Document ID: EPA-HQ-OPP-2006-0178-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-22T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

	Date:	January 9, 2007

	Subject:	Lactofen.  Addition of New Uses:  Fruiting Vegetables (Crop
Group 8) and Okra.  PRIA R17.  Summary of Analytical Chemistry and
Residue Data.  PP#5E6930.

DP Barcode:	D333151	Decision Number:	356302

PC Code:	128888	MRID Nos.:	46531301 and 46597201-46597203

40 CFR 180.	432

Chemical Class:	Diphenyl ether herbicide (Group 14)

	

	From:	Christine L. Olinger, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

	Through:	Donna Davis, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

		Michael S. Metzger, Chief

		Reregistration Branch 1

		Health Effects Division (7509P)

	To:	Dan Kenny/Joanne Miller

		Herbicide Branch

		Registration Division (7505P)

This document was originally prepared under contract by Dynamac
Corporation (2275 Research Blvd, Suite 300; Rockville, MD 20850;
submitted 07/18/2006).  The document has been reviewed by the Health
Effects Division (HED) and revised to reflect current Office of
Pesticide Programs (OPP) policies.

Executive Summary

Lactofen is a selective contact, diphenyl ether herbicide (Group 14)
that is structurally related to acifluorfen and is classified as a
threshold carcinogen by EPA (Lactofen - Report of the Cancer Assessment
Review Committee; 5/22/02).  Lactofen is currently registered by Valent
U.S.A. Corporation for preemergence and/or postemergence use on cotton,
peanuts, snap beans, and soybeans for the control of broadleaf weeds,
such as nightshades, morning glories, pigweed, and ragweed.  

Valent U.S.A. corporation, in coordination with the Interregional
Research Project No. 4 (IR-4), has proposed to amend the use pattern for
the 2 lb/gal emulsifiable concentrate (EC) formulation of lactofen
(Cobra® Herbicide; EPA Reg. No. 59639-34) to include uses on fruiting
vegetables (Crop Group 8) and okra in AL, AR, FL, GA, MS, NC, SC, TN,
and VA.  The proposed uses include directed, shielded application to row
middles made pre- or post-transplant at 0.3-0.5 lb ai/A/application for
a maximum seasonal application rate of 1.0 lb ai/A.  A 30-day PHI is
proposed.  

In conjunction with the amended use request, IR-4 has proposed, in
PP#5E6390, the establishment of permanent tolerances for the residues of
lactofen and its associated metabolites containing the diphenyl ether
linkage expressed as lactofen in/on the following raw agricultural
commodities:

Vegetable, fruiting, group	0.01 ppm

Okra	0.01 ppm

Tolerances for residues of lactofen in/on raw agricultural commodities
are established under 40 CFR §180.432(a) and are expressed in terms of
the herbicide lactofen, 1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate.  Tolerances are
established for snap bean, cotton seed, peanut, and soybean seed at 0.01
ppm, and for cotton gin products at 0.02 ppm [40 CFR §180.432(a)]. 

The qualitative nature of the residue of lactofen in plants is
adequately understood based on acceptable studies depicting the
metabolism of [14C]lactofen in soybeans, peanuts, and tomatoes. 
Although the quantities of individual metabolites vary between crops,
the data indicate that the metabolic pathway is similar between crops. 
The metabolism of lactofen initially involves reduction of the nitro
group to an amino group, with or without loss of the ethyl ester side
chains to form the preliminary diphenyl ether metabolites:  amino
lactofen (PPG-1576), N-formyl lactofen (PPG-2597), desethyl lactofen
(PPG-947), acifluorfen (PPG-947), and amino acifluorfen (PPG-2053). 
Subsequent conjugation of these primary metabolites through their
carboxyl and amino groups results in the formation of complex soluble
and insoluble polar components.  Following formation of acifluorfen, the
diphenyl ether bond may be cleaved in a glutathione-mediated reaction to
form a glutathione conjugate with the 2-nitrobenzoic acid moiety. 
Subsequent degradation of the glutathione moiety to cysteine forms
S-(carboxy-4-nitrophenyl)cysteine (CNPC).  

The tolerance expression for lactofen formerly included lactofen and
metabolites containing the diphenyl ether linkage.  In 2000, HED
concluded that only the parent compound need be included in the
tolerance expression and risk assessment for plant commodities, assuming
the pre-harvest interval is 45 days or greater.

Although the proposed use of lactofen on fruiting vegetables reflects a
30-day PHI, based on the available crop field trial data reflecting
nonquantifiable residues in tomato and pepper, HED concludes that the
tolerance expression for fruiting vegetables and okra need only include
parent lactofen.  

There are no livestock feedstuffs associated with the proposed uses on
fruiting vegetables and okra.  Therefore, no livestock metabolism data,
enforcement methods, storage stability data, or feeding studies are
required to support this petition.

Acceptable gas chromatography with electron capture detection (GC/ECD)
methods are available in the Pesticide Analytical Manual (PAM) Vol. II
for the enforcement of tolerances of lactofen and metabolites in plant
commodities.  A modified version of Method B is listed in the U.S. EPA
Index of Pesticide Analytical Methods under lactofen.  Samples from the
pepper and tomato field trials were analyzed using established GC/ECD
enforcement methods or modified versions of established enforcement
methods.  The validated limits of quantitation (LOQs) were 0.01 ppm for
peppers from the 1991 trial, and 0.02 ppm for samples from all other
trials.  The methods are adequate for data collection based on
acceptable method validation and concurrent recovery data.

The maximum storage intervals of samples of peppers and tomatoes from
harvest to analysis were 60 days for peppers and 56 days for tomatoes. 
A concurrent freezer storage stability study was conducted in
conjunction with the 1990 magnitude of the residue study on tomatoes,
which demonstrated that residues of lactofen and metabolites PPG-847,
PPG-947, and PPG-2597 were relatively stable in/on tomatoes stored
frozen for up to 68 days; residues of PPG-1576 were found to decline
(~40%) during storage for 68 days.  SEQ CHAPTER \h \r 1   The submitted
data are adequate to support the storage intervals and conditions of
samples from the fruiting vegetable crop field trials.

The submitted crop field trial data for pepper and tomato do not meet
the recommendations in the guidance for guideline no. 860.1500 because
of inadequate geographic representation.  However, due to the very low
residues, and the available data are in a region to that similar to
those requested in this petition for a tolerance with a regional
registration, HED will not request any additional data for the proposed
use.  Although inadequate, the data indicate that residues of lactofen
were below the LOQ (<0.01-<0.02 ppm) in/on samples following application
of lactofen according to the proposed use pattern.  

No crop field trial data were submitted to support the proposed use on
okra.  Okra will be added to the fruiting vegetable crop group (Personal
communication, B. Schneider 10/13/06), so the tomato and pepper data may
be translated to okra.

Additional data/information are required to support the available
confined rotational and limited rotational crop data; however, the
available data indicate that the nature of the residue in rotational
crops is adequately understood and that plantback intervals are not
needed for the proposed use on fruiting vegetables.

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry
Deficiencies

HED has examined the residue chemistry database for lactofen.  Pending
submission of a revised Section B (see requirements under Directions for
Use) and a revised Section F (see requirements under Proposed
Tolerances), there are no residue chemistry issues that would preclude
granting unconditional regional registration for the requested use of
lactofen on the fruiting vegetables crop group and okra in AL, AR, FL,
GA, MS, NC, SC, TN, and VA or establishment of tolerances with regional
registration for residues of lactofen per se as follows:

Vegetable, fruiting, group 8	0.02 ppm

Okra	0.02 ppm

Note that the tolerances for regional registration should be placed in
section (c) of 180.432.

A human health risk assessment is forthcoming.

860.1200 Directions for Use

The label must be amended to specify that the applications may not
include two post-transplant applications.  Finally, the label must be
amended to reflect either a 30-day RTI or a minimum post-transplant
interval of 18 days for tomatoes.

The label should specify examples of fruiting vegetables in the use
directions to avoid confusion.

OPPTS 860.1550 Proposed Tolerances

The proposed tolerance for the fruiting vegetables crop group should be
revised to reflect the recommended tolerance expression and the correct
commodity definition, “Vegetable, fruiting, group 8,” and the
recommended level of 0.02 ppm.

 The proposed tolerance for okra should be revised to reflect the
recommended tolerance expression and the recommended level of 0.02 ppm.

860.1500 Crop Field Trials

If the petitioner wishes to pursue a national section 3 registration
then at least one trial with a small-fruited tomato should be submitted
with the additional field trials.

Background

The chemical structure and nomenclature of lactofen are presented in
Table 1. The physicochemical properties of the technical grade of
lactofen are presented in Table 2.

Table 1.	Lactofen Nomenclature.

Chemical structure	

Common name	Lactofen

Company experimental name	PPG-844

IUPAC name	ethyl
O-[5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-2-nitrobenzoyl]-DL-lactate

CAS name	2-ethoxy-1-methyl-2-oxoethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate

CAS registry number	77501-63-4

End-use product (EP)	2 lb/gal EC (Cobra ® Herbicide; EPA Reg. No.
59639-34) 

Chemical structure of acifluorfen (PPG-847)	

5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid

Chemical structure of desethyl lactofen (PPG-947) 	

1-(carboxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate

Chemical structure of amino lactofen (PPG-1576)	

1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-aminobenzoate

Chemical structure of N-formyl lactofen (PPG-2597)	

1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-formamidobenzoate

Chemical structure of PPG-1530; Isomer A (internal standard)	

1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-6-nitrobenzoate

Table 2.	Physicochemical Properties of Lactofen.

Parameter	Value	Reference

Melting point/range	>250°C	444470031

pH	7.2 (on Pure Active Ingredient, 1% solution) at 25°C	444470031

Density (specific gravity)	1.34 at 24°C	444470031

Water solubility	0.97 ppm at 25°C

0.945 ± 0.131 ppm (column elution method at 20 ± 1 °C)	444470031

444609022

Solvent solubility		       g/100 g at 23 °C

kerosene                   15.6

2-ethyl-1-hexanol     18.4

N-decanol                 10.1

lactic acid                   0.9

Lactofen is miscible at all proportions with the following solvents at
-18°C or higher:

DMSO, monochlorotoluene, dipropylene glycol dibenzoate, isophorone,
cyclohexanone, mixed xylene, ethylene dichloride, acetone, DMF, amyl
acetate, methyl isobutyl ketone.	444470031

Vapor pressure	3.69 ± 1.73 x 10-5 Pa (2.8 x 10-7 mm Hg)	444609012

Dissociation constant, pKa	Not required	D241826, 1/16/98, H. Podall

Octanol/water partition coefficient, Log(KOW)	1 x 105 at ambient
temperature, estimated value	444609032

UV/visible absorption spectrum	In Review 3	444470033

1  RD Memorandum, D241826, 1/16/98, H. Podall.

2  RD Memorandum D242241, 2/5/98, S. Mathur.

3 D332587, C. Olinger, In Review. 

860.1200  Directions for Use

Valent has included the proposed used directions under Section B of the
petition and a supplemental label for the 2 lb/gal EC formulation of
lactofen (Cobra® Herbicide; EPA Reg. No. 59639-34).    SEQ CHAPTER \h
\r 1  The proposed uses are presented in Table 3.

Table 3.  Summary of Directions for Use of Lactofen.

Applic. Timing; Type; and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Fruiting vegetables and okra

Pre-transplant Post-transplant;

Directed to row middles; 

Ground, shielded	2 lb/gal EC

[59639-34]	0.3-0.5	2	1.0

(implied)	30	Use is restricted to AL, AR, FL, GA, MS, NC, SC, TN, and
VA.  Applications are to be made in 20-50 gal/A.  Pre-transplant: 
Applications are to be made a minimum of 10 days prior to transplanting.

Post-transplant:  Applications are to be made to using an adjuvant such
as crop oil concentrate at 1% v:v or a nonionic surfactant at 0.25% v:v.
 Tomato plants must be at least 16” in height prior to post-transplant
application.  Peppers must have been transplanted at least 45 days
before making a post-transplant application.

There are currently no plantback restrictions on the supplemental or
master label (acceptance date 10/8/04)

Conclusions.  The submitted information concerning the proposed use
pattern is adequate to allow evaluation of the submitted data for
fruiting vegetables and okra.

The label must be amended to specify that the applications may not
include two post-transplant applications; the submitted crop field trial
for peppers reflected only one post-transplant application.  The
available tomato field trial data reflect a 30- to 37-day RTI with
post-transplant applications made 18-42 days after transplanting.  The
label must be amended to reflect either a 30-day RTI or a minimum
post-transplant interval of 18 days for tomato.   Finally, the label
should provide examples of fruiting vegetables in the use directions
(fruiting vegetables such as tomatoes, peppers, and eggplant).  

860.1300 Nature of the Residue - Plants

D263857, 5/4/00, C. Olinger

D265469, 4/26/00, C. Olinger

Adequate studies are available depicting the metabolism of [14C]lactofen
in soybeans, peanuts, and tomatoes.  Although the quantities of
individual metabolites vary between crops, the data indicate that the
metabolic pathway is similar between crops.  The metabolism of lactofen
initially involves reduction of the nitro group to an amino group, with
or without loss of the ethyl ester side chains to form the preliminary
diphenyl ether metabolites:  amino lactofen (PPG-1576), N-formyl
lactofen (PPG-2597), desethyl lactofen (PPG-947), acifluorfen (PPG-947),
and amino acifluorfen (PPG-2053).  Subsequent conjugation of these
primary metabolites through their carboxyl and amino groups results in
the formation of complex soluble and insoluble polar components. 
Additional data from a peanut metabolism study indicate that following
formation of acifluorfen, the diphenyl ether bond may be cleaved in a
glutathione-mediated reaction to form a glutathione conjugate with the
2-nitrobenzoic acid moiety.  Subsequent degradation of the glutathione
moiety to cysteine forms S-(carboxy-4-nitrophenyl)cysteine (CNPC), which
was the most abundant metabolite detected in peanut hay.  Free and
conjugated 5-hydroxy-2-nitrobenzoic acid (HNBA) detected in nutmeats and
hay may result from either loss of the cysteine moiety or from direct
cleavage of the acifluorfen metabolite. 

The tolerance expression for lactofen formerly included lactofen and
metabolites containing the diphenyl ether linkage.  Specifically, the
enforcement method is capable of determining lactofen, acifluorfen
(PPG-847), des-ethyl lactofen (PPG-947), amino lactofen (PPG-1576), and
N-formyl lactofen (PPG-2597).  In 2000 HED concluded that only the
parent compound need be included in the tolerance expression and risk
assessment for plant commodities, assuming the pre-harvest interval is
45 days or greater.

Conclusions.  Although the proposed use of lactofen on fruiting
vegetables reflects a 30-day PHI, based on the available crop field
trial data reflecting nonquantifiable residues in tomato and pepper, HED
believes that the decision to include parent only in the tolerance
expression for fruiting vegetables is appropriate.  

860.1300 Nature of the Residue - Livestock

There are no livestock feedstuffs associated with the proposed uses on
fruiting vegetables and okra.  Therefore, data requirements for
livestock metabolism are not relevant to this tolerance petition.

860.1340 Residue Analytical Methods

D263857, 5/4/00, C. Olinger

Enforcement methods:  The Pesticide Analytical Manual (PAM), Vol. II
lists three GC/ECD methods (Methods I, A, and B) for determining
residues of lactofen and metabolites in plant commodities.  For Method
I, residues of lactofen are extracted with acetonitrile:triethylamine
(ACN:TEA, 99:1, v:v), followed by partitioning with hexane for oily
matrices.  Residues are then purified by silica gel column
chromatography and analyzed by GC/ECD using a DB-5 column.  The Agency
validated this method down to a limit of 0.01 ppm using soybeans.

Method A is similar to Method I, except that the extracted residues are
base (NaOH) hydrolyzed, converting lactofen to acifluorfen, which is
then methylated with diazomethane.  The derivatized residues are then
purified by silica gel column chromatography and analyzed by GC/ECD
using a DB-1701 column.  Method B (Chevron Method RM-28, 3/12/90) is
essentially identical to Method I, except that it allows for the use of
an alternative column (DB-1701) with GC/ECD analysis for confirmation of
residues.

In conjunction with the petitions for use of lactofen on cotton and
peanuts, Method RM-28 was revised by changing the extraction solvent
from ACN:TEA to ethanol:water:TEA (94:5:1, v:v:v) and adding a
water:dichloromethane (DCM) partitioning step after solvent extraction. 
The modified method (RM-28B) was rewritten to clarify the procedures and
renamed Method RM-28D.  This method has been successfully radiovalidated
and has undergone a successful independent laboratory validation and
petition method validation (PMV).  Method RM-28D is currently listed in
the U.S. EPA Index of Pesticide Analytical Methods under lactofen.  

Data collection methods:  Samples from the pepper and tomato field
trials were analyzed using established GC/ECD enforcement methods or
modified versions of established enforcement methods.  Pepper samples
from the 1991 trial and tomato samples from the 1990 trials were
analyzed for residues of lactofen and its metabolites PPG-1576,
PPG-2597, PPG-847, and PPG-947 using method RM-28.  The method was
performed essentially as written for analysis of tomatoes, but was
modified significantly for analysis of peppers.  Modifications to the
analytical method for peppers included:  (1) conducting the ACN:hexane
partitioning earlier in the procedure; (2) separation of the acid
metabolites (PPG-847 and PPG-947) from lactofen and the ester
metabolites (PPG-1576 and PPG-2597) for analysis; and (3) addition of a
two-column clean-up procedure for the acid metabolites.  Samples of
peppers and tomatoes from the 2003 trials were analyzed for residues of
lactofen per se using a modified version of method RM-28D:  method
RM-28D-2 (rev. 8/12/03).  

Using the modified version of method RM-28, samples from the 1991 pepper
field trial were extracted 2x with ACN containing 1% TEA:hexane (2:1,
v:v) and filtered, and the extracts were combined.  Following phase
separation, the ACN phase was extracted with two additional aliquots of
hexane; all hexane phases were discarded.  The ACN extract was combined
with 5% NaCl solution and partitioned 3x with hexane.  The resulting
extracts were combined to yield an aqueous ACN extract and a hexane
extract.  The hexane extracts, containing lactofen and the ester
metabolites, were concentrated and applied to a silica gel column for
clean-up.  Residues were eluted with DCM:hexane (70:30, v:v), and the
eluate was concentrated, combined with an internal standard mixture of
CGA-1530 (lactofen Isomer A) and CGA-1827 (standard was not identified),
and reserved for GC analysis.  The aqueous ACN extract, containing the
acid metabolites, was acidified with 6 N HCl and extracted 3x with
toluene.  The combined toluene extracts were applied to a basic alumina
column, and residues were eluted with 1% sodium bicarbonate solution. 
The eluate was acidified with 6 N HCl and extracted 3x with DCM. 
Diazomethane was added to the combined DCM extracts to methylate the
acid metabolites, and the mixture was reduced to dryness and
re-dissolved in benzene, then applied to a second alumina column. 
Residues were eluted with benzene, concentrated, combined with the
internal standard mixture, and reserved for GC analysis.  Lactofen and
the ester metabolites were determined using an SPB-5 column, and the
acid metabolites were determined using a DB-1701 column.  The validated
LOQ was 0.01 ppm (lowest limit of method validation; LLMV), and the
reported LOD was 0.005 ppm for lactofen and each metabolite.

Using method RM-28, samples from the 1990 tomato field trials were
extracted 2x with ACN containing 1% TEA and filtered.  The resulting
extract was evaporated to dryness, re-dissolved in 5% NaCl solution,
then partitioned with DCM (3x).  The resulting DCM phases were combined,
reduced to dryness, dissolved in ACN, and combined with diazomethane to
methylate the acid metabolites.  The methylated extract was dissolved in
DCM:hexane (70:30, v:v), and applied to a silica gel column.  Residues
were eluted with DCM:hexane (70:30, v:v), and the eluate was
concentrated, combined with an internal standard of CGA-1530 in toluene,
and reserved for GC analysis using a DB-5 or DB-1701 column.  The
validated LOQ (LLMV) was 0.02 ppm, and the LOD was 0.01 ppm for lactofen
and each metabolite.

Using method RM-28D-2, samples of peppers and tomatoes from the 2003
trials were extracted 2x with ethanol and filtered.  The combined
extracts were reduced by rotary evaporation and sonicated with ACN
saturated with hexane, followed by 5% NaCl solution, and hexane.  The
resulting ACN:water phase was re-extracted 2x with hexane, and the
hexane extracts were combined with the original hexane phase.  The
combined hexane phase was evaporated to dryness and redissolved in
toluene:hexane (1:2, v:v), then applied to a silica gel column for
clean-up.  Residues were eluted with hexane:diethyl ether (60:40, v:v),
and the eluate was evaporated to dryness and dissolved in toluene for
analysis by GC/ECD on a DB-17 column.  The validated LOQ was 0.02 ppm
(LLMV), and the reported LOD was 0.01 ppm for lactofen in both matrices.

Conclusions.  The available and submitted residue analytical methods
data are adequate to satisfy data requirements for purposes of the
subject petition.  Adequate tolerance enforcement methods are available
for plant commodities, and residues of lactofen and metabolites were
determined in the submitted crop field trial data using acceptable
methods.

860.1360 Multiresidue Methods

Acceptable data are available on the recovery of lactofen and its four
plant metabolites (PPG-847, PPG-947, PPG-1576, and PPG-2597) through
Multiresidue Method Testing Protocols.  The FDA PESTDATA database (dated
06/05) indicates that residues of lactofen per se are completely
recovered through multiresidue method Section 304 (Protocol F); no data
are available on the recovery of lactofen through Sections 302 and 303
(Protocols D and E.  Metabolite PPG-1576 is partially recovered (54-85%)
through Section 304 but metabolites PPG-847, PPG-947, and PPG-2597 are
not recovered through Sections 303 and 304.  Metabolite PPG-847 and
PPG-947 are partially recovered (49-78%) through Section 402 (Protocol
B).  

860.1380 Storage Stability

A concurrent storage stability study was conducted with the crop field
trials submitted in support of this action.  Untreated samples of tomato
from the 1990 magnitude of the residue study were fortified with
lactofen, PPG-847, PPG-947, PPG-1576, and PPG-2597 at 0.1 ppm each, and
stored frozen.  Stored samples were analyzed at 0-day and following
frozen storage for 32 and 68 days.  Residues of lactofen, and all
metabolites except PPG-1576 appeared to be relatively stable in/on
tomatoes stored frozen for up to 68 days.  Residues of PPG-1576 were
found to decline in tomatoes, to ~60% of original value after 68 days of
storage.  

The maximum storage intervals of samples from harvest to analysis were
60 days for peppers and 56 days for tomatoes.  Samples were stored
frozen at ~-20 °C.

Conclusions.  The submitted storage stability data are adequate to
support the storage intervals and conditions of samples from the
fruiting vegetable crop field trials.  Because residues of PPG-1576 were
found to be below the LOD in/on all tomato samples and below the LOQ
in/on all pepper samples that were analyzed for residues of PPG-1576, no
correction for potential decline during storage is needed.

860.1400 Water, Fish, and Irrigated Crops

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

860.1460 Food Handling

There are no proposed/registered 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
fruiting vegetables and okra.  Therefore, data requirements pertaining
to meat, milk, poultry, and eggs are not relevant to this tolerance
petition.

860.1500 Crop Field Trials

D265469, 4/26/00, C. Olinger

46531301.der.doc (includes review of MRIDs 46597201-46597203)

Table 4.	Summary of Residue Data from Crop Field Trials with Lactofen

Crop matrix	Total Applic. Rate

 (lb ai/A)	PHI (days)	Residue Levels (ppm) of Lactofen per se

	n	Min.	Max.	HAFT 1	Median	Mean	Std. Dev.

Fruiting Vegetables Crop Group 8

 (proposed use = 1.0 lb ai/A total application rate, 30-day PHI)

Pepper	0.98-1.1	30	6	<0.01	<0.02	<0.02	<0.01	<0.01	0.0

Tomato	0.96	28-30	2	<0.02	<0.02	<0.02	<0.01	<0.01	0.0

	1.5	30	10	<0.02	<0.02	<0.02	<0.01	<0.01	0.0

	4.9	30	2	<0.02	<0.02	<0.02	<0.01	<0.01	0.0

1  HAFT = Highest average field trial result.

Valent U.S.A. Corporation has submitted field trial data for lactofen on
the representative crops, pepper and tomato, of the fruiting vegetables
group, crop group 8.  A total of three pepper trials were conducted in
Zone 3 (FL) during the 1991 (one bell pepper trial) and 2003 (one bell
and one nonbell pepper trial) growing seasons.  A total of four tomato
field trials were conducted in Zone 3 (FL) during the 1990 (three
trials) and 2003 (one trial) growing seasons.  Geographic representation
is inadequate.  All of the pepper and tomato field trials were conducted
in Zone 3; however, the petitioner is proposing use of lactofen on
fruiting vegetables in Zones 2, 3, and 4.

We note that both tomato varieties used in the crop field trials produce
medium to large fruits.

For the pepper field trials, the 2 lb/gal EC formulation of lactofen was
applied at each test location as one pre-transplant and one
postemergence directed soil application to row middles at 0.49-0.51 lb
ai/A/application for a total seasonal application rate of 0.98-1.1 lb
ai/A (1x the maximum proposed seasonal application rate).  Shielded
spray equipment was used in the 2003 trials.  The first applications
were made one or 12 days prior to transplanting, and the second
applications were made at 46- to 67-day retreatment intervals.  First
applications were made in spray volumes of 31-33 gal/A, and second
applications were made in spray volumes of 55-59 gal/A; nonionic
surfactant (NIS) or crop oil concentrate (COC) adjuvants were added to
the spray mixtures for second applications.  Mature peppers were
harvested 30 days following the second application.

For the tomato field trials, the 2 lb/gal EC formulation of lactofen was
applied at each test location as one pre- or early post-transplant
application and one to two postemergence directed soil applications to
row middles at ~0.5 lb ai/A/application for total seasonal application
rates of 0.96 lb ai/A (2003 field trial) or 1.5 lb ai/A (1990 trials);
the 2003 trial included a treatment plot with two applications at an
exaggerated rate of ~2.5 lb ai/A/application for a total seasonal
application rate of ~5 lb ai/A.  The seasonal application rates of 1.0
and 1.5 lb ai/A correspond to 1x and 1.5x the maximum proposed seasonal
application rate for fruiting vegetables.  Shielded spray equipment was
used for all trials.  The first applications were made one or 12 days
prior to transplanting or 5 days post-transplant; second applications
were made at 30- to 37-day retreatment intervals; and third applications
were made at 14- to 16-day retreatment intervals.  First applications
were made in spray volumes of 31-34 gal/A, and second and third
applications were made in spray volumes of 55-60 gal/A; NIS or crop COC
adjuvants were added to the spray mixtures for all applications except
the pre-transplant applications at the 2003 trial.  Mature tomatoes were
harvested 28-30 days following the last application.

The maximum storage intervals of samples from harvest to analysis were
60 days for peppers and 56 days for tomatoes.  A freezer storage
stability study was conducted in conjunction with the 1990 magnitude of
the residue study on tomatoes.  Residues of lactofen and metabolites
PPG-847, PPG-947, and PPG-2597 appeared to be relatively stable in/on
tomatoes stored frozen for up to 68 days.  Residues of PPG-1576 were
found to decline in tomatoes, to ~60% of original value after 68 days of
storage.  These data are adequate to support the storage intervals and
conditions of samples from the fruiting vegetable crop field trials. 
Because residues of PPG-1576 were found to be below the LOD in/on all
tomato samples and below the LOQ in/on all pepper samples that were
analyzed for residues of PPG-1576, no correction for potential decline
during storage is needed.

Samples from the pepper and tomato field trials were analyzed using
established gas GC/ECD enforcement methods or modified versions of
established enforcement methods.  Pepper samples from the 1991 trial and
tomato samples from the 1990 trials were analyzed for residues of
lactofen and its metabolites PPG-1576, PPG-2597, PPG-847, and PPG-947
using method RM-28 (Method B of PAM Vol. II).  The method was performed
essentially as written for analysis of tomatoes, but was modified
significantly for analysis of peppers.  Samples of peppers and tomatoes
from the 2003 trials were analyzed for residues of lactofen per se using
method RM-28D-2 (rev. 8/12/03); method RM-28D is listed in the U.S. EPA
Index of Pesticide Analytical Method.  The validated LOQs were 0.01 ppm
for peppers from the 1991 trial, and 0.02 ppm for samples from all other
trials.  The methods are adequate for data collection based on
acceptable method validation and concurrent recovery data.  

The results of the fruiting vegetable crop field trials are presented in
Table 4.  Residues of lactofen and metabolites were each below the LOQ
(<0.01 ppm for the 1991 pepper field trials and <0.02 ppm for remaining
pepper and tomato field trials) in/on all samples of pepper and tomato
harvested ~30 days following a single pre- or early post-transplant and
one to two postemergence directed soil applications to row middles at
~0.5 lb ai/A/application for total seasonal application rates of ~1-1.5
lb ai/A.  

No residue decline data were included in the submission; however,
because residues were below the LOQ in/on all samples, these data are
not required.

Conclusions.  Although the submitted pepper and tomato crop field trial
data are inconsistent with the recommended data in the crop field trial
guidance, due to the early season use and lack of detectable residues,
they are sufficient for a tolerance with a regional registration
requested by the petitioner. 

For the proposed use on fruiting vegetables, soil characteristics data
were not provided for two pepper field trials and one tomato trial;
however, these data are not required at this time because most of the
relevant information is available from a reliable public source.  For
future submissions, the petitioner is advised that soil characteristics
data must be provided for field trials reflecting applications to soil. 
Although only one of the three tomato field trials reflected application
according to the proposed use pattern (two applications at a maximum
seasonal rate of 1.0 lb ai/A), because residues of lactofen and all
metabolites following application at 1.5x were below the LOQ (<0.01 ppm
each) in/on all samples of tomatoes from the remaining two trials, these
trials are acceptable.  

Samples from the 2003 field trials were not analyzed for the lactofen
metabolites that are still under consideration for inclusion in the
tolerance expression for crops harvested at PHIs <45 days.  HED had
previously indicated that this decision would be revisited for any
future registrations with PHIs of less than 45 days.  Because residues
of lactofen and all metabolites were below the LOQ in all samples
analyzed from the 1990 and 1991 field trials, and provided these results
are confirmed in the additional field trials required below, HED
believes that the current tolerance of lactofen per se will be
acceptable for tolerances resulting from the proposed use of lactofen on
fruiting vegetables.

No crop field trial data were submitted to support the proposed use on
okra.  Okra will be added to the fruiting vegetable crop group (Personal
communication, B. Schneider 10/13/06), so the tomato and pepper data may
be translated to okra.

Geographic representation is inadequate for the fruiting vegetables crop
group.  The petitioner has proposed use in Zones 2, 3, and 4; however,
only data from Zone 3 were submitted.  Due to the lack of detectable
residues, and that Zones 2 and 4 are adjacent to Zone 3, no additional
data are required to support the requested tolerance.  The available
field trial data for pepper and tomato indicate that residues will not
exceed the proposed tolerance for residues of lactofen per se in/on the
fruiting vegetables crop group 8 and okra at 0.02 ppm.

If the petitioner wishes to pursue a national section 3 registration in
the future, then at least one of the additional tomato field trials must
reflect application to a tomato variety that bears small fruit. 

860.1520 Processed Food and Feed

A processing study is not required for tomatoes because no detectable
residues were observed in tomatoes following treatment at 5x the maximum
proposed application rate (~5 lb ai/A).

 

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

Analytical standards for lactofen, its metabolites PPG-947, PPG-1576,
and PPG-2597, and the internal standard PPG-1530 are currently available
in the National Pesticide Standards Repository (personal communication
with D. Wright, 7/17/06).  Although a standard for metabolite PPG-847
has not been submitted, because the current tolerance expression for
lactofen is restricted to lactofen per se, and because the submitted
crop field trial data suggest that the current tolerance expression is
appropriate for the proposed use on fruiting vegetables, a standard for
PPG-847 is not required at this time.

860.1850 Confined Accumulation in Rotational Crops

D263857, 5/4/00, C. Olinger

D222025 and D285906, 7/21/04, N. Dodd

An acceptable confined rotational crop study in root crops indicated
that there was minimal uptake of radioactivity in carrots and radishes
planted between 42 and 119 days after treatment of soil with
[14C]lactofen.  

A confirmatory study was conducted on lettuce, carrots, radish and
wheat, which indicated that total radioactive residues (TRR) were <0.02
ppm in all rotational crops except wheat grain (0.10 ppm), forage (0.12
ppm), and straw (0.27 ppm).  Residues in wheat grain were not
characterized/identified.  Residues in wheat forage and straw were
extracted with methanol and analyzed by GC/ECD.  Lactofen per se was not
detected (<0.05 ppm) in either wheat forage or straw, and no metabolites
were identified.  

Additional storage stability information/data were required for the
confirmatory study; however, it was concluded that, pending receipt of
storage stability data, the study would be adequate to indicate that
residues of lactofen per se will not occur in rotational crops planted
in soil treated with lactofen at the rate of 0.92 lb ai/A (~1x the
maximum proposed seasonal rate for fruiting vegetables) at plantback
intervals of 72 days for wheat, 221 days for radish, or 291 days for
carrots and lettuce.  

860.1900 Field Accumulation in Rotational Crops

EAB Memo, 9/30/86, S. Simko

D222025 and D285906, 7/21/04, N. Dodd

A field rotational crop study was previously reviewed by EAB.  Lactofen
(2 lb/gal EC) was applied to silt loam and loam soils located in OH, MN,
and MO at 0.25-1.0 lb ai/A.  The plantback intervals were 1-339 days for
wheat, 55-368 days for lettuce, and 55-368 days for radishes.  Residues
of lactofen and metabolites PPG-847, PPG-947, PPG-1576, and PPG-2053
(not a residue of concern) were <0.05 ppm in wheat planted >1 day,
radishes planted >35 days, and lettuce planted >55 days following
application of the 2 lb/gal EC formulation at 0.25-1.0 lb ai/A.  

Additional data pertaining to the field conditions and the analytical
method for PPG-2053 were required for the field rotational crop studies;
however, HED concluded that the available confined and field rotational
crop data on wheat (a grain crop), lettuce (a leafy vegetable), and
radish/carrot (root crops) are adequate to indicate that residues of
lactofen per se are not taken up by rotational crops after soil is
treated at up to 0.50 lb ai/A (0.5x the maximum seasonal rate for
fruiting vegetables).  In support of proposed uses on cotton and peanut,
HED previously concluded that no rotational crop restriction was needed
based on reported residues of lactofen per se in treated crops (<0.01
ppm in snap bean, cottonseed, soybean, peanut, and, with one exception,
in cotton gin byproducts).

Conclusions.  The available confined rotational and field rotational
crop data, though inadequate, are sufficient to indicate that plantback
restrictions are not required for the proposed use of lactofen on
fruiting vegetables.

860.1550 Proposed Tolerances

Current tolerances [40 CFR §180.432(a)] for lactofen in/on plant
commodities are expressed in terms of the herbicide lactofen,
1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate.  

There are no established or proposed Codex, Canadian, or Mexican MRLs
for residues of lactofen in any crop.  Therefore, there are no
harmonization issues with respect to U.S. tolerances. 

In support of the proposed uses on the fruiting vegetables crop group 8
and okra, the petitioner has proposed to establish tolerances for the
residues of lactofen and its associated metabolites containing the
diphenyl ether linkage expressed as lactofen in/on the fruiting
vegetables crop group and okra at 0.01 ppm for each crop.  The proposed
tolerances are presented in Table 5.

Acceptable field trial data for the fruiting vegetables crop group were
submitted.  The available field trial data will support tolerances with
a regional registration for residues of lactofen per se in/on the
fruiting vegetables crop group and okra at 0.02 ppm.  

The proposed tolerances for the fruiting vegetables crop group and okra
should be revised to reflect the recommended tolerance expression and
the correct commodity definition as specified in Table 5. 

We note that the Tolerance Assessment Spreadsheet was not used to
calculate the proposed tolerance for fruiting vegetables and okra
because residues were below the limit of quantitation in/on all samples.

Table 5. 	Tolerance Summary for Lactofen

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

Vegetable, fruiting, group	0.01	0.02	Vegetable, fruiting, group 8

Okra	0.01	0.02

	

References

DP Barcode:	None

Subject:	EAB. Rotational Crop Review 

From:		J. Simko

To:		S. Creeger

Date:		9/30/86

MRIDs:	Acc. Nos. 071228 and 071228

DP Barcode:	RD D241826

Subject:	TGAI Product Chemistry Review/Action:  345.  Reg. File Symbol
No.:  59639-94.  Chemical:  Lactofen—76.7% pure.  Company:  Valent
U.S.A. Corp. 

From:		H. Podall

To:		S. Stanton

Date:		1/16/98

MRIDs:	44447001-44447003

DP Barcode:	RD D242241

Subject:	Product Chemistry Review of TGAI.  Reg./File Symbol No.: 
59639-94.  Product Name:  Lactofen Technical. 

From:		S. Mathur

To:		J. Miller

Date:		2/5/98

MRIDs:	44460901-44460903

DP Barcode:	D265469

Subject:	Lactofen:  HED Metabolism Assessment Review Committee Decision
Memorandum; Chemical No. 128888. 

From:		C. Olinger and E. Mendez

To:		G. Kramer

Date:		4/26/00

MRIDs:	None

DP Barcode:	D263857

Subject:	Tolerance Reassessment of Lactofen:  Product and Residue
Chemistry Considerations; PC Code:  128888. 

From:		C. Olinger

To:		S. Stanton and C. Scheltema

Date:		5/4/00

MRIDs:	None

DP Barcode:	None

Subject:	Lactofen - Report of the Cancer Assessment Review Committee 

From:		S. Diwan

To:		R. Fricke

Date:		5/22/02

MRIDs:	None

DP Barcode:	D222025 and D285906

Subject:	Lactofen.  Registration for Use on Cotton and Peanut.  Summary
of Analytical Chemistry and Residue Data.  Petition Numbers 9F03798
(Cotton) and 8F03591 (Peanut).

From:		N. Dodd

To:		J. Miller/J. Stone

Date:		7/21/04

MRIDs:	00117578, 43871501, 43871502, 43871503, 44156102, 44156103, and
44156104

  SEQ CHAPTER \h \r 1 Attachments:  

International Residue Limit Status sheet

Template Version September 2005



INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  1-(carboethoxy)ethyl
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate	Common Name:
Lactofen

	X Proposed tolerance

□ Reevaluated tolerance

□  Other	Date:   06/17/06

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

√ No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#5E6930

DP Barcode:  D356302

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due definition (step 8/CXL): N/A	Reviewer/Branch:  L. Cheng (RAB3)

	Residue definition:  Lactofen per se

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

Vegetable, fruiting, group	0.01

Okra	0.01

	Limits for Canada	Limits for Mexico

√ No Limits

□ No Limits for the crops requested	√  No Limits

□  No Limits for the crops requested

Residue definition: N/A

	Residue definition:  N/A

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

	Notes/Special Instructions:  

$

l 17, 2006.

 PAGE   

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Lactofen	Summary of Analytical Chemistry and Residue Data	Barcode: 
D333151

Page   PAGE  9  of   NUMPAGES  19