Document ID: EPA-HQ-OPP-2008-0458-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-07-15T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF                  

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES        

MEMORANDUM

Date:	 		March 2, 2009

Subject:	Fenamidone.  Human Health Risk Assessment  to Support Section 3
Proposals to Add New Uses on the Root Vegetable Subgroup 1B (except
radish), Okra, Turnip Greens, Cilantro Leaves, Grapes Grown East of the
Rocky Mountains and Rotational Crop Uses for Field Corn, Sweet Corn and
Soybeans.

PC Code:  046679	DP Barcode:  D353909

MRID No.:  None	Registration No.:  264-695

Petition No.:  7E7350, 8F7410	Regulatory Action:   Section 3
Registration

Assessment Type:  Single Chemical Aggregate	Reregistration Case No.: N/A

TXR No.:  N/A	CAS No.:  161326-34-7

From:		Donna S. Davis, Chemist

		Alexandra LaMay, Biologist

		Byong-Han Chin, Toxicologist

		Registration Action Branch VII

		Health Effects Division (7509P)

Thru:		Michael S. Metzger, Chief

		Registration Action Branch VII

		Health Effects Division (7509P)

	

To:		Susan Stanton

		Barbara Madden, Minor Use Team Leader

		Daniel Rosenblatt, Chief

		Integration Minor Use and Emergency Response Branch

		Registration Division (7505P) 

		Rosemary Kearns

		Tony Kish, PM 22

		Cynthia Giles-Parker, Chief

		Fungicide Branch

		Registration Division (7505P)

	Attached please find the most recent HED human health risk assessment
for the existing and newly proposed uses of fenamidone.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc223318199"  1.0	Executive
Summary	  PAGEREF _Toc223318199 \h  4  

  HYPERLINK \l "_Toc223318200"  Regulatory Recommendations and Data
Needs	  PAGEREF _Toc223318200 \h  5  

  HYPERLINK \l "_Toc223318201"  2.0	Ingredient Profile	  PAGEREF
_Toc223318201 \h  6  

  HYPERLINK \l "_Toc223318202"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc223318202 \h  6  

  HYPERLINK \l "_Toc223318203"  2.2	Structure and Nomenclature	  PAGEREF
_Toc223318203 \h  8  

  HYPERLINK \l "_Toc223318204"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc223318204 \h  8  

  HYPERLINK \l "_Toc223318205"  3.0	Hazard Characterization	  PAGEREF
_Toc223318205 \h  9  

  HYPERLINK \l "_Toc223318206"  3.1	Hazard Profile	  PAGEREF
_Toc223318206 \h  9  

  HYPERLINK \l "_Toc223318207"  3.2	FQPA Considerations	  PAGEREF
_Toc223318207 \h  10  

  HYPERLINK \l "_Toc223318208"  3.3	Dose-Response Assessment	  PAGEREF
_Toc223318208 \h  12  

  HYPERLINK \l "_Toc223318209"  3.4	Endocrine Disruption	  PAGEREF
_Toc223318209 \h  13  

  HYPERLINK \l "_Toc223318210"  4.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc223318210 \h  13  

  HYPERLINK \l "_Toc223318211"  4.1	Metabolism and Environmental
Degradation	  PAGEREF _Toc223318211 \h  13  

  HYPERLINK \l "_Toc223318212"  4.2 	Analytical Methodology	  PAGEREF
_Toc223318212 \h  13  

  HYPERLINK \l "_Toc223318213"  4.2.1	Data Collection Methodology	 
PAGEREF _Toc223318213 \h  13  

  HYPERLINK \l "_Toc223318214"  4.2.2	Enforcement Methodology	  PAGEREF
_Toc223318214 \h  14  

  HYPERLINK \l "_Toc223318215"  4.3	Drinking Water Residue Profile	 
PAGEREF _Toc223318215 \h  14  

  HYPERLINK \l "_Toc223318216"  4.4	Food Residue Profile	  PAGEREF
_Toc223318216 \h  15  

  HYPERLINK \l "_Toc223318217"  4.5	Tolerances and International Residue
Limits	  PAGEREF _Toc223318217 \h  18  

  HYPERLINK \l "_Toc223318218"  4.6	Dietary Exposure and Risk	  PAGEREF
_Toc223318218 \h  19  

  HYPERLINK \l "_Toc223318219"  4.6.1.	Acute Dietary Exposure/Risk	 
PAGEREF _Toc223318219 \h  19  

  HYPERLINK \l "_Toc223318220"  4.6.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc223318220 \h  19  

  HYPERLINK \l "_Toc223318221"  4.6.3	Cancer Dietary Risk	  PAGEREF
_Toc223318221 \h  20  

  HYPERLINK \l "_Toc223318222"  4.6.4	Acute and Chronic Dietary Exposure
and Risk Summary	  PAGEREF _Toc223318222 \h  20  

  HYPERLINK \l "_Toc223318223"  5.0 	Residential Exposure/ Risk Pathway	
 PAGEREF _Toc223318223 \h  20  

  HYPERLINK \l "_Toc223318224"  6.0 	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc223318224 \h  21  

  HYPERLINK \l "_Toc223318225"  7.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc223318225 \h  21  

  HYPERLINK \l "_Toc223318226"  8.0	Occupational Exposure	  PAGEREF
_Toc223318226 \h  21  

  HYPERLINK \l "_Toc223318227"  8.1 	Occupational Handler Exposure	 
PAGEREF _Toc223318227 \h  21  

  HYPERLINK \l "_Toc223318228"  8.2  	Occupational Postapplication
Exposure	  PAGEREF _Toc223318228 \h  23  

  HYPERLINK \l "_Toc223318229"  8.3 	REI	  PAGEREF _Toc223318229 \h  25 

  HYPERLINK \l "_Toc223318230"  9.0	Data Needs and Label Recommendations
  PAGEREF _Toc223318230 \h  25  

  HYPERLINK \l "_Toc223318231"  9.1	Toxicology	  PAGEREF _Toc223318231
\h  25  

  HYPERLINK \l "_Toc223318232"  9.2	Residue Chemistry	  PAGEREF
_Toc223318232 \h  25  

  HYPERLINK \l "_Toc223318233"  9.3	Occupational and Residential
Exposure	  PAGEREF _Toc223318233 \h  25  

  HYPERLINK \l "_Toc223318234"  10.0	Environmental Justice	  PAGEREF
_Toc223318234 \h  25  

  HYPERLINK \l "_Toc223318235"  11.0	Human Studies	  PAGEREF
_Toc223318235 \h  26  

  HYPERLINK \l "_Toc223318236"  References	  PAGEREF _Toc223318236 \h 
26  

  HYPERLINK \l "_Toc223318237"  Attachment 1.  Chemical Structures	 
PAGEREF _Toc223318237 \h  28  

  HYPERLINK \l "_Toc223318238"  Attachment 2.  Acute Toxicity of
Fenamidone	  PAGEREF _Toc223318238 \h  30  

  HYPERLINK \l "_Toc223318239"  Attachment 3.  Toxicity Profile for
Fenamidone	  PAGEREF _Toc223318239 \h  31  

  HYPERLINK \l "_Toc223318240"  Attachment 4.  International Residue
Limit Status Sheet	  PAGEREF _Toc223318240 \h  34  

  HYPERLINK \l "_Toc223318241"  Attachment 5.  Justification for
Immunotoxicity Study	  PAGEREF _Toc223318241 \h  36  

 1.0	Executive Summary

Fenamidone is a broad-spectrum foliar fungicide currently registered for
application to a variety of field crops including, bulb vegetables,
tuberous and corm vegetables, fruiting vegetables and leafy vegetables. 
IR-4 is proposing to expand the label for the formulated product,
Reason® 500 SC (soluble concentrate) to include fenamidone new uses on
the root vegetable subgroup 1B (excluding radishes), turnip greens,
okra, cilantro and grapes grown east of the Rocky Mountains.  Bayer
CropScience, the registrant for fenamidone, is requesting rotational
crop tolerances to support a plant-back interval (PBI) of 30 days for
field corn, sweet corn and soybeans.  

Fenamidone has low acute toxicity via the oral, dermal, and inhalation
routes.  It is a moderate eye irritant, but is not a dermal irritant or
a dermal sensitizer.  The liver is the target organ in chronic studies
in the rat, mouse, and dog.  The thyroid is also a target organ in the
rat.  Fenamidone did not demonstrate any qualitative or quantitative
increased susceptibility in the rat and rabbit developmental toxicity
studies or the 2-generation rat reproduction study.  In the rat
reproduction study (Sprague Dawley rat), decreased absolute brain weight
and pup body weight occurred at the same dose levels as decreased
absolute brain weight and parental body weight, food consumption, and
increased liver and spleen weight.  Developmental toxicity was observed
in the rat only at the limit dose.  Fenamidone did not produce
developmental toxicity in the rabbit or reproductive toxicity in the
rat.  Fenamidone is not likely to be a human carcinogen.  No
treatment-related effects were observed on motor activity or in the
functional observation battery (FOB) parameters measured in the
subchronic neurotoxicity study in rats.  In this subchronic
neurotoxicity study, marginal decreases in brain weights were observed
only in high dose males.  In the acute neurotoxicity study in rats, the
most commonly observed clinical sign was staining/soiling of the
anogenital region.  Other day-1 FOB findings included mucous in the
feces, hunched posture and unsteady gait.  In a developmental
neurotoxicity study in Wistar rats, no neurobehavioral effects and no
neuropathological changes were observed at any dose in the offspring,
but decreased body weight was observed during pre- and post-weaning. 
Confirmatory data in the form of an abbreviated DNT in the Sprague
Dawley rat with measurements of brain weight and brain morphometric data
has been previously requested.  Currently, HED notes no evidence of
immunotoxicity for fenamidone; however, as specified in the new 40CFR
Part 158 data requirements, an immunotoxicity study on fenamidone should
be conducted.  

The residue chemistry database for fenamidone is considered complete. 
The current tolerance enforcement method, a liquid chromatographic
method coupled with tandem mass spectrum detection (LC/MS/MS) is
suitable to enforce the new plant tolerances proposed in this petition. 
HED notes that since residues of fenamidone are detected through FDA
Multi-Residue Method Protocol D, this protocol can also serve as an
enforcement methodology.  There are no issues with respect to
international harmonization as a result of the proposed new uses that
are the subject of this petition.  

Conservative acute and chronic dietary risk assessments were conducted
which used maximum field trial residue values, assumed 100 percent crop
treated (% CT) for all commodities, incorporated DEEM™ default
processing factors for many processed commodities and included modeled
estimates for drinking water.  Acute and chronic dietary (food and
water) risks from the existing and newly proposed uses of fenamidone are
not of concern.  

Since there are no registered residential uses for fenamidone, aggregate
exposure estimates include food and drinking water only.  Acute and
chronic aggregate risks are not of concern for the existing and newly
proposed uses of fenamidone 

For occupational handlers, dermal and inhalation MOEs do not exceed
HED’s level of concern provided the label specified PPE which includes
gloves is maintained.  Occupational postapplication MOEs do not exceed
HED’s level of concern for both short- and intermediate-term exposures
with baseline dermal PPE.  The proposed label REI of 12 hours is
consistent with the Worker Protection Standard.  

This assessment relies in part on data from studies in which adult human
subjects were intentionally exposed to a pesticide.  These studies,
which comprise the Pesticide Handlers Exposure Database (PHED), have
been determined to require a review of their ethical conduct, and
received that review.  The studies in PHED were considered appropriate
(or ethically conducted) for use in risk assessments.

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

Regulatory Recommendations and Data Needs

Provided the data needs summarized below are addressed, there are no
human health risks of concern that would preclude the establishment of
the following tolerances:  

Under 40 CFR §180. 579 for residues of fenamidone

Vegetable, root, except sugar beet, subgroup 1B, except
radish……....0.15 ppm

Okra…………………………………………………………
………..…3.5 ppm

Cilantro,
leaves………………………………………………………..
…60 ppm

Grapes (East of the Rocky Mountains
Only)…………………..…..……1.0 ppm

Note to RD:  The recommended tolerance of 0.15 ppm on crop subgroup 1B,
excluding radishes will cover residues of fenamidone in/on carrots. 
Since a separate carrot tolerance is no longer required, it can be
removed from the 40CFR §180. 579.  An import tolerance is currently
established for residues of fenamidone on grapes and is listed in the 40
CFR 180.579 as “grapes (imported)” at 1.0 ppm.  HED recommends that
the 40 CFR 180.579 be modified to delete “(imported)” and to add a
footnote to the grape stating that the grape tolerance is applicable
only to grapes grown east of the Rocky Mountains.

Under 40 CFR 180.579(d) for residues of fenamidone and its metabolite
RPA 717879

Corn, field,
grain……………………………………………..0.04 ppm

Corn, sweet, kernel plus cob with husks removed.….………..0.04 ppm

Corn, sweet,
forage…………………………………………...0.20 ppm

Corn, field,
forage……………………………………….……0.30 ppm

Corn, sweet,
stover……………………………………………0.45 ppm

Corn, field,
stover…………………………………………….0.30 ppm

Soybean,
seed……………………………………….………...0.04 ppm

Soybean,
forage…………………………………….………....0.15 ppm

Soybean,
hay……………………………………………..……0.25 ppm

Prior to a favorable recommendation, HED requests the following:

The proposed Reason® 500 SC Reason label should be amended to limit use
on turnip cultivars for root production only.  If the petitioner should
wish to remove this label restriction and support the establishment of a
turnip green tolerance, a ruminant feeding study reflecting a
concentration in the diet which brackets the newly calculated maximum
reasonably balanced diet for dairy cattle would be required. 

The petitioners should submit revised section Fs reflecting the
commodity definitions and levels shown above.  

As the following data are considered confirmatory in nature, HED
requests that they be addressed as conditions of registration.

An abbreviated DNT in the Sprague Dawley rat with measurements of brain
weight and brain morphometric data to confirm findings in the full DNT
conducted in the Wistar rat. 

While no evidence of immunotoxicity was seen in the fenamidone database,
as specified in the new 40 CFR Part 158 data requirements, an
immunotoxicity study on fenamidone should be conducted.  

2.0	Ingredient Profile

2.1	Summary of Proposed Uses

D352806, D. Davis, 12/18/08

D357372, A. LaMay, 2/24/09

Fenamidone is a broad-spectrum foliar fungicide currently registered for
application to a variety of field crops including, bulb vegetables,
tuberous and corm vegetables, fruiting vegetables and leafy vegetables. 
Fenamidone is a chiral compound with the technical product consisting of
98.5% S-fenamidone.  Tolerances are established for residues of
fenamidone in raw agricultural commodities, animal commodities and for
inadvertent residues under 40 CFR §180.579. 

IR-4 is proposing to expand the label for the formulated product,
Reason® 500 SC (soluble concentrate) to include fenamidone new uses on
crop subgroup 1B, excluding radishes, turnip greens, okra, cilantro and
grapes grown east of the Rocky Mountains.  The petitioner has provided
proposed label directions for the new uses.  A summary of the use
directions for these crops is shown in Table 2.1.  

Table 2.1.  Summary of Directions for Use of Fenamidone on New 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

Crop Subgroup 1B (root vegetables except sugar beets), excluding
radishes which includes:

Beet, garden; burdock, edible; celeriac; chervil, turnip-rooted;
chicory; ginseng; horseradish; parsley, turnip-rooted; parsnip; radish,
oriental; rutabaga; salsify; salsify, black; salsify, Spanish; skirret;
turnip.

Foliar by ground, air or chemigation equipment	Reason® 500 SC

4.13 lb ai/gal	0.27	not specified	0.80	14	14-day RTI1

Okra

Foliar by ground, air or chemigation equipment.	Reason® 500 SC

4.13 lb ai/gal	0.18-0.27	not specified	0.80	14	14-day RT

Turnip Greens

Foliar by ground, air or chemigation equipment.	Reason® 500 SC

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

Cilantro

Foliar by ground, air or chemigation equipment.	Reason® 500 SC

4.13 lb ai/gal	0.27	not specified	0.80	2	5- to 10-day RTI

Grapes – Grown East of the Rocky Mountains Only

Foliar by ground, air or chemigation equipment.	Reason® 500 SC

4.13 lb ai/gal	0.0892	not specified	0.27	30	10- to 14-day RTI

for use on grapes grown east of the Rocky Mountains only

1 RTI is retreatment interval

At this time, HED is recommending against the establishment of a
tolerance for residues of fenamidone on turnip greens; therefore, the
label should be modified to specify use on turnip cultivars grown for
root production only.  The use directions for the commodities in crop
subgroup 1B, excluding radishes, and for the individual commodities of
okra, cilantro, and grapes grown east of the Rockies are adequate to
support those new uses.  

In addition, Bayer CropScience, the registrant for fenamidone, is
proposing to amend the Reason® 500 SC label to allow rotation to field
corn, sweet corn and soybean with a 30-day plant back interval (PBI) in
fenamidone treated fields.  HED concludes that adequate use directions
reflecting this amended use have been submitted.  No revisions to the
label with respect to the rotational crop uses are required and the data
support the requested 30-day PBI.

2.2	Structure and Nomenclature

Table 2.2, below contains a summary of the test compound nomenclature. 
Additional fenamidone information, including stereoisomer structures and
metabolite nomenclature and structures is contained in Attachment 1.

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)

2.3	Physical and Chemical Properties

 

Table 2.3, below contains a summary of the physicochemical properties of
Fenamidone.

Table 2.3.  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

3.0	Hazard Characterization

D314116, T. Bloem, 6/21/07

3.1	Hazard Profile

Fenamidone has low acute toxicity via the oral, dermal, and inhalation
routes.  It is a moderate eye irritant, but is not a dermal irritant or
a dermal sensitizer.  The acute oral assay tests indicated that female
rats were more sensitive to the parent than male rats.  

The target organs in chronic studies in the mouse and dog were the liver
and in rat were the liver and thyroid.  In the chronic toxicity rat
study, the systemic NOAEL was based on diffuse C-cell hyperplasia of the
thyroid in both sexes as the most sensitive indicator of toxicity.  At
higher doses, follicular cells and the liver were affected.  The
similarity in the systemic NOAELs and the type of toxicity observed
(primarily liver) for the 90-day rat studies with the parent and plant
metabolites (RPA 412636, RPA 412708, and RPA 410193) demonstrated that,
on a subchronic basis, the plant metabolites were not more toxic than
the parent.  Fenamidone is not likely to be a human carcinogen.  All
mutagenicity studies were negative for both the parent and plant
metabolites (RPA 412636, RPA 412708, and RPA 410193).

Fenamidone did not demonstrate any qualitative or quantitative increased
susceptibility in the rat and rabbit developmental toxicity studies or
the 2-generation rat reproduction study.  In rabbits, there were no
developmental effects up to the highest dose tested and in the presence
of maternal toxicity.  In the rat, developmental findings and maternal
findings both occurred at the limit dose.  In the reproduction study
(Sprague Dawley rat), decreased absolute brain weight and pup body
weight occurred at the same dose levels as decreased absolute brain
weight and parental body weight, food consumption, and increased liver
and spleen weight.  There were no effects on fertility and other
measured reproductive parameters.  In the acute neurotoxicity study in
rats, the most commonly observed clinical sign was staining/soiling of
the anogenital region at 500 and 2000 mg/kg.  These findings were
observed at low incidences and were consistent with those observed on
day 1 of the FOB.  Other day-1 FOB findings included mucous in the feces
of the 500 and 2000 mg/kg males and females; hunched posture when
walking or sitting in the 2000 mg/kg females; and unsteady gait in the
500 and 2000 mg/kg females.  In the subchronic neurotoxicity (Sprague
Dawley rat), marginal decrease in brain weights were observed only in
high dose males.  Additionally, fenamidone displayed decreased brain
weight in F1 female adults and F2 female offspring in the rat
reproduction study.  Other evidence of neurotoxicity (clinical signs
such as lethargy, prostration, tremors, eye closure, unsteady gait) was
observed in a mouse bone marrow micronucleus assay with plant
metabolites (RPA 412636 and RPA 412708; see attachment 1 for chemical
structures).  

Based on the evidence of clinical signs of neurotoxicity and decreases
in brain weights observed in Sprague-Dawley rats in two studies (males
in subchronic and in the F1 and F2 females in the reproduction), HED
requested that a developmental neurotoxicity (DNT) study be conducted
with Sprague Dawley rats.  The Registrant, however, submitted a DNT
study conducted with Wistar rats.  In this study, no maternal toxicity
was observed at doses up to 4700 ppm (429 mg/kg/day).  The offspring
systemic toxicity manifested as decreased body weight (9-11%) and body
weight gain (8-20%) during pre-weaning and decreased body weight (4-6%)
during post-weaning.  The offspring NOAEL was 1000 ppm (92.3 mg/kg/day).
 

or the proposed new uses are ≥ 10,000; therefore these uses would meet
the criteria required to grant a waiver for the 28-day inhalation study
(HED Standard Operating Procedure (SOP) 2002.01: Guidance: Waiver
Criteria for Multiple-Exposure Inhalation Toxicity Studies, 08/15/02). 
Therefore, a 28-day inhalation study is not required to support the new
uses that are the subject of this risk assessment. 

As specified in the new 40 CFR Part 158 data requirements, an
immunotoxicity study on fenamidone should be conducted.  EPA has
evaluated the available fenamidone toxicity data to determine whether an
additional database uncertainty factor is needed to account for
potential immunotoxicity.  Due to the lack of evidence of immunotoxicity
for fenamidone, EPA concluded that an additional factor (UFDB) for
database uncertainties is not needed to account for potential
immunotoxicity.  The justification for requiring the immunotoxicity
study is included in this review as Attachment 5.

The results of the acute toxicity studies for technical fenamidone are
included in this assessment as Attachment 2.  The toxicity profile for
fenamidone is summarized in Attachment 3. 

3.2	FQPA Considerations

No quantitative or qualitative evidence of increased susceptibility of
rat or rabbit fetuses to in utero exposure in the developmental toxicity
studies was observed.  There was no developmental toxicity in rabbit
fetuses up to 100 mg/kg/day (HDT), which resulted in an increased
absolute liver weight in the does.  Since the liver was identified as
one of the principal target organs in rodents and dogs, the occurrence
of this finding in rabbits at 30 and 100 mg/kg/day was considered strong
evidence of maternal toxicity.  In the rat developmental study,
developmental toxicity manifested as decreased fetal body weight and
incomplete fetal ossification in the presence of maternal toxicity in
the form of decreased body weight and food consumption at the limit dose
(1,000 mg/kg/day).  The effects at the limit dose were comparable
between fetuses and dams.  No quantitative or qualitative evidence of
increased susceptibility was observed in the 2-generation reproduction
study in rats.  In that study, both the parental and offspring LOAELs
were based on decreased absolute brain weight in female F1 adults and
female F2 offspring at 89.2 mg/kg/day.  At 438.3 mg/kg/day, parental
effects consisted of decreased body weight and food consumption, and
increased liver and spleen weight.  Decreased pup body weight was also
observed at the same dose level of 438.3 mg/kg/day.  There were no
effects on reproductive performance up to 438.3 mg/kg/day (HDT).

While the subchronic and the reproduction studies were conducted with
the Sprague-Dawley strain of rats, the DNT study was conducted with
Wistar rats. There was no maternal toxicity at the highest dose tested
(429 mg/kg/day). There were no neurobehavioral effects and no
neuropathological changes at any dose in the offspring.  The offspring
NOAEL was 92.3 mg/kg/day based on decreased body weight (9-11%) and body
weight gain (8-20%) during pre-weaning and decreased body weight (4-6%)
during post-weaning at 429 mg/kg/day (LOAEL).  These results indicated
an increased susceptibility of offspring. The concern for the increased
susceptibility observed in the DNT, however, is low because: 1) of the
lack of  neurobehavioral or neuropathological changes in the offspring
at any dose; 2) the endpoints used for the various risk assessment
scenarios are much more sensitive than that of the decreased bodyweight
of the offspring occurring at almost half the limit-dose (429
mg/kg/day); 3) the NOAELs of  10.4, 5.4 and 2.83 mg/kg/day used for
short-, intermediate-and long term risk assessments, respectively, are
considerably (9-45 fold) lower than the offspring NOAEL of 92.3
mg/kg/day in the DNT.

In response to the Agency’s classification of the DNT study as
unacceptable/guideline, the Registrant, Bayer Crops Science (BCS)
contended that the principal reason BCS chose to use the Wistar rat was
because all DNT studies performed at BCS have used only this rat strain.
 Using a strain other than Wistar was not a feasible option in the
absence of validation studies and historical control data for other
strains which might have been utilized.  

On June 17, 2008, the HED's Hazard Science Policy Council (HASPOC)
reviewed the Registrant's rationale and concluded that an abbreviated
DNT study should be conducted in the Crl:CD(SD)BR strain of rat with
measurement of the following endpoints only: brain weight and brain
morphometry. The HASPOC further determined that there is no need to
apply a database uncertainty factor at the present time, pending receipt
and review of this abbreviated DNT study (TXR: 0054626).

Based on these data and the residue information used in the dietary risk
assessments, HED concludes that the FQPA factor may be reduced to 1x for
the following reasons:

No qualitative or quantitative increased susceptibility in the
developmental toxicity studies (rat and rabbit)

No qualitative or quantitative increased susceptibility in the two
generation reproduction study (rat)

Low concern for residual uncertainties in the DNT study (rat) since
there is a well established offspring NOAEL which is 45x greater than
the NOAEL used to establish the chronic dietary endpoint

Residue values used in the dietary risk assessments are unlikely to
underestimate risk.

3.3	Dose-Response Assessment

Table 3.3, below, contains a summary of the fenamidone points of
departure for use in dietary, and non-dietary risk assessments.  

Table 3.3.  Summary of Toxicological Doses and Endpoints for Fenamidone
for Use in Dietary and Non-Dietary Human Health Risk Assessments 

Exposure

Scenario	Point of Departure	Uncertainty/

FQPA SF	RfD, PAD or LOC for Risk Assessment	Study and Toxicological
Effects

Acute Dietary

(All populations)	NOAEL = 125 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1	Acute RfD = 1.25 mg/kg/day

Acute PAD = 1.25 mg/kg/day	Acute Neurotoxicity in Rats:  LOAEL = 500
mg/kg/day based on urination, staining/soiling of the anogenital region,
mucous in the feces, and unsteady gait in the females

Chronic Dietary 

(All populations)	NOAEL= 2.83 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1	Chronic RfD = 0.0283 mg/kg/day

Chronic PAD = 0.0283 mg/kg/day	2 Year Chronic Toxicity/Carcinogenicity
in Rats:  LOAEL = 7.07/9.24 mg/kg/day (M/F) based on increase in
severity of diffuse thyroid C-cell hyperplasia in both sexes

Incidental Oral

Short-Term 

(1- 30 days)	NOAEL = 10.4 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1	Residential LOC for MOE = 100	90-Day Feeding in Rats:  LOAEL
= 68.27 mg/kg/day based on increased liver weights and incidences of
ground glass appearance of the hepatocytes in males.

Incidental Oral

Intermediate-Term

(1-6 months)	NOAEL = 5.45 mg/kg/day-	UFA= 10x

UFH= 10x

FQPA SF= 1	Residential LOC for MOE <100	2-Generation Reproduction Study
in Rats:

LOAEL = 89.2 mg/kg/day based on decreased absolute brain weight in
female F1 adults and female F2 offspring.

Dermal and Inhalation

Short-Term

(1-30 days)	Oral NOAEL = 10.4 mg/kg/day

10% Dermal Absorption (DA)

100% Inhalation Absorption (IA)	UFA= 10x

UFH= 10x

FQPA SF= 1	Residential LOC for MOE <100

Occupational LOC for MOE <100	90-Day Feeding in Rats:  LOAEL = 68.27
mg/kg/day based on increased liver weights and incidences of ground
glass appearance of the hepatocytes in males.

Dermal and Inhalation Intermediate-Term 

(1 – 6 months)	Oral NOAEL = 5.45 mg/kg/day

10% DA

100% IA	UFA= 10x

UFH= 10x

FQPA SF= 1	Residential LOC for MOE <100

Occupational LOC for MOE <100	2-Generation Reproduction Study in Rats

LOAEL = 89.2 mg/kg/day based on decreased absolute brain weight in
female F1 adults and female F2 offspring.

Dermal and Inhalation Long-Term (>6 months)	Oral NOAEL = 2.83 mg/kg/day

10% DA

100% IA	UFA= 10x

UFH= 10x

FQPA SF= 1	Residential LOC for MOE <100

Occupational LOC for MOE <100	2-Year Chronic Toxicity/Carcinogenicity in
Rats:  LOAEL = 7.07/9.24 mg/kg/day [M/F] based on increase in severity
of diffuse thyroid C-cell hyperplasia in both sexes.

Cancer	Based on the negative carcinogenic potential of fenamidone in
rats and mice, HED classified fenamidone as “not likely” to be a
human carcinogen by all relevant routes of exposure.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

3.4	Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  When the appropriate
screening and/or testing protocols being considered under the Agency’s
Endocrine Disrupter Screening Program (EDSP) have been developed and
vetted, fenamidone may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	Dietary Exposure/Risk Characterization

4.1	Metabolism and Environmental Degradation

D314116, T. Bloem, 6/21/07, Human Health Risk Assessment

TXR 0052287, T. Bloem, 5/25/04, MARC Memorandum

The nature of the residue in plants, animals, rotational crops and water
is adequately understood based on previously submitted data detailed in
the citation above.  The residues of concern for tolerance setting and
risk assessment purposes are summarized in the table below.

Table 4.1.  Fenamidone Residues of Concern 

Matrix	Tolerance Expression	Residues for Risk Assessment

Registered/proposed primary crops excluding root vegetables	fenamidone
fenamidone, RPA 717879 (DADK-Fen), RPA 408056 (DA-Fen), RPA 405862

Root vegetables	fenamidone	fenamidone, RPA 413255

Animal commodities 	fenamidone, RPA 717879 (DADK-Fen)	fenamidone, RPA
717879 (DADK-Fen), RPA 408056 (DA-Fen)

Rotational Crops	fenamidone, RPA 717879 (DADK-Fen)	fenamidone, RPA
717879 (DADK-Fen), and RPA 408056 (DA-Fen) (free and conjugated)

Water

Fenamidone, RPA 412636, RPA 412708, RPA 411639, RPA 413255, RPA 409446,
and RPA 410995

4.2 	Analytical Methodology

4.2.1	Data Collection Methodology

D357372, A. LaMay, 2/24/09, Residue Chemistry Chapter

Rotational crop field trial data for field corn, sweet corn and soybeans
were generated using Bayer CropScience analytical method RP0002P0801. 
Briefly, the method involves extracting residues of fenamidone, RPA
717879, and RPA 408056 from field corn, sweet corn and soybean samples
with aqueous acetone.  Extracts were filtered and acidified and residues
were quantified using HPLC/MS/MS (high performance liquid chromatography
with electrospray ionization/tandem mass spectrometry detection). 
Residues are reported as parent compound and the combined residues of
RPA 717879 and RPA 408056, converted to RPA 717879.  HED notes that the
residue of concern for risk assessment purposes in rotational crops
includes RPA 408056 (free and conjugated).  The registrant has not
provided sufficient evidence to demonstrate that residues of RPA 408056
conjugated are converted to RPA 717879 during the hydrolysis step of
this analytical method.  Therefore, HED does not consider the method
adequately validated for conjugated residues of RPA 408056.  The method
RP0002P0801 has been adequately validated and is acceptable for
determining residues of fenamidone, RPA 717879 and RPA 408056 (free) in
field corn grain, field corn forage, field corn stover, sweet corn
kernel plus cob with husk removed (K + CWHR), sweet corn forage sweet
corn stover, soybean seed, soybean forage and soybean hay.  The lower
limit of method validation (LLMV) is 0.020 ppm for each analyte in all
matrices.

 

4.2.2	Enforcement Methodology

D352806, D. Davis, 12/18/08, Residue Chemistry Chapter

D357372, A. LaMay, 2/24/09, Residue Chemistry Chapter

The current tolerance enforcement method entitled RPA407213:  method of
Analysis for RPA 407213 and its Metabolites RPA 717879, RPA 408056 and
RPA 405862 (MRID No. 45385918), a liquid chromatographic method coupled
with tandem mass spectrum detection (LC/MS/MS) has been radiovalidated. 
Further the method has undergone successful ILV (independent laboratory
validation) as well as validation by the Agency on a number of
commodities including potato, cucumber, cantaloupe, lettuce, onion,
tomato (fruit, paste, and puree), spinach, and wheat (forage, hay,
straw, grain, bran, flour, shorts, germ, and middlings).  HED concludes
that this method is also suitable to enforce the new plant tolerances
proposed in this petition.  HED notes that since residues of fenamidone
are detected through FDA Multi-Residue Method Protocol D (see below),
this protocol can also serve as an enforcement methodology.

4.3	Drinking Water Residue Profile

D352807, J. Hetrick, 10/9/08, Drinking Water Assessment

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) and were
incorporated directly into the acute and chronic dietary assessments.  

Monitoring data are not available for residues of fenamidone and its
metabolites in water; therefore EFED has provided modeled values for
ground and surface water.  The modeled EDWCs (estimated drinking water
concentrations) are reported for total fenamidone residues, which
includes parent and its degradation products, RPA 412636, RPA 412108,
RPA 411639, RPA 413255, RPA 409446, and RPA 410995.  Surface water EDWCs
were calculated using a Tier II model for surface water PRZM (Version
3.122) and EXAMS (Version 2.98.04) using the PE5 platform.  The EDWC in
ground water were estimated using SCI-GROW (Version 2.3).  EDWCs in
surface source water were corrected using the default percent crop area
factor (0.87).  The default PCA was applied because fenamidone can be
used on numerous crops.  No water treatment effects were considered in
this assessment.  These models and their descriptions are available at
the EPA internet site:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .

aximum Tier II EDWCs of total fenamidone residues in surface source
water are not expected to exceed 47.88 μg/L for the 1 in 10 year daily
peak concentration, 12.86 μg/L for the 1 in 10 year annual average
concentration, and 6.89 μg/L for the 30 year annual average
concentration.  The maximum concentration of total fenamidone residues
in shallow groundwater are not expected to exceed 176 μg/L.  

4.4	Food Residue Profile

D352806, D. Davis, 12/18/08, Residue Chemistry Chapter

D357372, A. LaMay, 2/24/09, Residue Chemistry Chapter

Plant Commodities

No new residue data were provided to support the requested new uses on
the root vegetable subgroup 1B (except radish), okra, turnip greens,
cilantro and grapes grown east of the Rocky Mountains.  IR-4 has
proposed to translate residue data and tolerance levels for these new
commodities from existing use information.  With the exception of the
use on turnip greens, HED concurs with the proposed translations. 
Carrot data will be translated to members of the root vegetable subgroup
1B (except radish).  Non-bell pepper data will be translated to okra and
parsley data will be translated to cilantro.  Previously submitted
European data will be translated to support a domestic use on grapes
grown east of the Rocky Mountains.  While HED concurs with the
translation of data from the leafy brassica greens subgroup 5B to turnip
greens, the establishment of a use on turnip greens would result in a
significant increase in the dietary burden for livestock.  At this time
there is insufficient data to determine the extent to which residues of
fenamidone would transfer to ruminant commodities as a result of the
feeding of fenamidone treated turnip greens; therefore, HED is currently
recommending against the requested tolerance on turnip greens and is
requiring that the label be amended to allow uses on turnip cultivars
grown for root production only. 

An adequate number of field trials with appropriate geographic
representation have been provided to allow HED to establish rotational
crop tolerances to support a 30-day PBI for field corn, sweet corn and
soybeans.  Sufficient storage stability data are available to support
the field trial data and the data were generated using an appropriate
data collection method.  Rotational crop field trial samples were
analyzed for residues of fenamidone and the combined residue of its
metabolites RPA 717879 (DADK-Fen) and free RPA 408056 (DA-Fen),
converted to RPA 717879 and reported as RPA 717879.  The method limit of
quantitation (LOQ) for both fenamidone and RPA 717879 is 0.02 ppm. 
Combined residues of fenamidone and its metabolites were <0.04 ppm in
field corn grain, sweet corn kernel plus cob with husk removed (K +
CWHR), and soybean seed.  Combined residues of parent and metabolites
ranged from <0.04 ppm – 0.028 ppm in field corn forage and from <0.04
ppm – 0.17 ppm in field corn stover.  Combined residues of fenamidone
and its metabolites ranged from <0.04 ppm – 0.12 ppm in sweet corn
forage and from <0.04 ppm - 0.35 ppm in sweet corn stover.  Residues of
parent and metabolites ranged from <0.04 ppm – 0.10 ppm in soybean
forage and from <0.04 ppm – 0.17 ppm in soybean hay.  Residue values
are summarized in the table below.



Table 4.4.1.  Summary of Fenamidone Residues from the Rotational Crop
Trials on Corn and Soybean.       

Crop Matrix	Applic. Rate

(lb ai/A)	PBI (days)	Combined Residues (ppm)*    

	Mean	Std. Dev.	HAFT 	Min.	Max.

Soybean (proposed use = 0.27 lb ai/A total application rate, 30-day PBI)
      

Forage	0.796 – 0.813	 30	0.054	0.020	0.10 	<0.04 	0.10

Hay	0.796 – 0.813	 30	 0.072	 0.037	0.17 	 <0.04	 0.17

Seed	0.796 – 0.813	 30	 <0.04	 0.001	<0.04 	 <0.04	 <0.04

Field Corn (proposed use = 0.27 lb ai/A total application rate, 30-day
PBI)       

Forage	0.798 - 0.820 	 30	 0.066	0.055 	0.28 	<0.04 	0.28 

Grain	 0.798 – 0.820	 30	 <0.04	 0.001	<0.04	 <0.04	 <0.04

Stover	 0.798 – 0.820	30	0.062	0.038	0.17	<0.04	0.17

Sweet Corn (proposed use = 0.27 lb ai/A total application rate, 30-day
PBI)       

Forage 	0.797 – 0.826 	 30	 0.055	0.025 	0.12 	<0.04 	0.12 

K+CWHR	 0.797 – 0.826	 30	 <0.04	 0.001	<0.04	 <0.04	 <0.04

Stover	0.797 – 0.826	30	0.092	0.077	0.35	<0.04	0.35

*Combined residues are parent compound and metabolites RPA 717879
(DADK-Fen) and free RPA 408056 (DA-Fen), converted to RPA 717879 and
reported as RPA 717879.

Residues of conjugated RPA 405862 were not reported for field corn,
sweet corn, or soybean rotation crops, but are a residue of concern in
rotational crops for risk assessment purposes.  In the absence of data
on conjugated RPA 405862, HED will translate information on the relative
ratios of residues of conjugated RPA 405862 to RPA 717879 from related
crops to derive a conservative risk assessment.  Residues to be used in
dietary risk assessment are shown in the table below.  

Table 4.4.2.  Summary of Fenamidone Residue Values for Dietary Risk
Assessment

Crop/Commodity	Residue Value (ppm)	Comment

Field Corn and processed commodities	0.218	Maximum rotational crop field
corn residue data reported <0.02 ppm for fenamidone and <0.02 ppm for
combined residues of RPA 717879 and RPA 405862 (free).  Residues of
conjugated RPA 405862 were not reported, but are a residue of concern in
rotational crops.  Residues of RPA 405862 were 8.5x residues of RPA
717879 from the wheat confined rotational crop study.  Total residue of
concern for field corn and processed commodities is calculated as 0.02
ppm (fenamidone) + 0.02 ppm (RPA 717879 and free RPA 405862) + 0.02 x
8.9 (ratio to yield conjugated RPA 405862) = 0.218 

Sweet Corn (K + CWHR)	0.218	Maximum rotational crop sweet corn (K+CWHR)
residue data reported <0.02 ppm for fenamidone and <0.02 ppm for
combined residues of RPA 717879 and RPA 405862 (free).  Residues of
conjugated RPA 405862 were not reported, but are a residue of concern in
rotational crops.  Residues of RPA 405862 were 8.5x residues of RPA
717879 from the wheat confined rotational crop study .  Total residue of
concern for sweet corn (K+CWHR) is calculated as 0.02 ppm (fenamidone) +
0.02 ppm (RPA 717879 and free RPA 405862) + 0.02 x 8.9 (ratio to yield
conjugated RPA 405862) = 0.218 

Soybean seed and processed commodities	0.232	Maximum rotational crop
soybean seed residue data reported <0.02 ppm for fenamidone and <0.02
ppm for combined residues of RPA 717879 and RPA 405862 (free).  Residues
of conjugated RPA 405862 were not reported, but are a residue of concern
in rotational crops.  Residues of RPA 405862 were 9.6x residues of RPA
717879 from the highest confined rotational crop study (turnips).  Total
residue of concern for soybean seed and processed commodities  is
calculated as 0.02 ppm (fenamidone) + 0.02 ppm (RPA 717879 and free RPA
405862) + 0.02 x 9.6 (ratio to yield conjugated RPA 405862) = 0.232 

Processed Commodities

The only processed commodities associated with this petition are those
associated with field corn grain and soybean seed processing.  Bayer
CropScience has submitted a data waiver request based on a rotational
crop study where either soybeans or field corn were planted at a 30-day
PBI following application to the soil at a 5X rate.    Given that this
request is for a rotational crop use, that residues in field corn grain
and soybean seed were <LLMV (<0.04 ppm) in all the rotational crops
trials with a 30-PBI following treatment to the soil at a 1X application
rate, and that no detectable residues were seen in field corn grain and
soybean seed from a 30-day PBI with a 5X soil application rate, HED
concurs that no additional processing data are required.  Detectable
residues of fenamidone are not expected in field corn and soybean
processed commodities and tolerances for processed field corn and
soybean commodities are not required.    

Animal Commodities

Field corn grain, forage, stover, aspirated grain fractions and milled
byproducts, as well as sweet corn forage stover and cannery waste and
soybean seed, forage, hay, aspirated grain fractions, meal, hulls and
silage are all animal feed items.  HED has determined that the animal
feed items associated with field corn, sweet corn and soybean are not
likely to result in residues in feed items which are higher than
residues in feed items currently used to calculated dietary burden. 
Therefore, these new rotational crop uses are not likely to increase the
dietary burden for ruminants, poultry or swine and no new animal
tolerances are required.

Turnip greens are fed exclusively to dairy cattle; therefore, HED has
calculated a maximum reasonably balanced diet (MRBD) for dairy cattle
based on the recent guidance on revised Table 1 considerations (June
2008).  A revised dairy cattle diet which includes turnip greens results
in a substantial increase in the MRBD as shown in the table below.  



Table 4.4.3.  Fenamidone MRBD Calculations for Dairy Cattle

Crop1	Residue (ppm)2	%Dry Matter2	% Diet	Residue in Diet

	Dairy Cattle	Dairy Cattle

Wheat hay (R)	3.16	88	15	0.54

Turnip greens (R)	29.21	30	30	29.21

Wheat milled byproducts (CC)	0.62	88	30	0.21

Turnip root	0.17	15	5	0.06

Carrot (CC)	0.17	12	10	0.14

Cottonseed meal (PC)	0.08	89	10	0.01

Total	30.17

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

2  For 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 –
highest field trial value used for combined residues.

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, 2.3 ppm, and 7.9 ppm.  Milk was collected throughout the
study and muscle, fat, liver, and kidney were collected at sacrifice. 
The current MRBD for dairy cattle including the newly proposed use on
turnip greens would results in a MRBD of 30 ppm which exceeds the
highest dose tested in the lactating dairy cattle study by more than
3-fold.   HED concludes that it is not possible to determine if revised
milk and meat tolerances might be required as a result of feeding dairy
cattle treated turnip greens; therefore, HED does not consider the
turnip green use adequately supported by residue data. 

A ruminant feeding study reflecting a concentration in the diet which
brackets the newly calculated MRBD would be required to support the
requested use on turnip greens. 

4.5	Tolerances and International Residue Limits

Tolerance recommendations for the root vegetable subgroup 1B (except
radish), okra, cilantro and grapes are translated from existing uses as
described in Section 4.4 of this memorandum.   

Tolerance level recommendations for field corn grain, sweet corn (K +
CWHR) and soybean seed are based on the combined LOQs for the parent
compound and residues converted to RPA 717879.  Tolerance
recommendations for the remaining rotational crop tolerances were
derived using the MRL calculator with combined fenamidone and RPA 717879
residues.

There are no Codex, Canadian or Mexican MRLs (maximum residue levels)
for residues of fenamidone in any of the commodities that are the
subject of this risk assessment.  There are no issues with respect to
international harmonization as a result of the proposed new uses that
are the subject of this petition.  The IRL (international residue limit)
status sheet is included in this document as Attachment 4.



Table 4.5. 	Tolerance Summary for Fenamidone.

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

40 CFR §180.579(a)

Vegetables, root, except sugar beet, subgroup 1B, except radish	0.2	0.15
Vegetable, root, except sugar beet, subgroup 1B, except radish

Turnip, leaves	55	--	Cannot recommend for a tolerance at this time.

Turnip, greens

Okra	3.5	3.5

	Coriander, leaves	60	60	Cilantro, leaves

Grape	1.0	1.0	For use on grapes grown east of the Rocky Mountains only

40 CFR §180.579(d)

Corn, field, grain	0.02	0.04	Tolerance is the sum of the method LOQs

Corn, sweet, kernel plus cob with husks removed	0.02	0.04	Tolerance is
the sum of the method LOQs

Corn, field, forage	0.50	0.30

	Corn, sweet, forage	0.15	0.20

	Corn stover	0.35	0.30	Corn, field, stover

0.45	Corn, sweet, stover

Soybean, seed	0.02	0.04	Tolerance is the sum of the method LOQs

Soybean, forage	0.20	0.15

	Soybean, hay	0.20	0.25

	

4.6	Dietary Exposure and Risk

D362172, D. Davis, 2/23/09, Dietary Exposure and Risk Memorandum

4.6.1.	Acute Dietary Exposure/Risk

A conservative acute dietary risk assessment was conducted which used
maximum field trial residue values, assumed 100 percent crop treated (%
CT) for all commodities, incorporated DEEM™ default processing factors
for many processed commodities and included modeled drinking water
estimates.  The estimated exposure (food and water) to the U.S.
population from the existing and proposed new uses of fenamidone
resulted in an estimated risk equivalent to 3% of the acute population
adjusted dose (aPAD) at the 95th percentile.  The most highly exposed
subpopulation was children 1 - 2 years with an estimated exposure
equivalent to 5% of the aPAD at the 95th percentile.  There are no acute
dietary risks of concern for the existing and newly proposed uses of
fenamidone.  Acute dietary results for all subgroups are shown in Table
4.6.4, below.

4.6.2	Chronic Dietary Exposure/Risk

A conservative chronic dietary risk assessments was conducted which used
maximum field trial residue values, assumed 100 % CT for all
commodities, incorporated DEEM™ default processing factors for many
processed commodities and included modeled drinking water estimates. 
The estimated exposure (food and water) to the U.S. population from the
existing and proposed new uses of fenamidone resulted in an estimated
risk equivalent to 51% of the chronic population adjusted dose (cPAD). 
The most highly exposed subpopulation was children 1 – 2 years with an
estimated exposure equivalent to 88% of the cPAD.  There are no chronic
dietary risks of concern associated with the existing and newly proposed
uses of fenamidone.  Chronic dietary results for all subgroups are shown
in Table 4.6.4, below.

4.6.3	Cancer Dietary Risk

Fenamidone is not likely to be a human carcinogen; therefore a cancer
dietary risk assessment is not required for this chemical.  

4.6.4	Acute and Chronic Dietary Exposure and Risk Summary

Table 4.6.4.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for Fenamidone

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.041604	3	0.014373	51	N/A	N/A

All Infants (< 1 year old)	0.048649	4	0.021424	76	N/A	N/A

Children 1-2 years old	0.062413	5	0.024944	88

Children 3-5 years old	0.056283	4	0.022475	79

Children 6-12 years old	0.042732	3	0.015420	54

Youth 13-19 years old	0.035419	3	0.011678	41

Adults 20-49 years old	0.038239	3	0.013151	46

Adults 50+ years old	0.040975	3	0.013959	49

Females 13-49 years old	0.040306	3	0.013261	47

N/A is “not applicable”.  Populations with highest exposure are
shown in bold.  

* PAD = population adjusted dose.

5.0 	Residential Exposure/ Risk Pathway

There are no proposed residential uses of fenamidone that result in
residential exposure; therefore, residential handler and post
application exposure and risk assessments were not conducted for
fenamidone.

6.0 	Aggregate Risk Assessments and Risk Characterization

There are no proposed uses which result in residential exposures;
therefore, aggregate risk assessments should consider exposure from food
and water only.  Since the dietary exposure analysis included both food
and drinking water estimates, the exposure and risk estimates presented
in Sections 4.6.1 and 4.6.2 represent aggregate acute and aggregate
chronic exposure and risk, respectively.  There are no acute or chronic
aggregate risks of concern for the existing and proposed uses of
fenamidone.

7.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to fenamidone and any other
substances and fenamidone does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that fenamidone has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

  TC \l1 "8.0	Cumulative Risk Characterization/Assessment 

8.0	Occupational Exposure

D352806, A. LaMay, 2/24/09

An occupational exposure/risk estimate assessment was conducted for
proposed IR-4 uses on the root vegetable subgroup 1B (except radish),
okra, turnip Greens, cilantro and grapes grown east of the Rocky
Mountains.  No occupational assessment was conducted for proposed uses
on rotational crops of field corn, sweet corn and soybeans, as there is
no direct application to these crops.

8.1 	Occupational Handler Exposure

Since Reason( 500 SC Fungicide’s proposed label is intended for
professional use, an occupational handler assessment was conducted.  The
occupational risk assessment was completed assuming the maximum label
application rate of 0.267 lb ai/ acre for root vegetables, okra, turnip
greens, and cilantro, and maximum proposed label application rate of
0.0892 lb ai/A for grapes East of the Rocky Mountains.

Pesticide handler exposure to Reason( 500 SC is likely to occur during
its use in a variety of occupational environments.  The anticipated use
patterns and current labeling indicate several occupational exposure
scenarios based on types of equipment and techniques that can
potentially be used for Reason( 500 SC applications.  The quantitative
exposure/risk assessment developed for occupational handlers of
fenamidone is based on the following scenarios.  A handler would
mix/load or apply fenamidone for each crop by:

- mixing/loading liquid for aerial application 

- mixing/loading liquid for groundboom

- mixing/loading liquid for airblast (grapes only)

- applying sprays by an enclosed cockpit fixed-wing aircraft

- applying sprays with groundboom (open cab)

- applying sprays with airblast (grapes only)

- flagging for aerial spray application 

Exposure scenarios were assessed with baseline dermal and inhalation
exposure, as well as with dermal PPE (i.e., long pants, long sleeved
shirt, socks plus shoes, gloves) as is the PPE on the proposed label to
mitigate risk.

Occupational dermal and inhalation daily dose values were calculated and
are presented in this document.  For occupational handlers, dermal and
inhalation MOEs above 100 do not exceed HED’s level of concern.  All
occupational exposure risk estimates for Reason( 500 SC formulation, for
short- and intermediate- term exposures for handlers, do not exceed
HED’s level of concern with minimum dermal PPE (single layer plus
gloves) and baseline inhalation protection (no respirator).  Short-term
aggregated MOEs range from 2,200 to 58,000; and intermediate-term
aggregated MOEs range from 1,000 to 26,000 (Table 8.1).  The proposed
label requires the use of single layer plus gloves for handlers.    

Table 8.1: Short- and Intermediate-Term Exposures and Risks for
Occupational Handlers of Fenamidone 

Exposure Scenario	Application Rate (lb ai/ acre)1	Area Treated Daily2
(acres)	

Baseline Dermal MOE3	Baseline plus gloves Dermal MOE4	Baseline
Inhalation MOE5	

Total MOE6 with Baseline Dermal and Inhalation 	Total MOE7 with Baseline
plus gloves Dermal and Baseline Inhalation

Mixer/Loader Scenarios

Open Mixing, Liquids, Aerial/ Chemigation, IR-4 Vegetables (ST)	0.267
350

	27	3,400	6,500	27	2,200

Open Mixing, Liquids, Aerial/ Chemigation, IR-4 Vegetables (IT)

	12	1,500	2,900	12	1,000

Open Mixing, Liquids, Aerial/ Chemigation, Grapes (ST)	0.0892

80	10,000	19,000	80	6,700

Open Mixing, Liquids, Aerial/ Chemigation, Grapes (IT)

	36	4,600	8,700	36	3,000

Open Mixing, Liquids, Groundboom, IR-4 Vegetables (ST)	0.267	80	120
15,000	28,000	120	9,700

Open Mixing, Liquids, Groundboom, IR-4 Vegetables (IT)

	53	6,700	13,000	53	4,400

Open Mixing, Liquids, Groundboom, Grapes (ST)	0.0892

350	44,000	85,000	350	29,000

Open Mixing, Liquids, Groundboom, Grapes (IT)

	160	20,000	38,000	160	13,000

Open Mixing, Liquids, Airblast, Grapes (ST)

40	700	89,000	170,000	700	58,000

Open Mixing, Liquids, Airblast, Grapes (IT)

	320	40,000	76,000	310	26,000

Applicator Scenarios

Spray, Aerial, Enclosed, IR-4 Vegetables (ST)*	0.267	350	14,000	110,000
13,000

Spray, Aerial, Enclosed, IR-4 Vegetables (IT)*

	6,400	51,000	5700

Spray, Aerial, Enclosed, Grapes (ST)*	0.0892

4,200	340,000	38,000

Spray, Aerial, Enclosed, Grapes (IT)*

	19,000	150,000	17,000

Spray, Groundboom, Open, IR-4 Vegetables (ST)	0.267	80	24,000	24,000
46,000	16,000	16,000

Spray, Groundboom, Open, IR-4 Vegetables (IT)

	11,000	11,000	21,000	7,200	7,200

Spray, Groundboom, Open, Grapes (ST)	0.0892

73,000	73,000	140,000	48,000	48,000

Spray, Groundboom, Open, Grapes (IT)

	33,000	33,000	62,000	21,000	21,000

Spray, Airblast, Grapes (ST)

40	5,700	8,500	45,000	5,000	7,200

Spray, Airblast, Grapes (IT)

	2,500	3,800	20,000	2,300	3,200

Flagger Scenarios

Liquid, Flagger, IR-4 Vegetables (ST)	0.267	350	7,100	2,2000	6,500	5,400
5,000

Liquid, Flagger, IR-4 Vegetables (IT)

	3,200	10,000	2,900	2,400	2,300

Liquid, Flagger, Grapes (ST)	0.0892

21,000	67,000	19,000	16,000	15,000

Liquid, Flagger, Grapes (IT)

	9,500	30,000	8,700	7,200	6,800

1Application rates are based on maximum values found on the label.

2Area treated daily values are from the EPA HED estimates of acreage
treated in a single day for each exposure scenario of concern.

Daily Dermal Dose = (Dermal Unit Exposure (mg ai /lb ai) * Application
Rate (lb ai /A) * Area Treated (A /day))/ Body Weight (70 kg for
short-term durations and 60 kg for intermediate-term durations) * Dermal
Absorption Factor of 10% (0.1)

Daily Inhalation Dose = (Inhalation Unit Exposure (µg ai / lb ai) *
Conversion Factor (1 mg /1000 µg) * Application Rate (lb ai /A) * Area
Treated (A /day)) / Body Weight (70 kg for short-term durations and 60
kg for intermediate-term durations) 

3Baseline Dermal MOE =  PoD (NOAEL of 10.4 mg/kg/day for ST durations
and 5.45 mg/kg/day for IT durations)/ Daily dermal dose (mg/kg/day). 
Baseline dermal exposure assesses use of single layer clothing, no
gloves.

4Baseline plus gloves Dermal MOE =  PoD (NOAEL of 10.4 mg/kg/day for ST
durations and 5.45 mg/kg/day for IT durations)/ Daily dermal dose
(mg/kg/day).  Baseline plus gloves dermal exposure assesses use of
single layer clothing, plus gloves.

5Baseline Inhalation MOE = PoD (NOAEL of 10.4 mg/kg/day for ST durations
and 5.45 mg/kg/day for IT durations) / Daily inhalation dose
(mg/kg/day).  Baseline inhalation exposure assesses no respirator
protection.

6Total MOE with Baseline Dermal and Inhalation = 1/ (1/Baseline Dermal
MOE + 1/Baseline Inhalation MOE)

7Total MOE with Baseline plus gloves Dermal and Inhalation = 1/
(1/Baseline Dermal plus gloves MOE + 1/Baseline Inhalation MOE)

*Enclosed Cab Aerial Application has only Engineering Control Protection
for Dermal and Inhalation routes of exposure

8.2  	Occupational Postapplication Exposure

HED expects that postapplication exposure will occur for fenamidone
application.  Since no postapplication data were submitted in support of
this proposed use, exposures during postapplication activities were
estimated using dermal transfer coefficients from ExpoSAC Policy #3.1:
Agricultural Transfer Coefficients, August 2000.  

A postapplication dermal exposure assessment was conducted; short-term
dermal MOEs (Table 8.2.1 range from 300 (High exposure activities for
Brassica crop) to 9,100 (low exposure activities for vine trellis crops)
and intermediate-term dermal MOEs (Table 8.2.2) range from 140 (high
exposure for Brassica crop) to 4,100 (low exposure to vine trellis
crops).  Occupational postapplication MOEs for the exposure scenario do
not exceed HED’s level of concern (MOEs > 100) for both short- and
intermediate-term exposures with baseline dermal PPE.  PPE is usually
not required for worker re-entry, and therefore these postapplication
risk estimates are based on baseline dermal PPE.  

  SEQ CHAPTER \h \r 1  Table 8.2.1 –   SEQ CHAPTER \h \r 1 Fenamidone
Occupational Postapplication Short-Term Risks

(Reflecting Label Maximum Application Rates)

Crop Group	Application Rate

 (lb a.i/acre)	MOE on Day 0

Low	Medium	High	Very High

Root Vegetables (except sugar beet, subgroup 1B, except radish)	0.267
5100	1000	610	N/A

Fruiting Vegetables (okra)	0.267	3000	2200	1500	N/A

Brassica (Turnip greens)	0.267	760	380	300	N/A

Leafy Vegetables (Cilantro)	0.267	3000	1000	610	N/A

Vine trellis crops (Grapes)	0.0892	9100	4500	910	450

MOE = PoD (NOAEL of 10.4 mg/kg/day) / Daily Dose (mg/kg/day)

  SEQ CHAPTER \h \r 1  Table 8.2.2 –   SEQ CHAPTER \h \r 1 Fenamidone
Occupational Postapplication Intermediate-Term Risks

(Reflecting Label Maximum Application Rates)

Crop Group	Application Rate

 (lb a.i/acre)	MOE on Day 0 

Low	Medium	High	Very High

Root Vegetables (except sugar beet, subgroup 1B, except radish)	0.267
2300	450	270	N/A

Fruiting Vegetables (okra)	0.267	1400	970	680	N/A

Brassica (Turnip greens)	0.267	340	170	140	N/A

Leafy Vegetables (Cilantro)	0.267	1400	450	270	N/A

Vine trellis crops (Grapes)	0.0892	4100	2000	410	N/A

MOE = PoD (NOAEL of 5.45 mg/kg/day) / Daily Dose (mg/kg/day)

8.3 	REI

Fenamidone is classified as Toxicity Category III for acute oral, acute
dermal and primary eye irritation; and as Toxicity Category IV for acute
inhalation and primary skin irritation.  It is not a dermal sensitizer. 
Therefore, the WPS REI of 12 hour is sufficient to protect agricultural
workers.  Exposure to treated crop can be expected on the day of
application (t=0) as the REI is 12 hours.

9.0	Data Needs and Label Recommendations

9.1	Toxicology

As the following data are considered confirmatory in nature, HED
requests that they be addressed as conditions of registration.

An abbreviated DNT in the Sprague Dawley rat with measurements of brain
weight and brain morphometric data to confirm findings in the full DNT
conducted in the Wistar rat. 

While no evidence of immunotoxicity was seen in the fenamidone database,
as specified in the new 40 CFR Part 158 data requirements, an
immunotoxicity study on fenamidone should be conducted.  

9.2	Residue Chemistry

Prior to a favorable recommendation, HED requests the following:

The proposed Reason® 500 SC Reason label should be amended to limit use
on turnip cultivars for root production only.  If the petitioner should
wish to remove this label restriction and support the establishment of a
turnip green tolerance, a ruminant feeding study reflecting a
concentration in the diet which brackets the newly calculated maximum
reasonably balanced diet for dairy cattle would be required. 

The petitioners should submit revised section Fs reflecting the
commodity definitions and levels shown in Table 4.5.

9.3	Occupational and Residential Exposure

None

10.0	Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

11.0	Human Studies

This assessment relies in part on data from studies in which adult human
subjects were intentionally exposed to a pesticide.  These studies,
which comprise the Pesticide Handlers Exposure Database (PHED), have
been determined to require a review of their ethical conduct, and
received that review.  The studies in PHED were considered appropriate
(or ethically conducted) for use in risk assessments.

References

Fenamidone (PC Code 046679) - Human-Health Risk Assessment for Proposed
Uses on Cotton, Tobacco, Carrot, Sunflower, Brassica Vegetables (group
5), Leafy (except Brassica) Vegetables (group 4), Fruiting Vegetables
(group 8) and Strawberry (rotational crop).  D314116, T. Bloem, 6/21/07.

Fenamidone:  3rd HIARC Report, TXR # 0052379, W. Dykstra, 2/19/04.

Fenamidone HASPOC Report, TXR # 0054626, R. Mitkus, 6/19/07.

Fenamidone MARC Memorandum, TXR # 0052287, T. Bloem, 5/25/04.

Fenamidone:  Residue Chemistry Summary Document to Support New Uses and
Tolerances on the Root Vegetable Subgroup 1B (except radish), Okra,
Turnip Greens, Cilantro Leaves and Grapes Grown East of the Rocky
Mountains.  D352806, D. Davis, 12/18/08.

Fenamidone:  Residue Chemistry Summary Document to Support 	New
Rotational Crop Uses and Tolerances on Field Corn, Sweet Corn and
Soybean.  D357372, A. LaMay, 2/24/09.

Fenamidone Drinking Water Assessment for Total Residues in Surface and
Water for Uses on Root vegetables (except sugar beets; Subgroup 1B,
except radishes), okra, turnip greens, cilantro, and grapes East of the
Rockies.  D352807, J. Hetrick, 10/9/08.

Fenamidone – Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for Section 3 Registration Actions
to Add New Uses on the Root Vegetable Subgroup 1B (except radish), Okra,
Turnip Greens, Cilantro Leaves, Grapes Grown East of the Rocky Mountains
and Rotational Crop Uses for Field Corn, Sweet Corn and Soybeans. 
D362172, D. Davis, 2/23/09.

Fenamidone: Occupational Exposure/Risk Assessment for Proposed New Use
of Fenamidone on Root vegetables (except sugar beet, subgroup 1B, except
radish), okra, turnip greens, cilantro, and grapes east of the Rocky
Mountains. D352806, A. LaMay, 2/24/09

Attachment 1.  Chemical Structures

Structure and Nomenclature Information for Fenamidone and its
Metabolites

Name	Structure

Fenamidone; RPA 407213

 

 

14C-C-phenyl-fenamidone

DA-Fen; RPA 408056 (racemic mixture)

RPA 405862 (racemic mixture)

RPA 410193 (S enantiomer)

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

DADK-Fen; 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.  Acute Toxicity of Fenamidone

Table 4:  Acute Toxicity of Fenamidone Technical.

Guideline

No.	Study Type	MRID #	Results	Toxicity Category

81-1	Acute Oral	45386011	LD50 = 2028 mg/kg (F)

LD50 > 5000 mg/kg (M)	III

81-2	Acute Dermal	45386012	LD50 > 2000 mg/kg	III

81-3	Acute Inhalation	45386013	LC50 > 2.1 m/L	IV

81-4	Primary Eye Irritation	45386015	moderate irritant	III

81-5	Primary Skin Irritation	45386014	non-irritating	IV

81-6	Dermal Sensitization	45386016	not a sensitizer	not applicable

Attachment 3.  Toxicity Profile for Fenamidone

Guideline No./Study Type	Results

870.3100a	

90-Day oral toxicity rodents with parent- rat	NOAEL = 29.68/35.39
mg/kg/day in males and  females, respectively.

LOAEL = 305.48/337.19 mg/kg/day in males and females, respectively,
based on decreased body weights, body weight gains, and food consumption
in males and females, enlargement and prominent germinal centers in the
spleen in males, and periportal vacuolation and bile duct hyperplasia in
the liver of males.

870.3100a

90-Day oral toxicity rodents with parent-rat	NOAEL = 10.41/12.00
mg/kg/day in males and  females, respectively.

LOAEL = 68.27/83.33 mg/kg/day in males and females, respectively, based
on increased liver weights and incidence of ground glass appearance of
the hepatocytes (mostly centrilobular) in the males. 

870.3100a

90-Day oral toxicity rodents with the RPA 412636 plant metabolite-rat.
NOAEL = 6.419/7.725 mg/kg/day in males and females, respectively.

LOAEL = 32.860/39.111 mg/kg/day in the males and females, respectively,
based on increased liver weights, liver enlargement, centrilobular
hepatocyte hypertrophy and vacuolation, and follicular epithelial height
of the thyroid in males. 

870.3100a

90-Day oral toxicity rodents with RPA 410193 plant metabolite-rat	NOAEL
= 9.4/11.5 mg/kg/day in males and females, respectively.

LOAEL = 93.3/114.9 mg/kg/day in males and females, respectively, based
on liver enlargement and increased liver weights and cholesterol in the
males and on incidences of centrilobular hepatocellular hypertrophy in
the males and females.

870.3100b

90-Day oral toxicity rodents with parent-mice	NOAEL = 44.49/54.13
mg/kg/day in the males and females, respectively.

LOAEL = 220.17/273.86 mg/kg/day in the males and females, respectively,
based on mild hepatotoxicity as evidenced by increased liver weights and
incidences of pale liver and hepatic microvacuolation in the males and
decreased cholesterol and increased incidence of prominent lobulation of
the liver in the females.

870.3150b

90-Day oral toxicity non-rodents with parent-dogs	NOAEL =500 mg/kg/day
for males and females (HDT)

LOAEL = not determined

870.3200

21-Day dermal toxicity- rat	NOAEL = 1000 mg/kg/day in females. Not
established in males.

LOAEL = 1000 mg/kg/day in males based on decreased body weight, body
weight gain and food consumption.  The LOAEL was not observed in
females. 

870.3700a

Prenatal developmental with parent-rats 	Maternal NOAEL = 150 mg/kg/day

Maternal LOAEL = 1000 mg/kg/day based on decreased  body weight gains,
and decreased food consumption.

Developmental NOAEL = 150 mg/kg/day 

Developmental LOAEL = 1000 mg/kg/day based on decreased fetal weights
and incomplete ossification.

870.3700b

Prenatal developmental with parent-rabbits 	Maternal NOAEL = 10
mg/kg/day

Maternal LOAEL = 30 mg/kg/day based on increased liver weights.

Developmental NOAEL = 100 mg/kg/day

Developmental LOAEL = not observed.

870.3800

Reproduction and fertility effects with parent- rat	Parental/Systemic
NOAEL = 4.04/5.45 mg/kg/day in males and in females

Parental/Systemic LOAEL = 68.6/89.2 mg/kg/day in males and females based
on decreased absolute brain weight in F1 females. 

Reproductive/Offspring NOAEL = 4.04/5.45 mg/kg/day in males and females.

Reproductive/Offspring LOAEL = 68.6/89.2 based on decreased absolute
brain weight in F2 female pups.

870.4100b

Chronic toxicity (1 year)-dogs	NOAEL = 100 mg/kg/day in males and
females

LOAEL = 1000 mg/kg/day in males and females based on increased liver
weight, triglycerides, and biliary proliferation in males, and alkaline
phosphatase activity in both sexes.

870.4300

Chronic/Carcinogenicity - rats	NOAEL = 2.83/3.63 mg/kg/day in males and
females, respectively. 

LOAEL = 7.07/9.24  mg/kg/day in males and females based on an increase
in severity of diffuse thyroid C-cell hyperplasia in both sexes. .

Carcinogenic potential is considered negative. 

870.4200b

Carcinogenicity - mice	NOAEL = 47.5/63.8 mg/kg/day in males and in
females, respectively

LOAEL = 525.5/690.5 mg/kg/day in males and in females based on decreased
body weight, weight gain, food efficiency, increased food consumption
and absolute and relative (to body) liver weights and liver nuclear
pleomorphism in both sexes.

870.5265

Gene Mutation

with parent	Fenamidone was non-mutagenic when tested up to or cytotoxic
levels, in presence and absence of activation, in S. typhimurium strains
TA98, TA100, TA102, TA1535 and TA1537.

870.5265

Gene Mutation

with RPA 410193	RPA 410193  was non-mutagenic when tested up to 5,000
ug/plate or cytotoxic levels, in presence and absence of activation, in
S. typhimurium strains TA98, TA100, TA1535, and TA1537 and E. coli
strain WP2uvA. 

870.5265

Gene Mutation

with RPA 412708	RPA 412708  was non-mutagenic when tested up to 5,000
ug/plate or cytotoxic levels, in presence and absence of activation, in
S. typhimurium strains TA98, TA100, TA1535, and TA1537 and E. coli
strain WP2uvrA.

870.5265

Gene Mutation

with RPA 412636	RPA 412636 was non-mutagenic when tested up to 5,000
ug/plate or cytotoxic levels, in presence and absence of activation, in
S. typhimurium strains TA98, TA100, TA1535, and TA1537  and E. coli
strain WP2uvrA.

870.5300

Mouse lymphoma cell/mammalian activation gene forward mutation assay
(L5178Y hgprt) with parent	Fenamidone was non-mutagenic at doses up to
the limit of solubility (1600 ug/mL) in both the presence and absence of
S9 metabolic activation.

870.5300

Mouse lymphoma cell/mammalian activation gene forward mutation assay
(L5178Y hgprt) with RPA 412636.	RPA 412636 was non-mutagenic at doses up
to the limit of solubility (1600 ug/mL) in both the presence and absence
of S9 metabolic activation.

870.5300

Mouse lymphoma cell/mammalian activation gene forward mutation assay
(L5178Y hgprt) with RPA 410193.	RPA 410193 was non-mutagenic at doses up
to the limit of solubility (800 ug/mL) in both the presence and absence
of S9 metabolic activation.

870.5375

In vitro mammalian cytogenetics (Chromosomal aberration assay in human
peripheral blood) with parent.	There was evidence of chromosome
aberrations induce over background both in the presence and absence of
S-9 activation.

870.5395

In vivo Mouse Micronucleus

with parent.	Fenamidone was negative for chromosomal aberrations in the
cytogenetic assay when administered singly or for 2 days to CD-1 mice up
to 2000 mg/kg/day.

870.5395

In vivo mouse micronucleus

with RPA 412636	RPA 412636 was not clastogenic in the mouse micronucleus
test up to 350 mg/kg (HDT).

870.5395

In vivo mouse micronucleus with RPA 412708	RPA 412708 was not
clastogenic in the mouse micronucleus assay when tested once daily for 2
days up to cytotoxic levels of 150 mg/kg.

870.5395

In vivo mouse micronucleus with RPA 410193	RPA 410193 was not
clastogenic in the mouse micronucleus assay when tested once daily for 2
days up to cytotoxic levels of 2000 mg/kg.

870.5550

Unscheduled DNA synthesis

with parent	Fenamidone did not produce any evidence of unscheduled DNA
synthesis, as determined by radioactive tracer procedures (nuclear
silver grain counts),  in rat primary hepatocyte cultures exposed up to
cytotoxic levels.

870.5550

Unscheduled DNA synthesis

with parent	Fenamidone did not produce any evidence of unscheduled DNA
synthesis, as determined by radioactive tracer procedures (nuclear
silver grain counts),  in rat primary hepatocyte cultures exposed up to
cytotoxic levels.

870.6200a

Acute Neurotoxicity-rat	NOAEL = 125 mg/kg/day

LOAEL = 500 mg/kg/day based on urination, staining/soiling of the
anogenital region, mucous in the feces, and unsteady gait in females.

870.6200b

Subchronic Neurotoxicity Screening Battery-rat	NOAEL = 73.5/83.4
mg/kg/day in males and females, respectively.

LOAEL = 392.3/414.2 mg/kg/day in males and females based on decreased
absolute brain weight in males, and decreased body weight, weight gains,
and food consumption in both sexes.

870.6300

maternal NOAEL ≥ 429 mg/kg/day

maternal LOAEL not established

offpsring NOAEL = 92.3 mg/kg/day

offspring LOAEL = 429 mg/kg/day based on decreased body weight (9-11%)
and body weight gain (8-20%) during pre-weaning and decreased body
weight (4-6%) during post-weaning

870.7485

Metabolism and pharmacokinetics - rat	In a rat metabolism study with
C14- labeled fenamidone, Sprague-Dawley rats receive doses of 3 mg/kg
(single, low dose), 3 mg/kg x 14 days (repeated low dose) and 300 mg/kg
(high dose).  Fenamidone was well absorbed and rapidly excreted,
primarily in the urine and bile, at the low dose and repeated low dose. 
At 300 mg/kg, biliary excretion was not measured, although fecal
excretion was 50-68% of the dose. Tissue levels of radioactivity were
primarily found in the liver at the single low dose and in the thyroid
in the repeated and high dose studies. Metabolite identification
included RPA 408056 (racemic form of RPA 412708) and RPA 717879 (racemic
mixture of RPA 412636)

870.7600

Dermal Penetration-rat	Dermal penetration approximated 10% using the EPA
protocol for 10 hours of exposure.

Attachment 4.  International Residue Limit Status Sheet

  SEQ CHAPTER \h \r 1 INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:

(4H-Imidazol-4-one, 3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3
(phenylamino)-, (S)-)	Common Name:

Fenamidone	v Proposed tolerance

( Reevaluated tolerance

( Other	Date:

12/10/2008

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

√ No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition
Number: 7E7350

DP Barcode: 352806

Other Identifier:

Residue definition (step 8/CXL): N/A	Reviewer/Branch:  D. Davis & A.
LaMay/RRB1

	Residue definition: “Tolerances are established for residues of
fenamidone (4H-Imidazol-4-one,
3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3 (phenylamino)-, (S)-)
from the application of the fungicide fenamidone”

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

Crop Subgroup 1B (Root Vegetables, Except Sugar Beet), Excluding Radish
0.15 ppm

Turnip, forage, tops	55 ppm

Turnip, greens	55 ppm

Okra	3.5 ppm

Cilantro, leaves	60 ppm

Grapes (grown east of the Rockies only)	1.0 ppm

Field Corn grain (incl. processed commodities)	0.02 ppm

Sweet Corn Grain (K+CWHR)	0.02 ppm

Sweet Corn Forage	0.15 ppm

Field Corn Forage	0.50 ppm

Corn Stover	0.35 ppm

Soybean Seed	0.02 ppm

Soybean Forage	0.20 ppm

Soybean Hay	0.20 ppm

Limits for Canada	Limits for Mexico

( No Limits

( No Limits for the crops requested	√ No Limits

( No Limits for the crops requested

Residue definition:

(5S
)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidaz
ol-4-one

	Residue definition: N/A

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

Grapes	1.0

	Notes/Special Instructions:

S.Funk, 12/12/2008.

Attachment 5.  Justification for Immunotoxicity Study

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

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e to produce adverse effects (i.e., suppression) on the immune system.
Immunosuppression is a deficit in the ability of the immune system to
respond to a challenge of bacterial or viral infections such as
tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or
neoplasia.  Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic endpoints are inadequate to
characterize a pesticide’s potential immunotoxicity.  While data from
hematology, lymphoid organ weights, and histopathology in routine
chronic or subchronic toxicity studies may offer useful information on
potential immunotoxic effects, these endpoints alone are insufficient to
predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

Fenamidone	Human Health Risk Assessment	D353909

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