Document ID: EPA-HQ-OPP-2007-0940-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-24T04:00Z

<EPA Registration Division contact: Sidney Jackson, (703) 305-7610>

Docket ID:  EPA-HQ-OPP-2007-0940

<Interregional Research Project No. 4 (IR-4)>

<PP#: 7E7234>

	EPA has received a pesticide petition (PP) [7E7234] from the IR-4
Project Headquarters, 500 College Road East, Suite 201 W, Princeton, NJ 
08540 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part
180.516 by establishing a tolerance for residues of

the fungicide fludioxonil 4-(2,
2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in or on the
raw agricultural commodities: tomato at 0.4 parts per million (ppm),
tomatillo at 0.4 ppm, tomato, paste at 1.0 ppm, avocado at 0.45 ppm,
black sapote at 0.45 ppm, canistel at 0.45 ppm, mamey sapote at 0.45
ppm, mango at 0.45 ppm, papaya at 0.45 ppm, sapodilla at 0.45 ppm, star
apple at 0.45 ppm, herb subgroup 19A, fresh at 13 ppm, herb subgroup
19A, dried at 55 ppm, leaves of root and tuber vegetables at 40 ppm,
root vegetables, except sugar beet subgroup at 0.5 ppm, lemon at 0.25
ppm, lime at 0.25 ppm, cucurbits at 0.6 ppm, tuberous and corm
vegetables, except potato subgroup at 4.0 ppm.

Upon approval of the aforementioned tolerances, it is proposed that 40
CFR 180.516 be amended to remove the established tolerances for the
residues of fludioxonil:  4-(2,
2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile in or on the
raw agricultural commodities: herb subgroup 19A, fresh at 10 ppm, herb
subgroup 19A, dried at 65 ppm, and carrot at 0.75 ppm, turnip, greens at
10 ppm.

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of  FDDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
Additional data may be needed before EPA rules on the petition.

<A. Residue Chemistry>

<1. Plant metabolism.  The metabolism of fludioxonil is adequately
understood for the purpose of the proposed tolerances.  

>

<2. Analytical method. Syngenta has developed and validated analytical
methodology for enforcement purposes. This method (Syngenta Crop
Protection Method AG-597B) has passed an Agency petition method
validation for several commodities, and is currently the enforcement
method for fludioxonil. This method has also been forwarded to the Food
and Drug Administration for inclusion into PAM II. An extensive database
of method validation data using this method on various crop commodities
is available.    >

<3. Magnitude of residues. Complete residue data to support the
requested tolerances have been submitted. The requested tolerances are
adequately supported.  

>

In support of the requested tolerances, IR-4 conducted the following
trials:  Tomato trials were conducted in the field in Maryland, New
York, Florida (two trials), North Carolina, California (five trials),
New Mexico (two trials), Washington, and Wisconsin; greenhouse trials
were conducted in New Jersey, Texas, Tennessee, and Colorado.  Avocado
field trials were conducted in Florida (Region 3), Texas (Region 6), and
four trials in California (Region 10).  Parsley trials were conducted in
Florida (Region 3), California (Region 10), Ohio (Region 5), and Oregon
(Region 12).  In the radish study, magnitude of residue data were
collected from New York (Region 1), two trials in Florida (Region 3),
Ohio (Region 5), California (Region 10), and Washington (Region 11).  In
the lemon study, five trials were conducted in California (Region 10). 
In the sweet potato study, a post-harvest trial was conducted in
California (Region 10) and North Carolina (Region 2).  In the cucurbit,
Group 9, trials, 18 field trials were conducted in 10 states:  five
trials in California (Region 10), two trials in Florida (Region 3), two
trials in Georgia (Region 2), two trials in Illinois (Region 5), one
trial in Michigan (Region 5), one trial in New York (Region 1), one
trial in North Carolina (Region 2), one trial in South Carolina (Region
2), two trials in Texas (Region 6), and one trial in Wisconsin (Region
5).               

<B. Toxicological Profile

>

An assessment of toxic effects caused by fludioxonil is discussed in
Unit III. A. and Unit III. B. of the Federal Register published by EPA
dated August 2, 2002 (67 FR 50354) (FRL-7188-7) and is repeated in part
below.                        

Carcinogenic and Other Toxicity

<>

Study Type             	Results

Carcino-genicity rats      	NOAEL = 590 mg/kg/day (M) and 715 mg/kg/day
(F). LOAEL: 851 mg/kg/day (M) and 1,008 mg/kg/ day (F) based on reduced
survival (F), decreased body weights (M), bile duct hyperplasia (M) and
severe nephropathy(both sexes). No evidence of carcinogenicity.

In vivo Rat hepatocyte micronucleus assay                	Male rats were
orally dosed at 50, 250, and 1,250 mg/kg and hepatocytes were harvested.
There was no evidence of a significant increase in micronucleated
hepatocytes in treated groups in comparison to controls.

Unscheduled DNA synthesis assay  	There was no evidence that unscheduled
DNA synthesis, as determined by nuclear silver grain counts, was induced
in hepatocyte cultures obtained from male rats dosed at 2,500 or 5,000
mg/kg.

Summary of Toxicological Dose and Endpoints for Fludioxonil for Use in
Human Risk Assessment

Exposure Scenario       	Dose Used in Risk Assessment, UF               
      	FQPA SF and Level of Concern for Risk Assessment     	Study and
Toxicological Effects

Acute Dietary females 13-50 years of age                                
                            	NOAEL = 100 mg/kg/day 

UF = 100

Acute RfD = 1.0 mg/kg/day.                         	FQPA SF = 1X 

aPAD = acute RfD ÷ FQPA 

SF = 1.0 mg/kg/day.                           	Developmental Toxicity
Study – rat

Developmental LOAEL =1,000 mg/kg/day based on increased incidence of
fetuses and litters dilated renal pelvis and with dilated ureter

Chronic Dietary all populations                                         
                                                         	NOAEL= 3.3
mg/kg/day UF = 100

Chronic RfD = 0.03 mg/ kg/day.                                          
                                             	FQPA SF = 1X 

cPAD = chronic RfD FQPA SF = 0.03 mg/kg/day.                            
                                                                        
1 year chronic toxicity study – dog

LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs

Incidental Oral, Short-Term                                             
                                                       	NOAEL = 10
mg/kg/day                                                               
                             	LOC for MOE = 100	Rabbit developmental
study

LOAEL = 100 mg/kg/day based on decreased weight gain during gestation

Incidental Oral, Intermediate-Term                                      
                                                     	NOAEL = 3.3
mg/kg/day    	LOC for MOE = 100        	1 year chronic toxicity study -
dog 

LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs

Short-and Intermediate Term Dermal (1-30 days and 1-6 months)
(Residential)                                        	None              
      	No systemic toxicity      was seen at the limit dose (1,000
mg/kg/day) in the 28-day dermal toxicity study in rats  	Endpoint was
not selected                                                   

Long-Term (several months-lifetime) Dermal (Residential)                
                                                                      
Oral study

NOAEL = 3.3 mg/kg/day (dermal penetration =  40%).                      
                                                                        
        	LOC for MOE = 100 (Occupational) 

LOC for MOE = 100 (Residential).                         	1 year chronic
toxicity study - dog 

LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs

Short-Term (1-30 Days) Inhalation (Residential)                         
                                                              	Oral
NOAEL = 10 mg/kg/ day (inhalation absorption rate = 100%)               
            	LOC for MOE = 100 (Occupational)

LOC for MOE = 100(Residential).                        	Rabbit
developmental study

LOAEL = 100 mg/kg/day based on decreased weight gain during gestation

Intermediate-term (1 month - 6 months) Inhalation (Residential)	Oral
NOAEL = 3.3 mg/kg/ day (inhalation absorption rate = 100%)              
          	LOC for MOE = 100                        (Occupational) 

LOC for MOE = 100(Residential).                            	 1 year
chronic toxicity study - dog                                     LOAEL =
35.5 mg/kg/day based on decreased weight gain in female dogs

Long-Term (several months-lifetime) Inhalation (Residential)   	Oral
NOAEL = 3.3 mg/kg/day (inhalation absorption rate = 100%)         	LOC
for MOE = 100(Occupational)  LOC for MOE = 100(Residential).            
                       	1 year chronic toxicity study – dog

LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs

<>

<6. Animal metabolism. The metabolism of fludioxonil in rats is
adequately understood.

                                                                        
                                                                        
                                                                        
                                                        >

<7. Metabolite toxicology. The residue of concern for tolerance setting
purposes is the parent compound. Consequently, there is no additional
concern for toxicity of metabolites.         

>

<8. Endocrine disruption. Fludioxonil does not belong to a class of
chemicals known for having adverse effects on the endocrine system. No
estrogenic effects have been observed in the various short- and
long-term studies conducted with various mammalian species.             
                            

C. Aggregate Exposure>

<1. Dietary exposure.  Tier III acute and chronic dietary exposure
evaluations were performed for fludioxinil using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.14) from Exponent.  Empirically
derived processing factors for apple juice (0.09X), apple pomace
(6.77X), tomato puree (0.34X), tomato paste (1.1X), and citrus oil (50X)
were used in these assessments.  The apple juice processing factor was
used as a surrogate for pear juice.  All other processing factors used
the DEEMTM defaults.  All consumption data for these assessments was
taken from the USDA’s Continuing Survey of Food Intake by individuals
(CSFII) with the 1994-96 consumption database and the Supplemental CSFII
children’s survey (1998) consumption database.  These exposure
assessments included all current and proposed new uses for fludioxinil
including tomato, tomatillo, avocado, black sapote, canistel, mamey
sapote, mango, papaya, sapodilla, star apple, fresh and dried herbs
(Crop Group 19A), root vegetables (Crop Group 1B), leaves of root and
tuber vegetables (Crop Group 2), lemon and lime.  These assessments
utilized residue data from field trials where fludioxonil was applied at
the maximum intended use rate and samples were harvested at the minimum
pre-harvest interval (PHI) to obtain maximum residues.  Percent of crop
treated values were estimated based upon economic, pest and competitive
pressures.  Secondary residues in animal commodities were estimated
based on theoretical worst-case, yet nutritionally adequate animal diets
and transfer information from feeding studies.>

<i. Food.  Acute exposure.  The acute dietary (food only) risk
assessment for females 13 to 49 years old (the only population subgroup
for which an acute toxicological endpoint has been established) was
performed using an acute reference dose (aRfD) of 1.0 mg/kg-bw/day,
based upon a rat teratology study with a no observable adverse effect
level (NOAEL) of 100 mg/kg/day and an uncertainty factor (UF) of 100X
for intra- and inter-species variations; no additional FQPA safety
factor was applied.  For the purpose of the aggregate risk assessment,
the exposure value was expressed in terms of margin of exposure (MOE),
which was calculated by dividing the no observable adverse effect level
(NOAEL) by the exposure for each population subgroup.  In addition,
exposure was expressed as a percent of the acute reference dose (%aRfD).
 Acute exposure to the females 13-49 years subpopulation resulted in a
MOE of 1,940 (5.2% of the acute RfD of 1.0 mg/kg-bw/day).  Since the
Benchmark MOE for this assessment was 100 and since EPA generally has no
concern for exposures below 100% of the RfD, Syngenta believes that
there is a reasonable certainty that no harm will result from dietary
(food) exposure to residues arising from the current and proposed uses
for fludioxonil.

Chronic exposure.  The chronic reference dose (RfD) for fludioxonil is
0.033 mg/kg-bw/day, based upon a one-year study in dogs with a NOAEL of
3.3 mg/kg-bw/day and an uncertainly factor of 100X; no additional FQPA
safety factor was applied.  For the purpose of the aggregate risk
assessment, the exposure values were expressed in terms of margin of
exposure (MOE), which was calculated by dividing the no observable
adverse effect level (NOAEL) by the exposure for each population
subgroup.  In addition, exposure was expressed as a percent of the
reference dose (%RfD).  Chronic exposure to the most exposed
sub-population (children 1 and 2 years old) resulted in a MOE of 732
(13.7% of the chronic RfD of 0.033 mg/kg-bw/day).  Since the Benchmark
MOE for this assessment was 100 and since EPA generally has no concern
for exposures below 100% of the RfD, Syngenta believes that there is a
reasonable certainty that no harm will result from dietary (food)
exposure to residues arising from the current and proposed uses for
fludioxonil.

>

<ii. Drinking water. Estimated Drinking Water Concentrations (EDWCs) for
fludioxonil were determined using Tier 1 screening models, FIRST which
estimates pesticide concentration in surface water and SCI-GROW which
estimates pesticide concentration in ground water.  The modeling was
conducted using chosen environmental fate data applying EPA’s guidance
for selecting inputs and the current highest labeled use rate for
fludioxonil.  The professional turf use pattern of 0.68 lb a.i./A with
three applications at 14 day intervals was used.  The FIRST model
calculated EDWCs of 72.291 ppb and 30.325 ppb for acute and chronic
surface water, respectively.  The SCI-GROW model calculated an EDWC
level of 2.00E-01 ppb for ground water.  Since the surface water EDWCs
exceed the ground water EDWC, the FIRST surface water values were used
for risk assessment purposes and will be considered protective for any
ground water concentration concerns.  

 into the DEEM-FCID™ software to obtain acute dietary (food and water)
exposures.  Drinking water exposures at the 99.9th percentile to
fludioxinil for females 13-49 years old (the only population subgroup
for which an acute toxicological endpoint has been established) resulted
in a MOE of 61,920 (0.2% of the aRfD of 1.0 mg/kg-bw/day).  Since the
Benchmark MOE for this assessment was 100, and since the EPA generally
has no concern for exposures below 100% of the aRfD, Syngenta believes
that there is a reasonable certainty that no harm will result from acute
drinking water exposure to residues arising from all current and
proposed uses of fludioxinil.

Chronic Exposure from Drinking Water:  The chronic EDWC of 30.325 ppb
(0.030325 ppm) was incorporated with food residues as “water, direct
and indirect, all sources” directly into the DEEM-FCID™ software to
obtain chronic dietary (food and water) exposures.  Chronic drinking
water exposure to the U.S. population resulted in a MOE of 5,164 (1.9%
of the cRfD of 0.033 mg/kg-bw/day).  The most exposed sub-population was
children 1-2 years old, with a MOE of 3,477 (2.8% of the cRfD of 0.033
mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and
since the EPA generally has no concern for exposures below 100% of the
cRfD, Syngenta believes that there is a reasonable certainty that no
harm will result from chronic drinking water exposure to residues
arising from all current and proposed uses of fludioxinil.

Cancer.  A chronic cancer exposure analysis was not performed, since
there is no evidence of human carcinogenic potential for fludioxinil.  

	>

<2. Non-dietary exposure.  There is a potential residential
post-application exposure to adults and children entering residential
areas treated with fludioxonil.  Fludioxonil is currently registered for
professionally applied uses on turf grass and ornamentals in residential
landscapes.  No residential handler exposures are anticipated, however,
short- and intermediate-term dermal (adults and children) and incidental
oral ingestion (children) post-application residential exposures are
anticipated based on the use pattern for turf grass.  In a recent
fludioxonil aggregate EPA risk assessment, short- and intermediate-term
dermal endpoints were not selected due to the NOAEL of 1,000 mg/kg/day
(highest dose tested) in the 28-day dermal toxicity study in rats and
also since there were no developmental concerns.  The Agency concluded
that there were no significant post-application exposures anticipated
from treated landscape ornamentals and limited their residential risk
assessment to incidental oral ingestion by children following
residential lawn applications.  The Syngenta short- and
intermediate-term residential risk assessments were based on the maximum
Medallion® label rate for turf grass of 0.68 lb a.i./A (0.50 oz
product/1000ft2) with a maximum of three applications allowed per year
(0.68 lb a.i./A x 3 apps = 2 lb a.i./A/year).  In these residential risk
assessments, a short-term NOAEL of 10 mg/kg-bw/day from a rabbit
developmental study and an intermediate-term NOAEL of 3.3 mg/kg/day from
a one year chronic toxicity study were selected.  The residential risk
assessments were limited to children since the only route of exposure
was incidental oral ingestion via hand-to-mouth activity and
object-to-mouth (grass and soil ingestion).  The combined short-term MOE
for children 1-6 years was 785, and the combined intermediate-term MOE
for children 1-6 years was 259; both are above the Benchmark MOE of 100
for these assessments.

>

<D. Cumulative Effects>

<Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 
Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether
to establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.”  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
fludioxinil and any other substances, and fludioxinil does not appear to
produce a toxic metabolite produced by other substances.  For the
purposes of this tolerance action, the EPA has not assumed that
fludioxinil has a common mechanism of toxicity with other substances.

>

<E. Safety Determination>

<	1. U.S. population. An acute toxicological endpoint has not been
established for the U.S. population, so an acute exposure assessment was
not performed for the U.S. population.  The chronic aggregate exposure
analysis showed that exposure from all current and proposed fludioxinil
uses resulted in a MOE of 1,772 (5.6% of the cRfD of 0.033 mg/kg-bw/day)
for the U.S. population, which exceeds the Benchmark MOE of 100.  A
cancer exposure analysis was not performed, since there is no evidence
of human carcinogenic potential for fludioxinil.  The short- and
intermediate term aggregate assessments resulted in MOEs of 2,301 and
1,771, respectively, for the U.S. population, both of which exceed the
Benchmark MOE of 100.  Based on the completeness and reliability of the
toxicity data supporting these petitions, Syngenta believes that there
is a reasonable certainty that no harm will result from aggregate
exposure from all current and proposed uses of fludioxinil.

>

<2. Infants and children. An acute toxicological endpoint has not been
established for infants and children, so an acute exposure assessment
was not performed for infants and children.  The chronic aggregate
exposure analysis showed that exposure from all established and proposed
fludioxinil uses resulted in a MOE of 605 (16.5% of the cRfD of 0.033
mg/kg-bw/day) for children 1-2 years old, which exceeds the Benchmark
MOE of 100.  A cancer exposure analysis was not performed, since there
is no evidence of human carcinogenic potential for fludioxinil.  The
short- and intermediate term aggregate assessments resulted in MOEs of
366 and 191, respectively, for children 1-2 years old, both of which
exceed the Benchmark MOE of 100.  Based on the completeness and
reliability of the toxicity data supporting these petitions, Syngenta
believes that there is a reasonable certainty that no harm will result
from aggregate exposure from all current and proposed uses of
fludioxinil.

B*

/

2

I

L

\

_

p

s

B*

B*

B*

B*

B*

B*

$s

‡

Š

Ÿ

§

Ã

Æ

Ê

Ë

ç

ê

²

³

Ù

Þ

ä

B*

B*

B*

B*

sis was not performed, since there is no evidence of human carcinogenic
potential for fludioxinil.  The short- and intermediate term aggregate
assessments resulted in MOEs of 3,108 and 2,260, respectively, for
females 13-49 years old, both of which exceed the Benchmark MOE of 100. 
Based on the completeness and reliability of the toxicity data
supporting these petitions, Syngenta believes that there is a reasonable
certainty that no harm will result from aggregate exposure from all
current and proposed uses of fludioxinil.

>

<F. International Tolerances>

	There are no Codex maximum residue levels established for fludioxonil. 
 

 PAGE   

 PAGE   8