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Flutolanil (AgrEvo). August 7, 1998. Pesticide Tolerance. Final Rule. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/August/Day-07/p20899.htm
[Federal Register: August 7, 1998 (Volume 63, Number 152)]
[Rules and Regulations]
[Page 42249-42257]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07au98-28]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 180 and 185
[OPP-300697; FRL-6021-7]
RIN 2070-AB78
Flutolanil; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes time-limited tolerances, to expire
on December 31, 2000, for residues of the fungicide flutolanil N-(3-(1-
methylethoxy)phenyl)-2-(trifluoromethyl)benzamide and its metabolites
converted to 2-(trifluoromethyl)benzoic acid and calculated as
flutolanil in or on the raw agricultural commodities rice grain at 2.0
parts per million (ppm) and rice straw at 8.0 ppm and in or on the
processed food or feed commodities rice hulls at 7.0 ppm and rice bran
at 3.0 ppm when present therein as a result of application of the
fungicide to growing crops. AgrEvo USA Company requested the tolerances
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 August 7, 1998. Objections and
requests
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for hearings must be received by EPA on or before October 6, 1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300697], 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-300697], 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, CM #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 or
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-300697]. 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 L. 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, Rm 247, 1921
Jefferson Davis Hwy., Arlington, VA, (703) 308-9354, e-mail:
waller.mary@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: In the Federal Register of June 23, 1998 (63
FR 34176)(FRL-5795-1), EPA, issued a notice pursuant to section 408 of
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e)
announcing the filing of pesticide petition (PP) 4F4380 for tolerances
by AgrEvo USA Co., Little Falls Centre One, 2711 Centerville Rd.,
Wilmington, DE 19808. This notice included a summary of the petition
prepared by AgrEvo USA Co., the registrant. There were no comments
received in response to the notice of filing.
The petition requested that 40 CFR 180.484 be amended by
establishing tolerances for residues of the fungicide flutolanil N-(3-
(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide and its
metabolites converted to 2-(trifluoromethyl)benzoic acid and calculated
as flutolanil in or on the raw agricultural commodities rice grain at
2.0 ppm and rice straw at 8.0 ppm and in or on the processed food or
feed commodities rice hulls at 7.0 ppm and rice bran at 3.0 ppm when
present therein as a result of application of the fungicide to growing
crops.
I. Risk Assessment and Statutory Findings
New 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 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. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health. An uncertainty factor (sometimes
called a ``safety factor'') of 100 is commonly used since it is assumed
that people may be up to 10 times more sensitive to pesticides than the
test animals, and that one person or subgroup of the population (such
as infants and children) could be up to 10 times more sensitive to a
pesticide than another. In addition, EPA assesses the potential risks
to infants and children based on the weight of the evidence of the
toxicology studies and determines whether an additional uncertainty
factor is warranted. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100 percent or less of the
RfD) is generally considered acceptable by EPA. EPA generally uses the
RfD to evaluate the chronic risks posed by pesticide exposure. For
shorter term risks, EPA calculates a margin of exposure (MOE) by
dividing the estimated human exposure into the NOEL from the
appropriate animal study. Commonly, EPA finds MOEs lower than 100 to be
unacceptable. This hundredfold MOE is based on the same rationale as
the hundredfold uncertainty factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base,
[[Page 42251]]
and based on the effects seen for different durations and routes of
exposure, determines which risk assessments should be done to assure
that the public is adequately protected from any pesticide exposure
scenario. Both short and long durations of exposure are always
considered. Typically, risk assessments include ``acute'', ``short-
term'', ``intermediate term'', and ``chronic'' risks. These assessments
are defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of FQPA,
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from
food, water, and residential uses when reliable data are available. In
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all
three sources are not typically added because of the very low
probability of this occurring in most cases, and because the other
conservative assumptions built into the assessment assure adequate
protection of public health. However, for cases in which high-end
exposure can reasonably be expected from multiple sources (e.g.
frequent and widespread homeowner use in a specific geographical area),
multiple high-end risks will be aggregated and presented as part of the
comprehensive risk assessment/characterization. Since the toxicological
endpoint considered in this assessment reflects exposure over a period
of at least 7 days, an additional degree of conservatism is built into
the assessment; i.e., the risk assessment nominally covers 1-7 days
exposure, and the toxicological endpoint/NOEL is selected to be
adequate for at least 7 days of exposure. (Toxicity results at lower
levels when the dosing duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.The
TMRC is a ``worst case'' estimate since it is based on the assumptions
that food contains pesticide residues at the tolerance level and that
100% of the crop is treated by pesticides that have established
tolerances. If the TMRC exceeds the RfD or poses a lifetime cancer risk
that is greater than approximately one in a million, EPA attempts to
derive a more accurate exposure estimate for the pesticide by
evaluating additional types of information (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
Percent of crop treated estimates are derived from federal and
private market survey data. Typically, a range of estimates are
supplied and the upper end of this range is assumed for the exposure
assessment. By using this upper end estimate of percent of crop
treated, the Agency is reasonably certain that exposure is not
understated for any significant subpopulation group. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations
including several regional groups, to pesticide residues. For this
pesticide, the most highly exposed population subgroup was not
regionally based.
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
flutolanil and to make a determination on aggregate exposure,
consistent with section 408(b)(2), for time-limited tolerances for
residues of flutolanil N-(3-(1-methylethoxy)phenyl)-2-
(trifluoromethyl)benzamide and its metabolites converted to 2-
(trifluoromethyl)benzoic acid and calculated as flutolanil in or on the
raw agricultural commodities rice grain at 2.0 ppm and rice straw at
8.0 ppm and in or on the processed food or feed commodities rice hulls
at 7.0 ppm and rice bran at 3.0 ppm. EPA's assessment of the dietary
exposures and risks associated with establishing the tolerance follows.
A. Toxicological Data Base
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 flutolanil are
discussed below.
1. Acute studies. Acute toxicity studies, except for the acute
dermal study, were classified as Toxicity Category IV. The acute dermal
study places technical flutolanil in Toxicity Category III (Caution).
Data show minimal to slight irritation to the eye. Flutolanil is not a
dermal sensitizer and is non-irritating to skin.
2. Subchronic toxicity testing. i. A subchronic feeding study in
rats was conducted for 3 months. Flutolanil was orally administered at
dose levels of 0, 500, 4,000 or 20,000 ppm (0, 37, 299 or 1,512
milligrams/kilograms/day (mg/kg/day) in males and 0, 44, 339 or 1,743
mg/kg/day in females). The systemic Lowest Observed Effect Level (LOEL)
is 299 mg/kg/day based on increased absolute and relative liver
weights. The systemic No Observed Effect Level (NOEL) is 37 mg/kg/day.
ii. A subchronic oral toxicity study in dogs was conducted for 90
days. Flutolanil was administered orally via
[[Page 42252]]
gelatin capsules at dose levels of 0, 80, 400 or 2,000 mg/kg/day. The
LOEL for this study was 400 mg/kg/day based on systemic signs of
toxicity in the form of enlarged livers and increased severity of
glycogen deposition in both males and females. The NOEL was 80 mg/kg/
day.
iii. In a 21-day repeated dose dermal toxicity study, flutolanil
was administered dermally to rats in 15 applications at doses of 0 or
1,000 mg/kg/day. No LOEL was established for systemic or dermal
toxicity. The NOEL for dermal effects was > 1,000 mg/kg/day (limit
dose) and the systemic toxicity NOEL was also > 1,000 mg/kg/day (limit
dose).
3. Chronic toxicity studies. A 2-year dog feeding study was
conducted using doses of 0, 50, 250, or 1,250 mg/kg/day. The LOEL is
250 mg/kg/day based on evidence of systemic toxicity in the form of
increased incidence of clinical toxic signs (emesis, salivation and
soft stool), lower body weight gains and decreased food consumption.
The NOEL is 50 mg/kg/day.
4. Carcinogenicity. i. In a 2-year combined chronic toxicity/
carcinogenicity study, technical grade flutolanil was administered in
the diet to rats at dose levels of 0, 40, 200, 2,000, or 10,000 ppm (0,
1.8, 8.7, 86.9, or 460 mg/kg/day for males and 0, 2.1, 10, 103.1 or
535.8 mg/kg/day for females. The LOEL for systemic toxicity for males
is 460.5 mg/kg/day and 535.8 mg/kg/day for females based on reduced
body weight and body weight gain in males, along with decreased
absolute and relative weights in females. The NOEL for systemic
toxicity is 86.9 mg/kg/day for males and 103.1 mg/kg/day for females.
Flutolanil was not carcinogenic under the conditions of this study.
ii. A carcinogenicity study in mice was conducted for 78 weeks in
which technical flutolanil was administered in the diet at 0, 300,
1,500, 7,000 or 30,000 ppm (0, 32, 162, 735, or 3,333 mg/kg/day for
males and 0, 34, 168, 839, or 3,676 mg/kg/day for females). The LOEL
for systemic toxicity is 3,333 mg/kg/day in males and 839 mg/kg/day for
females based on significant decreases in body weight gains in the high
dose tested. The NOEL is 735 mg/kg/day in males and 162 mg/kg/day in
females. Flutolanil was not carcinogenic under the conditions of this
study.
5. Developmental toxicity. i. In a developmental toxicity study in
rats, flutolanil was administered orally via oral gavage at dose levels
of 0, 40, 200 or 1,000 mg/kg/day on gestational days (GDs) 6-15,
inclusive. No maternal toxicity was observed at any dose level. No
compound-related effects were observed at any dose level for
developmental toxicity. No Maternal LOEL was established. The maternal
NOEL is > 1,000 mg/kg/day (limit dose). A developmental LOEL was not
established. The developmental NOEL is > 1,000 mg/kg/day (limit dose).
ii. In a developmental toxicity study, rabbits were administered
flutolanil via oral gavage at dose levels of 0, 40, 200 or 1,000 mg/kg/
day on GDs 6-18, inclusive. No significant maternal or developmental
toxicity was noted at the dose levels tested. The maternal toxicity
NOEL is > 1,000 mg/kg/day, the developmental toxicity LOEL is > 1,000
mg/kg/day and the developmental toxicity NOEL is > 1,000 mg/kg/day.
6. Reproductive toxicity. i. In a three-generation reproduction and
developmental study, flutolanil was administered in the diet to rats at
0, 1,000 or 10,000 ppm (equivalent to 0, 63.7 or 661.8 mg/kg/day in
males and 0, 86.3 or 880.8 mg/kg/day for females). For the reproduction
segment of this study, flutolanil at the highest levels produced
offspring systemic toxicity in the form of reduced pup body weights and
body weight gains in both males and females. There was no treatment
related clinical toxicity signs, mortality, differences in food
consumption or efficiency and water consumption. No treatment related
effects were noted on mating performance, duration of pregnancy and
litter size. Provided gross examination data was limited. Organ weights
showed increases in absolute and relative liver weights in the high
dose males and females across generations. This effect is consistent
with observations found in other chronic toxicity studies. The
offspring systemic toxicity LOEL is 661.8 mg/kg/day. The offspring
systemic toxicity NOEL is 63.7 mg/kg/day. For the developmental
segment, there may have been an effect in both dose groups in the form
of reduced fetal body weights. Fetal examinations showed no treatment
related effects on gross or skeletal examinations. Visceral examination
revealed a possible treatment related increase in enlargement of the
renal pelvis (statistically significant in the high dose group). These
studies were classified as supplementary due to deficiencies. A
discussion of the study is included because the reference dose (RfD)
was established based on this study.
ii. In a two-generation reproductive toxicity study, technical
flutolanil was administered daily in the diet to rats at 0, 200, 2,000
or 20,000 ppm (during premating, for males 0, 16, 159, or 1,625 mg/kg/
day and for females 0, 19, 190, or 1,936 mg/kg/day. No compound-related
parental effects were observed in either sex or generation.
Consequently, the LOEL for parental toxicity was not determined and the
NOEL for parental toxicity is > 1,625 mg/kg/day (exceeds limit dose).
7. Mutagenicity. Mutagenicity studies included: In vitro
Aberrations in Don Cells, Mouse Micronucleus, Mammalian Cells in
Culture Cytogenetics Assay in Human Lymphocytes, Salmonella and E. coli
Reverse Mutation Assays, In vitro Unscheduled DNA Synthesis Assays in
Primary Rat Hepatocytes, and Gene Mutation in Cultured Mammalian Cells
(Mouse Lymphoma Cells). The In vitro Aberrations in Don Cells study was
positive for inducing chromosomal aberrations in cultured Chinese
hamster lung cells in the presence of metabolic activation. All other
studies were negative.
8. Metabolism. In a metabolism study in rats, disposition and
metabolism of 14C-flutolanil was investigated at a low oral dose of 20
mg/kg/day, repeated low oral doses of 20 mg/kg for 14 days, and a
single high dose of 1,000 mg/kg. Absorption of flutolanil was
incomplete at the single low and high doses, but appeared to be
increased after repeated low oral dosing. There were no appreciable
tissue levels of flutolanil at study termination. At the single low
oral dose, excretion in urine and feces was equivalent, with
approximately 40% of an administered dose excreted via each route in
male and female rats. Repeated low dosing resulted in an increased
percentage in urine (approximately 70%) with a corresponding decrease
in fecal excretion. At the single high dose, the majority of the
radioactivity (66-78%) was excreted via the feces, with less than 10%
found in urine. Identification of urinary and fecal metabolites by TLC
showed the presence of the major metabolite M4 (desisopropylflutolanil)
in urine in all dose groups. In feces, radioactivity was excreted
mainly as parent compound, with limited conversion to M4.
9. Neurotoxicity. There have been no clinical neurotoxic signs or
other types of neurotoxicity observed in any of the evaluated
toxicology studies.
10. Other toxicological considerations. Flutolanil has a complete
data base and no other toxicological concerns have been identified in
the evaluated studies.
B. Toxicological Endpoints
1. Acute toxicity. EPA has determined that data do not indicate the
potential for adverse effects after a single dietary exposure.
2. Short - and intermediate - term toxicity. No appropriate
endpoints were
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identified for short - term (1-7 days), or intermediate-term (1 week to
several months) exposure.
3. Chronic toxicity. EPA has established the Reference dose (RfD)
for flutolanil at 0.63 mg/kg/day. This RfD is based on the reproductive
toxicity study in rats with a NOEL of 63 mg/kg/day and an uncertainty
factor of 100.
4. Carcinogenicity. Using its Guidelines for Carcinogen Risk
Assessment published September 24, 1986 (51 FR 33992), EPA has
classified flutolanil as a Group E chemical--``Evidence of Non-
carcinogenicity for Humans'' --based on the results of carcinogenicity
studies in two species. The doses tested are adequate for identifying a
cancer risk.
C. Exposures and Risks
1. From food and feed uses. Tolerances have been established (40
CFR 180.484 and 185.3385) for flutolanil N-(3-(1-methylethoxy)phenyl)-
2-(trifluoromethyl)benzamide and its metabolites converted to 2-
(trifluoromethyl)benzoic acid and calculated as flutolanil in or on the
raw agricultural commodities peanuts, peanut hay and hulls, meat, milk,
poultry and eggs and the processed food commodity peanut meal. Time-
limited tolerances were previously established for the raw agricultural
commodities rice grain and rice straw and for the processed food
commodities rice hulls and rice bran. These time-limited tolerances
expired and are being reestablished in today's action. Risk assessments
were conducted by EPA to assess dietary exposures and risks from
flutolanil 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. EPA did not identify an acute dietary
toxicological endpoint and thus, flutolanil is not considered to pose
an acute dietary risk.
ii. Chronic exposure and risk. Chronic dietary (food only) exposure
analyses were performed using tolerance level residues and 100 percent
crop treated information to estimate the Theoretical Maximum Residue
Contribution (TMRC) for the general population and 22 subgroups. The
existing flutolanil tolerances and the added tolerances for rice
commodities result in an exposure that is equivalent to 0.2% of the RfD
for the U.S. population and 0.5% for children (1-6 years old). Even
without refinement, the chronic dietary risk exposure to flutolanil
appears to be minimal for use of flutolanil on rice and does not exceed
the RfD for any of the subgroups.
2. From drinking water. There is no established Maximum Contaminant
Level for residues of flutolanil in drinking water. No Health Advisory
Levels for flutolanil in drinking water have been established. The
``Pesticides in Groundwater Database'' has no information concerning
flutolanil. Estimates of ground and surface water concentrations for
flutolanil were determined based on a maximum annual application rate
of 1.0 pound active ingredient/acre. The surface water numbers are
based on the results of a Generic Environmental Concentration (GENEECX/
beta version) model. The modeling results indicated that flutolanil has
the potential to contaminate surface waters through erosion of soil
particles to which flutolanil is adsorbed or through off-site draining
of rice paddy water containing the chemical. The ground water numbers
are based on a screening tool, SCI-GROW, which tends to overestimate
the true concentration in the environment. These modeling results
indicate that flutolanil will not be found in significant
concentrations in groundwater. For acute effects, the surface water
estimated environmental concentration (EEC) was determined to be 565
parts per billion (ppb). For chronic effects the surface water EEC was
542 ppb. The estimated groundwater concentration for both acute and
chronic effects is 0.399 ppb
i. Acute exposure and risk. No acute risk is expected from
exposure to flutolanil.
ii. Chronic exposure and risk. Chronic exposure is calculated based
on surface water. Chronic exposure from ground water is lower. Chronic
exposure (mg/kg/day) is calculated by multiplying the concentration in
water in mg/l by the daily consumption (2l/day for male and female
adults and 1l/day for children) and dividing this figure by average
weight (70 kg for males, 60 kg for females and 10 kg for children). For
adult males, exposure is 0.015 mg/kg/day; for adult females, 0.018 mg/
kg/day; and for children, 0.054 mg/kg/day. Chronic risk (non-cancer)
from surface water, using EPA's conservative model for estimating
exposure through surface water, was calculated to be 2.4% of the Rfd
for males, 2.9% for females and 8.6% for children.
3. From non-dietary exposure. Flutolanil is not currently
registered for use on non-food sites. Therefore, acute, short - and
intermediate-term and chronic (non-cancer) occupational or residential
risk assessments are not required
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.'' The Agency believes that ``available
information'' in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
EPA does not have, at this time, available data to determine
whether flutolanil has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides
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for which EPA has followed a cumulative risk approach based on a common
mechanism of toxicity, flutolanil 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 flutolanil has a
common mechanism of toxicity with other substances.
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. No acute dietary risks were identified.
2. Chronic risk. Using the unrefined exposure assumptions described
above, EPA has concluded that aggregate exposure to flutolanil from
food will utilize 0.2% of the RfD for the U.S. population. The major
identifiable subgroup with the highest aggregate exposure is children
(1-6 years old) which is discussed below. 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. Despite the
potential for exposure to flutolanil in drinking water, EPA does not
expect the aggregate exposure to exceed 100% of the RfD.
3. Short- and intermediate-term risk. Short- and intermediate-term
aggregate exposure takes into account chronic dietary food and water
(considered to be a background exposure level) plus indoor and outdoor
residential exposure. No short- or intermediate-term risk is expected
from the use of flutolanil.
4. Aggregate cancer risk for U.S. population. Flutolanil is
classified as Category E: not carcinogenic in two acceptable animal
studies. Since flutolanil is not carcinogenic, there would be no
expected risk of cancer in humans from the use of flutolanil.
5. Conclusion. EPA concludes that there is a reasonable certainty
that no harm will result from aggregate exposure to flutolanil
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 flutolanil, EPA considered data from
developmental toxicity studies in the rat and rabbit and a three-
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 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. Developmental toxicity studies-- a. Rats. No maternal toxicity
was observed at any dose level. No compound-related effects were
observed at any dose level for developmental toxicity. A maternal LOEL
was not established. The maternal NOEL is <gr-thn-eq> 1,000 mg/kg/day
(limit dose). A developmental LOEL was not established. The
developmental NOEL is <gr-thn-eq> 1,000 mg/kg/day (limit dose).
b. Rabbits. In the developmental toxicity study in rabbits, no
significant maternal or developmental toxicity was noted at the dose
levels tested. The maternal toxicity LOEL is > 1,000 mg/kg/day and the
maternal toxicity NOEL is <gr-thn-eq> 1,000 mg/kg/day. The
developmental toxicity LOEL is > 1,000 mg/kg/day and the developmental
toxicity NOEL is <gr-thn-eq> 1,000 mg/kg/day.
iii. Reproductive toxicity study-- a. Rats. In the 3-generation
reproduction and development study in rats, systemic toxicity was noted
in offspring at the highest dose in the form of reduced pup body
weights and body weight gains during the lactation period and
subsequent reduced adult body weights in both males and females. There
were no treatment related clinical toxicity signs, mortality,
differences in food consumption or efficiency and water consumption. No
treatment related effects were noted on mating performance, duration of
pregnancy and litter size. Organ weights showed increases in absolute
and relative liver weights in the high dose males and females across
generations. This effect is consistent with observations found in other
chronic toxicity studies. The offspring systemic toxicity LOEL is 661.8
mg/kg/day. The offspring systemic toxicity NOEL is 63.7 mg/kg/day. For
the developmental segment, there may have been an effect in both dose
groups in the form of reduced fetal body weights. Fetal examinations
showed no treatment related effects on gross or skeletal examinations.
Visceral examination revealed a possible treatment related increase in
enlargement of the renal pelvis in the high dose group.
b. Rats. In a two-generations reproductive toxicity study, no
compound-related parental effects were observed in either sex or
generation. The LOEL for parental toxicity was not determined and the
NOEL for parental toxicity is > 1,625 mg/kg/day (exceeds limit dose).
iv. Pre- and post-natal sensitivity. The pre- and post-natal
toxicology data base for flutolanil is complete with respect to current
toxicological data requirements. Based on the developmental and
reproductive toxicity studies discussed above, there does not appear to
be an extra sensitivity for pre- or post-natal effects.
v. Conclusion. EPA concludes that reliable data support use of the
hundredfold uncertainty factor and that an additional tenfold factor is
not needed to ensure the safety of infants and children from dietary
exposure.
2. Acute risk. No acute dietary risk has been identified.
3. Chronic risk. Using the conservative exposure assumptions
described above, EPA has concluded that exposure to flutolanil from
food will utilize 0.2% of the Rfd for the U.S. population and 0.5% for
children 1-6 years 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. Despite the potential for exposure
to flutolanil in drinking water and from non-dietary, non-occupational
exposure, EPA does not expect the aggregate exposure to exceed 100% of
the RfD. EPA concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
flutolanil residues.
4. Short- or intermediate-term risk. No appropriate endpoints were
identified for short- or intermediate-term exposure, therefore, no
unreasonable adverse effects are expected to result from the use of
flutolanil.
[[Page 42255]]
5. Conclusion. EPA concludes that there is a reasonable certainty
that no harm will result to infants and children from aggregate
exposure to flutolanil residues.
III. Other Considerations
A. Endocrine Disrupter Effects
EPA is required to develop a screening program to determine whether
certain substances (including all pesticides and inerts) ``may have an
effect in humans that is similar to an effect produced by a naturally
occurring estrogen, or such other endocrine effect ....'' The Agency is
currently working with interested stakeholders, including other
government agencies, public interest groups, industry and research
scientists in developing a screening and testing program and a priority
setting scheme to implement this program. Congress has allowed 3 years
from the passage of FQPA (August 3, 1999) to implement this program. At
that time, EPA may require further testing of this active ingredient
and end use products for endocrine disrupter effects.
B. Metabolism In Plants and Animals
1. Plants. Based on the three metabolism studies on peanuts, rice
and cucumbers (which indicate a similar metabolic route for crops in
three different crop groups), the nature of the residues is adequately
understood. The residues of concern for flutolanil consist of
flutolanil N-(3-(1-methylethoxy)phenyl)-2-trifluoromethyl)benzamide and
identified metabolites containing the common moiety, 2-trifluoromethyl
benzanilide. The tolerance expression takes cognizance of this and is
expressed in the terms of the analytical derivative of this common
moiety. The residue of concern in plants consists of flutolanil and
metabolites convertible to the methyl ester of 2-trifluoromethyl
benzoic acid.
2. Animals. The nature of the residue in animals is adequately
understood. The residues of concern in animal commodities are
flutolanil and identified metabolites containing the common moiety, 2-
trifluoromethyl benzanilide and that can be converted to the methyl
ester of 2-trifluoromethyl benzoic acid. .
C. Analytical Enforcement Methodology
The residue analytical method will be forwarded to FDA for
publication after the Agency has concluded its review of the
independent validation of the method which is currently under review.
This method is available for limited distribution from: By mail, Calvin
Furlow, 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.
Office location and telephone number: Crystal Mall #2, Rm. 101FF, 1921
Jefferson Davis Hwy., Arlington, VA 22202 (703) 305-5229. The method
has the following disclaimer: This method is for use only by
experienced chemists who have demonstrated knowledge of the principles
of trace organic analysis; and have proven skills and abilities to run
a complex residue analytical method obtaining accurate results at the
part per billion level. Users of this method are expected to perform
additional method validation prior to using the method for either
monitoring or enforcement. The method can detect gross misuse.
D. Magnitude of Residues
The residues of flutolanil and its metabolites converted to 2-
(trifluoromethyl)benzoic acid resulting from the use on rice will not
exceed 2.0 ppm in rice grain, 8.0 ppm in rice straw, 7.0 ppm in rice
hulls or 3.0 ppm in rice bran. Residue data for animal commodities
indicated that the currently established tolerances are adequate to
cover the use of flutolanil on rice.
E. International Residue Limits
There are no Codex, Canadian or Mexican residue limits established
for flutolanil on rice. Therefore, no compatibility problems exist for
the proposed tolerances on rice.
F. Rotational Crop Restrictions.
Rotational crop restrictions for rice include: 240 day restriction
for soybeans or grain sorghum and 12 months for all other crops except
peanuts and rice.
IV. Conclusion
Therefore, time-limited tolerances, to expire on December 31, 2000,
are established for the residues of the fungicide flutolanil N-(3-(1-
methylethoxy)phenyl)-2-(trifluoromethyl)benzamide and its metabolites
converted to 2-(trifluoromethyl)benzoic acid and calculated as
flutolanil in or on the raw agricultural commodities rice grain at 2.0
ppm and rice straw at 8.0 ppm and in or on the processed food or feed
commodities rice hulls at 7.0 ppm and rice bran at 3.0 ppm when present
therein as a result of application of the fungicide to growing crops.
The tolerances are time-limited to allow the Agency adequate time to
review additional residue studies and to review the method validation
for flutolanil which have already been submitted.
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 October 6, 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
[[Page 42256]]
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-300697] (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 Highway, 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
This final rule establishes time-limited 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 these tolerances and exemptions that are
established on the basis of a petition under FFDCA section 408(d), such
as the time-limited tolerances 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 was published on May 4, 1981 (46 FR 24950) and was
provided to the Chief Counsel for Advocacy of the Small Business
Administration.
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
40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
40 CFR Part 185
Environmental protection, Food additives, Pesticides and pests.
Dated: July 29, 1998.
Arnold E. Layne,
Acting Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180 --[AMENDED]
1. In part 180:
a. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
b. Section 180.484 is amended as follows:
i. By adding a paragraph heading ``General'' to paragraph (a).
ii. By redesignating the text in paragraph (a) as paragraph (a)(1),
``Permanent tolerances.''
iii. By adding paragraph (a)(2).
iv. By adding a heading to paragraph (b) and removing and reserving
the text of the paragraph.
v. By adding paragraphs (c) and (d) with headings and reserving the
text of those paragraphs.
The added text reads as follows:
Sec. 180.484 Flutolanil; tolerances for residues.
(a) General -- (1) Permanent tolerances. * * *
(2) Time-limited tolerances. Time-limited tolerances are
established for the residues of the fungicide flutolanil N-(3-(1-
methylethoxy)phenyl)-2-(trifluoromethyl)benzamide and its metabolites
converted to 2-(trifluoromethyl) benzoic acid and calculated as
flutolanil in or on the following agricultural commodities:
------------------------------------------------------------------------
Parts Expiration/
Commodity per Revocation
million Date
------------------------------------------------------------------------
Rice, grain.................................... 2.0 12/31/00
Rice, straw.................................... 8.0 12/31/00
Rice, bran..................................... 3.0 12/31/00
Rice, hulls.................................... 7.0 12/31/00
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
PART 185 --[AMENDED]
2. In part 185:
a. The authority citation for part 185 continues to read as
follows:
[[Page 42257]]
Authority: 21 U.S.C. 348.
Sec. 180.3385 [Removed]
b. In Sec. 185.3385, in the table to paragraph (a), the entry for
``peanut meal'' is transferred and alphabetically added to the table in
paragraph (a)(1) of Sec. 180.484. The remainder of Sec. 185.3385 is
removed.
[FR Doc. 98-20899 Filed 8-6-98; 8:45 am]
BILLING CODE 6560-50-F .