 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (5/5/2011)>

<EPA Registration Division contact: [Shaja Joyner (PM-20) 703-308-3194]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green and brackets, i.e., “[insert
company name],” with the information specific to your action.>

<TEMPLATE:>

<[Syngenta Crop Protection]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Syngenta Crop Protection], [P. O. Box 18300, Greensboro, NC  27409]
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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	[fludioxonil:  [4-(2,
2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile] in or on the
raw agricultural commodity [] at []  >

<	

Leafy petioles subgroup 04B, at 14 parts per million

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 tolerance, eight crop-field trials were
conducted with various commercially available celery cultivars, and the
soil types and meteorological conditions at the eight trial sites
adequately represented the diversity of conditions under which celery
may be commercially grown.  These trial sites satisfied the requirements
of OPPTS 860.1500 for number and regional distribution.  The study
design consisted of 2 plots at each trial site: a non-treated control
(UTC) plot and a treated (TRT) plot.  The TRT plot received four
broadcast foliar applications of 14 oz product/acre/application (or 56
oz product/acre/ season), which equates to 0.328 lb cyprodinil/acre +
0.219 lb fludioxonil/acre (or a seasonal rate of 1.3 lb Cyprodinil/acre
+ 0.9 lb Fludioxonil/acre).  The treatments were applied with a tank-mix
volume of 15 - 40 gallons/acre (GPA) at the minimum 7-day retreatment
interval (RTI), and the raw agricultural commodity (RAC) was harvested
on the day of the last application to support a 0-day pre-harvest
interval (PHI).  This use pattern would be the ‘worst-case’
application as per the proposed-use label.

            

<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 fludioxonil using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.16) from Exponent.  These
exposure assessments included all current uses as well as a proposed
foliar use on celery plus pending foliar uses on peppers (bell and
non-bell) and spinach, a irrigation use on ginseng, and post-harvest
uses on pineapples, potatoes, tropical fruits and tomatoes.  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. 
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. 
Percent of crop treated values were estimated based upon economic, pest
and competitive pressures.  Secondary residues in animal commodities
were estimated based on “maximum reasonably balanced diets” and
transfer information from metabolism 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 observed 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 observed 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 1,182 or 8.5% of the aRfD (Benchmark MOE = 100; aRfD= 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 dietary (food) exposure to residues arising from
the current, pending 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 observed adverse
effect level (NOAEL) by the exposure for each population subgroup.  In
addition, exposure was expressed as a percent of the chronic reference
dose (%cRfD).  Chronic exposure to the U.S. population resulted in a MOE
of 708 or 14.1% of the cRfD (Benchmark MOE = 100; cRfD = 0.033
mg/kg-bw/day).  Chronic exposure to the most exposed subpopulation
(children 1-2 years old) resulted in a MOE of 243 or 41.1% of the cRfD
(Benchmark MOE = 100; cRfD = 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 dietary
(food) exposure to residues arising from the current, pending and
proposed uses for fludioxonil.

>

<ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of fludioxonil were determined using Tier l SCI-GROW, which estimates
pesticide concentrations in ground water and Tier II PRZM/EXAMS which
estimates pesticide concentrations in surface water.  This drinking
water assessment was conducted to assess all currently registered uses,
the pending uses on spinach, peppers, ginseng, potatoes, pineapples,
tropical fruits, and tomatoes as well as the proposed use on celery. 
For ground water, the currently registered use on professional turf
provided the highest EDWC of 2.02E-01 ppb (acute and chronic).  For
surface water, the currently registered field grown and landscape
ornamental provided the highest acute EDWC of 44.102 ppb and the
currently registered use on turf provided the highest chronic EDWC of
32.79 ppb.  No Percent Cropped Area (PCA) adjustments were made for the
surface water EDWCs.  Since the surface water EDWCs exceed the ground
water EDWC, the surface water values were used for risk assessment
purposes and will be considered protective for any ground water exposure
concerns.

Acute Exposure from Drinking Water:  The acute EDWC of 44.102 ppb
(0.044102 ppm) was incorporated with food residues as “water, direct
and indirect, all sources” directly into the DEEM-FCID™ software to
obtain acute dietary (food and water) exposures.  Drinking water
exposures at the 99.9th percentile to fludioxonil for females 13-49
years old (the only population subgroup for which an acute toxicological
endpoint has been established) resulted in a MOE of 97,847 (0.1% 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, pending and proposed fludioxonil uses.

Chronic Exposure from Drinking Water:  The chronic EDWC of 32.79 ppb
(0.03279 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 4,775 (2.1%
of the cRfD of 0.033 mg/kg-bw/day).  The most sensitive sub-population
was all infants (<1 year old), with a MOE of 1,456 (6.9% 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, pending and proposed fludioxonil uses. 

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

	>

<2. Non-dietary exposure.  There is a potential for 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.  The Syngenta short-term and intermediate-term residential
risk assessments were based on the maximum 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 was selected as
well as an intermediate-term NOAEL of 3.3 mg/kg-bw/day from a one year
dog feeding study.  Residential post-application dermal assessments were
not conducted since short-term and intermediate-term dermal endpoints
were not established by the EPA and there were no developmental concerns
with fludioxonil.  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 784
and the combined intermediate-term MOE for children 1-6 years was 445. 
Since the Benchmark MOE for this assessment was 100, Syngenta believes
that there is a reasonable certainty that no harm will result from
exposures arising from residential uses of fludioxonil.

>

<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 the
EPA has followed a cumulative risk approach based on a common mechanism
of toxicity, the 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, the EPA has not assumed that
fludioxonil 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 fludioxonil
uses resulted in a MOE of 617 or 16.2% of the cRfD (Benchmark MOE = 100;
cRfD= 0.033 mg/kg-bw/day).  A cancer exposure analysis was not performed
since there is no evidence of human carcinogenic potential for
fludioxonil.  Since the worst-case aggregate MOE of 617 exceeds the
benchmark MOE of 100, Syngenta believes that there is a reasonable
certainty that no harm will result from aggregate exposure to residues
arising from all current, pending and proposed fludioxonil uses,
including anticipated dietary exposure from food, water, and all other
types of non-occupational exposures.

>

<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
fludioxonil uses resulted in a MOE of 226 or 44.2% of the cRfD
(Benchmark MOE = 100; cRfD= 0.033 mg/kg-bw/day) for children (1-2 years
old).  A cancer exposure analysis was not performed, since there is no
evidence of human carcinogenic potential for fludioxonil.  The short-
term aggregate assessment resulted in MOE of 403, for the children (1-6
years old) population subgroup (Benchmark MOE = 100).  The intermediate-
term aggregate assessment resulted in MOE of 169, for the children (1-6
years old) population subgroup (Benchmark MOE = 100).   Since the
worst-case aggregate MOE of 169 exceeds the Benchmark MOE of 100,
Syngenta believes that there is a reasonable certainty that no harm will
result from aggregate exposure to residues arising from all current,
pending and proposed fludioxonil uses, including anticipated dietary
exposure from food, water, and all other types of non-occupational
exposures.

3. Females 13-49 years of age.  The acute aggregate exposure analysis
showed that exposure to all current, pending and proposed fludioxonil
uses would result in a MOE of 1,168 or 8.6% of the aRfD (Benchmark MOE =
100; aRfD= 1.0 mg/kg-bw/day)) for females 13-49 years old.  The chronic
aggregate exposure analysis showed that exposure to all current and
proposed fludioxonil uses would result in a MOE of 761 or 13.1% of the
cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg-bw/day) for females 13-49
years old. A cancer exposure analysis was not performed, since there is
no evidence of human carcinogenic potential for fludioxonil.  Since the
worst-case aggregate MOE of 761 exceeds the Benchmark MOE of 100,
Syngenta believes that there is a reasonable certainty that no harm will
result from aggregate exposure to residues arising from all current,
pending and proposed fludioxonil uses, including anticipated dietary
exposure from food, water, and all other types of non-occupational
exposures.

>

<F. International Tolerances>

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Codex Maximum Residue Limits (MRLs) for residues of fludioxonil per se
have been established on a number of commodities, including apples,
beans, berries, cabbage, citrus fruits, cucumber, egg plant, kiwifruit,
lettuce, melons (except watermelon), peas (dry), peas (pods and
succulent=immature seeds), peas (pods and succulent seeds), peppers,
sweet, pome fruits, squash, summer, straw and fodder (dry) of cereal
grains, tomato, and potato.

  

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