |
|           |                | **NA**        | mg/kg/day.             |
+-----------+----------------+---------------+------------------------+
| Intermed  | **None**       | **            | Quantitative risk      |
| iate-Term |                | Residential** | assessment is not      |
|           |                | LOC for MOE = | required since the     |
| Dermal (1 |                | **NA**        | 28-day dermal study    |
| to 6      |                |               | did not show any       |
| months)   |                | **O           | dermal or systemic     |
|           |                | ccupational** | effects at the limit   |
|           |                | LOC for MOE = | dose of 1000           |
|           |                | **NA**        | mg/kg/day.             |
+-----------+----------------+---------------+------------------------+
| Long-Term | **None**       | **            | Quantitative risk      |
| Dermal    |                | Residential** | assessment is not      |
| (\>6      |                | LOC for MOE = | required since no      |
| months)   |                | **NA**        | long-term exposure is  |
|           |                |               | expected in this       |
|           |                | **O           | assessment             |
|           |                | ccupational** |                        |
|           |                | LOC for MOE = |                        |
|           |                | **NA**        |                        |
+-----------+----------------+---------------+------------------------+
| S         | Oral NOAEL =   | **            | **90-Day oral rat**    |
| hort-Term | **12**         | Residential** |                        |
| I         | mg/kg/day      | LOC for MOE = | LOAEL = **60**         |
| nhalation |                | **NA**        | mg/kg/day based on     |
| (1 to 30  | (inhalation    |               | **kidney hyaline       |
| days)     | absorption     | **O           | deposition.**          |
|           | rate = 100%)   | ccupational** |                        |
|           |                | LOC for MOE = |                        |
|           |                | **100**       |                        |
+-----------+----------------+---------------+------------------------+
| Intermed  | Oral NOAEL =   | **            | **90-Day oral rat**    |
| iate-Term | **12**         | Residential** |                        |
| I         | mg/kg/day      | LOC for MOE = | LOAEL = **60**         |
| nhalation |                | **NA**        | mg/kg/day based on     |
| (1 to 6   | (inhalation    |               | **kidney hyaline       |
| months)   | absorption     | **O           | deposition.**          |
|           | rate = 100%)   | ccupational** |                        |
|           |                | LOC for MOE = |                        |
|           |                | **100**       |                        |
+-----------+----------------+---------------+------------------------+
| Long-Term | **None**       | **Residential | Quantitative risk      |
| I         |                | or            | assessment is not      |
| nhalation |                | O             | required since no      |
| (\>6      |                | ccupational** | long-term exposure is  |
| months)   |                | LOC for MOE = | expected in this       |
|           |                | **NA**        | 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**

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**

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**

**5.1 Pesticide Metabolism and Environmental Degradation**

1.  **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 \[^14^C\]- 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, \[^14^C\]-
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
[\<]{.underline}5.9% TRR from the low treatment and [\<]{.underline}
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 ([\<]{.underline} 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
([\<]{.underline} 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 [\<]{.underline}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
(-CONH~2~) functional groups in the molecule.

2.  **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, \[pyridyl-^14^C\]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.

3.  **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 \[^14^C\]
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.

4.  **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.

5.  **Pesticide Metabolism and Environmental Degradation**

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 (K~d~) values ranging between 0.00 and 0.2, indicating a
potential for leaching and runoff in the open environment. Average K~d~
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      |           |                       |                      |
| Meta    |           |                       |                      |
| bolites |           |                       |                      |
| and     |           |                       |                      |
| Deg     |           |                       |                      |
| radates |           |                       |                      |
| i       |           |                       |                      |
| ncluded |           |                       |                      |
| in the  |           |                       |                      |
| Flo     |           |                       |                      |
| nicamid |           |                       |                      |
| Risk    |           |                       |                      |
| Ass     |           |                       |                      |
| essment |           |                       |                      |
| and     |           |                       |                      |
| To      |           |                       |                      |
| lerance |           |                       |                      |
| Expre   |           |                       |                      |
| ssion** |           |                       |                      |
+=========+===========+=======================+======================+
| **M     |           | **Residues included   | **Residues included  |
| atrix** |           | in**                  | in**                 |
|         |           |                       |                      |
|         |           | **Risk Assessment**   | **Tolerance          |
|         |           |                       | Expression**         |
+---------+-----------+-----------------------+----------------------+
| Plants  | Primary   | Flonicamid, TFNA,     | Flonicamid, TFNA,    |
|         | Crop      | TFNA-AM and TFNG      | TFNA-AM and TFNG     |
+---------+-----------+-----------------------+----------------------+
|         | R         | Flonicamid, TFNA,     | Flonicamid, TFNA,    |
|         | otational | TFNA-AM and TFNG      | TFNA-AM and TFNG     |
|         | Crop      |                       |                      |
+---------+-----------+-----------------------+----------------------+
| Li      | Ruminant  | Flonicamid, TFNA and  | Flonicamid, TFNA and |
| vestock |           | TFNA-AM               | TFNA-AM              |
+---------+-----------+-----------------------+----------------------+
|         | Poultry   | Flonicamid, TFNA and  | Flonicamid, TFNA and |
|         |           | TFNA-AM               | TFNA-AM              |
+---------+-----------+-----------------------+----------------------+
| D       |           | Flonicamid, TFNA,     | Not Applicable       |
| rinking |           | TFNG-AM, TFNG,        |                      |
| Water   |           | TFNA-OH, TFNA-AM      |                      |
+---------+-----------+-----------------------+----------------------+

8.  **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 -       |   | **    |   | **Acute      |   | **Chronic |   | **Cancer      |
| Agricultural    |   | PCA** |   | Value**      |   | Value**   |   | Value**       |
| Commodity**     |   |       |   |              |   |           |   |               |
|                 |   |       |   | (1-in-10     |   | (1-in-10  |   | (Overall      |
|                 |   |       |   | year Peak)   |   | year      |   | Annual        |
|                 |   |       |   |              |   | Annual    |   |               |
|                 |   |       |   | ppb          |   | Mean)     |   | Mean Value)   |
|                 |   |       |   |              |   |           |   |               |
|                 |   |       |   |              |   | ppb       |   | ppb           |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| FL -- cabbage   | 0 |       | 4 |              | 0 |           | 0 |               |
|                 | . |       | . |              | . |           | . |               |
|                 | 8 |       | 4 |              | 7 |           | 4 |               |
|                 | 7 |       |   |              | 8 |           | 3 |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| CA- lettuce     | 0 |       | 4 |              | * |           | 0 |               |
|                 | . |       | . |              | * |           | . |               |
|                 | 8 |       | 4 |              | 1 |           | 9 |               |
|                 | 7 |       |   |              | . |           | 0 |               |
|                 |   |       |   |              | 5 |           |   |               |
|                 |   |       |   |              | * |           |   |               |
|                 |   |       |   |              | * |           |   |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| OR -- hops      | 0 |       | 2 |              | 0 |           | 0 |               |
|                 | . |       | . |              | . |           | . |               |
|                 | 8 |       | 1 |              | 6 |           | 5 |               |
|                 | 7 |       |   |              | 0 |           | 0 |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| ID -- potato    | 0 |       | 3 |              | 1 |           | 0 |               |
|                 | . |       | . |              | . |           | . |               |
|                 | 8 |       | 1 |              | 0 |           | 9 |               |
|                 | 7 |       |   |              |   |           | 7 |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| ME -- potato    | 0 |       | 5 |              | * |           | 0 |               |
|                 | . |       | . |              | * |           | . |               |
|                 | 8 |       | 0 |              | 1 |           | 8 |               |
|                 | 7 |       |   |              | . |           | 2 |               |
|                 |   |       |   |              | 5 |           |   |               |
|                 |   |       |   |              | * |           |   |               |
|                 |   |       |   |              | * |           |   |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| NC -- sweet     | 0 |       | 5 |              | 1 |           | 0 |               |
| potato          | . |       | . |              | . |           | . |               |
|                 | 8 |       | 1 |              | 2 |           | 7 |               |
|                 | 7 |       |   |              |   |           | 0 |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+
| FL -- carrot    | 0 |       | 9 |              | 0 |           | 0 |               |
|                 | . |       | . |              | . |           | . |               |
|                 | 8 |       | 8 |              | 9 |           | 4 |               |
|                 | 7 |       |   |              | 4 |           | 6 |               |
+-----------------+---+-------+---+--------------+---+-----------+---+---------------+

9.  **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.

1.  **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**

***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    | **cPAD    | **Exposure     | **% cPAD**           |
| Subgroup**      | (mg/      | (mg/kg/day)**  |                      |
|                 | kg/day)** |                |                      |
+-----------------+-----------+----------------+----------------------+
|                 |           | **DEEM-FCID**  | **DEEM-FCID**        |
+-----------------+-----------+----------------+----------------------+
| General U.S.    | 0.04      | 0.004095       | 10                   |
| Population      |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| All Infants (\< | 0.04      | 0.006087       | 15                   |
| 1 year old)     |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| **Children 1-2  | **0.04**  | **0.009070**   | **23**               |
| years old**     |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Children 3-5    | 0.04      | 0.007205       | 18                   |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Children 6-12   | 0.04      | 0.004483       | 11                   |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Youth 13-19     | 0.04      | 0.003280       | 8                    |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Adults 20-49    | 0.04      | 0.003513       | 9                    |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Females 13-49   | 0.04      | 0.003504       | 9                    |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+
| Adults 50+      | 0.04      | 0.003978       | 10                   |
| years old       |           |                |                      |
+-----------------+-----------+----------------+----------------------+

**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**

**6.1 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** **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**

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**

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**

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**

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**

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**

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/.]{.underline}

**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**

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:

1)  Mixer/loaders using open pour loading of dry flowables;

2)  Applicators using open-cab ground-boom sprayers;

3)  Applicators using open-cab airblast sprayers;

4)  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.      |         |         |             |              |
| S                 |         |         |             |              |
| hort-Intermediate |         |         |             |              |
| Term Occupational |         |         |             |              |
| Exposure and Risk |         |         |             |              |
| Estimates for     |         |         |             |              |
| Flonicamid**      |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Unit Exposure^1^  | Applic. | Units   | Avg. Daily  | MOE^5^       |
|                   | Rate^2^ | Tre     | Exposure^4^ |              |
| mg ai/lb handled  |         | ated^3^ |             | Short &      |
|                   | lb      |         | mg ai/kg    | Intermediate |
|                   | ai/unit |         | bw/day      | term         |
+-------------------+---------+---------+-------------+--------------+
| *Mixer/Loader     |         |         |             |              |
| Open Pour Dry     |         |         |             |              |
| Flowable*         |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Inhal. 0.00077    | 0.089   | 350     | Inhal.      | 35,000       |
|                   |         |         | 0.000343    |              |
+-------------------+---------+---------+-------------+--------------+
| *Applicator Open  |         |         |             |              |
| Cab Ground Boom*  |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Inhal. 0.00074    | 0.089   | 200     | Inhal.      | 64,000       |
|                   |         |         | 0.000188    |              |
+-------------------+---------+---------+-------------+--------------+
| *Applicator Open  |         |         |             |              |
| Cab Airblast*     |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Inhal. 0.0045     | 0.089   | 40      | Inhal.      | 52,000       |
|                   |         |         | 0.000229    |              |
+-------------------+---------+---------+-------------+--------------+
| *Aerial           |         |         |             |              |
| Applicator*       |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Inhal. 0.000068   | 0.089   | 350     | Inhal.      | 400,000      |
|                   |         |         | 0.00003     |              |
+-------------------+---------+---------+-------------+--------------+
| *Flagger (Liquid  |         |         |             |              |
| formulations)*    |         |         |             |              |
+-------------------+---------+---------+-------------+--------------+
| Inhal 0.00035     | 0.089   | 350     | Inhal.      | 77,000       |
|                   |         |         | 0.000156    |              |
+-------------------+---------+---------+-------------+--------------+

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**

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**

**10.1 Toxicology**

None identified

**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

**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  | P       | Esta    | Reco    | Comments; *Correct   |
| Subgroup      | roposed | blished | mmended | Commodity            |
|               | To      | To      | To      | Definition*          |
|               | lerance | lerance | lerance |                      |
|               | (ppm)   | (ppm)   | (ppm)   |                      |
+---------------+---------+---------+---------+----------------------+
| **Tolerances  |         |         |         |                      |
| for combined  |         |         |         |                      |
| residues of   |         |         |         |                      |
| flonicamid    |         |         |         |                      |
| and its       |         |         |         |                      |
| metabolites   |         |         |         |                      |
| TFNA,         |         |         |         |                      |
| TFNA-AM, and  |         |         |         |                      |
| TFNG**        |         |         |         |                      |
|               |         |         |         |                      |
| **\[40 CFR    |         |         |         |                      |
| 180.6         |         |         |         |                      |
| 13(a)(1)\]:** |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| *Brassica*,   | 16      | \--     | 16      |                      |
| leafy greens, |         |         |         |                      |
| subgroup 5B   |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| Hop, dried    | 7.0     | \--     | 7.0     |                      |
| cones         |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| Mustard       | \--     | 11      | 16      | Residues in/on       |
| greens        |         |         |         | 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,       | 16      | \--     | None    |                      |
| greens        |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| Vegetable,    | 0.45    | \--     | 0.60    | Recommended          |
| root, except  |         |         |         | tolerance based on   |
| sugar beet,   |         |         |         | crop field trial     |
| subgroup 1B   |         |         |         | data                 |
+---------------+---------+---------+---------+----------------------+
| Vegetable,    | 0.2     | \--     | 0.20    |                      |
| tuberous and  |         |         |         |                      |
| corm,         |         |         |         |                      |
| subgroup 1C   |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| **Tolerances  |         |         |         |                      |
| for combined  |         |         |         |                      |
| residues of   |         |         |         |                      |
| flonicamid    |         |         |         |                      |
| and its       |         |         |         |                      |
| metabolites   |         |         |         |                      |
| TFNA-AM and   |         |         |         |                      |
| TFNA in/on    |         |         |         |                      |
| livestock     |         |         |         |                      |
| commodities   |         |         |         |                      |
| \[40 CFR      |         |         |         |                      |
| 180.6         |         |         |         |                      |
| 13(a)(2)\]:** |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| 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 | \--     | 0.02    | 0.03    |                      |
| byproducts    |         |         |         |                      |
+---------------+---------+---------+---------+----------------------+
| 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**

**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            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | \-          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | no          | \-          |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | \-          | \-          |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5xxx Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5xxx Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | yes         | yes         |
| 870.6200b 90 Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | no          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | no          | \-          |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | \-          | \-          |
|                                         |             |             |
| > Acute Oral (rat)                      | \-          | \-          |
| >                                       |             |             |
| > Subchronic Oral (rat)                 | \-          | \-          |
| >                                       |             |             |
| > Six-month Oral (dog)                  |             |             |
+-----------------------------------------+-------------+-------------+

**A2.0 Acute Toxicity of Flonicamid Technical**

**A3.0 Flonicamid Technical**

+---------------+--------------------+--------------------------------+
| **Flonicamid  |                    |                                |
| Technical (PC |                    |                                |
| Code 128016)  |                    |                                |
| Toxicology    |                    |                                |
| Profile**     |                    |                                |
+===============+====================+================================+
| **Guideline   | **MRID No. (year)/ | **Results**                    |
| No./ Study    | Classification     |                                |
| Type**        | /Doses**           |                                |
+---------------+--------------------+--------------------------------+
| 870.3100a     | 45656721 (2002)/   | NOAEL = 200 ppm (12.11         |
|               |                    | mg/kg/day, males); 1000 ppm    |
| 90-Day oral   | acc                | (72.3 mg/kg/day, females)      |
| toxicity      | eptable-guideline/ |                                |
| rodents       |                    | LOAELs = 1000 ppm (60.0        |
| (rats)        | 0, 50 (males) ,    | mg/kg/day, males) based on     |
|               | 200, 1000, 2000    | hyaline deposition in the      |
|               | (males), or 5000   | kidney; 5000 ppm (340          |
|               | (females) ppm      | mg/kg/day, females) based on   |
|               | (3.08, 12.11,      | hyaline deposition in the      |
|               | 60.0, or 119.4     | kidney and centrilobular       |
|               | mg/kg/day, males & | hypertrophy in the liver.      |
|               | 14.52, 72.3, or    |                                |
|               | 340.1 mg/kg/day,   | 28-day range-finding:          |
|               | females)           |                                |
|               |                    | NOAEL = 100 ppm (7.47          |
|               | 28-day             | mg/kg/day, males); 1000 ppm    |
|               | range-finding:     | (81.9 mg/kg/day, females)      |
|               | 45656720 (2002)/   |                                |
|               | acceptable         | LOAELs = 500 ppm (36.45        |
|               | (non-guideline)/   | mg/kg/day, males); based on    |
|               | 0, 50 (males),     | hyaline deposition in the      |
|               | 500, 1000, 5000 or | kidney; 5000 ppm (372.6        |
|               | 10000 (females)    | mg/kg/day, females) based on   |
|               | ppm ( 3.61, 7.47,  | hyaline deposition in the      |
|               | 36.45, 73.8, or    | kidney, centrilobular          |
|               | 353.4 mg/kg/day,   | hypertrophy in the liver,      |
|               | males & 8.36,      | anemia and increased           |
|               | 41.24, 81.9,       | cholesterol.                   |
|               | 372.6, or 642      |                                |
|               | mg/kg/day,         |                                |
|               | females)           |                                |
+---------------+--------------------+--------------------------------+
| 870.3100b     | 45656719 (2001)/   | NOAEL is 100 ppm (males: 15.25 |
|               |                    | mg/kg bw/day, females: 20.10   |
| 90-Day oral   | acceptable         | mg/kg bw/day)                  |
| toxicity      | (non-guideline)/   |                                |
| rodents       |                    | LOAEL is 1000 ppm (males:      |
| (mice)        | 0, 100, 1000 or    | 153.9 mg/kg bw/day; females:   |
|               | 7,000 ppm (0,      | 191.5 mg/kg bw/day) based on   |
|               | 15.25, 153.9 or    | extramedullary hematopoiesis   |
|               | 1069 mg/kg bw/day  | of the spleen.                 |
|               | in males, and 0,   |                                |
|               | 20.10, 191.5, or   | Many of the tissues/organs     |
|               | 1248 mg/kg bw/day  | recommended by Guideline       |
|               | in females)        | 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      | 45646722 (2001)/   | NOAEL is 8 mg/kg/day in males  |
|               |                    | and 20 mg/kg/day for females.  |
| 90-Day oral   | acceptable -       | LOAEL is 20 mg/kg/day in males |
| toxicity      | guideline/         | and 50 mg/kg/day in females,   |
| (nonrodents-  |                    | based on acute clinical signs  |
| dogs)         | 0, 3, 8, 20, or 50 | in males and females           |
|               | (females) mg/kg    | (vomiting, first observed on   |
|               | bw/day             | 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      | 45656723 (2001)/   | NOAEL is 1000 mg/kg/day        |
|               | acceptable -       |                                |
| 28-Day dermal | guideline/ 0, 20,  | LOAEL is \>1000 mg/kg/day.     |
| toxicity      | 150, or 1000       |                                |
|               | mg/kg/day          |                                |
| (rats)        |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.3700a     | 45656724 (2002)/   | Maternal                       |
|               | acceptable -       |                                |
| Prenatal      | guideline/ 0, 20,  | NOAEL is 100 mg/kg bw/day      |
| developmental | 100 or 500 mg/kg   |                                |
| toxicity      | bw/day             | LOAEL is 500 mg/kg bw/day,     |
| (rats)        |                    | 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     | 45854611 &         | Maternal                       |
|               | 45854610 (2002)/   |                                |
| Prenatal      | acceptable -       | NOAEL is 7.5 mg/kg/day         |
| developmental | guideline/ 0, 2.5, |                                |
| toxicity      | 7.5, or 25         | LOAEL is 25 mg/kg/day, based   |
| (rabbits)     | mg/kg/day          | on decreased body weights,     |
|               |                    | body weight gains, and food    |
|               |                    | consumption.                   |
|               |                    |                                |
|               |                    | Developmental                  |
|               |                    |                                |
|               |                    | NOAEL is ≥ 25 mg/kg/day        |
|               |                    |                                |
|               |                    | LOAEL is not established.      |
+---------------+--------------------+--------------------------------+
| 870.3800      | 45854613 and       | Parental                       |
|               | 45854612 (2002)/   |                                |
| Reproduction  | acceptable -       | NOAEL is 50 ppm (equivalent to |
| and fertility | guideline/ 0, 50,  | 3.7/4.4 mg/kg/day \[M/F\]).    |
| effects       | 300, or 1800 ppm   |                                |
| (rats)        | (0/0, 3.7/4.4,     | LOAEL is 300 ppm (equivalent   |
|               | 22.3/26.5, and     | to 22.3/26.5 mg/kg/day         |
|               | 132.9/153.4 mg/kg  | \[M/F\]) based on increased    |
|               | bw/day \[M/F\])    | 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     | 45854614 (2003)/   | NOAEL is 8 mg/kg/day.          |
|               |                    |                                |
| Chronic       | acceptable -       | LOAEL is 20 mg/kg/day, based   |
| toxicity      | guideline/         | on acute clinical signs        |
| (dogs)        |                    | (vomiting, mostly within the   |
|               | 0, 3, 8, or 20     | first week), clinical          |
|               | mg/kg/day          | pathology at 12 months (higher |
|               |                    | reticulocytes counts) in males |
|               |                    | and females.                   |
+---------------+--------------------+--------------------------------+
| 870.4200b     | 45854615 &         | NOAEL was not established.     |
|               | 45854616 (2003)/   |                                |
| Ca            | acceptable -       | LOAEL is 250 ppm (equivalent   |
| rcinogenicity | guideline/ 0, 250, | to 29/38 mg/kg/day \[M/F\]),   |
| (mice)        | 750, or 2250 ppm   | based on minimal to moderate   |
|               | (0/0, 29/38,       | centrilobular hepatocellular   |
|               | 88/112, or 261/334 | hypertrophy, minimal to severe |
|               | mg/kg/day \[M/F\]) | 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     | 46205801           | NOAEL is 80 ppm (equivalent to |
|               | (                  | 10/12 mg/kg/day in             |
| Ca            | 2004)/acceptable - | males/females).                |
| rcinogenicity | guideline/ 0, 10,  |                                |
| (mice)        | 25, 80, 250 ppm    | LOAEL is 250 ppm (equivalent   |
|               | \[males: 0, 1.20,  | to 30/36 mg/kg/day in          |
|               | 3.14, 10.0, 30.3   | males/females) based on lung   |
|               | mg/kg/day;         | masses and terminal bronchiole |
|               | females: 0, 1.42,  | epithelial cell                |
|               | 3.67, 11.8, 36.3   | hyperplasia/hypertrophy in     |
|               | mg/kg/day\]        | 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      | 45863801 (2002)/   | NOAEL is 200 ppm (equivalent   |
|               | acceptable -       | to 7.32/8.92 mg/kg/day in      |
| Combined      | guideline/ 0, 50   | males/females).                |
| Chronic/ca    | (males), 100       |                                |
| rcinogenicity | (males), 200,      | LOAEL is 1000 ppm (equivalent  |
| (rats)        | 1000, or 5000      | to 36.5/44.1 mg/kg/day in      |
|               | (females) ppm      | males/females) based on        |
|               | (0/0, 1.84, 3.68,  | decreased body weights and     |
|               | 7.32/8.92,         | body weight gains, and         |
|               | 36.5/44.1, and 219 | increased incidences of        |
|               | mg/kg/day \[M/F\]) | 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      | 45656725 (2002)/   | Negative                       |
|               | acceptable -       |                                |
| Bacterial     | guideline/ 61.7 to |                                |
| reverse       | 5000 µg/plate +/-  |                                |
| mutation      | S9                 |                                |
+---------------+--------------------+--------------------------------+
| 870.5100      | 45854617 (2002)/   | Negative for metabolite TFNA   |
|               | acceptable -       |                                |
| Bacterial     | guideline/ 33 to   |                                |
| system,       | 5000 ug/plate +/-  |                                |
| mammalian     | S9                 |                                |
| activation    |                    |                                |
| gene mutation |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.5100      | 45854618 (2002)/   | Negative for metabolite        |
|               | acceptable -       | TFNA-AM                        |
| Bacterial     | guideline/ 33 to   |                                |
| system,       | 5000 ug/plate +/-  |                                |
| mammalian     | S9                 |                                |
| activation    |                    |                                |
| gene mutation |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.5100      | 45854619 (2002)/   | Negative for metabolite        |
|               | acceptable -       | TFNG-AM                        |
| Bacterial     | guideline/ 33 to   |                                |
| system,       | 5000 ug/plate +/-  |                                |
| mammalian     | S9                 |                                |
| activation    |                    |                                |
| gene mutation |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.5100      | 45854620 (2002)/   | Negative for metabolite        |
|               | acceptable -       | TFNA-OH                        |
| Bacterial     | guideline/ 33 to   |                                |
| system,       | 5000 ug/plate +/-  |                                |
| mammalian     | S9                 |                                |
| activation    |                    |                                |
| gene mutation |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.5100      | 45854621 (2002)/   | Negative for metabolite TFNG   |
|               | acceptable -       |                                |
| Bacterial     | guideline/ 5 to    |                                |
| system,       | 5000 ug/plate +/-  |                                |
| mammalian     | S9                 |                                |
| activation    |                    |                                |
| gene mutation |                    |                                |
+---------------+--------------------+--------------------------------+
| 870.5300      | 45656726 (2002)/   | Negative                       |
|               | acceptable -       |                                |
| In vitro      | guideline/ 28.3 to |                                |
| mammalian     | 2290 µg/mL initial |                                |
| cell gene     | test, and 143 to   |                                |
| mutation      | 2290 µg/mL repeat. |                                |
+---------------+--------------------+--------------------------------+
| 870.5375      | 45656727 (2002)/   | Negative                       |
|               | acceptable -       |                                |
| In vitro      | guideline/ 573,    |                                |
| Cytogenetics  | 1145 and 2290      |                                |
|               | µg/mL              |                                |
+---------------+--------------------+--------------------------------+
| 870.5395      | 45656728 (2002)/   | Negative                       |
|               | acceptable -       |                                |
| In vivo       | guideline/ twice   |                                |
| cytogenetic   | orally by          |                                |
| (             | intragastric       |                                |
| micronucleus) | gavage at doses of |                                |
| test in mice  | 250, 500 and 1000  |                                |
|               | mg/kg/day for      |                                |
|               | males and 125, 250 |                                |
|               | and 500 mg/kg/day  |                                |
|               | for females        |                                |
+---------------+--------------------+--------------------------------+
| Non-guideline | 45854622 (2002)/   | Was not positive for nuclear   |
|               | unacceptable       | migration up to 1500 mg/kg     |
| Other         | (non-guideline)/   |                                |
| genotoxicity, | single doses of    |                                |
| in vivo Comet | 375, 750 and 1500  |                                |
| assay         | mg/kg              |                                |
+---------------+--------------------+--------------------------------+
| Non-guideline | 45854623 (2002)/   | Is not genotoxic in            |
|               | acceptable         | hepatocytes from treated rats  |
| Unscheduled   | (non-guideline)/   |                                |
| DNA synthesis | once orally at 600 |                                |
|               | and 2000 mg/kg     |                                |
+---------------+--------------------+--------------------------------+
| 870.6200a     | 45854624 (2002)/   | NOAEL is 600 mg/kg in males    |
|               | unacceptable -     | and 300 mg/kg in females.      |
| Acute         | guideline/ 0, 100, |                                |
| neurotoxicity | 300, 600 (males),  | LOAEL is 1000 mg/kg based on   |
| screening     | or 1000 mg/kg/day  | mortality and signs of         |
| battery       |                    | toxicity (decreased motor      |
| (rats)        |                    | 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     | 45854702 (2003)/   | NOAEL is 200/1000 ppm          |
|               | acceptable -       | (equivalent to 13/81 mg/kg/day |
| Subchronic    | guideline/ 0, 200, | \[M/F\]).                      |
| neurotoxicity | 1000, or 10,000    |                                |
| screening     | ppm (0/0, 13/16,   | LOAEL is 1000/10,000 ppm       |
| battery       | 67/81, or 625/722  | (equivalent to 67/722          |
| (rats)        | mg/kg/day \[M/F\]) | 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      | 45656729 (2001)/   | IKI-220 was rapidly absorbed   |
|               | acceptable -       | and excreted with no apparent  |
| Metabolism    | guideline/ pilot   | differences between the sexes. |
| and           | excre­tion study,   | By 48 hours after treatment,   |
| pha           | single oral dose   | \~93% of the administered dose |
| rmacokinetics | 0.85 or 21 mg/kg   | had been eliminated and by 168 |
| (rats)        | and pilot          | hours \~96% was eliminated.    |
|               | pharmacokinetic    | The primary route of           |
|               | study, single oral | elim­ina­tion was the urine,     |
|               | dose of 2 or 50    | accounting for \~90% of the    |
|               | mg/kg              | 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      | 45863802 to -5,    | Appears that the overall       |
|               | 45854703 (2002)/   | recovery of radioactive dose   |
| Metabolism    | acceptable -       | from all group was 94-99% by   |
| and           | guideline/ 2 or    | 168 hours post-dose.           |
| pha           | 400 mg/kg          | Absorption was rapid and       |
| rmacokinetics |                    | extensive, detected in plasma  |
| (rats)        |                    | 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:  | Common Name:   | X Proposed          | Date:      |
| N-(cyanomet     |                | tolerance           | 4/24/2007  |
| hyl)-4-trifluor | Flonicamid     |                     |            |
| omethyl)-3-pyri |                |  Reevaluated       |            |
| dinecarboximide |                | tolerance           |            |
|                 |                |                     |            |
|                 |                |  Other             |            |
+-----------------+----------------+---------------------+------------+
| Codex Status    |                | U. S. Tolerances    |            |
| (Maximum        |                |                     |            |
| Residue Limits) |                |                     |            |
+-----------------+----------------+---------------------+------------+
| X No Codex      |                | Petition Number:    |            |
| proposal step 6 |                | PP#6E7081           |            |
| or above        |                |                     |            |
|                 |                | DP#: 329381         |            |
| ⁯Codex proposal  |                |                     |            |
| step 6 or above |                | Other Identifier:   |            |
| for the crops   |                | Decision #368509    |            |
| requested       |                |                     |            |
+-----------------+----------------+---------------------+------------+
| Residue         |                | Reviewer/Branch:    |            |
| definition      |                | Amelia Acierto,     |            |
| (step 8/CXL):   |                | RAB3                |            |
| N/A             |                |                     |            |
+-----------------+----------------+---------------------+------------+
|                 |                | Residue definition: |            |
|                 |                | Flonicamid and      |            |
|                 |                | metabolites TFNA    |            |
|                 |                | (4-trifl            |            |
|                 |                | uoromethylnicotinic |            |
|                 |                | acid), TFNA-AM      |            |
|                 |                | (4-trifluorom       |            |
|                 |                | ethylnicotinamide), |            |
|                 |                | and TFNG            |            |
|                 |                | \[N-(4-trifluo      |            |
|                 |                | romethylnicotinoyl) |            |
|                 |                | glycine\]Number     |            |
|                 |                | range CHAPTERNumber |            |
|                 |                | range CHAPTER       |            |
+-----------------+----------------+---------------------+------------+
| Crop (s)        | MRL (mg/kg)    | Crop(s)             | Tolerance  |
|                 |                |                     | (ppm)      |
+-----------------+----------------+---------------------+------------+
|                 |                | Vegetable, root,    | 0.45       |
|                 |                | except sugar beet,  |            |
|                 |                | subgroup 1B         |            |
+-----------------+----------------+---------------------+------------+
|                 |                | Radish, tops        | 16         |
+-----------------+----------------+---------------------+------------+
|                 |                | Vegetable, tuberous | 0.2        |
|                 |                | and corm, subgroup  |            |
|                 |                | 1C                  |            |
+-----------------+----------------+---------------------+------------+
|                 |                | *Brassica*, leafy   | 16         |
|                 |                | greens, subgroup 5B |            |
+-----------------+----------------+---------------------+------------+
|                 |                | Turnip, greens      | 16         |
+-----------------+----------------+---------------------+------------+
|                 |                | Hop, dried cones    | 7.0        |
+-----------------+----------------+---------------------+------------+
|                 |                | Okra                | 0.4        |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
| Limits for      |                | Limits for Mexico   |            |
| Canada          |                |                     |            |
+-----------------+----------------+---------------------+------------+
| X No Limits     |                | X No Limits         |            |
|                 |                |                     |            |
|  No Limits for |                |  No Limits for the |            |
| the crops       |                | crops requested     |            |
| requested       |                |                     |            |
+-----------------+----------------+---------------------+------------+
| Residue         |                | Residue definition: |            |
| definition N/A  |                | N/A                 |            |
+-----------------+----------------+---------------------+------------+
| Crop(s)         | MRL (mg/kg)    | Crop(s)             | MRL        |
|                 |                |                     | (mg/kg)    |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
|                 |                |                     |            |
+-----------------+----------------+---------------------+------------+
| Notes/Special   |                |                     |            |
| Instructions:   |                |                     |            |
| S. funk,        |                |                     |            |
| 04/25/2007.     |                |                     |            |
+-----------------+----------------+---------------------+------------+