UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:		19-September-2007

Subject:	Fenamidone (PC Code 046679) - Human-Health Risk Assessment for
Proposed Uses on Cotton, Carrot, Sunflower, Brassica Vegetables (group
5), Leafy (except Brassica) Vegetables (group 4), Fruiting Vegetables
(group 8) and Strawberry (rotational crop).

Registration #:	5E6925	DP #:	344279

Decision #:	355885	40 CFR 	180.579

From:		Thomas Bloem, Chemist

				P.V. Shah, Toxicologist

			Kelly Lowe, Environmental Scientist

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

Thru:		P.V. Shah, Ph.D., Acting Branch Chief

			RAB1/HED (7509P)

To:			Tony Kish/Rosemary Kearns (RM 22); Barbara Madden/Shaja Brothers
(RM 05)

			Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the proposed/registered uses of fenamidone.  A summary of
the findings and an assessment of human risk resulting from the
registered and proposed uses are provided in this document.  The risk
assessment, residue chemistry review, and dietary exposure assessment
were provided by Tom Bloem (RAB1), the hazard characterization by P.V.
Shah  (RAB1), the occupational/residential exposure assessment by Kelly
Lowe (RAB1), and the drinking water assessment by J. Hetrick of the
Environmental Fate and Effects Division (EFED).

The current document is a revision of a recently completed fenamidone
human-health risk assessment (D314116, T. Bloem et al., 21-Jun-2007) and
differs from this previous assessment  in the following sections:  (1)
additional characterization of the Food Quality Protection Act (FQPA)
Safety Factor (SF); (2) additional characterization of the aniline
exposure assessment; and (3) removal of the tobacco residue and smoker
exposure assessments.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc177951290"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc177951290 \h  3

  HYPERLINK \l "_Toc177951291"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc177951291 \h  8

  HYPERLINK \l "_Toc177951292"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc177951292 \h  9

  HYPERLINK \l "_Toc177951293"  3.1  Hazard Profile	  PAGEREF
_Toc177951293 \h  9

  HYPERLINK \l "_Toc177951294"  3.3  Dose-Response Assessment	  PAGEREF
_Toc177951294 \h  12

  HYPERLINK \l "_Toc177951295"  3.4  Endocrine Disruption	  PAGEREF
_Toc177951295 \h  12

  HYPERLINK \l "_Toc177951296"  4.1  Summary of Registered and Proposed
Uses	  PAGEREF _Toc177951296 \h  14

  HYPERLINK \l "_Toc177951297"  4.2  Dietary Exposure/Risk Pathway
PAGEREF _Toc177951297 \h  15

  HYPERLINK \l "_Toc177951298"  4.3  Water Exposure/Risk Pathway
PAGEREF _Toc177951298 \h  20

  HYPERLINK \l "_Toc177951299"  4.5  Residential Exposure/Risk Pathway
PAGEREF _Toc177951299 \h  23

  HYPERLINK \l "_Toc177951300"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc177951300 \h  24

  HYPERLINK \l "_Toc177951301"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc177951301 \h  24

  HYPERLINK \l "_Toc177951302"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc177951302 \h  25

  HYPERLINK \l "_Toc177951303"  7.1  Occupational Handler Exposure
PAGEREF _Toc177951303 \h  25

  HYPERLINK \l "_Toc177951304"  7.2  Occupational Post-Application
Exposure	  PAGEREF _Toc177951304 \h  26

  HYPERLINK \l "_Toc177951305"  7.3  REI	  PAGEREF _Toc177951305 \h  26

  HYPERLINK \l "_Toc177951306"  8.0  DATA NEEDS/LABEL REQUIREMENTS
PAGEREF _Toc177951306 \h  28

  HYPERLINK \l "_Toc177951307"  8.1  Toxicity Data Requirements
PAGEREF _Toc177951307 \h  28

  HYPERLINK \l "_Toc177951308"  8.2  Residue Chemistry Data Requirements
  PAGEREF _Toc177951308 \h  28

  HYPERLINK \l "_Toc177951309"  8.3  Occupational/Residential	  PAGEREF
_Toc177951309 \h  28

  HYPERLINK \l "_Toc177951310"  Attachment 1:  Chemical Structures
PAGEREF _Toc177951310 \h  28

  HYPERLINK \l "_Toc177951311"  Attachment 2:  Toxicity Profile of
Fenamidone Technical	  PAGEREF _Toc177951311 \h  28

 1.0  EXECUTIVE SUMMARY

Background:  Fenamidone (Bayer CropScience) 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)).
Fenamidone is also registered for application to commercially grown
ornamentals in green houses and saran houses (not for residential use)..
 The most recent Section 3 fenamidone risk assessment was completed on
23-June-2004 (D297216, M. Clock-Rust et al.).

Hazard Characterization and Dose Response:  The existing toxicological
database for fenamidone supports the establishment of permanent
tolerances for residues of fenamidone in/on the commodities proposed in
this action.  Fenamidone has low acute toxicity via the oral, dermal,
and inhalation routes with all studies being in Toxicity Category III or
IV (see Table 4).  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 no-observed adverse-effect level (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.  The carcinogenic potential was
negative for mice dosed up to the limit dose with liver effects seen as
the systemic toxicity.  In rats, fenamidone did produce a statistically
significant increase (p< 0.01 for both trend and pair-wise comparison)
in benign, endometrial stromal polyps at 5,000 ppm (highest dose tested;
MRIDs 45400010, 45400011, 45386105).  Consultation with an EPA
consulting pathologist resulted in these findings being characterized as
benign proliferate lesions that do not progress to malignant carcinomas
or sarcomas.  Based on these findings, the HED Hazard Identification
Assessment Review Committee (HIARC) classified fenamidone as “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 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 functional observational battery (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 neurotoxicity summarized above, HED requested a
DNT study conducted with Sprague Dawley rats.  The petitioner 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).  The results of this DNT study suggest increased
susceptibility of offspring to fenamidone; however, the concern for
increased susceptibility is low since there is a well established NOAEL
protecting the offspring and the NOAEL used for establishing the chronic
reference dose (cRfD; see below) is approximately 45x below the NOAEL
observed for the offspring toxicity in the DNT study.

There is confidence that the sensitivity of any developmental
neurological effects have been identified.  EPA required a DNT based on
a marginal decrease in brain weight in high doses males in the
subchronic neurotoxicity study in rats, decreased brain weight in female
adults and female offspring in the two-generation reproduction study,
and clinical signs that may be indicative of neurotoxic effects at
relatively high doses in several studies.  A DNT was conducted and
showed no neurotoxic effects.  Because, however, the DNT was conducted
in a different strain of rat (Wistar) than the studies that showed brain
effects (Sprague-Dawley), EPA has required that an abbreviated DNT be
conducted in the Sprague-Dawley rat that focuses on brain effects.  Due
to the clear NOAEL from the existing DNT as well as the clear NOAELs in
the studies evidencing brain effects, EPA regards the abbreviated DNT as
confirmatory in nature and unlikely to change the characterization or
magnitude of the risk for fenamidone. The Hazard Assessment and Policy
Council (HASPOC) reviewed these data and determined that the 10x
database uncertainty factor due to lack of DNT should be removed.

he proposed uses are ≥490 and in order to grant a waiver for a 28-day
inhalation toxicity study the calculated MOEs must be >1000 (HED
Standard Operating Procedure (SOP) 2002.01: Guidance: Waiver Criteria
for Multiple-Exposure Inhalation Toxicity Studies, 08/15/02).
Therefore, HED requests that the petitioner

submit a 28-day fenamidone inhalation toxicity study.

Dose-Response Assessment and FQPA Decision:  The HIARC selected
endpoints for fenamidone risk assessment (TXR # 0052379).  A 100-fold
uncertainty factor (10x for interspecies extrapolation and 10x for
intraspecies variation) was incorporated into the acute and chronic
reference dose (RfD).  The acute population-adjusted dose (aPAD) and the
chronic population-adjusted dose (cPAD) are equal to the acute and
chronic RfDs, respectively, divided by the FQPA Safety Factor (SF).
Based on the toxicological considerations and the residue assumptions
made in the acute and chronic dietary analyses, the risk assessment team
concluded that the FQPA SF may be reduced to 1x.  Therefore, the acute
and chronic PADs are equal to the acute and chronic RfDs.  Fenamidone is
classified as “not likely to be carcinogenic to humans” by all
relevant routes of exposure based on adequate studies in two animal
species; therefore, cancer risk assessments are not required.  In
estimating MOEs, the level of concern (LOC) is for MOEs <100 for the
dermal and inhalation risk assessments.  A 10% dermal absorption factor
and a 100% inhalation absorption factor were recommended by HIARC for
use in the route-to-route extrapolation.  The toxicological endpoints
relevant to this assessment are summarized below.

acute dietary (general population)	NOAEL = 125 mg/kg/day	acute RfD and
aPAD = 1.25 mg/kg/day

chronic dietary	NOAEL = 2.83 mg/kg/day	chronic RfD and cPAD = 0.0283
mg/kg/day

short-term dermal	oral NOAEL = 10.4 mg/kg/day	LOC for MOEs <100
(occupational)

intermediate-term dermal	oral NOAEL = 5.45 mg/kg/day	LOC for MOEs <100
(occupational)

short-term inhalation	oral NOAEL = 10.4 mg/kg/day	LOC for MOEs <100
(occupational)

intermediate-term inhalation	oral NOAEL = 5.45 mg/kg/day	LOC for MOEs
<100 (occupational)

Dietary Exposure/Risk Assessment:  The acute/chronic dietary exposure
analyses were conducted using the Dietary Exposure Evaluation Model -
Food Consumption Intake Database (DEEM-FCID(, ver. 2.03).  DEEM-FCID(
incorporates food consumption data from the United States Department of
Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals
(CSFII; 1994-1996 and 1998).  The acute/chronic analyses incorporated
conservative residue estimates, 100% crop treated, and DEEM( (ver. 7.81)
default or experimentally determined processing factors. The acute and
chronic dietary analyses also incorporated the Screening Concentration
in Ground Water (SCI-GROW) estimate resulting from application of
fenamidone to carrots (178 ppb; highest acute/chronic estimate; 3 x
0.267 lb ai/acre).  The acute dietary exposure estimates were (5% aPAD
(95th %; children 1-2 years old were the most highly exposed population)
and the chronic dietary exposure estimates were (82% cPAD (children 1-2
years old were the most highly exposed population) and are, therefore,
not of concern to HED.

Aggregate Exposure/Risk Assessment:  Since there are no
registered/proposed uses which result in residential exposures, only
acute and chronic aggregate exposure assessments, considering exposure
from food and water, are required.  Since the dietary exposure analysis
included the drinking water estimates, the discussion and exposure
estimates presented above represent aggregate acute and aggregate
chronic exposure.

Occupational Exposure/Risk Assessment:  Pesticide handlers are
anticipated to have short-term and potentially intermediate-term dermal
and inhalation exposures to fenamidone based on the proposed uses.  Both
foliar (all proposed crops except sunflower) and seed treatment
(sunflower and cotton) applications of fenamidone are proposed.
Therefore, foliar and seed treatment exposure assessment were conducted.
 Since chemical-specific unit exposure data are not available, the
Pesticide Handler’s Exposure Database (PHED) Surrogate Table (August,
1998) was used to provide estimates of handler unit exposure from foliar
applications, as well as information provided in HED Exposure Science
Assessment Council (ExpoSAC) SOP No. 14 and 15 with regards to exposure
assessment for commercial seed treaters.  Combined MOEs (dermal and
inhalation) for handlers performing mixing/loading activities without
gloves (baseline assessment level) ranged from 8 to 6,400 for short-term
exposures and from 4 to 2,900 for intermediate-term exposures.  However,
when mixer/loaders wear waterproof gloves as required by the proposed
label, all MOEs are >100 for both short- and intermediate-term exposures
and are, therefore, not of concern to HED.  Combined MOEs (dermal and
inhalation) for aerial and groundboom applicators were >100 at the
baseline level for short- and intermediate-term exposures and are,
therefore, not of concern to HED.  For commercial seed treaters, all
MOEs are >100 and are, therefore, not of concern to HED.

In terms of postapplication exposure, workers entering treated fields to
perform scouting, irrigation and hand harvesting are anticipated to have
short-term dermal exposures.  The MOE for potential post-application
exposure is 320 for short-term dermal exposures using the ExpoSAC SOP
No. 003 for determination of dislodgeable foliar residues (DFR) and are,
therefore, not of concern to HED.  The restricted-entry interval (REI)
on the proposed label is 12 hours and is appropriate based on an acute
toxicity profile of Category III/IV for fenamidone.

Recommendation for Tolerances and Registration:  Provided the
petitioner submits revised Sections B and F, the toxicological, residue
chemistry, and occupational/residential databases support a conditional
registration and establishment of the permanent tolerances listed in
Table 1 for residues of fenamidone per se (4H-Imidazol-4-one,
3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino); strawberry
tolerances are for fenamidone and RPA 717879).  An unconditional
registration will be established upon submission of data which
adequately addresses the following deficiencies:

●28-day inhalation toxicity study

●modified DNT in the Sprague Dawley rat with measurement of the
following endpoint: brain weights (samples should be retained for
possible morphometric measurements); this study is necessary to confirm
the lack of brain weight changes in the Wistar rat DNT

●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
hydrolysate of the carrot top (organic and aqueous phase) and carrot
root extracts from the metabolism study (ChemSAC minutes 30-May-2007).

●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).

●PMV for the plant and livestock enforcement methods.

Table 1:  HED-Recommended Tolerances.

HED-Recommended Tolerances

Matrix	Tolerance

(ppm)

180.579(a)(1); tolerances for residue of fenamidone per se

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

Cotton, gin byproducts	0.02

Cotton, undelinted seed	0.02

180.579(d); tolerances for residue of fenamidone and RPA 717879

Strawberry	0.02

1  currently-established lettuce (head and leaf) and tomato raw
agricultural commodity (RAC) tolerances may be deleted

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

The fenamidone nomenclature is summarized in Table 2, and the
physicochemical properties are summarized in Table 3.

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 pointse	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

-3rd HIARC Report; W. Dykstra, 19-Feb-2004, TXR # 0052379

-HASPOC Report; D335872, R. Mitkus, 19-Jun-2007

Attachment 2 includes an updated toxicity profile for fenamidone
(inclusion of the DNT study submitted with the current petition).

3.1  Hazard Profile

The existing toxicological database for fenamidone supports the
establishment of permanent tolerances for residues of fenamidone in/on
the commodities proposed in this action.  Fenamidone has low acute
toxicity via the oral, dermal, and inhalation routes with all studies
being in Toxicity Category III or IV (see Table 4).  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.  The carcinogenic potential was negative for mice dosed up
to the limit dose with liver effects seen as the systemic toxicity.  In
rats, fenamidone did produce a statistically significant increase (p<
0.01 for both trend and pair-wise comparison) in benign, endometrial
stromal polyps at 5,000 ppm (highest dose tested; MRIDs 45400010,
45400011, 45386105).  Consultation with an EPA consulting pathologist
resulted in these findings being characterized as benign proliferate
lesions that do not progress to malignant carcinomas or sarcomas.  Based
on these findings, the HIARC classified fenamidone as “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 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 neurotoxicity summarized above, HED requested a
DNT study conducted with Sprague Dawley rats.  The petitioner 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).  The results of this DNT study suggest increased
susceptibility of offspring to fenamidone; however, the concern for
increased susceptibility is low since there is a well established NOAEL
protecting the offspring and the NOAEL used for establishing the chronic
reference dose (cRfD; see below) is approximately 45x below the NOAEL
observed for the offspring toxicity in the DNT study.  HASPOC reviewed
these data and determined that the 10x database uncertainty factor due
to lack of DNT should be removed.  However, since this study was
conducted using Wistar rats rather than Sprague Dawley rat as requested,
the HASPOC requested a modified DNT in the Sprague Dawley rat with
measurement of the following endpoint: brain weights (samples should be
retained for possible morphometric measurements); this study is
necessary to confirm the lack of brain weight changes in the Wistar rat
DNT.

The HIARC recommended a dermal-absorption factor of 10% based on the
results of an acceptable dermal absorption study in rats (MRID
45386111).  A 24-hour low-dose skin absorption value (8.59%) was rounded
up to 10% to allow for some continued absorption from skin after
exposure was discontinued.  The HIARC requested a 28-day inhalation
toxicity study as a condition of registration.  HED notes that
fenamidone has low volatility and low inhalation toxicity (Category IV);
however, the inhalation MOEs for the proposed uses are ≥490 and in
order to grant a waiver for a 28-day inhalation toxicity study the
calculated MOEs must be >1000 (HED Standard Operating Procedure (SOP)
2002.01: Guidance: Waiver Criteria for Multiple-Exposure Inhalation
Toxicity Studies, 08/15/02).  Therefore, HED requests that the
petitioner submit a 28-day fenamidone inhalation toxicity study.

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

3.2  FQPA Considerations

Based on toxicological considerations summarized below and the residues
assumptions made in the acute and chronic dietary analyses, HED
concludes that the FQPA SF may be reduced to 1x.

FQPA SF Toxicological 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).  The DNT study
conducted with Wistar rats showed no maternal toxicity up to 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 with a NOAEL of 92.3
mg/kg/day.  The results of this DNT study suggest increased
susceptibility of offspring to fenamidone; however, the concern for
increased susceptibility is low since there is a well established NOAEL
protecting the offspring and the NOAEL used for establishing the chronic
reference dose (cRfD; see below) is approximately 45x below the NOAEL
observed for the offspring toxicity in the DNT study.

There is confidence that the sensitivity of any developmental
neurological effects have been identified.  EPA required a DNT based on
a marginal decrease in brain weight in high doses males in the
subchronic neurotoxicity study in rats, decreased brain weight in female
adults and female offspring in the two-generation reproduction study,
and clinical signs that may be indicative of neurotoxic effects at
relatively high doses in several studies.  A DNT was conducted and
showed no neurotoxic effects.  Because, however, the DNT was conducted
in a different strain of rat (Wistar) than the studies that showed brain
effects (Sprague-Dawley), EPA has required that an abbreviated DNT be
conducted in the Sprague-Dawley rat that focuses on brain effects.  Due
to the clear NOAEL from the existing DNT as well as the clear NOAELs in
the studies evidencing brain effects, EPA regards the abbreviated DNT as
confirmatory in nature and unlikely to change the characterization or
magnitude of the risk for fenamidone.

Based on these data, HED concludes that the FQPA factor for increased
susceptibility may be reduced to 1x for the following reasons:  (1) no
qualitative or quantitative increased susceptibility in the
developmental toxicity studies (rat and rabbit); (2) no qualitative or
quantitative increased susceptibility in the two generation reproduction
study (rat);and (3) 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.

3.3  Dose-Response Assessment

Table 5 on the next page is a summary of the fenamidone endpoints for
dietary, residential, and occupational risk assessments.

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 recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the 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. For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).  When additional
appropriate screening and/or testing protocols being considered under
the Agency’s EDSP have been developed, fenamidone may be subjected to
further screening and/or testing to better characterize effects related
to endocrine disruption.

Table 5:  Summary of Toxicological Dose and Endpoints for Fenamidone1.

Exposure

Scenario	Dose (mg/kg/day); UF	FQPA SF* and LOC for

Risk Assessment	Endpoint for Risk Assessment

Acute Dietary

general population including infants and children	NOAEL = 125 mg/kg/day

UF = 100

aRfD =1.25 mg/kg/day	FQPA SF = 1x

aPAD = aRfD ÷ FQPA SF

=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

UF = 100

cRfD = 0.0283 mg/kg/day	FQPA SF- 1X

cPAD = cRfD ÷ FQPA SF

= 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)

Residential Only	NOAEL= 10.4 mg/kg/day	Residential LOC 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)

Residential Only	NOAEL= 5.45 mg/kg/day	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

Short-Term

(1 - 30 days)2	Oral NOAEL= 10.4 mg/kg/day	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.

Dermal

Intermediate-Term

(1 - 6 Months)2	Oral NOAEL= 5.45 mg/kg/day	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

Long-Term

(> 6 Months)2	Oral NOAEL= 2.83 mg/kg/day 	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.

Inhalation

Short-Term

(1 - 30 days)3	Oral NOAEL= 10.4 mg/kg/day 	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.

Inhalation

Intermediate-Term

(1 - 6 Months)3	Oral NOAEL= 5.45 mg/kg/day	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.

Inhalation

Long-Term

(>6 Months)3	Oral NOAEL= 2.83 mg/kg/day	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 	Classification:  “not likely”

1  UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic), RfD =
reference dose, MOE (margin of exposure) = NOAEL ÷ exposure; LOC =
level of concern

2  use a dermal-penetration factor of 10% for route-to-route
extrapolation

3  absorption via inhalation route is presumed to be equivalent to oral
absorption

4.0  EXPOSURE ASSESSMENT

●Residue Chemistry Summary; D314318, T. Bloem, 14-Jun-2007

●Dietary Exposure; 336201, T. Bloem, 14-Jun-2007

●EFED Drinking Water Assessment; D332878, J. Hetrick, 14-May-2007

4.1  Summary of Registered and Proposed Uses

Registered Uses:  Fenamidone (Reason® 500SC; EPA Reg. No. 264-695) is
currently registered for application to lettuce (head and leaf), bulb
vegetables, cucurbit vegetables, tuberous and corm vegetables, and
tomato with tolerances for residues of fenamidone per se ranging from
0.02-20 ppm (40 CFR 180.579).  The HED reviews associated with these
crops and the first Reason® 500SC stamped label of 8-Oct-2004 indicated
a maximum single/seasonal application rates of 0.267/1.07 lb ai/acre
(D281887, T. Bloem, 18-Jul-2002; D297216, T. Bloem, 25-May-2004).
However, the most recent Reason® 500SC stamped label (20-Jan-2006)
indicated maximum single/seasonal application rates of 0.267/0.80 lb
ai/acre.  Fenamidone (Fenstar; EPA Reg. No. 432-1389) is also registered
for application to commercially grown ornamentals in green houses and
saran houses (1.8 lb ai/acre; not for residential use; D297638, M. Dow,
13-Jan-2004).

Proposed Uses:  Bayer CropScience is proposing the application of
Reason® 500 SC (EPA Reg. No. 264-695; 4.13 lb ai/gallon;
suspension-concentrate) to 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 6 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.  The label indicates a 12-hour REI and that
workers are to wear protective gloves.  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 6:  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

4.2  Dietary Exposure/Risk Pathway

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; 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).

The petitioner elected to submit a new N-phenyl fenamidone metabolism
study conducted with carrot (tops and roots; 46921101.der.wpd).  The
major residues identified in the carrot root (TRR = 0.040 ppm) and top
(TRR = 30.490 ppm) were 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 Section 4.4 below), HED concludes the
residues of concern in the proposed/registered crops are as defined in
Table 7.

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 Section 4.4 below).  Therefore, for the currently
proposed crops, HED concludes the residues of concern in livestock are
as defined in Table 7.  These conclusions will be reevaluated if
additional crops are requested.

Magnitude of the Residue - Plants:  HED concludes that the application
scenarios and geographical representation of the leafy vegetable (except
Brassica), Brassica (cole) leafy vegetable, fruiting vegetable, cotton,
sunflower, and carrot field trial data fulfill the data requirements
suggested in OPPTS 860.1500 and 860.1520.  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; also since the tomato and carrot field trial
data did not include an adjuvant, HED requests that the petitioner
revise the label to indicate that the addition of an adjuvant is
appropriate for all the proposed crops excluding tomato and carrot.
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 per se are appropriate.  Except for
cottonseed and sunflower seed matrices (limit of quantitation (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 raw
agricultural commodity (RAC) tolerances may be deleted.  A revised
Section F is requested.

Based on a 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 highest
dosing level 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 study 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 liquid chromatograph/mass spectrometer/mass
spectrometer (LC/MS/MS) method for enforcement of the registered plant
tolerances.  Adequate method validation, radiovalidation, and 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 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 this 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).

Table 7:  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)

water	not applicable	fenamidone, RPA 412636, RPA 412708, RPA 411639, RPA
413255, RPA 409446, RPA 410995RPA-412636

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

4.3  Water Exposure/Risk Pathway

Drinking Water Fate Assessment:  Biotransformation (metabolism) under
aerobic conditions and direct photolysis in water are the major routes
of transformation of fenamidone in the environment.  Fenamidone
half-lives were 5 to 8 days in aerobic soils,  67 to 128 days in aerobic
water-sediments, and 5.8 days in water exposed to summer sunlight
(direct photolysis).  Fenamidone is highly persistent in anaerobic
water-sediment systems (half-life longer than 1000 days).  Adsorption of
fenamidone onto soils is moderate (mean Koc less than 388).  Therefore,
fenamidone is not persistent in soil or in shallow water under aerobic
conditions.  Under field conditions, the half-lives of fenamidone ranged
from to 9 to 82 days.  Given that biotransformation is the major route
of degradation and considering the widespread, potential use areas of
different soils, microbial population and activity, water bodies,
climates/meteorology, and agricultural practices, high variability in
persistence in soil and water-sediment systems is to be expected.
Likewise, variability in type and relative amount of products would also
be expected.  The MARC reviewed the environmental fate data for
fenamidone and concluded that the residue of concern in water are as
described in  Table 7.

Modeling and Drinking Water Estimates:  Since there are no available
fenamidone water monitoring data, the drinking water assessment is based
solely on model-estimated exposure concentrations in ground and surface
water.  Estimates were performed for combined residues of parent
fenamidone, RPA 412636, RPA 412708, RPA 411639, RPA 413255, RPA 409446,
RPA 410995RPA-412636 (see Attachment 1 for metabolite structures).  EFED
generated the surface water and ground water estimates using the
Pesticide Root Zone Model  SEQ CHAPTER \h \r 1 /Exposure Analysis
Modeling System (PRZM/EXAMS) and SCI-GROW (Tier 1) models, respectively.
 Table 8 is a summary of the modeled water concentrations.

Table 8:  Estimated Drinking Water Concentrations for Fenamidone (ppb).

	Acute	Chronic	Long-term average

Surface (PRZM/EXAMS)1	41.661	11.881	5.991

Ground (SCI-GROW)2	178	178	178

1  acute estimate based on application to peppers in FL (single/seasonal
rates of 0.267/0.80 lb ai/acre; RTI = 5 days) and the chronic and long
term estimates based on application to lettuce in CA  (single/seasonal
rates of 0.267/0.80 lb ai/acre; RTI = 5 days); the default 0.87 PCA was
assumed for both

2  SCI-GROW estimate assuming a single/seasonal rate of 0.267/0.80 lb
ai/acre; RTI = 5 days

4.4  Dietary Exposure Analysis

HED generated dietary exposure estimates for exposure to fenamidone and
its residues of concern other than aniline and for exposure to aniline;
HED notes that the metabolism/ degradation of fenamidone and/or its
metabolites to aniline is theoretical and the dietary exposure conducted
here is considered conservative.  The following paragraphs are summaries
of these analyses.

-Apr-2004).  For ruminant commodities, LOQ residues were assumed based
on residues of concern ≤LOQ at 3.4x the maximum reasonable dietary
burden (MRDB; 3.4x was the highest level tested; 180.6(a)(3) for hog and
poultry).  The acute/chronic analyses also incorporated the SCI-GROW
ground water estimate resulting from application of fenamidone to
carrots (178 ppb; highest acute/chronic estimate; 3 x 0.267 lb ai/acre).
 The acute dietary exposure estimates were (5% aPAD (95th%; children 1-2
years old were the most highly exposed population) and the chronic
dietary exposure estimates were (82% cPAD (children 1-2 years old were
the most highly exposed population) and are, therefore, not of concern
to HED.  Tables 9 and 10 are summaries of the acute and chronic dietary
exposure estimates.

Table 9:  Summary of Acute Dietary Exposure.

Population Subgroup	aPAD (mg/kg/day)	Acute (95th percentile)

Exposure (mg/kg/day)	%aPAD

General U.S. Population	1.25	0.040621	3

All Infants (< 1 year old)

0.047689	4

Children 1-2 years old

0.059961	5

Children 3-5 years old

0.053302	4

Children 6-12 years old

0.041143	3

Youth 13-19 years old

0.034314	3

Adults 20-49 years old

0.037755	3

Adults 50+ years old

0.040498	3

Females 13-49 years old

0.039529	3

Table 10:  Summary of Chronic Dietary Exposure.

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.0283	0.013777	49

All Infants (< 1 year old)

0.020762	73

Children 1-2 years old

0.023093	82

Children 3-5 years old

0.020811	74

Children 6-12 years old

0.014404	51

Youth 13-19 years old

0.011047	39

Adults 20-49 years old

0.012722	45

Adults 50+ years old

0.013610	48

Females 13-49 years old

0.012825	45

Aniline:  Based on toxicological data summarized in IRIS, aniline
causes hematopoietic effects and is a probable human carcinogen
(http://www.epa.gov/iris/subst/0350.htm).  Since hematopoietic effects
are not considered as single-dose effects, an acute dietary analysis to
aniline is not warranted.  Based on the literature, it can be concluded
that the chronic (non-cancer) toxicity to aniline appears to occur at
higher doses than fenamidone.  Based on this conclusion and since the
residue estimates generated for aniline are less than the remaining
residues related to fenamidone (see below), HED concludes that a chronic
risk assessment which results in exposure to fenamidone which are not of
concern to HED will also result in chronic exposures to aniline which
are not of concern to HED (i.e. aniline has lower residues and higher
endpoint).  Therefore, only a cancer analysis for potential exposure to
aniline was conducted.  The following paragraphs are summaries of the
cancer analysis.

HED performed a conservative cancer risk assessment for potential
exposure to aniline(s) derived from fenamidone.  For quantitative cancer
risk assessment, IRIS provides a slope factor which is the result of
application of a low-dose extrapolation procedure and is presented as
the risk per day (mg/kg/day; slope factor = 0.0057 mg/kg/day).
Multiplying the slope factor by an exposure estimate yields a risk level
(slope factor is similar to HED’s Q1*).  Using the conservative
residue estimates summarized below, the IRIS slope factor, and
DEEM-FCID( (ver. 2.03; 100% crop treated and DEEM( (ver. 7.81) default
processing factors assumed), the estimated lifetime cancer risk for the
US population due to exposure to N-phenyl compounds derived from
fenamidone is 3 x 10-6 (HED evaluates cancer exposure to the US
population only). In general, HED’s LOC is for exposures which result
in lifetime cancer risks >3 x 10-6.  Since the dietary exposure analysis
assumed 100% crop treated, DEEM( (ver. 7.81) default processing factors,
and conservative residues estimates (see below), HED concludes that the
cancer risk to aniline(s) derived from fenamidone is not of concern to
HED.

Primary Crops:  The combined concentration of unknown and bound residues
in N-phenyl potato tuber (0.036 ppm) and tomato (0.024 ppm) metabolism
studies were used as conservative estimates of aniline(s) in tuberous
and corm vegetables and fruiting vegetable, respectively.  The TRR in
grape pulp from the C-phenyl metabolism study  (0.098 ppm) was used as a
conservative estimate of N-phenyl compounds in juice and wine (lettuce,
potato, and tomato C- and N-phenyl metabolism studies indicate that TRR
in each are similar indicating that this is a conservative assumption).

The field trials monitored for residues of fenamidone, RPA 717879, RPA
408056, and RPA 405862.  RPA 408056 and RPA 717879 contain only the
C-phenyl ring with the maximum combined residues of these compound in
the field trials of 0.517 ppm.  As a estimate of potential N-phenyl
compounds, HED assumed residues of 0.517 ppm for all registered/proposed
commodities, excluding those which had a maximum combined residues of
fenamidone, RPA 717879, RPA 408056, and RPA 405862 of <0.517 ppm; for
these commodities, the maximum combined residue of fenamidone, RPA
717879, RPA 408056, and RPA 405862 was assumed.  Based on the unknown
and bound residues in the potato and tomato metabolism studies and/or
since fenamidone was identified as the principal residue in the
metabolism studies, HED concludes that these are conservative estimates
of potential aniline(s) residues in the proposed/registered crops.

Livestock:  The feed commodities associated with the
currently-registered/proposed crops are cotton, sunflower, carrot,
potato, and wheat (inadvertent residues in wheat as a result of crop
rotation).  HED has concluded that residues which contain both rings or
contain only the N-phenyl will be insignificant in rotational crops
(MARC memo; T. Bloem et al., 25-May-2004).  Therefore, wheat is not a
source of N-phenyl compounds.  The cotton, sunflower, and potato field
trial/processing studies resulted in residues of fenamidone, RPA 717879,
RPA 408056, and RPA 405862 <LOQ following treatment at ≤5x the
registered/proposed rate (the metabolism studies demonstrated that
fenamidone is the principal residue); therefore, HED concludes that the
dietary contribution to livestock from these commodities is
insignificant.  For carrot, residues of fenamidone were ≤0.11 ppm
which results in a beef/dairy cattle dietary burden of 0.09 ppm (carrot
is not a poultry or swine feed commodity; carrot metabolism demonstrated
that fenamidone is the principal residue in carrot root).  Assuming a
0.09 ppm dietary and the total radioactive residues form the N-phenyl
ruminant metabolism study  (45385910.der.wpd), the following residue
estimates were generated:  milk - 0.0005, meat byproducts - 0.006,
muscle - 0.00005, and fat - 0.0002 ppm.  As these estimates are based on
TRRs, HED concludes that they are conservative estimates of potential
aniline(s) residues in ruminants.

4.5  Residential Exposure/Risk Pathway

There are no registered or proposed residential uses of fenamidone that
result in residential exposure.  Spray drift is always a potential
source of exposure to residents nearby to spraying operations.  This is
particularly the case with aerial application, but, to a lesser extent,
could also be a potential source of exposure from groundboom application
methods.  The Agency has been working with the Spray Drift Task Force,
EPA Regional Offices and State Lead Agencies for pesticide regulation
and other parties to develop the best spray drift management practices.
The Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT® computer model to its risk assessments for pesticides applied
by air, orchard airblast and ground hydraulic methods.  After the policy
is in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift and risks associated
with aerial as well as other application types where appropriate.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

HED does not aggregate exposure from cigarette smoke with any other
route of exposure.  Therefore, since there are no registered/proposed
uses which result in residential exposures, only acute and chronic
aggregate exposure assessments, considering exposure from food and
water, are required.  Since the dietary exposure analysis included the
drinking water estimates, the discussion and exposure estimates
presented in Section 4.4 represent aggregate acute and aggregate chronic
exposure.

6.0  CUMULATIVE RISK

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 for 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 assumed that fenamidone does not have 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 OPP 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/ .

7.0  OCCUPATIONAL EXPOSURE

D317338, M. Dow, 1-Jun-2005; D338017, K. Lowe, 1-Jun-2007

HED notes that the occupational exposure memos mentioned above do not
include an assessment for the proposed carrot application.  However, the
D317338 ORE memo does include an assessment for the registered potato
application scenario.  Since the proposed carrot application scenario is
identical to that evaluated for potato, HED concludes that the potato
and carrot exposure estimates will be identical.  The proposed use
directions are summarized in Table 6 (12-hour REI).

7.1  Occupational Handler Exposure

The discussion of occupational pesticide handler exposure and risk is
divided into two parts; the first addressing foliar applications to
cotton, carrot, and the various vegetables and the second addressing
seed treatment of cotton and sunflower seed.

Foliar Applications:  Based on these proposed use patterns, HED expects
the most highly exposed occupational pesticide handlers are likely to
be:  (1) mixer/loader using open-pour of liquids supporting aerial
operations; (2) applicator using open-cab, ground-boom equipment; and
(3) applicator using fixed-wing aircraft.

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998).   For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline”; that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves, as well as for “baseline” and the use of protective gloves
or other personal protective equipment (PPE) as might be necessary.  The
product labels direct applicators and other handlers to wear a
long-sleeve shirt, long pants, chemical-resistant gloves and shoes plus
socks.

HED believes most exposure durations will be short-term (1 - 30 days).
However, the ExpoSAC maintains it is possible for commercial applicators
to be exposed to intermediate-term exposure durations (1 - 6 months).
In addition, the short- and intermediate-term toxicological endpoints
are the same; therefore, the estimates of risk for short-term duration
exposures are protective of those for intermediate-term duration
exposures.  Long-term exposures are not expected; therefore, a long-term
assessment was not conducted.

Table 10 presents the estimated risks for workers based on the short-
and intermediate-term dermal and inhalation exposures at baseline, and
with additional PPE. HED has determined that risks are not of concern
(i.e. MOEs>100) as long as workers wear protective gloves as indicated
on the labels.

Seed Treatment:  For seed treatment applications, Bayer submitted
exposure assessments for workers performing seed-treatment operations
(MRIDs 465011-03 and 465011-04).  To conduct the assessments, Bayer
utilized the same software used by HED to calculate exposure and risk to
workers involved in commercial seed treatment.  The software is a
“calculator” (Excel spreadsheet) developed by HED and Gustafson Seed
Company.  Bayer used the maximum rate of application (0.05 lb ai/cwt for
cotton and 0.19 lb ai/cwt for sunflower) and followed the HED ExpoSAC
SOPs No. 14 and 15 with regards to exposure assessment for commercial
seed treaters.  HED confirmed Bayer’s assumptions/inputs and summary
results are presented in Table 11.  A MOE of ≥100 is adequate to
protect occupational pesticide handlers.  For commercial seed treaters,
all MOEs are > 100; therefore, the risks are not of concern to HED.

7.2  Occupational Post-Application Exposure

HED expects that postapplication exposure will occur since fenamidone is
applied as a foliar spray.  Since no postapplication data were submitted
in support of this registration action, exposures during postapplication
activities were estimated using dermal-transfer coefficients from the
ExpoSAC Policy Number 3.1: Agricultural Transfer Coefficients, August
2000.  It is the intention of ExpoSAC that this SOP will be periodically
updated to incorporate additional information about agricultural
practices in crops and new data on transfer coefficients.  Much of this
information will originate from exposure studies currently being
conducted by the Agricultural Re-entry Task Force (ARTF), from further
analysis of studies already submitted to the Agency, and from studies in
the published scientific literature.

As a Tier I, screening-level assessment, HED has utilized the highest
identified transfer coefficient (TC; 5,000 cm²/hr for hand harvest of
Brassica vegetables).  Compound-specific data were not available for
fenamidone.  Therefore, HED assumes 20% of the application rate is
available as DFR on day zero after application.  This is adapted from
the ExpoSAC SOP No. 003 (7 May 1998 - Revised 7 August 2000).  HED
considers this practice to be conservative, that is to say, protective.
The following convention was used to estimate post-application exposure.

-Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR µg/cm2 x TC cm2/hr x
hr/day x 0.001 mg/µg ÷ 70 kg bw

-Surrogate DFR = application rate x 20% available as DFR x (1-D)t x 4.54
x 108 µg/lb x 2.47 x 10-8 A/cm2

-DFR = 0.267 lb ai/acre x 0.20 x 4.54 x 108 µg/lb x 2.47 x 10-8 A/cm2 =
0.59 µg/cm²

-ADD = 0.59 µg/cm² x 5,000 cm²/hr x 8 hr/day x 0.001 mg/µg x 10 %
(dermal absorption) ÷ 70kg bw = 0.033 mg ai/kg bw/day

-MOE = NOAEL ( ADD;  10.4 mg a.i./kg bw/day ( 0.033 mg a.i./kg bw/day =
315.

≥100 is adequate to protect agricultural workers.  Since the estimated
short-term exposure MOE is greater than 100, the proposed uses do not
exceed HED’s LOC.  HED believes post-application exposures are
short-term (1 - 30 days).  It is highly improbable that a worker could
be exposed to day-0 residues continuously for 1 - 6 months (i.e.,
intermediate-term exposures).  Therefore, intermediate-term risks are
not calculated.

7.3  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 interim Worker Protection Standard (WPS) REI of 12 hours
is sufficient to protect agricultural workers.

Table 10:  Estimated Exposures and Risk to Pesticide Handlers Applying
Fenamidone.

Unit Exposure1

(mg ai/lb ai handled)	Units Treated2

(acres/day)	Avg. Daily Dose3mg ai/kg bw/day	MOE4	Combined MOE5

Short term	Intermediate term	Short term	Intermediate term	Short term
Intermediate term

Mixer/Loader -Liquid - Open Pour support aerial operations

dermal baseline - 2.9 (HC)	1200	1.33	1.55	8	4	baseline - 8

SL w/gloves - 650	baseline - 4

SL w/gloves - 290

SL w/gloves - 0.023 (HC)

0.011	0.012	990	440

inhal baseline - 0.0012 (HC)

0.0055	0.0064	1890	850

Applicator - Groundboom - Open Cab

dermal baseline - 0.014 (HC)	350	0.0011	0.0012	9700	4400	baseline - 6400

SL w/gloves - 6400	baseline - 2900

SL w/gloves - 2900

SL w/gloves - 0.014 (HC)

0.0011	0.0012	9700	4400

inhal baseline - 0.00074 (HC)

0.00056	0.00066	18400	8300

Applicator - Aerial

dermal baseline - 0.0050 (MC)	1200	0.0023	0.0027	4500	2000	baseline -
4000	baseline - 1800

inhal baseline - 0.000068 (MC)

0.00031	0.00036	33000	15000

1  unit Exposure = mg ai/lb ai handled; taken from PHED Surrogate
Exposure Guide (August 1998); dermal baseline = dermal single layer of
work clothing no gloves; SL w/gloves = dermal single layer work clothing
with gloves; inhal baseline = no respirator; engineering control =
closed cockpit, no gloves.  HC = high  confidence data;  MC = medium
confidence data; LC = low confidence data

2  acres Treated  are derived from ExpoSAC SOP. No. 9.1 (Rev. 25 Sept.
2001)

3  average daily dose (ADD) = unit Exposure x application rate x units
treated x absorption factor ( body weight;  10% absorption for dermal
exposure and 100 % absorption for  inhalation exposures; 70 kg body
weight for short-term exposure and 70 kg body weight for
intermediate-term exposure

4  MOE = NOAEL ÷ ADD; NOAEL = 10.4 mg ai/kg bw/day for short term
dermal and inhalation and 5.45 mg ai/kg bw/day for intermediate-term
dermal  and inhalation exposures

5  combined MOE = NOAEL ÷ total ADD; total ADD = dermal ADD +
inhalation ADD

Table 11:  Short- & Intermediate-Term Exposure and Risk to Commercial
Cotton and Sunflower Seed Treaters Using Fenamidone.

	Daily Dose (mg ai/kg bw/day)	Short-term MOE	Intermediate-term MOE

	Dermal	Inhalation	Dermal	Inhalation	Combined	Dermal	Inhalation	Combined

Cotton Seed Treatment

Loader/applicator with gloves	0.0026	0.00039	4000	27000	3500	2100	14000
1800

Bag sewer no gloves	0.00071	0.00026	15000	40000	11000	7700	21000	5600

Bagger no gloves	0.001	0.00018	10000	58000	8800	5500	30000	4600

Multiple Activities with glove	0.0048	0.0018	2200	5800	1600	1100	3000
830

Seed Planters with glove	0.00064	0.000087	16000	120000	14000	8500	63000
7500

Sunflower Seed Treatment

Loader/applicator with gloves	0.0059	0.00088	1800	12000	1500	920	6200
800

Bag sewer	0.0016	0.00059	6500	18000	4700	3400	9200	2500

Bagger	0.0023	0.00041	4500	25000	3800	2400	13000	2000

Multiple Activities	0.011	0.0041	950	2500	690	500	1300	360

Seed Planters	0.00054	0.000073	19000	140000	17000	10000	75000	8900

8.0  DATA NEEDS/LABEL REQUIREMENTS

8.1  Toxicity Data Requirements

●28-day inhalation toxicity study

●modified DNT in the Sprague Dawley rat with measurement of the
following endpoint: brain weights (samples should be retained for
possible morphometric measurements); this study is necessary to confirm
the lack of brain weight changes in the Wistar rat DNT

8.2  Residue Chemistry Data Requirements

●Revised Section B.

●Revised Section F.

●PMV for the 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
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●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).

8.3  Occupational/Residential

●none

Attachment 1:  Chemical Structures

Attachment 2:  Toxicity Profile of Fenamidone Technical

RDI: RAB1 review (13-June-2007)

T. Bloem:S10945:PY1:(703)-605-0217(7509P)

Attachment 1:  Chemical Structures

Name	Structure

fenamidone; RPA 407213

14C-C-phenyl-fenamidone

RPA 408056 (racemic mixture)

RPA 412708 (S-enantiomer)

RPA 405862 (racemic mixture)

RPA 410193 (S enantiomer)

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

RPA 717879 (racemic mixture)

RPA 412636 (S-enantiomer)

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:  Toxicity Profile of Fenamidone Technical

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.

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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

Developmental neurotoxicity study	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.

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page   PAGE  24  of   NUMPAGES  33


[Federal Register Volume 82, Number 173 (Friday, September 8, 2017)]
[Notices]
[Pages 42560-42561]
[FR Doc No: 2017-19037]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

[Docket No. USCG-2016-1084]

Navigation and Vessel Inspection Circular (NVIC) 05-17;
Guidelines for Addressing Cyber Risks at Maritime Transportation
Security Act (MTSA) Regulated Facilities

AGENCY: Coast Guard, DHS.

ACTION: Notice of availability and request for comments; extension of
comment period.

-----------------------------------------------------------------------

SUMMARY: The Coast Guard is extending the comment period for its notice
of availability and request for comments, published on July 12, 2017.
The notice announced the availability of the draft Navigation and
Vessel Inspection Circular (NVIC) 05-17 entitled Guidelines for
Addressing Cyber Risks at Maritime Transportation Security Act (MTSA)
Regulated Facilities, and requested public comments on the draft. The
comment period was set to close on September 11, 2017. The Coast Guard
has received requests to extend the comment period by 30 days due to
the conditions caused by hurricane Harvey, which prevent some members
of the public from submitting comments by the original deadline.

DATES: Comments and related material must reach the Coast Guard on or
before October 11, 2017.

ADDRESSES: You may submit comments identified by docket number USCG-
2016-1084 using the Federal eRulemaking Portal at http://www.regulations.gov. See the ``Public Participation and Request for
Comments'' portion of the SUPPLEMENTARY INFORMATION section of the July
12, 2017 notice for further instructions on submitting comments.

FOR FURTHER INFORMATION CONTACT: If you have questions on this notice,
call or email, Jason Warren, Coast Guard; telephone<PHONE_NUMBER>, email
<EMAIL_ADDRESS>or LCDR Josephine Long, Coast Guard; telephone
202-372-1109, email<EMAIL_ADDRESS>

    Dated: September 5, 2017.
R.D. Manning,
Captain, U.S. Coast Guard, Chief, Office of Port and Facility
Compliance.
[FR Doc. 2017-19037 Filed 9-7-17; 8:45 am]
BILLING CODE 9110-04-P