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Fludioxonil (Novartis). October
7, 1998, Pesticide Tolerances.
Final Rule. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/October/Day-07/p26902.htm
[Federal Register: October 7, 1998 (Volume 63, Number 194)]
[Rules and Regulations]
[Page 53820-53826]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07oc98-986]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300738; FRL-6036-8]
RIN 2070-AB78
Fludioxonil; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of
fludioxonil (4-(2,2-difluoro 1,3 benzodioxol-4-yl)-1H-pyrrole-3-
carbonitrile) in or on the following raw agricultural commodities
(RACs): rape seed, rape forage, peanuts, meat (hulls removed), peanut
hay, sunflower seed, leafy vegetables except brassica, brassica leafy
vegetables, legume vegetables, foliage of legume vegetables, fruiting
vegetables except cucurbits, cucurbit vegetables, forage, fodder, and
straw of cereal grains, grass, forage, fodder, and hay, and non-grass
animal feeds at 0.01 parts per million (ppm); root and tuber
vegetables, leaves of root and tuber vegetables, bulb vegetables,
cereal grains, and herbs and spices at 0.02 ppm; and cotton seed and
cotton gin byproducts at 0.05 ppm. Novartis Crop Protection, Inc,
requested this tolerance under the Federal Food, Drug and Cosmetic Act
(FFDCA), as amended by the Food Quality Protection Act of 1996 (Pub. L.
104-170).
DATES: This regulation is effective October 7, 1998. Objections and
requests for hearings must be received by EPA on or before December 7,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300738], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300738], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e mail) to: opp docket@epamail.epa.gov. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300738]. No Confidential Business Information (CBI) should
be submitted through e mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Mary Waller, Registration
Division [7505C], Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e mail address: Crystal Mall #2, 1921
Jefferson Davis Hwy., Arlington, VA, 703-308-9354, e mail:
waller.mary@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: In the Federal Register of August 26, 1998
63 FR 45497 (FRL-6023-4), EPA issued a notice pursuant to section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a
announcing the filing of a pesticide petition (PP 8F4978) for
tolerances by Novartis Crop Protection, Inc., 410 Swing Road,
Greensboro, NC 27419. This notice included a summary of the petition
prepared by Novartis Crop Protection Inc., the registrant. >
Transfer interrupted!
response to the Notice of Filing.
The petition requested that 40 CFR 180.516 be amended by
establishing tolerances for residues of fludioxonil in or on the
following RACs: rape seed and rape forage (reported as canola in the
Notice of Filing), peanuts, meat (hulls removed) and peanut hay
(reported as peanuts in the Notice of Filing), sunflower seed, 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 except cucurbits (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; cotton seed, and cotton gin byproducts at 0.05 ppm.
I. Risk Assessment and Statutory Findings
Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) defines ``safe'' to
[[Page 53821]]
mean that ``there is a reasonable certainty that no harm will result
from aggregate exposure to the pesticide chemical residue, including
all anticipated dietary exposures and all other exposures for which
there is reliable information.'' This includes exposure through
drinking water and in residential settings, but does not include
occupational exposure. Section 408(b)(2)(C) requires EPA to give
special consideration to exposure of infants and children to the
pesticide chemical residue in establishing a tolerance and to ``ensure
that there is a reasonable certainty that no harm will result to
infants and children from aggregate exposure to the pesticide chemical
residue.....''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 and a complete description of
the risk assessment process, see the Final Rule on Bifenthrin Pesticide
Tolerances (62 FR 62961, November 26, 1997) (FRL-5754-7).
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of
fludioxonil and to make a determination on aggregate exposure,
consistent with section 408(b)(2), for tolerances in or on the
following raw agricultural commodities (RACs): rape seed, rape forage,
peanuts, meat (hulls removed), peanut hay, sunflower seed, leafy
vegetables except brassica, brassica leafy vegetables, legume
vegetables, foliage of legume vegetables, fruiting vegetables except
cucurbits, cucurbit vegetables, forage, fodder, and straw of cereal
grains, grass, forage, fodder, and hay, and non-grass animal feeds at
0.01 ppm; root and tuber vegetables, leaves of root and tuber
vegetables, bulb vegetables, cereal grains, and herbs and spices at
0.02 ppm; and cotton seed and cotton gin byproducts at 0.05 ppm. EPA's
assessment of the dietary exposures and risks associated with
establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by fludioxonil are
discussed below.
1. A battery of acute toxicity studies place technical fludioxonil
in Toxicity Category IV for oral, inhalation, and dermal irritation
studies, and Category III for dermal and eye irritation studies.
Fludioxonil is not a skin sensitizer.
2. A subchronic oral toxicity study in rats dosed orally with
technical fludioxonil at levels of 0, 0.8, 6.6, 64, 428, and 1,283 mg/
kg/day (males); 0, 1.0, 7.1, 70, 462, and 1,288 mg/kg/day (females)
resulted in the Lowest-Observed-Adverse-Effect Level (LOAEL) of 428 mg/
kg/day in males and 462 mg/kg/day in females, based on the increased
incidence of microscopic pathology of the kidney and liver and the
deceased body weight gain. The No-Observed-Adverse-Effect level (NOAEL)
is 64 mg/kg/day in males; 70 mg/kg/day in females.
3. In a subchronic oral toxicity study, fludioxonil technical was
administered to dogs for 13 weeks at 0, 200, 2,000, and 15,000/10,000
ppm (15,000 ppm for 17 days and 10,000 ppm from day 18 until study
termination). These dose levels correspond to nominal doses of 0, 5,
50, or 375/250 mg/kg/day, as actual intake data were not provided. A
LOAEL of 2,000 ppm in males and females was determined based on the
observation of diarrhea. The NOAEL is 5 mg/kg/day in males and females.
4. In a subchronic oral toxicity study, technical fludioxonil was
administered to mice at doses of 0, 1.3, 13.9, 144, 445, or 1,052 mg/
kg/day (males); 0, 1.9, 16.8, 178, 559, or 1,307 mg/kg/day (females).
The LOAEL is 1,052 mg/kg/day in males, and 1,307 mg/kg/day in females,
based on decreased body weight gain in female mice, changes in serum
chemistry in male and female mice, increased liver to body weight
ratio, and the increased incidence of nephropathy and centrilobular
hypertrophy of the liver in both sexes. The NOAEL is 445 mg/kg/day in
males and 559 mg/kg/day in females.
5. In a 28 day repeated dermal toxicity test, rats were dosed with
technical fludioxonil under occlusive dressing (6 hrs/day, 5 days/week,
for 4 weeks) at 0, 40, 200, and 1,000 mg/kg/day. The dermal irritation
LOAEL and NOAEL are both greater than 1,000 mg/kg for males and
females. The systemic toxicity LOAEL is 1,000 mg/kg for females based
on increased AST and adrenal weight, and 1,000 mg/kg for males based on
increased creatinine and adrenal weight and the systemic toxicity NOAEL
is 200 mg/kg/day for males and females.
6. In a chronic oral toxicity study, dogs were dosed with
technical fludioxonil for 52 weeks at 0, 3.1, 33.1, and 297.8 mg/kg/day
(males); 3.3, 35.5, and 330.7 mg/kg/day (females). The LOAEL for male
dogs is 297.8 mg/kg/day based on decreased body weight, hematology
alterations (increased platelets and fibrin), clinical chemistry
alterations (increased cholesterol and alkaline phosphatase) and
increased liver weight. The LOAEL for female dogs is 35.5 mg/kg/day
based on a marked decrease in body weight gain for weeks 1-13 and 1-52
of the study. The NOAEL is 33.1 mg/kg/day for male dogs and 3.3 mg/kg/
day for female dogs.
7. In a combined chronic toxicity/carcinogenicity study, rats were
fed technical fludioxonil at 0, 10, 30, 100, 1,000, and 3,000 ppm
(males: 0, 0.37, 1.1, 3.7, 37 and 113 mg/kg/day; females: 0, 0.44, 1.3,
4.4, 44, and 141 mg/kg/day) for either 12 or 24 months. In addition,
rats from the control and 3,000 ppm groups were fed the test diets for
12 months and then allowed to recover for 1 month prior to sacrifice.
There was no treatment related effect on food or water consumption.
Males dosed at 1,000 and 3,000 ppm and females dosed at 3,000 ppm
exhibited a number of effects including higher incidence of dark stool
and urine, staining (mostly blue) around the pelvic region and abdomen,
higher frequency of diarrhea (males only), and decreased body weight
gain. Females dosed at 3,000 ppm had some evidence of slight anemia at
the 12 month evaluation. At necropsy, males at the 3,000 ppm dose level
exhibited an increased incidence of enlarged livers and kidneys with
discolored foci or general discoloration and an increased severity of
progressive nephropathy; kidneys with cysts were reported at both the
1,000 and 3,000 ppm dose levels. For females in the 1,000 and 3,000 ppm
dose levels there was an increase incidence of discoloration of the
kidneys. Males and females in the 3,000 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 3,000 ppm group; however, the increase in males was
not statistically significant. The 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, 1,000 and 3,000
ppm groups, respectively). Males and females in the 3,000 ppm group had
an increased incidence of basophilic foci in the liver; males also had
an increase in hepatocellular hypertrophy. The LOAEL
[[Page 53822]]
for males and females was 113 and 141 mg/kg/day, respectively (3,000
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. 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 3,000 ppm group. The 3,000 ppm level is
considered adequate for carcinogenicity testing based on decreased body
weight and 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.
8. A carcinogenicity study in mice administered technical
fludioxonil in the diet at 0, 10, 100, 1,000, and 3,000 ppm (0, 1.1,
11.3, 112, and 360 mg/kg/day for males and 0, 1.4, 13.5, 133, and 417
mg/kg/day for females). Male mice at 360 mg/kg/day level exhibited
clinical toxicity in the form of an incidence of ``convulsed'' when
handled. No significant effects on body weight, weight gain, food
consumption, hematology, or microscopic non neoplastic pathology were
reported in either sex. Increased liver weight (9%) and spleen weight
(34%) were observed in male mice at the 360 mg/kg/day dose level, which
correlated with the macroscopic observations of enlarged spleen and
raised foci of liver. Female mice showed a statistically significant
increase in liver weight at the 417 mg/kg dose level and this is also
supported by the macroscopic observation of enlarged liver. Other
macroscopic changes in female mice were an increased incidence of
enlarged thymus, spleen, mediastinal lymph node, and liver and an
increased incidence of lymphoma in these organs. The LOAEL is 112 mg/
kg/day for male mice, based on the increased incidence of clinical
toxicity and 417 mg/kg/day for female mice, based on the increased
liver weight and the increased incidence of macroscopic pathology. The
NOAEL is 11.3 mg/kg/day and 133 mg/kg/day in male and female mice,
respectively. There was evidence of carcinogenicity in female mice
based on increased incidence of lymphomas, which contributed to death.
This effect was due to the early onset and high incidence of lymphoma
at the 3,000 ppm dose relative to the control group. Total incidence of
lymphoma was 11/59, 10/59, 13/60, 12/60, and 18/60 for the 0, 10, 100,
1,000, and 3,000 ppm dose levels in female mice, respectively. This
increase in total lymphoma was significant by a trend test, but not by
a pair wise comparison. Whether an adequate dose level was used in this
study to assess the carcinogenic potential of fludioxonil is
complicated by the observation of an increased lymphoma incidence at
the 3,000 ppm dose level. This dose level produced some systemic
effects, such as an increased incidence of male mice which
``convulsed'' when handled and macroscopic pathology in both sexes. But
this dose level produced no significant effects on body weight gain,
food consumption, hematology, or microscopic non neoplastic pathology
in either sex.
In a second carcinogenicity study in mice fludioxonil technical
was administered in the diet at nominal dose levels of 0, 3, 30, 5,000,
and 7,000 ppm (0, 0.33, 3.3, 590, and 851 mg/kg/ day in males; 0, 0.41,
4.1, 715, and 1,008 mg/kg/day for females). The 7,000 ppm dose level in
males and females produced significant systemic effects in addition to
significant nephropathy, which contributed to death in a majority of
test animals. Survival in female mice was below 25% and exceeded the
guideline criteria for survival in a mouse carcinogenicity study.
Changes in liver weights were observed in both sexes at the 5,000 and
7,000 ppm dose levels, but could not be related to histological
alterations in the liver. The LOAEL is estimated at 851 mg/kg/day in
males, and 1,008 mg/kg/day in females. The NOAEL is 590 mg/kg/day in
males, and 715 mg/kg/day in females. The 7,000 ppm dose is adequate for
testing carcinogenic potential in male mice, based on the significant
systemic effects and nephropathy observed at this dose. For female
mice, the 7,000 ppm dose level is considered excessive, based on the
reduction in survival of the test animals. There was no evidence of
increased incidence of tumors in this study for male or female mice.
9. In a developmental toxicity (teratology) study, pregnant rats
(gestation days 6-15 inclusive) were administered technical fludioxonil
at 0, 10, 100, and 1,000 mg/kg/day by oral gavage. Maternal toxicity
was evident at 1,000 mg/kg/day with a 16% reduction in corrected body
weight gain. Developmental toxicity was evident at the 1,000 mg/kg/day
dose with increased fetal and litter incidence of dilated renal pelvis
and dilated ureter. Based on these observations, the Maternal LOAEL and
Developmental toxicity LOAEL are at 1,000 mg/kg/day and the Maternal
NOAEL and Developmental toxicity NOAEL are at 100 mg/kg/day.
10. In another developmental toxicity study, rabbits (gestation
days 6 through 18) were dosed with technical fludioxonil by oral gavage
at 0, 10, 100, and 300 mg/kg/day. Minimal maternal toxicity was noted
in the mid and high dose groups as less body weight during the dosing
period (gestation days 6 through 18) and dosing plus post dosing period
(gestation days 6 through 28). The high dose group consumed less food
than the control group during the dosing period, the post dosing period
(gestation days 19 through 28), the dosing plus post dosing period, and
for the overall gestation period. However, food efficiency was
decreased in the mid and high dosed groups during the dosing plus post
dosing periods, and for the entire gestation period. The Maternal
Toxicity LOAEL is 100 mg/kg/day and the Maternal Toxicity NOAEL is 10
mg/kg/day based on decreased body weight gains and decreased food
efficiency. No developmental toxicity was noted at the dose levels
tested. The Developmental Toxicity LOAEL is greater than 300 mg/kg/day
and the Developmental Toxicity NOAEL is equal to or greater than 300
mg/kg/day.
11. In a reproductive toxicity study, rats received 0, 2.19,
22.13, and 221.61 mg/kg/day (males) and 0, 2.45, 24.24, and 249.67 mg/
kg/day (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. The Parental Systemic Toxicity NOAEL is
22.13 mg/kg/day for males, and 24.24 mg/kg/day for females based on
clinical observations, reduced body weight and 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. The
Reproductive/Developmental Toxicity NOAEL is 22.13 mg/kg/day for males
and 24.24 mg/kg/day for females based on reduced pup body weights.
12. Gene mutation and other genotoxic effects were studied using
fludioxonil technical:
i. Ames Salmonella assay with and without metabolic activation
provided evidence of cytotoxicity at 1,250 and 5,000 micrograms/plate
(<greek-m>g/plate) concentrations.
ii. Unscheduled DNA Synthesis assay (in vitro) indicated
cytotoxicity at 313 <greek-m>g/ml.
iii. Chromosome aberrations assay (in vitro) in Chinese hamster
ovary (CHO) cells with and without S9 activation provided convincing
evidence that
[[Page 53823]]
fludioxonil is a clastogen and polyploidy inducer.
iv. Chromosome Aberrations assay (in vitro) in Chinese hamster bone
marrow cells noted occurrence of hyperploidy in one mid-dose female and
trisomy in one high dose male.
v. Micro nucleus assay (in vitro) using rat hepatocytes provided no
definitive conclusions as to dose related increase in micro nucleate
hepatocytes and therefore, this study will be repeated.
vi. Dominant Lethal assay indicated no test material induced
dominant lethal mutations in male mouse germinal cells sampled over the
entire period of spermatogenesis.
vii. Point Mutation test in CHO cells (in vitro) with and without
S9 activation produced no increase in the number of thioguanine
resistant colonies, mutant frequency, or mutant factor.
viii. Mouse Micro nucleus assay using mouse bone morrow Micro
nucleus test produced no statistically significant increase in number
of micronucleated polychromatic erythrocytes in male and female mice.
B. Toxicological Endpoints
1. Acute toxicity. Fludioxonil exhibits very low mammalian toxicity
when tested by the oral route. There is no concern for an acute dietary
risk. The available data do not indicate any evidence of significant
toxicity from 1 day or single event exposure by oral route.
2. Short and intermediate term toxicity. Subchronic studies
conducted with fludioxonil contain no end points suggesting the need
for short term occupational or residential risk assessments for the
dermal route of exposure. For intermediate term, the recommended LOAEL
and NOAEL are 50 mg/kg/day and 5 mg/kg/day, respectively from the 13
week oral toxicity study in dogs. For the intermediate term risk
assessment, the 50 mg/kg/day is used as the NOAEL, since the effects of
concern are believed to occur at doses in excess of 50 mg/kg/day.
3. Chronic toxicity. EPA has established the RfD for fludioxonil
at 0.03 mg/kg/day. This RfD is based on the 1 year oral toxicity study
in dogs with a NOAEL of 3.3 mg/kg/day in females and an uncertainly
factor of 100 to account for both interspecies extrapolation and
intraspecies variability.
4. Carcinogenicity. Fludioxonil has been classified as a Group D
chemical 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.
C. Exposures and Risks
1. From food and feed uses. Tolerances have been established at 40
CFR 180.516 for residues of fludioxonil in or on potatoes and time
limited tolerances under the Section 18 program have been established
for apricot, nectarines, peaches, and plums. Risk assessments were
conducted by EPA to assess dietary exposures from fludioxonil as
follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1 day or single exposure. There is no concern for an acute dietary
exposure to fludioxonil. The available data do not indicate any
evidence of significant toxicity from 1 day or single event exposure by
oral route.
ii. Chronic exposure and risk. Fludioxonil is currently registered
for seed treatment uses on corn, sorghum, and potatoes and for
greenhouse uses on non food crops. Section 18 requests have been
approved for post harvest treatment on apricots, nectarines, peaches,
and plums. There is no reasonable expectation of residues on corn and
sorghum as a result of treatment of corn and sorgham seed, therefore,
these uses did not require tolerances and no exposure was assumed to
result from these registered uses. Potatoes has a tolerance of 0.02 ppm
and apricots, nectarines, peaches, plums have a time limited tolerance
of 5 ppm. There are no residential uses for fludioxonil; therefore no
chronic residential exposure is expected. Based on a Novigen Dietary
Exposure Evaluation Model (DEEM) and using conservative assumptions
(100% of crops treated and tolerance level residues) and a chronic RfD
of 0.03 mg/kg/day, EPA estimates the chronic exposure to fludioxonil
from food will utilize 22% of the chronic RfD for the most highly
exposed population subgroup, (non-nursing infants < 1 year old). All
other population subgroups have risk estimates below that of the non-
nursing infants.
2. From drinking water. There are no maximum contaminant levels or
health advisory levels established for residues of fludioxonil in
drinking water. In view of the currently registered use patterns and
the proposed seed treatment of food and feed crops at very low levels
(1.13 to 2.26 grams of active ingredient (ai) per 100 lbs seed),
fludioxonil is not expected to impact ground or surface waters. Thus
the likelihood of residues of fludioxonil entering in drinking water is
considered negligible.
3. From non-dietary exposure. Fludioxonil is not currently
registered for any residential non-food uses. Therefore, oral, dermal,
and inhalation exposure from residential uses is not expected.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) 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.''
Fludioxonil is a representative of a new class of plant protection
agents derived from the structure of a naturally occurring plant
antibiotic called pyrrolnitrin. EPA does not have, at this time,
available data to determine whether fludioxonil has a common mechanism
of toxicity with other substances or how to include this pesticide in a
cumulative risk assessment. Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, 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 Final Rule for Bifenthrin Pesticide Tolerances (62 FR 62961,
November 26, 1997).
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Chronic risk. Using the Theoretical Maximum Residue Contribution
(TMRC) exposure assumptions described in this preamble, EPA has
concluded that aggregate exposure to fludioxonil from food will utilize
22% of the RfD for the most highly exposed population subgroup. The
major identifiable subgroup with the highest aggregate exposure is the
non-nursing infants, < 1 year old. EPA generally has no concern for
exposures below 100% of the RfD because the RfD represents the level at
or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health.
2. Short- and intermediate-term risk. Short- and intermediate-term
aggregate exposure takes into account chronic dietary food and water
(considered to be
[[Page 53824]]
a background exposure level) plus indoor and outdoor residential
exposure. Fludioxonil is not registered for indoor uses. Based on
registered and proposed uses, exposure to fludioxonil from drinking
water is not expected.
3. Aggregate cancer risk for U.S. population. Fludioxonil has been
classified as a Group D chemical not classifiable as to human
carcinogenicity. The available carcinogenicity studies in the rat and
mouse show some increase in the combined tumors only in the female rat
above that in the concurrent controls. However, this statistical
increase in liver tumors in female rats was only at the high dose. Some
of this significant increase was due to the lack of any liver tumors in
the concurrent control, whereas the historical control from the same
lab indicated a range of 1.4 to 15% for combined liver tumors.
Therefore, based on available information, EPA believes that this
pesticide does not pose a significant cancer risk.
4. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to fludioxonil residues.
E. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children-- i. In general. In
assessing the potential for additional sensitivity of infants and
children to residues of fludioxonil, EPA considered data from
developmental toxicity studies in the rat and rabbit and a 2-generation
reproduction study in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre and post natal toxicity and the
completeness of the database unless EPA determines that a different
margin of safety will be safe for infants and children. Margins of
safety are incorporated into EPA risk assessments either directly
through use of a margin of exposure (MOE) analysis or through using
uncertainty (safety) factors in calculating a dose level that poses no
appreciable risk to humans. EPA believes that reliable data support
using the standard uncertainty factor (usually 100 for combined inter
and intra species variability) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor.
ii. Pre- and post-natal sensitivity. The toxicity data base for
fludioxonil includes acceptable prenatal developmental toxicity studies
in rats and rabbits and an acceptable 2-generation reproduction study
in rats. The data did not suggest any additional sensitivity to the
embryo or neonate following in utero or early postnatal exposure to
fludioxonil. In the rat developmental study, the Maternal NOAEL and the
Developmental (fetal and pup) NOAEL were both 100 mg/kg/day. In the
rabbit developmental study, the Maternal NOAEL was 10 mg/kg/day. No
developmental toxicity was noted at any dosing level. The Developmental
NOAEL was set equal to or greater than 300 mg/kg/day, the highest dose
tested. Results from the 2-generation reproduction study for rats
indicated a Developmental/Reproduction NOAEL of 22.13 mg/kg/day for
males and 24.24 mg/kg/day for females. The Developmental/Reproductive
NOAEL is at least 600 fold higher then the RfD (0.03 mg/kg/day), and
should be protective for infants and children.
iii. Conclusion. There is a complete toxicity data base for
fludioxonil and exposure data is complete or is estimated based on data
that reasonably accounts for potential exposures.
2. Chronic risk. Using the exposure assumptions described in Unit
II.C. of this preaamble, EPA has concluded that aggregate exposure to
fludioxonil from food will utilize 22% of the RfD for infants and
children. EPA generally has no concern for exposures below 100% of the
RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. As exposure from drinking water, non-dietary, or
non-occupational sources are not anticipated, EPA does not expect
aggregate exposure to exceed 100% of RfD.
3. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to fludioxonil
residues.
III. Other Considerations
A. Metabolism In Plants and Animals
Plant metabolism studies in potatoes, rice, and wheat were
previously submitted. Additional studies on cotton and soybeans were
provided in conjunction with the proposed use. There is minimal uptake
of the active ingredient when applied as a seed treatment. Based on
these studies, EPA concludes that the nature of fludioxonil residues in
plants are adequately understood and the residue of concern is the
parent compound. Two animal metabolism studies conducted in ruminant
and poultry indicate that there is no reasonable expectation of finite
residues of fludioxonil in ruminant tissues, milk, poultry tissues, and
eggs.
B. Analytical Enforcement Methodology
The Ciba-Geigy Analytical Method AG-597B has been adequately
validated for use in enforcing the proposed tolerances. The method may
be requested from: Calvin Furlow, PRRIB, IRSD (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. Office location and telephone number: Rm 101FF,
Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA 22202, (703-
305-5229).
C. Magnitude of Residues
The submitted field trial data on cucumber, leaf lettuce, radish,
succulent peas, and wheat indicate that residue levels were less than
the limit of quantitation (LOQ) in each crop. The submitted residue
data support the following proposed tolerance levels of fludioxonil.
The RAC and the respective tolerance ppm are: rape seed (0.01 ppm),
rape forage (0.01 ppm), sunflower seed (0.01 ppm), peanuts, meat (hulls
removed) (0.01 ppm), peanut hay (0.01 ppm), leafy vegetables except
brassica (0.01 ppm), brassica (cole) leafy vegetables (0.01 ppm),
legume vegetables (0.01 ppm), foliage of legume vegetables (0.01 ppm),
fruiting vegetables except cucurbits (0.01 ppm), cucurbit vegetables
(0.01 ppm), forage, fodder, and straw of cereal grains (0.01 ppm),
grass, forage, fodder, and hay (0.01 ppm), non-grass animal feeds (0.01
ppm), root and tuber vegetables (0.02 ppm), leaves and roots of tuber
vegetables (0.02 ppm), bulb vegetables, (0.02 ppm), cereal grains (0.02
ppm), herbs and spices (0.02 ppm), cotton, undelinted seed (0.05 ppm),
and cotton gin byproducts (0.05 ppm).
D. International Residue Limits
There are currently no established or proposed maximum residue
limits
[[Page 53825]]
(MRLs) in Canada, CODEX, or Mexico for fludioxonil residues in/on crops
and crop groups included in this submission. Therefore, problems with
compatibility of tolerances/MRLs do not exist.
IV. Conclusion
Therefore, tolerances are established for residues of fludioxonil
in the following RACs at (ppm): rape seed (0.01 ppm), rape forage (0.01
ppm), sunflower seed (0.01 ppm), peanuts, meat (hulls removed) (0.01
ppm), peanut hay (0.01 ppm), leafy vegetables except brassica (0.01
ppm), brassica (cole) leafy vegetables (0.01 ppm), legume vegetables
(0.01 ppm), foliage of legume vegetables (0.01 ppm), fruiting
vegetables except cucurbits (0.01 ppm), cucurbit vegetables (0.01 ppm),
forage, fodder, and straw of cereal grains (0.01 ppm), grass, forage,
fodder, and hay (0.01 ppm), non-grass animal feeds (0.01 ppm), root and
tuber vegetables (0.02 ppm), leaves and roots of tuber vegetables (0.02
ppm), bulb vegetables, (0.02 ppm), cereal grains (0.02 ppm), herbs and
spices (0.02 ppm), cotton, undelinted seed (0.05 ppm), and cotton gin
byproducts (0.05 ppm)].
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance regulation issued by EPA under
new section 408(e) and (l)(6) as was provided in the old section 408
and in section 409. However, the period for filing objections is 60
days, rather than 30 days. EPA currently has procedural regulations
which govern the submission of objections and hearing requests. These
regulations will require some modification to reflect the new law.
However, until those modifications can be made, EPA will continue to
use those procedural regulations with appropriate adjustments to
reflect the new law.
Any person may, by December 7, 1998, file written objections to any
aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27). A request for a hearing
will be granted if the Administrator determines that the material
submitted shows the following: There is genuine and substantial issue
of fact; there is a reasonable possibility that available evidence
identified by the requestor would, if established, resolve one or more
of such issues in favor of the requestor, taking into account
uncontested claims or facts to the contrary; and resolution of the
factual issues in the manner sought by the requestor would be adequate
to justify the action requested (40 CFR 178.32). Information submitted
in connection with an objection or hearing request may be claimed
confidential by marking any part or all of that information as
Confidential Business Information (CBI). Information so marked will not
be disclosed except in accordance with procedures set forth in 40 CFR
part 2. A copy of the information 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.
VI. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number [OPP-300738] (including any comments and data submitted
electronically). 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 public
record is located in Room 119 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
Electronic comments may be sent directly to EPA at:
opp-docket@epamail.epa.gov.
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
A. Certain Acts and Executive Orders
This final rule establishes tolerances under FFDCA section 408(d)
in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since tolerances and exemptions that are established
on the basis of a petition under FFDCA section 408(d), such as the
tolerance in this final rule, do not require the issuance of a proposed
rule, the requirements of the Regulatory Flexibility Act (RFA) (5
U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions published on May
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
[[Page 53826]]
B. Executive Order 12875
Under Executive Order 12875, entitled Enhancing the
Intergovernmental Partnership (58 FR 58093, October 28, 1993), EPA may
not issue a regulation that is not required by statute and that creates
a mandate upon a State, local, or tribal government, unless the Federal
government provides the funds necessary to pay the direct compliance
costs incurred by those governments. If the mandate is unfunded, EPA
must provide to OMB a description of the extent of EPA's prior
consultation with representatives of affected State, local, and tribal
governments, the nature of their concerns, copies of any written
communications from the governments, and a statement supporting the
need to issue the regulation. In addition, Executive Order 12875
requires EPA to develop an effective process permitting elected
officials and other representatives of State, local, and tribal
governments ``to provide meaningful and timely input in the development
of regulatory proposals containing significant unfunded mandates.''
Today's rule does not create an unfunded Federal mandate on State,
local, or tribal governments. The rule does not impose any enforceable
duties on these entities. Accordingly, the requirements of section 1(a)
of Executive Order 12875 do not apply to this rule.
C. Executive Order 13084
Under Executive Order 13084, entitled Consultation and Coordination
with Indian Tribal Governments (63 FR 27655, May 19,1998), EPA may not
issue a regulation that is not required by statute, that significantly
or uniquely affects the communities of Indian tribal governments, and
that imposes substantial direct compliance costs on those communities,
unless the Federal government provides the funds necessary to pay the
direct compliance costs incurred by the tribal governments. If the
mandate is unfunded, EPA must provide to OMB, in a separately
identified section of the preamble to the rule, a description of the
extent of EPA's prior consultation with representatives of affected
tribal governments, a summary of the nature of their concerns, and a
statement supporting the need to issue the regulation. In addition,
Executive Order 13084 requires EPA to develop an effective process
permitting elected officials and other representatives of Indian tribal
governments ``to provide meaningful and timely input in the development
of regulatory policies on matters that significantly or uniquely affect
their communities.''
Today's rule does not significantly or uniquely affect the
communities of Indian tribal governments. This action does not involve
or impose any requirements that affect Indian tribes. Accordingly, the
requirements of section 3(b) of Executive Order 13084 do not apply to
this rule.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This rule is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: September 29, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. In Sec. 180.516 by revising paragraph (a) to read as follows:
Sec. 180.516 Fludioxonil; tolerances for residues.
(a) General. Tolerances are established for residues of the
fungicide fludioxonil (4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-
pyrrole-3-carbonitrile) in or on the following commodities:
------------------------------------------------------------------------
Parts
Commodity per
million
------------------------------------------------------------------------
Bassica (cole) leafy vegetables................................ 0.01
Bulb vegetables................................................ 0.02
Cereal grains.................................................. 0.02
Cotton gin byproducts.......................................... 0.05
Cotton, undelinted seed........................................ 0.05
Cucurbit vegetables............................................ 0.01
Foliage of legume vegetables................................... 0.01
Forage, fodder, and straw of cereal grains..................... 0.01
Fruiting vegetables except cucurbits........................... 0.01
Grass, forage, fodder, and hay................................. 0.01
Herbs and spices............................................... 0.02
Leafy vegetables except Brassica............................... 0.01
Leaves and roots of tuber vegetables........................... 0.02
Legume vegetables.............................................. 0.01
Non-grass animal feeds......................................... 0.01
Peanut hay..................................................... 0.01
Peanuts, meat (hulls removed).................................. 0.01
Rape forage.................................................... 0.01
Rape seed...................................................... 0.01
Root and tuber vegetables...................................... 0.02
Sunflower seed................................................. 0.01
------------------------------------------------------------------------
* * * * *
[FR Doc. 98-26902 Filed 10-6-98; 8:45 am]
BILLING CODE 6560-50-F