Document ID: EPA-HQ-OPP-2006-0848-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-24T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		14-June-2007

Subject:	Fenamidone in/on Cotton, Tobacco, Carrot, Sunflower, Brassica
Vegetables (group 5), Leafy (except Brassica) Vegetables (group 4),
Fruiting Vegetables (group 8), and Strawberry (rotational crop). 
Summary of Analytical Chemistry and Residue Data.

Registration #s:	5F6898, 5E6924, 5E6925, 6E7109, 264-693-Fenbamidone
Technical, 

264-695 - Reason® 500SC	DP #s:	314318, 324905, 333079, 333091, 333363,
336200, 336202, 338016

Decision #s:	353140, 353142, 355880, 355882, 355885, 370420, 371779	40
CFR 	180.579

MRIDs	46440801, 46440802, 46440803, 46440804, 46440805, 46518301,
46518401, 46518402, 46518403, 46921101, 46970401, 46970402, 46927101

From:		Tom Bloem, Chemist

			Registration Action Branch 1, Health Effects Division (RAB1/HED;
7509P)

Through:	George F. Kramer, Ph.D., Senior Chemist

			RAB1/HED (7509P)

To:			Tony Kish/Rosemary Kearns (RM 22); Barbara Madden/Susan Stanton
(RM 05)

			Registration Division (RD; 7505P)

Bayer CropScience proposed the application of fenamidone to cotton (seed
treatment and at planting application; tolerance exemption) and tobacco.
 The Interregional Research Project Number 4 (IR-4) proposed the
application of fenamidone to carrot, sunflower (seed treatment),
Brassica leafy vegetables, leafy (except Brassica) vegetables, and
fruiting vegetables.  The following permanent tolerances were proposed
for residues of fenamidone
((5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-im
idazol-4-one (RPA 407213; see attachment 1 for structures): 

Carrot	0.15 ppm

Sunflower	0.08 ppm

Vegetable, brassica, head and stem, subgroup 5a	4.0 ppm

Vegetable, brassica, leafy greens, subgroup 5b	35 ppm

Vegetable fruiting, group 8	2.0 ppm

Vegetable, leafy, except brassica, 4	35 ppm

Strawberries (rotational crop)	0.02 ppm

Executive Summary

Background:  Fenamidone (see attachment 1 for structures) is a chiral
compound with the technical product consisting of 98.5% S-fenamidone. 
Fenamidone is a broad-spectrum foliar fungicide belonging to the
imidazolinone class of chemicals called quinone outside inhibitors
(QOIs).  These compounds inhibit the quinone outside site within the
electron transport system in susceptible fungi species.  Fenamidone is
currently registered for application to lettuce (head and leaf), bulb
vegetables, cucurbit vegetables, tuberous and corm vegetables, tomato,
and grape with tolerances for residues of fenamidone per se ranging from
0.02-20 ppm (40 CFR 180.579(a)(1)).  Tolerances have been established
for the combined residues of fenamidone and RPA 717879 as a result of
secondary residues in milk (0.01 ppm) and ruminant fat (0.10 ppm), meat
(0.10 ppm), and meat byproducts (0.10 ppm; 40 CFR 180.579(a)(2)) and in
wheat as a result of crop rotation (0.10-0.50 ppm; 40 CFR 180.579(d)).  

Application Scenarios:  Bayer CropScience is proposing the application
of Reason® 500 SC (EPA Reg. No. 264-695; 4.13 lb ai/gallon;
suspension-concentrate) to tobacco and cotton (seed treatment and at
planting application) and IR-4 is proposing the application of Reason®
500 SC to Brassica leafy vegetables, leafy vegetables (except Brassica),
fruiting vegetables, sunflowers (seed treatment), and carrot.  HED has
previously approved the application of fenamidone (Reason® 500 SC) to
tomato and lettuce at single application rates, retreatment intervals
(RTIs), and preharvest intervals (PHIs) identical to that proposed for
fruiting vegetable and leafy vegetables (except Brassica) crop groups
and seasonal application rates greater than that proposed as part of the
current petition (1.06 lb ai/acre; 0.80 lb ai/acre currently proposed). 

Table 4 is a summary of the proposed application scenarios.  Application
via ground (minimum of 15 gallons per acre (GPA)), aerial (minimum of 5
GPA), and chemigation equipment are permitted.  The label recommends the
addition of a spreader/sticker to the spray solution.  As a resistance
management strategy, the proposed label states that no more than one
application should be made before alternating with a fungicide with a
different mode of action.  The proposed label indicates that crops on
the label may be rotated immediately following the last application, to
wheat and strawberries 30 days after the last application, and all other
crops one year after the last application.  The sunflower seed treatment
instructions indicate that all treated seed must be dyed with an EPA
approved dye/colorant.  HED requests that the petitioner submit a
revised Section B with the following changes:

●Treated cottonseed must be dyed with an EPA approved dye/colorant.

●The tomato and carrot field trials did not include an adjuvant in the
spray solution (all other field trials included an adjuvant); therefore,
the label should indicate that the addition of an adjuvant to the spray
solution is appropriate for all relevant crops excluding tomato and
carrot.

●Restriction prohibiting the application to crops grown in
greenhouses.

Nature of the Residue - Plants:  The HED Metabolism Assessment Review
Committee (MARC) reviewed metabolism studies conducted with potato
(C-phenyl and N-phenyl labeled studies), tomato (C-phenyl and N-phenyl
labeled studies), lettuce (C-phenyl and N-phenyl labeled studies), and
grape (C-phenyl labeled study).  The major residues identified in these
studies were fenamidone, RPA 408056, RPA 405862, and RPA 717879.  The
identification of RPA 408056, and RPA 717879 indicates that the C-phenyl
and N-phenyl rings may be separated during metabolism.  Based on the
structure of these compounds, separation of the rings may result in the
formation of aniline(s).  The N-phenyl metabolism studies did not
include standards containing only the N-phenyl ring.  Therefore, the
metabolic fate of the N-phenyl ring was not determined.  The petitioner
subsequently analyzed aniline, nitroanilines (2- and 4-nitroaniline),
and aminophenols (2-, 3-, and 4-aminophenol) using the same instrumental
systems used in the plant metabolism studies.  These data indicate that
non-conjugated aniline(s) residues in plant extracts are low ((0.006
ppm; these data exclude the wrapper leaves sample).  However, as the
petitioner indicated for potato, aniline(s) may react with plant
constituents to form conjugated residues.  HED notes that the
identification/characterization procedures performed in the N-phenyl
tomato and lettuce metabolism studies resulted in identification of 76%
and 88% of the total radioactive residue (TRR), respectively.  However,
since only 6% of the TRR was identified in the N-phenyl potato study and
based on the toxicological effects of aniline (probable human
carcinogen; US EPA Integrated Risk Information System (IRIS) -
http://www.epa.gov/iris/subst/0350.htm), the MARC requested that the
petitioner hydrolyze the extractable and nonextractable residues from
the N-phenyl studies to determine if conjugated aniline(s) are present
and concluded that pending the submission of these data, the nature of
the residue in plants is not understood (TXR 0052287, T. Bloem et al.,
25-May-2004).  

fenamidone (29-89% TRR) and RPA 413255 (<1-18% TRR).  Residues of RPA
411639, RPA 410193, RPA 410995, RPA 409446, and RPA 407213-dimer were
also identified at ≤7% TRR.  Total identified residues in carrot root
and top were 65% TRR and 96% TRR, respectively.  Aniline, aminophenol,
and/or nitroaniline were not present in the unhydrolyzed carrot top (99%
TRR) and root (81% TRR) extracts; to determine if conjugates of
aniline(s) were present, the carrot top and root extracts were
hydrolyzed with 1M HCl (1 hour; 100(C) and 1M NaOH (1 hour; 100(C). 
Aniline, aminophenol, and/or nitroaniline were not identified in the
carrot-top acid hydrolysate or the carrot-root acid and base
hydrolysates.  However, aniline and nitroaniline may be present in the
carrot-top base hydrolysate.  The petitioner indicated that the
formation of aniline(s) was as a result of cleavage of the N-phenyl ring
from intact parent/metabolites during the base hydrolysis procedure. 
The study did not include a control experiment demonstrating this
hypothesis.  In addition, alkaline hydrolysis of the carrot root extract
did not result in the formation of aniline and nitroaniline despite the
presence of many of the same metabolites in the root extract as were
present in the carrot top extract.  

HED requests that the petitioner perform control experiments to
determine if the parent/metabolites identified in the carrot metabolism
study degrade to aniline when exposed to the base hydrolysis procedures
used on the carrot metabolism study.  If these experiments do not
demonstrate degradation, then HED requests that the petitioner submit
information concerning the identify and magnitude of the residues in the
alkaline hydrolysate of the carrot top (organic and aqueous phase) and
carrot root extracts (Chemistry Science Advisory Committee (ChemSAC)
minutes 30-May-2007).  Pending the submission of the these data and
based on a conservative dietary risk analysis to potential aniline
exposure from fenamidone which resulted in exposure estimates that are
not of concern to HED (see HED Risk Assessment; D314116, T. Bloem et
al., in draft), HED concludes the residues of concern in the
proposed/registered crops are as defined in Table 5.  

Nature of the Residue - Livestock:  The MARC reviewed goat and hen
metabolism studies conducted with fenamidone labeled in the C-phenyl and
N-phenyl rings.  The major residues identified in the goat and hen
studies were fenamidone, RPA 717879, and RPA 408056.  The identification
of RPA 717879, RPA 408056, and RPA 408056-OH in the livestock metabolism
studies indicates that the C-phenyl and N-phenyl rings are separated
during metabolism.  Based on the structure of these compounds, the
separation of the rings may result in the formation of aniline(s). 
Since only (12% of the TRR was identified in samples collected from the
N-phenyl studies and since the petitioner did not include standards
containing only the N-phenyl ring, HED concludes that the nature of the
residue in livestock has not been adequately delineated (MARC memo; T.
Bloem et al., 25-May-2004). 

HED performed a conservative dietary risk analysis to potential aniline
exposure from fenamidone with the resulting exposure estimates not of
concern to HED (see HED Risk Assessment; D314116, T. Bloem et al., in
draft).  Therefore, for the currently proposed crops, HED concludes the
residues of concern in livestock are as defined in Table 5.  These
conclusions will be reevaluated if additional crops are requested.  

Magnitude of the Residue - Plants:  The geographical representation of
the leafy vegetable (except Brassica), Brassica (cole) leafy vegetable,
fruiting vegetable, cotton, sunflower, carrot, and tobacco field trial
data fulfill the data requirements suggested in OPPTS 860.1500.  HED
notes that excluding the sunflower (conducted at 1.0x the proposed rate)
and cotton (see below) field trials, the application rates were 1.0x the
proposed single application rate and 1.3-1.4x the proposed seasonal
rate.  Based on the residue decline data, HED concludes that the final
application, which was conducted at 1x the proposed rate, will drive the
magnitude of the residue in/on these crops and addition field trial data
or adjustment of the magnitude of the residue for the exaggerated
seasonal application rate are unnecessary.  

The cotton label specifies directions for both seed treatment and
in-furrow at planting application (treated seed may also receive the
in-furrow application at planting).  The field trial data employed only
the in-furrow application.  The seeding rate for cotton is 10 lbs seed
per acre (  HYPERLINK
"http://deltafarmpress.com/mag/farming_adjusting_price_cotton/" 
http://deltafarmpress.com/mag/farming_adjusting_price_cotton/ ) which
translates to a fenamidone application rate of 0.019 lb ai/acre for the
seed treatment application.  Since this rate is 7% of the in-furrow
application and since residues were less than the limit of quantitation
(LOQ) in/on cottonseed and cotton gin byproducts following application
at the proposed in-furrow rate and since residues were <LOQ in/on
cottonseed following application at 4.9x the proposed in-furrow rate,
HED concludes that additional cotton residue data are unnecessary.  The
petitioner also submitted exaggerated rate sunflower (5x) field trial
data which resulted in <LOQ residues in the RAC and previously submitted
an adequate tomato processing study which resulted in the establishment
of tomato paste and puree tolerances (fenamidone is currently registered
for application to tomato).

The field trial and processing samples were analyzed for residues of
fenamidone RPA 717879, RPA 408056, and RPA 405862 using adequately
validated methods (storage interval has also been validated). Since none
of the field trial data were conducted on greenhouse grown crops, HED
requests that the petitioner submit a revised Section B prohibiting the
application to crops grown in greenhouses.  Provided a revised Section B
is submitted and based on the field trial and processing data, HED
concludes that the tolerances listed in Table 1 for residues of
fenamidone are appropriate (except for cotton and sunflower matrices
(LOQ tolerances), tolerances were calculated using the maximum residue
limit (MRL) tolerance spreadsheet calculator).  HED notes that the
currently-established lettuce (head and leaf) and tomato RAC tolerances
may be deleted.  A revised Section F is requested.  

Base on the tobacco pyrolysis study which demonstrated the degradation
of fenamidone to aniline, HED is concerned that fenamidone may be
degrading to aniline during the processing or cooking of treated crops. 
As a result, HED requests that the petitioner submit a processing study
as designated in Annex 1 of the following European Union document:  ( 
HYPERLINK
"http://ec.europa.eu/food/plant/protection/resources/app-e.pdf" 
http://ec.europa.eu/food/plant/protection/resources/app-e.pdf ).  The
procedure involves the hydrolysis of radiolabeled fenamidone at various
pHs and temperatures and identification of the resulting transformation
products, if any (N-phenyl radiolabeled fenamidone should be employed). 
Depending on the results from this study, additional data may be
requested (ChemSAC minutes 30-May-2007).  

Magnitude of the Residue - Livestock:  The following ruminant tolerances
for residues of fenamidone and RPA 717879 are currently established
(D297216, T. Bloem, 25-May-2004; poultry tolerances are not currently
established):  fat (beef, goat, and sheep) - 0.10 ppm, meat (beef, goat,
and sheep) - 0.10 ppm, meat byproducts  (beef, goat, and sheep) - 0.10
ppm, milk - 0.02 ppm.  The feed commodities associated with the
currently-requested crops are carrot (beef/dairy cattle), cotton
(beef/dairy cattle, hog, and poultry), and sunflower (beef/dairy cattle,
hog, and poultry).  The current maximum reasonable dietary burdens
(MRDBs) for dairy cattle, beef cattle, poultry, and hog are 2.34 ppm,
2.10 ppm, 0.58 ppm, and 0.37 ppm, respectively.  Based on the available
data, HED made the following conclusions:   

Poultry - A poultry feeding study has not been submitted.  Based on the
TRRs (C-phenyl - (0.216 ppm; N-phenyl - (0.111 ppm) in the poultry
metabolism study (conducted at 27x (C-phenyl) and 19x (N-phenyl) the
poultry dietary burden), HED concludes that there is no reasonable
expectation of finite residues in poultry commodities (40 CFR
180.6(a)(3)).  A poultry feeding study and poultry tolerances are not
required.

Ruminant - A lactating dairy cattle feeding study was previously
submitted and reviewed by HED (45386004.der.wpd; D297216, T. Bloem,
25-May-2004).  The cattle were dosed with fenamidone for 35 days at
dietary feeding levels of 0.3x/0.4x/2.4x, 1.0x/1.1x/7.0x, and
3.4x/3.8x/24x the dairy/beef/hog MRDBs.  Milk was collected throughout
the study and muscle, fat, liver, and kidney were collected at
sacrifice.  Because of low residue levels, only samples from the 7.9 ppm
(highest level) dosing group were analyzed.  Following dosing of cattle
with fenamidone at 7.9 ppm, residues of fenamidone and its metabolites
RPA 717879 and RPA 408056 were less than the limit of detection (LOD =
<0.0033 ppm each) in milk samples collected over the course of the
dosing period and were <LOD (<0.017 ppm each) in samples of muscle, fat,
liver, and kidney collected at sacrifice.  Quantifiable residues of
fenamidone were observed in one sample of milk fat at 0.011 ppm; the
other two milk fat samples bore detectable residues of fenamidone at
levels below the <LOQ (<0.01 ppm).  Residues of RPA 717879 and RPA
408056 were <LOD (<0.0033 ppm each) in the milk fat samples.  Therefore,
the petitioner has demonstrated that hog tolerances are unnecessary as
residues were <LOQ following dosing at 24x the hog MRDB.  Based on the
current dairy/beef cattle MRDB and since the petitioner has not
demonstrated that residues are <LOQ in cattle tissue and milk
commodities following dosing at 10x the MRDB, HED concludes that the
currently-established ruminant LOQ tolerances are appropriate.  

Nature/Magnitude of the Residue - Rotational Crops:  The residues of
concern in rotational crops for purposes of tolerance enforcement are
fenamidone and RPA 717879 and the residues of concern in rotational
crops for purposes of risk assessment are fenamidone, RPA 717879, and
RPA 408056 (free and conjugated; storage stability data validating the
confined rotational crop study storage intervals and conditions are
required; MARC memo, T. Bloem et al., 25-May-2004).  The proposed label
indicates that a treated field may be rotated to a labeled crop
immediately following the last application, to wheat and strawberries 30
days after the last application, and all other crops one year after the
last application.  

The petitioner has previously submitted limited (radish, spinach, and
wheat; 45385903.der.wpd) and extended (wheat (30-day plantback interval
(PBI)); 45386002.der.wpd) field rotational crop studies and as part of
the current petition submitted an extended strawberry (30-day PBI) field
rotational crop study. The limited study did not monitor for residues of
RPA 408056 conjugates; therefore, this study can not be used for
determination of an appropriate PBI (if tolerances are not established,
PBI established at the interval where residues of concern are <LOQ).  

Based on the extended wheat rotational crop study (employed application
rate of fenamidone 1.3-1.4x the maximum currently proposed rate), HED
previously concluded that a 30-day PBI is appropriate for wheat along
with the establishment of the following tolerance for residues of
fenamidone and RPA 717879 (these tolerances have been established;
D281887, T. Bloem, 18-Jul-2002):  wheat forage - 0.15 ppm, wheat hay -
0.50 ppm, wheat straw - 0.35 ppm, and wheat grain - 0.10 ppm.  Since the
wheat study employed an exaggerated rate as compared to the currently
proposed application rates and since wheat tolerances are currently
established, HED concludes that a 30-day PBI for wheat is appropriate
for the currently requested crops.  In addition, the strawberry field
rotational crop indicated that residues of fenamidone, RPA 408056, RPA
405862, and RPA 717879 are <LOQ in/on strawberries planted 30 days after
application at 1.3x the proposed seasonal application rate.  Therefore,
provided a strawberry tolerance of 0.02 ppm for residues of fenamidone
is established, HED concludes that the proposed rotational crop
restrictions are appropriate.  

Analytical Enforcement Method - Plants:  The petitioner previously
proposed a liquid chromatograph/mass spectrometer/mass spectrometer
(LC/MS/MS) method for enforcement of the registered plant tolerances. 
Adequate method validation, radiovalidation, and independent laboratory
validation (ILV) data have been submitted (45385916.der.wpd).  HED notes
that the Multiresidue Methods (MRMs) may serve as a confirmatory method
(see below).  The proposed enforcement method has been forwarded to the
Analytical Chemistry Branch (ACB) for petition method validation (PMV;
D278954, T. Bloem, 15-Nov-2001).  As this method has been validated
in/on a number of commodities (potato, cucumber, cantaloupe, lettuce,
onion, tomato (fruit, paste, and puree), spinach, and wheat (forage,
hay, straw, grain, bran, flour, shorts, germ, and middlings) and
provided the PMV is successful, HED concludes that this method can be
employed as a tolerance-enforcement method for the currently proposed
crops.  

Analytical Enforcement Method - Livestock:  Fat, meat, and meat
byproduct ruminant tolerances are currently established at 0.10 ppm and
a milk tolerance is currently established at 0.02 ppm for the combined
residues of fenamidone and RPA 717879 (D297216, T. Bloem, 25-May-2004). 
The petitioner submitted methods for enforcement of these tolerances and
HED forwarded these methods to ACL for PMV (D306587, T. Bloem,
8-Sep-2004; 46304003.der.wpd; 46304001.der.wpd); these methods were
adequately radiovalidated and validated by an independent laboratory.  A
successful PMV is required prior to these method serving as an
enforcement method.  

Food and Drug Administration (FDA) MRMs:  Fenamidone, RPA 408056, RPA
717879, and RPA 405862 were tested through FDA MRMs.  Residues of
fenamidone and all three metabolites were completely recovered from
fortified lettuce using Protocol D.  Low recoveries of fenamidone were
observed from Protocols E (31%) and F (54%).  Metabolites RPA 408056,
RPA 717879, and RPA 405862 were not recovered using Protocols E and F. 
Protocol B was not tested because fenamidone and its metabolites are not
acids or phenols, and Protocol A was not fully tested because the
compounds were not found to naturally fluoresce.  These data have been
forwarded to the FDA for further evaluation (D284103, T. Bloem,
11-Jul-2002).

Recommendations:  Provided the petitioner submits revised Sections B
and F, the residue chemistry database supports a conditional
registration and establishment of the tolerances listed in Table 1 for
residues of fenamidone (4H-Imidazol-4-one,
3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)) per se. 
An unconditional registration may be appropriate upon submission of the
remaining residue chemistry deficiencies listed below.  A human-health
risk assessment will be prepared as a separate document. 

Table 1:  HED-Recommended Tolerances.

Matrix	Tolerance (ppm)

Carrot	0.15

Sunflower	0.02

Vegetable, Brassica, head and stem, subgroup 5a	5.0

Vegetable, Brassica, leafy greens, subgroup 5b	55

Vegetable, fruiting, group 8 (except nonbell pepper) 1	1.0

Pepper, nonbell	3.5

Vegetable, leafy, except Brassica, group 41	60

Strawberry	0.02

Cotton, gin byproducts	0.02

Cotton, undelinted seed	0.02

1  currently established tomato, head lettuce, and leaf lettuce
tolerances
sh畯摬戠⁥敤敬整൤匍浵慭祲漠⁦敒楳畤⁥桃浥獩牴⁹
敄楦楣湥楣獥ഺ

●Revised Section B.

●Revised Section F.

●PMV for the proposed plant and livestock enforcement methods. 

●HED requests control experiments to determine if the
parent/metabolites identified in the carrot metabolism study degrade to
aniline when exposed to the base hydrolysis procedures used on the
carrot metabolism study.  If these experiments do not demonstrate
degradation, then HED requests that the petitioner submit information
concerning the identify and magnitude of the residues in the alkaline
hydrolysa整漠⁦桴⁥慣牲瑯琠灯⠠牯慧楮⁣湡⁤煡敵畯⁳
桰獡⥥愠摮挠牡潲⁴潲瑯攠瑸慲瑣⁳牦浯琠敨洠瑥扡汯
獩⁭瑳摵⁹䌨敨卭䍁洠湩瑵獥㌠ⴰ慍⵹〲㜰⸩

●Degradation of fenamidone to aniline was demonstrated in the tobacco
pyrolysis study.  HED is concerned that fenamidone may be degrading to
aniline during the processing or cooking of treated crops.  As a result,
HED requests that the petitioner submit a processing study as designated
in Annex 1 of the following European Union document:  (  HYPERLINK
"http://ec.europa.eu/food/plant/protection/resources/app-e.pdf" 
http://ec.europa.eu/food/plant/protection/resources/app-e.pdf ).  The
procedure involves the hydrolysis of radiolabeled fenamidone at various
pHs and temperatures and identification of the resulting transformation
products, if any (N-phenyl radiolabeled fenamidone should be employed). 
Depending on the results from this study, additional data may be
requested (ChemSAC minutes 30-May-2007).  

●Storage stability data validating the confined rotational crop study
(D281887, T. Bloem, 18-Jul-2002).

Background Information

Fenamidone is a chiral compound with the technical product consisting of
98.5% S-fenamidone. Fenamidone is a broad-spectrum foliar fungicide
belonging to the imidazolinone class of chemicals called quinone outside
inhibitors (QOIs).  These compounds inhibit the quinone outside site
within the electron transport system in susceptible fungi species. 
Table 2 is a summary of the test compound nomenclature and Table 3 is a
summary of the physiochemical properties.  

Common name	fenamidone

Company experimental name	RPA 407213

IUPAC name	(S)-1-anilino-4-methyl-2-methylthio-4-phenylimidazolin-5-one

CAS name
(5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imi
dazol-4-one

CAS registry number	161326-34-7

End-use product (EP)	Reason® 500 SC (44.4% S-fenamidone; 4.13 lb
ai/gal; EPA Reg. No. 264-695)

Table 3:  Physicochemical Properties of Technical Grade Fenamidone. 

Parameter	Value	Reference

Melting point/range	Pure:  137 °C, Technical:  135.5 °C	MRID 45385708

pH	5.7	MRID 45385714

Density	Pure:  1.290 g/mL	MRID 45385708

Water solubility 	0.0078 g/L at 20 °C	MRID 45385712

Solvent solubility (under ambient conditions)	330 g/L in methylene
chloride

250 g/L in acetone

106 g/L in ethyl acetate

86 g/L in acetonitrile

43 g/L in methanol

40 g/L in toluene

0.3 g/L in heptane	MRID 45385712

Vapor pressure	2.60 x 10-9 mm Hg at 20 °C	MRID 45385711

Dissociation constant, pKa	Does not dissociate in the pH range of 1-13
MRID 45385714

Octanol/water partition coefficient, Log(KOW)	631 (2.8)	MRID 45385713

UV/visible absorption spectrum	Primary absorbance:  203 nm

Secondary absorbance:  230 nm	MRID 45385709

Detailed Considerations

860.1200  Directions for Use

Bayer CropScience is proposing the application of Reason® 500 SC (EPA
Reg. No. 264-695; 4.13 lb ai/gallon; suspension concentrate) to tobacco
and cotton (seed treatment and at planting application) and IR-4 is
proposing the application of Reason® 500 SC to Brassica leafy
vegetables, leafy vegetables (except Brassica), fruiting vegetables,
sunflowers (seed treatment), and carrot.  HED has previously approved
the application of fenamidone (Reason® 500 SC) to tomato and lettuce at
single application rates, RTIs, and PHIs identical to that proposed for
fruiting vegetable and leafy vegetables (except Brassica) crop groups
and seasonal application rates greater than that proposed as part of the
current petition (1.06 lb ai/acre; 0.80 lb ai/acre currently proposed). 

Table 4 is a summary of the proposed application scenarios.  Application
via ground (minimum of 15 GPA), aerial (minimum of 5 GPA), and
chemigation equipment are permitted.  The label recommends the addition
of a spreader/sticker to the spray solution.  As a resistance management
strategy, the proposed label states that no more than one application
should be made before alternating with a fungicide with a different mode
of action.  The proposed label indicates that a treated field may be
rotated to a labeled crop immediately following the last application, to
wheat and strawberries 30 days after the last application, and all other
crops one year after the last application.  The sunflower seed treatment
instructions indicate that all treated seed must be dyed with an EPA
approved dye/colorant.  HED requests that the petitioner submit a
revised Section B with the following changes:

●Treated cottonseed must be dyed with an EPA approved dye/colorant.

●The tomato and carrot field trials did not include an adjuvant in the
spray solution (all other field trials included an adjuvant); therefore,
the label should indicate that the addition of an adjuvant to the spray
solution is appropriate for all relevant crops excluding tomato and
carrot.

●Restriction prohibiting the application to crops grown in
greenhouses.

Table 4:  Summary of Directions for Use of Fenamidone on Crops.

App. Method	Formulation	App. Rate

(lb ai/acre)	Max. No. App. per Season	Max. Seasonal App. Rate (lb
ai/acre)	PHI (days)	Use Directions and Limitations

Leafy Vegetables (except Brassica); amaranth (leafy amaranth, Chinese
spinach, tampala), cardoon, celery, Chinese celery, celtuce, chervil,
chrysanthemum (edible-leaved), chrysanthemum (garland), corn salad,
cress (garden) cress (upland), dandelion, deck (sorrel), endive
(escarole), fennel Florence (finochio), lettuce (head and leaf), orach,
parsley, purslane (garden) purslane (winter), radicchio (red chicory),
rhubarb, spinach, spinach New Zeeland, spinach vine (Malabar spinach,
Indian spinach) Swiss Chard

Foliar, Broadcast 	4.13 lb ai/gal SC	0.18-0.27	not specified	0.80	2	5-
to 10-day RTI

Brassica (cole) Leafy Vegetables; broccoli, broccoli (Chinese, gai lon),
broccoli raab (rapini) Brussels sprouts, cabbage, cabbage Chinese (bok
choy), cabbage Chinese (napa), Cabbage Chinese mustard (gai choy),
cauliflower, cavalo broccolo, collards, kale, kohlrabi, mizuna, mustard
greens, mustard spinach, rape greens

Foliar, Broadcast 	4.13 lb ai/gal SC	0.18-0.27	not specified	0.80	2	5-
to 10-day RTI

Tomatoes, Peppers, and Other Fruiting Vegetables (except Cucurbits);
eggplant, groundcherry, pepino, pepper (bell, chili, cooking, pimento,
sweet), tomatillo, tomato

Foliar, Broadcast	4.13 lb ai/gal SC	0.18-0.27	not specified	0.80	14	5-
to 10-day RTI

cotton

Applied to the open furrow during seeding	4.13 lb ai/gal SC	0.27	1	0.27
--	3-5 GPA

Seed Treatment	4.13 lb ai/gal SC	0.05 lb ai/100

lb seed	--	--	--	treated seed may also receive the open furrow during
seeding application

sunflower

Seed Treatment	4.13 lb ai/gal SC	0.19 lb ai/100

lb seed	--	--	--	slurry or mist-type seed treatment equipment

carrot

Foliar, Broadcast	4.13 lb ai/gal SC	0.27	not specified	0.80	14	14- to
21-day RTI

tobacco

Pre-plant Incorporated and Foliar, Broadcast	4.13 lb ai/gal SC	0.18-0.27
not specified	0.80	3	5- to 10-day RTI; do not apply to tobacco in
greenhouses

860.1300 Nature of the Residue - Plants/Livestock

Plants:  The MARC reviewed metabolism studies conducted with potato
(C-phenyl and N-phenyl labeled studies), tomato (C-phenyl and N-phenyl
labeled studies), lettuce (C-phenyl and N-phenyl labeled studies), and
grape (C-phenyl labeled study).  The major residues identified in these
studies were fenamidone, RPA 408056, RPA 405862, and RPA 717879.  The
identification of RPA 408056, and RPA 717879 indicates that the C-phenyl
and N-phenyl rings may be separated during metabolism.  Based on the
structure of these compounds, separation of the rings may result in the
formation of aniline(s).  The N-phenyl metabolism studies did not
include standards containing only the N-phenyl ring.  Therefore, the
metabolic fate of the N-phenyl ring was not determined.  The petitioner
subsequently analyzed aniline, nitroanilines (2- and 4-nitroaniline),
and aminophenols (2-, 3-, and 4-aminophenol) using the same instrumental
systems used in the plant metabolism studies.  These data indicate that
non-conjugated aniline(s) residues in plant extracts are low ((0.006
ppm; these data exclude the wrapper leaves sample).  However, as the
petitioner indicated for potato, aniline(s) may react with plant
constituents to form conjugated residues.  HED notes that the
identification/characterization procedures performed in the N-phenyl
tomato and lettuce metabolism studies resulted in identification of 76%
and 88% of the TRR, respectively.  However, since only 6% of the TRR was
identified in the N-phenyl potato study and based on the toxicological
effects of aniline (probable human carcinogen; US EPA IRIS -
http://www.epa.gov/iris/subst/0350.htm), the MARC requested that the
petitioner hydrolyze the extractable and nonextractable residues from
the N-phenyl studies to determine if conjugated aniline(s) are present
and concluded that pending the submission of these data, the nature of
the residue in plants is not understood (TXR 0052287, T. Bloem et al.,
25-May-2004).  

≤7% TRR.  Total identified residues in carrot root and top were 96%
TRR and 65% TRR, respectively.  Aniline, aminophenol, and/or
nitroaniline were not present in the unhydrolyzed carrot top (99% TRR)
and root (81% TRR) extracts; to determine if conjugates of aniline(s)
were present, the carrot top and root extracts were hydrolyzed with 1M
HCl (1 hour; 100(C) and 1M NaOH (1 hour; 100(C).  Aniline, aminophenol,
and/or nitroaniline were not identified in the carrot-top acid
hydrolysate or the carrot-root acid and base hydrolysates.  However,
aniline and nitroaniline may be present in the carrot-top base
hydrolysate.  The petitioner indicated that the formation of aniline(s)
was as a result of cleavage of the N-phenyl ring from intact
parent/metabolites during the base hydrolysis procedure.  The study did
not include a control experiment demonstrating this hypothesis.  In
addition, alkaline hydrolysis of the carrot root extract did not result
in the formation of aniline and nitroaniline despite the presence of
many of the same metabolites in the root extract as were present in the
carrot top extract.  

HED requests that the petitioner perform control experiments to
determine if the parent/metabolites identified in the carrot metabolism
study degrade to aniline when exposed to the base hydrolysis procedures
used on the carrot metabolism study.  If these experiments do not
demonstrate degradation, then HED requests that the petitioner submit
information concerning the identify and magnitude of the residues in the
alkaline hydrolysate of the carrot top (organic and aqueous phase) and
carrot root extracts (ChemSAC minutes 30-May-2007).  Pending the
submission of the these data and based on a conservative dietary risk
analysis to potential aniline exposure from fenamidone which resulted in
exposure estimates that are not of concern to HED (see HED Risk
Assessment; D314116, T. Bloem et al., in draft), HED concludes the
residues of concern in the proposed/registered crops are as defined in
Table 5.

Livestock:  The MARC reviewed goat and hen metabolism studies conducted
with fenamidone labeled in the C-phenyl and N-phenyl rings.  The major
residues identified in the goat and hen studies were fenamidone, RPA
717879, and RPA 408056.  The identification of RPA 717879, RPA 408056,
and RPA 408056-OH in the livestock metabolism studies indicates that the
C-phenyl and N-phenyl rings are separated during metabolism.  Based on
the structure of these compounds, the separation of the rings may result
in the formation of aniline(s).  Since only (12% of the TRR was
identified in samples collected from the N-phenyl studies and since the
petitioner did not include standards containing only the N-phenyl ring,
HED concludes that the nature of the residue in livestock has not been
adequately delineated (MARC memo; T. Bloem et al., 25-May-2004). 

HED performed a conservative dietary risk analysis to potential exposure
to anilines with the resulting exposure estimates at levels which are
not of concern to HED (see HED Risk Assessment; D314116, T. Bloem et
al., in draft).  Therefore, for the currently proposed crops, HED
concludes that new N-phenyl livestock metabolism studies are unnecessary
and the residues of concern in livestock for purpose of tolerance
enforcement are fenamidone and RPA 717879 and the residues of concern
for purpose of risk assessment are fenamidone, RPA 717879, and RPA
408056.  These conclusions will be reevaluated if additional crops are
requested.  

Table 5:  Residues of Concern in Proposed Crops, Livestock, Rotational
Crops, and Water.

Matrix	Tolerance Expression	Residues for Risk Assessment

registered/proposed crops excluding carrot1	fenamidone	fenamidone, RPA
408056, RPA 717879, RPA 405862

carrot1	fenamidone	fenamidone, RPA 413255

livestock2	fenamidone, RPA 717879	fenamidone, RPA 717879, RPA 408056

rotational Crops3	fenamidone, RPA 717879	fenamidone, RPA 717879, and RPA
408056 (free and conjugated)

1  These decisions should not be translated to other crops.

2  The residues of concern in livestock are based on the
currently-registered/proposed crops; if additional crops are requested
these decisions will be reevaluated.

3  Storage stability data validating the confined rotational crop study
storage intervals and conditions are necessary.

860.1340 Residue Analytical Methods - Plants

46440803.der.doc

Data Gathering Method:  The field trial samples were analyzed for
residues of fenamidone, RPA 717879, RPA 408056, and RPA 405862 using a
LC/MS/MS method.    SEQ CHAPTER \h \r 1 Briefly, the ground samples were
mixed with hydromatrix and packed into stainless steel
accelerated-solvent extraction (ASE) cells.  The samples were extracted
with acetone:water (7:3, v:v) using ASE at 50 ºC for three, 5 minute
cycles (1500 psi).  The cottonseed, cotton gin byproducts, and tobacco
extracts were purified through a silica, carbon, alumina, and sodium
sulfate solid phase extraction (SPE) column while the carrot and
sunflower extracts were purified through a alumina A SPE column
(remaining samples did not require an SPE column clean-up).  The
extracts were diluted with water and analyzed by LC/MS/MS.  Residues
were reported in fenamidone equivalents.  The validated LOQ for all
analyte/matrices was 0.02 ppm.  Since the method is similar to a
previously radiovalidated method (45385915.der.wpd) and since adequate
method validation and/or concurrent validation for all analyte/matrices
were received, HED concludes that the analytical method is acceptable
for data gathering purposes.  Based on the recoveries of RPA 408056 and
RPA 405862 residues in cured tobacco, HED concluded that these residues
should be corrected for the combined average recovery at 0.02 ppm and
0.20 ppm of 67% and 73%, respectfully.  

Tolerance Enforcement:  As part of a previous registration, the
petitioner proposed a LC/MS/MS plant enforcement method.  Briefly, plant
matrix samples are extracted with acetonitrile (ACN):water (80:20, v:v),
cleaned up on an HR-P polystyrene divinylbenzene cartridge and by amino
SPE.  and analyzed by LC/MS/MS.  Adequate method validation and ILV data
have been submitted for several commodities (45385915.der.wpd; potato,
cucumber, cantaloupe, lettuce, onion, tomato (fruit, paste, and puree),
spinach, and wheat (forage, hay, straw, grain, bran, flour, shorts,
germ, and middlings).  Adequate radiovalidation has also been submitted.
 HED also notes that the MRMs may serve as a confirmatory method (see
below).  The proposed enforcement method has been forwarded to the ACB
for PMV (D278954, T. Bloem, 15-Nov-2001).  As this method has been
validated in/on a number of commodities (potato, cucumber, cantaloupe,
lettuce, onion, tomato (fruit, paste, and puree), spinach, and wheat
(forage, hay, straw, grain, bran, flour, shorts, germ, and middlings)
and provided the PMV is successful, HED concludes that this method can
be employed as a tolerance-enforcement method for the currently proposed
crops.  

860.1340 Residue Analytical Methods - Livestock

Fat, meat, and meat byproduct ruminant tolerances are currently
established at 0.10 ppm and a milk tolerance is currently established at
0.02 ppm for the combined residues of fenamidone and RPA 717879
(D297216, T. Bloem, 25-May-2004).  The petitioner submitted methods for
enforcement of these tolerances and HED forwarded these methods to ACL
for PMV (D306587, T. Bloem, 8-Sep-2004; 46304003.der.wpd;
46304001.der.wpd); these methods were adequately radiovalidated and
validated by an independent laboratory.  A successful PMV is required
prior to this method serving as an enforcement method.  

860.1360 FDA MRMs

Fenamidone, RPA 408056, RPA 717879, and RPA 405862 were tested through
FDA MRMs.  Residues of fenamidone and all three metabolites were
completely recovered from fortified lettuce using Protocol D.  Low
recoveries of fenamidone were observed from Protocols E (31%) and F
(54%).  Metabolites RPA 408056, RPA 717879, and RPA 405862 were not
recovered using Protocols E and F.  Protocol B was not tested because
fenamidone and its metabolites are not acids or phenols, and Protocol A
was not fully tested because the compounds were not found to naturally
fluoresce.  These data have been forwarded to the FDA for further
evaluation (D284103, T. Bloem, 11-Jul-2002).

860.1380 Storage Stability

46518301.der.doc (sunflower), 46927101.der.doc (carrot)

 (≤330 days), celery (≤313 days), spinach (≤213 days), cottonseed
(≤279 days), cotton gin byproducts (≤268 days), pepper (≤313
days), mustard green (≤285 days), broccoli (≤343 days), cabbage
(≤381 days), sunflower (≤438 days), carrot (≤155 days), and
tobacco (≤342 days) samples were analyzed for residues of fenamidone,
RPA 408056, RPA 405862, and RPA 717879 within the indicated intervals.
The petitioner has submitted the following fenamidone, RPA 408056, RPA
405862, and RPA 717879 storage stability data validating these
matrices/intervals (indicated interval is the longest interval tested): 
(1) ~7 months in/on cottonseed and cotton gin byproducts, ~6 months in
cottonseed hulls and meal, ~1 month in cottonseed oil, ~14 months in/on
cucumber, ~13 months in/on leaf lettuce, ~12 months in/on bulb onions,
~13 months in/on potato tubers and in potato chips, ~12 months in potato
flakes and potato wet peel, ~12 months in/on tomatoes, ~13 months in
tomato paste and tomato puree, and ~13 months in/on wheat forage, grain,
hay, and straw (45385914.der.wpd); (2) 438 days in/on sunflower seed
(46518301.der.doc); and (3) 224 days in/on carrot root
(46927101.der.doc).  

860.1480 Meat/Milk/Poultry/Eggs

Based on the currently registered/proposed crops, the residues of
concern in livestock for purpose of tolerance enforcement are fenamidone
and RPA 717879 (see “Nature of the Residue - Livestock” section). 
The following tolerances for residues of fenamidone and RPA 717879 are
currently established (D297216, T. Bloem, 25-May-2004):  fat (beef,
goat, and sheep) - 0.10 ppm, meat (beef, goat, and sheep) - 0.10 ppm,
meat byproducts  (beef, goat, and sheep) - 0.10 ppm, milk - 0.02 ppm. 
The feed commodities associated with the currently-requested crops are
carrot (beef/dairy cattle), cotton (beef/dairy cattle, hog, and
poultry), and sunflower (beef/dairy cattle, hog, and poultry).  MRDB
calculations are presented in Table 6.  

Table 6:  MRDB Calculations.

crop1	residue (ppm)2	%dry matter2	% diet	residue in diet

	dairy	beef	poultry	hog	dairy	beef	poultry	hog

wheat grain (CC)	0.62	89	--	--	70	--	--	--	0.43	--

wheat forage (R)	1.08	25	25	40	--	--	1.08	1.73	--	--

wheat hay (R)	3.16	88	25	--	--	--	0.90	--	--	--

wheat milled byproducts (CC)	0.62	88	30	30	10	50	0.21	0.21	0.06	0.31

carrot (CC)	0.17	12	10	10	--	--	0.14	0.14	--	--

sunflower meal (PC)	0.08	92	--	--	--	20	--	--	--	0.02

cottonseed (PC)	0.08	88	--	20	--	--	--	0.02	--	--

cottonseed meal (PC)	0.08	89	10	--	20	--	0.01	--	0.02	--

Total	2.34	2.10	0.51	0.33

1  R= roughage; PC = protein concentrate; CC = carbohydrate concentrate.

2  Fr wheat, combined fenamidone, RPA 717879, and RPA 408056 (free and
conjugated; inadvertent residues in wheat as a result of crop rotation;
for calculation see D297216, T. Bloem, 25-May-2004); for the other
crops, combined fenamidone, RPA 717879, RPA 408056, and RPA 405862.

3  % dry matter not used in diet burden calculations for poultry and
hog.

Ruminants:  A lactating dairy cattle feeding study was previously
submitted and reviewed by HED (45386004.der.wpd; D297216, T. Bloem,
25-May-2004).  The cattle were dosed with fenamidone for 35 days at
dietary feeding levels of 0.8 ppm (0.3x/0.4x/2.4x dairy/beef/hog MRDBs),
2.3 ppm (1.0x/1.1x/7.0x dairy/beef/hog MRDBs), and 7.9 ppm
(3.4x/3.8x/24x dairy/beef/hog MRDBs).  Milk was collected throughout the
study and muscle, fat, liver, and kidney were collected at sacrifice. 
Because of low residue levels, only samples from the 7.9 ppm dosing
group were analyzed.  

Following dosing of cattle with fenamidone for 35 days at 7.9 ppm,
residues of fenamidone and its metabolites RPA 717879 and RPA 408056
were <LOD (LOD = <0.0033 ppm each) in milk samples collected over the
course of the dosing period and were <LOD (<0.017 ppm each) in samples
of muscle, fat, liver, and kidney collected at sacrifice.  Quantifiable
residues of fenamidone were observed in one sample of milk fat at 0.011
ppm; the other two samples bore detectable residues of fenamidone at
levels below the LOQ (<0.01 ppm).  Residues of RPA 717879 and RPA 408056
were <LOD (<0.0033 ppm each) in the milk fat samples.  Therefore, the
petitioner has demonstrated that hog tolerances are unnecessary as
residues were <LOQ following dosing at 24x the hog MRDB.  Based on the
current dairy/beef cattle MRDB and since the petitioner has not
demonstrated that residues are <LOQ in cattle tissue and milk
commodities following dosing at 10x the MRDB, HED concludes that the
currently-established ruminant LOQ tolerances are appropriate.  

Poultry - A poultry feeding study has not been submitted.  Based on the
TRRs (C-phenyl - (0.216 ppm; N-phenyl - (0.111 ppm) in the poultry
metabolism study (conducted at 27x (C-phenyl) and 19x (N-phenyl) the
poultry dietary burden), HED concludes that there is no reasonable
expectation of finite residues in poultry commodities (40 CFR
180.6(a)(3)).  A poultry feeding study and poultry tolerances are not
required.

860.1500 Crop Field Trials

46518401.de1.doc (broccoli and cabbage), 46518401.de2.doc (broccoli and
cabbage), 46518402.de1.doc (mustard green), 46518402.de2.doc (mustard
green), 46518403.de1.doc (pepper), 46518403.de2.doc (pepper),
46440804.de1.doc (celery and spinach), 46440804.de2.doc (celery and
spinach), 46518301.der.doc (sunflower), 46440801.der.doc (cotton),
46440805.der.doc (strawberry), 46972101.der.doc (carrot),
46970402.der.doc (tobacco pyrolysis), 46970401.der.doc (tobacco)

The petitioner is requesting registration for application of fenamidone
to leafy vegetables (except Brassica) crop group 4, Brassica (cole)
leafy vegetables crop group 5, fruiting vegetables crop group 8, cotton
(seed treatment and at planting application), sunflower (see treatment),
carrot, and tobacco.  HED notes that fenamidone is currently registered
for application to tomato (fruiting vegetable) and lettuce (leafy,
except Brassica vegetable).  The following paragraphs are summaries of
the field trial data submitted in support of this request.  Since none
of the field trials were conducted in a greenhouse, HED request a
revised Section B prohibiting the application to greenhouse grown crops.
 

Leafy Vegetables (except Brassica) Crop Group 4:  Fenamidone is
currently registered for foliar application to lettuce (head and leaf;
D281887, T. Bloem, 18-Jul-2002).  In support of this registration, head
lettuce and leaf lettuce field trial were submitted which resulted in
combined residues of fenamidone, RPA 717879, RPA 408056, and RPA 405862
of <0.756-11.8 ppm and <0.08-<17.6 ppm in/on field-grown head lettuce
and leaf lettuce, respectively, harvested 2 days following four foliar
applications of the 4.17 lb ai/gal SC formulation at 0.26-0.31 lb
ai/acre (1.0-1.1x/1.3-1.4x the currently proposed single/seasonal rate;
6-8-day RTI; an adjuvant was added to the spray solution).  Tables 7
(fenamidone per se) and 8 (combined fenamidone, RPA 717879, RPA 408056,
and RPA 405862) are summaries of the lettuce (head and leaf) field trial
data.  Based on these data, HED recommended for the head lettuce and
leaf lettuce tolerances for residues of fenamidone per se, of 15 ppm and
20 ppm, respectively (no additional lettuce (head and leaf) field trial
data were requested). 

The petitioner is currently requesting registration for foliar
application of fenamidone to leafy vegetables (except Brassica) crop
group and submitted celery and spinach residue data as part of this
request (46440804.de1.doc).  Celery and spinach were harvested 2 days
following four foliar applications of the 4.13 lb ai/gal SC formulation
of fenamidone at ~0.267 lb ai/acre (1.0x/1.4x the proposed
single/seasonal rate; 3-6-day RTI; an adjuvant was added to the spray
solution).  Combined residues of fenamidone, RPA 717879, RPA 408056, and
RPA 405862 in/on celery and spinach were ≤20.2 ppm and ≤32.6 ppm,
respectively (method and storage interval were adequately validated). 
Tables 7 (fenamidone per se) and 8 (combined fenamidone, RPA 717879, RPA
408056, and RPA 405862) are summaries of the celery and spinach field
trial data.  The petitioner also submitted data which indicated that
combined residues of fenamidone, RPA 717879, RPA 408056, and RPA 405862
declined <0.1x-0.2x in trimmed celery stalks, <0.1x in trimmed and
washed celery stalks, 0.8x in washed spinach leaves, and 0.6x in washed
and cooked spinach (46440804.de2.doc).  HED notes that cooking may
result in the degradation of fenamidone, RPA 717879, RPA 408056, and/or
RPA 405862 to an unquantified compound(s) which has equal/greater
toxicity to fenamidone.

Conclusions:  The geographical representation of the lettuce (head and
leaf), celery, and spinach field trial data fulfill the data
requirements suggested in OPPTS 860.1500 for a leafy vegetables (except
Brassica) crop group registration.  HED notes that these field trials
employed 1.0x the proposed single application rate but 1.3-1.4x the
proposed seasonal rate.  Based on the residue decline data which
indicated that combined residues of fenamidone, RPA 717879, RPA 408056,
and RPA 405862 reduced 36% (celery), 70% (spinach), and 99% (leaf
lettuce) as the PHI increased from 0 to 7 days, HED concludes that the
final application, which was conducted at 1x the proposed rate, will
drive the magnitude of the residue in/on leafy vegetables (except
Brassica).  Based on the head lettuce, leaf lettuce, celery, and spinach
field trial data and the tolerance spreadsheet calculator, tolerances
for the combined residues of fenamidone per se of 18 ppm, 45 ppm, 45
ppm, and 60 ppm were recommended (see attachment 2).  Provided the
petitioner submits a revised Section B and since the maximum residues
and recommended tolerances are within 5x, HED concludes that a leafy
vegetables (except Brassica) crop group tolerance of 60 ppm for residues
of fenamidone per se is appropriate (the currently established leaf
lettuce and head lettuce tolerances should be deleted).  

Brassica (cole) Leafy Vegetable Crop Group 5:  The petitioner is
requesting registration for foliar application of fenamidone to Brassica
(cole) leafy vegetable crop group and submitted broccoli, cabbage, and
mustard green residue data as part of this request (46518401.de1.doc and
46518402.de1.wpd).  Broccoli, cabbage, and mustard green were harvested
2 days following four foliar applications of the 4.13 lb ai/gal SC
formulation of fenamidone at ~0.267 lb ai/acre (1.0x/1.4x the proposed
single/seasonal rate; 4-6-day RTI; an adjuvant was added to the spray
solution).  Combined residues of fenamidone, RPA 717879, RPA 408056, and
RPA 405862 in/on broccoli, cabbage, and mustard green were ≤3.723 ppm,
0.745 ppm, and ≤32.986 ppm, respectively (method and storage interval
were adequately validated).  Tables 7 (fenamidone per se) and 8
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862) are
summaries of the broccoli, cabbage, and mustard green field trial data. 
The petitioner also submitted data which indicated that combined
residues of fenamidone, RPA 717879, RPA 408056, and RPA 405862 declined
0.7x in washed broccoli, concentrated 1.3x in washed/cooked broccoli,
declined <0.1x in trimmed/washed/cooked cabbage, declined 0.8x in washed
mustard greens, and declined 0.4x in washed/cooked mustard greens
(46518401.de2.doc and 46518402.de2.wpd).  HED notes that cooking may
result in the degradation of fenamidone, RPA 717879, RPA 408056, and/or
RPA 405862 to an unquantified compound(s) which has equal/greater
toxicity to fenamidone.

Conclusions:  The geographical representation of the broccoli, cabbage,
and mustard green field trial data fulfill the data requirements
suggested in OPPTS 860.1500 for a Brassica (cole) leafy vegetables crop
group registration or crop subgroup 5a and 5b tolerances.  HED notes
that these field trials employed 1.0x the proposed single application
rate but 1.4x the proposed seasonal rate.  Based on the residue decline
data which indicated that combined residues of fenamidone, RPA 717879,
RPA 408056, and RPA 405862 reduced 52% (broccoli), 43% (cabbage), and
87% (mustard green) as the PHI increased from 0 to 7 days, HED concludes
that the final application, which was conducted at 1x the proposed rate,
will drive the magnitude of the residue in/on the Brassica (cole) leafy
vegetables.  Based on the broccoli, cabbage, and mustard green field
trial data and the tolerance spreadsheet calculator, tolerances for
residues of fenamidone per se of 5.0 ppm, 1.3 ppm, and 55 ppm were
recommended (see attachment 2).  Since the maximum residues and
recommended tolerances are not within 5x, HED concludes that a crop
group tolerance is not appropriate but that crop subgroup tolerances are
appropriate.  Provided the petitioner submits a revised Section B and
based on the submitted residue data, HED concludes that a head and stem
Brassica crop subgroup 5a tolerance of 5.0 ppm and a leafy Brassica
greens crop subgroup 5b tolerance of 55 ppm for residues of fenamidone
per se are appropriate. 

Fruiting Vegetables Crop Group 8:  Fenamidone is currently registered
for foliar application to tomato (D281887, T. Bloem, 18-Jul-2002).  In
support of this registration, tomato field trial data were submitted
which resulted in combined residues of fenamidone, RPA 717879, RPA
408056, and RPA 405862 of <0.08-<0.860 ppm in/on tomatoes (including
small varieties) harvested 14 days following four or six foliar
applications of the 4.17 lb ai/gal SC formulation at ~0.27 lb ai/acre
(1.0x/1.4x the currently proposed single/seasonal rate; 6-8-day RTI) or
0.18 lb ai/acre (0.7x/1.4x the currently proposed single/seasonal rate;
6-8-day RTI), respectively.  The study did not specify if an adjuvant
was added to the spray solution.  Tables 7 (fenamidone per se) and 8
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862) are
summaries of the tomato field trial data.  Based on these data, HED
recommended for a tomato tolerance for the combined residues of
fenamidone, RPA 717879, RPA 408056, and RPA 405862 of 1.0 ppm (no
additional tomato field trial data were requested). 

were ≤0.264 ppm and ≤1.775 ppm, respectively (method and storage
interval were adequately validated).  Tables 7 (fenamidone per se) and 8
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862) are
summaries of the pepper field trial data.  The petitioner also submitted
data which indicated that combined residues of fenamidone, RPA 717879,
RPA 408056, and RPA 405862 declined 0.5x for washed peppers and 0.2x for
washed/cooked peppers (46518403.de2.doc).  HED notes that cooking may
result in the degradation of fenamidone, RPA 717879, RPA 408056, and/or
RPA 405862 to an unquantified compound(s) which has equal/greater
toxicity to fenamidone.

Conclusions:  The geographical representation of the tomato and pepper
field trial data fulfill the data requirements suggested in OPPTS
860.1500 for a fruiting vegetable crop group registration.  HED notes
that these field trials employed 1.0x the proposed single application
rate but 1.4x the proposed seasonal rate.  Based on the residue decline
data which indicated that combined residues of fenamidone, RPA 717879,
RPA 408056, and RPA 405862 reduced 65% (bell pepper) and 34-73% (tomato)
as the PHI increased from 0 to 21 (bell pepper) and 7 to 35 days
(tomato; nonbell pepper decline data were not submitted), HED concludes
that the final application, which were conducted at 0.7-1.0x the
proposed rate, will drive the magnitude of the residue in/on fruiting
vegetables.  

Since information concerning the addition of an adjuvant to the tomato
spray solution was not provided as part of the tomato field trial
studies, HED requests that a revised Section B be submitted indicating
that an adjuvant may be added to the spray solution for all fruiting
vegetables except tomato.  Based on the tomato, bell pepper, and nonbell
pepper field trial data and the tolerance spreadsheet calculator,
tolerances for the residues of fenamidone per se of 1.0 ppm, 0.40 ppm,
and 3.5 ppm were recommended (see attachment 2).  Since the pepper and
nonbell pepper maximum residues and recommended tolerances are not
within 5x, HED concludes that a fruiting vegetable crop group tolerance
is not appropriate.  Based on the residue data and since tomato is the
major food commodity in the fruiting vegetable crop group, HED concludes
that it is appropriate to set nonbell pepper and fruiting vegetable
(except nonbell pepper) tolerances.  Therefore, provided the petitioner
submits a revised Section B, HED concludes that the following tolerance
for residues of fenamidone per se are appropriate:  fruiting vegetable
(except nonbell pepper) - 1.0 ppm and nonbell peppers - 3.5 ppm (the
currently established tomato tolerance should be deleted).  

0.267 lb ai/acre (1.0x the proposed in-furrow at planting application
rate; the planted seed did not receive the seed treatment application). 
Cottonseed samples were collected at all of the field trials and cotton
gin byproduct samples were harvested at 7 of the field trials using
picker (n=3) or stripper (n=4) equipment.  Combined residues of
fenamidone, RPA 717879, RPA 408056, and RPA 405862 in/on cottonseed and
cotton gin byproducts were both <0.08 ppm (method and storage interval
were adequately validated).  Residues were also nonquantifiable (<0.08
ppm) in/on cottonseed harvested from a plot which received an
exaggerated in-furrow at planting application of 1.335 lb ai/acre (4.9x
the proposed rate).  Tables 7 (fenamidone per se) and 8 (combined
fenamidone, RPA 717879, RPA 408056, and RPA 405862) are summaries of the
cotton field trial data.  

Conclusions:  The geographical representation of the cotton field trial
data fulfill the data requirements suggested in OPPTS 860.1500 for
cotton.  HED notes that the proposed label specifies a seed treatment
application at 0.19 lb ai/100 pounds seed and indicates that treated
seed may also receive the in-furrow application at planting.  The
seeding rate for cotton is 10 lbs seed per acre (  HYPERLINK
"http://deltafarmpress.com/mag/farming_adjusting_price_cotton/" 
http://deltafarmpress.com/mag/farming_adjusting_price_cotton/ ) which
translates to a fenamidone application rate of 0.019 lb ai/acre for the
seed treatment application.  Since this rate is 7% of the in-furrow
application and since residues were <LOQ in/on cottonseed and cotton gin
byproducts following application at the proposed in-furrow rate and <LOQ
in/on cottonseed following application at 4.9x the proposed in-furrow
rate, HED concludes that additional cotton residue data are unnecessary.
 Therefore, HED concludes that cottonseed and cotton gin byproduct
tolerances for residues of fenamidone per se of 0.02 ppm and 0.02 ppm,
respectively, are appropriate.  

Sunflower:  The petitioner is requesting registration for application of
fenamidone to sunflower for seed treatment purposes and submitted
sunflower residue data in support of this request (46518301.der.doc).
Sunflower seeds were harvested 104-146 days after planting of seed
treated with a 4.13 lb ai/gal SC formulation at 0.19 lb ai/100 lb of
seed (1x the proposed rate).  Combined residues of fenamidone, RPA
717879, RPA 408056, and RPA 405862 in/on the harvested sunflower seeds
were <0.08 ppm (method and storage interval were adequately validated). 
Residues were also nonquantifiable (<0.08 ppm) in/on sunflower seed
grown from seed treated at an exaggerated rate of 0.95 lb ai/100 lb of
seed (5x the proposed rate).  Tables 7 (fenamidone per se) and 8
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862) are
summaries of the sunflower field trial data.  

Conclusions:  The geographical representation of the sunflower field
trial data fulfill the data requirements suggested in OPPTS 860.1500 for
sunflower.  Based on the sunflower seed field trial data, HED concludes
that a sunflower seed tolerance for residues of fenamidone per se of
0.02 ppm is appropriate.  

Carrot:  The petitioner is requesting registration for foliar
application of fenamidone to carrot and submitted carrot residue data in
support of this request (46927101.der.doc).  Carrot root samples were
harvested 13-16 days after four foliar applications of the 4.13 lb
ai/gal SC formulation of fenamidone at ~0.267 lb ai/acre (1.0x/1.4x the
proposed single/seasonal rate; an adjuvant was not added to the spray
solution).  The first application was made prior to or just after crop
emergence with the second application made 6-8 days later.  The third
application was made during root development, 28-104 days after the
second application with the fourth application made 6-8 days later. 
Combined residues of fenamidone, RPA 717879, RPA 408056, and RPA 405862
in/on the harvested carrot root were ≤0.125 ppm (method and storage
interval were adequately validated).  Tables 7 (fenamidone per se) and 8
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862) are
summaries of the carrot field trial data.  

Conclusions:  The geographical representation of the carrot field trial
data fulfill the data requirements suggested in OPPTS 860.1500 for
carrot.  HED notes that these field trials employed 1.0x the proposed
single application rate but 1.4x the proposed seasonal rate.  The
residue decline data indicated that residues of fenamidone increased as
the PHI increased from 3 to 15 days and then dropped slightly as the PHI
increased to 29 days.  Since the proposed PHI is 14 days, HED concludes
that the final application, which was conducted at 1.0x the proposed
rate, will drive the magnitude of the residue in/on carrot.  

The carrot field trials did not included in adjuvant in the spray
solution; therefore, a revised Section B is requested which indicates
that the addition of an adjuvant to the carrot spray solution is not
appropriate.  Provided the petitioner submits a revised Section B and
based on the carrot field trial data and the tolerance calculator, HED
concludes that a carrot tolerance for residues of fenamidone per se of
0.15 ppm is appropriate.  

Tobacco:  The petitioner is requesting registration for foliar
application of fenamidone to tobacco and submitted a tobacco pyrolysis
study (46970402.der.doc) and a tobacco field trial study
(46970401.der.doc).  In the pyrolysis study, unfiltered cigarettes were
fortified with 14C-N-phenyl-fenamidone or 14C-C-phenyl-fenamidone to a
concentration of 10.9-12.6 ppm (n=5 for each label; see attachment 1 for
radiolabel position).  The cigarettes were placed in a smoking apparatus
and the resulting side stream smoke and main stream smoke were
separately filtered and passed through several traps.  The major residue
identified in the smoke (main (smoker) and side stream (second hand
smoke)) and cigarette butt was fenamidone (N-phenyl - 61.9% administered
dose (AD); C-phenyl - 74.4% AD) followed by aniline (N-phenyl - 11.0%
AD); RPA 408056 and RPA 405862 were also identified at ≤1.4% AD. 
Unidentified residues accounted for a total of ≤5% AD.  An unknown
eluting at 21 minutes (specified as D-1 by the petitioner) was
identified in the N-phenyl extracts at a total of 1.6% AD.  The
remaining unknowns totalled 3.4% AD.  Carbon monoxide and carbon dioxide
were also identified at 6.3% AD and 6.0% AD, respectively, for the
N-phenyl study and 0.9% AD and 6.5% AD, respectively, for the C-phenyl
study.  Total identified residues accounted for 86.1% AD for the
N-phenyl study and 83.1% for the C-phenyl study.  

The tobacco field trial study employed four applications of a 4.17 lb
ai/gallon SC fenamidone formulation at ~0.27 lbs ai/acre (1.0x/1.4x the
proposed single/seasonal rate; an adjuvant was added to the final three
spray solutions).  The first application was made prior to planting and
was incorporated into the soil to a depth of 2-4 inches.  Tobacco plants
were planted on the day of or one day after the preplant application. 
The second application was 52-72 days after the first application and
the third and fourth applications were made 12-14 days after the
previous application.  Single control and duplicate fresh tobacco leaf
samples were collected 3 days after the final application.  A second set
of control (single) and treated (duplicate) samples were collected 3
days after the final application and cured (flue cured (N=2) and air
cured (n=1)).  Combined residues of fenamidone, RPA 717879, RPA 408056,
and RPA 405862 in/on fresh and cured tobacco leaves were ≤10.5 ppm and
≤127 ppm, respectively (average residues of 75.2 ppm; method and
storage interval were validated).  Fenamidone accounted for 94-98% and
85-98% of the total residue in fresh and cured tobacco, respectively. 
Table 8 includes a summary of the tobacco field trial data.  

Conclusions:  The petitioner has fulfilled the residue chemistry data
necessary for a tobacco registration. Since tobacco is a non-food/feed
use, tolerances are unnecessary.  The human-health effects of these data
and the resulting conclusions concerning registration will be addressed
in the human-health risk assessment (D314116, T. Bloem et al. in draft).



Table 7:  Summary of Residue Data from Crop Field Trials with
Fenamidone (residues of Fenamidone per se).

Commodity	Total Applic.

Rate (lb ai/acre)	PHI (days)	Residue Levels (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

leafy vegetables (except Brassica) crop group

celery, untrimmed 

leaf stalk	1.064-1.073	2	12	2.03	19.83	18.31	6.36	8.82	6.21

spinach, leaves	1.072-1.092	2	12	6.03	32.40	30.53	16.30	16.66	9.18

head lettuce	1.064-1.117	2	17	0.82	11.70	10.72	4.02	4.73	2.92

leaf lettuce	1.052-1.115	2	18	0.97	17.50	15.90	6.40	6.88	5.11

Brassica (cole) leafy vegetables

broccoli, flower heads and stems	1.060-1.093	2	12	0.31	2.72	2.21	0.90
1.12	0.77

cabbage, heads with wrapper leaves	1.052-1.079	2	12	0.07	0.65	0.52	0.22
0.26	0.20

mustard greens	1.060-1.088	2	16	9.34	32.41	29.08	20.38	20.32	8.01

fruiting vegetables crop group

tomato	1.005-1.084 

(4 x 0.27)	14	34	0.02	0.80	0.79	0.29	0.29	0.22

	1.005-1.084 

(6 x 0.18)	14	34	0.02	0.78	0.64	0.21	0.26	0.20

bell pepper	1.053-1.128	14	12	0.01	0.20	0.19	0.07	0.08	0.06

nonbell pepper	1.055-1.069	13-14	6	0.06	1.66	1.56	1.20	0.94	0.72

cotton, undelinted seed	0.258-0.272	127-190	24	0.02	0.02	0.02	0.02	0.02
0

cotton, gin byproducts	0.258-0.272	127-178	12	0.02	0.02	0.02	0.02	0.02	0

sunflower seed	0.19 lb ai per 100 lbs seed	104-146	18	0.02	0.02	0.02
0.02	0.02	0

	0.95 lb ai per 100 lbs seed	114-145	4	0.02	0.02	0.02	0.02	0.02	0

carrot root	1.023-1.100	13-16	26	0.02	0.11	0.10	0.04	0.05	0.03

tobacco	since tobacco tolerances are unnecessary a summary of these data
are not provided

1  Residues <LOQ were assumed to be =LOQ for calculation of median,
mean, and std dev.

2  HAFT = Highest Average Field Trial.



Table 8:  Summary of Residue Data from Crop Field Trials with Fenamidone
(combined fenamidone, RPA 717879, RPA 408056, and RPA 405862).

Commodity	Total Applic.

Rate (lb ai/acre)	PHI (days)	Residue Levels (ppm)1

	n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

leafy vegetables (except Brassica) crop group

celery, untrimmed 

leaf stalk	1.064-1.073	2	12	2.11	20.16	18.60	6.51	9.02	6.32

spinach, 

leaves	1.072-1.092	2	12	6.15	32.55	30.67	16.60	16.84	9.21

head lettuce	1.064-1.117	2	17	0.88	11.79	10.80	4.08	4.80	2.93

leaf lettuce	1.052-1.115	2	18	1.03	17.58	15.97	6.46	6.95	5.11

Brassica (cole) leafy vegetables

broccoli, flower heads and stems	1.060-1.093	2	12	0.52	3.27	2.65	1.02
1.39	0.86

cabbage, heads with wrapper leaves	1.052-1.079	2	12	0.13	0.74	0.61	0.29
0.34	0.21

mustard greens	1.060-1.088	2	16	9.54	32.99	29.21	20.52	20.52	8.03

fruiting vegetables crop group

tomato	1.005-1.084 

(4 x 0.27)	14	30	0.08	0.86	0.85	0.35	0.34	0.22

	1.005-1.084 

(6 x 0.18)	14	30	0.08	0.84	0.70	0.27	0.32	0.20

bell pepper	1.053-1.128	14	12	0.09	0.26	0.25	0.13	0.14	0.06

nonbell pepper	1.055-1.069	13-14	6	0.12	1.78	1.56	1.28	1.02	0.72

cotton, undelinted seed	0.258-0.272	127-190	24	0.08	0.08	0.08	0.08	0.08
0

cotton, gin byproducts	0.258-0.272	127-178	12	0.08	0.08	0.08	0.08	0.08	0

sunflower seed	0.19 lb ai per 100 lbs seed	104-146	18	0.08	0.08	0.08
0.08	0.08	0

	0.95 lb ai per 100 lbs seed	114-145	4	0.08	0.08	0.08	0.08	0.08	0

carrot root	1.023-1.100	13-16	26	0.08	0.17	0.16	0.10	0.11	0.03

fresh tobacco leaves	1.066-1.106	3	6	3.70	10.5	10.3	8.23	7.33	3.02

cured tobacco leaves	1.066-1.106	3	6	12.9	127	126	86.4	75.2	49.7

1  Residues <LOQ were assumed to be =LOQ for calculation of median,
mean, and std dev.

2  HAFT = Highest Average Field Trial.

860.1520 Processed Food and Feed

Of the proposed crops/crop groups, only tomato (paste and puree), cotton
(meal, hulls, and oil) and sunflower (meal and oil) possess processed
commodities as defined in Table 1 of OPPTS 860.1000.  The paragraphs
below summarize the currently-available processing data for these crops
and HED notes the following:  

Degradation of fenamidone to aniline was demonstrated in the tobacco
pyrolysis study (aniline is a probable human carcinogen; US EPA IRIS -
http://www.epa.gov/iris/subst/0350.htm).  HED is concerned that
fenamidone may be degrading to aniline during the processing or cooking
of treated crops.  As a result, HED requests that the petitioner submit
a processing study as designated in Annex 1 of the following European
Union document:  (  HYPERLINK
"http://ec.europa.eu/food/plant/protection/resources/app-e.pdf" 
http://ec.europa.eu/food/plant/protection/resources/app-e.pdf ).  The
procedure involves the hydrolysis of radiolabeled fenamidone at various
pHs and temperatures and identification of the resulting transformation
products, if any (N-phenyl radiolabeled fenamidone should be employed). 
Depending on the results from this study, additional data may be
requested (ChemSAC minutes, 30-May-2007).  

Tomato:  Fenamidone is currently registered for application to tomato
and the petitioner submitted an adequate tomato processing study to
support this registration (45386001.der.wpd; D297216, T. Bloem,
25-May-2004).  Tomatoes were harvested 14 days following foliar
application at 6.7x the proposed seasonal rate.  The harvested tomatoes
were processed into tomato puree and tomato paste according to simulated
commercial procedures and analyzed for fenamidone, RPA 717879, RPA
405862, and RPA 408056 (analytical method and storage intervals were
validated).  Fenamidone, RPA 717879, and RPA 405862 were found to
concentrate in tomato puree (1.8x, 2.4x, and 24x, respectively) and
paste (2.7x, 3.8x, and 44x, respectively).  Residues of RPA 408056 were
nondetectable in puree and paste.  The combined residues of fenamidone
and its metabolites RPA 717879, RPA 408056, and RPA 405862 concentrated
in tomato puree and paste at 2.1x and 3.4x, respectively.  Based on
these data and the tomato field trial data, tolerances of 2.2 ppm and
2.0 ppm for residues of fenamidone were established in/on tomato paste
and puree, respectively; in light of the currently recommended fruiting
vegetable (except nonbell pepper) tolerance of 1.0 ppm, HED concludes
that the tomato paste and puree tolerances remain acceptable.  

Sunflower:  As part of the sunflower field trial study, the petitioner
submitted data which indicated that residue of fenamidone, RPA 717879,
RPA 408056, and RPA 405862 were <LOQ (<0.02 ppm) in/on sunflower seed
following seed treatment at 0.95 lb ai/100 lb of seed (5x the proposed
rate); therefore, a sunflower seed processing study and tolerances in/on
sunflower seed processed commodities are unnecessary.

Cotton:  As part of the cotton field trial data, the petitioner
submitted data which indicated that residues of f fenamidone, RPA
717879, RPA 408056, and RPA 405862 were <LOQ (<0.02 ppm) in/on
cottonseed following an in-furrow at planting application at 1.335 lb
ai/acre (4.9x the proposed in-furrow application rate).  HED notes that
the proposed label also specifies a seed treatment application at 0.19
lb ai/100 pounds seed and indicates that treated seed may also receive
the in-furrow application at planting.  The seeding rate for cotton is
10 lbs seed per acre (  HYPERLINK
"http://deltafarmpress.com/mag/farming_adjusting_price_cotton/" 
http://deltafarmpress.com/mag/farming_adjusting_price_cotton/ ) which
translates to a fenamidone application rate of 0.019 lb ai/acre for the
seed treatment application.  Since this rate is 7% of the in-furrow
application and since residues were <LOQ in/on cottonseed following
application at 4.9x the proposed in-furrow application rate, HED
concludes that additional cotton residue data are unnecessary and
tolerances in/on the cottonseed processed commodities are unnecessary.  

860.1850 Confined Accumulation in Rotational Crops

46440805.der.doc

A confined rotational crop study conducted with fenamidone labeled in
the C-phenyl ring has been previously reviewed by HED (D281887, T.
Bloem, 18-Jul-2002).  Lettuce, turnip, and barley were planted 30, 120,
and 365 days after treatment at 1.8-2.2x maximum proposed seasonal
application rate.  TRR accumulated >0.01 ppm in all commodities and
PBIs.  Radioactivity was lowest in turnip roots and highest in barley
chaff and straw; TRR generally decreased as the PBI increased. 
Fenamidone was not identified in any rotational crop commodity.  The
major residues identified were a conjugate of RPA 408056 (8-73% TRR) and
RPA 717879 (2-29% TRR; these compounds contain only the C-phenyl ring).
RPA 408056 (1-6% TRR) and RPA 405862 (4% TRR; contains both rings) were
also identified.  A significant quantity of the extracted TRR was shown
to be composed of unknowns (chromatographically unretained or slightly
retained - 3.9-55.7% TRR).  Based on the structure of the parent
compound, the characteristics shown under acid hydrolysis and dansyl
chloride derivitization, and TLC/HPLC analysis, the petitioner
tentatively identified the polar metabolites as being composed of amino
acids.    

Since fenamidone was the major residue identified in the primary crop
metabolism and field trial studies and since neither fenamidone nor any
other compound containing both the C- and N-phenyl rings of fenamidone
was identified in the confined field rotational crop study, it is likely
that the identified C-phenyl compounds result from soil metabolism. 
Therefore, if N-phenyl compounds are found in rotational crops, they are
likely to derive from soil metabolism.  Based on the structure of the
compounds identified in the aerobic soil metabolism study, separation of
the N-phenyl rings and C-phenyl rings is possible with the N-phenyl
rings forming aniline or nitroaniline.  Based on the estimated 4 day
half-life for mineralization of aniline to CO2 (EPA aniline fact sheet;
http://www.epa.gov/chemfact/anali-sd.pdf) and since the petitioner has
determined that aniline and nitroanilines were not present in the
aerobic soil metabolism study  (EFED Review; D303236, S. Termes,
25-May-2004), HED concludes that a N-phenyl confined rotational crop
study is unnecessary.  The residues of concern in rotational crops for
purposes of tolerance enforcement are fenamidone and RPA 717879 and the
residues of concern in rotational crops for purposes of risk assessment
are fenamidone, RPA 717879, and RPA 408056 (free and conjugated; storage
stability data validating the confined rotational crop study storage
intervals and conditions are required; MARC memo, T. Bloem et al.,
25-May-2004).  

860.1900 Field Accumulation in Rotational Crops

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As indicated above, the residues of concern in rotational crops for
tolerance enforcement are fenamidone and RPA 717879 and for risk
assessment are fenamidone, RPA 717879, and RPA 408056 (free and
conjugated).  The petitioner has previously submitted limited (radish,
spinach, and wheat; 45385903.der.wpd) and extended (wheat (30-day PBI);
45386002.der.wpd) field rotational crop studies and as part of the
current petition submitted an extended strawberry (30-day PBI) field
rotational crop study (46440805.der.doc).  The limited study did not
monitor for residues of RPA 408056 conjugates; therefore, this study can
not be used for determination of an appropriate PBI (if tolerances are
not established, PBI established at the interval where residues of
concern are <LOQ).  

The extended wheat rotational crop employed a single broadcast spray
application of fenamidone to bare soil at 1.05-1.10 lb ai/acre (1.3-1.4x
the maximum currently proposed rate); wheat was planted 30 days after
application.  HED previously concluded that a 30-day PBI is appropriate
for wheat along with the establishment of the following tolerance for
residues of fenamidone and RPA 717879:  wheat forage - 0.15 ppm, wheat
hay - 0.50 ppm, wheat straw - 0.35 ppm, and wheat grain - 0.10 ppm
(D281887, T. Bloem, 18-Jul-2002).  Since the wheat study employed an
exaggerated rate as compared to the currently proposed application
rates, HED concludes that a 30-day PBI for wheat is appropriate for the
currently requested crops.  In addition, based on the strawberry field
rotational crop study (see below) and provided a strawberry tolerance of
0.02 ppm for residues of fenamidone is established, a 30-day PBI for
strawberry is appropriate.  

The proposed label indicates that a treated field may be rotated to a
labeled crop immediately following the last application, to wheat and
strawberries 30 days after the last application, and all other crops one
year after the last application.  Based on the currently available data
and provided a revised Section F is submitted, HED concludes that these
rotational crop restrictions are appropriate.  

46440805.der.doc:  The strawberry field rotational crop study submitted
with the current petition was conducted in Regions 1 (n=1), 2 (n=1), 3
(n=1l), 5 (n=1), 10 (n=3), and 12 (n=1).    SEQ CHAPTER \h \r 1 At each
trial site, four foliar broadcast applications of a 4.13 lb ai/gal
soluble concentrate (SC) formulation of fenamidone were made to the
primary crop (a leafy vegetable, cucurbit, or fruiting vegetable) at
0.267 lb ai/acre (1.0x/1.4x the proposed single/seasonal application
rates).  The primary crop was tilled into the ground ~2 days after the
last application, and strawberries were planted as a rotational crop 28
to 30 days after the last application to the primary crop.  Strawberries
were collected at normal harvest.

Samples of rotated strawberries were analyzed for residues of
fenamidone, RPA 408056, RPA 405862, and RPA 717879 (method and storage
interval was adequately validated).  Residues of fenamidone, DA
fenamidone, DK fenamidone, and DADK fenamidone were each less than the
LOQ (<0.02 ppm) in strawberries.  

OPPTS 860.1550 Proposed/Recommended Tolerances

Table 9 is a summary of the proposed and HED-recommended tolerances for
residues of fenamidone per se (tolerance for strawberry are for the
combined residues of fenamidone and RPA 717879).  A revised Section F is
requested.  There are currently no established Codex, Canadian, or
Mexican MRLs for residues of spinetoram in/on the commodities listed in
Table 9; therefore, harmonization is not an issue.

Table 9:  Petitioner-Proposed and HED-Recommended Tolerances.

Petitioner-Proposed Tolerances	HED-Recommended Tolerances

Matrix	Tolerance

(ppm)	Matrix	Tolerance

(ppm)

Carrot	0.15	Carrot	0.15

Sunflower	0.08	Sunflower	0.02

Vegetable, brassica, head and stem, subgroup 5a	4.0	Vegetable, Brassica,
head and stem, subgroup 5a	5.0

Vegetable, brassica, leafy greens, subgroup 5b	35	Vegetable, Brassica,
leafy greens, subgroup 5b	55

Vegetable, fruiting, group 8	2.0	Vegetable, fruiting, group 8 (except
nonbell pepper)	1.0

Pepper, nonbell	3.5

Vegetable, leafy, except brassica 4	35	Vegetable, leafy, except
Brassica, group 4	60

Strawberries	0.02	Strawberry	0.02

none proposed	Cotton, gin byproducts	0.02

	Cotton, undelinted seed	0.02

RDI: RAB1 Chemist (6-June-2007)

T. Bloem:10945S:PY1:(703)605-0217:7590P

Attachment 1:  Chemical Structures

Attachment 2:  Tolerance Spreadsheet Calculator Results

Attachment 1: Chemical Structures

Name	Structure

fenamidone; RPA 407213

 

 

14C-C-phenyl-fenamidone

RPA 408056 (racemic mixture)

RPA 405862 (racemic mixture)

RPA 410193 (S enantiomer)

5-methyl-5-phenyl-3-phenylamino-imidazolidin-2,4-dione

RPA 717879 (racemic mixture)

RPA 413255

(5S)-5-methyl-2-(methylthio)-3-[(2-nitrophenyl)amino]-5-phenyl-3,5-dihyd
ro-4H-imidazol-4-one

RPA 411639

(5S)-5-methyl-2-(methylthio)-3-[(4-nitrophenyl)amino]-5-phenyl-3,5-dihyd
ro-4H-imidazol-4-one

RPA 410995

RPA 409446

 

RPA 407213-dimer

Attachment 2:  Tolerance Spreadsheet Calculator Results



Fenamidone	Residue Chemistry Summary	D314318

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