Document ID: EPA-HQ-OPP-2008-0302-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-07-23T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		November 27, 2007 

SUBJECT:	Fludioxonil.  Human Health Risk Assessment for a Section 18
Emergency Tolerance on Starfruit.  

Petition #	07FL05	

PC Code:	071503

DP #:	344676	

Class:	Fungicide

Decision #:	384501	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:	William Cutchin, Acting Senior Scientist 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		

		George Kramer, Ph.D., Chemist 

		Dana Vogel, Branch Chief

		Registration Action Branch 1 (RAB 1)

		Health Effects Division (HED) (7509P)

TO:		Andrea Conrath, RM Team 05

		RIMUERB/RD (7505P)

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc183935918"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc183935918 \h  4  

  HYPERLINK \l "_Toc183935919"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc183935919 \h  11  

  HYPERLINK \l "_Toc183935920"  2.1	Summary of Proposed Use	  PAGEREF
_Toc183935920 \h  11  

  HYPERLINK \l "_Toc183935921"  2.2	Structure and Nomenclature	  PAGEREF
_Toc183935921 \h  11  

  HYPERLINK \l "_Toc183935922"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc183935922 \h  12  

  HYPERLINK \l "_Toc183935923"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc183935923 \h  12  

  HYPERLINK \l "_Toc183935924"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc183935924 \h  12  

  HYPERLINK \l "_Toc183935925"  3.1.1	Database Summary	  PAGEREF
_Toc183935925 \h  14  

  HYPERLINK \l "_Toc183935926"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc183935926 \h  14  

  HYPERLINK \l "_Toc183935927"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc183935927 \h  14  

  HYPERLINK \l "_Toc183935928"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc183935928 \h  14  

  HYPERLINK \l "_Toc183935929"  3.1.2	Dose-response	  PAGEREF
_Toc183935929 \h  14  

  HYPERLINK \l "_Toc183935930"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc183935930 \h  16  

  HYPERLINK \l "_Toc183935931"  3.3	FQPA Considerations	  PAGEREF
_Toc183935931 \h  16  

  HYPERLINK \l "_Toc183935932"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc183935932 \h  16  

  HYPERLINK \l "_Toc183935933"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc183935933 \h  16  

  HYPERLINK \l "_Toc183935934"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc183935934 \h  16  

  HYPERLINK \l "_Toc183935935"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc183935935 \h  16  

  HYPERLINK \l "_Toc183935936"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc183935936 \h  16  

  HYPERLINK \l "_Toc183935937"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc183935937 \h  16  

  HYPERLINK \l "_Toc183935938"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc183935938 \h  17  

  HYPERLINK \l "_Toc183935939"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc183935939 \h  17  

  HYPERLINK \l "_Toc183935940"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc183935940 \h  17  

  HYPERLINK \l "_Toc183935941"  3.5.1    Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc183935941 \h  17  

  HYPERLINK \l "_Toc183935942"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc183935942 \h  17  

  HYPERLINK \l "_Toc183935943"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc183935943 \h  18  

  HYPERLINK \l "_Toc183935944"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc183935944 \h  18  

  HYPERLINK \l "_Toc183935945"  3.5.5	Dermal Absorption	  PAGEREF
_Toc183935945 \h  18  

  HYPERLINK \l "_Toc183935946"  3.5.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc183935946 \h  18  

  HYPERLINK \l "_Toc183935947"  3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc183935947 \h  18  

  HYPERLINK \l "_Toc183935948"  3.5.8	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc183935948 \h  19  

  HYPERLINK \l "_Toc183935949"  3.5.9	Classification of Carcinogenic
Potential	  PAGEREF _Toc183935949 \h  19  

  HYPERLINK \l "_Toc183935950"  3.5.10	Summary of Toxicological Doses
and Endpoints for Fludioxonil for Use in Human Risk Assessments	 
PAGEREF _Toc183935950 \h  19  

  HYPERLINK \l "_Toc183935951"  3.6	Endocrine disruption	  PAGEREF
_Toc183935951 \h  20  

  HYPERLINK \l "_Toc183935952"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc183935952 \h  21  

  HYPERLINK \l "_Toc183935953"  4.1	Incident Reports	  PAGEREF
_Toc183935953 \h  21  

  HYPERLINK \l "_Toc183935954"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc183935954 \h  21  

  HYPERLINK \l "_Toc183935955"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc183935955 \h  21  

  HYPERLINK \l "_Toc183935956"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc183935956 \h  21  

  HYPERLINK \l "_Toc183935957"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc183935957 \h  21  

  HYPERLINK \l "_Toc183935958"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc183935958 \h  21  

  HYPERLINK \l "_Toc183935959"  5.1.4	Analytical Methodology	  PAGEREF
_Toc183935959 \h  21  

  HYPERLINK \l "_Toc183935960"  5.1.5	Environmental Degradation	 
PAGEREF _Toc183935960 \h  22  

  HYPERLINK \l "_Toc183935961"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc183935961 \h  22  

  HYPERLINK \l "_Toc183935962"  5.1.7	Drinking Water Residue Profile	 
PAGEREF _Toc183935962 \h  23  

  HYPERLINK \l "_Toc183935963"  5.1.8	Food Residue Profile	  PAGEREF
_Toc183935963 \h  23  

  HYPERLINK \l "_Toc183935964"  5.1.9	International Residue Limits	 
PAGEREF _Toc183935964 \h  24  

  HYPERLINK \l "_Toc183935965"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc183935965 \h  25  

  HYPERLINK \l "_Toc183935966"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc183935966 \h  25  

  HYPERLINK \l "_Toc183935967"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc183935967 \h  26  

  HYPERLINK \l "_Toc183935968"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc183935968 \h  26  

  HYPERLINK \l "_Toc183935969"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc183935969 \h  27  

  HYPERLINK \l "_Toc183935970"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc183935970 \h  27  

  HYPERLINK \l "_Toc183935971"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc183935971 \h  28  

  HYPERLINK \l "_Toc183935972"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc183935972 \h  28  

  HYPERLINK \l "_Toc183935973"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc183935973 \h  28  

  HYPERLINK \l "_Toc183935974"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc183935974 \h  29  

  HYPERLINK \l "_Toc183935975"  7.4	Chronic Aggregate Risk	  PAGEREF
_Toc183935975 \h  30  

  HYPERLINK \l "_Toc183935976"  7.5	Cancer Aggregate Risk	  PAGEREF
_Toc183935976 \h  30  

  HYPERLINK \l "_Toc183935977"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc183935977 \h  30  

  HYPERLINK \l "_Toc183935978"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc183935978 \h  31  

  HYPERLINK \l "_Toc183935979"  9.1	Occupational Handler Risk	  PAGEREF
_Toc183935979 \h  31  

  HYPERLINK \l "_Toc183935980"  9.2	Occupational Post-Application Risk	 
PAGEREF _Toc183935980 \h  33  

  HYPERLINK \l "_Toc183935981"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc183935981 \h  33  

  HYPERLINK \l "_Toc183935982"  Appendix A:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc183935982 \h  35  

  HYPERLINK \l "_Toc183935983"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc183935983 \h  35  

  HYPERLINK \l "_Toc183935984"  A.2	Toxicity Profiles	  PAGEREF
_Toc183935984 \h  36  

  HYPERLINK \l "_Toc183935985"  A.3	Executive Summaries	  PAGEREF
_Toc183935985 \h  36  

  HYPERLINK \l "_Toc183935986"  Appendix B:  REFERENCES (in MRID order)	
 PAGEREF _Toc183935986 \h  50  

  HYPERLINK \l "_Toc183935987"  Appendix C:  REVIEW OF HUMAN RESEARCH	 
PAGEREF _Toc183935987 \h  52  

 

1.0	EXECUTIVE SUMMARY

The State of Florida has submitted a Section 18 emergency exemption
petition for use of the fungicide fludioxonil
[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile], on
carambola (starfruit) as a post-harvest fruit dip (PP# 07FL05).

Fludioxonil is a non-systemic fungicide that is in the phenylpyrrole
class of chemicals.  The target pest, Dothiorella spp., causes fruit rot
diseases on harvested fruit.  The product requested for use is Scholar®
SC Fungicide (EPA Reg. No. 100–1242).  Scholar® is registered to
Syngenta Crop Protection, Inc. (Syngenta) and is a soluble concentrate
liquid formulation that contains 1.92 lb (20.4 %) active ingredient (ai)
fludioxonil per gallon.  It is to be applied as a post-harvest fruit dip
or “directed spray.”  The rate of application is 16-32 fl oz/100
gallons of dip or spray solution (0.24-0.48 lb ai/100 gallons of
solution).

Tolerances for residues of fludioxonil have been established under 40
CFR §180.516.   Under this section, current tolerances range from 0.01
ppm in/on a variety of commodities to 500 ppm in grapefruit (citrus)
oil.

A time-limited 5.0 ppm tolerance for pomegranate is listed in 40 CFR
§180.516(b).  The tolerance was set to expire in 2006.  A 2004 risk
assessment performed by the EPA (DP#s: 292567, 293233, 298001 and
306183; L. Jones) determined that the tolerance should be made
permanent.  For this action, ARIA has included the tolerance of 5.0 ppm
for pomegranate.

Proposed Tolerances

The tolerance request for post-harvest dip use of fludioxonil on
carambola has been submitted by the State of Florida.  ARIA senior
scientists have determined that the 10 ppm citrus crop group tolerance
is adequate to extend to include carambola.  

No field trials were submitted for the proposed use.  Syngenta has
previously performed magnitude of residue studies for a number of fruit
crops, including pome and citrus crop groups.  These studies can be
extended to this proposal.  

Under PP# 07FL05, the State of Florida requests the establishment of a
time-limited tolerance for fludioxonil in/on carambola.  ARIA has
determined that a 10 ppm tolerance should be adequate for this proposed
use.  

The most recent human health risk assessment for fludioxonil was
conducted in conjunction with submitted data, requested as conditions of
registrations, and label amendments for another fludixonil fungicide
product (DP #: 325149, W. Wassell, 11/08/2006).  This 2006 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

The toxicological database for fludioxonil is adequate to support the
requested tolerance according to the guideline requirements for a
food-use chemical. 

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 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.

The HED Cancer Peer Review Committee (CPRC) 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

The HED Hazard Identification Assessment Review Committee (HIARC)
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 since no
systemic toxicity was seen at the highest dose tested of 1000 mg/kg/day
in the 28-day dermal toxicity study in rats and also since there were no
developmental concerns.

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 product requested for use is Scholar® SC Fungicide (EPA Reg. No.
100–1242).  Scholar® is a soluble concentrate liquid formulation that
contains 1.92 lb (20.4 % ai) fludioxonil per gallon.  It is to be
applied as a post-harvest fruit dip or “directed spray.”  Either the
dip or directed spray is conducted in the packing house.  Directed
sprays occur within a hooded area over a conveyer and fruit is treated
as it passes through.  Fruit dips are accomplished as fruit is conveyed
through a “bath” and on to the packing line or storage facility. 
All application is automated.  The rate of application is 16-32 fl
oz/100 gallons of dip or spray solution (0.24-0.48 lb ai/100 gallons of
solution).  One post-harvest application will be made.

No new residue chemistry information was submitted for this action.  The
following summary information comes from residue chemistry data
previously submitted to and reviewed by the Agency (DP#: 287808, T.
Bloem, 2/12/2003). 

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

 

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

Water Exposure and Risk

 tc \l2 "4.3 Water Exposure/Risk Pathway   EFED provided estimated
drinking water concentrations (EDWCs) 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)
(version 1.0) model for groundwater.  The use site with the highest
application rate is turf.

Based on the modeling results using FIRST, surface water concentrations
of fludioxonil are 132 ppb for the estimated peak concentration (acute)
and 49 ppb for the estimated mean concentration (chronic).   Groundwater
sources were not included in this assessment, as the EDWCs for this
water source are minimal in comparison to surface water (0.11 ppb for
both acute and chronic concentrations). 

Acute and Chronic Dietary Exposure Results and Characterization

The acute and chronic dietary risk assessments assumed tolerance-level
residues for most 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 assessment was conducted for the
general U.S. population and all population subgroups.  Anticipated
residues for the chronic assessment were generated from apple,
grapefruit, lemon, lime, orange, and pear field trials.  Anticipated
residues for the chronic assessment were also determined from processing
studies for apple, grapefruit, lemon, lime and orange juices. 
DEEM-FCID( default processing factors were used in all other instances. 
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 fludioxnoil 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 HIARC 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 range from 100-130, exceeding the target MOE of 100, with
the exception that the MOE for children 1-2 years old is 100, rounded. 
ARIA has determined that this raises no concern for 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 use pattern, ARIA believes that there is no
“applicator” in the common sense of the term.   An individual must
prepare the dip/spray solution however the “application” process is
automated, i.e., fruit is treated in one way or the other as it passes
on a conveyer.  Therefore, the only occupational pesticide handler
exposure is the individual preparing the treatment solution.  That
activity is essentially the same as it would be for a mixer/loader
supporting aerial or ground spray operations.  Therefore, the
“occupational handler” assessment is based upon the activities of a
mixer/loader using open pour loading of liquids.  

Although the carambola harvest time may span several months, ARIA does
not expect exposures to exceed short-term duration (1 – 30 days).  It
is unlikely that handlers and packers would be exposed continuously for
30 days or more.  However, short-term and intermediate-term duration
exposures are assessed.  

A MOE of exposure of 100 is adequate to protect occupational pesticide
handlers.  Since the estimated MOEs > 100 (MOEs ranged from 6,000 to
15,625), 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://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food 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 data needs for fludioxonil.

Recommendations for Tolerances/Registration

ARIA recommends that a time-limited tolerance of 10 ppm be established
for residues of fludioxonil in/on starfruit.  

2.0	INGREDIENT PROFILE

Summary of Proposed Use

The product requested for use is Scholar® SC Fungicide (EPA Reg. No.
100–1242), a soluble concentrate liquid formulation that contains 1.92
lb (20.4 %) ai fludioxonil per gallon.  It is to be applied as a
post-harvest fruit dip or “directed spray.”   Either the dip or
directed spray is conducted in the packing house.  Directed sprays occur
within a hooded area over a conveyer and fruit is treated as it passes
through.  Fruit dips are accomplished as fruit is conveyed through a
“bath” and on to the packing line or storage facility.  All
application is automated.  The rate of application is 16-32 fl oz/100
gallons of dip or spray solution (0.24-0.48 lb ai/100 gallons of
solution).  One post-harvest application will be made.  

There are some unforeseeable conditions relative to carambola harvest
such as volumes of fruit available for harvest at specific times. 
Therefore, the Section 18 request is based, to some degree, on
experience with pome and stone fruit harvest and the use of fludioxonil.
 It appears that up to 3,000 lb of fruit may be treated with a single
100 gallon mix.  Further, it appears that up to 200,000 lb of fruit per
load may be treated.   

2.2	Structure and Nomenclature

Structure:

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

Common Name:	fludioxonil

PC Code Number:	071503

CAS Registry No.:	131341-86-1

Empirical Formula:	C12H6F2N2O2

Molecular Weight:	248.2

2.3	Physical and Chemical Properties

Product chemistry data for fludioxonil was previously reviewed (DP#s:
206301, 206304, 206328, and 206331, S. Willet, 3/1/1995; DP#: 216233, S.
Willet, 8/17/1995).  There are no impurities present which are expected
to cause residue concerns.

Vapor Pressure:	2.9 x 10-9 mm Hg at 25° C

Water solubility:	1.8 mg/l at 25° C

Melting Point:	200°C

Density:		1.54 g/ml at 20° C

pH:			8-9

log Pow:		4.12  at 25° C

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 dose,
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 reproductive 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.  The
HED CPRC 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.  The LOAEL was >1000
mg/kg/day.

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.

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.  This risk
assessment relies in part on data from studies in which adult human
subjects were intentionally exposed to a pesticide or other chemical.  

  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 and also since there were no developmental concerns.  In the
developmental rat study, the maternal toxicity (decreased body weight)
is protective of developmental toxicity occurring at the same dose level
of fludioxonil.  Consequently, because the maternal effect of decreased
body weight would be detected in the 28-day dermal toxicity study, the
short- and intermediate-term dermal endpoints were not based on the rat
developmental NOAEL of 100 mg/kg/day.

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 rats, excretion in the
feces is greater than excretion via the urine. 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.

  TC \l3 "3.3.2	Evidence of Neurotoxicity 

3.3.3	Developmental Toxicity Studies

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, 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.  Fetal toxicity was manifested as
decreased weight gain in pups.  Since maternal and fetal 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 set 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 the HIARC on
September 7, 1999 (Memo, W. Dykstra and B. Tarplee, 13-OCT-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 and also since there were no developmental concerns.  In the
developmental rat study, the maternal toxicity (decreased body weight)
is protective of developmental toxicity occurring at the same dose level
of fludioxonil.  Consequently, because the maternal effect of decreased
body weight would be detected in the 28-day dermal toxicity study, the
short- and intermediate-term dermal endpoints were not based on the rat
developmental NOAEL of 100 mg/kg/day.  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.

  TC \l3 "3.5.10	Classification of Carcinogenic Potential 

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

Table 3.5.10 Summary of Toxicological Doses and Endpoints for
Fludioxonil for Use in Dietary and Non-Occupational Human Helath 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 required	

No hazard identified and therefore quantification is not required. There
are no developmental concerns 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

No new residue chemistry information was submitted for this action.  The
following summary information comes from residue chemistry data
previously submitted to and reviewed by the agency (DP#: 287808, T.
Bloem, 2/12/2003).

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). 

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 methods used in previous field trial studies were similar to a
method validated by the Analytical Chemistry Branch (ACB) (DP#: 217129,
S. Willett, 8/14/1995; DP#: 258865, W. Donovan, 12/17/1999; DP#: 272959,
W. Donovan, 3/9/2001).  Since adequate method validation and concurrent
recoveries were attained in the field trial studies, HED concluded that
the ACB validated method is appropriate for enforcement.  

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
previously provided by EFED, summarized in a memo (DP#s: 285197, 285514,
286372 and 286717, J. Ravenscroft, 1/2/2003) 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.”   

EDWCs were calculated for fludioxonil residues using EFED’s FIRST
model for surface water and the SCI-GROW (version 1.0) model for
groundwater.  The use site with the highest application rate is turf.

Based on the modeling results using FIRST, surface water concentrations
of fludioxonil are 132 ppb for the estimated peak concentration (acute)
and 49 ppb for the estimated mean concentration (chronic).   Groundwater
sources were not included in this assessment, as the EDWCs for this
water source are minimal in comparison to surface water (0.11 ppb for
both acute and chronic concentrations). 

 TC \l3 "5.1.9	Drinking Water Residue Profile 

5.1.8	Food Residue Profile

The tolerance request for post-harvest dip use of fludioxonil on
carambola has been submitted by the State of Florida.  ARIA senior
scientists have determined that the 10 ppm citrus crop group tolerance
is adequate to extend to include carambola.  

No field trials were submitted for the proposed use.  Syngenta has
previously performed magnitude of residue studies for a number of fruit
crops, including pome and citrus crop groups, which were reviewed by EPA
(DP#: 287808, T. Bloem, 2/12/2003).  These studies can be extended to
this proposal.

There are some unforeseeable conditions relative to carambola harvest
such as volumes of fruit available for harvest at specific times. 
Therefore, the Section 18 request is based, to some degree, on
experience with pome and stone fruit harvest and the use of fludioxonil.
 

  TC \l3 "5.1.10	Food Residue Profile 

5.1.9	International Residue Limits

Harmonization is not an issue for this Section 18 request for
fludioxonil residues on carambola.

 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 #:
345986, 11/19/2007).

 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 132
ppb, previously 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 yrs old was
0.137655 mg/kg/day, which 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 values for apple, grapefruit, lemon,
lime, orange, and pear were generated from field trials.  Anticipated
residues were also determined from processing studies for apple,
grapefruit, lemon, lime and orange juices; therefore, processing factors
were set to 1x for these processed commodities.  DEEM-FCID( default
processing factors were used for all other processed commodities.  The
mean drinking water estimate of 49 ppb, previously provided by EFED, was
directly incorporated into the chronic assessment.  For the U.S.
population the exposure for food and water utilized 47% of the cPAD. 
The chronic dietary risk estimate for the highest reported exposed
population subgroup, children 1-2 years old, is 86% 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	0.013966	47

All Infants (< 1 year old)

0.018184	61

Children 1-2 years old

0.025647	86

Children 3-5 years old

0.022144	74

Children 6-12 years old

0.015622	52

Youth 13-19 years old

0.011367	38

Adults 20-49 years old

0.012816	43

Adults 50+ years old

0.013146	44

Females 13-49 years old	0.137655	14	0.013290	44

5.2.3	Cancer Dietary Risk

The HIARC 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.  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 fludioxnoil 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 HIARC 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.  

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 HED’s level of concern for residential exposures (MOEs < 100).

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, the HIARC 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	0.018184	0.013	320

Children (1-2 years)	10	100	0.025647	0.013	260

Children (3-5 years)	10	100	0.022144	0.013	290

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	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)	3.3	100	0.018184	0.0074	130

Children (1-2 years)	3.3	100	0.025647	0.0074	100

Children (3-5 years)	3.3	100	0.022144	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
100, rounded.  ARIA has determined that this raises no concern for
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 post-harvest use of fludioxonil on
carambola (DP#: 344830, M. Dow, 10/17/2007).  This is the only new use
being proposed.

The use pattern summary is taken from the State of Florida’s FIFRA
Section 18 request.  The product requested for use is Scholar® SC
Fungicide (EPA Reg. No. 100–1242).  Scholar® is a soluble concentrate
liquid formulation that contains 1.92 lb (20.4%) ai fludioxonil per
gallon.  It is to be applied as a post-harvest fruit dip or “directed
spray”.   Either the dip or directed spray is conducted in the packing
house.  Directed sprays occur within a hooded area over a conveyer and
fruit is treated as it passes through.  Fruit dips are accomplished as
fruit is conveyed through a “bath” and on to the packing line or
storage facility.  All application is automated.  The rate of
application is 16-32 fl oz/100 gallons of dip or spray solution
(0.24-0.48 lb ai/100 gallons of solution).  One post-harvest application
will be made.  

In the Section 18 request, there are some unforeseeable conditions
relative to carambola harvest such as volumes of fruit available for
harvest at specific times.  Therefore, the Section 18 request is based,
to some degree, on experience with pome and stone fruit harvest and the
use of fludioxonil.  It appears that up to 3,000 lb of fruit may be
treated with a single 100 gallon mix.  Further, it appears that up to
200,000 lb of fruit per load may be treated.   According to the Section
18 request, that requires 4 gallons of formulation i.e., 7.68 lb ai.  

9.1	Occupational Handler Risk

Based upon the proposed use pattern, ARIA believes that there is no
“applicator” in the common sense of the term.  An individual must
prepare the dip/spray solution however the “application” process is
automated, i.e., fruit is treated in one way or the other as it passes
on a conveyer.  Therefore, the only occupational pesticide handler
exposure is the individual preparing the treatment solution.  That
activity is essentially the same as it would be for a mixer/loader
supporting aerial or ground spray operations.  Therefore, the
“occupational handler” assessment is based upon the activities of a
mixer/loader using open pour loading of liquids.  

No chemical specific data are available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).   For pesticide handlers, it is HED policy to present
estimates of dermal exposure for “baseline” that is, with a single
layer of work clothing consisting of a long sleeved shirt, long pants,
shoes plus socks and no protective gloves and with a single layer of
work clothing and the use of protective gloves or other PPE as might be
necessary. 

The Section 18 request directs the use of PPE consisting of long-sleeved
shirt, long pants, shoes plus socks and waterproof gloves.  The product
label does not appear to list PPE.

Relevant to the assessment herein, the HIARC did not identify a dermal
toxicological endpoint.  An assessment of dermal exposure and risk is
not necessary.   However, the HIARC 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.  An intermediate-term (1-6
months) inhalation toxicological endpoint was also identified from a one
year dog feeding study with a NOAEL of 3.3 mg ai/kg bw/day.  

Although the carambola harvest time may span several months, ARIA does
not expect exposures to exceed short-term duration (1–30 days).  It is
unlikely that handlers and packers would be exposed continuously for 30
days or more.  However, short-term and intermediate-term duration
exposures are assessed.

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

Unit Exposure1

mg ai/lb handled	Active Ingredient

Handled/Day2	Avg. Daily Exposure3

mg ai/kg bw/day	MOE4

Mixer/Loader Open Pour Loading Liquids

Inhal.   0.0012	

32 lb ai/day	

Inhal.  0.00064

0.00055	Short term

15,625	Intermediate

Term

6,000

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Inhal. = Inhalation.  Units = mg
ai./pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2. Amount handler per day calculated based on Section 18 request

3.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated  (
Body Weight (60 kg for short-term, 70 kg for intermediate-term).  

4.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL)  ( ADD.    The short-term inhalation NOAEL is 10.0 mg ai./kg
bw/day from a developmental study and the intermediate-term NOAEL is 3.3
mg ai./kg bw/day is from a 1 year feeding study.

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 expects negligible inhalation
exposure to persons handling treated fruit in preparation for storage or
shipment.   The proposed uses do not exceed ARIA’s level of concern.  

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

There are no outstanding data needs for fludioxonil.  No label
amendments are required for this action.

Dietary Exposure Memorandum

	Fludioxonil Acute and Chronic Dietary Exposure Assessment for the
Section 18 Request Proposing Tolerances for Residues of Fludioxonil on
Carambola.  PP# 07FL05, B. Hanson, DP#: 345986, 11/19/2007.

Drinking Water Memorandum

	Memo, DP#s: 285197, 285514, 286372 and 286717, J. Ravenscroft, 1/2/2003

	

Residue Chemistry Data Review Memorandum

	Memo, DP#: 287808, T. Bloem, 2/12/2003

Occupational and Residential Exposure Memorandum

	Fludioxonil – Occupational Exposure/Risk Assessment for the Section
18 Use of Fludioxonil on Carambola (Star Fruit); DP #: 344830; M. Dow;
10/17/2007.

Risk Assessment Document

	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 

Study Selected:  Developmental Toxicity – Rabbit

MRID No.: 43080035

Executive Summary:   Please see the summary below for Developmental
Toxicity – Rabbit.

870.31050	Oral Subchronic Toxicity - Nonrodent 

Study Selected:  Developmental Toxicity – Rabbit

MRID No.: 43080035

Executive Summary:   Please see the summary below for Developmental
Toxicity – Rabbit.

870.3250 	Intermediate-Term Dermal Toxicity – Dog

Studies Selected: None

MRID No.: None

Executive Summary:  A reassessment of the 21 day dermal toxicity study
in rats determined that the systemic NOAEL should be changed from 200
mg/kg/day to 1000 mg/kg/day.  The previous LOAEL was based on a 10%
increase in adrenal gland weight which did not achieve statistical
significance and was not dose-related.  Additionally, there was no
corroborative histopathology.  Also, there was no decreased body weight
or decreased weight gain in the 21-day study, which was the most
sensitive indicators of toxicity in other rat studies. The revised NOAEL
was set at the limit dose of 1000 mg/kg/day for dermal systemic
toxicity. 

Comments about Study/Endpoint: No systemic toxicity was seen at the
highest dose tested of 1,000 mg/kg/day during the 21 days of exposure in
rats.  There were no developmental concerns in rats or rabbits. 
Therefore, there is no hazard and no quantification is required for the
short and intermediate dermal exposure scenario.

870.3465		90-Day Inhalation – Rat

Study Selected: One Year Dog Feeding Study			

MRID No.:43080031

Executive Summary:	See chronic summary.  

Dose/Endpoint for Risk Assessment:  NOAEL of 3.3 mg/kg/day based on
decreased weight gain of 31% at 35.5 mg/kg/day in female dogs during the
weeks 1-13 of exposure in the study.

Comments about Study/Endpoint: The oral toxicity NOAEL of 3.3 mg/kg/day
is the lowest NOAEL in the toxicology data base and the effect of
decreased weight gain during weeks 1-13 of exposure is appropriate for
the intermediate-term human exposure duration since this effect occurs
during for the appropriate period of dosing.  Since an oral study is
being used, an inhalation absorption factor of 100% is needed for
route-to-route extrapolation.

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. 

Dose and Endpoint for Establishing RfD:  Developmental toxicity NOAEL is
100 mg/kg/day based on increased fetal and litter incidence of dilated
renal pelvis and dilated ureter at the LOAEL of 1000 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factor: The fetal effects are
presumed to occur after a single exposure (dose) and these in utero
effects are relevant for the population subgroup of concern (females
13-50).

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.

Dose/Endpoint for Risk Assessment: The maternal toxicity NOAEL of 10
mg/kg/day based on decreased body weight gain and decreased food
efficiency at the LOAEL of 100 mg/kg/day was selected.

Comments about Study/Endpoint: The endpoint is appropriate for the
population of concern (infants and children) and the duration of
exposure in the study (13 days) is appropriate for the short term
incidental oral scenario.

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. 

Dose and Endpoint for Establishing RfD: NOAEL of 3.3 mg/kg/day based on
marked decrease in weight gain in female dogs at the LOAEL of 35.5
mg/kg/day.

Uncertainty Factor(s):  100 [10x for interspecies differences and 10x
for intra species variations]

Comments about Study/Endpoint/Uncertainty Factor: This study is
appropriate because, although the endpoint is decreased body weight gain
in female dogs, significant liver and kidney toxicity was seen in males
at the next higher dose.

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.

A.3.7	Neurotoxicity

No acute or subchronic neurotoxicity studies were available for review
by the Committee.  The 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.

870.6300		Developmental Neurotoxicity - Rat

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, the HIARC determined that a developmental
neurotoxicity study was not required.

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

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