  SEQ CHAPTER \h \r 1 							

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

March 6, 2008	PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

  

MEMORANDUM

SUBJECT:	Fluopicolide:  Human Health Risk Assessment for the
Establishment of Tolerances for Use on Root Vegetables (Subgroup 1A),
Leaves of Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group
3), and Head and Stem Brassica (Subgroup 5A). PC Code: 027412, Petition
No: 7E7172, DP Number: 336216

		Regulatory Action:  Section 3 Registration Action

Risk Assessment Type: Single Chemical/Aggregate

FROM:	Felecia Fort, Risk Assessor 

		Reregistration Branch 1

		

		Amelia Acierto, Chemist

		Kelly O’Rourke, Biologist

		Myron Ottley, Toxicologist

		Registration Action Branch 3

		Health Effects Division (7509P)

THROUGH:	Donna S. Davis, Senior Chemist

	Reregistration Branch 1

Health Effects Division (7509P)

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

		Fungicide Branch

		Registration Division (7505P)

The Health Effects Division (HED) has conducted a human health risk
assessment to estimate the risk to human health that will result from
proposed and registered uses of the fungicide fluopicolide.  The
Interregional Research Project No. 4 (IR-4) on behalf of the
Agricultural Experiment Stations of AZ, CA, FL, GA, MI, ND, OR, and WA
has submitted a petition, PP#7E7172, proposing the establishment of
tolerances in/on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A).  Under a pending petition  (PP#5F7016, DP#
327026), fluopicolide was proposed for use on grape, potato, sweet
potato, cucurbit vegetables, fruiting vegetables, and leafy vegetables
(except Brassica), reflecting similar use patterns.  

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc192533349"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc192533349 \h  3  

  HYPERLINK \l "_Toc192533350"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc192533350 \h  6  

  HYPERLINK \l "_Toc192533351"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc192533351 \h  6  

  HYPERLINK \l "_Toc192533352"  2.2	Structure and Nomenclature	  PAGEREF
_Toc192533352 \h  8  

  HYPERLINK \l "_Toc192533353"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc192533353 \h  9  

  HYPERLINK \l "_Toc192533354"  3.0	HAZARD CHARACTERIZATION/ASSESSMENT	 
PAGEREF _Toc192533354 \h  9  

  HYPERLINK \l "_Toc192533355"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc192533355 \h  9  

  HYPERLINK \l "_Toc192533356"  3.2	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc192533356 \h  10  

  HYPERLINK \l "_Toc192533357"  3.3	Endocrine Disruption	  PAGEREF
_Toc192533357 \h  12  

  HYPERLINK \l "_Toc192533358"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc192533358 \h  12  

  HYPERLINK \l "_Toc192533359"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc192533359 \h  12  

  HYPERLINK \l "_Toc192533360"  4.1.1	Pesticide Metabolism and
Analytical Methods	  PAGEREF _Toc192533360 \h  12  

  HYPERLINK \l "_Toc192533361"  4.1.2	Drinking Water Residue Profile	 
PAGEREF _Toc192533361 \h  13  

  HYPERLINK \l "_Toc192533362"  4.1.3	Food Residue Profile	  PAGEREF
_Toc192533362 \h  14  

  HYPERLINK \l "_Toc192533363"  4.1.4	International Residue Limits	 
PAGEREF _Toc192533363 \h  15  

  HYPERLINK \l "_Toc192533364"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc192533364 \h  15  

  HYPERLINK \l "_Toc192533365"  5.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE AND RISK	  PAGEREF _Toc192533365 \h  16  

  HYPERLINK \l "_Toc192533366"  5.1   Residential Handler Exposure and
Risk	  PAGEREF _Toc192533366 \h  17  

  HYPERLINK \l "_Toc192533367"  5.2   Residential Postapplication
Exposure and Risk	  PAGEREF _Toc192533367 \h  17  

  HYPERLINK \l "_Toc192533368"  5.3   Recreational Postapplication
Exposure	  PAGEREF _Toc192533368 \h  18  

  HYPERLINK \l "_Toc192533369"  5.4   Off Target Non-Occupational
Exposure	  PAGEREF _Toc192533369 \h  18  

  HYPERLINK \l "_Toc192533370"  6.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc192533370 \h  19  

  HYPERLINK \l "_Toc192533371"  6.1	Acute Aggregate Risk	  PAGEREF
_Toc192533371 \h  19  

  HYPERLINK \l "_Toc192533372"  6.2	Short-Term Aggregate Risk.	  PAGEREF
_Toc192533372 \h  19  

  HYPERLINK \l "_Toc192533373"  6.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc192533373 \h  20  

  HYPERLINK \l "_Toc192533374"  6.4	Long-Term Aggregate Risk	  PAGEREF
_Toc192533374 \h  20  

  HYPERLINK \l "_Toc192533375"  6.5	Cancer Risk	  PAGEREF _Toc192533375
\h  20  

  HYPERLINK \l "_Toc192533376"  7.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc192533376 \h  21  

  HYPERLINK \l "_Toc192533377"  8.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc192533377 \h  21  

  HYPERLINK \l "_Toc192533378"  8.1	Handler Exposure and Risk	  PAGEREF
_Toc192533378 \h  21  

  HYPERLINK \l "_Toc192533379"  8.2   Occupational Postapplication
Exposure and Risk	  PAGEREF _Toc192533379 \h  24  

  HYPERLINK \l "_Toc192533380"  9.0	DATA NEEDS/LABEL REQUIREMENTS	 
PAGEREF _Toc192533380 \h  26  

  HYPERLINK \l "_Toc192533381"  9.1	Toxicology	  PAGEREF _Toc192533381
\h  26  

  HYPERLINK \l "_Toc192533382"  9.2	Residue Chemistry	  PAGEREF
_Toc192533382 \h  26  

  HYPERLINK \l "_Toc192533383"  9.3	Occupational and Residential
Exposure	  PAGEREF _Toc192533383 \h  27  

  HYPERLINK \l "_Toc192533384"  10.0 	REFERENCES	  PAGEREF _Toc192533384
\h  27  

  HYPERLINK \l "_Toc192533385"  Appendix A:  Toxicity Profile	  PAGEREF
_Toc192533385 \h  28  

  HYPERLINK \l "_Toc192533386"  Appendix B:  Chemical Structures	 
PAGEREF _Toc192533386 \h  36  

  HYPERLINK \l "_Toc192533387"  Appendix C:  Tolerance Summary	  PAGEREF
_Toc192533387 \h  44  

 

  SEQ CHAPTER \h \r 1 1.0	EXECUTIVE SUMMARY

The Health Effects Division (HED) of EPA's Office of Pesticide Programs
has evaluated the toxicity and exposure databases for the pesticide
active ingredient fluopicolide, and has conducted a human health risk
assessment.  Fluopicolide is a fungicide with a toxic
degradate/metabolite, 2,6-dichlorobenzamide (BAM); however, this risk
assessment addresses risks from fluopicolide residues alone.  Risks
associated BAM will be addressed in a separate human health risk
assessment which is being conducted concurrently.  Risks from food,
water, and residential exposure are evaluated in this risk assessment. 
It also includes an occupational assessment which evaluates risks to
workers.  The principal registrant for fluopicolide is Valent U.S. A.
Corporation.  

Fluopicolide is a fungicide that controls a wide range of diseases
including downy mildews, late blight), and some Pythium species.  There
are existing tolerances for residues of fluopicolide on imported grapes.
 Recently, HED reviewed a petition requesting the establishment of
tolerances for residues of fluopicolide in/on tuberous and corm
vegetables subgroup 1C; vegetable, leafy, except Brassica, group 4;
vegetable, fruiting, group 8; vegetable, cucurbit, group 9; grape; and
raisins; the proposed tolerance on wheat is for indirect and inadvertent
residues in rotational wheat commodities (PP#5F7016).   

The submitted toxicology data base for technical fluopicolide is
complete.  No additional studies are required to support the proposed or
registered uses of fluopicolide.  The database is considered sufficient
to clearly define the toxicity of fluopicolide.  

In general, the toxicology studies conducted on fluopicolide demonstrate
few or no biologically significant toxic effects at relatively low-dose
levels in animal studies and only mild or no toxic effects at high
doses.   The subchronic and chronic toxicity studies showed that the
primary effects of fluopicolide are in the liver.  The toxicological
database indicates that technical grade fluopicolide has relatively low
acute toxicity (Category III and IV).  Fluopicolide is not a dermal
sensitizer, primary eye irritant, or primary skin irritant. 
Fluopicolide is also not neurotoxic, carcinogenic, nor mutagenic. 
Fluopicolide is not a developmental or reproductive toxicant.  There is
no evidence of increased susceptibility of rat or rabbit fetuses to in
utero or post-natal exposure to fluopicolide.  No toxic effects were
observed in studies in which fluopicolide was administered by the dermal
routes of exposure.

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.   A 1X FQPA Safety Factor is recommended 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.    Furthermore, the exposure assessments are
unlikely to underestimate risk.

Acute and cancer dietary exposure and risk assessments were not
conducted for fluopicolide.  An acute dietary assessment was not
conducted because an endpoint attributable to a single dose was not
identified from the available data.  A cancer dietary assessment was not
conducted because fluopicolide is not likely to be carcinogenic to
humans.  HED selected a chronic RfD of 0.50 mg/kg/day (NOAEL = 50
mg/kg/day; Uncertainty Factor = 100).  This chronic RfD is based on the
chronic oral toxicity study in dogs in which increased incidences of
clinical signs (emesis, salivation, and soft stool) occurred following
65 weeks of exposure.  

ups (≤11% cPAD).   The chronic dietary (food and drinking water)
exposure assessment was a conservative assessment using tolerance level
residues and assuming that 100% of the crop was treated.  

There are no new residential uses associated with this petition, however
in addition to food and drinking water, the use currently registered use
pattern for fluopicolide is expected to result in exposure to the
general population through residential settings from use on turf. 
Exposure to fluopicolide from use on residential turfgrass and
recreational sites, such as golf courses, has been evaluated in an
earlier assessment (D326082, K. O’Rourke, 10/09/07).  For short-term
non-occupational handler exposure, the total MOEs for residential
handlers are well above the level of concern (LOC) of 100, and are not
of concern.  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
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 also not of concern.

In accordance with the FQPA, an aggregate assessment was conducted which
considered pesticide exposure and risk from the residential, food, and
water pathways.  These exposures included adults applying fluopicolide
in a residential setting (dermal and inhalation exposure),
postapplication exposure to adults and children (dermal exposure), and
postapplication oral exposure to children (by putting hands or objects
in their mouth or by ingesting dirt).   The estimated aggregate
short-term risks for all of the exposure scenarios that were calculated
were below HED’s level of concern. 

Exposures can also occur for occupational handlers loading or applying
fluopicolide, as well as through postapplication exposure.   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 label) with MOEs ranging from 110 to
19,000.  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, and therefore, are not of concern. 
The fluopicolide technical material has been classified in Toxicity
Category 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.

	

Regulatory Recommendation

Pending submission of a revised label and  Section F (as noted below),
and further provided the residue chemistry deficiencies cited in Section
9.2 of this document are satisfied as a condition of registration, HED
has no objection to the registration of the requested uses of
fluopicolide excluding sugar beet and carrot and establishment of
tolerances for fluopicolide as follows:

Tolerances to be established under 180.627 (a) General. (1)

Tolerances are established 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):

Vegetable, root, subgroup 1A except sugar beet and carrot 	……..0.15
ppm

Vegetable, leaves of root and tuber, group 2
…………..…………15.0 ppm

Vegetable, bulb, group
3-07……………………………………….7.0 ppm

Brassica, head and stem, subgroup
5A…………………………….5.0 ppm

Note, due to recent changes in the subgroup definitions, the tolerances
recommended above will cover all crops for which IR-4 has requested a
use with the exception of carrots and sugar beets.

  

The following revisions to the label are required prior to registration:

The proposed PHI for root and tuber vegetables must be revised to 7
days. 

Until all field rotational crop 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 bulb vegetables,
Brassica head and stem vegetables, cucurbit vegetables, fruiting
vegetables, grapes, leafy vegetables, root vegetables, tuberous and corm
vegetables, and wheat, with a 0-day PBI for bulb vegetables, Brassica
head and stem vegetables, cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables, root vegetables, and tuberous and corm
vegetables, and a 30-day PBI for wheat.  

A revised Section F should be submitted as follows:

The proposed tolerance expression should be revised to reflect the
correct chemical name for fluopicolide.

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
9.

A revised Section F should be submitted to propose for Vegetable, bulb,
group 3-07 and delete the list of individual crops under these
subgroups.  

Additional residue chemistry data deficiencies identified in Section 9.2
should be addressed as a condition of registration.

Based on the decision made under PP#5F7016, HED will not consider
granting the new uses of fluopicolide associated with livestock
food/feed commodities (carrots and sugar beets) until the requirements
for livestock metabolism studies including feeding studies with
fluopicolide and BAM are fulfilled.

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 Registered/Proposed Uses 

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide in/on imported grapes at 2.0 ppm and raisins at 6.0 pm.
There are currently no registered uses of fluopicolide in the U.S.
although Valent U.S.A. Corporation has submitted a petition, PP#5F7016,
proposing the establishment of tolerances for residues of fluopicolide
in/on tuberous and corm vegetables subgroup 1C; vegetable, leafy, except
Brassica, group 4; vegetable, fruiting, group 8; vegetable, cucurbit,
group 9; grape; and raisins; the proposed tolerance on wheat is for
indirect and inadvertent residues in rotational wheat commodities.  HED
has reviewed and has recommended in favor of granting the requested
registrations and establishment of tolerances for fluopicolide on the
raw agricultural commodities proposed except for potato and wheat which
are livestock food/feed commodities.

The Interregional Research Project No. 4 (IR-4) on behalf of the
Agricultural Experiment Stations of AZ, CA, FL, GA, MI, ND, OR, and WA
has submitted a petition, PP#7E7172, proposing the establishment of
tolerances for residues of the fungicide fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] in/on the following raw agricultural commodities (RAC).

Root vegetables subgroup 1-A 	0.15 ppm

Leaves of root and tuber vegetables, group 2 	13 ppm

Bulb vegetables, group 3 	6 ppm

Chive, fresh leaves 	6 ppm

Chive, Chinese, fresh leaves 	6 ppm

Daylily, bulb 	6 ppm

Elegans hosta 	6 ppm

Fritillaria, bulb 	6 ppm

Fritillaria, leaves	6 ppm

Garlic, Serpent, bulb 	6 ppm

Kurrat 	6 ppm

Lady’s leek 	6 ppm

Leek, wild 	6 ppm

Lily, bulb 	6 ppm

Onion, Beltsville bunching	6 ppm

Onion, Chinese, bulb 	6 ppm

Onion, fresh 	6 ppm

Onion, macrostem 	6 ppm

Onion, pearl	6 ppm

Onion, potato, bulb 	6 ppm

Onion, tree, tops 	6 ppm

Shallot, bulb 	6 ppm

Shallot, fresh leaves 	6 ppm

Head and stem Brassica subgroup 5-A	5 ppm

In conjunction with this petition, IR-4 is requesting an amended
registration of the Valent U.S.A Corporation end-use product, V-10161 4
SC, a 4 lb ai/gal suspension concentrate (SC) formulation which is
equivalent to a flowable concentrate (FlC) formulation of fluopicolide
with EPA File Symbol No. 59639-RUN. The product is being proposed for
use on Brassica head and stem vegetables, bulb vegetables, and leaves of
root and tuber vegetables excluding potato and sweet potato.  The
product is proposed for four foliar applications at up to 0.125 lb
ai/A/application at a 7 to 14-day retreatment interval (RTI) for all
crops with a maximum seasonal rate of 0.375 lb ai/A and a 2-day
preharvest interval (PHI).  The 4 lb ai/gal SC formulation is to 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 proposed use pattern is
summarized in Table 1.

Table 2.1  Summary of Proposed Fluopicolide Use Pattern

Formulation 1	Applic. Rate 

(lb ai/A)	Applic. Interval (days)	Max. Seasonal Applic. Rate 2

(lb ai/A)	PHI (days)	Use Directions and Limitations 3

Brassica Vegetables (head and stem)

V-10161 4 SC	0.094-0.125	7 - 14	0.375	2	Application to be made in a
minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.  A tank mix with another labeled product with activity on
downy mildew and phytophthora must be used for resistance management on
head and stem Brassica.

Bulb Vegetables

V-10161 4 SC	0.094-0.125	7 - 14	0.375	2	Application to be made in a
minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.  A tank mix with another labeled product with activity on
downy mildew and botrytis must be used for resistance management on bulb
vegetables.

Root and Tuber Vegetables

V-10161 4 SC	0.094-0.125	7 - 14	0.375	2	Application to be made in a
minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.  A tank mix with another labeled product with activity on
pythium must be used for resistance management on root and tuber
vegetables.

1 V-10161 4 SC [Reg No. 59639-RUN] contains 39.5% fluopicolide (4 lbs
ai/gallon). 

2 Three applications per season at maximum rate.

3 Apply only 2 sequential applications before alternating with an
effective fungicide from a different resistance management group.

2.2	Structure and Nomenclature 

The nomenclature of fluopicolide is summarized in Table 2.2., and the
physicochemical properties are summarized in Table 2.3.  

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.

HAZARD CHARACTERIZATION/ASSESSMENT

	3.1	Hazard and Dose-Response Characterization

The hazard characterization for fluopicolide is discussed in detail in
the document entitled 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.  [N. Dodd, D325091, 11/21/07].  The conclusions from that
assessment remain unchanged. 

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.

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
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.  Finally, HED used similarly conservative assumptions to
assess post-application exposure of children as well as incidental oral
exposure of toddlers.		

	3.2	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

The toxicity endpoints and doses for risk assessment were selected based
upon the available toxicity data and the use exposure information on
fluopicolide. 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.  The selected endpoints and
doses are presented below.

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.

	3.3	Endocrine Disruption  

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

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, fluopicolide
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption. 

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION tc "5.0	Dietary Exposure/Risk
Characterization" 

	4.1	Pesticide Metabolism and Environmental Degradation

		4.1.1	Pesticide Metabolism and Analytical Methods 

No new plant or livestock metabolism data or analytical methods were
submitted with the subject petition.  For detailed information, please
refer to the document titled 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 [ 11/21/07, N. Dodd].  To summarize, metabolism
studies with lettuce and potato were previously submitted in conjunction
with PP#5F7016, and a metabolism study with grape was submitted in
conjunction with PP#5E6903.   For the purposes of this petition, the
nature of the residue in plants is adequately understood.  HED
determined that the residue of concern for the tolerance expression for
primary crops is the parent, fluopicolide.  The residues of concern for
the risk assessment for primary crops except tuberous and corm
vegetables are fluopicolide (parent) and BAM.  HED recommended that (in
addition to parent and BAM) PCA should be included in the risk
assessment for tuberous and corm vegetables. 

This petition does not require tolerances in/on livestock.  However,
there are ruminant feed items (i.e., sugar beets and carrot culls)
associated with this petition for which ruminant metabolism studies are
required.  The ruminant metabolism studies submitted previously by the
Valent USA (PP#5F7016) were incomplete and required additional
information to support the ruminant metabolism studies. Based on the
decision made under PP#5F7016, HED will not consider granting the new
uses of fluopicolide associated with livestock food/feed commodities
(carrots and sugar beets) until the requirements for livestock
metabolism studies including feeding studies with fluopicolide and BAM
are fulfilled.

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, ACB/BEAD, 3/14/07).  The LOQ for fluopicolide (parent) is
0.01 ppm.  Currently, no tolerances for ruminant, swine, or poultry
commodities are required to support the proposed uses; therefore,
enforcement methods for these livestock commodities are not required.
However, if a tolerance is needed in the future, confirmatory procedures
or an interference study will be required for the LC/MS/MS Method 303-02
to be considered adequate for enforcement purposes.  If it is determined
in the future that tolerances for poultry commodities are needed, an
enforcement method would be required for poultry commodities.  

Acceptable data collection methods are available to determine the
residues of concern in both plant and livestock commodities.  Adequate
multiresidue methods testing data are also available from the earlier
petition (PP#5F7016) which indicate that the multiresidue methods are
not appropriate for determining residues of fluopicolide.

		4.1.2	Drinking Water Residue Profile  tc "5.1.8	Drinking Water Residue
Profile " \l 3 

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, which are the uses that are
expected to yield the highest estimated environmental concentrations
(EECs).  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 µg/L (ppb) for the 1 in 10 year annual peak concentration (acute)
 

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

6.14 µg/L (ppb) 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.  

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 4.2	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.



		4.1.3	Food Residue Profile 

Root vegetable, subgroup 1A 

Leaves of root and tuber vegetable, group 2

Pending submission of additional storage stability data, the submitted
carrot, radish and sugar beet field trial data are adequate to satisfy
data requirements.  The number and locations of the field trials are in
accordance with OPPTS Guideline 860.1500 for root vegetable, subgroup
1A.  The use pattern of the field trials adequately reflects the use
pattern proposed for root and tuber vegetables other than potato and
sweet potato.  The available field trial data will support a tolerance
for residues of fluopicolide in/on root vegetables, subgroup 1A at 0.15
ppm.  Although the residue decline data for sugar beet roots indicate a
slight increase in residues at a 10-day sampling interval, based on the
submitted data, residues are not likely to exceed the recommended
tolerance of 0.15 ppm.  Adequate data submitted for the tops of radish
and sugar beet is also available to support the recommended tolerance
for the leaves of root and tuber vegetable, group 2 at 15 ppm; this
exceeds the proposed tolerance of 13 ppm.

Vegetable, bulb, group 3-07

IR-4 submitted field trial data for fluopicolide on bulb and green
onions, the representative crops of the bulb vegetable crop group 3-07. 
The submitted bulb and green onion field trial data reflect the use of
three broadcast foliar applications of a 4 lb ai/gal SC formulation of
fluopicolide at total seasonal rates of 0.355-0.366 lb ai/A, with a
2-day PHI.  An acceptable method was used for quantitation of residues
in/on bulb and green onions; however, the available storage stability
data do not support the study storage durations for bulb and green
onions.  Pending submission of additional storage stability data, the
submitted bulb vegetable field trial data are adequate to satisfy data
requirements.   The residues of fluopicolide generally decreased with
increasing sampling interval in/on bulb and green onions.  Residues of
BAM and PCA were nondetectable in/on bulb onions from all sampling
intervals.  Residues of BAM in/on green onions increased slightly from
the 1-day sampling interval to the 7-day sampling interval; residues of
PCA in/on the respective samples were nondetectable.

Brassica, head and stem, subgroup 5A

IR-4 has submitted field trial data for fluopicolide on broccoli and
cabbage, the representative crops of the head and 	stem Brassica
subgroup 5A.  The submitted broccoli and cabbage field trial data
reflect the use of three broadcast foliar applications of a 4 lb ai/gal
SC formulation of fluopicolide at total seasonal rates of 0.352-0.364 lb
ai/A, with a 2-day PHI.  An acceptable method was used for quantitation
of residues in/on broccoli and cabbage.  Maximum residues of
fluopicolide were 0.69 ppm in/on broccoli, 3.93 ppm in/on cabbage with
wrapper leaves, and 2.63 ppm in/on cabbage without wrapper leaves. 
Maximum residues of BAM were <0.01 ppm (LOQ) in/on broccoli, and 0.02
ppm and 0.01 ppm in/on cabbage with and without wrapper leaves,
respectively.  Maximum residues of PCA were 0.02 ppm in/on all samples
of broccoli and cabbage.  The available storage stability data indicate
that residues of fluopicolide, BAM, and PCA are reasonably stable under
frozen storage conditions for a maximum of 30 months in/on cabbage
leaves, grape, potato tuber, and wheat grain.  The maximum storage
duration from harvest to analysis for the current petition was 35 months
for broccoli and 40 months for cabbage.  Although the storage stability
data for cabbage leaves would support Brassica vegetables, the available
data are not sufficient to support the full storage durations of the
study period.  Additional data to support the full duration of the
storage stability study period should be submitted. 

		4.1.4	International Residue Limits  tc "5.2.10	International Residue
Limits " \l 3 

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

	4.2	Dietary Exposure and Risk  tc "5.2  Dietary Exposure and Risk " \l
2 

A chronic dietary exposure assessment (using tolerance-level residues
and assuming all crops are treated (100 %CT), and was conducted for the
general U.S. population and various population subgroups.  Exposure to
drinking water was incorporated directly into the dietary assessment
using the chronic (annual average) concentration for surface water
generated by the first approximation rice model.  This assessment
concludes that the chronic dietary exposure estimates are below HED’s
level of concern (<100% cPAD) for the general U.S. population and all
population subgroups.  The dietary exposure is estimated at 0.014472
mg/kg/day for the general U.S. population (7% of the chronic Population
Adjusted Dose (cPAD)) and 0.022354 mg/kg/day (11% of the cPAD) for
children 1-2 yrs, the population subgroup with highest estimated chronic
dietary exposure to fluopicolide.  

Table 4.2.1:  Results of the Chronic Dietary Risk Analysis 

Population Subgroup	Chronic Dietary

	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.014472	7

All Infants (< 1 year old)	0.008784	4

Children 1-2 years old	0.022354	11

Children 3-5 years old	0.019967	10

Children 6-12 years old	0.014955	8

Youth 13-19 years old	0.011643	6

Adults 20-49 years old	0.014271	7

Adults 50+ years old	0.014074	7

Females 13-49 years old	0.014280	7

			Note:  Most highly exposed subgroup is bolded

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE AND RISK 

A residential exposure and risk assessment was previously conducted
(D326082, K. O’Rourke, 10/09/07) for two products containing
fluopicolide (i.e., V-10161 VPP Fungicide and V-10162 VPP Fungicide)
which were proposed for application to residential turfgrass and
recreational sites.  The exposure scenarios and risk are summarized in
the following sections.

The products 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.  

	5.1   Residential Handler Exposure and Risk	

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 the 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, the Total
MOEs for residential handlers are well above the LOC of 100, and are not
of concern.  

Table 5.1.  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.	

	5.2   Residential Postapplication Exposure and Risk

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 transferrable residue (TTR) data were not available.  The
assessment was based on generic assumptions for 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 short-/intermediate-term MOEs for each scenario
are above the LOC of 100, and are not of concern.  As mentioned
previously, the same toxicity endpoint and study were selected to
evaluate all routes of exposure; therefore, the MOEs were combined.  As
shown in Table 5.2.1, 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 5.2.1.  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)]

	5.3   Recreational Postapplication Exposure

Recreational exposures to turf (including 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.

	5.4   Off Target Non-Occupational Exposure

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.  

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.

6  SEQ CHAPTER \h \r 1 .0	Aggregate Risk Assessments and Risk
Characterization

In accordance with the FQPA, the Agency must consider aggregate
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, the Agency considers both the route and duration of exposure. 
For fluopicolide, 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.

	6.1	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.

	6.2	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
5.2.1) have been combined with average dietary exposure estimates (as an
estimated of background dietary exposure; Table 4.2.1) to assess
short-term aggregate exposure. Since aggregate MOEs in Table 6.2 are
greater than 100, they represent risk estimates that are below HED’s
level of concern.

Table 6.2.  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	0.014472	0.036238	390

All Infants (<1 year old)	20	100	0.2	0.008784	0.044514	380

Children 1-2 years old	20	100	0.2	0.022354	0.044514	300

Children 3-5 years old	20	100	0.2	0.019967	0.044514	310

Children 6-12 years old	20	100	0.2	0.014955	0.044514	340

Youth 13-19 years old	20	100	0.2	0.011643	0.036238	420

Adults 20-49 years old	20	100	0.2	0.014271	0.036238	400

Adults 50+ years old	20	100	0.2	0.014074	0.036238	400

Females 13-49 years old	20	100	0.2	0.014280	0.036238	400

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)]

6.3	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 

6.4	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 4.2.  As
shown in Table 4.2.1, the chronic risk estimates are below HED’s level
of concern for all population subgroups.

6.5	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.

7  SEQ CHAPTER \h \r 1 .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.  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, will be
evaluated in a concurrent document.

8.0	Occupational Exposure/Risk Pathway

Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on Brassica, Bulb Vegetables, and Root and
Tuber Vegetables, DP Number: D347228, K. O’Rourke, 12/13/07.

	8.1	Handler Exposure and Risk

There is a potential for 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).  

Chronic exposure is not expected for the proposed use patterns
associated with fluopicolide.  

Estimated short-/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
absorption in the lung was assumed to be 100 percent.  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. 
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.  

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 label).  The Total
short/intermediate-term MOEs range from 110 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 4. 

HED recognizes that it is feasible for the same individual to mix/load
and apply formulations with the groundboom sprayer, 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 MOE for these combined
activities for groundboom application of fluopicolide would be above the
LOC of 100 (i.e., approximately 110). 

The minimum level of PPE for handlers is based on acute toxicity for the
end-use product.  The Registration Division (RD) is responsible for
ensuring that PPE listed on the label is in compliance with the Worker
Protection Standard (WPS).

	Table 8.1.  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	Brassica, Bulb, and Root & Tuber Vegetables	0.13	350	0.81

0.0065 (gloves)	0.00091	25	2,700

(2) Mixing/Loading Liquid for Groundboom application or Chemigation	2.9
-	0.0012

0.13	80	0.19	0.00021	110	-

Applicator

(3) Applying Sprays with Fixed-wing Aircraft	0.005	-	0.000068	Brassica,
Bulb, and Root & Tuber Vegetables	0.13	350	0.0014	0.000052	14,000	-

(4) Applying Sprays with Open Cab Groundboom 	0.014	-	0.00074

0.13	80	0.00090	0.00013	19,000	-

Flagger

(5) Flagging to Support Aerial Applications	0.011	-	0.00035	Brassica,
Bulb, and Root & Tuber Vegetables	0.13	350	0.0031	0.00027	6,000	-



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 the scenario in which the MOE does not
reach 100 at baseline.  Values are reported in the PHED Surrogate
Exposure Guide dated August 1998.

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 label:
V-10161 4 SC (Reg No. 59639-RUN).

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.

	8.2   Occupational Postapplication Exposure and Risk

This registration action for fluopicolide involves application to
agricultural crops.  Postapplication inhalation exposure is expected to
be negligible; however, dermal exposure is possible for workers entering
treated areas to tend or harvest crops.  A dislodgeable foliar residue
(DFR) study was previously submitted by the registrant (MRID#: 46708641)
for use in assessing postapplication activities.  This study is
considered to be acceptable, and the data were used to estimate exposure
from activities associated with agricultural crops.  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).  

In addition to DFR, 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).  As shown in Table 5, the short-/intermediate-term
MOEs are greater than 100 on the day of application for all agricultural
crops.  

The fluopicolide technical material has been classified in Toxicity
Category 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
label indicates an REI of 12 hrs, which is in compliance with the WPS.

Table 8.2.  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

Brassica Vegetables	0.13	0	0.42	2,000	Irrigation, scouting, thinning,
weeding immature plants	480





4,000	Scouting mature plants	240





5,000	Hand harvesting, irrigation, pruning, topping, tying mature plants
190

Bulb Vegetables,

Root & Tuber Vegetables

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 label: V-10161 4 SC (Reg No.
59639-RUN).

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.  Values
in bold indicate when 1 day, or longer, is necessary for the MOE to
reach 100.

   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.

	

	9.0	DATA NEEDS/LABEL REQUIREMENTS

9.1	Toxicology  TC \l2 "10.1	Toxicology 

	None.

9.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

860.1200 Directions for Use

	

The proposed PHI for root and tuber vegetables must be revised to 7
days. 

Until all field rotational crop 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 bulb vegetables,
Brassica head and stem vegetables, cucurbit vegetables, fruiting
vegetables, grapes, leafy vegetables, root vegetables, tuberous and corm
vegetables, and wheat, with a 0-day PBI for bulb vegetables, Brassica
head and stem vegetables, cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables, root vegetables, and tuberous and corm
vegetables, and a 30-day PBI for wheat.  

860.1550 Proposed Tolerances

The proposed tolerance expression should be revised to reflect the
correct chemical name for fluopicolide.

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
9.

A revised Section F should be submitted to propose for Vegetable, bulb,
group 3-07 and delete the list of individual crops under these
subgroups.  

860.1380 Storage Stability

6.	Additional storage stability data are required to support the
Brassica head and stem, bulb, and root vegetable crop field trials. 
Storage stability studies with a representative root or tuber vegetable
(reflecting analysis of roots and tops) and a Brassica vegetable must be
conducted.  The requested data for a root or tuber vegetable may be
translated to bulb vegetables.  The required studies should reflect the
storage conditions of samples from the crop field trials and should
include storage intervals of up to 47 months for the root or tuber
vegetable and 45 months for the Brassica vegetable.  If residues are
found to be unstable in any representative commodity, additional storage
stability data studies will normally be required on additional
commodities of that group [see OPPTS 860.1380(c)(5)(ii)(D)].  

860.1900 Field Accumulation in Rotational Crops

7.	As required under PP#5F7016, the petitioner must submit a limited
field rotational crop study conducted at a 12-month PBI with
representative leafy vegetable, and  root vegetable crops.  If the
results of the limited field rotational crop study 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.

9.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational and
Residential Exposure 

	None.

10.0 	REFERENCES

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, N. Dodd,
11/21/07

Fluopicolide.  PP#7E7172.  Petition for Establishment of Tolerances for
Use on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A).  Summary of Analytical Chemistry and Residue
Data, A. Acierto, 3/05/08.  

Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on Brassica, Bulb Vegetables, and Root and
Tuber Vegetables, DP Number: D347228, K. O’Rourke, 12/13/07.

Fluopicolide Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action for
the Proposed Uses on Root Vegetables (Subgroup 1A), Leaves of Root and
Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A),  DP Number: 349721, S. Piper, 3/06/08

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



Appendix A:  Toxicity Profile 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

	90-Day oral toxicity (mouse)	46474114 (2000)

Acceptable/guideline

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.



Appendix B:  Chemical Structures  

 	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%

8

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瑹国4Āate of 0.36 lb ai/A (≈1x); 21-day PHI.

 Lettuce: MRID 46708520; two foliar applications for a total seasonal
rate of 0.36 lb ai/A (≈1x); 35-day PHI.

 Potato: MRID 46708521; two foliar applications for a total seasonal
rate of 0.36 lb ai/A (≈1x); 20-day PHI.

 Rotational Crops: MRID 46708546; bare soil treatment at 0.36 lb ai/A
(≈1x) and PBIs of 29 or 365 days.

 Ruminants: MRIDs 46708514 and 46708518; cows were dosed 7 days at 10 or
10.55 ppm.

 Poultry: MRIDs 46708515 and 46708519; hens were dosed 14 days at 10 or
10.7 ppm. 

 Rats: MRID 46474242; one oral dose of [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 Summary

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
C1.  HED notes that individual tolerances for the members of the Bulb
Vegetables, group 3 will not be needed since a crop group tolerance
would be appropriate.  Please note the pre-existing Crop Group 3 is now
titled Crop Group 3-07 (Pesticide Tolerance Crop Group Program, Federal
Register, Vol. 72, No. 235, 12/7/2007).

  

Table C1. 	Tolerance Summary for Fluopicolide.

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

Tolerances to be established under “(a) General”:

Root vegetable subgroup 1-A	0.15	0.15	Vegetable, root, subgroup 1A

Leaves of root and tuber vegetables, group 2	13	15	Vegetable, leaves of
root and tuber, group 2

Bulb vegetables, group 3	6	Remove	Tolerances should be proposed for
Vegetable, bulb, group 3-07



Bulb vegetables, group 3-07	None proposed	7.0	Vegetable, bulb, group
3-07



Daylily, bulb 	6	Remove

	Individual tolerances are not required for members of the Vegetable,
bulb, group 3-07



Garlic, Serpent, bulb	6



Lily, bulb	6



Onion, Chinese, bulb	6



Onion, pearl	6



Onion, potato, bulb	6



Shallot, bulb	6



Chive, fresh leaves 	6



Chive, Chinese, fresh leaves	6



Elgans hosta	6



Fritillaria, bulb	6



Fritillaria, leaves	6



Kurrat	6



Lady’s leek	6



Leek, wild	6



Onion, Beltsville bunching	6



Onion, fresh	6



Onion, macrostem	6



Onion, tree, tops	6



Shallot, fresh leaves	6



Head and stem Brassica subgroup 5-A 	5	5	Brassica, head and stem,
subgroup 5A



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