  SEQ CHAPTER \h \r 1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		July 16, 2009             

Ingredient:  Fluopyram.  Report of the Residues of Concern Knowledgebase
Subcommittee (ROCKS).  

 

PC Code:  080302	DP Barcode:  D367115

Decision No.:  393949	Registration No.:  264-RNTI; 432-RUIL; 264-RNTT

Petition No.:  8F7358	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  NA	Case No.:  NA

TXR No.:  NA	CAS No.:  658066-35-4

MRID No.:  NA	40 CFR:  180.xxx



From:		Edward Scollon, ROCKS Executive Secretary

		Health Effects Division (HED) (7509P)

Through:		Christine L. Olinger, ROCKS Co-Chair

		Mary Ko Manibusan, ROCKS Co-Chair

		HED (7509P)

To:		Fluopyram Risk Assessment Team

		Risk Assessment Branch III (RAB III)

		HED (7509P)

The ROCKS met on June 4, 2009 to discuss the residues of concern for the
fungicide fluopyram in food and drinking water.  This was a joint
meeting between the US EPA, EU (Germany), and PMRA (Canada).  As such,
the residues of concern for risk assessment and tolerance expression for
each party are reviewed in this document.  

Team Members:

Leung Cheng, Myron Ottley, Sheila Healy, Steve Funk, Whang Phang, Paula
Deschamp

ROCKS Members Attended:

Mary Manibusan, Christine Olinger, Rick Loranger, George Kramer, Edward
Scollon, Ray Kent, Greg Orrick

EFED Attended:

Mohammed A. Ruhman, Mah Shamim

PMRA Attended (via teleconference):

Isabelle Pilote, Michael Honeyman, Minoli Silva

EU Attended (via teleconference):

Thomas Kuhl, Bernd Stein, Steffen Matezki

Material Reviewed:

Summary of toxicological data and residue chemistry

Summary of EU residue field trials

Environmental Degradates for Fluopyram, DP#365542, MA Ruhman, June 1,
2009

DEREK for Windows evaluations for fluopyram, lactame, AE
C656948-7-hydroxy,  AE C656948-benzamide, AE C656948-E-olefine, and AE
C656948-Z-olefine available upon request

Committee Recommendation:

	

Table 1.  Summary of Metabolites and Degradates to be included in the
Risk Assessment.*

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crops	fluopyram (fluopyram + benzamide (M25) for legumes
and oil seed crops)	fluopyram

	Rotational Crops



Livestock	Ruminants	Fluopyram + benzamide (M25) +7-OH-fluopyram +
olefins (E,Z) (M02, M03)	Fluopyram + benzamide (M25)

	Poultry	Fluopyram + benzamide (M25) + olefins (E,Z) (M02, M03)

	Drinking Water	fluopyram	Not Applicable

* Chemical names and abbreviations can be found in Table 1.

ROCKS Recommendation for Tolerance Expression Language

Section (a)(1) would be for plants; (a)(2) is for livestock

 (a)(1) General.  Tolerances are established for residues of the
fungicide fluopyram, including its metabolites and degradates, in or on
the commodities in the table.  Compliance with the tolerance levels
specified below is to be determined by measuring only fluopyram
(N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethy
l)benzamide).

 (a)(2) General.  Tolerances are established for residues of the
fungicide fluopyram, including its metabolites and degradates, in or on
the commodities in the table.  Compliance with the tolerance levels
specified below is to be determined by measuring only the sum of
fluopyram
(N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethy
l)benzamide) and its benzamide metabolite
[2-(trifluoromethyl)-benzamide], calculated as the stoichiometric
equivalent of fluopyram, in or on the commodity.

Rationale:

Drinking Water Degradates (US only)

Environmental fate studies indicate that the parent fluopyram is stable
under environmental conditions.  Reported half-lives range from 89 days
in field and aqueous photolysis studies to >1000 days in
aerobic/anaerobic water/sediment systems.  Fluopyram is mobile in soil
and can therefore, be expected to occur in surface water runoff and/or
in ground water leachate.  

Four metabolites were identified in aerobic soil metabolism studies:  AE
C656948-7-hydroxy, AE C656948-benzamide, AE C656948-pyridyl carboxylic
acid (PCA), and lactame.  None of the metabolites exceeded 10% of
applied nor were any of the metabolites considered more toxic than the
parent.

 

AE C656948-7-hydroxy, AE C656948-benzamide, and AE C656948-PCA, were
also tracked in field dissipation studies.  AE C656948-7-hydroxy, though
structurally similar to the parent, was only found at 1-3% of the
fluopyram levels.  AE C656948-PCA (1.2-18%) and AE C656948-benzamide
(0.2-16.2%) were more abundant but showed rapid declines.  Lactame, a
proposed metabolite of parent fluopyram, was present at low levels in
the soil system (1.2%) and as a major metabolite in the aqueous
photolysis study (13%).  Lactame is structurally dissimilar from parent
fluopyram but would only be expected to form at significant levels in
clear, shallow water.  Based upon the low abundance of the metabolites
in the soil studies and their rapid dissipation in the field studies,
minimal exposure is expected through drinking water.  Furthermore, none
of the metabolites are considered more toxic than the parent. 
Therefore, ROCKS concurs with the risk assessment team that the
metabolites are not considered of concern.   

Residues of Concern for Monitoring (Enforcement) and Risk Assessment

Primary and Rotational Crops

The metabolism in plants is relatively limited.  In plant metabolism
studies, unchanged parent accounted for >90% of the residues in grapes,
beans, and potatoes and 70% of the residue in red bell peppers.  While
several metabolites were quantified (most <1% TRR), only AE
C656948-benzamide exceeded 10% TRR in succulent and dry beans (52-64%).

Measureable quantities of parent and metabolites
(AE C656948-pyridyl-acetic acid (PAA), AE C656948-pyridyl-carboxylic
acid (PCA) and AE C656948-benzamide) were also found in succulent (at
full maturity) and dry beans during European field trials.  These
metabolites were not measured in US field trials.

Of the major metabolites, AE C656948-benzamide, PAA and PCA result from
hydrolysis of the ethylene bridge; AE C656948-benzamide is a phenyl
cleavage product and PPA and PCA are pyridyl cleavage products.   AE
C656948-methyl-sulfoxide results from the substitution of the chlorine
atom in PCA.  None of the metabolites, or their conjugates, are expected
to be more toxic than the parent fluopyram.  Furthermore, inclusion of
both phenyl and pyridyl metabolites as fluopyram equivalents for either
risk assessment or tolerance expression, would overestimate total
exposure to fluopyram.  Parent fluopyram by itself is expected to an
adequate measure of misuse in primary crops.  In addition, parent
fluopyram can be measured by some of the FDA multiresidue methods (MRM)
while the benzamide metabolite does not lend itself to MRM analysis. 
Therefore, ROCKS recommends fluopyram only for tolerance expression. 
For risk assessment, ROCKS recommends fluopyram only, except for legumes
and oil seeds.  For these commodities, ROCKS recommends fluopyram +
AE C656948-benzamide due to the high levels of the latter in the bean
metabolism studies.  

In confined rotational crop studies, parent fluopyram also accounted for
the majority of residue.  However, AE C656948-7-hydroxy (up to 39% TRR,
plus its conjugate (up to 16% TRR)) was found in Swiss chard at all
rotation intervals, and the methylsulfoxide metabolite was predominant
in wheat grain at longer rotation intervals.  The latter metabolite was
detected up to 0.10 ppm in field rotational wheat trials and the AE
C656948-7-hydroxy compound was found only in wheat straw at 0.10 ppm
level.  AE C656948-Benzamide (up to 39% TRR) was also present in Swiss
chard.  Since the AE C656948-7-hydroxy and the benzamide were not
significant residues in the field rotational studies, the ROCKS
recommends that the residue of concern be parent only.  Although the
methyl sulfoxide was found in wheat grain at higher levels than parent
in the EU rotational field studies, there will be target uses of
fluopyram on grains in the US that will drive risks from those crops.  

International Harmonization

The EU and PMRA are in agreement with ROCKS’ recommended inclusion of
fluopyram only for tolerance expression in primary and rotational crops.
 The US and PMRA are in agreement to include fluopyram only for risk
assessment, except for legumes and oil seeds, which include parent
fluopyram + AE C656948-benzamide.  The EU recommends inclusion of
fluopyram + AE C656948-benzamide + AE C656948-7-hydroxy + AE
C656948-7-hydroxy conjugates, AE C656948-7-OH-GA and AE C656948-8-OH-GA,
for risk assessment.  AE C656948-7-OH-GA and AE C656948-8-OH-GA are
glucosylated conjugates of AE C656948-7-hydroxy.  At this meeting, the
EU explained that they tend to include all quantifiable residues in
dietary risk assessment, as opposed to US policy of including only those
compounds which pose potential risk greater to or equal the parent
chemical.  ROCKS determined these additional metabolites were not of
concern.  The additional metabolites are not expected to be more toxic
than the parent compound.  DEREK for Windows analysis of fluopyram, AE
C656948-benzamide, AE C656948-7-hydroxy, and AE C656948 E- and
Z-olefines did not indicate any alerts.  However, the lack of alerts for
fluopyram indicates that DEREK may be of limited use for this chemical. 
There are minimal toxicity concerns for the conjugates as these are
likely to be more soluble in water, which would enhance in vivo
clearance.  The residue levels of these metabolites are low relative to
the parent fluopyram.

Refer to Table 2 for a comparison of residues of concern between the US,
PMRA, and the EU recommended residues of concern.

Livestock Commodities

The metabolism in livestock is more extensive than was found in plant
studies.  The major residues identified at varying sampling intervals
include parent, AE C656948-benzamide, AE C656948-7-hydroxy, and
AE C656948 E- and Z-olefines.  In the egg and poultry metabolism
studies, AE C656948-benzamide (up to 99% TRR) accounted for the
majority of residue in egg, muscle, fat, and liver.  Parent fluopyram
(18%) was found in eggs and AE C656948 -olefines (14%) in the liver. 
Similarly in the goat, AE C656948-benzamide accounted for the majority
of residue (up to 99% TRR) in milk, muscle, fat, liver, and kidney. 
Fluopyram (46%), AE C656948-7-hydroxy (22%), and AE C656948 -olefines
(33%) were found at lower levels in milk, muscle, and fat.  The phenyl
metabolite, AE C656948-benzamide, was a major metabolite in both plant
and livestock metabolism studies.  However, the pyridyl metabolites, AE
C656948-pyridyl-acetic acid (PAA) and AE C656948-pyridyl-carboxylic acid
(PCA), were not present in the livestock studies.  While the fate of the
pyridyl portion of the molecule is unknown, ROCKS determined tolerance
expression and risk assessment decisions could be made without fully
elucidating the livestock metabolic pathway.  Calculating the benzamide
residues in terms of parent equivalents would likely account for the
unknown pyridyl metabolites.  Feeding studies confirmed the rapid
transformation of parent fluopyram; AE C656948-benzamide was the only
major residue in edible poultry matrices while fluopyram,
AE C656948-benzamide and AE C656948 -olefines were measured in the
milk and meat of dairy cattle.  In the cattle study, the levels of
benzamide metabolite were significantly higher than the parent in many
samples.

Therefore, ROCKS recommends fluopyram + AE C656948-benzamide for
tolerance enforcement in ruminant and poultry commodities; fluopyram +
AE C656948-benzamide + AE C656948-7-hydroxy fluopyram + AE C656948 E-
and Z-olefines for risk assessments in ruminant commodities; and
fluopyram + AE C656948-benzamide + AE C656948 E- and Z-olefines for
risk assessment in poultry.

EU/Canada

The US, EU, and Canada are in agreement on parent fluopyram +
AE C656948-benzamide for purposes of tolerance enforcement in
livestock.  The US, EU, and Canada are also in agreement regarding which
compounds to include for risk assessment of poultry commodities. 
However, consistent with their decisions for plants, the EU has proposed
the inclusion of the conjugated metabolites, AE C656948-7-OH-GA and AE
C656948-8-OH-GA, for risk assessments in ruminants.

Attachments:  Chemical Names and Structures 

Attachment 1 – Plant and Livestock Metabolites and Degradates

Attachment 2 – Drinking Water Degradates



Table 2.  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expressions.

Matrix	US	EU	Canada

	RA	TOL	RA	TOL	RA	TOL

Plants	Primary Crop	Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops)	Fluopyram
Fluopyram + benzamide (M25) + 7-OH-fluopyram (M08) + 7-OH-Glc (M11) +
7-OH-Glc-MA(M12)	Fluopyram	Fluopyram + 

(Fluopyram + benzamide for legumes and oil seed crops)	Fluopyram

	Rotational Crop	Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops)	Fluopyram
Fluopyram + benzamide (M25) + 7-OH-fluopyram (M08) + 7-OH-Glc (M11) +
7-OH-Glc-MA(M12)	Fluopyram	Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops)	Fluopyram

Livestock	Ruminant	Fluopyram + benzamide + 7-OH-fluopyram + olefins (E,
Z)	Fluopyram + benzamide	Fluopyram + benzamide + 7-OH-fluopyram (M08)+
olefins (E, Z) + 7-OH-CA(M09) + 7-OH-GA (M20b)	Fluopyram + benzamide
Fluopyram + benzamide + 7-OH-fluopyram + olefins (E, Z)	Fluopyram +
benzamide

	Poultry	Fluopyram + benzamide + olefins (E, Z)	Fluopyram + benzamide
Fluopyram + benzamide + olefins (E, Z) 	Fluopyram + benzamide	Fluopyram
+ benzamide +  olefins (E, Z)	Fluopyram + benzamide

Drinking Water	Fluopyram	Not Applicable	Not Applicable	Not Applicable
Not Applicable	Not Applicable



lAttachment 1:  Plant and Livestock Metabolites and Degradates



AE C656948-8-OH-GA; M20



AE C656948-di-OH-GA; M21



AE C656948-benzamide; AE F148815; BCS-AA10014; M25



AE C656948-hydroxyethyl-di-glc; M36



AE C656948-hydroxyethyl-GA; M37



AE C656948-pyridyl-acetic acid (PAA); M40



AE C656948-pyridyl-carboxylic acid (PCA); M43
3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid



AE C656948-methyl-sulfoxide; M45	3-(methylsulfinyl)-5-(trifluoromethyl)
pyridine-2-carboxylic acid

 

AE C656948-enol-GA; M04



 AE C656948-benzoyl-serine; M24
N-acetyl-O-[2-(trifluoromethyl)benzoyl]-serine

 

AE C656948-benzamide-N,O-GA; M32
1-O-{[2-(trifluoromethyl)-benzoyl]amino}-beta-D-glucopyranuronic acid



AE C656948-ethyl-diol; M38	1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]
ethane-1,2-diol



AE C656948-hydroxy-PAA; M41
[3-chloro-5-(trifluoromethyl)pyridin-2-yl](hydroxy)acetic acid

 

AE C656948-pyridyl-methyl-cystein; M44
N-acetyl-S-{[3-chloro-5-(trifluoromethyl) pyridin-2-yl]methyl}cysteine



      Attachment 2:  Fluopyram and Its Major Environmental Degradates.

Code Name/ Synonym	Chemical Name	Chemical Structure

PARENT

fluopyram; AE C656948

	CAS:
N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl
)benzamide

CAS-no: 

Formula: C17H17ClF4N4O5S

MW: 500.86 g/mol

 

























METABOLITES

AE C656948-7-hydroxy; BCS-AA10065; M08

	N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-hydroxyethyl}-2-(trif
luoromethyl)benzamide

Formula: C16H11ClF6N2O2































 Lactame
2,9-bis(trifluromethyl)-6,7-dihydropyridol[2,3-e][2]benza-zocin-8(5H)-on
e

Formula: C16H10F6N2O

 



































AE C656948-benzamide; AE F148815; BCS-AA10014; M25
2-(trifluoromethyl)benzamide

Formula: C8H6F3NO































AE C656948-pyridyl-carboxylic acid (PCA); M43

	3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid

Formula: C7H3ClF3NO2

































AE C656948-methyl-sulfoxide; M45

	3-(methylsulfinyl)-5-(trifluoromethyl) pyridine-2-carboxylic acid

Formula: C8H6F3NO3S

 































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