Document ID: EPA-HQ-OPP-2007-1192-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-04T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		September 15, 2008

Subject:	Famoxadone.  Human Health Risk Assessment for the Proposed Food
Use of Famoxadone on Bulb Vegetables, Crop Group 3; Leafy Greens,
Subgroup 4A; Leaf Petioles, Subgroup 4B; and Cilantro.  

PC Code:  	113202	DP Barcode:	347669 & 347672

Decision No.:	386103 & 386104	Registration No.:	352-604

Petition No.:	7E7280, 7E7281	Regulatory Action:	Section 3

Assessment Type:	Single Chemical Human Health Risk Assessment
Registration Case No.:	None

TXR No.:	None	CAS No.:	131807-57-3

MRID No.:	None	40 CFR:	§180.587

  SEQ CHAPTER \h \r 1 From:		  SEQ CHAPTER \h \r 1 Breann Hanson,
Biologist

			Alternative Risk Integration and Assessment (ARIA) Team

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

			Registration Division (RD) (7505P)

Through:		  SEQ CHAPTER \h \r 1 William Cutchin, Acting Senior Branch
Scientist

				ARIA

				RIMUERB/RD (7505P)

		

				AND

		

				Douglas Dotson, Ph.D., Chemist

				Christina Swartz, Branch Chief

			Registration Action Branch 2 (RAB2)

			Health Effects Division (HED) (7509P)

To:	Susan Stanton/Dan Rosenblatt, RM Team 05 

			RIMUERB/RD (7505P)

	  SEQ CHAPTER \h \r 1 

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA 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 proposed and currently registered uses of the active
ingredient famoxadone. 

In this document, ARIA has conducted an assessment of the human exposure
and health risks resulting from these proposed uses and all currently
registered uses.  The overall risk assessment and dietary risk
assessment were provided by Breann Hanson, the residue chemistry
assessment by William Cutchin, the water exposure assessment by James
Lin (Environmental Fate and Effects Division (EFED)) and the
occupational exposure assessment by Mark Dow.  

This risk assessment incorporates all current, pending and proposed
tolerances for famoxadone as of September 15, 2008.

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc209236847"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc209236847 \h  5  

  HYPERLINK \l "_Toc209236848"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc209236848 \h  11  

  HYPERLINK \l "_Toc209236849"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc209236849 \h  11  

  HYPERLINK \l "_Toc209236850"  2.2	Structure and Nomenclature	  PAGEREF
_Toc209236850 \h  12  

  HYPERLINK \l "_Toc209236851"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc209236851 \h  13  

  HYPERLINK \l "_Toc209236852"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc209236852 \h  13  

  HYPERLINK \l "_Toc209236853"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc209236853 \h  14  

  HYPERLINK \l "_Toc209236854"  3.1.1	Database Summary	  PAGEREF
_Toc209236854 \h  14  

  HYPERLINK \l "_Toc209236855"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc209236855 \h  14  

  HYPERLINK \l "_Toc209236856"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc209236856 \h  14  

  HYPERLINK \l "_Toc209236857"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc209236857 \h  14  

  HYPERLINK \l "_Toc209236858"  3.1.2	Toxicological Effects	  PAGEREF
_Toc209236858 \h  14  

  HYPERLINK \l "_Toc209236859"  3.1.3	Dose-response	  PAGEREF
_Toc209236859 \h  17  

  HYPERLINK \l "_Toc209236860"  3.1.4	FQPA	  PAGEREF _Toc209236860 \h 
17  

  HYPERLINK \l "_Toc209236861"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc209236861 \h  17  

  HYPERLINK \l "_Toc209236862"  3.3	FQPA Considerations	  PAGEREF
_Toc209236862 \h  18  

  HYPERLINK \l "_Toc209236863"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc209236863 \h  18  

  HYPERLINK \l "_Toc209236864"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc209236864 \h  18  

  HYPERLINK \l "_Toc209236865"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc209236865 \h  19  

  HYPERLINK \l "_Toc209236866"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc209236866 \h  20  

  HYPERLINK \l "_Toc209236867"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc209236867 \h  22  

  HYPERLINK \l "_Toc209236868"  3.3.6	Pre-and/or Post-natal Toxicity	 
PAGEREF _Toc209236868 \h  22  

  HYPERLINK \l "_Toc209236869"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc209236869 \h  22  

  HYPERLINK \l "_Toc209236870"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc209236870 \h  22  

  HYPERLINK \l "_Toc209236871"  3.3.7	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc209236871 \h  23  

  HYPERLINK \l "_Toc209236872"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc209236872 \h  24  

  HYPERLINK \l "_Toc209236873"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc209236873 \h  24  

  HYPERLINK \l "_Toc209236874"  3.5.1    Acute Reference Dose (aRfD)	 
PAGEREF _Toc209236874 \h  24  

  HYPERLINK \l "_Toc209236875"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc209236875 \h  25  

  HYPERLINK \l "_Toc209236876"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc209236876 \h  25  

  HYPERLINK \l "_Toc209236877"  3.5.5	Dermal Absorption	  PAGEREF
_Toc209236877 \h  25  

  HYPERLINK \l "_Toc209236878"  3.5.6	Dermal Exposure: Short-Term (1-30
Days) Exposure	  PAGEREF _Toc209236878 \h  26  

  HYPERLINK \l "_Toc209236879"  3.5.7	Dermal Exposure: Intermediate-Term
(1-6 Months) Exposure	  PAGEREF _Toc209236879 \h  27  

  HYPERLINK \l "_Toc209236880"  3.5.8	Dermal Exposure: Long-Term (> 6
Months) Exposure	  PAGEREF _Toc209236880 \h  28  

  HYPERLINK \l "_Toc209236881"  3.5.9	Inhalation Exposure: Short-Term
(1-30 Days)	  PAGEREF _Toc209236881 \h  28  

  HYPERLINK \l "_Toc209236882"  3.5.10	Inhalation Exposure:
Intermediate-Term (1-6 Months)	  PAGEREF _Toc209236882 \h  29  

  HYPERLINK \l "_Toc209236883"  3.5.11	Inhalation Exposure: Long-Term (>
6 Months)	  PAGEREF _Toc209236883 \h  29  

  HYPERLINK \l "_Toc209236884"  3.5.12	Level of Concern for Margin of
Exposure	  PAGEREF _Toc209236884 \h  29  

  HYPERLINK \l "_Toc209236885"  3.5.13	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc209236885 \h  30  

  HYPERLINK \l "_Toc209236886"  3.5.14	Classification of Carcinogenic
Potential	  PAGEREF _Toc209236886 \h  30  

  HYPERLINK \l "_Toc209236887"  3.5.15	Summary of Toxicological Doses
and Endpoints for Famoxadone for Use in Human Risk Assessments	  PAGEREF
_Toc209236887 \h  31  

  HYPERLINK \l "_Toc209236888"  3.6	Endocrine Disruption	  PAGEREF
_Toc209236888 \h  32  

  HYPERLINK \l "_Toc209236889"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc209236889 \h  33  

  HYPERLINK \l "_Toc209236890"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc209236890 \h  33  

  HYPERLINK \l "_Toc209236891"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc209236891 \h  33  

  HYPERLINK \l "_Toc209236892"  5.1.1	Metabolism in Primary Crops and
Livestock Commodities.	  PAGEREF _Toc209236892 \h  33  

  HYPERLINK \l "_Toc209236893"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc209236893 \h  33  

  HYPERLINK \l "_Toc209236894"  5.1.3	Analytical Methodology	  PAGEREF
_Toc209236894 \h  34  

  HYPERLINK \l "_Toc209236895"  5.1.4	Multiresidue Methods	  PAGEREF
_Toc209236895 \h  35  

  HYPERLINK \l "_Toc209236896"  5.1.5	Storage Stability	  PAGEREF
_Toc209236896 \h  35  

  HYPERLINK \l "_Toc209236897"  5.1.6	Magnitude of the Reside in Plants	
 PAGEREF _Toc209236897 \h  35  

  HYPERLINK \l "_Toc209236898"  5.1.7	Magnitude in Meat, Milk, Poultry,
and Eggs	  PAGEREF _Toc209236898 \h  37  

  HYPERLINK \l "_Toc209236899"  5.1.8	Confined and Field Rotational
Crops	  PAGEREF _Toc209236899 \h  37  

  HYPERLINK \l "_Toc209236900"  5.1.9	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc209236900 \h  37  

  HYPERLINK \l "_Toc209236901"  5.1.10	Drinking Water Residue Profile	 
PAGEREF _Toc209236901 \h  38  

  HYPERLINK \l "_Toc209236902"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc209236902 \h  38  

      HYPERLINK \l "_Toc209236904"  5.2.1        Acute Dietary
Exposure/Risk  PAGEREF _Toc209236904 \h  38  

  HYPERLINK \l "_Toc209236905"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc209236905 \h  38  

  HYPERLINK \l "_Toc209236906"  5.2.2	Cancer Dietary Risk	  PAGEREF
_Toc209236906 \h  39  

  HYPERLINK \l "_Toc209236907"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc209236907 \h  39  

  HYPERLINK \l "_Toc209236908"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc209236908 \h  42  

  HYPERLINK \l "_Toc209236909"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc209236909 \h  42  

  HYPERLINK \l "_Toc209236910"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc209236910 \h  42  

  HYPERLINK \l "_Toc209236911"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc209236911 \h  43  

  HYPERLINK \l "_Toc209236912"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc209236912 \h  43  

  HYPERLINK \l "_Toc209236913"  9.1	Handler Exposure and Risk	  PAGEREF
_Toc209236913 \h  43  

  HYPERLINK \l "_Toc209236914"  9.2	Post-Application Exposure Risk	 
PAGEREF _Toc209236914 \h  46  

  HYPERLINK \l "_Toc209236915"  9.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc209236915 \h  47  

  HYPERLINK \l "_Toc209236916"  10.0	TOLERANCE SUMMARY	  PAGEREF
_Toc209236916 \h  47  

  HYPERLINK \l "_Toc209236917"  11.1	Toxicology	  PAGEREF _Toc209236917
\h  50  

  HYPERLINK \l "_Toc209236918"  11.2	Residue Chemistry	  PAGEREF
_Toc209236918 \h  51  

  HYPERLINK \l "_Toc209236919"  11.3	Occupational and Residential
Exposure	  PAGEREF _Toc209236919 \h  51  

  HYPERLINK \l "_Toc209236920"  12.0	REFERENCES	  PAGEREF _Toc209236920
\h  51  

  HYPERLINK \l "_Toc209236921"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc209236921 \h  53  

  HYPERLINK \l "_Toc209236922"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc209236922 \h  53  

  HYPERLINK \l "_Toc209236923"  A.2   Toxicity Profiles	  PAGEREF
_Toc209236923 \h  54  

  HYPERLINK \l "_Toc209236924"  A.3  Executive Summaries	  PAGEREF
_Toc209236924 \h  54  

  HYPERLINK \l "_Toc209236925"  Appendix B:  Metabolism Assessment	 
PAGEREF _Toc209236925 \h  67  

  HYPERLINK \l "_Toc209236926"  Appendix C:  Tolerance Reassessment
Summary and Table	  PAGEREF _Toc209236926 \h  67  

  HYPERLINK \l "_Toc209236927"  Appendix D:  Review of Human Research	 
PAGEREF _Toc209236927 \h  67  

  HYPERLINK \l "_Toc209236928"  Appendix E:	International Residue Limit
Status	  PAGEREF _Toc209236928 \h  68  

 	

1.0 EXECUTIVE SUMMARY  TC \l1 "1.0 EXECUTIVE SUMMARY 

Background

This document is a human health risk assessment to support two
Interregional Research Project No. 4 (IR-4) requests for the
establishment of permanent tolerances for residues of famoxadone in/on
leaf petioles, subgroup 4B (PP#7E7280) and on leafy greens, subgroup 4A;
bulb vegetables, group 3 and on cilantro, leaves (PP#7E7281). 
Famoxadone,
[3-anilo-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione], is an
oxazolidinedione fungicide.  It inhibits oxidative phosphorylation in
the fungal mitochondria and is highly active against spore germination
and mycelial growth.  Famoxadone is presently registered in the United
States for food/feed uses on   SEQ CHAPTER \h \r 1 fruiting vegetables,
crop group 8; cucurbit vegetables, crop group 9; caneberrries, subgroup
13A; grapes (regional registration); potatoes; and head lettuce.

The end-use product (EP) proposed for this registration action is
Tanos® Fungicide (EPA Reg. No. 352-604), a dry flowable (DF)
formulation containing 25% active ingredient (ai) cymoxanil plus 25% ai
famoxadone.  This document addresses only the human health risks
associated with famoxadone; the human health risks associated with
cymoxanil will be addressed in a separate risk assessment.

The most recent human health risk assessment for famoxadone was
conducted in conjunction with a request for the establishment of
tolerances for residues on grapes, hops and caneberries, subgroup 13A
(DP#: 331969, B. Hanson, 3/7/2007). 

This document includes dietary (food and drinking water), occupational
(handler and post-application), residue chemistry and aggregate
assessments. 

Proposed Uses

The petitioner wishes to amend the product label for Tanos® Fungicide
to include new uses on bulb vegetables, crop group 3; leafy greens,
subgroup 4A; leaf petioles, subgroup 4B, and cilantro.  Tanos®
Fungicide is proposed for multiple foliar sprays using ground or aerial
equipment at maximum seasonal rates of 1.31 lb ai/A for bulb vegetables
and spinach, and at 0.75 lb ai/A for leafy greens (except spinach) and
leaf petioles.  The proposed preharvest intervals (PHIs) on these crops
range from 1 to 3 days.  

Toxicology and Dose-Response

The toxicity data base for famoxadone is considered complete, although
the Agency has requested additional information pertaining to effects
observed in the chronic dog study.  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.  HED classified famoxadone as “not likely to be
carcinogenic to humans.” As such, cancer risk assessments are not
warranted.

Previously selected doses and endpoints for use in human health risk
assessments have been used in this current risk assessment for
famoxadone. 

HED has concluded that there is no evidence of increased sensitivity of
infants and children to famoxadone; however the FQPA safety factor has
been retained as a 10X database uncertainty factor for the chronic
dietary assessment to account for both the lack of an NOAEL in the study
chosen for risk assessment as well as the extrapolation from subchronic
dosing to chronic exposure and risk assessment.  In addition, a 3X
database uncertainty factor was retained for the lack of an NOAEL for
intermediate-term dermal and inhalation risk assessments.

The toxicology database is adequate to choose endpoints for the purposes
of risk assessment.  The scientific quality is relatively high and the
toxicity profile can be characterized for all effects, including
neurotoxicity, developmental and reproductive effects, and
immunotoxicity.

Residue Chemistry

The nature of the residue in primary crops is adequately understood
based on acceptable metabolism studies conducted on grapes, potatoes,
and tomatoes.  The metabolic profiles in the tested primary crops were
similar in that the majority (90+ % total radioactive residues) of the
residue consisted of surface residues of famoxadone.  However, the
pathways and metabolites in each crop differed slightly.  HED has
determined that residue of concern in plant commodities, for the
purposes of risk assessments and tolerance expression, is famoxadone per
se based on crops which are currently registered.  However,   SEQ
CHAPTER \h \r 1 HED believes that a metabolism study with an oilseed or
grain crop is needed in the future to complete a general understanding
of the nature of the residue in all target crops.

The nature of the residue in rotational crops is inadequately
understood.  A confined rotational crop study has been previously
submitted but was deemed incomplete because of inadequate
characterization of radioactive residues.  HED has determined that there
is not enough evidence to exclude residues of parent and the metabolites
IN-MQ613, IN-KZ534 or IN-KZ007 from the risk assessment due to the
experimental design of the confined rotational crop study.  Once the
nature of the residue in rotational crops is understood, the residues of
concern for the tolerance expression will be determined, and the
residues for risk assessment may be redefined.

  SEQ CHAPTER \h \r 1 Based on the data from the confined study
indicating that famoxadone is the principal residue in rotated wheat
matrices at 30 days, the overall low level of residues in the confined
rotational crop study, and on the lack of famoxadone residues in the
submitted limited field rotational study, HED recommended that the label
for formulations containing famoxadone be modified to indicate that
crops listed on the famoxadone label may be planted back at any time;
cereal grains may be planted back following a minimum plant back
interval (PBI) of 30 days; and all other crops may be planted back
following a minimum PBI of one year.

There are no livestock feedstuffs associated with the proposed uses on
the crops addressed herein.  Therefore, data requirements for animal
metabolism, residue analytical methods for animal commodities, storage
stability data for animal commodities, and animal feeding studies are
not relevant to this tolerance petition.

There is an adequate enforcement method, high pressure liquid
chromatography with ultra-violet detector (HPLC/UV; Method AMR 3705-95,
Revision No. 2), for determination of famoxadone residues in/on plant
commodities.    SEQ CHAPTER \h \r 1 This analytical method has undergone
a successful independent laboratory validation (ILV).  The method has
undergone agency validation.    SEQ CHAPTER \h \r 1 The limit of
quantitation (LOQ) was reported to be 0.02 ppm for grapes, tomatoes,
barley and wheat grain, and 0.05 ppm for barley/wheat straw and green
forage.  Also, Protocol D from the FDA Multiresidue Methods recovers
famoxadone from wine, grapes, and tomatoes.  At this time, the
analytical method does not address all of the residues of concern in
rotational crops.

The data-collection methods used in the field trials were adequately
validated.  Onion samples were analyzed for famoxadone using a method
adapted from the liquid chromatography with mass spectroscopy detection
method.  Spinach, celery, and head lettuce samples were also analyzed
for famoxadone. 

There are adequate storage stability data to support the integrity of
samples collected from field studies.  Concurrent storage stability
studies show that residues of famoxadone are reasonably stable under
frozen storage conditions for up to 9 months in/on celery, 26 months
in/on spinach, 27 months in/on green onion, 29 months in/on dry bulb
onion, and 15 months in/on leaf lettuce.  There are no storage stability
issues or corrections that need to be applied to the various magnitude
of the residue studies.

The submitted residue data for green onion and dry bulb onion were
conducted according to the proposed use rate and PHI.  The maximum
residues of famoxadone were 0.23 ppm for dry bulb onion and 16.0 ppm for
green onion.  The onion field trials are inadequate to establish a crop
group tolerance because of wide variability of residues (88x) among the
representative commodities.  However, the data are adequate to support
the establishment of subgroup tolerances on bulb onion, subgroup 3-07A,
and green onion, subgroup 3-07B.  A revised Section F is required for
tolerances of 0.45 ppm on onion, bulb, subgroup 3-07A, and 40 ppm on
onion, green, subgroup 3-07B.  Since the onion, bulb, subgroup 3-07A and
onion, green, subgroup 3-07B includes them, the requested tolerances on
daylily, bulb; garlic, serpent, bulb; lily, bulb; Chinese, bulb; onion,
pearl; onion, potato, bulb; shallot, bulb; chive, fresh leaves; chive,
Chinese, fresh leaves; elegans hosta; fritillaria, leaves; kurrat;
lady's leek; leek, wild; onion, Beltsville bunching; onion, fresh;
onion, macrostem; onion, tree, tops; and shallot, fresh leaves; should
be removed from the proposed Section F.

The representative crops for leafy vegetables (except Brassica) crop
group 4 are leaf and head lettuce, spinach, and celery.  A famoxadone
tolerance of 10 ppm has been established previously for head lettuce. 
The submitted residue data for leaf lettuce, spinach, and celery are
adequate to fulfill the residue field trial data requirements for those
crops.  HED’s statistical tolerance generator recommends tolerances of
30 ppm on leaf lettuce, 50 ppm on spinach, and 25 ppm on celery.  The
seasonal application rate for spinach is nearly 2x the proposed seasonal
application rate for the remainder of the crop group, and the residue
field trial data for spinach are higher than the data for the other
representative commodities.  The recommended spinach tolerance is 5x as
high as the existing head lettuce tolerance.  For these reasons, ARIA
recommends that the tolerance for spinach be established separately from
the leafy vegetables (except Brassica) crop group.  A revised Section F
for spinach at 50 ppm is required.

The remaining residue field trial data on the representative crops for
leafy vegetables (except Brassica) crop group 4 are adequate to support
a crop group tolerance for residues of famoxadone at 30 ppm.  However,
in order to harmonize with Canada, ARIA recommends for a tolerance at 25
ppm.  A revised Section F for leafy vegetable (except Brassica), group
4, except spinach at 25 ppm is required.

No data have been submitted for the residues of famoxadone on cilantro. 
Cilantro is not currently a member of the leafy greens, crop group 4,
except spinach.  However, since data for parsley have been determined to
be adequate to support tolerances on cilantro, and parsley is a member
of crop group 4A, the data for head and leaf lettuce are adequate to
support a tolerance of 25 ppm on cilantro.

As there are no regulated processed commodities associated with celery,
spinach, onion, or lettuce, no processing studies are required for this
petition.

See Table 10.0 for the proposed tolerances associated with this action.

Dietary Risk (Food and Drinking Water)

Drinking Water

 the highest EDWC for chronic exposure are 0.189 μg/L (ppb) in surface
water and 0.010 μg/L (ppb) in ground water.  The assessment was based
on the proposed leafy greens (subgroup 4A) and leafy petioles (subgroup
4B) use.  The PRZM/EXAMS Model was used to estimate surface water
concentrations and the SCIGROW Model was used to estimate groundwater
concentrations.

Food

Based on toxicological considerations from HED, acute and cancer
assessments were not required.  It previously determined that there was
no appropriate endpoint for use in assessing acute dietary exposure and
classified famoxadone as a “not likely carcinogen.” 

The chronic dietary exposure analysis for famoxadone is a highly refined
assessment, using anticipated residues (ARs), average reduction factors
and percent crop treated (%CT) information.  The chronic dietary
endpoint applies to all population subgroups, including infants and
children.  The estimated chronic dietary exposure (food and water) from
famoxadone does not exceed ARIA’s level of concern for any population
subgroup.  Food and water exposure occupies 47% of the cPAD for the US
population and 58% of the cPAD for adults 20-49 years old, the subgroup
with the highest exposure. 

Non-Occupational and Residential Risk

There are no residential uses for famoxadone at this time.

Aggregate Risk

An aggregate risk assessment was performed for chronic dietary exposure
(food + water).  Acute and cancer aggregate risk assessments 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 do not exceed ARIA’s level of
concern.  Since the chronic aggregate risk exposures include only food
and water, and the chronic dietary analyses included both, no further
calculations are necessary.

Occupational Exposure and Risk

Workers may be exposed to famoxadone during mixing, loading, and
application activities associated with agricultural crops.  Occupational
pesticide handlers may also be exposed while preparing sprinkler
irrigation systems for use as an application vehicle.  ARIA believes
such activities are similar to those of a mixer/loader supporting aerial
applications.  Therefore, a separate assessment for persons preparing
solutions for use in an irrigation system was not performed.  No
chemical-specific data were available with which to assess potential
exposure to pesticide handlers, so estimates of exposure to pesticide
handlers are based upon surrogate study data available in the Pesticide
Handler’s Exposure Database (PHED), Version 1.1 of August 1998.  

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 famoxadone
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 margin of exposure (MOE) of 100 or more is sufficient to protect
occupational pesticide handlers.  Occupational handler assessments
indicate that all MOEs are above the levels of concern at the baseline
level (total MOEs = 3,200 – 40,300).  Post-application MOEs are also
above the levels of concern (MOE = 2,000).  The 12-hour restricted entry
interval (REI) appearing on the label is appropriate for this chemical. 

Environmental Justice

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

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

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (Appendix D) have been determined to require a
review of their ethical conduct, and have received that review.

Additional Data Needs and Recommendations:

Pending submission of a revised Section B, the resolution of data
deficiencies for confined rotational crops, and the submission of a
revised Section F (see requirements under Section 11, Data Needs and
Label Recommendations), there are no residue chemistry issues or other
major deficiencies that would preclude granting a conditional
registration for the requested uses of famoxadone.    SEQ CHAPTER \h \r
1 ARIA recommends in favor of establishing the tolerances as listed
below, and detailed in Table 10.0. 

Onion, bulb, subgroup 3-07A	0.45 ppm

Onion, green, subgroup 3-07B	40 ppm

Leafy vegetables (except Brassica), group 4, except spinach	25 ppm

Spinach	50 ppm

Cilantro, leaves	25 ppm

2.0	INGREDIENT PROFILE

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.

A summary of the proposed uses associated with these petitions is
presented in Table 2.1.  The nomenclature and physicochemical properties
of famoxadone are presented below in Tables 2.2 and 2.3.

2.1	Summary of Proposed Uses

Table 2.1.  Summary of Proposed Directions for Use of Famoxadone.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Max. Single Applic. Rate 

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

(lb ai/A)	PHI

(days)

Bulb Vegetables, Group 3

(Including Chive, fresh leaves; Chive, Chinese, fresh leaves; Daylily,
bulb; Elegans hosta; Fritillaria, bulb; Fritillaria, leaves; Garlic,
bulb; Garlic, great-headed bulb; Garlic, serpent, bulb; Kurrat; Lady’s
leek; Leek, wild; Lily, bulb; Onion, Beltsville bunching; Onion, bulb;
Onion, Chinese, bulb; Onion, fresh; Onion, green; Onion, macrostem;
Onion, pearl; Onion, potato, bulb; Onion, tree, tops; Onion, Welsh;
Shallot, bulb; and Shallot, fresh leaves)

Foliar spray

Ground (20 GPA), Aerial (min 5 GPA), or Chemigation	Tanos®

[352-604]	0.16	Not specified	1.31	3

	Use Directions and Limitations:  Begin applications prior to the onset
of disease development.  Make preventive applications on a 5- to 7-day
schedule.  Tanos® Fungicide must be tank-mixed with a contact fungicide
which has a different mode of action (e.g., Manex copper, Kocide®,
chlorothalonil, etc.) appropriate for the targeted disease.  Do not
alternate or tank mix with other Group 11 fungicides (all strobilurins
or fenamidone) or with fungicides to which resistance has developed.  In
a cropping season, no more than 50% of the total applications should
contain Tanos® Fungicide or other Group 11 fungicides.

Leafy Greens, Subgroup 4A

(Including:  Amaranth (Chinese spinach); Arugula (roquette); Chervil;
Chrysanthemum, edible-leaved; Chrysanthemum, garland; Cilantro, fresh
leaves; Corn salad; Cress, garden; Cress, upland; Dandelion; Dock
(sorrel); Endive (escarole); Lettuce, head; Lettuce, leaf; Orach;
Parsley; Purslane, garden; Purslane, winter; Radicchio (red chicory);
Spinach; Spinach, New Zealand; and Spinach, vine)

Leaf Petioles, Subgroup 4B

(Including Cardoon; celery; celery, Chinese; celtuce; fennel, Florence;
rhubarb; Swiss chard)

Foliar spray

Ground (20 GPA), 

Aerial (5 GPA), or Chemigation	Tanos®

[352-604]	0.16	Not specified	0.75 (for all crops except spinach) 

1.31 (spinach)	1

	Use Directions and Limitations:  Begin applications prior to the onset
of disease development.  Make preventive applications on a 5- to 7-day
schedule.  Tanos® Fungicide must be tank-mixed with a contact fungicide
which has a different mode of action (e.g., copper, Kocide®, mancozeb,
manzate®, chlorothalonil, etc.) appropriate for the targeted disease. 
In a cropping season, no more than 50% of the total applications should
contain Tanos® Fungicide or other Group 11 fungicides.  Do not make
more than one application before alternating with a fungicide that has
different mode of action.  

Conclusions:  The proposed uses of Tanos® Fungicide on bulb vegetables,
crop group 3, leafy greens, subgroup 4A, and leaf petioles, subgroup 4B
are adequate to allow evaluation of the submitted residue data. 
However, the label should be revised to specify the following rotational
crop restrictions:  “Crops listed on the famoxadone label may be
planted back at any time; cereal grains may be planted back following a
minimum plant back interval of 30 days; and all other crops may be
planted back following a minimum plant back interval of one year.”

2.2	Structure and Nomenclature

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

2.3	Physical and Chemical Properties

Table 2.3	Physicochemical Properties of Famoxadone.

Parameter	Value	Reference

Melting point/range	  SEQ CHAPTER \h \r 1 140.3- 141.8°C	DP#s: 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 1.310 g/mL at 20°C

	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 

3.0	4.6

5.0	4.8

7.0	4.7

9.0	              5.6

	UV/visible absorption spectrum	NA

	

3.0	HAZARD CHARACTERIZATION

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

was previously evaluated by HED (TXR Number 0051819, 4/16/2003).  The
toxicology database was characterized in HED’s Risk Assessment for the
use of famoxadone on various crops (DP#: 276070, M. Doherty, 4/29/2003).
 

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

  TC \l3 "3.1.1	Database Summary 3.1.1.1	Studies available and
considered (animal, human, general literature)

Studies available and considered include acute oral, dermal, inhalation,
eye irritation, dermal irritation, and skin sensitization; subchronic;
chronic, carcinogenicity, immunotoxicity reproductive/developmental, and
neurotoxicity.

Mode of action, metabolism, toxicokinetic data

Famoxadone is an oxazolidinedione.  It is highly active against spore
germination and mycelial growth of sensitive fungi.  The biochemical
mechanism of action of famoxadone is inhibition of the fungal
mitochondrial respiratory chain at Complex III, resulting in a decreased
production of ATP by the fungal cell.  It presumably has the same
mechanism of action in mammalian cells.  Data have not been submitted,
however, to verify this presumption.  HED is not aware of any other
pesticidal chemicals to which famoxadone is structurally similar.

In metabolism studies in rats, famoxadone was rapidly absorbed, but only
about 40% of the administered dose (AD) was absorbed.  Most of the AD
(87-96%) was eliminated in the feces within 24 hours; very little
(3-12%) was eliminated in the urine.  Less than 1% remained in the
tissues after 120 hours. Unchanged parent (51-84% of AD) and two
hydroxylated metabolites (IN-KZ534 and IN-KZ007) were the major
components recovered in the feces.  No unchanged parent was found in the
urine.  An enterohepatic circulation (about 30-39% of the AD) was
observed; glucuronide and sulfate conjugates of eight components
(including IN-KZ532 and IN-ML815) were identified in the bile.  No
significant qualitative or quantitative differences were observed for
sex, dose level, or repeated dosing.  In metabolism studies in rats and
dogs, no biologically significant qualitative differences were observed
between rats and dogs in absorption, distribution, metabolism, or
excretion (other than a somewhat longer half-life of famoxadone in the
body of dogs as compared to rats).   

Sufficiency of studies/data

The available studies provide sufficient information to determine
whether, and to what extent, famoxadone poses a human health hazard (see
Appendix A for acute and repeated dose studies/findings).  Acute and
chronic reference doses for dietary risks as well as doses for
non-dietary risks are based on guideline acceptable studies with
well-characterized endpoints and NOAEL/LOAEL values.  The available
studies have been thoroughly evaluated for guideline acceptability by
individual reviewers and peer-review committees and the database is
considered sufficient to characterize and quantify risk.

3.1.2	Toxicological Effects

The toxicology data base for famoxadone is considered adequate for risk
assessment purposes.  

Acute Toxicity:  Technical grade famoxadone, a white solid powder of
97.8% purity, has minimal to moderate acute toxicity.  The acute oral
LD50 in male and female rats and mice was >5000 mg/kg (Toxicity Category
IV); the acute dermal LD50 in rabbits was >2000 mg/kg (Toxicity Category
III); and the acute inhalation LC50 in rats was >5.3 mg/L (Toxicity
Category IV).  In a primary eye irritation study in rabbits, it was
moderately irritating (Toxicity Category III); in a primary skin
irritation study in rabbits, it was moderately irritating (Toxicity
Category III); and in a dermal sensitization study in guinea pigs, it
was negative for dermal sensitization.

Subchronic and Chronic Toxicity:  In subchronic and chronic feeding
studies in rats, mice, dogs and Cynomolgus monkeys, famoxadone generally
caused decreased body weights and body weight gains, often accompanied
by decreased food consumption and food efficiency.  A mild regenerative
hemolytic anemia was also regularly observed in these animals as
evidenced by decreased erythrocyte counts, hemoglobin and/or hematocrit,
increased reticulocytes, and other related changes in hematologic
parameters.  Secondary effects of the anemia were frequently observed in
the spleen (increased spleen weight, congestion, deposition of
hemosiderin pigment, extramedullary hematopoiesis), in the bone marrow
(compensatory erythropoiesis), and in the liver (increased Kupffer cell
pigment, increased bile pigment).  Famoxadone also induced a mild
hepatotoxicity in treated animals characterized by elevated levels of
clinical chemistry enzymes indicative of liver damage (increased
alkaline phosphatase, alanine aminotransferase, aspartate
aminotransferase, and/or sorbitol dehydrogenase) and by
histopathological lesions in the liver (single cell or focal necrosis,
hepatocellular degeneration, diffuse fatty change, foci of eosinophilic
cellular alteration, apoptosis, increased mitotic figures).  Adaptive
hepatocellular responses indicating stimulation of the liver
microsomal/peroxisomal enzyme system were also regularly observed, but
were not considered to be adverse effects of the test material.  These
adaptive responses were characterized by enlarged livers, increased
liver weights and liver/body weight ratios, hepatocellular hypertrophy,
increased cytochrome P-450 levels and/or increased peroxisomal
beta-oxidation rate.  Both the anemia and the hepatotoxicity were mild
and did not significantly compromise the overall health status of the
treated animals.  In repeated dose studies, the anemia, which occurred
early in the studies, oftentimes appeared to be fully compensated for in
the latter stages of the studies.  Although the hepatotoxicity persisted
throughout the duration of the studies, it was mild or moderate in
intensity and not severe or life-threatening.

Additional treatment-related effects were observed in dogs that were not
observed in other species.  In a 13-week feeding study, clinical signs
of neurotoxicity (myotonic twitches) were observed in male and female
dogs at the highest dose tested throughout the duration of the study. 
These twitches were not observed, however, at lower doses in the same
study or in a 1-year feeding study in dogs.  Also, in both male and
female dogs, famoxadone induced treatment-related cataracts in the lens
of the eyes in the 13-week feeding study and in the 1-year feeding
study.  The eye effects were observed at dose levels below those at
which any other effects were observed in any other species and served as
the basis for many of the risk assessments in humans.  Since famoxadone
did not cause similar effects in the eyes of rats, mice, or Cynomolgus
monkeys (in a special study), the possibility that the cataracts in dog
eyes might be a species-specific effect was considered.  No mechanistic
studies or other convincing data/information were submitted, however, to
support this possibility.  Available metabolism (toxicokinetic) studies
in rats and dogs were considered, but no biologically significant
qualitative or quantitative differences were observed in absorption,
distribution, metabolism, or excretion (other than a somewhat longer
half-life of famoxadone in the body of dogs as compared to rats).  The
registrant hypothesized that in dogs reduction of cellular ATP
(resulting from inhibition of oxidative phosphorylation in mitochondria)
might increase lens hydration or increase susceptibility of the eye to
oxidative stress and lead to cataract formation, but there is no
experimental evidence to support this hypothesis. 

Reproductive and Developmental Toxicity:  In a developmental toxicity
study in rats, no developmental toxicity was observed in the fetuses at
the highest dose tested.  Transient decreases in body weight gain and
food consumption were noted in the dams in this study.  In a
developmental toxicity study in rabbits, an increased incidence of
abortions was observed.  The does which aborted also had markedly
decreased body weight, body weight gain and food consumption.  There was
also an equivocal increase in % postimplantation loss and mean number of
resorptions per doe in this study.  Since it could not be determined
whether the abortions were due to maternal toxicity or due to an effect
on reproductive/developmental mechanisms, the LOAELs in this study for
both maternal toxicity and developmental toxicity were considered to be
the same (viz 1000 mg/kg/day); and the NOAELs for both maternal toxicity
and developmental toxicity to also be the same (viz 350 mg/kg/day).  The
does (maternal toxicity) and fetuses (developmental toxicity) were
considered to be equally sensitive to the test material.  This study
does not indicate an increased susceptibility of fetuses, as compared to
does, to famoxadone.  In a 2-generation reproduction study in rats, the
NOAEL for parental toxicity was 11.3 mg/kg/day based on decreased body
weight, body weight gain, and food consumption; and hepatotoxicity.  The
NOAEL for offspring toxicity was also 11.3 mg/kg/day based on decreased
body weights for F1 and F2 pups throughout lactation.  No reproductive
toxicity was observed in this study at the highest dose tested.  The
results in the two developmental toxicity studies and the reproduction
study demonstrated no quantitative or qualitative evidence of increased
susceptibility of fetuses or pups, as compared to adults, to famoxadone.
 

Neurotoxicity and Immunotoxcity:  In an acute neurotoxicity study in
rats, equivocal evidence of a possible slight neurotoxic effect at the
limit dose of 2000 mg/kg was observed.  In this study, an increased
incidence of palpebral (eyelid) closure was observed, but only in males
and only on day 1.  Other than the clinical observations in the 13-week
feeding study in dogs of myotonic twitching in the high dose level male
and female animals, in none of the other toxicity studies on famoxadone,
including a subchronic neurotoxicity study in rats, was there any
toxicologically significant evidence of treatment-related neurotoxicity.
 In 28-day immunotoxicity studies in rats and mice, no evidence of
immunotoxicity was observed.  In a 28-day dermal study in rats, the
observed systemic effects were very similar to those observed in oral
studies in rats.  No dermal irritation was observed.

Carcinogenicity:  In carcinogenicity studies in male and female rats and
in male and female mice, famoxadone did not demonstrate any biologically
significant evidence of carcinogenic potential.  Famoxadone is
classified as “not likely to be carcinogenic to humans.”

3.1.3	Dose-response

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 acute reference dose
(aRfD) or acute population adjusted dose (aPAD) for the general
population or females 13-50 years old.  For chronic dietary exposure,
the toxicology 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 FQPA factor of 10X
was retained (in addition to the conventional 100X UF) for the lack of a
NOAEL in the study, and for the use of a subchronic study for chronic
exposure and risk assessment.  The cRfD is 0.0014 mg/kg/day. 

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
intermediate-term and long-term occupational dermal and inhalation
exposures, the toxicology endpoint was selected from the same subchronic
feeding study in dogs, but was based on microscopic lens lesions
(cataracts) in the eyes of female dogs, which were first observed at
week 12.  For intermediate-term exposures, the target MOE is 300 (based
on the standarad uncertainty factors (UF) of 100X and an additional 3X
UF retained for LOAEL to NOAEL extrapoloation)..  For long-term
exposures, the target MOE is 1000 (based on the standard 100X
uncertainty factors, as well as a 10X UF retained to account for the
lack of an NOAEL, and for the subchronic to chronic extrapolation).
However, it is noted that there are no long-term exposure scenarios
associated with the current and proposed uses for famoxadone.  For
dermal exposures, a 5% dermal absorption factor was used for
route-to-route extrapolation.  This factor was derived from comparison
of the LOAEL for male rats from a 28-day dermal study to the LOAEL for
male rats from a 28-day feeding study.  For inhalation exposures, the
default value of 100% inhalation absorption was used.

3.1.4	FQPA

HED previously concluded that the hazard and exposure data for
famoxadone indicate there is no evidence of quantitative or qualitative
increased susceptibility, as compared to adults, of rat or rabbit
fetuses to in utero exposure to famoxadone in the developmental toxicity
studies.  No evidence of quantitative or qualitative increased
susceptibility, as compared to adults, of rat fetuses or neonates was
observed in the 2-generation reproduction study.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

In metabolism studies in rats, famoxadone was rapidly absorbed, but only
about 40% of the administered dose (AD) was absorbed.  Most of the AD
(87-96%) was eliminated in the feces within 24 hours; very little
(3-12%) was eliminated in the urine.  Less than 1% remained in the
tissues after 120 hours.  Unchanged parent (51-84% of AD) and two
hydroxylated metabolites (IN-KZ534 and IN- KZ007) were the major
components recovered in the feces.  No unchanged parent was found in the
urine.  An enterohepatic circulation (about 30-39% of the AD) was
observed; glucuronide and sulfate conjugates of eight components
(including IN-KZ532 and IN-ML815) were identified in the bile.  No
significant qualitative or quantitative differences were observed for
sex, dose level, or repeated dosing.  In a metabolism study in dogs, no
biologically significant qualitative differences were observed between
rats and dogs in absorption, distribution, metabolism, or excretion
(other than a somewhat longer half-life of famoxadone in the body of
dogs as compared to rats).

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

With respect to FQPA hazard considerations, HED concluded that the
toxicology database for famoxadone is complete.

The available toxicology data base for famoxadone includes the following
acceptable studies:

Developmental toxicity study, rats			OPPTS 870.3700, MRID 44302426 

Developmental toxicity study, rabbits		OPPTS 870.3700, MRID 44946218

2-Generation reproduction study, rats			OPPTS 870.3800, MRID 44302428

Acute neurotoxicity study, rats			OPPTS 870.6200, MRID 44302414    

Subchronic neurotoxicity study, rats 			OPPTS 870.6200, MRID 44302421

The following guideline studies are not available:

Acute delayed neurotoxicity study, hens		OPPTS 870.6100

Developmental neurotoxicity study, rats		OPPTS 870.6300

Evidence of Neurotoxicity

With respect to FQPA hazard considerations, HED concluded that there is
not a concern for neurotoxicity resulting from exposure to famoxadone.

In an acute neurotoxicity study in rats, equivocal evidence of a
possible slight neurotoxic effect at the limit dose of 2000 mg/kg was
observed.  An increased incidence of palpebral (eyelid) closure was
observed; but only in males and only on day 1.  

In a 13-week feeding study in dogs, continuous myotonic twitching in the
high dose level (>20 mg/kg/day) male and female animals was observed. 
These twitches were first observed approximately four hours after
feeding on day 21 and thereafter were regularly observed (particularly
after feeding) throughout the entire remaining duration of the study in
spite of the dose level for these animals being reduced from 1000 ppm to
600 ppm on day 37.  In addition, one female dog in this high dose group
also had convulsions and ataxia on day 34.  Myotonic twitching was not
observed, however, in any of the dogs at any time at lower dose levels
of about 10 mg/kg/day in either this 13-week study or in a 1-year
feeding study in dogs.  Also, toxicologically significant signs of
neurotoxicity were not observed in any of the other studies on
famoxadone in any species (including rats, mice and monkeys) at any
time. 

Developmental Toxicity Studies

Executive Summary:  In a developmental toxicity study (MRID 44302426 and
44946217), famoxadone technical (97.4% a.i.; Batch #  DPX-JE874-221) was
administered orally via gavage to 25 female Crl:CD®BR rats/group at
dose levels of 0, 125, 250, 500, or 1000 mg/kg/day on GD 7 through 16. 
All dams were sacrificed on GD 22 and their fetuses were removed by
cesarean section and examined.  

When compared to concurrent controls, no treatment-related changes were
observed in mortality, clinical signs, body weights, adjusted (for
gravid uterine weight) body weights, gross pathology, fetal weights, sex
ratios, pre-implantation or post-implantation losses, or the number of
corpora lutea, implantations, resorptions, live fetuses, or dead fetuses
per dam.

At 500 and 1000 mg/kg/day, an initial decrease (p(0.05) in food
consumption was observed during GDs 7-9 ((11-14%), which resulted in an
initial decrease (p(0.05) in body weight gain (-1.0 g each vs. 4.6 g in
concurrent controls) during this interval.  In addition, food
consumption was increased (p(0.05) during GDs 17-22 ( (10%) in the 1000
mg/kg/day dams. 

The maternal LOAEL is 500 mg/kg/day based on transient decreases in food
consumption and body weight gains.  The maternal NOAEL is 250 mg/kg/day.

No developmental toxicity was observed in external, visceral or skeletal
examinations of fetuses.  The developmental toxicity LOAEL was not
observed.  The developmental toxicity NOAEL is 1000 mg/kg/day (limit
dose).

This developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the requirements for a developmental
study in the rat (OPPT 870.3700a; OECD 414).

Executive Summary:  In a developmental toxicity study (MRID 44946218 and
44946219), famoxadone technical (97.4% a.i.; Batch #  DPX-JE874-221) was
administered orally via gavage to 20 female Hra:(NZW) SPF rabbits/group
at dose levels of 0, 100, 350, or 1000 mg/kg bw/day on GD 7 through 19
in a dosing volume of 10 mL/kg.  All does were sacrificed on GD 29 and
their fetuses were removed by cesarean section and examined.  

There was a significant (p(0.05) trend with increasing dose in the
number of does experiencing abortions.  At 1000 mg/kg/day, 4 of 17
maternal animals aborted during GDs 19-23.  Food consumption was
markedly decreased during the treatment period in all 4 of the 1000
mg/kg/day does that aborted, resulting in markedly lower body weights
and body weight gains than controls during the treatment period.  Gross
examination of one doe that aborted revealed a hairball (trichobezoar)
in its stomach.  No macroscopic findings were noted in the other three
1000 mg/kg/day does that aborted.  Two does at 100 mg/kg/day also
aborted, but these abortions were not considered to be treatment-related
since no abortions were observed at the higher dose level of 350
mg/kg/day.  The number of animals having small and/or tan stools and/or
small amount or no stools was increased (p(0.05; Cochran-Armitage trend
test) at 1000 mg/kg/day during the treatment period (6/20 treated vs
0/20 controls) and post-treatment period (3/19 treated vs 0/20
controls). 

The maternal toxicity LOAEL is 1000 mg/kg/day, based on abortions in
4/17 does, markedly decreased food consumption, body weights, and body
weight gains in the same 4 does, and increased numbers of does with
abnormal or little or no stools.  The maternal toxicity NOAEL is 350
mg/kg/day.

Since it cannot be determined whether the treatment-related abortions
observed in 4/17 does at 1000 mg/kg/day are due to maternal toxicity or
developmental toxicity (or both), these abortions are also considered to
be treatment-related developmental effects.  Other than the abortions,
no fetal deaths were observed in any group of animals in this study.

The % postimplantation loss and mean number of resorptions/doe were both
increased at 1000 mg/kg/day as compared to the controls and lower dose
groups.  However, both increases fell within the historical control
range for each parameter and the relationship to treatment with the test
material is considered to be equivocal.  Fetal weights were comparable
in treated groups and controls.  There were no treatment-related
skeletal retardations.  No treatment-related external, visceral, or
skeletal variations or malformations were noted.

The developmental toxicity LOAEL is 1000 mg/kg/day, based on abortions
in 4/17 does and equivocal increases in % postimplantation loss and mean
number of resorptions/doe.  The developmental toxicity NOAEL is 350
mg/kg/day.

This developmental toxicity study in the rabbit is classified
Acceptable/Guideline and satisfies the requirements for a developmental
toxicity study in the rabbit (OPPTS 870.3700; OECD 414).

Reproductive Toxicity Study

Executive Summary:  In a two-generation reproduction toxicity study with
one set of litters per generation (MRID 44302428), famoxadone technical
(97.4% a.i.; batch # DPX-JE874-221) was administered continuously in the
diet to Crl:CD®BR rats (30/sex/dose) at nominal dose levels of 0, 20,
200, or 800 ppm (equal to premating dose levels for P animals of 0,
1.14/1.45, 11.3/14.2 and 44.7/53.3 mg/kg/day, M/F).  The P animals were
given test article diet formulations for approximately 10 weeks prior to
mating to produce the F1 litters.  After weaning, F1 animals
(30/sex/dose) were selected, equalized by sex, to become the F1 parents
of the F2 generation and were given the same concentration of test
formulation as their dam.  F1 animals were given test formulations for
approximately 15 weeks prior to mating to produce the F2 litters.

No parental mortalities occurred.  Clinical signs and reproductive
performance (mating index, fertility index, and gestation length) were
unaffected by treatment.  Estrous cycles and sperm parameters were not
evaluated.

At 800 ppm, clinical chemistry results suggested that the liver was the
target organ of toxicity.  In the males, increases (p(0.05) in alkaline
phosphatase, alanine aminotransferase, aspartate aminotransferase,
sorbitol dehydrogenase, and bilirubin were observed in the P and F1
generations.  Additionally in the males, increased (p(0.05) cholesterol
was observed in the P generation, and decreased (p(0.05) triglycerides
were observed in both generations.  In the females, the following
differences (p(0.05) from concurrent controls were observed:  (i)
increased alkaline phosphatase in the F1 generation; (ii) increased
cholesterol in the P and F1 generations; and (iii) decreased
triglycerides in the P and F1 generations.  The peroxisomal β-oxidation
rate was also increased (p(0.05) in both sexes of the P and F1
generations.  

Additionally at 800 ppm, increased (p(0.05) absolute and relative (to
body weight) liver weights were noted in the P and F1 females.  Gross
pathological examination revealed the following findings in the F1
animals (vs. 0/30 controls):  (i) liver foci in a single male and a
single female; (ii) liver discoloration in a single male; and (iii)
large liver in a single female.  Histopathologically, minimal focal
fatty change in the liver of a single F1 female and mild to moderate
eosinophilic focus of cellular alteration in the liver of a single male
and a single female were noted (vs. 0/30 controls).  Although
histopathological effects in the liver of parental males and females
appeared to be minimal in this study, data from several other subchronic
and chronic feeding studies in rats clearly indicated the liver to be a
target organ based on clinical chemistry, histopathological and other
pertinent findings at this dose level (800 ppm) and higher dose levels
of famoxadone.  Based on a weight-of-the-evidence evaluation of all the
available studies and data, it is concluded that the histopathological
effects observed in the livers of male and female rats in this
reproduction study, although minimal, are treatment-related.  

Decreased body weights, body weight gains, and food consumption at 800
ppm indicated that the test substance caused systemic toxicity in
addition to liver toxicity.  Body weights were decreased (p(0.05) in the
P and F1 generations throughout premating (except days 0-21 in the P
generation males), gestation, and lactation (except LD21 in both
generations).  Body weight gains were decreased (p(0.05) in the males
and females of both generations during premating and in the females
during GDs 0-7; however, a compensatory increase (p(0.05) in body weight
gains was observed during lactation in both generations.  Food
consumption was decreased (p(0.05) in both sexes of both generations
throughout most of premating.  During gestation, food consumption was
decreased (p(0.05) in the P females on GDs 0-7, 7-14, and 0-14, and in
the F1 females on GDs 0-7 and 0-14.

Other findings noted at 800 ppm included the following:  (i) increased
(p(0.05) blood urea nitrogen in the P and F1 males and the F1 females;
(ii) decreased (p(0.05) globulins in the F1 males and the P and F1
females; and (iii) dilatation of the kidneys in the F1 females.

A dose-dependent decrease (p(0.05) in alanine aminotransferase was
observed in the 20, 200, and 800 ppm females of the P generation; the
toxicological importance of this finding is unclear.  The only other
findings noted at 200 ppm were increased (p(0.05) cholesterol in the P
and F1 generations and decreased (p(0.05) body weight gains in the F1
females on GDs 0-7 ((26%).

No treatment-related findings were noted at 20 ppm.

The LOAEL for parental toxicity is 800 ppm (44.7/53.3 mg/kg/day, M/F)
based on hepatotoxicity and decreased body weights, body weight gains,
and food consumption.  The NOAEL is 200 ppm (11.3/14.2 mg/kg/day, M/F).

Pup viability, sex ratios, implantation sites, live and dead fetuses,
litter size, lactation index, and gross pathology were unaffected by
treatment.  Sexual maturation and organ weights were not evaluated.

Decreased pup weights were observed in the 800 ppm F1 ((7-9%) and F2
((6-9%) litters throughout lactation (except for LD 1 in the F2 pups). 
No other treatment-related findings were noted.

No treatment-related findings were noted at 200 or 20 ppm.

The LOAEL for offspring toxicity is 800 ppm (44.7/53.3 mg/kg/day, M/F)
based on decreased pup weight.  The NOAEL is 200 ppm (11.3/14.2
mg/kg/day, M/F).  The LOAEL for reproductive performance was not
observed.  The NOAEL for reproductive performance is 800 ppm (44.7/53.3
mg/kg/day, M/F).

This reproductive study in the rat is Acceptable/Guideline and satisfies
the guideline requirements for a two-generation reproduction study
(OPPTS 870.3800; OECD 416) in the rat.

3.3.5	Additional Information from Literature Sources

	

No additional information is available from the literature.

3.3.6	Pre-and/or Post-natal Toxicity

HED concluded that there is not a concern for pre- and/or postnatal
toxicity resulting from exposure to famoxadone.   

3.3.6.1	Determination of Susceptibility

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.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties

Since there was no evidence of increased susceptibility of fetuses/pups,
there are no concerns or residual uncertainties for pre-natal and/or
post-natal toxicity.   

3.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

Based on the weight of evidence presented, HED concluded that there is
not a concern for developmental neurotoxicity resulting from exposure to
famoxadone.

Evidence that suggests requiring a DNT study:

Treatment-related clinical signs of neurotoxicity (myotonic twitching,
particularly after feeding) in male and female dogs starting on day 21
and continuing throughout entire duration of 13-week feeding study at
the highest dose tested (23.8/21.2 mg/kg/day in males and 23.3/20.1
mg/kg/day in females).  Myotonic twitching was not observed, however, at
any time at the next lower dose tested (10.0 mg/kg/day in males and 10.1
mg/kg/day in females).  No other signs of neurotoxicity, including a
neuropathologic examination of nervous system tissues, were observed in
this study.

Evidence that does not support a need for a DNT study:

Although clinical signs of neurotoxicity were observed in dogs in the
13-week study at the highest dose tested (>20 mg/kg/day), this effect
was not observed at lower doses of about 10 mg/kg/day in the same
13-week study or in a subsequently performed 1-year feeding study in
dogs.  Also, toxicologically significant signs of neurotoxicity were not
observed in any of the other studies on famoxadone in any species
(including rats, mice or monkeys) at any time.  In addition, pre- and
postnatal studies in rats and rabbits demonstrated no increased
susceptibility of fetuses or neonates to famoxadone as compared to
adults.  Toxicologically significant neurotoxic effects would not be
expected to occur in an additional study in rats.  The clinical signs of
neurotoxicity (muscle twitches) observed only in dogs, only in males and
only at the highest dose tested, would not be anticipated to occur in a
developmental neurotoxicity study in rats. 

In the 1-year feeding study in dogs, no myotonic twitches or any other
signs of neurotoxicity were observed at the highest dose tested (8.8
mg/kg/day in males and 9.3 mg/kg/day in females).  

Other than a slightly increased incidence of palpebral (eyelid) closure
in the acute neurotoxicity study in rats (only in male rats, only on day
1, only at the limit dose of 2000 mg/kg/day), no signs of neurotoxicity
were observed in any of the studies on rats (including a subchronic
neurotoxicity study in rats), mice, rabbits or monkeys, even at the
highest dose levels tested.  

In developmental toxicity studies on rats and rabbits, treatment-related
increased incidences of malformations of nervous system organs/tissues
were not observed.

In developmental toxicity studies on rats and rabbits, treatment-related
increased susceptibility of fetuses, as compared to adults, to in utero
exposure to famoxadone was not demonstrated.

In the 2-generation reproduction study on rats, no increased
susceptibility of the neonates, as compared to adults, was demonstrated
for famoxadone.

FQPA Safety Factor for Infants and Children

There are no residual uncertainties for pre-natal and/or post-natal
toxicity.  HED concluded that the FQPA Safety Factor need not be
retained for purposes unique to the FQPA; however, the FQPA factor was
retained as either a 3X LOAEL-to-NOAEL, or 10X combined LOAEL-to-NOAEL
and subchronic-to-chronic uncertainty factor for the purpose of
intermediate-term and chronic/long-term exposure durations.  The
combined safety factor of 300X (intermediate-term exposures) or 1000X
(long-term exposures) for famoxadone is considered to provide an
adequate margin of safety during development because the point of
departure (POD) is based on selection of a conservative endpoint,
microscopic evidence of cataracts in a dog 13 week dietary study.  A
NOAEL was not identified for this endpoint.  An uncertainty factor of 3X
was retained to account for LOAEL to NOAEL extrapolation and, for
long-term endpoints, the use of a subchronic study instead of a chronic
study.  These factors (total 10X for chronic dietary exposure; 3X for
intermediate-term exposure) should provide adequate protection during
development, based on several considerations.  First, the LOAEL appeared
to be a threshold effect level based on the minimal findings observed. 
The endpoint (microscopically visible lenticular degeneration in
females) was of minimal severity at the lowest dose tested (1.4
mg/kg/day).  This finding would probably have very little effect on
vision and no evidence of cataracts was observed in the ophthalmologic
examination.  Second, although the microscopic data in the chronic dog
study was not considered acceptable due to fixation artifact, there was
no evidence of cataracts in the ophthalmologic examination at a similar
dose (1.2 mg/kg/day), suggesting that progression with time was minimal
at that dose.  Finally, there was no evidence of cataracts in monkeys
administered famoxadone for one year at doses up to 1000 mg/kg/day.  The
lack of cataracts in a primate species provides suggestive evidence that
humans may be less sensitive than dogs for this effect, although
additional data are required to show species-specificity.  

Hazard Identification and Toxicity Endpoint Selection

3.5.1    Acute Reference Dose (aRfD)  

  TC \l3 "3.5.1    Acute Reference Dose (aRfD) - Females age 13-49 

Study Selected:   None 

MRID No.:   None

Executive Summary:   None

Dose and Endpoint for Establishing aRfD:   Not applicable

Uncertainty Factor (UF):  Not applicable 

Comments about Study/Endpoint/Uncertainty Factor:  No toxicological
endpoint attributable to a single oral dose was identified in the
available toxicology studies on famoxadone that would be applicable to
females (13-50 years) or to the general population (including infants
and children).   

3.5.2	Chronic Reference Dose (cRfD) 

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

Study Selected: 13-Week Feeding Study in Dogs

MRID No.: 44302419

Executive Summary:  See Appendix A, Guideline [§ 870.3150] 

Dose and Endpoint for Risk Assessment: LOAEL of 1.4 mg/kg/day, based on
treatment-related microscopic lens lesions (cataracts) in eyes of female
dogs.  A NOAEL could not be determined.

Uncertainty Factor(s): 1000 (10X for inter-species extrapolation, 10X
for intra-species variation; and an additional 10X for the use of a
LOAEL and the use of a subchronic study.  A combined uncertainty factor
of 10X is considered adequate for both LOAEL to NOAEL and subchronic to
chronic extrapolation due to (1) the minimal severity of the finding,
which was not accompanied by cataracts observable in ophthalmologic
examination and is unlikely to cause significant visual impairment, (2)
lack of observable cataracts in the chronic dog study (microscopic data
were inadequate due to fixation artifact), suggesting minimal
progression with time and (3) lack of cataract formation in the monkey
administered famoxadone up to 1000 mg/kg/day for one year.

Comments about Study/Endpoint/Uncertainty Factor:  This endpoint is
based on an oral study, which is the route of interest for a dietary
risk estimate.  This study and endpoint were selected because they would
address the concerns for toxic effects observed in all the other
available studies for this chronic risk assessment.  Although a chronic
dog study is available, it was not selected for the cRfD based on issues
pertaining to fixation artifacts in the eye and interpretation of
cataract findings in the ocular lens (the critical effect) that as yet
have not been resolved and therefore do not allow a reliable selection
of the study NOAEL and/or LOAEL.  

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

  TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Since no residential uses for famoxadone have been proposed, HED
deferred selection of toxicology endpoints and doses for this exposure
scenario at this time.  

3.5.5	Dermal Absorption

Dermal Absorption Factor:   5% 

  TC \l3 "3.5.5	Dermal Absorption 

A dermal absorption study is not available.  The percent dermal
absorption is estimated by comparing the LOAEL for male rats from a
28-day dermal study (MRID 44946209) to the LOAEL for male rats from a
specially designed 28-day feeding study (MRID 44946207). 

The LOAEL for male rats from the 28-day dermal study was 500 mg/kg/day,
based on increased alkaline phosphatase, alanine aminotransferase, and
sorbitol dehydrogenase; and mild hepatotoxicity in the liver (apoptosis,
increased mitotic figures).  Also at 500 mg/kg/day, adaptive
hepatocellular responses indicating enzyme induction were observed
(increased liver weight, hepatocellular hypertrophy).  The LOAEL for
male rats in this study appeared to be close to a threshold dose level. 
A LOAEL for female rats was not observed in this study (LOAEL >1000
mg/kg/day, highest dose tested, limit dose).   

The 28-day feeding study in rats was performed after the 90-day feeding
study in rats (MRID 44302415) and was specially designed to help predict
the threshold for liver cytotoxicity and to assist in determining
appropriate dose levels for the chronic/carcinogenicity study in rats. 
Accordingly, data on body weight, clinical signs of toxicity, and serum
activities of liver-specific enzymes and serum concentration of
triglycerides were measured, but data on other standard toxicology
endpoints were not collected since these endpoints were evaluated in the
previously conducted 90-day study (e.g. food consumption, hematology,
gross pathology, organ weights and microscopic pathology).  In this
28-day study, the NOAEL for male rats was 300 ppm and the LOAEL was 400
ppm, based on increased alkaline phosphatase, alanine aminotransferase,
aspartate aminotransferase and sorbitol dehydrogenase.  The LOAEL of 400
ppm was estimated to be equivalent to 25 mg/kg/day, based on data from
the 90-day study.  

  LOAEL from 28-day feeding study          =       25 mg/kg/day    x  
100   =    5% 

  LOAEL from 28-day dermal study           =     500 mg/kg/day 

Comments: In the first HED report on the topic (1/22/2003; TXR No.
0051462), the percent dermal absorption was estimated to be 10%, based
on a comparison of the LOAEL for male rats from the 28-day dermal study
(500 mg/kg/day) to the “LOAEL” for male rats from the 45-day time
point in the 90-day feeding study (800 ppm, equal to 52.1 mg/kg/day). 
This “LOAEL” at the 45-day time point was considered at the time to
be based on the same effects (except for increased liver weight) seen in
the 28-day dermal study which were increases in liver-specific enzymes
(observed at 45 and 90 days) and histopathology in the liver (apoptosis,
increased mitotic figures and hepatocellular hypertrophy).  However, it
is now concluded that since the histopathology in the liver was not
observed until termination of the study at 90-days, the only common
toxicological endpoints between the results in the 28-day dermal study
and the 45-day time point in the 90-day feeding study are, in fact,  the
increases in liver-specific enzymes (which were substantially increased
at the “LOAEL” of 800 ppm or 52.1 mg/kg/day, but not increased at
the “NOAEL” of 200 ppm).  Since the same liver-specific enzymes were
increased in the 28-day feeding study (at the LOAEL of 400 ppm or 25
mg/kg/day, but not at the NOAEL of 300 ppm), and this LOAEL appeared to
be close to the threshold dose level, as in the dermal study, it was
concluded the results in the 28-day feeding study more closely mimicked
the results in the 28-day dermal study than did the results in the
90-day feeding study. 

3.5.6	Dermal Exposure: Short-Term (1-30 Days) Exposure 

  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: 13-Week Feeding Study in Dogs 

MRID No.: 44302419

Executive Summary:  See 3.5.2 Chronic Reference Dose (cRfD) (above).  

Dose and Endpoint for Risk Assessment: NOAEL of 10.0 mg/kg/day, based on
myotonic twitches.  At the next highest dose of 23.8/23.3 (M/F)
mg/kg/day, treatment-related myotonic twitches were observed in male and
female dogs starting on day 21.  Other effects observed in male and
female dogs at 23.8/23.3 mg/kg/day during the first 36 days of the study
were decreased body weight, body weight gain, food consumption, and food
efficiency; slight anemia (first observed at 5 weeks); and hyperkalemia
(first observed at 5 weeks).  In addition, convulsions were observed in
one female dog on day 34.  None of these effects were observed in any
male or female dog at 10.0/10.1 (M/F) mg/kg/day at any time during the
study.

Comments about Study/Endpoint/Uncertainty Factors:   This endpoint is
based on an oral study with a NOAEL of 10.0 mg/kg/day.  A 5% dermal
absorption factor should be used for route-to-route extrapolation for
this risk assessment.   

The cataracts observed in the male and female dogs in this 13-week study
(in males at >10 mg/kg/day and in females at >1.4 mg/kg/day) were not
observed in any dogs until the clinical examinations of the eyes at week
12 (the only clinical examination in this study).  In the 1-year dog
study, however, clinical examinations of the eyes were conducted at 1,
2, 8, 12, 16, 20, 25, 40 and 50 weeks.  No cataracts were observed in
any dogs in the 1-year study until the clinical examination at 12 weeks.
 No cataracts were noted in the clinical examination at 8 weeks.  Since
cataracts did not occur in the eyes of dogs until sometime after 8 weeks
(56 days), this would not be an appropriate endpoint on which to base a
short-term (1-30 days) risk assessment.

A 28-day dermal study in rats is available, but was not used as the
basis for this short-term dermal risk assessment because the selected
toxicity endpoint (myotonic twitches) has not been observed in this or
in any other studies in rats.  The study and endpoint selected for this
risk assessment are protective of effects observed in all the available
studies for this short-term timeframe.   

3.5.7	Dermal Exposure: Intermediate-Term (1-6 Months) Exposure 

Study Selected: 13-Week Feeding Study in Dogs 

MRID No.: 44302419

Executive Summary:  See 3.5.2 Chronic Reference Dose (cRfD) (above).

Dose and Endpoint for Risk Assessment:  LOAEL of 1.4 mg/kg/day, based on
treatment-related microscopic lens lesions (cataracts) in eyes of female
dogs.  A NOAEL could not be determined. 

Comments about Study/Endpoint:  The endpoint selected for this exposure
scenario is based on an oral study and therefore a 5% dermal absorption
factor should be used for route-to-route extrapolation for this risk
assessment.  The duration of this study (13-weeks) is appropriate for an
intermediate-term (1-6 months) risk assessment.  The endpoint selected
for risk assessment (microscopic lens lesions) was observed at
termination of the study at 13 weeks.  

3.5.8	Dermal Exposure: Long-Term (> 6 Months) Exposure

Study Selected: 13-Week Feeding Study in Dogs    

 

MRID No.: 44302419

Executive Summary:  See 3.5.2 Chronic Reference Dose (cRfD) (above).

Dose and Endpoint for Risk Assessment:    LOAEL of 1.4 mg/kg/day, based
on treatment-related microscopic lens lesions (cataracts) in eyes of
female dogs.  A NOAEL could not be determined. 

Comments about Study/Endpoint:  This dose/endpoint/study was also
selected for long-term dietary risk assessment.  The endpoint selected
for this exposure scenario is based on an oral study and therefore a 5%
dermal absorption factor should be used for route-to-route extrapolation
for this risk assessment. 

Although a 1-year chronic feeding study in dogs is available, it was not
selected as the basis for this long-term dermal risk assessment.  In
view of the considerable uncertainty relating to the microscopic
findings in the eyes of all dogs in this study and the resulting
uncertainty with regard to determining a NOAEL for eye effects, HED
decided to not use the results from this 1-year study for the purpose of
determining an endpoint for this exposure scenario at this time.  Based
on a consideration of both clinical examination findings and
histopathological findings in the eyes of dogs in both the 90-day and
1-year studies, the lowest dose at which evidence of cataracts was
actually observed was in the female dogs in the 90-day study at the dose
of 1.4 mg/kg/day, at which dose treatment-related histopathological
findings, but not clinical examination findings, were observed at 90
days.  The study and endpoint selected for this risk assessment are
protective of effects observed in all the available studies for this
long-term timeframe.   

3.5.9	Inhalation Exposure: Short-Term (1-30 Days) 

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

Study Selected: See 3.5.6 Short-Term Dermal (1 - 30 days) Exposure
(above).  

MRID No.: See 3.5.6 Short-Term Dermal (1 - 30 days) Exposure (above).  

Executive Summary:  See 3.5.6 Short-Term Dermal (1 - 30 days) Exposure
(above).  

Dose and Endpoint for Risk Assessment: NOAEL of 10.0 mg/kg/day, based on
myotonic twitches.  At the next highest dose of 23.8/23.3 (M/F)
mg/kg/day, treatment-related myotonic twitches were observed in male and
female dogs starting on day 21.  Other effects observed in male and
female dogs at 23.8/23.3 mg/kg/day during the first 36 days of the study
were decreased body weight, body weight gain, food consumption, and food
efficiency; slight anemia (first observed at 5 weeks); and hyperkalemia
(first observed at 5 weeks).  In addition, convulsions were observed in
one female dog on day 34.  None of these effects were observed in any
male or female dog at 10.0/10.1 (M/F) mg/kg/day at any time during the
study.  

    

Comments about Study/Endpoint/Uncertainty Factors:   There is no
inhalation study of any duration (other than acute studies) available on
famoxadone.  Since an oral dose was selected, absorption via the
inhalation route is assumed to be equivalent to oral absorption.  

3.5.10	Inhalation Exposure: Intermediate-Term (1-6 Months)

Study Selected: See 3.5.7 Intermediate-Term Dermal (1 - 6 months)
Exposure (above). 

MRID No.:  See 3.5.7 Intermediate-Term Dermal (1 - 6 months) Exposure
(above).

Executive Summary:  See 3.5.7 Intermediate-Term Dermal (1 - 6 months)
Exposure (above).

 

Dose and Endpoint for Risk Assessment: LOAEL of 1.4 mg/kg/day, based on
treatment-related microscopic lens lesions (cataracts) in eyes of female
dogs.  A NOAEL could not be determined.  

Comments about Study/Endpoint/Uncertainty Factors:   There is no
inhalation study of any duration (other than acute studies) available on
famoxadone.  Since an oral dose was selected, absorption via the
inhalation route is assumed to be equivalent to oral absorption.

3.5.11	Inhalation Exposure: Long-Term (> 6 Months)

Study Selected: See 3.5.8 Long-Term Dermal (> 6 Months) Exposure
(above).

MRID No.:  See 3.5.8 Long-Term Dermal (> 6 Months) Exposure (above)

Executive Summary:  See 3.5.8 Long-Term Dermal (> 6 Months) Exposure
(above)

Dose and Endpoint for Risk Assessment: LOAEL of 1.4 mg/kg/day, based on
treatment-related microscopic lens lesions (cataracts) in eyes of female
dogs.  A NOAEL could not be determined.

Comments about Study/Endpoint/Uncertainty Factors:   There is no
inhalation study of any duration (other than acute studies) available on
famoxadone.  Since an oral dose was selected, absorption via the
inhalation route is assumed to be equivalent to oral absorption.  

3.5.12	Level of Concern for Margin of Exposure

Since no residential uses for famoxadone have been proposed, HED
deferred selection of target Margins of Exposure (MOEs) for residential
uses at this time.  The target MOEs for occupational exposure risk
assessments are noted below, in Table 3.5.12.

Table 3.5.12 Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100 (a)	300 (b)	1000 (c)

Inhalation	100 (a)	300 (b)	1000 (c)

Residential (Non-Dietary) Exposure

Oral	N/A	N/A	N/A

Dermal	N/A	N/A	N/A

Inhalation	N/A	N/A	N/A

(a)   This is based on the conventional uncertainty factor of 100X (10X
for intraspecies extrapolation and 10X for interspecies variation)

(b)   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.  A 3X UF (as opposed to a 10X) is adequate because in the
13-week study, at the LOAEL of 40 ppm (1.4 mg/kg/day), the cataracts
were observed only during the microscopic examination of the lens of
female dogs and were not observed at all during the clinical (in life)
examinations of the eyes of these same dogs at 12 weeks.  At 40 ppm, the
testing laboratory reported only minimal swelling of the lens fibers in
a small area of the lens in only one eye of a single female dog.  In a
subsequent microscopic reading of the same 40 ppm slides by another
pathologist (Dr. Ralph Heywood), the lesion was reported in a single eye
of 2 dogs and in both eyes of 2 dogs, but in all cases was described as
only minimal lenticular degeneration.  Therefore, although
treatment-related cataracts were observed in these female dogs at 40
ppm, they were of only minimal intensity and probably had very little
effect on the overall vision of these dogs.  Considering the minimal
intensity of these eye findings at the LOAEL of 40 ppm, HED has
concluded an additional Uncertainty Factor of 3X would be adequate for
this risk assessment scenario. 

(c)   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.  

3.5.13	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

Since no residential uses for famoxadone have been proposed, aggregate
risk includes only food and water exposures.   

3.5.14	Classification of Carcinogenic Potential

HED classified famoxadone as “not likely to be carcinogenic to
humans” according to the EPA Draft Proposed Guidelines for Carcinogen
Risk Assessment (July 2, 1999).  This classification is based on the
lack of evidence of carcinogenicity in male and female rats and in male
and female mice in acceptable carcinogenicity studies on the technical
grade product.

  

3.5.15	Summary of Toxicological Doses and Endpoints for Famoxadone for
Use in Human Risk Assessments

Table 3.5.1.5 Summary of Toxicological Doses and Endpoints for
Famoxadone Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary [All Populations]	NOAEL= none	N/A	N/A	No toxicological
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	UFA= 10x

UFH=10x

FQPA SF= 10x

[combined UFL, UFS]]	Chronic RfD = 0.0014

mg/kg/day

cPAD = 0.0014 mg/kg/day	13-Week Feeding Study in Dogs:

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in
eyes of female dogs.  A NOAEL could not be determined because 1.4
mg/kg/day was the lowest dose tested in the female dogs in this study.  

Incidental Oral

[all durations]	N/A	N/A	N/A	No residential uses for famoxadone have been
proposed.

Dermal Short-Term (1-30 days)	NOAEL= 10 mg/kg/day

DAF = 5%	UFA= 10x

UFH=10x

FQPA SF= 1x	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)	LOAEL=1.4 mg/kg/day

DAF = 5%	UFA= 10x

UFH=10x

FQPA SF= 3x

[UFL,]	Occupational LOC for MOE = 300

	13-Week Feeding Study in Dogs:

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in
eyes of female dogs.  A NOAEL could not be determined because 1.4
mg/kg/day was the lowest dose tested in the female dogs in this study.

[Note – there are currently no intermediate-term exposure scenarios
for famoxadone]

Dermal 

Long Term [>6 months]	LOAEL=1.4 mg/kg/day

DAF = 5%	UFA= 10x

UFH=10x

FQPA SF= 3x

[combined UFL, UFS]]	Occupational LOC for MOE = 1000

	13-Week Feeding Study in Dogs:

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in
eyes of female dogs.  A NOAEL could not be determined because 1.4
mg/kg/day was the lowest dose tested in the female dogs in this study.

[Note – there are currently no long-term exposure scenarios for
famoxadone]

Inhalation Short- Term (1-30 days)	NOAEL= 10 mg/kg/day

IAF = 100%	UFA= 10x

UFH=10x

FQPA SF= 1x	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)	LOAEL=1.4 mg/kg/day

IAF = 100%	UFA= 10x

UFH=10x

FQPA SF= 3x

[UFL,]	Occupational LOC for MOE = 300

	13-Week Feeding Study in Dogs:

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in
eyes of female dogs.  A NOAEL could not be determined because 1.4
mg/kg/day was the lowest dose tested in the female dogs in this study.

[Note – there are currently no intermediate-term exposure scenarios
for famoxadone]

Inhalation Long Term [>6 months]	LOAEL=1.4 mg/kg/day

IAF = 100%	UFA= 10x

UFH=10x

FQPA SF= 3x

[combined UFL, UFS]]	Occupational LOC for MOE = 1000

	13-Week Feeding Study in Dogs:

LOAEL = 1.4 mg/kg/day based on microscopic lens lesions (cataracts) in
eyes of female dogs.  A NOAEL could not be determined because 1.4
mg/kg/day was the lowest dose tested in the female dogs in this study.

[Note – there are currently no long-term exposure scenarios for
famoxadone]

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

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

 

3.6	Endocrine Disruption

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there were scientific
bases for including, as part of the program, 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, famoxadone may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

  SEQ CHAPTER \h \r 1 The OPP Incident Data System (7/23/2003) indicates
that in 2002 there were 14 reported incidents, involving 1 minor human
incident, 1 domestic animal incident, 6 for minor plant damage, and 6
for minor property damage.  However, there are no new public health data
or pesticide epidemiology data to report at this time.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

5.1	Pesticide Metabolism and Environmental Degradation

Metabolism in Primary Crops and Livestock Commodities.

The available plant metabolism studies with famoxadone on tomatoes,
grapes, and potatoes have been deemed scientifically acceptable and
adequate to delineate the nature of famoxadone-related residues in crops
petitioned under PP#0F06070.  HED determined that for the petitioned
crops, the residue of concern for both tolerance enforcement and risk
assessment 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 in the future.

There are no livestock feedstuffs associated with the proposed uses on
celery, spinach, onion, and leaf lettuce.  Therefore, data requirements
for livestock metabolism are not relevant to this tolerance petition.

Metabolism in Rotational Crops

A confined rotational study was conducted with [14C[-phenoxypheynl
or-phenyl amino famoxadone formulated as a water dispersible granule and
applied at 0.36 lb ai/A, 0.32X the maximum proposed seasonal rate. 
Total 14C residues in soil, immature and mature lettuce, sugar beet and
wheat samples were determined by oxygen combustion and LSC.  Famoxadone,
IN-MQ613, IN-KZ534 and IN-KZ007 were identified in the secondary crops. 
The data are acceptable for wheat commodities, excluding grain; TRR in
grain was high enough to warrant identification and characterization,
but residues were not extracted, identified or characterized. 
Insufficient data are available on lettuce and sugar beet commodities at
PBIs beyond 30 days.

Analytical Methodology

hod/detector response was linear (r > 0.999) within the range of
0.01-3.0 μg/mL.  Percent recoveries were within guideline levels of
70-120% with acceptable standard deviations (±20%).

Extraction efficiency of incorporated 14C-labelled famoxadone was
evaluated in plant matrices.  The extraction efficiency of the residue
extraction method as compared to the metabolism extraction methodology
was adequate for famoxadone in all matrices evaluated.

Data-collection methods

Onion samples were analyzed for famoxadone using a method adapted from
the DuPont Method 9822 entitled “Magnitude of Residues of Cymoxanil
and Famoxadone in Tomatoes Following Application of DPX-KP481 50WG
Fungicide at Maximum Label Rates-USA-2002”.  Spinach, celery, and head
lettuce samples were analyzed for famoxadone using modified versions of
DuPont method 13753 “Analytical Method for the Determination of
Famoxadone in Spinach (Leafy Vegetables) Using LC/MS”.

For the modified Method 9822, residues were extracted with ACN:water,
partitioned into the ACN layer with NaCl, and cleaned up by SPE.  Then
the extracts were concentrated, partitioned with hexane, cleaned up
using Florisil column chromatography and analyzed using LC/MS/MS.  The
statistically calculated LOQ for famoxadone was 0.03 ppm for green onion
and 0.05 ppm for dry bulb onion.  The limit of detection (LOD) was 0.01
ppm for green onion and 0.02 ppm for dry bulb onion.  The lower limit of
method validation (LLMV) for famoxadone was 0.05 ppm.

For the modified Method 13752, samples were extracted with ACN:water,
partitioned into the ACN phase with NaCl, and cleaned up using SPE. 
Then the extracts were concentrated under nitrogen stream, partitioned
with hexane, and cleaned up using SPE.  The cleaned extract was
concentrated under nitrogen stream, reconstituted with methanol and
0.02% aqueous formic acid, and analyzed using LC/MS/MS.  The
statistically calculated LOQ for celery was 0.03 ppm, and the LOD was
0.01 ppm.  For spinach, the LOQ was 0.0004 ppm, and the LOD was 0.0001
ppm.  For lettuce, the LOQ for famoxadone was 0.013 ppm, and the LOD was
0.005 ppm.

In each field trial, the method was adequately validated with control
samples of the representative commodity fortified with famoxadone at
0.05-25 ppm.

5.1.4	Multiresidue Methods

Famoxadone has been evaluated under the EPA’s multiresidue method
testing.  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.

5.1.5	Storage Stability

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

5.1.6	Magnitude of the Reside in Plants

The IR-4 has submitted magnitude of the residue studies for onion, leaf
lettuce, spinach, and celery in support of proposed tolerances discussed
in this document.  These studies have been reviewed, and the conclusions
of field trial DERs are reproduced.

Vegetable, Bulb (Group 3)

Onions (Green and Dry Bulb)

The submitted residue data for green onion and dry bulb onion, which are
the representative commodities of bulb vegetables, crop group 3, are
adequate to fulfill data requirements.  The number and locations of crop
field trials are in accordance with OPPTS Guideline 860.1500.  The
trials reflect the proposed use pattern.  However, the residue levels in
the two types of onions vary by a factor of approximately 88x, which
indicate that a crop group tolerance on bulb vegetables is
inappropriate.  The residue data for green onion and dry bulb onion were
separately entered into the Agency’s tolerance spreadsheet as
specified by the Guidance for Setting Pesticide Tolerances Based on
Field Trial Data SOP to determine appropriate tolerance levels; see
Appendix II.  The spreadsheet recommends tolerances of 40 ppm on green
onion and 0.45 ppm on dry bulb onion.  Since dry bulb onions and green
onions are representative commodities for onion, bulb, subgroup 3-07A
and onion, green, subgroup 3-07B, respectively, the data are adequate to
support tolerances on the subgroups.  A revised Section F is required
for tolerances of 0.45 ppm for onion, bulb, subgroup 3-07A, and 40.0 ppm
for onion, green, subgroup 3-07B.

Since the onion, bulb, subgroup 3-07A includes them, the requested
tolerances on daylily, bulb; garlic, serpent, bulb; lily, bulb; Chinese,
bulb; onion, pearl; onion, potato, bulb; and shallot, bulb; should be
removed from the proposed Section F.

 

Similarly, since the onion, green, subgroup 3-07B includes them, the
requested tolerances on chive, fresh leaves; chive, Chinese, fresh
leaves; elegans hosta; fritillaria, leaves; kurrat; lady's leek; leek,
wild; onion, Beltsville bunching; onion, fresh; onion, macrostem; onion,
tree, tops; and shallot, fresh leaves; should be removed from the
proposed Section F.

Leafy vegetables (except Brassica) (Group 4)

Leaf lettuce, Spinach and Celery

The representative crops for leafy vegetables (except Brassica) crop
group 4 are leaf and head lettuce, spinach, and celery.  A famoxadone
tolerance of 10 ppm has been established previously for head lettuce.

The submitted residue data for leaf lettuce, spinach, and celery are
adequate to fulfill the residue field trial data requirements for those
crops.  The number and locations of the crop field trials are in
accordance with OPPTS Guideline 860.1500 and the trials reflect the
proposed use patterns.   The submitted residue data were entered into
the Agency’s tolerance spreadsheet as specified by the Guidance for
Setting Pesticide Tolerances Based on Field Trial Data SOP to determine
appropriate tolerance levels.  The spreadsheet recommends individual
tolerances of 30 ppm on leaf lettuce, 50 ppm on spinach, and 25 ppm on
celery.  The seasonal application rate for spinach is nearly 2x the
proposed seasonal application rate for the remainder of the crop group,
and the residue field trial data for spinach are higher than the data
for the other representative commodities.  The recommended spinach
tolerance is 5x as high as the existing head lettuce tolerance.  For
these reasons, ARIA recommends that the tolerance for spinach be
established separately from the leafy vegetables (except Brassica) crop
group.  A revised Section F for spinach at 50 ppm is required.

The remaining residue field trial data are adequate to support a crop
group tolerance for residues of famoxadone at 30 ppm.  However, Canada
has indicated that a tolerance of 25 ppm will be established for leaf
petioles, subgroup 4B at 25.0 ppm (email, D. MacGillivray, PMRA, Health
Canada, 5/14/08).  Since the highest residue found on any of the leafy
vegetables (except Brassica) crop group, except spinach is 22.0 ppm,
harmonization with Canada is possible.  ARIA recommends for a tolerance
at the level recommended by Canada.  A revised Section F for leafy
vegetable (except Brassica), group 4, except spinach at 25 ppm is
required.

The proposed tolerances for crop groups 4A and 4B should also be removed
from Section F.

Herb and Spice, Crop Group 19

Cilantro leaves

No data were submitted for the residues of famoxadone on cilantro. 
Cilantro is not currently a member of the leafy greens, crop subgroup
4A, except spinach.  However, since data for parsley have been
determined to be adequate to support tolerances on cilantro
(Reviewer’s Guide, B. Schneider, 6/14/2002), and parsley is a member
of leafy greens, crop subgroup 4A, the data for head and leaf lettuce
are adequate to support a tolerance on cilantro.  

ARIA concludes that the data for the head and leaf lettuce are adequate
to support the requested tolerance of 25.0 ppm on cilantro.  

5.1.7	Magnitude in Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed uses on
celery, spinach, onion, and leaf lettuce.  Therefore, data requirements
pertaining to meat, milk, poultry, and eggs are not relevant to this
tolerance petition.

5.1.8	Confined and Field Rotational Crops

A field accumulation in rotational crops study was conducted on radish,
spinach and wheat.  Although the data were classified as scientifically
acceptable, the experimental design did not include the analysis of the
residues of concern for rotational crops.  Prior to analyzing for
additional residues in the field rotational crop samples the petitioner
should address data gaps regarding the nature of the residue in
rotational crops.

Pending the new confined rotational study or upgrade of the existing
study, the rotational crop restrictions noted in OPPTS Guideline
860.1200 Directions for Use are required.

5.1.9	Pesticide Metabolites and Degradates of Concern

Table 5.1.9.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Famoxadone 	Famoxadone 

	Rotational Crop	Famoxadone, IN-MQ613, IN-KZ534 and IN-KZ007	Famoxadone,
IN-MQ613, IN-KZ534 and IN-KZ007

Livestock

	Ruminant	N/A	N/A

	Swine	N/A	N/A

	Poultry	N/A	N/A

Drinking Water

	Famoxadone	Famoxadone

5.1.10	Drinking Water Residue Profile

The drinking water residues used in this assessment were provided by the
Environmental Fate and Effects Division (EFED) in a memoranda “Tier II
Drinking Water Exposure Assessment for Famoxadone Use on Leafy Greens
subgroup 4A, Bulb Vegetables Group 3, Cilantro and Caneberry subgroup
13A and Leaf Petioles subgroup 4B” (DP#s: 347671 & 347674, J. Lin,
4/30/2008).   

For famoxadone parent compound the highest EDWC resulting from the
proposed new uses for chronic exposure are 0.189 μg/L (ppb) in surface
water and 0.010 μg/L (ppb) in ground water.  These values generally
represent upper-bound estimates of the concentrations that might be
found in surface water and groundwater resulting from the use of
famoxadone.  The assessment was based on the proposed leafy greens
(subgroup 4A) and leafy petioles (subgroup 4B) use.  The PRZM/EXAMS
Model was used to estimate surface water concentrations and the SCIGROW
Model was used to estimate groundwater concentrations.

5.2	Dietary Exposure and Risk

A dietary (food + drinking water) exposure analysis for famoxadone was
conducted by ARIA (DP#: 354336, B. Hanson, 7/8/2008).  

5.2.1	Acute Dietary Exposure/Risk

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

Chronic Dietary Exposure/Risk

The analyses summarized in Table 5.2.2 (below) are based on average
field trial values and anticipated residues with processing factors used
to refine residue estimates of some processed commodities.  Reduction
factors were also determined for leafy vegetables.  Percent crop treated
information was also provided by BEAD.  Dietary exposure via drinking
water was also included in these assessments.  Even with the
conservative assumptions utilized, the risk estimates are well below
ARIA’s level of concern.  The most highly exposed population subgroup
is adults 20-49 years old, which utilizes 58% of the cPAD.  

TABLE 5.2.2.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for Famoxadone.  

Population Subgroup1	DEEM Acute Dietary Analysis,

95th Percentile	DEEM Chronic Dietary Analysis

	Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% cPAD

General U.S. Population	

NA 2

	0.000658	47

All Infants (< 1 year old)

0.000414	30

Children 1-2 years old

0.000707	51

Children 3-5 years old

0.000614	44

Children 6-12 years old

0.000413	30

Youth 13-19 years old

0.000387	28

Adults 20-49 years old

0.000818	58

Adults 50+ years old

0.000597	43

Females 13-49 years old

0.000544	39

1 Values for the population with the highest risk for each type of risk
assessment are bolded.  

2 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups.

Cancer Dietary Risk

HED classified famoxadone as “not likely to be carcinogenic to
humans.”  Therefore, quantification of human cancer risk was not
necessary. 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

For the previous assessment, the dietary exposure analyses used average
field trial values for crops and anticipated residues for ruminant fat,
liver, and milk fat.  Empirical processing factors were used to refine
the residue estimates of processed tomato, pepper, potato, and grape
commodities.  Average field trial values and processing factors are
taken from the famoxadone residue chemistry summary document (DP#:
287253, M. Doherty, 4/16/2003).  Anticipated residues were also
calculated from the mean levels for grapes, hops and caneberries,
subgroup 13A (DP#: 323682 & 333260, W. Cutchin, 11/29/2006).  

For the current assessment, anticipated residues were derived from the
current residue chemistry memoranda (DP# 349184 & 349198; W. Cutchin;
4/14/2008) from the mean levels for leafy greens (subgroup 4A), leafy
petioles (subgroup 4B), cilantro, spinach, and dry bulb/green onions. 

Leafy vegetables are both washed and have outer wrapper leaves removed
before eaten; therefore reduction factors can be determined for such
instances.  A reduction factor for wrapper to no-wrapper (0.22x) was
determined from DER 44946430 for leaf lettuce, which was summarized in
an HED memorandum (DP#: 271377 & 287253, M. Doherty, 4/18/2003).  A
reduction factor was also determined for unwashed to washed leaf lettuce
(0.59x) from the current residue chemistry memoranda.

Residue levels and processing factors used in the dietary exposure
analyses are shown in Table 5.3.a.  

Table 5.3.a.  Residue Levels Used in Chronic Dietary Assessment for
Famoxadone.

RAC	Food Form	Residue Level, ppm	Processing Factor	Comments

Grape	RAC	0.44	Not Applicable	Grape AR

Grape	Juice	0.44	0.01	Grape AR

Grape	Raisin	0.44	1.9	Grape AR

Grape	Wine and Sherry	0.44	0.01	Grape AR

Potato	Chips	0.01	1	Potato AR

Potato	Dry (granules/flakes)	0.01	1	Potato AR

Potato	Flour	0.01	1	Potato AR

Potato	Tuber, w/ peel	0.01	Not Applicable	Potato AR

Potato	Tuber, w/o peel	0.01	1	Potato AR

Lettuce, Head	RAC	0.28	Not Applicable	Lettuce AR (w/o wrapper) x washing
reduction

Eggplant	RAC	0.35	Not Applicable	Bell Pepper AR

Okra	RAC	1.31	Not Applicable	Non-bell Pepper AR

Pepper	Bell	0.35	Not Applicable	Bell Pepper AR

Pepper	Bell, Dried	0.35	1.65 (tomato)	Bell Pepper AR

Pepper	Nonbell	1.31	Not Applicable	Non-bell Pepper AR

Pepper	Nonbell, Dried	1.31	1.65 (tomato)	Non-bell Pepper AR

Tomatillo	RAC	0.28	Not Applicable	Tomato AR

Tomato	RAC	0.28	Not Applicable	Tomato AR

Tomato	Paste	0.28	1.3	Tomato AR

Tomato	Puree	0.28	0.4	Tomato AR

Tomato	Dried	0.28	1.65	Tomato AR

Tomato	Juice	0.28	0.3	Tomato AR

Balsam pear	RAC	0.05	Not Applicable	Cucumber AR

Caneberries, subgroup 13A	RAC	2.01	Not Applicable	Caneberry AR

Cantaloupe	RAC	0.13	Not Applicable	Cantaloupe AR

Casaba	RAC	0.13	Not Applicable	Cantaloupe AR

Chayote	RAC	0.11	Not Applicable	Summer Squash AR

Chinese waxgourd	RAC	0.05	Not Applicable	Cucumber AR

Cilantro	RAC	0.28	Not Applicable	Lettuce AR (w/o wrapper) x washing
reduction

Cucumber	RAC	0.05	Not Applicable	Cucumber AR

Honeydew melon	RAC	0.13	Not Applicable	Cantaloupe AR

Hops	RAC	34.16	Not Applicable	Hop AR

Leafy Greens, subgroup 4A	RAC	1.11	Not Applicable	Leaf Lettuce, washed
AR x wrapper reduction 

Leaf Petioles, subgroup 4B	RAC	4.43	Not Applicable	Washed Celery AR

Onion, dry bulb	RAC	0.07	Not Applicable	Onion, dry bulb AR

Onion, green	RAC	6.11	Not Applicable	Green Onion AR

Pumpkin	RAC	0.11	Not Applicable	Summer Squash AR

Pumpkin	Seed	0.11	Not Applicable	Summer Squash AR

Squash, summer	RAC	0.11	Not Applicable	Summer Squash AR

Squash, winter	RAC	0.11	Not Applicable	Summer Squash AR

Watermelon	RAC	0.13	Not Applicable	Cantaloupe AR

Watermelon	Juice	0.13	1	Cantaloupe AR

Soybean	seeds	0.02	1	Recommended tolerance level  - 05MN13

Soybean	flour	0.02	1	Recommended tolerance level  - 05MN13

Soybean	flour-babyfood	0.02	1	Recommended tolerance level  - 05MN13

Soybean	soy milk	0.02	1	Recommended tolerance level  - 05MN13

Soybean	soy milk-babyfood	0.02	1	Recommended tolerance level  - 05MN13

Soybean	oil	0.02	

1	Recommended tolerance level  - 05MN13

Soybean	oil-babyfood	0.02	1	Recommended tolerance level  - 05MN13

Spinach	RAC	4.33	Not Applicable	Spinach, washed AR x wrapper reduction 

Fat of cattle, goats, and sheep	RAC	0.0075	Not Applicable	AR from a
dietary burden of 0.0405 ppm

Liver of cattle, goats, and sheep	RAC	0.00285	Not Applicable

	AR from a dietary burden of 0.0405 ppm

Milk, fat	RAC	0.00506	Not Applicable	AR from a dietary burden of 0.0305
ppm

The previous dietary exposure analyses used a Screening-Level Usage
Analysis (SLUA), provided by BEAD, for %CT information of current uses
of famoxadone (J. Alsadek, 8/31/2006).

For this current petition, BEAD provided projected percent crop treated
(PPCT) estimates (DP#: 349850 & 349852, A. Halvorson, 4/7/2008) for
celery, lettuce, spinach and grapes.   Famoxadone is to be registered
for use on grapes grown east of the Rockies only.

PPCT information is listed in Table 5.3.b, below.

Table 5.3.b.  Percent Crop Treated Information Used in Chronic Dietary
Exposure Analysis                       

Commodity	Percent of Crop Treated

Celery	39

Cucumbers	5

Grapes, wine	5

Grapes, table	5

Grape, juice	50

Lettuce, head	67

Lettuce, other	62

Peppers	5

Potatoes	5

Pumpkins	5

Spinach	39

Squash	<1*

Tomatoes	10

Watermelons	<1*

       * Value rounded to 1.

RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

Famoxadone is not intended for use in public or residential settings. 
Therefore, residential exposure is not expected, and no residential risk
assessment was performed.  

6.1	Other (Spray Drift, etc.)

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 the ground application method employed for famoxadone. 
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.  On
a chemical by chemical basis, 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 database 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 with specific products with significant risks
associated with drift.

AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA and HED must consider and aggregate
famoxadone pesticide exposures and risks from three major sources: food,
drinking water, and residential exposures.  In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED and ARIA have considered both the route and
duration of exposure.  Since there was no acute dietary endpoint
selected, an acute aggregate risk assessment is not required.  Further,
no residential uses are registered or proposed, therefore the only
potential aggregate risk is due to chronic dietary exposure from food
and water.  Refer to section 5.2.2 for the long-term aggregate risk
(chronic dietary and drinking water) estimates.  Chronic aggregate risk
does not exceed ARIA’s level of concern.

CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

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

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

9.1	Handler Exposure and Risk

Based upon the proposed use pattern, ARIA believes the most highly
exposed occupational pesticide handlers will be mixer/loaders using
open-pour loading of a dry flowable formulation; applicators using
open-cab ground-boom sprayers, applicators using open-cab airblast
sprayers, and aerial applicators.  Occupational pesticide handlers may
also be exposed while preparing sprinkler irrigation systems for use as
an application vehicle.  ARIA believes such activities are similar to
those of a mixer/loader supporting aerial applications. Therefore, a
separate assessment for persons preparing solutions for use in an
irrigation system was not performed.   

ARIA believes pesticide handlers will be exposed to short-term duration
(1-30 days) exposures but not for intermediate-term duration (1-6
months) exposures.  Although multiple applications are likely, they
should not be consecutive applications and famoxadone 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).  Therefore, only short-term duration exposures were assessed.

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The HED ExpoSAC SOP Number 12
(3/29/2000) 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 PHED Surrogate Exposure Guide
(August 1998).  ARIA 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
monitoring data support this and ARIA presents them in this way. 
Conversely, for equipment types such as fixed-wing aircraft, groundboom
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, ARIA determines the most appropriate
levels of 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).  

gory A (such as butyl rubber, natural rubber, neoprene rubber or nitrile
rubber), all ≥ 14 mils.  

The short-term exposure duration (1 – 30 days) dermal and inhalation
toxicological endpoints were identified from a 13-week feeding study in
the dog.  The NOAEL is the same for each route of exposure and is 10.0
mg ai/kg bw/day.  The effects seen were myotonic twitches in male and
female dogs starting on day 21.  There is a 5.0 % dermal absorption
factor for use in calculating dermal exposure.  A 70 kg body weight is
used for risk calculations.  ARIA assumes 100 % absorption via the
inhalation route of exposure.  A MOE of 100 is adequate to protect
occupational pesticide handlers.  See Table 9.1 for a summary of
exposures and risks to occupational pesticide handlers from exposures to
famoxadone.

HED classified famoxadone as "not likely to be carcinogenic in humans"
therefore a cancer risk assessment is not necessary.

See Table 9.1 for a summary of exposures and risks to occupational
pesticide handlers.

Table 9.1 Summary of Exposures & Risks 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 Supporting Aerial Operations

Dermal:

SLNoGlove      0.066 LC

SLWithGlove   0.066 HC

Inhal.            0.00077 HC	0.156

lb ai/A	350 A/day	Dermal:

SLNoGlove    0.00257

SLWithGlove 0.00257

Inhal.              0.0006	No Glove

3,200

With Glove

3,200

Applicator - Ground-boom - Open-cab

Dermal:

SLNoGlove       0.014 HC

SLWithGlove    0.014 MC

Inhal.              0.00074 HC	0.156

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.000312

SLWithGlove 0.000312

Inhal.              0.00033	No Glove

15,600

With Glove

15,600

Applicator – Airblast – Open Cab

Dermal:

SLNoGlove       0.36 HC

SLWithGlove    0.24 HC

Inhal.              0.0045 HC	0.156

lb ai/A	40 A/day	Dermal:

SLNoGlove    0.0016

SLWithGlove 0.0011

Inhal.              0.0004	No Glove

5,000

With Glove

6,700

Aerial Applicator (Pilots not required to wear gloves)

Dermal:

SLNoGlove       0.0050 MC

Inhal.               0.000068 MC	0.156

lb ai/A	350 A/day	Dermal:

SLNoGlove    0.000195

Inhal.              0.000053	No Glove

40,300

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 Section 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 (ADD) = Unit Exposure * Applic. Rate * Units
Treated * absorption factor (5.0 % dermal absorption; 100 % inhalation
absorption) ( 70 kg Body Weight

5.  MOE = Margin of Exposure = 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 ARIA’s level of concern.

9.2	Post-Application Exposure Risk

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified transfer
coefficients (TC) (cm²/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified.   

The highest TC for either leafy green vegetables, bulb vegetables and
caneberries is 2,500 cm2/hr for hand harvesting or thinning of leafy
green vegetables, as well as for hand harvesting of celery.  As a
“screening” level assessment, RD herein uses the TC of 2,500 cm2/hr
for hand harvesting or thinning.

The TCs used in this assessment are from an interim TC SOP developed by
HED’s ExpoSAC using proprietary data from the ARTF database (SOP #
3.1).  It is the intention of HED’s ExpoSAC that this SOP will be
periodically updated to incorporate additional information about
agricultural practices in crops and new data on TCs.  Much of this
information will originate from exposure studies currently being
conducted by the ARTF, from further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, 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).  

The following convention may be used to estimate post-application
exposure.  

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 .  

0.156 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.349 µg/cm2 , therefore,

0.349 µg/cm2 * 2,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.05 (% dermal
absorption) ( 70 kg bw = 0.00499 mg/kg bw/day.

MOE = NOAEL ( ADD then 10.0 mg/kg bw/day ( 0.00499 mg/kg bw/day = 2,000.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  The most conservative estimate (i.e.,
highest exposure/risk) of post-application exposure results in MOEs >
100.  Therefore, the proposed risk does not exceed ARIA’s level of
concern.  

9.3	Restricted Entry Interval (REI)

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 is 12 hours.  That is adequate to protect
agricultural workers from postapplication exposures to famoxadone.  The
Tanos® label lists a REI of 12 hours.  

10.0	TOLERANCE SUMMARY

HED has determined that the residue of concern for plant commodities,
for the purposes of tolerance and risk assessment, is famoxadone per se.
  Tolerances for famoxadone residues can be found at 40 CFR §180.587.  

Codex MRLs, expressed as famoxadone per se, have been established for
some plant commodities but not for the crops addressed herein.  Canada
is currently in the process of establishing a tolerance of 25 ppm for
crop subgroup 4B, leaf petioles.  An International Residue Limit form is
appended to this risk assessment.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels. 
The residue data for green onion, dry bulb onion, leaf lettuce, spinach,
and celery were entered into the tolerance spreadsheet (Appendix II).

The spreadsheet recommends individual tolerances of 40 ppm on green
onion and 0.45 ppm on dry bulb onion.  The tolerance levels recommended
on these two types of onions vary by a factor of approximately 88x. 
These data suggest that a crop group tolerance on bulb vegetables is
inappropriate because of the wide variability in field trial residues. 
The available data will, however, support subgroup tolerances of 0.45
ppm on onion, bulb, subgroup 3-07A, and 40 ppm on onion, green, subgroup
3-07B.

The spreadsheet recommends individual tolerances of 30 ppm on leaf
lettuce, 50 ppm on spinach, and 25 ppm on celery.  The proposed seasonal
application rate for spinach is nearly 2x the proposed seasonal
application rate for the remainder of the crop group, and the residue
field trial data for spinach are higher than the data for the other
representative commodities.  The recommended spinach tolerance is 5x as
high as the existing head lettuce tolerance.  For these reasons, ARIA
recommends that the tolerance for spinach be established separately from
the leafy vegetables (except Brassica) crop group.  ARIA recommends that
the tolerance for spinach be established at 50 ppm.

The remaining residue field trial data are adequate to support a crop
group tolerance for residues of famoxadone at 30 ppm.  However, Canada
has indicated that a tolerance of 25 ppm will be established for leaf
petioles, subgroup 4B at 25 ppm.  Since the highest residue found on any
of the leafy vegetables (except Brassica) crop group, except spinach is
22 ppm, harmonization with Canada is possible.  ARIA recommends for a
tolerance for leafy vegetable (except Brassica), group 4, except spinach
at 25 ppm.

No data have been submitted for the residues of famoxadone on cilantro. 
Cilantro is not currently a member of the leafy greens, crop subgroup
4A, except spinach.  However, since data for parsley have been
determined to be adequate to support tolerances on cilantro, and parsley
is a member of crop subgroup 4A, the data for head and leaf lettuce are
adequate to support a tolerance on cilantro.  ARIA concludes that the
data for the head and leaf lettuce (except cucurbits) are adequate to
support a tolerance of 25 ppm on cilantro.

A summary of recommended tolerances for the current petition is listed
in Table 10.0, below.

Table 10.0.   Tolerance Summary for Famoxadone.

Commodity	Proposed 

Tolerance (ppm)	Recommended 

Tolerance (ppm)	Comments; Correct Commodity Definition

Leafy greens, subgroup 4A	50	Not needed	The recommended tolerance for
leafy vegetables (except Brassica), group 4, except spinach will cover
expected residues resulting from the proposed use.

Leaf petioles, subgroup 4B	25	Not needed	The recommended tolerance for
leafy vegetables (except Brassica), group 4, except spinach will cover
expected residues resulting from the proposed use.

Leafy vegetables (except Brassica), group 4, except spinach	None	25	The
data indicate that a tolerance on the group except spinach is
appropriate.

Spinach	None	50	The data indicate that a tolerance for spinach should be
separate from group 4.

Cilantro, leaves	50	25	Based on parsley as a member of crop subgroup 4A

Vegetable, bulb, group 3	40	Not needed	The available data suggest that a
tolerance for Bulb Vegetables, Crop Group 3 is inappropriate because of
the wide variability in field trial residues among the representative
commodities. 

Onion, bulb, subgroup 3-07A	-	0.45	The available data support subgroup
tolerance of 0.45 ppm for onion, bulb, subgroup 3-07A

Onion, green, subgroup 3-07B	-	40	The available data will support
subgroup tolerance of 40 ppm for onion, green, subgroup 3-07B.

Chive, fresh leaves	40	Not needed	The recommended tolerance for onion,
green, subgroup 3-07B will cover expected residues resulting from the
proposed use.

Chive, Chinese, fresh leaves	40	Not needed	The recommended tolerance for
onion, green, subgroup 3-07B will cover expected residues resulting from
the proposed use.

Daylily, bulb	40	Not needed	The recommended tolerance for onion, bulb,
subgroup 3-07A will cover expected residues resulting from the proposed
use.

Elegans hosta	40	Not needed	The recommended tolerance for onion, green,
subgroup 3-07B will cover expected residues resulting from the proposed
use.

Fritarillia, bulb	40	Not needed	The recommended tolerance for onion,
bulb, subgroup 3-07A will cover expected residues resulting from the
proposed use.

Fritarillia, leaves	40	Not needed	The recommended tolerance for onion,
green, subgroup 3-07B will cover expected residues resulting from the
proposed use.

Garlic, Serpent, bulb	40	Not needed	The recommended tolerance for onion,
bulb, subgroup 3-07A will cover expected residues resulting from the
proposed use.

Kurrat	40	Not needed	The recommended tolerance for onion, green,
subgroup 3-07B will cover expected residues resulting from the proposed
use.

Lady’s Leek	40	Not needed	The recommended tolerance for onion, green,
subgroup 3-07B will cover expected residues resulting from the proposed
use.

Leek, wild	40	Not needed	The recommended tolerance for onion, green,
subgroup 3-07B will cover expected residues resulting from the proposed
use.

Lily, bulb	40	Not needed	The recommended tolerance for onion, bulb,
subgroup 3-07A will cover expected residues resulting from the proposed
use.

Onion, Beltsville bunching	40	Not needed	The recommended tolerance for
onion, green, subgroup 3-07B will cover expected residues resulting from
the proposed use.

Onion, Chinese, bulb	40	Not needed	The recommended tolerance for onion,
bulb, subgroup 3-07A will cover expected residues resulting from the
proposed use.

Onion, fresh	40	Not needed	The recommended tolerance for onion, green,
subgroup 3-07B will cover expected residues resulting from the proposed
use.

Onion, macrostem	40	Not needed	The recommended tolerance for onion,
green, subgroup 3-07B will cover expected residues resulting from the
proposed use.

Onion, pearl	40	Not needed	The recommended tolerance for onion, bulb,
subgroup 3-07A will cover expected residues resulting from the proposed
use.

Onion, potato, bulb	40	Not needed	The recommended tolerance foronion,
bulb, subgroup 3-07A will cover expected residues resulting from the
proposed use.

Onion, tree, tops	40	Not needed	The recommended tolerance for onion,
green, subgroup 3-07B will cover expected residues resulting from the
proposed use.

Shallot, bulb	40	Not needed	The recommended tolerance for onion, bulb,
subgroup 3-07A will cover expected residues resulting from the proposed
use.

Shallot, fresh leaves	40	Not needed	The recommended tolerance for onion,
green, subgroup 3-07B will cover expected residues resulting from the
proposed use.

Leaf petioles, subgroup 4B	None	25	The recommended subgroup tolerance is
based on adequate data from celery.

11.0	DATA NEEDS AND LABEL RECOMMENDATIONS

The scientific quality and completeness of the available toxicology data
base are considered adequate according to the Subdivision F Guidelines
and Part 158 Data Requirements to support the registration and proposed
tolerances for famoxadone.   

11.1	Toxicology

There exists considerable uncertainty relating to the microscopic
findings in the eyes of all dogs in the 1-year chronic feeding study and
a resulting uncertainty with regard to determining a NOAEL for eye
effects in this study.  Because of these uncertainties, HED decided to
not use the results from this 1-year study for the purpose of
determining a cRfD for famoxadone at this time.  In order to resolve
these uncertainties, HED strongly recommends that DuPont convene a
Pathology Working Group (PWG), in full accordance with the provisions
specified in EPA Pesticide Regulation (PR) Notice 94-5, and report the
results to EPA for its further evaluation of this study.  Requiring the
1-year feeding study in dogs be repeated was also considered by HED, but
a decision on this requirement was deferred pending submission by DuPont
of the PWG report and of mechanistic studies designed to elucidate the
mechanism of action of famoxadone in the eyes of dogs and other species.

DuPont believes the effect in dog eyes is a species-specific effect and
therefore is not relevant to the assessment of risk in humans.  However,
the cataractogenic mechanism of action of famoxadone is unknown and
DuPont provided no mechanistic studies to support the claim of species
specificity other than comparative metabolism studies in rats and dogs
in which no biologically significant qualitative differences were
observed in absorption, distribution, metabolism, or excretion (other
than a somewhat longer half-life of famoxadone in the body of dogs as
compared to rats).  HED has concluded, however, that there is
insufficient data/information available at this time to support a
species specific effect for induction of cataracts in dogs.  In this
regard, HED strongly recommends that DuPont  perform mechanistic studies
designed to elucidate the mechanism of action of famoxadone in dogs and
other species and provide additional plausible evidence and rationale,
if possible, to support the possible species specificity of this
chemical in dogs.  

No inhalation toxicity study, other than an acute inhalation toxicity
study in rats, is available for famoxadone.  HED has determined that if
the target MOE of 300 for the intermediate-term (1-6 months) inhalation
exposure risk assessment for occupational workers cannot be met, then a
90-day subchronic inhalation toxicity study in dogs (OPPTS 870.3465)
will be required to be performed and submitted.  This study will have to
be performed in dogs, rather than in rats, because the hazard endpoint
of concern (cataracts) has not been observed in any of the studies in
rats.  Alternatively, the registrant may provide evidence demonstrating
that the cataract formation in dogs is, in fact, species-specific (i.e.
not relevant to humans).  In that event, a study in rats will suffice.  

11.2	Residue Chemistry

The following are deficiencies noted from the residue chemistry
memorandum.

860.1200 Directions for Use

The rotational crop restriction listed on the product label for Tanos®
Fungicide should be revised to specify the following: “Crops listed on
the famoxadone label may be planted back at any time; cereal grains may
be planted back following a minimum plant back interval of 30 days; and
all other crops may be planted back following a minimum plant back
interval of one year.”

860.1850 Confined Rotational Crops

As requested in PP#0F06070 (DP#s: 287253 & 271377, M. Doherty,
4/18/2003), a new confined rotational crop study reflecting 1x the
maximum registered seasonal rate is required.  Alternatively, the
reviewed study (MRID 44946411) may be upgraded to acceptable status
pending characterization and identification of radioactive residues. 
Pending the new confined rotational study or upgrade of the existing
study, the rotational crop restrictions noted in 860.1200 Directions for
Use are required. 

860.1550 Proposed Tolerances

A summary of the recommended tolerances along with recommendations for
commodity definitions are presented in Table 10.0.  The petitioner is
required to submit a revised Section F to reflect the recommendations in
Table 10.0.

11.3	Occupational and Residential Exposure

No additional data is required. 

12.0	REFERENCES

Endpoint Selection Document

Famoxadone.  Second Report of the Hazard Identification Assessment
Review Committee, E. Budd, TXR No. 0051819, 4/16/2003.

Dietary Exposure Memorandum

Famoxadone.  Acute and Chronic Dietary (Food and Water) Exposure
Assessments for the Petition Proposing Tolerances for Residues of
Famoxadone on Bulb Vegetables, Crop Group 3; Leafy Greens, Subgroup 4A;
Leaf Petioles, Subgroup 4B; and Cilantro, DP#: 349186 & 349194, B.
Hanson, 5/27/2008.

Drinking Water Memorandum

Tier II Drinking Water Exposure Assessment for Famoxadone Use on Leafy
Greens subgroup 4A, Bulb Vegetables Group 3, Cilantro and Caneberry
subgroup 13A and Leaf Petioles subgroup 4B; DP#: 347671, 347674; J. Lin;
4/30/2008.

Residue Chemistry Data Reviews

Famoxadone.  Section 3 Registration on Bulb Vegetables, Crop Group 3;
Leafy Greens, Subgroup 4A; Leaf Petioles, Subgroup 4B; and Cilantro. 
Summary of Analytical Chemistry and Residue Data.  PP#7E7280 & 7E7281,
DP#: 349184 & 349198, W. Cutchin, 4/14/2008.

Occupational and Residential Exposure Memorandum

Famoxadone - Occupational Exposure/Risk Assessment for the Proposed New
Uses of Famoxadone on Leafy Greens Crop Subgroup 4A, Bulb Vegetables
Crop Group 3, Cilantro Leaves and Caneberries (Crop Subgroup 13A); DP#
349187; M. Dow; 2/22/2008.	

Famoxadone – Occupational Exposure/Risk Assessment for the Proposed
New Use of Famoxadone on Leaf Petiole Vegetables, Crop Subgroup 4B; DP#:
349201; M. Dow; 2/22/2008.

	

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

yes	yes

yes

yes

no

yes

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5375    Mutagenicity—Gene Mutation – CHO cells	

870.5395    Mutagenicity— In vivo rat bone marrow	

870.5550    Mutagenicity—Other Genotoxic Effects- UDS assay		yes

yes

yes

yes

yes	yes

no

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800    Immunotoxicity		yes

yes

yes	yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no	-

The requirements (40 CFR 180.587) for food use for famoxadone are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

A.2   Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2.	Acute Toxicity Profile for Famoxadone

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute Oral

Rats	44302407	M: LD50 > 5000 mg/kg

F: LD50 > 5000 mg/kg	IV

870.1100	Acute Oral

Mice

	44302408	M: LD50 > 5000 mg/kg

F: LD50 > 5000 mg/kg	IV

870.1200	Acute Dermal

Rabbits

	44302409	M: LD50 > 2000 mg/kg

F: LD50 > 2000 mg/kg	III

870. 1300	Acute Inhalation

Rats	44302410	M: LC50 > 5.3 mg/L

F: LC50 > 5.3 mg/L	IV

870.2400	Primary Eye Irritation

Rabbits	44302411	Moderate irritation

	III

870.2500	Primary Skin Irritation

Rabbits	44302412	Mild irritation	IV

870.2500	Primary Skin Irritation

Rabbits	44946205	Moderate irritation	III

870.2600	Dermal Sensitization

Guinea Pigs	44302413	Negative for dermal sensitization	N/A

A.3  Executive Summaries TC \l2 "A.3  Executive Summaries 

A.3.1	Subchronic Toxicity

870.3100	90-Day Oral Toxicity – Rat

870.3100	90-Day Oral Toxicity - Mouse

870.3150 90-Day Oral Toxicity – Dog

MRID No.: 44302419 

Executive Summary:  In a 13-week subchronic oral study (MRID 44302419,
44302420) , DPX-JE874 technical (lot # DPX-JE874-221, 97.4% purity) was
administered by diet to 4 beagle dogs/sex/group at doses of 0, 40, 300,
or 1000 ppm (equal to 0, 1.3/1.4, 10.0/10.1, or 23.8/23.3 mg/kg/day in
males/females).  However, from day 37 to the end of the study at 90-91
days, the 1000 ppm treatment groups were given 600 ppm (equal to
21.2/20.1 mg/kg/day in males/females) due to clinical signs of toxicity
including continuous myotonic twitching and, in one female, convulsions.

All animals survived to the scheduled sacrifice.  Urinalyses and gross
pathology were unaffected by treatment.  The eye lens was a target
organ.  At Week 12, treatment-related slight bilateral posterior
cortical cataracts were observed at 1000/600 ppm in 2/4 males and 2/4
females and at 300 ppm in 2/4 males and 1/4 females.  Additionally, at
termination, microscopic examination of the lens of the eyes revealed
treatment-related lesions at 1000/600 ppm in 3/4 males and 4/4 females,
at 300 ppm in 4/4 males and 4/4 females, and at 40 ppm in 1/4 females. 
The lenticular cataracts observed in the dogs during the ocular
examinations were characterized histologically as predominantly
consisting of a small focal zone of swollen lens fibers at the Y suture
of the posterior lens capsule.

Slight anemia was apparent in the treated animals.  Decreased (p(0.05 or
0.01) erythrocytes, hemoglobin, hematocrit and increased MCV (not in 40
ppm females) were observed in the 40 and 300 ppm females and at 1000/600
ppm in both sexes at Weeks 5 and/or 12.  Decreased (p(0.05) hemoglobin
was observed in the 300 ppm males at Week 12.  However, at 40 ppm and
300 ppm in both males and females, this anemic condition was minor, and
the biological relevance was equivocal.

At 1000/600 ppm, additional adverse effects were noted in both sexes. 
Body weights were decreased (p(0.05 or 0.01) in males throughout the
study (NS at Week 13) and in females throughout the study (NS at Week
7).  Body weight gains were decreased (p(0.05 or 0.01) at Weeks 0-4. 
Decreased (p(0.05 or 0.01) food consumption was observed during Weeks
1-6 (NS in females at Week 6).  Decreased (p(0.01) food efficiency was
observed in both sexes during the initial 2-3 weeks.  

Clinical findings included myotonic twitches in both males and females
that were first observed  approximately 4 hours following feeding on Day
21, and thereafter the twitches were regularly observed throughout the
study.  One 1000 ppm female had convulsions and ataxia on Day 34.  In
the females, soft stools were generally observed throughout the study;
decreased defecation and diarrhea were also observed. 

Potassium was increased (p(0.05) at 1000/600 ppm in fasted males at Week
5 and females at Weeks 5 and 12; and in non-fasted males at Week 5
(p(0.01) and  females at Week 5 (NS).  The Sponsor suggested the
hyperkalemia may have caused the myotonic twitches; however, myotonic
twitches oftentimes were observed even when there was not a significant
increase in potassium.  Furthermore, non-fasted potassium levels were
within historical control ranges with the exception of a minor increase
in the 1000/600 ppm females at Week 5. Consequently, there is
insufficient evidence to conclude that hyperkalemia was the cause of the
myotonic twitches in this study. 

At 1000/600 ppm, decreased (p(0.05 or 0.01) absolute and relative (to
body weight) testes and epididymides weights were observed (relative
testes weight, NS).  Bilateral immature seminiferous tubules were also
observed at 1000/600 ppm.  Weight decreases in the testes and
epididymides sometimes occur in dogs when body weight gain is suppressed
before the dogs reach sexual maturity.  Therefore, the toxicological
significance of these findings are equivocal. 

The LOAEL in male dogs was 300 ppm (equal to 10.0 mg/kg/day) based on
increased incidence of lenticular cataracts and microscopic lens
lesions.  The NOAEL in male dogs was 40 ppm (equal to 1.3 mg/kg/day). 
The LOAEL in female dogs was 40 ppm (equal to 1.4 mg/kg/day) based on
one dog with a treatment-related microscopic lens lesion.  The NOAEL in
female dogs could not be ascertained (<40 ppm, equal to <1.4 mg/kg/day,
lowest dose level tested).

This 90-day oral toxicity study in the dog is Acceptable/Guideline
(§82-1b) and satisfies the guideline requirements for a 90-day oral
toxicity study in the dog.

Dose and Endpoint for Establishing cRfD:   LOAEL of 1.4 mg/kg/day, based
on treatment-related microscopic lens lesions (cataracts) in eyes of
female dogs.  A NOAEL could not be determined.

Uncertainty Factor(s): 1000 (10X for inter-species extrapolation, 10X
for intra-species variation; and an additional 10X for the use of a
LOAEL and the use of a subchronic study.  

Comments about Study/Endpoint/Uncertainty Factor:  This endpoint is
based on an oral study, which is the route of interest for a dietary
risk estimate.  This study and endpoint were selected because they would
address the concerns for toxic effects observed in all the other
available studies for this chronic risk assessment.   

In this 13-week feeding study in dogs, the testing laboratory reported a
treatment-related microscopic lens lesion (cataracts) in the eyes of 1/4
female dogs at 40 ppm.  However, in a subsequent examination of the same
microscopic eye slides by Dr. Ralph Heywood (toxicology consultant to
DuPont), he reported the same microscopic lens lesion (cataracts) in the
eyes of all four female dogs at 40 ppm and in all male and female dogs
at both of the higher dose levels of 300 and 1000/600 ppm.  Dr.
Heywood’s findings are presented in his report to DuPont (1).  The
HIARC concluded that the histopathological evidence of cataracts
observed in the lens of the female dogs in this 13-week feeding study in
dogs at 40 ppm (equal to 1.4 mg/kg/day), although not supported by
findings of cortical cataracts during clinical examinations of the same
dogs, was nevertheless sufficient evidence of a treatment-related effect
on which to base the LOAEL for female dogs in this study.  Also, since
40 ppm was the lowest dose tested, there is no NOAEL for the female dogs
in this study (i.e. the NOAEL for the female dogs is below 1.4
mg/kg/day).

A 1-year chronic feeding study in dogs (MRID 44302422) is also
available, but was not selected as the basis for the cRfD.  The doses
tested in this study were 0, 10, 20, 40, or 300 ppm (equal to 0, 0.3,
0.6, 1.2 and 8.8 mg/kg/day in males and 0, 0.3, 0.6, 1.2 and 9.3
mg/kg/day in females).  The testing laboratory reported a NOAEL of 40
ppm (1.2 mg/kg/day) for treatment-related lens lesions (cataracts) in
the eyes of male and female dogs in this study based on both clinical
examination findings and histopathological findings.  No other
treatment-related adverse findings were observed in either the male or
female dogs in this study.  After examining the same microscopic eye
slides in a subsequent evaluation, however, Dr. Ralph Heywood
(toxicology consultant to DuPont) stated that in his opinion the
microscopic sections of the eyes from all the dogs in this 1-year study
had a serious fixation artifact that affected all sections examined such
that only prominent degeneration was detectable, and as a consequence, a
no-effect level could not be reliably determined with any degree of
confidence (1).  Based on this statement (and additional similar
statements) by Dr. Heywood in his report to DuPont (MRID 44946216), the
HIARC concluded that this fixation artifact, which was also briefly
mentioned in the report on this study by the testing laboratory, may
have had a profound effect on the interpretation of the
histopathological findings in the eyes of all dogs in this study.  In
view of the considerable uncertainty relating to the microscopic
findings in the eyes of all dogs in this study and the resulting
uncertainty with regard to determining a NOAEL for eye effects,
particularly since the histopathological findings were observed to be
more sensitive than the clinical findings in the 13-week feeding study
on dogs, the HIARC decided to not use the results from this 1-year study
for the purpose of determining a cRfD for famoxadone at this time.  In
order to resolve these uncertainties, HIARC strongly recommends that
DuPont convene a Pathology Working Group (PWG), in full accordance with
the provisions specified in EPA Pesticide Regulation (PR) Notice 94-5,
and report the results to EPA for its further evaluation of this study. 
Requiring the 1-year feeding study in dogs be repeated was also
considered by HIARC, but a decision on this requirement was deferred
pending submission by DuPont of the PWG report and of mechanistic
studies designed to elucidate the mechanism of action of famoxadone in
the eyes of dogs and other species (see below).

Based on a consideration of both clinical examination findings and
histopathological findings in the eyes of dogs in both the 13-week and
1-year feeding studies, the HIARC determined that the lowest dose at
which evidence of cataracts was actually observed (the LOAEL) was in the
female dogs in the 13-week study at the dose of 1.4 mg/kg/day, at which
dose treatment-related histopathological findings, but not clinical
examination findings, were observed at 13 weeks.  The HIARC was not able
at this time to establish a NOAEL for cataracts in the eyes of dogs in
either the 90-day or 1-year feeding studies.

The HIARC also considered additional information available to them
relating to eye cataracts in dogs and other species (including monkeys
and humans), various mechanisms of action of known cataractogenic agents
and other pertinent information on the potential relevance of eye
cataracts in dogs to risk assessment in humans.  Much of the information
was submitted by DuPont and included reports and discussions by Ralph
Heywood (toxicology consultant to DuPont) (1) and by Susan MacKenzie
(DuPont toxicologist)(2).  Documents prepared by the European
Commission, Health & Consumer Protection Directorate-General (3) and by
the European Commission, Directorate-General Health & Consumer
Protection (4) during their evaluation of the toxicological properties
of famoxadone prior to its being registered in many European countries
were considered (both documents were provided to EPA by DuPont). 
Finally, comments by Dr. John Pletcher (consulting pathologist to
HED/EPA) (5); and pertinent information from the general literature and
various other sources were also considered. 

Famoxadone did not induce cataracts in the eyes of rats, mice, or
Cynomolgus monkeys in subchronic and/or chronic studies at the doses
tested.  Based on the findings in these studies, DuPont believes the
effect in dog eyes is a species-specific effect and therefore is not
relevant to the assessment of risk in humans.  However, the
cataractogenic mechanism of action of famoxadone is unknown and DuPont
provided no mechanistic studies to support the claim of species
specificity other than comparative metabolism studies in rats and dogs
in which no biologically significant qualitative differences were
observed in absorption, distribution, metabolism, or excretion (other
than a somewhat longer half-life of Famoxadone in the body of dogs as
compared to rats).  Since the biochemical mechanism of action of
Famoxadone is inhibition of the mitochondrial respiratory chain at
Complex III, resulting in a decreased production of ATP by the cell,
DuPont has hypothesized that in dogs reduction of cellular ATP might
increase lens hydration or increase susceptibility of the eye to
oxidative stress and lead to cataract formation, but there is no
experimental evidence to support this hypothesis.  Therefore, HIARC
concluded that there is insufficient data/information available at this
time to support a species specific effect for induction of cataracts in
dogs.  In this regard, HIARC strongly recommends that DuPont perform
mechanistic studies designed to elucidate the mechanism of action of
famoxadone in dogs and other species and provide additional plausible
evidence and rationale, if possible, to support the possible species
specificity of this chemical in dogs.  In the interim, since there are
no mechanistic data on famoxadone that supports DuPont’s belief that
the cataracts observed in the eyes of dogs are a species-specific
effect, the possibility that famoxadone may induce cataracts in humans
after repeated exposures cannot be dismissed and this effect is
considered by HIARC to be relevant to the assessment of risk in humans
at this time.  It is noted that these conclusions by HIARC are fully
consistent with the conclusions previously reached by the European
Commission regarding species specificity and relevance of the eye
findings in dogs to the assessment of risk to humans.

870.3200	21/28-Day Dermal Toxicity – Rat

870.3465	90-Day Inhalation – Rat

A.3.2	Pre-natal Developmental Toxicity

870.3700a Pre-natal Developmental Toxicity Study – Rat

870.3700b Pre-natal Developmental Toxicity Study – Rabbit

A.3.3	Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

A.3.4	Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

MRID No.  44302430

Executive Summary:  In a combined chronic toxicity/carcinogenicity study
(MRIDs 44302430, 44946212, 44302431 and  44946213), DPX-JE874 technical
(97.4% a.i.; Batch #:  DPX-JE874-221) was administered in the diet to 92
Crl:CD®BR rats/sex/group at nominal doses of  0, 10, 40, 200, or 400
ppm (equal to 0/0, 0.42/0.53, 1.62/2.15, 8.37/10.7, and 16.8/23.0
mg/kg/day [M/F], respectively).  At approximately 2 weeks and again at 1
year, 10 rats/sex/dose were sacrificed and a subset evaluated for
hepatic cellular proliferation (5 males/dose and 5 controls of each sex
and 5 high-dose females) or hepatic peroxisomal β-oxidation activity
and cytochrome P450 content (5 rats/sex/dose).  In addition, 10
rats/sex/dose were sacrificed at 1 year (interim sacrifice).  All
surviving male rats were sacrificed at 23 months and all surviving
female rats at 24 months.   

Mortality, clinical signs, food consumption, ophthalmoscopic findings,
clinical chemistry parameters, urinalysis and organ weights for both
sexes at all doses were unaffected by treatment. No treatment-related
adverse differences in any parameter were observed in the 10, 40, or 200
ppm males or in the 10 or 40 ppm females.

In the 400 ppm males, decreased (p<0.05) erythrocytes and increased
(p<0.05) reticulocytes, mean corpuscular volume, and mean corpuscular
hemoglobin were observed at up to 12 months.  These hemolytic changes
were accompanied by increased incidences of extramedullary
hematopoiesis, macrophage pigment and congestion in the spleen and of
mixed hyperplasia in the bone marrow at the 1 year sacrifice.  Minimal
changes indicative of hepatotoxicity were also observed in the 400 ppm
males at 1 year.  At the 1- and 2-year sacrifices, significant  (p<0.05)
trends in the incidence of several liver microscopic findings were
observed including an increased incidence of focal cystic degeneration,
focal hepatocellular degeneration, eosinophilic focus of cellular
alteration (some moderate in severity) and centrilobular hypertrophy at
the 1-year sacrifice; and an increased incidence of eosinophilic focus
of cellular alteration and centrilobular hypertrophy at the 2-year
sacrifice.  Focal hepatocellular degeneration was only minimally
increased over controls at the 2-year sacrifice.  In addition at the
1-year sacrifice, there was an increase (p<0.05) in the rate of hepatic
peroxisomal β-oxidation in the 400 ppm males ((69%); the rate was also
increased in the 200 ppm males ((40%), but the difference was not
statistically significant.  The rate of  β-oxidation was not determined
at 2 years.  However, an increased incidence of liver tumors was not
observed.  In addition, the BrdU labeling index assay indicated a lack
of sustained increase in hepatocellular proliferation in the males.  At
approximately 2 weeks, an increase (p<0.05) compared to controls in the
BrdU labeling index was observed in the 400 ppm males ((864%).  At the
1-year sampling interval, an increase was also observed ((109%) at the
high-dose, but the difference was less pronounced than at the 2-week
interval and it was not statistically significant.   

In the 400 ppm females, decreased (p<0.05) mean body weight, mean
cumulative body weight gains and food efficiency were generally observed
throughout the study.  Decreased (p<0.05) erythrocytes, hemoglobin and
hematocrit, indicative of a slight anemia were observed at up to 18
months.  In addition, increased (p<0.05) reticulocytes were noted at 3
months.  Grossly at the 2-year sacrifice, an increased incidence of
liver discoloration was observed.  There were significant (p<0.05)
trends in the incidence of microscopic findings in the liver of these
females including: increased Kupffer cell pigment (hemosiderin) and
centrilobular hypertrophy observed at the 1-year sacrifice; and
apoptosis, focal hepatocellular degeneration and centrilobular
hypertrophy observed at the 2-year sacrifice.  There was an increase
(p<0.05) in total hepatic cytochrome P450 content in the 400 ppm females
at 1 year, which correlated with increased hepatocellular hypertrophy
observed in these animals at the 1-year sacrifice.

In the 200 ppm females, mean cumulative body weight gain was decreased
10% below that of the control group over the duration of the study (days
0-713).  Although not statistically significant, this decrease is
considered to be a treatment-related adverse effect.  Signs of slight
hemolytic anemia were also observed at various times during the first 6
months of the study in the 200 ppm females.  These signs included
decreased (p<0.05) erythrocytes (also noted at 18 months), hemoglobin,
hematocrit and mean corpuscular volume.  Although not associated with
secondary microscopic findings indicating anemia, these effects were
nevertheless considered to be treatment-related adverse findings.  At
the 1 year sacrifice, increased hepatic cytochrome P-450 content and an
increased incidence of hepatocellular hypertrophy were also observed,
but were considered to be an adaptive hepatocellular response and not an
adverse effect.

The LOAEL for males is 400 ppm (equal to 16.8 mg/kg/day) based on slight
hemolytic anemia with compensatory erythropoiesis and microscopic
changes (focal cystic degeneration, focal hepatocellular degeneration,
and eosinophilic foci of cellular alteration) observed in the liver. 
The LOAEL for females is 200 ppm (equal to 10.7 mg/kg/day) based on
decreased body weight gain and slight hemolytic anemia.  Other
treatment-related effects observed at 400 ppm in males and at 400 and
200 ppm in females were either secondary responses to the hemolytic
anemia (in males) or adaptive hepatocellular responses indicating a
physiological stimulation of the liver enzyme system (in males and
females).  The NOAEL is 200 ppm in males (equal to 8.37 mg/kg/day) and
is 40 ppm in females (equal to 2.15 mg/kg/day).

When all animals were combined excluding those sacrificed after 1 year,
there was a significant  (p<0.05) dose-related trend in the incidence of
testicular interstitial cell adenomas (Leydig cell adenoma); an
increased incidence of testicular adenomas was observed in the 400 ppm
males (3/62 treated vs 0/62 controls [4.8% treated]); the incidence was
just within the historical control range (0-4.9%).  There was no
increased incidence of interstitial cell hyperplasia, and the incidence
of adenomas in the 400 ppm males (4.8%) was not significantly increased
when compared to the historical control mean (2.6%).

Under the conditions of this study, a treatment-related increased
incidence of tumors was not observed in either the male or female rats. 

This combined chronic toxicity/carcinogenicity study in the rats is
Acceptable/Guideline and satisfies the guideline requirement for a
combined chronic toxicity/carcinogenicity study (OPPTS 870.4300/OECD
453) in rats. 

Discussion of Tumor Data:  Under the conditions of this study, a
treatment-related increased incidence of tumors was not observed in
either the male or female rats.

Adequacy of the Dose Levels Tested:  The dose levels tested in this
study (highest dose tested = 400 ppm; equal to 16.8 mg/kg/day in males
and to 23.0 mg/kg/day in females) are considered adequate to assess the
carcinogenic potential of Famoxadone in male and female rats.  

In male rats at 400 ppm (16.8 mg/kg/day), the following
treatment-related effects were observed during the first 12 months of
the study: decreased erythrocytes (10-14%), decreased hematocrit (9%)
and increased reticulocytes (67-97%); hyperplasia of the bone marrow;
extramedullary hematopoiesis and increased macrophage pigment in the
spleen; increased focal cystic degeneration, focal hepatocellular
degeneration and eosinophilic foci of cellular alteration in the liver;
and signs of adaptive hepatocellular response including increased
hepatocellular hypertrophy and induction of hepatic beta-oxidation.  At
termination of the study at 2 years, the previously observed anemia (and
secondary effects in bone marrow and spleen) were no longer evident, but
signs of hepatotoxicity including increased focal hepatocellular
degeneration and eosinophilic foci of cellular alteration, remained as
did increased hepatocellular hypertrophy.   

In female rats at 400 ppm (23.0 mg/kg/day), the following
treatment-related effects were observed throughout the study: decreased
body weight (4-18%), decreased body weight gain (13-25%) and decreased
food efficiency (9-25%).  In addition, the following treatment-related
effects were observed during the first 12-18 months of the study:
decreased erythrocytes (8-17%), decreased hematocrit (8-11%), and
decreased hemoglobin (6-11%); increased Kupffer cell pigment in the
liver; and signs of adaptive hepatocellular response including increased
hepatocellular hypertrophy and induction of hepatic P-450 enzymes.  At
termination of the study at 2 years, the previously observed anemia (and
secondary effects in the liver) were no longer evident, but signs of
hepatotoxicity including increased focal hepatocellular degeneration and
apoptosis were observed as well as increased hepatocellular hypertrophy.
  

Additional support for the adequacy of the dose levels employed in the
2-year study in rats is provided in the 13-week study in rats.  In the
13-week study, the LOAEL for male rats was 200 ppm (13.0 mg/kg/day),
based on mild hemolytic anemia and decreased serum glucose.  At the next
higher dose level of 800 ppm (52.1 mg/kg/day), the following additional
treatment-related effects were observed: decreased body weight, body
weight gain, food consumption, and food efficiency; compensatory
erythropoiesis and secondary responses to anemia in the bone marrow and
spleen; increased alkaline phosphatase, alanine aminotransferase,
aspartate aminotransferase, and sorbitol dehydrogenase; increased serum
bilirubin; increased urine urobilinogen; microscopic signs of 
hepatotoxicity in the liver (focal degeneration, bile duct hyperplasia,
apoptosis); and adaptive hepatocellular responses, including
hepatocellular hypertrophy and increased hepatic peroxisomal
beta-oxidation rate,  indicating enzyme induction.  In the 13-week
study, the LOAEL for female rats was 200 ppm (16.6 mg/kg/day), based on
mild hemolytic anemia, decreased serum globulin, and adaptive
hepatocellular responses, including hepatocellular hypertrophy and
increased hepatic peroxisomal beta-oxidation rate, indicating enzyme
induction.  At the next higher dose level of 800 ppm (65.7 mg/kg/day),
the additional treatment-related effects observed were very similar to
those observed in the male rats at 800 ppm.  

870.4100b Chronic Toxicity - Dog

A.3.5	Carcinogenicity

870.4200a Carcinogenicity Study – Rat

870.4200b Carcinogenicity (feeding) – Mouse

MRID No.: 44302424

 for hepatic cellular proliferation; and 5 mice/sex/dose were evaluated
for hepatic peroxisomal β-oxidation activity and cytochrome P450
content.  All surviving mice were sacrificed at 18 months.

Overall mortality, clinical signs, body weight, body weight gains, food
consumption, food efficiency, ophthalmoscopic findings and hematological
parameters for both sexes at all doses were unaffected by treatment.  
No adverse treatment-related differences in any parameter were observed
in the 5 and 50 ppm groups.   

A trend (p<0.05) in the incidence of amyloid deposition was observed in
many organs in the females.  A treatment-related increased incidence of
amyloid was observed in the skin, kidneys and some of the organs of the
digestive, reproductive, glandular, hematopoietic, circulatory, and
endocrine organ systems of the 2000 ppm females.  In addition, there was
a significant trend (p<0.05) in the incidence of mortality due to
amyloidosis in the females (13% mortality in the 2000 ppm females vs
3-5% in the controls and other treated females).

Differences in liver weights, and gross and microscopic changes
indicated treatment-related slight hepatotoxicity in the 2000 ppm male
and female animals.  An increase (p<0.05) in absolute and relative (to
body and brain) liver weights were observed in the males ((28-30%) and
females((52-57%). Grossly, a minimal increase in the incidence of large,
discolored livers was also observed in the males (10-23% treated vs
0-17% controls) and females (12-15% treated vs 3-5% controls). At the
terminal sacrifice, statistically significant (p<0.05) trends in the
incidence of several histopathological findings were observed in the
liver.  In the 2000 ppm males, increased incidences of minimal to mild
centrilobular hypertrophy (93% treated vs 0% controls) and minimal
increased Kupffer cell pigment (lipofuscin and hemosiderin; 43% treated
vs 15% controls) were observed.  Minor increases in the incidence of
focal necrosis, generally minimal (23% treated vs 10% controls) and
minimal diffuse fatty change (7% treated vs 0% controls) were also
observed in the high-dose males.  In the females, minimal to mild
centrilobular/panlobular hypertrophy (28-50% vs 0-2% controls) was
observed.  Minimal to moderate increased Kupffer cell pigment (72%
treated vs 43% controls) and minor increases in the incidence of minimal
apoptosis and sinusoidal dilation and mild to moderate central necrosis
(3-10% treated vs 0-2% controls) were also observed.  

In the 700 ppm group, increased (p<0.05) absolute and relative (to body
and brain) liver weights and increased (p<0.05) incidences of
centrilobular/panlobular hypertrophy were observed.  These findings were
considered adaptive changes to treatment with DPX-JE874.

The BrdU labeling index assay showed no statistically significant
increases in hepatic cellular proliferation.  Induction of hepatic
peroxisomes and total P450 was observed in the 700 and 2000 ppm males
and females at 2 weeks and 9 months.  The differences (p<0.05) from
controls in β-oxidation and total hepatic P450 content at 2 weeks did
not increase in magnitude at the 9 month interval.  These findings
correlated to the increases in liver weights and hepatocellular
hypertrophy observed in the 700 ppm group and the increase in liver
weights, and increased incidence of gross and microscopic liver findings
in the 2000 ppm group.

The Sponsor submitted a supplement (MRID44946211) to the carcinogenicity
study in which the adequacy of the selection of 2000 ppm as the
high-dose level for male mice is discussed. The Sponsor stated that
retrospective analysis of the data suggested that 3500 ppm would likely
have been tolerated by the male mice as the highest dose level for the
carcinogenicity study.  It was also stated that the data from the 14-,
28- and 90-day studies indicated a plateau for effects on hepatic
biochemical parameters and hepatocellular injury at (2000 ppm. 
According to the Sponsor, the plateau effect suggests that the toxicity
profile in male mice dosed at 3500 ppm would not have been markedly
different from male mice dosed at 2000 ppm.  The Sponsor then concluded
that 2000 ppm was the appropriate high dose to assess oncogenicity in
male mice.  The reviewers do not agree with the Sponsor.  The short-term
studies indicated that a dose of 3500 ppm should have been selected for
the male mice in the carcinogenicity study.  Only slight signs of
hepatotoxicity were observed in the 2000 ppm males in the
carcinogenicity study indicating that a higher dose would have been
appropriate.

The LOAEL for males is 2000 ppm (equal to 274 mg/kg/day) based on slight
hepatotoxicity, including focal necrosis, diffuse fatty change and
increased Kupffer cell lipofuscin pigment.  The NOAEL for males is 700
ppm (equal to 96 mg/kg/day).  The LOAEL for females is 2000 ppm (equal
to 392 mg/kg/day) based on an increased incidence of amyloidosis and
slight hepatotoxicity, including apoptosis and increased Kupffer cell
lipofuscin pigment.  The NOAEL for females is 700 ppm (equal to 130
mg/kg/day).  

At the doses tested, there were no treatment-related increases in tumor
incidence when compared to controls.  Dosing was considered just barely
adequate in the males.  Only slight hepatotoxicity was observed in the
2000 ppm males.  Dosing was considered adequate in the females based on
an increased incidence of amyloidosis and slight hepatotoxicity. 

This carcinogenicity study in the mouse is Acceptable/Guideline and does
satisfy the guideline requirement for a carcinogenicity study [OPPTS
870.4200b/OECD 451] in male and female mice.  It appears, however, that
the male mice could have tolerated a higher dose. 

Discussion of Tumor Data:  At the doses tested, there were no
treatment-related increases in tumor incidence when compared to
controls.  

Adequacy of the Dose Levels Tested:  The dose levels tested in this
study for the female mice (highest dose tested = 2000 ppm; equal to 392
mg/kg/day) are considered adequate to assess the carcinogenic potential
of famoxadone.  In female mice at 2000 ppm (392 mg/kg/day), a
treatment-related increased incidence of amyloid deposition was observed
in the skin, kidneys and numerous organs of the digestive, reproductive,
glandular, hematopoietic, circulatory, and endocrine systems.  There was
also a significant trend (p<0.05) in the incidence of mortality due to
amyloidosis in the females (13% mortality in the 2000 ppm females vs
3-5% in the controls and other treated females).  In addition, slight
hepatotoxicity (slightly increased incidences of apoptosis, and
increased Kupffer cell lipofuscin pigment) was observed in the liver of
the female mice at 2000 ppm.  In this study at dose levels of 700 ppm
(130 mg/kg/day) and higher, adaptive hepatocellular responses indicating
enzyme induction were also observed, but these adaptive responses were
not considered to be adverse.   

The dose levels tested in this study for the male mice (highest dose
tested = 2000 ppm; equal to 274 mg/kg/day) are considered to be just
barely adequate to assess the carcinogenic potential of famoxadone.  In
male mice at 2000 ppm (274 mg/kg/day), the only toxicologically
significant treatment-related effect was slight hepatotoxicity as
evidenced by slightly increased incidences of focal necrosis (23% vs 10%
in controls), diffuse fatty change (7% vs 0% in controls), foci of
eosinophilic cellular alteration (10% vs 0% in controls), and increased
Kupffer cell lipofuscin pigment (43% vs 15% in controls).  In this study
at dose levels of 700 ppm (96 mg/kg/day) and higher, adaptive
hepatocellular responses indicating enzyme induction were also observed,
but these adaptive responses were not considered to be adverse.  No
anemia was observed in the male mice in this study.  Based on results in
previously conducted 14-, 28- and 90-day studies in male mice, a highest
dose level of greater than 2000 ppm probably should have been selected
for the male mice in this carcinogenicity study.  In the 90-day study,
the NOAEL for male mice was 350 ppm (62.4 mg/kg/day) and the LOAEL was
3500 ppm (534 mg/kg/day), based on mild hemolytic anemia with secondary
responses (increased hemosiderin) in the spleen, and mild hepatotoxicity
in the liver (single cell necrosis, focal necrosis, diffuse fatty
change, and increased bile pigment).  In this 90-day study at dose
levels of 350 ppm (62.4 mg/kg/day) and higher, adaptive hepatocellular
responses indicating enzyme induction were also observed, but these
adaptive responses were not considered to be adverse.  Clinical
chemistries other than plasma protein were not performed in the 90-day
study, but in the 14-day study clinical chemistries were performed and
in this study at a dose level of 3500 ppm, the following serum enzymes
were increased: alkaline phosphatase (71%), sorbital dehydrogenase
(41%), and alanine aminotransferase (54%).  In the 28-day study, at dose
levels of 2000, 2500 and 3000 ppm, alkaline phosphatase was increased at
14 and 28 days and adaptive hepatocellular responses were also observed
at these same dose levels.  Alkaline phosphatase was also slightly
increased at 500 and 1000 ppm in this study (at 14 days only).  Overall,
mild, but toxicologically significant, hemolytic anemia and
hepatotoxicity were observed at a dose level of 3500 ppm in these
studies.  At lower dose levels, the hepatotoxicity observed, although
treatment-related, was probably not toxicologically significant. 

HED concluded that under the conditions of this study, there was no
biologically significant evidence of carcinogenic potential of the test
substance.

A.3.6	Mutagenicity

Although famoxadone may have a weak mutagenic potential, this potential
is not considered to be toxicologically significant at this time.  In 3
gene mutation studies, results were negative without and with rat S-9
activation in a reverse gene mutation study using S. typhimurium/E. coli
and in 2 forward gene mutation studies using CHO cells at the HGPRT
locus.  In 3 chromosome studies, a weak clastogenic effect (increased
percentage of aberrant cells) was observed in 2 separate in vitro
chromosomal aberration studies in human lymphocytes when tested without
rat S-9 activation.  When tested with rat S-9 activation, a clastogenic
effect was not observed.  In an in vivo micronucleus study in mice using
bone marrow cells, the results were negative.  In 4 other mutagenicity
studies, although a positive response (increased net nuclear grain
counts) was observed in an in vitro unscheduled DNA synthesis assay in
primary rat hepatocyte cultures, results in 2 repeat studies were
negative.  Also, results in an in vivo/in vitro UDS assay in primary rat
hepatocyte cultures derived from male rats given oral doses of
famoxadone were negative. 

A.3.7	Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen: Not Required

870.6200 Acute Neurotoxicity Screening Battery:  Not Required

870.6200 Subchronic Neurotoxicity Screening Battery:  Not Required

870.6300 Developmental Neurotoxicity Study:  Not Required

A.3.8	Metabolism

870.7485	Metabolism – Rat

In metabolism studies in rats, famoxadone was rapidly absorbed, but only
about 40% of the administered dose (AD) was absorbed. Most of the AD
(87-96%) was eliminated in the feces within 24 hours; very little
(3-12%) was eliminated in the urine. Less than 1% remained in the
tissues after 120 hours. Unchanged parent (51-84% of AD) and two
hydroxylated metabolites (IN-KZ534 and IN-KZ007) were the major
components recovered in the feces. No unchanged parent was found in the
urine. An enterohepatic circulation (about 30-39% of the AD) was
observed; glucuronide and sulfate conjugates of eight components
(including IN-KZ532 and IN-ML815) were identified in the bile. No
significant qualitative or quantitative differences were observed for
sex, dose level, or repeated dosing.  

870.7600	Dermal Absorption – Rat

Dermal Absorption Factor:   5% 

A dermal absorption study is not available.  The percent dermal
absorption is estimated by comparing the LOAEL for male rats from a
28-day dermal study (MRID 44946209) to the LOAEL for male rats from a
specially designed 28-day feeding study (MRID 44946207). 

The LOAEL for male rats from the 28-day dermal study was 500 mg/kg/day,
based on increased alkaline phosphatase, alanine aminotransferase, and
sorbitol dehydrogenase; and mild hepatotoxicity in the liver (apoptosis,
increased mitotic figures).  Also at 500 mg/kg/day, adaptive
hepatocellular responses indicating enzyme induction were observed
(increased liver weight, hepatocellular hypertrophy).  The LOAEL for
male rats in this study appeared to be close to a threshold dose level. 
A LOAEL for female rats was not observed in this study (LOAEL >1000
mg/kg/day, highest dose tested, limit dose).   

The 28-day feeding study in rats was performed after the 90-day feeding
study in rats (MRID 44302415) and was specially designed to help predict
the threshold for liver cytotoxicity and to assist in determining
appropriate dose levels for the chronic/carcinogenicity study in rats. 
Accordingly, data on body weight, clinical signs of toxicity, and serum
activities of liver-specific enzymes and serum concentration of
triglycerides were measured, but data on other standard toxicology
endpoints were not collected since these endpoints were evaluated in the
previously conducted 90-day study (e.g. food consumption, hematology,
gross pathology, organ weights and microscopic pathology).  In this
28-day study, the NOAEL for male rats was 300 ppm and the LOAEL was 400
ppm, based on increased alkaline phosphatase, alanine aminotransferase,
aspartate aminotransferase and sorbitol dehydrogenase.  The LOAEL of 400
ppm was estimated to be equivalent to 25 mg/kg/day, based on data from
the 90-day study.  

  LOAEL from 28-day feeding study          =       25 mg/kg/day    x  
100   =    5% 

  LOAEL from 28-day dermal study           =     500 mg/kg/day 

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endpoints between the results in the 28-day dermal study and the 45-day
time point in the 90-day feeding study are, in fact,  the increases in
liver-specific enzymes (which were substantially increased at the
“LOAEL” of 800 ppm or 52.1 mg/kg/day, but not increased at the
“NOAEL” of 200 ppm).  Since the same liver-specific enzymes were
increased in the 28-day feeding study (at the LOAEL of 400 ppm or 25
mg/kg/day, but not at the NOAEL of 300 ppm), and this LOAEL appeared to
be close to the threshold dose level, as in the dermal study, it was
concluded the results in the 28-day feeding study more closely mimicked
the results in the 28-day dermal study than did the results in the
90-day feeding study. 

Appendix B:  Metabolism Assessment

  TC \l1 "Appendix B:  Metabolism Assessment 

In metabolism studies in rats, famoxadone was rapidly absorbed, but only
about 40% of the administered dose (AD) was absorbed. Most of the AD
(87-96%) was eliminated in the feces within 24 hours; very little
(3-12%) was eliminated in the urine. Less than 1% remained in the
tissues after 120 hours. Unchanged parent (51-84% of AD) and two
hydroxylated metabolites (IN-KZ534 and IN-KZ007) were the major
components recovered in the feces. No unchanged parent was found in the
urine. An enterohepatic circulation (about 30-39% of the AD) was
observed; glucuronide and sulfate conjugates of eight components
(including IN-KZ532 and IN-ML815) were identified in the bile. No
significant qualitative or quantitative differences were observed for
sex, dose level, or repeated dosing.  In a metabolism study in dogs, no
biologically significant qualitative differences were observed between
rats and dogs in absorption, distribution, metabolism, or excretion
(other than a somewhat longer half-life of famoxadone in the body of
dogs as compared to rats).   

Appendix C:  Tolerance Reassessment Summary and Table

See Table 10.0. TC \l1 "Appendix C:  Tolerance Reassessment Summary and
Table 

Appendix D:  Review of Human Research

No MRID - PHED Surrogate Exposure Guide

Appendix E:	International Residue Limit Status

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

 Other	Date:  1/31/2008

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

 No Codex proposal step 6 or above

  No Codex proposal step 6 or above for the crops requested	Petition
Number:  7E7280

DP#:   349184

Other Identifier:  

Residue definition (step 8/CXL):  famoxadone	Reviewer/Branch:  W.
Cutchin/ARIA

	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	Leafy greens, subgroup 4A	50

Grapes	2	Cilantro, leaves	50

Vegetable, bulb, group 3	40

Chive, fresh leaves	40

Chive, Chinese, fresh leaves	40

Daylily, bulb	40

Elegans hosta	40

Fritarillia, bulb	40

Fritarillia, leaves	40

Garlic, Serpent, bulb	40

Kurrat	40

Lady’s Leek	40

Leek, wild	40

Lily, bulb	40

Onion, Beltsville bunching	40

Onion, Chinese, bulb	40

Onion, fresh	40

Onion, macrostem	40

Onion, pearl	40

Onion, potato, bulb	40

Onion, tree, tops	40

Shallot, bulb	40

Shallot, fresh leaves	40

Limits for Canada	Limits for Mexico

X   No Limits

@

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؀   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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