**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/21/07

**[MEMORANDUM]{.underline}**

SUBJECT: **Fluopicolide**: Human Health Risk Assessment for Proposed
Uses on Tuberous and Corm Vegetables, Leafy Vegetables (except
*Brassica*), Fruiting Vegetables, Cucurbit Vegetables, Grapes, Turf, and
Ornamentals, and for Indirect or Inadvertent Residues on the Rotational
Crop Wheat. PC Code: 027412, Petition No: 5F7016, DP Number: 325091.

Regulatory Action: Section 3 Registration Action

> Risk Assessment Type: Single Chemical/Aggregate

FROM: Nancy Dodd, Risk Assessor

Registration Action Branch 3

Health Effects Division (7509P)

AND

Amelia Acierto, Chemist

Kelly O'Rourke, Biologist

Myron Ottley, Toxicologist

Registration Action Branch 3

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

> Registration Action Branch 3
>
> Health Effects Division (7509P)

AND

> Christine Olinger, Chemist
>
> Mary Elissa Reaves, Ph.D., Toxicologist
>
> Risk Assessment Review Committee
>
> Health Effects Division (7509P)

TO: Janet Whitehurst/Tony Kish, RM Team #22

Fungicide Branch

Registration Division (7505P)

Valent U.S.A. Corporation has submitted a petition for tolerances for
the fungicide fluopicolide in/on tuberous and corm vegetables, leafy
vegetables (except *Brassica*), fruiting vegetables, cucurbit
vegetables, grapes, and the rotational crop wheat. Uses on turf
(residential, commercial, golf course, and sod farms) and ornamental
plants (landscapes, commercial greenhouses, and nurseries) are also
proposed. The Registration Division of the Office of Pesticide Programs
(OPP) has requested that HED 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 the requested uses of fluopicolide.

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide,
2,6-dichloro-*N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide,
on *grape* at 2.0 ppm and *grape, raisin* at 6.0 ppm for a use on
imported grapes (DP #315502, N. Dodd, 1/31/07). No livestock tolerances
have been established. No Codex, Canadian, or Mexican Maximum Residue
Limits (MRLs) or tolerances have been established for fluopicolide.

The residue chemistry and the toxicological databases support the
establishment of the following tolerances for the fungicide
fluopicolide. Provided the deficiencies regarding the Sections B and F
are resolved (and provided that the Human Health Risk Assessment for BAM
is adequate), conditional registration for the requested uses of
fluopicolide can be granted and the tolerances as stated below can be
established. The conditional registration can be converted to
unconditional registration when the remaining deficiency cited in
Section 10.0 of this document is resolved.

> **Tolerances to be established for residues of the fungicide
> fluopicolide \[2,6-dichloro-**
>
> ***N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide\]**
> as an indicator of combined residues of fluopicolide and its
> metabolite, 2,6-dichlorobenzamide, **under "(a) *General*":**
>
> Grape\* 2.0 ppm
>
> Grape, raisin\* 6.0 ppm
>
> Vegetable, cucurbit, group 9 0.50 ppm
>
> Vegetable, fruiting, group 8 1.6 ppm
>
> Vegetable, leafy, except *Brassica*, group 4 25 ppm
>
> Vegetable, tuberous and corm, except potato, subgroup 1D 0.02 ppm
>
> \* These tolerances have been established for imported grapes (40 CFR
> §180.627).

**Note to RD: HED is recommending a revision of the tolerance expression
for fluopicolide in/on plants to address issues of quantifiable residues
of 2,6-dichlorobenzamide (BAM) in/on plants resulting from fluopicolide
application. BAM is also a metabolite of the registered herbicide
dichlobenil.**

A summary of the findings and an assessment of human risk resulting from
fluopicolide uses on tuberous and corm vegetables, leafy vegetables
(except *Brassica*), fruiting vegetables, cucurbit vegetables, and
grapes are provided in this document. The residue chemistry assessment
was provided by Amelia Acierto, the occupational and residential
exposure assessment by Kelly O'Rourke, the hazard characterization by
Myron Ottley, and the dietary exposure assessment and risk assessment by
Nancy Dodd of RAB3.

Two of the products (V-10162 Premix and V-10162 VPP Fungicide) contain a
second active ingredient (propamocarb hydrochloride) which may have
different PPE and REI requirements**. It is the responsibility of the
Registration Division to make certain that the label PPE and REIs for
these products is protective of both fluopicolide and propamocarb
hydrochloride exposure**.

For V-10162 Premix (EPA File Symbol No. 59639-RUE), **the proposed uses
of the second active ingredient on cucurbit vegetables, fruiting
vegetables, head and leaf lettuce, potato, turf, and ornamentals are not
evaluated in this document;** the adequacy of the proposed use
directions and the availability of adequate supporting residue data will
be addressed in a separate review.

2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or
environmental degradate of both the fungicide fluopicolide and the
herbicide dichlobenil. Because the toxicological endpoints of BAM and
fluopicolide are different, **a separate human health risk assessment
(DP #345918, N. Dodd, 11/21/07) for BAM is being concurrently
conducted.** The BAM assessment evaluates BAM resulting from both
fluopicolide and dichlobenil; BAM from fluopicolide alone has not been
assessed. Registration of the proposed fluopicolide uses is dependent on
the adequacy of both Human Health Risk Assessments.

**Table of Contents**

**1.0** **Executive Summary** [6](#__RefHeading___Toc185228014)

**2.0** **Ingredient Profile** [12](#__RefHeading___Toc185228015)

2.1 Summary of Proposed Uses [12](#__RefHeading___Toc185228016)

2.2 Structure and Nomenclature [15](#__RefHeading___Toc185228017)

**3.0** **Hazard Characterization/Assessment**
[16](#__RefHeading___Toc185228018)

3.1 Hazard and Dose-Response Characterization
[16](#__RefHeading___Toc185228019)

3.1.1 Database Summary [16](#__RefHeading___Toc185228020)

3.1.1.1 Studies available and considered (animal, human, general
literature) [17](#__RefHeading___Toc185228021)

3.1.1.2 Mode of action, metabolism, toxicokinetic data
[17](#__RefHeading___Toc185228022)

3.1.1.3 Sufficiency of studies/data [17](#__RefHeading___Toc185228023)

3.1.2 Toxicological Effects [17](#__RefHeading___Toc185228024)

3.1.3 Dose-response [19](#__RefHeading___Toc185228025)

3.1.4 FQPA [19](#__RefHeading___Toc185228026)

3.1.5 The Report to the European Commission
[20](#__RefHeading___Toc185228027)

3.2 Absorption, Distribution, Metabolism, Excretion (ADME**)**
[20](#__RefHeading___Toc185228028)

3.3 FQPA Considerations [21](#__RefHeading___Toc185228029)

3.3.1 Adequacy of the Toxicity Database
[21](#__RefHeading___Toc185228030)

3.3.2 Evidence of Neurotoxicity [21](#__RefHeading___Toc185228031)

3.3.3 Developmental Toxicity Studies [23](#__RefHeading___Toc185228032)

3.3.4 Reproductive Toxicity Study [26](#__RefHeading___Toc185228033)

3.3.5 Additional Information from Literature Sources
[28](#__RefHeading___Toc185228034)

3.3.6 Pre-and/or Post-natal Toxicity [28](#__RefHeading___Toc185228035)

3.3.6.1 Determination of Susceptibility
[28](#__RefHeading___Toc185228036)

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility [28](#__RefHeading___Toc185228037)

3.3.7 Recommendation for a Developmental Neurotoxicity Study
[29](#__RefHeading___Toc185228038)

3.4 Safety Factor for Infants and Children
[29](#__RefHeading___Toc185228039)

3.5 Hazard Identification and Toxicity Endpoint Selection
[29](#__RefHeading___Toc185228040)

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49
[29](#__RefHeading___Toc185228041)

3.5.2 Acute Reference Dose (aRfD) - General Population
[30](#__RefHeading___Toc185228042)

3.5.3 Chronic Reference Dose (cRfD) - [30](#__RefHeading___Toc185228043)

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)
[31](#__RefHeading___Toc185228044)

3.5.5 Dermal Absorption [31](#__RefHeading___Toc185228045)

3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)
[32](#__RefHeading___Toc185228046)

3.5.7 Inhalation Exposure (Short-, Intermediate- and Long-Term)
[33](#__RefHeading___Toc185228047)

3.5.8 Level of Concern for Margin of Exposure
[33](#__RefHeading___Toc185228048)

3.5.9 Recommendation for Aggregate Exposure Risk Assessment
[34](#__RefHeading___Toc185228049)

3.5.10 Classification of Carcinogenic Potential
[34](#__RefHeading___Toc185228050)

3.5.11 Summary of Toxicological Doses and Endpoints for Fluopicolide for
Use in Human Risk Assessments [35](#__RefHeading___Toc185228051)

3.6 Endocrine disruption [36](#__RefHeading___Toc185228052)

4.0 Public Health and Pesticide Epidemiology Data
[36](#__RefHeading___Toc185228053)

**5.0** **Dietary Exposure/Risk Characterization**
[36](#__RefHeading___Toc185228054)

5.1 Pesticide Metabolism and Environmental Degradation
[36](#__RefHeading___Toc185228055)

5.1.1 Metabolism in Primary Crops [36](#__RefHeading___Toc185228056)

5.1.2 Metabolism in Rotational Crops [37](#__RefHeading___Toc185228057)

5.1.3 Metabolism in Livestock [37](#__RefHeading___Toc185228058)

5.1.4 Analytical Methodology [38](#__RefHeading___Toc185228059)

5.1.5 Environmental Degradation [39](#__RefHeading___Toc185228060)

5.1.6 Comparative Metabolic Profile [40](#__RefHeading___Toc185228061)

5.1.7 Toxicity Profile of Major Metabolites and Degradates
[40](#__RefHeading___Toc185228062)

5.1.8 Pesticide Metabolites and Degradates of Concern
[41](#__RefHeading___Toc185228063)

5.1.9 Drinking Water Residue Profile [43](#__RefHeading___Toc185228064)

5.1.10 Food Residue Profile [44](#__RefHeading___Toc185228065)

5.1.11 International Residue Limits [56](#__RefHeading___Toc185228066)

5.2 Dietary Exposure and Risk [56](#__RefHeading___Toc185228067)

5.2.1 Acute Dietary (Food and Drinking Water) Exposure/Risk
[57](#__RefHeading___Toc185228068)

5.2.2 Chronic Dietary (Food and Drinking Water) Exposure/Risk
[57](#__RefHeading___Toc185228069)

5.2.3 Cancer Dietary Risk [58](#__RefHeading___Toc185228070)

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information
[58](#__RefHeading___Toc185228071)

**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** [58](#__RefHeading___Toc185228072)

6.1. Residential Handler Exposure [58](#__RefHeading___Toc185228073)

6.2. Residential Postapplication Exposure
[59](#__RefHeading___Toc185228074)

6.3 Other (Recreational Exposure; Spray Drift)
[62](#__RefHeading___Toc185228075)

**7.0** **Aggregate Risk Assessments and Risk Characterization**
[63](#__RefHeading___Toc185228076)

7.1 Acute Aggregate Risk [63](#__RefHeading___Toc185228077)

7.2 Short-Term Aggregate Risk [63](#__RefHeading___Toc185228078)

7.3 Intermediate-Term Aggregate Risk [64](#__RefHeading___Toc185228079)

7.4 Long-Term Aggregate Risk [64](#__RefHeading___Toc185228080)

7.5 Cancer Risk [64](#__RefHeading___Toc185228081)

**8.0** **Cumulative Risk Characterization Assessment**
[65](#__RefHeading___Toc185228082)

**9.0** **Occupational Exposure/Risk Pathway**
[65](#__RefHeading___Toc185228083)

9.1 Short-/Intermediate-/Long-Term Handler Risk
[65](#__RefHeading___Toc185228084)

9.2 Short-/Intermediate-/Long-Term Postapplication Risk
[69](#__RefHeading___Toc185228085)

**10.0** **Data Needs and Label Requirements**
[73](#__RefHeading___Toc185228086)

10.1 Toxicology [73](#__RefHeading___Toc185228087)

10.2 Residue Chemistry [73](#__RefHeading___Toc185228088)

10.3 Occupational and Residential Exposure
[77](#__RefHeading___Toc185228089)

**References:** [77](#__RefHeading___Toc185228090)

**Appendix A: Toxicology Assessment** [78](#__RefHeading___Toc185228091)

A.1 Toxicology Data Requirements [78](#__RefHeading___Toc185228092)

A.2 Toxicity Profiles [79](#__RefHeading___Toc185228093)

A.3 Executive Summaries [86](#__RefHeading___Toc185228094)

**Appendix B: Metabolism Assessment**
[113](#__RefHeading___Toc185228095)

B.1 Metabolism Guidance and Considerations
[113](#__RefHeading___Toc185228096)

B.2 Tabular Summary of Fluopicolide and its Metabolites and Degradates
[114](#__RefHeading___Toc185228097)

**Appendix C: Tolerance Assessment Summary and Table**
[127](#__RefHeading___Toc185228098)

**Appendix D: Review of Human Research**
[128](#__RefHeading___Toc185228099)

**1.0 Executive Summary**[]{#__RefHeading___Toc185228014 .anchor}

**Use Profile:** Fluopicolide is a fungicide that controls a wide range
of *Oomycete* (Phycomycete) diseases including downy mildews
(*Plasmopara*, *Pseudoperonospara*, *Peronospora*, and *Bremia*), late
blight (*Phytophthora*), and some *Pythium* species. Fluopicolide
appears to interfere with mitosis and cell division resulting in the
rapid destabilization of fungal cell structures; this pesticidal mode of
action has been characterized as novel and unique and unlike the known
modes of action of other registered fungicides.

There are existing tolerances for residues of fluopicolide on imported
grapes. This risk assessment addresses proposed domestic registrations
for agricultural crops \[tuberous and corm vegetables, leafy vegetables
(except *Brassica*), fruiting vegetables, cucurbit vegetables, and
grapes\], turf (residential, commercial, golf course, and sod farms),
and ornamental plants (landscapes, commercial greenhouses, and
nurseries).

Four foliar applications of an SC (suspendable concentrate; also called
an aqueous flowable concentrate) or an FlC (an aqueous flowable
concentrate) are to be made at the maximum seasonal application rate of
0.34-0.375 lb active ingredient/acre (ai/A). Minimum retreatment
intervals of 7-12 days and a preharvest interval of 2-21 days are to be
observed.

\[Note: Two of the products (V-10162 Premix and V-10162 VPP Fungicide)
contain a second active ingredient (propamocarb hydrochloride) which may
have different PPE and REI requirements**. It is the responsibility of
the Registration Division to make certain that the label PPE and REIs
for these products is protective of both fluopicolide and propamocarb
hydrochloride exposure**.

For V-10162 Premix (EPA File Symbol No. 59639-RUE), the proposed uses of
the second active ingredient on cucurbit vegetables, fruiting
vegetables, head and leaf lettuce, potato, turf, and ornamentals are not
evaluated in this document; the adequacy of the proposed use directions
and the availability of adequate supporting residue data will be
addressed in a separate review.\]

**Human Health Risk Assessment:**

**This assessment includes fluopicolide residues of concern other than
BAM. Because it has a different toxicity profile, BAM is assessed in a
separate Human Health Risk Assessment.**

**Fluopicolide Toxicity/Hazard:**

The database for fluopicolide is adequate for purposes of risk
assessment. Fluopicolide has demonstrated low to moderate acute toxicity
by the oral (Toxicity Category III), dermal (IV) and inhalation routes
(IV). It is not an eye (IV) or dermal irritant (IV) and is not a dermal
sensitizer. Repeat exposure studies result mainly in changes in body
weight and weight gain at oral dose levels of 109 mg/kg/day and above in
rats, mice and dogs. No definitive cross-species target organ was
identified in subchronic or chronic studies with fluopicolide. Adverse
liver effects (hepatic oval cell proliferation and altered liver cell
foci) were observed in mice at dose levels of 551 mg/kg/day and above. A
dermal subchronic toxicity study showed no systemic or local effects at
the limit dose.

Fluopicolide is not likely to be carcinogenic to humans. There was no
evidence of carcinogenicity in rats, but hepatocellular adenomas were
observed in mice at dose levels of 551 mg/kg/day and above.
Developmental toxicity in the rabbit occurred only at doses that caused
severe maternal toxicity (including death). In the rat, developmental
effects were seen only at high dose levels (700 mg/kg/day) in the
presence of maternal toxicity. Similarly, offspring effects (body
weight, kidney) occurred only at levels causing toxicity in parents of
the multi-generation reproductive toxicity study. No evidence of
neurotoxicity was seen in acute or subchronic oral rat neurotoxicity
studies.

Available *in vivo* dermal absorption data on fluopicolide indicated a
dermal absorption factor of 37% in rats. *In vitro* dermal absorption
data suggested that fluopicolide will penetrate human skin at a
substantially lower rate (up to eight times less) than rat skin,
providing confidence that a 37% dermal absorption factor is conservative
for use in this risk assessment.

The rabbit developmental and rat chronic/carcinogenicity studies were
considered co-critical for endpoint selection. The toxicological profile
for fluopicolide suggests that increased durations of exposure (i.e.,
90-day versus chronic) does not significantly increase the severity of
observed effects. The rabbit developmental and rat chronic/cancer
studies were therefore considered for all exposure scenarios. For the
rabbit developmental study, the maternal LOAEL was 60 mg/kg/day based on
death, abortions/premature deliveries (late-term), decreased food
consumption, and decreased body weight gain. The maternal NOAEL was 20
mg/kg/day. In the combined chronic toxicity/carcinogenicity study in
rats the LOAEL was 109 mg/kg/day based on decreased body weight gain and
increased thyroid weight and increased incidence of thyroid lesions with
NOAEL of 31.5 mg/kg/day. The NOAEL/LOAEL from the rabbit developmental
was used for the point of departure since it is protective of effects
observed from similar dosing of the chronic/carcinogenicity rat study.

Uncertainty factors were 10x for extrapolation from animals to humans
(interspecies variation) and 10x for potential variation in sensitivity
among members of the human population (intraspecies variation).

[]{.mark}

HED recommends that the FQPA Safety Factor be reduced to 1X because
there is a complete toxicity database for fluopicolide and there is no
evidence of susceptibility following *in utero* and/or postnatal
exposure in the rabbit and rat developmental toxicity studies or in the
2-generation rat reproduction study. There is low concern for
qualitative susceptibility observed in the rat developmental toxicity
study because the offspring effects (reduced growth and skeletal

defects) and late-term abortions are well characterized and accompanied
by maternal toxicity near the limit dose. Protection of the maternal
effects also protects for any effects that may occur during development.
There are no residual uncertainties concerning pre- and post-natal
toxicity and there are no neurotoxicity concerns. A conservative
endpoint from the rabbit developmental study was used for all exposure
scenarios. Furthermore, the dietary food exposure assessment is also
conservative since it utilizes tolerance level residues and 100% crop
treated (CT). Conservative (protective) assumptions were used in the
ground and surface water modeling to assess exposure to fluopicolide in
drinking water. HED used similarly conservative assumptions to assess
post-application exposure of children as well as incidental oral
exposure of toddlers.

**Dietary Exposure (Food and Drinking Water):**

As determined by HED, the residue of concern for the tolerance
expression for domestic primary plants is fluopicolide (parent) as an
indicator of combined residues of fluopicolide and its metabolite
2,6-dichorobenzamide. Residues considered in the risk assessment for
domestic primary plants except tuberous and corm vegetables are parent
and BAM. For tuberous and corm vegetables, the residues of concern
include parent, BAM, and 3-chloro-5-trifluoromethylpyridine-2-carboxylic
acid (PCA; AE C657188). Based on its structure, the metabolite PCA is
not expected to be more toxic than parent.

It should be noted that tolerances on livestock commodities will not be
established at this time because HED is not recommending for
establishment of tolerances on potato and the rotational crop wheat, the
only fluopicolide crops with livestock feed items. Tolerances on
rotational crops will not be established at this time because HED is
recommending for rotational crop restrictions.

Residues included in the drinking water risk assessment are parent
fluopicolide and the metabolite BAM based on two aerobic soil metabolism
studies. BAM was a major degradate in the aerobic soil metabolism
studies, present at levels up to 40%.

Since residues are expected from both fluopicolide and BAM, two dietary
assessments were conducted to be health protective. One dietary
assessment was conducted for fluopicolide residues of concern in food
and drinking water from uses of fluopicolide (discussed in this
Assessment), and a second dietary assessment was conducted for residues
of BAM in food and drinking water from uses of fluopicolide and
dichlobenil (discussed in the BAM Human Health Risk Assessment, DP
#345918, N. Dodd, 11/21/07).

The chronic dietary (food and drinking water) exposure assessment for
fluopicolide was a conservative assessment using the recommended
tolerance levels and assuming that 100% of the crop was treated.
Residues of fluopicolide are detectable in most crops and they tend to
be higher in leafy vegetables. The available processing data indicate
that residues concentrate in raisins, processed potato waste, wheat
milled byproducts, and to a lesser degree in tomato processed
commodities. No residues are expected to occur in livestock commodities
since no crops in this petition have livestock feed items.

The chronic dietary (food and drinking water) exposure to fluopicolide
is below HED's level of concern for the general U.S. population and all
population subgroups. The chronic dietary exposure estimates are 6% of
the chronic Population Adjusted Dose (cPAD) for the general U.S.
population and 9% cPAD for children 1-2 years old, the most highly
exposed subgroup.

**Residential Exposure:**

Fluopicolide is proposed for use on residential turfgrass and
recreational sites such as golf courses. The proposed labels do not
prohibit application by home-owners; therefore, short-term
non-occupational handler exposure was evaluated. Residential
postapplication exposure via the inhalation route is expected to be
negligible; however, dermal exposure is likely for adults and children
entering treated lawns. Toddlers may also experience exposure via
incidental non-dietary ingestion (i.e., hand-to-mouth, object-to-mouth
(turfgrass), and soil ingestion) during postapplication activities on
treated turf.

The total Margins of Exposure (MOEs) for residential handlers are well
above the LOC of 100, and are not of concern. Residential
short-/intermediate-term postapplication MOEs were estimated for "Day 0"
exposure (i.e., the day of application). The total
short-/intermediate-term MOEs for adults (including handler exposure
which could co-occur with postapplication exposure) and children are 550
and 450, respectively. These total MOEs are greater than the LOC of 100
on the day of application, and therefore, are not of concern.

**Aggregate Risk:**

In examining acute aggregate risk, HED assumed that the only pathway of
exposure relevant to the acute time frame is dietary exposure (i.e., any
non-dietary exposures are short- and/or intermediate-term duration).
Therefore, the acute aggregate risk would be composed of exposures to
residues in food and drinking water; however, an acute dietary
assessment was not conducted because an endpoint attributable to a
single dose was not identified from the available data for fluopicolide.

Short-term exposures (1-30 days of continuous exposure) may occur as a
result of activities on treated turf. Exposures related to turf
activities have been combined with chronic dietary exposure estimates
(as an estimate of background dietary exposure) to assess short-term
aggregate exposure. Since the aggregate MOEs are greater than 100, they
represent risk estimates that are below HED's level of concern.

The intermediate-term aggregate risk is the same as calculated for
short-term aggregate risk.

In examining long-term aggregate risk, HED has assumed that the only
pathway of exposure relevant to that time frame is dietary exposure
(*i.e*., any non-dietary exposures are short- and/or intermediate-term
in duration). Therefore, the long-term aggregate risk is composed of
exposures to fluopicolide residues in food and drinking water and is
equivalent to the chronic dietary risk. The chronic risk estimates are
below HED's level of concern for all population subgroups.

**Occupational Exposure/Risk:**

The results of the *handler* occupational exposure and risk assessment
indicate that risks are not of concern with baseline clothing, or in
some cases, when gloves are worn (which is required on the proposed
labels). The Total MOEs range from 100 to 19,000; and therefore, are not
of concern.

The results of the occupational *postapplication* exposure and risk
assessment indicate that:

-   MOEs for agricultural uses are greater than 100 on the day of
    application (or the day after application for grapes, for which a
    restricted entry interval of one day may be needed ), and therefore,
    are not of concern.

-   MOEs for turf and ornamental (nursery stock) uses are greater than
    100 on the day of application, and are not of concern

-   Ornamental use (for cut flowers) at the [maximum rate]{.underline}
    requires 6 days for residues to decline to a level at which MOEs
    reach 100. However, when the minimum proposed rate is used, MOEs
    reach 100 on the day after application.

**Environmental Justice Considerations:**

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,\"
<http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup's
food consumption. Extensive data on food consumption patterns are
compiled by the USDA under the Continuing Survey of Food Intake by
Individuals (CSFII) and are used in pesticide risk assessments for all
proposed/registered food uses/tolerances of a pesticide. These data are
analyzed and categorized by subgroups based on age, season of the year,
ethnic group, and region of the country. Additionally, OPP is able to
assess dietary exposure to smaller, specialized subgroups and exposure
assessments are performed when conditions or circumstances warrant.
Further considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure from traditional dietary patterns among
specific subgroups.

**Review of Human Research:**

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies (listed in Appendix D) have been determined to
require a review of their ethical conduct. They are also subject to
review by the Human Studies Review Board. The listed studies have
received the appropriate review.

**Additional Data Needs:**

Pending submission of revised Sections B and F (and provided that the
Human Health Risk Assessment for BAM is adequate), there are no data
gaps related to toxicology, residue chemistry, or
occupational/residential exposure that would preclude conditional
registrations and permanent tolerances for residues of the herbicide
fluopicolide.[Number range CHAPTER]{.mark}

[]{.mark}

**Residue Chemistry Deficiencies**

The recommended conditional registrations can be converted to
unconditional registrations when the remaining deficiency concerning
storage stability, which is cited in Section 10.2 of this document, is
resolved.

**Toxicology Deficiencies**

None.

**Occupational and Residential Exposure Deficiencies**

None.

**2.0 Ingredient Profile**

[]{#__RefHeading___Toc185228015 .anchor}

Fluopicolide
(2,6-dichloro-*N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide;
AE C638206; V10161) is a fungicide which is placed in both the benzamide
and pyridine class of compounds.

Fluopicolide controls a wide range of *Oomycete* (Phycomycete) diseases
including downy mildews (*Plasmopara*, *Pseudoperonospara*,
*Peronospora*, and *Bremia*), late blight (*Phytophthora*), and some
*Pythium* species. Fluopicolide appears to interfere with mitosis and
cell division resulting in the rapid destabilization of fungal cell
structures; this pesticidal mode of action has been characterized as
novel and unique and unlike the known modes of action of other
registered fungicides. In the plant, fluopicolide is a mesosystemic
fungicide; it translocates toward the stem tips via the xylem but it
does not translocate toward the roots.

2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil. A separate
human health risk assessment is being concurrently conducted for BAM
from both fluopicolide and dichlobenil.

**2.1 Summary of Proposed Uses**[]{#__RefHeading___Toc185228016 .anchor}

Valent submitted proposed labels for two products to be used on
food/feed crops: V-10161 4 SC (suspendable concentrate), a 4 lb ai/gal
FlC (an aqueous flowable concentrate) formulation with EPA File Symbol
No. 59639-RUN; and V-10162 Premix, a FlC (an aqueous flowable
concentrate) formulation containing 0.52 lb/gal of fluopicolide and 5.2
lb/gal of propamocarb hydrochloride, with EPA File Symbol No. 59639-RUE.

Valent also submitted labels for non-food uses: V-10161 VPP Fungicide
(EPA File Symbol No. 59639-RUR), an aqueous flowable formulation
containing 4 lb ai/gal, for use on turfgrass and ornamental plants, and
V-10162 VPP Fungicide (EPA File Symbol No. 59639-RUG), an aqueous
flowable formulation containing 0.52 lb/gal of fluopicolide and 5.2
lb/gal of propamocarb hydrochloride, for use on turfgrass and ornamental
plants.

The proposed use directions for fluopicolide are presented in Table 2.1
below. Although a second active ingredient (propamocarb hydrochloride)
is included in two formulations, the application rates presented in the
table below reflect the ai fluopicolide only. The proposed uses of
propamocarb hydrochloride on cucurbit vegetables, fruiting vegetables,
head and leaf lettuce, and potato (on the label for V-10162 Premix; EPA
File Symbol No. 59639-RUE) and on turfgrass and ornamental plants (on
the label for V-10162 VPP Fungicide; EPA File Symbol No. 59639-RUG) are
not evaluated in this document; the adequacy of the proposed use
directions and the availability of adequate supporting residue data will
be addressed in a separate review.

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 28%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="13"><strong>Table 2.1. Summary of Directions for Use of
Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th colspan="2">Applic. Timing, Type, and Equip.</th>
<th colspan="2"><p>Formulation</p>
<p>[EPA Reg. No.]</p></th>
<th><p>Applic. Rate</p>
<p>(lb ai/A)</p></th>
<th colspan="3">Max. No. Applic. per Season</th>
<th colspan="2"><p>Max. Seasonal Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[g ai/ha]</p></th>
<th>PHI (days)</th>
<th colspan="2">Use Directions and Limitations*</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="13">Cucurbit Vegetables [Acorn Squash; Balsam Apple; Balsam
Pear; Bittermelon; Butternut Squash; Calabaza; Cantaloupe; Chayote,
Fruit; Chinese Cucumber; Chinese Okra; Chinese Preserving Melon; Chinese
Waxgourd; Citron Melon; Cucumber; Cucuzza; Gherkin; Gourd, Edible;
Hechima; Hubbard Squash; Hyotan; <em>Momordica</em> spp; Muskmelon;
Pumpkin; Spaghetti Squash; Summer Squash; Watermelon; Winter
Squash]</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td>0.09-0.125</td>
<td colspan="3">4</td>
<td colspan="2">0.375</td>
<td>2</td>
<td colspan="2" rowspan="2"><p>Applications are to be made in a minimum
of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.</p>
<p>Retreatment Interval (RTI) is 10 days.</p></td>
</tr>
<tr class="odd">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10162 Premix</td>
<td>0.09-0.11</td>
<td colspan="3">4</td>
<td colspan="2">0.34</td>
<td>2</td>
</tr>
<tr class="even">
<td colspan="13">Fruiting Vegetables [Bell Pepper; Chili Pepper; Cooking
Pepper; Eggplant; Groundcherry (<em>Physalis</em> spp.); Pepino;
Pimento, Sweet Pepper; Tomatillo; Tomato]</td>
</tr>
<tr class="odd">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td>0.09-0.125</td>
<td colspan="3">4</td>
<td colspan="2">0.375</td>
<td>2</td>
<td colspan="2" rowspan="2"><p>Application to be made in a minimum of 20
gal/A using ground equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 7 days.</p></td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10162 Premix</td>
<td>0.09-0.11</td>
<td colspan="3">4</td>
<td colspan="2">0.34</td>
<td>2</td>
</tr>
<tr class="odd">
<td colspan="13">Grapes</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td>0.09-0.125</td>
<td colspan="3">4</td>
<td colspan="2">0.375</td>
<td>21</td>
<td colspan="2"><p>Application to be made in a minimum of 20 gal/A using
ground equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 12 days.</p></td>
</tr>
<tr class="odd">
<td colspan="13">Leafy Vegetables (except <em>Brassica</em> Vegetables)
[Amaranth, Chinese Spinach; Arugula, Roquette; Cardoon; Celery; Celtuce;
Chinese Celery; Chervil; Chrysanthemum, Edible-leaved; Chrysanthemum,
Garland; Corn Salad; Cress, Garden; Cress, Upland; Dandelion; Dock,
Sorrel; Endive, Escarole; Fennel; Florence; Lettuce, Head and Leaf;
Orach; Parsley; Purslane, Garden; Purslane, Winter; Radicchio, Red
Chicory; Rhubarb; Spinach; Spinach, New Zealand; Spinach, Vine; Swiss
Chard]</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td>0.09-0.125</td>
<td colspan="3">4</td>
<td colspan="2">0.375</td>
<td>2</td>
<td colspan="2"><p>Application to be made in a minimum of 20 gal/A using
ground equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 10 days.</p></td>
</tr>
<tr class="odd">
<td colspan="13">Lettuce, Head and Leaf</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10162 Premix</td>
<td>0.09-0.11</td>
<td colspan="3">4</td>
<td colspan="2">0.34</td>
<td>2</td>
<td colspan="2"><p>Application to be made in a minimum of 20 gal/A using
ground equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 10 days.</p></td>
</tr>
<tr class="odd">
<td colspan="13"></td>
</tr>
<tr class="even">
<td colspan="13">Potato</td>
</tr>
<tr class="odd">
<td>Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td colspan="3">0.09-0.125</td>
<td>4</td>
<td colspan="2">0.375</td>
<td colspan="3">7</td>
<td><p>Application to be made in a minimum of 20 gal/A using ground
equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 10 days.</p></td>
</tr>
<tr class="even">
<td>Postemergence</td>
<td colspan="2">V-10162 Premix</td>
<td colspan="3">0.09-0.11</td>
<td>4</td>
<td colspan="2">0.34</td>
<td colspan="3">7</td>
<td><p>Application to be made in a minimum of 20 gal/A using ground
equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 10 days.</p></td>
</tr>
<tr class="odd">
<td colspan="13">Sweet Potato</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2">V-10161 4 SC</td>
<td>0.09-0.125</td>
<td colspan="3">4</td>
<td colspan="2">0.375</td>
<td>7</td>
<td colspan="2"><p>Application to be made in a minimum of 20 gal/A using
ground equipment or 5 gal/A using aerial equipment.</p>
<p>RTI is 10 days.</p></td>
</tr>
<tr class="odd">
<td colspan="13">Turf (Residential, Commercial, Golf Course, Sod
Farms)</td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2"><p>V-10161</p>
<p>VPP Fungicide</p></td>
<td>0.27</td>
<td colspan="3">2</td>
<td colspan="2">0.54</td>
<td>N/A</td>
<td colspan="2" rowspan="2">Apply in a minimum volume of 2 gal/1000
ft<sup>2</sup>. Application intervals are 14 days.</td>
</tr>
<tr class="odd">
<td colspan="2">Postemergence</td>
<td colspan="2"><p>V-10162</p>
<p>VPP Fungicide</p></td>
<td>0.21</td>
<td colspan="3">2</td>
<td colspan="2">0.42</td>
<td>N/A</td>
</tr>
<tr class="even">
<td colspan="13">Ornamental Plants (Bedding plants, Conifers, Flowering
plants, Foliage plants, Ground covers, Non-bearing fruit and nut trees,
Ornamentals [container-, bench-, or bed-grown in greenhouses or outdoor
nurseries), Ornamental trees, Shrubs, Vines)</td>
</tr>
<tr class="odd">
<td colspan="2">Postemergence</td>
<td colspan="2"><p>V-10161</p>
<p>VPP Fungicide</p></td>
<td><p>Spray: 0.27-0.54</p>
<p>Drench: 6.8-27</p></td>
<td colspan="3" rowspan="2">No more than 2 applications per cropping
cycle.</td>
<td colspan="2">Not stated</td>
<td>NA</td>
<td colspan="2" rowspan="2"><p><u>Foliar spray:</u> Apply spray mixture
to all plant surfaces to the point of runoff (approximately 100
gal/20,000 ft<sup>2</sup>). Minimum application intervals are 14
days.</p>
<p><u>Drench:</u> Use enough solution to wet the root zones of plants
(see label charts for volume appropriate to pot, bed, and flat size).
Minimum application intervals are 14 days.</p></td>
</tr>
<tr class="even">
<td colspan="2">Postemergence</td>
<td colspan="2"><p>V-10162</p>
<p>VPP Fungicide</p></td>
<td><p>Spray: 0.21-0.42</p>
<p>Drench: 5.3-21</p></td>
<td colspan="2">Not stated</td>
<td>NA</td>
</tr>
</tbody>
</table>

\*Additional General Use Directions and Limitations:

The proposed label for the 4 lb ai/gal FlC formulation (V-10161 4 SC)
specifies that the product must always be applied in a tank mix with
fungicides from different target site of action groups that are
registered for the same use and that are effective against the pathogens
of concern. The label specifies that the minimum labeled rate of each
fungicide in the tank mix should be used. The label for the 0.52 lb/gal
FlC formulation, which also contains propamocarb hydrochloride, states
that the product may be used in tank mixtures with fungicides from
different target site of action groups that are registered for the same
use. The label specifies that the minimum labeled recommended rate of
each fungicide in the tank mix should be used.

Applications are to begin when crop and/or environmental conditions
favor disease development. A maximum of two sequential fluopicolide
applications are to be made before alternating with an effective
fungicide from a different resistance management group.

The following tank mixes are recommended on the label for the 4 lb
ai/gal FlC formulation: mefenoxam or other labeled product with activity
on downy mildew and *Phytophthora* for cucurbit and fruiting vegetables;
Flint® (trifloxystrobin), Pristine® (pyraclostrobin and boscalid), or
Procure® (triflumizole), or other labeled products with activity on
downy mildew for grapes; strobilurin (Group 11 fungicides) or Aliette®
(fosetyl-Al), or other products listed on the label with activity on
downy mildew for leafy vegetables; and mefenoxam or other products
listed on the label with activity on *Phytophthora* for potato and sweet
potato. The label specifies that all use directions specified on each
label must be followed for any product to be tank mixed with V-10161 4
SC.

The 0.52 lb/gal FlC formulation allows tank-mixing with other labeled
pesticides although no specific tank mixes were recommended.

A restricted entry interval of 12 hours has been proposed. The following
rotational crop restrictions are proposed for the 4 lb/gal FlC
formulation: a 0-day PBI for cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables, and tuber vegetables; a 30-day PBI for wheat;
and a 12-month PBI for all other crops. The 0.52 lb/gal FlC formulation
specifies the same rotational crop restrictions except that a 120-day
PBI is proposed for wheat.

HED concludes that the submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed use;
however, until all field rotational crop and livestock data requirements
have been satisfied, [the proposed rotational crop restrictions must be
modified to state that crops may not be rotated to any crops other than
cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, and
tuberous and corm vegetables (except potato) with a 0-day
PBI.]{.underline} Refer to Section 10.2 for recommended label revisions.

**2.2 Structure and Nomenclature**[]{#__RefHeading___Toc185228017
.anchor}

+-------------------+--------------------------------------------------+
| **Table 2.2.      |                                                  |
| Fluopicolide      |                                                  |
| Nomenclature**.   |                                                  |
+===================+==================================================+
| Chemical          | ![](media/image2.wmf){width="2.2in"              |
| structure         | height="0.93125in"}                              |
+-------------------+--------------------------------------------------+
| Empirical Formula | C~14~H~8~Cl~3~F~3~N~2~O                          |
+-------------------+--------------------------------------------------+
| Common name       | Fluopicolide                                     |
+-------------------+--------------------------------------------------+
| Company           | AE C638206                                       |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | 2,6-dichloro-*N*-\[3-chlor                       |
|                   | o-5-(trifluoromethyl)-2-pyridylmethyl\]benzamide |
+-------------------+--------------------------------------------------+
| CAS name          | 2,6-dichloro-*N*-\[\[3-chloro-5-                 |
|                   | (trifluoromethyl)-2-pyridinyl\]methyl\]benzamide |
+-------------------+--------------------------------------------------+
| CAS Registry      | 239110-15-7                                      |
| Number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use products  | V-10161 4SC Fungicide (39.5% fluopicolide; EPA   |
| (EPs)             | File Symbol No. 59639-RUN)                       |
|                   |                                                  |
|                   | V-10161 Premix Fungicide (5.54% fluopicolide and |
|                   | 55.4% propamocarb; EPA File Symbol No.           |
|                   | 59639--RUE)                                      |
+-------------------+--------------------------------------------------+
| Chemical Class    | Fungicide                                        |
+-------------------+--------------------------------------------------+
| Known Impurities  | None                                             |
| of Concern        |                                                  |
+-------------------+--------------------------------------------------+

**2.3 Physical and Chemical Properties**

+---------------------+--------------------------------+--------------+
| **Table 2.3.        |                                |              |
| Physicochemical     |                                |              |
| Properties of       |                                |              |
| Fluopicolide.**     |                                |              |
+=====================+================================+==============+
| Parameter           | Value                          | Reference    |
+---------------------+--------------------------------+--------------+
| Molecular Weight    | 383.59                         | \*           |
+---------------------+--------------------------------+--------------+
| Melting point/range | 149 °C                         | MRID         |
|                     |                                | 46474015^1^  |
+---------------------+--------------------------------+--------------+
| pH                  | 6.5 at 22.0 °C (1% suspension) | MRID         |
|                     |                                | 46474013^1^  |
+---------------------+--------------------------------+--------------+
| Density             | 1.65 g/cm^3^ (30 °C)           | MRID         |
|                     |                                | 46474016^1^  |
+---------------------+--------------------------------+--------------+
| Water solubility    | 2.86 mg/L at pH 4              | MRID         |
| (20 °C)             |                                | 46474021^1^  |
|                     | 2.80 mg/L at pH 7              |              |
|                     |                                |              |
|                     | 2.80 mg/L at pH 9              |              |
+---------------------+--------------------------------+--------------+
| Solvent solubility  | n-Hexane: 0.20                 | MRID         |
| (g/L at 20 °C)      |                                | 46474022^1^  |
|                     | Ethanol: 19.2                  |              |
|                     |                                |              |
|                     | Toluene: 20.5                  |              |
|                     |                                |              |
|                     | Ethyl acetate: 37.7            |              |
|                     |                                |              |
|                     | Acetone: 74.7                  |              |
|                     |                                |              |
|                     | Dichloromethane: 126           |              |
|                     |                                |              |
|                     | Dimethyl sulfoxide: 183        |              |
+---------------------+--------------------------------+--------------+
| Vapor pressure (25  | 8.03 x 10^-7^ Pa               | MRID         |
| °C)                 |                                | 46474023^1^  |
+---------------------+--------------------------------+--------------+
| Dissociation        | No evidence of ionization in   | MRID         |
| constant (pKa)      | the pH range of 1.9 to 9.8     | 46474017^1^  |
+---------------------+--------------------------------+--------------+
| Octanol/water       | Log P~OW~ = 3.26 at pH 7.8 and | MRID         |
| partition           | 22 ± 1 °C                      | 46474018^1^  |
| coefficient         |                                |              |
| Log(K~OW~)          |                                |              |
+---------------------+--------------------------------+--------------+
|                     | Log P~OW~ = 2.9 at pH 4.0, 7.3 | MRID         |
|                     | and 9.1 and 40 °C              | 46474019^1^  |
+---------------------+--------------------------------+--------------+
| UV/visible          | Absorption maxima wavelengths  | MRID         |
| absorption spectrum | (nm):                          | 46474014^1^  |
|                     |                                |              |
|                     | In methanol: 203 and 271       |              |
|                     |                                |              |
|                     | In methanol/HCl: 202 and 270   |              |
|                     |                                |              |
|                     | In methanol/NaOH: 219 and 271  |              |
+---------------------+--------------------------------+--------------+

\*The molecular weight was calculated from the Periodic Table.

**3.0 Hazard Characterization/Assessment**
[]{#__RefHeading___Toc185228018 .anchor}

**3.1 Hazard and Dose-Response
Characterization**[]{#__RefHeading___Toc185228019 .anchor}

**3.1.1 Database Summary**[]{#__RefHeading___Toc185228020 .anchor}

The toxicology database for fluopicolide (AC 638206) submitted by Bayer
CropScience AG is

complete and deemed adequate for hazard assessment and for FQPA
evaluation.

An important fluopicolide metabolite, 2,6-dichlorobenzamide (BAM) is
considered in this risk assessment, and its hazard
characterization/assessment appears in the BAM Human Health Risk
Assessment (DP #345918, N. Dodd, 11/21/07).

**3.1.1.1 Studies available and considered (animal, human, general
literature)** []{#__RefHeading___Toc185228021 .anchor}

[Fluopicolide]{.underline} (AC638206)

[Acute]{.underline}- oral, dermal, inhalation, eye irritation, skin
irritation, dermal sensitization

> [Subchronic]{.underline}- oral 90-day rat, oral 90-day mouse (2
> studies), oral 90-day dog
>
> [Chronic]{.underline}- oral rat (combined chronic/carcinogenicity) and
> oral dog
>
> [Reproductive/developmental]{.underline}- oral developmental rat and
> rabbit, rat reproduction/fertility
>
> [Other]{.underline}- acute and subchronic rat neurotoxicity, oral
> mouse carcinogenicity, mutagenicity studies (*in vitro and in vivo*),
> metabolism/pharmacokinetics studies and phenobarbital 28-day
> hepatotoxicity mouse studies (2 studies)

**3.1.1.2 Mode of action, metabolism, toxicokinetic
data**[]{#__RefHeading___Toc185228022 .anchor}

Fluopicolide is a fungicide that is effective in controlling plant
disease caused by *Oomycetes*. The biological activity is mesosystemic
in that it controls pathogens on contact through translocation toward
the stem tips and not the roots. The exact mode of action of disease
control has not been fully determined. The test substance is mostly used
on grapes and raisins. For detailed metabolism and toxicokinetic data,
please refer to Section 3.2.

**3.1.1.3 Sufficiency of studies/data**[]{#__RefHeading___Toc185228023
.anchor}

The toxicity database is complete for fluopicolide (see Appendixes A-2
through A-4 for toxicity profile tables) and is adequate for risk
assessment evaluations and determination of FQPA. All studies evaluated
were deemed acceptable and met guideline criteria except for one reverse
gene mutation study. This study was unacceptable because purity of the
test material was not provided; however, there were enough adequate
studies for gene mutation that this does not constitute a data gap.

**3.1.2 Toxicological Effects**[]{#__RefHeading___Toc185228024 .anchor}

**NOAEL and LOAEL:** The no-observed-adverse-effect level (NOAEL) is the
dose level at which no adverse effects were noted. The
lowest-observed-adverse-effect level (LOAEL) is the lowest dose level at
which effects of toxicological significance are observed. These two
parameters are adequately provided in the studies for fluopicolide.

**Acute toxicity:** Fluopicolide has moderate toxicity with no deaths
noted in male or female rats at doses of \> 2000 mg/kg when given
orally, and \> 4000 mg/kg dermally. Following inhalation exposure, an
LC~50~ of \>1.789 to \< 5.16 mg/L was calculated. Toxicity was observed
primarily in the inhalation studies and included a decrease in body
weight, decrease in mean body temperature and signs of irritation
(piloerection, hunched posture, reddened nostrils). Slight eye
irritation occurred in the form of chemosis and corneal opacities, but
all effects were gone by 72 hours. No dermal irritation occurred, and
the test substance was not a skin sensitizer.

**Subchronic toxicity:** The most common effect observed in the 90 day
studies was a decrease in body weight gain. Weight gain was markedly
decreased in male and female rats in a subchronic study at doses that
exceeded the limit dose (1668-1673 mg/kg/day), and male and female rats
in a subchronic neurotoxicity study had reduced body weight gain at
doses of 780.6 and 125.2 mg/kg/day, respectively. There was no effect on
weight gain in dogs or mice in subchronic studies. Besides effects on
body weight and body weight gain, no definitive cross-species target
organ was identified in subchronic studies with fluopicolide. No organ
lesions were found in dogs administered up to 1000 mg/kg/day for 90
days. Male rats had hypertrophy of the zona glomerulosa in the adrenal
gland, trabecular hyperostosis of the bone joint, and decreased bone
marrow cellularity after exposure to 1668 mg/kg/day for 90 days. Similar
lesions in the adrenal gland and bone marrow were found in female rats
administered 119 mg/kg/day for 90 days. In mice, females administered
965 mg/kg/day showed an increased incidence of hepatic oval cell
proliferation.

**Chronic toxicity:** As in the subchronic studies, the main effect in
the chronic studies was a decrease in body weight gain with no
definitive cross-species target organ identified. Male dogs had reduced
weight gain after exposure to 1000 mg/kg/day for one year; body weight
of females was not affected. Mice had severely decreased body weight and
body weight gain with administration of 551.0 and 772.3 mg/kg/day to
males and females, respectively, for 18 months. Male and female rats had
decreased weight gain after exposure to 109.4 and 142.2 mg/kg/day for 2
years, respectively. No organ lesions were found in dogs administered up
to 1000 mg/kg/day for 52 weeks. Thyroid cystic follicular hyperplasia
was seen in male rats after 109.4 mg/kg/day for two years. In mice,
altered liver cell foci were seen in males and females given 551.0 or
772.3 mg/kg/day, respectively, for 18 months.

**Carcinogenicity:** No evidence for carcinogenicity was seen in rats
administered fluopicolide in food for 24 months. Treatment of rats did
not result in an increase in overall tumor incidence or an increase in
the incidence of any specific type of tumor. In contrast, mice had an
increased incidence of hepatocellular adenoma following administration
of 3200 ppm in the diet for 18 months (551.0 and 772.3 mg/kg/day for
males and females, respectively).

**Developmental toxicity:** In developmental toxicity studies, maternal
toxicity was clearly evident only in rabbits as increased mortality,
abortion, and decreased body weight gain at 60 mg/kg/day, the highest
dose tested. Minimal maternal toxicity was observed in rats dosed with
700 mg/kg/day; slightly reduced body weight gain did not result in lower
absolute body weight. At the same dose affecting the dam, 700 mg/kg in
rats and 60 mg/kg in rabbits, fetal growth was affected in both species
and observed as decreases in body weight and crown-rump length. Also, at
700 mg/kg, delays in fetal ossification and increased incidence of
skeletal defects were observed in rat fetuses, with neither of these
effects seen in rabbit fetuses. No external or visceral abnormalities
were observed in either species. In the rat, the developmental effects
observed (developmental delays and skeletal defects) were judged to be
qualitatively more severe than the minimal maternal toxicity (decreased
body weight gain) observed, suggesting a greater qualitative
susceptibility in the fetus compared to that of the dam. This issue is
further discussed in Sections 3.3.6.1 and 3.3.6.2.

**Reproductive toxicity:** Reproductive performance was not affected in
a two-generation reproduction toxicity study in which fluopicolide was
administered to male and female rats at nominal dietary concentrations
of 0, 100, 500, or 2000 ppm (0, 7.4-8.8, 36.4-43.7, 144.6-179.9
mg/kg/day, respectively, for males and 0, 8.1-9.4, 41.0-46.9,
159.7-193.9 mg/kg/day, respectively, for females). Evidence of parental
toxicity in the high-dose groups included decreased body weight gain in
F~0~ females and kidney toxicity in F~0~ and F~1~ males and females.
Kidney lesions consisted of cortical tubular basophilia or dilation,
medullary granular casts, cortical scarring, interstitial inflammation,
and/or corticomedullary mineralization. Body weight of the high-dose
F~1~ and F~2~ pups was significantly less than that of the controls
beginning on lactation day 14. The high-dose pups had decreased weight
gain throughout the 28-day lactation interval. Overall weight gain
during lactation was decreased by 8-9% of the control level in the
high-dose F~1~ male and female pups and by 11-14% in the high-dose F~2~
male and female pups. No other effects on offspring growth or survival
were noted in either generation.

**Neurotoxicity:** No evidence of neurotoxicity was seen in acute or
subchronic oral rat neurotoxicity studies with fluopicolide. In the
acute study, a transient decrease in body temperature was the only
finding in male and female rats given a single dose of 2000 mg/kg. Brain
weight, brain morphometry, and neuropathology were not affected by
treatment.

**Dermal toxicity:** Acute dermal toxicity studies showed that
fluopicolide was only a slight dermal irritant (Tox. Category IV). A
dermal subchronic toxicity study showed no systemic or local effects at
the limit dose.

**3.1.3 Dose-response**[]{#__RefHeading___Toc185228025 .anchor}

HED has selected the most sensitive and protective endpoints from the
database to develop the risk assessment. Appropriate endpoints were
selected for the chronic dietary exposure scenario, incidental oral
short-term and intermediate-term scenarios, dermal all time periods, and
inhalation all time periods. Further discussions in regards to the
studies chosen for each endpoint are included in Section 3.5.

**3.1.4 FQPA**[]{#__RefHeading___Toc185228026 .anchor}

Data are adequate for evaluation of effects resulting from *in utero*
and post-natal exposure. Acceptable developmental toxicity studies were
conducted in rodents and non-rodents, and a reproductive toxicity study
in rodents was available. Developmental toxicity was found in both rats
and rabbits at doses equal to those resulting in maternal toxicity so no
quantitative susceptibility was observed. Of the developmental studies,
rabbits were clearly more sensitive than rats. In the rat developmental
study, the developmental effects observed (developmental delays and
skeletal defects) were judged to be qualitatively more severe than the
minimal maternal toxicity (decreased body weight gain) observed. These
developmental effects occurred at 700 mg/kg with a NOAEL of 60 mg/kg. In
contrast, severe maternal toxicity was observed in rabbits and therefore
fetal loss was observed at 60 mg/kg with the maternal NOAEL of 20 mg/kg.
In the multigeneration rat study, neither quantitative nor qualitative
susceptibility was observed. Although there was apparent evidence of
increased qualitative susceptibility in the rat developmental study, the
more sensitive species (rabbit) has been used for the point of departure
in the risk assessment. Therefore, the 10X FQPA safety factor may be
reduced to 1X.

**3.1.5 The Report to the European Commission**

[]{#__RefHeading___Toc185228027 .anchor}

The Report and Proposed Decision of the United Kingdom made to the
European Commission under article 8(1) of 91/414/ECC (EU Monograph, MRID
46821401) has set the following limits:

1.  Acute RfD = 0.18 mg/kg/day based on impaired growth and
    histopathological changes in the liver and kidney at the LOAEL of
    106 mg/kg bw/day in a subchronic neurotoxicity study. The NOAEL is
    18 mg/kg/day, and the aRfD of 0.18 mg/kg bw/day allows for a
    100-fold uncertainty factor.

2.  Chronic RfD = 0.08 mg/kg/day based on increased liver weights,
    enlarged liver, masses and nodules and increased incidences of
    hepatocellular hepatocyte hypertrophy at the LOAEL of 64.5 mg/kg/day
    for the males an 91.9 mg/kg/day for the females (the mid-dose level)
    in a 78-week mouse study. The NOAEL is 7.9 mg/kg/day (the low-dose
    level) and the chronic RfD (Acceptable Daily Intake) of 0.08 allows
    for a 100-fold uncertainty factor for inter- and intra-species
    differences. A companion chronic rat study showed adverse effects
    occurring at the LOAEL of 31.5 mg/kg/day (the mid-dose level), with
    a NOAEL of 8.4 mg/kg/day (the low-dose level).

HED has not identified an endpoint in the available studies which can be
attributed to a single exposure; hence, HED has not set an acute RfD.

HED has reviewed the 78-week mouse study (MRID 46474130) mentioned
above, concluding that statistically- and toxicologically-significant
effects occurred at 551 mg/kg/day, (the high dose levels) only in both
studies, with the mid-dose level being the NOAEL. The EU Monograph
document identifies the mid-dose level as the LOAEL and the low-dose
levels as the NOAEL.

Since the developmental rabbit study provided endpoints at levels which
are more protective than the levels in these chronic studies
(NOAEL/LOAEL = 20/60 mg/kg/day), HED's chronic endpoints are based on
the rabbit developmental toxicity study. HED also considers the 104-week
study in rats just mentioned (MRID 46474139) to be the co-critical study
for determining the chronic RfD.

**3.2 Absorption, Distribution, Metabolism, Excretion (ADME)**
[]{#__RefHeading___Toc185228028 .anchor}

Several studies were available on metabolism and disposition for
fluopicolide in rats. The studies

demonstrated rapid absorption, metabolism and excretion within 72 hours
after oral dosing. The

main metabolites were oxidative N-dealkylation cleavage products. The
primary routes of excretion for the parent compound were fecal (68.8 -
72.4%) and urinary (18.8 - 21.4%) with metabolites identified in both
urine and feces. Up to 49 metabolites were identified in the urine,
while the main compound in the feces was identified as the parent. No
gender-related variability was observed in any of the studies. Following
administration of the fluopicolide, highest concentrations were found in
the intestines and its contents. The next highest concentrations were
found in the liver, kidneys and adrenals. However, based upon tissue
burden, neither the parent compound nor its metabolites appear to
undergo any significant tissue sequestration.

A metabolite of fluopicolide, 2,6-dichlorobenzamide or BAM, is formed
following hydroxylation of the parent molecule and cleavage of the
straight chain bridge to form the amide. Following oral administration
of BAM itself, it is found in the kidney and liver, and most of the
radioactivity (82%) is found in the urine, with 13% found in the feces.

Existing data show that BAM produces toxicity at lower levels than
fluopicolide but it is a minor metabolite of fluopicolide. When
fluopicolide is administered to the rat, only about 0.09% of the total
administered radioactivity 8 hours post-dosing is identified as BAM.

**3.3 FQPA Considerations**[]{#__RefHeading___Toc185228029 .anchor}

**3.3.1 Adequacy of the Toxicity
Database**[]{#__RefHeading___Toc185228030 .anchor}

Data for fluopicolide are adequate for evaluation of the FQPA factor.

**3.3.2 Evidence of Neurotoxicity**[]{#__RefHeading___Toc185228031
.anchor}

Acute and subchronic neurotoxicity studies have been conducted with
fluopicolide in rats. The

only notable functional observational battery (FOB) finding was a lower
body temperature in

males and females six hours after a single oral dose of 2000 mg/kg/day.
No clinical signs of

toxicity or effects on motor activity were observed in either study. In
acute inhalation lethality

studies, there were no treatment-related effects on a battery of reflex
measurements evaluated the

day after exposure; however, mean body temperature was decreased after
exposure.

[Acute Neurotoxicity in rats- fluopicolide]{.underline}

In an acute neurotoxicity study (MRID 46474218; summarized in MRID
46474217), groups of fasted, 6- to 7-week old CD rats (10/sex) were
given a single oral dose of AE C638206 (95.9% a.i., batch/lot
#OP2050046) in 1% methylcellulose at doses of 0, 10, 100, or 2000 mg/kg
bw and observed for 15 days. Doses were based on a range-finding study
in which single doses of 50 mg/kg induced behavioral changes (MRID
46474219). Neurobehavioral assessment (functional observational battery
\[FOB\] and motor activity testing) was performed in 10
animals/sex/group pretreatment, on Day 1 (at six hours post-dosing, the
time of peak effect), and on Days 8 and 15. Cholinesterase activity was
not determined. At study termination, 5 animals/sex/group were
euthanized and perfused *in situ* for neuropathological examination. Of
the perfused animals, the control and high-dose groups were subjected to
histopathological evaluation of brain and peripheral nervous system
tissues.

There was no effect of treatment on body weight, body weight gain, food
consumption, food efficiency, brain weight, brain measurements (cerebral
hemispheres), or incidence of gross or microscopic lesions. Lower body
temperature in the high-dose males and females at the time of peak
effect (6 hours post-dosing) on the day of treatment (Day 1) was the
only treatment-related observation during the FOB. This sign was not
observed on Days 8 or 15. A statistically significant decrease in
forelimb grip strength in females in the 2000 mg/kg group on Day 8,
reduced motor activity of males in the 2000 mg/kg treatment group on Day
1, and increased motor activity in females in the 2000 mg/kg group on
Day 15 were considered incidental to treatment as these effects were not
clearly dose-related and were not observed in the other sex.

**The LOAEL for AE C638206 in male and female rats was 2000 mg/kg, based
on the transient effect of lower body temperature. The NOAEL for male
and female rats was 100 mg/kg. Note: HED has determined that a change in
body temperature is not a single dose effect.**

This neurotoxicity study is classified as **Acceptable/Nonguideline.**
Upon receipt of provided positive control neuropathology data are
submitted by the conducting laboratory, this study can be upgraded to
Acceptable/Guideline, satisfying the guideline requirement for an acute
neurotoxicity study in rats (870.6200; OECD 424).

[Subchronic Neurotoxicity in rats- fluopicolide]{.underline}

In a subchronic neurotoxicity study (MRID 46474221), Technical Grade AE
C638206 (97.8% a.i., Batch \# OP2050046) was administered to 10 CD
rats/sex at dietary concentrations of 0, 200, 1400, or 10,000 ppm for 13
weeks. Time-weighted average doses were 0, 15.0, 106.6, or 780.6
mg/kg/day, respectively, for males and 0, 18.0, 125.2, or 865.8
mg/kg/day, respectively, for females. Neurobehavioral assessment
(functional observational battery \[FOB\] and motor activity testing)
was performed on all animals pre-test and at weeks 4, 8, and 13. At
study termination, 6 animals/sex/group were euthanized and perfused in
situ for neuropathological examination. Of the perfused animals, control
and high-dose rats were subjected to histopathological evaluation of
brain and peripheral nervous system tissues. Positive control data for
FOB and motor activity testing were submitted in MRID 46474222 and were
summarized in MRID 46474220.

All animals survived to scheduled sacrifice. No treatment-related
clinical signs of toxicity or gross lesions were observed in any group.
FOB findings and motor activity were similar between the treated and
control groups.

Mean body weight of the low-dose males and females was similar to the
controls throughout the study. Mid- and high-dose males and females had
slightly lower body weight than that of the control group beginning at
week 1 but these data were not analyzed statistically. Overall body
weight gain by the high-dose males and females and mid-dose females was
81%, 72%, and 87% (p ≤ 0.05 or 0.01), respectively, of the respective
control levels. The most pronounced effect on body weight gain in the
high-dose groups was during weeks 0-1 when males and females gained 56%
and 63%, respectively, of the control level. Weight gain by the mid-dose
groups appeared to be consistently less than that of controls at each
weekly interval. Food consumption by the high-dose males and females was
slightly less than that of the controls for most weekly intervals of the
study. Excessive food scatter was observed by the mid- and high-dose
males and by all treated female groups. Overall food conversion
efficiency by the high-dose males and females and mid-dose females was
87%, 79%, and 89%, respectively, of the respective control levels. The
most pronounced effect on food efficiency in the high dose groups was
during week 1 when males and females were 62% and 69%, respectively, of
the control level.

Treatment-related lesions observed in the liver (hypertrophy) of males
and females and the male kidney (hyaline droplets) were not considered
adverse or relevant to humans.

**Therefore, the systemic and neurotoxicity LOAEL for AE C638206 in male
and female rats is 10,000 and 1400 ppm, respectively (780.6 and 125.2
mg/kg/day for males and females, respectively) based on decreased body
weight gain, food consumption, and food efficiency. The NOAEL for males
and females was 1400 and 200 ppm, respectively (106.6 and 18.0 mg/kg/day
for males and females, respectively).**

This neurotoxicity study is classified as **Acceptable/Nonguideline.**
Upon submission of positive control neuropathology data by the
conducting laboratory, this study can be upgraded to
Acceptable/Guideline, satisfying the guideline requirement for a
subchronic neurotoxicity study in rats (870.6200; OECD 424).

**3.3.3 Developmental Toxicity Studies**[]{#__RefHeading___Toc185228032
.anchor}

Developmental toxicity studies have been conducted with fluopicolide in
the rat and rabbit. The rabbit was clearly the more sensitive species.
For example, both maternal and developmental effects occurred at a much
lower dose level in the rabbit, compared to the rat. The maternal and
developmental NOAELs/LOAELs are 60/700 mg/kg/day for the rat and 20/60
mg/kg/day for the rabbit.

In addition, the effects observed in both dams and offspring were more
severe in rabbit, compared with the rat. Maternal toxicity in the rat
was limited to marginally reduced body weight gain, while in the rabbit,
maternal toxicity consisted of death, abortions/premature deliveries,
decreased food consumption, and decreased body weight gain.
Developmental effects in the rat consisted of developmental delays and
skeletal defects. In the rabbit, developmental delays, premature
deliveries and abortions were observed and were due to severe maternal
toxicity.

[Developmental Toxicity in rats- fluopicolide]{.underline}

In a developmental toxicity study (MRID 46474120), AE C638206 (97.6 and
97.8% a.i., lot/batch \# PP/241024/2 & PP241067/1) was administered to
23 female Sprague-Dawley rats/dose by gavage at dose levels of 0, 5, 60,
or 700 mg/kg bw/day from days 7 through 20 of gestation. On gestation
day (GD) 21, dams were sacrificed and subjected to gross necropsy.
Approximately one-half of the fetuses were fixed in alcohol, examined
for external defects, checked for visceral anomalies, and then fixed and
examined for skeleton and cartilage defects. The remaining one-half of
the fetuses were examined for external defects and then examined for
visceral abnormalities by Wilson's slicing technique. The total number
of fetuses examined (number of litters) was 284(22), 291(21), 297(22),
and 274(21) for the 0, 5, 60, and 700 mg/kg bw/day groups, respectively.

Treatment with 700 mg/kg bw/day was only minimally toxic to the pregnant
dams. Mean absolute body weight values were statistically decreased
(p\<0.05) at several time points as compared to controls, but were not
biologically relevant at only 97-98% of control levels. No statistically
significant differences were noted in body weight gain at any intervals.
However, body weight gain over GD 7-21, both corrected and not corrected
for the gravid uterine weight, was bordering on biological significance
at 92% and 88%, respectively, of controls. No significant differences
were noted in clinical signs and feed consumption, or during gross
necropsy.

**Therefore, the maternal toxicity LOAEL for AE C638206 in rats is 700
mg/kg bw/day based on marginally reduced body weight gain, and the
maternal toxicity NOAEL is 60** **mg/kg bw/day.**

No adverse, treatment-related, statistically significant effects on
pregnancy rates, number of corpora lutea, pre- or post implantation
losses, resorptions/dam, fetuses/litter, or fetal sex ratio were
observed in the treated groups compared with the controls. No dams had
complete litter resorption. No treatment-related defects or external or
visceral variations were observed in any group.

Decreased fetal growth was noted in the high-dose group as evidenced by
significant decreases in mean fetal weight (3.4 g vs. 3.7 g for
controls), crown/rump length (34.8 mm vs. 36.2 mm for controls), mean
placental weight (0.52 g vs. 0.57 for controls), and delays in
ossification of sacral vertebra (arch/centra), sternebra, and 5^th^
metacarpal or 5^th^ metatarsal of the forepaw or hindpaw, respectively.
The high-dose group also had slightly elevated litter incidences of
skeletal defects of the thoracic vertebra (arch: aplasia, dysplasia,
fused, fused with attached rib; 4 fetuses from 3/21 litters affected),
thoracic vertebra (centra: aplasia, dysplasia, fragmented, fused,
dislocated; 10 fetuses from 6/21 litters affected), and ribs (aplasia,
dysplasia, shortened, fused, anlage of only 9; 6 fetuses from 3/21
litters affected) compared to the control incidence of 0/22 litters
affected.

**Therefore, the developmental toxicity LOAEL for AE C638206 in rats is
700 mg/kg bw/day based on delays in fetal growth (decreased fetal
weight, crown/rump length, delays in ossification) and skeletal defects
of the thoracic vertebra and ribs. The developmental toxicity NOAEL is
60** **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.

[Developmental Toxicity in rabbits- fluopicolide]{.underline}

In a developmental toxicity study (MRID 46474122) AE C638206
\[Fluopicolide; 97.8% a.i.; batch numbers PP/241024/2 and PP241067/1
(mixed sample)\] was administered to 23 mated female Chbb:HM(SPF)
Kleinrusse (Himalayan) rabbits/dose by gavage in 1% (w/v)
methylcellulose in deionized water at dose levels of 0, 5, 20, or 60
mg/kg bw/day on gestation days (GDs) 6 through 28, inclusive. On GD 29,
the surviving dams were sacrificed and necropsied. Gravid uterine
weight, corpora lutea counts, and the numbers and positions of live and
dead fetuses, early resorptions and late resorptions, empty implantation
sites and "conceptuses" were recorded. Fetuses were weighed, measured
crown-to-rump, subjected to external, visceral, and skeletal
examinations, including cross-sectioning of the eyes, brain, heart, and
kidneys. The number of fetuses (litters) examined in the control, low-,
mid-, and high-dose groups was 157 (22), 132 (20), 147 (21), and 32 (5),
respectively.

Treatment-related clinical signs included deaths of 3 high-dose animals
(on GDs 24, 25, and 29) following hypoactivity, decreased defecation
and/or decreased hay consumption over the preceding 1-5 days; one
decedent also had a bristling haircoat and red discoloration of the
urine on the day prior to death. Fifteen high-dose animals aborted or
delivered prematurely (during GD 22-28); five of these also showed
hypoactivity, decreased defecation, decreased hay consumption, abnormal
("pultaceous") feces, and/or red discoloration of the urine. One
surviving high-dose animal had increased salivation on GD 14. At the
highest dose level, there were treatment-related decreases in body
weight gain during GD 10-23 (approximately 54-70% of the control levels)
and mean weight loss by this group during GD 23-29 (-41.4 g. vs. +123.6
g. for controls). Mean daily food consumption of the high dose-animals
was decreased to 73-89% of controls during GD 8-23 (n.s) and to 46-57%
of controls during GD 23-29 (p\<0.05). Red discoloration of the urine
was noted from two additional high-dose animals at necropsy for a total
of five affected (3 in life and 2 post mortem); this finding is
considered treatment-related and possibly adverse.

**The maternal LOAEL** **for Fluopicolide in Himalayan rabbits is 60
mg/kg bw/day, based on death, abortions/premature deliveries, decreased
food consumption, and decreased body weight gain. The maternal NOAEL is
20 mg/kg bw/day.**

At the highest dose level, there were significant decreases in mean
fetal crown-rump length (94% of controls; p\<0.05) and mean fetal weight
(86%; p\<0.05). There were no treatment-related effects on live litter
size, numbers of dead fetuses or resorptions, or postimplantation loss.
Fetal sex ratio and placental weight were not affected by treatment.
There were no treatment-related increases in the fetal or litter
incidences of major or minor defects, variations, or retardations, and
no evidence of altered ossification was seen.

**The developmental LOAEL for Fluopicolide in Himalayan rabbits is 60
mg/kg bw/day, based on abortions, premature deliveries, and decreased
fetal body weight and crown-rump length. The developmental NOAEL is 20
mg/kg bw/day.**

This developmental toxicity study in the rabbit is classified
**Acceptable/Guideline** and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700b; OECD 414) in the rabbit.
Excessive maternal toxicity was seen at the highest dose level; however,
the dose levels were appropriately spaced, and the small number of
litters did not preclude the evaluation of the potential developmental
toxicity of fluopicolide.

**3.3.4 Reproductive Toxicity Study**[]{#__RefHeading___Toc185228033
.anchor}

Reproductive performance was not affected in a two-generation
reproduction toxicity study in

which fluopicolide was administered to male and female rats. The most
common effect was a

decrease in body weight gain in both the parental animals and offspring.

[Reproductive Toxicity in rats- fluopicolide]{.underline}

In a two-generation reproduction study (MRID 46474124 and 46474125), AE
C638206 (95.9% a.i., batch/lot \# OP2050046) was administered to 28 F~0~
generation and 24 F~1~ generation male and female Crl:CD®(SD)IGS BR rats
at concentrations of 0, 100, 500, or 2000 ppm. The dietary levels
corresponded to doses of 0, 7.4, 36.4, and 144.6 mg/kg bw/day,
respectively, for F~0~ males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for
F~1~ males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F~0~ females; and
0, 9.4, 46.9, and 193.9 mg/kg bw/day for F~1~ females. The premating
period was 10 weeks. The males received the treated or control diets
continuously until sacrificed when almost all their litters were weaned,
and the females received the diets during premating, mating, gestation,
and lactation until sacrifice after weaning their litters.

No treatment-related effects were observed on survival or clinical signs
in any group of parental male or female rats in either generation.
Absolute body weight and weight gain were significantly decreased but
were within 10% of that of controls in F~0~ and F~1~ males during
premating/postmating periods and in female rats during premating except
as noted below. High-dose F~0~ females gained up to 14% (p\<0.01) less
weight than controls and high-dose F~1~ males weighed 11% (p\<0.01) less
than controls on day 4 of premating because of the significantly
decreased male pup weight at weaning. Food consumption was significantly
decreased during a few weekly intervals in high-dose F~0~ and F~1~ males
and females, but was within 10% of that of controls. Food efficiency was
not significantly affected by treatment of male or female rats in either
generation. No treatment-related effect was observed on body weight,
weight gain, food consumption, or food efficiency in low- or mid-dose
male or female rats of either generation.

In high-dose pregnant females, body weight was significantly decreased
by 7% on GD 6 and 13 in the F~0~ generation and by 10-11% throughout
gestation in the F~1~ generation compared with that of controls. Both
generations gained 14-16% (p\<0.01) less weight than controls during the
first 13 days of gestation, but weight gain was similar to or greater
than that of controls after GD 13. A 13% decrease in body weight gain in
mid-dose F~0~ females during GD 0-6 was not accompanied by a decrease in
body weight. High-dose F~0~ and F~1~ lactating females had body weight
up to 8% and 13% (p\<0.01) less, respectively, than controls, but weight
gain was not significantly affected. High-dose F~0~ and F~1~ females
consumed up to 12% (p\<0.01) less food than controls during the first 13
days of lactation.

Postmortem evaluation showed treatment-related and toxicologically
significant effects only in the kidneys. High-dose F~0~ and F~1~ males
had small, statistically significant increases in absolute and relative
kidney weights and high-dose F~0~ and F~1~ females had significant
increases in relative kidney weight. No treatment-related gross lesions
were observed in male or female rats in either generation.
Treatment-related and toxicologically significant histopathologic
lesions were observed in the kidneys of high-dose F~0~ and F~1~ male and
female rats. The incidences of cortical tubular basophilia, medullary
granular casts, and cortical scarring were significantly increased in
high-dose F~0~ and F~1~ males compared with the control incidences. The
incidence of interstitial inflammation was significantly increased in
high-dose F~0~ males. The increased incidences of cortical tubular
dilatation and cortical granular casts in high-dose F~1~ males did not
reach statistical significance but were considered treatment related. In
high-dose F~0~ and F~1~ female rats, the incidences of cortical tubular
basophilia and cortical tubular dilatation were significantly increased
and the increased incidence of corticomedullary mineralization was not
statistically significant but was considered treatment related.

**The lowest-observed-adverse-effect level (LOAEL) for systemic toxicity
of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg bw/day in males and
159.7-193.3 mg/kg bw/day in females) based on decreases in weight gain
in F~0~ females and kidney toxicity in F~0~ and F~1~ males and females.
The no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4-43.7 mg/kg
bw/day in males and 41.0-46.9 mg/kg bw/day in females).**

Evaluation of reproductive parameters showed no treatment-related
effects on estrous cycle periodicity or length, sperm measures (motility
or sperm count), precoital interval, gestation length, or reproductive
indices (mating, conception, fertility, and gestation) in either
generation. The numbers of implantation sites and viable litters were
similar in the treated and control groups in both generations. No
treatment-related gross or microscopic lesions were observed in
reproductive organs.

**The lowest-observed-adverse-effect level (LOAEL) for reproductive
toxicity of AE C638206 in rats was not determined; therefore the
no-observed-adverse-effect level (NOAEL) is \>2000 ppm (\>179.9 mg/kg
bw/day in males and \>193.3 mg/kg bw/day in females).**

No treatment-related effects were observed on the behavior or other
clinical signs of offspring of either generation. No treatment-related
effects were observed on litter size, sex ratio, or any survival index
(postimplantation survival, live birth, viability, and lactation
indices) in F~1~ or F~2~ offspring. The day of attainment of sexual
maturation and the body weight at attainment were not affected by
treatment with the test material in male or female F~1~ offspring. Body
weight was significantly reduced by 7-13% in high-dose group F~1~ and
F~2~ male and female pups 14, 21, and 28 days old. Weight gain over the
28-day postnatal period was significantly decreased by 8-9% in high-dose
F~1~ male and female pups and by 11-14% in high-dose F~2~ male and
female pups compared with that of controls due primarily to decreases in
weight gain occurring after postnatal day 7. Statistically significant
changes in organ weights in F~1~ and F~2~ weanlings (absolute and/or
relative spleen, thymus and/or brain) were not accompanied by gross
lesions in these organs and microscopic examinations were not conducted.

**The lowest-observed-adverse-effect level (LOAEL) for offspring
toxicity of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg by/day in
males and 159.7-193.3 mg/kg bw/day in females) based on decreases in
body weight and weight gain F~1~ and F~2~ male and female pups. The
no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4--43.7 mg/kg
bw/day for males and 41.0-46.9 mg/kg bw/day in females).**

Kidney toxicity was observed in the parental animals at the high-dose
level; therefore, the animals in this study were adequately dosed to
assess both reproductive and offspring toxicity.

This study is **Acceptable/Guideline** and it satisfies the guideline
requirement for a two-generation reproductive study (OPPTS 870.3800);
OECD 416 in rats.

**3.3.5 Additional Information from Literature
Sources**[]{#__RefHeading___Toc185228034 .anchor}

Available is *The Report and Proposed Decision of the United Kingdom
made to the European Commission* under article 8(1) of 91/414/ECC (EU
Monograph, MRID 46821401). This monograph is discussed briefly in
Section 5.1.11.

**3.3.6 Pre-and/or Post-natal Toxicity**[]{#__RefHeading___Toc185228035
.anchor}

There was evidence of qualitative susceptibility in the prenatal rat
study. However, no prenatal susceptibility (quantitative or qualitative)
was observed in the more sensitive species (rabbit). Therefore, this
risk assessment is protective of the potential qualitative (but not
quantitative) susceptibility that was observed in the rat prenatal
study.

**3.3.6.1 Determination of
Susceptibility**[]{#__RefHeading___Toc185228036 .anchor}

There was no prenatal susceptibility in the developmental rabbit study
with fluopicolide; developmental effects occurred only at doses that
caused severe maternal toxicity. Additionally, there also was no pre-
and/or post-natal susceptibility in the rat multi-generation
reproduction study; adverse effects in the offspring occurred at doses
that also caused maternal toxicity.

There was qualitative, but not quantitative susceptibility observed in
the developmental rat study with fluopicolide. At a dose of 700
mg/kg/day, pregnant rats showed only minimally decreased body weight
gain, while the fetuses showed reduced growth and skeletal defects. This
was determined to be qualitative susceptibility.

**3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility**[]{#__RefHeading___Toc185228037
.anchor}

Since there was evidence of increased susceptibility of offspring
following exposure to fluopicolide in the rat developmental study, a
Degree of Concern Analysis was performed to: 1) determine the level of
concern for the effects observed when considered in the context of all
available toxicity data; and 2) identify any residual uncertainties
after establishing toxicity endpoints and traditional uncertainty
factors to be used in the risk assessment for this chemical. If residual
uncertainties are identified, an examination is made whether these
residual uncertainties can be addressed by an FQPA safety factor and, if
so, the size of the factor needed.

It is concluded that there is low concern for the qualitative
susceptibility that was observed in the rat because:

-   the offspring toxicity was well characterized and was accompanied by
    maternal toxicity;

-   there was a clear NOAEL/LOAEL for offspring toxicity;

-   the developmental effects were observed at a high dose level only
    (700 mg/kg/day) which is close to the limit dose;

-   there was an absence of corroborating evidence from other studies,
    in that qualitative susceptibility was not demonstrated in the
    rabbit developmental study or the rat multigeneration reproduction
    study;

-   the dose/endpoint selected for all risk assessments is considerably
    lower (rabbit maternal NOAEL 20 mg/kg/day) and would address the
    concerns for offspring toxicity seen in this rat study.

Therefore, there are no residual uncertainties for pre- and/or
post-natal toxicity.

**3.3.7 Recommendation for a Developmental Neurotoxicity Study**

[]{#__RefHeading___Toc185228038 .anchor}

The available data on the toxicity of fluopicolide do not support the
recommendation for a developmental neurotoxicity study. Prenatal
exposure resulting in delayed growth and skeletal effects did not result
in central nervous system malformations. While offspring growth was
affected at the same dose that also affected parental animals, no
functional or behavioral changes were reported in adults or pre- or
post-weaning pups (complete neurotoxicity evaluation not done). Clinical
signs suggestive of neurotoxicity were not observed in any study at
doses that caused systemic toxicity such as decreased body weight or
histopathologic lesions. No gross or microscopic pathology was found in
neurologic tissues from animals on acute and subchronic neurotoxicity
studies or on general subchronic and chronic studies.

**3.4 Safety Factor for Infants and Children**

[]{#__RefHeading___Toc185228039 .anchor}

Based on the hazard and exposure data, the fluopicolide risk assessment
team has recommended that the FQPA Safety Factor be reduced to 1X
because there is a complete toxicity database for fluopicolide and
exposure data are complete or are estimated based on data that
reasonably account for potential exposures. There is no evidence of
susceptibility following *in utero* and/or postnatal exposure in the
rabbit developmental toxicity study or in the 2-generation rat
reproduction study. There is low concern for qualitative susceptibility
observed in the rat developmental toxicity study for a number of reasons
discussed in Section 3.3.6.2, including the position that the regulatory
point of departure (20 mg/kg/day) for the expected exposure scenarios is
well below the LOAEL (700 mg/kg/day) for rat developmental toxicity.
There are no residual uncertainties concerning pre- and post-natal
toxicity and no neurotoxicity concerns. The dietary food exposure
assessments were performed based on 100%CT and tolerance-level residues
and conservative (protective) assumptions in the ground and surface
water modeling were used to assess exposure to fluopicolide in drinking
water. HED used similarly conservative assumptions to assess
post-application exposure of children as well as incidental oral
exposure of toddlers. Based on these data and conclusions, the FQPA
Safety Factor can be reduced to 1X.

**3.5 Hazard Identification and Toxicity Endpoint
Selection**[]{#__RefHeading___Toc185228040 .anchor}

**3.5.1 Acute Reference Dose (aRfD) - Females age
13-49**[]{#__RefHeading___Toc185228041 .anchor}

[Study Selected:]{.underline} None. An endpoint attributable to a single
dose was not identified from the available data.

[MRID No]{.underline}**:** None

[Executive summary:]{.underline} None

[Dose and Endpoint for Risk Assessment]{.underline}: None

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** None

**3.5.2 Acute Reference Dose (aRfD) - General
Population**[]{#__RefHeading___Toc185228042 .anchor}

[Study Selected:]{.underline} None. An endpoint attributable to a single
dose was not identified from the available data. **Note: HED has
determined that a change in body temperature in the acute neurotoxicity
study is not a single dose effect.**

[MRID No]{.underline}**:** None

[Executive summary:]{.underline} None

[Dose and Endpoint for Risk Assessment]{.underline}: None

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** None

**3.5.3 Chronic Reference Dose (cRfD)** []{#__RefHeading___Toc185228043
.anchor}

**Two studies were selected for establishing points of departure and are
considered co-**

**critical. Each study is discussed below.**

[Study Selected (one of two):]{.underline} developmental toxicity \--
rabbit OPPTS **3700b**

[MRID No]{.underline}**:** 46474122

[Executive summary**:**]{.underline} See Section 3.3.3.

[Dose and Endpoint for Risk Assessment]{.underline}**:** Maternal NOAEL
of 20 mg/kg/day, based on death, abortions/premature deliveries,
decreased food consumption and decreased body weight at 60 mg/kg/day.

[Study Selected (two of two):]{.underline} chronic/oncogenicity \-- rat
OPPTS **4200a**

[MRID No]{.underline}**:** 46474139

[Executive summary**:**]{.underline} See Appendix A.3.5.

[Dose and Endpoint for Risk Assessment]{.underline}: NOAEL of 31.5
mg/kg/day, based on decreases in body weight gain and an increase in
thyroid organ weight with corresponding increases in the incidence of
thyroid lesions at the LOAEL of 109.4 mg/kg/day.

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** The
rabbit developmental and rat chronic/cancer study were used to determine
the Chronic RfD. The dosing scheme was similar between these two studies
with a NOAEL/LOAEL of 20 / 60mg/kg/day in rabbits and a NOAEL/LOAEL of
31.5 / 109.4 mg/kg/day for the chronic/cancer rat study. Although the
chronic study matches the chronic exposure scenario more appropriately
than the rabbit developmental study, the rabbit is the more sensitive
species for fluopicolide. The rabbit developmental study therefore
provides conservative endpoints for the chronic exposure scenario.

**Chronic RfD** **= [20.0 mg/kg/day]{.underline} = 0.2 mg/kg/day**

**100**

**3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)**
[]{#__RefHeading___Toc185228044 .anchor}

[Study Selected:]{.underline} developmental toxicity \-- rabbit OPPTS
870.**3700b**

[MRID No]{.underline}**:** 46474122

[Executive summary**:**]{.underline} See Section 3.3.3.

[Dose and Endpoint for Risk Assessment]{.underline}**:** Maternal NOAEL
of 20 mg/kg/day, based on death, abortions/premature deliveries,
decreased food consumption and decreased body weight at 60 mg/kg/day.

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** The
rabbit is the most sensitive species for fluopicolide. This rabbit
developmental study provides endpoints appropriate of short and
intermediate term exposure which are more protective of populations than
any other available study

**3.5.5 Dermal Absorption**[]{#__RefHeading___Toc185228045 .anchor}

For the purposes of this risk assessment, a dermal absorption factor of
37% can be used. It is the highest level of absorption reported in a
guideline rat dermal penetration study (MRID 46708638, summarized below)
and, therefore, the most conservative/protective number available. In
addition, an [in]{.underline} [vitro]{.underline} study (MRID 46708637)
using human skin suggests that dermal penetration of fluopicolide is
expected to be considerably less for humans, compared with rats. This
provides confidence that the dermal absorption factor of 37% for
fluopicolide will not be exceeded.

In a dermal penetration study (MRID 46708638), \[^14^C-Phenyl\]-AE
C638206 (Fluopicolide; 99.8% radiochemical purity; Batch No. SEL/1200)
in a commercial concentrate (or aqueous dilution of a concentrate for
the low dose) was applied to the skin of 5 male Sprague-Dawley rats/time
point/dose. The dose (1.43 or 659 μg/cm^2^ skin) was applied to 12 cm^2^
skin and removed after 8 hours. The animals were sacrificed at 8, 24,
72, or 144 hours after application. Additionally, 2 male rats/time
point/dose were treated similarly in a preliminary study and were
sacrificed at 24, 72, or 144 hours, except only 1 rat was treated with
the low dose in the 144 hour group.

Recovery of the applied dose was 91-109%. The distribution profile of
radioactivity was qualitatively similar between the two dose groups. The
majority of the administered dose (41-69% of the low dose and 87-91% of
the high dose) was recovered from the swabs used to remove the test
compound from the skin after 8 hours of treatment. A total of 56-81%
(low dose) or 92-95% (high dose) was considered not absorbed. After 144
hours, only 2-7% remained at the dose site and was considered available
for absorption. Estimates of dermal absorption were based on the sum of
urine + feces + cage wash + tissues + treated skin + stratum corneum.
Dermal absorption ranged from 3-8% (high dose) to 22-37% (low dose). In
the main studies, dermal absorption was greatest at 24 hours after
application, but there was no clear evidence for increased dermal
absorption with time at either dose. Although there was not a
time-dependent increase in total dermal absorption at either dose, there
was a time-dependent increase in absorption through the stratum corneum
at the low dose (but not the high dose).

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

In a non-guideline *in vitro* dermal penetration study (MRID 46708637),
\[^14^C-Phenyl\]-AE C638206 (Fluopicolide; 99.8% radiochemical purity;
Batch No. SEL/1200) was applied to excised human and rat skin in a
suspension concentrate formulation (EXP 11120A) at 2 dose
concentrations, 1.9 and 744 μg/cm^2^ skin. Flow-through diffusion cells
were prepared for each skin type at each dose level (n=7/group).
Dermatomed membranes of approximately 300 µm thickness were tested for
permeability prior to treatment. Receptor fluid samples were collected
each hour after treatment for 24 hours. At 8 hours after test compound
application, the skin was swabbed with a mild detergent solution. After
24 hours, the experiment was terminated, and the skin membranes were
tape stripped. The initial 2 tape strips were assumed to represent the
residual (non-absorbed) dose. Subsequent tape strips, the remaining
skin, and the receptor fluid remaining in the cell and outlet tubing at
the end of the experiment were also assayed. Radioactivity was
determined by liquid scintillation counting. Results for 5-7 skin
samples/species/dose were reported.

Total recovery was 92.3-96.5%. The total amounts of applied
radioactivity absorbed within 24 hours at the high dose level were
0.022% in humans and 0.172% in rats, while at low dose levels the
amounts absorbed were 1.454% in humans and 14.26% in rats. Therefore,
the amount of radioactive material absorbed was 7.8 times greater for
rat skin than for human skin at the high dose level, and 9.8 times
greater for rat skin than human skin at the low dose level. These data
indicate that dermal penetration studies in the rat will provide a very
conservative estimate of dermal absorption in humans for risk
assessment.

This study is **acceptable/non-guideline**.

**3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)**
[]{#__RefHeading___Toc185228046 .anchor}

[Study Selected:]{.underline} developmental toxicity \-- rabbit OPPTS
870.3700b

[MRID No]{.underline}**:** 46474122

[Executive summary**:**]{.underline} See Section 3.3.3.

[Dose and Endpoint for Risk Assessment]{.underline}**:** Although the
rat dermal toxicity study (28-day; MRID 46708614) resulted in no
systemic toxicity or local effects at the limit dose (1000 mg/kg/day),
the rabbit developmental toxicity study was chosen since the rabbit is
the most sensitive species for fluopicolide. The maternal NOAEL is 20
mg/kg/day, based on death, abortions/premature deliveries, decreased
food consumption and decreased body weight at 60 mg/kg/day.

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** This
rabbit developmental study provides endpoints protective of short,
intermediate, and long-term exposure. Based on available data, a dermal
absorption factor of 37% can be used. A rat dermal subchronic study
showed no local or systemic effects at dose levels up to 1000 mg/kg/day,
indicating that the use of the rabbit developmental study endpoint(s)
provides adequate protection to all populations.

**3.5.7 Inhalation Exposure (Short-, Intermediate- and Long-Term)**
[]{#__RefHeading___Toc185228047 .anchor}

[Study Selected:]{.underline} developmental toxicity \-- rabbit OPPTS
870.3700b

[MRID No]{.underline}**:** 46474122

[Executive summary**:**]{.underline} See Section 3.3.3.

[Dose and Endpoint for Risk Assessment]{.underline}**:** Maternal NOAEL
of 20 mg/kg/day, based on death, abortions/premature deliveries,
decreased food consumption and decreased body weight at 60 mg/kg/day.

[Comments on Study/Endpoint/Uncertainty Factors]{.underline}**:** A
repeat dose inhalation toxicity study is not available for this risk
assessment. The rabbit developmental study provides endpoints protective
of short, intermediate, and long-term exposure and is considered
appropriate for this risk assessment. Inhalation and oral toxicity are
assumed to be equivalent.

**3.5.8 Level of Concern for Margin of
Exposure**[]{#__RefHeading___Toc185228048 .anchor}

The following MOEs would apply to the non-dietary endpoints selected in
this section (Section 3.5) but not used for this risk assessment.

+-----------------------+-----------+-----------------+--------------+
| **Table 3.5.8 Summary |           |                 |              |
| of Levels of Concern  |           |                 |              |
| for Risk              |           |                 |              |
| Assessment.**         |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Route**             | **Sho     | **Inte          | *            |
|                       | rt-Term** | rmediate-Term** | *Long-Term** |
|                       |           |                 |              |
|                       | **(1 - 30 | **(1 - 6        | **(\> 6      |
|                       | Days)**   | Months)**       | Months)**    |
+-----------------------+-----------+-----------------+--------------+
| **Occupational        |           |                 |              |
| (Worker) Exposure**   |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Dermal**            | 100       | 100             | 100          |
+-----------------------+-----------+-----------------+--------------+
| **Inhalation**        | 100       | 100             | 100          |
+-----------------------+-----------+-----------------+--------------+
| **Incidental oral**   | 100       | 100             | 100          |
+-----------------------+-----------+-----------------+--------------+
| **Residential         |           |                 |              |
| Exposure**            |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Dermal**            | 100       | 100             | 100          |
+-----------------------+-----------+-----------------+--------------+
| **Inhalation**        | 100       | 100             | 100          |
+-----------------------+-----------+-----------------+--------------+

**3.5.9 Recommendation for Aggregate Exposure Risk
Assessments**[]{#__RefHeading___Toc185228049 .anchor}

Residential exposure from dermal, inhalation and incidental oral
exposure routes can be aggregated, because the endpoint (death,
abortions/premature deliveries, decreased food consumption and decreased
body weight) for these routes was selected from a single study.

Similarly, for occupational (worker) exposure, dermal and inhalation
exposures can be combined because the endpoint (death,
abortions/premature deliveries, decreased food consumption and decreased
body weight) and study are the same for each.

**3.5.10 Classification of Carcinogenic
Potential**[]{#__RefHeading___Toc185228050 .anchor}

In accordance with the EPA's Final Guidelines for Carcinogen Risk
Assessment (March, 2005), the HED Cancer Assessment Review Committee
classified Fluopicolide as **"not likely to be carcinogenic to humans"**
based on convincing evidence that a non-genotoxic, mitogenic mode of
action for liver tumors was established in the mouse and that the
carcinogenic effects were not likely at doses that do not cause
perturbations of the liver. Quantification of carcinogenic potential is
not required. The cRfD, which is based on the developmental rabbit
study, is protective of both chronic and carcinogenic effects.

**3.5.11 Summary of Toxicological Doses and Endpoints for Fluopicolide
for Use in Human Risk Assessments**[]{#__RefHeading___Toc185228051
.anchor}

+--------+----------+-----------+---------+---------------------------+
| *      |          |           |         |                           |
| *Table |          |           |         |                           |
| 3.5.11 |          |           |         |                           |
| S      |          |           |         |                           |
| ummary |          |           |         |                           |
| of     |          |           |         |                           |
| T      |          |           |         |                           |
| oxicol |          |           |         |                           |
| ogical |          |           |         |                           |
| Doses  |          |           |         |                           |
| and    |          |           |         |                           |
| End    |          |           |         |                           |
| points |          |           |         |                           |
| for    |          |           |         |                           |
| Fluopi |          |           |         |                           |
| colide |          |           |         |                           |
| for    |          |           |         |                           |
| Use in |          |           |         |                           |
| D      |          |           |         |                           |
| ietary |          |           |         |                           |
| and    |          |           |         |                           |
| Occupa |          |           |         |                           |
| tional |          |           |         |                           |
| Human  |          |           |         |                           |
| Health |          |           |         |                           |
| Risk   |          |           |         |                           |
| A      |          |           |         |                           |
| ssessm |          |           |         |                           |
| ents** |          |           |         |                           |
+--------+----------+-----------+---------+---------------------------+
| *      | **Point  | **Uncerta | **RfD,  | **Study and Toxicological |
| *Expos | of       | inty/FQPA | PAD,    | Effects**                 |
| ure/** | Dep      | Safety    | Level   |                           |
|        | arture** | Factors** | of      |                           |
| **Scen |          |           | Concern |                           |
| ario** |          |           | for     |                           |
|        |          |           | Risk    |                           |
|        |          |           | Asses   |                           |
|        |          |           | sment** |                           |
+--------+----------+-----------+---------+---------------------------+
| Acute  | None     | None      | None    | **An endpoint             |
| D      |          |           |         | attributable to a single  |
| ietary |          |           |         | dose was not identified   |
|        |          |           |         | from the available        |
| (all   |          |           |         | data.**                   |
| popula |          |           |         |                           |
| tions) |          |           |         |                           |
+--------+----------+-----------+---------+---------------------------+
| C      | Maternal | UF~A~=10x | Chronic | **Developmental Toxicity  |
| hronic |          |           | RfD =   | Study in Rabbits**        |
| D      | NOAEL=20 | UF~H~=10x |         |                           |
| ietary | m        |           | 0.2     | LOAEL (maternal) = 60     |
| (all   | g/kg/day | FQPA SF = | mg      | mg/kg/day based on death, |
| popula |          | 1X        | /kg/day | abortions/ premature      |
| tions) |          |           |         | deliveries, decreased     |
|        |          |           | cPAD =  | food consumption and body |
|        |          |           | 0.2     | weight gain.              |
|        |          |           | mg      |                           |
|        |          |           | /kg/day | **Co-critical:            |
|        |          |           |         | Chronic/Oncogenicity      |
|        |          |           |         | Study in Rats**           |
|        |          |           |         |                           |
|        |          |           |         | NOAEL = 31.5 mg/kg/day.   |
|        |          |           |         |                           |
|        |          |           |         | LOAEL = 109.4 mg/kg/day   |
|        |          |           |         | based on decreased body   |
|        |          |           |         | weight gain and increased |
|        |          |           |         | thyroid weight and        |
|        |          |           |         | increased incidence of    |
|        |          |           |         | thyroid lesions.          |
+--------+----------+-----------+---------+---------------------------+
| Inci   | Maternal | UF~A~=10x | MOE =   | **Developmental Toxicity  |
| dental | NOAEL =  |           | 100     | Study in Rabbits**        |
| Oral   | 20       | UF~H~=10x | (occupa |                           |
| Inter  | m        |           | tional) | LOAEL (maternal) = 60     |
| mediat | g/kg/day | FQPA SF = |         | mg/kg/day based on death, |
| e-Term |          | 1X        | MOE =   | abortions/ premature      |
|        |          |           | 100     | deliveries, decreased     |
| (1 - 6 |          |           | (resid  | food consumption and body |
| m      |          |           | ential) | weight gain.              |
| onths) |          |           |         |                           |
+--------+----------+-----------+---------+---------------------------+
| Dermal | Maternal | UF~A~=10x | MOE =   | **Developmental Toxicity  |
| Short- | NOAEL =  |           | 100     | Study in Rabbits**        |
| I      | 20       | UF~H~=10x | (occupa |                           |
| nterme | m        |           | tional) | LOAEL (maternal) = 60     |
| diate- | g/kg/day | FQPA SF = |         | mg/kg/day based on death, |
| and    |          | 1X        | MOE =   | abortions/ premature      |
| Lon    |          |           | 100     | deliveries, decreased     |
| g-Term |          | 37%       | (resid  | food consumption and body |
| (1-30  |          | dermal    | ential) | weight gain.              |
| days,  |          | a         |         |                           |
| 1-6    |          | bsorption |         | **Co-critical:            |
| m      |          |           |         | Chronic/Oncogenicity      |
| onths, |          |           |         | Study in Rats**           |
| and    |          |           |         |                           |
| \>6    |          |           |         | NOAEL = 31.5 mg/kg/day.   |
| m      |          |           |         |                           |
| onths) |          |           |         | LOAEL = 109.4 mg/kg/day   |
|        |          |           |         | based on decreased body   |
|        |          |           |         | weight gain and increased |
|        |          |           |         | thyroid weight and        |
|        |          |           |         | increased incidence of    |
|        |          |           |         | thyroid lesions.          |
+--------+----------+-----------+---------+---------------------------+
| Inha   | Maternal | UF~A~=10x | MOE =   | **Developmental Toxicity  |
| lation | NOAEL =  |           | 100     | Study in Rabbits**        |
| Short- | 20       | UF~H~=10x | (occupa |                           |
| I      | m        |           | tional) | LOAEL (maternal) = 60     |
| nterme | g/kg/day | FQPA SF = |         | mg/kg/day based on death, |
| diate- |          | 1X        | MOE =   | abortions/ premature      |
| and    |          |           | 100     | deliveries, decreased     |
| Lon    |          | (i        | (resid  | food consumption and body |
| g-term |          | nhalation | ential) | weight gain.              |
| (1-30  |          | and oral  |         |                           |
| days,  |          | toxicity  |         | []{.mark}                 |
| 1-6    |          | are       |         |                           |
| m      |          | assumed   |         | **Co-critical:            |
| onths, |          | to be     |         | Chronic/Oncogenicity      |
| and    |          | eq        |         | Study in Rats**           |
| \>6    |          | uivalent) |         |                           |
| m      |          |           |         | NOAEL = 31.5 mg/kg/day.   |
| onths) |          |           |         |                           |
|        |          |           |         | LOAEL = 109.4 mg/kg/day   |
|        |          |           |         | based on decreased body   |
|        |          |           |         | weight gain and increased |
|        |          |           |         | thyroid weight and        |
|        |          |           |         | increased incidence of    |
|        |          |           |         | thyroid lesions.          |
+--------+----------+-----------+---------+---------------------------+
| Cancer | Classif  |           |         |                           |
| (oral, | ication: |           |         |                           |
| d      | **"Not   |           |         |                           |
| ermal, | Likely   |           |         |                           |
| inhal  | to be    |           |         |                           |
| ation) | Carc     |           |         |                           |
|        | inogenic |           |         |                           |
|        | to       |           |         |                           |
|        | Hu       |           |         |                           |
|        | mans"**. |           |         |                           |
+--------+----------+-----------+---------+---------------------------+

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures. NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level. UF = uncertainty factor.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
potential variation in sensitivity among members of the human population
(intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted
dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of
exposure. LOC = level of concern. N/A = not applicable.

**3.6 Endocrine disruption**[]{#__RefHeading___Toc185228052 .anchor}

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).

**4.0 Public Health and Pesticide Epidemiology Data.**

No information is available since fluopicolide has not been previously
registered for use in the U.S.A. []{#__RefHeading___Toc185228053
.anchor}

**5.0 Dietary Exposure/Risk
Characterization**[]{#__RefHeading___Toc185228054 .anchor}

**5.1 Pesticide Metabolism and Environmental
Degradation**[]{#__RefHeading___Toc185228055 .anchor}

**5.1.1 Metabolism in Primary Crops**[]{#__RefHeading___Toc185228056
.anchor}

The qualitative nature of the residues of fluopicolide in the primary
plants \[cucurbit vegetables, fruiting vegetables, grapes, leafy
vegetables (except *Brassica*), and tuberous and corm vegetables\] is
adequately understood based on adequate metabolism studies on grape,
lettuce, and potato. The metabolism in grape, lettuce, and potato was
found to be similar. The majority of radioactivity was found on the
surface of foliage samples (grape, lettuce, and potato) and fruit
samples (grape). Fluopicolide was the primary residue identified in
grape fruit, lettuce leaves, and potato tubers, accounting for \~51-98%
TRR. The metabolites 2,6-dichlorobenzamide (BAM;AE C653711) and
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE C657188)
were found in foliarly-treated grape fruit and lettuce leaves at \<4%
TRR each ([refer]{.underline} to Appendix B for chemical structures of
fluopicolide metabolites). In lettuce which had received soil drench
application, BAM was found (17-20% TRR), and both BAM and PCA were found
in potato tubers (12-26% TRR each). One additional metabolite (AE
C643890;
2,6-dichloro-*N*-\[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl\]-3-hydroxybenzamide)
was identified in grape, lettuce, and potato commodities at \<3% TRR.

Fluopicolide is metabolized slowly to 2,6-dichlorobenzamide (BAM; AE
C653711) and 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA;
AE C657188), via cleavage of the bond between the carbon attached to the
pyridine ring and the amide nitrogen of the parent compound, and to AE
C643890
(2,6-dichloro-*N*-\[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl\]-3-hydroxybenzamide)
via hydroxylation of the phenyl ring in the parent compound. Based on
the results of the soil drench applications in lettuce, fluopicolide is
metabolized in soil to BAM, which is then taken up by the lettuce plant.
(HED notes that because of the radiolabel of the test substance used for
the soil drench applications, the metabolite PCA would not have been
observed.)

**5.1.2 Metabolism in Rotational Crops**[]{#__RefHeading___Toc185228057
.anchor}

The qualitative nature of the residues of fluopicolide in rotational
crops is adequately understood based on adequate confined rotational
crop studies on lettuce, radish, and wheat. The metabolism of
fluopicolide in rotational crops appears to be more extensive than that
observed in primary crops (grapes, lettuce, and potato). In addition to
fluopicolide, BAM, and PCA, four other metabolites
\[2,6-dichloro-3-hydroxybenzamide (AE C657378; 3-OH-BAM),
3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid (AE
1344122; P1X), 3-chloro-5-(trifluoromethyl)-2-pyridine carboxamide (AE
C653598), and 3-chloro-5-(trifluoromethyl)-2-pyridinol (AE B102859)\]
were observed in the confined rotational crop studies that were not
observed in the primary crop metabolism studies. The confined rotational
crop data indicate the potential for quantifiable fluopicolide and
metabolites to occur in rotational crops.

Rotational crops were planted 29, 133, and 365 days following treatment
of bare soil with \[U-^14^C-phenyl\]fluopicolide or
\[2,6-^14^C-pyridinyl\]fluopicolide at 0.36 lb ai/A. Total radioactive
residues (TRR) were ≥0.01 ppm in all rotated crop matrices. TRR were
highest in 29-day PBI matrices, and ranged from 0.083 ppm in radish root
and wheat grain to 13.56 ppm in wheat straw. TRR decreased at the
133-day PBI, ranging from 0.02 ppm in radish root to 0.84 ppm in wheat
straw. Residues increased slightly at the 365-day PBI, ranging from 0.02
ppm in radish root to 2.37 ppm in wheat straw. The principal residues
identified were fluopicolide, AE C653711 (BAM), AE C657188 (PCA), AE
C657378 (3-OH-BAM), and AE 1344122 (P1X). Fluopicolide was found at
\>0.01 ppm in all matrices at all PBIs with the exception of wheat grain
at the 133- and 365-day PBIs.

**5.1.3 Metabolism in Livestock**[]{#__RefHeading___Toc185228058
.anchor}

In ruminants, a large portion of the dosed radioactivity (75-84%) was
excreted. Fluopicolide was the major residue identified in milk (29%
TRR) and fat (64-76%); it was found at low levels in muscle, liver, and
kidney (\<3% TRR). Fluopicolide appears to be metabolized in ruminants
via hydroxylation of the chlorophenyl ring in two positions to form AE
0712556 and AE C643890; these metabolites were found in liver and kidney
at \<7% TRR each. Each of these metabolites is then conjugated with
sulfate or glucuronic acid, or hydroxylated in a second position and
then conjugated with sulfate or glucuronic acid. A small amount of BAM
was found in milk (4% TRR). No PCA was found in any cattle matrix.

In poultry, based on the study conducted with fluopicolide radiolabeled
in the phenyl ring, a large portion of the dosed radioactivity was
excreted (up to 95%). Fluopicolide was identified at low levels in egg
white, egg yolk, and fat (≤11% TRR); it was not identified in liver or
skin. The major metabolite identified in egg white and fat was
Metabolite 1, a methyl sulfone conjugate of fluopicolide, at 51%
TRR(0.022 ppm) in egg white and 38% TRR (0.023 ppm) in fat. The major
residue identified in liver was BAM, at 37% TRR (0.361 ppm); this
metabolite was not found in any other matrix.

Deficiencies were noted in both the ruminant and poultry metabolism
studies including sample storage and storage stability. Further details
may be found in the referenced residue chemistry summary document.

**5.1.4 Analytical Methodology**[]{#__RefHeading___Toc185228059 .anchor}

[Plant Methods]{.underline}

*Enforcement method:* The LC/MS/MS method, Method RM-43C-2 (MRID
47073701), is an adequate enforcement method for determination of
fluopicolide (parent) in plants (DP #329578, C. Stafford, Analytical
Chemistry Branch/Biological and Economic Analysis Division (ACB/BEAD),
3/14/06\[*07*\]). The LOQ for fluopicolide (parent) is 0.01 ppm.

*Data Collection Methods:* Acceptable data collection methods, LC/MS/MS
Methods 00782, 00782/M001, 00782/M002, and 00782/M003, or modified
versions of these methods, were used in the storage stability, crop
field trial, processing, and field rotational crop studies associated
with this petition. Method 00782/M002 determines residues of
fluopicolide (parent), BAM, PCA, and P1X. Method 00782/M003 determines
3-OH-BAM. Radiovalidation data have been submitted which indicate that
the extraction procedures of Methods 00782/M002 and 00782/M003
adequately extract aged residues of fluopicolide, BAM, PCA, P1X, and
3-OH-BAM from grape and wheat straw samples. Adequate method validation
data were submitted. An independent laboratory validation was conducted
on Method 00782/M002. All methods were validated with an LOQ of 0.01 ppm
for each analyte in each commodity.

[Livestock Methods]{.underline}

*Enforcement Method*: Method AR 303-02, the LC/MS/MS method described
below, is not acceptable as an enforcement method. A confirmatory
procedure is required. Also, an analytical reference standard for the
metabolite 2,6-dichlorobenzamide (BAM) must be sent to USEPA, National
Pesticide Standards Repository/Analytical Chemistry Branch/OPP, 710
Mapes Road, Fort George G. Meade, MD 20755-5350.

*Data Collection Method:* Valent U.S.A. Corporation's LC/MS/MS method,
Method AR 303-02 (MRID 46708516), which determines residues of
fluopicolide and its metabolites AE C653711 (BAM) and AE C657188 (PCA)
in/on milk, meat, fat, liver, and kidney of cattle, is adequate for data
collection. Adequate method validation data (recovery data) have been
submitted. Radiovalidation data are not required because the extraction
solvents used in the method are similar to those used in the cattle
metabolism study. The validated limits of quantitation (LOQs) for each
analyte are 0.01 ppm for milk, 0.02 ppm for meat, and 0.05 ppm for fat,
liver, and kidney.

[Multiresidue Methods]{.underline}

Adequate multiresidue method testing data (MRID 46708525) have been
submitted for fluopicolide and BAM. These data indicate that the
multiresidue methods are not appropriate for determining residues of
fluopicolide and BAM using some matrices. Protocol C testing of
fluopicolide and BAM indicated that these compounds were found to
chromatograph with sufficient response on all tested modules except
DG18. Fluopicolide and BAM were tested under Protocol D, using tomato as
the representative nonfatty matrix, and F, using potato chips as the
representative fatty matrix. Fluopicolide and BAM were found to be
unrecoverable when tested under Protocol D due to matrix interference.
Therefore, further testing under Protocol E was not conducted. BAM was
found to be unrecoverable when tested under Protocol F. Fluopicolide had
small recoveries (29-42%) from a representative fatty matrix, potato
chips, under Protocol F. The data will be forwarded to FDA.

The FDA PESTDATA database dated 1/94 ([PAM,]{.underline} Volume I,
Appendix I) indicates that BAM is completely recovered (\>80%) using
Section 302, and not recovered using Sections 303 and 304.

**5.1.5 Environmental Degradation**[]{#__RefHeading___Toc185228060
.anchor}

The fate and behavior in the environment were summarized in DP#325804
(J. Lin, 3/7/07): "Based on chemical properties and laboratory
environmental fate studies, fluopicolide will not volatilize from soil
or aqueous solution. Neither photolysis nor hydrolysis is expected to be
a significant degradative pathway for the dissipation of fluopicolide.
Photolysis does, however, enhance the degradation of fluopicolide soil
degradates. The primary pathway for dissipation of fluopicolide is by
microbial or mineral-catalyzed degradation in soil. Fluopicolide is
unlikely to leach in soil but its moderate water solubility suggests the
potential for runoff in storm or irrigation water. This potential is
significantly mitigated by an increase in fluopicolide soil binding over
time. Laboratory studies suggest moderate persistence in soil and
persistence in sediment under anaerobic conditions. However field
studies, with multiple degradative pathways operating simultaneously,
suggest only moderate persistence.

"The major routes of degradation for fluopicolide and its degradates in
laboratory studies are photodegradation in water and on soil and aerobic
microbial degradation. Laboratory studies predict that fluopicolide
should persist in soil and aquatic environments. Degradation in soil was
slow with a mean half-life of 413 days. In an aerobic aquatic system,
fluopicolide slowly partitioned into the sediment and degraded from the
water-sediment system with half-lives of 699 to 866 days. In an
anaerobic aquatic system, fluopicolide partitions from water into
sediment (water dissipation half-lives of 21.6 to 24.7 days), then
slowly degrades with system half-lives of 967 to 1553 days. A mean K~OC~
value of 340 suggests that fluopicolide could leach in soil but this
leaching potential should abate due to a time dependent increase in
K~OC~. Field studies support the conclusion that fluopicolide will not
leach. In the soil environment, fluopicolide degradation was faster with
half-lives of 72 to 315 days (mean 181 days) in terrestrial field
studies with no significant leaching of parent."

BAM can be produced by aerobic soil metabolism. After formation, there
is a potential for BAM to move into ground water. BAM can be very mobile
and persistent under aerobic and anaerobic conditions.

**5.1.6 Comparative Metabolic Profile** []{#__RefHeading___Toc185228061
.anchor}

In the rat, fluopicolide was readily absorbed and rapidly excreted. The
major metabolites identified appeared to be oxidative N-dealkylation
cleavage products, including BAM at 0.09% of the total administered dose
in rats. The radioactivity concentrations in any given tissue
consistently represented considerably less than 1% of the administered
dose within 24 hours of administration.

Residues are not expected to occur in livestock commodities (ruminants
and poultry) as a result of the proposed and established uses. In the
livestock metabolism studies, the major residues ([\>]{.underline} 10%
TRR) in ruminants were fluopicolide (parent) and the dihydroxy
glucuronide of fluopicolide; the major residues in poultry were
fluopicolide (parent), BAM, AE 0712556
(2,6-dichloro-*N*-\[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl\]-4-hydroxybenzamide),
Metabolite 1
(2,6-dichloro-*N*-{\[3-chloro-5-(trifluoromethyl)pyridin-2-yl\]methyl}-3-(methylsulfonyl)benzamide),
and the dihydroxy sulfate of fluopicolide.

With the possible exception of potatoes, residues are expected to occur
in primary (treated) plants. In the plant metabolism studies,
fluopicolide (parent) is the major residue in plants after foliar
application. In the potato metabolism study, BAM and PCA also occurred
at levels \> 10% TRR. Fluopicolide is metabolized slowly to BAM, PCA,
and AE C643890
(2,6-dichloro-*N*-\[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl\]-3-hydroxybenzamide).
The majority of the residue after foliar application and short
preharvest intervals is on the surface of the plant.

More extensive metabolism was observed in rotational crops than in
primary crops. In addition to residues found in primary crops, four
additional metabolites were found in the confined rotational crop study.
The confined rotational crop studies indicate the potential for
occurrence of quantifiable residues of fluopicolide and metabolites in
rotational crops. The major residues ([\>]{.underline}10% TRR) found in
the confined rotational crop study were fluopicolide (parent), BAM, PCA,
AE C643840 (in wheat), 3-OH-BAM, and P1X.

**5.1.7 Toxicity Profile of Major Metabolites and
Degradates**[]{#__RefHeading___Toc185228062 .anchor}

The metabolites/degradates included in the risk assessment for one or
more matrices include BAM, PCA, and P1X.

BAM (2,6-dichlorobenzamide; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil. The
toxicity of BAM has been recently reviewed (BAM Human Health Risk
Assessment, DP #345918, N. Dodd, 11/21/07). The acute and chronic
studies were sufficient to evaluate human hazard potential. BAM
demonstrated moderate acute toxicity (Category III) via the oral route
of exposure. Because the subchronic and chronic toxicity of BAM is
considered less than or equal to that of dichlobenil (parent herbicide)
based on submitted and published toxicity studies, the acute toxicity of
BAM via the inhalation and dermal routes is expected to be less than or
equal to that of dichlobenil. In the case of fluopicolide, the toxicity
profile is different from that of BAM. The small cPAD (0.0045 mg/kg/day)
for BAM is based on decreased body weight and decreased body weight gain
in the chronic oral toxicity study (dog). There was no evidence that BAM
was either mutagenic or clastogenic in submitted genotoxicity studies.
In the absence of carcinogenicity study data for a second species, HED
considers the carcinogenic potential of BAM to be similar to that of
dichlobenil, the parent compound having the greatest carcinogenic
potential. Dichlobenil is classified as "Group C, possible human
carcinogen", with the RfD approach utilized for quantification of human
cancer risk. BAM is considered to be neurotoxic. No evidence of
endocrine modulation was observed in any study with BAM. An FQPA SF of
10X for database uncertainty is applied to acute and chronic dietary and
incidental oral exposure scenarios for incompleteness of the database
with regard to the systemic neurotoxic potential of BAM, including
olfactory toxicity) and also, in the case of acute dietary exposure, use
of a LOAEL to extrapolate to a NOAEL.

PCA (3-chloro-5-trifluoromethylpyridine-2-carboxylic acid; AE C657188)
is not expected to be more toxic than parent fluopicolide, based on its
structure.

P1X (3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid; AE
1344122) is not expected to be more toxic than parent fluopicolide,
based on its structure.

**5.1.8 Pesticide Metabolites and Degradates of
Concern**[]{#__RefHeading___Toc185228063 .anchor}

As shown in Table 5.1.8 below, HED has determined that the residue of
concern for the tolerance expression in the domestic primary plants
(cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, and
tuberous and corm vegetables) is fluopicolide (parent) as an indicator
of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide. For the risk assessment, the residues of concern
in the domestic primary plants except tuberous and corm vegetables are
fluopicolide (parent) and 2,6-dichlorobenzamide (BAM). For tuberous and
corm vegetables, the residues of concern for the risk assessment are
fluopicolide (parent), BAM, and
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA).

As determined by HED, the residue of concern for the tolerance
expression for rotational crops is fluopicolide (parent) as an indicator
of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide. The residues of concern for the risk assessment
are fluopicolide (parent) and BAM for all rotational crops except the
grain of cereal grains used as human food. The residues of concern for
the risk assessment for the grain portion of cereal grain rotational
crops used as human food are fluopicolide (parent), BAM, PCA, and
3-methylsulfinyl-5-fluoromethylpyridine-2-carboxylic acid (P1X; AE
1344122).

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil. BAM is a minor metabolite of fluopicolide. BAM is
included in the tolerance expression for dichlobenil because it is a
major metabolite/degradate of dichlobenil.

The residues of concern in livestock commodities are tentative since
additional information is needed to support the ruminant and poultry
metabolism studies. Pending submission of the required additional data,
HED has tentatively determined that the residue of concern in livestock
commodities for a tolerance expression is 2,6-dichlorobenzamide (BAM).
For the risk assessment, the residues of concern are fluopicolide
(parent) and BAM.

Based on two aerobic soil metabolism studies, fluopicolide (parent) and
BAM are the residues of concern in drinking water. BAM was a major
metabolite in these aerobic soil metabolism studies, present at levels
up to 40%.

+---------------+----------------+--------------------+----------------+
| **Table       |                |                    |                |
| 5.1.8.        |                |                    |                |
| Summary of    |                |                    |                |
| Metabolites   |                |                    |                |
| and           |                |                    |                |
| Degradates to |                |                    |                |
| be included   |                |                    |                |
| in the Risk   |                |                    |                |
| Assessment    |                |                    |                |
| and Tolerance |                |                    |                |
| Expression**  |                |                    |                |
+===============+================+====================+================+
| Matrix        |                | Residues included  | Residues       |
|               |                | in Risk            | included in    |
|               |                | Assessment^1^      | Tolerance      |
|               |                |                    | Expression^1^  |
+---------------+----------------+--------------------+----------------+
| Plants        | Primary Crops  |                    |                |
|               |                |                    |                |
| (Tuberous and |                |                    |                |
| Corm          |                |                    |                |
| Vegetables,   |                |                    |                |
| Leafy         |                |                    |                |
| Vegetables    |                |                    |                |
| (except       |                |                    |                |
| *Brassica*),  |                |                    |                |
| Fruiting      |                |                    |                |
| Vegetables,   |                |                    |                |
| Cucurbit      |                |                    |                |
| Vegetables,   |                |                    |                |
| and           |                |                    |                |
|               |                |                    |                |
| Grapes)       |                |                    |                |
+---------------+----------------+--------------------+----------------+
|               | All primary    | fluopicolide       | fluopicolide   |
|               | crops except   | (parent) and BAM   | (parent) as an |
|               | Tuberous and   |                    | indicator of   |
|               | Corm           |                    | combined       |
|               | Vegetables     |                    | residues of    |
|               |                |                    | fluopicolide   |
|               |                |                    | and BAM        |
+---------------+----------------+--------------------+----------------+
|               | Tuberous and   | fluopicolide       |                |
|               | Corm           | (parent), BAM, and |                |
|               | Vegetables     | PCA                |                |
+---------------+----------------+--------------------+----------------+
|               | Rotational     |                    |                |
|               | Crops          |                    |                |
+---------------+----------------+--------------------+----------------+
|               | All rotational | fluopicolide       | fluopicolide   |
|               | crops except   | (parent) and BAM   | (parent) as an |
|               | cereal grains  |                    | indicator of   |
|               |                |                    | combined       |
|               |                |                    | residues of    |
|               |                |                    | fluopicolide   |
|               |                |                    | and BAM        |
+---------------+----------------+--------------------+----------------+
|               | Cereal grains: | fluopicolide       |                |
|               | grain for      | (parent), BAM,     |                |
|               | human food     | PCA, and P1X       |                |
+---------------+----------------+--------------------+----------------+
|               | Cereal grains: | fluopicolide       |                |
|               | fo             | (parent) and BAM   |                |
|               | rage/hay/straw |                    |                |
|               | and grain for  |                    |                |
|               | livestock feed |                    |                |
+---------------+----------------+--------------------+----------------+
| Livestock     | Ruminant       | fluopicolide       | BAM            |
|               |                | (parent) and BAM   |                |
+---------------+----------------+--------------------+----------------+
|               | Poultry        |                    |                |
+---------------+----------------+--------------------+----------------+
| Drinking      |                | fluopicolide       | Not applicable |
| Water         |                | (parent) and BAM   |                |
+---------------+----------------+--------------------+----------------+

^1^ The residues of concern for primary and rotational crops were
determined in a RARC1 meeting on 7/19/07. The residues of concern in
livestock were discussed in a meeting on 11/5/07; the residues of
concern in livestock are tentative since additional information is
needed to support the ruminant and poultry metabolism studies.

**5.1.9 Drinking Water Residue Profile**[]{#__RefHeading___Toc185228064
.anchor}

*Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes,
Vegetables, Potatoes and Turf*, DP #325804, James Lin, 3/7/07.

No monitoring data were available for fluopicolide. Drinking water
residues of fluopicolide (parent) were modeled for exposures resulting
from uses on grapes, vegetables, and turf. The drinking water residues
were incorporated directly into the dietary assessment, i.e., the water
residues were incorporated in the Dietary Exposure Evaluation Model
(DEEM-FCID) into the food categories "water, direct, all sources" and
"water, indirect, all sources."

Surface water concentrations were estimated using the Tier II model PRZM
(Pesticide Root Zone Model) version 3.12/ EXAMS (Exposure Analysis
Modeling System) version 2.98. Ground water concentrations were
estimated using the Tier I SCI-GROW (Screening Concentration in Ground
Water) model.

Based on modeling results, the estimated surface water (drinking water)
concentrations for fluopicolide are:

26.81 ug/L for the 1 in 10 year annual peak concentration (acute)

**8.34** ug/L for the 1 in 10 year annual mean concentration (non-cancer
chronic) and

6.14 ug/L for the 30 year annual mean concentration (cancer/chronic).

The 1 in 10 year annual peak (acute) was derived from modeling
fluopicolide use on Florida peppers with ground applications. The 1 in
10 year annual mean (non-cancer chronic) was derived from modeling
fluopicolide use on California lettuce with aerial applications. The
30-year annual mean concentration (cancer/chronic) was derived from
fluopicolide use on California lettuce with aerial applications. These
values were highest among all modeling scenarios examined.

The SCI-GROW estimated ground water (drinking water) concentrations for
fluopicolide are not expected to exceed **0.64 μg/L**, which was based
on 2 applications to turf of 0.270 lb ai/acre per application.

This chronic dietary assessment used the value of **8.34 ug/L (ppb)**
for drinking water.

HED (Paula Deschamp, Amelia Acierto, Nancy Dodd, Kelly O'Rourke, and
Myron Ottley) and EFED (Thuy Nguyen and James Lin) met on April 12, 2007
to determine the residues to include in the drinking water risk
assessment. It was determined, based on two aerobic soil metabolism
studies, that the residues of concern in drinking water are parent
fluopicolide and the degradate BAM. BAM was a major degradate, present
at levels up to 40%. Table 5.1.9 below presents the estimations of
parent fluopicolide only. Estimated concentrations of BAM in drinking
water are addressed in the BAM Human Health Risk Assessment (DP#345918,
N. Dodd, 11/ 21/07).

+--------------------------+---------------------+---------------------+
| **Table 5.1.9 Summary of |                     |                     |
| Estimated Surface Water  |                     |                     |
| and Groundwater          |                     |                     |
| Concentrations for       |                     |                     |
| Fluopicolide (Parent).** |                     |                     |
+==========================+=====================+=====================+
|                          | Fluopicolide        |                     |
|                          | (parent)            |                     |
+--------------------------+---------------------+---------------------+
|                          | Surface Water       | Groundwater Conc.,  |
|                          | Conc., ppb ^a^      | ppb ^b^             |
+--------------------------+---------------------+---------------------+
| Acute                    | 26.81               | 0.64                |
+--------------------------+---------------------+---------------------+
| Chronic (non-cancer)     | **8.34**            | 0.64                |
+--------------------------+---------------------+---------------------+
| Chronic (cancer)         | 6.14                | 0.64                |
+--------------------------+---------------------+---------------------+
| ^a^ From the Tier II     |                     |                     |
| PRZM-EXAMS - Index       |                     |                     |
| Reservoir model. Input   |                     |                     |
| parameters are based on  |                     |                     |
| CA lettuce with aerial   |                     |                     |
| application and a        |                     |                     |
| maximum seasonal use     |                     |                     |
| rate of 0.375 lb ai/A.   |                     |                     |
|                          |                     |                     |
| ^b^ From the SCI-GROW    |                     |                     |
| model assuming a maximum |                     |                     |
| seasonal use rate of     |                     |                     |
| 0.54 lb ai/A, a K~oc~ of |                     |                     |
| 349 mL/g, and a          |                     |                     |
| half-life of 413 days.   |                     |                     |
+--------------------------+---------------------+---------------------+

**5.1.10 Food Residue Profile**[]{#__RefHeading___Toc185228065 .anchor}

**Reference**:

*Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for
Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, and Grapes and for Indirect or
Inadvertent Residues on the Rotational Crop Wheat. Summary of Analytical
Chemistry and Residue Data, DP Number 326080, Amelia Acierto, 11/19/07*.

[Crop Field Trials]{.underline}

Adequate field trial data for tuberous and corm vegetables, leafy
vegetables (except *Brassica*), fruiting vegetables, cucurbit
vegetables, and grapes are available, pending submission of additional
storage stability data/information for leafy vegetables. In all field
trials, three foliar applications of a 40% suspension concentrate (SC)
formulation were made for a total of 0.35-0.40 lb ai/A/season (\~1x the
proposed seasonal rate). An adequate number of geographically
representative field trials were conducted:

nineteen field trials on potato (the representative crop for the
tuberous and corm vegetable subgroup 1C);

twenty-eight field trials on the representative crops for the leafy
vegetables crop group: seven field trials on celery, seven on head
lettuce, seven on leaf lettuce, and seven on spinach;

twenty-two field trials on the representative crops of the fruiting
vegetable crop group: seven field trials on bell pepper, three on a
non-bell pepper (chili pepper), and twelve on tomato;

twenty-one field trials on the representative commodities of the
cucurbit vegetable crop group: nine field trials on muskmelon
(cantaloupe), six on cucumber, and six on summer squash;

and sixteen field trials on grapes.

[]{.mark}

[Tuberous and corm vegetable, subgroup 1C (MRID 46708537)]{.underline}

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 14%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>TABLE 5.1.10.1 Summary of Residue Data from
Crop Field Trials with Fluopicolide.</strong></td>
</tr>
<tr class="even">
<td rowspan="2">Matrix</td>
<td rowspan="2"><p>Total Applic. Rate</p>
<p>(lb a.i./A)</p>
<p>[kg a.i./ha]</p></td>
<td rowspan="2">PHI (days)</td>
<td colspan="7"><p>Residue Levels<sup>*</sup></p>
<p>(ppm)</p></td>
</tr>
<tr class="odd">
<td>n</td>
<td>Min.</td>
<td>Max.</td>
<td>HAFT</td>
<td><p>Median</p>
<p>(STMdR)</p></td>
<td><p>Mean</p>
<p>(STMR)</p></td>
<td>Std. Dev.</td>
</tr>
<tr class="even">
<td colspan="10"></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="even">
<td>Potatoes</td>
<td><p>0.350 to 0.372</p>
<p>[0.392 to 0.417]</p></td>
<td>6 to 8</td>
<td>38</td>
<td>&lt;0.01</td>
<td>0.0126</td>
<td>&lt;0.01 (0.0088)</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.0012</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>BAM (AE C653711)</strong></td>
</tr>
<tr class="even">
<td>Potatoes</td>
<td><p>0.350 to 0.372</p>
<p>[0.392 to 0.417]</p></td>
<td>6 to 8</td>
<td>38</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>PCA (AE C657188)</strong></td>
</tr>
<tr class="even">
<td>Potatoes</td>
<td><p>0.350 to 0.372</p>
<p>[0.392 to 0.417]</p></td>
<td>6 to 8</td>
<td>38</td>
<td>&lt;0.01</td>
<td>0.0447</td>
<td>0.0438</td>
<td>&lt;0.01</td>
<td>&lt; 0.010</td>
<td>0.009</td>
</tr>
</tbody>
</table>

\*HAFT = Highest Average Field Trial.

BAM and PCA are not expressed as parent equivalents.

[Leafy vegetable, except *Brassica*, group 4 (MRIDs 46708533, 46708534,
46708539, 46708540)]{.underline}

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 5.1.10.2 Summary of Residue Data from
Group 4 Crop Field Trials with Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2">Commodity</th>
<th rowspan="2"><p>Total Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[kg ai/ha]</p></th>
<th rowspan="2">PHI (days)</th>
<th colspan="7">Residue Levels (ppm)</th>
</tr>
<tr class="header">
<th>n</th>
<th>Min.</th>
<th>Max.</th>
<th>HAFT<sup>1</sup></th>
<th>Median</th>
<th>Mean</th>
<th>Std. Dev.</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="10"><strong>CELERY (proposed use = 0.375 lb ai/A total
application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Celery</td>
<td><p>0.354-0.365</p>
<p>[0.397-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>0.037</td>
<td>13.6</td>
<td>9.9</td>
<td>1.23</td>
<td>2.73</td>
<td>3.70</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Celery</td>
<td><p>0.354-0.365</p>
<p>[0.397-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>0.041</td>
<td>0.039</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Celery</td>
<td><p>0.354-0.365</p>
<p>[0.397-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>0.024</td>
<td>0.020</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>HEAD LETTUCE (proposed use = 0.375 lb ai/A
total application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="even">
<td>Head lettuce</td>
<td>0.350-0.368 (0.392-0.414)</td>
<td>2</td>
<td>14</td>
<td>0.455</td>
<td>7.15</td>
<td>6.34</td>
<td>2.39</td>
<td>2.68</td>
<td>2.06</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="even">
<td>Head lettuce</td>
<td>0.350-0.368 (0.392-0.414)</td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>0.0132</td>
<td>0.012</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="even">
<td>Head lettuce</td>
<td>0.350-0.368 (0.392-0.414)</td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>LEAF LETTUCE (proposed use = 0.375 lb ai/A
total application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Leaf lettuce</td>
<td><p>0.349-0.364</p>
<p>[0.391-0.408]</p></td>
<td>2</td>
<td>14</td>
<td>0.444</td>
<td>11.7</td>
<td>9.78</td>
<td>6.43</td>
<td>6.37</td>
<td>2.96</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Leaf lettuce</td>
<td><p>0.349-0.364</p>
<p>[0.391-0.408]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>0.038</td>
<td>0.031</td>
<td>&lt;0.01</td>
<td>0.012</td>
<td>0.010</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Leaf lettuce</td>
<td><p>0.349-0.364</p>
<p>[0.391-0.408]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>SPINACH (proposed use = 0.375 lb ai/A total
application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="even">
<td>Spinach</td>
<td><p>0.357-0.365</p>
<p>[0.400-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>5.43</td>
<td>16.8</td>
<td>16.2</td>
<td>8.53</td>
<td>9.71</td>
<td>3.87</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="even">
<td>Spinach</td>
<td><p>0.357-0.365</p>
<p>[0.400-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>0.022</td>
<td>0.188</td>
<td>0.170</td>
<td>0.065</td>
<td>0.072</td>
<td>0.047</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="even">
<td>Spinach</td>
<td><p>0.357-0.365</p>
<p>[0.400-0.410]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>0.119</td>
<td>0.076</td>
<td>0.013</td>
<td>0.022</td>
<td>0.025</td>
</tr>
</tbody>
</table>

^1^ HAFT = Highest average field trial result.

[Fruiting vegetable, group 8 (MRIDs 46708530, 46708535, and
46708536)]{.underline}

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 5.1.10.3 Summary of Residue Data from
Group 8 Crop Field Trials with Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2">Commodity</th>
<th rowspan="2"><p>Total Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[kg ai/ha]</p></th>
<th rowspan="2">PHI (days)</th>
<th colspan="7">Residue Levels (ppm)</th>
</tr>
<tr class="header">
<th>n</th>
<th>Min.</th>
<th>Max.</th>
<th>HAFT<sup>1</sup></th>
<th>Median</th>
<th>Mean</th>
<th>Std. Dev.</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="10"><strong>BELL PEPPER (proposed use = 0.375 lb ai/A total
application rate, 7-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Bell pepper</td>
<td><p>0.349-0.358</p>
<p>[0.391-0.401]</p></td>
<td>2</td>
<td>14</td>
<td>0.0411</td>
<td>0.557</td>
<td>0.523</td>
<td>0.099</td>
<td>0.156</td>
<td>0.163</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Bell pepper</td>
<td><p>0.349-0.358</p>
<p>[0.391-0.401]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Bell pepper</td>
<td><p>0.349-0.358</p>
<p>[0.391-0.401]</p></td>
<td>2</td>
<td>14</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>CHILI PEPPER (proposed use = 0.375 lb ai/A
total application rate, 7-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="even">
<td>Chili pepper</td>
<td><p>0.355-0.363</p>
<p>[0.398-0.407]</p></td>
<td>2</td>
<td>6</td>
<td>0.0837</td>
<td>0.576</td>
<td>0.516</td>
<td>0.300</td>
<td>0.302</td>
<td>0.198</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="even">
<td>Chili pepper</td>
<td><p>0.355-0.363</p>
<p>[0.398-0.407]</p></td>
<td>2</td>
<td>6</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="even">
<td>Chili pepper</td>
<td><p>0.355-0.363</p>
<p>[0.398-0.407]</p></td>
<td>2</td>
<td>6</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>TOMATO (proposed use = 0.375 lb ai/A total
application rate, 7-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Tomato</td>
<td><p>0.356-0.368</p>
<p>[398.9-412.8]</p></td>
<td>2</td>
<td>24</td>
<td>0.015</td>
<td>0.420</td>
<td>0.375</td>
<td>0.145</td>
<td>0.150</td>
<td>0.094</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Tomato</td>
<td><p>0.356-0.368</p>
<p>[398.9-412.8]</p></td>
<td>2</td>
<td>24</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Tomato</td>
<td><p>0.356-0.368</p>
<p>[398.9-412.8]</p></td>
<td>2</td>
<td>24</td>
<td>&lt;0.01</td>
<td>0.013</td>
<td>0.012</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
</tbody>
</table>

^1^ HAFT = Highest average field trial result.

[Cucurbit vegetable, group 9 (MRIDs 46708531, 46708532, and
46708538)]{.underline}

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 5.1.10.4 Summary of Residue Data from
Group 9 Crop Field Trials with Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2">Commodity</th>
<th rowspan="2"><p>Total Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[kg ai/ha]</p></th>
<th rowspan="2">PHI (days)</th>
<th colspan="7">Residue Levels (ppm)</th>
</tr>
<tr class="header">
<th>n</th>
<th>Min.</th>
<th>Max.</th>
<th>HAFT<sup>1</sup></th>
<th>Median</th>
<th>Mean</th>
<th>Std. Dev.</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="10"><strong>CANTALOUPE (proposed use = 0.375 lb ai/A total
application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Cantaloupe</td>
<td><p>0.352-0.362</p>
<p>[0.395-0.406]</p></td>
<td>2</td>
<td>18</td>
<td>&lt;0.01</td>
<td>0.258</td>
<td>0.181</td>
<td>0.055</td>
<td>0.068</td>
<td>0.061</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Cantaloupe</td>
<td><p>0.352-0.362</p>
<p>[0.395-0.406]</p></td>
<td>2</td>
<td>18</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Cantaloupe</td>
<td><p>0.352-0.362</p>
<p>[0.395-0.406]</p></td>
<td>2</td>
<td>18</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>CUCUMBER (proposed use = 0.375 lb ai/A total
application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="even">
<td>Cucumber</td>
<td><p>0.349-0.361</p>
<p>(0.391-0.405)</p></td>
<td>2</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.057</td>
<td>0.050</td>
<td>0.020</td>
<td>0.024</td>
<td>0.0147</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="even">
<td>Cucumber</td>
<td><p>0.349-0.361</p>
<p>(0.391-0.405)</p></td>
<td>2</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="even">
<td>Cucumber</td>
<td><p>0.349-0.361</p>
<p>(0.391-0.405)</p></td>
<td>2</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>SUMMER SQUASH (proposed use = 0.375 lb ai/A
total application rate, 10-day minimum RTI, 2-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Summer squash</td>
<td><p>0.354-0.367</p>
<p>[0.399-0.411]</p></td>
<td>2</td>
<td>12</td>
<td>0.0135</td>
<td>0.0506</td>
<td>0.0448</td>
<td>0.0322</td>
<td>0.0301</td>
<td>0.0120</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Summer squash</td>
<td><p>0.354-0.367</p>
<p>[0.399-0.411]</p></td>
<td>2</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Summer squash</td>
<td><p>0.354-0.367</p>
<p>[0.399-0.411]</p></td>
<td>2</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.0207</td>
<td>0.0173</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.0060</td>
</tr>
</tbody>
</table>

^1^ HAFT = Highest average field trial result.

[Grape (MRID 46708541)]{.underline}

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 5.1.10.5 Summary of Residue Data from
Grape Field Trials with Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2">Commodity</th>
<th rowspan="2"><p>Total Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[kg ai/ha]</p></th>
<th rowspan="2">PHI (days)</th>
<th colspan="7">Residue Levels (ppm)</th>
</tr>
<tr class="header">
<th>n</th>
<th>Min.</th>
<th>Max.</th>
<th>HAFT<sup>1</sup></th>
<th>Median</th>
<th>Mean</th>
<th>Std. Dev.</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="10"><strong>GRAPE (proposed use = 0.375 lb ai/A total
application rate, 12-day minimum RTI, 21-day PHI)</strong></td>
</tr>
<tr class="even">
<td colspan="10"><strong>Fluopicolide</strong></td>
</tr>
<tr class="odd">
<td>Grape</td>
<td><p>0.346-0.401</p>
<p>[0.387-0.449]</p></td>
<td>20-21</td>
<td>32</td>
<td>0.065</td>
<td>1.10</td>
<td>0.985</td>
<td>0.210</td>
<td>0.312</td>
<td>0.289</td>
</tr>
<tr class="even">
<td colspan="10"><strong>BAM</strong></td>
</tr>
<tr class="odd">
<td>Grape</td>
<td><p>0.346-0.401</p>
<p>[0.387-0.449]</p></td>
<td>20-21</td>
<td>32</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td colspan="10"><strong>PCA</strong></td>
</tr>
<tr class="odd">
<td>Grape</td>
<td><p>0.346-0.401</p>
<p>[0.387-0.449]</p></td>
<td>20-21</td>
<td>32</td>
<td>&lt;0.01</td>
<td>0.013</td>
<td>0.012</td>
<td>&lt;0.01</td>
<td>&lt; 0.01</td>
<td>NA</td>
</tr>
</tbody>
</table>

^1^ HAFT = Highest average field trial result.

[Processing Studies (MRIDs 46708542, 46708543, 46708544, and 46708545)\
]{.underline}

Adequate processing data for grapes, potatoes, tomatoes, and rotated
wheat are available pending submission of additional storage stability
data/information on residues of 3-OH-BAM and P1X on wheat grain stored
frozen for 20 months. The available processing data indicate that
residues of fluopicolide are not likely to concentrate in grape juice,
potato chips and flakes, or wheat flour. Residues of fluopicolide were
found to concentrate in raisins, processed potato waste (wet peels),
tomato paste and puree, and wheat milled byproducts (bran, germ,
middlings, and shorts). The processing data indicate that the proposed
tolerance of 6 ppm for raisins is appropriate. In addition, a tolerance
for processed potato waste must be proposed at 0.05 ppm and a tolerance
for wheat milled byproducts must be proposed at 0.07 ppm.

No data have been submitted on aspirated grain fractions. Since data
indicate that residues of fluopicolide concentrate in wheat milled
byproducts, HED concludes that residue data and a tolerance for
aspirated grain fractions (AGF) at 0.07 ppm is required. HED could base
the tolerance for AGF on the available wheat processing data, but would
require confirmatory residue data on AGF as a condition of registration.

Separate tolerances for tomato processed commodities are not needed, as
residues in these commodities are not expected to exceed the recommended
tolerance of 1.6 ppm for the fruiting vegetable group.

  ----------------------------------------------------------------------------------------
  Number range                                                                    
  CHAPTER**Table                                                                  
  5.1.10.6 Summary                                                                
  of Processing                                                                   
  Factors for                                                                     
  Fluopicolide.**                                                                 
  ----------------- ----------------- -------------- -------- -------- ---------- --------
  RAC               Processed         Average                                     
                    Commodity         Processing                                  
                                      Factor ^1^                                  

                                      Fluopicolide   BAM      PCA      3-OH-BAM   P1X

  Grape             Juice             \<1x           ≤1x      ≤1x      NA         NA

                    Raisins           3.4x           4x       4x       NA         NA

  Potato            Chips             NC             NC       NC       NA         NA

                    Flakes            NC             NC       NC       NA         NA

                    Wet peels         4.0x^2^        NC       NC       NA         NA

  Tomato            Paste             2.4x           NC       NC       NA         NA

                    Puree             1.4x^3^        NC       ≥1x      NA         NA

  Wheat             Bran              3.0x           \~1.7x   1.9x     3.0x       2.2x

                    Flour             \~0.4x         \~0.7x   1x       \~0.3x     0.6x

                    Middlings         1.5x           \~1.1x   1.3x     1x         1x

                    Shorts            2.0x           \~1.2x   1.8x     1.5x       1.4x

                    Germ              4.7x           \~1.8x   0.9x     1.5x       0.7x
  ----------------------------------------------------------------------------------------

^1^ NC = Not calculated; a processing factor could not be calculated for
this matrix as residues were below the LOQ in both the RAC and the
processed commodity. NA = Not applicable. Estimated (\~) processing
factors were calculated when residues were reported below the LOQ in the
RAC and/or the processed matrix.

^2^ The observed processing factor (\>4.9x) exceeded the theoretical
value of 4.0x; therefore, the theoretical value of 4.0x will be used.

^3^ The observed processing factors for puree (1.7-1.8x) exceeded the
theoretical value of 1.4x; therefore, the theoretical value of 1.4x will
be used.

[Field Accumulation in Rotational Crops (46708547)]{.underline}

*Wheat*: Pending submission of additional storage stability data,
adequate field rotational crop data have been submitted to support the
proposed 30-day plantback interval (PBI) for wheat. The data indicate
that rotational crop tolerances are needed for wheat forage, hay, grain,
and straw.

Additional storage stability data are needed reflecting the stability of
3-OH-BAM and P1X in wheat grain for 21 months and for all analytes
(fluopicolide, BAM, 3-OH-BAM, PCA and P1X) in wheat forage and straw for
24 months. The available storage stability data for wheat straw will be
translated to wheat hay.

Twenty-one field trials were conducted on the rotational crop wheat in
the U.S.A. Three broadcast foliar applications of a 4 lb ai/gal
suspension concentrate formulation \[equivalent to a flowable
concentrate (FlC) formulation\] were made to a primary crop of potatoes
or to bare ground (one TX trial only) for a total of 0.346-0.372 lb
ai/A/season (\~1x the maximum proposed seasonal rate). Potatoes were
harvested \~7 days after the last application, and wheat was planted as
a rotational crop 29-37 days after the last application. Residues in
wheat forage, hay, grain, and straw were determined at normal commercial
harvest. Considering all matrices, residues of fluopicolide (parent)
were \<0.01-0.50 ppm. Residues of the metabolites were individually
lower than the parent in all matrices.

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 12%" />
<col style="width: 4%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="11"><strong>Table 5.1.10.7 Summary of Residue Data in
Rotational Wheat Commodities Following Treatment of a Primary Crop with
Fluopicolide.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2">Commodity</th>
<th rowspan="2"><p>Applic. Rate</p>
<p>(lb ai/A)</p>
<p>[g ai/ha]</p></th>
<th rowspan="2"><p>PBI</p>
<p>(days)</p></th>
<th rowspan="2">Analyte</th>
<th colspan="7">Residue Levels (ppm)</th>
</tr>
<tr class="header">
<th>n</th>
<th>Min.</th>
<th>Max.</th>
<th>HAFT<sup>1</sup></th>
<th>Median</th>
<th>Mean</th>
<th>Std. Dev.</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td rowspan="5">Wheat, forage</td>
<td rowspan="5"><p>0.346-0.372</p>
<p>[388-417]</p></td>
<td rowspan="5">29-37</td>
<td>Fluopicolide</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.213</td>
<td>0.160</td>
<td>0.027</td>
<td>0.044</td>
<td>0.047</td>
</tr>
<tr class="even">
<td>BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.123</td>
<td>0.106</td>
<td>0.019</td>
<td>0.028</td>
<td>0.027</td>
</tr>
<tr class="odd">
<td>3-OH-BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.050</td>
<td>0.045</td>
<td>0.013</td>
<td>0.019</td>
<td>0.012</td>
</tr>
<tr class="even">
<td>PCA</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.043</td>
<td>0.027</td>
<td>0.010</td>
<td>0.013</td>
<td>0.007</td>
</tr>
<tr class="odd">
<td>P1X</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.064</td>
<td>0.057</td>
<td>0.012</td>
<td>0.018</td>
<td>0.013</td>
</tr>
<tr class="even">
<td rowspan="5">Wheat, hay</td>
<td rowspan="5"><p>0.346-0.372</p>
<p>[388-417]</p></td>
<td rowspan="5">29-37</td>
<td>Fluopicolide</td>
<td>42</td>
<td>0.014</td>
<td>0.501</td>
<td>0.364</td>
<td>0.051</td>
<td>0.100</td>
<td>0.119</td>
</tr>
<tr class="odd">
<td>BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.102</td>
<td>0.095</td>
<td>0.010</td>
<td>0.022</td>
<td>0.024</td>
</tr>
<tr class="even">
<td>3-OH-BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.160</td>
<td>0.133</td>
<td>0.032</td>
<td>0.048</td>
<td>0.044</td>
</tr>
<tr class="odd">
<td>PCA</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.064</td>
<td>0.055</td>
<td>0.010</td>
<td>0.018</td>
<td>0.013</td>
</tr>
<tr class="even">
<td>P1X</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.073</td>
<td>0.070</td>
<td>0.025</td>
<td>0.028</td>
<td>0.017</td>
</tr>
<tr class="odd">
<td rowspan="5">Wheat, grain</td>
<td rowspan="5"><p>0.346-0.372</p>
<p>[388-417]</p></td>
<td rowspan="5">29-37</td>
<td>Fluopicolide</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.014</td>
<td>0.014</td>
<td>0.010</td>
<td>0.010</td>
<td>0.001</td>
</tr>
<tr class="even">
<td>BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.010</td>
<td>0.010</td>
<td>0.000</td>
</tr>
<tr class="odd">
<td>3-OH-BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.010</td>
<td>0.010</td>
<td>0.000</td>
</tr>
<tr class="even">
<td>PCA</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.062</td>
<td>0.060</td>
<td>0.011</td>
<td>0.016</td>
<td>0.011</td>
</tr>
<tr class="odd">
<td>P1X</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.075</td>
<td>0.075</td>
<td>0.019</td>
<td>0.025</td>
<td>0.020</td>
</tr>
<tr class="even">
<td rowspan="5">Wheat, straw</td>
<td rowspan="5"><p>0.346-0.372</p>
<p>[388-417]</p></td>
<td rowspan="5">29-37</td>
<td>Fluopicolide</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.350</td>
<td>0.338</td>
<td>0.034</td>
<td>0.055</td>
<td>0.075</td>
</tr>
<tr class="odd">
<td>BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.050</td>
<td>0.050</td>
<td>0.010</td>
<td>0.015</td>
<td>0.011</td>
</tr>
<tr class="even">
<td>3-OH-BAM</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.081</td>
<td>0.078</td>
<td>0.026</td>
<td>0.031</td>
<td>0.019</td>
</tr>
<tr class="odd">
<td>PCA</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.043</td>
<td>0.040</td>
<td>0.010</td>
<td>0.012</td>
<td>0.007</td>
</tr>
<tr class="even">
<td>P1X</td>
<td>42</td>
<td>&lt;0.01</td>
<td>0.055</td>
<td>0.049</td>
<td>0.020</td>
<td>0.021</td>
<td>0.011</td>
</tr>
</tbody>
</table>

^1^ HAFT = Highest average field trial result.

The petitioner has proposed a PBI of one year for all crops other than
cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables,
tuber vegetables, and wheat. Because the confined rotational crop data
indicated the potential for quantifiable residues of fluopicolide in/on
rotated crops at a one-year PBI, additional field rotational crop data
must be submitted. Until the data are submitted, crops may not be
rotated to crops not listed on the label.

Limited field rotational crop studies must be conducted at a 12-month
PBI with representative leafy vegetable, root vegetable, and cereal
grain crops. (Although the petitioner is proposing a 30-day PBI for
wheat and has submitted supporting field rotational crop data, limited
field rotational crop data for another cereal grain, preferably a small
grain, are needed to represent all grain crops other than wheat that may
be rotated at a 12-month PBI.) If the results of the limited field
rotational crop studies indicate the potential for quantifiable
fluopicolide residues of concern in/on rotational crops at a 12-month
PBI, then extensive field rotational crop studies will be required for
all crops the petitioner wishes to allow for rotation at a 12-month PBI.

[Meat, Milk, Poultry, and Eggs (MRIDs 46708528 and
46708529)]{.underline}

There are livestock feedstuffs associated with the proposed uses on
potato and rotated wheat. The dietary burdens of fluopicolide to
livestock, based on reasonably balanced diets and tolerance-level
residues, are presented in Table 5.1.10.8. The dietary burdens are 0.21
ppm for beef cattle, 0.29 ppm for dairy cattle, and 0.035 ppm for swine
and poultry (e-mail, J. Stokes, 4/30/07).

  --------------------------------------------------------------------------------
  **Table 5.1.10.8                                                 
  Calculation of                                                   
  Dietary Burdens of                                               
  Fluopicolide                                                     
  Residues to                                                      
  Livestock.**                                                     
  ------------------ --------- ----------- --------- ------------- ---------------
  Feedstuff          Type^1^   \% Dry      \%        Recommended   Dietary
                               Matter^2^   Diet^2^   Tolerance     Contribution
                                                     (ppm)         (ppm)^3^

  **Beef Cattle R:                                                 
  15%; CC: 75 %; PC:                                               
  10%**                                                            

  Wheat, hay         R         88          15        0.50          0.08

  Potato, processed  CC        15          30        0.05          0.10
  waste                                                            

  Wheat, milled      CC        88          40        0.07          0.032
  byproducts                                                       

  CC (untreated)     CC        N/A         5         N/A           \--

  PC (untreated)     PC        N/A         10        N/A           **\--**

  TOTAL BURDEN       \--       \--         100       \--           **0.21**

  **Dairy Cattle R:                                                
  45%; CC: 45 %; PC:                                               
  10%**                                                            

  Wheat, hay         R         88          40        0.50          0.23

  R (untreated)      R         N/A         5         N/A           \--

  Potato, processed  CC        15          10        0.05          0.033
  waste                                                            

  Wheat, milled      CC        88          35        0.07          0.028
  byproducts                                                       

  PC (untreated)     PC        N/A         10        N/A           **\--**

  TOTAL BURDEN       \--       \--         100       \--           **0.29**

  **Poultry CC: 75                                                 
  %; PC: 25%**                                                     

  Wheat, milled      CC        88          50        0.07          0.035
  byproducts                                                       

  CC (untreated)     CC        N/A         25        N/A           \--

  PC (untreated)     PC        N/A         25        N/A           **\--**

  TOTAL BURDEN       \--       \--         100       \--           **0.035**

  **Swine CC: 85 %;                                                
  PC: 15%**                                                        

  Wheat, milled      CC        88          50        0.07          0.035
  byproducts                                                       

  CC (untreated)     CC        N/A         35        N/A           \--

  PC (untreated)     PC        N/A         15        N/A           **\--**

  TOTAL BURDEN       \--       \--         100       \--           **0.035**
  --------------------------------------------------------------------------------

^1^ R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

^2^ OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

^3^ Contribution = (\[tolerance /% DM\] X % diet) for beef and dairy
cattle; contribution = (\[tolerance\] X % diet) for poultry and swine.

^4^ N/A: Not applicable. Tolerances/uses of fluopicolide have not been
registered or proposed for this feedstuff.

In addition, since there are likely to be measurable residues of the
fluopicolide metabolite, BAM in livestock feedstuffs, and HED has
determined that the residues of concern in livestock commodities
includes BAM, HED has also calculated a BAM dietary burden in connection
with the Human Health Risk Assessment for BAM \[*2,6-Dichlorobenzamide
(BAM ) as a Metabolite/Degradate of Fluopicolide and Dichlobenil. Human
Health Risk Assessment for Proposed Uses of Fluopicolide on Tuberous and
Corm Vegetables, Leafy Vegetables (except Brassica), Fruiting
Vegetables, Cucurbit Vegetables, Grapes, Turf, and Ornamentals, and for
Indirect or Inadvertent Residues on the Rotational Crop Wheat*, DP
#345918, N. Dodd, 11/21/07\].

Wet apple pomace is the only livestock feed associated with crops with
established/pending [dichlobenil]{.underline} tolerances. Wet apple
pomace is fed to beef and dairy cattle. There are no poultry or swine
feedstuffs associated with the established/pending uses of dichlobenil.

Feed items from potatoes (potato culls and processed potato waste) and
wheat (grain, forage, hay, straw, aspirated grain fractions, milled
byproducts) are the only livestock feeds from [fluopicolide]{.underline}
uses on tuberous and corm vegetables, leafy vegetables, fruiting
vegetables, cucurbit vegetables, grapes, and the rotational crop wheat.

The dietary burdens of BAM residues in livestock from dichlobenil and
fluopicolide uses, based on reasonably balanced diets, are presented in
the table below. The dietary burdens of BAM are 0.13 ppm for beef
cattle, 0.12 ppm for dairy cattle, and 0.009 ppm for swine and poultry.

  -------------------------------------------------------------------------------
  **Table 5.1.10.9                                                 
  Calculation of                                                   
  Dietary Burdens of                                               
  BAM Residues in                                                  
  Livestock from                                                   
  Fluopicolide and                                                 
  Dichlobenil                                                      
  Uses.\***                                                        
  -------------------- --------- ----------- --------- ----------- --------------
  Feedstuff            Type^1^   \% Dry      \%        BAM Maximum Dietary
                                 Matter^2^   Diet^2^   Residues    Contribution
                                                       (ppm)       (ppm)^3^

  **Beef Cattle R:                                                 
  15%; CC: 75 %; PC:                                               
  10%**                                                            

  Wheat, hay           R         88          15        0.102       0.017

  Potato, processed    CC        15          30        0.05^4^     0.10
  waste                                                            

  Wheat, milled        CC        88          40        0.018^5^    0.0082
  byproducts                                                       

  CC (untreated)       CC        N/A         5         N/A^6^      \--

  PC (untreated)       PC        N/A         10        N/A         **\--**

  TOTAL BURDEN         \--       \--         100                   **0.13**

  **Dairy Cattle R:                                                
  45%; CC: 45 %; PC:                                               
  10%**                                                            

  Wheat, hay           R         88          40        0.102       0.046

  R (untreated)        R         N/A         5         N/A         \--

  Wet apple pomace     CC        40          10        0.271       0.068

  Wheat, milled        CC        88          35        0.018^5^    0.0072
  byproducts                                                       

  PC (untreated)       PC        N/A         10        N/A         **\--**

  TOTAL BURDEN         \--       \--         100                   **0.12**

  **Poultry CC: 75 %;                                              
  PC: 25%**                                                        

  Wheat, milled        CC        88          50        0.018^5^    0.009
  byproducts                                                       

  CC (untreated)       CC        N/A         25        N/A         \--

  PC (untreated)       PC        N/A         25        N/A         **\--**

  TOTAL BURDEN         \--       \--         100                   **0.009**

  **Swine CC: 85 %;                                                
  PC: 15%**                                                        

  Wheat, milled        CC        88          50        0.018^5^    0.009
  byproducts                                                       

  CC (untreated)       CC        N/A         35        N/A         \--

  PC (untreated)       PC        N/A         15        N/A         **\--**

  TOTAL BURDEN         \--       \--         100                   **0.009**
  -------------------------------------------------------------------------------

^1^ R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

^2^ OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

^3^ Contribution = (\[tolerance /% DM\] X % diet) for beef and dairy
cattle; contribution = (\[tolerance\] X % diet) for poultry and swine.

^4^The value of 0.05 ppm for processed potato waste is based on a
concentration factor for wet peel of 4.9x and the LOQ (0.01 ppm) as the
BAM residue in the RAC samples.

^5^ Residues of BAM in wheat grain (field accumulation in rotational
wheat study: MRID 46708547) were below the calculated LOD of
0.0029-0.0077 ppm; the LOQ is 0.01 ppm. BAM concentration factors are
1.7x for wheat bran, 0.7x for flour, 1.1x for middlings, 1.2x for
shorts, and 1.8x for germ. The value of 0.018 ppm for wheat milled
byproducts and aspirated grain fractions is based on the highest
concentration factor of 1.8x for BAM and a grain (RAC) residue of 0.01
ppm (LOQ) for BAM.

^6^ N/A: Not applicable.

[Fluopicolide]{.underline}

*Cattle:* Valent U.S.A. Corporation submitted a cattle feeding study
with fluopicolide. Three treatment groups of three dairy cows each were
dosed orally with fluopicolide in the feed at dose rates corresponding
to 0.5, 1.7, and 5.7 ppm (dry feed weight) for 28 consecutive days.
(These dosing levels as compared to the dietary burden are 1.7x, 5.9x,
and 20x, respectively, for dairy cattle and 2.4x, 8.1x, and 27x,
respectively, for beef cattle.

Samples of cattle matrices were analyzed for residues of fluopicolide,
AE C653711 (BAM), and AE C657188 (PCA) using LC/MS/MS Method No. AR
303-02. This method is adequate for data collection based on acceptable
method recoveries. The validated limits of quantitation (LOQs) were
0.010 ppm for each analyte in milk, 0.020 ppm for each analyte in
muscle, and 0.050 ppm for each analyte in fat, liver, and kidney. HED
notes that, for Method No. AR 303-02 to be an enforcement method (for
any future livestock tolerances), radiovalidation data would be needed;
such data are not required for this petition since tolerances on
livestock commodities are not required.

The submitted dairy cattle feeding study data are acceptable. At the 5.7
ppm dose level (the highest dose level), maximum residues of
fluopicolide (parent) were 0.024 ppm in milk and 0.018 ppm cream.
Residues of fluopicolide were below the LOQ in all samples of milk
tested from the 0.5 ppm dose group (study days 1 and 4) and the 1.7 ppm
dose group (study days 1, 4, 7, and 10). Residues of fluopicolide were
below the LOQ in all tissue samples (\<0.020 ppm in muscle and \<0.050
ppm in fat, liver, and kidney) from the highest dosing level, and
residues of BAM and PCA were below the LOQ in all milk samples (\<0.010
ppm) and tissue samples (\<0.020 ppm in muscle and \<0.050 ppm in fat,
liver, and kidney) from the highest dosing level.

*Poultry*: Valent U.S.A. submitted a request to waive the requirements
for a poultry feeding study (MRID 46708529) on the basis that
anticipated residues in poultry would be far below the method LOQ of
0.05 ppm for tissues.

HED concurs with the request for a waiver of the poultry feeding study.
No poultry feeding study in which fluopicolide is fed is required based
on the poultry metabolism studies and the calculated dietary burden of
0.035 ppm (see Table 5.1.10.8). The available poultry metabolism data
(MRID 46708515) yielded maximum observed residues of fluopicolide
(parent) in egg: 17 ppb in egg yolk, equivalent to 5.8 ppb in whole egg
(31.0% yolk x 17 ppb +58.0% egg white x 1 ppb = 5.8 ppb in whole egg)
and maximum residues of BAM of 361 ppb parent equivalents (178 ppb BAM
equivalents) in liver following dosing at 10.7 ppm (306x the dietary
burden). The expected maximum residues at a 1x dosing level would be
0.000019 ppm for fluopicolide in whole egg and 0.0012 ppm for BAM in
parent equivalents (0.00058 ppm in BAM equivalents) in liver. These
calculated residues are \<LOQ of the submitted analytical method, for
which the stated limits of quantitation (LOQs) for each analyte are 0.01
ppm for milk, 0.02 ppm for meat, and 0.05 ppm for fat, liver, and
kidney. The available data indicate that a poultry feeding study is not
required to support the proposed uses. There is no reasonable
expectation of finite residues of fluopicolide (parent) in poultry
commodities \[40 CFR §180.6(a)(3)\].

[BAM]{.underline}

A BAM ruminant feeding study was not submitted with this petition. Given
the likelihood of measurable residues of BAM in livestock feed items as
a result of treating RACs with fluopicolide (refer to DP #340366, N.
Dodd, 11/21/07 and DP #345918, N. Dodd, 11/21/07), a 28-day BAM ruminant
feeding study must be submitted or referenced and livestock tolerances
must be proposed to support use of fluopicolide on crops with associated
livestock feed items and rotation to crops with associated livestock
feed items. HED has determined that tolerances at the limit of
quantitation of the analytical method are needed for ruminant
commodities.

***Conclusions*:** The submitted fluopicolide dairy cattle feeding study
data are acceptable. At the 5.7 ppm dose level, residues of fluopicolide
(parent) were 0.024 ppm in milk and 0.018 ppm cream. Residues of
fluopicolide were below the LOQ in all tissue samples (\<0.020 ppm in
muscle and \<0.050 ppm in fat, liver, and kidney) from the highest
dosing level, and residues of BAM and PCA were below the LOQ in all milk
samples (\<0.010 ppm) and tissue samples (\<0.020 ppm in muscle and
\<0.050 ppm in fat, liver, and kidney) from the highest dosing level.

To support uses with associated livestock feed items, a BAM ruminant
feeding study must be submitted or referenced. Pending review of the
28-day BAM ruminant feeding study, HED tentatively concludes that finite
residues of BAM may be present in ruminant commodities as a result of
feeding fluopicolide treated feed items. To support uses with associated
livestock feed items, the petitioner should propose tolerances for milk,
meat by products, fat and muscle of cattle, goat, horse, and sheep at
the analytical method limit of quantitation (LOQ) for each commodity.
The validated limits of quantitation (LOQs) for the LC/MS/MS method
303-02 for BAM are 0.01 ppm for milk, 0.02 ppm for meat, and 0.05 ppm
for fat, liver, and kidney.

Note: Potato and the rotational crop wheat are the only fluopicolide
crops with associated livestock feed items. Provided that the potato use
will not be registered at this time and rotational crop restrictions to
limit rotation to crops on the label will be established at this time,
there will be no livestock feedstuffs associated with the proposed
fluopicolide uses. In that case, this use would fall under 40 CFR
§180.6(a)(3) since there would be no reasonable expectation of finite
residues in livestock commodities from application of fluopicolide.

[Poultry]{.underline}: Valent U.S.A. submitted a request to waive the
requirements for a poultry feeding study (MRID 46708529).

EPA calculated a poultry dietary burden of 0.035 (see Table 5). The
poultry feeding levels of 1 and 10 ppm in the poultry metabolism study
using \[2,6-^14^C-pyridinyl\]fluopicolide correspond to 29x and 286x ,
respectively, of the dietary burden. The poultry feeding levels of 1.2
and 10.7 ppm in the poultry metabolism study using
\[U-^14^C-phenyl\]fluopicolide correspond to 34x and 306x ,
respectively, of the dietary burden. TRR following dosing at 1 ppm using
\[2,6-^14^C-pyridinyl\]fluopicolide were 0.001-0.004 ppm in egg white,
0.001-0.018 ppm in egg yolk, 0.002-0.004 ppm in fat, 0.031-0.052 ppm in
liver, 0.002-0.003 ppm in skin (with fat), and 0.001-0.002 ppm in
muscle. TRR following dosing at 10 ppm using
\[2,6-^14^C-pyridinyl\]fluopicolide were 0.004-0.023 ppm in egg white,
0.004-0.104 ppm in egg yolk, 0.014-0.044 ppm in fat, 0.237-0.357 ppm in
liver, 0.013-0.039 ppm in skin, and 0.007-0.015 ppm in muscle. Total
radioactive residues (TRR) following dosing with
\[U-^14^C-phenyl\]fluopicolide at 1.2 ppm were 0.002-0.018 ppm in egg
white, 0.001-0.024 ppm in egg yolk, 0.004-0.007 ppm in fat, 0.086-0.224
ppm in liver, 0.004-0.011 ppm in skin (including subcutaneous fat), and
0.003-0.006 ppm in muscle. TRR following dosing with
\[U-^14^C-phenyl\]fluopicolide at 10.7 ppm were 0.005-0.072 ppm in egg
white, 0.003-0.224 ppm in egg yolk, 0.042-0.099 ppm in fat, 0.602-1.69
ppm in liver, 0.060-0.087 ppm in skin, and 0.031-0.047 ppm in muscle.
The maximum fluopicolide (parent) residues found were in egg: 17 ppb in
egg yolk, equivalent to 5.8 ppb in whole egg (31.0% yolk x 17 ppb +58.0%
egg white x 1 ppb = 5.8 ppb in whole egg; North, M.O, and Bell, D. D.,
*Commercial Chicken Production Manual, 4^th^ ed., 1990*). The maximum
residues of BAM were 361 ppb parent equivalents (178 ppb BAM
equivalents) in liver following dosing with
\[U-^14^C-phenyl\]fluopicolide at 10.7 ppm (306x the dietary burden).

No poultry metabolism data for the fluopicolide metabolite, BAM was
submitted or referenced. However, given the very low calculated dietary
BAM dietary burden, HED concludes that it is unlikely that there will be
measurable residues of BAM in poultry commodities as a result of the
proposed uses on fluopicolide.

**Conclusions:** No poultry feeding studies are required for either
fluopicolide or BAM based on the available metabolism studies and the
calculated dietary burdens. There is no reasonable expectation of finite
residues of fluopicolide (parent) in poultry commodities \[40 CFR
§180.6(a)(3)\].

**5.1.11 International Residue Limits**[]{#__RefHeading___Toc185228066
.anchor}

No Codex, Canadian, or Mexican maximum residue limits (MRLs) or
tolerances have been established for fluopicolide.

**5.2 Dietary Exposure and Risk**[]{#__RefHeading___Toc185228067
.anchor}

References:

*Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for
Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, and Grapes and for Indirect or
Inadvertent Residues on the Rotational Crop Wheat. Summary of Analytical
Chemistry and Residue Data, DP Number326080, Amelia Acierto, 11/19/07*.

***Fluopicolide** Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action on
Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes, and the Rotational
Crop Wheat,* DP Number 340365, N. Dodd, 11/21/07.

Dietary exposure assessments were conducted using the Dietary Exposure
Evaluation Model DEEM-FCID™, Version 2.03, which uses food consumption
data from the U.S. Department of Agriculture's Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. Two dietary
exposure assessments were conducted: one (discussed in this document)
for residues of fluopicolide (i.e., parent for water and most crops; for
tuberous and corm crops, parent and PCA; and for the grain used as human
food of cereal grains as rotational crops, parent, PCA, and P1X) in food
and drinking water, and one (discussed in a separate document) for
combined residues of BAM in food and drinking water from uses of both
fluopicolide and dichlobenil.

**5.2.1 Acute Dietary (Food and Drinking Water)
Exposure/Risk**[]{#__RefHeading___Toc185228068 .anchor}

An acute dietary assessment was not conducted because an endpoint
attributable to a single dose was not identified from the available data
for fluopicolide.

**5.2.2 Chronic Dietary (Food and Drinking Water)
Exposure/Risk**[]{#__RefHeading___Toc185228069 .anchor}

The chronic dietary (food and drinking water) exposure analysis which
was conducted for fluopicolide residues on tuberous and corm vegetables,
leafy vegetables (except *Brassica*), fruiting vegetables, cucurbit
vegetables, grapes, and the rotational crop wheat was a conservative
assessment using the recommended tolerance levels (except for tuberous
and corm vegetables and wheat) and assuming that 100% of the crop was
treated. Some processing studies were available; default processing
factors were used in cases where an adequate processing study was not
available for particular matrices in DEEM[^TM^]{.smallcaps}. Since
residues may be expected to occur in rotational crops, a label
restriction is recommended against rotation to crops which are not on
the label.. Based on a dairy cattle feeding study and a poultry
metabolism study, no livestock tolerances are required.

The results of the chronic dietary (food and drinking water) exposure
analysis which was conducted for fluopicolide residues on tuberous and
corm vegetables, leafy vegetables (except *Brassica*), fruiting
vegetables, cucurbit vegetables, grapes, and the rotational crop wheat
are reported in Table 5.2.2 below. The chronic dietary (food and
drinking water) exposure to fluopicolide is below HED's level of concern
for the general U.S. population and all population subgroups. The
chronic dietary exposure estimates are 6% cPAD for the general U.S.
population and 9% cPAD for children 1-2 years old, the most highly
exposed subgroup.

  ------------------------- ----------------- --------------- ------------------
  **Table 5.2.2 Result of                                     
  Chronic Dietary (Food and                                   
  Drinking Water) Exposure                                    
  and Risk Estimates for                                      
  Fluopicolide\***                                            

  **Population Subgroup**   **cPAD,           **DEEM-FCID**   
                            mg/kg/day**                       

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

  **Chronic Dietary                                           
  Estimates**                                                 

  U.S. Population           0.2               0.011999        6

  All infants (\< 1 yr old)                   0.007826        4

  Children 1-2 yrs old                        **0.018460**    **9**

  Children 3-5 yrs old                        0.016718        8

  Children 6-12 yrs old                       0.012418        6

  Youth 13-19 yrs old                         0.009748        5

  Adults 20-49 yrs old                        0.011822        6

  Adults 50+ yrs old                          0.011590        6

  Females 13-49 yrs old                       0.012034        6

  **Cancer Dietary                                            
  Estimate**                                                  

  U.S. Population           Classification:                   
                            "**Not Likely to                  
                            be Carcinogenic                   
                            to Humans**"                      
  ------------------------- ----------------- --------------- ------------------

\*Parent fluopicolide is included in the exposure calculation for all
crops and drinking water. For

tuberous and corm vegetables, parent and PCA are included. For wheat
grain, parent, PCA, and

P1X are included. BAM is excluded because it is assessed in food and
drinking water in

DP #345918, N. Dodd, 11/21/07.

**5.2.3 Cancer Dietary Risk**[]{#__RefHeading___Toc185228070 .anchor}

Fluopicolide is not likely to be carcinogenic to humans; therefore, a
cancer risk assessment was not conducted for parent fluopicolide.

**5.3 Anticipated Residue and Percent Crop Treated (%CT)
Information**[]{#__RefHeading___Toc185228071 .anchor}

Anticipated residues/percent crop treated (% CT) data were not needed to
refine this risk assessment for fluopicolide so they were not used.

**6.0 Residential (Non-Occupational) Exposure/Risk
Characterization**[]{#__RefHeading___Toc185228072 .anchor}

*Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O'Rourke, 10/9/07.*

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites. They may be applied to turf at rates
ranging from 0.21 to 0.27 lb ai/A, for two applications at an interval
of 14 days. The labels do not prohibit homeowners from using these
products; therefore, residential handlers may receive short-term dermal
and inhalation exposure to fluopicolide when mixing, loading and
applying the formulations. Residential postapplication exposure via the
inhalation route is expected to be negligible; however, dermal exposure
is likely for adults and children entering treated lawns. Toddlers may
also experience exposure via incidental non-dietary ingestion (i.e.,
hand-to-mouth, object-to-mouth (turfgrass), and soil ingestion) during
postapplication activities on treated turf.

Estimated short- and intermediate-term dermal, inhalation and incidental
oral (for toddlers) exposures were compared to the conservative oral
NOAEL of 20 mg/kg/day from a rabbit developmental toxicity study in
which death, abortions/premature deliveries, decreased food consumption,
and decreased body weight gain were observed at the LOAEL of 60
mg/kg/day. Because this endpoint is from an oral study, the estimated
dermal exposures were adjusted by applying a 37 percent dermal
absorption rate (based on a dermal penetration study in the rat), while
inhalation toxicity is assumed to be equivalent to oral toxicity. In
addition, this endpoint is applicable to all populations including
females 13+ years old; therefore, a 60-kg body weight was used in the
calculations. Where appropriate, the resulting dermal, inhalation, and
incidental oral MOEs were combined into total MOEs because the same dose
and endpoint were chosen to evaluate all routes of exposure. The FQPA
safety factor was removed (i.e., reduced to 1x) for all potential
exposure scenarios; therefore, the level of concern (LOC) for
non-occupational risk is for margins of exposure (MOEs) \<100.

**6.1 Residential Handler Exposure**[]{#__RefHeading___Toc185228073
.anchor}

HED's Draft Standard Operating Procedures (SOPs) for Residential
Exposure Assessments, and Recommended Revisions (HED Policy Number 11,
revised 22 Feb 2001), were used as the basis for all residential handler
exposure calculations. Data from the Outdoor Residential Exposure Task
Force (ORETF) (MRID \# 44972201) were used in this assessment in place
of PHED data for the garden hose-end sprayer scenario, which provided
more confidence in the exposure estimate. As shown in Table 6.1, the
Total MOEs for residential handlers are well above the LOC of 100, and
are not of concern.

+-------------------------+--------+-------+-------+---------+------+
| **Table 6.1. Handler    |        |       |       |         |      |
| Exposure and Risk       |        |       |       |         |      |
| Estimates for           |        |       |       |         |      |
| Residential Lawn        |        |       |       |         |      |
| Applicators**           |        |       |       |         |      |
+-------------------------+--------+-------+-------+---------+------+
| **Handler Scenario**    | *      | *     | *     | **Short |      |
|                         | *Appli | *Area | *Unit | -/Inter |      |
|                         | cation | Tr    | Exp   | mediate |      |
|                         | Rate   | eated | osure | -Term** |      |
|                         | ^1^**  | ^2^** | ^3^** |         |      |
|                         |        |       |       |         |      |
|                         | **(lb  | **(ac | **(   |         |      |
|                         | a      | res/d | mg/lb |         |      |
|                         | i/A)** | ay)** | ai)** |         |      |
+-------------------------+--------+-------+-------+---------+------+
|                         |        |       |       | **Daily | **T  |
|                         |        |       |       | Dose    | otal |
|                         |        |       |       | ^4^**   | MOE  |
|                         |        |       |       |         | ^    |
|                         |        |       |       | *       | 5^** |
|                         |        |       |       | *(mg/kg |      |
|                         |        |       |       | /day)** |      |
+-------------------------+--------+-------+-------+---------+------+
| \(1\) Mix/load and spot | 0.27   | 0.023 | De    | Dermal: | 5    |
| application of liquid   |        |       | rmal: |         | ,200 |
| formulation             |        | (     |       | 0.0038  |      |
| (low-pressure hand      |        | 1,000 | 100   |         |      |
| sprayer)                |        | f     |       |         |      |
|                         |        | t^2^) |       |         |      |
+-------------------------+--------+-------+-------+---------+------+
|                         |        |       | I     | Inha    |      |
|                         |        |       | nhala | lation: |      |
|                         |        |       | tion: |         |      |
|                         |        |       |       | 0.      |      |
|                         |        |       | 0.030 | 0000031 |      |
+-------------------------+--------+-------+-------+---------+------+
| \(2\) Mix/load and      | 0.27   | 0.50  | De    | Dermal: | 2    |
| broadcast application   |        |       | rmal: |         | ,200 |
| of liquid formulation   |        |       |       | 0.0092  |      |
| (garden hose-end        |        |       | 11    |         |      |
| sprayer)                |        |       |       |         |      |
+-------------------------+--------+-------+-------+---------+------+
|                         |        |       | I     | Inha    |      |
|                         |        |       | nhala | lation: |      |
|                         |        |       | tion: |         |      |
|                         |        |       |       | 0       |      |
|                         |        |       | 0.017 | .000038 |      |
+-------------------------+--------+-------+-------+---------+------+

^1^ Application rate is based on maximum values found in proposed
labels: V-10161 VPP Fungicide (Reg No. 59639-RUR), and V-10162 VPP
Fungicide (Reg. No. 59639-RUG).

^2^ Area treated is based on the area that can be reasonably treated in
a single day based on the application method (standard EPA/OPP/HED
values).

^3^ Dermal unit exposure values represent short pants and short-sleeved
shirt; inhalation values represent no respirator. Values for
low-pressure handwand are reported in the PHED Surrogate Exposure Guide
dated August 1998, and those for hose-end sprayer were obtained from the
ORETF data.

^4^ Daily Absorbed Dose (mg/kg/day) = (\[unit exposure \* % absorption\]
\* Application rate \* Area treated) / 60 kg, where dermal absorption is
37% and inhalation absorption is assumed to be 100%.

^5^ Short-/Intermediate-Term Total MOE = NOAEL (20 mg/kg/day) / Total
Daily Absorbed Dose (dermal + inhalation). The LOC is 100.

**6.2. Residential Postapplication
Exposure**[]{#__RefHeading___Toc185228074 .anchor}

Residential postapplication exposure via the inhalation route is
expected to be negligible; however, dermal exposure is likely for adults
and children entering treated lawns. Toddlers may also experience
exposure via incidental non-dietary ingestion (i.e., hand-to-mouth,
object-to-mouth \[turfgrass\], and soil ingestion) during
postapplication activities on treated turf. The postapplication risk
assessment is based on generic assumptions as specified by the
Recommended Revisions to the Residential SOPs and recommended approaches
by HED's Science Advisory Council for Exposure (ExpoSAC).

The following postapplication exposure scenarios resulting from lawn
treatment were assessed: (1) adult and toddler postapplication dermal
exposure; (2) toddlers' incidental ingestion of pesticide residues on
lawns from hand-to-mouth transfer; (3) toddlers' object-to-mouth
transfer from mouthing of pesticide-treated turfgrass; and (4) toddlers'
incidental ingestion of soil from pesticide-treated residential areas.

Turf transferable residue (TTR) data were not available. The assessment
was based on generic assumptions per TTR and transfer coefficients, as
specified by the Recommended Revisions to the Residential SOPs and
recommended approaches by HED's Science Advisory Council for Exposure
(ExpoSAC).

The exposure and risk estimates for the residential exposure scenarios
are assessed for the day of application (day "0") because it is assumed
that adults and toddlers could contact the lawn immediately after
application. The equations used for the exposure calculations and the
results are presented in Tables 6.2.1 through 6.2.5.

The exposure estimates are based on some upper-percentile (i.e., maximum
application rate, initial amount of transferable residue and duration of
exposure) and some central tendency (i.e., surface area and body weight)
assumptions and are considered to be representative of high-end
exposures. The uncertainties associated with this assessment stem from
the use of an assumed amount of pesticide available from turf, and
assumptions regarding transfer of chemical residues and hand-to mouth
activity. The estimated exposures are believed to be reasonable high-end
estimates based on observations from chemical-specific field studies and
professional judgement.

The short-/intermediate-term MOEs for each scenario are above the LOC of
100, and are not of concern. As mentioned previously, the same toxicity
study was selected to evaluate all routes of exposure; therefore, the
MOEs were combined. As shown in Table 6.2.5, the Total
short-/intermediate-term MOEs for adults (including handler exposure
which could co-occur with postapplication exposure) and children are 550
and 450, respectively. These Total MOEs are greater than the LOC of 100
on the day of application, and therefore, are not of concern.

+------+------+------+-------+-------+------+-----+-------+----------+
| **T  |      |      |       |       |      |     |       |          |
| able |      |      |       |       |      |     |       |          |
| 6.   |      |      |       |       |      |     |       |          |
| 2.1. |      |      |       |       |      |     |       |          |
| Pos  |      |      |       |       |      |     |       |          |
| tapp |      |      |       |       |      |     |       |          |
| lica |      |      |       |       |      |     |       |          |
| tion |      |      |       |       |      |     |       |          |
| De   |      |      |       |       |      |     |       |          |
| rmal |      |      |       |       |      |     |       |          |
| Expo |      |      |       |       |      |     |       |          |
| sure |      |      |       |       |      |     |       |          |
| and  |      |      |       |       |      |     |       |          |
| Risk |      |      |       |       |      |     |       |          |
| from |      |      |       |       |      |     |       |          |
| Tre  |      |      |       |       |      |     |       |          |
| ated |      |      |       |       |      |     |       |          |
| Law  |      |      |       |       |      |     |       |          |
| ns** |      |      |       |       |      |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+
| **   | *    | **   | **Fra | *     | **De | **B | **    | **Dermal |
| Subg | *App | Post | ction | *Turf | rmal | ody | Daily | MOE      |
| roup | lica | -app | of ai | Tr    | Tran | We  | D     | ^3^**    |
| E    | tion | lica | Tr    | ansfe | sfer | igh | ermal |          |
| xpos | Ra   | tion | ansfe | rable | C    | t** | Dose  |          |
| ed** | te** | day  | rable | Re    | oeff |     | ^2^** |          |
|      |      | (    | from  | sidue | icie | **  |       |          |
|      | *    | t)** | the   | ^1^** | nt** | (kg | **(mg |          |
|      | *(lb |      | Foli  |       |      | )** | /kg/d |          |
|      | ai/  |      | age** | **(µ  | **   |     | ay)** |          |
|      | A)** |      |       | g/cm^ | (cm^ |     |       |          |
|      |      |      |       | 2^)** | 2^/h |     |       |          |
|      |      |      |       |       | r)** |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+
|      |      |      |       |       |      |     |       | **S      |
|      |      |      |       |       |      |     |       | hort-/** |
|      |      |      |       |       |      |     |       |          |
|      |      |      |       |       |      |     |       | **Int    |
|      |      |      |       |       |      |     |       | ermediat |
|      |      |      |       |       |      |     |       | e-term** |
+------+------+------+-------+-------+------+-----+-------+----------+
| Ad   | 0.27 | 0    | 0.05  | 0.15  | 14   | 60  | 0.027 | 740      |
| ults |      |      |       |       | ,500 |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+
| Chil |      |      |       |       | 5    | 15  | 0.039 | 520      |
| dren |      |      |       |       | ,200 |     |       |          |
+------+------+------+-------+-------+------+-----+-------+----------+

^1^ Turf Transferable Residue ~Postapplication\ day~ (µg/cm^2^)=
Application rate (lb ai/A) x Fraction of ai Transferable from the
Foliage x (1- Fraction of Residue That Dissipates Daily, 0.1)
^Postapplication\ day^ x 4.54E+8 µg/lb x 2.47E-8 A/cm^2^

^2^ Daily Dermal Dose = (Turf Transferable Residue (µg/cm^2^) x
Absorption Factor (0.37) x Dermal Transfer Coefficient (cm^2^/hr) x
Exposure Time (2 hrs/day) x 0.001 mg/µg\] / \[Body Weight (kg)\]

^3^ Dermal MOE = Dermal NOAEL / Daily Dermal Dose; where
Short-/Intermediate-term NOAEL = 20 mg/kg/day.

<table>
<colgroup>
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 6.2.2. Postapplication Oral Hand-to-Mouth
Exposure and Risk for Children from Treated Lawns</strong></td>
</tr>
<tr class="even">
<td rowspan="2"><p><strong>Application Rate</strong></p>
<p><strong>(lb ai/A)</strong></p></td>
<td rowspan="2"><strong>Post-application day (t)</strong></td>
<td rowspan="2"><strong>Fraction of ai Transferable from the
Foliage</strong></td>
<td rowspan="2"><p><strong>Turf Transferable Residue
<sup>1</sup></strong></p>
<p><strong>(µg/cm<sup>2</sup>)</strong></p></td>
<td rowspan="2"><p><strong>Hand Surface Area</strong></p>
<p><strong>(cm<sup>2</sup>/event)</strong></p></td>
<td rowspan="2"><strong>Saliva Extraction Factor</strong></td>
<td rowspan="2"><p><strong>Frequency</strong></p>
<p><strong>(events/ hr)</strong></p></td>
<td rowspan="2"><p><strong>Body Weight</strong></p>
<p><strong>(kg)</strong></p></td>
<td rowspan="2"><p><strong>Daily Dose<sup>2</sup></strong></p>
<p><strong>(mg/kg/day)</strong></p></td>
<td><strong>Oral MOE<sup>3</sup></strong></td>
</tr>
<tr class="odd">
<td><p><strong>Short-/</strong></p>
<p><strong>Int-term</strong></p></td>
</tr>
<tr class="even">
<td>0.27</td>
<td>0</td>
<td>0.05</td>
<td>0.15</td>
<td>20</td>
<td>50%</td>
<td>20</td>
<td>15</td>
<td>0.0040</td>
<td>5,000</td>
</tr>
</tbody>
</table>

^1^ Turf Transferable Residue ~Postapplication\ day~ (µg/cm^2^)=
Application rate (lb ai/A) x Fraction of ai Transferable from the
Foliage x (1- Fraction of Residue That Dissipates Daily, 0.1)
^Postapplication\ day^ x 4.54E+8 µg/lb x 2.47E-8 A/cm^2^

^2^ Daily Dose = (Turf Transferable Residue (µg/cm^2^) x Hand Surface
Area (cm^2^/event) x Saliva Extraction factor x Frequency (events/hr) x
0.001 mg/ µg x Exposure time (2 hrs/day)\] / \[Body Weight (kg)\]

^3^ Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term
NOAEL = 20 mg/kg/day.

+---------+--------+--------+--------+--------+--------+------+------+
| **Table |        |        |        |        |        |      |      |
| 6.2.3.  |        |        |        |        |        |      |      |
| P       |        |        |        |        |        |      |      |
| ostappl |        |        |        |        |        |      |      |
| ication |        |        |        |        |        |      |      |
| Oral    |        |        |        |        |        |      |      |
| O       |        |        |        |        |        |      |      |
| bject-t |        |        |        |        |        |      |      |
| o-Mouth |        |        |        |        |        |      |      |
| (Tur    |        |        |        |        |        |      |      |
| fgrass) |        |        |        |        |        |      |      |
| E       |        |        |        |        |        |      |      |
| xposure |        |        |        |        |        |      |      |
| and     |        |        |        |        |        |      |      |
| Risk    |        |        |        |        |        |      |      |
| for     |        |        |        |        |        |      |      |
| C       |        |        |        |        |        |      |      |
| hildren |        |        |        |        |        |      |      |
| from    |        |        |        |        |        |      |      |
| Treated |        |        |        |        |        |      |      |
| Lawns** |        |        |        |        |        |      |      |
+---------+--------+--------+--------+--------+--------+------+------+
| **Appl  | **P    | **Fr   | **Gr   | **Ing  | **     | **D  | **   |
| ication | ost-** | action | ass/Ob | estion | Body** | aily | Oral |
| Rate**  |        | of ai  | ject** | Rate** |        | D    | MOE^ |
|         | *      | Transf |        |        | **We   | ose^ | 3^** |
| **(lb   | *appli | erable | **R    | **(    | ight** | 2^** |      |
| ai/A)** | cation | from   | esidue | cm^2^/ |        |      |      |
|         | day**  | the    | ^1^**  | day)** | **     | **(  |      |
|         |        | Fol    |        |        | (kg)** | mg/k |      |
|         | *      | iage** | **     |        |        | g/da |      |
|         | *(t)** |        | (µg/cm |        |        | y)** |      |
|         |        |        | ^2^)** |        |        |      |      |
+---------+--------+--------+--------+--------+--------+------+------+
|         |        |        |        |        |        |      | **S  |
|         |        |        |        |        |        |      | hort |
|         |        |        |        |        |        |      | -/** |
|         |        |        |        |        |        |      |      |
|         |        |        |        |        |        |      | **In |
|         |        |        |        |        |        |      | t-te |
|         |        |        |        |        |        |      | rm** |
+---------+--------+--------+--------+--------+--------+------+------+
| 0.27    | 0      | 0.29   | 0.88   | 25     | 15     | 0.   | 14   |
|         |        |        |        |        |        | 0015 | ,000 |
+---------+--------+--------+--------+--------+--------+------+------+

^1^Grass/Object residue ~Postapplication\ day~ (µg/cm^2^) = Application
rate (lb ai/A) x Fraction of ai Transferable from the Foliage (from
MRID#: 46708641) x (1- Fraction of Residue That Dissipates Daily)
^Postapplication\ day^ x 4.54E+8 µg/lb x 2.47E-8 A/cm^2^

^2^ Daily Dose = \[Grass reside (µg/cm^2^) x Ingestion rate (cm^2^/day)
x 0.001 mg/µg\] / \[Body Weight (kg)\]\]

^3^Oral MOE = Oral NOAEL / Daily Dose; where Short-/Intermediate-term
NOAEL = 20 mg/kg/day.

+---------+---------+-------+--------+-------+---------+------------+
| **Table |         |       |        |       |         |            |
| 6.2.4.  |         |       |        |       |         |            |
| P       |         |       |        |       |         |            |
| ostappl |         |       |        |       |         |            |
| ication |         |       |        |       |         |            |
| Inc     |         |       |        |       |         |            |
| idental |         |       |        |       |         |            |
| Soil    |         |       |        |       |         |            |
| In      |         |       |        |       |         |            |
| gestion |         |       |        |       |         |            |
| E       |         |       |        |       |         |            |
| xposure |         |       |        |       |         |            |
| and     |         |       |        |       |         |            |
| Risk    |         |       |        |       |         |            |
| for     |         |       |        |       |         |            |
| C       |         |       |        |       |         |            |
| hildren |         |       |        |       |         |            |
| from    |         |       |        |       |         |            |
| Treated |         |       |        |       |         |            |
| Lawns** |         |       |        |       |         |            |
+---------+---------+-------+--------+-------+---------+------------+
| **Appl  | **F     | **S   | **Ing  | **B   | **Daily | **Oral     |
| ication | raction | oil** | estion | ody** | Do      | MOE^3^**   |
| Rate**  | of ai   |       | Rate** |       | se^2^** |            |
|         | R       | **Re  |        | **Wei |         |            |
| **(lb   | etained | sidue | **(mg/ | ght** | *       |            |
| ai/A)** | in the  | ^1^** | day)** |       | *(mg/kg |            |
|         | Soil**  |       |        | **(   | /day)** |            |
|         |         | **(µg |        | kg)** |         |            |
|         |         | /g)** |        |       |         |            |
+---------+---------+-------+--------+-------+---------+------------+
|         |         |       |        |       |         | **Short-/  |
|         |         |       |        |       |         | Intermedi  |
|         |         |       |        |       |         | ate-term** |
+---------+---------+-------+--------+-------+---------+------------+
| 0.27    | 1       | 2.0   | 100    | 15    | 0       | 1,500,000  |
|         |         |       |        |       | .000014 |            |
+---------+---------+-------+--------+-------+---------+------------+

^1^ Soil residue ~Postapplication\ day\ zero~ (µg/cm^2^) = Application
rate (lb ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 µg/lb x
2.47E-8 A/cm^2^ x 0.67 cm^3^/g soil

^2^ Daily Dose = \[Soil reside (µg/g) x Ingestion rate (mg/day) x
0.000001 g/µg\] / \[Body Weight (kg)\]\]

^3^ Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term
NOAEL = 20 mg/kg/day.

+-----------------------+----------+---------+------------+-----------+
| **Table 6.2.5.        |          |         |            |           |
| Aggregate Exposure    |          |         |            |           |
| and Risk Estimates    |          |         |            |           |
| from Residential      |          |         |            |           |
| Lawn**s               |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| **Scenario**          | **TTR/   | *       | **Short-/  | **Total   |
|                       | GR/SR~0~ | *PDR~0- | Int-Term** | MOE ^4^** |
| **and**               | (        | norm~** |            |           |
|                       | µg/cm^2^ |         | **MOE      |           |
| **Pathway**           | or g)    | **(mg/  | ^3^**      |           |
|                       | ^1^**    | kg/day) |            |           |
|                       |          | ^2^**   |            |           |
+-----------------------+----------+---------+------------+-----------+
|                       |          |         |            | **        |
|                       |          |         |            | Short-/** |
|                       |          |         |            |           |
|                       |          |         |            | **I       |
|                       |          |         |            | nt-Term** |
+-----------------------+----------+---------+------------+-----------+
| **Adult's Scenarios** |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| \(1\) Handler         | N/A      | 0.0092  | 2,200      | 550       |
| (Dermal)              |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| \(1\) Handler         | N/A      | 0       | 520,000    |           |
| (Inhalation)          |          | .000038 |            |           |
+-----------------------+----------+---------+------------+-----------+
| \(2\) Dermal          | 0.15     | 0.027   | 740        |           |
| Postapplication       |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| **Children's          |          |         |            |           |
| Scenarios -- All      |          |         |            |           |
| Postapplication**     |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| \(1\) Dermal          | 0.15     | 0.039   | 520        | 450       |
+-----------------------+----------+---------+------------+-----------+
| \(2\) Hand-to-Mouth   | 0.15     | 0.0040  | 5,000      |           |
+-----------------------+----------+---------+------------+-----------+
| \(3\) Mouthing        | 0.88     | 0.0015  | 14,000     |           |
| Grass/Object          |          |         |            |           |
+-----------------------+----------+---------+------------+-----------+
| \(4\) Soil Ingestion  | 2.0      | 0       | 1,500,000  |           |
|                       |          | .000014 |            |           |
+-----------------------+----------+---------+------------+-----------+

^1^ TTR=turf transferable residue on day "0\"; GR=grass/object residue
on day "0\"; SR~0~=soil residue on day "0\".

^2^ PDR~0norm~=potential dose rate on day "0".

^3^ MOE = NOAEL/PDR; where Short-/Intermediate-term NOAEL = 20
mg/kg/day.

^4^ Total MOE = 1/ \[(1/MOE~Dermal~) + (1/MOE~Hand-to-Mouth~) +
(1/MOE~Grass~) + (1/MOE~Soil~)\]

**6.3 Other (Recreational Exposure; Spray
Drift)**[]{#__RefHeading___Toc185228075 .anchor}

*Recreational exposures* to turf (including from playing golf) are
expected to be similar to, or in many cases less than, those evaluated
in section 5.2 Residential Postapplication Exposure and Risk; therefore,
a separate recreational exposure assessment was not included.

*Spray drift* is always a potential source of exposure to residents
nearby to spraying operations. This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
fluopicolide. 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. 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 and risks
associated with aerial as well as other application types where
appropriate.

Please note that as indicated in this assessment, fluopicolide is
directly applied to residential turf and does not result in exposures of
concern. It is unlikely that the potential for risk of exposure to spray
drift from the agricultural uses would be higher than that estimated for
contact with treated turf.

**7.0 Aggregate Risk Assessments and Risk
Characterization**[]{#__RefHeading___Toc185228076 .anchor}

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites. There is a potential for short- and
intermediate-term non-occupational exposure to fluopicolide during
mixing, loading, application, and postapplication activities. Chronic
exposure is not expected for the proposed use patterns associated with
fluopicolide.

**7.1 Acute Aggregate Risk**

[]{#__RefHeading___Toc185228077 .anchor}

An acute dietary assessment was not conducted because an endpoint
attributable to a single dose was not identified from the available data
for fluopicolide.

**7.2 Short-Term Aggregate Risk**.[]{#__RefHeading___Toc185228078
.anchor}

Short-term exposures (1 to 30 days of continuous exposure) may occur as
a result of activities on treated turf. The same dose and endpoint were
chosen to evaluate all routes of exposure (oral, dermal, and
inhalation); therefore, all exposures related to turf activities (Table
6.2.5) have been combined with chronic dietary exposure estimates (as an
estimated of background dietary exposure; Table 5.2.2) to assess
short-term aggregate exposure. Since aggregate MOEs in Table 7.2 are
greater than 100, they represent risk estimates that are below HED's
level of concern.

+---------+--------+--------+---------+----------+----------+----------+
| **Table |        |        |         |          |          |          |
| 7.2.    |        |        |         |          |          |          |
| Sho     |        |        |         |          |          |          |
| rt-Term |        |        |         |          |          |          |
| and     |        |        |         |          |          |          |
| Int     |        |        |         |          |          |          |
| ermedia |        |        |         |          |          |          |
| te-Term |        |        |         |          |          |          |
| Ag      |        |        |         |          |          |          |
| gregate |        |        |         |          |          |          |
| Risk    |        |        |         |          |          |          |
| Calcula |        |        |         |          |          |          |
| tions** |        |        |         |          |          |          |
|         |        |        |         |          |          |          |
| ***(I   |        |        |         |          |          |          |
| nhalati |        |        |         |          |          |          |
| on/Oral |        |        |         |          |          |          |
| /Dermal |        |        |         |          |          |          |
| En      |        |        |         |          |          |          |
| dpoints |        |        |         |          |          |          |
| and     |        |        |         |          |          |          |
| NOAELs  |        |        |         |          |          |          |
| are the |        |        |         |          |          |          |
| S       |        |        |         |          |          |          |
| ame)*** |        |        |         |          |          |          |
+=========+========+========+=========+==========+==========+==========+
| Pop     | *      |        |         |          |          |          |
| ulation | Short- |        |         |          |          |          |
|         | or     |        |         |          |          |          |
|         | Interm |        |         |          |          |          |
|         | ediate |        |         |          |          |          |
|         | *-Term |        |         |          |          |          |
|         | Sc     |        |         |          |          |          |
|         | enario |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
|         | NOAEL  | LOC^1^ | Max     | Average  | Res      | A        |
|         |        |        | Al      |          | idential | ggregate |
|         | mg/    |        | lowable | Food &   | Exp      | MOE      |
|         | kg/day |        |         | Water    | osure^3^ |          |
|         |        |        | Expo    |          |          | (food    |
|         |        |        | sure^2^ | Exposure | m        | and      |
|         |        |        |         |          | g/kg/day |          |
|         |        |        | mg      | m        |          | residen  |
|         |        |        | /kg/day | g/kg/day |          | tial)^4^ |
+---------+--------+--------+---------+----------+----------+----------+
| General | 20     | 100    | 0.2     | 0.011999 | 0.036238 | 420      |
| U.S.    |        |        |         |          |          |          |
| Pop     |        |        |         |          |          |          |
| ulation |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| All     | 20     | 100    | 0.2     | 0.007826 | 0.044514 | 380      |
| Infants |        |        |         |          |          |          |
| (\<1    |        |        |         |          |          |          |
| year    |        |        |         |          |          |          |
| old)    |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| C       | 20     | 100    | 0.2     | **0.     | 0.044514 | 320      |
| hildren |        |        |         | 018460** |          |          |
| 1-2     |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| C       | 20     | 100    | 0.2     | 0.016718 | 0.044514 | 330      |
| hildren |        |        |         |          |          |          |
| 3-5     |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| C       | 20     | 100    | 0.2     | 0.012418 | 0.044514 | 350      |
| hildren |        |        |         |          |          |          |
| 6-12    |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| Youth   | 20     | 100    | 0.2     | 0.009748 | 0.036238 | 440      |
| 13-19   |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| Adults  | 20     | 100    | 0.2     | 0.011822 | 0.036238 | 420      |
| 20-49   |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| Adults  | 20     | 100    | 0.2     | 0.011590 | 0.036238 | 420      |
| 50+     |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+
| Females | 20     | 100    | 0.2     | 0.012034 | 0.036238 | 410      |
| 13-49   |        |        |         |          |          |          |
| years   |        |        |         |          |          |          |
| old     |        |        |         |          |          |          |
+---------+--------+--------+---------+----------+----------+----------+

^1^ UF~A~ = 10x (extrapolation from animal to human (interspecies);
UF~H~ = 10x potential variation in sensitivity among members of the
human population (intraspecies); FQPA SF = 1x. 10 x 10 x 1 = 100.

^2^ Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 20 mg/kg/day ÷
100 = 0.2 mg/kg/day.

^3^ Residential Exposure = \[Oral exposure + Dermal exposure +
Inhalation Exposure\], calculated by adding PDR values shown in Table
6.3.5 above. Residential exposures were calculated for adults (60 mg bw)
and children (15 mg bw).

^4^ Aggregate MOE = \[NOAEL / (Avg Food & Water Exposure + Residential
Exposure)\]

**7.3 Intermediate-Term Aggregate Risk**

The intermediate-term aggregate risk is the same as calculated above for
the short-term aggregate risk.[]{#__RefHeading___Toc185228079 .anchor}

**7.4 Long-Term Aggregate Risk**[]{#__RefHeading___Toc185228080 .anchor}

In examining long-term aggregate risk, HED has assumed that the only
pathway of exposure relevant to that time frame is dietary exposure
(*i.e*., any non-dietary exposures are short- and/or intermediate-term
in duration). Therefore, the long-term aggregate risk is composed of
exposures to fluopicolide residues in food and drinking water and is
equivalent to the chronic dietary risk discussed in Section 5.2. As
shown in Table 5.2.2, the chronic risk estimates are below HED's level
of concern for all population subgroups.

**7.5 Cancer Risk**[]{#__RefHeading___Toc185228081 .anchor}

Fluopicolide has been classified as "not likely to be carcinogenic to
humans." As such, an estimate of cancer risk is not warranted for parent
fluopicolide.

**8.0 Cumulative Risk
Characterization/Assessment**[]{#__RefHeading___Toc185228082 .anchor}

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 fluopicolide (parent) and any
other substances and fluopicolide 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 fluopicolide
(parent) has a common mechanism of toxicity with other substances. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA's Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA's website at
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

BAM, the common metabolite of fluopicolide and dichlobenil, is evaluated
in the concurrent document (DP #345918, N. Dodd, 11/21/07).

**9.0 Occupational Exposure/Risk
Pathway**[]{#__RefHeading___Toc185228083 .anchor}

*Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O'Rourke, 10/9/07.*

Estimated short- and intermediate-term dermal and inhalation exposures
were compared to the oral NOAEL of 20 mg/kg/day from a rabbit
developmental toxicity study in which death, abortions/premature
deliveries, decreased food consumption, and decreased body weight gain
were observed at the LOAEL of 60 mg/kg/day. Because this endpoint is
from an oral study, the estimated dermal exposures were adjusted by
applying a 37 percent dermal absorption rate (based on a dermal
penetration study in the rat), while oral and inhalation toxicity is
assumed to be equivalent. In addition, this endpoint is applicable to
all populations including females 13+ years old; therefore, a 60-kg body
weight was used in the calculations. Where appropriate, resulting dermal
and inhalation MOEs were combined into total MOEs because the same dose
and endpoint were chosen to evaluate both routes of exposure. The level
of concern (LOC) for occupational risk is for margins of exposure (MOEs)
\<100.

**9.1 Short-/Intermediate-/Long-Term Handler
Risk**[]{#__RefHeading___Toc185228084 .anchor}

There is a potential for short- and intermediate-term exposure to
fluopicolide during mixing, loading, and application activities. No
chemical-specific handler exposure data were submitted in support of
this registration. 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 Standard Operating
Procedure #7, dated 1/28/99). The handler exposure data for the turf
handgun sprayer scenario are from the Outdoor Residential Exposure Task
Force (ORETF) (MRID \# 44972201), rather than from PHED. The ORETF data
were designed to replace the present PHED data with higher-confidence,
higher quality data that contain more replicates than the PHED data for
those scenarios.

The results of the handler occupational exposure and risk assessment
indicate that risks are not of concern with baseline clothing, or when
gloves are worn (which is required on the proposed labels). Dermal and
inhalation MOEs were combined into Total MOEs because the same dose and
endpoint were chosen to evaluate both routes of exposure. The level of
concern (LOC) for occupational risk is for margins of exposure (MOEs)
\<100. The Total Short/Intermediate-Term MOEs range from 100 to 19,000,
which reach or exceed the LOC of 100, and are not of concern. Exposure
assumptions and MOEs for occupational handlers are summarized in Table
9.1.

<table>
<colgroup>
<col style="width: 25%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="11"><strong>Table 9.1. Summary of MOEs for Occupational
Handlers of Fluopicolide</strong></th>
</tr>
<tr class="odd">
<th rowspan="2"><strong>Exposure Scenario (Scenario #)</strong></th>
<th colspan="2"><strong>Dermal Unit Exposure (mg/lb ai)
<sup>1</sup></strong></th>
<th rowspan="2"><p><strong>Inhalation</strong></p>
<p><strong>Unit</strong></p>
<p><strong>Exposure</strong></p>
<p><strong>(mg/lb ai)<sup>2</sup></strong></p></th>
<th rowspan="2"><strong>Use Site</strong></th>
<th rowspan="2"><p><strong>Application</strong></p>
<p><strong>Rate</strong></p>
<p><strong>(lb ai/A)<sup>3</sup></strong></p></th>
<th rowspan="2"><p><strong>Area Treated</strong></p>
<p><strong>(A/day) <sup>4</sup></strong></p></th>
<th colspan="2"><p><strong>Daily Dose</strong></p>
<p><strong>(mg/kg/day) <sup>5</sup></strong></p></th>
<th colspan="2"><p><strong>Total</strong></p>
<p><strong>Short-/Int-term MOE <sup>6</sup></strong></p></th>
</tr>
<tr class="header">
<th><strong>Baseline</strong></th>
<th><p><strong>PPE</strong></p>
<p><strong>(gloves)</strong></p></th>
<th><strong>Dermal</strong></th>
<th><strong>Inhalation</strong></th>
<th><strong>Baseline</strong></th>
<th><p><strong>PPE</strong></p>
<p><strong>(gloves)</strong></p></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="11"><strong>Mixer/Loader</strong></td>
</tr>
<tr class="even">
<td>(1) Mixing/Loading Liquid for Aerial application or Chemigation</td>
<td>2.9</td>
<td>0.023</td>
<td>0.0012</td>
<td>Veg, Potatoes</td>
<td>0.13</td>
<td>350</td>
<td><p>0.81</p>
<p>0.0065 (gloves)</p></td>
<td>0.00091</td>
<td>25</td>
<td>2,700</td>
</tr>
<tr class="odd">
<td rowspan="4">(2) Mixing/Loading Liquid for Groundboom application or
Chemigation</td>
<td rowspan="4">2.9</td>
<td rowspan="4">0.023</td>
<td rowspan="4">0.0012</td>
<td>Veg, Potatoes</td>
<td>0.13</td>
<td>80</td>
<td>0.19</td>
<td>0.00021</td>
<td>110</td>
<td>-</td>
</tr>
<tr class="even">
<td>Turf</td>
<td>0.27</td>
<td>80</td>
<td><p>0.39</p>
<p>0.0031 (gloves)</p></td>
<td>0.00043</td>
<td>52</td>
<td>5,700</td>
</tr>
<tr class="odd">
<td>Ornamentals (drench)</td>
<td>27</td>
<td>40</td>
<td><p>19</p>
<p>0.15 (gloves)</p></td>
<td>0.021</td>
<td>1</td>
<td>110</td>
</tr>
<tr class="even">
<td>Ornamentals</td>
<td>0.54</td>
<td>40</td>
<td><p>0.39</p>
<p>0.0031 (gloves)</p></td>
<td>0.00043</td>
<td>52</td>
<td>5,700</td>
</tr>
<tr class="odd">
<td rowspan="2">(3) Mixing/Loading Liquid for Airblast application</td>
<td rowspan="2">2.9</td>
<td rowspan="2">-</td>
<td rowspan="2">0.0012</td>
<td>Grapes</td>
<td>0.13</td>
<td>40</td>
<td>0.093</td>
<td>0.00010</td>
<td>210</td>
<td>-</td>
</tr>
<tr class="even">
<td>Ornamentals</td>
<td>0.54</td>
<td>20</td>
<td>0.19</td>
<td>0.00022</td>
<td>100</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="11"><strong>Applicator</strong></td>
</tr>
<tr class="even">
<td>(4) Applying Sprays with Fixed-wing Aircraft</td>
<td>0.005</td>
<td>-</td>
<td>0.000068</td>
<td>Veg, Potatoes</td>
<td>0.13</td>
<td>350</td>
<td>0.0014</td>
<td>0.000052</td>
<td>14,000</td>
<td>-</td>
</tr>
<tr class="odd">
<td rowspan="3">(5) Applying Sprays with Open Cab Groundboom</td>
<td rowspan="3">0.014</td>
<td rowspan="3">-</td>
<td rowspan="3">0.00074</td>
<td>Veg, Potatoes</td>
<td>0.13</td>
<td>80</td>
<td>0.00090</td>
<td>0.00013</td>
<td>19,000</td>
<td>-</td>
</tr>
<tr class="even">
<td>Turf</td>
<td>0.27</td>
<td>80</td>
<td>0.0019</td>
<td>0.00027</td>
<td>9,400</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Ornamentals</td>
<td>0.54</td>
<td>40</td>
<td>0.0019</td>
<td>0.00027</td>
<td>9,400</td>
<td>-</td>
</tr>
<tr class="even">
<td rowspan="2">(6) Applying Sprays with Open Cab Airblast Sprayer</td>
<td rowspan="2">0.36</td>
<td rowspan="2">-</td>
<td rowspan="2">0.0045</td>
<td>Grapes</td>
<td>0.13</td>
<td>40</td>
<td>0.012</td>
<td>0.00039</td>
<td>1,700</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Ornamentals</td>
<td>0.54</td>
<td>20</td>
<td>0.024</td>
<td>0.00081</td>
<td>810</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="11"><strong>Flagger</strong></td>
</tr>
<tr class="odd">
<td>(7) Flagging to Support Aerial Applications</td>
<td>0.011</td>
<td>-</td>
<td>0.00035</td>
<td>Veg, Potatoes</td>
<td>0.13</td>
<td>350</td>
<td>0.0031</td>
<td>0.00027</td>
<td>6,000</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="11"><strong>Mixer/Loader/Applicator</strong></td>
</tr>
<tr class="odd">
<td>(8) Mixing/Loading Liquid and Applying with Handgun Sprayer</td>
<td>no data</td>
<td>0.50</td>
<td>0.0019</td>
<td>Turf</td>
<td>0.27</td>
<td>5</td>
<td><p>0.0042</p>
<p>(gloves)</p></td>
<td>0.000043</td>
<td>no data</td>
<td>4,800</td>
</tr>
<tr class="even">
<td>(9) Mixing/Loading Liquid and Applying with Low-Pressure
Handwand</td>
<td>100</td>
<td>0.43</td>
<td>0.03</td>
<td>Turf</td>
<td><p>0.0031</p>
<p>(lb ai/gal)</p></td>
<td><p>40</p>
<p>(gal/day)</p></td>
<td>0.076</td>
<td>0.000062</td>
<td>260</td>
<td>-</td>
</tr>
<tr class="odd">
<td>(10) Mixing/Loading Liquid and Applying with High-Pressure
Handwand</td>
<td>no data</td>
<td>2.5</td>
<td>0.12</td>
<td>Ornamentals</td>
<td><p>0.0025</p>
<p>(lb ai/gal)</p></td>
<td><p>1,000</p>
<p>(gal/day)</p></td>
<td><p>0.039</p>
<p>(gloves)</p></td>
<td>0.005</td>
<td>no data</td>
<td>460</td>
</tr>
<tr class="even">
<td rowspan="2">(11) Mixing/Loading Liquid and Applying with Backpack
Sprayer</td>
<td rowspan="2">no data</td>
<td rowspan="2">2.5</td>
<td rowspan="2">0.03</td>
<td>Turf</td>
<td><p>0.0031</p>
<p>(lb ai/gal)</p></td>
<td><p>40</p>
<p>(gal/day)</p></td>
<td><p>0.0019</p>
<p>(gloves)</p></td>
<td>0.000062</td>
<td>no data</td>
<td>10,000</td>
</tr>
<tr class="odd">
<td>Ornamentals</td>
<td><p>0.0025</p>
<p>(lb ai/gal)</p></td>
<td><p>40</p>
<p>(gal/day)</p></td>
<td><p>0.0015</p>
<p>(gloves)</p></td>
<td>0.000050</td>
<td>no data</td>
<td>13,000</td>
</tr>
</tbody>
</table>

^1^ Baseline dermal unit exposure values represent long pants, long
sleeved shirts, shoes, and socks; PPE values represent the addition of
chemical-resistant gloves for those scenarios in which the MOEs do not
reach 100 at baseline or those for which data are not available without
gloves. Values are reported in the PHED Surrogate Exposure Guide dated
August 1998, except for the handgun value which was obtained from ORETF.

^2^ Inhalation unit exposure values represent no respirator. Values are
reported in the PHED Surrogate Exposure Guide dated August 1998.

^3^ Application rates are based on maximum values found in proposed
labels: V-10161 4 SC (Reg No. 59639-RUN), V-10162 Premix (Reg. No.
59639-RUE), V-10161 VPP Fungicide (Reg No. 59639-RUR), and V-10162 VPP
Fungicide (Reg. No. 59639-RUG).

^4^ Daily area treated is based on the area or gallons that can be
reasonably applied in a single day for each exposure scenario of concern
based on the application method and formulation/packaging type.
(standard EPA/OPP/HED values).

^5^ Daily Dose (mg/kg/day) = Unit Exposure \* % Absorption \*
Application rate \* Area treated} / 60 kg; where dermal absorption is
37% and inhalation absorption is assumed to be 100%.

^6^ Short-/Intermediate-Term MOE = NOAEL (20 mg/kg/day) / (Daily Dermal
Dose + Daily Inhalation Dose). The LOC is 100.

HED recognizes that it is feasible for the same individual to mix/load
and apply formulations with the groundboom and airblast sprayers,
however, appropriate data are not available in PHED for which unit
exposure values for these combined activities can be derived. HED does
not recommend simply adding the unit exposure values for each job
function because any extrapolation error (i.e., exposure from the amount
ai handled in the study to that of a real-life application) would be
magnified, leading to greater uncertainty. For information and
characterization purposes, even with the over-estimation uncertainty,
the MOEs for these combined activities for groundboom and airblast
application of fluopicolide would be above the LOC of 100 (i.e., ranging
from 110 to 3,600).

The minimum level of PPE for handlers is based on acute toxicity for the
end-use products. Two of the products (V-10162 Premix and V-10162 VPP
Fungicide) contain a second active ingredient (propamocarb
hydrochloride) which may have additional PPE requirements. The
Registration Division (RD) is responsible for ensuring that PPE listed
on the label is in compliance with the Worker Protection Standard (WPS)
relative to **both fluopicolide and propamocarb hydrochloride
exposure**.

**9.2 Short-/Intermediate-/Long-Term Postapplication
Risk**[]{#__RefHeading___Toc185228085 .anchor}

This registration action for fluopicolide involves application to
agricultural crops as well as turf (residential and commercial lawns,
golf courses, and sod farms) and ornamentals (landscapes, commercial
greenhouses, and nurseries). Postapplication inhalation exposure is
expected to be negligible; however, dermal exposure is possible for
workers entering treated areas to tend or harvest crops, mow/maintain
turfgrass, or tend ornamentals in nurseries and greenhouses. A
dislodgeable foliar residue (DFR) study was submitted by the registrant
(MRID#: 46708641) for use in assessing postapplication activities. The
study results are summarized below:

> **Dislodgeable Foliar Residue (DFR) Study on Leaf Lettuce (MRID#
> 46708641):**
>
> EXP 11067B, a soluble concentrate formulation containing 40%
> fluopicolide, was applied three times to leaf lettuce at two test
> sites (Pennsylvania and California). Applications were made at a rate
> of 0.119 lbs ai/A, at 4- to 6-day intervals. Triplicate leaf punch
> samples were collected before and after each application, and at 1, 3,
> 5, 7, 10, 14, 21, 28 and 35 days after the final application for both
> sites. The application method, rate, and number of treatments were
> relevant to the use pattern proposed by the product label; however,
> the application intervals were shorter than the proposed 10 days. The
> overall mean field fortification recoveries were 80.5% for the
> Pennsylvania site and 81.1% for the California site. At the PA site,
> the maximum average residue was detected 8 hours after the last
> treatment (0.42 μg/cm^2^) and declined to 0.012 μg/cm^2^ after 14
> days, with all residues \<LOQ by 21 days after the last treatment
> (note that rainfall was 6 inches greater than the 10-year historical
> average during the study period). At the CA site, the maximum average
> residue was detected 1 day after the last treatment (0.45 μg/cm^2^)
> and declined to 0.0047 μg/cm^2^ after 35 days, with residues in two of
> three samples \<LOQ by 21 and 35 days after the last treatment. The
> estimated half-life values were 2.5 days (r^2^ = 0.97) and 4.8 days
> (r^2^ = 0.77) for leaf lettuce at the PA and CA sites, respectively.

This study is considered to be acceptable, and the data were used to
estimate exposure from activities associated with agricultural crops and
ornamentals. The data regression analyses (assuming pseudo first-order
kinetics) from both sites indicate that the initial dislodgeable residue
is 29% of the application rate. Because rainfall at the Pennsylvania
site was significantly above average during the study period, California
data were used to estimate the dissipation rate (14% per day). A turf
transferable residue (TTR) study was not available. Therefore, turf
scenario calculations were based on standard turf residue assumptions
(i.e., initial transferable fraction is 5% of the application rate, and
dissipation is 20% per day).

In addition to DFR and TTR, transfer coefficients (Tc) are used to
relate the residue values to activity patterns, which take place after
application, to estimate potential human exposure. The transfer
coefficients used in this assessment are from an interim transfer
coefficient guidance document developed by HED's Science Advisory
Council for Exposure using proprietary data from the Agricultural
Re-entry Task Force (ARTF) database (SOP# 3.1).

Postapplication MOEs were estimated for "Day 0\" exposure (i.e., the day
of application). In cases where the MOE was less than the LOC of 100 on
Day 0, residue dissipation data/assumptions were used to determine the
day for which the MOE would reach 100 (i.e., not of concern). As shown
in Table 5, the short-/intermediate-term MOEs are greater than 100 on
the day of application for all agricultural crops except grapes, for
which a restricted entry interval (REI) of one day may be necessary to
reach the LOC. For turf and nursery stock ornamentals (Table 6), MOEs
reach 100 on the day of application and are not of concern. However, for
cut flowers, an [REI of 4 to 6 days]{.underline} may be necessary to
achieve an MOE of 100 when the [maximum label application
rate]{.underline} is used. Alternatively, when the [minimum label
rate]{.underline} is used, an interval of only [one day]{.underline} may
be needed. Note that ornamental-specific DFR data were not available,
and that the residues were based on data from a lettuce DFR study which
may have introduced extrapolation error. The ornamental postapplication
exposure estimates could be refined with the use of ornamental-specific
DFR data.

The fluopicolide technical material has been classified in Toxicity
Categories III-IV for acute dermal and primary skin irritation, and
Category III for primary eye irritation. Per the Worker Protection
Standard (WPS), a 12-hr restricted entry interval (REI) is required for
chemicals classified under Toxicity Category III/IV. The proposed
fluopicolide labels indicate an REI of 12 hrs, which is in compliance
with the WPS for uses that reach an MOE of 100 on the day of
application.

Fluopicolide is also intended for non-agricultural use sites (e.g., golf
course) to which the WPS does not apply; the labels appropriately
contain language cautioning unprotected persons to keep out of treated
areas until sprays have dried.

\[Note: Two of the products (V-10162 Premix and V-10162 VPP Fungicide)
contain a second active ingredient (propamocarb hydrochloride) which may
have a different REI requirement**. It is the responsibility of the
Registration Division to make certain that the label REIs for these
products is protective of both fluopicolide and propamocarb
hydrochloride exposure**.\]

+------+------+---+-----+-----+-----------------------------+-------+
| **T  |      |   |     |     |                             |       |
| able |      |   |     |     |                             |       |
| 9.   |      |   |     |     |                             |       |
| 2.1. |      |   |     |     |                             |       |
| Sum  |      |   |     |     |                             |       |
| mary |      |   |     |     |                             |       |
| of   |      |   |     |     |                             |       |
| E    |      |   |     |     |                             |       |
| stim |      |   |     |     |                             |       |
| ated |      |   |     |     |                             |       |
| Post |      |   |     |     |                             |       |
| -app |      |   |     |     |                             |       |
| lica |      |   |     |     |                             |       |
| tion |      |   |     |     |                             |       |
| MOEs |      |   |     |     |                             |       |
| for  |      |   |     |     |                             |       |
| Agri |      |   |     |     |                             |       |
| cult |      |   |     |     |                             |       |
| ural |      |   |     |     |                             |       |
| Cro  |      |   |     |     |                             |       |
| ps** |      |   |     |     |                             |       |
+======+======+===+=====+=====+=============================+=======+
| **Cr | *    | * | **  | *   | **Activity ^4^**            | **Sho |
| op** | *App | * | DFR | *TC |                             | rt-/I |
|      | lica | D | ^3  | ^4  |                             | nt-** |
|      | tion | A | ^** | ^** |                             |       |
|      | Ra   | T |     |     |                             | *     |
|      | te** | ^ | **  | **  |                             | *Term |
|      |      | 2 | (μg | (cm |                             | MOE   |
|      | *    | ^ | /cm | ^2^ |                             | ^5^** |
|      | *(lb | * | ^2^ | /hr |                             |       |
|      | a    | * | )** | )** |                             |       |
|      | i/A) |   |     |     |                             |       |
|      | ^    |   |     |     |                             |       |
|      | 1^** |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Frui | 0.13 | 0 | 0   | 500 | Irrigation, scouting,       | 1,900 |
| ting |      |   | .42 |     | thinning, weeding immature  |       |
| Ve   |      |   |     |     | plants                      |       |
| geta |      |   |     |     |                             |       |
| bles |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 700 | Irrigation and scouting     | 1,400 |
|      |      |   |     |     | mature plants               |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 1,  | Hand harvesting, pruning,   | 960   |
|      |      |   |     | 000 | staking, tying              |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Cucu |      | 0 | 0   | 500 | Irrigation, scouting,       | 1,900 |
| rbit |      |   | .42 |     | thinning, weeding immature  |       |
| &    |      |   |     |     | plants                      |       |
| L    |      |   |     |     |                             |       |
| eafy |      |   |     |     |                             |       |
| Ve   |      |   |     |     |                             |       |
| geta |      |   |     |     |                             |       |
| bles |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 1,  | Irrigation, scouting,       | 640   |
|      |      |   |     | 500 | weeding mature plants       |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 2,  | Hand harvesting, pulling,   | 380   |
|      |      |   |     | 500 | pruning, and thinning       |       |
|      |      |   |     |     | mature plants               |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Gr   |      | 0 | 0   | 500 | Hedging, irrigation,        | 1,900 |
| apes |      |   | .42 |     | scouting, hand weeding      |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 1,  | Scouting                    | 960   |
|      |      |   |     | 000 |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 5,  | Hand harvest, leaf pulling, | 190   |
|      |      |   |     | 000 | thinning, pruning,          |       |
|      |      |   |     |     | training/tying              |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 10, | Girdling and cane turning   | 96    |
|      |      |   |     | 000 |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | * | 0   |     |                             | **    |
|      |      | * | .36 |     |                             | 110** |
|      |      | 1 |     |     |                             |       |
|      |      | * |     |     |                             |       |
|      |      | * |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Pota |      | 0 | 0   | 300 | Irrigation, scouting,       | 3,200 |
| toes |      |   | .42 |     | thinning, weeding immature  |       |
| &    |      |   |     |     | plants                      |       |
| S    |      |   |     |     |                             |       |
| weet |      |   |     |     |                             |       |
| Pota |      |   |     |     |                             |       |
| toes |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 1,  | Irrigation and scouting     | 640   |
|      |      |   |     | 500 | mature plants               |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 2,  | Hand harvesting             | 380   |
|      |      |   |     | 500 |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+

> ^1^ Maximum application rate from proposed labels: V-10161 4 SC (Reg
> No. 59639-RUN), V-10162 Premix (Reg. No. 59639-RUE)
>
> ^2^ DAT = Days after treatment needed to reach the LOC of 100; DAT 0 =
> The day of treatment, after sprays have dried; assumed to be
> approximately 12 hours.
>
> ^3^: DFR (µg/cm^2^) = dislodgeable foliar residues corresponding to
> DAT, based on results from a chemical-specific DFR study conducted on
> lettuce (MRID 46708641).
>
> ^4^ TC (cm^2^/hr) = transfer coefficients and associated activities
> from ExpoSAC Policy Memo #003.1 "Agricultural Transfer Coefficients",
> 8/17/2000.
>
> ^5^ MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose.
>
> Daily Dose = \[(TTR or DFR x TC x 37% Dermal absorption x 8-hr
> Exposure Time)\] / \[(CF: 1000 µg/mg) x (60-kg Body Weight)\]
>
> Short-/intermediate-term NOAEL = 20 mg/kg/day. The LOC is 100.

+------+------+---+-----+-----+-----------------------------+-------+
| **T  |      |   |     |     |                             |       |
| able |      |   |     |     |                             |       |
| 9.   |      |   |     |     |                             |       |
| 2.2. |      |   |     |     |                             |       |
| Sum  |      |   |     |     |                             |       |
| mary |      |   |     |     |                             |       |
| of   |      |   |     |     |                             |       |
| E    |      |   |     |     |                             |       |
| stim |      |   |     |     |                             |       |
| ated |      |   |     |     |                             |       |
| Post |      |   |     |     |                             |       |
| -app |      |   |     |     |                             |       |
| lica |      |   |     |     |                             |       |
| tion |      |   |     |     |                             |       |
| MOEs |      |   |     |     |                             |       |
| for  |      |   |     |     |                             |       |
| Turf |      |   |     |     |                             |       |
| and  |      |   |     |     |                             |       |
| O    |      |   |     |     |                             |       |
| rnam |      |   |     |     |                             |       |
| enta |      |   |     |     |                             |       |
| ls** |      |   |     |     |                             |       |
+======+======+===+=====+=====+=============================+=======+
| **Cr | *    | * | **  | *   | **Activity ^4^**            | **Sho |
| op** | *App | * | TTR | *TC |                             | rt-/I |
|      | lica | D | or  | ^4  |                             | nt-** |
|      | tion | A | DFR | ^** |                             |       |
|      | Ra   | T | ^3  |     |                             | *     |
|      | te** | ^ | ^** | **  |                             | *Term |
|      |      | 2 |     | (cm |                             | MOE   |
|      | *    | ^ | **  | ^2^ |                             | ^5^** |
|      | *(lb | * | (μg | /hr |                             |       |
|      | a    | * | /cm | )** |                             |       |
|      | i/A) |   | ^2^ |     |                             |       |
|      | ^    |   | )** |     |                             |       |
|      | 1^** |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| **Tu |      |   |     |     |                             |       |
| rf** |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Turf | 0.27 | 0 | 0   | 3,  | Mowing and other            | 790   |
|      |      |   | .15 | 400 | maintenance activities      |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 6,  | Sod harvesting and          | 390   |
|      |      |   |     | 800 | transplanting               |       |
+------+------+---+-----+-----+-----------------------------+-------+
| *    |      |   |     |     |                             |       |
| *Orn |      |   |     |     |                             |       |
| amen |      |   |     |     |                             |       |
| tals |      |   |     |     |                             |       |
| --   |      |   |     |     |                             |       |
| Nur  |      |   |     |     |                             |       |
| sery |      |   |     |     |                             |       |
| Sto  |      |   |     |     |                             |       |
| ck** |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Nur  | 0.54 | 0 | 1.8 | 100 | Hand pruning containerized  | 2,300 |
| sery |      |   |     |     | ornamentals                 |       |
| S    |      |   |     |     |                             |       |
| tock |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      |   |     | 400 | Harvesting, ball/burlap     | 580   |
|      |      |   |     |     | containerized ornamentals   |       |
+------+------+---+-----+-----+-----------------------------+-------+
| *    |      |   |     |     |                             |       |
| *Orn |      |   |     |     |                             |       |
| amen |      |   |     |     |                             |       |
| tals |      |   |     |     |                             |       |
| --   |      |   |     |     |                             |       |
| Cut  |      |   |     |     |                             |       |
| F    |      |   |     |     |                             |       |
| lowe |      |   |     |     |                             |       |
| rs** |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Cut  | 0.54 | 0 | 1.8 | 500 | Pinching                    | 460   |
| Flo  |      |   |     |     |                             |       |
| wers |      |   |     |     |                             |       |
|      |      |   |     |     |                             |       |
| (max |      |   |     |     |                             |       |
| imum |      |   |     |     |                             |       |
| r    |      |   |     |     |                             |       |
| ate) |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | 0 | 1.8 | 5,  | Hand harvesting, pruning,   | 45    |
|      |      |   |     | 100 | thinning, pinching          |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | 5 | 0   |     |                             | 96    |
|      |      |   | .83 |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | * | 0   |     |                             | **    |
|      |      | * | .71 |     |                             | 110** |
|      |      | 6 |     |     |                             |       |
|      |      | * |     |     |                             |       |
|      |      | * |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
| Cut  | 0.27 | 0 | 0   | 500 | Pinching                    | 920   |
| Flo  |      |   | .88 |     |                             |       |
| wers |      |   |     |     |                             |       |
|      |      |   |     |     |                             |       |
| (min |      |   |     |     |                             |       |
| imum |      |   |     |     |                             |       |
| r    |      |   |     |     |                             |       |
| ate) |      |   |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | 0 | 0   | 5,  | Hand harvesting, pruning,   | 91    |
|      |      |   | .88 | 100 | thinning, pinching          |       |
+------+------+---+-----+-----+-----------------------------+-------+
|      |      | * | 0   |     |                             | **    |
|      |      | * | .75 |     |                             | 110** |
|      |      | 1 |     |     |                             |       |
|      |      | * |     |     |                             |       |
|      |      | * |     |     |                             |       |
+------+------+---+-----+-----+-----------------------------+-------+

> ^1^ Maximum application rate from proposed labels: V-10161 VPP
> Fungicide (Reg No. 59639-RUR), and V-10162 VPP Fungicide (Reg. No.
> 59639-RUG). The foliar application rate was used for ornamentals.
>
> ^2^ DAT = Days after treatment needed to reach the LOC of 100; DAT 0 =
> The day of treatment, after sprays have dried; assumed to be
> approximately 12 hours.
>
> ^3^ Turf transferable residues: TTR (µg/cm^2^) = Application rate (lb
> ai/A) x CF (4.54E+8 µg/lb) x CF (2.47E-8 A/cm^2^) x Initial Fraction
> of ai Retained on the Foliage (standard assumptions of 5% for turf)\]
>
> Ornamental dislodgeable foliar residues corresponding to DAT, based on
> results from a chemical-specific DFR study conducted on lettuce (MRID
> 46708641).
>
> ^4^ TC (cm^2^/hr) = transfer coefficients and associated activities
> from ExpoSAC Policy Memo #003.1 "Agricultural Transfer Coefficients",
> 8/17/2000.
>
> ^5^ MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose.
>
> Daily Dose = \[(TTR or DFR x TC x 37% Dermal absorption x 8-hr
> Exposure Time)\] / \[(CF: 1000 µg/mg) x (60-kg Body Weight)\]
>
> Short-/intermediate-term NOAEL = 20 mg/kg/day. The LOC is 100.

**10.0 Data Needs and Label
Requirements**[]{#__RefHeading___Toc185228086 .anchor}

**10.1 Toxicology**[]{#__RefHeading___Toc185228087 .anchor}

None.

**10.2 Residue Chemistry**[]{#__RefHeading___Toc185228088 .anchor}

Pending submission of revised Sections B and F (and provided that the
Human Health Risk Assessment for BAM is adequate), there are no Residue
Chemistry data gaps that would preclude conditional registrations and
permanent tolerances for residues of the fungicide fluopicolide as
follows. The remaining deficiency (in Part A below) regarding storage
stability must be resolved as a condition of registration.[Number range
CHAPTER]{.mark}

[]{.mark}

> **Tolerances to be established for residues of the fungicide
> fluopicolide \[2,6-dichloro-**
>
> ***N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide\]**
> as an indicator of combined residues of fluopicolide and its
> metabolite 2,6-dichlorobenzamide **under "(a) *General*":**
>
> Grape 2.0 ppm
>
> Grape, raisin 6.0 ppm
>
> Vegetable, cucurbit, group 9 0.50 ppm
>
> Vegetable, fruiting, group 8 1.6 ppm
>
> Vegetable, leafy, except *Brassica*, group 4 .25 ppm
>
> Vegetable, tuberous and corm, except potato, subgroup 1D .0.02 ppm

[Deficiencies (Part A)]{.underline}

[860.1200 Directions for Use]{.underline}

-   Sufficient rotational crop data is not available to support the
    proposed rotational crop restrictions. The Section B/label must be
    modified to state that rotation is limited only to those crops on
    the current label.

-   A revised Section B/label must be submitted to delete the proposed
    use on potato.

[860.1550 Proposed Tolerances]{.underline}

-   The petitioner should submit a revised Section F which reflects the
    crop groups, tolerance levels and commodity definitions specified
    above and in Table 9 of this document.

[860.1380 Storage Stability]{.underline}

-   Additional storage stability data are needed for celery and spinach
    reflecting a storage interval of 38 months. One study should be
    conducted on any representative leafy vegetable.

**HED doe [not]{.underline} recommend for the following tolerances at
this time. Provided the remaining deficiencies (in Part B below) are
resolved, the following tolerances could be established:**

> Tolerances for residues of the fungicide fluopicolide
> \[2,6-dichloro-*N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide\]
> as an indicator of combined residues of fluopicolide and its
> metabolite 2,6-dichlorobenzamide in/on the following raw agricultural
> commodities (RACs):
>
> Potato, processed potato waste 0.05 ppm
>
> Vegetable, tuberous and corm, subgroup 1C 0.02 ppm
>
> Tolerances for residues of 2,6-dichlorobenzamide in/on the following
> food commodities:
>
> Cattle, fat 0.05 ppm
>
> Cattle, meat 0.02 ppm
>
> Cattle, meat byproducts 0.05 ppm
>
> Goat, fat 0.05 ppm
>
> Goat, meat 0.02 ppm
>
> Goat, meat byproducts 0.05 ppm
>
> Horse, fat 0.05 ppm
>
> Horse, meat 0.02 ppm
>
> Horse, meat byproducts 0.05 ppm
>
> Milk 0.01 ppm
>
> Sheep, fat 0.05 ppm
>
> Sheep, meat 0.02 ppm
>
> Sheep, meat byproducts 0.05 ppm
>
> Tolerances for indirect or inadvertent residues of the fungicide
> fluopicolide
> \[2,6-dichloro-*N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide\]
> as an indicator of combined residues of fluopicolide and its
> metabolite 2,6-dichlorobenzamide in/on the following raw agricultural
> commodities (RACs):
>
> Wheat, forage 0.20 ppm
>
> Wheat, grain 0.02 ppm
>
> Wheat, hay 0.50 ppm
>
> Wheat, milled byproducts 0.07 ppm
>
> Wheat, straw 0.50 ppm
>
> Wheat, aspirated grain fractions 0.07 ppm

[Deficiencies (Part B)]{.underline}

[860.1200 Directions for Use]{.underline}

-   Until all field rotational crop data requirements have been
    satisfied, the proposed rotational crop restrictions must be
    modified to state that rotation is limited only to those crops on
    the current label: cucurbit vegetables, fruiting vegetables, grapes,
    leafy vegetables, tuberous and corm vegetables, and wheat. A 0-day
    PBI for cucurbit vegetables, fruiting vegetables, grapes, leafy
    vegetables, and tuberous and corm vegetables, and a 30-day PBI for
    wheat are supported by the available data..

[860.1340 Residue Analytical Methods]{.underline}

-   HED has determined that tolerances are required for ruminant
    commodities. Method 303-02 has been reviewed and is not acceptable
    as an enforcement method. A confirmatory procedure is required for
    the LC/MS/MS Method 303-02 to be considered an adequate enforcement
    method for ruminant commodities.

-   An analytical reference standard for the metabolite
    2,6-dichlorobenzamide (BAM) must be sent to USEPA, National
    Pesticide Standards Repository/Analytical Chemistry Branch/OPP, 710
    Mapes Road, Fort George G. Meade, MD 20755-5350.

[860.1550 Proposed Tolerances]{.underline}

-   The petitioner should submit a revised Section F which reflects the
    crop groups, tolerance levels and commodity definitions specified in
    Table 10 of this document.

[860.1300 Nature of the Residue - Livestock]{.underline}

-   For the fluopicolide phenyl-^14^C-labeled cow metabolism study (MRID
    46708514), the

> petitioner should provide complete sample history information for
> samples from the study, including not only dates of collection, but
> also dates of storage, radioassay, extraction, and analysis. If sample
> analyses were not completed within 6 months of sample collection, the
> petitioner must provide data demonstrating that the metabolic profile
> was stable in the affected matrices during storage.

-   For the fluopicolide pyridinyl-^14^C-labeled cow metabolism study
    (MRID 46708518):

    -   Storage stability data are required to support the study. If
        samples were stored for greater than 6 months, the petitioner
        should provide data showing stability of the metabolic profile
        of the affected matrices for the duration of the storage period
        and under the conditions that the samples were stored.

    -   The petitioner must clarify the identification of two peaks in
        liver methanol/water extract (retention times of 43 and 47
        minutes) to state whether the text on page 65 (which states that
        the metabolites are sulfate conjugates) or the results reported
        in Table 10 of MRID 46708518 (which indicate that one is a
        sulfate conjugate and one is a glucuronide conjugate) are
        correct, and to further explain how the retention times for
        these metabolites were correlated with the identified
        metabolites in urine and kidney.

    -   The petitioner should correct the flowchart for omental fat
        (Figure 10) to include the correct TRR value for this matrix
        (0.039 ppm).

    -   The petitioner should recalculate the radioactivity levels
        and/or clarify the results for the HPLC analysis of any extract
        in which the calculated LOQ was too high to allow meaningful
        interpretation of the chromatogram.

-   For the hen metabolism study reported in MRID 46708515:

    -   The petitioner should provide complete sample history
        information for samples from the study, including not only dates
        of collection but also dates of storage, radioassay, extraction,
        and analysis. If sample analyses were not completed within 6
        months of sample collection, the petitioner should provide data
        demonstrating that the metabolic profile was stable in the
        affected matrices during the storage period and under the
        conditions that the samples were stored.

    -   The petitioner should submit copies of the LC/MS chromatograms
        of metabolite AE C653711 (BAM) in liver as well as the
        corresponding chromatogram of the reference standard. These
        chromatograms were referenced in the submission (MRID 46708515,
        page 113) but were not included.

-   The hen metabolism study conducted with
    \[2,6-^14^C-pyridinyl\]fluopicolide (MRID 46708519) is incomplete
    but upgradeable. The samples from this study were not extracted
    until \>6 months after sample collection. The petitioner should
    provide data showing stability of the metabolic profile for the
    duration of the storage period and under the conditions that the
    samples were stored.

[860.1380 Storage Stability]{.underline}

-   To support the wheat field rotational crop study, storage stability
    data are needed reflecting the stability of P1X in wheat grain for
    21 months and of fluopicolide and BAM in wheat forage and straw for
    24 months. The additional storage stability data for residues of P1X
    in wheat grain is also required to support the wheat processing
    study.

[860.1480 Meat, Milk, Poultry and Eggs]{.underline}

-   Since BAM may occur in livestock feed items and livestock (ruminant)
    commodities, a BAM ruminant feeding study must be submitted or
    referenced and livestock tolerances at the limit of quantitation of
    the method must be proposed.

[860.1520 Processed Food & Feed]{.underline}

-   No data have been submitted on aspirated grain fractions. Since data
    indicate that residues of fluopicolide concentrate in wheat milled
    byproducts, HED concludes that residue data and a tolerance for
    aspirated grain fractions (AGF) is required. HED could base the
    tolerance for AGF on the available wheat processing data, but would
    require confirmatory residue data on AGF as a condition of
    registration.

[860.1900 Field Accumulation in Rotational Crops]{.underline}

-   In the confined rotational crop study, residues of fluopicolide
    \>0.01 ppm were observed in/on all rotational crop commodities at
    all PBIs, with the exception of wheat grain at the 133- and 365-day
    PBIs. Based on these results and the proposed rotational crop
    restrictions, limited field rotational crop studies should be
    conducted at 1, 4, and 12-month PBIs with any representative leafy
    vegetable, root vegetable, and cereal grain crops. Although the
    petitioner is proposing a 30-day PBI for wheat and has submitted
    supporting field rotational crop data, limited field rotational crop
    data for wheat as a representative cereal grain are also needed at
    4- and 12-month PBIs. If the results of the limited field rotational
    crop study indicate the potential for quantifiable fluopicolide
    residues of concern in/on rotational crops at the desired PBI, then
    extensive field rotational crop studies will be required for all
    crops. Residues of parent, BAM, PCA and P1X should be determined in
    the field rotational crop studies.

**10.3 Occupational and Residential
Exposure**[]{#__RefHeading___Toc185228089 .anchor}

None.

**References:**[]{#__RefHeading___Toc185228090 .anchor}

*Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for
Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes and on the Rotational
Crop Wheat. Summary of Analytical Chemistry and Residue Data,, DP
Number326080, Amelia Acierto,11/19/07*.

[]{.mark}

***Fluopicolide** Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action on
Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes, and the Rotational
Crop Wheat,* DP Number 340365, N. Dodd, 11/21/07.

*Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O'Rourke, 10/9/07.*

*Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes,
Vegetables, Potatoes and Turf*, DP #325804, James Lin, 3/7/07.

**Appendix A: Toxicology Assessment**[]{#__RefHeading___Toc185228091
.anchor}

**A.1 Toxicology Data Requirements**[]{#__RefHeading___Toc185228092
.anchor}

The requirements (40 CFR 158.340) for food use for fluopicolide 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 28-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^1^      |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes^1^      |
|                                         |             |             |
| 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         |
|                                         |             |             |
| 870.5375 Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5395 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          | \-          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | no          | \-          |
|                                         |             |             |
| > Acute Oral (rat)                      | no          | \-          |
| >                                       |             |             |
| > Subchronic Oral (rat)                 | no          | \-          |
| >                                       |             |             |
| > Six-month Oral (dog)                  |             |             |
+-----------------------------------------+-------------+-------------+

^1^ Endpoint is met with combined chronic toxicity/carcinogenicity study
in rats.

**A.2 Toxicity Profiles**[]{#__RefHeading___Toc185228093 .anchor}

+-------+----------------------+--------+---------------------+--------+
| **    |                      |        |                     |        |
| Table |                      |        |                     |        |
| A.2.1 |                      |        |                     |        |
| Acute |                      |        |                     |        |
| Tox   |                      |        |                     |        |
| icity |                      |        |                     |        |
| Pr    |                      |        |                     |        |
| ofile |                      |        |                     |        |
| of    |                      |        |                     |        |
| Fl    |                      |        |                     |        |
| uopic |                      |        |                     |        |
| olide |                      |        |                     |        |
| Techn |                      |        |                     |        |
| ical, |                      |        |                     |        |
| and   |                      |        |                     |        |
| Sel   |                      |        |                     |        |
| ected |                      |        |                     |        |
| M     |                      |        |                     |        |
| etabo |                      |        |                     |        |
| lites |                      |        |                     |        |
| and   |                      |        |                     |        |
| Form  |                      |        |                     |        |
| ulati |                      |        |                     |        |
| ons** |                      |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| *     | **Study Type**       | **MRI  | **Results**         | **To   |
| *Guid |                      | D(s)** |                     | xicity |
| eline |                      |        |                     | Cate   |
| No.** |                      |        |                     | gory** |
+-------+----------------------+--------+---------------------+--------+
| 870   | [Acute oral \[rat\]  | 46     | LD~50~≥ 2000 mg/kg  | III    |
| .1100 | Fluop                | 708601 | (f)                 |        |
|       | icolide]{.underline} |        |                     | III    |
|       |                      | 46     | LD~50~ ≥ 2000 mg/kg |        |
|       | Technical 98.3% (AE  | 709903 | (m/f)               | III    |
|       | C638206)             |        |                     |        |
|       |                      | 46     | LD~50~ ≥ 2000 mg/kg |        |
|       | Formulation SC 40    | 709803 | (m/f)               |        |
|       | (AE C638206)         |        |                     |        |
|       |                      |        |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | [Acute oral \[rat\]  | 42     | LD~50~ ≥ 1538/1144  | III    |
| .1100 | Meta                 | 940201 | mg/kg (m/f)         |        |
|       | bolites]{.underline} |        |                     | II     |
|       |                      | 46     | LD~50~ ≥ 2000/300   |        |
|       | 2                    | 708602 | mg/kg (m/f)         | III    |
|       | ,6-dichlorobenzamide |        |                     |        |
|       | (BAM)                | 46     | LD~50~≥2000 mg/kg   |        |
|       |                      | 708603 | (m/f)               |        |
|       | 1,3-chloro-5         |        |                     |        |
|       | (trifluoromethyl)    |        |                     |        |
|       |                      |        |                     |        |
|       | p                    |        |                     |        |
|       | yridine-2-carboxylic |        |                     |        |
|       | acid (PCA)           |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | Acute dermal \[rat\] | 46     | LD~50~ ≥ 5000 mg/kg | IV     |
| .1200 |                      | 708605 |                     |        |
|       | Technical 97.7% (AE  |        | LD~50~ ≥ 4000 mg/kg | III    |
|       | C638206)             | 46     |                     |        |
|       |                      | 709904 | LD~50~ ≥4000 mg/kg  | III    |
|       | Formulation SC40 (AE |        |                     |        |
|       | C638206)             | 46     |                     |        |
|       |                      | 709804 |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | Acute inhalation     | 46     | LC~50~ ≥ 5.16 mg/L  | IV     |
| .1300 | \[rat\]              | 708606 |                     |        |
|       |                      |        | LC~50~ ≥ 1.789 mg/L | III    |
|       | Technical (AE        | 46     |                     |        |
|       | C638206)             | 709905 | LC~50~ ≥ 3.195 mg/L | IV     |
|       |                      |        |                     |        |
|       | Formulation SC40 (AE | 46     |                     |        |
|       | C638206)             | 709805 |                     |        |
|       |                      |        |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | Acute eye irritation | 46     | slight conjuctival  | IV     |
| .2400 | \[rabbit\]           | 708607 | irritation          |        |
|       |                      |        |                     | III    |
|       | Technical 97.7% (AE  | 46     | chemosis/corneal    |        |
|       | C638206)             | 709906 | opacity in both     | III    |
|       |                      | 46     | studies             |        |
|       | Formulation SC40 (AE | 709806 |                     |        |
|       | C638206)             |        |                     |        |
|       |                      |        |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | Acute dermal         | 46     | None (PDII = 0.00)  | IV     |
| .2500 | irritation           | 708650 |                     |        |
|       | \[rabbit\]           |        | slight (PDII =      | IV     |
|       |                      | 46     | 0.08)               |        |
|       | Technical 97.7% (AE  | 709907 |                     | IV     |
|       | C638206)             |        | slight (PDII =      |        |
|       |                      | 46     | 0.25)               |        |
|       | Formulation SC40 (AE | 709807 |                     |        |
|       | C638206)             |        |                     |        |
|       |                      |        |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+
| 870   | Skin sensitization   | 46     | Negative            | no     |
| .2600 | \[guinea pig\]       | 708608 | (Magnusson-Kligman) | n-sens |
|       |                      |        |                     | itizer |
|       | Technical 97.7% (AE  | 46     | Negative (Buehler)  |        |
|       | C638206)             | 709908 |                     |        |
|       |                      |        | Negative (Modified  |        |
|       | Formulation SC40 (AE | 46     | Buehler)            |        |
|       | C638206)             | 709808 |                     |        |
|       |                      |        |                     |        |
|       | Formulation SC61 (AE |        |                     |        |
|       | B066752)             |        |                     |        |
+-------+----------------------+--------+---------------------+--------+

+--------+------------+-----------------+------------------------------+
| *      |            |                 |                              |
| *Table |            |                 |                              |
| A.2.2  |            |                 |                              |
| Subch  |            |                 |                              |
| ronic, |            |                 |                              |
| C      |            |                 |                              |
| hronic |            |                 |                              |
| and    |            |                 |                              |
| Other  |            |                 |                              |
| To     |            |                 |                              |
| xicity |            |                 |                              |
| P      |            |                 |                              |
| rofile |            |                 |                              |
| of     |            |                 |                              |
| Fl     |            |                 |                              |
| uopico |            |                 |                              |
| lide** |            |                 |                              |
+========+============+=================+==============================+
| **Gui  | **Study    | **MRID No.      | **Results**                  |
| deline | Type**     | (year)/         |                              |
| No.**  |            | Classification  |                              |
|        |            | /Doses**        |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 28-day     | 46708609 (2000) | NOAEL = 980/1242 mg/kg/day;  |
| 0.3050 | dietary    |                 | the limit dose).             |
|        | toxicity   | Accep           |                              |
|        | (mouse)    | table/Guideline | The LOAEL was not observed.  |
|        |            |                 |                              |
|        |            | M/F: 0/0,       |                              |
|        |            | 0.95/1.19,      |                              |
|        |            | 10.4/12.9,      |                              |
|        |            | 100/129,        |                              |
|        |            | 980/1242        |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 28-day     | 46708610 (2000) | NOAEL = 17.4/17.9 mg/kg/day  |
| 0.3050 | dietary    |                 | in males/females).           |
|        | toxicity   | Accep           |                              |
|        | (rat)      | table/Guideline | The LOAEL = 174/184          |
|        |            |                 | mg/kg/day (M/F) based on     |
|        |            | M/F: 0/0,       | decreased body weight gain   |
|        |            | 1.8/1.8,        | and food conversion in       |
|        |            | 17.4/17.9,      | females and nephrotoxicity   |
|        |            | 174/184, and    | in males.                    |
|        |            | 1720/1820       |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 28-day     | 46708611 (2003) | NOAEL = 151.6/167.1          |
| 0.3050 | dietary    |                 | mg/kg/day.                   |
|        | toxicity   | Accep           |                              |
|        | (rat)      | table/Guideline | LOAEL = 1495.3/1615.5        |
|        |            |                 | mg/kg/day based on decreased |
|        | AE 1344122 | M/F: 0/0,       | body weights and body weight |
|        | (Fl        | 1.5/1.7,        | gains in both sexes, and     |
|        | uopicolide | 14.9/16.8,      | nephrotoxicity in females.   |
|        | m          | 151.6/167.1,    |                              |
|        | etabolite) | 1495.3/1615.5   |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 28-day     | 46708612 (2003) | NOAEL = 159.2/230.6          |
| 0.3050 | dietary    |                 | mg/kg/day.                   |
|        | toxicity   | Accep           |                              |
|        | (rat)      | table/Guideline | LOAEL = 1775.0/1930.8        |
|        |            |                 | mg/kg/day based on decreases |
|        | AE C657378 | M/F: 0/0,       | in body weight and body      |
|        | (a         | 1.6/2.1,        | weight gain (males);         |
|        | Fl         | 16.2/20.4,      | increased absolute (females) |
|        | uopicolide | 159.2/230.6,    | and relative liver weight    |
|        | m          | and             | (both sexes) and relative    |
|        | etabolite) | 1775.0/1930.8   | kidney weight (males);       |
|        |            | mg/kg/day       | increased cholesterol (both  |
|        |            |                 | sexes); and                  |
|        |            |                 | histopathological effects in |
|        |            |                 | the liver (females), the     |
|        |            |                 | kidneys (males), and thyroid |
|        |            |                 | (both sexes).                |
+--------+------------+-----------------+------------------------------+
| 87     | 28-day     | 46708613 (2000) | NOAEL = 1000 mg/kg/day       |
| 0.3050 | oral       |                 | (limit dose).                |
|        | toxicity   | Acceptabl       |                              |
|        | (dog)      | e/Non-guideline | LOAEL was not observed.      |
|        |            |                 |                              |
|        |            | 0, 10, 100,     |                              |
|        |            | 1000 mg/kg/day  |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 46474112 (2000) | NOAEL = 109 mg/kg/day for    |
| 0.3100 | oral       |                 | males; 8.4 mg/kg/day for     |
|        | toxicity   | Accep           | females                      |
|        | (rat)      | table/guideline |                              |
|        |            |                 | LOAEL = 1668 mg/kg/day for   |
|        |            | M: 0, 7.4, 109, | males and 119 mg/kg/day for  |
|        |            | 1668 mg/kg/d    | females based on hypertrophy |
|        |            |                 | of the zona glomerulosa in   |
|        |            | F: 0, 8.4, 119, | the adrenal gland (M/F),     |
|        |            | 1673 mg/kg/day  | decreased cellularity of the |
|        |            |                 | bone marrow (M/F), and       |
|        |            |                 | trabecular hyperostosis of   |
|        |            |                 | the bone joint (M)           |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 46474114 (2000) | NOAEL = 1092 mg/kg/day      |
| 0.3100 | oral       |                 | (M/F)                        |
|        | toxicity   | Accep           |                              |
|        | (mouse)    | table/guideline | LOAEL = not identified       |
|        |            |                 |                              |
|        |            | M/F: 0, 5.5,    |                              |
|        |            | 53, 545 or 1092 |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 46474116 (2001) | NOAEL = 770 mg/kg/day for   |
| 0.3100 | oral       |                 | males; 207 mg/kg/day for     |
|        | toxicity   | Accep           | females                      |
|        | (mouse)    | table/guideline |                              |
|        |            |                 | LOAEL = not identified for   |
|        |            | M: 0, 10.4,     | males; 965 mg/kg/day for     |
|        |            | 37.8, 161, 770  | females based on increased   |
|        |            | mg/kg/d         | incidence of liver oval cell |
|        |            |                 | proliferation                |
|        |            | F: 0, 12.6,     |                              |
|        |            | 52.8, 207, 965  |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 46474118 (2000) | NOAEL = 1000 mg/kg/day (M/F) |
| 0.3150 | oral       |                 |                              |
|        | toxicity   | Accep           | LOAEL = not identified (M/F) |
|        | (dog)      | table/guideline |                              |
|        |            |                 |                              |
|        |            | M&F: 0, 5, 70,  |                              |
|        |            | 1000 mg/kg/day  |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 21/28-Day  | 46708614 (2003) | NOAEL = 1000 mg/kg/day       |
| 0.3200 | dermal     |                 |                              |
|        | toxicity   | Acceptable      | LOAEL \> 1000 mg/kg/day      |
|        | (species)  | Guideline       |                              |
|        |            |                 | No local or systemic         |
|        |            | 0, 100, 250,    | toxicity observed            |
|        |            | 500, 1000       |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 46708615 (2000) | NOAEL/LOAEL not determined.  |
| .3700a | dev        |                 | Only four animals/group.     |
|        | elopmental | Acceptabl       | Purpose of study was to      |
|        | in (rat)   | e/non-guideline | determine high-dose level    |
|        |            |                 | for 46474120.                |
|        | Pilot      | F: 500, 1000    |                              |
|        | study      | mg/kg/day (GD   |                              |
|        |            | 7-20)           |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 46474120 (2001) | **Maternal** NOAEL = 60      |
| .3700a | dev        |                 | mg/kg/day                    |
|        | elopmental | Accep           |                              |
|        | in (rat)   | table/guideline | LOAEL = 700 mg/kg/day based  |
|        |            |                 | on decreased body weight     |
|        |            | F: 0, 5, 60,    | gain                         |
|        |            | 700 mg/kg/day   |                              |
|        |            | (GD 7-20)       | **Developmental** NOAEL = 60 |
|        |            |                 | mg/kg/day                    |
|        |            |                 |                              |
|        |            |                 | LOAEL = 700 mg/kg/day based  |
|        |            |                 | on delayed fetal growth and  |
|        |            |                 | skeletal defects             |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 46708616 (2000) | Maternal NOAEL = 25          |
| .3700b | dev        |                 | mg/kg/day                    |
|        | elopmental | Acceptabl       |                              |
|        | in         | e/non-guideline | LOAEL = 50 mg/kg/day based   |
|        | (rabbit)   |                 | on reduced defecation and    |
|        |            | F: 25, 50, 100, | abortion in a single dose    |
|        | Pilot      | 250, 500, or    |                              |
|        | study      | 1000 mg/kg      | Developmental NOAEL = 1000   |
|        |            | bw/day          | mg/kg/day                    |
|        |            |                 |                              |
|        |            | (GD 6-28)       | LOAEL = not observed         |
+--------+------------+-----------------+------------------------------+
| 870    | Prenatal   | 46474122 (2001) | **Materna**l NOAEL = 20      |
| .3700b | dev        |                 | mg/kg/day                    |
|        | elopmental | Accep           |                              |
|        | in         | table/guideline | LOAEL = 60 mg/kg/day based   |
|        | (rabbit)   |                 | on death, abortion/premature |
|        |            | F: 0, 5, 20, 60 | delivery, decreased food     |
|        |            | mg/kg/day (GD   | consumption and weight gain  |
|        |            | 6-28)           |                              |
|        |            |                 | **Developmenta**l NOAEL = 20 |
|        |            |                 | mg/kg/day                    |
|        |            |                 |                              |
|        |            |                 | LOAEL = 60 mg/kg/day based   |
|        |            |                 | on abortion/premature        |
|        |            |                 | delivery, decreased fetal    |
|        |            |                 | body weight and crown-rump   |
|        |            |                 | length                       |
+--------+------------+-----------------+------------------------------+
| 87     | Re         | 46474124 (2003) | **Parental/Systemic** NOAEL  |
| 0.3800 | production |                 | = 36.4/41.0 mg/kg/day (M/F)  |
|        | and        | 46474125        |                              |
|        | fertility  | (additional     | LOAEL = 144.6/159.7          |
|        | effects    | data, 2004)     | mg/kg/day (M/F) based on     |
|        |            |                 | kidney toxicity in males and |
|        | (rat)      | 46474126        | females and decreased weight |
|        |            | (range-finding, | gain in females.             |
|        |            | 2002)           |                              |
|        |            |                 | **Reproductive** NOAEL =     |
|        |            | Accep           | 144.6/159.7 mg/kg/day (M/F) |
|        |            | table/guideline |                              |
|        |            |                 | LOAEL = not identified.      |
|        |            | M: 0, 7.4,      |                              |
|        |            | 36.4, 144.6     | **Offspring** NOAEL =        |
|        |            | mg/kg/d         | 36.4/41.0 mg/kg/day (M/F)    |
|        |            |                 |                              |
|        |            | F: 0, 8.1,      | LOAEL = 144.6/159.7          |
|        |            | 41.0, 159.7     | mg/kg/day (M/F) based on     |
|        |            | mg/kg/day       | decreased body weight and    |
|        |            |                 | weight gain.                 |
+--------+------------+-----------------+------------------------------+
| 870    | Chronic    | 44674128 (2002) | NOAEL = 300 mg/kg/day (M);   |
| .4100b | toxicity   |                 | 1000 mg/kg/day (F)          |
|        | (dog)      | Accep           |                              |
|        |            | table/guideline | LOAEL = 1000 mg/kg/day based |
|        |            |                 | on decreased body weight     |
|        |            | M&F: 0, 70,     | gain (M); not identified (F) |
|        |            | 300, 1000       |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Carci      | 46474130 (2003) | NOAEL = 64.5/91.9 mg/kg/day  |
| .4200b | nogenicity |                 | (M/F)                        |
|        |            | Accep           |                              |
|        | (mouse)    | table/guideline | LOAEL = 551.0/772.3          |
|        |            |                 | mg/kg/day (M/F) based on     |
|        |            | M: 0, 7.9,      | decreased body weight and    |
|        |            | 64.5, 551.0     | weight gain and liver        |
|        |            | mg/kg/d         | lesions.                     |
|        |            |                 |                              |
|        |            | F: 0, 11.5,     | **no evidence of             |
|        |            | 91.9, 772.3     | carcinogenicity**            |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Chronic/   | 46474139 (2003) | NOAEL = 31.5/41.0 mg/kg/day  |
| 0.4300 | Carci      |                 | (M/F)                        |
|        | nogenicity | Accep           |                              |
|        |            | table/guideline | LOAEL = 109.4/142.2          |
|        | (rat)      |                 | mg/kg/day based on decreased |
|        |            | M: 0, 2.1, 8.4, | body weight gain (M/F) and   |
|        |            | 31.5, 109.4     | thyroid toxicity (M).        |
|        |            | mg/kg/day       |                              |
|        |            |                 | **no evidence of             |
|        |            | F: 0, 2.8,      | carcinogenicity**            |
|        |            | 10.8, 41.0,     |                              |
|        |            | 142.2 mg/kg/day |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Gene       | 46474146 (2001) | negative (non-mutagenic)     |
| 0.5100 | Mutation   |                 | Upgradeable if purity for    |
|        |            | Unaccep         | test material is given.      |
|        | (*         | table/guideline |                              |
|        | Salmonella |                 | negative (non-mutagenic)     |
|        | typ        | 1.6- 5000       |                              |
|        | himurium*) | µg/plate        | negative (non-mutagenic)     |
|        |            |                 |                              |
|        |            | 46474202 (2001) | negative (non-mutagenic      |
|        |            |                 |                              |
|        |            | Accep           | positive (mutagenic)         |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | 1.6- 5000       |                              |
|        |            | µg/plate        |                              |
|        |            |                 |                              |
|        |            | 46474148 (2001) |                              |
|        |            |                 |                              |
|        |            | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | 1.6- 5000       |                              |
|        |            | µg/plate        |                              |
|        |            |                 |                              |
|        |            | 46474144 (2001) |                              |
|        |            |                 |                              |
|        |            | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | 1.6- 5000       |                              |
|        |            | µg/plate        |                              |
|        |            |                 |                              |
|        |            | 46474142 (2004) |                              |
|        |            |                 |                              |
|        |            | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | AE638206 (batch |                              |
|        |            | mixture of      |                              |
|        |            | PP/241067/1 and |                              |
|        |            | PP/241024)      |                              |
|        |            |                 |                              |
|        |            | 5 - 5000        |                              |
|        |            | µg/plate        |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Gene       | 46474204 (2000) | negative (non-mutagenic)     |
| 0.5300 | mutation   |                 |                              |
|        |            | Accep           |                              |
|        | (Chinese   | table/guideline |                              |
|        | hamster    |                 |                              |
|        | lung       | AE638206 (batch |                              |
|        | cells)     | mixture of      |                              |
|        |            | PP/241067/1 and |                              |
|        |            | PP/241024)      |                              |
|        |            |                 |                              |
|        |            | 1.2- 3820 µg/mL |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Cy         | 46474208 (2001) | negative for chromosome      |
| 0.5375 | togenetics |                 | aberrations                  |
|        |            | Accep           |                              |
|        |            | table/guideline | positive for aberrations     |
|        |            |                 | without S9 activation        |
|        |            | 1.22 to 625     |                              |
|        |            | µg/mL           |                              |
|        |            |                 |                              |
|        |            | 46474206 (2004) |                              |
|        |            |                 |                              |
|        |            | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | AE638206 (batch |                              |
|        |            | mixture of      |                              |
|        |            | PP/241067/1 and |                              |
|        |            | PP/241024)      |                              |
|        |            |                 |                              |
|        |            | 3.2 to 100      |                              |
|        |            | µg/mL           |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Mi         | 46474214 (2003) | negative at doses up to 600  |
| 0.5395 | cronucleus |                 | mg/kg                        |
|        |            | Accep           |                              |
|        | (mouse)    | table/guideline | negative at doses up to 2000 |
|        |            |                 | mg/kg                        |
|        |            | 150, 300 or 600 |                              |
|        |            | mg/kg/day       | negative at dose of 2000     |
|        |            |                 | mg/kg                        |
|        |            | 46474210 (2005) |                              |
|        |            |                 |                              |
|        |            | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | AE638206 (batch |                              |
|        |            | mixture of      |                              |
|        |            | PP/241067/1 and |                              |
|        |            | PP/241024)      |                              |
|        |            |                 |                              |
|        |            | 200, 600 or     |                              |
|        |            | 2000 mg/kg/day  |                              |
|        |            |                 |                              |
|        |            | 46474212 (2005) |                              |
|        |            |                 |                              |
|        |            | Acceptable      |                              |
|        |            | guideline AE    |                              |
|        |            | C638206 (Batch  |                              |
|        |            | No. OP 2050046  |                              |
|        |            | at 2000         |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | U          | 42169839 (1989) | negative at concentration up |
| 0.5550 | nscheduled |                 | to 300 µg/mL in cultured rat |
|        | DNA        | Accep           | hepatocytes                  |
|        | Synthesis  | table/guideline |                              |
|        |            |                 |                              |
|        | (rat       |                 |                              |
|        | he         |                 |                              |
|        | patocytes) |                 |                              |
+--------+------------+-----------------+------------------------------+
| (no    | Other      | 46474216 (2000) | negative at concentrations   |
| OPPTS  | Ge         |                 | up to 2000 mg/kg in          |
| no./   | notoxicity | Accep           | hepatocytes from treated     |
| FIFRA  |            | table/guideline | rats                         |
| test   | U          |                 |                              |
| gui    | nscheduled | AE638206 (batch |                              |
| deline | DNA        | mixture of      |                              |
| 84-2)  | synthesis  | PP/241067/1 and |                              |
|        | (rat       | PP/241024)      |                              |
|        | he         |                 |                              |
|        | patocytes) | 600 or 2000     |                              |
|        |            | mg/kg           |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Acute      | 46474218 (2002) | NOAEL = 100 mg/kg (M/F)      |
| .6200a | neu        |                 |                              |
|        | rotoxicity | 46474219        | LOAEL = 2000 mg/kg (M/F)     |
|        | screening  | (range-finding, | based on transiently lowered |
|        | battery    | 2002)           | body temperature.            |
|        |            |                 |                              |
|        | (rat)      | Accep           |                              |
|        |            | table/guideline |                              |
|        |            |                 |                              |
|        |            | M/F: 0, 10,     |                              |
|        |            | 100, 2000 mg/kg |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Subchronic | 46474221 (2002) | NOAEL = 106.6/18.0 mg/kg/day |
| .6200b | neu        |                 | (M/F)                        |
|        | rotoxicity | 46474222        |                              |
|        | screening  | (positive       | LOAEL = 780.6/125.2          |
|        | battery    | control, 2002)  | mg/kg/day based on decreased |
|        |            |                 | body weight gain, food       |
|        |            | Accep           | consumption, and food        |
|        |            | table/guideline | efficiency.                  |
|        |            |                 |                              |
|        |            | M: 0, 15.0,     |                              |
|        |            | 106.6, 780.6    |                              |
|        |            | mg/kg/day       |                              |
|        |            |                 |                              |
|        |            | F: 0, 18.0,     |                              |
|        |            | 125.2, 865.8    |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Dev        | None            |                              |
| 0.6300 | elopmental |                 |                              |
|        | neu        |                 |                              |
|        | rotoxicity |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 46474242        | rapid absorption, metabolism |
| 0.7485 | and        | (2004)-main     | and excretion; main          |
|        | pharma     | studies         | metabolites were oxidative   |
|        | cokinetics |                 | N-dealkylation cleavage      |
|        |            | 46474241 (2001) | products. Primary route of   |
|        | (rat)      |                 | excretion is fecal and       |
|        |            | 46474244 (2003) | urinary with little          |
|        |            |                 | accumulation in the tissues. |
|        |            | 46474226 (2003) |                              |
|        |            |                 |                              |
|        |            | 46474239 (2003) |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 46708632 (2002) | Most of the metabolites      |
| 0.7485 | and        |                 | observed were derivatives of |
|        | pharma     | Acceptable      | AE C638206 fitting well with |
|        | cokinetics | Non-guideline   | the prior known metabolites, |
|        |            |                 | implying cysteine or         |
|        | (rat)      |                 | *N*-acetyl-cysteine          |
|        |            |                 | introduction on the phenyl   |
|        |            |                 | ring from gluthione          |
|        |            |                 | conjugation, hydroxylation,  |
|        |            |                 | or other conjugations.       |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 46708636 (2002) | AE C657188 (PCA) showed high |
| 0.7485 | and        |                 | (87%) absorption but low (14 |
|        | pharma     | Acceptable      | -- 21%) metabolism.          |
|        | cokinetics | Guideline       | Excretion is mainly through  |
|        |            |                 | the urine, with a minor      |
|        | (rat)      |                 | portion in the feces.        |
|        |            |                 |                              |
|        | AE C657188 |                 |                              |
|        | (PCA)      |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 46708633 (2003) | Absorption: 50-79%.          |
| 0.7485 | and        |                 | Metabolized extensively to   |
|        | pharma     | 46708634 (2003) | 18 identified compounds. The |
|        | cokinetics |                 | majority of the              |
|        |            | 46708635 (2003) | radioactivity was associated |
|        | (rat)      |                 | with a mercapturic acid      |
|        |            | Acceptable      | conjugate of                 |
|        | AE C653711 | Guideline       | hydroxyl-chlorobenzamide     |
|        | (2,        |                 | (15-5-26.2%), present in the |
|        | 6-dichloro |                 | urine Excretion mainly       |
|        | -benzamide |                 | through urine and feces.     |
+--------+------------+-----------------+------------------------------+
| 87     | Dermal     | 46708638 (2003) | In vivo study                |
| 0.7600 | p          |                 |                              |
|        | enetration | Acceptable      | Dermal Penetration rate: 37% |
|        |            | Guideline       |                              |
|        | (rat)      |                 |                              |
|        |            | 1.43, 659       |                              |
|        |            | ug/cm^2^ skin   |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Dermal     | 46708637 (2003) | In vitro study               |
| 0.7600 | p          |                 |                              |
|        | enetration | Acceptable      | Rat skin dermal penetration  |
|        |            | Non-guideline   | rate is 7.8 times greater    |
|        | (co        |                 | than human skin.             |
|        | mparative) | 1.9, 744        |                              |
|        |            | ug/cm^2^ skin   |                              |
+--------+------------+-----------------+------------------------------+

**A.3 Executive Summaries**[]{#__RefHeading___Toc185228094 .anchor}

**A.3.1 Subchronic Toxicity**

**870.3050 28-day oral -- mouse**

In this 28-day oral toxicity study (MRID 46708609), 5 CRL CD-1 (ICR) BR
mice/sex/dose were treated daily with AE C638206 (Fluopicolide; 99.0%
a.i.; Batch No. CDB234187-1) in the diet at nominal concentrations of 0,
6, 64, 640, or 6400 ppm (equivalent to 0/0, 0.95/1.19, 10.4/12.9,
100/129, and 980/1242 mg/kg/day in males/females) for 28 days.

No adverse treatment-related effects were observed on mortality,
clinical signs, body weight, body weight gains, food consumption, food
conversion, hematology, clinical chemistry, organ weight, or gross or
histological pathology.

Alanine aminotransferase was increased (p\<=0.01) in the \>=640 ppm
males (incr 81-148%), and alkaline phosphokinase was increased (not
statistically significant \[NS\]) by 131% in the 6400 ppm males. These
increases were outside the normal range (not reported) of historical
control data. Absolute and relative to body liver weights were increased
(p\<=0.01) by 33-58% in the 6400 ppm group. Relative liver weight was
increased (p\<=0.01) by 19% in the 640 ppm females. An increase in
incidence and severity of minimal to moderate centrilobular hepatocyte
hypertrophy was noted in the 640 and 6400 ppm groups.

Alanine aminotransferase was not increased sufficiently to categorize as
an adverse response, and, due to variation, it was unclear if the
alkaline phosphatase values were actually increased at 6400 ppm.
Centrilobular hepatocyte hypertrophy with increased liver weight is
characteristic of an adaptive response. In the absence of definitive
evidence of hepatoxicity, all these effects were not considered adverse
in this 28-day study.

**The LOAEL was not observed. The NOAEL is 6400 ppm (equivalent to
980/1242 mg/kg/day; the limit dose).**

This study is classified **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents. Although an adverse effect was not observed,
the limit dose was tested.

**870.3050 28-day oral -- rat**

In this 28-day oral toxicity study (MRID 46708610), 5 Sprague Dawley
rats/sex/dose were treated daily with AE C638206 (Fluopicolide; 99.9%
a.i.; Batch No. CDB234167-2) in the diet at nominal concentrations of 0,
20, 200, 2000, or 20,000 ppm (equivalent to 0/0, 1.8/1.8, 17.4/17.9,
174/184, and 1720/1820 mg/kg/day) for 4 weeks.

No adverse treatment-related effects were observed on mortality,
clinical signs, functional observational battery, motor activity,
opthalmoscopic examination, or hematology.

At \>=2000 ppm, dose-dependent decreases (not statistically significant
\[NS\]; decr 7-15%) in body weights were noted throughout treatment in
females. Overall (Days 1-29) body weight gains were also decreased in
the females by 30-36%. Food conversion was decreased by 19-68% for 2-3/4
weeks in females. Water consumption was increased in the males by
18-27%. Pale kidneys were observed bilaterally in the males (3/5 each
treated group vs 0/5 controls). Histological evidence of nephrotoxicity
in males included an increased incidence and severity of minimal to
severe renal tubular eosinophilic proteinaceous material (5/5 each
treated group vs 0/5 controls) and increased severity of minimal to
severe phloxine tartrazine positive granulation (4-5/5 moderate to
severe in treated groups vs 1/5 in controls). Cholesterol levels
increased (p\<=0.01) by 29-70% in both sexes, and was considered
equivocal evidence of hepatotoxicity with the corroborating evidence of
increased hepatocellular hypertrophy at \>=200 ppm and increased liver
weights at 20,000 ppm.

At 20,000 ppm, the following findings of systemic toxicity were noted:
(i) decreased body weight throughout treatment and decreased overall
(Days 1-29) body weight gain in the males; (ii) transiently decreased
food consumption in both sexes during Week 1; (iii) decreased food
conversion in the males at Weeks 1 and 4; and (iv) increased water
consumption in the females. Increased absolute liver weight was noted in
males and increased relative to body liver weights were observed in both
sexes; enlarged liver was observed in males. An increased incidence of
slight to moderate hydronephrosis was noted in the male kidney.

**The LOAEL was 2000 ppm (equivalent to 174/184 mg/kg/day in
males/females) based on decreased body weight gain and food conversion
in females and nephrotoxicity in males. The NOAEL is 200 ppm (equivalent
to 17.4/17.9 mg/kg/day in males/females).**

This study is classified **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents.

**870.3050 28-day oral -- rat**

In this 28-day oral toxicity study (MRID 46708611), 10 Wistar
rats/sex/dose were treated daily with AE 1344122 (Fluopicolide
metabolite; 98.8% a.i.; Batch No. YG3228) in the diet at nominal
concentrations of 0, 20, 200, 2000, or 20,000 ppm (equivalent to 0/0,
1.5/1.7, 14.9/16.8, 151.6/167.1, and 1495.3/1615.5 mg/kg/day) for 4
weeks.

No adverse, treatment-related effects were observed on mortality,
clinical signs, food consumption, ophthalmoscopic findings, hematology,
clinical chemistry, organ weights, or gross pathological findings.

Throughout treatment at 20,000 ppm, decreased body weights were observed
in both sexes. On Day 28, body weight was decreased (p\<=0.05) by 7% in
the males. Overall (Days 1-28) body weight gains were decreased by
17-18% in the 20,000 ppm group.

Nephrotoxicity was evident in the 20,000 ppm females. Urinary volume was
increased (p\<=0.01) by 100%, and an increased number of coarsely
granular casts was observed in the urine (18-150 casts per rat in 9/10
treated females vs 0 casts in 10/10 controls). Minimal to moderate
tubular degeneration/regeneration and single cell necrosis were each
seen in 8 females at 20,000 ppm and were not observed in any other dose
group.

In the 20,000 ppm males, increased incidences of scabs,
chromodacryorrhea, a mat aspect in the cornea, and soiled fur were
considered equivocal findings.

**The LOAEL was 20,000 ppm (equivalent to 1495.3/1615.5 mg/kg/day in
males/females) based on decreased body weights and body weight gains in
both sexes, and nephrotoxicity in females. The NOAEL is 2000 ppm
(equivalent to 151.6/167.1 mg/kg/day in males/females).**

This study is classified **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents.

3050. **28-day oral -- rat**

In a 28-day oral toxicity study (MRID 46708612), AE C657378 (a
Fluopicolide metabolite, 98.3% a.i.; Batch \# 1119-DC/3) was
administered in the diet to 10 Wistar rats/sex/dose at dose levels of 0,
20, 200, 2000, or 20,000 ppm (equivalent to 0/0, 1.6/2.1, 16.2/20.4,
159.2/230.6, and 1775.0/1930.8 mg/kg/day \[M/F\], respectively) for 4
weeks.

No treatment-related effects on mortality, clinical signs, food
consumption, ophthalmic findings, FOB, or gross pathology findings were
observed at any dose.

At 20,000 ppm, the males exhibited decreases (p\<=0.05) in body weight
during Weeks 3 and 4 (decr 8-10%) and body weight gain during Week 2
(decr 19%) and overall (Days 1-29, calculated by reviewers; decr 18%).
Hematological effects were limited to increased (p\<=0.05) platelets in
both sexes (incr 14-18%).

The liver was affected at 20,000 ppm as indicated by increased
(p\<=0.05) absolute (incr 25%, females) and relative (incr 14-23%, both
sexes) organ weight and cytoplasmic change in the periportal hepatocytes
(9/10 treated vs. 0 controls, females) accompanied by a concurrent
reduction in periportally stored fat (0/10 treated vs. 4 controls,
females). In addition, cholesterol was increased (p\<=0.05) by 40-44% in
both sexes.

Additionally in the 20,000 ppm males, increases were noted in relative
kidney weight (incr 15%) and in incidence and severity of basophilic
cortical tubules (9/10 treated vs. 5 controls). Mean urine volume was
decreased (p\<=0.01) by 30% as well.

Histopathological effects noted in the thyroid at 20,000 ppm included
granular or clumpy alteration of the follicular colloid in the males (9
treated vs. 2 controls) and females (10 treated vs. 0 controls) and
flattening of the epithelium of the peripherally located follicles in
the males (2 treated vs. 0 controls).

In the thymus, increased histiocytosis was noted in both sexes (4-5
treated vs. 1-2 controls) at 20,000 ppm; however, as the mean severity
score was similar among the groups, this finding was considered to be
equivocal.

**The LOAEL is 20,000 ppm (equivalent to 1775.0/1930.8 mg/kg/day
\[M/F\]) based on decreases in body weight and body weight gain (males);
increased absolute (females) and relative liver weight (both sexes) and
relative kidney weight (males); increased cholesterol (both sexes); and
histopathological effects in the liver (females), the kidneys (males),
and thyroid (both sexes). The NOAEL is 2000 ppm (equivalent to
159.2/230.6 mg/kg/day \[M/F\]).**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3050; OECD 407) for a 28-day repeated
dose oral toxicity study in the rat.

3051. **28-day oral -- dog**

In this non-guideline 28-day oral toxicity study (MRID 46708613), AE
C638206 (Fluopicolide; 96.9% a.i.; Batch Nos. PP241024/2 and PP241067/1)
in 1% (w/v) aqueous methyl cellulose was administered daily via gavage
in a dose volume of 5 mL/kg to 2 beagle dogs/sex/dose group at dose
levels of 0, 10, 100, or 1000 mg/kg/day for at least 28 days.

No unscheduled deaths occurred during the study. There were no effects
of treatment on clinical signs, body weights, body weight gains, food
consumption, ophthalmoscopy, hematology, urinalysis, or histopathology.

In one male at 1000 mg/kg/day: cholesterol was increased on Days 14
(5.56 mmol/L) and 29 (7.72 mmol/L) compared to the mean values for this
animal during pre-treatment (3.76 mmol/L) and the mean for the two
control dogs during treatment (3.33 mmol/L). Additionally in this dog:
absolute liver weight was increased by 34% over the mean of the two
control dogs; relative (to body) liver weight was increased by 44% over
the control mean; and liver enlargement was noted in all lobes at
necropsy. There were no treatment-related microscopic findings in the
liver. Therefore, the minor increases in cholesterol, liver weights, and
liver enlargement in this male are not considered adverse. The increased
liver weights and the liver enlargement noted in this animal may be
indicative of an adaptive response to the test material.

**The LOAEL was not observed. The NOAEL is 1000 mg/kg/day (limit
dose).**

This 28-day repeated dose oral toxicity study in dogs is classified
**acceptable/non-guideline**.

**870.3100 90-Day Oral Toxicity -- Rat**

In a 90-day oral toxicity study (MRID 46474112) Fluopicolide (Lot \# AE
C638206 00 1C99 0005; 97.2% a.i.) was administered to groups of 10 male
and 10 female Sprague Dawley rats in a diet containing 0, 100, 1400 or
20,000 ppm (equivalent to 0, 7.4, 109 or 1668 mg/kg/day for males, and
8.4, 119 or 1673 mg/kg/day for females) for 13 weeks. Ten additional
rats/sex from the control and high dose group were maintained on control
diet for a further four weeks to determine the reversibility of any
effects seen.

Two nontreatment-related mortalities were noted in the high dose group.
Body weight gain over the course of the 20,000 ppm treatment was reduced
by 41% in males and 29% in females, while the corresponding mean food
consumption was reduced by 22% and 19% (p\<0.01). Body weight gain was
dramatically affected the first week of the study as evidenced by
essentially no weight gain at the highest dose as compared to controls
that gained an average of 58 g for males and 39 g for females. Reduced
food consumption was also most dramatic during this week at about 50%
for both sexes. Water consumption was 43% higher for females relative to
the controls (p\<0.01) during this same time frame and was somewhat
higher for the remainder of the study. An increase in urinary volume and
a slight decrease in specific gravity was observed in females only which
corresponds to the increased water intake. No toxicologically relevant
hematological or clinical chemistry findings were noted. Microscopic
examination showed a minimal to slight hypertrophy of the zona
glomerulosa in the adrenal of 17/20 of the rats at the highest dose
level compared to one of each sex in the controls, and minimal changes
were seen in 3/10 females at the 1400 ppm level. Minimum to slight
trabecular hyperostosis of the bone joint was observed in 7/10 males and
all females at the 20,000 ppm level compared to 0/10 males and 3/10
females in the control group. Decreased cellularity of the bone marrow
was observed for 7/10 males and 9/10 females at 20,000 ppm, and in 8/10
females at 1400 ppm compared to 0/10 males and 1/10 females in the
control group. No treatment-related effects were observed at the 100 ppm
dose level.

Following the four week off-dose period there was a complete or partial
recovery of all treatment-related effects.

**The LOAEL is 20,000 ppm in the diet (1668 mg/kg/day) for males based
on hypertrophy of the zona glomerulosa in the adrenal, trabecular
hyperostosis of the bone joint, and decreased cellularity of the bone
marrow. The LOAEL for females is 1400 ppm in the diet (119 mg/kg/day)
based on** **hypertrophy of the zona glomerulosa in the adrenal and
decreased cellularity of the bone marrow. The NOAEL is 1400 ppm (109
mg/kg/day) for males and 100 ppm (7.9 mg/kg/day) for females.**

This 90-day oral toxicity study in the rat is **Acceptable/Guideline**
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in the rat.

**870.3100 90-Day Oral Toxicity -- Mouse**

In a 90-day oral toxicity study (MRID 46474114), Fluopicolide (96.9%
a.i., batch/lot #AE C638206 00 1C99 0005) was administered to10 Crl:
CD-1 (ICR) BR mice/sex/dose in diet at concentrations of 0, 32, 320,
3200, or 6400 ppm (equivalent to 0, 5.5, 53, 545, or 1092 mg/kg bw/day).

There were no compound related effects on mortality, clinical signs of
toxicity or measured hematological parameters. The overall body weight
gain was reduced by 22%-32% in females at 3200 ppm and 20% in males at
6400 ppm. At 3200 ppm, there were statistically significant increases in
alanine aminotransferase activity in males and females (79%-98% and
116%-147%, respectively), and in aspartate aminotransferase (39%-69%)
activity in males. A statistically significant increase was also noted
at 6400 ppm in alkaline phosphatase activity (106%) in males.

At 3200 ppm, both absolute and relative liver weights increased (33%-60%
and 36%-78%, respectively) in both sexes. The microscopic examination
revealed hepatocellular hypertrophy in all males of the top two dose
groups, all females in the 6400 ppm dose group, and 9/10 females in the
3200 ppm dose group. These findings were accompanied by the presence of
slight focal hepatocytic necrosis in 2/10 females at 3200 ppm and 3/10
males and 3/10 females at 6400 ppm. Minimal to slight centrilobular
hepatocytic hypertrophy in the liver was also seen in 9/10 males and
minimal hypertrophy in 1/10 females at 320 ppm. **A LOAEL was not
identified in this study. The NOAEL is the highest dose tested, 6400 ppm
(1092 mg/kg/day).**

This 90-day oral toxicity study in the mouse is
**Acceptable/Guideline,** and satisfies the guideline requirement for a
90-day oral toxicity study (OPPTS 870.3100; OECD 408) in mice.

In a 90-day oral toxicity study (MRID 46474116, summarized in MRID
46474115), AE C638206 (Fluopicolide, 95.9% a.i., Batch \# OP2050046) was
administered to 10 C57BL/6JICO mice/sex/dose in the diet at
concentrations­ of 0, 50, 200, 800, or 3200 ppm (approximately 10.4,
37.8, 161, or 770 mg/kg/day for males and 12.6, 52.8, 207, or 965
mg/kg/day for females, respectively). Doses were selected based on
previous results from a 90-day mouse dietary study with AE C638206 using
Crl:CD1 (1 CR) Br mice (MRIDs 46474114 and 46474113).

There were nine deaths that appeared unrelated to treatment (no
dose-response relationship). There were no adverse effects on clinical
signs or neurological parameters noted for the surviving animals.
Although body weight of males and females in the 3200 ppm group was
lower by 7-10% early in the study, final mean body weights were
comparable with the controls (both 97% of controls). The overall weight
gain was slightly reduced in males in the 800 and 3200 ppm groups and in
females in the 3200 ppm group (86-93% of control gain). There were some
clinical chemistry variations such as slight decreases in the
concentration of albumin and total cholesterol in animals treated with
800 ppm of AE C638206 and slightly increased alkaline phosphatase enzyme
activity in males in the 3200 ppm group.

There was a slight dose-related increase in absolute (110 - 125% of
control) and relative (114 - 130% of control) liver weight in animals
treated with 800 ppm of AE C638206. These weight changes were associated
with a diffused centrilobular hepatocellular liver hypertrophy.
Microscopic examination revealed this lesion in 4/8 and 8/8 surviving
male mice (control: 0/8) and in 8/9 and 10/10 surviving female mice
(control: 0/8) at 800 and 3200 ppm of AE C638206, respectively. In
addition, there was a dose-related increase in liver oval cell
proliferation in females: 2/9, 2/9, 3/10, 4/9, and 8/10 in the control
through the high dose groups, respectively. The toxicological
significance of dark coloration of the liver in 4/8 males and 9/10
females treated with 3200 ppm was not determined.

**Under the conditions of this study, the LOAEL for AE C638206 in male
mice is not established; the LOAEL for female is 3200 ppm based on liver
oval cell proliferation. The NOAEL for AE C638206 in male mice is 3200
ppm and for female mice is 800 ppm.**

This 90-day oral toxicity study in the mouse is
**Acceptable/Guideline,** and satisfies the guideline requirement for a
90-day oral toxicity study (OPPTS 870.3100; OECD 408).

**870.3150 90-Day Oral Toxicity -- Dog**

In a subchronic oral toxicity study (MRID 46474118) AE C638206 (97.7%,
Lot Nos. PP/241024/2 and PP/241067/1) was administered to 4 beagle
dogs/sex/dose by oral gavage at concentrations of 0, 5, 70 and 1000
mg/kg/day for 13 weeks.

There were no significant compound-related effects on mortality,
clinical signs, food consump­tion, food efficiency, body weight/body
weight gain, opthalmoscopic examinations, urinalysis, hematology,
clinical chemistry, organ weight, gross pathology or histopathology.
Increased liver weight in males and females receiving 1000 mg/kg/day AE
C 638206 was considered an expo­sure-related effect, however, there were
no correlative changes in clinical pathology or histo­patho­logy. A
marginal effect on body weight gain was also seen in males and females
dosed with 70 and 1000 mg/kg/day.

**A LOAEL was not determined for AE C638206 in male and female dogs in
this study. The NOAEL was 1000 mg/kg/day, the highest dose
administered.**

This 90-day oral toxicity study in the dog is **Acceptable/Guideline**
and satisfies the requirement for a 90-day oral toxicity study (OPPTS
870.3150; OECD 409) in a non-rodent.

**870.3200 21/28-Day Dermal Toxicity -- Rat**

In a 28-day dermal toxicity study (MRID 46708614) AE C638206
(fluopicolide; 97.7% a.i., Batch \# 2050190/PP241024/2) was applied to
the shaved skin of 10 Wistar rats/sex/dose at dose levels of 0, 100,
250, 500, or 1000 mg/kg/day (limit dose), 6 hours/day for 5days/week
during a 28-day period.

No compound-related effects were observed in mortality, clinical signs
of toxicity, body weight, body weight gain, food consumption,
ophthalmoscopic exams, hematology, clinical chemistry, absolute or
relative organ weights, or gross or microscopic pathology in either sex.

**The LOAEL was not observed. The NOAEL for local and systemic toxicity
is 1000 mg/kg/day.**

This study is classified as **acceptable guideline** and satisfies the
guideline requirement for a 28-day dermal toxicity study (OPPTS
870.3200; OECD 410) in rats.

**870.3465 90-Day Inhalation -- Rat**

No studies available.

**A.3.2 Prenatal Developmental Toxicity**

**870.3700a Prenatal Developmental Toxicity Study -- Rat**

In a developmental toxicity study (MRID 46474120), AE C638206 (97.6 and
97.8% a.i., lot/batch \# PP/241024/2 & PP241067/1) was administered to
23 female Sprague-Dawley rats/dose by gavage at dose levels of 0, 5, 60,
or 700 mg/kg bw/day from days 7 through 20 of gestation. On gestation
day (GD) 21, dams were sacrificed and subjected to gross necropsy.
Approximately one-half of the fetuses were fixed in alcohol, examined
for external defects, checked for visceral anomalies, and then fixed and
examined for skeleton and cartilage defects. The remaining one-half of
the fetuses were examined for external defects and then examined for
visceral abnormalities by Wilson's slicing technique. The total number
of fetuses examined (number of litters) was 284(22), 291(21), 297(22),
and 274(21) for the 0, 5, 60, and 700 mg/kg bw/day groups, respectively.

Treatment with 700 mg/kg bw/day was only minimally toxic to the pregnant
dams. Mean absolute body weight values were statistically decreased
(p\<0.05) at several time points as compared to controls, but were not
biologically relevant at only 97-98% of control levels. No statistically
significant differences were noted in body weight gain at any intervals.
However, body weight gain over GD 7-21, both corrected and not corrected
for the gravid uterine weight, was bordering on biological significance
at 92% and 88%, respectively, of controls. No significant differences
were noted in clinical signs and feed consumption, or during gross
necropsy.

**Therefore, the maternal toxicity LOAEL for AE C638206 in rats is 700
mg/kg bw/day based on slightly reduced body weight gain, and the
maternal toxicity NOAEL is 60** **mg/kg bw/day.**

No adverse, treatment-related, statistically significant effects on
pregnancy rates, number of corpora lutea, pre- or post implantation
losses, resorptions/dam, fetuses/litter, or fetal sex ratio were
observed in the treated groups compared with the controls. No dams had
complete litter resorption. No treatment-related malformations or
external or visceral variations were observed in any group.

Decreased fetal growth was noted in the high-dose group as evidenced by
significant decreases in mean fetal weight (3.4 g vs. 3.7 g for
controls), crown/rump length (34.8 mm vs. 36.2 mm for controls), mean
placental weight (0.52 g vs. 0.57 for controls), and delays in
ossification of sacral vertebra (arch/centra), sternebra, and 5^th^
metacarpal or 5^th^ metatarsal of the forepaw or hindpaw, respectively.
The high-dose group also had slightly elevated litter incidences of
skeletal defects of the thoracic vertebra (arch: aplasia, dysplasia,
fused, fused with attached rib; 4 fetuses from 3/21 litters affected),
thoracic vertebra (centra: aplasia, dysplasia, fragmented, fused,
dislocated; 10 fetuses from 6/21 litters affected), and ribs (aplasia,
dysplasia, shortened, fused, anlage of only 9; 6 fetuses from 3/21
litters affected) compared to the control incidence of 0/22 litters
affected.

**Therefore, the developmental toxicity LOAEL for AE C638206 in rats is
700 mg/kg bw/day based on delays in fetal growth (decreased fetal
weight, crown/rump length, delays in ossification) and skeletal defects
of the thoracic vertebra, and ribs and the developmental toxicity NOAEL
is 60** **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.

**870.3700a Prenatal Developmental Toxicity Study -- Rat**

In a developmental toxicity study (MRID 46708615), AE C638206
(Fluopicolide; 97.6% w/w, Batch #s PP/241024/2 and PP/241067/1) in 1%
(w/v) aqueous methyl cellulose was administered via gavage to 4 Hsd:
Sprague Dawley rats/dose group at dose levels of 500 or 1000 mg/kg
bw/day at a dose volume of 5 mL/kg from gestation days (GD) 7-20. On GD
21, females were euthanized to perform a cesarean section, and their
uterine contents were examined.

All animals survived until scheduled termination. At 1000 mg/kg/day,
pultaceous feces was observed in 2/4 rats from GD 10 through GD 12 and
in 1/4 rats on GD 13. There were no clinical signs of toxicity in the
500 mg/kg/day group.

Body weight gains were lower than normal throughout the treatment period
at 1000 mg/kg/day. However, the lack of concurrent or historical control
data made interpretation of the data problematic. Weight gain was
comparable prior to treatment (19.6-22.0 g) for GD 1-7. At 500 and 1000
mg/kg/day, respectively, body weight gains were: 7.0 and 3.0 g for GD
7-10; 17.0 and 15.4 g for GD 10-14; 23.5 and 19.3 g for GD 14-17; 31.8
and 12.0 for GD 17-19; and 25.5 and 19.7 g for GD 19-21. Thus, body
weight gains at 1000 mg/kg/day were consistently lower than at 500
mg/kg/day throughout the study. Body weight gains for the overall
treatment period (GD 7-21) were 104.8 g at 500 mg/kg/day and 69.4 g at
1000 mg/kg/day.

Again, the lack of concurrent or historical control data made
interpretation of the food consumption data difficult. It was stated
that food consumption showed a marked initial decrease in the 1000
mg/kg/day group during GD 7-10 and a slight decrease in the 500
mg/kg/day during this interval. During pre-treatment, food consumption
in both groups averaged from 13.3-15.0 g/animal/day during GD 1-4 and
from 18.2-19.7 g/animal/day during GD 4-7. In contrast to the Sponsor's
assertion, food consumption at the beginning of treatment during GD 7-10
(16.5-17.07 g/animal/day) was comparable to these pre-treatment values
(13.3-19.7 g/animal/day) in both dose groups. However, food consumption
during GD 17-19 (19.8 g/animal/day) and 19-21 (20.2 g/animal/day) at
1000 mg/kg/day was lower than the 500 mg/kg/day group during GD 17-19
(25.2 g/animal/day) and 19-21 (22.9g/animal/day). Food consumption was
comparable between the two groups and consistent across time during the
remaining treatment intervals.

There were no abortions, premature deliveries, or dead fetuses in either
group. One animal in the 1000 mg/kg/day group had only a single
implantation site which was empty. This total litter loss was excluded
from all calculations. At 1000 mg/kg/day, the number of early
resorptions (17 total; 5.7/dam) resulted in a post-implantation loss of
31.7%, leaving a total of 28 fetuses (9.3/litter). At 500 mg/kg/day, the
post-implantation loss was 0% because there were no early resorptions,
late resorptions, or fetal deaths, resulting in a total of 52 fetuses
(13.0/litter). The lower number of live fetuses at 1000 mg/kg/day was
reflected in the lower litter weight at this dose (26.9 g) compared to
the 500 mg/kg/day group (40.6 g). Fetal and placental weights and
crown/rump length were only minimally lower at 1000 mg/kg/day compared
to the 500 mg/kg/day group. Because the skeleton was not examined, any
possible delays in ossification could not be assessed. There were no
remarkable external findings in the fetuses.

In summary, the available data indicate that: body weights, food
consumption, and fetal growth were lower at 1000 mg/kg/day than at 500
mg/kg/day; post-implantation loss was higher at 1000 mg/kg/day than at
500 mg/kg/day; and incidences of pultaceous feces were noted at 1000
mg/kg/day. Thus, the reviewers conclude that the high dose in the
definitive developmental toxicity study in the rat should be between 500
and 1000 mg/kg/day. However, the reviewers considered it inappropriate
to determine a NOAEL and LOAEL based on the lack of a control group and
the fact that only two dose groups were employed.

This range-finding study is classified as **acceptable/non-guideline**.

**870.3700b Prenatal Developmental Toxicity Study -- Rabbit**

In a developmental toxicity study (MRID 46474122) AE C638206
\[Fluopicolide; 97.8% a.i.; batch numbers PP/241024/2 and PP241067/1
(mixed sample)\] was administered to 23 mated female Chbb:HM(SPF)
Kleinrusse (Himalayan) rabbits/dose by gavage in 1% (w/v)
methylcellulose in deionized water at dose levels of 0, 5, 20, or 60
mg/kg bw/day on gestation days (GDs) 6 through 28, inclusive. On GD 29,
the surviving dams were sacrificed and necropsied. Gravid uterine
weight, corpora lutea counts, and the numbers and positions of live and
dead fetuses, early resorptions and late resorptions, empty implantation
sites and "conceptuses" were recorded. Fetuses were weighed, measured
crown-to-rump, subjected to external, visceral, and skeletal
examinations, including cross-sectioning of the eyes, brain, heart, and
kidneys. The number of fetuses (litters) examined in the control, low-,
mid-, and high-dose groups was 157 (22), 132 (20), 147 (21), and 32 (5),
respectively.

Treatment-related clinical signs included deaths of 3 high-dose animals
(on GDs 24, 25, and 29) following hypoactivity, decreased defecation
and/or decreased hay consumption over the preceding 1-5 days; one
decedent also had a bristling haircoat and red discoloration of the
urine on the day prior to death. Fifteen high-dose animals aborted or
delivered prematurely (during GD 22-28); five of these also showed
hypoactivity, decreased defecation, decreased hay consumption, abnormal
("pultaceous") feces, and/or red discoloration of the urine. One
surviving high-dose animal had increased salivation on GD 14. At the
highest dose level, there were treatment-related decreases in body
weight gain during GD 10-23 (approximately 54-70% of the control levels)
and mean weight loss by this group during GD 23-29 (-41.4 g. vs. +123.6
g. for controls). Mean daily food consumption of the high dose-animals
(in g/100 g bw) was decreased to 73-89% of controls during GD 8-23 (n.s)
and to 46-57% of controls during GD 23-29 (p\<0.05). Red discoloration
of the urine was noted from two additional high-dose animals at necropsy
for a total of five affected (3 in life and 2 post mortem); this finding
is considered treatment-related and possibly adverse.

**The maternal LOAEL** **for Fluopicolide in Himalayan rabbits is 60
mg/kg bw/day, based on death, abortions/premature deliveries, decreased
food consumption, and decreased body weight gain. The maternal NOAEL is
20 mg/kg bw/day.**

At the highest dose level, there were significant decreases in mean
fetal crown-rump length (94% of controls; p\<0.05) and mean fetal weight
(86%; p\<0.05). There were no treatment-related effects on live litter
size, numbers of dead fetuses or resorptions, or postimplantation loss.
Fetal sex ratio and placental weight were not affected by treatment.
There were no treatment-related increases in the fetal or litter
incidences of major or minor defects, variations, or retardations, and
no evidence of altered ossification was seen.

**The developmental LOAEL for Fluopicolide in Himalayan rabbits is 60
mg/kg bw/day, based on abortions, premature deliveries, and decreased
fetal body weight and crown-rump length. The developmental NOAEL is 20
mg/kg bw/day.**

This developmental toxicity study in the rabbit is classified
**Acceptable/Guideline** and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700b; OECD 414) in the rabbit.
Excessive maternal toxicity was seen at the highest dose level; however,
the dose levels were appropriately spaced, and the small number of
litters did not preclude the evaluation of the potential developmental
toxicity of fluopicolide.

**870.3700b Prenatal Developmental Toxicity Study -- Rabbit**

In a range-finding developmental toxicity study (MRID 46708616), AE
C638206 (Fluopicolide; 97.6-97.8% w/w, Batch #s PP/241024/2 and
PP/241067/1) in 1% (w/v) aqueous methyl cellulose was administered daily
via oral gavage to 4 Himalayan rabbits/dose group at dose levels of 25,
50, 100, 250, 500, or 1000 mg/kg bw/day at a dose volume of 5 mL/kg from
gestation days (GD) 6-28. On GD 29, females were euthanized to perform a
cesarean section, and their uterine contents were examined.

At 100 mg/kg/day, one female was killed following abortion on GD 22. All
remaining animals in the 100 mg/kg/day groups and above were found dead
or killed moribund between GD 13 and 23. Prior to death, these animals
exhibited general clinical signs of toxicity, including: uncoordinated
gait/movements, prone position, hypoactivity, hyperactivity, discolored
urine, stupor, coat bristling, ataxia, respiratory sounds, and decreased
defecation and hay consumption.

At 50 mg/kg/day, one animal had decreased defecation on GD 28 and
discoloration in the cage tray on GD 29. This animal aborted on GD 29.
There were no other mortalities, abortions, moribund animals or clinical
signs of toxicity in the 25 and 50 mg/kg/day groups.

It was stated that body weight gains and food consumption were decreased
during the treatment period at 100 mg/kg/day and above. However, the
lack of concurrent or historical control data made interpretation of the
data problematic. During pre-treatment, food consumption in all groups
ranged from 42.8-107.1 g/animal/day during GD 0-3 and from 62.7-104.3
g/animal/day during GD 3-6, and all groups gained weight (30.7-81.8 g)
from GD 0-6. For the first week of treatment (GD 6-13), body weight
gains were -11.7, 30.8, -96.5, -50.0, -124.5, and -198.8 g in the 25,
50, 100, 250, 500, and 1000 mg/kg/day groups, respectively. After this
point, body weight gains in the 100 mg/kg/day groups and above were not
presented due to mortality. Body weight gains for the overall (GD 6-29)
treatment period were 173.3 g at 25 mg/kg/day and 12.5 g at 50
mg/kg/day. Food consumption for GD 6-8 and GD 8-10 was lower at 500 and
1000 mg/kg/day (17.3-34.4 g/animal/day) compared to the remaining groups
(72.6-103.6 g/animal/day). For GD 10-13, food consumption was lower at
100 mg/kg/day and above (2.2-37.2 g/animal/day) compared to the lower
dose groups (87.8-90.4 g/animal/day). A dose-dependent decrease in total
food consumption was evident in all dose groups, with 2540.0, 2106.0,
1015.3, 941.0, 577.8, and 589.5 g/animal/day consumed in the 25, 50,
100, 250, 500, and 1000 mg/kg/day groups, respectively. The apparent
effect on total food consumption at 100 mg/kg/day and above is
confounded by the mortalities in these groups.

**The maternal LOAEL is 50 mg/kg/day based on reduced defecation and
abortion in a single doe. The maternal NOAEL is 25 mg/kg/day.**

The 50 mg/kg/day doe which aborted had 6 dead fetuses. There were no
other findings which could be attributed to treatment. The numbers of
litters, live fetuses, dead fetuses, and resorptions, and
post-implantation loss were similar between the two groups. The litter,
placental, and fetal weights were comparable between the two groups.
There were no remarkable external findings in the fetuses.

**The developmental LOAEL was not observed. The developmental NOAEL is
1000 mg/kg/day (limit dose).**

Based on the 100% mortality in the animals at 100 mg/kg/day and above
and the minimal findings at 50 mg/kg/day, the reviewers conclude that
the high dose in the definitive developmental toxicity study in the
rabbit should be 50 mg/kg/day.

This range-finding study is classified as **acceptable/non-guideline**.

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects -- Rat**

In a two-generation reproduction study (MRID 46474124 and 46474125), AE
C638206 (95.9% a.i., batch/lot \# OP2050046) was administered to 28 F~0~
generation and 24 F~1~ generation male and female Crl:CD®(SD)IGS BR rats
at concentrations of 0, 100, 500, or 2000 ppm. The dietary levels
corresponded to doses of 0, 7.4, 36.4, and 144.6 mg/kg bw/day,
respectively, for F~0~ males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for
F~1~ males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F~0~ females; and
0, 9.4, 46.9, and 193.9 mg/kg bw/day for F~1~ females. The premating
period was 10 weeks. The males received the treated or control diets
continuously until sacrificed when almost all their litters were weaned,
and the females received the diets during premating, mating, gestation,
and lactation until sacrifice after weaning their litters.

No treatment-related effects were observed on survival or clinical signs
in any group of parental male or female rats in either generation.
Absolute body weight and weight gain were significantly decreased but
were within 10% of that of controls in F~0~ and F~1~ males during
premating/postmating periods and in female rats during premating except
as noted below. High-dose F~0~ females gained up to 14% (p\<0.01) less
weight than controls and high-dose F~1~ males weighed 11% (p\<0.01) less
than controls on day 4 of premating because of the significantly
decreased male pup weight at weaning. Food consumption was significantly
decreased during a few weekly intervals in high-dose F~0~ and F~1~ males
and females, but was within 10% of that of controls. Food efficiency was
not significantly affected by treatment of male or female rats in either
generation. No treatment-related effect was observed on body weight,
weight gain, food

consumption, or food efficiency in low- or mid-dose male or female rats
of either generation.

In high-dose pregnant females, body weight was significantly decreased
by 7% on GD 6 and 13 in the F~0~ generation and by 10-11% throughout
gestation in the F~1~ generation compared with that of controls. Both
generations gained 14-16% (p\<0.01) less weight than controls during the
first 13 days of gestation, but weight gain was similar to or greater
than that of controls after GD 13. A 13% decrease in body weight gain in
mid-dose F~0~ females during GD 0-6 was not accompanied by a decrease in
body weight. High-dose F~0~ and F~1~ lactating females had body weight
up to 8% and 13% (p\<0.01) less, respectively, than controls, but weight
gain was not significantly affected. High-dose F~0~ and F~1~ females
consumed up to 12% (p\<0.01) less food than controls during the first 13
days of lactation.

Postmortem evaluation showed treatment-related and toxicologically
significant effects only in the kidneys. High-dose F~0~ and F~1~ males
had small, statistically significant increases in absolute and relative
kidney weights and high-dose F~0~ and F~1~ females had significant
increases in relative kidney weight. No treatment-related gross lesions
were observed in male or female rats in either generation.
Treatment-related and toxicologically significant histopathologic
lesions were observed in the kidneys of high-dose F~0~ and F~1~ male and
female rats. The incidences of cortical tubular basophilia, medullary
granular casts, and cortical scarring were significantly increased in
high-dose F~0~ and F~1~ males compared with the control incidences. The
incidence of interstitial inflammation was significantly increased in
high-dose F~0~ males. The increased incidences of cortical tubular
dilatation and cortical granular casts in high-dose F~1~ males did not
reach statistical significance but were considered treatment related. In
high-dose F~0~ and F~1~ female rats, the incidences of cortical tubular
basophilia and cortical tubular dilatation were significantly increased
and the increased incidence of corticomedullary mineralization was not
statistically significant but was considered treatment related.

**The lowest-observed-adverse-effect level (LOAEL) for systemic toxicity
of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg bw/day in males and
159.7-193.3 mg/kg bw/day in females) based on decreases in weight gain
in F~0~ females and kidney toxicity in F~0~ and F~1~ males and females.
The no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4-43.7 mg/kg
bw/day in males and 41.0-46.9 mg/kg bw/day in females).**

Evaluation of reproductive parameters showed no treatment-related
effects on estrous cycle periodicity or length, sperm measures (motility
or sperm count), precoital interval, gestation length, or reproductive
indices (mating, conception, fertility, and gestation) in either
generation. The numbers of implantation sites and viable litters were
similar in the treated and control

groups in both generations. No treatment-related gross or microscopic
lesions were observed in reproductive organs.

**The lowest-observed-adverse-effect level (LOAEL) for reproductive
toxicity of AE**

**C638206 in rats was not determined; therefore the
no-observed-adverse-effect level**

**(NOAEL) is \>2000 ppm (\>179.9 mg/kg bw/day in males and \>193.3 mg/kg
bw/day in**

**females).**

No treatment-related effects were observed on the behavior or other
clinical signs of offspring of either generation. No treatment-related
effects were observed on litter size, sex ratio, or any survival index
(postimplantation survival, live birth, viability, and lactation
indices) in F~1~ or F~2~ offspring. The day of attainment of sexual
maturation and the body weight at attainment were not affected by
treatment with the test material in male or female F~1~ offspring. Body
weight was significantly reduced by 7-13% in high-dose group F~1~ and
F~2~ male and female pups 14, 21, and 28 days old. Weight gain over the
28-day postnatal period was significantly decreased by 8-9% in high-dose
F~1~ male and female pups and by 11-14% in high-dose F~2~ male and
female pups compared with that of controls due primarily to decreases in
weight gain occurring after

postnatal day 7. Statistically significant changes in organ weights in
F~1~ and F~2~ weanlings

(absolute and/or relative spleen, thymus and/or brain) were not
accompanied by gross lesions in these organs and microscopic
examinations were not conducted.

**The lowest-observed-adverse-effect level (LOAEL) for offspring
toxicity of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg by/day in
males and 159.7-193.3 mg/kg bw/day in females) based on decreases in
body weight and weight gain F~1~ and F~2~ male and female pups. The
no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4--43.7 mg/kg
bw/day for males and 41.0-46.9 mg/kg bw/day in females).**

Kidney toxicity was observed in the parental animals at the high-dose
level; therefore, the

animals in this study were adequately dosed to assess both reproductive
and offspring toxicity.

This study is **Acceptable/Guideline** and it satisfies the guideline
requirement for a two-

generation reproductive study (OPPTS 870.3800); OECD 416 in rats.

**A.3.4 Chronic Toxicity**

**870.4100a (870.4300) Chronic Toxicity -- Rat**

A combined chronic toxicity/carcinogenicity study in rats is included in
section A.3.5 below.

**870.4100b Chronic Toxicity -- Dog**

In a chronic toxicity study (MRID 46474128) AE C638206 (95.9%, Lot No.
OP2050046) was administered to 5 beagle dogs/sex/dose by oral gavage at
concentrations of 0, 70, 300 and 1000 mg/kg/day for 52 weeks.

There were no significant compound-related effects based on mortality,
clinical signs, food consumption, opthalmoscopic examinations,
urinalysis, hematology, clinical chemistry, organ weight, gross
pathology or histopathology. Body weight gain was inhibited in males
treated with 1000 mg fluopicolide/kg/day. Although increased cholesterol
concentrations at the end of the study were statistically significant
and slightly above the historical range in females treated with 1000
mg/kg/day, there were no correlative changes indicating an
exposure-related effect on lipid metabolism in these animals. One female
in the 300 mg/kg/day dosage group died during the study, however, the
death was not conclusively associated with exposure to fluopicolide.

**The LOAEL for** **AE C638206 in male dogs was 1000 mg/kg/day based on
decreased body weight gain. The NOAELs were 300 and 1000 mg/kg/day for
males and females, respectively.**

This chronic study in the dog is **Acceptable/Guideline** and satisfies
the requirement for a chronic oral study \[OPPTS 870.4100, OECD 452\] in
a non-rodent.

**A.3.5 Carcinogenicity**

**870.4200a Carcinogenicity Study -- rat**

In a combined chronic toxicity/carcinogenicity study (MRID 46474139), AE
C638206 (Fluopicolide, 95.9%, a.i.; Batch No. OP2050046) was
administered to 60 Crl:CD (SD) IGS BR rats/sex/dose in the diet at
concentrations of 0 (controls), 50, 200, 750 or 2500 ppm (equivalent to
0, 2.1, 8.4, 31.5 or 109.4 mg/kg bw/day in males and 0, 2.8, 10.8, 41.0
or 142.2 mg/kg bw/day in females) for up to 104 weeks. An additional 20
animals/sex/dose were administered the same concentration and sacrificed
after 52 weeks of treatment for a interim sacrifice. A third set of 10
animals/sex/dose were fed the treated diet at the same concentrations
for 52 weeks followed by 13 weeks of being fed basal diet prior to
sacrifice in a recovery study. A report, MRID 46474138, which consisted
of a summary of the study profile was provided as an additional source
of information.

Statistical analysis showed no increased incidence of mortality in any
of the treated groups compared to controls. The only clinical signs
observed were in the females rats and consisted of yellow perigenital
staining, brown staining of the pinna and brown staining of the dorsum.
Statistical significance was not evaluated for these clinical signs.
Yellow perigenital staining and the brown staining of the pinna was
observed primarily in the 2500 ppm females in the main study with these
signs beginning around week 13 and increasing to weeks 47-53 when they
were observed in 21-31% of the females at 2500 ppm. Both effects then
started to diminish and were

seen in few animals (\<5%) by the end of the second year. Similar
results were observed in the 52 week study. Brown staining of the dorsum
was observed but was not seen in a concentration-related increase,
affecting controls as well as treated females. These clinical signs
appear to be of low toxicological significance due to a lack of
corresponding urinalysis, clinical chemistry or histopathology effects
identified, and they were transient with most effects minimizing after
the first year. While palpable masses were observed and monitored, there
was not a treatment-related increase in the incidence of these masses.

There was no statistically significant difference in body weight in any
of the treated groups. A statistically significant (p\< 0.05 or p\<0.01)
decrease in mean body weight gain was observed in weeks 0-1 in both
studies at the highest dose in males (33%) and females (28%), compared
to controls. In the main study, a statistically significant (p\<0.01)
decrease was also seen in the females at 200 (20%) and 750(32%) ppm
groups. The only significant decrease in body weight gain in weeks 1-2
of the main study was in males at 2500 ppm and females at 50 and 2500
ppm, and these gains were decreased 11% in the males and 15 and 42% in
the females, respectively, compared to controls. After this time, body
weight and body weight gain remained lower than controls (n.s.) with the
overall body weight gain of the 2500 ppm group being 11% and 17% less
than controls in the males and females, respectively. In the animals
dosed for 52 weeks, the similar effect of decreased body weight gain in
the highest dosed males and females was

observed with statistical significance in the first 2 weeks. Both male
and female rats had

comparable body weight gain by the end of the recovery period. A
corresponding decrease in

food consumption and food efficiency was observed in the highest dosed
group of males and females during the first two weeks of treatment;
however, statistical analysis was not included in the report.

Statistical differences in hematology and clinical chemistry were not
toxicologically significant. Those observed were minor, sporadic and did
not have a clear treatment-related association.

Statistically significant increases (p\<0.01 or 0.05) in relative (to
body weight) and absolute kidney (122- 137%), thyroid (154-163%) and
liver (122-134%) weights were observed in the males at 2500 ppm in the
main study. These same increases were observed in the males at 2500 ppm
in the 52 week study, except for absolute kidney weight. Females at 2500
ppm in the 52 week study had statistically significant increases in
relative, but not absolute, liver and kidney weights; this was
associated with a significant decrease in terminal body weight.

Males had a statistically significant increase in the incidence of and
severity of non-neoplastic microscopic lesions in the thyroid, kidney
and liver in the main study. A corresponding increase (p\< 0.05) in the
incidence of enlarged kidneys and thyroids were present in the males at
2500 ppm compared to controls on gross observation. On histopathological
examination, an increased incidence of thyroid cystic follicular
hyperplasia was present in the males and observed in 0/60, 1/37, 0/37,
4/35 and 7/60 (p \< 0.05) in the controls, 50, 200, 750 or 2500 ppm
males. Lesions in the kidney were those associated with the alpha
-2u-globulin accumulation normally present in male aged rats and are not
considered adverse or applicable to human risk assessment. The liver
effect, centrilobular hepatocyte hypertrophy, observed both at 52 and
104 weeks was considered to be an adaptive change due to treatment.
During the recovery period, all lesions present were reversed except for
a slight increase in the severity of the renal cortical tubular
basophilia in the males. Females had no statistically significant
differences in lesions in any of the dose groups in either the toxicity
or the main study.

**The lowest-observed-adverse effect level (LOAEL) for AE C638206 in
rats is 2500 ppm (109.4 and 142.2 mg/kg/day for males and females,
respectively) based on decreases in body weight gain (M and F) and an
increase in thyroid organ weight with corresponding increases in the
incidence of thyroid lesions (M only). The no-observed-adverse effect
level (NOAEL) for AE C638206 is 750 ppm (31.5 and 41.0 in males and
females, respectively).**

At the doses tested, there was not a treatment related increase in tumor
incidence of any type in animals dosed with up to 2500 ppm AE C638206
for up to 104 weeks. Dosing was considered adequate based on the
decreased body weight gain in the male and female rats at 2500 ppm, and
the non-neoplastic lesions observed at 2500 ppm in males. While effects
were minimal in the female, a reproductive study, MRID 46474124 (main
study) and 46474125 (supplemental study histopathological evaluation of
liver and kidneys) indicated kidney toxicity (microscopic

lesions) in male and female rats in both parental generations and
decreased body weight

gain in the F~0~ females treated with AC638206 for 16 weeks at 2000 ppm
indicating adequate dosing in this study at 2500 ppm.

This chronic/carcinogenicity study in the rat is
**Acceptable/Guideline** and satisfies the guideline requirement for a
chronic/carcinogenicity study \[(OPPTS 870.4300); OECD 453\] in rats.

**870.4200b Carcinogenicity (feeding) -- Mouse**

In a carcinogenicity study (MRID 46474130) AE C638206 (Fluopicolide)
(95.9% a.i., batch #OP2050046) was administered to 50 C57BL/6
mice/sex/dose in the diet at dietary levels of 0, 50, 400, or 3200 ppm
(equivalent to 0, 7.9, 64.5, 551.0 mg/kg bw/day for males, and 0, 11.5,
91.9, and 772.3 mg/kg bw/day for females) for 18 months. Satellite
groups of 10 C57BL/6 mice/sex/dose were similarly treated for 12 months.
Historical control incidences of hepatocellular lesions were provided
(MRID 46474135).

The incidence of mortality and clinical signs was similar in treated and
control groups. Body weights and body weight gains of only the 3200 ppm
animals were significantly decreased throughout the study. After 78
weeks, the body weight of 3200 ppm males was 20% lower and of females
was 16% lower than of the control group, and overall body weight gains
were 45% lower for males and 35% lower for females. Food consumption was
decreased in the 3200 ppm satellite and main group animals up to 18%
throughout the study. The overall (week 1-78) food efficiency was
decreased 40% for males and 30% for females at 3200 ppm. Hematology
evaluations were not conducted, and there were no treatment-related
changes in serum enzyme activities. After 52 weeks, absolute and
relative liver weights were significantly increased in 400 ppm males
(15-30%), and in 3200 ppm males and females (35-99%). After 78 weeks,
liver weights were increased in both sexes at 400 ppm (15-33%) and 3200
(46-81%). At both 400 and 3200 ppm, the liver weight increases were
correlated with a significant increase in the incidence of hepatocyte
hypertrophy after 52 and 78 weeks, in males and females. The hypertrophy
is likely a non-specific adaptive response to a xenobiotic and is not
considered adverse. The 3200 ppm animals had statistically significant
increases in the incidence of enlarged liver and altered liver cell foci
(most common type was acidophilic) after 78 weeks, and a non-significant
increase after 52 weeks (2/10 for each lesion).

**The LOAEL for AE C638206 in mice is 3200 ppm for both sexes (551.0
mg/kg/day for males, 772.3 mg/kg/day for females), based on severely
decreased body weights and body weight gains and liver lesions in both
sexes. The NOAEL is 400 ppm in both sexes (64.5 mg/kg/day for males,
91.9 mg/kg/day for females).**

At the doses tested, there was a treatment related increase in the
incidence of hepatocellular adenoma when compared to controls. The 3200
ppm animals had statistically significant increases in hepatocellular
adenoma in both sexes after 78 weeks, and a small increase after 52
weeks. The adenoma incidence after 78 weeks at 0, 50, 400 and 3200 ppm
was 5/50, 0/50, 5/50, and 11/50, respectively, for males, and 1/50,
2/50, 0/50, and 16/50, respectively, for females. After 52 weeks,
hepatocellular adenoma was found in 3/10 high-dose females but no males.
The adenomas were correlated with an increased incidence of liver masses
and nodules at necropsy. Dosing was considered adequate based on
decreased body weight gains, decreased food efficiency, and liver
lesions seen in both sexes at the high dose.

This carcinogenicity study is **Acceptable/Guideline** and satisfies
guideline requirements for a carcinogenicity study \[OPPTS 870.4200b;
OECD 451\] in mice.

**A.3.6 Mutagenicity**

**Gene Mutation**

+-----------------------+----------------------------------------------+
| Guideline 84-2,       | dose range: 1.6 to 5000 µg/plate             |
| Reverse gene mutation |                                              |
|                       | **No increases in revertant colonies were    |
| MRID 46474146         | found in either test series at               |
|                       | concentrations up to the limit dose, 5000    |
| U                     | µg/plate. Therefore, AEC638206 00 IC99 0005  |
| nacceptable/guideline | is considered nonmutagenic in the            |
|                       | conventional battery of bacterial strains.** |
|                       |                                              |
|                       | This study was considered                    |
|                       | unacceptable/guideline because purity        |
|                       | information for the test material was not    |
|                       | provided.                                    |
+-----------------------+----------------------------------------------+
| Guideline 84-2,       | dose range: 1.6 to 5000 µg/plate             |
| Reverse gene mutation |                                              |
|                       | **No increases in revertant colonies were    |
| MRID 46474202         | found in either test series at               |
|                       | concentrations up to the limit dose, 5000    |
| acceptable/guideline  | µg/plate. Therefore, AEC638206 00 IC99 0001  |
|                       | is considered nonmutagenic in the            |
|                       | conventional battery of bacterial strains.** |
+-----------------------+----------------------------------------------+
| Guideline 84-2,       | dose range: 1.6 to 5000 µg/plate             |
| Reverse gene mutation |                                              |
|                       | **No increases in revertant colonies were    |
| MRID 46474148         | found in either test series at               |
|                       | concentrations up to the limit dose, 5000    |
| acceptable/guideline  | µg/plate. Therefore, AEC638206 00 IB99 0002  |
|                       | is considered nonmutagenic in the            |
|                       | conventional battery of bacterial strains.** |
+-----------------------+----------------------------------------------+
| Guideline 84-2,       | dose range: 1.6 to 5000 µg/plate             |
| Reverse gene mutation |                                              |
|                       | **No increases in revertant colonies were    |
| MRID 46474144         | found in either test series at               |
|                       | concentrations up to the limit dose, 5000    |
| acceptable/guideline  | µg/plate. Therefore, AEC638206 Technical is  |
|                       | considered nonmutagenic in the conventional  |
|                       | battery of bacterial strains.**              |
+-----------------------+----------------------------------------------+
| Guideline 84-2,       | dose range: 5 to 5000 µg/plate               |
| Reverse gene mutation |                                              |
|                       | **AE C638206 (fluopicolide) is considered    |
| MRID 46474142         | mutagenic at precipitating concentrations in |
|                       | the conventional battery of bacterial        |
| acceptable/guideline  | strains.**                                   |
+-----------------------+----------------------------------------------+

**Cytogenetics**

+-----------------------+----------------------------------------------+
| Guideline 84-2, *in   | 1.2 to 3820 µg/mL, 0.4 to 120 µg/mL and      |
| vitro* mammalian      | 0.313 to 60 µg/mL with and without           |
| cells in culture/gene | activation                                   |
| mutation assay in     |                                              |
| Chinese hamster lung  | **No concentration in any of the three       |
| cells                 | experiments was a biologically relevant,     |
|                       | reproducible increase in mutant colonies     |
| MRID 46474204         | found at concentrations up to the highest    |
|                       | subcytotoxic levels. Both positive controls  |
| Acceptable/guideline  | showed marked increases.**                   |
+-----------------------+----------------------------------------------+
| Guideline 84-2, *in   | 1.25 to 625 µg/mL without activation and     |
| vivo* mammalian       | 4.88 to 625 µg/mL with activation            |
| chromosome            |                                              |
| aberrations           | **In the presence of ≥50% reduction in the   |
|                       | MI, no statistically significant increases   |
| MRID 46474208         | in the structural or numerical (polyploidy)  |
|                       | aberrant metaphases were found at any test   |
| Acceptable/guideline  | concentration in either trial, compared to   |
|                       | marked (p≤0.001) increases in both positive  |
|                       | controls.**                                  |
+-----------------------+----------------------------------------------+
| Guideline 84-2, *in   | 3.2 to 100 µg/mL with and without            |
| vitro* mammalian      | activation; 0.1 to 6.3 µg/mL without         |
| chromosome            | activation                                   |
| aberrations           |                                              |
|                       | **This batch mixture of AE C638206 is        |
| MRID 46474206         | considered a clastogen in the *in vitro*     |
|                       | Chinese hamster lung (V79) cell system in    |
| Acceptable/guideline  | the absence of S9 activation.**              |
+-----------------------+----------------------------------------------+
| Guideline 84-2, *in   | IP injection of 150, 300 or 600 mg/kg/day    |
| vivo* mammalian       |                                              |
| cytogenetics          | **No dose up to the HDT was a significantly  |
|                       | increased number of mPCEs recorded, in the   |
| MRID 46474214         | presence of a statistically increased ratio  |
|                       | of PCEs to NCEs (evidence of interference    |
| Acceptable/guideline  | with erythropoiesis), either when compared   |
|                       | to vehicle controls, or to the laboratory's  |
|                       | 8-year historical control data base. The     |
|                       | positive control registered a marked         |
|                       | increase in mPCEs, in the absence of any     |
|                       | alteration of erythropoietic effects.**      |
+-----------------------+----------------------------------------------+
| Guideline 84-2, *in   | Two oral doses of 200, 600, or 2000          |
| vivo* mammalian       | mg/kg/day, 24 hours apart                    |
| cytogenetics          |                                              |
|                       | **No adverse clinical signs were observed    |
| MRID 46474210         | during the main study. The ratio of          |
|                       | polychromatic to normochromatic erythrocytes |
| Acceptable/guideline  | was unaffected by treatment. Additionally,   |
|                       | at no dose level up to the limit dose, (2000 |
|                       | mg/kg/day), were increased numbers of mPCEs  |
|                       | induced by the test article, compared with   |
|                       | the marked increases observed in CPA-treated |
|                       | cells.**                                     |
+-----------------------+----------------------------------------------+

**Other Genotoxicity**

+-----------------------+----------------------------------------------+
| Guideline (no \#      | 600 or 2000 mg/kg                            |
| given), Unscheduled   |                                              |
| DNA synthesis in      | **There was no evidence (or a dose-related   |
| hepatocytes           | positive response) that unscheduled DNA      |
|                       | synthesis, as determined by radioactive      |
| MRID 46474216         | tracer procedures (nuclear silver grain      |
|                       | counts) was induced at either timed          |
| acceptable/guideline  | sacrifice in rats exposed to the test        |
|                       | material up to the limit dose (2000          |
|                       | mg/kg).**                                    |
+-----------------------+----------------------------------------------+

**A.3.7 Neurotoxicity**

**870.6100 Delayed Neurotoxicity Study -- Hen**

Not required for this chemical.

**870.6200 Acute Neurotoxicity Screening Battery**

In an acute neurotoxicity study (MRID 46474218; summarized in MRID
46474217), groups of fasted, 6- to 7-week old CD rats (10/sex) were
given a single oral dose of AE C638206 (95.9% a.i., batch/lot
#OP2050046) in 1% methylcellulose at doses of 0, 10, 100, or 2000 mg/kg
bw and observed for 15 days. Doses were based on a range-finding study
in which single doses of 50 mg/kg induced behavioral changes (MRID
46474219). Neurobehavioral assessment (functional observational battery
\[FOB\] and motor activity testing) was performed in 10
animals/sex/group pretreatment, on Day 1 (at six hours post-dosing, the
time of peak effect), and on Days 8 and 15. Cholinesterase activity was
not determined. At study termination, 5 animals/sex/group were
euthanized and perfused *in situ* for neuropathological examination. Of
the perfused animals, the control and high-dose groups were subjected to
histopathological evaluation of brain and peripheral nervous system
tissues.

There was no effect of treatment on body weight, body weight gain, food
consumption, food efficiency, brain weight, brain measurements (cerebral
hemispheres), or incidence of gross or microscopic lesions. Lower body
temperature in the high-dose males and females at the time of peak
effect (6 hours post-dosing) on the day of treatment (Day 1) was the
only treatment-related observation during the FOB. This sign was not
observed on Days 8 or 15. A statistically significant decrease in
forelimb grip strength in females in the 2000 mg/kg group on Day 8,
reduced motor activity of males in the 2000 mg/kg treatment group on Day
1, and increased motor activity in females in the 2000 mg/kg group on
Day 15 were considered incidental to treatment as these effects were not
clearly dose-related and were not observed in the other sex.

**The LOAEL for AE C638206 in male and female rats was 2000 mg/kg, based
on the transient effect of lower body temperature. The NOAEL for male
and female rats was 100 mg/kg.**

This neurotoxicity study is classified as **Acceptable/Guideline,** and
satisfies the guideline

requirement for an acute neurotoxicity study in rats (870.6200; OECD
424) provided positive

control neuropathology data are submitted by the conducting laboratory.

**870.6200 Subchronic Neurotoxicity Screening Battery**

In a subchronic neurotoxicity study (MRID 46474221), Technical Grade AE
C638206 (97.8% a.i., Batch \# OP2050046) was administered to 10 CD
rats/sex at dietary concentrations of 0, 200, 1400, or 10,000 ppm for 13
weeks. Time-weighted average doses were 0, 15.0, 106.6, or 780.6
mg/kg/day, respectively, for males and 0, 18.0, 125.2, or 865.8
mg/kg/day, respectively, for females. Neurobehavioral assessment
(functional observational battery \[FOB\] and motor activity testing)
was performed on all animals pre-test and at weeks 4, 8, and 13. At
study termination, 6 animals/sex/group were euthanized and perfused in
situ for neuropathological examination. Of the perfused animals, control
and high-dose rats were subjected to histopathological evaluation of
brain and peripheral nervous system tissues. Positive control data for
FOB and motor activity testing were submitted in MRID 46474222 and were
summarized in MRID 46474220.

All animals survived to scheduled sacrifice. No treatment-related
clinical signs of toxicity or gross lesions were observed in any group.
FOB findings and motor activity were similar between the treated and
control groups.

Mean body weight of the low-dose males and females was similar to the
controls throughout the study. Mid- and high-dose males and females had
slightly lower body weight than that of the control group beginning at
week 1 but these data were not analyzed statistically. Overall body
weight gain by the high-dose males and females and mid-dose females was
81%, 72%, and 87% (p  0.05 or 0.01), respectively, of the respective
control levels. The most pronounced effect on body weight gain in the
high-dose groups was during weeks 0-1 when males and females gained 56%
and 63%, respectively, of the control level. Weight gain by the mid-dose
groups appeared to be consistently less than that of controls at each
weekly interval. Food consumption by the high-dose males and females was
slightly less than that of the controls for most weekly intervals of the
study. Excessive food scatter was observed by the mid- and high-dose
males and by all treated female groups. Overall food conversion
efficiency by the high-dose males and females and mid-dose females was
87%, 79%, and 89%, respectively, of the respective control levels. The
most pronounced effect on food efficiency in the high dose groups was
during week 1 when males and females were 62% and 69%, respectively, of
the control level.

Treatment-related lesions observed in the liver (hypertrophy) of males
and females and the male kidney (hyaline droplets) were not considered
adverse or relevant to humans.

**Therefore, the systemic and neurotoxicity LOAEL for AE C638206 in male
and female rats is 10,000 and 1400 ppm, respectively (780.6 and 125.2
mg/kg/day for males and females, respectively) based on decreased body
weight gain, food consumption, and food efficiency. The NOAEL for males
and females was 1400 and 200 ppm, respectively (106.6 and 18.0 mg/kg/day
for males and females, respectively).**

The study is classified as **Acceptable/Guideline** and does satisfy the
guideline requirement for a subchronic neurotoxicity study in rats
(870.6200b) provided positive control neuropathology data are submitted
by the conducting laboratory.

**870.6300 Developmental Neurotoxicity Study**

Not required for this chemical.

**A.3.8 Metabolism**

**870.7485 Metabolism - Rat**

Five studies (MRIDs 46474226, 46474239, 46474241, 46474242, and
46474244) were conducted to examine the metabolism and disposition of AE
C638206 (fluopicolide) in male and female Sprague-Dawley CD rats
following single doses of \[^14^C-2,6-pyridyl\]-AE C638206 at 10 mg/kg
bw or \[^14^C-2,6-pyridyl\]-AE C538206 and \[^14^C-U-phenyl\]-AE C638206
at 10 and 100 mg/kg bw. Rats were subjected to the dosing regimens above
using \[^14^C-2,6-pyridyl\]-AE C538206 (lot nos. 903AE-3 and GAR
2034-/4; \>99% and 97% radiochemical purity) or \[^14^C-U-phenyl\]-AE
C538206 (lot no. CFQ 12747; 99.1% radiochemical purity) and nonlabeled
test article (batch no. R001737, 99.3% chemical purity). Excretion,
tissue distribu­tion, pharmacokinetics (blood/plasma), and metabolite
profiles were determined. In MRID 46474242, metabolite profiles were
assessed in urine and fecal extracts of male and female rats given a
single oral 10 mg/kg bw dose of \[^14^C-2,6-pyridyl\]-AE C638206 and
sacrificed at 48 hours post-dosing.

There were no biologically significant treatment-related effects noted
during the course of the study. Overall recovery of administered
radioactivity was an acceptable 93.9-103.6%. The data supported the
contention that AE C538206 is readily absorbed and rapidly excreted
within 72 hours following a single oral dose of 10 mg/kg. Fecal
elimination accounted for 68.8-72.4% of the administered radioactivity
whereas urinary excretion accounted for only 18.8-21.4% of the
administered radioactivity. In the bile excretion study (MRID 46474244),
51.7% of the adminis­tered radioactive dose in both sexes was excreted by
the cannulated bile duct indicating a significant portion of the
radioactivity recovered in feces is derived from hepatic metabolism of
AE C638206. Time-course blood/plasma and tissue studies revealed rapid
absorption and distribution of administered radioactivity to all organs
and tissues followed by moderately rapid excretion with reduction to
background levels in most tissues and organs within 72 hours. Tissue
concentrations peaked at 6-7 hours post-dosing and about 96% of the peak
tissue concentrations were dissipated between 6-7 hours and 168 hours
post-dose. Absorption and excretory patterns did not exhibit
gender-related variability, but blood/plasma kinetic studies (MRID
46474226) suggest near-saturation of absorption at the high dose (100
mg/kg bw). Based upon tissue burden data, neither AE C638206 nor its
metabolites appear to undergo any significant tissue sequestration. With
the exception of transiently higher levels in the liver, kidneys, and
intestines during the elimination phase, radioactivity concentrations in
any given tissue consistently represented considerably less than 1% of
the administered dose within 24 hours of administration of AE C638206.

Both urinary and fecal metabolites were quantified by HPLC and most were
identified using HPLC or HPLC/MS in conjunction with known standards.
The major metabolites identified appeared to be oxidative N-dealkylation
cleavage products. Extraction efficiency appeared to be excellent and
most components in both of the matrices examined (urine and feces) were
adequately quantified and characterized. The available data, based upon
studies using \[^14^C-2,6-pyridyl\]-AE C638206, affirmed the metabolism
pathway (Appendix, Figure 1) proposed by the investigators.

These metabolism studies (MRID 46474226, 46474239, 46474241, 46474242,
and 46474244) are, collectively, **Acceptable/Guideline** and satisfy
the requirements for a Metabolism and Pharmacokinetics Study
\[OPPTS 870.7485 (§85-1)\]. The studies were properly designed,
conducted and reported.

**870.7485 Metabolism - Rat**

In a non-guideline metabolite identification study (MRID 46708632), five
pooled urine samples from rats given a single oral dose (amount not
provided) of \[Pyridyl-2,6-^14^C\]AE C638206 (Batch/Lot \# and
radiochemical purity not provided) were analyzed by LC/MS(MS). Urine was
pooled from male rats at 0-6, 6-24, and 24-48 h after administration of
the radiolabeled test substance, while urine from females was pooled at
0-6 and 24-48 h post-administration. Structure proposals of identified
metabolites and corresponding fragmentation schemes and spectra were
generated.

Thirty-six metabolite structures (or sets of alternative structures)
were proposed for all relevant signals of the five urine samples. Six
metabolites identified in a previously performed rat metabolism study
and two metabolites identified in non-animal metabolism studies were
confirmed. Most of the metabolites observed were derivatives of AE
C638206 fitting well with the prior known metabolites, implying cysteine
or *N*-acetyl-cysteine introduction on the phenyl ring from gluthione
conjugation, hydroxylation, or other conjugations. For some compounds
containing no chlorine, polar biomolecules or bioconjugates with no
relationship to the parent instead of the proposed metabolites can not
be excluded.

This metabolite identification study in the rat is classified
**acceptable/non-guideline**.

**870.7485 Metabolism - Rat**

In a metabolism study (MRID 46708636) \[Pyridyl-2,6-^14^C\]-AE C657188
(Batch \# DCR25/1; radiochemical purity 99.0%) suspended in aqueous
0.75% methyl cellulose was administered by oral gavage to four Sprague
Dawley (SD) rats/sex at a dose level of 10 mg/kg. The recovery of
radioactivity over five days was determined, and the concentrations of
radioactivity in tissues and excreta were determined. Metabolites were
identified and quantified in the urine and feces. AE C657188
\[3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid\] is a
significant plant metabolite of fluopicolide (AE C638206); therefore,
the present study was performed to assess the absorption, distribution,
metabolism, and excretion of this compound.

[]{.mark}

Total radioactivity recovered was 93-94% of the administered dose, with
no sex differences observed. The majority of the radioactivity was
recovered in the urine, while feces was a lesser route of elimination.
The minimum levels of absorption were estimated from the total recovery
of radioactivity in urine, cage washes, and tissues. From these, it was
estimated that at least 87% of the administered dose was absorbed,
indicating high oral bioavailability. Very little radioactivity remained
in the tissues 120 h post-dosing. Low levels of radioactivity were only
detected in the residual carcass and the skin and fur. These data did
not suggest bioaccumulation; however, tissue concentrations were assayed
at only one time point.

The test compound was not appreciably metabolized. HPLC analyses of
urine and fecal extract samples resolved up to nine peaks in the urine
and three peaks in the feces; however, only one major peak was detected
in both urine and feces. The retention time of this peak corresponded to
that of unmetabolized parent. This was confirmed by co-chromatography
and MS/MS of the urine and fecal extracts spiked with \[^14^C\]-AE
C657188. Parent accounted for a total of 79-86% of the administered
dose. All other peaks were \<1.4% of the administered dose, and were not
identified.

This metabolism study in the rat is classified **acceptable/guideline**
and satisfies the guideline requirement for a Tier 1 metabolism study
\[OPPTS 870.7485, OECD 417\] in rats.

**870.7485 Metabolism -- Rat**

AE C653711 (2,6-dichlorobenzamide) is a soil metabolite of fluopicolide
(AE C638206) that is taken up into crops to form crop residues;
therefore, the present study was performed to assess the absorption,
distribution, metabolism, and excretion of this compound. In a series of
metabolism studies (MRIDs 46708633, 46708634, and 46708635)
\[Phenyl-U-^14^C\]-AE C653711 (Batch \# SEL/1059; radiochemical purity
\>98%) suspended in aqueous 0.75% methyl cellulose was administered by
oral gavage to three groups of Sprague Dawley rats/sex. Two groups of
four rats/sex were given a single dose of \[^14^C\]-AE C653711 at dose
levels of 10 or 150 mg/kg. A third group of five rats/sex was given 14
daily doses of \[^14^C\]-AE C653711 at a dose level of 10 mg/kg. The
recovery of radioactivity over six days (seven days for the single high
dose group) was determined, and the concentrations of radioactivity in
tissues and excreta were determined. Metabolites were identified and
quantified in the urine and feces.

[]{.mark}

Total recovery ranged from 92.2-98.6% of the administered doses, with no
differences observed between sexes, dose levels, or single or multiple
doses. The majority of the radioactivity was recovered in the urine.
Absorption and excretion of the test compound was relatively rapid. The
minimum levels of absorption were estimated from the total recovery of
radioactivity in urine, cage washes, and tissues to be at least
77.7-85.9% of the administered dose, indicating high oral
bioavailability. Excretion of radioactivity in the urine and feces was
mostly complete by 48 (single low dose study) to 72 (single high dose
and repeat low dose studies) h post-dosing. The tissues (including the
residual carcass) accounted for \<2.2% of the administered dose 144 or
168 h post-dosing. In general, the highest concentrations of
radioactivity were detected in the kidneys, liver, Harderian gland, skin
(and fur), and adrenals.

The test compound was extensively metabolized to at least 18 compounds.
The majority of radioactivity in urine and fecal extract samples was
present as parent and a mercapturic acid conjugate of
hydroxyl-chlorobenzamide. Metabolic profiles were qualitatively similar
across dose levels, multiple doses had no appreciable effect on
metabolism, and generally, no differences were noted between sexes. In
excreta, parent and identified compounds accounted for 50.3-78.6% of the
administered dose. Unidentified metabolites accounted for 8.2-14.6% of
the administered dose, but each compound represented \<5% of the
administered dose. The total administered dose accounted for in the
analyzed excreta was 64.4-90.2%.

Parent compound accounted for 13.0-24.6% of the total radioactivity
eliminated, and was found in both urine and fecal extracts. The majority
of the radioactivity was associated with a mercapturic acid conjugate of
hydroxyl-chlorobenzamide (15-5-26.2%), present in the urine. Other
metabolites present at \>5% of the administered dose were identified,
and included the cysteine and *O*-glucuronide conjugates of
chlorobenzamide (3.4-6.6%), the cysteine conjugate of
hydroxy-chlorobenzamide (1.9-12.4%), the *O*-sulfate conjugate of
dichlorobenzamide/thiomethyl-chlorobenzamide (5.4-13.8%), and
3-hydroxy-chlorobenzamide (2.7-7.3%; detected in the high dose study
only).

This metabolism study in the rat is classified **acceptable/guideline**
and satisfies the guideline requirement for a Tier 1 metabolism study
\[OPPTS 870.7485, OECD 417\] in rats.

**870.7600 Dermal Absorption -- Rat**

In a dermal penetration study (MRID 46708638), \[^14^C-Phenyl\]-AE
C638206 (Fluopicolide; 99.8% radiochemical purity; Batch No. SEL/1200)
in a commercial concentrate (or aqueous dilution of a concentrate for
the low dose) was applied to the skin of 5 male Sprague-Dawley rats/time
point/dose. The dose (1.43 or 659 μg/cm^2^ skin) was applied to 12 cm^2^
skin and removed after 8 hours. The animals were sacrificed at 8, 24,
72, or 144 hours after application. Additionally, 2 male rats/time
point/dose were treated similarly in a preliminary study and were
sacrificed at 24, 72, or 144 hours, except only 1 rat was treated with
the low dose in the 144 hour group.

Recovery of the applied dose was 91-109%. The distribution profile of
radioactivity was qualitatively similar between the two dose groups. The
majority of the administered dose (41-69% of the low dose and 87-91% of
the high dose) was recovered from the swabs used to remove the test
compound from the skin after 8 hours of treatment. A total of 56-81%
(low dose) or 92-95% (high dose) was considered not absorbed. After 144
hours, only 2-7% remained at the dose site and was considered available
for absorption. Estimates of dermal absorption were based on the sum of
urine + feces + cage wash + tissues + treated skin + stratum corneum.
**Dermal absorption ranged from 3-8% (high dose) to 22-37% (low dose)**.
In the main studies, dermal absorption was greatest at 24 hours after
application, but there was no clear evidence for increased dermal
absorption with time at either dose. Although there was not a
time-dependent increase in total dermal absorption at either dose, there
was a time-dependent increase in absorption through the stratum corneum
at the low dose (but not the high dose).

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

In a non-guideline *in vitro* dermal penetration study (MRID 46708637),
\[^14^C-Phenyl\]-AE C638206 (Fluopicolide; 99.8% radiochemical purity;
Batch No. SEL/1200) was applied to excised human and rat skin in a
suspension concentrate formulation (EXP 11120A) at 2 dose
concentrations, 1.9 and 744 μg/cm^2^ skin. Flow-through diffusion cells
were prepared for each skin type at each dose level (n=7/group).
Dermatomed membranes of approximately 300 µm thickness were tested for
permeability prior to treatment. Receptor fluid samples were collected
each hour after treatment for 24 hours. At 8 hours after test compound
application, the skin was swabbed with a mild detergent solution. After
24 hours, the experiment was terminated, and the skin membranes were
tape stripped. The initial 2 tape strips were assumed to represent the
residual (non-absorbed) dose. Subsequent tape strips, the remaining
skin, and the receptor fluid remaining in the cell and outlet tubing at
the end of the experiment were also assayed. Radioactivity was
determined by liquid scintillation counting. Results for 5-7 skin
samples/species/dose were reported.

Total recovery was 92.3-96.5%. The total amounts of applied
radioactivity absorbed within 24 hours at the high dose level were
0.022% in humans and 0.172% in rats, while at low dose levels the
amounts absorbed were 1.454% in humans and 14.26% in rats. Therefore,
**the amount of radioactive material absorbed was 7.8 times greater for
rat skin than for human skin at the high dose level, and 9.8 times
greater for rat skin than human skin at the low dose level.** These data
indicate that dermal penetration studies in the rat will provide a very
conservative estimate of dermal absorption in humans for risk
assessment.

This study is **acceptable/non-guideline**.

**A.3.9 Special/Other Studies**

None.

**Appendix B: Metabolism Assessment**[]{#__RefHeading___Toc185228095
.anchor}

**B.1 Metabolism Guidance and Considerations**
[]{#__RefHeading___Toc185228096 .anchor}

Fluopicolide is a fungicide to be used on tuberous and corm vegetables,
leafy vegetables (except *Brassica*), fruiting vegetables, cucurbit
vegetables, grapes, turf, and ornamental plants. Tolerances have been
proposed for these crops and the rotational crop wheat. Four foliar
applications are to be made to cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables, potatoes, and sweet potatoes at the maximum
seasonal application rate of 0.34-0.375 lb ai/A. Minimum retreatment
intervals of 7-12 days and a preharvest interval of 2-21 days are to be
observed.

2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil. BAM is a
minor metabolite/degradate of fluopicolide. BAM is included in the
tolerance expression for dichlobenil because it is a major
metabolite/degradate of dichlobenil.

HED (Paula Deschamp, Amelia Acierto, Nancy Dodd, Kelly O'Rourke, and
Myron Ottley) and EFED (Thuy Nguyen and James Lin) met on April 12, 2007
to determine the residues to include in the drinking water risk
assessment. It was determined based on two aerobic soil metabolism
studies that the residues to be included in the drinking water risk
assessment are parent fluopicolide and the metabolite/degradate BAM. BAM
was a major metabolite/degradate, present at levels up to 40%.

HED has determined that the residue of concern for the tolerance
expression in the domestic primary plants (cucurbit vegetables, fruiting
vegetables, grapes, leafy vegetables, and tuberous and corm vegetables)
is fluopicolide (parent) as an indicator of combined residues of
fluopicolide and its metabolite 2,6-dichlorobenzamide. For the risk
assessment, the residues of concern in the domestic primary plants
except tuberous and corm vegetables are fluopicolide (parent) and
2,6-dichlorobenzamide (BAM). For tuberous and corm vegetables, the
residues of concern for the risk assessment are fluopicolide (parent),
BAM, and 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA).

As determined by HED, the residue of concern for the tolerance
expression for rotational crops is fluopicolide (parent) as an indicator
of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide. The residues of concern for the risk assessment
are fluopicolide (parent) and BAM for all rotational crops except the
grain of cereal grains used as human food. The residues of concern for
the risk assessment for the grain portion of cereal grain rotational
crops used as human food are fluopicolide (parent), BAM, PCA, and
3-methylsulfinyl-5-fluoromethylpyridine-2-carboxylic acid (P1X; AE
1344122).

The residues of concern in livestock commodities are tentative since
additional information is needed to support the ruminant and poultry
metabolism studies. Pending submission of additional data, HED has
tentatively determined that the residue of concern in livestock
commodities for a tolerance expression is 2,6-dichlorobenzamide (BAM).
For the risk assessment, the residues of concern in livestock
commodities have been tentatively determined to be fluopicolide (parent)
and BAM.

**B.2 Tabular Summary of Fluopicolide and its Metabolites and
Degradates**[]{#__RefHeading___Toc185228097 .anchor}

+--------------+------+-----------+---------+------------------------+
| **Table B.2  |      |           |         |                        |
| Summary of   |      |           |         |                        |
| Fluopicolide |      |           |         |                        |
| and its      |      |           |         |                        |
| Metabolites  |      |           |         |                        |
| and          |      |           |         |                        |
| Degradates** |      |           |         |                        |
+==============+======+===========+=========+========================+
| Chemical     | Ma   | Percent   |         | Structure              |
| Name (other  | trix | TRR (PPM) |         |                        |
| names in     |      | ^1^       |         |                        |
| parenthesis) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              |      | M         | Mat     |                        |
|              |      | atrices - | rices - |                        |
|              |      | Major     | Minor   |                        |
|              |      | Residue,  | R       |                        |
|              |      | [\>]      | esidue, |                        |
|              |      | {.underli | \       |                        |
|              |      | ne}10%TRR | <10%TRR |                        |
+--------------+------+-----------+---------+------------------------+
| 2,6-dichl    | *    |           |         | ![](media/image        |
| oro-*N*-\[\[ | *Pri |           |         | 2.wmf){width="1.875in" |
| 3-chloro-5-( | mary |           |         | height="               |
| trifluoromet | Crop |           |         | 0.7972222222222223in"} |
| hyl)-2-pyrid | s**: |           |         |                        |
| inyl\]methyl |      |           |         |                        |
| \]-benzamide |      |           |         |                        |
|              |      |           |         |                        |
| (f           |      |           |         |                        |
| luopicolide) |      |           |         |                        |
|              |      |           |         |                        |
| (AE C638206) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Gr   | 87.4 -    |         |                        |
|              | apes | 91.2%     |         |                        |
|              | (fr  |           |         |                        |
|              | uit) | (0.910 -  |         |                        |
|              |      | 1.15 ppm) |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 95.9 --   |         |                        |
|              | tuce | 96.4%     |         |                        |
|              |      |           |         |                        |
|              | (ma  | (12.84 -  |         |                        |
|              | ture | 13.98     |         |                        |
|              | lea  | ppm)      |         |                        |
|              | ves) |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Po   | 51.1 --   |         |                        |
|              | tato | 70.2%     |         |                        |
|              | (ma  |           |         |                        |
|              | ture | (0.037 -  |         |                        |
|              | tu   | 0.041     |         |                        |
|              | ber) | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (29  |           |         |                        |
|              | -day |           |         |                        |
|              | PBI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 11.1-     |         |                        |
|              | tuce | 35.8%     |         |                        |
|              |      |           |         |                        |
|              |      | (0.108-   |         |                        |
|              |      | 0.112 ppm |         |                        |
|              |      | )         |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 24.5-     |         |                        |
|              | dish | 51.1%     |         |                        |
|              | top  |           |         |                        |
|              |      | (1.072-   |         |                        |
|              |      | 1.644     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 41.1-     |         |                        |
|              | dish | 47.9%     |         |                        |
|              | root |           |         |                        |
|              |      | (0.048-   |         |                        |
|              |      | 0.069     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 33.7-     |         |                        |
|              | heat | 36.6%     |         |                        |
|              | fo   |           |         |                        |
|              | rage | (1.445-   |         |                        |
|              |      | 1.812     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 27.3%     | 1.8%    |                        |
|              | heat |           |         |                        |
|              | g    | (0.043    | (0.046  |                        |
|              | rain | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 23.1-     |         |                        |
|              | heat | 34.9%     |         |                        |
|              | s    |           |         |                        |
|              | traw | (2.462-   |         |                        |
|              |      | 3.132     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 41.5%     | 2.1%    |                        |
|              | tuce |           |         |                        |
|              |      | (0.024    | (0.013  |                        |
|              |      | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 25.2%     | 3.8%    |                        |
|              | dish |           |         |                        |
|              | top  | (0.106    | (0.076  |                        |
|              |      | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 24.2-     |         |                        |
|              | dish | 55.8%     |         |                        |
|              | root |           |         |                        |
|              |      | (0.       |         |                        |
|              |      | 009-0.018 |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 27.8%     | 4.8%    |                        |
|              | heat |           |         |                        |
|              | fo   | (0.068    | (0.042  |                        |
|              | rage | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 2.9-    |                        |
|              | heat |           | 7.3%    |                        |
|              | g    |           |         |                        |
|              | rain |           | (0.004- |                        |
|              |      |           | 0.005   |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 27.5%     | 7.2%    |                        |
|              | heat |           |         |                        |
|              | s    | (0.277    | (0.172  |                        |
|              | traw | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **   |           |         |                        |
|              | Rumi |           |         |                        |
|              | nant |           |         |                        |
|              | s:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Fat  | 73.4-     |         |                        |
|              |      | 76.3%     |         |                        |
|              |      |           |         |                        |
|              |      | (0.0312-  |         |                        |
|              |      | 0.034     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ki   |           | 1.0-    |                        |
|              | dney |           | 1.8%    |                        |
|              |      |           |         |                        |
|              |      |           | (0.003, |                        |
|              |      |           | 0.003   |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 0.9-    |                        |
|              | iver |           | 2.9%    |                        |
|              |      |           |         |                        |
|              |      |           | (       |                        |
|              |      |           | 0.0055- |                        |
|              |      |           | 0.013   |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Milk | 28.6%     |         |                        |
|              |      |           |         |                        |
|              |      | (0.0054   |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Mu   |           | 2.9%    |                        |
|              | scle |           |         |                        |
|              |      |           | (0.0007 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Po |           |         |                        |
|              | ultr |           |         |                        |
|              | y:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  |           | 2.5%    |                        |
|              | w    |           |         |                        |
|              | hite |           | (0.     |                        |
|              |      |           | 001ppm) |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 10.5- 11% |         |                        |
|              | yolk |           |         |                        |
|              |      | (0.005-   |         |                        |
|              |      | 0.017     |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Fat  | 15.6%     | 6%      |                        |
|              |      |           |         |                        |
|              |      | (0.004    | (0.004  |                        |
|              |      | ppm)      | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| 2,6-dichl    | *    |           |         | ![](me                 |
| orobenzamide | *Pri |           |         | dia/image3.wmf){width= |
|              | mary |           |         | "1.1458333333333333in" |
| (BAM)        | Crop |           |         | height="               |
|              | s:** |           |         | 0.7909722222222222in"} |
| (AE C653711) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Gr   |           | 2.0%    |                        |
|              | apes |           |         |                        |
|              | (fr  |           | (0.026  |                        |
|              | uit) |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 0.9%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.112  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Po   | 25.4%     |         |                        |
|              | tato |           |         |                        |
|              |      | (0.021    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (29  |           |         |                        |
|              | -day |           |         |                        |
|              | PBI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 81.2%     |         |                        |
|              | tuce |           |         |                        |
|              |      | (0.822    |         |                        |
|              |      | pm)       |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 65.3%     |         |                        |
|              | dish |           |         |                        |
|              | top  | (4.381    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 43.2%     |         |                        |
|              | dish |           |         |                        |
|              | root | (0.062    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 6.3%    |                        |
|              | heat |           |         |                        |
|              | fo   |           | (0.312  |                        |
|              | rage |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 3.6%    |                        |
|              | heat |           |         |                        |
|              | g    |           | (0.006  |                        |
|              | rain |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 3.4%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.461  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 87.0%     |         |                        |
|              | tuce |           |         |                        |
|              |      | (0.539    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 87.5%     |         |                        |
|              | dish |           |         |                        |
|              | top  | (1.755    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 60.9%     |         |                        |
|              | dish |           |         |                        |
|              | root | (0.022    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 14.8%     |         |                        |
|              | heat |           |         |                        |
|              | fo   | (0.128    |         |                        |
|              | rage | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 17.9%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.010    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 5.1%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.121  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **   |           |         |                        |
|              | Rumi |           |         |                        |
|              | nant |           |         |                        |
|              | s:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Milk |           | 3.9%    |                        |
|              |      |           |         |                        |
|              |      |           | (0.0007 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Po |           |         |                        |
|              | ultr |           |         |                        |
|              | y:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    | 37%       |         |                        |
|              | iver |           |         |                        |
|              |      | (0.361    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
| 3-chloro-5-  | *    |           |         | ![](me                 |
| trifluoromet | *Pri |           |         | dia/image4.wmf){width= |
| hylpyridine- | mary |           |         | "1.3194444444444444in" |
| 2-carboxylic | Crop |           |         | height="               |
| acid         | s:** |           |         | 0.9208333333333333in"} |
|              |      |           |         |                        |
| (PCA)        |      |           |         |                        |
|              |      |           |         |                        |
| (AE C657188) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Gr   |           | 2.3%    |                        |
|              | apes |           |         |                        |
|              | (fr  |           | (0.024  |                        |
|              | uit) |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 0.6%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.078  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Po   | 12.0%     |         |                        |
|              | tato |           |         |                        |
|              |      | (0.007    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (29  |           |         |                        |
|              | -day |           |         |                        |
|              | PBI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 17.4%     |         |                        |
|              | tuce |           |         |                        |
|              |      | (0.053    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 10.4%     |         |                        |
|              | dish |           |         |                        |
|              | top  | (0.217    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 33.5%     |         |                        |
|              | dish |           |         |                        |
|              | root | (0.039    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 43.0%     |         |                        |
|              | heat |           |         |                        |
|              | fo   | (1.844    |         |                        |
|              | rage | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 69.6%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (1.809    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 7.0%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.494  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 11.8%     |         |                        |
|              | tuce |           |         |                        |
|              |      | (0.007    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 27.1%     |         |                        |
|              | dish |           |         |                        |
|              | top  | (0.114    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   | 10.0%     |         |                        |
|              | dish |           |         |                        |
|              | root | (0.003    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 8.2%    |                        |
|              | heat |           |         |                        |
|              | fo   |           | 0.020   |                        |
|              | rage |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 14.2%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.025    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 4.1%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.042  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| 2,           | *    |           |         | ![](me                 |
| 6-dichloro-* | *Pri |           |         | dia/image5.wmf){width= |
| N*-\[(3-chlo | mary |           |         | "2.0069444444444446in" |
| ro-5-trifluo | Crop |           |         | height="               |
| romethylpyri | s:** |           |         | 0.7493055555555556in"} |
| din-2-yl)met |      |           |         |                        |
| hyl\]-3-hydr |      |           |         |                        |
| oxybenzamide |      |           |         |                        |
|              |      |           |         |                        |
| (AE C643890) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Gr   |           | 0.2%    |                        |
|              | apes |           |         |                        |
|              | (fr  |           | (0.002  |                        |
|              | uit) |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Po   |           | 1.7-    |                        |
|              | tato |           | 2.4%    |                        |
|              |      |           |         |                        |
|              |      |           | (0.00   |                        |
|              |      |           | 1-0.003 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | Crop |           |         |                        |
|              | s(29 |           |         |                        |
|              | -day |           |         |                        |
|              | PBI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 1.4,    |                        |
|              | heat |           | \<1.5%  |                        |
|              | fo   |           |         |                        |
|              | rage |           | (0.060, |                        |
|              |      |           | \<0.074 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 13.1%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.021    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ki   |           | 6.8%    |                        |
|              | dney |           |         |                        |
|              |      |           | (0.0207 |                        |
|              |      |           | ppm)    |                        |
|              |      |           |         |                        |
|              |      |           | 2.6% \* |                        |
|              |      |           |         |                        |
|              |      |           | (0.005  |                        |
|              |      |           | ppm)\*  |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 1.6%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.0105 |                        |
|              |      |           | ppm)    |                        |
|              |      |           |         |                        |
|              |      |           | 4.0%\*  |                        |
|              |      |           |         |                        |
|              |      |           | (0.018  |                        |
|              |      |           | ppm)\*  |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Po |           |         |                        |
|              | ultr |           |         |                        |
|              | y:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 3       |                        |
|              | iver |           | .1%\*\* |                        |
|              |      |           |         |                        |
|              |      |           | (0.030  |                        |
|              |      |           | p       |                        |
|              |      |           | pm)\*\* |                        |
+--------------+------+-----------+---------+------------------------+
| 2,6-dic      | **Ro |           |         | ![](me                 |
| hloro-3-hydr | tati |           |         | dia/image6.wmf){width= |
| oxybenzamide | onal |           |         | "1.1291666666666667in" |
|              | C    |           |         | height="               |
| (3-OH-BAM)   | rops |           |         | 1.1652777777777779in"} |
|              | (29  |           |         |                        |
| (BAM-OH)     | -day |           |         |                        |
|              | PBI  |           |         |                        |
| (AE C657378) | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 32.7%     |         |                        |
|              | heat |           |         |                        |
|              | fo   | (1.619    |         |                        |
|              | rage | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 13.6%     |         |                        |
|              | heat |           |         |                        |
|              | s    | (1.844    |         |                        |
|              | traw | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PBI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 59.3%     |         |                        |
|              | heat |           |         |                        |
|              | fo   | (         |         |                        |
|              | rage | 0.513ppm) |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 24.5%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.013    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 28.0%     |         |                        |
|              | heat |           |         |                        |
|              | s    | (0.663    |         |                        |
|              | traw | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
| 3-methy      | **Ro |           |         | ![](me                 |
| lsulfinyl-5- | tati |           |         | dia/image7.wmf){width= |
| trifluoromet | onal |           |         | "1.4097222222222223in" |
| hylpyridine- | C    |           |         | height="               |
| 2-carboxylic | rops |           |         | 0.9215277777777777in"} |
| acid         | (29  |           |         |                        |
|              | -day |           |         |                        |
| (P1X)        | PBI  |           |         |                        |
|              | ):** |           |         |                        |
| (AE 1344122) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  | 13.0%     |         |                        |
|              | tuce |           |         |                        |
|              |      | (0.039    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 3.3%    |                        |
|              | dish |           |         |                        |
|              | top  |           | (0.069  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 9.6%    |                        |
|              | dish |           |         |                        |
|              | root |           | (0.011  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 3.8%    |                        |
|              | heat |           |         |                        |
|              | fo   |           | (0.163  |                        |
|              | rage |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 13.1%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.341    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 7.7%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.544  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 7.8%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.005  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 5.1%    |                        |
|              | dish |           |         |                        |
|              | top  |           | (0.022  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 5.3%    |                        |
|              | dish |           |         |                        |
|              | root |           | (0.002  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 18.3%     |         |                        |
|              | heat |           |         |                        |
|              | fo   | (0.045    |         |                        |
|              | rage | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 64.9%     |         |                        |
|              | heat |           |         |                        |
|              | g    | (0.116    |         |                        |
|              | rain | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    | 14.2%     |         |                        |
|              | heat |           |         |                        |
|              | s    | (0.143    |         |                        |
|              | traw | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
| 3-ch         | **Ro |           |         | ![](me                 |
| loro-5-(trif | tati |           |         | dia/image8.wmf){width= |
| luoromethyl) | onal |           |         | "1.1993055555555556in" |
| -2-pyridinol | C    |           |         | height="               |
|              | rops |           |         | 0.6645833333333333in"} |
| (AE B102859) | (29  |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 5.3%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.016  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 4.8%    |                        |
|              | dish |           |         |                        |
|              | top  |           | (0.100  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Ro |           |         |                        |
|              | tati |           |         |                        |
|              | onal |           |         |                        |
|              | C    |           |         |                        |
|              | rops |           |         |                        |
|              | (365 |           |         |                        |
|              | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 3.7%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.002  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 6.0%    |                        |
|              | dish |           |         |                        |
|              | top  |           | (0.025  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 9.9%    |                        |
|              | heat |           |         |                        |
|              | fo   |           | (0.024  |                        |
|              | rage |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| 3-c          | **Ro |           |         | ![](m                  |
| hloro-5-(tri | tati |           |         | edia/image9.wmf){width |
| fluoromethyl | onal |           |         | ="1.448611111111111in" |
| )-2-pyridine | C    |           |         | height="0.91875in"}    |
| carboxamide  | rops |           |         |                        |
|              | (365 |           |         |                        |
| (AE C653598) | -day |           |         |                        |
|              | PHI  |           |         |                        |
|              | ):** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Let  |           | 9.0%    |                        |
|              | tuce |           |         |                        |
|              |      |           | (0.005  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ra   |           | 9.5%    |                        |
|              | dish |           |         |                        |
|              | top  |           | (0.003  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 6.3%    |                        |
|              | heat |           |         |                        |
|              | fo   |           | (0.015  |                        |
|              | rage |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | W    |           | 4.8%    |                        |
|              | heat |           |         |                        |
|              | s    |           | (0.048  |                        |
|              | traw |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| 2,6-dichloro | **   |           |         | ![](me                 |
| -*N*-\[(3-ch | Rumi |           |         | dia/image10.wmf){width |
| loro-5-trifl | nant |           |         | ="2.196527777777778in" |
| uoromethyl-2 | s:** |           |         | height="               |
| -pyridyl)met |      |           |         | 0.8118055555555556in"} |
| hyl\]-4-hydr |      |           |         |                        |
| oxybenzamide |      |           |         |                        |
|              |      |           |         |                        |
| (AE 0712556) |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Ki   |           | 3.3%    |                        |
|              | dney |           |         |                        |
|              |      |           | (0.0098 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 1.2%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.0076 |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **Po |           |         |                        |
|              | ultr |           |         |                        |
|              | y:** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 41.2%     |         |                        |
|              | w    |           |         |                        |
|              | hite | (0.005)   |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 15.9%\]   |         |                        |
|              | yolk |           |         |                        |
|              |      | (0.014    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Fat  | 47.3%     |         |                        |
|              |      |           |         |                        |
|              |      | (0.012    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 5.9%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.016  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| 2            | **Po |           |         | ![](med                |
| ,6-dichloro- | ultr |           |         | ia/image11.wmf){width= |
| *N*-{\[3-chl | y:** |           |         | "2.2395833333333335in" |
| oro-5-(trifl |      |           |         | height="               |
| uoromethyl)p |      |           |         | 0.7597222222222222in"} |
| yridin-2-yl\ |      |           |         |                        |
| ]methyl}-3-( |      |           |         |                        |
| methylsulfon |      |           |         |                        |
| yl)benzamide |      |           |         |                        |
|              |      |           |         |                        |
| (Metabolite  |      |           |         |                        |
| 1)           |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 51%       |         |                        |
|              | w    |           |         |                        |
|              | hite | (0.022    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Fat  | 38%       |         |                        |
|              |      |           |         |                        |
|              |      | (0.023    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
| Hydroxy      | **   |           |         | ![](me                 |
| glucuronide  | Rumi |           |         | dia/image12.wmf){width |
| of           | nant |           |         | ="2.334722222222222in" |
| fluopicolide | s:** |           |         | height="               |
|              |      |           |         | 0.7909722222222222in"} |
+--------------+------+-----------+---------+------------------------+
|              | Ki   | []{.mark} | 4.7%    |                        |
|              | dney |           |         |                        |
|              |      |           | (0.009  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    | []{.mark} | 4.9%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.022  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | **P  |           |         |                        |
|              | oult |           |         |                        |
|              | ry** |           |         |                        |
+--------------+------+-----------+---------+------------------------+
| Dihydroxy    | **   |           |         | ![](med                |
| glucuronide  | Rumi |           |         | ia/image13.wmf){width= |
| of           | nant |           |         | "2.2868055555555555in" |
| fluopicolide | s:** |           |         | height="               |
|              |      |           |         | 0.8020833333333334in"} |
+--------------+------+-----------+---------+------------------------+
|              | Ki   | 10.0%     |         |                        |
|              | dney |           |         |                        |
|              |      | 0.019 ppm |         |                        |
+--------------+------+-----------+---------+------------------------+
| Hydroxy      | **   |           |         | ![](me                 |
| sulfate of   | Rumi |           |         | dia/image14.wmf){width |
| fluopicolide | nant |           |         | ="2.282638888888889in" |
|              | s:** |           |         | height=                |
|              |      |           |         | "2.386111111111111in"} |
+--------------+------+-----------+---------+------------------------+
|              | Ki   |           | 5.2     |                        |
|              | dney |           | %\*\*\* |                        |
|              |      |           |         |                        |
|              |      |           | (0.010  |                        |
|              |      |           | ppm     |                        |
|              |      |           | )\*\*\* |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 2.4%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.011  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  |           | 7.1%    |                        |
|              | yolk |           |         |                        |
|              |      |           | (0.006  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 1       |                        |
|              | iver |           | .0-1.4% |                        |
|              |      |           |         |                        |
|              |      |           | (0.00   |                        |
|              |      |           | 3-0.004 |                        |
|              |      |           | ppm)    |                        |
|              |      |           |         |                        |
|              |      |           | Check   |                        |
|              |      |           | 4       |                        |
|              |      |           | 6708519 |                        |
+--------------+------+-----------+---------+------------------------+
| Dihydroxy    | **   |           |         | ![](me                 |
| sulfate of   | Rumi |           |         | dia/image15.wmf){width |
| fluopicolide | nant |           |         | ="2.270138888888889in" |
|              | s:** |           |         | height="               |
|              |      |           |         | 0.9041666666666667in"} |
+--------------+------+-----------+---------+------------------------+
|              | ki   |           | R       |                        |
|              | dney |           | eported |                        |
|              |      |           | with    |                        |
|              |      |           | hydroxy |                        |
|              |      |           | sulfate |                        |
|              |      |           | above   |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 22.5%     |         |                        |
|              | w    |           |         |                        |
|              | hite | (0.003    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | Egg  | 34.0%     |         |                        |
|              | yolk |           |         |                        |
|              |      | (0.015    |         |                        |
|              |      | ppm)      |         |                        |
+--------------+------+-----------+---------+------------------------+
|              | L    |           | 1.9%    |                        |
|              | iver |           |         |                        |
|              |      |           | (0.005  |                        |
|              |      |           | ppm)    |                        |
+--------------+------+-----------+---------+------------------------+
| ^1^Grapes:   |      |           |         |                        |
| MRID         |      |           |         |                        |
| 46474025;    |      |           |         |                        |
| three foliar |      |           |         |                        |
| applications |      |           |         |                        |
| for a total  |      |           |         |                        |
| seasonal     |      |           |         |                        |
| rate of 0.36 |      |           |         |                        |
| lb ai/A      |      |           |         |                        |
| (≈1x);       |      |           |         |                        |
| 21-day PHI.  |      |           |         |                        |
|              |      |           |         |                        |
| Lettuce:     |      |           |         |                        |
| MRID         |      |           |         |                        |
| 46708520;    |      |           |         |                        |
| two foliar   |      |           |         |                        |
| applications |      |           |         |                        |
| for a total  |      |           |         |                        |
| seasonal     |      |           |         |                        |
| rate of 0.36 |      |           |         |                        |
| lb ai/A      |      |           |         |                        |
| (≈1x);       |      |           |         |                        |
| 35-day PHI.  |      |           |         |                        |
|              |      |           |         |                        |
| Potato: MRID |      |           |         |                        |
| 46708521;    |      |           |         |                        |
| two foliar   |      |           |         |                        |
| applications |      |           |         |                        |
| for a total  |      |           |         |                        |
| seasonal     |      |           |         |                        |
| rate of 0.36 |      |           |         |                        |
| lb ai/A      |      |           |         |                        |
| (≈1x);       |      |           |         |                        |
| 20-day PHI.  |      |           |         |                        |
|              |      |           |         |                        |
| Rotational   |      |           |         |                        |
| Crops: MRID  |      |           |         |                        |
| 46708546;    |      |           |         |                        |
| bare soil    |      |           |         |                        |
| treatment at |      |           |         |                        |
| 0.36 lb ai/A |      |           |         |                        |
| (≈1x) and    |      |           |         |                        |
| PBIs of 29   |      |           |         |                        |
| or 365 days. |      |           |         |                        |
|              |      |           |         |                        |
| Ruminants:   |      |           |         |                        |
| MRIDs        |      |           |         |                        |
| 46708514 and |      |           |         |                        |
| 46708518;    |      |           |         |                        |
| cows were    |      |           |         |                        |
| dosed 7 days |      |           |         |                        |
| at 10 or     |      |           |         |                        |
| 10.55 ppm.   |      |           |         |                        |
|              |      |           |         |                        |
| Poultry:     |      |           |         |                        |
| MRIDs        |      |           |         |                        |
| 46708515 and |      |           |         |                        |
| 46708519;    |      |           |         |                        |
| hens were    |      |           |         |                        |
| dosed 14     |      |           |         |                        |
| days at 10   |      |           |         |                        |
| or 10.7 ppm. |      |           |         |                        |
|              |      |           |         |                        |
| Rats: MRID   |      |           |         |                        |
| 46474242;    |      |           |         |                        |
| one oral     |      |           |         |                        |
| dose of      |      |           |         |                        |
| \[^14^C-2,6- |      |           |         |                        |
| pyridyl\]-AE |      |           |         |                        |
| C638206 at   |      |           |         |                        |
| 10 mg/kg bw. |      |           |         |                        |
| The major    |      |           |         |                        |
| metabolites  |      |           |         |                        |
| in urine and |      |           |         |                        |
| feces were   |      |           |         |                        |
| oxidative    |      |           |         |                        |
| N-           |      |           |         |                        |
| dealkylation |      |           |         |                        |
| cleavage     |      |           |         |                        |
| products.    |      |           |         |                        |
|              |      |           |         |                        |
| Water:       |      |           |         |                        |
|              |      |           |         |                        |
| \*AE         |      |           |         |                        |
| C643890/ AE  |      |           |         |                        |
| 0712556      |      |           |         |                        |
|              |      |           |         |                        |
| \*\*Also     |      |           |         |                        |
| includes AE  |      |           |         |                        |
| 0608000      |      |           |         |                        |
|              |      |           |         |                        |
| \*\*\* Also  |      |           |         |                        |
| includes     |      |           |         |                        |
| dihydroxy    |      |           |         |                        |
| sulfate of   |      |           |         |                        |
| fluopicolide |      |           |         |                        |
+--------------+------+-----------+---------+------------------------+

**Appendix C: Tolerance Assessment Summary and Table**

HED is recommending a revision of the proposed tolerance expression for
fluopicolide in/on plants to address issues of quantifiable residues
2,6-dichlorobenzamide (BAM) in/on RACs resulting from fluopicolide
application. HED has determined that the terminal residue of concern in
cucurbit vegetable, fruiting vegetable, grape, leafy vegetable, and
tuberous and corm vegetable commodities for the tolerance expression is
fluopicolide
\[2,6-dichloro-*N*-\[\[3-chloro-5-(trifluoromethyl)-2-pyridinyl\]methyl\]benzamide\]
as an indicator of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide.

No Codex, Canadian, or Mexican MRLs have been established for
fluopicolide.

Based on the cattle feeding study and the poultry metabolism study
conducted with fluopicolide, finite residues of fluopicolide are not
expected to occur in livestock commodities. Pending submission of
additional livestock metabolism data, a BAM ruminant feeding study, and
EPA validation of the proposed livestock enforcement method, HED has
tentatively determined that the residue of concern for a future
tolerance expression in livestock commodities is BAM and that ruminant
livestock tolerances at the limit of quantitation of the method will be
needed to register crops with associated livestock feeds. For a future
risk assessment including crops with associated livestock feeds, the
residues of concern in livestock commodities have been tentatively
determined to be parent fluopicolide and BAM.

Pending submission of the requested storage stability data/information,
adequate field trial data are available for tuberous and corm vegetables
(subgroup 1C and 1D), leafy vegetables (except *Brassica*, group 4),
fruiting vegetables (group 8), cucurbit vegetables (group 9), and
grapes. The available field trial data will support tolerances for
residues of fluopicolide in/on grape at 2.0 ppm, the cucurbit vegetable
group at 0.50 ppm, the fruiting vegetable group at 1.6 ppm, the leafy
vegetable, except *brassica*, group at 25 ppm, and the tuberous and corm
vegetable subgroup at 0.02 ppm. Because the majority of residues in
potatoes were below the LOQ, the tolerance spreadsheet in the Agency's
*Guidance for Setting Pesticide Tolerances Based on Field Trial Data*
was not utilized for determining an appropriate tolerance level for the
tuberous and corm vegetable subgroup. The data indicate that the
proposed tolerances of 0.8 ppm and 20 ppm for the fruiting vegetable and
leafy vegetable crop groups are too low; increased tolerances of 1.6 ppm
and 25 ppm are needed.

Pending submission of the requested storage stability information,
adequate extensive field rotational crop data are available for wheat
forage, hay, grain, and straw. The available field trial data will
support tolerances for indirect or inadvertent residues of fluopicolide
in/on wheat forage at 0.20 ppm, wheat hay at 0.50 ppm, wheat grain at
0.02 ppm, and wheat straw at 0.50 ppm. For wheat grain, the majority of
residues were below the LOQ; therefore, the tolerance spreadsheet was
not used for wheat grain.

Adequate processing data for grapes, potatoes, tomatoes, and wheat are
available pending submission of the requested storage stability
data/information. The available processing data indicate that residues
of fluopicolide are not likely to concentrate in grape juice, in potato
chips and flakes, or in wheat flour. Residues of fluopicolide were found
to concentrate in raisins, processed potato waste (wet peels), tomato
paste and puree, and wheat milled byproducts (bran, germ, middlings, and
shorts). The processing data indicate that the proposed tolerance of 6
ppm for raisins is appropriate. In addition, a tolerance for processed
potato waste must be proposed at 0.05 ppm, and tolerances for wheat
milled byproducts and aspirated grain fractions must be proposed at 0.07
ppm. Separate tolerances for tomato processed commodities are not needed
as residues in these commodities are not expected to exceed the
recommended tolerance of 1.6 ppm for the fruiting vegetable group.

The available cattle feeding study data indicate that tolerances for
ruminant and swine commodities are not needed to support the requested
fluopicolide uses. The need for tolerances for poultry commodities will
be determined after the required poultry metabolism data have been
submitted.

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
C.1. Tolerances to be established when rotational crop and livestock
issues are resolved are specified in Table C.2.

  ------------------------------------------------------------------------
  **Table C.1.                                     
  Tolerance Summary                                
  for Fluopicolide.**                              
  -------------------- ------------- ------------- -----------------------
  Commodity            Proposed      Recommended   Comments; *Correct
                       Tolerance     Tolerance     Commodity Definition*
                       (ppm)         (ppm)         

  **Tolerances to be                               
  established under                                
  "(a) *General*"                                  
  (1):**                                           

  **Tuberous and corm                              
  vegetables subgroup                              
  1C**                                             

  Arracacha            0.02          0.02          *Vegetable, tuberous
                                                   and corm, except
                                                   potato, subgroup 1D*

  Arrowroot            0.02                        

  Artichoke, Chinese   0.02                        

  Artichoke, Jerusalem 0.02                        

  Canna, edible        0.02                        

  Cassava, bitter and  0.02                        
  sweet                                            

  Chayote (root)       0.02                        

  Chufa                0.02                        

  Dasheen              0.02                        

  Ginger               0.02                        

  Leren                0.02                        

  Sweet potato         0.02                        

  Tanier               0.02                        

  Turmeric             0.02                        

  Yam bean             0.02                        

  Yam, true            0.02                        

  **Vegetable, leafy,                              
  except**                                         
  *brassica***, group                              
  4**                                              

  Head Lettuce         20            25            *Vegetable, leafy,
                                                   except brassica, group
                                                   4*

  Leaf Lettuce         20                          

  Spinach              20                          

  Arugula              20                          

  Chervil              20                          

  Chinese spinach      20                          

  Corn salad           20                          

  Dandelion            20                          

  Dock (sorrel)        20                          

  Edible chrysanthemum 20                          

  Endive               20                          

  Garden cress         20                          

  Garden purslane      20                          

  Garland              20                          
  Chrysanthemum                                    

  New Zealand spinach  20                          

  Orach                20                          

  Parsley              20                          

  Red chicory          20                          

  Upland cress         20                          

  Vine spinach         20                          

  Winter purslane      20                          

  Cardoon              20                          

  Celery               20                          

  Celtuce              20                          

  Chinese celery       20                          

  Fennel               20                          

  Rhubarb              20                          

  Swiss chard          20                          

  **Vegetable,                                     
  fruiting, group 8**                              

  Tomato/Cherry tomato 0.8           1.6           *Vegetable, fruiting,
                                                   group 8*

  Sweetpepper          0.8                         

  Bell pepper          0.8                         

  Chili pepper         0.8                         

  Cooking pepper       0.8                         

  Pimiento             0.8                         

  Eggplant             0.8                         

  Groundcherry         0.8                         

  Pepino               0.8                         

  Tomatillo            0.8                         

  **Vegetable,                                     
  cucurbit, group 9**                              

  Cantaloupe           0.4           0.50          *Vegetable, cucurbit,
                                                   group 9*

  Citron melon         0.4                         

  Muskmelon            0.4                         

  Watermelon           0.4                         

  Chayote (fruit)      0.4                         

  Chinese waxgourd     0.4                         

  Cucumber             0.4                         

  Gherkin              0.4                         

  Gourd, edible        0.4                         

  Momordica spp        0.4                         

  Pumpkin              0.4                         

  Squash, summer       0.4                         

  Squash, winter       0.4                         

  **Other**                                        

  Grape                2             2.0           

  Raisins              6             6.0           *Grape, raisin*
  ------------------------------------------------------------------------

  ------------------------------------------------------------------------
  **Table C.2.                                     
  Tolerance Summary                                
  for Fluopicolide (To                             
  be Established when                              
  All Deficiencies are                             
  Resolved).**                                     
  -------------------- ------------- ------------- -----------------------
  Commodity            Proposed      Recommended   Comments; *Correct
                       Tolerance     Tolerance     Commodity Definition*
                       (ppm)         (ppm)         

  **Tolerances to be                               
  established under                                
  "(a) *General*"                                  
  (1):**                                           

  **Tuberous and corm                              
  vegetables subgroup                              
  1C**                                             

  Potato               0.02          0.02          *Vegetable, tuberous
                                                   and corm, subgroup 1C*

  **Other**                                        

  Potato, processed    None proposed 0.05          
  potato waste                                     

  **Tolerances to be                               
  established under                                
  "(a) *General*"                                  
  (2):**                                           

  Cattle fat           None proposed 0.05 ppm      *Cattle, fat*

  Cattle meat          None proposed 0.02 ppm      *Cattle, meat*

  Cattle meat          None proposed 0.05 ppm      *Cattle, meat
  byproducts                                       byproducts*

  Goat fat             None proposed 0.05 ppm      *Goat, fat*

  Goat meat            None proposed 0.02 ppm      *Goat, meat*

  Goat meat byproducts None proposed 0.05 ppm      *Goat, meat byproducts*

  Horse fat            None proposed 0.05 ppm      *Horse, fat*

  Horse meat           None proposed 0.02 ppm      *Horse, meat*

  Horse meat           None proposed 0.05 ppm      *Horse, meat
  byproducts                                       byproducts*

  Milk                 None proposed 0.01 ppm      *Milk*

  Sheep fat            None proposed 0.05 ppm      *Sheep, fat*

  Sheep meat           None proposed 0.02 ppm      *Sheep, meat*

  Sheep meat           None proposed 0.05 ppm      *Sheep, meat
  byproducts                                       byproducts*

  **Tolerances to be                               
  established under                                
  "(d) *Indirect or                                
  inadvertent                                      
  residues*":**                                    

  Wheat forage         0.2           0.20          *Wheat, forage*

  Wheat grain          0.02          0.02          *Wheat, grain*

  Wheat hay            0.5           0.50          *Wheat, hay*

  Wheat straw          0.5           0.50          *Wheat, straw*

  Wheat, milled        None proposed 0.07          
  byproducts                                       

  Wheat, aspirated     None proposed 0.07          
  grain fractions                                  
  ------------------------------------------------------------------------

[]{#__RefHeading___Toc185228098 .anchor}

**Appendix D: Review of Human Research**[]{#__RefHeading___Toc185228099
.anchor}

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies, listed below, have been determined to require a
review of their ethical conduct. They are also subject to review by the
Human Studies Review Board. The listed studies have received the
appropriate review.

Klonne, D. (1999) Integrated Report for Evaluation of Potential
Exposures to Homeowners and Professional Lawn Care Operators Mixing,
Loading, and Applying Granular and Liquid Pesticides to Residential
Lawns: Lab Project Number: OMA005: OMA001: OMA002. Unpublished study
prepared by Riceerca, Inc., and Morse Laboratories. 2213 p. (MRID
44972201).

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database,
Version 1.1. Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995.