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ENVIRONMENTAL PROTECTION AGENCY
Environmental Protection Agency
CFR Citation: 40 CFR Part 180
OPP ID: [OPP-2003-0130; FRL-7310-9]
NOTICE: RULES
ACTION: Pesticides; tolerances in food, animal feeds, and raw agricultural commodities:
DOCUMENT ACTION: Final rule.
SUBJECT CATEGORY: Famoxadone; Pesticide Tolerance
DATES: This regulation is effective July 2, 2003. Objections and requests for hearings, identified by docket ID number OPP20030130, must be received on or before September 2, 2003.
DOCUMENT SUMMARY: This regulation establishes tolerances for residues of famoxadone (3anilino5methyl5(4phenoxyphenyl)1,3oxazolidine2,4 dione) in or on vegetables, fruiting, group 8 (except tomato) at 4.0 parts per million (ppm), tomato at 1.0 ppm; vegetables cucurbit, group 9 at 0.30 ppm; lettuce, head at 10.0 ppm; potato at 0.02 ppm; grape at 2.50 ppm; grape, raisin at 4.0 ppm; fat of cattle, horses, goats, sheep at 0.02 ppm; liver of cattle, horses, goats, sheep at 0.05 ppm; and milk fat (reflecting negligible residues in whole milk) at 0.060 ppm. E.I. Dupont Nemours and Company (Dupont) requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA). These reflect the first food tolerances for this fungicide in the United States.
SUMMARY: Famoxadone,
SUPPLEMENTAL INFORMATION
I. General InformationA. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to: [sbull] Crop production (NAICS 111)
[sbull] Animal production (NAICS 112
[sbull] Food manufacturing (NAICS 311)
[sbull] Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket identification (ID) number OPP20030130. The
official public docket consists of the documents specifically
referenced in this action, any public comments received, and other
information related to this action. Although a part of the official
docket, the public docket does not include Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute. The official public docket is the collection of materials
that is available for public viewing at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/. A frequently updated
electronic version of 40 CFR part 180 is available at http://www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180_00.html , a
beta site currently under development. To access the OPPTS Harmonized
Guidelines referenced in this document, go directly to the guidelines
at http://www.epa.gov/opptsfrs/home/guidelin.htm.
An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I.B.1. Once in the system, select ``search,'' then key in the appropriate docket ID number.
II. Background and Statutory Findings
In the Federal Register of January 10, 2001 (66 FR 1981) (FRL6760 8), EPA issued a notice pursuant to section 408 of FFDCA, 21 U.S.C. 346a, as amended by FQPA (Public Law 104170), announcing the filing of a pesticide petition (PP 0F6070) for establishing tolerances for potatoes at 0.05 ppm, curcurbit vegetable crop group (cucumbers, melon, squash) at 0.7 ppm; fruiting vegetable crop group (tomatoes, and peppers) at 1.0 ppm; and head lettuce at 15 ppm by Dupont, P.O. Box 80038, Wilmington, DE 198800038. That notice included a summary of the petition prepared by Dupont, the registrant. There were no comments received in response to the notice of filing.
In a second Federal Register of August 1, 2001 (66 FR 39762) (FRL 67892), EPA issued a notice pursuant to section 408 of FFDCA, 21 U.S.C. 346a, as amended by FQPA (Public Law 104170), announcing the filing of a pesticide petition (PP 7E4847) for establishing a tolerance for grapes at 2.0 parts per million by Dupont, P.O. Box 80038, Wilmington, DE 198800038. That notice included a summary of the petition prepared by Dupont, the registrant. The Agency received a written comment from the World Wildlife Fund (WWF) dated August 31, 2001. The Agency's response to this comment can be found at Unit III.B.
The initial petitions requested that 40 CFR 180.587 be amended by establishing tolerances for residues of the fungicide famoxadone (3 anilino5methyl5(4phenoxyphenyl)1,3oxazolidine2,4dione) in or on potatoes at 0.05 ppm; cucurbit vegetable crop group at 0.7 ppm; fruiting vegetable crop group at 1.0 ppm; head lettuce at 15 ppm; grapes at 2.0 ppm; and raisins at 4.0 ppm.
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) of the FFDCA defines ``safe'' to mean that ``there is a reasonable certainty that no harm will
[[Page 39463]]
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) of the FFDCA 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 of the FFDCA and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997) (FRL 57547).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of the FFDCA, 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 and to make a determination on aggregate exposure, consistent with section 408(b)(2) of the FFDCA, for tolerances for residues of famoxadone on vegetables, fruiting, group 8 (except tomato) at 4.0 ppm; tomato at 1.0 ppm; vegetables, cucurbit, group 9 at 0.30 ppm; lettuce, head at 10.0 ppm; potato at 0.02 ppm; grape at 2.50 ppm; grape, raisin at 4.0 ppm; fat of cattle, horses, goats, sheep at 0.02 ppm; liver of cattle, horses, goats, sheep at 0.05 ppm and milk, fat (reflecting negligible residues in whole milk) at 0.060 ppm. EPA's assessment of 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 famoxadone are
discussed in Table 1 of this unit as well as the noobservedadverse
effectlevel (NOAEL) and the lowestobservedadverseeffectlevel (LOAEL) from the toxicity studies reviewed.
Table 1.Subchronic, Chronic, and Other Toxicity
Guideline No. Study Type Results
870.3100 90Day oral toxicity in NOAEL = Male (M): 3.3 milligrams/kilogram/
rats day (mg/kg/day); Female (F): 4.2 mg/kg/
day.
LOAEL = M: 13.0 mg/kg/day based on mild
hemolytic anemia and decreased glucose. F:
16.6 mg/kg/day based on decreased body
weight gain, food consumption, and food
efficiency; mild hemolytic anemia and
decreased globulin.
870.3100 90Day oral toxicity in NOAEL = M: 62.4 mg/kg/day; F: 79.7 mg/kg/
mice day.
LOAEL = M: 534 mg/kg/day based on mild
hemolytic anemia with secondary responses
in spleen and mild hepatotoxicity in the
liver. F: 757 mg/kg/day based on mild
hemolytic anemia with secondary responses
in spleen and mild hepatotoxicity in the
liver.
870.3150 90Day oral toxicity in NOAEL = M: 1.3 mg/kg/day; F: 1.4 mg/kg/day
nonrodents (dogs) LOAEL = M: 10.0 mg/kg/day based on lens
cataracts in eyes. At 23.8/21.2 mg/kg/day,
also myotonic twitches (starting on day
21); decreased body weight, body weight
gain, food consumption, and food
efficiency; slight anemia and
hyperkalemia. F: 1.4 mg/kg/day based on
lens cataracts in eyes. At 10.1 mg/kg/day,
no additional effects. At 23.3/20.1 mg/kg/
day, same effects as for males at 23.8/
21.2 mg/kg/day.
870.3200 28Day dermal toxicity in NOAEL = M: 250 mg/kg/day; F: 1,000 mg/kg/
rats day
LOAEL = M: 500 mg/kg/day based on increased
alkaline phosphatase, alanine
aminotransferase and sorbitol
dehydrogenase; and mild hepatotoxicity in
the liver. F: none (>1,000 mg/kg/day). No
dermal irritation in M or F.
870.3700 Prenatal developmental in Maternal NOAEL = 250 mg/kg/day
rats LOAEL = 500 mg/kg/day based on transient
decreased body weight gain and food
consumption.
Developmental NOAEL = 1,000 mg/kg/day
LOAEL = none (>1,000 mg/kg/day
870.3700 Prenatal developmental in Maternal NOAEL = 350 mg/kg/day
nonrodents (rabbits) LOAEL = 1,000 mg/kg/day based on abortions;
decreased body weight, body weight gain,
and food consumption; and abnormal stools.
Developmental NOAEL = 350 mg/kg/day
LOAEL = 1,000 mg/kg/day based on abortions
and equivocal increases in
postimplantation loss and mean resorptions
per dose. [[Page 39464]]
870.3800 Reproduction and fertility Parental/Systemic NOAEL = M/F: 11.3/14.2 mg/
effects (rats) kg/day
LOAEL = M/F: 44.7/53.3 mg/kg/day based on
decreased body weight, body weight gain,
and food consumption; and hepatotoxicity
in the liver.
Reproductive NOAEL = M/F: 44.7/53.3 mg/kg/
day
LOAEL = M/F: none (>44.7/53.3 mg/kg/day
Offspring NOAEL = M/F: 11.3/14.2 mg/kg/day
LOAEL = M/F: 44.7/53.3 mg/kg/day based on
decreased body weights for F
870.6200 Acute neurotoxicity NOAEL = M: 1,000 mg/kg F: 2,000 mg/kg.
screening battery (rats) LOAEL = M: 2,000 mg/kg based on decreased
body weight gain and food consumption (on
days 12); and palpebral (eyelid) closure
(on day 1 only). F: none (>2,000 mg/kg).
870.6200 Subchronic neurotoxicity NOAEL = M: 11.7 mg/kg/day F: 14.4 mg/kg/
screening battery (rats) day.
LOAEL = M: 47 mg/kg/day based on decreased
body weight, body weight gain, food
consumption and food efficiency. F:59 mg/
kg/day based on decreased body weight,
body weight gain, food consumption and
food efficiency. No evidence of
neurotoxicity in M or F.
870.7800 Immunotoxicity study, rats NOAEL = M: 14 mg/kg/day. F: 16 mg/kg/day.
(28days) LOAEL = M: 55 mg/kg/day based on decreased
body weight, body weight gain, food
consumption, and food efficiency; and
increased spleen weights (probably due to
increased pigment in spleen). F: 57 mg/kg/
day based on decreased body weight, body
weight gain, food consumption, and food
efficiency; and increased spleen weights
(probably due to increased pigment in
spleen). No evidence of immunotoxicity in
M or F.
870.7800 Immunotoxicity study,mice NOAEL = M: 1186 mg/kg/day. F: 417 mg/kg/
(28days) day.
LOAEL = M: none (>1,186 mg/kg/day). F:
1,664 mg/kg/day based on increased spleen
weights (probably due to increased pigment
in spleen). No evidence of immunotoxicity
in M or F.
870.7485 Metabolism and Only about 40% of the administered dose was
pharmacokinetics, rats absorbed. Most of the administered dose
(876%) was eliminated in the feces within
24 hours; very little (312%) was
eliminated in the urine. Unchanged parent
(5184% of administered dose) and 2
hydroxylated metabolites (INKZ534 and IN
KZ007) were the major components recovered
in the feces. No significant qualitative
or quantitative differences were observed
for sex, dose level, or repeated dosing.
870.7485 Metabolism and Absorption was limited. Most of the
pharmacokinetics, dogs administered dose (62%) was eliminated in
(males only) the feces within 24 hours; very little
(about 8%)was eliminated in the urine.
Initially, unchanged parent (9497% of
radioactivity in feces) was recovered in
the feces, but later (>24 hrs) unchanged
parent (1235% of radioactivity in feces),
INKZ007 (213% of radioactivity in feces)
and INML815 (49% of radioactivity in
feces) were recovered. Even later (>48
hrs), trace amounts of the hydroxylated
metabolites INKZ532 and INKZ534 were
also identified in the feces. B. Toxicological Endpoints
The dose at which no adverse effects are observed (the NOAEL) from the toxicology study identified as appropriate for use in risk assessment is used to estimate the toxicological level of concern (LOC). However, the lowest dose at which adverse effects of concern are identified (the LOAEL) is sometimes used for risk assessment if no NOAEL was achieved in the toxicology study selected. An uncertainty factor (UF) is applied to reflect uncertainties inherent in the extrapolation from laboratory animal data to humans and in the variations in sensitivity among members of the human population as well as other unknowns. An UF of 100 is routinely used, 10X to account for interspecies differences and 10X for intraspecies differences.
For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (acute RfD or chronic RfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factors (SF) is retained due to concerns unique to the FQPA, this additional factor is applied to the RfD by dividing the RfD by such additional factor. The acute or chronic Population Adjusted Dose (aPAD or cPAD) is a modification of the RfD to accommodate this type of FQPA SF.
For nondietary risk assessments (other than cancer) the UF is used to determine the LOC. For example, when 100 is the appropriate UF (10X to account for interspecies differences and 10X for intraspecies differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and compared to the LOC.
The linear default risk methodology (Q*) is the primary method
currently used by the Agency to quantify carcinogenic risk. The Q*
approach assumes that any amount of exposure will lead to some degree
of cancer risk. A Q* is calculated and used to estimate risk which
represents a probability of occurrence of additional cancer cases
(e.g., risk is expressed as 1 x 10\6\ or one in a million).
Under certain specific circumstances, MOE calculations will be used for
the carcinogenic risk assessment. In this nonlinear approach, a
``point of departure'' is identified below which carcinogenic effects
are not expected. The point of departure is typically a NOAEL based on
an endpoint related to cancer effects though it may be a different
value derived from the dose response curve. To estimate risk, a ratio
of the point of departure to exposure (MOE
[[Page 39466]]
Table 2.Summary of Toxicological Dose and Endpoints for Famoxadone for Use in Human Risk Assessment
FQPA SF* and Level of
Exposure Scenario Dose Used in Risk Concern for Risk Study and Toxicological
Assessment, UF Assessment Effects
Acute Dietary Not applicable Not applicable No appropriate endpoint
(Females 1350 years of age)......... attributable to a
singleoral dose was
identified in the
available toxicology
studies on famoxadone.
Acute Dietary Not applicable Not applicable No appropriate endpoint
(General population including infants attributable to a
and children). singleoral dose was
identified in the
available toxicology
studies on famoxadone.
Chronic Dietary LOAEL= 1.4 mg/kg/day FQPA SF = 1 13Week feeding study
(All populations).................... UF = 1,000\a\.......... cPAD = chronic RfD/FQPA in dogs.\b\
Chronic RfD = 0.0014 mg/ SF. LOAEL = 1.4 mg/kg/day
kg/day. Chronic PAD = 0.0014 mg/ based on microscopic
kg/day. lens lesions
(cataracts) in eyes of
female dogs.
Cancer Not applicable Not applicable Classification: Not
(Oral, dermal, and inhalation)....... Likely to be
carcinogenic to
humans.
* The reference to the FQPA SF refers to any additional SF retained due to concerns unique to the FQPA.
\a\ The UF of 1,000 includes the conventional 100 and an additional 10 for the use of the LOAEL and dose from a subchronic (13week) study for chronic risk assessment.
\b\ Regarding the chronic RfD for famoxadone, a 1year chronic feeding study in dogs is available, but was
determined to not be an appropriate study for use in chronic risk assessment at this time. Although the
testing laboratory reported a NOAEL of 1.2 mg/kg/day for treatmentrelated lens lesions (cataracts) in the
eyes of the male and female dogs, a subsequent evaluation by a consulting pathologist of the microscopic
sections of the eyes from all dogs in this study strongly suggested that a serious fixation artifact affected
all the eye sections such that only prominent cataracts were detectable and as a consequence, a NOAEL could
not be reliably determined with any degree of confidence. Considering this second evaluation, the Agency
concluded that this fixation artifact may have had a profound effect on the interpretation of the
histopathological findings in the eyes of all dogs in this study. In view of the considerable uncertainty
relating to the microscopic findings in the eyes of all dogs in this study and the resulting uncertainty with
regard to determining a NOAEL for eye effects, the Agency decided to not use the results from this 1year
study for the purpose of determining a chronic RfD for famoxadone at this time. Based on a consideration of
findings in the eyes of dogs in both the 13week and 1year feeding studies, it was determined that the lowest
dose at which evidence of cataracts was actually observed was in the female dogs in the 13week study at the
lowest dose tested of 1.4 mg/kg/day (the LOAEL). This 13week study, rather than the 1year study, was
selected to be the most appropriate study for chronic risk assessment at this time. Since a LOAEL, rather than
a NOAEL, and a subchronic study, rather than a chronic study, were used to determine the chronic RfD, an
additional 10x UF was added to the conventional UF of 100x. The chronic RfD (LOAEL of 1.4 mg/kg/day/UF of
1,000) for famoxadone was determined to be 0.0014 mg/kg/day.
The comment received from WWF concerned a toxicity issue in
particular: The potential for famoxadone to be an endocrine disruptor.
WWF quoted the notice of filing which was written by Dupont. ``Chronic,
lifespan and multigenerational bioassays in mammals and acute and
subchronic studies on aquatic organisms and wildlife did not reveal
endocrine effects. Any endocrine related effects would have to have
been detected in this definitive array of required tests. The
probability of any such effects due to agricultural uses of famoxadone
is negligible.'' WWF stated that pursuant to FQPA, the Agency is
establishing a new endocrine disruptor screening and testing program
because existing toxicology protocols are not adequate to detect
endocrine disruption. Therefore, Dupont's evaluation of the endocrine
disruptor potential is incomplete and consequently misleading. WWF also urges the Agency to consider not only evidence of
increasedsusceptibility, but also the significance of endocrine
disruptor data gaps when determining the FQPA SF for famoxadone.
In response to the WWF the Agency notes that FQPA requires EPA to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect... EPA has been working with interested stakeholders to develop a screening and testing program as well as a prioritysetting scheme. In the available toxicity studies on famoxadone, no evidence of endocrinerelated effects was observed. However, famoxadone may be subjected to further screening and/or testing to better characterize potential effects related to endocrine disruption when additional appropriate screening and/or testing protocols have been developed by the Agency's Endocrine Disruptor and Testing Advisory Committee (EDSTAC).
C. Exposure Assessment
1. Dietary exposure from food and feed uses. Tolerances are being established for (40 CFR 180.587) for the residues of famoxadone, in or on a variety of raw agricultural commodities. Risk assessments were conducted by EPA to assess dietary exposures from famoxadone in food as follows:
i. Acute exposure. Acute dietary risk assessments are performed for a fooduse pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a one day or single exposure. No toxicological endpoint attributable to a single oral dose was identified in the available toxicology studies on famoxadone that would be applicable to females (1350 years) or to the general population (including infants and children). Therefore, famoxadone is not expected to pose an acute dietary risk.
ii. Chronic exposure. In conducting this chronic dietary risk assessment the Dietary Exposure Evaluation Model (DEEM\TM\) analysis evaluated the individual food consumption as reported by respondents in the USDA 19941996 and 1998nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity. The following assumptions were made for the chronic exposure assessments: Anticipated residues based upon average field trial values and assumptions that 100% of each crop is treated with famoxadone.
iii. Cancer. The Agency has classified famoxadone as not likely to be
[[Page 39467]]
carcinogenic to humans. As such, famoxadone is not expected to pose a cancer dietary risk.
iv. Anticipated residue and percent crop treated (PCT) information.
Section 408(b)(2)(E) of the FFDCA authorizes EPA to use available data and information on the anticipated residue levels of pesticide residues in food and the actual levels of pesticide chemicals that have been measured in food. If EPA relies on such information, EPA must require that data be provided 5 years after the tolerance is established, modified, or left in effect, demonstrating that the levels in food are not above the levels anticipated. Following the initial data submission, EPA is authorized to require similar data on a time frame it deems appropriate. No PCT information was used in the risk assessment. The Agency used 100% which would over estimate exposure.
2. Dietary exposure from drinking water.
The Agency lacks monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for famoxadone in drinking water because this is a new chemical. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of famoxadone.
The Agency uses the FQPA Index Reservoir Screening Tool (FIRST) or the Pesticide Root Zone/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and SCIGROW, which predicts pesticide concentrations in groundwater. In general, EPA will use FIRST (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a screeninglevel assessment for surface water. The FIRST model is a subset or metamodel of the PRZM/EXAMS model that uses specific highend runoff scenario for pesticides. FIRST incorporates an index reservoir environment and a percent crop area (PCA), while PRZM/ EXAMS incorporate an index reservoir environment, PCA, all available information on the pesticide's fate and use pattern, and sitespecific cropping information.
None of these models include consideration of the impact processing (mixing, dilution, or treatment) of raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models by the Agency at this stage is to provide a screen for sorting out pesticides for which it is highly unlikely that drinking water concentrations would exceed human health levels of concern.
Since the models used are considered to be screening tools in the risk assessment process, the Agency does not use estimated environmental concentrations (EECs) from these models to quantify drinking water exposure and risk as a %RfD or %PAD. Instead drinking water levels of comparison (DWLOCs) are calculated and used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, and from residential uses. Since DWLOCs address total aggregate exposure to famoxadone they are further discussed in the aggregate risk sections in Unit E.
Based on the PRZM/EXAMS and SCIGROW models the EECs of famoxadone for chronic exposures are estimated to be 0.47 parts per billion (ppb) for surface water and 0.23 ppb for ground water.
3. From nondietary exposure. The term ``residential exposure'' is used in this document to refer to nonoccupational, nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets).
Famoxadone is not registered for use on any sites that would result in residential exposure.
4. Cumulative exposure to substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''
EPA does not have, at this time, available data to determine whether famoxadone 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, famoxadone 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 famoxadone 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. Safety Factor for Infants and Children
1. In general. Section 408 of the FFDCA provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base on toxicity and exposure 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.
2. Prenatal and postnatal sensitivity. The Agency concluded that there is not a concern for pre and/or postnatal toxicity resulting from exposure to famoxadone.
No quantitative or qualitative evidence of increased susceptibility, as compared to adults, of rat or rabbit fetuses to in utero exposure to famoxadone was observed in the developmental toxicity studies. No quantitative or qualitative evidence of increased susceptibility, as compared to adults, of rat fetuses or neonates was observed in the 2generation reproduction study.
In the rat developmental toxicity study, the NOAEL for maternal toxicity was 250 mg/kg/day and the LOAEL was 500 mg/kg/day, based on transient decreases in body weight gain and food consumption. At 1,000 mg/kg/day, no additional treatmentrelated effects were observed in the dams. No developmental toxicity was observed in the rat study. The NOAEL for developmental toxicity was 1,000 mg/kg/day, the highest dose tested.
In the rabbit developmental toxicity study, the maternal and
developmental NOAELs and LOAELs were the same. The NOAEL for maternal
toxicity and developmental toxicity was 350 mg/kg/day. The LOAEL for
maternal toxicity was 1,000 mg/kg/day, based on abortions in 4 out of
17 does; markedly decreased body weight, reduced body weight gain and
reduced food consumption in the same 4 does, and increased number of
does with abnormal or little or no stools. The LOAEL for developmental
toxicity was 1,000 mg/kg/day; based on abortions in 4 out of 17 does;
and equivocal increases in percent post implantation loss and mean number of resorptions
[[Page 39468]]
per doe. In the rabbit study, maternal toxicity (does) and
developmental toxicity (fetuses) are considered to be equally sensitive
to the test material. Therefore, based on the results in these two
developmental toxicity studies in rats and rabbits, no increased
susceptibility of the fetuses (as compared to adults) was demonstrated for famoxadone.
In the 2generation reproduction study in rats, the NOAEL for
parental toxicity was 200 ppm (equal to 11.3/14.2 mg/kg/day, M/F) and
the LOAEL was 800 ppm (44.7/53.3 mg/kg/day, M/F), based on decreased
body weight, body weight gain, and food consumption; and heptotoxicity
in the liver. Also, at 800 ppm, adaptive hepatocellular responses
indicating enzyme induction were observed. No reproductive toxicity was
observed in this study. The NOAEL for reproductive toxicity was 800 ppm
(44.7/53.3 mg/kg/day, M/F), the highest dose tested. In this same
study, the NOAEL for offspring toxicity was 200 ppm (equal to 11.3/14.2
mg/kg/day, M/F) and the LOAEL was 800 ppm (44.7/53.3 mg/kg/day, based
on decreased body weights for F
3. Neurotoxicity. The Agency concluded that there is not a concern for developmental neurotoxicity resulting from exposure to famoxadone and that a developmental neurotoxicity study is not required.
Although clinical signs of neurotoxicity were observed in dogs in the 13week study at the highest dose tested (>20 mg/kg/day), this effect was not observed at lower doses of about 10 mg/kg/day in the same 13week study or in a subsequently performed 1year feeding study in dogs. Also, toxicologically significant signs of neurotoxicity were not observed in any of the other studies on famoxadone in any species (including rats, mice, or monkeys) at any time. In addition, pre and postnatal studies in rats and rabbits demonstrated no increased susceptibility of fetuses or neonates to famoxadone as compared to adults. Toxicologically significant neurotoxic effects would not be expected to occur in an additional study in rats. The clinical signs of neurotoxicity (muscle twitches) observed only in dogs, only in males, and only at the highest dose tested, would not be anticipated to occur in a developmental neurotoxicity study in rats.
4. Conclusion. The Agency concluded that the toxicology database was complete for FQPA purposes and that there are no residential uncertainties for pre/postnatal toxicity. Based on the hazard data, the Agency recommended the special FQPA SF be reduced to 1x. The famoxadone risk assessment team evaluated the quality of the exposure data; and, based on these data, recommended that the special FQPA SF be reduced to 1x. The recommendation is based on the following:
i. There is no quantitative or qualitative evidence of increased susceptibility of rat and rabbit fetuses to in utero exposure in developmental studies. There is no quantitative or qualitative evidence of increased susceptibility of rat offspring in the multigeneration reproduction study.
ii. The chronic dietary food exposure assessment utilizes average field trial residue data and for all proposed uses, 100% crop treated is assumed. The chronic assessment is somewhat refined and based on reliable data derived from studies designed to produce worstcase residues and unlikely to underestimate exposure.
E. Aggregate Risks and Determination of Safety
To estimate total aggregate exposure to a pesticide from food, drinking water, and residential uses, the Agency calculates DWLOCs which are used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOC values are not regulatory standards for drinking water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food and residential uses. In calculating a DWLOC, the Agency determines how much of the acceptable exposure (i.e., the PAD) is available for exposure through drinking water e.g., allowable chronic water exposure (mg/kg/day) = cPAD (average food + residential exposure). This allowable exposure through drinking water is used to calculate a DWLOC.
A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weights. Default body weights and consumption values as used by the USEPA Office of Water are used to calculate DWLOCs: 2 liter (L)/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg (child). Default body weights and drinking water consumption values vary on an individual basis. This variation will be taken into account in more refined screeninglevel and quantitative drinking water exposure assessments. Different populations will have different DWLOCs. Generally, a DWLOC is calculated for each type of risk assessment used: Acute, shortterm, intermediateterm, chronic, and cancer.
When EECs for surface water and groundwater are less than the calculated DWLOCs, OPP concludes with reasonable certainty that exposures to the pesticide in drinking water (when considered along with other sources of exposure for which OPP has reliable data) would not result in unacceptable levels of aggregate human health risk at this time. Because OPP considers the aggregate risk resulting from multiple exposure pathways associated with a pesticide's uses, levels of comparison in drinking water may vary as those uses change. If new uses are added in the future, OPP will reassess the potential impacts of residues of the pesticide in drinking water as a part of the aggregate risk assessment process.
1. Acute risk. No appropriate endpoint attributable to a single oral dose was identified in the available toxicology studies on famoxadone. Therefore, no acute risk from famoxadone is not expected.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to
famoxadone from food will utilize 36% of the cPAD for the U.S.
population, 76% of the cPAD for Children ages 12 and 68% of the cPAD
for Children ages 35. Children ages 12 are expected to be the most
highly exposed subpopulation to famoxadone. There are no residential
uses for famoxadone. In addition, there is potential for chronic
dietary exposure to famoxadone in drinking water. After calculating
DWLOCs and comparing them to the EECs for surface and ground water, EPA
does not expect the aggregate exposure to exceed 100% of the cPAD, as shown in Table 3 of this unit:
Table 3.Aggregate Risk Assessment for Chronic (NonCancer) Exposure to Famoxadone
Surface Water EEC Ground Water EEC
Population Subgroup cPAD mg/kg/day % cPAD (Food) (ppb) (ppb) Chronic DWLOC (ppb)
U.S. Population 0.0014 36% 0.47 0.23 31 [[Page 39469]]
Children 12 years old 0.0014 76% 0.47 0.23 3.4
Children 35 years old 0.0014 68% 0.47 0.23 4.5
3. Shortterm risk. Shortterm aggregate exposure takes into account residential exposure plus chronic exposure to food and water (considered to be a backgroundexposure level). Famoxadone is not registered for use on any sites that would result in residential exposure. Therefore, the aggregate risk is the sum of the risk from food and water, which do not exceed the Agency's level of concern.
4. Intermediateterm risk. Intermediateterm aggregate exposure takes into account residential exposure plus chronic exposure to food and water (considered to be a backgroundexposure level). Famoxadone is not registered for use on any sites that would result in residential exposure. Therefore, the aggregate risk is the sum of the risk from food and water, which do not exceed the Agency's level of concern.
5. Aggregate cancer risk for U.S. population. Famoxadone is classified as ``not likely to be carcinogenic to humans.'' As such, no cancer risk is expected.
6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, including infants and children, from aggregate exposure to famoxadone residues.
IV. Other Considerations
A. Analytical Enforcement Methodology
Famoxadone was screened through multiresidue methods listed in the Pesticide Analytical Manual Volume I (PAM Vol. I), Third Edition (January 1994), using Protocols C to E. Protocols A and B were not used because famoxadone does not have an nmethyl carbamate structure (Protocol A), nor is it an acid or phenol (Protocol B). Protocol C showed good analytical response using the electroncapture detector (ECD) and nitrogenphosphorus detector (NPD). Good recoveries were obtained for the analysis of wine, grapes, and tomatoes (92138%) using Protocol D. Food commodities can be analyzed for famoxadone residues using the appropriate extraction method with the mixed ether elution system, resulting in recovery values of 92 to 108%.
The multiresidue methods testing appears to be scientifically acceptable and has been sent to the FDA for further evaluation. Preliminary analysis suggests that Protocol D may be appropriate for analysis of famoxadone in plant matrices and has the potential to be the primary enforcement method.
Adequate enforcement methodology is available to enforce the tolerance expression. The method may be requested from: Chief, Analytical Chemistry Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 207555350; telephone number: (410) 3052905; email address: residuemethods@epa.gov. B. International Residue Limits
No CODEX maximum residue limits currently exist for famoxadone: Maximum Residue Levels (MRLs) have been established for potatoes in the Netherlands at 0.02 ppm and for grapes in Germany at 2.0 ppm. V. Conclusion
Therefore, tolerances are established for residues of famoxadone (3anilino5methyl5(4phenoxyphenyl)1,3oxazolidine2,4dione) in or on vegetables, fruiting, group 8 (except tomato) at 4.0 ppm; tomato at 1 ppm; vegetables cucurbit, group 9 at 0.30 ppm; lettuce, head at 10.0 ppm; potato at 0.02 ppm grape at 2.50 ppm (import only); raisin at 4.0 ppm (import only); fat of cattle, horses, goats, sheep at 0.02 ppm; liver of cattle, horses, goats, sheep at 0.05 ppm; and milk, fat (reflecting negligible residues in whole milk) at 0.060 ppm. VI. Objections and Hearing Requests
Under section 408(g) of the FFDCA, as amended by the FQPA, any
person may file an objection to any aspect of this regulation and may
also request a hearing on those objections. The EPA procedural
regulations which govern the submission of objections and requests for
hearings appear in 40 CFR part 178. Although the procedures in those
regulations require some modification to reflect the amendments made to
the FFDCA by the FQPA, EPA will continue to use those procedures, with
appropriate adjustments, until the necessary modifications can be made.
The new section 408(g) of the FFDCA provides essentially the same
process for persons to ``object'' to a regulation for an exemption from
the requirement of a tolerance issued by EPA under new section 408(d)
of FFDCA, as was provided in the old sections 408 and 409 of the FFDCA.
However, the period for filing objections is now 60 days, rather than 30 days.
A. What Do I Need to Do to File an Objection or Request a Hearing?
You must file your objection or request a hearing on this regulation in accordance with the instructions provided in this unit and in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number OPP20030130 in the subject line on the first page of your submission. All requests must be in writing, and must be mailed or delivered to the Hearing Clerk on or before September 2, 2003.
1. Filing the request. Your objection must specify the specific provisions in the regulation that you object to, and the grounds for the objections (40 CFR 178.25). If a hearing is requested, the objections must include a statement of the factual issues(s) on which a hearing is requested, the requestor's contentions on such issues, and a summary of any evidence relied upon by the objector (40 CFR 178.27). Information submitted in connection with an objection or hearing request may be claimed confidential by marking any part or all of that information as 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.
Mail your written request to: Office of the Hearing Clerk (1900C),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 204600001. You may also deliver your request to the
Office of the Hearing Clerk in Rm.104, Crystal Mall
[[Page 39470]]
telephone number for the Office of the Hearing Clerk is (703) 6030061.
2. Tolerance fee payment. If you file an objection or request a hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or request a waiver of that fee pursuant to 40 CFR 180.33(m). You must mail the fee to: EPA Headquarters Accounting Operations Branch, Office of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please identify the fee submission by labeling it ``Tolerance Petition Fees.''
EPA is authorized to waive any fee requirement ``when in the judgement of the Administrator such a waiver or refund is equitable and not contrary to the purpose of this subsection.'' For additional information regarding the waiver of these fees, you may contact James Tompkins by phone at (703) 3055697, by email at tompkins.jim@epa.gov, or by mailing a request for information to Mr. Tompkins at Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001.
If you would like to request a waiver of the tolerance objection fees, you must mail your request for such a waiver to: James Hollins, Information Resources and Services Division (7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 204600001.
3. Copies for the Docket. In addition to filing an objection or hearing request with the Hearing Clerk as described in Unit VI.A., you should also send a copy of your request to the PIRIB for its inclusion in the official record that is described in Unit I.B.1. Mail your copies, identified by docket ID number OPP20030130, to: Public Information and Records Integrity Branch, Information Resources and Services Division (7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001. In person or by courier, bring a copy to the location of the PIRIB described in Unit I.B.1. You may also send an electronic copy of your request via email to: oppdocket@epa.gov. Please use an ASCII file format and avoid the use of special characters and any form of encryption. Copies of electronic objections and hearing requests will also be accepted on disks in WordPerfect 6.1/8.0 or ASCII file format. Do not include any CBI in your electronic copy. You may also submit an electronic copy of your request at many Federal Depository Libraries. B. When Will the Agency Grant a Request for a Hearing?
A request for a hearing will be granted if the Administrator determines that the material submitted shows the following: There is a 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(s) in the manner sought by the requestor would be adequate to justify the action requested (40 CFR 178.32).
VII. Statutory and Executive Order Reviews
This final rule establishes a tolerance under section 408(d) of the FFDCA 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). Because this rule has been exempted from review under Executive Order 12866 due to its lack of significance, this rule is not subject to Executive Order 13211, Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, May 22, 2001). This final rule does not c
FOR FURTHER INFORMATION CONTACT Dennis M. McNeilly, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW.,Washington, DC 20460
0001; telephone number: (703) 3086742; email address:
mcneilly.dennis@epa.gov.
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