UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/21/07 

  

MEMORANDUM

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]benzami
de, 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

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc185228014 \h  6 

2.0	Ingredient Profile	  PAGEREF _Toc185228015 \h  12 

2.1	Summary of Proposed Uses	  PAGEREF _Toc185228016 \h  12 

2.2	Structure and Nomenclature	  PAGEREF _Toc185228017 \h  15 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc185228018 \h  16 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc185228019 \h
 16 

3.1.1	Database Summary	  PAGEREF _Toc185228020 \h  16 

3.1.1.1	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc185228021 \h  17 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc185228022 \h  17 

3.1.1.3	Sufficiency of studies/data	  PAGEREF _Toc185228023 \h  17 

3.1.2	Toxicological Effects	  PAGEREF _Toc185228024 \h  17 

3.1.3	Dose-response	  PAGEREF _Toc185228025 \h  19 

3.1.4	FQPA	  PAGEREF _Toc185228026 \h  19 

3.1.5	The Report to the European Commission	  PAGEREF _Toc185228027 \h 
20 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc185228028 \h  20 

3.3	FQPA Considerations	  PAGEREF _Toc185228029 \h  21 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc185228030 \h  21 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc185228031 \h  21 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc185228032 \h  23 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc185228033 \h  26 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc185228034 \h  28 

3.3.6	Pre-and/or Post-natal Toxicity	  PAGEREF _Toc185228035 \h  28 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc185228036 \h  28 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility	  PAGEREF _Toc185228037 \h  28 

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc185228038 \h  29 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc185228039 \h 
29 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc185228040 \h  29 

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc185228041 \h  29 

3.5.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc185228042 \h  30 

3.5.3	Chronic Reference Dose (cRfD) -	  PAGEREF _Toc185228043 \h  30 

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc185228044 \h  31 

3.5.5	Dermal Absorption	  PAGEREF _Toc185228045 \h  31 

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc185228046 \h  32 

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)	 
PAGEREF _Toc185228047 \h  33 

3.5.8	Level of Concern for Margin of Exposure	  PAGEREF _Toc185228048 \h
 33 

3.5.9	Recommendation for Aggregate Exposure Risk Assessment	  PAGEREF
_Toc185228049 \h  34 

3.5.10	Classification of Carcinogenic Potential	  PAGEREF _Toc185228050
\h  34 

3.5.11	Summary of Toxicological Doses and Endpoints for Fluopicolide for
Use in Human Risk Assessments	  PAGEREF _Toc185228051 \h  35 

3.6	Endocrine disruption	  PAGEREF _Toc185228052 \h  36 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc185228053 \h  36 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc185228054 \h 
36 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc185228055 \h  36 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc185228056 \h  36 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc185228057 \h  37 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc185228058 \h  37 

5.1.4	Analytical Methodology	  PAGEREF _Toc185228059 \h  38 

5.1.5	Environmental Degradation	  PAGEREF _Toc185228060 \h  39 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc185228061 \h  40 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc185228062 \h  40 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc185228063 \h  41 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc185228064 \h  43 

5.1.10	Food Residue Profile	  PAGEREF _Toc185228065 \h  44 

5.1.11	International Residue Limits	  PAGEREF _Toc185228066 \h  56 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc185228067 \h  56 

5.2.1	Acute Dietary (Food and Drinking Water) Exposure/Risk	  PAGEREF
_Toc185228068 \h  57 

5.2.2	Chronic Dietary (Food and Drinking Water) Exposure/Risk	  PAGEREF
_Toc185228069 \h  57 

5.2.3	Cancer Dietary Risk	  PAGEREF _Toc185228070 \h  58 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc185228071 \h  58 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc185228072 \h  58 

6.1. Residential Handler Exposure	  PAGEREF _Toc185228073 \h  58 

6.2. Residential Postapplication Exposure	  PAGEREF _Toc185228074 \h  59


6.3 Other (Recreational Exposure; Spray Drift)	  PAGEREF _Toc185228075
\h  62 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc185228076 \h  63 

7.1 Acute Aggregate Risk	  PAGEREF _Toc185228077 \h  63 

7.2 Short-Term Aggregate Risk	  PAGEREF _Toc185228078 \h  63 

7.3 Intermediate-Term Aggregate Risk	  PAGEREF _Toc185228079 \h  64 

7.4 Long-Term Aggregate Risk	  PAGEREF _Toc185228080 \h  64 

7.5 Cancer Risk	  PAGEREF _Toc185228081 \h  64 

8.0	Cumulative Risk Characterization Assessment	  PAGEREF _Toc185228082
\h  65 

9.0 	Occupational Exposure/Risk Pathway	  PAGEREF _Toc185228083 \h  65 

9.1 Short-/Intermediate-/Long-Term Handler Risk	  PAGEREF _Toc185228084
\h  65 

9.2 Short-/Intermediate-/Long-Term Postapplication Risk	  PAGEREF
_Toc185228085 \h  69 

10.0	Data Needs and Label Requirements	  PAGEREF _Toc185228086 \h  73 

10.1	Toxicology	  PAGEREF _Toc185228087 \h  73 

10.2	Residue Chemistry	  PAGEREF _Toc185228088 \h  73 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc185228089 \h 
77 

References:	  PAGEREF _Toc185228090 \h  77 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc185228091 \h  78 

A.1	Toxicology Data Requirements	  PAGEREF _Toc185228092 \h  78 

A.2	Toxicity Profiles	  PAGEREF _Toc185228093 \h  79 

A.3	Executive Summaries	  PAGEREF _Toc185228094 \h  86 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc185228095 \h  113 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc185228096 \h 
113 

B.2	Tabular Summary of Fluopicolide and its Metabolites and Degradates	 
PAGEREF _Toc185228097 \h  114 

Appendix C:  Tolerance Assessment Summary and Table	  PAGEREF
_Toc185228098 \h  127 

Appendix D:  Review of Human Research	  PAGEREF _Toc185228099 \h  128 

 

1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

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).    

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 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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
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.  SEQ CHAPTER \h \r 1 

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

  TC \l1 "2.0	Ingredient Profile 

Fluopicolide
(2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide; 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  TC \l2 "2.1	Summary of Proposed Uses 

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 2.1.	Summary of Directions for Use of Fluopicolide.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

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

 (lb ai/A)

[g ai/ha]	PHI (days)	Use Directions and Limitations*

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; Momordica spp; Muskmelon; Pumpkin;
Spaghetti Squash; Summer Squash; Watermelon; Winter Squash]

Postemergence

	V-10161 4 SC	0.09-0.125	4	0.375	2	Applications are to be made in a
minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

Retreatment Interval (RTI) is 10 days.

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	2

	Fruiting Vegetables [Bell Pepper; Chili Pepper; Cooking Pepper;
Eggplant; Groundcherry (Physalis spp.); Pepino; Pimento, Sweet Pepper;
Tomatillo; Tomato]

Postemergence	V-10161 4 SC	0.09-0.125	4	0.375	2	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 7 days.

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	2

	Grapes

Postemergence	V-10161 4 SC	0.09-0.125	4	0.375	21	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 12 days.

Leafy Vegetables (except Brassica 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]

Postemergence	V-10161 4 SC	0.09-0.125	4	0.375	2	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 10 days.

Lettuce, Head and Leaf

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	2	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 10 days.



Potato

Postemergence	V-10161 4 SC	0.09-0.125	4	0.375	7	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 10 days.

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	7	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 10 days.

Sweet Potato

Postemergence	V-10161 4 SC	0.09-0.125	4	0.375	7	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

RTI is 10 days.

Turf (Residential, Commercial, Golf Course, Sod Farms)

Postemergence	V-10161

VPP Fungicide	0.27	2	0.54	N/A	Apply in a minimum volume of 2 gal/1000
ft2.  Application intervals are 14 days.

Postemergence	V-10162

VPP Fungicide	0.21	2	0.42	N/A

	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)

Postemergence	V-10161

VPP Fungicide	Spray: 0.27-0.54

Drench: 6.8-27	No more than 2 applications per cropping cycle.	Not
stated	NA	Foliar spray:  Apply spray mixture to all plant surfaces to
the point of runoff (approximately 100 gal/20,000 ft2).  Minimum
application intervals are 14 days.

Drench:  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.

Postemergence	V-10162

VPP Fungicide	Spray: 0.21-0.42

Drench: 5.3-21

Not stated	NA

	*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.  Refer to
Section 10.2 for recommended label revisions.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

Table 2.2.		Fluopicolide Nomenclature.

Chemical structure	

Empirical Formula	C14H8Cl3F3N2O

Common name	Fluopicolide

Company experimental name	AE C638206 

IUPAC name
2,6-dichloro-N-[3-chloro-5-(trifluoromethyl)-2-pyridylmethyl]benzamide 

CAS name
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzami
de 

CAS Registry Number	239110-15-7 

End-use products (EPs)	V-10161 4SC Fungicide (39.5% fluopicolide; EPA
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 of Concern	None



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 464740151

pH 	6.5 at 22.0 (C (1% suspension) 	MRID 464740131

Density 	1.65 g/cm3 (30 °C)	MRID 464740161

Water solubility (20 (C) 	2.86 mg/L at pH 4

2.80 mg/L at pH 7

2.80 mg/L at pH 9 	MRID 464740211

Solvent solubility (g/L at 20 (C) 	n-Hexane:	0.20

Ethanol:	19.2

Toluene:	20.5

Ethyl acetate:	37.7

Acetone:	74.7

Dichloromethane:	126

Dimethyl sulfoxide:	183 	MRID 464740221

Vapor pressure (25 (C) 	8.03 x 10-7 Pa 	MRID 464740231

Dissociation constant (pKa) 	No evidence of ionization in the pH range
of 1.9 to 9.8 	MRID 464740171

Octanol/water partition coefficient Log(KOW) 	Log POW = 3.26 at pH 7.8
and 22 ± 1 (C 	MRID 464740181

	Log POW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 (C 	MRID 464740191

UV/visible absorption spectrum 	Absorption maxima wavelengths (nm): 

	In methanol:	203 and 271

	In methanol/HCl:	202 and 270

	In methanol/NaOH:	219 and 271 	MRID 464740141

*The molecular weight was calculated from the Periodic Table.

3.0	Hazard Characterization/Assessment   tc  \l 1 "3.0	Hazard
Characterization/Assessment" 

3.1	Hazard and Dose-Response Characterization tc  \l 2 "3.1	Hazard and
Dose-Response Characterization" 

3.1.1	Database Summary tc  \l 3 "3.1.1	Database Summary " 

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)  tc  \l 4 "3.1.1.1	Studies available and considered (animal,
human, general literature)" 

Fluopicolide (AC638206)

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization

Subchronic- oral 90-day rat, oral 90-day mouse (2 studies), oral 90-day
dog

Chronic- oral rat (combined chronic/carcinogenicity) and oral dog

Reproductive/developmental- oral developmental rat and rabbit, rat
reproduction/fertility

Other- 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 tc  \l 4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data " 

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 tc  \l 4 "3.1.1.3	Sufficiency of
studies/data " 

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 tc  \l 3 "3.1.2	Toxicological Effects " 

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 LC50 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
F0 females and kidney toxicity in F0 and F1 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 F1 and F2
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 F1
male and female pups and by 11-14% in the high-dose F2 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 tc  \l 3 "3.1.3	Dose-response" 

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 tc  \l 3 "3.1.4	FQPA" 

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

 tc  \l 3 "3.1.5	The Report to the European Commission" 

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:

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.

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)  tc  \l 2
"3.2	Absorption, Distribution, Metabolism, Excretion (ADME)" 

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 tc  \l 2 "3.3	FQPA Considerations" 

3.3.1	Adequacy of the Toxicity Database tc  \l 3 "3.3.1	Adequacy of the
Toxicity Database" 

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

3.3.2	Evidence of Neurotoxicity tc  \l 3 "3.3.2	Evidence of
Neurotoxicity" 

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

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

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 tc  \l 3 "3.3.3	Developmental
Toxicity Studies " 

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

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 5th
metacarpal or 5th 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

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 tc  \l 3 "3.3.4	Reproductive Toxicity
Study" 

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

In a two-generation reproduction study (MRID 46474124 and 46474125), AE
C638206 (95.9% a.i., batch/lot # OP2050046) was administered to 28 F0
generation and 24 F1 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 F0 males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for F1
males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F0 females; and 0, 9.4,
46.9, and 193.9 mg/kg bw/day for F1 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 F0 and F1 males during
premating/postmating periods and in female rats during premating except
as noted below.  High-dose F0 females gained up to 14% (p<0.01) less
weight than controls and high-dose F1 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 F0
and F1 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 F0 generation and by 10-11% throughout
gestation in the F1 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 F0 females during GD 0-6 was not accompanied by a decrease in
body weight.  High-dose  F0 and F1 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 F0 and F1 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 F0 and F1 males had
small, statistically significant increases in absolute   and relative
kidney weights and high-dose F0 and F1 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 F0 and F1 male and female rats.  The
incidences of cortical tubular basophilia, medullary granular casts, and
cortical scarring were significantly increased in high-dose F0 and F1
males compared with the control incidences.  The incidence of
interstitial inflammation was significantly increased in high-dose F0
males.  The increased incidences of cortical tubular dilatation and
cortical granular casts in high-dose F1 males did not reach statistical
significance but were considered treatment related.  In high-dose F0 and
F1 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 F0 females and kidney toxicity in F0 and F1 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 F1 or F2 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 F1 offspring.  Body
weight was  significantly reduced by 7-13% in high-dose group F1 and F2
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
F1 male and female pups and by 11-14% in high-dose F2 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 F1 and F2 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 F1 and F2 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 tc  \l 3 "3.3.5
Additional Information from Literature Sources" 

 

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 tc  \l 3 "3.3.6	Pre-and/or
Post-natal Toxicity" 

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 tc  \l 4 "3.3.6.1	Determination
of Susceptibility " 

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 tc  \l 4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility" 

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

 tc  \l 3 "3.3.7	Recommendation for a Developmental Neurotoxicity Study"


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

 tc  \l 2 "3.4	Safety Factor for Infants and Children" 

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 tc  \l 2 "3.5
Hazard Identification and Toxicity Endpoint Selection" 

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49 tc  \l 3 "3.5.1
Acute Reference Dose (aRfD) - Females age 13-49" 

Study Selected:  None.  An endpoint attributable to a single dose was
not identified from the available data.

MRID No:  None

Executive summary:  None

Dose and Endpoint for Risk Assessment:  None

Comments on Study/Endpoint/Uncertainty Factors:  None

3.5.2	Acute Reference Dose (aRfD) - General Population tc  \l 3 "3.5.2
Acute Reference Dose (aRfD) - General Population " 

Study Selected:  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:  None

Executive summary:  None

Dose and Endpoint for Risk Assessment:  None

Comments on Study/Endpoint/Uncertainty Factors:  None

3.5.3	Chronic Reference Dose (cRfD)  tc  \l 3 "3.5.3	Chronic Reference
Dose (cRfD) - " 

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

critical.  Each study is discussed below.

Study Selected (one of two):   developmental toxicity -- rabbit		OPPTS
3700b	

MRID No:  46474122	

Executive summary:  See Section 3.3.3.

 

Dose and Endpoint for Risk Assessment:  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):   chronic/oncogenicity -- rat		OPPTS 4200a	

MRID No:  46474139	

Executive summary:  See Appendix A.3.5. 

Dose and Endpoint for Risk Assessment:  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:  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   =    
0.2 mg/kg/day

                                                                     100

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)  tc  \l 3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) " 

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b	

MRID No:  46474122	

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  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:  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 tc  \l 3 "3.5.5	Dermal Absorption" 

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 vitro 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.

 μg/cm2 skin) was applied to 12 cm2 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),
[14C-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/cm2 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)  tc  \l 3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)" 

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b	

MRID No:  46474122	

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  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:  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)  tc  \l
3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)" 

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b	

MRID No:  46474122	

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  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:  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 tc  \l 3 "3.5.8	Level of
Concern for Margin of Exposure " 

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	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 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 tc  \l 3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessment" 

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 tc  \l 3 "3.5.10
Classification of Carcinogenic Potential" 

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 tc  \l 3 "3.5.11	Summary of
Toxicological Doses and Endpoints for Fluopicolide for Use in Human Risk
Assessments " 

Table 3.5.11   Summary of Toxicological Doses and Endpoints for
Fluopicolide for Use in Dietary and Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary 

(all populations)	None	None	None	An endpoint attributable to a single
dose was not identified from the available data.

Chronic Dietary (all populations)	Maternal

NOAEL=20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X	Chronic RfD = 

0.2 mg/kg/day

cPAD = 0.2 mg/kg/day	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

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.

Incidental Oral Intermediate-Term

(1 - 6 months)	Maternal  NOAEL = 20 mg/kg/day	UFA=10x

UFH=10x

FQPA SF = 1X	MOE = 100 (occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

Dermal Short-  Intermediate- and Long-Term (1-30 days, 1-6 months, and
>6 months)	Maternal  NOAEL = 20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X

37% dermal absorption	MOE = 100 (occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

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.

Inhalation Short- Intermediate- and Long-term (1-30 days,  1-6 months,
and >6 months)	Maternal  NOAEL = 20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X

(inhalation and oral toxicity are assumed to be equivalent)	MOE = 100
(occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

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.

Cancer (oral, dermal, inhalation)	Classification:  “Not Likely to be
Carcinogenic to Humans”.



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

3.6	Endocrine disruption tc  \l 2 "3.6	Endocrine disruption" 	

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

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.    TC \l1 "4.0	Public Health and
Pesticide Epidemiology Data  

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

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 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-hydrox
ybenzamide) 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-hydro
xybenzamide) 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  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

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.

 ≥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  TC \l3 "5.1.3	Metabolism in Livestock 

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.  

 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  TC \l3 "5.1.4	Analytical Methodology 

Plant Methods

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

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

 

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,  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 TC \l3 "5.1.5	Environmental Degradation 

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 KOC value of 340 suggests that fluopicolide could leach in soil
but this leaching potential should abate due to a time dependent
increase in KOC. 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  TC \l3 "5.1.6	Comparative Metabolic
Profile 

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 (> 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-hydroxy
benzamide), Metabolite 1
(2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-(me
thylsulfonyl)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-hydro
xybenzamide).  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 (>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 TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates 

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  TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

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 in Risk Assessment1	Residues included in
Tolerance Expression1

Plants

(Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, and 

Grapes)	Primary Crops

	All primary crops except Tuberous and Corm Vegetables	fluopicolide
(parent) and BAM	fluopicolide (parent) as an indicator of combined
residues of fluopicolide and BAM

	Tuberous and Corm Vegetables	fluopicolide (parent), BAM, and PCA



Rotational Crops

	All rotational crops except cereal grains	fluopicolide (parent) and BAM
fluopicolide (parent) as an indicator of combined residues of
fluopicolide and BAM



	Cereal grains: grain for human food	fluopicolide (parent), BAM, PCA,
and P1X 



Cereal grains: forage/hay/straw and grain for livestock feed
fluopicolide (parent) and BAM 

	Livestock	Ruminant	fluopicolide (parent) and BAM 	BAM

	Poultry



Drinking Water	fluopicolide (parent) and BAM	Not applicable

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  TC \l3 "5.1.9	Drinking Water
Residue Profile 

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 Conc., ppb a	Groundwater Conc., 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 Koc of 349 mL/g, and a half-life of 413 days.



5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

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

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.

Tuberous and corm vegetable, subgroup 1C (MRID 46708537)

TABLE 5.1.10.1	  Summary of Residue Data from Crop Field Trials with
Fluopicolide.

Matrix	Total Applic. Rate

(lb a.i./A)

[kg a.i./ha]	PHI (days)	Residue Levels*

(ppm)



	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.



Fluopicolide

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	0.0126	<0.01 (0.0088)	<0.01	<0.01
0.0012

BAM (AE C653711)

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	<0.01	NA	NA	NA	NA

PCA (AE C657188)

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	0.0447	0.0438	<0.01	< 0.010	0.009

*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)   

 

Table 5.1.10.2	Summary of Residue Data from Group 4 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

CELERY (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Celery	0.354-0.365

[0.397-0.410]	2	14	0.037	13.6	9.9	1.23	2.73	3.70

BAM

Celery	0.354-0.365

[0.397-0.410]	2	14	<0.01	0.041	0.039	NA	NA	NA

PCA

Celery	0.354-0.365

[0.397-0.410]	2	14	<0.01	0.024	0.020	NA	NA	NA

HEAD LETTUCE (proposed use = 0.375 lb ai/A total application rate,
10-day minimum RTI, 2-day PHI)

Fluopicolide

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	0.455	7.15	6.34	2.39	2.68
2.06

BAM

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	<0.01	0.0132	0.012	<0.01
<0.01	NA

PCA

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	<0.01	<0.01	NA	NA	NA	NA

LEAF LETTUCE (proposed use = 0.375 lb ai/A total application rate,
10-day minimum RTI, 2-day PHI)

Fluopicolide

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	0.444	11.7	9.78	6.43	6.37	2.96

BAM

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	<0.01	0.038	0.031	<0.01	0.012	0.010

PCA

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	<0.01	<0.01	<0.01	NA	NA	NA

SPINACH (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Spinach	0.357-0.365

[0.400-0.410]	2	14	5.43	16.8	16.2	8.53	9.71	3.87

BAM

Spinach	0.357-0.365

[0.400-0.410]	2	14	0.022	0.188	0.170	0.065	0.072	0.047

PCA

Spinach	0.357-0.365

[0.400-0.410]	2	14	<0.01	0.119	0.076	0.013	0.022	0.025

1  HAFT = Highest average field trial result.

Fruiting vegetable, group 8 (MRIDs 46708530, 46708535, and 46708536) 

Table 5.1.10.3	Summary of Residue Data from Group 8 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

BELL PEPPER (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	0.0411	0.557	0.523	0.099	0.156	0.163

BAM

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	<0.01	<0.01	NA	NA	NA	NA

PCA

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	<0.01	<0.01	NA	NA	NA	NA

CHILI PEPPER (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	0.0837	0.576	0.516	0.300	0.302	0.198

BAM

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	<0.01	<0.01	NA	NA	NA	NA

PCA

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	<0.01	<0.01	NA	NA	NA	NA

TOMATO (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Tomato	0.356-0.368

[398.9-412.8]	2	24	0.015	0.420	0.375	0.145	0.150	0.094

BAM

Tomato	0.356-0.368

[398.9-412.8]	2	24	<0.01	<0.01	NA	NA	NA	NA

PCA

Tomato	0.356-0.368

[398.9-412.8]	2	24	<0.01	0.013	0.012	NA	NA	NA

1  HAFT = Highest average field trial result.

Cucurbit vegetable, group 9 (MRIDs 46708531, 46708532, and 46708538) 

Table 5.1.10.4	Summary of Residue Data from Group 9 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

CANTALOUPE (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	0.258	0.181	0.055	0.068	0.061

BAM

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	<0.01	NA	NA	NA	NA

PCA

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	<0.01	NA	NA	NA	NA

CUCUMBER (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	0.057	0.050	0.020	0.024	0.0147

BAM

Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	<0.01	NA	NA	NA	NA

PCA

Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	<0.01	NA 	NA	NA 	NA

SUMMER SQUASH (proposed use = 0.375 lb ai/A total application rate,
10-day minimum RTI, 2-day PHI)

Fluopicolide

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	0.0135	0.0506	0.0448	0.0322	0.0301	0.0120

BAM

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	<0.01	<0.01	NA	NA	NA	NA

PCA

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	<0.01	0.0207	0.0173	<0.01	<0.01	0.0060

1 HAFT = Highest average field trial result.

Grape (MRID 46708541)

Table 5.1.10.5	Summary of Residue Data from Grape Field Trials with
Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

GRAPE (proposed use = 0.375 lb ai/A total application rate, 12-day
minimum RTI, 21-day PHI)

Fluopicolide

Grape	0.346-0.401

[0.387-0.449]	20-21	32	0.065	1.10	0.985	0.210	0.312	0.289

BAM

Grape	0.346-0.401

 [0.387-0.449]	20-21	32	<0.01	<0.01	NA	NA	NA	NA

PCA

Grape	0.346-0.401

 [0.387-0.449]	20-21	32	<0.01	0.013	0.012	<0.01	< 0.01	NA

1  HAFT = Highest average field trial result.

Processing Studies (MRIDs 46708542, 46708543, 46708544, and 46708545) 

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.

  SEQ CHAPTER \h \r 1 Table 5.1.10.6		Summary of Processing Factors for
Fluopicolide.

RAC	Processed Commodity	Average 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	4.0x2	NC	NC	NA	NA

Tomato	Paste	2.4x	NC	NC	NA	NA

	Puree	1.4x3	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)

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 5.1.10.7	Summary of Residue Data in Rotational Wheat Commodities
Following Treatment of a Primary Crop with Fluopicolide.

Commodity	Applic. Rate

(lb ai/A)

[g ai/ha]	PBI

(days)	Analyte	Residue Levels (ppm)





n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Wheat, forage	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.213	0.160	0.027	0.044	0.047



	BAM	42	<0.01	0.123	0.106	0.019	0.028	0.027



	3-OH-BAM	42	<0.01	0.050	0.045	0.013	0.019	0.012



	PCA	42	<0.01	0.043	0.027	0.010	0.013	0.007



	P1X	42	<0.01	0.064	0.057	0.012	0.018	0.013

Wheat, hay	0.346-0.372

[388-417]	29-37	Fluopicolide	42	0.014	0.501	0.364	0.051	0.100	0.119



	BAM	42	<0.01	0.102	0.095	0.010	0.022	0.024



	3-OH-BAM	42	<0.01	0.160	0.133	0.032	0.048	0.044



	PCA	42	<0.01	0.064	0.055	0.010	0.018	0.013



	P1X	42	<0.01	0.073	0.070	0.025	0.028	0.017

Wheat, grain	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.014	0.014	0.010	0.010	0.001



	BAM	42	<0.01	<0.01	<0.01	0.010	0.010	0.000



	3-OH-BAM	42	<0.01	<0.01	<0.01	0.010	0.010	0.000



	PCA	42	<0.01	0.062	0.060	0.011	0.016	0.011



	P1X	42	<0.01	0.075	0.075	0.019	0.025	0.020

Wheat, straw	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.350	0.338	0.034	0.055	0.075



	BAM	42	<0.01	0.050	0.050	0.010	0.015	0.011



	3-OH-BAM	42	<0.01	0.081	0.078	0.026	0.031	0.019



	PCA	42	<0.01	0.043	0.040	0.010	0.012	0.007



	P1X	42	<0.01	0.055	0.049	0.020	0.021	0.011

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)

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	Type1	% Dry Matter2	% Diet2	Recommended Tolerance (ppm)
Dietary Contribution (ppm)3

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

Wheat, hay	R	88	15	0.50	0.08

Potato, processed waste	CC	15	30	0.05	0.10

Wheat, milled byproducts	CC	88	40	0.07	0.032

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 waste	CC	15	10	0.05	0.033

Wheat, milled byproducts	CC	88	35	0.07	0.028

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

TOTAL BURDEN	--	--	100	--	0.29

Poultry  CC: 75 %;  PC: 25%

Wheat, milled byproducts	CC	88	50	0.07	0.035

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 byproducts	CC	88	50	0.07	0.035

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 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 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	Type1	% Dry Matter2	% Diet2	BAM Maximum Residues (ppm)	Dietary
Contribution (ppm)3

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

Wheat, hay	R	88	15	0.102	0.017

Potato, processed waste	CC	15	30	 0.054	0.10

Wheat, milled byproducts	CC	88	40	0.0185	0.0082

CC (untreated)	CC	N/A	5	N/A6	--

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 byproducts	CC	88	35	0.0185	0.0072

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

TOTAL BURDEN	--	--	100

0.12

Poultry  CC: 75 %;  PC: 25%

Wheat, milled byproducts	CC	88	50	0.0185	0.009

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 byproducts	CC	88	50	0.0185	0.009

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. 

4The 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

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

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:  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 [2,6-14C-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-14C-phenyl]fluopicolide correspond to 34x and 306x , respectively, of
the dietary burden.  TRR following dosing at 1 ppm using
[2,6-14C-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
[2,6-14C-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-14C-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-14C-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, 4th ed., 1990).  The
maximum residues of BAM  were 361 ppb parent equivalents (178 ppb BAM
equivalents) in liver following dosing with [U-14C-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 TC \l3 "5.1.11	International Residue
Limits 

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

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk 

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.

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 TC \l3
"5.2.1	Acute Dietary (Food and Drinking Water) Exposure/Risk 

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 TC \l3
"5.2.2	Chronic Dietary (Food and Drinking Water) Exposure/Risk 

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 DEEMTM.  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, mg/kg/day	DEEM-FCID



Exposure, mg/kg/day	% PAD

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 TC \l3 "5.2.3	Cancer Dietary Risk  

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 TC
\l2 "5.3	Anticipated Residue and Percent Crop Treated (%CT) Information 

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  TC
\l1	“6.0	Residential (Non-Occupational) Exposure/Risk
Characterization” 

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 TC \l2 "6.1. Residential Handler
Exposure 

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	Application Rate 1

 (lb ai/A)	Area Treated 2

(acres/day)	Unit Exposure 3

(mg/lb ai)	Short-/Intermediate-Term





Daily Dose 4

(mg/kg/day)	Total MOE 5

(1) Mix/load and spot application of liquid formulation (low-pressure
hand sprayer)	0.27	0.023

(1,000 ft2)	Dermal:

100	Dermal:

0.0038	5,200



	Inhalation:

0.030	Inhalation:

0.0000031

	(2) Mix/load and broadcast application of liquid formulation (garden
hose-end sprayer)	0.27	0.50	Dermal:

11	Dermal:

0.0092	2,200



	Inhalation:

0.017	Inhalation:

0.000038

	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 TC \l2 "6.2. Residential
Postapplication Exposure 

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.



Table 6.2.1.  Postapplication Dermal Exposure and Risk from Treated
Lawns



Subgroup Exposed	

Application Rate

 (lb ai/A)	

Post-application day (t)	

Fraction of ai Transferable from the Foliage	

Turf Transferable Residue 1

(µg/cm2)	

Dermal Transfer Coefficient

(cm2/hr)	

 Body Weight

(kg)	

 Daily Dermal Dose 2

(mg/kg/day)

	

Dermal MOE 3









Short-/

Intermediate-term

Adults	0.27	0	0.05	0.15	14,500	

60	0.027	740

Children



	5,200	

15	0.039	520

1 Turf Transferable Residue Postapplication day (µg/cm2)= 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/cm2

2 Daily Dermal Dose = (Turf Transferable Residue (µg/cm2) x Absorption
Factor (0.37) x Dermal Transfer Coefficient (cm2/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 6.2.2.  Postapplication Oral Hand-to-Mouth Exposure and Risk for
Children from Treated Lawns



Application Rate

 (lb ai/A)	

Post-application day (t)	

Fraction of ai Transferable from the Foliage	

Turf Transferable Residue 1

(µg/cm2)	

Hand Surface Area 

(cm2/event)	

Saliva Extraction Factor 	

 Frequency

(events/ hr)	

Body Weight

(kg)	

 Daily Dose2

(mg/kg/day)

	

Oral MOE3









	Short-/ 

Int-term



0.27	

0	

0.05	

0.15	

20	

50%	

20	

15	0.0040	5,000

1 Turf Transferable Residue Postapplication day (µg/cm2)= 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/cm2

2 Daily Dose = (Turf Transferable Residue (µg/cm2) x Hand Surface Area
(cm2/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.  Postapplication Oral Object-to-Mouth (Turfgrass) Exposure
and Risk for Children from Treated Lawns 



Application Rate

 (lb ai/A)	

Post-

application day 

(t)	

Fraction of ai Transferable from the Foliage	

Grass/Object

Residue 1

(µg/cm2)	

Ingestion Rate

(cm2/day)	

Body 

Weight

(kg)	

 Daily Dose2

(mg/kg/day)	

Oral MOE3







	Short-/

Int-term



0.27	

0	

0.29	

0.88	

25	

15	0.0015	14,000

1Grass/Object residue Postapplication day (µg/cm2) = 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/cm2

2 Daily Dose  = [Grass reside (µg/cm2) x Ingestion rate (cm2/day) x
0.001 mg/µg] / [Body Weight (kg)]]

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



Table 6.2.4. Postapplication Incidental Soil Ingestion Exposure and Risk
for Children from Treated Lawns 

Application Rate

 (lb ai/A)	

Fraction of ai Retained in the Soil	

Soil

Residue 1

(µg/g)	

Ingestion Rate

(mg/day)	

Body 

Weight

(kg)	

 Daily Dose2

(mg/kg/day)	

Oral MOE3







Short-/ Intermediate-term



0.27	1	

2.0	

100	15	0.000014	1,500,000

1 Soil residue Postapplication day zero (µg/cm2) = Application rate (lb
ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 µg/lb x 2.47E-8
A/cm2 x 0.67 cm3/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
Lawns



Scenario 

and 

Pathway	

TTR/GR/SR0 (µg/cm2 or g) 1	

PDR0-norm

(mg/kg/day) 2	

Short-/ Int-Term

 MOE 3	

Total MOE 4





Short-/

Int-Term

Adult’s Scenarios



(1) Handler (Dermal) 	N/A	0.0092	2,200	550



(1) Handler (Inhalation) 	N/A	0.000038	520,000

	

(2) Dermal Postapplication	0.15	0.027	740

	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 Grass/Object	0.88	0.0015	14,000

	

(4) Soil Ingestion	2.0	0.000014	1,500,000

	1 TTR=turf transferable residue on day “0"; GR=grass/object residue
on day “0"; SR0=soil residue on day “0".

2 PDR0norm=potential dose rate on day “0”.

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

4 Total MOE = 1/ [(1/MOEDermal) + (1/MOEHand-to-Mouth) + (1/MOEGrass) +
(1/MOESoil)]

6.3	Other (Recreational Exposure; Spray Drift) TC \l2 "6.3 Other
(Recreational Exposure; Spray Drift) 

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  TC \l1	“7.0
Aggregate Risk Assessments and Risk Characterization” 

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

 TC \l2 "7.1 Acute Aggregate Risk 

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. TC \l2 "7.2 Short-Term Aggregate Risk 

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.  Short-Term and Intermediate-Term Aggregate Risk Calculations


(Inhalation/Oral/Dermal Endpoints and NOAELs are  the Same)



Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC1 

	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE

(food and

residential)4

General U.S. Population	20	100	0.2	0.011999	0.036238	420

All Infants (<1 year old)	20	100	0.2	0.007826	0.044514	380

Children 1-2 years old	20	100	0.2	0.018460	0.044514	320

Children 3-5 years old	20	100	0.2	0.016718	0.044514	330

Children 6-12 years old	20	100	0.2	0.012418	0.044514	350

Youth 13-19 years old	20	100	0.2	0.009748	0.036238	440

Adults 20-49 years old	20	100	0.2	0.011822	0.036238	420

Adults 50+ years old	20	100	0.2	0.011590	0.036238	420

Females 13-49 years old	20	100	0.2	0.012034	0.036238	410

1 UFA  = 10x (extrapolation from animal to human (interspecies); UFH =
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. TC \l2 "7.3 Intermediate-Term Aggregate
Risk 

7.4	Long-Term Aggregate Risk TC \l2 "7.4 Long-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 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 TC \l2 "7.5 Cancer Risk 

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  TC \l1 "8.0	Cumulative
Risk Characterization Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to 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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
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  TC \l1 "9.0 	Occupational
Exposure/Risk Pathway 

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  TC \l2 "9.1
Short-/Intermediate-/Long-Term Handler Risk 

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 9.1.  Summary of  MOEs for Occupational Handlers of
Fluopicolide

Exposure Scenario (Scenario #)	Dermal Unit Exposure (mg/lb ai) 1
Inhalation

Unit

Exposure

(mg/lb ai)2	Use Site	Application 

Rate 

(lb ai/A)3	Area Treated

(A/day) 4	Daily Dose

(mg/kg/day) 5	Total 

Short-/Int-term MOE 6

	Baseline	PPE

(gloves)



	Dermal	Inhalation	Baseline	PPE

(gloves)

Mixer/Loader

(1) Mixing/Loading Liquid for Aerial application or Chemigation	2.9
0.023	0.0012	Veg, Potatoes	0.13	350	0.81

0.0065 (gloves)	0.00091	25	2,700

(2) Mixing/Loading Liquid for Groundboom application or Chemigation	2.9
0.023	0.0012	Veg, Potatoes	0.13	80	0.19	0.00021	110	-





Turf	0.27	80	0.39

0.0031 (gloves)	0.00043	52	5,700





Ornamentals (drench)	27	40	19

0.15 (gloves)	0.021	1	110





Ornamentals	0.54	40	0.39

0.0031 (gloves)	0.00043	52	5,700

(3) Mixing/Loading Liquid for Airblast application	2.9	-	0.0012	Grapes
0.13	40	0.093	0.00010	210	-





Ornamentals	0.54	20	0.19	0.00022	100	-

Applicator

(4) Applying Sprays with Fixed-wing Aircraft	0.005	-	0.000068	Veg,
Potatoes	0.13	350	0.0014	0.000052	14,000	-

(5) Applying Sprays with Open Cab Groundboom 	0.014	-	0.00074	Veg,
Potatoes	0.13	80	0.00090	0.00013	19,000	-





Turf	0.27	80	0.0019	0.00027	9,400	-





Ornamentals	0.54	40	0.0019	0.00027	9,400	-

(6) Applying Sprays with Open Cab Airblast Sprayer	0.36	-	0.0045	Grapes
0.13	40	0.012	0.00039	1,700	-





Ornamentals	0.54	20	0.024	0.00081	810	-

Flagger

(7) Flagging to Support Aerial Applications	0.011	-	0.00035	Veg,
Potatoes	0.13	350	0.0031	0.00027	6,000	-

Mixer/Loader/Applicator

(8) Mixing/Loading Liquid and Applying with Handgun Sprayer	no data	0.50
0.0019	Turf	0.27	5	0.0042

(gloves)	0.000043	no data	4,800

(9) Mixing/Loading Liquid and Applying with Low-Pressure Handwand	100
0.43	0.03	Turf	0.0031

(lb ai/gal)	40

(gal/day)	0.076	0.000062	260	-

(10) Mixing/Loading Liquid and Applying with High-Pressure Handwand	no
data	2.5	0.12	Ornamentals	0.0025

(lb ai/gal)	1,000

(gal/day)	0.039

(gloves)	0.005	no data	460

(11) Mixing/Loading Liquid and Applying with Backpack Sprayer	no data
2.5	0.03	Turf	0.0031

(lb ai/gal)	40

(gal/day)	0.0019

(gloves)	0.000062	no data	10,000





Ornamentals	0.0025

(lb ai/gal)	40

(gal/day)	0.0015

(gloves)	0.000050	no data	13,000



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  TC \l2 "9.2
Short-/Intermediate-/Long-Term Postapplication Risk 

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):

0.42 μg/cm2) and declined to 0.012 μg/cm2 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/cm2) and declined to 0.0047
μg/cm2 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 (r2 = 0.97) and 4.8 days (r2 = 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 may be
necessary to achieve an MOE of 100 when the maximum label application
rate is used.  Alternatively, when the minimum label rate is used, an
interval of only one day 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.]

Table 9.2.1.  Summary of Estimated Post-application MOEs for
Agricultural Crops

Crop	Application Rate

(lb ai/A) 1	DAT 2	DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	Short-/Int-

Term MOE 5

Fruiting Vegetables	0.13	0	0.42	500	Irrigation, scouting, thinning,
weeding immature plants	1,900





700	Irrigation and scouting mature plants	1,400





1,000	Hand harvesting, pruning, staking, tying	960

Cucurbit & Leafy Vegetables

0	0.42	500	Irrigation, scouting, thinning, weeding immature plants	1,900





1,500	Irrigation, scouting, weeding mature plants	640





2,500	Hand harvesting, pulling, pruning, and thinning mature plants	380

Grapes

0	0.42	500	Hedging, irrigation, scouting, hand weeding	1,900





1,000	Scouting	960





5,000	Hand harvest, leaf pulling, thinning, pruning, training/tying	190





10,000	Girdling and cane turning	96



1	0.36

	110

Potatoes & Sweet Potatoes

0	0.42	300	Irrigation, scouting, thinning, weeding immature plants	3,200





1,500	Irrigation and scouting mature plants	640





2,500	Hand harvesting	380

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/cm2) = dislodgeable foliar residues corresponding to DAT,
based on results from a chemical-specific DFR study conducted on lettuce
(MRID 46708641).

4 TC (cm2/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.



Table 9.2.2.  Summary of Estimated Post-application MOEs for Turf and
Ornamentals

Crop	Application Rate

(lb ai/A) 1	DAT 2	TTR or DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	Short-/Int-

Term MOE 5

Turf

Turf	0.27	0	0.15	

3,400	Mowing and other maintenance activities	790







6,800	Sod harvesting and transplanting	390

Ornamentals – Nursery Stock

Nursery Stock	0.54	0	1.8	100	Hand pruning containerized ornamentals
2,300





400	Harvesting, ball/burlap containerized ornamentals	580

Ornamentals – Cut Flowers

Cut Flowers

(maximum rate)	0.54	0	1.8	500	Pinching	460



0	1.8	5,100	Hand harvesting, pruning, thinning, pinching	45



5	0.83

	96



6	0.71

	110

Cut Flowers

(minimum rate)	0.27	0	0.88	500	Pinching	920



0	0.88	5,100	Hand harvesting, pruning, thinning, pinching	91



1	0.75

	110

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/cm2) = Application rate (lb ai/A)
x CF (4.54E+8 µg/lb) x CF (2.47E-8 A/cm2) 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 (cm2/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  TC \l1 "10.0	Data Needs and
Label Requirements 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

	None.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

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.  SEQ CHAPTER
\h \r 1 

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)

860.1200 Directions for Use

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

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

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 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]benzam
ide] 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]benzam
ide] 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)

860.1200 Directions for Use

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

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

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

For the fluopicolide phenyl-14C-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-14C-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 [2,6-14C-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

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

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

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

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  TC \l2 "10.3	Occupational
and Residential Exposure 

	None.

References:  TC \l1 "References: 

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.

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 tc  \l 1 "Appendix A:  Toxicology
Assessment" 

A.1	Toxicology Data Requirements tc  \l 2 "A.1	Toxicology Data
Requirements"  

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	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    28-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes1

yes

yes1

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5375    Mutagenicity—Structural Chromosomal Aberrations	

870.5395   Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

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

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

1 Endpoint is met with combined chronic toxicity/carcinogenicity study
in rats.A.2	Toxicity Profiles tc  \l 2 "A.2	Toxicity Profiles  

Table A.2.1	Acute Toxicity Profile of Fluopicolide Technical, and
Selected Metabolites and Formulations

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

870.1100	Acute oral [rat] Fluopicolide

Technical 98.3% (AE C638206)

Formulation SC 40 (AE C638206)

Formulation SC61 (AE B066752)	

46708601

46709903

46709803	

LD50≥  2000  mg/kg (f)

LD50 ≥ 2000  mg/kg (m/f)

LD50 ≥ 2000  mg/kg (m/f)	

III

III

III

870.1100	Acute oral [rat] Metabolites

2,6-dichlorobenzamide (BAM)

1,3-chloro-5 (trifluoromethyl)

pyridine-2-carboxylic acid (PCA)	

42940201

46708602

46708603	

LD50 ≥ 1538/1144  mg/kg (m/f)

LD50 ≥ 2000/300 mg/kg (m/f)

LD50≥2000 mg/kg (m/f)	

III

II

III

870.1200	Acute dermal [rat]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)	

46708605

46709904

46709804	

LD50 ≥ 5000 mg/kg

LD50 ≥ 4000 mg/kg

LD50 ≥4000 mg/kg	

IV

III

III

870.1300	Acute inhalation [rat]

Technical (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)	

46708606

46709905

46709805	

LC50 ≥ 5.16 mg/L

LC50 ≥ 1.789 mg/L

LC50 ≥ 3.195 mg/L	

IV

III

IV

870.2400	Acute eye irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)	

46708607

46709906 46709806	

slight conjuctival irritation

chemosis/corneal opacity in both studies	

IV

III

III

870.2500	Acute dermal irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)	

46708650

46709907

46709807	

None (PDII = 0.00)

slight (PDII = 0.08)

slight (PDII = 0.25)	

IV

IV

IV

870.2600	Skin sensitization [guinea pig]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)	

46708608

46709908

46709808	

Negative (Magnusson-Kligman)

Negative (Buehler)

Negative (Modified Buehler)	

non-sensitizer



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

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3050	28-day dietary toxicity (mouse)	46708609 (2000)

Acceptable/Guideline

M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129,  980/1242 mg/kg/day 	NOAEL =
980/1242 mg/kg/day; the limit dose).

The LOAEL was not observed.  

870.3050	28-day dietary toxicity (rat)	46708610 (2000)

Acceptable/Guideline 

M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day	NOAEL =
17.4/17.9 mg/kg/day in males/females).

The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain
and food conversion in females and nephrotoxicity in males.  

870.3050	28-day dietary toxicity (rat)

AE 1344122 (Fluopicolide metabolite)	46708611 (2003)

Acceptable/Guideline 

M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day	NOAEL
= 151.6/167.1 mg/kg/day.

LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body
weight gains in both sexes, and nephrotoxicity in females. 



870.3050	28-day dietary toxicity (rat)

AE C657378 (a Fluopicolide metabolite)	46708612 (2003) 

Acceptable/Guideline 

M/F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6, and 1775.0/1930.8 mg/kg/day
NOAEL  =  159.2/230.6 mg/kg/day.

LOAEL = 1775.0/1930.8 mg/kg/day 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).

870.3050	28-day oral toxicity (dog)

	46708613 (2000)

Acceptable/Non-guideline 

0, 10, 100, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (limit dose).

LOAEL was not observed.  



870.3100

	90-Day oral toxicity (rat)	46474112 (2000)

Acceptable/guideline

M: 0, 7.4, 109, 1668 mg/kg/d

F: 0, 8.4, 119, 1673 mg/kg/day	NOAEL = 109 mg/kg/day for males; 8.4
mg/kg/day for females

LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on
hypertrophy of the zona glomerulosa in the adrenal gland (M/F),
decreased cellularity of the bone marrow (M/F), and trabecular
hyperostosis of the bone joint (M)

870.3100

1092 mg/kg/day (M/F)

LOAEL = not identified

870.3100

	90-Day oral toxicity (mouse)	46474116 (2001)

Acceptable/guideline

M: 0, 10.4, 37.8, 161, 770 mg/kg/d

F: 0, 12.6, 52.8, 207, 965 mg/kg/day	NOAEL = 770 mg/kg/day for males;
207 mg/kg/day for females

LOAEL = not identified for males; 965 mg/kg/day for females based on
increased incidence of liver oval cell proliferation

870.3150

	90-Day oral toxicity (dog)	46474118 (2000)

Acceptable/guideline

M&F: 0, 5, 70, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (M/F)

LOAEL = not identified (M/F)

870.3200

	21/28-Day dermal toxicity (species)	46708614 (2003)

Acceptable Guideline

0, 100, 250, 500, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

No local or systemic toxicity observed

870.3700a

	Prenatal developmental in (rat)

Pilot study	46708615 (2000)

Acceptable/non-guideline

F: 500, 1000 mg/kg/day (GD 7-20)	NOAEL/LOAEL not determined.  Only four
animals/group. Purpose of study was to determine high-dose level for
46474120.

870.3700a

	Prenatal developmental in (rat)	46474120 (2001)

Acceptable/guideline

F: 0, 5, 60, 700 mg/kg/day (GD 7-20)	Maternal NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on decreased body weight gain

Developmental NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on delayed fetal growth and skeletal defects

870.3700b

	Prenatal developmental in (rabbit)

Pilot study	46708616 (2000)

Acceptable/non-guideline

F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day

(GD 6-28)	Maternal NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on reduced defecation and abortion in a
single dose

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b

	Prenatal developmental in (rabbit)	46474122 (2001)

Acceptable/guideline

F: 0, 5, 20, 60 mg/kg/day (GD 6-28)	Maternal NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on death, abortion/premature delivery,
decreased food consumption and weight gain

Developmental NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased
fetal body weight and crown-rump length

870.3800

	Reproduction and fertility effects

(rat)	46474124 (2003)

46474125 (additional data, 2004)

46474126 (range-finding, 2002)

Acceptable/guideline

M: 0, 7.4, 36.4, 144.6 mg/kg/d

F: 0, 8.1, 41.0, 159.7 mg/kg/day	Parental/Systemic NOAEL = 36.4/41.0
mg/kg/day (M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males
and females and decreased weight gain in females.

Reproductive NOAEL = 144.6/159.7 mg/kg/day (M/F)

LOAEL = not identified.

Offspring NOAEL = 36.4/41.0 mg/kg/day (M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and
weight gain.

870.4100b

	Chronic toxicity (dog)	44674128 (2002)

Acceptable/guideline

M&F: 0, 70, 300, 1000 mg/kg/day	NOAEL = 300 mg/kg/day (M); 1000
mg/kg/day (F)

LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not
identified (F)

870.4200b

	Carcinogenicity

(mouse)	46474130 (2003)

Acceptable/guideline

M: 0, 7.9, 64.5, 551.0 mg/kg/d

F: 0, 11.5, 91.9, 772.3 mg/kg/day	NOAEL = 64.5/91.9 mg/kg/day (M/F)

LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and
weight gain and liver lesions.

no evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity

(rat)	46474139 (2003)

Acceptable/guideline

M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day

F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day	NOAEL = 31.5/41.0 mg/kg/day (M/F)

LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F)
and thyroid toxicity (M).

no evidence of carcinogenicity



870.5100 	Gene Mutation

 (Salmonella typhimurium)	46474146 (2001)

Unacceptable/guideline

1.6- 5000 µg/plate

46474202 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474148 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474144 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474142 (2004)

Acceptable/guideline

AE638206 (batch mixture of  PP/241067/1 and PP/241024)

5 - 5000 µg/plate

	negative (non-mutagenic) Upgradeable if purity for test material is
given. 

negative (non-mutagenic)

negative (non-mutagenic)

negative (non-mutagenic

positive (mutagenic)



870.5300 	Gene mutation

 (Chinese hamster lung cells)	46474204 (2000)

Acceptable/guideline

AE638206 (batch mixture of  PP/241067/1 and PP/241024)

1.2- 3820 µg/mL	negative (non-mutagenic)

870.5375 	Cytogenetics	

46474208 (2001)

Acceptable/guideline

1.22 to 625 µg/mL

46474206 (2004)

Acceptable/guideline

AE638206 (batch mixture of PP/241067/1 and PP/241024)

3.2 to 100 µg/mL

	

negative for chromosome aberrations

positive for aberrations without S9 activation

870.5395

	Micronucleus

 (mouse)	

46474214 (2003)

Acceptable/guideline

150, 300 or 600 mg/kg/day

46474210 (2005)

Acceptable/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

	

negative at doses up to 600 mg/kg

negative at doses up to 2000 mg/kg 

negative at dose of 2000 mg/kg

870.5550	Unscheduled DNA Synthesis

(rat hepatocytes)	42169839 (1989)

Acceptable/guideline	negative at concentration up to 300 µg/mL in
cultured rat hepatocytes 

(no OPPTS no./ FIFRA test guideline 84-2)	Other Genotoxicity 

Unscheduled DNA synthesis (rat hepatocytes)	46474216 (2000)

Acceptable/guideline

AE638206 (batch mixture of PP/241067/1 and PP/241024)

 600 or 2000 mg/kg	negative at concentrations up to 2000 mg/kg in
hepatocytes from treated rats

870.6200a 

	Acute neurotoxicity screening battery

(rat)	46474218 (2002)

46474219 (range-finding, 2002)

Acceptable/guideline

M/F: 0, 10, 100, 2000 mg/kg	NOAEL = 100 mg/kg (M/F)

LOAEL = 2000 mg/kg (M/F) based on transiently lowered body temperature.

870.6200b

	Subchronic neurotoxicity screening battery	46474221 (2002)

46474222 (positive control, 2002)

Acceptable/guideline

M: 0, 15.0, 106.6, 780.6 mg/kg/day

F: 0, 18.0, 125.2, 865.8 mg/kg/day	NOAEL = 106.6/18.0 mg/kg/day (M/F)

LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food
consumption, and food efficiency.

870.6300

	Developmental neurotoxicity	None

	870.7485

	Metabolism and pharmacokinetics

(rat)	46474242 (2004)-main studies

46474241 (2001)

46474244 (2003)

46474226 (2003)

46474239 (2003)

	rapid absorption, metabolism and excretion; main metabolites were
oxidative N-dealkylation cleavage products. Primary route of excretion
is fecal and urinary with little accumulation in the tissues.

870.7485

	Metabolism and pharmacokinetics

(rat)	46708632 (2002)

Acceptable Non-guideline	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.

870.7485

	Metabolism and pharmacokinetics

(rat)

AE C657188 (PCA)	46708636 (2002)

Acceptable Guideline	AE C657188 (PCA) showed high (87%) absorption but
low (14 – 21%) metabolism.  Excretion is mainly through the urine,
with a minor portion in the feces.

870.7485

	Metabolism and pharmacokinetics

(rat)

AE C653711 (2,6-dichloro-benzamide	46708633 (2003)

46708634 (2003)

46708635 (2003)

Acceptable Guideline	Absorption: 50-79%.  Metabolized extensively to 18
identified compounds.  The majority of the radioactivity was associated
with a mercapturic acid conjugate of hydroxyl-chlorobenzamide
(15-5-26.2%), present in the urine  Excretion mainly through urine and
feces.  

870.7600	Dermal penetration

(rat)	46708638 (2003)

Acceptable Guideline

1.43, 659 ug/cm2 skin	In vivo study

Dermal Penetration rate:  37%

870.7600	Dermal penetration

(comparative)	46708637 (2003)

Acceptable Non-guideline

1.9, 744 ug/cm2 skin

	In vitro study

Rat skin dermal penetration rate  is 7.8 times greater than human skin.



A.3	Executive Summaries tc  \l 2 "A.3	Executive Summaries" 

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.

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.

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

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 5th
metacarpal or 5th 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 F0
generation and 24 F1 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 F0 males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for F1
males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F0 females; and 0, 9.4,
46.9, and 193.9 mg/kg bw/day for F1 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 F0 and F1 males during
premating/postmating periods and in female rats during premating except
as noted below.  High-dose F0 females gained up to 14% (p<0.01) less
weight than controls and high-dose F1 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 F0
and F1 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 F0 generation and by 10-11% throughout
gestation in the F1 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 F0 females during GD 0-6 was not accompanied by a decrease
in body weight.  High-dose  F0 and F1 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 F0 and F1 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 F0 and F1 males had
small, statistically significant increases in absolute and relative
kidney weights and high-dose F0 and F1 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 F0 and F1 male and female rats.  The incidences
of  cortical tubular basophilia, medullary granular casts, and cortical
scarring were significantly increased in high-dose F0 and F1 males
compared with the control incidences.  The incidence of interstitial
inflammation was significantly increased in high-dose F0 males.  The
increased incidences of cortical tubular dilatation and cortical
granular casts in high-dose F1 males did not reach statistical
significance but were considered treatment related.  In high-dose F0 and
F1 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 F0 females and kidney toxicity in F0 and F1 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 F1 or F2 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 F1 offspring.  Body
weight was significantly reduced by 7-13% in high-dose group F1 and F2
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
F1 male and female pups and by 11-14% in high-dose F2 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
F1 and F2 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 F1 and F2 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 F0 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).

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, Reverse gene mutation

MRID 46474146

Unacceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IC99 0005 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, Reverse gene mutation

MRID 46474202

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IC99 0001 is considered nonmutagenic in the conventional
battery of bacterial strains. 

Guideline 84-2, Reverse gene mutation

MRID 46474148

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IB99 0002 is considered nonmutagenic in the conventional
battery of bacterial strains.

Guideline 84-2, Reverse gene mutation

MRID 46474144

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 Technical is considered nonmutagenic in the conventional
battery of bacterial strains.

Guideline 84-2, Reverse gene mutation

MRID 46474142

acceptable/guideline

	dose range:  5 to 5000 µg/plate

AE C638206 (fluopicolide) is considered mutagenic at precipitating
concentrations in the conventional battery of bacterial strains.



	Cytogenetics

Guideline 84-2, in vitro mammalian cells in culture/gene mutation assay
in Chinese hamster lung cells

MRID 46474204

Acceptable/guideline

	1.2 to 3820 µg/mL,  0.4 to 120 µg/mL and 0.313 to 60 µg/mL with and
without activation

No concentration in any of the three experiments was a biologically
relevant, reproducible increase in mutant colonies found at
concentrations up to the highest subcytotoxic levels.  Both positive
controls showed marked increases. 

Guideline 84-2, in vivo mammalian chromosome
aber慲楴湯൳前䑉㐠㐶㐷〲സ捁散瑰扡敬术極敤楬敮܍⸱
㔲琠⁯㈶‵枵洯⁌楷桴畯⁴捡楴慶楴湯愠摮㐠㠮‸潴㘠
㔲딠⽧䱭眠瑩⁨捡楴慶楴湯

In the presence of  ≥50% reduction in the MI, no statistically
significant increases in the structural or numerical (polyploidy)
aberrant metaphases were found at any test concentration in either
trial, compared to marked (p≤0.001) increases in both positive
controls. 

Guideline 84-2, in vitro mammalian chromosome aberrations

MRID 46474206

Acceptable/guideline

	3.2 to 100 µg/mL with and without activation; 0.1 to 6.3 µg/mL
without activation

This batch mixture of AE C638206 is considered a clastogen in the in
vitro Chinese hamster lung (V79) cell system in the absence of S9
activation. 

Guideline 84-2, in vivo mammalian cytogenetics

MRID 46474214

Acceptable/guideline

	IP injection of 150, 300 or 600 mg/kg/day

No dose up to the HDT was a significantly increased number of mPCEs
recorded, in the presence of a statistically increased ratio of PCEs to
NCEs (evidence of interference 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 vivo mammalian cytogenetics

MRID 46474210

Acceptable/guideline

	Two oral doses of 200, 600, or 2000 mg/kg/day, 24 hours apart

No adverse clinical signs were observed during the main study. The ratio
of polychromatic to normochromatic erythrocytes 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 # given),  Unscheduled DNA synthesis in hepatocytes

MRID 46474216

acceptable/guideline	600 or 2000 mg/kg

There was no evidence (or a dose-related positive response) that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures (nuclear silver grain counts) was induced at either timed
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 [14C-2,6-pyridyl]-AE C638206 at 10 mg/kg bw or
[14C-2,6-pyridyl]-AE C538206 and [14C-U-phenyl]-AE C638206 at 10 and 100
mg/kg bw.  Rats were subjected to the dosing regimens above using
[14C-2,6-pyridyl]-AE C538206 (lot nos. 903AE-3 and GAR 2034-/4; >99% and
97% radiochemical purity) or [14C-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 [14C-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 [14C-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-2,6-14C]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-2,6-14C]-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.

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
[14C]-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-14C]-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 [14C]-AE C653711 at dose levels of
10 or 150 mg/kg.  A third group of five rats/sex was given 14 daily
doses of [14C]-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.

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), [14C-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/cm2 skin) was applied to 12 cm2
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),
[14C-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/cm2 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 TC \l1 "Appendix B:  Metabolism
Assessment  

	B.1	Metabolism Guidance and Considerations  tc  \l 2 "B.1	Metabolism
Guidance and Considerations"  

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
tc  \l 2 "B.2	Tabular Summary of Fluopicolide and its Metabolites and
Degradates" 

	Table B.2    Summary of Fluopicolide and its Metabolites and Degradates



Chemical Name (other names in parenthesis)	

Matrix	Percent TRR (PPM) 1	Structure



Matrices - Major Residue, >10%TRR	Matrices - Minor Residue, <10%TRR

	2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]-benza
mide

(fluopicolide)

(AE C638206)	Primary Crops:	



	Grapes (fruit)	87.4 - 91.2%

(0.910 - 1.15 ppm)



	Lettuce

(mature leaves)	95.9 – 96.4%

(12.84 - 13.98 ppm)	 



Potato (mature tuber)	51.1 – 70.2%

(0.037 - 0.041 ppm)



	Rotational Crops (29-day PBI): 



Lettuce	11.1- 35.8%

(0.108- 0.112 ppm )



	Radish top	24.5- 51.1%

(1.072- 1.644 ppm)



	Radish root	41.1- 47.9%

(0.048- 0.069 ppm)



	Wheat forage	33.7- 36.6%

(1.445- 1.812 ppm)



	Wheat grain	27.3%

(0.043 ppm)	1.8%

(0.046 ppm)



Wheat straw	23.1- 34.9%

(2.462- 3.132 ppm)



	Rotational Crops (365-day PHI):



Lettuce	41.5%

(0.024 ppm)	2.1%

(0.013 ppm)



Radish top	25.2%

(0.106 ppm)	3.8%

(0.076 ppm)



Radish root	24.2- 55.8%

(0.009-0.018 ppm)



	Wheat forage	27.8%

(0.068 ppm)	4.8%

(0.042 ppm)



Wheat grain

2.9- 7.3%

(0.004- 0.005 ppm)



Wheat straw	27.5%

(0.277 ppm)	7.2%

(0.172 ppm)



Ruminants:



Fat	73.4- 76.3%

(0.0312- 0.034 ppm)



	Kidney

1.0- 1.8%

(0.003, 0.003  ppm)



Liver

0.9- 2.9%

(0.0055- 0.013 ppm)



Milk	28.6%

(0.0054 ppm)



	Muscle

2.9%

(0.0007 ppm)



Poultry:



Egg white

2.5%

(0.001ppm)



Egg yolk	10.5- 11%

(0.005- 0.017 ppm)



	Fat	15.6%

(0.004 ppm)	6%

(0.004 ppm)

	2,6-dichlorobenzamide

(BAM)

(AE C653711)

	Primary Crops:	



	Grapes (fruit)

2.0%

(0.026 ppm)



Lettuce



0.9%

(0.112 ppm)



Potato	25.4%

(0.021 ppm)	





Rotational Crops (29-day PBI):



Lettuce	81.2%

(0.822 pm)



	Radish top	65.3%

(4.381 ppm)



	Radish root	43.2%

(0.062 ppm)



	Wheat forage



6.3%

(0.312  ppm)



Wheat grain

3.6%

(0.006 ppm)



Wheat straw

3.4%

(0.461 ppm)



Rotational Crops (365-day PHI):



Lettuce	87.0%

(0.539 ppm)



	Radish top	87.5%

(1.755 ppm)



	Radish root	60.9%

(0.022 ppm)



	Wheat forage	14.8%

(0.128 ppm)



	Wheat grain	17.9%

(0.010 ppm)



	Wheat straw

5.1%

(0.121 ppm)



Ruminants:





Milk

3.9%

(0.0007 ppm)



Poultry:



Liver	37%

(0.361 ppm)



3-chloro-5-trifluoromethylpyridine-2-carboxylic acid

(PCA)

(AE C657188)	Primary Crops:	



	Grapes (fruit)

2.3%

(0.024 ppm)



Lettuce

0.6%

(0.078 ppm)



Potato	12.0%

(0.007 ppm)



	Rotational Crops (29-day PBI):



Lettuce	17.4%

(0.053 ppm)



	Radish top	10.4%

(0.217 ppm)



	Radish root	33.5%

(0.039 ppm)



	Wheat forage	43.0%

(1.844 ppm)



	Wheat grain	69.6%

(1.809 ppm)



	Wheat straw

7.0%

(0.494 ppm)



Rotational Crops (365-day PHI):



Lettuce	11.8%

(0.007 ppm)



	Radish top	27.1%

(0.114 ppm)



	Radish root	10.0%

(0.003 ppm)



	Wheat forage

8.2%

0.020 ppm)



Wheat grain	14.2%

(0.025 ppm)



	Wheat straw

4.1%

(0.042 ppm)

	2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydro
xybenzamide

(AE C643890)	Primary Crops:	



	Grapes (fruit)

0.2%

(0.002 ppm)





Potato

1.7- 2.4%

(0.001-0.003 ppm)



Rotational Crops(29-day PBI):



Wheat forage

1.4, <1.5%

(0.060, <0.074 ppm)



Wheat grain	13.1%

(0.021 ppm)



	Rotational Crops (365-day PHI):



Kidney

6.8%

(0.0207 ppm)

2.6% *

(0.005 ppm)*



Liver

1.6%

(0.0105 ppm)

4.0%*

(0.018 ppm)*



Poultry:



Liver

3.1%**

(0.030 ppm)**

	2,6-dichloro-3-hydroxybenzamide

(3-OH-BAM)

(BAM-OH)

(AE C657378)

	Rotational Crops (29-day PBI):	

                          

	Wheat forage	32.7%

(1.619 ppm)



	Wheat straw	13.6%

(1.844 ppm)



	Rotational Crops (365-day PBI):



Wheat forage	59.3%

(0.513ppm)



	Wheat grain	24.5%

(0.013 ppm)



	Wheat straw	28.0%

(0.663 ppm)



3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid

(P1X)

(AE 1344122)

	Rotational Crops (29-day PBI):	  

  

                       

                          

                            

	Lettuce	13.0%

(0.039 ppm)



	Radish top

3.3%

(0.069 ppm)



Radish root

9.6%

(0.011 ppm)



Wheat forage

3.8%

(0.163 ppm)



Wheat grain	13.1%

(0.341 ppm)



	Wheat straw

7.7%

(0.544 ppm)



Rotational Crops (365-day PHI):



Lettuce

7.8%

(0.005 ppm)



Radish top

5.1%

(0.022 ppm)



Radish root

5.3%

(0.002 ppm)



Wheat forage	18.3%

(0.045 ppm)



	Wheat grain	64.9%

(0.116 ppm)



	Wheat straw	14.2%

(0.143 ppm)



3-chloro-5-(trifluoromethyl)-2-pyridinol

(AE B102859)	Rotational Crops (29-day PHI):	                            
 



	Lettuce

5.3%

(0.016 ppm)



Radish top

4.8%

(0.100 ppm)



Rotational Crops (365-day PHI):



Lettuce

3.7%

(0.002 ppm)



Radish top

6.0%

(0.025 ppm)



Wheat forage

9.9%

(0.024 ppm)

	3-chloro-5-(trifluoromethyl)-2-pyridine carboxamide

(AE C653598)	Rotational Crops (365-day PHI):	                           
 

	Lettuce

9.0%

(0.005 ppm)



Radish top

9.5%

(0.003 ppm)



Wheat forage

6.3%

(0.015 ppm)



Wheat straw

4.8%

(0.048 ppm)

	2,6-dichloro-N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-4-hydroxy
benzamide

(AE 0712556)

	Ruminants:	     

                                 

	Kidney

3.3%

(0.0098 ppm)



Liver

1.2%

(0.0076 ppm)



Poultry:



Egg white	41.2%

(0.005)



	Egg yolk	15.9%]

(0.014 ppm)



	Fat	47.3%

(0.012 ppm)



	Liver

5.9%

(0.016 ppm)

	2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-(me
thylsulfonyl)benzamide

(Metabolite 1)	Poultry:	

	Egg white	51%

(0.022 ppm)



	Fat	38%

(0.023 ppm)



Hydroxy glucuronide of fluopicolide	Ruminants:	



	Kidney

4.7%

(0.009 ppm)



Liver

4.9%

(0.022 ppm)



Poultry

	Dihydroxy glucuronide of fluopicolide	Ruminants:	



	Kidney	10.0%

0.019 ppm



Hydroxy sulfate of fluopicolide	Ruminants:	

	Kidney

5.2%***

(0.010 ppm)***



Liver

2.4%

(0.011 ppm)



Egg yolk

7.1%

(0.006 ppm)



Liver

1.0-1.4%

(0.003-0.004 ppm)

Check 46708519

	Dihydroxy sulfate of fluopicolide	Ruminants:	

	kidney

Reported with hydroxysulfate above



Egg white	22.5%

(0.003 ppm)



	Egg yolk	34.0%

(0.015 ppm)



	Liver

1.9%

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 [14C-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]benzam
ide] 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.  

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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 Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

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 sweet 	0.02



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 Chrysanthemum 	20



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 Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

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 potato waste	None proposed	0.05

	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 byproducts	None proposed	0.05 ppm	Cattle, meat 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 byproducts	None proposed	0.05 ppm	Horse, meat 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 byproducts	None proposed	0.05 ppm	Sheep, meat 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 byproducts	None proposed	0.07

	Wheat, aspirated grain fractions	None proposed	0.07

	 TC \l1 "Appendix C:  Tolerance Assessment Summary and Table  



Appendix D:  	Review of Human Research TC \l1 "Appendix D:  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 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.

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഍഍倍条⁥ 景†–啎偍䝁卅尠‪牡扡捩尠‪䕍䝒䙅剏
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ക倍条⁥–䅐䕇ᐠ㌷―景ጠ丠䵕䅐䕇⁓ㄔ㠲ക倍条⁥–
䅐䕇ᐠ㈱ᔸ漠⁦–啎偍䝁卅ᐠ㈱ᔸ഍č഍

