Document ID: EPA-HQ-OPP-2007-0940-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-09-10T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		July 10, 2008 

SUBJECT:	Fludioxonil.  Human Health Risk Assessment for Section 3
Tolerances on Avocado, Carrot, Cucurbit, Lemon, Parsley, Radish, Sweet
Potato, Tomato, and Brassica Vegetables.  

PC Code:  071503	DP Barcode: 342827

Decision No.:  380887	Registration No.:  100-953

Petition No.:  7E7234	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical Human 

Health Risk Assessment	Case No.:  NA

TXR No.:  NA	CAS No.:  137-26-8

MRID No.:  NA	40 CFR:  §180.516

FROM:	Breann Hanson, Biologist 

		Alternative Risk Integration and Assessment (ARIA) Team

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

THROUGH:	John Redden, Team Leader 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		

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

		Robert Mitkus, Ph.D., Toxicologist 

		Dana Vogel, Branch Chief

		Registration Action Branch 1 (RAB 1)

		Health Effects Division (HED) (7509P)

TO:		Sidney Jackson/Barbara Madden, RM Team 05

		RIMUERB/RD (7505P)

ARIA of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that 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 the registered and proposed uses of fludioxonil
(4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile)
formulated as Switch™ 62.5 WG (water dispersible granule; 37.5%
cyprodinil and 25% fludioxonil; EPA Registration Number 100-953). The
Inter-regional Research Project No. 4 (IR-4) proposed Section 3
registrations for application of fludioxonil.  The registrant, Syngenta,
has also responded to conditions for the registration of fludioxonil on
carrots and Brassica vegetables by submitting additional residue data.

A summary of the findings and an assessment of human-health risk
resulting from the proposed uses of fludioxonil are provided in this
document.  The risk assessment and dietary exposure assessments were
prepared by Breann Hanson (ARIA), the occupational/residential exposure
assessment by M. Dow (ARIA), the residue chemistry assessment by William
Cutchin (ARIA) and the drinking water assessment by Cheryl Sutton of the
Environmental Fate and Effects Division (EFED).

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc203455676"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc203455676 \h  5  

  HYPERLINK \l "_Toc203455677"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc203455677 \h  14  

  HYPERLINK \l "_Toc203455678"  2.1	Summary of Proposed Use	  PAGEREF
_Toc203455678 \h  14  

  HYPERLINK \l "_Toc203455679"  2.2	Structure and Nomenclature	  PAGEREF
_Toc203455679 \h  14  

  HYPERLINK \l "_Toc203455680"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc203455680 \h  14  

  HYPERLINK \l "_Toc203455681"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc203455681 \h  15  

  HYPERLINK \l "_Toc203455682"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc203455682 \h  15  

  HYPERLINK \l "_Toc203455683"  3.1.1	Database Summary	  PAGEREF
_Toc203455683 \h  16  

  HYPERLINK \l "_Toc203455684"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc203455684 \h  16  

  HYPERLINK \l "_Toc203455685"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc203455685 \h  16  

  HYPERLINK \l "_Toc203455686"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc203455686 \h  17  

  HYPERLINK \l "_Toc203455687"  3.1.2	Dose-response	  PAGEREF
_Toc203455687 \h  17  

  HYPERLINK \l "_Toc203455688"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc203455688 \h  18  

  HYPERLINK \l "_Toc203455689"  3.3	FQPA Considerations	  PAGEREF
_Toc203455689 \h  18  

  HYPERLINK \l "_Toc203455690"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc203455690 \h  18  

  HYPERLINK \l "_Toc203455691"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc203455691 \h  18  

  HYPERLINK \l "_Toc203455692"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc203455692 \h  19  

  HYPERLINK \l "_Toc203455693"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc203455693 \h  19  

  HYPERLINK \l "_Toc203455694"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc203455694 \h  19  

  HYPERLINK \l "_Toc203455695"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc203455695 \h  19  

  HYPERLINK \l "_Toc203455696"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc203455696 \h  19  

  HYPERLINK \l "_Toc203455697"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc203455697 \h  20  

  HYPERLINK \l "_Toc203455698"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc203455698 \h  20  

  HYPERLINK \l "_Toc203455699"  3.5.1    Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc203455699 \h  20  

  HYPERLINK \l "_Toc203455700"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc203455700 \h  20  

  HYPERLINK \l "_Toc203455701"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc203455701 \h  20  

  HYPERLINK \l "_Toc203455702"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc203455702 \h  20  

  HYPERLINK \l "_Toc203455703"  3.5.5	Dermal Absorption	  PAGEREF
_Toc203455703 \h  21  

  HYPERLINK \l "_Toc203455704"  3.5.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc203455704 \h  21  

  HYPERLINK \l "_Toc203455705"  3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc203455705 \h  21  

  HYPERLINK \l "_Toc203455706"  3.5.8	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc203455706 \h  21  

  HYPERLINK \l "_Toc203455707"  3.5.9	Classification of Carcinogenic
Potential	  PAGEREF _Toc203455707 \h  21  

  HYPERLINK \l "_Toc203455708"  3.5.10	Summary of Fludioxonil
Toxicological Doses/Endpoints for Use in Risk Assessments	  PAGEREF
_Toc203455708 \h  22  

  HYPERLINK \l "_Toc203455709"  3.6	Endocrine disruption	  PAGEREF
_Toc203455709 \h  23  

  HYPERLINK \l "_Toc203455710"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc203455710 \h  23  

  HYPERLINK \l "_Toc203455711"  4.1	Incident Reports	  PAGEREF
_Toc203455711 \h  23  

  HYPERLINK \l "_Toc203455712"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc203455712 \h  23  

  HYPERLINK \l "_Toc203455713"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc203455713 \h  23  

  HYPERLINK \l "_Toc203455714"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc203455714 \h  23  

  HYPERLINK \l "_Toc203455715"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc203455715 \h  24  

  HYPERLINK \l "_Toc203455716"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc203455716 \h  24  

  HYPERLINK \l "_Toc203455717"  5.1.4	Analytical Methodology	  PAGEREF
_Toc203455717 \h  24  

  HYPERLINK \l "_Toc203455718"  5.1.5	Environmental Degradation	 
PAGEREF _Toc203455718 \h  24  

  HYPERLINK \l "_Toc203455719"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc203455719 \h  25  

  HYPERLINK \l "_Toc203455720"  5.1.7	Drinking Water Residue Profile	 
PAGEREF _Toc203455720 \h  25  

  HYPERLINK \l "_Toc203455721"  5.1.8	Food Residue Profile	  PAGEREF
_Toc203455721 \h  26  

  HYPERLINK \l "_Toc203455722"  5.1.9	International Residue Limits	 
PAGEREF _Toc203455722 \h  30  

  HYPERLINK \l "_Toc203455723"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc203455723 \h  30  

  HYPERLINK \l "_Toc203455724"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc203455724 \h  31  

  HYPERLINK \l "_Toc203455725"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc203455725 \h  31  

  HYPERLINK \l "_Toc203455726"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc203455726 \h  32  

  HYPERLINK \l "_Toc203455727"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc203455727 \h  32  

  HYPERLINK \l "_Toc203455728"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc203455728 \h  33  

  HYPERLINK \l "_Toc203455729"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc203455729 \h  33  

  HYPERLINK \l "_Toc203455730"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc203455730 \h  34  

  HYPERLINK \l "_Toc203455731"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc203455731 \h  34  

  HYPERLINK \l "_Toc203455732"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc203455732 \h  34  

  HYPERLINK \l "_Toc203455733"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc203455733 \h  35  

  HYPERLINK \l "_Toc203455734"  7.4	Chronic Aggregate Risk	  PAGEREF
_Toc203455734 \h  36  

  HYPERLINK \l "_Toc203455735"  7.5	Cancer Aggregate Risk	  PAGEREF
_Toc203455735 \h  36  

  HYPERLINK \l "_Toc203455736"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc203455736 \h  36  

  HYPERLINK \l "_Toc203455737"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc203455737 \h  37  

  HYPERLINK \l "_Toc203455738"  9.1	Occupational Handler Risk	  PAGEREF
_Toc203455738 \h  38  

  HYPERLINK \l "_Toc203455739"  9.2	Occupational Post-Application Risk	 
PAGEREF _Toc203455739 \h  39  

  HYPERLINK \l "_Toc203455740"  10.0	TOLERANCE SUMMARY	  PAGEREF
_Toc203455740 \h  39  

  HYPERLINK \l "_Toc203455741"  11.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc203455741 \h  40  

  HYPERLINK \l "_Toc203455742"  Appendix A:      TOXICOLOGY ASSSESSMENT	
 PAGEREF _Toc203455742 \h  44  

  HYPERLINK \l "_Toc203455743"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc203455743 \h  44  

  HYPERLINK \l "_Toc203455744"  A.2	Toxicity Profiles	  PAGEREF
_Toc203455744 \h  45  

  HYPERLINK \l "_Toc203455745"  A.3	Executive Summaries	  PAGEREF
_Toc203455745 \h  45  

  HYPERLINK \l "_Toc203455746"  Appendix B:	REFERENCES (in MRID order)	 
PAGEREF _Toc203455746 \h  56  

  HYPERLINK \l "_Toc203455747"  Appendix C:      REVIEW OF HUMAN
RESEARCH	  PAGEREF _Toc203455747 \h  58  

  HYPERLINK \l "_Toc203455748"  Appendix D:	INTERNATIONAL HARMONIZATION	
 PAGEREF _Toc203455748 \h  59  

  HYPERLINK \l "_Toc203455749"  Fludioxonil	  PAGEREF _Toc203455749 \h 
59  

 

1.0	EXECUTIVE SUMMARY

IR-4 submitted petitions (PP# 7E7234, 2E6462) for use of fludioxonil
(4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile)
tomato, tomatillo, avocado, black sapote, canistel, mame sapote, mango,
papaya, sapodilla, star apple, fresh herbs, dried herbs, root
vegetables, leaves of root and tuber vegetables, lemon, lime, cucurbits,
and tuberous and corm vegetables.   Fludioxonil is a contact fungicide
and is active through inhibition of protein kinase leading to reduced
growth and development.  The petitioner is proposing foliar application
of Switch™ 62.5 WG (water dispersible granule; 37.5% cyprodinil and
25% fludioxonil; EPA Registration Number 100-953) at a total of 0.22 -
0.88 lb ai/A/season for the requested commodities.  

Fludioxonil is registered for foliar application (grape, strawberry,
green onion, dry bulb onion, bushberry, caneberry, juneberry,
longonberry, pistachio, salal, and watercress), post-harvest application
(stone fruit), and for seed treatment purposes (numerous crops) with
tolerances for residues of fludioxonil ranging from 0.01 - 7.0 ppm (40
CFR 180.516(a)).  A Section 18 registration is also established for
post-harvest application to pomegranate with a tolerance for residues of
fludioxonil of 5.0 ppm (40 CFR 180.516(b)).  In addition, a tolerance of
10.0 ppm has been established for starfruit (PP#07L05) though it is not
listed in 40 CFR §180.516.  Currently there are no tolerances
established for residues of fludioxonil in/on livestock.

Proposed Tolerances

Section 3 Registrations for residues of fludioxonil were requested for
tomato; tomatillo; tomato, paste; avocado; black sapote; canistel; mamey
sapote; mango; papaya ; sapodilla; star apple; herb subgroup 19A, fresh;
herb subgroup 19A, dried; leaves of root and tuber vegetables; root
vegetables, except sugar beet subgroup; lemon; lime; cucurbits; and
tuberous and corm vegetables, except potato subgroup.

IR-4 also proposes, upon the approval of the aforementioned tolerances,
to remove established tolerances for residues of fludioxonil in or on
the following raw agricultural commodities; herb subgroup 19A, fresh;
herb subgroup 19A, dried; carrot; and turnip, greens.

Pending submission of revised Sections B and F (noted in Section 11.0),
ARIA recommends for the tolerances listed in Table 1.0, below.  The
registrations for the subject crops should be made conditional upon
resolution of the toxicology and the remaining residue chemistry data
gaps.

Table 1.0.  Tolerance Summary for Fludioxonil.

Commodity	Recommended Tolerance (ppm)	Comments (correct commodity
definition)

Tomato	0.50	Raised for harmonization issues

Tomatillo	0.50	Raised for harmonization issues

Tomato, paste	None

	Avocado 		0.45

	Black sapote 		0.45

	Canistel	0.45

	Mamey sapote	0.45

	Mango 	0.45

	Papaya 	0.45

	Sapodilla 	0.45

	Star apple 		0.45

	Herb Subgroup 19A, fresh 			10	Retain Established Tolerance

Herb Subgroup 19A, dried 			65	Retain Established Tolerance

Leaves of root and tuber vegetables	30	Leaves of root and tuber
vegetables, group 2

Root vegetables, except sugar beet subgroup	0.75	root vegetables,
(except sugar beet), subgroup 1B

Lemon 	None

	Lime 	None

	Cucurbits 	0.45	vegetable, cucurbit, crop group 9 

Tuberous and corm vegetables, except 

potato subgroup	3.5	vegetable, tuberous and corm (except potato),
subgroup 1D 

Carrot 	None	Remove Established Tolerance

Turnip, greens 	None	Remove Established Tolerance

Citrus oil	500

	Grapefruit oil	None	Remove Established Tolerance

The most recent human health risk assessment for fludioxonil was
conducted in conjunction with a Section 18 emergency exemption for
fludixonil on carambola (star fruit) (DP #: 344676, B. Hanson,
11/27/2007).  This risk assessment referred to another previous risk
assessment (DP#: 292567, L. Jones, 11/22/2004) for a summary of the
risks associated with previously registered uses of fludioxonil.

Human Health Risk Assessment

Toxicology/Hazard

Fludioxonil is of low acute toxicity, since technical fludioxonil is in
Toxicity Category III or IV for the full battery of acute tests and is
not a dermal sensitizer.  For subchronic and chronic toxicity, the
primary effects in the mouse and rat were similar and included decreased
body weight and food consumption associated with clinical pathological
and histopathological effects in the liver and kidney.  In the
subchronic dog study, diarrhea was the most sensitive indicator of
toxicity.  In contrast, decreased weight gain in females was the most
sensitive indicator of toxicity in the chronic toxicity study in dogs. 
Liver toxicity was observed in both dog studies at higher doses.  The
available data did not indicate a need for acute or subchronic
neurotoxicity studies. It was not teratogenic in rabbits.  In a rat
developmental toxicity study, it caused an increase in fetal incidence
and litter incidence of dilated renal pelvis at the limit dose (1000
mg/kg/day).  There was no quantitative or qualitative evidence of
increased susceptibility following in utero exposure to rats and rabbits
or following pre-/post-natal exposure to rats.

HED classified fludioxonil as a Group D - not classifiable as to human
carcinogenicity.  Fludioxonil was not mutagenic in the tests for gene
mutations.  However, based on the induction of polyploidy in the in
vitro Chinese hamster ovary cell cytogenetic assay and the suggestive
evidence of micronuclei induction in rat hepatocytes in vivo, additional
mutagenicity testing was performed in three studies specifically
designed to address the concerns regarding aneuploidy.  The results of
these assays were negative for aneuploidy activity.

In a 28-day dermal toxicity study in rats, the no observed adverse
effect level (NOAEL) was equal to or greater than 1000 mg/kg/day
(highest dose tested (HDT)) based on no significant adverse effects in
either sex.  

In a rat metabolism study, tissue distribution showed that terminal
residues were below the limit of detection (LOD) for most tissues except
the liver, kidneys, blood, and lungs. The major route of excretion was
the feces, with approximately 80% of the administered radioactivity
excreted by this route in male and female rats at both the low and high
dose.  The remaining radioactivity was excreted through urine.  In bile
duct-cannulated rats, approximately 70% of an administered radioactive
dose was excreted via this route, supporting the bile as the origin of
the fecal radioactivity.  There were no apparent sex- or dose-related
differences in the routes of excretion for fludioxonil.  Examination of
urine for metabolites of fludioxonil showed at least 20 metabolites,
each comprising a minor fraction of the administered dose (0.1-3.1%).  
There were no significant differences in urinary metabolites with sex or
dose.   

Dose Response Assessment

HED previously evaluated and re-assessed the toxicology database of
fludioxonil, established both acute and chronic Reference Doses (RfDs)
and addressed the potential enhanced sensitivity of infants and children
as required by FQPA (HED Doc. No. 013806, 10/13/1999; HED Doc. No.
0050427, 1/29/2002).  Additionally, the HIARC selected toxicological
endpoints for incidental oral exposure and re-evaluated endpoints for
occupational/ residential exposure risk assessments based on the
redefined exposure periods.  

In estimating margins of exposure (MOEs), the level of concern is for
MOEs less than 100 for the dermal and inhalation occupational and
residential exposure risk assessments. 

The acute RfD (for females 13-49 only) of 1.0 mg/kg/day is based on a
NOAEL of 100 mg/kg/day from a developmental toxicity study in the rat
and includes a 10x factor for interspecies extrapolation and a 10x
uncertainty factor (UF) for intraspecies variations.  The effect at the
next HDT level of 1000 mg/kg/day (lowest observed adverse effect level
[LOAEL]) was an increase in the fetal and litter incidence of dilated
renal pelvis and dilated ureter.  A FQPA SF of 1X was applied to the
acute dietary risk assessment. Therefore, the acute population adjusted
dose, aPAD, is 1.0 mg/kg/day for females 13-49 years old only.  An acute
dose and endpoint were not selected for the general U. S. population
(including infants and children) because there were no effects of
concern observed in oral toxicology studies, including maternal toxicity
in the developmental toxicity studies in rats and rabbits, that are
attributable to a single exposure. 

The chronic RfD of 0.03 mg/kg/day is based on a one year dog feeding
study.  The NOAEL of 3.3 mg/kg/day is based on decreased body weight
gain in females which occurred at the LOAEL for systemic toxicity of
35.5 mg/kg/day and includes a 10x factor for interspecies extrapolation
and a 10x factor for intraspecies variations.  A FQPA safety factor of
1X was applied to chronic dietary risk assessment.  Therefore, the
chronic population adjusted dose, cPAD, is 0.03 mg/kg/day. 

The short-term incidental oral endpoint is based on the NOAEL of 10
mg/kg/day for maternal toxicity in the rabbit developmental toxicity
study.  At the LOAEL of 100 mg/kg/day, there was decreased body weight
gain and feed efficiency during gestation.  The intermediate-term oral,
incidental endpoint was based on the NOAEL of 3.3 mg/kg/day from the
one-year dog feeding study.  At the LOAEL of 35.5 mg/kg/day, female dogs
had decreased body weight gain in the first 13 weeks of exposure. 

Short- and intermediate-term dermal endpoints were not selected; no
systemic toxicity was seen at the highest dose tested of 1000 mg/kg/day
in the 28-day dermal toxicity study in rats.  Dilated renal pelvis and
ureter were seen developmental effects; though these were not measured
in the dermal toxicity study.  However, it was seen at 1000 mg/kg/day in
the oral developmental toxicity study.  With dermal absorption at 40%
(upper bound estimate), the dermal equivalent dose is 2500 mg/kg/day for
the developmental effects.  Based on the lack of systemic toxicity in
the dermal toxicity study, developmental toxicity in the presence of
maternal toxicity at the limit dose in the oral developmental toxicity
study and the extremely high estimated dermal equivalent dose,
developmental toxicity via the dermal route is considered negligible.

The short-term inhalation endpoint is based on the maternal toxicity
oral NOAEL of 10 mg/kg/day in the rabbit developmental study.  At the
LOAEL of 100 mg/kg/day, there was decreased body weight gain and feed
efficiency during gestation.  The intermediate-term inhalation endpoint
is based on the systemic toxicity oral NOAEL of 3.3 mg/kg/day in the
one-year dog feeding study.  At the LOAEL of 35.5 mg/kg/day, there was
decreased body weight gain in female dogs. 

For aggregation of short- and intermediate-term risks, oral and
inhalation exposures can be combined, since the dose/endpoints are based
on a common endpoint.  Dermal exposure cannot be combined with oral and
inhalation, since a dose/endpoint was not identified for short-, and
intermediate-term dermal exposure risk assessments.  Since there was no
hazard from dermal exposure, no risk quantification is required for
these durations and there is no contribution to aggregate risk.  For
long-term risk assessments, oral, dermal, and inhalation exposures can
be combined, since each route of exposure is based on common target
organs (oral equivalents).

Dietary Exposure (Food/Water)

Residue Chemistry and Risk

The petitioner is proposing foliar application of Switch 62.5 WG
(water dispersible granule; 37.5% cyprodinil and 25% fludioxonil; EPA
Registration Number 100-953) at a total of 0.22 - 0.88 lb ai/A/season to
tomato, tomatillo, avocado, black sapote, canistel, mamey sapote, mango,
papaya, sapodilla, star apple, fresh herbs, dried herbs, root
vegetables, leaves of root and tuber vegetables, lemon, lime, cucurbits,
and tuberous and corm vegetables.  

The following summary information comes from residue chemistry data
submitted to and reviewed by the Agency (DP#: 345970, W. Cutchin,
5/20/2008). 

For purposes of tolerances and dietary risk assessment, HED previously
concluded that the residue of concern in plant commodities is
fludioxonil parent only.  Residues of concern in poultry, for purposes
of tolerance expression and risk assessment, are fludioxonil,
CGA-344623, and I-1 and the residues of concern in ruminant, for purpose
of tolerance expression and risk assessment, are fludioxonil and B-1.  

Adequate   SEQ CHAPTER \h \r 1 methods previously reviewed by the EPA
are available for enforcing tolerances in plant commodities.  These
methods have been validated or approved by the Analytical Chemistry
Branch of BEAD.  

The requested uses of fludioxonil result in expected residues on
livestock feed items: carrot culls at 0.75 ppm (cattle and swine), and
citrus pulp at 0.25 ppm (cattle).  Ruminant and poultry metabolism
studies have been previously reviewed.  Previous dietary burdens
determined that fludioxonil tolerances were not necessary for livestock
commodities. The revised dietary burdens are equal to or lower than the
previous burdens for beef, poultry, and swine; therefore, no livestock
tolerances are required for those commodities.  However, the reasonably
balanced livestock diet for dairy cattle is higher than the previous
diet.  Based on the previously reviewed ruminant metabolism study and
the revised dietary burden, tolerances would be required for kidney,
milk, and liver.  Because carrot culls are a minor livestock feed item,
which are used in very restricted circumstances, ARIA does not recommend
for livestock tolerances at this time.  However, as a condition of
registration, a livestock feeding study is required.  

 

Adequate confined and limited field rotational crop studies are
available, and HED previously concluded that the residue of concern in
rotational crops is only fludioxonil.

Water Exposure and Risk

The drinking water residues used in the dietary risk assessment were
provided by EFED (DP#: 342828, 348540; C. Sutton; 3/12/2008) and
incorporated directly into the dietary assessment.  

Estimated drinking water concentrations (EDWCs) were calculated for
fludioxonil residues using EFED’s FQPA Index Reservoir Screening Tool
(FIRST) model for surface water and the Screening Concentration in
Ground Water (SCI-GROW) model for groundwater.  These EDWCs were modeled
based on the use site with the highest application rate; i.e.
spray/foliar applications to turf grass.

Based on the modeling results using FIRST, surface water concentrations
of fludioxonil are 81.3 ppb for the estimated peak concentration (acute)
and 37.4 ppb for the estimated mean concentration (chronic). 
Groundwater EDWCs are minimal in comparison to surface water (0.20 ppb
for both acute and chronic concentrations). 

Acute and Chronic Dietary Exposure Results and Characterization

The acute dietary risk assessment assumed tolerance-level residues for
all commodities with existing and proposed tolerances and default 100%
crop treated (%CT) information.  The acute dietary risk assessment was
conducted for the population subgroup females 13-49 years old only. 
There were no appropriate toxicological effects attributable to a single
exposure (dose) for the general population or any other population
subgroups.  The chronic dietary risk assessment assumed tolerance-level
residues for most commodities with existing and proposed tolerances and
default 100%CT information.  The chronic assessment was conducted for
the general U.S. population and all population subgroups.  Anticipated
residue (AR) values for apple, grapefruit, lemon, lime, orange, and pear
were generated from field trial data for the chronic assessment.  ARs
were also determined from processing studies for apple, grapefruit,
lemon, lime and orange juices.  Since a tomato processing study
demonstrated that residues do not concentrate in tomato processed
commodities, these processing factors were set to 1.  DEEMM-FCID(
default processing factors were used for all other processed commodities
for the chronic assessment.  Drinking water estimates were directly
incorporated into the assessments.  The acute and chronic dietary risk
assessments for fludioxonil show that for all included commodities, the
acute and chronic dietary risk estimates are below ARIA’s level of
concern.

Non-Occupational and Residential Exposure/Risks

The current petition for fludioxonil is not expected to result in any
non-occupational/ residential exposures.  However, HED previously
assessed the use of fludioxonil in residential use scenarios to control
certain diseases of turfgrass and certain foliar, stem and root diseases
in ornamentals in residential landscapes (DP#: 282570, T. Swackhammer,
5/6/2002).  Since the product registered for residential uses,
Medallion® (EPA Reg. No. 100-769), is restricted for residential uses
to commercial applicators-only, and since HED did not select short- or
intermediate-term dermal endpoints, only a toddler post-application
assessment for incidental ingestion exposures to treated lawns was
included.  The MOEs for combined non-dietary oral exposures were 770 for
short-term exposures and 450 for intermediate-term exposures.  These do
not exceed the ARIA’s level of concern for residential exposures (MOEs
< 100).

Aggregate Exposure/Risks

Acute Aggregate Exposure

Acute aggregate risk estimates do not exceed ARIA's level of concern. 
Since the acute aggregate risk assessment includes only food and water,
and the acute dietary analysis included both, no further calculations
are necessary.  Since the acute dietary risk does not exceed ARIA’s
level of concern, the acute aggregate risk does not exceed ARIA’s
level of concern.

Short-term Aggregate Exposure (Food + Water + Residential) 

Post-application exposure from commercial application of fludioxonil on
residential turf is considered short-term, and is applicable to
toddlers.  For toddlers, dermal and non-dietary oral post-application
exposures may result from dermal contact with treated turf as well as
hand-to-mouth transfer of residues from turfgrass.  The target maximum
daily exposure to fludioxonil residues is 0.1 mg/kg/day.  The estimated
MOEs range from 260-320, exceeding the target MOE of 100.  Therefore the
short-term aggregate risk and exposure is not of concern to the Agency. 
  

Intermediate-term Aggregate Exposure (Food + Water + Residential)

Post-application exposure from commercial application of fludioxonil on
residential turf may possibly be considered intermediate-term, based on
the residential use pattern, and is applicable to toddlers.  The target
maximum exposure to fludioxonil residues is 0.03 mg/kg/day.  The
estimated MOEs exceed the target MOE of 100, with the exception that the
MOE for children 1-2 years old is just below 100.  Due to the
conservative nature of the dietary (assumes 100%CT) and residential
assessments, ARIA does not have any concern for the purposes of this
action.  Therefore the intermediate-term aggregate risk and exposure is
not of concern to the Agency.    

Chronic Aggregate Exposure

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

Occupational Exposure/Risks

Based upon the proposed new use patterns, ARIA believes the most highly
exposed occupational pesticide handlers will be mixer/loaders handling
water dispersible granules, mixer/loaders using open-pour loading of
wettable powders, applicators using open-cab ground-boom sprayers and
applicators using open-cab air-blast sprayers.  The tuberous & corm
vegetables are intended to be treated as a post-harvest “fruit” dip.
  Based upon previous experience with post-harvest dips, ARIA expects
the fruit will be handled in bulk and that the dipping will be automated
in semi-closed systems (i.e., the dip tanks are shielded or hooded). 
Therefore there is no applicator in the strict sense.  Although the
fludioxonil product is a wettable powder, ARIA believes that the
assessment of mixer/loaders supporting ground spray operations is
adequate to describe exposure and risk that might occur for handlers
preparing minibulk dip solutions.  

ARIA believes for the crops listed, the exposures will be short-term (1
- 30 days) duration exposures.  Treatment blocks are not expected to be
large in the sense of such field crops as corn, soybeans, cotton or
wheat.  ARIA believes it is highly unlikely that intermediate-term
exposures (30 days - 6 months) would occur.  

No dermal toxicological endpoint was identified for fludioxonil.  ARIA
assumes post-application inhalation exposures are negligible, especially
in view of the 12 hour restricted entry interval for these products. 
Therefore post-application exposure to fludioxonil is not assessed. 

A MOE of exposure of 100 is adequate to protect occupational pesticide
handlers.  Since the estimated MOEs > 100 (MOEs ranged from 15,000 to
440,000), the proposed uses do not exceed ARIA’s level of concern.  

Environmental Justice Consideration

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 (listed in Appendix C) have been determined to
require a review of their ethical conduct, and have received that
review.

Additional Data Needs

There are no outstanding occupational data needs for fludioxonil.

Toxicology Deficiencies

Revised Part 158 requires that immunotoxicity and neurotoxicity studies
be submitted.  

Residue Chemistry Deficiencies

Section B on root and tuber vegetables, except sugar beets should be
renamed root and tuber vegetables except sugar beets and radish as the
radish requested use is not supported by appropriate residue field trial
data.  Section B should also be revised to indicate that the use on
radish should be 2 applications at 0.22 lb ai/A with 7-day retreatment
intervals and a 7-day PHI. The petitioner has indicated that there will
be a restriction on the feeding of the leaves of root and tuber
vegetables.  This should also be added to the proposed Section B.

A revised Section F is required for the residues of fludioxonil on
vegetable, cucurbit, crop group 9 at 0.45 ppm.

The requested tolerances on lemon and lime should be removed from
Section F.

Section F should be revised removing the proposed changes in the herb
subgroup 19A, fresh and dried, and the established tolerances retained. 

A revised Section F is required for the residues of fludioxonil on root
vegetables, except sugar beet subgroup 1B at 0.75 ppm.  

A revised Section F is required for the residues of fludioxonil on the
leaves of root and tuber vegetables at 30 ppm. 

A revised Section F should be submitted for the tolerances of 0.50 ppm
on tomato and tomatillo.

A revised Section F is required for the residues of fludioxonil on
vegetable, tuberous and corm (except potato), subgroup 1D at 3.5 ppm.

ARIA recommends that the conditional registration not be removed and a
required mustard green field trial study in Region 4 remains
outstanding.

Recommendations for Tolerances/Registration

Pending submission of revised Sections B and F (noted in Section 11.0),
ARIA recommends for the tolerances listed in Table 10.0.  The
registrations for the subject crops should be made conditional upon
resolution of the toxicology and the remaining residue chemistry data
gaps.

2.0	INGREDIENT PROFILE

Summary of Proposed Use

The petitioner is proposing foliar application of Switch 62.5 WG
(water-dispersible granule; 37.5% cyprodinil and 25% fludioxonil; EPA
Registration Number 100-953) at a total of 0.22 - 0.88 lb ai/A/season to
tomato, tomatillo, avocado, black sapote, canistel, mame sapote, mango,
papaya, sapodilla, star apple, fresh herbs, dried herbs, root
vegetables, leaves of root and tuber vegetables, lemon, lime, cucurbits,
and tuberous and corm vegetables.  The labels are adequate to allow
evaluation of the residue field trial data, with the exception of root
and tuber vegetables, except sugar beets.  Section B on root and tuber
vegetables, except sugar beets should be renamed root and tuber
vegetables except sugar beets and radish as the radish requested use is
not supported by appropriate residue field trial data.  Section B should
also be revised to indicate that the use on radish should be 2
applications at 0.22 lb ai/A with 7-day retreatment intervals and a
7-day PHI.  The petitioner has indicated that there will be a
restriction on the feeding of the leaves of root and tuber vegetables. 

2.2	Structure and Nomenclature

Table 2.2.  Nomenclature of Test Compound.

Compound

	

Common name	

Fludioxonil

Company experimental names	

CGA-173506 and Fludioxonyl

IUPAC name	

4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile

CAS name	4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile

CAS #	131341-86-1

End-use products/EP	Switch 62.5 WG (EPA Reg. No. 100-953), Scholar 50 WP
(EPA Reg. No. 100-969)

2.3	Physical and Chemical Properties

Table 2.3  Physicochemical Properties of the Technical Grade
Fludioxonil.

Parameter	Value	Reference

Melting point	199.8°C	DER 46715501, G.

Kramer, 11/16/06

pH	8-9 @ 25°C (1% aqueous Dispersion)

	Density	1.54 g/cm3 typical at 23°C

	Water solubility (25 C)	1.8 mg/L

	Solvent solubility (mg/L @ 25°C)	Ethanol 44,000

Acetone 190,000

Toluene 2,700

n-Octanol 20,000

n-Hexane 7.8

	Vapor pressure (25°C)	2.9 x 10-9 mm Hg

	Dissociation constant, pKa	pKa1 <0

pKa2 ~ 14.1

	Octanol/water partition coefficient, Log(KOW)	4.12 @ 25°C

	UV/visible absorption spectrum	12,384 l/mol x cm @266 nm (neutral
solution)

12,327 l/mol x cm @ 265 nm (acidic solution)

11,790 l/mol x cm @ 271 nm (basic solution)

	

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0  HAZARD CHARACTERIZATION 

3.1	Hazard and Dose-Response Characterization

Fludioxonil is of low acute toxicity, since technical fludioxonil is in
Toxicity Category III or IV for the full battery of acute tests and is
not a dermal skin sensitizer.  It is slightly irritating to the eyes of
rabbits.  For the 90-day feeding studies in rodents (mice and rats),
subchronic toxicity included decreases in body weight and food
consumption associated with clinical and histopathological effects
demonstrating toxicity in the liver and kidney in both sexes.  The
chronic studies in rodents also showed a similar toxicologic profile as
seen in the subchronic studies with the primary target organs identified
as the liver and the kidney.  In the subchronic dog study, diarrhea in
both sexes was the most sensitive indicator of toxicity, although at
higher doses decreased body weight, slight reduction in red cells,
hemoglobin, and packed self volume, increased liver weight and bile duct
proliferation were also observed.  In the long-term dog study, decreased
weight gain in females was the most sensitive indicator of toxicity, but
liver toxicity was indicated by increased cholesterol and alkaline
phosphatase and increased relative liver weight in both sexes. 

The rat and rabbit developmental toxicity studies were tested at doses
that produced maternal toxicity.  In dams, there was a 16% reduction in
corrected body weight gain at 1000 mg/kg/day (HDT) and in does,
decreased weight gain and decreased feed efficiency occurred at the mid
and high dose levels of 100 and 300 mg/kg/day (HDT), respectively.  It
is evident, however, that the doses could have been higher in the rabbit
study.  In the rat, there was an increase in the number of fetuses and
litters with dilated renal pelvis and dilated ureter.  This finding was
considered to be related to maternal toxicity, rather than an indication
of increased susceptibility.  In the rabbit, there was no evidence of
developmental toxicity up to and including the highest dose tested.  The
2-generation rat reproductive study indicated that maternal (increased
clinical signs, decreased body weight, weight gain, and food
consumption) and offspring toxicity (decreased lactational weight gain
in pups) occurred at the same dose of 3000 ppm (HDT) indicating no
evidence of susceptibility. 

Fludioxonil has been classified as "Group D" - not classifiable as to
human carcinogenicity.  That is, the evidence is inadequate and cannot
be interpreted as showing either the presence or absence of a
carcinogenic effect.  In one mouse study, there was a significant trend
for malignant lymphomas in female mice up to 3000 ppm.  However, in a
second study up to 7000 ppm, the limit dose, there was no evidence of
carcinogenicity for either sex.  In female rats, but not males, there
was a statistically significant trend and pair-wise comparison between
the high dose (3000 ppm) and the control group for combined
hepatocellular adenomas and carcinomas only (p = 0.030).  No indications
of excessive toxicity were noted and the dose levels were adequate for
assessing the carcinogenic potential of fludioxonil in both sexes.  HED
determined that based on the increase in liver tumors in female rats
that was statistically significant for combined adenoma/carcinoma only,
the lack of tumorigenic response in male rats or in either sex of mice,
and the need for additional mutagenicity studies, a Group D
classification was appropriate.  

Fludioxonil was not mutagenic in the tests for gene mutations, which
included reverse mutation assays in S. typhimurium and in E. coli WP2
uvrA as well as mammalian gene mutation assay with in vitro Chinese
hamster V79 cultures.  Fludioxonil was also negative in the in vivo
Chinese bone marrow micronucleus assay, in vivo mouse micronucleus
assay, mouse dominant lethal assay and the unscheduled DNA synthesis
assay with primary mouse hepatocyte for detecting DNA damage.  However,
fludioxonil was clastogenic in both the in vitro Chinese hamster ovary
(CHO) mammalian assay and the in vivo rat hepatocyte micronucleus assay.
 Based on the positive clastogenic response in the in vitro chromosomal
aberration study in CHO cells, the question as to whether the induction
of polyploidy by fludioxonil ultimately leads to aneuploidy was further
investigated.  Additionally, in the in vivo chromosomal aberration assay
in Chinese hamsters, the occurrence of hyperploidy in one mid-dose
female and trisomy in one high dose male was noted.  In light of the
powerful induction of polyploidy in the in vitro Chinese hamster ovary
cell cytogenetic assay and  the suggestive evidence of micronuclei
induction in rat hepatocytes in vivo, fludioxonil technical was tested
in three studies specifically designed to resolve the issue of
aneuploidy.  All three studies were negative for aneuploidy activity.  

In a 28-day dermal toxicity study, groups of 5 male and 5 female
Sprague-Dawley rats were treated dermally once per day for 6 hours for
28 days with technical grade fludioxonil (97.5%) at dosage levels of 0,
40, 200 or 1000 mg/kg body weight.  The NOAEL is 1000 mg/kg/day based on
no significant adverse effects in either sex at any dose.

3.1.1	Database Summary

  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)

Acute, sub-chronic, chronic, reproductive and developmental studies were
available and considered when preparing this risk assessment.  

  TC \l4 "3.1.1.1	Studies available and considered (animal, human,
general literature) 

3.1.1.2	Mode of action, metabolism, toxicokinetic data

Fludioxonil is a phenylpyrrole derivative of an antibiotic produced by
the soil-borne bacterium Pseudomonas.  A suggested mode of action of
phenylpyrrole derivatives is inhibition of the transmembrane transport
associated with glucose phosphorylation.

3.1.1.3	Sufficiency of studies/data

The studies and data used when preparing this risk assessment are
sufficient for evaluating human health risk.

  TC \l4 "3.1.1.3	Sufficiency of studies/data 

3.1.2	Dose-response

The aPAD and cPAD are modifications of the acute and chronic RfDs to
accommodate the FQPA SF.  An acute RfD of 1.0 mg/kg/day was established
for the subpopulation group, females 13-49 years old only, based on a
NOAEL of 100 mg/kg/day from a developmental study in the rat and an
uncertainty factor of 100.  The effect at the next HDT level of 1000
mg/kg/day was an increase in the fetal and litter incidence of dilated
renal pelvis and dilated ureter.  This effect is presumed to occur after
a single exposure in utero and therefore, is considered to be
appropriate for this risk assessment.  The aPAD is 1.0 mg/kg/day for
females 13-49 years old only.  Therefore, the aPAD and the acute RfD are
equivalent.

An acute dose and endpoint were not selected for the general U.S.
population group (including infants and children) because there were no
effects of concern observed in oral toxicology studies, including
maternal toxicity in the developmental toxicity studies in rats and
rabbits, that are attributable to a single exposure (dose). 

The chronic RfD of 0.03 mg/kg/day was determined on the basis of a one
year dog feeding study and includes an uncertainty factor of 100.  The
NOAEL of 3.3 mg/kg/day was based on decreased body weight gain in
females which occurred at the LOAEL for systemic toxicity of 35.5
mg/kg/day in females.  This RfD was re-confirmed by the HIARC (W.
Dykstra and B. Tarplee, 10/13/1999).  A FQPA SF of 1X was applied for
chronic dietary risk assessment.  Therefore, the cPAD and the chronic
RfD are equivalent.

Short- and intermediate-term dermal endpoints were not selected due to
the NOAEL of 1000 mg/kg/day (HDT) in the 28-day dermal toxicity study in
rats.  The potential for developmental toxicity via the dermal route is
considered negligible. 

The short-term inhalation endpoint is based on the maternal toxicity
oral NOAEL of 10 mg/kg/day in the rabbit developmental study.  At the
LOAEL of 100 mg/kg/day, there was decreased body weight gain and feed
efficiency during gestation.  The intermediate-term inhalation endpoint
is based on the systemic toxicity oral NOAEL of 3.3 mg/kg/day in the
one-year dog feeding study.  At the LOAEL of 35.5 mg/kg/day, there was
decreased weight gain in female dogs.  Long-term dermal and inhalation
risk assessments are based on the oral NOAEL of 3.3 mg/kg/day in the
one-year toxicity study in dogs with the LOAEL of 35.5 mg/kg/day based
on decreased weight gain in females. A dermal absorption factor of 40%
and an inhalation absorption factor of 100% should be used for oral
NOAELs from oral toxicity endpoints in route-to-route extrapolations. 
The dermal absorption factor of 40% was based on a comparison of the
NOAEL of the high dose of 1000 mg/kg/day in the 28-day dermal toxicity
study in rats and the LOAEL of 428 mg/kg/day in the 90 day oral toxicity
study in rats and is considered an upper bound estimate.

For aggregation of short- and intermediate-term risks, oral and
inhalation exposures can be combined, since the dose/endpoints are based
on common target organs (oral equivalents).  Dermal exposure cannot be
combined with oral and inhalation, since a dose/endpoint was not
identified for short-, and intermediate-term dermal exposure risk
assessments.  Since there was no hazard from dermal exposure, no risk
quantification is required for these durations and there is no
contribution to aggregate risk.  For long-term risk assessments, oral,
dermal, and inhalation exposures can be combined, since each route of
exposure is based on common target organs (oral equivalents).

  TC \l3 "3.1.3	Dose-response 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of fludioxonil in rats is adequately understood. The
compound is rapidly absorbed and excreted.  In a metabolism study in
Sprague Dawley rats, when C14-Fludioxonil was given by gavage and bile
duct-cannulation to groups of (5/sex/dose) male and female rats,
absorption was estimated to be between 67-91%.  Tissue distribution
showed that terminal residues were below the limit of detection for most
tissues except the liver, kidneys, blood, and lungs.  The major route of
excretion was the feces, with approximately 80% of the administered
radioactivity excreted by this route in male and female rats at both the
low and high dose.  The remaining radioactivity was excreted through
urine.  In bile duct-cannulated rats, approximately 70% of an
administered radioactive dose was excreted via this route, supporting
the bile as the origin of the fecal radioactivity.  There were no
apparent sex- or dose-related differences in the routes of excretion for
fludioxonil.  Examination of urine for metabolites of fludioxonil showed
at least 20 metabolites, each comprising a minor fraction of the
administered dose (0.1-3.1%).  The major fraction was identified as a
sulfate conjugate of fludioxonil.  Feces contained one major peak on
HPLC, identified as parent fludioxonil by co-chromatography.  Bile was
observed with 7 peaks, 6 of which comprised less than 5% of the dose. 
The remaining peak, comprising 55.5% of the dose, was identified as a
glucuronide conjugate of fludioxonil.  There were no significant
differences in urinary metabolites with sex or dose.

Metabolism involves primarily oxidation at the 2 position of the pyrrole
ring, with minor amounts of oxidation at the 5 position of the pyrrole
ring and the 4 position of the phenyl ring. All of these oxidized
metabolites are conjugated with glucuronic acid and sulfuric acid and
then rapidly eliminated.

  TC \l2 "3.2	Absorption, Distribution, Metabolism, Excretion (ADME) 

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

The toxicology data base for fludioxonil is complete.

  TC \l3 "3.3.1	Adequacy of the Toxicity Database 

3.3.2	Evidence of Neurotoxicity

No acute or subchronic neurotoxicity studies were available for review
by the HIARC.  Increased incidence of convulsions in mice upon handling
in the 1000 and 3000 ppm groups in the 18 month mouse carcinogenicity
study was not associated with any neuropathological changes and were
considered to be agonal signs of toxicity.

3.3.3	Developmental Toxicity Studies

There was no evidence of increased susceptibility following in utero
exposure to rats and rabbits or following pre-/post-natal exposure to
rats.  In rats, developmental effects occurred in the presence of
maternal effects.  In rabbits, no developmental toxicity was seen up to
the highest dose tested which demonstrated maternal toxicity.  

3.3.4	Reproductive Toxicity Study

In the 2-generation rat reproduction study, offspring toxicity was seen
at the dose that produced parental toxicity.

  TC \l3 "3.3.4	Reproductive Toxicity Study 

3.3.5	Additional Information from Literature Sources

There were no additional relevant data available from the open
literature.

3.3.6	Pre-and/or Postnatal Toxicity 

There was no quantitative or qualitative evidence of increased
susceptibility following in utero exposure to rats and rabbits or
following pre-/post-natal exposure to rats.  In rats, there was an
increase in the number of fetuses and liters with dilated renal pelvis
and dilated ureter.  This finding was considered to be related to
maternal toxicity rather than an indication of increased susceptibility.
 Therefore, it is concluded that there is no evidence of increased
susceptibility in rats.  In rats, developmental effects occurred in the
presence of maternal effects.  In rabbits, no developmental toxicity was
seen up to the highest dose tested which demonstrated maternal toxicity.
 In the 2-generation rat reproduction study, offspring toxicity was seen
at the dose that produced parental toxicity.  The maternal toxicity was
manifested as increased clinical signs, decreased body weight, body
weight gain and food consumption.  Offspring toxicity was manifested as
decreased weight gain in pups.  Since maternal and offspring toxicity
were comparable, it was concluded that there is no increased
susceptibility in the 2-generation reproduction study.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

Rat and rabbit developmental studies and a 2-generation rat reproduction
study do not support the requirement for a developmental neurotoxicity
study.  There were no CNS malformations present in the developmental
toxicity studies in rats and rabbits.  In a 2-generation study in rats,
there were no findings in pups that were suggestive of changes in
neurological development, although no functional assessment was
performed.  Additionally, there was no evidence of neurotoxicity in
other studies. Therefore, it was determined that a developmental
neurotoxicity study was not required.

  TC \l3 "3.3.8	Rationale for the UFDB (when a DNT is recommended) 

3.4	FQPA Safety Factor for Infants and Children

The FQPA SFC has met on more than one occasion and has recommended that
the FQPA SF be revised to 1x for acute and chronic RfDs and residential
risk assessments (HED Doc. No. 013892, 12/13/1999).  

  TC \l2 "3.4	Safety Factor for Infants and Children 

  TC \l2 "3.3	FQPA Considerations 

3.5	Hazard Identification and Toxicity Endpoint Selection

  TC \l2 "3.5	Hazard Identification and Toxicity Endpoint Selection 

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49

An aRfD of 1.0 mg/kg/day was established for the subpopulation group,
females 13-49 years old only, based on a NOAEL of 100 mg/kg/day from a
developmental study in the rat and an uncertainty factor of 100.  The
effect at the next higher dose (the HDT) level of 1000 mg/kg/day was an
increase in the fetal and litter incidence of dilated renal pelvis and
dilated ureter.  This effect is presumed to occur after a single
exposure in utero and therefore, is considered to be appropriate for
this risk assessment.  The aPAD is 1.0 mg/kg/day for females 13-49 years
old only.  Therefore, the aPAD and the acute RfD are equivalent

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

3.5.2	Acute Reference Dose (aRfD) - General Population

A dose and endpoint attributable to a single exposure was not identified
for the general population, including infants and children, from the
available oral toxicity studies, including maternal toxicity in the
developmental toxicity studies in rats and rabbits that are attributable
to a single exposure (dose).

3.5.3	Chronic Reference Dose (cRfD) 

The chronic RfD of 0.03 mg/kg/day was determined on the basis of a one
year dog feeding study and includes an uncertainty factor of 100.  The
NOAEL of 3.3 mg/kg/day was based on decreased body weight gain in
females which occurred at the LOAEL for systemic toxicity of 35.5
mg/kg/day in females.  This RfD was originally established in the RfD
document dated September 26, 1995 and re-confirmed by HED on September
7, 1999 (Memo, W. Dykstra and B. Tarplee, 10/13/1999).  A FQPA SF of 1X
was applied for chronic dietary risk assessment.  Therefore, the cPAD
and the chronic RfD are equivalent.

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

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

The short-term incidental oral endpoint is 10 mg/kg/day based on the
NOAEL for maternal toxicity in the rabbit developmental study.  At the
LOAEL of 100 mg/kg/day, there was decreased body weight gain and feed
efficiency during gestation.  The intermediate-term incidental oral
endpoint was selected from the NOAEL of 3.3 mg/kg/day from the one year
dog feeding study.  At the LOAEL of 35.5 mg/kg/day, female dogs had
decreased body weight gain in the first 13 weeks of exposure.

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

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 	

A dermal absorption factor of 40% should be used for oral NOAELs from
oral toxicity endpoints in route-to-route extrapolations.  The dermal
absorption factor of 40% is based on a comparison of the NOAEL of the
high dose of 1000 mg/kg/day in the 28-day dermal toxicity study in rats
and the LOAEL of 428 mg/kg/day in the 90 day oral toxicity study in rats
and is considered an upper bound estimate.

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Short- and intermediate-term dermal endpoints were not selected due to
the NOAEL of 1000 mg/kg/day (HDT) in the 28-day dermal toxicity study in
rats.  The potential for developmental toxicity via the dermal route is
considered negligible.  Long-term dermal risk is based on the oral NOAEL
of 3.3 mg/kg/day in the one-year toxicity study in dogs with the LOAEL
of 35.5 mg/kg/day based on decreased weight gain in females.

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

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

The short-term inhalation endpoint is based on the maternal toxicity
oral NOAEL of 10 mg/kg/day in the rabbit developmental study.  At the
LOAEL of 100 mg/kg/day, there was decreased body weight gain and feed
efficiency during gestation.  The intermediate-term inhalation endpoint
is based on the systemic toxicity oral NOAEL of 3.3 mg/kg/day in the
one-year dog feeding study.  At the LOAEL of 35.5 mg/kg/day, there was
decreased weight gain in female dogs.  Long-term inhalation risk is
based on the oral NOAEL of 3.3 mg/kg/day in the one-year toxicity study
in dogs with the LOAEL of 35.5 mg/kg/day based on decreased weight gain
in females.

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

3.5.8	Recommendation for Aggregate Exposure Risk Assessments

For aggregation of short- and intermediate-term risks, oral and
inhalation exposures can be combined, since the dose/endpoints are based
on common target organs (oral equivalents). Dermal exposure cannot be
combined with oral and inhalation, since a dose/endpoint (hazard) was
not identified for short-, and intermediate-term dermal exposure risk
assessment.  Since there was no hazard from dermal exposure, no risk
quantification is required for these durations and there is no
contribution to aggregate risk.  For long-term risk assessments, oral,
dermal, and inhalation exposures can be combined, since each route of
exposure is based on common target organs (oral equivalents).

  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

3.5.9	Classification of Carcinogenic Potential

Fludioxonil has been classified as a “Group D” chemical - not
classifiable as to human carcinogenicity; based on the increase in liver
tumors in female rats that was statistically significant for combined
adenoma/carcinoma only and the lack of a tumorigenic response in male
rats or in either sex of the mouse.

3.5.10	Summary of Fludioxonil Toxicological Doses/Endpoints for Use in
Risk Assessments

Table 3.5.10 Summary of Toxicological Doses and Endpoints for
Fludioxonil for Use in Dietary and

Non-Occupational Human Health Risk Assessments  

EXPOSURE

SCENARIO	DOSE

(mg/kg/day)	ENDPOINT	STUDY

Females 13-50

Acute Dietary	NOAEL= 100

UF = 100	The increased incidence of fetuses and litters with dilated
renal pelvis and dilated ureter in rats	rat developmental study

	Acute RfD = 1.0 mg/kg/day

General Population

Acute Dietary 	An endpoint attributable to a single exposure was not
identified from the available oral toxicity studies, including maternal
toxicity in the developmental toxicity studies.

Chronic Dietary	

NOAEL = 3.3

UF = 100	Decreased weight gain in female dogs during weeks 1-52 of study
one-year dog feeding study

Chronic RfD = 0.03 mg/kg/day

Incidental Oral,

 Short-Term 	NOAEL= 10	Decreased weight gain during dosing period	rabbit
developmental study

Incidental Oral,

Intermediate-Term	NOAEL= 3.3	Decreased weight gain in female dogs during
weeks 1-13 of study	one-year dog feeding study

Dermal, Short-and Intermediate-Term 	not requird	No hazard identified
and therefore quantification is not required.  There are no
developmental concerns via the dermal route and no systemic toxicity was
seen following dermal exposure.

Dermal,

Long-Term 	Oral NOAEL= 3.3	decreased weight gain in female dogs during
weeks 1-52 of study.	one-year dog feeding study

Inhalation, 

Short-Term	Oral NOAEL= 10	decreased weight gain during dosing period
rabbit developmental  study

Inhalation, 

Intermediate-Term	Oral NOAEL= 3.3	decreased weight gain in female dogs
during weeks 1-13	one-year dog feeding study

Inhalation,

Long-Term	Oral NOAEL= 3.3	decreased weight gain in female dogs during
weeks 1-52 of study	one-year dog feeding study

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 was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, fludioxonil may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

4.1	Incident Reports

A search of OPP’s REFS Incident Data Reporting System revealed a total
of 4 records related to fludioxonil.  Three records related to
accidental ingestion of treated seeds.  The fourth record involved an
occupational exposure incident to a seed treatment formulation, but the
record indicated that it was uncertain whether fludioxonil was the cause
of the incident.  There were no additional relevant data available from
the open literature.

  TC \l2 "4.1	Incident Reports   TC \l2 "4.4	Other Pesticide
Epidemiology Published Literature 5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION

The following summary information comes from residue chemistry data
submitted to and reviewed by the agency (DP#: 345970, W. Cutchin,
5/20/2008).

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

For purposes of tolerances and dietary risk assessment, HED previously
concluded that the residue of concern in plant commodities is
fludioxonil parent only.  

5.1.2	Metabolism in Rotational Crops

The nature of the residue in rotational crops is adequately understood. 
The MARC concluded that the residue of concern in rotational crops is
fludioxonil parent only (DP#: 262022, W.Donovan and W.Dykstra,
1/18/2000). 

The proposed label indicates that only those crops listed on the label
may be rotated to a treated field at 0-day following treatment and all
other crops may be planted after 30 days.  Based on the results of the
confined and field rotational crop studies and the proposed application
rates, the label rotational crop restrictions are acceptable.     

5.1.3	Metabolism in Livestock

Residues of concern in poultry, for purposes of tolerance expression and
risk assessment, are fludioxonil, CGA-344623, and I-1 and the residues
of concern in ruminant, for purpose of tolerance expression and risk
assessment, are fludioxonil and B-1.  CGA-344623, I-1, and B-1 are
included as residues of concern since they contain the nitrile
functional group and constituted greater than 10% of the TRR in the
laying hen and/or lactating goat metabolism studies.

5.1.4	Analytical Methodology	

Plants

The method used in the field trial studies is a reissue of Method(s)
AG-597/AG-597A and has been validated extensively on a variety of crop
matrices to a lower limit of 0.01-0.05 ppm.  The method has successfully
undergone independent laboratory validation as well as an Agency
petition method validation (PMV) on corn grain and forage and grain
sorghum.  The method has been submitted to the FDA for inclusion in PAM
II and is considered adequate for enforcement purposes.  

Livestock

As tolerances for livestock commodities are not required, analytical
methods for livestock matrices are not required at the present time. 

  TC \l3 "5.1.4	Analytical Methodology 5.1.5	Environmental Degradation

Fludioxonil is persistent, with a laboratory soil half life of 220 days,
and field dissipation half lives of 95-440 days.  Photolysis is a major
route of degradation, with half-lives of 1.6 days in soil (near surface)
and 8.7 days in water (near surface).  Fludioxonil is slightly to
moderately mobile (FAO classification scheme) in soil (Koc = 991-2440
mL/goc) and is primarily a concern for surface waters.  Degradates of
fludioxonil are highly mobile; however, none of the four major
degradates are considered to be of toxicological concern.  

In order for fludioxonil to pose an ecological risk, it must reach
non-target organisms at concentrations sufficient to cause adverse
effects.  Ecosystems that are considered potentially at risk due to
applications of fludioxonil include water bodies adjacent to and
downstream of application sites.  Specific ecosystems of interest are
freshwater aquatic systems (e.g. wetlands, lakes and streams) and
estuarine/marine systems.  In addition, organisms (i.e. mammals, birds)
that inhabit the application site are also considered to be part of the
ecosystems potentially at risk.

5.1.6	Comparative Metabolic Profile

In a rat metabolism study, tissue distribution showed that terminal
residues were below the LOD for most tissues except the liver, kidneys,
blood, and lungs. The major route of excretion was the feces, with
approximately 80% of the administered radioactivity excreted by this
route in male and female rats at both the low and high dose.  The
remaining radioactivity was excreted through urine.  In bile
duct-cannulated rats, approximately 70% of an administered radioactive
dose was excreted via this route, supporting the bile as the origin of
the fecal radioactivity.  There were no apparent sex- or dose-related
differences in the routes of excretion for fludioxonil.  Examination of
urine for metabolites of fludioxonil showed at least 20 metabolites,
each comprising a minor fraction of the administered dose (0.1-3.1%).  
There were no significant differences in urinary metabolites with sex or
dose.  

Residues of concern in poultry, for purposes of tolerance expression and
risk assessment, are fludioxonil, CGA-344623, and I-1 and the residues
of concern in ruminant, for purpose of tolerance expression and risk
assessment, are fludioxonil and B-1.  CGA-344623, I-1, and B-1 were
included as residues of concern since they contain the nitrile
functional group and constituted greater than 10% of the TRR in the
laying hen and/or lactating goat metabolism studies.

Fludioxonil is the only compound found at concentrations >10% TRR in
most plants.  A comparison of a head lettuce metabolism study with
studies reviewed by the MARC indicates that the only lettuce-specific
metabolites identified are the lactic acid conjugates of CGA 173506 and
the glucose conjugate of CGA 344623.  Since the only unique metabolites
identified in the lettuce metabolism studies were conjugated forms of
compounds previously identified and the lettuce metabolism study also
resulted in only fludioxonil at concentrations greater >10% TRR, HED
concluded that the metabolic pathway in three dissimilar crops has been
demonstrated to be similar and the residues of concern in plants is
parent fludioxonil.

 TC \l3 "5.1.5	Environmental Degradation 

5.1.7	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED in the following memorandum: “Tier I Drinking Water
Assessment for the Fludioxonil Proposed New Use on Grapes; and the
Proposed IR-4 New Uses on Tomato, Avocado and Related Tropical Fruits,
Herb Subgroup 19A, Root Vegetables, Leaves of Root Vegetables, Lemon,
Lime, Cucurbits, and Tuberous and Corm Vegetables (Except Potato
Subgroup, Except Yam) (DP#: 342828, 348540; C. Sutton; 3/12/2008) and
incorporated directly into this dietary assessment.  Water residues were
incorporated in the DEEM-FCID into the food categories “water, direct,
all sources” and “water, indirect, all sources.” 

Estimated drinking water concentrations (EDWCs) were calculated for
fludioxonil residues using EFED’s FQPA Index Reservoir Screening Tool
(FIRST) model for surface water and the Screening Concentration in
Ground Water (SCI-GROW) model for groundwater.  These EDWCs were modeled
based on the use site with the highest application rate; i.e. turf (2 lb
ai/A/yr).

Based on the modeling results using FIRST, surface water concentrations
of fludioxonil are 81.3 ppb for the estimated peak concentration (acute)
and 37.4 ppb for the estimated mean concentration (chronic).  
Groundwater EDWCs are minimal in comparison to surface water (0.20 ppb
for both acute and chronic concentrations).

 TC \l3 "5.1.9	Drinking Water Residue Profile 

5.1.8	Food Residue Profile

The petitioner is proposing foliar application of Switch 62.5 WG
(water-dispersible granule; 37.5% cyprodinil and 25% fludioxonil; EPA
Reg. No.: 100-953) at a total of 0.22 - 0.88 lb ai/A/season to tomato,
tomatillo, avocado, black sapote, canistel, mame sapote, mango, papaya,
sapodilla, star apple, fresh herbs, dried herbs, root vegetables, leaves
of root and tuber vegetables, lemon, lime, cucurbits, and tuberous and
corm vegetables.  The labels are adequate to allow evaluation of the
residue field trial data, with the exception of root and tuber
vegetables, except sugar beets.  The petitioner has indicated that there
will be a restriction on the feeding of the leaves of root and tuber
vegetables.  

For tomato, avocado, parsley, radish, lemon and sweet potato, samples
were analyzed for residues of fludioxonil using Syngenta Method AG-597B,
a high performance liquid chromatography with ultraviolet detector
(HPLC/UV) method with minor modifications. For fludioxonil residues on
tomato, the lower limit of method validation (LLMV) was 0.02 ppm, and
the LOD and LOQ were 0.002 ppm and 0.007 ppm, respectively.   For
fludioxonil residues on avocado, the LOD and LOQ were 0.0055 ppm and
0.0164 ppm, respectively.  For fludioxonil residues on fresh parsley,
the LOD and LOQ were 0.010 ppm and 0.03 ppm, respectively.  The LOD and
LOQ for fludioxonil on dried parsley were 0.026 ppm and 0.077 ppm,
respectively.  For fludioxonil residues on radish, the LOD in/on radish
tops and roots were 0.003 ppm and 0.004 ppm, respectively.  The LOQ of
fludioxonil in/on radish tops and roots was 0.01 ppm.  For fludioxonil
residues on lemon, the LOD and LOQ were calculated as 0.0070 ppm and
0.021 ppm, respectively.  The LOD and LOQ in sweet potato were
calculated as 0.0057 ppm and 0.017 ppm, respectively. 

For cucurbit vegetables, samples were analyzed for residues of
fludioxonil using Syngenta Method AG-597B, with minor modifications. 
Residues of fludioxonil were determined using HPLC and triple-quadrapole
mass spectrometric (MS/MS) detection. The LOD of fludioxonil was 0.005
ppm for cantaloupe, cucumber, and squash samples.  The LOQ of
fludioxonil was 0.01 ppm for cantaloupe, cucumber, and squash samples. 
The methods used for data gathering, which are based on the enforcement
methods and are supported by concurrent recoveries, are adequate.  

Fludioxonil was tested according to the FDA Multiresidue Protocols C, D,
and E using sorghum, corn, and potatoes.  Recoveries were inadequate
using corn and sorghum; however, fludioxonil was recovered from
potatoes.  This information has been forwarded to the FDA (S. Willett,
1/3/1997).

All the submitted residue field trial studies were supported by adequate
simultaneous storage stability data that indicate that the residues of
fludioxonil are stable for the duration of the studies with the
exception of lemon.  Previously submitted data on lemon are sufficient
to indicate that fludioxonil residues are stable in lemons for the
duration of this study.

The requested uses of fludioxonil result in expected residues on
livestock feed items: carrot culls at 0.75 ppm (cattle and swine), and
citrus pulp at 0.25 ppm (cattle).  Ruminant and poultry metabolism
studies have been previously reviewed.  Previous dietary burdens
determined that fludioxonil tolerances were not necessary for livestock
commodities. The revised dietary burdens are equal to or lower than the
previous burdens for beef, poultry, and swine; therefore, no livestock
tolerances are required for those commodities.  However, the reasonably
balanced livestock diet for dairy cattle is higher than the previous
diet.  Based on the previously reviewed ruminant metabolism study and
the revised dietary burden, tolerances would be required for kidney,
milk, and liver.  Because carrot culls are a minor livestock feed item,
which are used in very restricted circumstances, ARIA does not recommend
for livestock tolerances at this time.  However, as a condition of
registration, a livestock feeding study is required.  

There is adequate number and geographic location of residue field trials
to support a tolerance registration on avocado.  The analytical results
show that after a total seasonal application rate of 0.88 lb ai/A at a
0-day PHI, the maximum fludioxonil residue was 0.19 ppm in treated
avocado fruit.  In addition, since avocado is the representative crop
for the proposed tropical crop group, the data also support tolerances
for black sapote, canistel, mamey sapote, mango, sapodilla, and star
apple as requested by the petitioner.  ARIA recommends for the requested
tolerances of fludioxonil on avocado, black sapote, canistel, mamey
sapote, mango, sapodilla, and star apple at 0.45 ppm. 

There is adequate number and geographic location of residue field trials
to support a tolerance registration on cucurbit.  At 7-day PHI, maximum
fludioxonil residues in cantaloupe, cucumber, and squash samples were
0.19, 0.08, and 0.03 ppm, respectively, after a total seasonal
application rate of 0.88 lb ai/A.  The rate used in the trials is higher
than the proposed rate; however, that is not a deficiency for this
petition.  The requested tolerances are not appropriate.  The data on
the three commodities, cantaloupes, cucumbers, and squash were analyzed
separately and the highest result of the three analyses, cantaloupes at
0.45 ppm, is the appropriate tolerance level.  

There is adequate number and geographic location of residue field trials
to support a tolerance registration on lemon.  The results from the
trials show that the maximum residue following a total application of
approximately 0.22 lb ai/A and a 0-day PHI was 0.19 ppm.  Since the
proposed uses are the same and these two citrus crops are similar in
size, the lemon data will also support a tolerance on lime.  There is an
existing fludioxonil tolerance on citrus fruit at 10 ppm as a result of
a post-harvest use.  That tolerance is adequate for the proposed uses on
lemon and lime.

There is adequate number and geographic location of residue field trials
to support a tolerance registration on parsley, fresh and dried.  The
analytical results show that at 6-7 days PHI, the maximum fludioxonil
residue was 3.87 ppm in fresh parsley and 22.29 ppm in dried parsley
after a total seasonal application rate of 0.88 lb ai/A.  Since there
are existing tolerances for herb subgroup 19A, fresh and dried and the
data from the parsley residue field trials do not exceed those
established tolerances using the same treatment pattern, no change in
the group tolerance is required.    

As a condition for the registration of fludioxonil on carrots, HED
required an additional carrot field trial, including residue decline
data).  In response, IR-4 has submitted the current carrot field trial
data.  IR-4 submitted field trial data supporting the use of fludioxonil
on carrots.  

Following four foliar applications totaling 0.90 lb ai/A, fludioxonil
residues in/on carrots were 0.48-0.69 ppm at 7-day PHI.  Fludioxonil
residues in/on carrots showed a slight but steady increase from 0 to
21-day PHI.  ARIA concludes that the condition of registration for
fludioxonil on carrots may be removed.

There is adequate number and geographic location of residue field trials
to support a tolerance registration on radish.  The petitioner requests
that the existing data for carrot be combined with the submitted radish
data and used in support of the requested tolerances on root vegetables,
except sugar beet.  It is OPP policy to analyze each representative crop
in a crop group separately and establish the group tolerance using the
highest of the individual analyses provided the data.  The appropriate
tolerance on radish is less than established carrot tolerance.  Provided
a revised Section F is received, ARIA recommends for a fludioxonil
tolerance on root vegetables, except sugar beet subgroup 1B at 0.75 ppm.
 Upon the establishment of the subgroup tolerance the existing
individual tolerance on carrots should be removed.  

The radish residue field crop trials were conducted at approximately
0.5x the proposed total use rate.  The petitioner requests that 4
applications for a total of 0.88 lb ai/A be approved for this crop
subgroup since there are radish types that have a longer growing season
than those in presented in the submitted trials and 4 applications would
be possible during their growing season.  Examination of the decline
data for carrots indicates that residues may be additive for root crops
and additional applications would possibly increase the resulting
residues on radish above the tolerance level.  ARIA recommends against
the proposed use rate.  Section B should be revised to indicate that the
use on radish be 2 applications at 0.22 lb ai/A with 7-day retreatment
intervals and a 7-day PHI.  

The petitioner is proposing a tolerance for leaves of root and tuber
vegetables, crop group 2 at 40 ppm.  The proposal is based on the
present tolerance for turnip greens at 10 ppm, which came from mustard
greens data and on the radish tops data in this petition.  There were 4
applications to mustard greens but only 2 applications to the radish
leaves resulting in half the total application rate.  The spray interval
was 7 days between the last 2 applications and a 0-day PHI in mustard
greens and 7-day PHI for radish.  IR-4 is requesting 4 applications on
leaves of root and tuber vegetables.  The residue data do support a
tolerance of 30 ppm on the leaves of root and tuber vegetables from the
data on radish top at the use rate of the submitted residue field
trials.  ARIA has determined that the use rate on radish cannot exceed
the rate used on the submitted residue field trials.  The use rate on
the remainder of the root and tuber vegetables may remain as proposed.  

There is adequate number and geographic location of residue field trials
to support a tolerance registration on sweet potato.  The maximum
fludioxonil residue was 2.17 ppm after a post-harvest dip application at
0.25 lb ai/100 gal water.  The data are adequate to support a tolerance
on the tuberous and corm vegetables (except potato) subgroup.  However,
the requested tolerances are not appropriate.  In addition, the
commodity definition is incorrect.  A revised Section F is required for
the residues of fludioxonil on vegetable, tuberous and corm (except
potato), subgroup 1D at 3.5 ppm.

There is adequate number and geographic location of residue field trials
to support a tolerance registration on tomato.  Analytical results show
that with a 0-day PHI, fludioxonil residues ranged from 0.014 to 0.229
ppm in treated tomato RAC samples grown in the field, and from 0.010 to
0.169 ppm in treated tomato RAC samples grown in a greenhouse.  The
tomato data will also support a tolerance on tomatillo.  ARIA recommends
for the requested tolerances of fludioxonil on tomato and tomatillo at
0.40 ppm.  However, the Codex tolerance limit is 0.5 ppm on tomato.  A
US tolerance lower than the Codex limit would cause a barrier to tomato
imports; therefore, the tomato and tomatillo tolerances should be
raised.  

As a condition for the registration of fludioxonil on Brassica
vegetables, HED required additional residue data from 5 field trials on
cabbage, two field trials on mustard greens, and one trial broccoli. 
Following four foliar applications totaling 0.88-0.93 lb ai/A,
fludioxonil residues were 0.06-1.11 ppm in/on cabbage at 6-8 day PHI,
1.01 and 1.04 ppm in/on mustard greens at 8-day PHI, and 0.11 and 0.14
ppm in/on broccoli at 8-day PHI.  Since the data for cabbage and
broccoli were produced with the appropriate use pattern, were of
sufficient number and correct locations as required by HED, and did not
exceed the established tolerance, ARIA concludes that the condition of
registration for fludioxonil on the Brassica, head and stem, subgroup 5A
may be removed.  HED also indicated that two trials on mustard greens
were required as a condition of registration.  Only one trial was
submitted.   Since the previously submitted data ranged so widely, the
additional trial would likely have an affect on the final tolerance
level.  Therefore, ARIA recommends that the conditional registration not
be removed and a required mustard green field trial study in Region 4
remains outstanding.

No citrus processing studies were submitted with this petition. 
Previous studies indicated that in citrus processed commodities
fludioxonil residues concentrate only on citrus oil at 61x and on pulp
at 2.1x.  The expected residues on citrus oil from this use at 9.76 ppm 
will not exceed the existing tolerance on citrus fruit and would be
considerably lower than the existing tolerance on grapefruit oil at 500
ppm.  Similarly, the expected residues on citrus pulp as a result of the
proposed use at 0.37 ppm will also not exceed the existing tolerance on
citrus fruit at 10 ppm.  No change in tolerances is required as a result
of the proposed use on lemon and lime.  

Fludioxonil was applied to tomato at a total of approximately 0.88 lb
ai/A, and harvested at 0-days PHI after final treatment.  Tomato RAC
samples were processed into puree and paste.  Fludioxonil residues
reduced in puree by a factor of 0.3x.  In paste samples, fludioxonil
residues were concentrated by factor of 1.1x.  The submitted tomato
processing study indicates that fludioxonil residues do not appreciably
concentrate in tomato processed commodities made from treated tomato
samples; therefore, tolerances are not required for tomato processed
commodities.

The proposed label indicates that only those crops listed on the label
may be rotated to a treated field at 0-day following treatment and all
other crops may be planted after 30 days.  Based on the results of the
confined and field rotational crop studies and the proposed application
rates, the label rotational crop restrictions are acceptable.     

  TC \l3 "5.1.10	Food Residue Profile 

5.1.9	International Residue Limits

There are no Canadian or Mexican Maximum Residue Limits (MRLs) for
residues of fludioxonil.  There are Codex limits on tomato (higher than
US; 0.5 ppm vs 0.40 ppm, proposed), herbs (equal to or lower than US),
cucurbits (lower than US), and carrot (lower than US).   Except for
tomato, the Codex MRLs are not a restriction on items for which there is
a significant import trade; therefore, there are no international
harmonization issues with these items.  Since having the US tolerance
lower than the Codex MRL would cause a barrier to tomato imports, the
tomato and tomatillo tolerances should be raised from 0.40 ppm to 0.50
ppm.  See Appendix D.  

 TC \l3 "5.1.11	International Residue Limits 

5.2	Dietary Exposure and Risk

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

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for Tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

For chronic dietary-exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

The dietary exposure analysis was performed by ARIA (B. Hanson, DP #:
342827, 6/17/2008).

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

An acute dietary assessment assuming tolerance-level residues for all
commodities with existing and proposed tolerances and default 100%CT
information was conducted for the population subgroup females 13-49
years old.  There were no appropriate toxicological effects attributable
to a single exposure (dose) for the general population or any other
population subgroups; therefore these population subgroups were not
included in this assessment.  The peak drinking water estimate of 81.3
ppb, provided by EFED, was directly incorporated into the acute
assessment.  The aPAD for females 13-49 years is 1.0 mg/kg/day.  For
food and drinking water, the exposure to females 13-49 years utilized
14% of the aPAD at the 95th percentile of exposure distribution (see
Table 5.2.2, below).  

  TC \l3 "5.2.1  Acute Dietary Exposure/Risk 

5.2.2	Chronic Dietary Exposure/Risk

A chronic dietary assessment assuming tolerance-level residues for most
commodities with existing and proposed tolerances and default 100%CT
information was conducted for the general population and all population
subgroups.  Anticipated residue (AR) values for apple, grapefruit,
lemon, lime, orange, and pear were generated from field trial data.  ARs
were also determined from processing studies for apple, grapefruit,
lemon, lime and orange juices.  Since a tomato processing study
demonstrated that residues do not concentrate in tomato processed
commodities, these processing factors were set to 1.  DEEMM-FCID(
default processing factors were used for all other processed
commodities.  The mean drinking water estimate of 37.4 ppb, provided by
EFED, was directly incorporated into the chronic assessment.  For the
U.S. population the exposure for food and water utilized 48% of the
cPAD.  The chronic dietary risk estimate for the highest reported
exposed population subgroup, children 1-2 years old, is 88% of the cPAD
(see Table 5.2.2, below).  

Table 5.2.2.  Summary of Dietary Exposure Risk (Food and Drinking Water)
for Fludioxonil

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary

	Dietary Exposure

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

(mg/kg/day)	% cPAD*

General U.S. Population	N/A	0.014371	48

All Infants (< 1 year old)

0.019681	66

Children 1-2 years old

0.026439	88

Children 3-5 years old

0.022796	76

Children 6-12 years old

0.016108	54

Youth 13-19 years old

0.011689	39

Adults 20-49 years old

0.013123	44

Adults 50+ years old

0.013566	45

Females 13-49 years old	0.138260	14	0.013593	45

5.2.3	Cancer Dietary Risk

HED classified fludioxonil as a “Group D” chemical – not
classifiable as to human carcionogenicity; therefore, quantification of
human cancer risk is not required and a cancer dietary assessment was
not performed.

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

Anticipated residue values for apple, grapefruit, lemon, lime, orange,
and pear were generated from field trials, see Table 5.3, below. 
Anticipated residues were determined from processing studies trials for
apple, grapefruit, lemon, lime and orange juices; therefore, processing
factors were set to 1x for these processed commodities.  Since a tomato
processing study demonstrated that residues do not concentrate in tomato
processed commodities, these processing factors were set to 1. 
DEEM-FCID( default processing factors were used for all other processed
commodities.

 

Table 5.3.  Anticipated Residue Values Used for Apple, Grapefruit,
Lemon, Lime, Orange and Pear Commodities

Commodity	Anticipated Residue (ppm)

Apple, whole

            juice	1.1

0.1

Grapefruit, whole

                   juice	2.6

0.74

Lemon, whole

              juice	1.7

0.02

Lime, whole

           juice	1.7

0.02

Orange1, whole

               juice	1.5

0.74

Pear, whole         	1.6

 No %CT information was considered in either the acute or the chronic
dietary analysis.  

6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

The current petition for fludioxonil results in no
residential/non-occupational exposures.  However, HED previously
assessed the use of fludioxonil in residential use scenarios to control
certain diseases of turfgrass and certain foliar, stem and root diseases
in ornamentals in residential landscapes (DP#: 282570, T. Swackhammer,
5/6/2002).  Since the product registered for residential uses,
Medallion® (EPA Reg. No. 100-769), is restricted for residential uses
to commercial applicators-only, and since HED did not select short- or
intermediate-term dermal endpoints, only a toddler post-application
assessment for incidental ingestion exposures to treated lawns was
included.  

The combined short-term oral exposure risk estimate, which includes
hand-to-mouth, object-to-mouth and soil ingestion pathways, was
previously determined to be 0.013 mg/kg bw/day, while the
intermediate-term was determined to be 0.0074 mg/kg bw/day.  It should
be noted that each of the incidental oral assessments (i.e.,
hand-to-mouth, object-to-mouth and soil ingestion) are considered
conservative.  Therefore, combining all the assessments is expected to
provide a highly conservative assessment of children’s incidental oral
exposure.

For a complete review of the potential risks and calculations associated
with residential uses of fludioxonil, please see the above mentioned T.
Swackhammer memo.

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 fludioxonil.
 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.

It is noted that the 0.68 lb ai/acre application rate for residential
turf was modeled to estimate post-application residential exposure of
toddlers.  As this rate is equal to or higher than many of the currently
registered agricultural application rates, this scenario is protective
of any exposure of farm children via spray drift from agricultural
fludioxonil applications.

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

	

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways.  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, ARIA considers both the route and duration of exposure.

7.1	Acute Aggregate Risk

	

Since the acute aggregate risk assessment includes exposure from food
and water only, and the acute dietary analysis that was performed
included both, no further calculations are necessary.  Since the acute
dietary risk does not exceed ARIA’s level of concern, the acute
aggregate risk does not exceed ARIA’s level of concern.

 TC \l2 "7.1	Acute Aggregate Risk 

7.2	Short-Term Aggregate Risk

In aggregating short-term risk, ARIA considers background chronic
dietary exposure (food + water) and short-term, residential non-dietary
oral and dermal exposures.  The label specifies that the residential
application of fludioxonil is restricted to commercial handlers. 
Therefore, only post-application exposure is expected to result from the
residential uses of fludioxonil.  For adults, post-application exposures
may result from dermal contact with treated turf.  For toddlers, dermal
and non-dietary oral post-application exposures may result from dermal
contact with treated turf as well as hand-to-mouth transfer of residues
from turfgrass.  However, HED did not select short- dermal endpoints for
fludioxonil.  Therefore, the short-term aggregate risk for fludioxonil
considers food, water, and residential non-dietary oral exposures (for
toddlers).

Table 7.2 summarizes the short-term aggregate exposure estimates to
fludioxonil residues.

Table 7.2.  Short-Term Aggregate Risk (Food, Drinking Water and
Residential Exposure)

Population	Short-Term Scenario

	NOAEL

mg/kg/day	LOC

MOE1	Average

Food + Water

Exposure

mg/kg/day	Oral Residential Exposure2

mg/kg/day	Aggregate MOE

(food, water

& residential)3

All Infants (< 1 year old)	10	100	0.019681	0.013	310

Children (1-2 years)	10	100	0.026439	0.013	250

Children (3-5 years)	10	100	0.022796	0.013	280

1 The level of concern (LOC) MOE is 100, based on inter- and
intra-species safety factors totaling 100.

2 Oral Residential Exposure = [Incidental Oral exposure from all
possible sources].

3 Aggregate MOE = [NOAEL ÷ (Avg. Food + Water Exposure + Residential
Exposure)].

All short-term aggregate risk estimates result in MOEs greater than 100.
 Short-term aggregate exposure to fludioxonil, as a result of all
registered and proposed uses, is below ARIA’s level of concern.

 TC \l2 "7.2	Short-Term Aggregate Risk 

7.3	Intermediate-Term Aggregate Risk

In aggregating intermediate-term risk, ARIA consider background chronic
dietary exposure (food + water) and intermediate-term, residential
non-dietary oral and dermal exposures.  Based on the residential use
pattern, there is a possibility, although unlikely, that a toddler may
experience intermediate-term exposures to fludioxonil residues on
treated lawns.  As with the short-term aggregate assessment, only
non-dietary exposures are included.  Therefore, the intermediate-term
aggregate risk for fludioxonil considers food, water, and residential
non-dietary oral exposures (for toddlers).

Table 7.3 summarizes the intermediate-term aggregate exposure estimates
to fludioxonil residues.

Table 7.3.  Intermediate-Term Aggregate Risk (Food, Drinking Water and
Residential Exposure)

Population	Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC

MOE1	Average

Food + Water

Exposure

mg/kg/day	Oral Residential Exposure2

mg/kg/day	Aggregate MOE

(food, water

& residential)3

All Infants (< 1 year old)	3.3	100	0.019681	0.0074	120

Children (1-2 years)	3.3	100	0.026439	0.0074	98

Children (3-5 years)	3.3	100	0.022796	0.0074	110

1 The level of concern (LOC) MOE is 100, based on inter- and
intra-species safety factors totaling 100.

2 Oral Residential Exposure = [Incidental Oral exposure from all
possible sources].

3 Aggregate MOE = [NOAEL ÷ (Avg. Food + Water Exposure + Residential
Exposure)].

All intermediate-term aggregate risk estimates result in MOEs greater
than 100, with the exception that the MOE for children 1-2 years old is
just below 100.  Due to the conservative nature of the dietary (assumes
100%CT) and residential assessments, ARIA does not have any concern for
the purposes of this action.  Intermediate-term aggregate exposure to
fludioxonil, as a result of all registered and proposed uses, is below
ARIA’s level of concern.

 TC \l2 "7.3	Intermediate-Term Aggregate Risk 

7.4	Chronic Aggregate Risk  TC \l2 "5.4  Chronic Aggregate Risk 

Since the chronic aggregate risk assessment includes exposure from food
and water only, and the chronic dietary analysis that was performed
included both, no further calculations are necessary.  Since the chronic
dietary risk does not exceed ARIA’s level of concern, the chronic
aggregate risk does not exceed ARIA’s level of concern.

7.5	Cancer Aggregate Risk  TC \l2 "5.5  Cancer Aggregate Risk 

Fludioxonil has been classified as a “Group D” chemical – not
classifiable as to human carcinogenicity; therefore, a cancer aggregate
risk assessment was not performed.      

 TC \l2 "7.5	Cancer Risk 

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to fludioxonil and any other
substances, and fludioxonil 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 fludioxonil 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

ARIA provided an assessment for the use of fludioxonil on tomato,
tomatillo, tropical fruit, herbs, root vegetables, lemon, lime,
cucurbits, tuberous and corm vegetables (DP#: 343968, 343967, M. Dow,
9/13/2007).  

The use pattern summary is taken from the Sections B of the IR-4
submissions and from the product labels.  ScholarTM contains 50.0 %, by
weight, fludioxonil ai in a wettable powder (WP) formulation.  Switch®
is a combination product which contains 37.5 %, by weight, cyprodinil ai
and 25.0 %, by weight, fludioxonil ai.  It is formulated as a WDG.  Both
product labels direct applicators and other handlers to wear personal
protective equipment (PPE) consisting of a long-sleeved shirt, long
pants, chemical resistant gloves made of any waterproof material and
shoes plus socks.

See Table 9.0 for a summary of the proposed use pattern.

Table 9.0 Summary of Proposed Use Pattern for Fludioxonil

Crop/Site	Tuberous & Corm Vegetables

Tomato & Tomatillo

Tropical Fruit

Herbs (Dried & Fresh)

Root Vegetables (except sugarbeet)

Lemon & Lime

Cucurbit crops

Pest	numerous species of plant pathogenic organisms

Method of Applic.	Airblast for the “tree” crops; ground boom for
“row” crops

Max. Applic. Rate	0.22 lb ai/A fludioxonil

Max. No. Applications	1 application as a root dip for tuberous & corm
vegetables

1 application/year for lemon, lime 

4 applications/season at the high rate for tomato, tomatillo, tropical
fruit, herbs and root vegetables.

Applic. Interval	n/a for tuberous & corm vegetables, lemon, lime 

All others 7- 10 days  

Preharvest Interval	 0-day for Tuberous & Corm Vegetables, Tomato &
Tomatillo, Tropical Fruit, Lemon & Lime

7 days for  Herbs (Dried & Fresh) and Root Vegetables (except sugarbeet)
  

1 day for Cucurbit crops  

Restricted Entry Interval	12 hours for ScholarTM and Switch®

Manufacturer	Syngenta Crop Protection

9.1	Occupational Handler Risk

Based upon the proposed new use patterns, ARIA believes the most highly
exposed occupational pesticide handlers will be mixer/loaders handling
water dispersible granules, mixer/loaders using open-pour loading of
wettable powders, applicators using open-cab ground-boom sprayers and
applicators using open-cab air-blast sprayers.  The tuberous & corm
vegetables are intended to be treated as a post-harvest “fruit” dip.
  Based upon previous experience with post-harvest dips, ARIA expects
the fruit will be handled in bulk and that the dipping will be automated
in semi-closed systems (i.e., the dip tanks are shielded or hooded).  
Therefore there is no applicator in the strict sense.  Although the
fludioxonil product is a wettable powder, ARIA believes that the
assessment of mixer/loaders supporting ground spray operations is
adequate to describe exposure and risk that might occur for handlers
preparing minibulk dip solutions.  

Chemical specific data were not available with which to assess pesticide
handler exposure.   Therefore surrogate data from studies in the
Pesticide Handler Exposure Database Version 1.1 (August 1998) PHED
SURROGATE EXPOSURE GUIDE were used to estimate mixer/loader and
applicator exposure.  The PHED does not contain unit exposure data for
water dispersible granular formulations.  However, HED believes the unit
exposure data for dry flowable formulations are suitable and appropriate
surrogates and are therefore used herein.

It is ARIA policy to assess handler exposure and risk using
“baseline” Personal Protective Equipment (PPE) which is comprised of
long sleeved shirt, long pants, and shoes plus socks and if necessary to
assess “baseline” plus the use of protective gloves or other PPE as
might be necessary or appropriate.   The product labels direct pesticide
handlers to wear a long sleeved shirt, long pants, water proof chemical
resistant gloves and shoes plus socks.

ARIA believes for the crops listed, the exposures will be short-term (1
- 30 days) duration exposures.  Treatment blocks are not expected to be
large in the sense of such field crops as corn, soybeans, cotton or
wheat.  ARIA believes it is highly unlikely that intermediate-term
exposures (30 days - 6 months) would occur.  

Relevant to the assessment herein, HED did not identify a dermal
toxicological endpoint.  An assessment of dermal exposure and risk is
not necessary.   However, HED did identify a short-term (1-30 days)
inhalation toxicological endpoint from a rabbit developmental study. 
The NOAEL is 10.0 mg ai/kg bw/day.  

For a summary of the estimated handler exposures and risks, see Table
9.1, below.  

Table 9.1  Summary of Exposure & Risk for Occupational Handlers Applying
Fludioxonil 

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

(Inhalation)

Mixer/Loader Open Loading Dry Flowable

Inhal.             0.00077 HC	0.22 lb ai/A	80 A/day	Inhal.          
0.0000226	440,000

Applicator Open-Cab Airblast

Inhal.             0.0045 HC	0.22 lb ai/A	40 A/day	Inhal.           
0.00066	15,000

Applicator Open-Cab Ground-boom

Inhal.             0.00074 HC	0.22 lb ai/A	80 A/day	Inhal.            
0.000217	46,000

1.  Unit Exposure = mg a.i./lb a.i. handled; taken from the Pesticide
Handler’s Exposure Database

PHED Surrogate Exposure Guide version 1.1; August 1998; Dermal: SLNG =
Single Layer of Work Clothing [ long sleeved shirt, long pants, shoes +
socks] NO Gloves.  SLWG = single layer work clothing [long sleeved
shirt, long pants, shoes + socks) WITH Gloves;  Inhalat. = Inhalation. 
HC = high  confidence data.

2.  Application Rate from Switch®  product label

3.  Acres Treated are derived from  Sci.Adv.Council for Exposure SOP.
No. 9.1 Rev. 25 SEP 01.

4.  Average Daily Dose (ADD) = Unit Exposure * Application Rate * Units
Treated  (  kg body weight.     Inhalation  exposures assume 100% 
absorption.   For fludioxonil use 60 kg bw (NOAEL taken from a
developmental study)

5.  Margin of Exposure (MOE) = NOAEL ( ADD.    NOAEL = No Observable
Adverse Effect Level (mg a.i./kg bw/day)  Fludioxonil - short-term
inhalation NOAEL = 10.0 mg a.i./kg bw/day.

A MOE of exposure of 100 is adequate to protect occupational pesticide
handlers.  Since the estimated MOEs > 100, the proposed uses do not
exceed ARIA’s level of concern.  

  TC \l2 "9.1	Short-/Intermediate-/Long-Term/Cancer (if needed) Handler
Risk 

9.2	Occupational Post-Application Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk 

There is no dermal toxicological endpoint identified therefore there is
no concern for dermal contact.  ARIA assumes post-application inhalation
exposures are negligible, especially in view of the 12 hour restricted
entry interval for these products.  Therefore post-application exposure
to fludioxonil is not assessed.

10.0	TOLERANCE SUMMARY	

There are no Canadian or Mexican Maximum Residue Limits (MRLs) for
residues of fludioxonil.  There are Codex limits on tomato (higher than
US; 0.5 ppm vs 0.40 ppm, proposed), herbs (equal to or lower than US),
cucurbits (lower than US), and carrot (lower than US).   Except for
tomato, the Codex MRLs are not a restriction on items for which there is
a significant import trade; therefore, there are no international
harmonization issues with these items.  Since having the US tolerance
lower than the Codex MRL would cause a barrier to tomato imports, the
tomato and tomatillo tolerances should be raised from 0.40 ppm to 0.50
ppm.  A revised Section F should be submitted for the tolerances of 0.50
ppm on tomato and tomatillo.

Table 10.0.  Tolerance Summary for Fludioxonil

Commodity	Established/Proposed

Tolerance (ppm)	Recommended

Tolerance (ppm)	Comments (correct commodity 

definition)

Tomato	0.40	0.50	Raised for harmonization issues

Tomatillo	0.4	0.50	Raised for harmonization issues

Tomato, paste	1.0	None

	Avocado 		0.45	0.45

	Black sapote 		0.45	0.45

	Canistel	0.45	0.45

	Mamey sapote	0.45	0.45

	Mango 	0.45	0.45

	Papaya 	0.45	0.45

	Sapodilla 	0.45	0.45

	Star apple 		0.45	0.45

	Herb Subgroup 19A,

 fresh 			13 (Requested)

10 (Established)	10	Retain Established Tolerance

Herb Subgroup 19A,

 dried 			55 (Requested)

65 (Established)	65	Retain Established Tolerance

Leaves of root and

tuber vegetables	40 (Requested)

0.02 (Established)	30	Leaves of root and tuber vegetables,

group 2

Root vegetables, except

sugar beet subgroup	0.50	0.75	root vegetables, (except sugar beet),

subgroup 1B

Lemon 	0.25	None

	Lime 	0.25	None

	Cucurbits 	0.60	0.45	vegetable, cucurbit, crop group 9 

Tuberous and corm

vegetables, except potato

 subgroup	4.0	3.5	vegetable, tuberous and corm

(except potato), subgroup 1D 

Carrot 	0.75	None	Remove Established Tolerance

Turnip, greens 	10	None	Remove Established Tolerance

Citrus oil	None	500

	Grapefruit oil	500	None	Remove Established Tolerance

11.0	DATA NEEDS AND LABEL RECOMMENDATIONS

No additional occupational risk data are required. The toxicology
database is essentially complete and there is no evidence of
neurotoxicity or immunotoxicity in the hazard database for fludioxonil.
While the new Part 158 requirement for an immunotoxicity study and acute
and subchronic neurotoxicity studies have not yet been fulfilled for
fludioxonil, the existing data are sufficient for endpoint selection for
exposure/risk assessment scenarios and for evaluation of the
requirements under the FQPA.   

Toxicology

The following is a toxicology deficiency;

Revised Part 158 requires immunoxicity and neurotoxicity studies be
submitted.  Note that data requirements pertaining to immunotoxicity
must be fulfilled as a condition of registration. 

Residue Chemistry

The following are residue chemistry deficiencies noted in the residue
chemistry chapter;

Section B on root and tuber vegetables, except sugar beets should be
renamed “root and tuber vegetables except sugar beets and radish” as
the radish requested use is not supported by appropriate residue field
trial data.  Section B should also be revised to indicate that the use
on radish should be 2 applications at 0.22 lb ai/A with 7-day
retreatment intervals and a 7-day PHI. The petitioner has indicated that
there will be a restriction on the feeding of the leaves of root and
tuber vegetables.  This should also be added to the proposed Section B.

As a condition of registration, a livestock feeding study is required.

A revised Section F is required for the residues of fludioxonil on
vegetable, cucurbit, crop group 9 at 0.45 ppm

The requested tolerances on lemon and lime should be removed from
Section F.

Section F should be revised removing the proposed changes in the herb
subgroup 19A, fresh and dried, and the established tolerances retained. 

A revised Section F is required for the residues of fludioxonil on root
vegetables, except sugar beet subgroup 1B at 0.75 ppm.  

A revised Section F is required for the residues of fludioxonil on the
leaves of root and tuber vegetables, group 2 at 30 ppm. 

A revised Section F should be submitted for the tolerances of 0.50 ppm
on tomato and tomatillo.

A revised Section F is required for the residues of fludioxonil on
vegetable, tuberous and corm (except potato), subgroup 1D at 3.5 ppm.

ARIA recommends that the conditional registration not be removed and a
required mustard green field trial study in Region 4 remains
outstanding.

Dietary Exposure Memorandum

	Acute and Chronic Dietary (Food and Water) Exposure Assessment for the
Petition Request Proposing Tolerances for Residues of Fludioxonil on
Avocado, Carrot, Cucurbit, Lemon, Parsley, Radish, Sweet Potato, Tomato,
and Brassica Vegetables.  PP# 7E7234, B. Hanson, DP#: 342827,
06/17/2008.

Drinking Water Memorandum

	Tier I Drinking Water Assessment for the Fludioxonil Proposed New Use
on Grapes; and the Proposed IR-4 New Uses on Tomato, Avocado and Related
Tropical Fruits, Herb Subgroup 19A, Root Vegetables, Leaves of Root
Vegetables, Lemon, Lime, Cucurbits, and Tuberous and Corm Vegetables
(Except Potato Subgroup, Except Yam). C. Sutton, DP#: 342828, 348540,
3/12/2008.

	

Residue Chemistry Data Review Memorandum

	Fludioxonil.  Section 3 Requests for the Uses on Avocado, Carrot,
Cucurbit, Lemon, Parsley, Radish, Sweet Potato, Tomato, and Brassica
Vegetables.  Summary of Analytical Chemistry and Residue Data.  W.
Cutchin, DP#: 345970, 349725, 5/20/2008

Occupational and Residential Exposure Memorandum

	Cyprodinil and Fludioxonil – Occupational Exposure/Risk Assessment
for Proposed New Uses of Cyprodinil and Fludioxonil on Tomato,
Tomatillo, Tropical Fruit, Herbs, Root Vegetables, Lemon, Lime,
Cucurbits, Kiwi Fruit, Tuberous and Corm Vegetables.; DP #: 343968,
343967; M. Dow; 9/13/2007.

Risk Assessment Document

	Fludioxonil.  Human Health Risk Assessment for a Section 18 Emergency
Tolerance on Starfruit. B. Hanson, DP#: 344676, 11/27/2007.

	Registration: 100-953; Fludioxonil in/on Onions and Strawberries
(PP#8E05026); Health Effects Division (HED Human-Health Risk Assessment;
W. Wassell, DP#: 325149, 11/08/2006.

	Fludioxonil: Amended Human Health Risk Assessment for Section 3
Tolerance Requests on Kiwi (Post-Harvest), Mustard Seed, Yam, Beans (Dry
and Succulent), Citrus, Leafy Greens except spinach, Melons, Pome Fruit
and Pomegranate; L. Jones, DP #s: 292567, 293233, 298001, 306183;
11/22/2004. 

HIARC

	Fludioxonil – Report of the Hazard Identification Assessment Review
Committee; W. Dykstra, HED Doc. No. 013806, 10/13/1999

	Fludioxonil- 2nd Report of the Hazard Identification Assessment Review
Committee; W. Dykstra, TXR No: 0050427, 1/29/2002.

Appendix A:  TOXICOLOGY ASSSESSMENT

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

no	yes

yes

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	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

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

no

no

no	--

--

--

--

--

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

--

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no

no

no

no	no

no

no

no

A.2	Toxicity Profiles

Table A.2.  Acute Toxicity of Fludioxonil

Guideline

 No.	

Study Type	

MRID #(S).	

Results	

Toxicity Category

81-1	

Acute Oral	

43124105	

LD50 > 5000 mg/kg	

          IV

81-2	

Acute Dermal	

43124106	

LD50 > 2000 mg/kg	

          III

81-3	

Acute Inhalation	

43080019	

LC50 = 2.636 m/L	

          IV

81-4	

Primary Eye  Irritation	

43124107	

slight irritant	

          III

81-5

 	

Primary Skin Irritation	

43124108	

non-irritating	

          IV

81-6	

Dermal Sensitization	

43080024	

not a sensitizer	

A.3	Executive Summaries

A.3.1	Subchronic Toxicity

870.3100	Oral Subchronic Toxicity – Rodent

Not applicable.

870.3105	Oral Subchronic Toxicity – Nonrodent

Not applicable.

870.3200	21-Day Dermal – Rat

Not applicable.

870.3250	90-Day Dermal – Rat

Not applicable.

870.3465	90-Day Inhalation – Rat

Not applicable.

A.3.2	Prenatal Developmental Toxicity

870.3700a 	Developmental Toxicity Study – Rodent

Study Selected:  Developmental Toxicity – Rat

MRID No.: 43080034

Executive Summary:  In a developmental toxicity study, CGA-173506
technical (97.5% a.i.) was administered by oral gavage in 0.5%
carboxymethyl cellulose to groups of 25 pregnant female Sprague-Dawley
rats on gestation days  6-15 inclusive at doses of 0, 10, 100, or 1000
mg/kg/day.  Maternal toxicity was evident at the 1000 mg/kg/day in the
form of a 16% reduction in corrected body weight gain.  Developmental
toxicity was evident at the 1000 mg/kg/day dose level in the form of an
increased fetal and litter incidence of dilated renal pelvis and dilated
ureter.  There were no Cesarean section observations and no significant
maternal histopathology.  The maternal toxicity NOAEL is 100 mg/kg/day
based on 16% decrease in corrected weight gain at the LOAEL of 1000
mg/kg/day.  The developmental NOAEL is 100 mg/kg/day based on the
increased fetal and litter incidence of dilated renal pelvis and dilated
ureter at the LOAEL of 1000 mg/kg/day. 

870.3700b 	Prenatal Developmental Toxicity Study – Nonrodent 

Study Selected:  Developmental Toxicity – Rabbit

MRID No.: 43080035

Executive Summary:  In a developmental toxicity study, fludioxonil
technical (97.5% a.i.) in a 0.5% methyl cellulose solution in distilled
water was administered by oral gavage to groups of NZW rabbits during
gestation days 6 through 18 at doses of 0, 10, 100, or 300 mg/kg/day. 
Minimal maternal toxicity was noted in the mid and high dose groups as
decreased body weight gain during the dosing period (gestation days 6
through 18), for the overall dosing plus post dosing period (gestation
days 6 through 28), for the entire gestation period, and for the
corrected body weight gains for the dosing plus post dosing periods. 
The high dose group consumed less food than the control during the
dosing period (gestation days 6-19), the post dosing period (gestation
days 19-28), the dosing plus post dosing period (gestation days 6-28)
and for the overall gestation period.  Food efficiency was decreased in
the mid and high dose groups during the dosing plus post dosing periods
(gestation days 6-28).  The maternal toxicity NOAEL was 10 mg/kg/day
based on decreased body weight gains and decreased food efficiency at
the LOAEL of 100 mg/kg/day.

No developmental toxicity was noted at the dose levels tested.  The
developmental toxicity NOAEL was equal to or greater than 300 mg/kg/day
and the developmental LOAEL was greater than 300 mg/kg/day.

A.3.3	Reproductive Toxicity

870.3800 	Reproduction and Fertility Effects – Rat

Study Selected:   Reproduction Toxicity Study - Rats

MRID No.: 43080036

Executive Summary:  In a reproductive toxicity study, rats received
either 0, 30, 300, or 3000 ppm (equivalent to 0, 2.19, 22.13, or 221.61
mg/kg/day for the males and 0, 2.45, 24.24, or 249.67 mg/kg/day for the
females) fludioxonil technical in the diet for 2 generations.  The
parental systemic toxicity LOAEL is 221.61 mg/kg/day for males and
249.67 mg/kg/day for females (3000 ppm) and the parental systemic
toxicity NOAEL is 22.13 mg/kg/day for males and 24.24 mg/kg/day for
females (300 ppm) based on clinical observations, reduced body weight
and body weight gains and reduced food consumption.  The
reproductive/developmental toxicity LOAEL is 221.61 mg/kg/day for males
and 249.67 mg/kg/day for females (3000 ppm) and the
reproductive/developmental toxicity NOAEL is 22.13 mg/kg/day for males
and 24.24 mg/kg/day for females (300 ppm) based on reduced pup body
weights.

 

A.3.4	Chronic Toxicity

870.4100b 	Chronic Toxicity – Nonrodent

Study Selected:   Chronic One-year Feeding Study - Dog

MRID No.: 43080031

Executive Summary:  In a chronic toxicity study, male and female beagle
dogs received CGA-173506 technical (97.5% a.i.) in the diet for 52 weeks
at doses of 0, 100, 1000, or 8,000 ppm (3.3, 33.1, or 297.8 mg/kg/day in
males and 3.3, 35.5, or 330.7 mg/kg/day in females).  At the 8000 dose
level, body weight in male dogs was decreased by 15% vs control for
weeks 1-52 and was decreased in female dogs by 19% vs control for weeks
1-52.  Increased platelets were observed in both sexes (11-31% in males,
21-24% in females) as was increased fibrin (15-48% in males, 3-10% in
females).  Cholesterol was increased 56-68% in male dogs, while alkaline
phosphatase was increased 22-36% in male dogs and 48-70% in female dogs.
 Relative liver weight was increased in both sexes by 27-36% at 8000
ppm, and enlarged liver was observed in 2 of 4 high dose female dogs
along with biliary epithelial cell proliferation in one high dose female
dog.  At 1000 ppm, body weight gain was decreased in female dogs to 69%
of control for weeks 1-13, and to 57% of control for weeks 1-52. The
NOAEL for males is 33.1 mg/kg/day and for females is 3.3 mg/kg/day.  At
the LOAEL of 297.8 mg/kg/day in males, there was decreased body weight,
clinical pathology alterations, and increased relative liver weight.  At
the LOAEL of 35.5 mg/kg/day in females, there was marked decrease in
body weight gain for weeks 1-13 and 1-52. 

A.3.5	Carcinogenicity

870.4200a 	Oncogenicity – Rat

Study Selected:   Combined Chronic Toxicity/Carcinogenicity Study - Rat

MRID No.: 43080037

Executive Summary:   See summary below for Combined Chronic
Toxicity/Carcinogenicity Study - Rat.  

870.4200b 	Oncogenicity – Mouse

Study Selected:  Carcinogenicity Study - Mouse

MRID No.: 43080032, 43080033

Executive Summary:  In a carcinogenicity study in mice fludioxonil
technical was administered in the diet to mice at nominal dose levels of
0, 10, 100, 1000, or 3000 ppm (0, 1.1, 11.3, 112, or 360 mg/kg/day for
male mice; 0, 1.4, 13.5, 133, or 417 mg/kg/day for female mice). 
Clinical toxicity was evident in male mice at the 1000 and 3000 ppm dose
levels in the form of increased incidence of male mice which
‘convulsed’ when handled.  There were no significant effects on body
weight, weight gain, food consumption, hematology, or microscopic
non-neoplastic pathology in either sex.  Increased liver weight (9%) and
spleen weight (34%) were observed in male mice at the 3000 ppm dose
level, which correlated with the macroscopic observations of enlarged
spleen and raised foci of the liver in male mice.  Female mice showed a
statistically significant increase in liver weight at the 3000 ppm dose
level, and this is supported by the macroscopic observation of enlarged
liver at the 3000 ppm dose level in female mice.  Other macroscopic
changes noted in female mice were an increased incidence of enlarged
thymus, spleen, mediastinal lymph node, and liver.  These macroscopic
observations were supported microscopically by increased incidence of
lymphoma in these organs.  The LOAEL is 112 mg/kg/day (1000 ppm) for
male mice, based on the increase in incidence of clinical toxicity in
male mice (specifically, the increased incidence of mice convulsing when
handled) and 417 mg/kg/day (3000 ppm) for female mice, based on the
increase in liver weight of female mice, and the increase in incidence
of macroscopic pathology.  The NOAEL is considered to be 11.3 mg/kg/day
(100 ppm) for male mice and 133 mg/kg/day (1000 ppm) for female mice.

There was evidence of carcinogenicity in this study in the form of a
statistically significant trend in female mice for lymphomas considered
to be contributory to death.  This effect was due to the early onset and
high incidence of lymphoma at the 3000 ppm dose relative to the control
onset and incidence.  Total incidence of lymphoma was stated to be
11/59, 10/59, 13/60, 12/60, and 18/60 for the 0, 10, 100, 1000, and 3000
ppm dose levels in female mice.  This increase in total lymphoma was
significant by a trend test but not pair wise comparison.

The question of the adequacy of the doses used in this study for
assessment of carcinogenic potential is complicated by the observation
of increased lymphoma incidence at a dose of 3000 ppm, which produced
some systemic effects (such as increased incidence of male mice which
‘convulsed’ when handled, and increased incidence of macroscopic
pathology in both sexes), but produced no significant effects on body
weight, weight gain, food consumption, hematology, or microscopic
non-neoplastic pathology in either sex.  If the tumors can be supported
as an effect of treatment, then this finding by itself can be used to
support the adequacy of dosing in this study. If, on the other hand, the
tumors are unrelated to treatment, then the doses used in this study are
not adequate.  The registrant has performed a second mouse study using
top doses of 5000 and 7000 ppm.

Executive Summary for Second Study:  In a second carcinogenicity study
in mice fludioxonil technical was administered in the diet at nominal
dose levels of 0, 3, 30, 5000, or 7000 ppm (0, 0.33, 3.3, 590, or 851
mg/kg/day for male mice; 0, 0.41, 4.1, 715, or 1008 mg/kg/day for female
mice).  At the 7000 ppm dose level, reduced survival was observed in
both sexes from week 53 of the study onward in comparison to control. 
Survival at 78 weeks in female mice exceeded the guideline limit by 5%. 
Body weight gain was reduced in male mice by 24-28%, but no significant
effects were seen in female mice.  Increases in the incidence of
discolored urine and stool, dyspnea, hypothermia, reduced activity, and
tremors were observed in both sexes.  Reduced red cell count (8-18% in
males, 23-30% in females), hemoglobin (13-20% in males, 27-30% in
females), and hematocrit (13-20% in males, 25-28% in females) were
observed at 12 and 18 months.  Liver weight was increased by 7-9% in
male mice and by 19-33% in female mice, and increased incidence of bile
duct hyperplasia and necrosis were observed only in male livers.  Kidney
weight was decreased by 21-24% in male mice but was increased by 15% in
female mice.   Marked to severe nephropathy was observed in both sexes,
and was a factor contributory to death in both sexes at 7000 ppm. 
Calcification and chronic inflammation were also present in increased
incidence at this dose for both sexes.  At 5000 ppm, survival in male
and female mice was reduced mildly, and body weight gain in male mice
was decreased by 8-15% vs control.  Discolored urine and stool were
observed in increased incidence in both sexes at this dose.  Minimal to
moderate nephropathy was observed in increased incidence for both male
and female mice, but was not a factor contributory to death at this
dose. 

 

In male and female mice, the 7000 ppm dose level produced significant
systemic effects in addition to significant nephropathy.  For both
sexes, the nephropathy at this dose was considered a factor contributory
to death in a majority of the mice.  In addition, survival in female
mice by the end of the study was below 25%, which exceeds the guideline
criteria for survival in a mouse carcinogenicity study.  Although
changes in liver weight were observed at both 5000 and 7000 ppm for male
and female mice, these changes could not be related to any histological
alterations in the liver.  Therefore, the LOAEL is considered to be 851
mg/kg/day in males; 1008 mg/kg/day in females (7000 ppm).  The NOAEL is
considered to be 590 mg/kg/day in males; 715 mg/kg/day in females (5000
ppm).

Discussion of Tumor Data:  	There was no evidence of increased incidence
of tumors in this study for male and female mice.

Adequacy of the Dose Levels Tested:  The 7000 ppm dose level is
considered adequate for testing of the carcinogenic potential in male
mice, based on the significant systemic effects and nephropathy observed
at this dose.  For female mice, the 7000 ppm dose level is considered
excessive, based on the reduction in survival at this dose which exceeds
the guideline limit.  An adequate dose for testing of carcinogenicity in
female mice is considered to be between 5000-7000 ppm, based on the
observation of significant systemic effects at 7000 ppm but excessive
reductions in survival, and a lack of sufficient effects at 5000 ppm,
supporting a dose level in between these 2 doses for female mice.

870.4300		Chronic/Oncogenicity

Study Selected:   Combined Chronic Toxicity/Carcinogenicity Study - Rat

MRID No.: 43080037

Executive Summary:   In a combined chronic toxicity/carcinogenicity
study, rats were fed fludioxonil technical in the diet at concentrations
of either 0, 10, 30, 100, 1000 or 3000 ppm for either 12 or 24 months
(males: 0, 0.37, 1.1, 3.7, 37 or 113 mg/kg/day, respectively; females:
0, 0.44, 1.3, 4.4, 44 or 141 mg/kg/day, respectively).  In addition,
rats from the control and 3000 ppm groups were fed the test diets for 12
months and then allowed to recover for one month prior to sacrifice. 

Males in the 1000 and 3000 ppm groups and females in the 3000 ppm group
had a higher incidence of dark stool and urine and staining (mostly
blue) around the pelvic region and abdomen.  The 3000 ppm group males
also had a higher frequency of diarrhea. Mean body weight and body
weight gain in the 3000 ppm group males and females were decreased in
comparison to the control throughout the study.  Body weight gain for
the 3000 ppm group males and females at Week 13 was 90 and 92% of the
control value, respectively.  There was no treatment-related effect on
food or water consumption.  Food efficiency was significantly reduced
for the 1000 and 3000 ppm group males during the first 13 weeks of the
study.

Females in the 3000 ppm group had some evidence of slight anemia at the
12-month evaluation.  At necropsy, there was an increased incidence in
the following changes in males: enlarged livers in the 3000 ppm group;
kidneys with cysts in the 1000 and 3000 ppm groups; and kidneys with
discolored foci or general discoloration in the 3000 ppm group. In the
females, there was an increased incidence of kidneys with general
discoloration in the 1000 and 3000 ppm groups.  There were no
treatment-related effects on organ weight.  On histopathology, males in
the 3000 ppm group had an increased incidence of kidney cysts and a
higher frequency and increased severity of progressive nephropathy.
Males and females in the 3000 ppm group had an increased incidence and
more severe grade of histopathological changes in the liver.

There was an increased incidence of hepatocellular tumors in both sexes
of the 3000 ppm group, however the increase in males was not
statistically significant.  The only statistically significant finding
in females was an increase in combined adenomas and carcinomas (0/70,
1/60, 0/60, 1/60, 2/60 and 5/70 in the 0, 10, 30, 100, 1000 and 3000 ppm
groups, respectively). Males and females in the 3000 ppm group had an
increased incidence of basophilic foci in the liver; males also had an
increase in hepatocellular hypertrophy.  There were no differences
between the control and the 3000 ppm group males or females in the
recovery phase evaluations.

The LOAEL for males and females was 113 and 141 mg/kg/day, respectively
(3000 ppm) based on decreased body weight and weight gain, slight anemia
in females at 12 months, and increased incidence and severity of
histopathology changes in the liver. The NOAEL for males and females was
37 and 44 mg/kg/day, respectively (1000 ppm).

Discussion of Tumor Data:  Fludioxonil technical was not carcinogenic in
male rats.  There was a statistically significant increase in the
incidence of combined adenomas and adenocarcinomas of the liver in
female rats in the 3000 ppm (141 mg/kg/day) group.

Adequacy of the Dose Levels Tested:  The 3000 ppm dose level was
considered adequate for carcinogenicity testing, based on decreased body
weight and body weight gain in both sexes, slight anemia in females at
12 months,  and an increased incidence and severity of liver
histopathology changes in both sexes.

A.3.6	Mutagenicity

870.5100 	Mutagenicty – Bacterial; Ames Salmonella Assay

MRID No.:  43080038

Executive Summary:  Fludioxonil technical was tested in two independent
trials for the ability to cause mutations in Salmonella typhimurium 
strains TA-1535, 1537, 98, and 100  in the absence and presence of
metabolic activation (Arochlor 1254 induced rat liver S-9).  Fludioxonil
technical was also tested for mutagenic effects on the
tryptophan-auxotrophic strain E. coli WP2uvrA.  Fludioxonil technical at
concentrations of 0, 20, 78, 313, 1250, or 5000 µg/plate in the absence
and presence of metabolic activation failed to produce an increase in
revertant colonies in either Salmonella or E. coli.  Doses greater than
313 µg/plate were insoluble.  There was evidence of cytotoxicity at the
1250 and 5000 µg/plate concentrations for the Salmonella strains
tested.  Positive controls appeared adequate for all strains of
Salmonella tested and for the strain of E. coli tested.  

 

870.5300 	Mutagenicty – Bacterial; Point Mutation Test – Chinese
hamster

MRID No.:  43152501

Executive Summary:  Fludioxonil technical was tested for the ability to
cause mutations in Chinese hamster V79 ovary cells in vitro in the
absence and presence of metabolic activation (Aroclor 1254 induced rat
liver S-9).   Cells were treated without microsomal activation for 21
hours and for 5 hours with microsomal activation.  Doses used were:
non-activation, 0.5-10.0 µg/ml (initial experiment); 1.0-20.0 µg/ml
(confirmatory experiment); activation, 1.5-30.0 µg/ml (initial
experiment); 3.0-60.0 µg/ml (confirmatory experiment).  Doses > 16
µg/ml in the absence of S9 reduced cell survival by >90%, and
approximately 20% of the cells survived treatment with 60 µg/ml in the
presence of S9.  Fludioxonil technical at the concentrations tested in
this study produced no increase in number of thioguanine-resistant
colonies, mutant frequency, or in the mutant factor in Chinese hamster
V79 cells in the absence or presence of metabolic activation.   Under
conditions of non-activation and activation, positive control materials
produced the expected increases in mutant frequency and the mutant
factor, indicating the sensitivity and validity of the assay.

870.5375 	Mutagenicty – Structural Chromosomal Aberrations; In vitro
Chromosomal Aberration

MRID No.:  43080040

Executive Summary:  In an in vitro chromosome aberration assay in
Chinese hamster ovary (CHO) cells, CHO cells were exposed to ten
non-activated and ten S9-activated doses of fludioxonil technical
ranging from 1.37 to 700 µg/ml for 3 hours and harvested 21 hours
postexposure.  Cultures treated with 0, 10.94, 21.88, or 43.75 µg/ml
-S9 or 0, 5.47, 10.94, 21.88, 43.75, 87.5, 175 or 350 µg/ml +S9 were
scored for chromosome aberrations.  In a subsequent experiment, cells
were exposed to nonactivated doses of 1.37-700 µg.ml for 24 hours and
were harvested immediately following treatment.  Cultures treated with
2.73, 5.47, or 10.94 µg/ml were examined for aberrant cells.  The S9
fraction was derived from Aroclor 1254-induced male RAI rats and the
test material was delivered to the test system in dimethyl sulfoxide
(DMSO).

Severe cytotoxicity occurred at nonactivated doses > 87.5 µg/ml (3 hour
cell treatment) and > 43.75 µg/ml (24 hour cell treatment).  In the
presence of S9 activation, the test material was less cytotoxic, with
severe cytotoxicity only observed at 700 µg/ml.  The nonactivated test
material induced structural aberrations and polyploidy at 21.88 and
43.75 µg/ml following the 3 hour treatment.  Following the continuous
24-hour exposure to the nonactivated test material, a dramatic
dose-related increase in polyploids was seen; increases were 4- to
82-fold higher than the solvent control at concentrations ranging from
2.73-10.94 µg/ml, respectively.  Under S9-activated conditions, a
doubling of the mitotic index (MI) at 175 and 350 µg/ml was not
accompanied by scorable chromosome damage at the high dose. However, as
the test material concentration was lowered, increased yields of both
structural and numerical aberrations occurred.  Peak clastogenesis was
noted at 87.5-175 µg/ml and increases in polyploidy of 8-, 53-, and
12-fold over the solvent control were induced at 43.75, 87.5, and 175
µg/ml, respectively. Although the test material was genotoxic in both
the absence and presence of S9 activation, the reduction of cytotoxicity
under S9 activated conditions permitted the detection of fludioxonil
technical as a powerful inducer of mitotic arrest.  As the S9-activated
dose decreased, increasing proportions of the treated population were
able to recover from mitotic block and manifest the chromosome damage in
the subsequent cell division.  Overall, the results indicating
nondisjunction of chromosomes point to an effect on the mitotic spindle.

870.5375 	Mutagenicty – Structural Chromosomal Aberrations; In vivo
Chromosomal Aberration

MRID No.:  43080042

Executive Summary:  In an in vitro cytogenetic assay in Chinese hamster
bone marrow cells, Chinese hamsters received either a single oral gavage
administration of 0, 1250, 2500, or 5000 mg/kg fludioxonil technical. 
Based on the analytical determinations, the applied concentration of the
high dose was 3785-4380 mg/kg.  At 16, 24, or 48 hours
post-administration of the high dose, animals were sacrificed and bone
marrow cells were collected and examined for structural and numerical
chromosome aberrations.  The harvest time for mid- and low-dose animals
was 24 hours.  The test material was delivered to the animals as
suspensions prepared in 0.5% carboxymethyl cellulose.  There was no
evidence of compound toxicity in the treated animals or cytotoxic
effects on the target cell.  There was also no indication that the test
material induced a clastogenic effect in male or female Chinese hamster
somatic cells.  Although less than the limit dose was tested, it is
unlikely that increasing the level to 5000 mg/kg would alter the
conclusions relative to structural chromosome damage.  The results with
the positive control confirmed the sensitivity of the test system to
detect damage to chromosome morphology in Chinese hamster bone marrow
cells.  Nevertheless, the occurrence of hyperploidy in one mid-dose
female and trisomy in one high dose male was noted. 

870.5395 	Mutagenicty – In Vivo Cytogenetics; In vivo Hepatocyte
Micronucleus Assay

MRID No.:  43080043

Executive Summary:  In an in vivo rat hepatocyte micronucleus assay,
male rats received either single oral gavage doses of 1250, 2500, or
5000 mg/kg fludioxonil either 3 days prior to mitogenic stimulation with
1000 mg/kg 4-acetylaminofluorene (4-AAF; Phase 1) or 29 hours
post-mitogenic stimulation (Phase 2).  Hepatocytes were recovered 3 days
post-treatment with 4-AAF (Phase 1) or 3 days post-treatment with the
test material (Phase 2), and harvested liver cells were scored for the
frequency of micronucleated hepatocytes (MHs). The test material was
delivered to the test animals as suspensions prepared in 0.5%
carboxymethyl cellulose.  The test material was neither overtly toxic to
the rats nor cytotoxic to the target cell.  In Phase 1, there was also
no significant or dose-related increase in MHs. However, results from
Phase 2 showed significant increases in MHs at the intermediate (p =
0.02) and low (p < 0.0001) dose but no increases at the high dose.  The
study author considered this finding to be of no biological
significance.  However, the results are striking because of their
similarity to the dose-response obtained in the in vitro Chinese hamster
ovary (CHO) cell cytogenetic assay conducted with fludioxonil technical
(see MRID # 43080040).  In this study, fludioxonil technical caused
profound mitotic arrest at the highest assayed dose, and since metaphase
block was complete, damage to the chromosomes was not apparent.  As the
dose decreased, the incidence of both structural and numerical
(polyploid) chromosome aberrations increased presumably because
sufficient cells recovered from the mitotic block and were able to
express the chromosome damage.  The findings are of particular interest
owing to the dramatic increases in polyploidy.  By analogy to the in
vitro results, the possibility exists, therefore, that a similar
mechanism may be operating in vivo in the rat hepatocytes but could not
be fully characterized with the available information.  Based on these
considerations, HED considers that sufficient doubts have been raised to
preclude us from reaching definitive conclusions and to justify the
recommendation that the study be repeated using lower doses.  HED
further believe that only Phase 2 warrants additional investigation
since the data do suggest that fludioxonil may only induce genetic
damage in actively dividing hepatocytes.

It is noted that an acceptable bone marrow micronucleus assay was
submitted (MRID 43080041).  Nevertheless, HED believes that the in vivo
rat hepatocyte study should be repeated since the utility of the study
in uncovering the mechanism(s) by which the test material could induce
genetic damage is of primary interest

870.5550 	Mutagenicty – Other; Unscheduled DNA Synthesis - Rat

MRID No.:  45050502

Executive Summary:  In an unscheduled DNA synthesis (UDS) assay, rat
hepatocyte cultures from male Sprague-Dawley rats orally dosed once with
fludioxonil (96.4% a.i. Lot/Batch# P.910007) in 0.5% carboxymethyl
cellulose at 2500 or 5000 mg/kg, were observed for DNA damage.
Hepatocytes were harvested after a 4-hour exposure to the test material
or vehicle alone; dimethylnitosamine (DMN; cell harvest after 2 hour
exposure) served as the positive control.  The criteria for a positive
mutagenic response was either, the mean gross number and the mean net
number of grains per nucleus with an increase at any dose level compared
to the vehicle control and the mean net value of 2.0 or higher; or the
percentage distribution of the gross and net numbers of grains show an
obvious shift to higher values at any dose level compared to the vehicle
control distribution.  In addition, an independent replicative DNA
synthesis (RDS) assay was performed to determine if the test compound
may cause hepatotoxicity.  The hepatocytes were harvested after a
38-hour exposure to the test compound (2500 or 5000 mg/kg), vehicle
alone, or positive control, 4-acetylaminofluorene (4-AAF). 

Fludioxonil was tested up to the limit dose (5000 mg/kg).  There was no
evidence that unscheduled DNA synthesis, as determined by nuclear silver
grain counts, was induced at 2500 or 5000 mg/kg.  The response for
induction of replicative DNA synthesis by fludioxonil was equivocal,
because only 1/4 of the 5000 mg/kg cultures showed an increase compared
to vehicle controls and none of the 2500 mg/kg cultures showed an
increase.  Vehicle control values were within the historical range and
the ability of the test system to detect DNA damaging agents was
adequately shown by the response induced by the positive controls.

870.5550 	Mutagenicty – Other; In Vitro Unscheduled DNA Synthesis
Assay

MRID No.:  43080039

Executive Summary: In two independently conducted in vitro unscheduled
DNA synthesis (UDS) assays, primary rat hepatocytes were exposed to
eight fludioxonil technical doses ranging from 4.1 to 5000 µg/ml
(initial trial) and six doses ranging from 4.1 to 1000 µg/ml
(confirmatory trial).  The test material was delivered to the test
system in dimethyl sulfoxide (DMSO).  Compound precipitation occurred at
doses > 37 µg/ml and cytotoxicity was apparent at 313 µg/ml.  There
was, however, no indication of genotoxicity at any insoluble (> 37
µg/ml) or soluble level (4.1 or 12.3 µg/ml).  Hepatocytes responded in
the expected manner to the genotoxic action of the positive controls. 

870.5550 	Mutagenicty – Other; Dominant Lethal Assay - Mice

MRID No.:  43080044

Executive Summary:  In a dominant lethal assay, male mice received
either a single oral gavage administration of 0, 1250, 2500, or 5000
mg/kg fludioxonil technical and were sequentially mated with untreated
females (1:2) for 8 consecutive weeks.  The test material was delivered
to the test system as suspensions prepared in 0.5% carboxymethyl
cellulose.  There was no evidence of compound toxicity in the treated
males, adverse effects on reproductive performance or cytotoxic effects
on the target cell. There was also no indication that the test material
induced dominant lethal mutations in male mouse germinal cells sampled
over the entire period of spermatogenesis.  The results with the
positive control confirmed the sensitivity of the test system to detect
genetic damage in male mouse germinal cells.  

870.5550 	Mutagenicty – Other; Point Mutation Test

MRID No.:  43152501

Executive Summary:  Fludioxonil technical was tested for the ability to
cause mutations in Chinese hamster V79 ovary cells in vitro in the
absence and presence of metabolic activation (Aroclor 1254 induced rat
liver S-9).   Cells were treated without microsomal activation for 21
hours and for 5 hours with microsomal activation.  Doses used were:
non-activation, 0.5-10.0 µg/ml (initial experiment); 1.0-20.0 µg/ml
(confirmatory experiment); activation, 1.5-30.0 µg/ml (initial
experiment); 3.0-60.0 µg/ml (confirmatory experiment).  Doses > 16
µg/ml in the absence of S9 reduced cell survival by >90%, and
approximately 20% of the cells survived treatment with 60 µg/ml in the
presence of S9.  Fludioxonil technical at the concentrations tested in
this study produced no increase in number of thioguanine-resistant
colonies, mutant frequency, or in the mutant factor in Chinese hamster
V79 cells in the absence or presence of metabolic activation.   Under
conditions of non-activation and activation, positive control materials
produced the expected increases in mutant frequency and the mutant
factor, indicating the sensitivity and validity of the assay.

870.5550 	Mutagenicty – Other; Micronucleus Assay - Mice

MRID No.:  43080041

Executive Summary:  In a mutagenicity study, fludioxonil technical
(97.5% a.i.) was evaluated in the mouse bone marrow micronucleus test to
detect possible damage of chromosomes or the mitotic apparatus. 
Fludioxonil at doses up to and including the limit dose of 5000 mg/kg
was not overtly toxic to the test animals, cytotoxic to the target
organ, and produced no statistically significant increase in the number
or percentage of micronucleated polychromatic erythrocytes in male and
female mice.

870.5550 	Mutagenicty – Other; Micronucleus Assay - Rat

MRID No.:  45050503

Executive Summary:  In a primary rat hepatocyte micronucleus assay, 6
male rats/dose were administered fludioxonil (96.4% a.i., Lot/Batch#
P.910007), in 0.5% carboxymethyl cellulose, once by oral gavage (10
mL/kg) at 50, 250, or 1250 mg/kg.  Approximately 30 hours prior to
dosing, the rats were treated with the known mitogen
4-acetylaminofluorene (4-AAF), in arachis oil, once by oral gavage (1000
mg/kg; dose volume 10 mL/kg). Cyclophosamide (CPA), in distilled water,
at 20 mg/kg was used as the positive control and was administered via
intraperitoneal injection (5 mL/kg).  Hepatocytes were harvested at
approximately 72 hours after treatment by in situ perfusion and scored
for micronuclei.

Fludioxonil was tested up to 1250 mg/kg. No clinical signs related to
treatment with fludioxonil were observed.  Dark yellow urine and
chromodacryorrhea one to two days after treatment with 4-AAF were
observed. Fludioxonil did not significantly increase the number of
micronucleated hepatocytes at any dose, compared to the vehicle control.
 The vehicle control values were within the historical range provided.
The positive control produced significant increases in micronucleated
hepatocytes.  Individual treated and positive control animals showed
marked increases in the frequency of hepatocytes in apoptosis; however,
the group means were not significantly different compared to the vehicle
control.  It was stated that the increase in apoptosis may be attributed
to synergistic effects of 4-AAF and fludioxonil or 4-AAF and the
positive control, respectively.

Based on the lack of a statistically significant increase in the number
of micronucleated hepatocytes in the treated groups, fludioxonil is
considered not to be mutagenic in rats in this in vivo micronucleus
assay.

870.6200	Neurotoxicity - Rat

Not applicable.

870.6300	Developmental Neurotoxicity – Rat

Not applicable.

A.3.8	Metabolism

870.7600		Dermal Absorption – Rat

An upper bound dermal absorption factor of 40% was extrapolated
comparing the ratio of the LOAEL of 428 mg/kg/day in the 90 day oral
toxicity study in rats and the NOAEL of 1000 mg/kg/day (assumed to be a
LOAEL; worst case scenario) in the 21-day dermal toxicity study in rats.

Appendix B:	REFERENCES (in MRID order)

43080019	Hartmann, P. (1989) Acute Inhalation Toxicity in the Rat:
CGA-173506 Technical: Lab Project Number: 881491. Unpublished study
prepared by Ciba-Geigy Limited. 30 p.

43080024	Schneider, P. (1988) Skin Sensitization Test in the Guinea Pig
with CGA-173506 Technical Maximisation Test Report: Lab Project Number:
881490. Unpublished study prepared by Ciba-Geigy Limited. 30 p.

43124105	Glaza, S. (1991) Acute Oral Toxicity Study of CGA-173506
Technical in Rats: Lab Project Number: HWI 10200144: AMENDMENT NO. 1:
TP3013. Unpublished study prepared by Hazleton Wisconsin, Inc. 29 p.

43124106	Hartmann, P. (1988) Acute Dermal Toxicity in the Rat with
CGA-173506 Technical: Lab Project Number: 881489: AMENDMENT NO. 1.
Unpublished study prepared by Ciba-Geigy Limited. 19 p.

43124107	Glaza, S. (1991) Primary Eye Irritation Study of CGA-173506
Technical in Rabbits: Lab Project Number: HWI 10200147A: TP2012.
Unpublished study prepared by Hazleton Wisconsin, Inc. 32 p.

43124108	Glaza, S. (1991) Primary Dermal Irritation Study of CGA-173506
Technical in Rabbits: Lab Project Number: HWI 10200146: TP3014.
Unpublished study prepared by Hazleton Wisconsin, Inc. 22 p.

43080031	Vallet, L. (1982) Toxicity Study by Repeated Oral (Dietary)
Administration for 52 Weeks in Beagle Dogs: CGA 173506 Technical: Lab
Project Number: 5577 TCC: 881174. Unpublished study prepared by Centre
International De Toxicologie. 547 p.

43080032	Chang, J.; Wyand, D. (1993) 18-Month Dietary Oncogenicity Study
with CGA-173506 in Mice: Lab Project Number: F-00019. Unpublished study
prepared by Ciba-Geigy Corp. 1354 p.

43080033	Chang, J.; Wyand, D. (1993) 18-Month Dietary Oncogenicity Study
with CGA-173506 in Mice: Final Report: Lab Project Number: F-00071.
Unpublished study prepared by Ciba-Geigy Corp. 1549 p.

43080034	Savary, M. (1988) Assessment of Possible Embryotoxic or
Teratogenic Effects in Rats by Oral Route: CGA 173506 Technical: Lab
Project Number: 4517 RSR: 881177. Unpublished study prepared by Centre
International De Toxicologie. 165 p.

43080035	Savary, M. (1989) Assessment of Possible Embryotoxic or
Teratogenic Effects in Rabbits by Oral Route: CGA 173506 Technical: Lab
Project Number: 4801 RSL: 881728. Unpublished study prepared by Centre
International De Toxicologie. 147 p.

43080036	Singh, A.; Hazelette, J.; Yau, E. (1992) A Two-generation
Reproductive Toxicity Study in Rats: CGA 173506 Technical: Lab Project
Number: 902001: 2-074-01: 3979. Unpublished study prepared by Ciba-Geigy
Corp., Pharmaceuticals Div. 1029 p.

43080037	Chang, J.; Richter, A. (1993) 2-Year Chronic Toxicity/
Oncogenicity Study in Rats: CGA 173506 Technical: Lab Project No.
F-00018. Unpublished study prepared by Ciba-Geigy Corp., Plant
Protection Div. 2347 p.

43080038	Ogorek, B. (1989) Salmonella/Mammalian-Microsome Mutagenicity
Test: CGA 173506 Technical: Lab Project Number: 881495. Unpublished
study prepared by Ciba-Geigy Limited, Genetic Toxicology. 65 p.

43080039	Hertner, T. (1989) Autoradiographic DNA Repair Test on Rat
Hepatocytes: CGA 173506 Technical: Lab Project Number: 881494.
Unpublished study prepared by Ciba-Geigy Limited. 105 p.

43080040	Strasser, F. (1989) Chromosome Studies on Chinese Hamster Ovary
Cell Line CCL 61 In vitro: CGA 173506 Technical: Lab Project Number:
881496. Unpublished study prepared by Ciba-Geigy Limited. 37 p.

43080041	Hertner, T. (1990) Micronucleus Test, Mouse: CGA 173506
Technical: Lab Project Number: 881493. Unpublished study prepared by
Ciba-Geigy Limited. 41 p.

43080042	Hertner, T. (1993) Chromosome Studies on Somatic Cells of
Chinese Hamster: CGA 173506 Technical: Lab Project Number: 923099.
Unpublished study prepared by Ciba-Geigy Limited. 32 p.

43080043	Meyer, A. (1991) In vivo Micronucleus Test on Rat Hepatocytes:
CGA 173506 Technical: Lab Project Number: 901145. Unpublished study
prepared by Ciba-Geigy Limited. 59 p.

43080044	Hertner, T. (1992) Dominant Lethal Test, Mouse, 8 Weeks: CGA
173506 Technical: Lab Project Number: 923068. Unpublished study prepared
by Ciba-Geigy Limited. 84 p.

43152501	Dollenmeier, P. (1989) CGA 173506 Technical: Point Mutation
Test with Chinese Hamster Cells V79: Lab Project Number: 881497.
Unpublished study prepared by Ciba-Geigy Ltd. 50 p.

45050502	Hertner, T. (1993) In vivo/In vitro Unscheduled and Replicative
DNA Synthesis in Rat Hepatocytes: CGA-173506 Technical: Final Report:
Lab Project Number: 641-93. Unpublished study prepared by Novartis Crop
Protection AG. 70 p. {OPPTS 870.5550}

45050503	Ogorek, B. (1999) In vivo Micronucleus Test on Rat Hepatocytes:
CGA-173506 Technical: Final Report: Lab Project Number: 1195-98:
9831167. Unpublished study prepared by Novartis Crop Protection AG. 40
p.

Appendix C:  REVIEW OF HUMAN RESEARCH

No MRID - PHED Surrogate Exposure Guide

Appendix D:	INTERNATIONAL HARMONIZATION

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:

(4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile

	Common Name:

Fludioxonil 	x Proposed tolerance

( Reevaluated tolerance

( Other	Date: 4/4/08

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: 7E7234 & 2E6462

DP#s: 345970 & 349725

$

þè

þè

!

#

O

P

Z

e

g

r

v

€

‚

‰

•

–

˜

œ

ž

Ÿ

¡

±

¹

º

Á

È

í

ï

ñ

û

P

Q

t

€

•

–

œ

Ÿ

É

ï

þè

û

ý

嬇ഀࣆȀ֠⃞਀娇ഀࣆȀπ⃞਀ĀY

jþ

萎ﱘ␱䀀&葝ﱘ摧ቛ6

j

hÚ

hÚ

萎ﱘꐓ&ꐔ!葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

h—

hÚ

萎ﱘ葝ﱘ摧ቛ6

h—

hÚ

hÚ

hÚ

萎ﱘ葝ﱘ摧ቛ6

h/

hÚ

h

萎ﱘ葝ﱘ摧ቛ6

hÚ

hÚ

hÚ

hÚ

态ú萎ﱘ葝ﱘ摧ቛ6

؀Ĥ萎ﱘ葝ﱘ摧ቛ6

옍)

萎ﱘ葝ﱘ摧ቛ6

h

萎ﱘ葝ﱘ摧ቛ6

옍)

옍)

萎ﱘ葝ﱘ摧ቛ6

萎ﱘ␱䀀Ȧ葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

퀄ꀂ瀅Ȉ

«

«

ú

ú

«

«

ú

«

«

«

«

옍)

a

b

萎ﱘ␷㠀$♀䠂$葝ﱘ摧ቛ6

hÎ

@

@

@

@

@

@

@

@

hÎ

hÎ

h7

$

h

h

h

h

$

h

h

h

h

kd

옍)

h

萎ﱘ葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

옍)

萎ﱘ␱䀀&葝ﱘ摧ቛ6

옍)

옍)

옍)

옍)

@

h/

@

@

옍)

옍)

葝ﱘ摧ᨚI

葝ﱘ摧ᨚI

옍)

฀墄ㇼ$葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

฀墄ㇼ$葝ﱘ摧ቛ6

h

h

态ú萎ﱘ葝ﱘ摧ቛ6

h

h

h

฀墄ㇼ$葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

฀墄ㇼ$葝ﱘ摧ቛ6

-

฀墄㟼$␸䠀$葝ﱘ摧ቛ6

萎ﱘ葝ﱘ摧ቛ6

h/

OJ

QJ

hŸ7

OJ

QJ

0.45

Star apple 	0.45

Basil	10	Herb Subgroup 19A, fresh 	10

Basil, dry	50	Herb Subgroup 19A, dried 	65 

Chives	10

Chives, dry	50

Leaves of root and tuber vegetables	40 

Root vegetables, except sugar beet subgroup	0.50

Citrus fruits	7	Lemon 	0.25

Citrus fruits	7	Lime 	0.25

Cucumber 

	0.3

	Cucurbits 	0.60

Tuberous and corm vegetables, except potato subgroup	4.0

Melons (except watermelon)	0.03

Squash, summer	0.3

Carrot	0.7	Carrot 	0.75

Turnip, greens 	10

Radish, tops	None

Citrus oil	None

Grapefruit oil	500

Limits for Canada	Limits for Mexico

( No Limits

( No Limits for the crops requested	( No Limits

( No Limits for the crops requested

Residue. 

4-(2,2-difluoro-1,3-benzodioxol-4-yl) 1Hpyrrole-

3-carbonitrile

	Residue definition: 

fludioxonil

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

	Notes/Special Instructions:  S.Funk, 04/08/2008.

 PAGE   36 

Page  of 60

 PAGE   37 

Page  of 60