Document ID: EPA-HQ-OPP-2006-0332-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-23T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:  	07/MARCH/2007

SUBJECT:	Famoxadone -- Human Health Risk Assessment to Support
Tolerances for Residues in/on Grapes, Hops and Caneberries, Crop
Subgroup 13A.

Petition #s:	5E7001

6E7099	

Chemical #:	113202

DP Num:	331969	

Class:	Fungicide

Decision Num:	369719	

Trade Name:	Tanos®

40 CFR:	§180.587	

EPA Reg. #:	352-604

FROM:	Breann Hanson, Biologist 

Alternative Risk Integration and Assessment (ARIA) Team

Risk Integration Minor Use and Emergency Response Branch  			
(RIMUERB)/Registration Division (RD) (7505P)

THROUGH:	William Cutchin, Acting Branch Senior Scientist 

		ARIA Team

RIMUERB /RD (7505P)

AND

			Christina Swartz, Branch Chief

	Registration Action Branch 2 (RAB2)

Health Effects Division (HED) (7509P)

TO:	Shaja Brothers, RM 05

RIMUERB/RD (7505P)

The International Research Project No. 4 (IR-4) has submitted petitions
for the fungicide famoxadone for new domestic registrations for use on
grapes east of the Rocky Mountains, hops, and caneberries, crop subgroup
13A (PP#5E7001 & 6E7099).  In this document, ARIA has conducted a human
health risk assessment to support these uses and all currently
registered uses.  The overall risk assessment was provided by Breann
Hanson, the residue chemistry data review and dietary risk assessment by
William Cutchin, and the occupational/residential exposure assessment by
Mark Dow.   This assessment does not address the combination
famoxadone/cymoxanil component of the product requested for use to
control spur blight, anthracnose, botrytis and fruit rot.  A risk
assessment for the proposed uses in currently being prepared for
cymoxanil.

This risk assessment incorporates all current, pending and proposed
tolerances for famoxadone as of March 7, 2007.

Table of Contents

  TOC \o "1-4" \u  1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc160956362 \h  5 

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc160956363 \h  8 

3.0	HAZARD CHARACTERIZATION	  PAGEREF _Toc160956364 \h  9 

3.1	Dose-Response Assessment	  PAGEREF _Toc160956365 \h  9 

3.2	FQPA Considerations	  PAGEREF _Toc160956366 \h  12 

3.3	Cumulative Risk	  PAGEREF _Toc160956367 \h  12 

3.4	Endocrine Disruption	  PAGEREF _Toc160956368 \h  12 

4.0	EXPOSURE ASSESSMENT	  PAGEREF _Toc160956369 \h  13 

4.1	Summary of Proposed Uses	  PAGEREF _Toc160956370 \h  13 

4.2	Dietary Exposure	  PAGEREF _Toc160956371 \h  15 

4.2.1	Residue Profile	  PAGEREF _Toc160956372 \h  15 

4.2.1.a.   Nature of the Residue - Plants and Livestock	  PAGEREF
_Toc160956373 \h  16 

4.2.1.b.   Residue Analytical Method	  PAGEREF _Toc160956374 \h  18 

4.2.1.c.   Multiresidue Methods	  PAGEREF _Toc160956375 \h  18 

4.2.1.d.   Storage Stability Data	  PAGEREF _Toc160956376 \h  19 

4.2.1.e.   Water, Fish, and Irrigated Crops	  PAGEREF _Toc160956377 \h 
19 

4.2.1.f.   Food Handling	  PAGEREF _Toc160956378 \h  19 

4.2.1.g.   Meat, Milk, Poultry and Eggs	  PAGEREF _Toc160956379 \h  19 

4.2.1.h.   Crop Field Trials	  PAGEREF _Toc160956380 \h  19 

4.2.1.i.   Processed Food/Feed	  PAGEREF _Toc160956381 \h  21 

4.2.1.j.   Confined/Field Accumulation in Rotational Crops	  PAGEREF
_Toc160956382 \h  22 

4.2.1.k.   International Harmonization of Tolerances	  PAGEREF
_Toc160956383 \h  22 

4.2.2	Drinking Water Analysis	  PAGEREF _Toc160956384 \h  22 

4.2.3	Dietary Analysis	  PAGEREF _Toc160956385 \h  23 

4.2.3.a	Acute Dietary	  PAGEREF _Toc160956386 \h  23 

4.2.3.b	Chronic Dietary	  PAGEREF _Toc160956387 \h  23 

4.2.3.c	Cancer Dietary	  PAGEREF _Toc160956388 \h  25 

4.3  	Occupational/Residential Exposure	  PAGEREF _Toc160956389 \h  25 

4.3.1	Summary of Use Patterns and Formulations	  PAGEREF _Toc160956390
\h  25 

4.3.2 	Occupational Exposure Assessment	  PAGEREF _Toc160956391 \h  25 

4.3.2.a	Occupational Post-Application Exposure Risk Assessment	  PAGEREF
_Toc160956392 \h  26 

4.3.3	Residential Exposure	  PAGEREF _Toc160956393 \h  27 

5.0	AGGREGATE RISK ASSESSMENTS AND CHARACTERIZATION	  PAGEREF
_Toc160956394 \h  27 

5.1	Acute Aggregate Risk  (food + water)	  PAGEREF _Toc160956395 \h  27 

5.2	Short/Intermediate-Term Aggregate Risk (food + water + residential)	
 PAGEREF _Toc160956396 \h  27 

5.3	Chronic Aggregate Risk (Food + Water)	  PAGEREF _Toc160956397 \h  28

5.4	Cancer Aggregate Risk	  PAGEREF _Toc160956398 \h  28 

6.0	DATA NEEDS	  PAGEREF _Toc160956399 \h  28 

6.1	Toxicology	  PAGEREF _Toc160956400 \h  28 

6.2	Residue Chemistry	  PAGEREF _Toc160956401 \h  28 

6.3	Occupational/Residential	  PAGEREF _Toc160956402 \h  29 

7.0	ATTACHEMENTS	  PAGEREF _Toc160956403 \h  29 

 

1.0	EXECUTIVE SUMMARY

General Background

Famoxadone is presently registered for food/feed uses on   SEQ CHAPTER
\h \r 1 fruiting vegetables, group 8; cucurbit vegetables, group 9;
potatoes; and head lettuce.  These uses were first registered in
connection with PP# 0F6070 along with the registrant’s (DuPont)
request for a Section 3 registration of Tanos® DF fungicide (EPA Reg.
No. 352-604), a mixed active ingredient formulation containing 25%
famoxadone and 25% cymoxanil.  Although there were no U.S. registrations
for grapes, tolerances are currently established for grape and raisin.

Tolerances for residues of famoxadone are listed in   SEQ CHAPTER \h \r
1 40 CFR §180.587 and are expressed in terms of famoxadone per se.  The
established tolerances for plant commodities range from 0.02 ppm on
potato to 10.0 ppm on head lettuce, and the established tolerances for
animal commodities range from 0.02 ppm on cattle fat to 0.05 ppm on
cattle liver.

Tolerances are proposed for the combined residues of famoxadone in or on
the following raw agricultural commodities (RACs):

Grapes	  2.5 ppm

Hops	   60 ppm

Caneberries, subgroup 13A	   11 ppm

The most recent HED human health risk assessment for famoxadone was
conducted in conjunction with a Section 18 quarantine use of a
famoxadone/flusilazole product for use on soybeans to control soybean
rust (D. McNeilly, DP Number: 319074, 17/04/2006).

Toxicology and Dose-Response 

Famoxadone has low acute toxicity and is classified in Acute Toxicity
Category III for acute dermal toxicity, primary eye irritation and
primary skin irritation.  It is classified in Category IV for acute
inhalation toxicity.  It is not a dermal sensitizer.

Previously selected doses and endpoints for use in human health risk
assessments have been used in this current risk assessment for
famoxadone. As there were no toxic effects attributable to a single
dose, an endpoint of concern was not identified to quantitate acute
dietary risk to the general population or to the subpopulation females
13-49 years old. Therefore, no acute reference dose (aRfD) or acute
population adjusted dose (aPAD) has been established.  An acute risk
assessment is not appropriate and was not conducted.  For chronic
dietary exposure, the endpoint was selected from a subchronic feeding
study in dogs in which the LOAEL was 1.4 mg/kg/day based on microscopic
lens lesions (cataracts) in the eyes of female dogs. An additional
uncertainty factor (UF) of 10 was retained in addition to the
conventional UF of 100 to account for the lack of a NOAEL and for the
use of a subchronic study. The cRfD is 0.0014 mg/kg/day. 

Since there are no residential uses for famoxadone, short-term and
intermediate-term aggregate risk assessments are not required. For
short-term occupational dermal and inhalation exposures, the toxicology
endpoint was selected from the subchronic feeding study in dogs in which
myotonic twitches were observed starting on day 21. For short-term
exposures, the target Margin of Exposure (MOE) is 100. For the
intermediate-term dermal and inhalation exposure risk assessments, the
MOE of 300 includes the conventional 100 and an additional 3X since a
LOAEL, rather than a NOAEL, was selected for risk assessments.  The
HIARC concluded an additional uncertainty factor of 3X would be adequate
for this risk assessment scenario.  For the long-term dermal and
inhalation exposure risk assessments, the MOE of 1000 includes the
conventional 100 and an additional 10X for the use of the LOAEL and dose
from a short-term study (13-weeks) for long-term risk assessment.  The
MOEs for dermal and inhalation exposures may be combined for
occupational exposure risk assessments because oral equivalents were
used for the dermal and inhalation routes of exposure.

The Cancer Assessment Review Committee (CARC) classified famoxadone as
“not likely to be carcinogenic to humans.” As such, cancer risk
assessments are not warranted.

HED previously concluded that the hazard and exposure data for
famoxadone support reducing the FQPA safety factor to account for
increased sensitivity of infants and children to 1X.  That conclusion is
still applicable to this petition.

Residue Chemistry

Residue chemistry data pertaining to the proposed use of famoxadone on
grapes, hops and caneberries were submitted and reviewed by ARIA (W.
Cutchin, DP Numbers: 323682 and 333260, 29/11/2006).  ARIA recommends a
2.5 ppm tolerance on grapes, an 80 ppm tolerance on hops and a 10 ppm
tolerance on caneberries, crop subgroup 13A.

Dietary Risk from Drinking Water Sources

The Environmental Fate and Effects Division (EFED) had previously
provided estimated drinking water concentrations (EDWCs) for the use of
famoxadone on potatoes, fruiting vegetables, cucurbit vegetables, and
head lettuce. These estimates were included in the HED review (M.
Doherty, DP Number: 276070, 29/04/2003).  Because the proposed IR-4
request involves very similar methods of application and similar use
rates than the uses considered under that review, there is no need to
provide revised EDWCs.  

The EFED estimated surface water drinking water concentration for the
total toxic residues of famoxadone is 0.47 g/L (1 in 10 year annual mean
concentration). The estimated concentration of the total toxic residues
of famoxadone for drinking water from shallow groundwater sources from
the Screening Concentration in Ground Water (SCIGROW) model is 0.23 g/L.

Dietary Exposure Analysis

ration of 0.47 μg/L (ppb) was used in the analysis.  The results of the
analysis indicate that chronic risk from the dietary (food + drinking
water) exposure to famoxadone will not exceed HED’s level of concern
for the general U.S. population and all population subgroups. 

Residential Risk

There are no residential uses for famoxadone at this time.

Occupational Exposure and Risk

Based upon the proposed use pattern, ARIA believes the most highly
exposed occupational pesticide handlers will be 1) mixer/loaders using
open-pour loading of a dry flowable formulation; 2) applicators using
open-cab airblast sprayers; 3) applicators using open-cab ground-boom
sprayers; and 4) aerial applicators.  

ARIA also believes occupational handlers will be exposed to short-term
duration exposures (1 - 30 days).   Although multiple applications are
likely, they should not be consecutive applications and should be
alternated with other fungicides with differing modes of action.  The
treatment interval is 5 - 7 days.  It is unlikely that handlers would be
exposed continuously for 30 or more days (i.e., intermediate-term
exposure).  

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOEs are > 100, the
proposed uses do not result in risks of concern. The lowest MOE is 312.

The interim Worker Protection Standard (WPS) REI of 12 hours is adequate
to protect agricultural workers except for those involved in cane
turning, training and girdling of table grapes.  For those activities in
conjunction with the maximum application rate, a MOE of 100 occurs on
Day After Treatment 3 for cymoxanil.  The REI listed on the Tanos®
label is 12 hours.

Aggregate Exposure and Risk Assessment

An aggregate risk assessment was performed for chronic dietary exposure
(food + water).  Acute and cancer aggregate risk assessment were not
performed because no toxic effects attributable to a single dose were
determined for acute toxicity and the CARC classified famoxadone as
“not likely to be carcinogenic to humans.”  Short- and
intermediate-term aggregate risks are not applicable due to a lack of
residential uses.

Chronic aggregate risk estimates did not exceed HED's level of concern. 
Since the chronic aggregate risk exposure includes only food and water
and the chronic dietary analysis included both, no further calculations
are necessary.  Since the chronic dietary risk does not exceed ARIA’s
level of concern, the chronic aggregate risk does not exceed ARIA’s
level of concern.

Recommendation for Tolerances

Pending receipt of the revised Section F, label revisions as recommended
in the analytical and residue chemistry memo (W. Cutchin, DP Numbers:
323682 and 333260, 29/11/2006) and that all requirements of the
cymoxanil risk assessment are addressed, ARIA  SEQ CHAPTER \h \r 1 
concludes that there are no data requirements that would preclude
IR-4’s amended registration request for Tanos® DF (EPA Reg. No.
352-604 and for establishment of the following famoxadone tolerances:

Grapes	  2.5 ppm

Hops	   80 ppm

Caneberries, subgroup 13A	   10 ppm

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

Famoxadone   SEQ CHAPTER \h \r 1 is one of the active ingredients
included in the fungicide Tanos® DF, a dry flowable formulation
containing 25% ai famoxadone + 25% ai cymoxanil.  Famoxadone is known to
inhibit the oxidative phosphorylation in the fungal mitochondria and is
highly active against spore germination and mycelial growth of sensitive
fungi.  The chemical structure and nomenclature of famoxadone are
presented in Table 1.  The physicochemical properties of famoxadone are
presented in Table 2.

Table 1.	Famoxadone Nomenclature.

Chemical structure	

Common name	Famoxadone

Company experimental name	DPX-JE874

IUPAC name
3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione

CAS name	5-methyl-5-(4
phenoxyphenyl)-3-(phenylamino)-2,4-oxazolidinedione

CAS registry number	131807-57-3

End-use product (EP)	50% DF formulation (DuPont™ Tanos® Fungicide;
EPA Reg. No. 352-604) contains 25% famoxadone and 25% cymoxanil

Table 2.	Physicochemical Properties of Famoxadone.

Parameter	Value	Reference

Melting point/range	  SEQ CHAPTER \h \r 1 140.3- 141.8°C	PP#0F06070 and
PP#7E04847; DP Num:271377 and 287253, M. Doherty, 4/18/03

pH	  SEQ CHAPTER \h \r 1 6.56 at 20°C

	Density	  SEQ CHAPTER \h \r 1 D204 = 1.310 g/mL

	Water solubility	  SEQ CHAPTER \h \r 1 pH		 g/L

unbuffered	  52

2		143

3		191

5		243

7		111

9		  38

	Solvent solubility	  SEQ CHAPTER \h \r 1 Solvent		g/L

acetone		274

acetonitrile	125

dichloromethane	239

ethyl acetate	125

hexane		    0.0476

methanol		  10.0

1-octanol		    1.87

toluene		  13.3

	Vapor pressure	  SEQ CHAPTER \h \r 1 6.4×10-4  mPa (4.8×10-9 mm Hg)

	Dissociation constant, pKa	  SEQ CHAPTER \h \r 1 Expected to be weakly
basic.  The dissociation constant could not be measured or inferred from
solubility or octanol water partition coefficient.

	Octanol/water partition coefficient, Log(KOW)	  SEQ CHAPTER \h \r 1 pH
Log Kow ± SD

3.0	4.59 ± 0.06

5.0	4.80 ± 0.13

7.0	4.65 ± 0.40

9.0	5.55 ± 0.26

	UV/visible absorption spectrum	NA

	

3.0	HAZARD CHARACTERIZATION tc "3.0  HAZARD CHARACTERIZATION" 

All toxicological data requirements for famoxadone have been satisfied. 
The database

was previously evaluated by HED (TXR Number 0051819, 16/04/03). The
toxicology database was characterized in HED’s Risk Assessment for the
use of famoxadone on various crops (M. Doherty, DP Number: 276070,
29/04/2003).  

3.1	Dose-Response Assessment  tc "3.1  Hazard Profile " \l 2 

A summary of the dose levels and toxicological endpoints for use in the
risk assessment are presented in Table 3 below. 

Table 3.  Summary of Toxicological Doses and Endpoints for Famoxadone
for Use in Human Risk Assessment

Exposure

Scenario	Dose Used in Risk Assessment,

 UF	FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Acute Dietary

general population including infants and children	NOAEL = none

UF = none

Acute RfD = none	N/A	No appropriate endpoint attributable to a single
oral dose was identified in the available toxicology studies on
famoxadone.

Chronic Dietary

all populations	LOAEL= 1.4 mg/kg/day

UF = 1000a

Chronic RfD = 0.0014

mg/kg/day

	FQPA SF = 1

Chronic PAD =

Chronic RfD

FQPA SF

Chronic PAD = 0.0014

mg/kg/day	13-Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based

microscopic lens lesions (cataracts) in eyes of female dogs.

Incidental Oral (All

Durations)	N/A	Residential LOC for

MOE = NA	No residential uses for Famoxadone have been proposed.

Dermal

Short-Term

(1 - 30 days)	Oral study NOAEL=

10.0 mg/kg/day

(dermal abs. rate = 5%)	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 100

	13-Week Feeding Study in Dogs

LOAEL = 23.3 mg/kg/day based on myotonic twitches in male and

female dogs starting on day 21.

Dermal

Intermediate-Term

(1 - 6 months)	Oral study LOAEL= 1.4

mg/kg/day

(dermal abs. rate = 5%)	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 300b

	13-Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on

microscopic lens lesions (cataracts) in eyes of female dogs.

Dermal

Long-Term

(> 6 months)

	Oral study LOAEL= 1.4

mg/kg/day

(dermal abs. rate = 5%)

	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 1000c

	13-Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on

microscopic lens lesions (cataracts) in eyes of female dogs.

Inhalation

Short-Term

(1 - 30 days)

	Oral study NOAEL=

10.0 mg/kg/day

(inhal. abs. rate = 100%)

	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 100

	13-Week Feeding Study in Dogs

LOAEL = 23.3 mg/kg/day based on myotonic twitches in male and

female dogs starting on day 21.

Inhalation

Intermediate-Term

(1 - 6 months)

	Oral study LOAEL= 1.4

mg/kg/day

(inhal. abs. rate = 100%)

	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 300b

	13-Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on

microscopic lens lesions (cataracts) in eyes of female dogs.

Inhalation

Long-Term

(> 6 months)

	Oral study LOAEL= 1.4

mg/kg/day

(inhal. abs. rate = 100%)

	Residential LOC for

MOE = NA

Occupational LOC for

MOE = 1000c

	13-Week Feeding Study in Dogs

LOAEL = 1.4 mg/kg/day based on

microscopic lens lesions (cataracts) in eyes of female dogs.

Cancer (oral, dermal, inhalation)	Classification: Not Likely to be
carcinogenic to humans

UF = uncertainty factor, FQPA SF = Special 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, LOC = level of concern, NA =
Not Applicable

a The UF of 1000x includes the conventional 100x and an additional 10x
for the lack of a NOAEL and for using the dose from a subchronic
(13-week) study for chronic risk assessment.

b The MOE of 300 includes the conventional 100x and an additional 3x
since a LOAEL, rather than a NOAEL, was selected for risk assessments.

c The MOE of 1000 includes the conventional 100x and an additional 10x
for the use of the LOAEL and dose from a subchronic (13-week) study for
long-term risk assessment.

Famoxadone is classified in Acute Toxicity Category III for acute dermal
toxicity, primary eye irritation and primary skin irritation.  It is
classified in Category IV for acute inhalation toxicity.  It is negative
as a dermal sensitizer

The current assessment uses HED’s previously selected doses and
endpoints for a human health risk assessment for famoxadone. As there
were no toxic effects attributable to a single dose, an endpoint of
concern was not identified to quantitate acute-dietary risk to the
general population or to the subpopulation females 13-49 years old.
Therefore, there is no aRfD or aPAD. For chronic dietary exposure, the
endpoint was selected from a subchronic feeding study in dogs in which
the LOAEL was 1.4 mg/kg/day based on microscopic lens lesions
(cataracts) in the eyes of female dogs. An additional UF of 10x was
retained for the lack of a NOAEL and the use of a subchronic study. The
cRfD is 0.0014 mg/kg/day. 

Since there are no residential uses for famoxadone, short-term and
intermediate-term aggregate risk assessments are not required. For
short-term occupational dermal and inhalation exposures, the toxicology
endpoint was selected from the subchronic feeding study in dogs in which
myotonic twitches were observed starting on day 21. For short-term
exposures, the target Margin of Exposure (MOE) is 100. For the
intermediate-term dermal and inhalation exposure risk assessments, the
MOE of 300 includes the conventional 100x and an additional 3X since a
LOAEL, rather than a NOAEL, was selected for risk assessments and due
the extrapolation for a subchronic to chronic exposure.  The HIARC
concluded an additional uncertainty factor of 3X would be adequate for
this risk assessment scenario.  For the long-term dermal and inhalation
exposure risk assessments, the MOE of 1000 includes the conventional 100
and an additional 10X for the use of the LOAEL and dose from a
short-term study (13-weeks) for long-term risk assessment.  The MOEs for
dermal and inhalation exposures may be combined for occupational
exposure risk assessments because oral equivalents were used for the
dermal and inhalation routes of exposure.

3.2	FQPA Considerations  tc "3.2  FQPA Considerations " \l 2 

HED previously concluded that the hazard and exposure data for
famoxadone support reducing the FQPA safety factor to account for
increased sensitivity of infants and children to 1X.  No quantitative or
qualitative evidence of increased susceptibility, as compared to adults,
of rat or rabbit fetuses to in utero exposure to famoxadone was observed
in the developmental toxicity studies. No quantitative or qualitative
evidence of increased susceptibility, as compared to adults, of rat
fetuses or neonates was observed in the 2-generation reproduction study.

3.3	Cumulative Risk

The Food Quality Protection Act (1996) stipulates that when determining
the safety of a pesticide chemical, EPA shall base its assessment of the
risk posed by the chemical on, among other things, available information
concerning the cumulative effects to human health that may result from
dietary, residential, or other non-occupational exposure to other
substances that have a common mechanism of toxicity.  The reason for
consideration of other substances is due to the possibility that
low-level exposures to multiple chemical substances that cause a common
toxic effect by a common mechanism could lead to the same adverse health
effect as would a higher level of exposure to any of the other
substances individually.  A person exposed to a pesticide at a level
that is considered safe may in fact experience harm if that person is
also exposed to other substances that cause a common toxic effect by a
mechanism common with that of the subject pesticide, even if the
individual exposure levels to the other substances are also considered
safe.

ARIA did not perform a cumulative risk assessment as part of this
tolerance action for famoxadone because HED has not yet initiated a
review to determine if there are any other chemical substances that have
a mechanism of toxicity common with that of famoxadone.  For purposes of
this tolerance action, EPA has assumed that famoxadone does not have a
common mechanism of toxicity with other substances.

3.4	Endocrine Disruption  tc "3.4  Endocrine Disruption " \l 2 

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate." 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was
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 the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, famoxadone may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT tc "4.0  EXPOSURE ASSESSMENT" 

4.1	Summary of Proposed Uses 

The petitioner submitted an undated draft specimen label for a 50% dry
flowable (DF) multiple active ingredient (MAI) formulation (Tanos®
fungicide; EPA Reg. No. 352-604) containing 25% cymoxanil and 25%
famoxadone.  In addition, the petitioner included the current accepted
registered label for the same formulation (dated 6/24/05) along with the
proposed use pattern for grapes (east of the Rocky Mountains) and hops
in Sections A and B of the petition, respectively. The product proposed
for amended use is presented in Table 4.  A summary of the proposed uses
on grapes (east of the Rocky Mountains) and hops is presented in Table
5.  We note that the use pattern from the undated draft label differs
from the use pattern proposed in Section B.

Table 4.  Summary of Proposed End-Use Products.

Trade Name	Reg. No.	ai (% of formulation)	Formulation Type	Target Crops
Target Pests	Label Date

Tanos® DF Fungicide	352-604	25% cymoxanil

25% famoxadone	Dry flowable (DF)	Grapes (east of the Rocky Mountains)

Hops	Downy mildew

Late blight	undated draft label

Table 5.  Summary of Directions for Use of Famoxadone.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Grapes (East of the Rocky Mountains)

Foliar spray

Ground, aerial, or chemigation	Section B;

[352-604]	0.25	Not specified (NS)	2.5	30

Undated specimen label;

[352-604]	0.094-0.125	3 per crop cycle	0.375 per crop cycle

1.125 per year	30	Applications may be made in a minimum of 20 gal/A
using ground equipment or 5 gal/A using aerial equipment with a 5- to
7-day retreatment interval.

Hops

Foliar spray

Ground, aerial, or chemigation	Section B; [352-604]	0.125-0.25	NS	1.5	7

Undated specimen label;

[352-604]	0.125-0.156	3 per crop cycle	0.469 per crop cycle

1.125 per year	7	Applications may be made in a minimum of 20 gal/A using
ground equipment or 10 gal/A using aerial equipment with a 5- to 7-day
retreatment interval.

Caneberries

Foliar spray

Ground or aerial	Tanos®

[352-604]	0.188	6	1.125	0	Applications may be made in a minimum of 20
gal/A using ground equipment or 5 gal/A using aerial equipment with 5-
to 7-day retreatment interval.

  SEQ CHAPTER \h \r 1 The following general use directions are also
specified for the 50% DF formulation containing 25% cymoxanil and 25%
famoxadone.    SEQ CHAPTER \h \r 1 Famoxadone, one of the active
ingredients, is a Group 11 (Qol-containing) fungicide, which also
includes all strobilurins and fenamidone.  The following recommendations
were made regarding resistance management.  Do not make more than one
application of Tanos® before alternating with a fungicide that has a
different mode of action, such as maneb, copper, captan, fosetyl-Al, or
dimethomorph.  Do not make more than three applications of Tanos® or
other Group 11 fungicides (all strobilurins or fenamidone) per cropping
cycle.  Do not alternate or tank mix with fungicides to which resistance
has developed.  A reentry interval (REI) of 12 hours is proposed.

The following rotational crop restrictions are specified on the undated
draft specimen label.  Crops listed on the label [cucurbits, grapes
(east of the Rocky Mountains), head lettuce, hops, peppers, potatoes,
and tomatoes] may be planted back at any time and all other crops may be
planted back following a minimum plantback interval of 30 days.

ARIA’s Conclusion:  The proposed uses of   SEQ CHAPTER \h \r 1 Tanos®
DF on hops and grapes grown east of the Rockies are inadequately
delineated because of discrepancies regarding the maximum single and
seasonal rates listed in Section B and the submitted specimen label. 
For hops, a label revision is required to allow consistency of use
pattern with the field trial data; the label must be revised to specify
a maximum of six foliar directed applications with 6- to 8-day RTIs at
0.25 lb famoxadone ai/A/application for a total seasonal rate of 1.5 lb
famoxadone ai/A and a 7-day PHI.  For grapes, the label must be revised
to comply with the HED ChemSAC’s determination that   SEQ CHAPTER \h
\r 1 residue data generated in Europe (France, Germany, Greece, and
Spain) for use of cymoxanil plus famoxadone on grapes could be
translated to support use on grapes grown east of the Rockies provided
the use patterns are identical or the use pattern is more restrictive
(i.e., lower application rates and longer PHI).  The proposed use on
grapes east of the Rockies should be revised to specify a maximum
seasonal rate of 1.07 lb famoxadone ai/A and a 28-day PHI.

The proposed use pattern on caneberries is adequate.     

4.2	Dietary Exposure tc "4.2  Dietary Exposure/Risk Pathway " \l 2 

4.2.1	Residue Profile

Overall, the results from the field trials are adequate to support
registration of famoxadone.

The results from the grape field trials show that residues of famoxadone
were 0.21-0.75 ppm in/on wine grapes harvested 28 days following the
last of ten foliar spray applications at a total rate of 0.899-1.099 lb
famoxadone ai/A.  Residue decline data show that famoxadone residues
generally decrease slightly in wine grapes with increasing preharvest
intervals.  The current tolerance of 2.50 ppm for grapes is appropriate
to support the proposed use.  

The residue data from the hop field trials indicate that residues of
famoxadone ranged from 14.70 ppm to 46.85 ppm in/on dried hops harvested
7-8 days after the last of six applications at a total rate of ~1.50 lb
ai/A.  Statistical analysis of the data show that a tolerance level of
80 ppm will be appropriate for hops.  A revised Section F for hops,
dried at 80 ppm is required.  

The results from the cranberry trials show that famoxadone residues
ranged from 0.40 ppm to 6.7 ppm on/in treated cranberries when the test
substance was applied at the proposed seasonal application rate of 1.125
lb ai/A using a 0-day PHI.  A residue decline study was not conducted by
the applicant.  Statistical analysis of the data show that a tolerance
level of 10 ppm will be appropriate for caneberries.  In addition, the
correct commodity definition is caneberries, subgroup 13A.  A revised
Section F for caneberries, subgroup 13A at 10 ppm is required.

4.2.1.a.   Nature of the Residue - Plants and Livestock

44946415.der (Tomato DER, L. Croteau, 4/7/03; M. Doherty , DP Number:
271377, 18/04/2003)

44302446.der (Grape DER, L. Croteau, 4/7/03; M. Doherty, DP Number:
271377, 18/04/2003)

44302448.der (Potato DER, L. Croteau, 4/7/03; M. Doherty, DP Number:
271377, 18/04/2003)

MARC Decision Memo (M. Doherty, DP Number: 288134, 12/03/2003)

Plants

Plant metabolism studies with famoxadone have been conducted on tomato,
grape, and potato.  The nature of the residue is adequately understood. 

Tomato

The storage stability of famoxadone in tomato samples was adequately
demonstrated under the storage conditions of the nature of the residue
study.  

The total radioactive residues (TRRs) were 0.2 ppm (POP) and 0.17 ppm
(PA) in the first immature tomato fruit sample collected immediately
after the 1st application.  The TRRs for samples collected immediately
prior to the 2nd application (Day 14) were 0.08 ppm for both the POP and
PA-labelled samples.  The concentration of the TRRs in mature fruit
collected 3 days after the 2nd application was 0.1 ppm (POP) and 0.06
ppm (PA).  The majority of the radioactive residues were extractable
(89-95% of the TRRs), with acetone extraction removing 78-88% of the
total radioactive residues.  Phosphate buffer extracts contained smaller
quantities (6-14% of the TRRs) with the highest buffer concentration
representing 0.02 ppm (Day 0 samples).  The concentration of
unextractable [14C]residues was <10% of the TRRs (<0.01 ppm) for all
samples.  The predominant residue extracted was famoxadone with
concentrations of 0.07 ppm (POP) and 0.05 ppm (PA) in the final harvest
mature fruit collected 3 days after the 2nd treatment.  No significant
metabolites were detectable in any tomato fruit extract.

Grape

The storage stability of famoxadone in grape samples was adequately
demonstrated under the storage conditions of the nature of the residue
study.

The majority of the 14C-residues in the leaves were characterized as
surface residues, accounting for more than 93% (range 88-98%) of the
total radioactivity from the [14C-POP]famoxadone and [14C-PA]famoxadone
treatments averaged over the four sampling intervals.  An average of
less than 7% (range 2-12%) of the radioactivity was incorporated into
the leaf tissue.  Surface residues on [14C-POP] famoxadone- and [14C-PA]
famoxadone-treated grape berries also averaged greater than 92% (range
87-98%) of the total radioactivity over the four sampling intervals.  An
average of less than 10% (range 2-21%) of the radioactivity was
incorporated into the grape tissue.

Famoxadone was the major radioactive component in grape leaves and
berries from both label treatments.  Greater than 98% (range 94-100%) of
the surface 14C-residues were identified as famoxadone.  IN-H3310 was
isolated from the surface residues of [14C-POP] famoxadone treated
leaves immediately after the second application.  This metabolite
accounted for less than 2% (range <0.1-1.4%) of the surface residues at
Days 7 and 14 in the study.

Potato

The storage stability of famoxadone in potato samples was adequately
demonstrated under the storage conditions used in this nature of the
residue study.

Greater than 50% (range 52-97%) of the total radiolabeled residues from
both the [ 14C-POP]- and [14C-PA] famoxadone treatment groups were
recovered as surface residues from the treated leaves.  No detectable
radiolabeled residues were found in either immature or mature tubers
(<0.01 mg/kg equivalent).  On average, greater than 90% (range 76-100%)
of the surface residues were identified as famoxadone. 
1-(4-phenoxyphenyl)ethanone (IN-H3310) was isolated as a minor
degradation product from the [14C-POP] famoxadone treated leaves (less
than 5% of the total plant residues).  No significant degradation
product was observed from the [14C-PA] famoxadone treated samples.

The isomeric ratio of famoxadone in the treatment solutions and in the
undegraded materials recovered from the leaf surfaces and leaf extracts
remained at approximately 50/50, indicating that no stereoselective
metabolism/degradation of famoxadone occurred in/on potato leaf
surfaces.

ARIA's Conclusion:  The available plant metabolism studies with
famoxadone on tomato, grape, and potato have been deemed scientifically
acceptable and adequate to delineate the nature of famoxadone-related
residues in those crops.  The nature of the residue studies are adequate
for the determination of famoxadone residues on grapes, hops, and
caneberries.  The residue of concern for both tolerance enforcement and
risk assessment for the purposes of this petition is famoxadone, per se.
 Although all the studies show famoxadone to be the predominant residue
in examined crops, there are slight differences in the metabolic profile
for each.  In order for the Agency to conclude that the metabolism of
famoxadone is adequately delineated in all crops, a metabolism study in
an oilseed or grain crop will need to be submitted.  

 tc \l4 "4.2.1.a.   Nature of the Residue - Plants and Livestock 

Livestock

There are no livestock feedstuffs associated with the proposed use on
grapes and hops.  Therefore, data requirements for livestock metabolism
are not relevant to this tolerance petition.

4.2.1.b.   Residue Analytical Method 

MRIDs 44579102, 449464419, 44331201, 44302451, 44946421, 449464418 (M.
Doherty, DP Numbers: 287253 and 271377, 18/04/03)

In conjunction with PP#0F6070 and PP#7E4847, a  SEQ CHAPTER \h \r 1 n
analytical method (AMR 3705-95; gas chromatography with
nitrogen/phosphorus detector (GC/NPD)) was developed for data gathering
and enforcement purposes to quantitate famoxadone and its co-formulated
active ingredient cymoxanil.  The principle of the method is
homogenization/extraction of sample matrices with aqueous acetonitrile,
cleanup by solvent partitioning into hexane followed by passage through
a Florisil column or various solid-phase extraction (SPE) cartridges,
and analysis/quantitation by GC/NPD or column switching high-performance
chromatography/ultraviolet HPLC/UV (tomato paste).  The enforcement
method for plant matrices has undergone adequate independent laboratory
validation (ILV).

Data-collection methods:  Samples of grapes addressed in this document
were analyzed for residues of famoxadone using a gas chromatography with
electron capture detector (GC/ECD) method [referenced as a multi-residue
enforcement method (DFG S 19 Modified) for the determination of
famoxadone in dry, high water, and oil crops].  Adequate concurrent
method recovery data have been submitted for this method.  The validated
method limit of quantitation (LOQ) is 0.02 ppm and the limit of
detection (LOD) was not reported.

Samples of dried hop cones were analyzed for residues of famoxadone
using the enforcement method (AMR 3705-95, Revision No. 2) with
modifications.  Adequate method validation and concurrent method
recovery data have been submitted for this method.  The lowest limit for
method validation (LLMV) is 0.5 ppm for famoxadone and the calculated
LOQ and LOD are 0.34 and 0.11 ppm, respectively, for residues of
famoxadone.

Caneberry samples were analyzed for famoxadone using an analytical
method entitled Residue Analysis of Famoxadone on Caneberry by GC/EC
Detection, Version #1.  Method validation resulted in a mean concurrent
recovery of famoxadone at all fortification levels of 93% ± 22.3 (n =
15).  An LOQ of 0.028 ppm and an LOD of 0.0092 ppm was reported for
caneberries.   

ARIA's Conclusion:  These are adequate methods available for tolerance
enforcement. 

4.2.1.c.   Multiresidue Methods

MRID 44302452 (M. Doherty, DP Numbers: 287253 and 271377, 18/04/2003)

  SEQ CHAPTER \h \r 1 Famoxadone was screened through multiresidue
methods listed in the Pesticide Analytical Manual Volume I (PAM Vol. I),
Third Edition (January 1994), using Protocols C to E.  Protocols A and B
were not used because famoxadone does not have an n-methyl carbamate
structure (Protocol A), nor is it an acid or phenol (Protocol B). 
Protocol C showed good analytical response using ECD and NPD.  Good
recoveries were obtained for the analysis of wine, grapes, and tomatoes
(92-138%) using Protocol D.  Grapes (red seedless) can be analyzed for
famoxadone residues using Protocol E involving extraction with the mixed
ether elution system, resulting in recovery values of 92 to 108%.

ARIA's Conclusion:  The multiresidue methods testing appears to be
scientifically acceptable and has been sent to the FDA for further
evaluation.  Preliminary analysis suggests that Protocol D may be
appropriate for analysis of famoxadone in plant matrices and has the
potential to be the primary enforcement method.

4.2.1.d.   Storage Stability Data

Samples collected from the field and processing studies were stored
frozen prior to residue analysis.  There are adequate storage stability
data to support the integrity of samples collected from field and
processing studies.  Residues of famoxadone are stable under frozen
storage conditions for up to 18 months in/on grapes, 8.3 months in/on
dried hops, and 7.2 months on caneberries.  There are no storage
stability issues or corrections that may need to be applied to the
various residue studies.

4.2.1.e.   Water, Fish, and Irrigated Crops

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

4.2.1.f.   Food Handling

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

4.2.1.g.   Meat, Milk, Poultry and Eggs

There are no livestock feedstuffs associated with the proposed use on
grapes, hops and caneberries.  Therefore, data requirements pertaining
to meat, milk, poultry, and eggs are not relevant to this tolerance
petition.

4.2.1.h.   Crop Field Trials

IR-4 has submitted magnitude of the residue studies in support of
tolerances discussed in this document.  These studies have been
reviewed, and the Executive Summaries of study DERs are reproduced below
followed by a crop conclusion.

Grape

46670202.der

44302458.der (Imported Grape DER; M. Doherty, DP Number: 271377,
18/04/2003)

IR-4 has submitted field trial data depicting the magnitude of the
residue of famoxadone in/on wine grapes.  A total of 10 field trials
were conducted in Europe on wine grapes during the 1999 growing season
in Greece (2 trials), Italy (2 trials), southern France (4 trials),
northern France (2 trials), and Germany (2 trials).  However, only
samples from northern France (2 trials) and Germany (2 trials) were
analyzed.  At each test location, a total of 10 foliar spray
applications of a water-dispersible granular (WG) formulation
(containing 22.5% famoxadone and 30% cymoxanil) were applied to wine
grapes during the growing season at progressive vine growth stages.  The
first seven applications were made at 0.060-0.107 lb famoxadone
ai/A/application followed by three applications made at 0.121-0.130 lb
famoxadone ai/A/application, for a total rate of 0.899-1.099 lb
famoxadone ai/A.  The petitioner indicated that this application
scenario was designed to incorporate high spray volume situations due to
large vines with excessive foliage.  Applications were made with a 6- to
8-day RTI, using ground equipment (knapsack or portable sprayer) in
~88-171 gal/A spray volumes; an adjuvant was not added to the spray
mixture.  Samples of mature wine grapes were harvested 28 days after the
last application (DALA).  At one location, additional immature grape
samples were collected 0, 1, 7, and 14 DALA to generate residue decline
data.

ARIA’s Conclusion:  The residue data from the current European field
trial submission (MRID 46670202) indicate that residues of famoxadone
were 0.21-0.75 ppm in/on wine grapes harvested 28 days following the
last of multiple foliar spray applications at a total rate of
0.899-1.099 lb famoxadone ai/A.  The residue data (44302458.der.wpd, M.
Doherty, 07/04/2003) that were previously submitted in support of the
import grape tolerance petition indicate that residues of famoxadone
were 0.07-2.14 ppm in/on wine grapes harvested approximately 28 days
following the last of multiple foliar spray treatments of Tanos® DF at
a total rate of 1.07 lb ai/A.

Based on the aggregate of field trial data, all of which were conducted
in Europe, the current tolerance of 2.5 ppm for grapes is appropriate to
support the proposed use of Tanos® DF on grapes grown east of the Rocky
Mountains pending label revision to conform to the HED’s ChemSAC
determination regarding data translation.  The label should be modified
to specify a maximum seasonal rate of ~1.1 lb ai/A and a 28-day PHI. 
The Agency’s tolerance spreadsheet was not used for grape because
previously submitted and reviewed European residue data were used to
establish the existing tolerance and support use in the Eastern U.S.

Hops

46670201.der

IR-4 has submitted field trial data depicting the magnitude of the
residue of famoxadone in/on dried hops.  A total of three hop field
trials were conducted in the United States in Zones 11 (ID and WA) and
12 (OR) during the 2000 growing season.  At each test location, hop
plants received six foliar directed applications of the test
formulation, Tanos® DF, a dry flowable formulation containing 25% ai
famoxadone + 25% ai cymoxanil,   SEQ CHAPTER \h \r 1 at ~0.25 lb
famoxadone ai/A/application with a 6- to 8-day retreatment interval for
a total seasonal rate of ~1.5 lb ai famoxadone/A.  No adjuvant was
included in the spray mixture.  Samples of fresh hop cones were
harvested 7-8 days after the last spray application, and cones were
dried 3 to approximately 20 hours after to sampling.

ARIA’s Conclusion:  The submitted data are adequate pending label
revision to reflect the parameters of field trial data.  HED is
recommending label revisions to specify a maximum single foliar
application rate of 0.25 lb ai/A, with a 6-8 day RTI, a maximum seasonal
rate of ~1.50 lb ai/A, and a 7-day PHI.  The hop data were entered into
the Agency’s tolerance spreadsheet (see Appendix I), and statistical
analysis of data shows that a tolerance level of 80 ppm will be
appropriate for hops.  A revised Section F for hops, dried at 80 ppm is
required.

Caneberries

46905801.der

The IR-4 has submitted field trial data for famoxadone on caneberries. 
Four supervised crop field trials were conducted in CA (two trials, U.S.
EPA Region 10), WA (U.S. EPA Region 12) and OR (U.S. EPA Region 12)
during the 2003 growing season.  In addition, three supervised crop
field trials were conducted in Canada, with one trial in British
Columbia (Canadian Region 12), one trial in Ontario (Canadian Region 5),
and one trial in Quebec (Canadian Region 5B).  Six foliar applications
of DPX-KP481 50WG (25% famoxadone) were applied at a rate of 0.75 lb
ai/A (0.188 lb/A famoxadone) at 6-8 day intervals (4.5 lb ai/A/season,
1.125 lb famoxadone/A/season).  Samples were collected on the day of the
last application (0-day PHI).  No adjuvants or additives were added to
the spray mixture for any of the above applications.  The number and
locations of field trials are in accordance with OPPTS Guideline
860.1500 (with some acceptable deviations).  

ARIA’s Conclusion:  The results from these trials show that famoxadone
residues ranged from 0.40 ppm to 6.7 ppm on/in treated caneberries when
the test substance was applied at the proposed seasonal application rate
of 1.125 lb ai/A using a 0-day PHI.  The cranberry data were entered
into the Agency’s tolerance spreadsheet, and statistical analysis of
the data show that a tolerance level of 10 ppm will be appropriate for
caneberries.  In addition, the correct commodity definition is
caneberries, subgroup 13A.  A revised Section F for caneberries,
subgroup 13A at 10 ppm is required.

4.2.1.i.   Processed Food/Feed tc \l4 "4.2.1.f.   Processed Food/Feed 

MRID 44302464 (M. Doherty, DP Numbers: 287253 and 271377, 18/04/2003)

HED’s   SEQ CHAPTER \h \r 1 ChemSAC, in a memo dated 19/04/2004,
concluded that European grape data could be used to support the use in
the eastern U.S.  They also pointed out that a processing study was
required to determine whether famoxadone residues concentrated in juice.
 Data were not required for raisins for a use limited to east of the
Rocky Mountains.

The petitioner previously submitted a European grape processing study
(MRID 44302464) in conjunction with PP#7E4847.  These data were reviewed
by the Agency (M. Doherty, DP Number: 287253 and 271377, 18/04/2003)
where it was reported that residues of famoxadone were below the LOQ of
0.02 ppm in juice processed from grapes bearing detectable residues. 
Assuming residues at ½ the LOQ, the processing factor for juice is
0.01x.  The empirical concentration factors are less than the
theoretical concentration factors for grape commodities.

ARIA’s Conclusion:  The field trials that supplied the grapes for
processing were conducted at 1x the field application rate.  Processing 
 SEQ CHAPTER \h \r 1 followed typical commercial practices for grapes,
and the residue data are supported by the analytical methods and storage
stability studies.  This study indicates that residues of famoxadone per
se do not concentrate in grape juice processed from grapes bearing
detectable famoxadone residues.  

The ChemSAC has also determined that data are not required for raisins
for a use limited to east of the Rocky Mountains since raisins are not
typically produced in that area.  Therefore, no change in the
established raisin tolerance is required.   

 

4.2.1.j.   Confined/Field Accumulation in Rotational Crops

Grapes, hops, and caneberries   SEQ CHAPTER \h \r 1 are crops which are
typically not rotated; therefore, the proposed uses are not relevant to
these topics.

4.2.1.k.   International Harmonization of Tolerances

A Codex MRL (CXL) has been established for grapes at 2 mg/kg.  The MRL
for grape is below the existing tolerance of 2.5 ppm.  A Codex MRL has
also been established for dry grape pomace at 7 mg/kg.  There are
currently no established Canadian or Mexican MRLs for famoxadone.  An
International Residue Limit Status sheet is attached to this review.

4.2.2	Drinking Water Analysis  tc "4.3  Water Exposure/Risk Pathway " \l
2 

EFED had previously provided estimated drinking water concentrations
(EDWCs) for the use of famoxadone on potatoes, fruiting vegetables,
cucurbit vegetables, and head lettuce. These estimates were included in
M. Doherty’s April 29, 2003 review (DP Number: 276070).  Because the
proposed IR-4 request involves very similar methods of application and
similar use rates than the uses considered under that review, there is
no need to provide revised EDWCs.  It should be pointed out that in the
previous review, scenarios were evaluated for tomatoes in California,
Pennsylvania, and Florida, potatoes in Maine and Idaho, lettuce in
Florida, cucumbers in Florida, and peppers in Florida. These scenarios
were chosen to estimate the concentration of famoxadone in surface
drinking water over a geographically dispersed range of areas
representative of crops proposed for famoxadone use.

 for the total toxic residues of famoxadone as 0.47 μg/L (1 in 10 year
annual mean concentration). The estimated concentration of the total
toxic residues of famoxadone for drinking water from shallow groundwater
sources from the SCIGROW model is 0.23 μg/L.

4.2.3	Dietary Analysis

A chronic dietary exposure assessment was conducted using the Dietary
Exposure Evaluation Model software with the Food Commodity Intake
Database (DEEM-FCID™, Version 2.03), which incorporates consumption
data from USDA’s Continuing Surveys of Food Intakes by Individuals
(CSFII), 1994-1996 and 1998.  The 1994-96, and 98 data are based on the
reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events.  Based on analysis of the 1994-96, and 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

4.2.3.a	Acute Dietary

There was no appropriate endpoint for assessing acute dietary exposure;
therefore, no acute dietary risk assessment was performed.  

4.2.3.b	Chronic Dietary

DEEM™ default processing factors and anticipated residues (ARs).  The
highest chronic drinking water concentration of 0.47 μg/L (ppb) was
used in this analysis.  The dietary exposure analysis also used a
Screening-Level Usage Analysis (SLUA), provided by the Biological and
Economic Analysis Division (BEAD), for %CT information of current uses
of famoxadone (J. Alsadek, 08/31/2006), see Table 6 below.  

Table 6.  Percent Crop Treated Information Used in Chronic Dietary
Exposure Analysis                       

Commodity	Percent of Crop Treated

Cucumbers	5

Peppers	5

Potatoes	5

Pumpkins	5

Squash

	<1

Tomatoes	10

Watermelons	<1

The results of the analysis indicate that chronic risk from the dietary
(food + drinking water) exposure to famoxadone is below HED’s level of
concern for the general U.S. population, and all population subgroups. 
The chronic dietary risk estimate for the highest reported exposed
population subgroup, children 1-2 years old, is 65% of the cPAD.  The
general US population utilizes 51% of the cPAD.

Table 7.  Summary of Results from Chronic DEEMTM  Analysis

Population Subgroup	Dietary Exposure

(mg/kg/day)	% cPAD*

General U.S. Population	0.000712	51

All Infants (< 1 year old)	0.000232	17

Children 1-2 years old	0.000915	65

Children 3-5 years old	0.000842	60

Children 6-12 years old	0.000517	37

Youth 13-19 years old	0.000424	30

Adults 20-49 years old	0.000883	63

Adults 50+ years old	0.000583	42

Females 13-49 years old	0.000524	37

* % PADs are reported to 2 significant figures.

The values for the highest exposed population for each type of risk
assessment are bolded.

4.2.3.c	Cancer Dietary

The Cancer Assessment Review Committee (CARC) classified famoxadone as
“not likely to be carcinogenic to humans.” Due to the
classification, no cancer dietary risk assessment was performed.

4.3  	Occupational/Residential Exposure

4.3.1	Summary of Use Patterns and Formulations

Based upon the proposed use pattern, RD believes the most highly exposed
occupational pesticide handlers will be 1) mixer/loaders using open-pour
loading of a dry flowable formulation; 2) applicators using open-cab
airblast sprayers, 3) applicators using open-cab ground-boom sprayers
and 4) aerial applicators.  

RD also believes occupational handlers will be exposed to short-term
duration exposures (1 - 30 days).   Although multiple applications are
likely, they should not be consecutive applications and should be
alternated with other fungicides.  The treatment interval is 5 - 7 days.
 It is unlikely that handlers would be exposed continuously for 30 or
more days (i.e., intermediate-term exposure).  

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The ExpoSAC SOP Number 12 (29 March
2000) directs that although the same individual may perform all those
tasks, they shall be assessed separately.  The available exposure data
for combined mixer/loader/applicator scenarios are limited in comparison
to the monitoring of these two activities separately.  These exposure
scenarios are outlined in the Pesticide Handler Exposure Database (PHED)
Surrogate Exposure Guide (August 1998).   HED has adopted a methodology
to present the exposure and risk estimates separately for the job
functions in some scenarios and to present them as combined in other
cases.  Most exposure scenarios for hand-held equipment (such as hand
wands, backpack sprayers, and push-type granular spreaders) are assessed
as a combined job function.  With these types of hand held operations,
all handling activities are assumed to be conducted by the same
individual.  The available PHED and other exposure data support this and
HED presents them in this way.  Conversely, for equipment types such as
fixed-wing aircraft, ground-boom tractors, or air-blast sprayers, the
applicator exposures are assessed and presented separately from those of
the mixers and loaders.  By separating the two job functions, HED/RD
determine the most appropriate levels of personal protective equipment
(PPE) for each aspect of the job without requiring an applicator to wear
unnecessary PPE that might be required for a mixer/loader (e.g.,
chemical resistant gloves may only be necessary during the pouring of a
liquid formulation).

4.3.2 	Occupational Exposure Assessment

itrile rubber), all ≥ 14 mils. 

Table 8. Summary of Exposure & Risk to Occupational Handlers From
Famoxadone

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer/Loader - Dry Flowable - Open Pour

Dermal:

SLNoGlove      0.066 LC

SLWithGlove   0.066 HC

Inhal.            0.00077 HC	0.1875

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.00177

SLWithGlove 0.00177

Inhal.              0.000413	No Glove

4,587

With Glove

4,587

Applicator - Ground-boom - Open-cab

Dermal:

SLNoGlove       0.014 HC

SLWithGlove    0.014 MC

Inhal.              0.00074 HC	0.1875

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.000375

SLWithGlove 0.000375

Inhal.              0.000396	No Glove

12,970

With Glove

12,970

Applicator - Air-blast - Open Cab

Dermal:

SLNoGlove       0.36 HC

SLWithGlove    0.24 MC

Inhal.                 0.0045 HC	0.1875

lb ai/A	40 A/day	Dermal:

SLNoGlove    0.00193

SLWithGlove 0.00129

Inhal.              0.000482	No Glove

4,149

With Glove

5,649

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.    Dermal =  Single Layer Work
Clothing No Gloves;  Single Layer  Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg a.i./pound of active ingredient handled.  Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2.  Applic. Rate. = Taken from IR-4 submission Sections B.  

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture;  ExpoSAC SOP  No. 9.1;  Revised 5 July 2000;

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated *
absorption factor (5.0 % dermal absorption; 100 % inhalation absorption)
( 70 kg Body Weight

5.  MOE = Margin of Exposure = No Observable  Adverse Effect Level
(NOAEL)  ( ADD.   The NOAELs for short- term dermal and inhalation
exposure durations are 10.0 mg a.i./kg bw/day.  They are identified from
the same toxicity study in the dog and cite the same toxic effects. 
Therefore dermal and inhalation exposures are summed then divided into
NOAEL to determine Margin of Exposure.

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to famoxadone.  The estimated MOEs are all > 100.   Therefore
the proposed new uses do not exceed RD’s level of concern.

4.3.2.a	Occupational Post-Application Exposure Risk Assessment

The risk assessment assumed individuals were re-entering the treated
area to perform post-application agricultural activities that may occur
and which may result in post-application exposures to pesticide
residues.  No chemical specific data were available with which to assess
potential exposure to pesticide handlers, so default assumptions were
used.

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.25 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.56 µg/cm2 , therefore,

0.56 µg/cm2 * 10,000 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.05 (% dermal
absorption) ( 70 kg bw = 0.032 mg/kg bw/day.

MOE = NOAEL ( ADD then 10.0 mg/kg bw/day ( 0.032 mg/kg bw/day = 312.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOEs are > 100, the
proposed use does not exceed HED’s level of concern.

Famoxadone is classified in Acute Toxicity Category III for acute dermal
toxicity, primary eye irritation and primary skin irritation.  It is
classified in Category IV for acute inhalation toxicity.  It is negative
as a dermal sensitizer.  Therefore, the interim Worker Protection
Standard (WPS) REI of 12 hours is adequate to protect agricultural
workers.  The REI listed on the Tanos® label is 12 hours. 

4.3.3	Residential Exposure

There are no residential uses associated with famoxadone.

 tc "4.4.5  Off Target Non-Occupational Exposure " \l 3 5.0	AGGREGATE
RISK ASSESSMENTS AND CHARACTERIZATION tc "5.0  AGGREGATE RISK
ASSESSMENTS AND RISK CHARACTERIZATION" 

5.1	Acute Aggregate Risk  tc "5.1  Acute Aggregate Risk " \l 2  (food +
water)

An acute aggregate risk assessment takes into account exposure estimates
from acute dietary consumption and drinking water. Since there was no
acute dietary endpoint selected, an acute aggregate risk assessment is
not required.

5.2	Short/ tc "5.2  Short-Term Aggregate Risk " \l 2 Intermediate-Term
Aggregate Risk (food + water + residential)

There are no residential uses associated with famoxadone, therefore
short-term and intermediate aggregate risk assessments were not
required.

5.3	Chronic Aggregate Risk (Food + Water)

Chronic aggregate risk estimates are below HED's level of concern.   tc
"5.4  Chronic Aggregate Risk " \l 2  Since the chronic aggregate risk
exposure includes only food and water and the chronic dietary analysis
included both, no further calculations are necessary.  Since the chronic
dietary risk does not exceed ARIA’s level of concern, the chronic
aggregate risk does not exceed ARIA’s level of concern.

5.4	Cancer Aggregate Risk

The Cancer Assessment Review Committee (CARC) classified famoxadone as
“not likely to be carcinogenic to humans.” Due to the
classification, no cancer aggregate risk assessment was performed.

6.0	DATA NEEDS tc "8.0  DATA NEEDS" 

6.1	Toxicology

None.

6.2	Residue Chemistry 

A revised Section F and label revisions as noted below:

860.1200 Directions for Use

Label amendments are required for Tanos® DF (EPA Reg. No. 352-604) to
reflect the parameters of field trial data for hops and to be consistent
with the HED’s ChemSAC determination regarding translation of residue
data for grapes.  

For hops, the label should be revised to specify a maximum foliar
application rate of 0.25 lb ai/A, with a 6-8 day retreatment interval
(RTI), a maximum seasonal rate of ~1.50 lb ai/A, and 7-day preharvest
interval (PHI). 

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, Germany, Greece, and Spain) for use of cymoxanil plus famoxadone on
grapes could be translated to support use on grapes east of the Rockies
provided the use patterns are identical or the use pattern is more
restrictive (i.e., lower application rates and longer PHI).  Therefore,
based on the European field trial data, the proposed use on grapes grown
east of the Rocky Mountains should be revised to specify a maximum
seasonal rate of ~1.1 lb ai/A and a 28-day PHI.

860.1500 Crop Field Trials

Statistical analysis of the data show that a tolerance level of 80 ppm
will be appropriate for hops. A revised Section F for hops, dried at 80
ppm is required.  

Statistical analysis of the data show that a tolerance level of 10 ppm
will be appropriate for caneberries.  In addition, the correct commodity
definition is caneberries, subgroup 13A.  A revised Section F for
caneberries, subgroup 13A at 10 ppm is required.  

 tc "8.2  Residue Chemistry " \l 2 

6.3	Occupational/Residential 

None.

7.0	ATTACHEMENTS

Attachment 1: MRL Status Sheet for Famoxadone

cc:

B. Hanson

Attachment 1: MRL Status Sheet for Famoxadone

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 
3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione	Common
Name:

Famoxadone	X Proposed tolerance

( Reevaluated tolerance

 No Codex proposal step 6 or above

  No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#5E7001

DP Num:  323682

Other Identifier:  

Residue definition (step 8/CXL):  famoxadone	Reviewer/Branch:  C.
Swartz/RAB2

	Residue definition:  famoxadone
(3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione)  SEQ
CHAPTER \h \r 1 

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

Grape pomace, Dry	7	Hops, dried	60

Grapes	2	Grape	2.50

	Limits for Canada	Limits for Mexico

X   No Limits

摧ᆂs

$

摧ᆂs

摧ᆂs܀   No Limits for the crops requested	X   No Limits

   No Limits for the crops requested

Residue definition  N/A	Residue definition:  N/A

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

Notes/Special Instructions:  S. Funk, 06/20/2006.

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 PAGE   29