Document ID: EPA-HQ-OPP-2007-0303-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-09T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

	Date:	30/NOV/2007

	Subject:	Fenhexamid.  Petition for Registration for Use on Asparagus. 
Summary of Analytical Chemistry and Residue Data.  Petition Number
7E7187.

DP Num::	346385	Decision Number:	375841

PC Code:	090209	MRID No.:	47065401

40 CFR 180.	553

Chemical Class:	Hydroxyanilide fungicide

	

	From:	Debra Rate, Biologist

		Alternative Risk Integration and Assessment (ARIA)

		Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB)

		Registration Division (RD) (7505P)

	Through:	William Cutchin, Acting Senior Branch Scientist

		ARIA

		RIMUERB/RD (7505P)

		

	To:	Breann Hanson, Biologist

		ARIA

		RIMUERB/RD (7505P)

This document was originally prepared under contract by Dynamac
Corporation (submitted 31/AUG/2007).  The document has been reviewed by
ARIA of RD and revised to reflect current Office of Pesticide Programs
(OPP) policies.

Executive Summary

Fenhexamid is a hydroxyanilide type fungicide registered for use as
broadcast foliar applications on a variety of fruit, nut and vegetable
crops and for post-harvest application to selected fruits.  Fenhexamid
has been classified as a reduced risk compound.  Permanent tolerances
are established for residues of fenhexamid
(N-(2,3-dichloro-4-hydroxyphenyl)-1-methyl cyclohexanecarboxamide) in/on
plant commodities at levels ranging from 0.02 to 30 ppm [40
CFR§180.553(a)].  No tolerances are established for fenhexamid residues
in livestock commodities.

In the U.S., fenhexamid is currently registered to Bayer CropScience and
Arysta LifeScience North America Corporation for uses on food/feed crops
and is formulated as 50% water-dispersible granules (WDG). 
Interregional Project No. 4 (IR-4) submitted a petition proposing the
use of fenhexamid (50% WDG) on asparagus for the control of gray mold
(Botrytis cinerea).  The proposed use is for multiple broadcast foliar
applications to mature ferns late in the season at up to 0.75 lb
ai/A/application with a minimum retreatment interval (RTI) of 7 days,
for a maximum of 3.0 lb ai/A/season.  Applications are restricted to the
use of ground equipment in a minimum volume of 40 gal/A.  The minimum
preharvest interval (PHI) is 90 days for asparagus grown in CA and 180
days for all other states.  In conjunction with this use, IR-4 is
proposing the following permanent tolerance for fenhexamid:

Asparagus	0.02 ppm

The nature of fenhexamid residues in plants is understood based on
adequate metabolism studies on grapes, tomatoes, and apples.  Fenhexamid
residues are non-systemic and primarily surface residues.  HED’s
Metabolism Assessment Review Committee (MARC) has concluded that only
residues of parent fenhexamid need to be included in the tolerance
expression and considered for risk assessment.

As the crop uses being purposed in this petition do not include any
regulated livestock feedstuffs, issues pertaining to livestock
metabolism, analytical methods and storage stability data for livestock
commodities, and residues in livestock commodities are not relevant to
the current petition. 

An adequate high performance liquid chromatography (HPLC) method using
electrochemical detection (ECD) is available for enforcing tolerances
for fenhexamid in/on plant commodities.  For this method, residues are
extracted with acetone, purified using a Chem Elute column, and analyzed
by HPLC/ELCD, using external standards.  The method limit of
quantitation (LOQ) is 0.02-0.05 ppm depending on the matrix.  In the
submitted asparagus field trials, residues of fenhexamid were determined
using a liquid chromatography (LC) mass spectrometry method (LC/MS). 
This method uses similar extraction and purification procedures to the
enforcement method, but uses MS for quantitation and confirmation of
residues.  The statistically calculated LOQ is 0.008 ppm and the
calculated limit of detection (LOD) is 0.003 ppm.  The lowest level of
method validation (LLMV) is 0.02 ppm.  The LC/MS method was adequately
validated prior to and in conjunction with the analysis of field trial
samples.

In conjunction with the field trials, adequate storage stability data
were submitted indicating that fenhexamid is stable at -21ºC in
asparagus for up to 7.1 months of storage.  These data adequately
support the maximum frozen storage duration (7.5 months) from the field
trials. 

The available asparagus field trial data are adequate and support the
proposed use pattern.  As previously approved by the Agency (ChemSAC
meeting 16/OCT/2002), two field trials were conducted at 5x the proposed
use rate and samples were harvested at the shortest possible PHI.  In 2
field trials conducted during 2003 in EPA growing Region 10 (CA),
fenhexamid (50% WDG) was applied to mature asparagus ferns in the fall
season as four broadcast foliar applications at rates of 3.7-3.8 lb ai/A
and at RTIs of 7-8 days, for a total of 15.1 lb ai/A (5x proposed use
rate).  Residues of fenhexamid were <0.02 ppm (<LOQ) in/on all 4 samples
of asparagus harvested at 92 or 100 DAT.

As there are no regulated processed commodities associated with
asparagus, no processing studies are required for this petition.  Data
pertaining to rotational crops are also not required for this petition
as asparagus is not rotated.  

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

No deficiencies were noted in the subject petition that would preclude
establishing a permanent tolerance for fenhexamid residues on asparagus.
 ARIA recommends establishing a permanent tolerance for fenhexamid in/on
asparagus at 0.02 ppm.  A human health risk assessment for fenhexamid is
forthcoming.

Background

Fenhexamid is a reduced risk, hydroxyanilide fungicide registered in the
U.S. for use on a variety of fruit, nut and vegetable crops for
controlling Botrytis cinerea and  Monolinia spp. (brown rot / blossom
blight / twig blight) and suppressing Uncinula necator (powdery mildew).
 Fenhexamid is a locally systemic, protectant fungicide that is absorbed
into the waxy layer of the cuticle.  It prevents fungal infections by
inhibiting germ tube elongation, mycelial growth and spore germination. 
Fenhexamid is currently registered in the U.S. to Bayer and Arysta and
is formulated as 50% WDGs for uses on food/feed crops.

IR-4 has submitted a petition (PP#7E7187) proposing the use of
fenhexamid on asparagus.

Table 1.	Fenhexamid  Nomenclature. tc "TABLE A.1.	Test Compound
Nomenclature" 

Compound

	

Common name	Fenhexamid

Company experimental name	KBR 2738

IUPAC name	2,3-dichloro-4-(1-methylcyclohexyl-carbonylamine)-phenol

CAS name	N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexanecarboxamide

CAS #	126833-17-8

End-use product/EP	50% WDG (ELEVATE® 50 WDG Fungicide, EPA Reg. No.
66330-35)

Table 2.	Physicochemical Properties of the Technical Grade Fenhexamid.

Parameter	Value	Reference

Melting point/range	153oC	Fenhexamid: Pesticide Fact Sheet (May 20,
1999)

Fenhexamid (KBR 2738)-a Botryticide from a New Chemical Class,
Pflanzenschutz-Nachrichten Bayer 52/1999, 2

pH	8.3 in 1% solution of water

	Density (20ºC)	1.34 g/ml

	Water solubility (mg/L at 20°C)	20

	Solvent solubility (g/L at 20°C)	dichloromethane – 31

2-propanol - 91

n-hexane - <0.1

Toluene – 5.7

	Vapor pressure at 25°C	7x10-9  Torr

	Dissociation constant (pKa)	7.3

	Octanol/water partition coefficient Log(KOW)	3.51 (pH 7, 20oC )

	UV/visible absorption spectrum	245 and 290 nm

	

860.1200  Directions for Use

In the U.S., a 50% WDG formulation of fenhexamid (ELEVATE 50 WDG
fungicide, 66330-35) is currently registered to Arysta for uses on
fruits, nuts and vegetables.  IR-4 is proposing the use of this 50% WDG
on asparagus.  An example label for the 50% WDG was provided and the
proposed use directions are summarized below in Table 3.

Table 3.  Summary of Directions for Use of Fenhexamid.

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 1

Asparagus

Broadcast foliar applications to asparagus in fern stage only.  Ground
equipment only	50% WDG

[66330-35]	0.75	4	3.0	180 (except CA)

90 (CA)	Apply only at the fern stage.  Treated ferns must be mowed down
or allowed to senesce prior to harvest of asparagus spears.  

Apply in a minimum of 40 gal/A.

The minimum RTI is 7 days. 

1	Do not apply through any type of irrigation system.  Do not replant
treated fields with food crops other than those with labeled uses within
30 days of the last application.

Conclusions.  The use directions are adequate to allow evaluation of the
residue data relative to the proposed use.  The available data from the
asparagus field trials conducted at a 5x use rate are adequate (ChemSAC
guidance (16/OCT/2002)), and support the proposed 1x use rate.

860.1300 Nature of the Residue - Plants

The nature of fenhexamid in plants is understood based on adequate
metabolism studies on grapes, tomatoes, and apples (DP Num: 244844 and
249061, G. Herndon, 25/MAR/1999).  The results from these studies
indicate that most of the terminal residue is unmetabolized parent. 
Fenhexamid residues are non-systemic and primarily surface residues. 
The MARC concluded that only residues of parent fenhexamid need to be
included in the tolerance expression (DP Num: 253792, G. Herndon,
11/MAR/1999).  For the purposes of this action, the nature of fenhexamid
residues in plants is adequately understood.  

860.1300 Nature of the Residue - Livestock

Since there are no asparagus feed items of regulatory interest, a
discussion of the metabolism of fenhexamid in livestock commodities is
not germane to this action.

860.1340 Residue Analytical Methods

An adequate HPLC/ECD method is available for enforcing tolerances for
fenhexamid in/on plant commodities.  A copy of this method is available
on EPA’s Website.  For this method, residues are extracted with
acetone, filtered and concentrated to an aqueous remainder.  The aqueous
fraction is then loaded onto a Chem Elute column, and residues are
eluted with cyclohexane:ethyl acetate (85:15).  Residues are
concentrated to dryness, redissolved in methanol and analyzed by
HPLC/ECD, using external standards. The method LOQ is 0.02-0.05 ppm
depending on the matrix.

Samples from the current asparagus field trails were analyzed for
residues of fenhexamid using an LC/MS method (Cornel Analytical
Laboratory Method, “Residue Analysis of Fenhexamid on Asparagus Using
LC with MS detection, Version #8”).  This method is similar to the
enforcement method, except that MS detection was used instead of ECD. 
For the LC/MS method, residues are extracted with acetone, concentrated
and purified using a Chem Elute column.  Residues are then analyzed by
LC/MS using external standards.  The m/z 302 and 304 ions are used for
quantitation and confirmation of residues.  The statistically calculated
LOQ is 0.008 ppm and the LOD is 0.003 ppm.  The method LOQ is 0.02 ppm. 
The LC/MS method was adequately validated prior to and in conjunction
with the analysis of field trial samples.

Conclusions.  The LC/MS method is adequate for collecting data on
fenhexamid residues in/on asparagus.

860.1360 Multiresidue Methods

Fenhexamid has been tested using the FDA multiresidue methods protocols.
 Fenhexamid was adequately recovered (>80%) from non-oily matrices using
Protocol B, but recovery from an oily matrix was only ca 15%.  The FDA
multiresidue method, Protocol B would be adequate as an enforcement
method for non-oily crops.

860.1380 Storage Stability

Adequate data are available indicating that fenhexamid is stable at
-20ºC for up to 12 months in tomatoes, 7.1-7.3 months in peaches and
cherries, 4.8 months in kiwifruit, and 6 months in ginseng roots (DP
Num: 285209, M. Nelson, 02/DEC/2003; and DP Num: 312266, W. Cutchin,
07/MAR/2005).

In conjunction with the asparagus field trials, a storage stability
study was also conducted using control samples of asparagus fortified
with fenhexamid at 0.2 ppm.  The fortified samples were stored under the
same conditions as the field trial samples.  At the end of the
analytical phase of the study, the stored sample was analyzed in
triplicate along with a control sample and a freshly fortified sample. 
The average recovery from the stored samples was 83%, indicating that
fenhexamid is stable in asparagus at ≤-21ºC for up to 7.1 months.  

Samples from the asparagus field trials were stored at -21°C for up to
228 days (7.5 months) prior to analysis.

Conclusions.  The storage stability data are adequate and support the
sample storage durations and conditions incurred in the asparagus field
trials.  

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

As there are no livestock feedstuffs associated with the proposed use on
asparagus, data requirements pertaining to meat, milk, poultry, and eggs
are not relevant to this tolerance petition

860.1500 Crop Field Trials

47065401.der, D. Rate, 29/NOV/2007 (asparagus)

IR-4 submitted data from exaggerated rate (5x) field trials to support
the proposed late-season use of fenhexamid (WDG) on asparagus.    SEQ
CHAPTER \h \r 1 The results from these tests are discussed below and the
residue data are summarized in Table 4.

≥90-day PHI)

Asparagus	15.1	92-100	4	<0.02	<0.02	<0.02	<0.02	<0.02	N/A

1	The calculated LOQ is 0.008 ppm and the method LOQ is 0.02 ppm.

2	HAFT = Highest average field trial result.

In 2 field trials conducted during 2003 in EPA growing Region 10 (CA),
fenhexamid (50% WDG) was applied to mature asparagus ferns in the fall
season as four broadcast foliar applications at rates of 3.7-3.8 lb ai/A
and at RTIs of 7-8 days, for a total of 15.11-15.14 lb ai/A (5x proposed
use rate).  Applications were made using ground equipment in volumes of
40-51 gal/A, and did not include the use of any spray adjuvants.  Single
control and duplicate treated samples of asparagus spears were harvested
from each test site the spring following application, 92 or 100 DAT. 
Samples were stored frozen for up to 228 days, a duration supported by
available storage stability data.

The LC/MS method used to determine residues of fenhexamid residues in/on
asparagus was adequately validated prior to and in conjunction with the
analysis of field trial samples.  The statistically calculated LOQ is
0.008 ppm and the LOD is 0.003 ppm.  The method LOQ was 0.02 ppm. 

Following four foliar applications of fenhexamid (WDG) to mature
asparagus ferns in the fall at rates totaling 15.1 lb ai/A (5x proposed
use rate), residues of fenhexamid were <0.02 ppm (<LOQ) in/on all 4
samples of asparagus harvested at 92 or 100 DAT.

Conclusions.  The submitted field trial data are adequate and support
the use of fenhexamid on mature asparagus ferns.  Although only two
field trials were conducted, HED (ChemSAC guidance (minutes
16/OCT/2002)) previously approved conducting a reduced set of field
trials using an exaggerated 5x application rate.  As residues of
fenhexamid were <LOQ in/on all four samples harvested at 92-100 DAT
following the 5x applications, residues are unlikely to be detectable in
asparagus spears harvested at 90 DAT following applications to mature
ferns at the proposed 1x rate.  The data support setting the tolerance
for residues of fenhexamid in/on asparagus at the method LOQ (0.02 ppm).

860.1520 Processed Food and Feed

HED does not require residue data for any processed commodities
associated with asparagus.  Therefore, data requirements for processed
food and feed are not relevant to this tolerance petition.

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

An analytical reference standard for fenhexamid is available at the
repository (Electronic communication, T. Cole, 20/AUG/2007).

860.1850/1900 Confined and Field Accumulation in Rotational Crops

Because asparagus is not rotated, no data pertaining to rotational crops
are required to support the proposed use.

860.1550 Proposed Tolerances

The Agency has determined that the residue of concern in plant
commodities is parent fenhexamid only.  Permanent tolerances are
established for residues of parent fenhexamid in/on plant commodities at
levels ranging from 0.02 ppm in/on almonds, nonbell peppers and
pistachios to 30.0 ppm in/on leafy greens (except spinach) and cilantro
leaves [40 CFR§180.553(a)].  No tolerances are established for
fenhexamid residues in livestock commodities.  The proposed and
recommended tolerance for asparagus is listed in Table 5.

In the available asparagus field trails conducted at 5x the proposed
rate, residues of fenhexamid were all <LOQ in/on all samples of
asparagus harvested at 92-100 DAT, which approximates the shortest PHI
(90 days).  Based on these data, fenhexamid residues are unlikely to be
detected following applications at the proposed 1x use rate.  Therefore,
the Agency recommends establishing the tolerance for asparagus at the
method LOQ of 0.02 ppm.

Canadian, Mexican and Codex Maximum Residue Limits (MRLs) are
established for fenhexamid on various fruit and vegetable crops
(Appendix I).  As with the U.S., the regulated residues for fenhexamid
under each organization include only parent compound.  As there are no
established or proposed Canadian, Mexican or Codex MRLs for fenhexamid
on asparagus, there are no issues for international harmonization for
the current petition.

Table 5. 	Tolerance Summary for Fenhexamid.

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

Asparagus	0.02	0.02	Adequate field trial data are available on
asparagus.

References

DP Num:	285209, 285214, 287732, and 287860	

Subject:	FENHEXAMID Residue Chemistry Summary Document for:  PP#2E6463 -
 Kiwifruit, PP#2E6496 - Fruiting Vegetables (Group 8) and Cucumber,
PP#3E6532 -  Leafy Greens (Subgroup 4A), except spinach, and Cilantro,
PP#3E6541 - Stone Fruit (Group 12), adding postharvest use and raise
existing tolerances

From:	M. Nelson

To:	S. Brothers/R. Forrest

Dated:	02/DEC/2003

MRID(s):	45682001, 45736601, 45736602, 45736603, 45736604, 45736605,
45736606, 45795601, 45817101, 45821101, 45821102, 45821103.

DP Num:	312266

Subject:	Fenhexamid.  Section 3 Use on Ginseng.  Summary of Analytical
Chemistry and Residue Data.  Petition Number 4E6859.

From:	W. Cutchin

To:	S. Jackson/R. Forrest

Dated:	07/MAR/2005

MIRD(s):	46371501

	

  SEQ CHAPTER \h \r 1 Attachments: 

Appendix I – International Residue Limit Status sheet

Appendix I - International Tolerances

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:
N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexanecarboxamide	Common
Name: Fenhexamid

	X Proposed tolerance

    Reevaluated tolerance

    Other	Date:  11/07/2007

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

    No Codex proposal step 6 or above

X No Codex proposal step 6 or above for the crops requested	Petition
Numbers: 7E7187

DP Number:  	346385

Other Identifier:  

Residue definition (step 8/CXL): Fenhexamid	Reviewer/Branch:  Debra
Rate/RIMUERB

	Residue definition:  Fenhexamid

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

Almond hulls	2	Asparagus	0.02

Almonds	0.02 (*)

Apricot	10

Blackberries	15

Blueberries	5

Cherries	7

Cucumber	1

Currants, Black, Red, White	5

Dewberries (including boysenberry and loganberries)	15

Dried grapes (currants, raisins, and sultanas)	25

Edible offal (mammalian)	0.05 (*)

Egg plant	2

Gherkin	1

Gooseberry	5

Grapes	15

Kiwifruit	15

Lettuce, Head	30

Lettuce, Leaf	30

Meat (from mammals other than marine mammals)	0.05 (*)

Milks	0.01 (*)

Nectarine	10

Peach	10

Peppers	2

Plums, including prunes	1

Raspberries, Red, Black	15

Squash, Summer	1

Strawberry	10

Tomato	2

Bilberry	5

Elderberries	5

Juneberries	5

Limits for Canada	Limits for Mexico

( No Limits

X No Limits for the crops requested	( No Limits



 

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Blackberries, loganberries, raspberries	20	Fresa (strawberry)	3

Apricots, cherries, peaches, nectarines	6	Vid (grapes)	4

Grapes	4

Raisins	6

Blueberries, currants, elderberries, gooseberries, huckleberries	4

Strawberries	3

Plums	0.5

Almonds	0.02

Tomato	1

Notes/Special Instructions: S.Funk, 11/07/2007

Page   PAGE  8  of   NUMPAGES  10 

Fenhexamid	Summary of Analytical Chemistry and Residue Data	DP Num:
346385