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Fludioxonil - Pesticide Petition Filing 8/98

[Federal Register: August 26, 1998 (Volume 63, Number 165)]
[Page 45497-45503]
From the Federal Register Online via GPO Access []
[PF-825; FRL-6023-4]
Notice of Filing of Pesticide Tolerance Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.

SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by the docket control number PF-825, must
be received on or before September 25, 1998.

ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following
the instructions under "SUPPLEMENTARY INFORMATION." No Confidential
Business Information (CBI) should be submitted through e-mail.
    Information submitted as a comment concerning this document may be

[[Page 45498]]

claimed confidential by marking any part or all of that information as
CBI. CBI should not be submitted through e-mail. Information marked as
CBI will not be disclosed except in accordance with procedures set
forth in 40 CFR part 2. A copy of the comment that does not contain CBI
must be submitted for inclusion in the public record. Information not
marked confidential may be disclosed publicly by EPA without prior
notice. All written comments will be available for public inspection in
Rm. 119 at the address given above, from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:

                                   Office location/
        Product Manager            telephone number          Address
Mark Dow......................  Rm. 214, CM #2, 703-    1921 Jefferson
                                 305-5533; e-mail:       Davis Hwy,
                                 Dow.mark@epamail.epa.   Arlington, VA
Mary L. Waller................  Rm. 247, CM #2, 703     Do.
                                 308-9354; e-mail:

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various raw food commodities under
section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21
U.S.C. 346a. EPA has determined that these petitions contain data or
information regarding the elements set forth in section 408(d)(2);
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports grantinig of the
petition. Additional data may be needed before EPA rules on the
    The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-825 (including comments and data submitted electronically as
described below). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The
official record is located at the address in "ADDRESSES".
    Electronic comments can be sent directly to EPA at:

    Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-825) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.

    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping

    Dated: August 10, 1998.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. The
petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.

1. Novartis Crop Protection, Inc.

PP 7E4919 and 8F4978

    EPA has received two pesticide petitions (7E4919 and 8F4978 from
Novartis Crop Protection, Inc., 410 Swing Road, Greensboro, NC 27419
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing tolerances for residues of fludioxonil (4-(2,2-difluoro-
1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile) in or on the raw
agricultural commodities: grapes at 1.00 parts per million (ppm)
(7E4919); canola, peanuts, sunflowers, leafy vegetables except brassica
(Crop Group 4); brassica leafy vegetables (Crop Group 5); legume
vegetables (Crop Group 6); foliage of legume vegetables (Crop Group 7);
fruiting vegetables (Crop Group 8); cucurbit vegetables (Crop Group 9);
forage, fodder, and straw of cereal grains (Crop Group 16); grass ,
forage, fodder, and hay (Crop Group 17); and non-grass animal feeds
(Crop Group 18) at 0.01 ppm; root and tuber vegetables (Crop Group 1);
leaves of root and tuber vegetables (Crop Group 2); bulb vegetables
(Crop Group 3); cereal grains (Crop Group 15); and herbs and spices
(Crop Group 19) at 0.02 ppm; and cotton at 0.05 ppm (8F4978). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; 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. The residues of
regulatory concern is the parent compound only. Metabolism in grapes
involves oxidation of the pyrrole ring, primarily at the 2 and 5
positions. Subsequent opening of the oxidized pyrrole ring yields a
metabolite with an amide plus a carboxylic acid group. This open-ring
metabolite undergoes further oxidation at the bridgehead carbon
followed by decarboxylation.
    2. Analytical method. Novartis has developed and validated
analytical methodology for enforcement purposes as part of the original
corn, sorghum, and potato registrations. This method (Novartis Crop
Protection Method AG-597B) has passed an Agency petition method
validation (PMV) and is currently the enforcement method for potatoes.
As part of this petition, Novartis has validated the method on the
crops, fractions, and crop representatives of each crop grouping
associated with this submittal. The method validation study (ABR-97060)
contains recovery data on over eighty individual substrates. In most
cases, a limit of quantitation of 0.01 ppm of fludioxonil was achieved.
For several very difficult substrates, a limit of quantitation of 0.02
ppm and for cotton substrates a limit of 0.05 ppm were achieved.

[[Page 45499]]

    For the analysis of grapes, grape juice, and wine the analytical
Method AG-579B14 is proposed as the regulatory enforcement method. It
has been validated by the Agency as an enforcement method for
fludioxonil as AG-57912. In Method AG-579B14, whole fruit or wine
samples are extracted with acetonitrile/water (90/10). Red and white
grapes, as well as red and white wine samples were analyzed by this
method. Recoveries (from 0.02 ppm to 1.0 ppm) ranged from 73% to 114%
with a mean of 92% (n=15).
    3. Magnitude of residues. Residue trials were conducted on cotton,
wheat, radishes, lettuce, cucumbers and peas in the major crop growing
areas of the U.S. in addition to residue trials previously on corn,
sorghum, potatoes and grapes. Several trials were conducted on each
crop. Rates were 0.5 x , 1.0 x , 2.5 x  and 5.0 x  of the proposed use
rate on all crops except cotton where 1.0 x  and 3.0 x  were used.
    From 6 cotton trials, field trash, gin trash, un-delinted seed and
cottonseed fractions (hulls, meal, refined oil) were analyzed for
fludioxonil at a method limit of determination of 0.05 ppm. At this
level, no quantifiable residues of fludioxonil were found in any RAC or
fraction at the proposed or the exaggerated (3 x ) rate.
    Seven trials were completed on wheat. At a method limit of
quantification of 0.02 ppm, no quantifiable residues of fludioxonil
were observed in any RAC at the proposed treatment rate or at rates up
to 5 x  the proposed treatment rate.
    Five trials were completed on radishes which represents the
absolute worst case for potential uptake of residues because of its
very rapid growth and short growing season (27-55 days in these
studies). Both root and top samples from all rates in all 5 trials were
analyzed at a method limit of determination of 0.01 ppm. No fludioxonil
residue (<0.01 ppm) was found in any root or top sample at the proposed
use rate or at rates up to 5 x  the proposed use rate.
    Mature lettuce leaves from all treatment rates of the 6 trials were
analyzed for fludioxonil at a method limit of determination of 0.01
ppm. No fludioxonil residue was found in any lettuce sample at the
proposed use rate or up to 5 x  the proposed use rate.
    Cucumbers from all treatment rates in all 6 trials were analyzed at
a method limit of determination of 0.01 ppm. No fludioxonil residue was
found in any cucumber sample at the proposed use rate or up to 5 x  the
proposed use rate.
    Peas with pods from 5 trials were analyzed at a method limit of
determination of 0.01 ppm. No fludioxonil residue was found in any pea
sample at the proposed use rate or at rates up to 5 x  the proposed use
    Thirty (30) field trials were conducted under maximum label rates
on ten varieties of grapes in the major grape-growing regions of
France, Switzerland, and Chile. Grape residue data were generated from
fifty (50) samples treated at the maximum use rate. Data on transfer to
grape juice were generated from sixteen (16) samples and data
concerning transfer to wine were based on twenty-six (26) samples.
Raisin data were produced from sixteen (16) samples.
    Supplemental data (including fifteen (15) decline curves) were
generated using exaggerated rates (due to multiple applications) on 89
additional samples of whole fruit. Supplemental data were also provided
on eight additional juice samples and on twelve additional wine
samples. Raisin data on eight samples were also provided. These data
demonstrate dose response, provide additional decline information,
provide additional information on transfer to juice and wine, and show
that residue data obtained from other grape-growing countries (Italy
and South Africa) fully support the results obtained from France,
Switzerland, and Chile. The raisin data also demonstrate no significant
concentration of residues.
    Analysis of mature grapes at harvest following a single foliar
application of fludioxonil at 500 grams a.i./ha at flowering, up to the
beginning of bunch closing, resulted in maximum whole fruit residues of
0.77 ppm. Similarly, analysis of grapes at harvest following two foliar
applications of fludioxonil at 250 grams a.i./ha/application at
flowering and again at stages up to fruit softening resulted in maximum
whole fruit residues of 0.33 ppm. These results suggest that the
application at flowering does not contribute to the residue in fruit.
The data fully support an import tolerance of 1 ppm on grapes imported
into the U.S..
    The data support a 60-day pre-harvest interval (PHI) as listed on
the GEOXE label for France. The data also support Chilean, Slovenian,
and Bosnian PHIs of 15-days, 7-days (berries) to 21-days (applications
to the vine), and 21-days, respectively for the combination product,
Switch . There is no PHI on the Swiss Switch label, but the second
application is limited by the label to mid-August, which results in a
PHI greater than 21 days.
    No significant concentration of residues was observed in grape
juice, wine, or raisins. Thus, tolerances are not required for these
processing fractions.

B. Toxicological Profile

    1. Acute toxicity. Fludioxonil and end use formulations have very
low toxicity to the mammalian species by the oral, dermal, or
inhalation route. The dose needed to kill 50% of animals was calculated
to be greater than 5,000 mg/kg (oral), 2,000 mg/kg (dermal), and 2.6
mg/L (inhalation) in these studies. The eye and skin irritations seen
in animals upon acute exposure indicate that no more than transient and
slight irritation. No sensitizing potential was noted with either the
technical material or the formulated product.
    2. Genotoxicity. Mutagenicity potential of fludioxonil was tested
in several studies. In the Chinese hamster ovary cell assay, some
clastogenic and polyploidogenic effects were seen at or near the
precipitating concentration of the test substance. However, results
were negative in the Ames assay, Chinese hamster V79 cell assay,
hepatocyte DNA repair assay, rat hepatocyte micronucleus test, mouse
bone marrow test, and Chinese hamster bone marrow test. A dominant
lethal test conducted in the mouse was also negative.
    3. Reproductive and developmental toxicity. Fludioxonil is not a
teratogen and does not affect reproduction or fertility. No fetal
toxicity was observed even at the highest dose tested in both the
rabbit (300 mg/kg) and the rat (1,000 mg/kg) teratogenicity studies. In
a two-generation rat reproduction study, a reduction of pup body weight
was seen at the highest feeding level of 3,000 ppm in the presence of
maternal toxicity. The NOEL was 300 ppm for both maternal and fetal
toxicity in this study.
    4. Subchronic toxicity. In a 90-day dietary toxicity study the
kidney and liver have been identified as target organs. In a subchronic
study in rats, the NOEL was 10 ppm based on liver toxicity. In a
subchronic study in mice, the NOEL was 100 ppm based on blue urine (a
metabolite); the maximum tolerated dose was 7,000 ppm. In a subchronic
study in dogs, the NOEL was 200 ppm based on clinical observations; the
maximum tolerated dose was 8,000 ppm.
    5. Chronic toxicity. In an 1-year chronic toxicity study in dogs,
the NOEL was 100 ppm based on body weight effects; the maximum
tolerated dose was 8,000 ppm.
    Two 18-month dietary oncogenicity studies were performed in mice.
While a NOEL of 1,000 ppm was clearly established in the first study,
its highest feeding level (3,000 ppm) did not meet the criteria for a
maximum tolerated dose. In the second 18-month study, the

[[Page 45500]]

maximum tolerated dose was determined to be 5,000 ppm based on kidney
effects. There were no treatment-related increases in neoplasia at any
dose level tested in either study.In a combined chronic toxicity/
oncogenicity study in rats, the incidence of liver tumors in top-dose
females (3,000 ppm) was marginally higher than the concurrent controls
but within historical control range. The NOEL for chronic toxicity was
1,000 ppm in both sexes.
    6. Animal metabolism. 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.
    7. Metabolite toxicology. The residues of concern for tolerance
setting purposes is the parent compound. Consequently, there is no
additional concern for toxicity of metabolites. In grapes, fludioxonil
is metabolized only to a limited extent. The metabolites thus formed
have also been found in the rat. The major metabolites are those that
result from the oxidation of the pyrrole ring and they are rapidly
excreted upon conjugation. Consequently, there is no additional concern
for toxicity of any metabolites in grapes.
    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 --i. Food. For purposes of assessing the
potential dietary exposure under the proposed tolerance, Novartis has
estimated aggregate exposure based on the theoretical maximum residue
concentration (TMRC) from the tolerance level of 1.0 ppm in or on
grapes and from the established or proposed tolerance levels. The TMRC
is a worse case estimate of dietary exposure since it is assumed that
100% of all crops for which tolerances are proposed or established are
treated and that pesticide residues are present at the tolerance
    Fludioxonil's current registered use for seed treatment on corn and
sorghum seeds does not contribute to dietary exposure because there are
no detectable residues. EPA has ruled that these uses are food uses not
requiring tolerances. For potato seed treatment, a tolerance of 0.02
ppm has been set. In conducting this exposure assessment, very
conservative assumptions have been used (i.e., 100% of potatoes and
grapes will contain fludioxonil residues at tolerance levels),
resulting in an overestimate of human exposure.
    ii. Drinking water. Exposure of the general population to residues
of fludioxonil from drinking water is considered unlikely for two
reasons: (1) the import tolerance for grapes would not lead to the
exposure of the general population to residues of pesticides in
drinking water; and (2) the movement of fludioxonil into groundwater is
highly unlikely due to its chemistry. In addition, the EPA has not
established a Maximum Contaminant Level for residues of fludioxonil in
drinking water.
    2. Non-dietary exposure. Non-occupational exposure for fludioxonil
has not been calculated since the current registration for fludioxonil
is limited to commercial crop production. Since the chemical is not
used in or around the home, Novartis considers the potential for non-
occupational exposure to the general population to be non-existent.

D. Cumulative Effects

    Consideration of a common mechanism of toxicity is not appropriate
at this time since Novartis is unaware of any reliable information that
indicates that toxic effects produced by fludioxonil would be
cumulative with those of any other chemical compounds. Consequently,
Novartis is considering the potential risks of only fludioxonil in its
aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based on the available chronic toxicity data,
EPA has set the Reference Dose (RfD) for fludioxonil at 0.03 mg/kg/day.
This RfD is based on a 1-year feeding study in dogs with a No Observed
Effect-Level (NOEL) of 3.3 mg/kg/day (100 ppm) and an uncertainty
factor of 100. No additional uncertainty factor was judged to be
necessary as body weight was the most sensitive indicator of toxicity
in that study.
    2. Infants and children. Using GENEEC water and aggregate exposures
(water plus diet) 5.65% and 5.75% of the RfD were obtained for the most
sensitive sub-populations, non-nursing infants and children (1-6
years), respectively. Aggregate exposure (water plus diet) utilizing
the summed SCI-GROW estimated water concentrations (turf and seed
treatment uses) resulted in an overall exposure of 1.72% of the RfD for
the U.S. population. Aggregated exposure (water plus dietary) to non-
nursing infants and children (1-6 years) was 3.49% and 4.69% of the
RfD, respectively, using the combined turf and seed treatment water
estimates. It should be noted that the aggregate exposure assessment
greatly overestimates exposure since both GENEEC and SCI-GROW models
generate extremely conservative and unrealistic water concentrations.
In addition, all non-detected residues were assumed to be at the limit
of quantitation and no market share adjustment was made. Therefore, a
more than reasonable certainty exists that no harm will result from
exposure to fludioxonil residues through food and water consumption if
the proposed uses are registered.

F. International Tolerances

    There are no Codex maximum residue levels established for residues
of fludioxonil.      (Mary L. Waller)

[FR Doc. 98-22428 Filed 8-25-98; 8:45 am]