Document ID: EPA-HQ-OPP-2010-0122-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-03-09T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  January 21, 2010

SUBJECT:	Fomesafen Sodium.  Petition for the Establishment of Tolerances
and Registration of New Uses on Potato and Tomato; and Response to Data
Gaps for Conditional Registration on Cotton, Dry Bean, and Snap Bean. 
Summary of Analytical Chemistry and Residue Data.

PC Code:  123802	DP Barcodes:  D365199 and D366116

Decision No.:  409397 and 415115	Registration No.:  100-993

Petition Nos:  9F7563 (potato and tomato),

  1E6228 (dry bean), 9F5068 (cotton), and 6E4653 (snap bean)	Regulatory
Action:  Amended Section 3

Risk Assessment Type:  NA	Case No.:  NA

TXR No.:  NA	CAS No.:  72178-02-0

MRID No.:  See MRID Summary Table	40 CFR:  §180.433

	

FROM:	Christine L. Olinger, Chemist  SEQ CHAPTER \h \r 1 

		Risk Assessment Branch VII

		Health Effects Division (7509P)

THROUGH:	Toiya Goodlow, Chemist

		Michael S. Metzger, Chief

		Risk Assessment Branch VII

		Health Effects Division (7509P)

TO:		Dan Kenny/Michael Walsh, PM Team 23

		Herbicide Branch   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

		Registration Division (7505P)

MRID Summary Table

MRID No.	Study Type	Comments

47473901	860.1300 Tomato 	New DER; 47473901.der.doc

47473902	860.1500 Tomato Crop Field Trials	New DER; 47473902.de1.doc

	860.1520 Tomato Processing Study	New DER; 47473902.de2.doc

47473903	860.1500 Potato Crop Field Trials	New DER; 47473903.de1.doc

	860.1520 Potato Processing Study	New DER; 47473903.de2.doc

47761901	860.1360 Multiresidue Methods	New DER; 47761901.der.doc

47761902	860.1380  Storage Stability	New DER; 47761902.der.doc

47761903-04	860.1340 Residue Analytical Methods	New DER 47761903.der.doc
(Includes MRID 47761904)

47761905	Response to Conditions of Registration	No DER generated;
registrant’s responses to deficiencies are incorporated in this
Summary Document.

  SEQ CHAPTER \h \r 1 This document was originally prepared under
contract by Dynamac Corporation (1901 Research Boulevard, Suite 220;
Rockville, MD 20850).  

Dynamac Program Manager:		Date:  10/14/2009

	Danilo Martinez

	

The document has been reviewed by the Health Effects Division (HED) and
revised to reflect current Office of Pesticide Programs (OPP) policies.

Executive Summary

Fomesafen sodium is a contact broadleaf herbicide in the diphenylether
chemical class.  The herbicide acts through inhibition of the enzyme
protoporphyrinogen oxidase (PPO) in plants.  The active ingredient was
originally registered on 09/11/1987 by Zeneca Ag Products and was
transferred to Syngenta Crop Protection, Inc. on 02/23/2001.  Fomesafen
is currently registered for use on the crops cotton, dry beans, snap
beans, and soybeans.  It is applied to treat various broadleaf weeds,
annual grasses, perennial weeds and sedges. 

Syngenta has proposed, in PP#9F7563, the establishment of permanent
tolerances for residues of fomesafen in/on the following raw
agricultural commodities:

Potato	0.025 ppm

Tomato	0.025 ppm

In support of the proposed tolerances and new crop uses, Syngenta has
submitted a tomato metabolism study and magnitude of the residue studies
on potatoes and tomatoes.  In addition, the petitioner has submitted
various residue chemistry studies in response to the data gaps
identified by as a condition of registration for a request previously
made by Syngenta and IR-4 to amend the Reflex® Herbicide.  This Summary
Document addresses the adequacy of the submitted residue chemistry data
in support of the proposed new uses on potatoes and tomatoes as well as
the adequacy of Syngenta’s responses to the conditions of
registration.

Reflex® Herbicide is proposed for one broadcast preemergence
application on potatoes after planting but before potato emergence at a
maximum rate of 0.25 lb ae/A and a 70-day preharvest interval (PHI).  On
tomatoes, Reflex® Herbicide is proposed for one broadcast preplant
non-incorporated preemergence application up to 7 days prior to
transplanting tomato seedlings at a maximum rate of 0.375 lb ae/A and a
70-day PHI.

The metabolism of fomesafen in soybean, cotton, and tomato has been
investigated.  The soybean and cotton metabolism studies were reviewed
in DP# 325801, and the tomato study was included as part of the current
petition package.  The cotton metabolism study has now been upgraded to
acceptable status based on Syngenta’s submission of the requested
information.  The terminal residue of concern in cotton is fomesafen.
The tomato metabolism study is acceptable and supports the proposed use
on tomatoes.  The terminal residue of concern in tomatoes is fomesafen. 

HED generally recommends that three metabolism studies on diverse crops
when a pesticide is to be used on several different commodities. 
Although three metabolism studies have been submitted, tomatoes,
soybeans and cotton are not sufficiently diverse to define the nature of
the residue in all crops.  Since no data on a root crop have been
provided that can be translated to the proposed use on potatoes, a
potato metabolism study, in which both the root and tops/foliage are
analyzed, is required to support the proposed use on potatoes.  HED
cannot recommend for a tolerance in/on potatoes until an adequate
metabolism study is submitted.

There are no livestock feedstuffs associated with the proposed use on
tomatoes.  The nature of the residue in ruminants is adequately
understood.  At this time no tolerances have been established on any
livestock commodity in association with the existing uses of fomesafen. 
Livestock feeding studies are not required to support the
proposed/registered uses of fomesafen.  Syngenta should note that if
additional uses are proposed in the future which result in an increase
in the dietary burdens, livestock feeding studies may be required. 

Adequate residue analytical methods are available for the purpose of
tolerance enforcement.  Syngenta submitted a new high performance liquid
chromatography method with tandem mass spectrometry detection (LC/MS/MS)
method (GRM045.01A) as an enforcement method.  The method uses
extraction procedures similar to previous methods, SPE cleanup
procedures, and the final determination step by LC/MS/MS technology for
analysis of fomesafen residues.  The validated limit of quantitation
(LOQ) of the method is 0.02 ppm.  Method GRM045.01A was adequately
validated at fortification levels of 0.02 ppm and 0.2 ppm in snap beans,
pinto beans (dry bean), corn oil, cotton, undelinted seed and gin
byproducts, and soybean forage, hay, and aspirated grain fractions. 
Methods for the determination of fomesafen residues of concern in
livestock commodities are not required at this time but may be required
in the future.  

The requirements for multiresidue method testing data for fomesafen are
fulfilled.  FDA multiresidue methods are not suitable for determining
residues of fomesafen; the submitted data will be forwarded to U.S. FDA
for further evaluation.  

Samples of raw and processed commodities of potatoes and tomatoes, which
were collected from the magnitude of the residue studies, were analyzed
for residues of fomesafen using a LC/MS/MS based on an liquid
chromatography with ultraviolet detection (HPLC/UV) method
(GAM-RM-001/86).  The method was adequately validated during concurrent
analysis of samples.  The lowest level of method of validation (LLMV)
was 0.025 ppm for each matrix.  

Analytical standards for fomesafen are currently available in the EPA
National Pesticide Standards Repository.

Adequate storage stability data are available to support the storage
conditions and durations of samples collected from the magnitude of the
residue studies on tomatoes.  Interim storage stability data were
additionally submitted for various crop commodities in response to a
data gap cited in DP# 325801, and the registrant intends to submit a
final report with analyses after 18 and 24 months of storage.  Residues
of fomesafen appear to be relatively stable in/on corn, wheat, soybean,
and cotton commodities through 13 months of storage.

The submitted field trial data for fomesafen on tomatoes are acceptable
and support the proposed uses.  An adequate number of trials were
conducted in the appropriate geographic regions at ~1x the maximum
proposed rate using Reflex® Herbicide, and the appropriate samples were
collected from each test around the proposed PHI.  All treated samples
bore residues below the LLMV (<0.025 ppm).  Based on these data, HED
recommends a tolerance of 0.025 ppm for residues of fomesafen in/on
tomatoes.

Provided the requested metabolism study does not indicate that there are
additional metabolites/degradates of concern, an adequate number of
field trials were conducted to support the proposed new use on potatoes.
 Residues of fomesafen were below the LLMV of 0.025 ppm in all trials. 
HED reiterates that a root/tuber metabolism study is required to support
this use.  If the new study identifies additional residues of concern,
then additional field trials reflecting analysis of the new residues
will be required to support this use.

The previously submitted cotton field trial data have now been upgraded
to acceptable status based on Syngenta’s submission of the requested
information pertaining to weather conditions, soil characteristics, and
raw data of field notes, calibration of equipment, and sampling
procedures that were employed in the conduct of the cotton trials.  The
Agency concludes that adequate residue data are available to support the
established tolerances of 0.025 ppm each for cotton gin byproducts and
undelinted cottonseed.

The results of submitted potato and tomato processing studies show that
residues of fomesafen were each below the LLMV (<0.025 ppm) in/on the
respective RACs following application of Reflex® Herbicide at 1x. 
Since the studies involved processing of RACs bearing nonquantifiable
residues, no measurable processing factors can be calculated.  Although,
the Agency would have preferred the use of exaggerated rates in the
conduct of the processing studies to yield RACs with quantifiable
residues, HED will not require additional processing data at this time.

The nature of the residue in rotational crops remains inadequately
understood.  Syngenta has previously been requested to conduct a new
confined rotational crop study reflecting separate application of CP-
and NP-label fomesafen at the maximum seasonal application rate to
rotatable crops.  According to Syngenta, a new confined rotational crop
study is ongoing and will be completed by 12/31/2009.  Satisfaction of
the confined rotational crop data should be a condition of these
registrations.

At this time, data are not available to support rotation to other crops
beyond those commodities that are currently registered and proposed as
primary crops; therefore, the registrant must revise the Reflex®
Herbicide label to permit immediate replanting of soybeans, cotton, dry
beans, snap beans, potatoes, and tomatoes only with a restriction that
other crops can only be planted 12 months after treatment or 18 months
after treatment if based on phytotoxicity concerns.

No Codex, Canadian, or Mexican MRLs have been established for residues
of fomesafen in/on potato or tomato.  Canadian MRLs have been
established for residues of fomesafen in/on dry beans, lima beans, snap
beans, and soybeans at 0.05 ppm, and a Mexican MRL of 0.05 mg/kg  has
been established for residues of fomesafen in/on soybeans.  The
registrant has advised the Agency that they intend to petition the
Canadian government for revised tolerances to address any potential
harmonization issues raised by establishing the new tolerances requested
in this action.

  SEQ CHAPTER \h \r 1 Regulatory Recommendations 

HED has examined the residue chemistry database for fomesafen sodium. 
Pending resolution of the deficiency pertaining to directions for use
and provided the submission of a confined rotational crop study is made
a condition of the registration, there are no residue chemistry issues
that would preclude granting the petitioner’s request to amend the
Reflex® Herbicide label for the purpose of adding the requested use on
tomatoes.  HED recommends a conditional registration for this herbicide
on the crops requested and/or the revision of 40 CFR §180.433 for the
establishment of tolerances for residues of fomesafen as follows:

Tomato	0.025 ppm

The registrant’s most recent Reflex® Herbicide label reflects
regional use of fomesafen on tomatoes.  However, the residue chemistry
data submitted in support of this action are of sufficient geographic
representation to support full U.S. registration; therefore, HED
recommends that these tolerances be listed in the general section of 40
CFR §180.433.

Tolerances for fomesafen residues are listed in 40 CFR §180.433. 
Currently, the single established tolerance is expressed in terms of
“sodium salt of fomesafen,
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzam
ide.”  HED has determined that the residue of concern for tolerance
expression is fomesafen.  Therefore, the established tolerance
expression should be revised to be expressed in terms of fomesafen, by
removing the phrase “sodium salt of” from 40 CFR §180.433(a).

Note to PM:  According to HED’s Interim Guidance on Tolerance
Expressions (5/27/09, S. Knizner), the tolerance expression for
fomesafen should be revised to state:

“Tolerances are established for residues of fomesafen, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only fomesafen
[5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenza
mide].”

A human health risk assessment is forthcoming.

Residue Chemistry Deficiencies

Deficiencies - Tomato Petition (9F7563)

The following deficiency must be resolved prior to granting of the
registration on tomatoes.

860.1200 Directions for Use

	·	At this time, data are not available to support rotation to other
crops beyond those commodities that are currently registered and
proposed as primary crops; therefore, the petitioner must revise the
Reflex® Herbicide label to permit immediate replanting of soybeans,
cotton, dry beans, snap beans, potatoes, and tomatoes only with a
restriction that other crops can only be planted 12 months after
treatment or 18 months after treatment if based on phytotoxicity
concerns.

The deficiency listed below must be fulfilled as a condition for the
registration of Reflex® Herbicide label to add the requested use on
tomatoes.

860.1850 Confined Accumulation in Crops

	·	The ongoing confined rotational crop study, which is expected to be
completed by 12/2009, should be submitted at the earliest possible
convenience.  Based on this future submission, HED will determine the
terminal residues of concern in rotational crops and will re-evaluate
the existing field rotational crop studies for determination of
appropriate plantback restrictions.

Deficiencies - Potato Petition (9F7563)

HED cannot recommend for the requested tolerance in/on potatoes due to
the lack of an adequate root/tuber metabolism study.  The following
study must be submitted to support the proposed tolerance.

860.1300  Plant Metabolism

	·	A potato metabolism study in which both the roots and tops are
analyzed is required to support the proposed use and tolerance on
potatoes.

Remaining Deficiencies – PP#s 1E6228 (Dry Bean), 9F5068 (Cotton), and
6E4653 (Snap Bean) 

All data gaps previously identified by HED (DP# 325801, 4/25/2006, D.
Davis) as a condition of registration under the petitions cited above
have now been adequately fulfilled except for the requirements for
confined rotational crop data noted above as well as the deficiency
pertaining to storage stability listed below.

860.1380 Storage Stability

	·	The registrant intends to submit a final storage stability report,
including analyses at 18 and 24 months.  When this study is submitted
the registrant should ensure that the dates documented in the report
should reflect the actual storage intervals, and not the proposed
intervals, as there was some discrepancy in the interim report.

Background

The chemical name and structure of fomesafen sodium and fomesafen are
listed below in Table 1.  The physicochemical properties of fomesafen
are listed in Table 2; data pertaining to the physicochemical properties
of fomesafen sodium are not available.

5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenza
mide, sodium salt

CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benza
mide, sodium salt

CAS registry number	108731-70-0

Compound	

Common name	Fomesafen

Company experimental name	Not provided.

IUPAC name
5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenza
mide

CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzam
ide

CAS registry number	72178-02-0

End-use product (EP)	Reflex® Herbicide, 2 lb ae/gal SL; EPA Reg. No.
100-993

Table 2.   Physicochemical Properties of Fomesafen.

Parameter	Value	Reference

Melting point/range	220-221 (C	HED Memo, 9/3/82, W. Anthony

pH	8.2 (94% TGAI)	CSF (EPA Reg. No. 100-1017; 10/13/00)

Density	1.28 g/cm3 at 20 (C	HED Memo, 9/10/86, C. Trichilo

Water solubility at 25 °C	600 g/L at pH 7

<10 ppm at pH 1-2

50 mg/L	HED Memo, 9/3/82, W. Anthony

HED Memo, 9/10/86, C. Trichilo

Solvent solubility	g/L

Acetone	                                300

Cyclohexanone	                150

Methanol	                                  25

Hexane	                                  0.5

Xylene                                      1.9	HED Memo, 9/10/86, C.
Trichilo

Vapor pressure	<7.5 x 10-7 mm Hg at 50 (C	The Pesticide Manual 1

Dissociation constant, pKa	2.7 at 20 (C

	Octanol/water partition coefficient, Log(KOW)	Log KOW = 2.9 at pH 1

	UV/visible absorption spectrum	Not available

	1  The Pesticide Manual, A World Compendium, The British Crop
Protection Council (toxnet.nlm.nih.gov).

860.1200 Directions for Use

The end-use product relevant to the potato and tomato petition
(PP#9F7563) is Reflex® Herbicide (EPA Reg. No. 100-993), a soluble
concentrate liquid (SL) formulation containing 22.8% sodium salt of
fomesafen as the active ingredient (equivalent to 2 lb ae/gal of
fomesafen).  Reflex® is a selective herbicide which may be applied
preplant surface, preemergence, and/or postemergence for control or
partial control of broadleaf weeds, grasses, and sedges in registered
crops cotton, dry beans, snap beans, and soybeans.  In support of the
proposed uses on potatoes and tomatoes, the petitioner submitted a draft
label for Reflex® Herbicide dated 4/27/2009.  A summary of the proposed
use directions for potatoes and tomatoes is presented in Table 3A.

Table 3A.  Summary of Proposed Use Directions of Reflex® Herbicide (EPA
Reg. No. 100-993; 2 lb ae/gal) on Potatoes and Tomatoes.

Applic. Timing, Type, and Equip.	Applic. Rate 

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

(lb ae/A)	PHI

(days)	Use Directions and Limitations

Potato

Broadcast preemergence application after planting but before potato
emergence

Ground/Aerial/Center pivot irrigation 	0.25	1	0.25	70	Refer to
Syngenta’s Regional Use Map for Reflex® 1 (summarized in the
‘General Use Directions’ below) for determination of maximum use
rate that may be applied in each geographic region.  Do not apply to any
field in Regions 2, 3, 4, or 5 more than once every two years.  Do not
apply to sweet potatoes or yams.  Do not apply as a preplant
incorporated application as crop injury may occur.  Do not apply to
emerged potato plants or severe crop injury will occur.

Tomato (Transplanted)

Broadcast preplant non-incorporated preemergence application up to 7
days prior to transplanting tomatoes

Ground/Aerial/Center pivot irrigation	0.25-0.375	1	0.375	70	Refer to
Syngenta’s Regional Use Map for Reflex® 1 (summarized in the
‘General Use Directions’ below) for determination of maximum use
rate that may be applied in each geographic region.  Do not apply to any
field in Regions 2, 3, 4, or 5 more than once every two years.

1  The draft label specifies five use regions with specific seasonal
maximum application rates.  The rates range with the label use Region 1
having the highest seasonal application rate reflects application at
0.375 lb ae/A each year and label use Region 5 with the lowest seasonal
application rate reflects application of up to 0.1875 lb ae/A in
alternate years.  Details of the seasonal maximums for all label use
Regions are presented below under “General Use Directions”.

General Use Directions

Syngenta’s regional use map for Reflex®:  The draft label specifies
that product may only be used in the eastern half of the U.S. 
Syngenta’s regional use map for Reflex® is subdivided into the
following five regions:

Region 1:  Reflex® may be applied at a maximum of 0.375 lb ae/A per
year in Region 1 per year which includes the following states or portion
of states:  AL, AR, FL, GA, LA, MS, MO (counties of Bollinger, Butler,
Cape Girardeu, Dunklin, Madison, Mississippi, New Madrid, Pemiscot,
Perry, Ripley, Scott, Stoddard, and Wayne), NC, OK (East of U.S. Highway
75 and East of Indian Nation Parkway), SC, TN, and TX (includes area
East of U.S. Highway 77 to State Road 239 including all of Calhoun
County).

Region 2:  Reflex® may be applied at a maximum of 0.375 lb ae/A in
alternate years in Region 2 which includes the following states or
portion of states:  DE, KY, MD, VA, WV, and South of Interstate 70 in
the following states:  IL, IN, and OH and all areas South of the
Interstate 80 to the intersection of U.S. Highway 15 and East of U.S.
Highway 15 and U.S. Highway 522 in PA.

Region 3:  Reflex® may be applied at a maximum of 0.313 lb ae/A in
alternate years in Region 3 which includes the following states or
portion of states:  CT, IA, ME, MA, MO (all counties except those listed
in Region 1), NH, NJ, NY, PA (all areas except those listed in Region
2), RI, VT, and WI (South of U.S. Highway 18 between Prairie Du Chien
and Madison, and South of Interstate 94 between Madison and Milwaukee),
and North of Interstate 70 in the following states:  IN, IL, and OH. 

Region 4:  Reflex® may be applied at a maximum of 0.25 lb ae/A in
alternate years in Region 4 which includes the following states or
portion of states:  KS (all counties East of or intersected by U.S.
Highway 281), MI (Southern Peninsula), MN (all areas South of Interstate
94), NE (all counties East of or intersected by U.S. Highway 281), and
WI (all areas, except those in Region 3, South of Interstate 94 from MN
state line to Eau Claire and South of U.S. Highway from Eau Claire to
Green Bay plus Barron, Chippewa, Clark, Door, Dunn, Eau Claire,
Kewaunee, Marathon, Menominee, Oconto, Polk, Shawano, and St. Croix
counties.  The following counties are excluded:  Adams, Marquette,
Portage, Waupaca, Waushara, and Wood).  ND (all areas East of Interstate
29 from Fargo South to the SD state line).  SD (all areas East of
Interstate 29 from the ND state line to Watertown, all areas East of
Highway 81 from Watertown to Madison and all areas East and South of
State Road 34 and U.S. Highway 281 to the NE state line.

Region 5:  Reflex® may be applied at a maximum of 0.1875 lb ae/A in
alternate years in Region 5 which includes the following states or
portion of states:  ND (all areas East of the U.S. Highway 281 except
those areas in Region 4), SD (all areas East of the U.S. Highway 281
except those areas in Region 4), and MN (all areas South of the U.S.
Highway 2 except those areas in Region 4).

Spray additives:  The draft label specifies that spray additives cleared
for use on growing crops under 40 CFR §180.1001 may be used in the
spray mixture.  A nonionic surfactant (NIS), crop oil concentrates
(COC), or other adjuvants may be used for postemergence applications
only.  Since the proposed uses on potatoes and tomatoes are either
preemergence or pretransplant, the use of surfactants is not needed when
Reflex® is applied to these crops.

Application equipment:  Ground applications are to be made in a minimum
of 10 gal/A, and aerial applications are to be made in a minimum of 5
gal/A.  Applications are not to be made through any type of irrigation
equipment except center pivot systems.  Reflex® alone or in tank
mixture with other herbicides on the label, which are registered for
center pivot application, may be applied in irrigation water
preemergence (after planting but before weeds or crop emerge) at
label-recommended rates.

Tank mixtures with other products registered for use on potatoes and
tomatoes:  The draft label provides mixing procedures for tank mixes but
does not specify specific tank mix partners for potatoes and tomatoes. 
The use directions state that, for tank mix combinations, the
recommendations, restrictions, and limitations for all products must be
followed and that the most restrictive labeling is to apply.  For
preemergence application in potatoes, Reflex® may be tank mixed with
other pesticide products registered for use in this way and timing in
potatoes.  For preplant non-incorporated preemergence applications prior
to transplanting tomatoes, Reflex® may also be tank mixed with other
pesticide products registered for use in this way and timing in
tomatoes.  

Rotational crop plantback intervals:  The draft label specifies that the
rotational crops listed in Table 3B may be planted after applying
Reflex® at recommended rates.

Table 3B.  Rotational Crop Plantback Intervals Listed on the Reflex®
Herbicide.

Crop To Be Planted	Minimum Rotation Interval

(Months After Last Reflex® Application)

Cotton, dry beans, potatoes, snap bean, soybeans, and transplanted
tomatoes	0

Small grains such as wheat, barley, and rye	4

Corn 1, peanuts, peas, rice, seed corn	10

To avoid crop injury, do not plant alfalfa, sunflowers, sugar beet,
sorghum 2, or any crop within	18

1  Use a 12 month minimum rotation interval for popcorn in the states of
OH, KY, IL, IN, IA, and Region 4 when applied at rates of 0.25 lb ae/A
or more.  Use 18 month minimum rotation for sweet corn in the states of
CT, ME, MA, NH, NY, RI, VT, and Region 5.

2  Sorghum may be planted back after 10 months in Region 1.

Additional consideration:  HED previously requested (DP# 325801,
4/25/2006, D. Davis) that the product label for Reflex® Herbicide be
revised to reflect a 45-day PHI for dry beans based on the submitted
data and remove Frontier as a recommended tank mix partner for snap
beans.  An examination of the draft label for Reflex® Herbicide
indicates that a 45-day PHI is now listed for dry beans and Frontier is
no longer listed as a tank mix partner for snap beans; therefore, this
data gap is fulfilled.

Conclusions.  The available draft label for Reflex® Herbicide is
adequate to allow evaluation of residue data relative to the proposed
use on potatoes and tomatoes.

At this time, data are not available to support rotation to other crops
beyond those commodities that are currently registered and proposed as
primary crops; therefore the petitioner must revise the Reflex®
Herbicide label to permit immediate replanting of soybeans, cotton, dry
beans, snap beans, potatoes, and tomatoes only with a restriction that
other crops can only be planted 12 months after treatment or 18 months
after treatment if based on phytotoxicity concerns.

860.1300 Nature of the Residue - Plants

Tomato

DER Reference List:  47473901.der.doc

Syngenta Crop Protection has submitted a study investigating the
metabolism of [trifluoromethylphenyl-U-14C]fomesafen (TMP label;
specific activity 55.8 µCi/mg) and [nitrophenyl-U-14C]fomesafen (NP
label; specific activity 56.2 µCi/mg) in tomatoes.  Each radiolabeled
test substance was formulated as Reflex™ Herbicide in water and
applied by spraying onto the bare ground soil of designated plots, four
days before tomato seedlings were transplanted into the plots.  The
target application rate was 0.375 lb ai/A (1x the proposed rate). 
Actual application rates were 0.369 lb ai/A for the TMP label and 0.385
lb ai/A for the NP label.  Ripe tomatoes were harvested 98 days after
treatment (DAT).  A second harvest, 104 DAT, provided additional red
ripe fruits and immature green fruits (both not analyzed) and foliage
for analysis that might generate more information of the metabolism of
the test substance.  The field phase of the study was conducted at an
outdoor field site maintained by Excel Research Services (Fresno, CA). 
The analytical phase of the study was performed by PTRL West, Inc.
(Hercules, CA).

Total radioactive residues (TRR) in tomato matrices were determined by
both combustion and the sum of ppm levels detected in extracts and the
post-extraction solids (PES).  The TRR in ripe tomatoes were very low
(0.005 and 0.002 ppm for the TMP and NP labels, respectively).  The TRR
in tomato foliage (0.084 and 0.080 ppm for the TMP and NP labels,
respectively) were at least 17x higher than fruits.

Residues in harvested matrices were extracted with acetonitrile:water
(1:1, v:v) twice, a procedure which adequately released the majority of
radioactivity.  Additional extraction with acetonitrile released no
radioactivity, and the post-extractions solid (PES) was devoid of
radioactivity as demonstrated by combustion.  The combined
acetonitrile:water extracts were analyzed by HPLC, which showed numerous
products that generally partitioned into water rather than organic
solvent (ethyl acetate).  The combined acetonitrile:water extracts were
acidified (pH ~1) and extracted with ethyl acetate to
characterize/identify residues by chromatographic techniques.  

From the TMP label study, the parent fomesafen was identified in fruits
(3.7% TRR) and foliage (2.4% TRR).  In addition, the metabolite
3-chloro-4-hydroxybenzoic acid (R052850) was detected in fruits
(5.5-6.9% TRR) but not in foliage.  A major unknown (up to 78.4% TRR)
was characterized as acid labile, to volatile residues.  All identified
residues were below 0.01 ppm. 

From the NP label study, fomesafen was identified in fruits (3.6% TRR)
and foliage (1.3% TRR).  Approximately 39.6% of the TRR in the extract
eluted at the solvent front and 31.6% at retention time 12.8 minutes. 
When the concentrated extract was partitioned between ethyl acetate and
water (pH ~4), all radiolabel was in the aqueous phase.  The extract was
reanalyzed by HPLC when two cysteine (Cys) conjugates became available
as reference standards.  The peak at ~13 min co-eluted with the Cys
conjugate of sulfonamide (R290493) and was detected in fruits
(31.1-31.6% TRR) and foliage (8.8% TRR).  The following metabolites were
additionally identified:  (i) 2-NO2-5-OH benzoic acid (R012156) in
fruits (5.9% TRR); and (ii) 2-NH2-5-OH benzoic acid (R089135) in fruits
(3.7% TRR).  

 

Tomato fruits and foliage were stored frozen for maximum durations of 70
and 36 days, respectively, prior to the completion of chromatographic
analyses.  No storage stability data were submitted and none are
required since sample integrity was maintained by appropriate freezer
storage and final analysis was completed within 70 days of sample
collection.

Based on the results of the conducted study, the petitioner provided a
proposed metabolic pathway of fomesafen in tomato.  As also found in a
concurrent confined accumulation study in rotational crops, the ether
bridge is cleaved by a nucleophilic addition of glutathione with
subsequent formation of cysteine conjugate(s) of the
nitro-[14C-U-phenyl] moiety and conjugation and/or oxidation of the
trifluoromethyl-[14C-U-phenyl] moiety as well as formation of polar weak
acid metabolites of each ring moiety.  14C-Incorporation into very polar
natural products is also likely.  According to the petitioner, these
findings are also similar and consistent with previous metabolism work
reported on fomesafen and acifluorfen (an analogous diphenyl ether
herbicide) with soybean foliage and cotton.  See Appendix II for the
chemical names and structures of metabolites identified.

Conclusions.  The submitted tomato metabolism study is adequate.  TRR in
ripe tomatoes were very low (0.005 and 0.002 ppm for the TMP and NP
labels, respectively) following application of the test substances at a
target rate of 0.375 lb ai/A.  In ripe tomatoes, fomesafen (3.6-3.7%
TRR) was identified as were the metabolites 3-chloro-4-hydroxybenzoic
acid (R052850) (5.5-6.9% TRR), 2-NO2-5-OH benzoic acid (R012156) (5.9%
TRR), and 2-NH2-5-OH benzoic acid (R089135) (3.7% TRR).  The cysteine
conjugate of sulfonamide (R290493) was a major product from the NP
radiolabel (31.1-31.6% TRR).  A major unknown from the TMP radiolabel
(up to 78.4% TRR) was characterized by the registrant as acid labile, to
volatile residues.  Although the corresponding %TRR appears high for
characterized/identified components, all residues were below 0.01 ppm. 
Residues in the rest of the tomato plant (foliage/stalks) was >10x
higher than in fruit and generally consisted of fomesafen and the same
metabolites.

Syngenta’s Response to Cotton Metabolism Study Data Gaps as a
Condition of Registration

Reference List:  47761905 (No DER generated)

HED previously reviewed (DP# 325801, 4/25/2006, D. Davis) a cotton
metabolism study (MRID 44754706) submitted by Syngenta in support of a
cotton tolerance petition (PP#9F5068).  Although the study was deemed
unacceptable to fulfill data requirements, HED concluded that the cotton
study may be upgraded pending submission of additional information
pertaining to the conduct and other experimental details.  In response,
Syngenta has submitted MRID 47761905 which provides responses to the
information requested.  The specific deficiencies are re-stated below
followed by the petitioner’s response and HED’s comments regarding
the adequacy of response.

Deficiency:  “The actual application rate for the higher treatment
rate must be provided (Syngenta only provided the target application
rate for plants treated at 1.5 lb ai/A).  The lighting and temperature
conditions used in the greenhouse should be provided.”

Syngenta’s response:  Sample calculations included in the cotton
metabolism report indicated that 2.15 mCi and 2.47 mCi
[2-chloro-4-(trifluoromethyl)phenoxy-U-14C] and
2-[nitrobenzamide-U-14C]fomesafen, respectively, at specific activities
of 54.5 and 62.5 Ci/mol were required to achieve an application rate of
1.5 lb ai/A to the test pots.  Dosing solutions for each label were
confirmed by scintillation counting of aliquots.  Application of
[2-chloro-4-(trifluoromethyl)phenoxy-U-14C]fomesafen (CF3 label) was
made to three pots and determined to be equivalent to 1.51, 1.51 and
1.51 lb ai/A.  Application of 2-[nitrobenzamide-U-14C]fomesafen (NO2
label) was also applied to three pots at rates of 1.55, 1.55 and 1.56 lb
ai/A.  Calculations of application rates are presented in Table 4.



 

(Note: table was copied directly from MRID 47761905.)

The exaggerated application rates (3x) were included in the study for
the sole purpose of generating adequate residues for characterization
and identification.  Documentation supporting the higher application
rate was included in the study notebooks and raw data.  

Lighting and temperature conditions in the greenhouse were adjusted
periodically to minimize temperature shifts.  Hygrothermograph records
maintained in the laboratory notebook indicate that typical temperatures
ranged 77-98 °C.  Lamps were used to irradiate the plants during early
morning (7 am-11 am) and mid-afternoon to evening (3 pm-11 pm).  As
warmer weather arrived, lamp schedules were changed to 6 am-9 am and 4
pm-10 pm to reduce the heat in the greenhouse.  Typical plant heights
were observed at harvest.  All harvested crops were grown to maturity in
good health and yield.

HED’s comments/conclusions:   The petitioner has provided the
calculations of the higher treatment rate used in the cotton metabolism
study.  The actual 3x applications rates were 1.51 and 1.55-1.56 lb ai/A
for the CF3 and NO2 labels, respectively.  The requested information
pertaining to lighting and temperature conditions used in the greenhouse
was provided and appeared optimum for the type of study conducted.  This
deficiency is resolved.

Deficiency:  “Syngenta must provide the dates of sample analysis for
all samples and all analyses.  If final analyses of cotton gin byproduct
samples were not completed within 6 months of sample collection,
Syngenta must provide evidence that the metabolite profile in samples
did not change during storage.  We note that based on the study
completion date, samples may have been stored >500 days prior to final
analysis.”

Syngenta’s response:  The RACs collected from cotton test plots
treated with 14C-fomesafen were extracted, chromatographically profiled,
and quantified within 3.5 months of harvest.  Additional analysis of the
samples was conducted beyond this point in order to isolate and
characterize the radioactive residues.  Comparison of chromatography
obtained towards the end of the analytical phase of the study indicated
a qualitatively similar chromatographic profile, thus providing evidence
for storage stability.

Cotton plants treated with CF3 and NO2 labeled fomesafen were grown to
maturity, harvested and separated into seed/fiber and gin byproducts. 
TRR in seeds from treatment at 0.5 lb ai/A were below 0.01 ppm for both
labels and were not extracted or profiled.  The TRR in gin byproducts
from cotton treated with either test compounds at both the 0.5 and 1.5
lb ai/A application rates were >0.01 ppm.  The samples were extracted,
profiled, and quantified in two chromatographic systems within 3.5
months of harvest (page 16 of MRID 47761905).  The cotton gin byproduct
extracts from the two 3x treatment samples were further analyzed to
characterize the radioactive residues.

In an effort to further characterize metabolites B, C, and D from the
CF3 labeled fomesafen treated gin byproducts, the aqueous extract from
the 3x treatment was subjected to semi-prep HPLC in January 1998 (page
17 of MRID 47761905).  The HPLC method employed in semi-prep analysis of
this extract was similar in nature to the HPLC method used to generate
the initial profiles (RR 97-056B).  Therefore, a comparison of the two
resulting chromatograms (page 20 of MRID 47761905) can be made for
storage stability purposes.  Such a comparison demonstrates the extracts
are qualitatively similar and, as such, provides evidence, that the
extract was stable under storage conditions.

Syngenta reported that approximately 10 months after harvest, an
additional analysis was conducted with the aqueous extracts of gin
byproducts treated with NO2 labeled fomesafen at the 3x rate in an
attempt to characterize metabolite G.  Metabolite G, isolated from an
aqueous extract, was subjected to hydrolysis and was characterized by
HPLC as a complex mixture of products.  No storage stability data were
collected to support this work.  Metabolite G, however, only represented
0.006 ppm (13.9% TRR) in gin byproducts treated at the 1x rate; thus,
additional characterization of this minor radioactive residue was not
necessary.  Therefore, Syngenta believes that the lack of storage
stability data for this sample does not impact any of the report
conclusions.

HED’s comments/conclusions:   The petitioner has provided the
requested dates of sample analysis for all samples and all analyses. 
Based on these dates, all samples were extracted, profiled, and
quantified within 3.5 months of harvest.  Efforts to further analyze the
aqueous extracts of gin byproducts treated at the 3x rate did result in
analytical work being conducted more than 6 months after harvest.  In
the case of the extracts coming from treatment with the NO2 labeled
fomesafen, no viable results in the characterization of the residues
were obtained due to low residue levels.  HED concurs with Syngenta’s
assessment that comparison of the resulting chromatography from the
aqueous extracts of gin byproducts resulting from CF3 labeled fomesafen
provided a qualitative profile similar to the definitive profile
obtained within 6 months of harvest and, therefore, provides evidence of
storage stability.  This deficiency is resolved.

Deficiency:  “There was a large difference between the total
extractable radioactivity and the total of the identified and
characterized radioactivity for each sample.  For samples treated at the
lower rate, Syngenta referred to this “fraction” as “total %
unknown.”  The total unknown fraction ranged 11.0-49.5% TRR
(0.009-0.112 ppm) in gin byproduct samples.  No explanation was
provided.  Syngenta also did not provide any quantitative
chromatographic raw data.  Syngenta must provide an explanation for this
apparent loss in radioactivity.  In addition, quantitative
chromatographic data should be provided for all chromatograms included
in the submission.”

Syngenta’s response:  The exaggerated application rate (3x) samples
were generated for the sole purpose of ensuring adequate radioactive
residues were available to aid in characterization and identification. 
As such, the material balance was quantitated on the 1x treatment rate. 
Unknown constituents in the 1x and 3x applications are an accumulation
of unresolved peaks and background radioactivity.  To illustrate this
point, raw data were used to recreate the quantitation of the CF3 label
and NO2 label (1x) organic and aqueous profiles and were presented in
Figures 2 and 3 MRID 47761905, respectively.  These profiles illustrated
that unknown peaks constitute multiple minor components and background
radioactivity.  All residues, except fomesafen, were at or below trigger
(≤0.010 ppm) in the organic profiles.  All residues, except metabolite
C, were at or below trigger (≤0.010 ppm) in the aqueous profiles. 
Fomesafen, metabolite C, and metabolite D were isolated for
characterization and identification by mass spectrometry.

Quantitation of unknown peaks in the exaggerated application rates was
not pursued as the study objective was to use these 3x treated crop
fractions for isolation, if necessary.  Chromatographic quantitation of
the CF3 labeled fomesafen (1x) unknowns had 0.020 ppm residue which
consisted of multiple minor components, none of which, except metabolite
C, had individual residues of >0.010 ppm.  No unknown residues (>0.010
ppm) requiring further characterization were present in NO2 labeled
fomesafen (1x) samples. 

HED’s comments/conclusions:   The petitioner responded to the above
deficiency by recreating the quantitation of organic and aqueous
extracts of cotton gin byproducts from the 1x study of the CF3 label and
NO2 label.  The unknowns comprised 32% and 8.9% TRR of the CF3 and NO2
labels, respectively.  Chromatographic quantitation of the CF3 labeled
fomesafen unknowns consisted of multiple minor components, none of
which, except metabolite C, had individual residues of >0.010 ppm.  No
unknown residues (>0.010 ppm) requiring further characterization were
present in NO2 labeled fomesafen (1x) samples.  Total accountability of
residues in gin byproducts treated at 1x was re-calculated at 106% and
90% the CF3 and NO2 labels, respectively. This deficiency is resolved.

Deficiency:  “Syngenta should provide an interpretation of the LC/MS
spectra that were included in the submission for Metabolites B-3 and C-1
and provide proposed structures for these metabolites, if possible.”

Syngenta’s response:  Structures were suggested in the raw data files
but were not included in the final report as the data to support
structural confirmation were limited.  A possible structure for
Metabolite B-3 is shown in Figure 1 while that for Metabolite C-1 is
shown in Figure 2.  Syngenta offered some possible interpretations below
which are consistent with the proposed structures.

Mass spectra for both peaks (B-3 and C-1) showed that they are
chlorinated (based on the isotope pattern of the base peak); they also
suggest that they are radiolabeled (based on the A+12 peak from the
fully labeled phenyl ring).  Therefore both rings are confirmed to be
intact for both moieties.

The spectrum for metabolite B-3 (Figure 1) showed a m/z 459 peak in
negative electro spray ionization (ESI) consistent with the deprotonated
sodium salt formed by loss of the acidic proton of the sulfonylbenzamide
functionality; i.e., [M-2H+Na]-.  An MS/MS experiment showed a cleavage
product ion at m/z 241 and a product ion at m/z 423 from loss of HCl
that was consistent with the dibenzodioxin product structure in Figure
4.  Syngenta opined that this type of intramolecular cyclization with
loss of HCl is a common process.

The negative electrospray spectrum for metabolite C1 showed a
deprotonated molecule at m/z 425, which was consistent with an aryl
sulfate conjugate structure as shown in Figure 2.  MS/MS product ions
were observed at m/z 329 (loss of –SO4) and m/z 393 (loss of 2
oxygens); as well as, m/z 97 (HSO4-) and m/z 80 (SO3-).  Because of the
rare occurrence of sulfate conjugates observed from the metabolism of
pesticides in plants, further evidence of structure C1 would be required
before this structure could be assigned with confidence.  Furthermore,
ambiguities observed in the MS data; for example, missing chlorine
isotopes and the apparent losses of multiple (3) units of 16,
demonstrate that the experiments were being conducted near the
performance limits of the instrument with respect to signal intensity
and chemical noise.  However, given the low residue levels in the
samples and limited capabilities of available LC/MS instruments,
compared to today’s standards, the MS data represent the best possible
results at the time the study was conducted, and no additional
supporting data was obtainable.

HED’s comments/conclusions:   The petitioner responded to the above
deficiency by assigning possible structure for Metabolites B-3 (Figure
1) and C-1 (Figure 2).  This deficiency is resolved.

Deficiency:  “Syngenta should provide an explanation for not making
any attempts to characterize the nonextractable radioactivity in gin
byproducts treated with NP label [14C]fomesafen at the higher rate. 
According to the requirements of OPPTS 860.1300, additional attempts to
extract this radioactivity should have been made (nonextractable
radioactivity was >10% TRR and >0.05 ppm).”

Syngenta’s response:  The NO2 label fomesafen samples (3x) were
generated to ensure adequate residues for identification and
characterization.  No additional attempts were made to characterize the
non-extractable radioactivity for gin byproducts treated with NO2 label
fomesafen at the higher rate because of the low residue (0.011 ppm) at
the 1x rate.

HED’s comments/conclusions:   HED concurs with Syngenta that no
further characterization of nonextractable residues in gin byproducts
treated with NP label [14C]fomesafen at the higher rate is required
because of the low residues at the 1x rate.  HED will consider the
residue characterization of cotton RACs from the 1x treatment rate as
adequate and the characterization of residues from the 3x treatment rate
as supplemental data.

In summary, the cotton metabolism study has now been upgraded to
acceptable status based on Syngenta’s submission of the requested
information pertaining to actual application rate for the higher
treatment rate, the lighting and temperature conditions used in the
greenhouse, the dates of sample analysis, quantitative data for the
unknowns and nonextractable residues, and the designation of possible
structures for Metabolites B-3 and C-1.  The supplementary data indicate
that following application of CF3-labeled fomesafen at 1x, approximately
61% TRR (0.040 ppm) resulted in extractable peaks (A-1, A-2, A-3,
fomesafen, B, C, D) in cotton gin byproducts with the parent fomesafen
comprising 11.6% TRR (0.008 ppm).  Following application of NO2-labeled
fomesafen at 1x, approximately 55% TRR (0.024 ppm) resulted in
extractable peaks (fomesafen, E, F, G) in cotton gin byproducts with
fomesafen comprising 27.0% TRR (0.012 ppm).



(Note: figure was copied directly from MRID 47761905.)



(Note: figure was copied directly from MRID 47761905.)



Potato

When a pesticide will be used on several different crops the Agency
requires plant metabolism studies on three diverse crops.  Currently
adequate tomato, soybean, and cotton metabolism studies are available
for fomesafen.  The HED Chemistry Science Advisory Council (ChemSAC)
specifically considered the need for metabolism studies for fomesafen in
a meeting on 7/25/2007.  According to the 07/25/2007 minutes, the
ChemSAC specifically recommended submission of a root/tuber metabolism
study because cotton and soybeans are considered similar within the
Agency and internationally (e.g., OECD).  Given this fact, ChemSAC
concluded that a potato metabolism study would still be required.  A
potato metabolism study, in which both the root and tops/foliage are
analyzed, is required to support the proposed use on potatoes.  HED
cannot recommend for a tolerance in/on potatoes until an adequate potato
metabolism study is submitted.

860.1300 Nature of the Residue - Livestock

MRID 00110508 (PP#2G2745, 1/28/83, A. Rathman, and PP#4F2997, 9/25/94,
A. Smith)

MRID 00135635 (PP#4F2997, 9/25/84, A. Smith)

Residue Chemistry Memo  DP# 325801, 4/25/06, D. Davis

Syngenta submitted a goat metabolism study in conjunction with the
temporary tolerance petition for soybeans (PP#2G2745).  A single goat
was dosed with [nitrophenyl-14C]fomesafen at 0.1 ppm in the diet for 7
days; the goat was sacrificed 16 hours after the final dose.  The dosing
level corresponds to ~2x and 5x the maximum theoretical dietary burdens
to beef and dairy cattle, respectively.  TRR reached a maximum in milk
of 0.0008 ppm on Day 3.  TRR were 0.003 ppm in liver, 0.004 ppm in
kidney, <0.003 ppm in meat, and <0.005 ppm in fat.  Approximately 70% of
the dosed radioactivity was excreted.  No residue characterization was
conducted because of low radioactivity levels.  

ed metabolites were
5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonylanthranilamid
e (compound XV) and 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)
anthranilic acid (compound V).  Compound XV was found at 10% TRR in
liver and 20.9% TRR in kidney, and compound V was found at 34.5% TRR in
liver and 33.9% TRR in kidney.  

oro-α,α,α-trifluoro-p-tolyloxy) anthranilic acid (compound V) and
5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonylanthranilamid
e (compound XV).  

Based on the residue levels in goat matrices following dosing at to
~184x and 468x the maximum theoretical dietary burdens to beef and dairy
cattle, respectively, HED concludes that the proposed/registered uses of
fomesafen on cotton, dry and snap beans, soybeans, potatoes, and
tomatoes result in a 40 CFR §180.6(a)(3) situation for livestock
commodities; i.e., there is no reasonable expectation of finite residues
in livestock commodities.  There are no poultry and swine feedstuffs
associated with the proposed uses.

860.1340 Residue Analytical Methods

MRID 40007101 (Enforcement method for soybean; PP#4F2997, CB No. 2253,
8/18/87, W. Chin)

MRIDs 44754703 and 44754704 (Enforcement method for cotton; DP# 325801,
4/25/06, D. Davis)

MRIDs 45093602 and 45093603 (Revised enforcement method for soybean; DP#
325801, 4/25/06, D. Davis)

Plant commodities

Enforcement methods

Three residue analytical methods have been submitted to the Agency for
the purpose of tolerance enforcement.  All of these methods quantitate
residues of fomesafen in/on crop commodities and are briefly described
below.

(i) The HPLC/UV method, GAM-RM-001/86, was submitted in the initial
soybean petition (PP#4F2997).  The method, entitled “The Determination
of PP021 in Soybeans - A High Performance Liquid Chromatography
Method”, involves the extraction of residues in crop samples with
acetonitrile:concentrated HCl (98:2, v:v).  The extract is diluted with
water and partitioned with hexane.  The aqueous phase is partitioned
with dichloromethane (DCM), and the DCM phase is cleaned up by
ion-exchange chromatography on an amino column for HPLC analysis using a
C18 column and UV detection at 290 nm.  The limit of quantitation (LOQ)
reported in the method is 0.01-0.02 ppm.  The method has successfully
passed an Agency tolerance method validation.

 

(ii) The GC/NPD method, TMR0836B, was submitted and reviewed in DP#
325801 to replace the existing HPLC/UV method for soybean commodities. 
The method is entitled “Determination of Fomesafen in Soybeans by Gas
Chromatography with Nitrogen/Phosphorus Detection.”  The new method
differs from the existing enforcement method in the use of GC/NPD for
analysis of extracts.  The extraction procedures of the method are
similar to those of the existing HPLC/UV method; however, in the new
method, fomesafen is converted to its methylated analog to allow GC
determination.  Briefly, residues in/on soybean forage, hay, and seed
samples are extracted with acidified ACN, and the extract is acidified
and partitioned with hexanes.  The resulting aqueous phase is
partitioned with DCM, and the DCM phase is redissolved in methyl
isobutyl ketone (MIBK).  The MIBK solution is mixed with iodomethane and
then heated to methylate fomesafen.  The methylated residues are cleaned
up on a silica gel column for GC/NPD analysis.  Results are reported in
terms of fomesafen.  The validated LOQ reported in the method is 0.02
ppm for soybean forage, hay, and seed.  A limit of detection (LOD) was
not reported; Syngenta estimated the LOD to be less than 10-20% of the
LOQ in these commodities. 

(iii) A GC/NPD method (TMR0800B) was submitted in the cotton petition
(PP#9F5068) and reviewed in DP# 325801.  The method is entitled
“Determination of Fomesafen in Cottonseed and Gin Trash by Gas
Chromatography.”  Using this method, residues in cotton matrices are
extracted with acidified ACN, and the extract is partitioned with
hexanes.  The resulting aqueous phase is partitioned with DCM, and the
DCM phase is redissolved in MIBK.  The MIBK solution is mixed with
iodomethane and then heated to methylate fomesafen.  The methylated
residues are cleaned up on a silica gel column for GC/NPD analysis. 
Results are reported in terms of fomesafen per se.  The validated LOQ
reported in the method is 0.02 ppm for cotton seed and gin byproducts. 
An LOD was not reported; Syngenta estimated the LOD to be less than
10-20% of the LOQ in cotton seed and gin byproducts.

HED’s review (DP# 325801, 4/25/06, D. Davis) of GC/NPD Methods
TMR0836B (soybeans) and TMR0800B (cotton) required the submission of
additional data before the methods can be deemed suitable for tolerance
enforcements.  The Agency required confirmatory raw data, the
modification of the method to incorporate extraction and analysis of
specific crop commodities, and the submission of confirmatory methods.  

Syngenta’s Response to Analytical Method Data Gaps as a Condition of
Registration

Reference List:	47761905 (No DER generated)

		47761903.der.doc (Includes MRID 47761904)

Syngenta has submitted MRID 47761905 which provides responses to the
information and data requested by the Agency.  For purposes of clarity,
the specific deficiencies pertaining to residue analytical methods are
re-stated below followed by the petitioner’s response as well as
HED’s comments regarding the adequacy of response.

Deficiency:  “Syngenta must submit raw data to support the method
validation data reported in MRIDs 44754703, 45093602, 45093603, 45268502
and 45268503.”

Syngenta’s response:  Syngenta has been unable to locate the method
validation raw data as requested.  In the absence of these raw data,
Syngenta undertook additional work to confirm the validity of the method
extraction procedure specified in the MRID numbers cited above. 
Specifically, soybean and cotton commodities, as well as dry beans, were
analyzed using an updated method, GRM045.01A.  This method utilizes the
same extraction procedure as the previous methods.  This method did
differ from the previous methods by the inclusion of a SPE clean-up
step, and the analysis was conducted using LC/MS/MS.  These results are
reported in MRIDs 47761903 and 47761904.  

HED’s comments/conclusions:   

Syngenta Crop Protection has submitted descriptions and validation data
for a new proposed enforcement method, Method GRM045.01A, which is
entitled “Fomesafen Analytical Method for the Determination of
Residues of Fomesafen in Crop Commodities by LC-MS/MS.”  This high
performance liquid chromatography with tandem mass spectrometry
detection (LC/MS/MS) method is based on previously submitted gas
chromatography with nitrogen phosphorus detection (GC/NPD) methods
(refer to DP# 325801, D. Davis, 4/25/06) developed by Zeneca AG.

Method GRM045.01A uses extraction procedures modified from the previous
GC/NPD methods.  In the revised method, fomesafen residues are extracted
with 1% hydrochloric acid in acetonitrile.  An aliquot is subjected to
an SPE cleanup and analyzed using LC/MS/MS.  A second ion transition may
be monitored for confirmation.  The LOQ is 0.02 ppm for fomesafen in
each matrix.  Representative spectra and linearity data were submitted
demonstrating adequate sensitivity.

No independent laboratory validation (ILV) or radiovalidation data have
been submitted for Method GRM045.01A.  Because the method is an
improvement on the previously established GC/NPD methods, these data
will not be required.  HED will also not request ACB/BEAD for a
tolerance method validation, and will forward the method to FDA for
inclusion in the Pesticide Analytical Manual (PAM) Volume II as an
enforcement method.  This deficiency is resolved.

Deficiency:  “Syngenta should modify GC/NPD Method No. TMR0836B to
include instructions for the extraction and analysis of dry bean, snap
bean, and aspirated grain fractions.  The modified method should then be
forwarded to FDA for inclusion in the Pesticide Analytical Manual (PAM)
Volume II.”

Syngenta’s response:  The new analytical method GRM045.01A meets this
requirement.

HED’s comments/conclusions:   LC/MS/MS method (GRM045.01A) is written
to include analysis of a wider variety of commodities (including snap
beans, dry beans, and soybean aspirated grain fractions) for residues of
fomesafen; special instructions are included in the analytical
procedures for separate extraction of residues in crop commodities
except for oil and for oil samples.  This deficiency is resolved.

Deficiency:  “Syngenta must propose alternative confirmatory methods
for the proposed new enforcement methods.  The currently proposed
confirmatory methods involve substitution of columns with only slight
polarity differences and likely very similar elution times and are not
considered sufficient for confirmation of an enforcement method.”

Syngenta’s response:   The new analytical method, (GRM045.01A), which
incorporates the highly specific LC/MS/MS detection, satisfies this
requirement.

is m/z 437→195; the ion transition m/z 437→222 is available as a
confirmation.

In summary, Syngenta has submitted a new LC/MS/MS method (GRM045.01A)
for analysis of fomesafen residues in crop commodities.  This method is
the updated version for previous Zeneca AG data-gathering methods
(TMR08055B, TMR0879B, TMR0800B, and TMR0881B).  The method uses
extraction procedures as previously described in the above-mentioned
methods, SPE cleanup procedures, and the final determination step by
LC/MS/MS technology for analysis of fomesafen residues.  The validated
LOQ of the method is 0.02 ppm.  Method GRM045.01A has been adequately
validated at fortification levels of 0.02 ppm and 0.2 ppm in snap beans,
pinto beans (dry bean), corn oil, cotton, undelinted seed and gin
byproducts, and soybean forage, hay, and aspirated grain fractions.

No radiovalidation data have been submitted for LC/MS/MS method
(GRM045.01A); however, because the extraction procedures of the method
are similar to those of the soybean metabolism study, radiovalidation
data are not needed.  Since LC/MS/MS method (GRM045.01A) appears to be a
superior method to the previously submitted methods for fomesafen due to
its state of the art technology and its specificity, HED will not
require independent laboratory validation data.  HED will also not
request ACB/BEAD for a TMV and will forward the method to FDA for
inclusion in the Pesticide Analytical Manual (PAM) Volume II as an
enforcement method.

Data-collection methods

Samples of raw and processed commodities of potatoes and tomatoes, which
were collected from the magnitude of the residue studies, were analyzed
for residues of fomesafen using a high performance liquid chromatography
method with tandem mass spectrometry detection based on an HPLC/UV
method (GAM-RM-001/86).  The method was adequately validated during
concurrent analysis of samples.  The lowest level of method of
validation (LLMV) was 0.025 ppm for each matrix.

Livestock commodities

Because there are no established or proposed tolerances for livestock
commodities, an enforcement method for livestock commodities is not
required.

860.1360 Multiresidue Methods

DER Reference List:  47761901.der.doc

Residue Chemistry Memo  DP# 325801, 4/25/06, D. Davis

HED (DP# 325801) previously required the submission of multiresidue
method testing data for fomesafen.  In response, the petitioner
submitted MRID 47761901.  The submission has been reviewed by HED, and
the Executive Summary of the study DER is reproduced below.

Syngenta Crop Protection has submitted multiresidue testing data for
fomesafen (free acid) following testing and analysis according to FDA
Multiresidue Test Guidelines in PAM Vol. I (1/94).  The Decision Tree
for MRM Testing found in the Multiresidue Protocols was followed in
determining the response patterns.  Fomesafen (free acid) was tested
through Protocols A, B, and C.  Protocols D, E, and F were not tested as
no residues were detected using Protocol C.  The compound was not tested
under Protocol G because it is not a substituted urea.

  

Fomesafen does not have an N-methylcarbamate structure and did not
produce a response on the fluorescence detector under Protocol A.  In
Protocol B testing, methylated fomesafen was not recovered from
Florisil; therefore, no additional work was performed under Protocol B.

Fomesafen (free acid) did not produce a response under Protocol C, using
gas chromatography with either the nitrogen phosphorus or the electron
capture detector (GC/NPD or GC/ECD).  Therefore, it was not tested using
Protocol D, E, or F.

Conclusions:  These data indicate that FDA multiresidue methods are not
suitable for determining residues of fomesafen.  The submitted data will
be forwarded to U.S. FDA for further evaluation.

860.1380 Storage Stability

DER Reference:  47761902.der.doc (corn, soybean, cotton, and wheat
matrices storage stability data)

DER Reference:  47473903.de1.doc (potato tuber concurrent storage
stability data)

DER Reference:  47473903.de2.doc (potato processed commodities
concurrent storage stability data)

DER Reference:  47473902.de1.doc (tomato fruit concurrent storage
stability data)

DER Reference:  47473902.de2.doc (tomato processed commodities
concurrent storage stability data)

Residue Chemistry Memo DP# 325801, 4/25/06, D. Davis

Sample storage duration and conditions  

The storage durations and conditions of potato and tomato samples from
the submitted magnitude of the residue and processing studies are
presented in Table 5.  Table 5 also includes the storage conditions and
durations of samples from the crop field trial, processing, and field
rotational crop studies which were submitted to support previous
petitions (PP#s 1E6228, 9F5068, and 6E4653).

Table 5.   Summary of Storage Conditions and Durations of Samples from
Crop Field Trial, Processing, and Field Rotational Crop Studies. 

Matrix	Storage Temperature  (°C)	Actual Storage Duration	Interval of
Demonstrated Storage Stability

Samples from Previous Petitions (PP#s 1E6228, 9F5068, and 6E4653)

reviewed under DP# 325801, 4/25/06, D. Davis

Cotton Field Trials (MRID 44754701)

Cotton gin byproducts	~-18	232-324 days

(7.6-10.7 months)	Storage stability data indicate that residues of
fomesafen appear to be erratic in/on cotton gin byproducts, but overall
show general stability; corrected stored recoveries were 69% at 2.5
months, 80% at 3.2 months, 142% at 8.8 months, and 68% at 14.6 months.

Soybean Processing Study (MRID 45093601)

Soybean hulls	-20	294 days

(9.7 months)	Storage stability data indicate that residues of fomesafen
appear to be relatively stable in/on soybean hulls stored frozen at -31
to -3 ºC for up to ~15 months.

Soybean refined oil

288 days

(9.5 months)	Storage stability data indicate that residues of fomesafen
appear to be relatively stable in/on soybean oil for up to ~9 months but
increased to a recovery of 149% by ~15 months.

Field Rotational Crop Study (MRID 00158936)1

Corn forage	-20	235-272 days

(7.7-8.9 months)	Storage stability data indicate that residues of
fomesafen appear to be relatively stable in/on corn K+CWHR, forage, and
stover, and wheat forage and straw stored frozen at -31 to -3 ºC for up
to ~15 months.

Corn cob

178-223 days

(5.8-7.3 months)

	Corn fodder

178-223 days

(5.8-7.3 months)

	Wheat forage

361-388 days

(11.9-12.7 months)

	Wheat straw

289-339 days

(9.5-11.1 months)

	Field Rotational Crop Study (MRID 45268501)

Field corn, forage	<-10	280-316 days

(9.2-10.4 months)	Storage stability data indicate that residues of
fomesafen appear to be relatively stable in/on corn forage and stover,
and wheat forage and straw stored frozen at -31 to -3 ºC for up to ~15
months.

Field corn, stover

239-279 days

(7.9-9.2 months)

	Sorghum, forage

232-289 days

(7.6-9.5 months)

	Sorghum, stover

182-273 days

(6.0-9.0 months)

	Samples from Current Petition (PP#9F7563)

Potato Field Trials and Processing Study (MRID 47473903)

Potato tuber	-40 to -6	316-399 days

(10.4-13.1 months)	Concurrent storage stability data indicate that
residues of fomesafen appear to be relatively stable for up to 420 days
in/on frozen potato tuber, 311 days in potato flakes, 308 days in potato
chips, and 307 days in wet potato peel. 

Potato, tuber (RAC)	-40 to -6	308 days

(10.1 months)

	Potato, flakes

299 days

(9.8 months)

	Potato, chips

298 days

(9.8 months)

	Potato, wet peel

293 days

(9.6 months)

	Tomato Field Trials and Processing Study (MRID 47473902)

Tomato fruit	-40 to -5	211-302 days

(6.9-9.9 months)	Concurrent storage stability data indicate that
residues of fomesafen appear to be relatively stable for up to 319 days
in/on tomato fruit and 236 days in tomato paste and puree.

Tomato, fruit (RAC)	-40 to -5	241 days

(7.9 months)

	Tomato, paste

229 days

(7.5 months)

	Tomato, puree

229 days

(7.5 months)

	1  For the field rotational crop study reported in MRID 00158936, the
dates of sample analysis were not provided.  The maximum storage
interval for each sample, based on the study completion date, was
calculated by the study reviewer.

Storage stability data

Storage stability data were concurrently generated with the
potato/tomato field and processing studies.  For each crop, control
samples of the respective matrices were fortified with fomesafen at
~0.25 ppm and placed in storage under the same frozen conditions as the
treated samples.  No zero-day analyses were conducted on the fortified
samples placed into storage.  Rather, triplicate stored samples were
analyzed along with a control sample and freshly fortified samples at an
interval reflecting the maximum storage intervals from the field and
processing studies.  Average corrected recovery ranges of fomesafen
were:  78-90% in potato tubers after 420 days, 79-99% in potato flakes
after 311 days, 72-77% in potato chips after 308 days, 71-81% in potato
wet peel after 307 days, 81-92% in tomato fruits after 319 days, 89-108%
in tomato paste after 236 days, and 87-109% in tomato puree after 236
days.  Although no 0-day analysis was conducted, the data indicate that
fomesafen is stable under frozen storage conditions at the maximum
intervals tested.  These data indicate that no corrections of residues
need to be applied to the study results.

Syngenta’s Response to Storage Stability Data Gaps as a Condition of
Registration

HED previously requested additional storage stability data to support
the storage conditions and intervals of samples collected from various
field and rotational crop studies (DP# 325801, 4/25/2006, D. Davis). 
The specific deficiency is re-stated below followed by the
petitioner’s response and HED’s comments regarding the adequacy of
response.

Deficiency:  Data are required depicting the stability of residues of
fomesafen in/on the following commodities:  cotton gin byproducts stored
frozen for up to 11 months; soybean hulls and oil stored frozen for up
to 10 months; corn cob stored frozen for up to 7 months; wheat forage
and straw during frozen storage for up to 13 months; and field corn or
sorghum forage and stover during frozen storage for up to 10 months.

Syngenta’s response:  The requested storage stability data have been
developed and are reported in MRID 47761902.  This interim report
included stability data through 13 months as required but the study will
continue with planned analysis at both 18 and 24 months.  Upon
completion of the analysis of the 24 month samples, the final report
will be submitted.  HED has reviewed the study submission; the Executive
Summary of the completed study DER is presented below.  

HED’s comments/conclusions:  Syngenta Crop Protection has submitted
interim storage stability data for fomesafen in corn kernel plus cob
with husks removed (K+CWHR), forage, and stover; cotton gin byproducts;
soybean hulls and oil; and wheat forage and straw.  These data were
submitted in response to data gaps for fomesafen storage stability data
to support use of the sodium salt on these crops (DP# 325801, D. Davis,
4/25/06).

Samples of eight commodities (corn K+CWHR, forage, and stover; cotton
gin byproducts; soybean hulls and oil; and wheat forage and straw) were
spiked with fomesafen at 1.00 ppm.  Fortified and unfortified samples
were stored at -31 to -3 °C.  The petitioner reports that samples of
each commodity were analyzed after 0, 1, 3, 6, and 13 months of storage,
with planned additional intervals of 18 and 24 months; however,
inspection of the fortification and analysis dates provided in MRID
47761902 yield different intervals.  The study was conducted by ADPEN
Laboratories, Inc. (Jacksonville, FL).

Crop samples were analyzed using Syngenta method GRM045.01B.  The
extraction and analysis procedures for this method are similar to those
of method GRM045.01A.  The validated LOQ is 0.02 ppm for fomesafen in
each crop matrix.

Residues of fomesafen appear to be relatively stable in/on corn K+CWHR,
forage, and stover, soybean oil and hulls, and wheat forage and straw
stored frozen at -31 to -3 ºC for up to ~15 months.  Residues of
fomesafen appear to be erratic in/on cotton gin byproducts, but overall
show general stability.  An adequately validated method was used for the
quantitation of fomesafen in the crop matrices tested in the storage
stability study.

The interim storage stability data adequately support the storage
conditions and intervals of crop commodity samples discussed in DP#
325801.  In the interim report, the petitioner reported that samples of
each commodity were analyzed after 0, 1, 3, 6, and 13 months of storage,
with planned additional intervals of 18 and 24 months.  When actual
storage intervals were recalculated using dates from the raw data,
samples were extracted after 0, 1.1-2.5, 3.2-4.0, 8.2-9.2, and 14.6-15.0
months.  It appears from the raw data that samples from the 0-, 1-, and
3-month storage intervals were fortified at later dates than samples
from the 6- and 13-month storage intervals.  The petitioner must explain
in the final report why the fortification times are different and why
the actual storage intervals differ so greatly from the nominal storage
intervals.

860.1400 Water, Fish, and Irrigated Crops

There are no proposed uses that are relevant to this guideline topic.

860.1460 Food Handling

There are no proposed uses that are relevant to this guideline topic.

860.1480 Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed use on
tomatoes.  Although, there are ruminant livestock feedstuffs associated
with the petition on potatoes, they are not addressed in this review,
due to the lack of a root/tuber metabolism study.  A ruminant feeding
study was not submitted and is not needed for the purpose of this
petition.  HED concludes that the registered uses of fomesafen on
cotton, dry and snap beans, and soybean and the proposed use of
fomesafen on potato result in a 40 CFR §180.6(a)(3) situation for
livestock commodities; there is no reasonable expectation of finite
residues in livestock.  Therefore, no livestock feeding studies are
required to support the proposed/registered uses of fomesafen sodium. 
Syngenta should note that if additional uses are proposed in the future
which result in an increase in the dietary burden, livestock feeding
studies may be required. 

860.1500 Crop Field Trials

DER Reference List	47473903.de1 (Potato)

			47473902.de1 (Tomato)

A summary of the reviewed crop field trial data for potato and tomato is
presented in Table 6.

Table 6.   Summary of Residue Data from Crop Field Trials with
Fomesafen.

Commodity	Total Applic. Rate

 (lb ae/A)	PHI (days)	Residue Levels  (ppm)

	n	Min.	Max.	HAFT1	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Potato

(Proposed use = One preemergence application after planting but before
crop emergence at 0.25 lb ae/A; 

70-day PHI)

Potato tubers	0.237-0.263	70-141	26	<0.025	<0.025	<0.025	0.025	0.025	---

Tomato

(Proposed use = One preplant non-incorporated preemergence application
up to 7 days prior to transplanting of tomatoes at 0.375 lb ae/A; 70 day
PHI)

Tomato fruit	0.373-0.399	71-104	24	<0.025	<0.025	<0.025	0.025	0.025	--

1  HAFT = Highest Average Field Trial.

Potato

  SEQ CHAPTER \h \r 1 Syngenta Crop Protection has submitted field trial
data for fomesafen on potatoes.  Thirteen trials were conducted in the
United States in Zones 1 (NY; 1 trial), 2 (MD, NC and NJ; 3 trials), 3
(FL; 1 trial), 5 (MI and WI; 2 trials), 8 (CO; 2 trials), and 11 (ID and
WA; 4 trials) during the 2006 growing season. 

At each test location, a single preemergence application of Reflex®
Herbicide (EPA Reg. No. 100-993) was made to potatoes at 0.237 to 0.263
lb ae (acid equivalents)/A.  Reflex® Herbicide is a soluble concentrate
liquid formulation containing 22.8% sodium salt of fomesafen as the
active ingredient (equivalent to 2 lb ae/gal of fomesafen). 
Applications were made using ground equipment in spray volumes of 16-36
gal/A without an adjuvant.  Samples of mature potatoes were collected at
a PHI of 70-141 days.  Additional samples were collected from one trial
to conduct a processed food and feed study; refer to the 860.1520 DER
for MRID 47473903 for the study details and results.

Samples of potatoes were analyzed for residues of fomesafen using a
LC/MS/MS method based on an HPLC/UV method (GAM-RM-001/86), entitled
“The Determination of PP021 in Soybeans – A High Performance Liquid
Chromatographic Method,” which is an enforcement method for fomesafen.
 The method was adequate for data collection based on adequate
concurrent recovery data.  The LLMV was 0.025 ppm for potato.

The maximum storage duration of potatoes from harvest to analysis was
399 days (13.1 months) for analysis of fomesafen.  Sample storage
conditions and durations are supported by concurrent storage stability
data.  However, zero-day data were not provided with the storage
stability study.  The petitioner is reminded that storage stability
studies should always include a zero-day sampling interval to ensure
that the samples were fortified properly [see OPPTS 860.1380(d)(6)(i)].

Residues of fomesafen were less than the LLMV (<0.025 ppm) in/on
potatoes harvested 70-141 days following a single pre-emergence
application of the 2 lb ae/gal SL formulation of fomesafen at a total
rate of 0.237-0.263 lb ae/A.

Tomato

  SEQ CHAPTER \h \r 1 Syngenta Crop Protection has submitted field trial
data for fomesafen on tomatoes.  Twelve trials were conducted in the
United States in Zones 1 (NY; 1 trial), 2 (NC; 1 trial), 3 (FL; 2
trials); 10 (CA and NM; 8 trials) during the 2006 growing season.  

At each test location, a single pre-transplant application of Reflex®
Herbicide (EPA Reg. No. 100-993) was made to tomatoes at 0.373 to 0.399
lb ae/A.  Reflex® Herbicide is a SL formulation containing 22.8% sodium
salt of fomesafen as the active ingredient (equivalent to 2 lb ae/gal of
fomesafen).  Applications were made using ground equipment in spray
volumes of 21-35 gal/A without an adjuvant.  Samples of mature tomatoes
were collected at a PHI of 71-104 days.  Additional samples were
collected from one trial to conduct a processed food and feed study;
refer to the 860.1520 DER for MRID 47473902 for the study details and
results.

Samples of tomatoes were analyzed for residues of fomesafen using a high
performance liquid chromatography method with tandem mass spectrometry
detection (LC/MS/MS) based on an HPLC/UV method (GAM-RM-001/86),
entitled “The Determination of PP021 in Soybeans – A High
Performance Liquid Chromatographic Method,” which is an enforcement
method for fomesafen.  The method was adequate for data collection based
on adequate concurrent recovery data.  The lowest level of method of
validation (LLMV) was 0.025 ppm for tomato.

The maximum storage duration of tomatoes from harvest to analysis was
302 days (9.9 months) for analysis of fomesafen.  Sample storage
conditions and durations are supported by concurrent storage stability
data.  However, zero-day data were not provided with the storage
stability study.  The petitioner is reminded that storage stability
studies should always include a zero-day sampling interval to ensure
that the samples were fortified properly [see OPPTS 860.1380(d)(6)(i)].

Residues of fomesafen were less than the  LLMV (<0.025 ppm) in/on
tomatoes harvested 71-104 days following a single pre-transplant
application of the 2 lb ae/gal SL formulation of fomesafen at a total
rate of 0.373-0.399 lb ae/A.

Conclusions.  The submitted field trial data for fomesafen on tomatoes
are acceptable and support the proposed uses.  An adequate number of
trials were conducted in the appropriate geographic regions at ~1x the
maximum proposed rate using Reflex® Herbicide, and the appropriate
samples were collected from each test around the proposed PHI.  All
treated samples bore residues below the LLMV (<0.025 ppm).  Based on
these data, HED recommends a tolerance of 0.025 ppm for residues of
fomesafen in/on tomatoes.

The submitted field trials for potatoes may be adequate, pending outcome
of the required metabolism study.  An adequate number of trials were
conducted in the appropriate geographic regions at ~1x the maximum
proposed rate using Reflex® Herbicide, and the appropriate samples were
collected from each test around the proposed PHI.  A potato metabolism
study is outstanding, as described in section 860.1300 above.  If the
new study does not identify any additional residues of concern, then the
field trial data are adequate.  However, if additional residues of
concern are found, then a full set of field trials reflecting analysis
of the additional residues will be required.

Syngenta’s Response to Cotton Field Trial Data Gaps as a Condition of
Registration

Reference List:  47761905 (No DER generated)

HED previously reviewed (DP# 325801, 4/25/2006, D. Davis) a magnitude of
the residue study on cotton (MRID 44754701) submitted by Syngenta in
support of a cotton tolerance petition (PP#9F5068).  Although the study
was deemed unacceptable to fulfill data requirements, HED concluded that
the cotton study may be upgraded pending submission of additional
information pertaining to the conduct and other experimental details. 
In response, Syngenta has submitted MRID 47761905 which provides
responses to the information requested.  The specific deficiencies are
re-stated below followed by the petitioner’s response and HED’s
comments regarding the adequacy of response.

Deficiencies:  “The available crop field trial data are adequate to
support the proposed use on cotton provided the following data are
provided:

·	A summary of weather conditions at the individual sites, indication
as to whether irrigation was used, and average historical data for
temperature and rainfall for the duration of the field intervals of the
trials. 

·	Soil characteristics data (percent organic matter, pH, and cation
exchange capacity) for the individual sites.

·	Raw data including at least:  (i) field notes and/or reports on
application (including which spray adjuvant was used), plot maintenance,
and sample harvest; (ii) calibration of application equipment (for
confirmation of application rate); and (iii) a specific description
(which may be in the field notes) as to how and where (within the plot)
the sample was taken and what was done to ensure that samples were
representative of the test plot.”

Syngenta’s response:  Raw data from the previously reviewed cotton
field trials were attached in Appendix 2 of MRID 47761905.  The raw data
provided specific details on the application, plot maintenance, and
sample harvest.  The raw data confirm the conditions reported in the
initial report.  The calibration of application equipment (for
confirmation of application rate) and weather conditions (NOAA
Climatological Data) were also provided in these reports.  At each trial
location, information pertaining to the soil type, percent organic
matter, pH and cation exchange capacity were provided from the Soil
Survey Geographic (SSURGO) Database.  

HED’s comments/conclusions to deficiencies:  The available cotton
field trial data have now been upgraded to acceptable status based on
Syngenta’s submission of the requested information pertaining to field
weather conditions, soil characteristics, raw data of field notes,
calibration of equipment, and sampling procedures that were employed in
the conduct of the cotton trials.  The Agency concludes that adequate
residue data are available to support the established tolerances of
0.025 ppm each for cotton gin byproducts and undelinted cottonseed. 
This deficiency is resolved.

860.1520 Processed Food and Feed

DER Reference List	47473903.de2 (Potato)

			47473902.de2 (Tomato)

The observed processing factors reported for potatoes and tomatoes,
resulting from treatment at 1x, are presented in Table 7.

  SEQ CHAPTER \h \r 1 Table 7.   Summary of Observed Processing Factors
for Fomesafen in Potatoes and Tomatoes Following Treatment at 1x.

RAC	Processed Commodity	Processing Factor

Potato, tuber	Flakes	NC1

	Chips	NC

	Wet peel	NC

Tomato, fruit	Paste 	NC

	Puree 	NC

1  NC = Not calculated.  The processing factor could not be calculated
because residues were below the LLMV (<0.025 ppm) in both the RAC and
the processed fractions.

Potato

Syngenta Crop Protection submitted magnitude of the residue data for
fomesafen on the processed commodities of potatoes.  Samples used for
processing were generated from one potato field trial conducted in ID
(Zone 11) during the 2006 growing season.  The test formulation used in
the trial was Reflex® Herbicide (EPA Reg. No. 100-993), a SL
formulation containing 22.8% sodium salt of fomesafen as the active
ingredient (equivalent to 2 lb ae/gal of fomesafen).  Potatoes were
harvested 130 days following a single preemergence application of a 2 lb
ae/gal SL formulation of fomesafen at 0.256 lb ae/A (~1x field
application rate).  Application was made using ground equipment in a
spray volume of 20 gal/A without an adjuvant.  The potatoes were
processed into potato flakes, chips and wet peel.

Samples of potatoes and potato processed commodities were analyzed for
residues of fomesafen using a high performance liquid chromatography
method with tandem mass spectrometry detection (LC/MS/MS) based on an
HPLC/UV method (GAM-RM-001/86), entitled “The Determination of PP021
in Soybeans – A High Performance Liquid Chromatographic Method,”
which is an enforcement method for fomesafen.  The method was adequate
for data collection based on adequate concurrent recovery data.  The
lowest level of method of validation (LLMV) was 0.025 ppm for potato
tuber and processed commodities flakes, chips, and wet peel.

The maximum storage duration of the processing study samples were 308
days (10.1 months) from harvest to analysis for potatoes (RAC) and 299
days (9.8 months), 298 days (9.8 months), and 293 days (9.6 months) from
processing to analysis for potato flakes, chips and wet peel,
respectively.  Sample storage conditions and durations are supported by
concurrent storage stability data.  However, zero-day data were not
provided with the storage stability study.  The petitioner is reminded
that storage stability studies should always include a zero-day sampling
interval to establish the residue levels present at the time samples are
placed into storage [see OPPTS 860.1380(d)(6)(i)].

Residues of fomesafen were less than the LLMV (<0.025 ppm) in/on the
potato tuber (RAC) and potato processed commodities.  Therefore,
concentration factors could not be calculated.  The petitioner is
reminded that samples used in processing studies should contain
field-treated quantifiable residues so that concentration factors can be
determined.  Field treatment of the processing samples should have been
done at exaggerated application rates to ensure that the samples were
fortified properly [see OPPTS 860.1520(c)(2)].

According to Tables 2 and 3 of OPPTS 860.1520, the theoretical
concentration factors for potato processed fractions are 4.0x for
processed waste (wet peel) and 4.7x for flakes/granules.

Tomato

Syngenta Crop Protection submitted magnitude of the residue data for
fomesafen on the processed commodities of tomatoes.  Samples used for
processing were generated from one tomato field trial conducted in CA
(Zone 10) during the 2006 growing season.  The test formulation used in
the trial was Reflex® Herbicide (EPA Reg. No. 100-993), a soluble
concentrate liquid (SL) formulation containing 22.8% sodium salt of
fomesafen as the active ingredient (equivalent to 2 lb ae/gal of
fomesafen).  Tomatoes were harvested 104 days following a single
pre-transplant application of a 2 lb ae/gal SL formulation of fomesafen
at 0.380 lb ae/A (~1x field application rate).  Application was made
using ground equipment in a spray volume of 25 gal/A without an
adjuvant.  The tomatoes were processed into tomato paste and puree using
standard commercial practices.

Samples of tomatoes and tomato processed commodities were analyzed for
residues of fomesafen using a high performance liquid chromatography
method with tandem mass spectrometry detection (LC/MS/MS) based on an
HPLC/UV method (GAM-RM-001/86), entitled “The Determination of PP021
in Soybeans – A High Performance Liquid Chromatographic Method,”
which is an enforcement method for fomesafen.  The method was adequate
for data collection based on adequate concurrent recovery data.  The
lowest level of method of validation (LLMV) was 0.025 ppm for tomato
fruit, paste, and puree.

The maximum storage duration of the processing study samples were 241
days (7.9 months) from harvest to analysis for tomatoes (RAC) and 229
days (7.5 months) from processing to analysis for tomato paste and
puree.  Sample storage conditions and durations are supported by
concurrent storage stability data.  However, zero-day data were not
provided with the storage stability study.  The petitioner is reminded
that storage stability studies should always include a zero-day sampling
interval to ensure the samples were fortified properly [see OPPTS
860.1380(d)(6)(i)].

Residues of fomesafen were less than the LLMV (<0.025 ppm) in/on the
tomato fruit (RAC) and tomato processed commodities.  Therefore,
concentration factors could not be calculated.  The petitioner is
reminded that samples used in processing studies should contain
field-treated quantifiable residues so that concentration factors can be
determined.  Field treatment of the processing samples should have been
done at exaggerated application rates to obtain sufficient residue
levels for this processing study [see OPPTS 860.1520(c)(2)].

According to Table 2 of OPPTS 860.1520, the theoretical concentration
factors are 5.5x for tomato paste and 1.4x for tomato puree.

Conclusions.  The results of submitted potato and tomato processing
studies show that residues of fomesafen were each below the LLMV (<0.025
ppm) in/on the respective RACs following application of Reflex®
Herbicide at ~1x.  Following processing of RACs bearing nonquantifiable
residues, no measurable processing factors can be calculated because the
processed commodities of potatoes and tomatoes also bore residues below
the LLMV (<0.025 ppm).  The Agency would have preferred the use of
exaggerated rates in the conduct of the processing studies to yield RACs
with quantifiable residues; the registrant provided no justification for
conducting the study at only a 1x rate.  Since the proposed use is for
preemergence/pre-transplant application and all RAC samples from the
current potato and tomato field trials show residues below the LLMV and
the residue data cover all significant growing regions for the crop
requested as delineated in OPPTS 860.1500, for the purpose of this
petition only, HED recommends a waiver for the conduct of new tomato
processing studies at exaggerated rates.

The submitted processing study for potatoes may be adequate, pending
outcome of the required metabolism study.  A potato metabolism study is
outstanding, as described in section 860.1300 above.  If the new study
does not identify any additional residues of concern, then the
processing study is adequate.  However, if additional residues of
concern are found, then a new processing study at exaggerated rates
reflecting analysis of the additional residues will be required.

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for fomesafen are currently available in the EPA
National Pesticide Standards Repository (personal communication with
Dallas Wright, ACB, 9/22/09).  The Repository has received from Syngenta
new standards for fomesafen on 9/3/2009; the standard has an expiration
date of  8/1/2012.

Analytical reference standards of fomesafen must be supplied and
supplies replenished as requested by the Repository.  The reference
standards should be sent to the Analytical Chemistry Lab, which is
located at Fort Meade, to the attention of either Theresa Cole or Thuy
Nguyen at the following address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

860.1850 Confined Accumulation in Rotational Crops

Reference List:	47761905 (No DER generated)

Residue Chemistry Memo  DP# 325801, 4/25/06, D. Davis

HED previously concluded (DP# 325801, 4/25/2006, D. Davis) that the
nature of the residue in rotational crops remains inadequately
understood and requested a new study.  In response, Syngenta has
submitted MRID 47761905 which provides a narrative response to the data
gap.  The specific deficiency is re-stated below followed by the
petitioner’s response and HED’s comments regarding the adequacy of
response.

Deficiency:  “If the registrant wishes to support a plant back
interval <12 months, they must conduct a new confined rotational crop
study.  The study should reflect separate application of CP- and
NP-label fomesafen at the maximum seasonal application rate to rotatable
crops.  The study should include the plantback intervals (PBIs) that
Syngenta wishes to include on product labels, up to 12 months.  For
complete guidance on the conduct of the study, OPPTS GLN 860.1850 should
be conducted.”

Syngenta’s response:  A confined rotational crop study is ongoing and
will be completed by 12/31/2009.

HED’s comments/conclusions:  The nature of the residue in rotational
crops remains inadequately understood.  Syngenta has previously been
requested to conduct a new confined rotational crop study reflecting
separate application of CP- and NP-label fomesafen at the maximum
seasonal application rate to rotatable crops.  According to Syngenta, a
new confined rotational crop study is ongoing and will be completed by
12/31/2009.

860.1900 Field Accumulation in Rotational Crops

Reference List:	47761905 (No DER generated)

Residue Chemistry Memo  DP# 325801, 4/25/06, D. Davis

HED previously summarized (DP# 325801, 4/25/2006, D. Davis) the
available field accumulation data for fomesafen.  The available data
consisted of:  (i) MRID 00110509 which was reviewed by the Environmental
Fate and Effects Division (EFED) and was found to contain numerous
deficiencies; (ii) MRID 00158936, a field rotational crop study on field
corn and winter wheat; and (iii) MRID 45268501, a field rotational crop
study on field corn and safened sorghum.  HED concluded that the
adequacy of these data cannot be determined until the nature of
fomesafen residues in rotational crops has been delineated.  The cited
HED review identified deficiencies from the submitted studies.  In
response, Syngenta has submitted MRID 47761905 which provides responses
to the data gap.  The specific deficiency is re-stated below followed by
the petitioner’s response and HED’s comments regarding the adequacy
of response.

Deficiency:  “At such time as the registrant has resolved any issues
and the nature of the residue in rotational crops is understood, if the
registrant wishes to pursue a plant back interval <12 months for wheat
and corn the following method validation data must be provided to
support submitted wheat and corn rotational crop data.  Data
demonstrating that recoveries of the internal standard are linear
relative to recoveries of fomesafen are required and information on the
timing of sample fortification is required.  Additionally, data to
support the reported method limit of quantitation of 0.01 ppm are
required, as is information on the identity of the matrices fortified in
the method validation.”

Syngenta’s response:   Crop samples collected from the field
rotational crop study were analyzed for residues of fomesafen following
ICI Plant Protection Division Residue Analytical Method (PPRAM) No. 66. 
Briefly, the prepared rotational crop samples were extracted by
homogenization with acetonitrile and then acidified with concentrated
HCl.  After filtration and the addition of water and hexane, fomesafen
was partitioned into dichloromethane and the residue taken up into
chloroform.  Co-extracted materials were removed by Fractosil adsorption
chromatography.  Final quantification was by 19F-nuclear magnetic
resonance spectroscopy (NMR) with internal standardization.  For example
in study PP021B046, in Experimental Data Sheet Reference NCA/80/2,
Internal Standard (R152748) at a concentration of 0.05 ppm was added to
all the samples by the addition of 2.5 mL of a 1.0 µg/mL standards
reference 554/7.  External Standard (fomesafen reference standard) at
concentrations of 0.05 ppm was added to the fortified recovery samples
by the addition of 2.5 mL of a 1.0 µg/mL standard reference 507/3.  Raw
data indicate that fortification of external recoveries, spiked with the
internal standard R152748 plus fomesafen reference standard took place
prior to extraction.  To support the reported LOQ of 0.01 ppm, the
petitioner provided calculation of results and limit of
determination/detection.  Residues were calculated using simple
proportion calculation:  

Response of sample (fomesafen)  x   Concentration of Internal Standard

Response of Internal Standard            Response ratio of fomesafen to
Internal Standard

The Response Ratio (RR) was calculated by running standards of equal
concentration of fomesafen and Internal Standard and calculating the
mean response.  During each analytical run of the study samples, an
assessment of the limit of determination (limit of detection) was
calculated from the baseline noise over the entire scan.  Where no peaks
of fomesafen were detected, residues were quoted in the report as less
than this calculated value.

Syngenta believes that an assessment of a theoretical LOQ may be made
from the study data.  The lowest fortification level in this study was
0.05 ppm.  For example in EDS NCA/86/2, an untreated control sample was
spiked with 0.05 ppm Internal Standard (R152748) + 0.05 ppm fomesafen
reference standard.  The mean measured baseline noise for the analytical
run at the retention time of fomesafen was 8 mm (l0, 7.5, 7 mm).  The
measured peak height of fomesafen was 159.5 mm.  The measured peak
height of Internal Standard was 138 mm.  Calculation of unknown sample
with example peak height of 32 mm (x4 baseline noise):  [32 ÷ 138]  x 
[0.05 ÷ 1.16]  = 0.009995 ppm.  Therefore, the LOQ when the analysis
was performed using this method has been calculated at 0.01 ppm.

Data were also included to demonstrate that the recoveries of the
internal standard are linear to the recoveries of fomesafen.  An
assessment was carried out as part of the validation of PPRAM 112. 
Samples were fortified with varying levels of fomesafen (0.1-5.0 ppm)
keeping the Internal Standard fortification at a constant 0.5 ppm.  A
calibration graph giving fomesafen fortification versus fomesafen
Internal Standard peak heights was plotted.  A straight line passing
through the origin was produced demonstrating that the instrument
response to fomesafen was linear relative to the response to the
internal standard.

Finally, in response to HED’s request to provide identity of the
matrices fortified in the method validation, Syngenta provided a table
detailing the procedural recoveries of the matrices tested.  The
recoveries presented in Table 8 were compiled by Syngenta from residue
trials performed between 1980 and 1985 where residues of fomesafen were
determined in crops following ICI Plant Protection Division Residue
Analytical Method (PPRAM No. 66).  Procedural recoveries were carried
out over expected residue levels for each matrix. 

Table 8.   Recoveries of Fomesafen Using PPRAM 066 Arising from
Supervised Residue Trials.

(Note – table was copied directly from MRID 47761905).

HED’s comments/conclusions:  Syngenta has adequately responded to
HED’s concerns and comments regarding the analytical method (PPRAM No.
66) used for the analysis of fomesafen from a previously submitted field
rotational crop study (MRID 00158936).  Syngenta has provided detailed
information/data concerning:  (i) when the fortification of external
recoveries were performed; (ii) data to support the reported LOQ of 0.01
ppm; (iii) data demonstrating that recoveries of the internal standard
are linear relative to recoveries of fomesafen; and (iv) information on
the identity of matrices fortified to validate the method.  This
deficiency is resolved.

Deficiency:  “Should HED determine that 2-chloro-4-trifluoromethyl
phenol is a residue of concern in rotated crops, the following method
validation data are required to support the submitted wheat and corn
rotational crop data.  Data to support the reported method limit of
quantitation are required, as are data demonstrating that the method can
extract weathered residues of 2-chloro-4-trifluoromethyl phenol from
field samples.”

Syngenta’s response:   To date, Syngenta is unaware of such a
determination being made by the Agency.

HED’s comments/conclusions:  The Agency will make a determination as
to what are the residues of concern in rotational crops when the results
of an ongoing confined rotational crop study are submitted.

At this time, data are not available to support rotation to other crops
beyond those commodities that are currently registered and proposed as
primary crops; therefore the registrant must revise the Reflex®
Herbicide label to permit immediate replanting of soybeans, cotton, dry
beans, snap beans, potatoes, and tomatoes only with a restriction that
other crops can only be planted 12 months after treatment or 18 months
after treatment if based on phytotoxicity concerns.

860.1550 Proposed Tolerances/Tolerance Reassessments for Fomesafen

Tolerances for fomesafen residues are listed in 40 CFR §180.433.  The
tolerance expression is in terms of “sodium salt of fomesafen,
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzam
ide.”  HED has determined that the residue of concern for tolerance
expression is fomesafen.  Therefore, the established tolerance
expression should be revised to be expressed in terms of fomesafen, by
removing the phrase “sodium salt of” from 40 CFR §180.433(a).  In
accordance with the HED Interim Guidance on Tolerance Expressions
(5/27/09, S. Knizner), the tolerance expression for fomesafen should be
revised to state:

“Tolerances are established for residues of fomesafen, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only fomesafen
[5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenza
mide].”

HED cannot recommend for the requested tolerance in/on potatoes due to
the lack of an adequate root/tuber metabolism study.

The available crop field trial data and revised analytical method will
support the proposed tolerance of 0.025 ppm for tomato.  As all residues
were below the LLMV (<0.025 ppm) in/on RAC samples treated at 1x, the
Agency’s tolerance spreadsheet was not used for determining the
recommended tolerances.  The petitioner’s draft label for Reflex®
Herbicide reflects regional use of fomesafen on tomatoes.  However, the
residue chemistry data submitted in support of this action are of
sufficient geographic representation to support full U.S. registration;
therefore, HED recommends that this tolerances be listed in the general
section of 40 CFR §180.433.

The previously submitted cotton field trial data have now been upgraded
to acceptable status based on Syngenta’s submission of the requested
field trial information.  The Agency concludes that adequate residue
data are available to support the established tolerances of 0.025 ppm
each for undelinted cottonseed and cotton gin byproducts.

No tolerances are required for meat, milk, poultry, and eggs for the
purpose of this petition.  Syngenta should note that if additional uses
are proposed in the future which result in an increase in the dietary
burden, livestock feeding studies and animal tolerances may be required.

No Codex, Canadian, or Mexican MRLs have been established for residues
of fomesafen in/on potato or tomato.  Canadian MRLs have been
established for residues of fomesafen in/on dry beans, lima beans, snap
beans, and soybeans at 0.05 ppm, and a Mexican MRL of 0.05 mg/kg  has
been established for residues of fomesafen in/on soybeans.  The
registrant has advised the Agency that they intend to petition the
Canadian government for revised tolerances to address any potential
harmonization issues raised by establishing the new tolerances requested
in this action.

A summary of the tolerance reassessment for fomesafen sodium is
presented in Table 9.  

Table 9.   Tolerance Summary for Fomesafen Sodium

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

Proposed Tolerance Under PP#9F7563

Tomato	0.025	0.025

	Tolerance Registered Under PP#9F5068

Cotton, gin byproducts	0.025	0.025

	Cotton, undelinted seed	0.025	0.025

	

References

DP#:	325801

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#d PP#6E4653.

From:	D. Davis

To:	J. Stone/J. Miller

Dated:	4/25/06

MRIDs:	00158936, 00158937, 40346603, 44754701-44754704, 44754706,
44727901, 45093601-45093604, 45237101, 45259801, 45268501-45268503,
45313001, & 45342601

CB#:	2253

Subject:	PP#4F2997.  Amendment of ICI’s Enforcement Analytical Method
GAM-RM-001/86.

From:	W. Chin

To:	R. Mountfort and Toxicology Branch

Dated:	8/18/87

MRIDs:	40007101

  SEQ CHAPTER \h \r 1 Attachments:  

Appendix I	International Residue Limit Status Sheet

Appendix II	Chemical Names and Structures of Metabolites Identified in
Tomato Metabolism Study (MRID 47473901)

Template Version September 2005

Appendix I

International Residue Limit Status Sheet

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzam
ide	Common Name:

Fomesafen	X Proposed tolerance

□ Reevaluated tolerance

□ Other	Date: 9/21/09

Codex Status (Maximum Residue Limits)	U. S. Tolerances

X No Codex proposal step 6 or above

□ No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#9F7563

DP#:  365199

Other Identifier:  

Residue definition (step 8/CXL): N/A	Reviewer/Branch:  M. Metzger/RAB7

	Residue definition:  fomesafen per se

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Potato	0.025

Tomato	0.025

	Limits for Canada	Limits for Mexico

□ No Limits

X  No Limits for the crops requested	□ No Limits

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	Notes/Special Instructions:

S.Funk, 10/05/2009.

Appendix II

Chemical Names of Metabolites Identified in Tomato Metabolism Study
(MRID 47473901)

Identification of Compounds from Tomato Metabolism Study.

Common name/code

Page   PAGE  44  of   NUMPAGES  44 

Fomesafen Sodium	Summary of Analytical Chemistry and Residue Data	DP#s: 
365199 and 366116