[Federal Register: August 10, 2005 (Volume 70, Number 153)]
[Rules and Regulations]
[Page 46410-46419]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10au05-5]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-2005-0156; FRL-7726-9]
Topramezone; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of
topramezone in or on field corn, pop corn, sweet corn, kidney, and
liver. BASF Corporation requested these tolerances under the Federal
Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality
Protection Act of 1996 (FQPA).
DATES: This regulation is effective August 10, 2005. Objections and
requests for hearings must be received on or before October 11, 2005.
ADDRESSES: To submit a written objection or hearing request follow the
detailed instructions as provided in Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a docket for this action under Docket
identification (ID) number OPP-2005-0156. All documents in the docket
are listed in the EDOCKET index at http://www.epa.gov/edocket. Although
listed in the index, some information is not publicly available, i.e.,
CBI or other information whose disclosure is restricted by statute.
Certain other material, such as copyrighted material, is not placed on
the Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available either
[[Page 46411]]
electronically in EDOCKET or in hard copy at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2,
1801 S. Bell St., Arlington, VA. This docket facility is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
docket telephone number is (703) 305-5805.
FOR FURTHER INFORMATION: Joanne I. Miller, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW.,Washington, DC 20460-0001; telephone
number: (703) 305-6224; e-mail address: miller.joanne@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. 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:
Crop production (NAICS 111), e.g., agricultural workers;
greenhouse, nursery, and floriculture workers; farmers.
Animal production (NAICS 112), e.g., cattle ranchers and
farmers, dairy cattle farmers, livestock farmers.
Food manufacturing (NAICS 311), e.g., agricultural
workers; farmers; greenhouse, nursery, and floriculture workers;
ranchers; pesticide applicators.
Pesticide manufacturing (NAICS 32532), e.g., agricultural
workers; commercial applicators; farmers; greenhouse, nursery, and
floriculture workers; residential users.
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 Access Electronic Copies of this Document and Other
Related Information?
In addition to using EDOCKET (http://www.epa.gov/edocket/), 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 E-CFR Beta Site Two at http://www.gpoaccess.gov/ecfr/.
To access the OPPTS Harmonized Guidelines referenced in this document,
go directly to the guidelines at http://www.epa.gpo/opptsfrs/home/guidelin.htm/
.
II. Background and Statutory Findings
In the Federal Register of June 11, 2003 (68 FR 34950) (FRL-7310-
4), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21
U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP
3F6568) by BASF Corporation, P.O. Box 13528, Research Triangle Park, NC
27709. The petition requested that 40 CFR 180.612 be amended by
establishing tolerances for residues of the herbicide topramezone, [3-
(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-2-methylphenyl)-(5-
hydroxyl-1-methyl-1H-pyrazol-4-yl)methanone, in or on corn, field,
forage; corn, field, grain; corn, field, stover; corn, pop, grain;
corn, pop, stover; corn, sweet, forage; corn, sweet, kernal plus cob
with husks removed; corn, sweet, stover; cattle, kidney; cattle, liver;
goat, kidney; goat, liver; hog, kidney; hog, liver; horse, kidney;
horse, liver; sheep, kidney; and sheep, liver at 0.05; 0.01; 0.05;
0.01; 0.05; 0.05; 0.01; 0.05; 0.02; 0.70; 0.20; 0.70; 0.20; 0.70; 0.20;
0.70; 0.20; and 0.70 parts per million (ppm), respectively. That notice
included a summary of the petition prepared by BASF Corporation, the
registrant. There were no comments received in response to the notice
of filing.
Section 408(b)(2)(A)(i) of 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 FFDCA 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) of 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 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-
5754-7).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of 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 FFDCA, for a tolerance for residues of topramezone on
cattle, kidney at 0.05 ppm; cattle, liver at 0.15 ppm; corn, field,
forage at 0.05 ppm; corn, field, grain at 0.01 ppm; corn, field, stover
at 0.05 ppm; corn, pop, grain at 0.01 ppm; corn, pop, stover at 0.05
ppm; corn, sweet, forage at 0.05 ppm; corn, sweet, kernal plus cob with
husks removed at 0.01 ppm; corn, sweet, stover at 0.05 ppm; goat,
kidney at 0.05 ppm; goat, liver at 0.15 ppm; horse, kidney at 0.05 ppm;
horse, liver at 0.15 ppm; sheep, kidney at 0.05 ppm; and sheep, liver
at 0.15 ppm, respectively.
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. Specific information on the studies received and the nature
of the toxic effects caused by topramezone are discussed in Table 1. of
this unit as well as the no observed adverse effect level (NOAEL) and
the lowest observed adverse effect level (LOAEL) from the toxicity
studies reviewed .
[[Page 46412]]
Table 1.--Subchronic, Chronic, and Other Toxicity
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Guideline No. Study Type Results
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870.3100 90-Day oral toxicity-- NOAEL = 1.1 milligrams/kilogram/day (mg/kg/
rodents (rat) day) males (M) and 2.1 mg/kg/day females
(F)
LOAEL = 2.1 mg/kg/day for males based on
diffuse degeneration in the pancreas and
was not established for females
----------------------------------------
870.3100 90-Day oral toxicity-- NOAEL = 2,289/3,010 mg/kg/day (M/F)
rodents (mouse) LOAEL = was not established
----------------------------------------
870.3150 90-Day oral toxicity-- NOAEL = 535/1,712 mg/kg/day (M/F)
nonrodents (dog) LOAEL = 1,511 mg/kg/day for males based on
decreased body-weight gain, impaired food
efficiency, and inflammation of the
urinary bladder and was not established
for females
----------------------------------------
870.3200 28-Day dermal toxicity NOAEL = 100/300 mg/kg/day (M/F)
(rat) LOAEL = 300 mg/kg/day males based on
thyroid follicular cell hypertrophy and
1,000 mg/kg/day females based on thyroid
follicular cell hypertrophy
----------------------------------------
870.3700 Prenatal developmental-- Maternal NOAEL = not established
rodents (rat) Maternal LOAEL = 100 mg/kg/day based on
decreased body-weight gains
Developmental NOAEL = not established
Developmental LOAEL = 100 mg/kg/day based
on decreased fetal body weight and
increased incidences of skeletal variation
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870.3700 Prenatal developmental-- Maternal NOAEL = not established
nonrodents (rabbit) Maternal LOAEL = 0.5 mg/kg/day based on
increased serum tyrosine level
Developmental NOAEL = 0.5 mg/kg/day
Developmental LOAEL = 5 mg/kg/day based on
alterations in skeletal ossification sites
and increased number of pairs of ribs
----------------------------------------
870.3700 Prenatal developmental-- Maternal NOAEL = not established
nonrodents (rabbit) Maternal LOAEL = 1.5 mg/kg/day based on
increased serum tyrosine level
Developmental NOAEL = not established
Developmental LOAEL = 1.5 mg/kg/day based
on an increased incidence of absent kidney
and ureter and increased incidences of
supernumerary thoracic vertebrae and
supernumerary 13\th\ rib
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870.3700 Prenatal developmental-- Maternal NOAEL = 5.0 mg/kg/day
nonrodents (rabbit) Maternal LOAEL = was not established
Developmental NOAEL = not established
Developmental LOAEL = 1.5 mg/kg/day for N33
and N17/CFR 1-2 based on increased
presence of supernumerary thoracic
vertebrae and supernumerary 13\th\ rib. No
effect was observed for N17/CFR 3 at 0.5
mg/kg/day (the only dose tested)
----------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental-- Maternal NOAEL = 450 mg/kg/day
nonrodents (rabbit) Maternal LOAEL = not established
Developmental NOAEL = not established
Developmental LOAEL = 5 mg/kg/day based on
visceral findings (fluid-filled abdomen,
pale liver, and dark content of the
stomach and intestines) and alterations in
skeletal development (i.e. incomplete
ossification of the vertebrae and talus,
and supernumerary thoracic vertebrae and
13\th\ rib)
----------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental-- Maternal NOAEL = 150 mg/kg/day
nonrodents (rabbit) Maternal LOAEL = 450 mg/kg/day based on
decreased body-weight, body-weight gains,
food consumption, and increased incidences
of abortion and lack of defecation
Developmental NOAEL = not established
Developmental LOAEL = 50 mg/kg/day based on
decreased fetal weight and increased
incidence of visceral malformations, and
skeletal malformations, variations, and
unclassified abnormalities
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870.3700 Prenatal developmental-- Maternal NOAEL = 450 mg/kg/day
nonrodents (rabbit) Maternal LOAEL = not established
Developmental NOAEL = 0.5 mg/kg/day
Developmental LOAEL = 5 mg/kg/day based on
increased presence of 27 pre-sacral
vertebrae and increased an incidence of
full supernumerary 13\th\ rib
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[[Page 46413]]
870.3700 Prenatal developmental-- Maternal NOAEL = 450 mg/kg/day
nonrodents (rabbit) Maternal LOAEL = not established
Developmental NOAEL = not established
Developmental LOAEL = 50 mg/kg/day based on
an increased incidence of extra sternebral
ossification sites and supernumerary
13\th\ rib
----------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental-- Maternal NOAEL = not established
nonrodents (mouse) Maternal LOAEL = 30 mg/kg/day based on
increased serum tyrosine level
Developmental NOAEL = 1,000 mg/kg/day
Developmental LOAEL = not established
----------------------------------------------------------------------------------------------------------------
870.3800 Reproduction and fertility Parental/Systemic NOAEL = 0.4/0.5 mg/kg/day
effects (rat) (M/F)
Parental/Systemic LOAEL = 4.2/4.6 mg/kg/day
(M/F) based on decreased body-weight, body-
weight gain in males, increased thyroid
and kidney weights of both sexes, and
microscopic findings in eyes, kidney, and
thyroid of both sexes
Reproductive NOAEL = 426.8/471.9 mg/kg/day
(M/F)
Reproductive LOAEL = not established
Offspring NOAEL = 0.4/0.5 mg/kg/day (M/F)
Offspring LOAEL = 4.2/4.6 mg/kg/day (M/F)
based on decreased pup weight and weight
gain in F2 male and female pups and
increased time to preputial separation in
the F1 males
----------------------------------------------------------------------------------------------------------------
870.4100 Chronic toxicity--rodents NOAEL = 0.4/0.5 mg/kg/day (M/F)
(rat) LOAEL = 3.9/5.3 mg/kg/day (M/F) based on
corneal opacity and pannus and chronic
keratitis in both sexes, and thyroid
hypertrophy in males
----------------------------------------------------------------------------------------------------------------
870.4100 Chronic toxicity--dogs NOAEL = 2.9/15.4 (M/F) mg/kg/day
LOAEL = 15.3 mg/kg/day (M) based on
increased incidence of thyroid C-cell
hyperplasia and 92 mg/kg/day (F) based on
decreased body-weight, body-weight gain,
and food efficiency
----------------------------------------------------------------------------------------------------------------
870.4200 Carcinogenicity--rats NOAEL = 0.4/0.5 mg/kg/day (M/F)
LOAEL = 3.6/4.7 mg/kg/day (M/F) based on
increased incidences of corneal opacity,
decreased body-weight and body-weight
gains (males only) and histopathological
evaluations in the thyroids, pancreas, and
eyes of both sexes
Neoplastic pathology showed increased
incidences of follicular cell adenomas in
the thyroid glands of both sexes
----------------------------------------------------------------------------------------------------------------
870.4300 Carcinogenicity--mice NOAEL = not established
LOAEL = 19/26 mg/kg/day (M/F) based on
decreased body-weight and body-weight
gains in males
No evidence of carcinogenicity
----------------------------------------------------------------------------------------------------------------
870.5100 Gene mutation No indication of a mutagenic response in
any strain at any level up to cytotoxic
concentrations either with or without S9
activation
----------------------------------------------------------------------------------------------------------------
870.5100 Gene mutation Based on these considerations, it was
concluded that there was confirmed
evidence of a mutagenic response in S.
typhimurium TA98 in the nonactivated
portion of both the plate incorporation
and preincubation assays. The effect was,
however, observed at high concentrations
(>= 3,000 [mu]g/plate-plate incorporation
and >= 2,500 [mu]g/plate-preincubation).
It was further concluded that the
mutagenic effect was likely due to
impurities in the test article because: 1)
The response was seen at high
concentrations including and exceeding the
limit dose, 2) bacterial gene mutation
assays conducted with other lots of the
test material were negative up to the
limit dose (see Master Record
Identification (MRID) Nos. 45902225
through 45902227, and 3) the active
ingredient (a.i.) used in the current
study has the lowest percentage of purity
(95.8% versus 97.7 to 99.3% a.i. for the
other lots)
----------------------------------------------------------------------------------------------------------------
870.5300 In vitro mammalian cell No indication that topramezone induced a
gene mutation mutagenic response, either in the presence
of absence of S9 activation
----------------------------------------------------------------------------------------------------------------
870.5375 In vitro mammalian Topramezone-induced a clastogenic response
chromosome aberration in the presence of S9 activation with
significant effects recorded only at an
insoluble limit concentration
----------------------------------------------------------------------------------------------------------------
870.5395 In vivo mouse bone morrow No evidence that topramezone was
micronucleus clastogenic or aneugenic
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870.5550 Unscheduled DNA synthesis No evidence that topramezone-induced UDS,
(UDS) as determined by radioactive tracer
procedures (nuclear silver grain counts)
at any concentration tested
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[[Page 46414]]
870.6200 Acute neurotoxicity NOAEL= 2,000 mg/kg/day, no neurotoxicity
screening battery (rat) observed
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870.6200 Subchronic neurotoxicity No neurotoxicity observed
(rat) Systemic NOAEL = not established
LOAEL = 4.2/5/0 mg/kg/day (M/F) based on
elevated levels of granular casts and
transitional epithelial cells in the
urinary sediment of the males, increased
incidences of corneal clouding in females,
minimal diffuse degeneration of the
pancreas (both sexes), and slight to
moderate flaky colloid in the thyroid of
the males
----------------------------------------------------------------------------------------------------------------
870.6300 Developmental Maternal NOAEL = not established
neurotoxicity (rat) Maternal LOAEL = 8 mg/kg/day based on
corneal opacities
Offspring NOAEL = not established
Offspring LOAEL = 8 mg/kg/day based on
decreased auditory startle reflex response
----------------------------------------------------------------------------------------------------------------
870.7485 Metabolism and Absorption of [\14\C]-topramezone following
pharmacokinetics a single oral dose was rapid but limited,
with the highest plasma concentrations
observed at 1 hour (first time point
measured). Oral absorption is estimated to
be approximately 20% of the administered
dose. The majority of the dose was
recovered within 48 hours in the feces (73-
91% dose) and urine (8-29% dose)
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870.7600 Dermal penetration The majority of the applied dose for each
group was not absorbed (91.0-98.3% dose),
with the greatest amount of the non-
absorbed material being recovered from the
skin wash (90.8-96.0% dose). Absorbed
radioactivity was low and accounted for
0.16-2.60% of the dose for all groups for
all exposures
----------------------------------------------------------------------------------------------------------------
B. Toxicological Endpoints
For hazards that have a threshold below which there is no
appreciable risk, 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.
Three other types of safety or uncertainty factors may be used:
``Traditional uncertainty factors;'' the ``special FQPA safety
factor;'' and the ``default FQPA safety factor.'' By the term
``traditional uncertainty factor,'' EPA is referring to those
additional uncertainty factors used prior to FQPA passage to account
for database deficiencies. These traditional uncertainty factors have
been incorporated by the FQPA into the additional safety factor for the
protection of infants and children. The term ``special FQPA safety
factor'' refers to those safety factors that are deemed necessary for
the protection of infants and children primarily as a result of the
FQPA. The ``default FQPA safety factor'' is the additional 10X safety
factor that is mandated by the statute unless it is decided that there
are reliable data to choose a different additional factor (potentially
a traditional uncertainty factor or a special FQPA safety factor).
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 an UF of
100 to account for interspecies and intraspecies differences and any
traditional uncertainty factors deemed appropriate (RfD = NOAEL/UF).
Where a special FQPA safety factor or the default FQPA safety factor is
used, 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 safety factor.
For non-dietary 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). An example of how such a probability risk is expressed
would be to describe the risk as one in one hundred thousand (1 X
10-\5\), one in a million (1 X 10-\6\), or one in
ten million (1 X 10-\7\). Under certain specific
circumstances, MOE calculations will be used for the carcinogenic risk
assessment. In this non-linear approach, a ``point of departure'' in
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
(MOEcancer = point of departure/exposures) is calculated.
A summary of the toxicological endpoints for topramezone used for
human risk assessment is shown in Table 2. of this unit:
[[Page 46415]]
Table 2.--Summary of Toxicological Dose and Endpoints for Topramezone for Use in Human Risk Assessment
----------------------------------------------------------------------------------------------------------------
Dose Used in Risk
Assessment, Special FQPA SF and
Exposure Scenario Interspecies and Level of Concern for Study and Toxicological
Intraspecies and any Risk Assessment Effects
Traditional UF
----------------------------------------------------------------------------------------------------------------
Acute Dietary (Females 13-50 years of NOAEL = 0.5 mg/kg/day Special FQPA SF = 1X Developmental Toxicity
age) UF = 100............... aPAD = acute RfD / Study in Rabbits
Acute RfD = 0.005 mg/kg/ Special FQPA SF = LOAEL = 5 mg/kg/day
day. 0.005 mg/kg/day. based on alterations
in skeletal
ossification sites and
increased number of
pairs of ribs
----------------------------------------------------------------------------------------------------------------
Acute Dietary (General population An endpoint of concern for the general population attributable to a
including infants and children) single dose was not identified in the hazard database
----------------------------------------------------------------------------------------------------------------
Chronic Dietary (All populations) NOAEL= 0.4 mg/kg/day Special FQPA SF = 1X Carcinogenicity Study
UF = 100............... cPAD = chronic RfD / in Rats
Chronic RfD = 0.004 mg/ Special FQPA SF = LOAEL = 3.6 mg/kg/day
kg/day. 0.004 mg/kg/day. based on increased
incidences of corneal
opacity, decreased
body-weight and body-
weight gains in males
and histopathological
evaluations in the
thyroid, pancreas, and
eyes of both sexes
----------------------------------------------------------------------------------------------------------------
Cancer (oral, dermal, inhalation) In accordance with the EPA Final Guidelines for Carcinogen Risk
Assessment (March 29, 2005), EPA classified topramezone as ``not likely
to be carcinogenic to humans at doses that do not alter rat thyroid
hormone homeostasis.'' EPA determined that quantification of human
cancer risk is not required since the NOAEL (0.4 mg/kg/day) for non-
cancer risk assessment is not expected to alter thyroid hormone
homeostasis nor result in thyroid tumor formation
----------------------------------------------------------------------------------------------------------------
Topramezone inhibits the 4-hydroxyphenylpyruvate dioxygenase (4-
HPPD) enzyme in the metabolism of tyrosine. Inhibition of this enzyme
results in increased serum tyrosine levels and eventually in adverse
effects in the animal with increased incidences of corneal opacity,
decreased body-weight, and body-weight gains. The petitioner conducted
eight rabbit studies to determine the NOAEL for increased serum
tyrosine levels as well as determine the NOAELs for systemic maternal
and fetal developmental toxicity endpoints that are not based on
tyrosine measurements.
There are well established NOAELs and LOAELs for the standard
endpoints for maternal and developmental toxicity in rabbits.
Currently, it is not known what level of inhibition of the 4-HPPD
enzyme results in an adverse effect. Therefore, the observation of
enzyme inhibition in the absence of systemic toxicity in maternal
animals or soft tissue or skeletal alterations in pups/offspring are
being considered to be a biomarker of exposure, not an adverse effect.
None of the data in the submitted studies permit a determination of the
percentage of increased tyrosine levels that result in detrimental or
adverse effects.
The lowest maternal LOAEL observed in the numerous rabbit
developmental toxicity studies was 0.5 mg/kg/day. It is not clear,
however, that this value is actually a LOAEL because it is based on
increased serum tyrosine levels. In this study it could not be
determined what dose would not induce increased serum tyrosine levels.
In fact, in no study could a ``no effect'' level be determined for
increased serum tyrosine levels in dams. However, a maternal NOAEL of 5
mg/kg/day was observed in another study based on systemic toxicity; in
this study tyrosine measurements were not performed. This study has the
lowest maternal NOAEL for systemic toxicity among the eight rabbit
developmental toxicity studies. Tyrosine levels were not measured for
fetuses in any of the rabbit developmental studies. There was a clear
developmental toxicity NOAEL of 0.5 mg/kg/day, based on skeletal
variations observed at 5 mg/kg/day.
The acute RfD for females 13-49 years of age is based on a NOAEL of
0.5 mg/kg/day for alterations in skeletal ossification sites in
rabbits. The chronic RfD is based on the NOAEL of 0.4 mg/kg/day in the
carcinogenicity study in rats. In this study the LOAEL was based on
increased incidence of corneal opacities, decrease in body weight gain,
liver, pancreas, and thyroid effects seen at 3.6 mg/kg/day.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. No tolerances have
been established (40 CFR 180.612) previously for the residues of
topramezone. Risk assessments were conducted by EPA to assess dietary
exposures from topramezone in food as follows:
i. Acute exposure. Quantitative acute dietary exposure and 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 one-day or single exposure.
In conducting the acute dietary risk assessment EPA used the
Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID\TM\), which incorporates food consumption
data as reported by respondents in the United States Department of
Agriculture (USDA) 1994-1996 and 1998 Nationwide Continuing Surveys of
Food Intake by Individuals (CSFII), and accumulated exposure to the
chemical for each commodity. The following assumptions were made for
the acute exposure assessments: For the acute analyses, tolerance-level
residues were assumed for all food commodities with proposed
topramezone tolerances, and it was assumed that all of the crops
included in the analysis were treated. Percent crop treated (PCT) and/
or anticipated residues were not used in the acute risk assessment.
ii. Chronic exposure. In conducting the chronic dietary risk
assessment EPA used the Dietary Exposure Evaluation Model software with
the Food Commodity Intake Database (DEEM-FCID\TM\), which incorporates
food consumption data as reported by respondents in the USDA 1994-1996
and 1998 Nationwide Continuing Surveys of Food Intake by Individuals
(CSFII), and accumulated exposure to the chemical for each commodity.
The following assumptions were made for
[[Page 46416]]
the chronic exposure assessments: For the chronic analyses, tolerance-
level residues were assumed for all food commodities with current or
proposed topramezone tolerances, and it was assumed that all of the
crops included in the analysis were treated. PCT and/or anticipated
residues were not used in the chronic risk assessment.
2. Dietary exposure from drinking water. The Agency lacks
sufficient monitoring exposure data to complete a comprehensive dietary
exposure analysis and risk assessment for topramezone in drinking
water. 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 topramezone.
The Agency uses the Generic Estimated Environmental Concentration
(GENEEC) or the Pesticide Root Zone Model/Exposure Analysis Modeling
System (PRZM/EXAMS) to estimate pesticide concentrations in surface
water and SCI-GROW, which predicts pesticide concentrations in ground
water. In general, EPA will use GENEEC (a tier 1 model) before using
PRZM/EXAMS (a tier 2 model) for a screening-level assessment for
surface water. The GENEEC model is a subset of the PRZM/EXAMS model
that uses a specific high-end runoff scenario for pesticides. GENEEC
incorporates a farm pond scenario, while PRZM/EXAMS incorporate an
index reservoir environment in place of the previous pond scenario. The
PRZM/EXAMS model includes a percent crop area factor as an adjustment
to account for the maximum percent crop coverage within a watershed or
drainage basin.
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
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), which are the model estimates of a
pesticide's concentration in water. EECs derived from these models are
used to quantify drinking water exposure and risk as a %RfD or %PAD.
Based on the PRZM/EXAMS and SCI-GROW models, the EECs of
topramezone for acute exposures are estimated to be 0.77 parts per
billion (ppb) for surface water and 0.0671 ppb for ground water. The
EECs for chronic exposures are estimated to be 0.14 ppb for surface
water and 0.0671 ppb for ground water.
3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets).
Topramezone is not registered for use on any sites that would
result in residential exposure.
4. Cumulative effects from 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.''
Unlike other pesticides for which EPA has followed a cumulative
risk approach based on a common mechanism of toxicity, EPA has not made
a common mechanism of toxicity finding as to topramezone and any other
substances and topramezone does not appear to produce a toxic
metabolite produced by other substances. However, EPA is aware of other
herbicides that inhibit the 4-HPPD enzyme (i.e. mesotrione and
isoxaflutole). Topramezone, isoxaflutole and mesotrione are known to
cause tyrosinemia. To ensure that the potential cumulative effects from
these pesticides are not of concern EPA examined three factors:
The extent to which the uses of these pesticides overlap.
The exposure assumptions used in the risk assessments for
each of the pesticides.
The risk characterization for each pesticide.
As explained Unit III.C.4.i.,ii., and iii., this analysis suggests
both that the individual risk characterizations for each pesticide are
highly overstated and that cumulative exposure to these pesticides,
even if they are later determined to share a common mechanism, is
unlikely to pose a risk of concern.
i. Pesticide uses. Topramezone, mesotrione, and isoxaflutole are
broad-spectrum herbicides used to control grassy and broadleaf weeds in
corn (the mesotrione label does not list grasses on the label). All
three active ingredients are in the phenylpyrazolyl ketone class of
chemicals and share the same mode of herbicidal action. They inhibit
the 4-HPPD enzyme and thereby impair caroteniod biosynthesis in the
chlorophyll synthesis pathway, leading to the breakdown in
chloroplasts. Therefore no more than one of these active ingredients
would be applied to the same field in the same growing season.
Topramezone is used post-emergent, mesotrione is used pre- and post-
emergent, and isoxaflutole is used pre-plant and pre-emergent. The
current PCT information for field corn indicates a 5-10% PCT for
isoxaflutole and 10-15% PCT for mesotrione. Sweet corn PCT is < 2.5 for
both chemicals. Maximum PCT projections for topramezone on field corn
and sweet corn, made by assuming that it will surely not overtake the
current leader(s) among herbicides on those crops (i.e. atrazine), are
68 and 60, respectively.
ii. Exposure assumptions. Highly-conservative assumptions were used
for the aggregate (food + water) risk assessments for each individual
assessment. First, it was assumed that 100% of the corn crop was
treated with all three of the pesticides. Second, each of the exposure
assessments assumed all corn in the diet would have residues present at
the tolerance level. In fact, residue data indicates that very low
levels of residues were detected in the grain for all three pesticides.
iii. Risk characterization. Even with the highly-conservative
assumptions, the individual aggregate risk for each of the active
ingredients is as follows:
The topramezone chronic dietary risk estimates (food +
water) were < 1% of the cPAD for the U.S. population and 1.2% of the
cPAD for the most highly exposed population subgroup (children 3-5
years old).
The mesotrione chronic dietary risk estimates (food +
water) were 15% of the cPAD for the U.S. population and 45% of the cPAD
for the most highly-exposed population subgroup (all infants (< 1 year
old)).
The chronic dietary risk estimates (food + water) for
residues of the 4-HPPD inhibitors (isoxaflutole + RPA 202248) were 18%
of the cPAD for the U.S. population and 40% of the cPAD for the most
highly-exposed population subgroup (children 3-5 years old).
In fact, even if one were to calculate the chronic dietary risk for
all three herbicides by combining the individual exposures and using
the most sensitive endpoint, the risk would not exceed the level of
concern. These pesticides do not share a common acute adverse effect.
[[Page 46417]]
Accordingly, because the use patterns, exposure assumptions, and
risk characterizations for the three pesticides do not suggest that any
potential cumulative effect would be at a level of concern, EPA
concludes it has adequately considered the potential cumulative effects
of topramezone and the pesticides for which it may possibly share a
common mechanism of toxicity.
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 policy statements
released by EPA's Office of Pesticide Programs concerning common
mechanism determinations and procedures for cumulating effects from
substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/
.
D. Safety Factor for Infants and Children
1. In general. Section 408 of 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 based on reliable data 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. In
applying this provision, EPA either retains the default value of 10X
when reliable data do not support the choice of a different factor, or,
if reliable data are available, EPA uses a different additional safety
factor value based on the use of traditional uncertainty factors and/or
special FQPA safety factors, as appropriate.
2. Increased sensitivity of the young. There is a potential of
increased quantitative susceptibility following in utero and/or pre-/
post-natal exposure in the developmental toxicity and developmental
neurotoxicity studies in rats because a NOAEL for parental or offspring
systemic toxicity was not established. However, the current NOAEL of
0.5 mg/kg/day for an acute RfD would provide a 200-fold lower dose
based on the most sensitive endpoint. In a developmental neurotoxicity
(DNT) study in rats, decreased auditory startle reflex was seen at the
LOAEL of 8 mg/kg/day in the presence of maternal toxicity manifested as
corneal opacity. Therefore, the susceptibility in this study could not
be assessed. However, the NOAEL for the chronic RfD is 0.4 mg/kg/day
based on the most critical tyrosine-mediated effects which is 20-fold
lower than the LOAEL for the DNT study. There is no evidence of
increased susceptibility following pre-/post-natal exposure to rats in
the two-generation reproduction study.
3. Conclusion. There is a complete toxicity data base for
topramezone and exposure data are complete or are estimated based on
data that reasonably accounts for potential exposures. Although there
is the potential for increased quantitative sensitivity in the young
from exposure to topramezone, the RfDs selected for evaluating the
safety of exposure provide a wide margin of safety for the effects seen
in the young. Accordingly, the additional 10X factor for the protection
of infants and children is removed.
E. Aggregate Risks and Determination of Safety
1. Acute risk. Using the exposure assumptions discussed in this
unit for acute exposure, the acute dietary exposure from food and
drinking water to topramezone will occupy 1.4 % of the aPAD for females
13 years and older.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to
topramezone from food and drinking water will utilize 0.6 % of the cPAD
for the U.S. population, 0.9 % of the cPAD for all infants (< 1 year
old), and 1.2 % of the cPAD for children 3-5 years old.
Topramezone 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.
3. 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, and to infants and children from aggregate
exposure to topramezone residues.
IV. Other Considerations
A. Analytical Enforcement Methodology
A proposed enforcement methodology (liquid chromatography (LC)/mass
spectrometry (MS)) 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 20755-5350;
telephone number: (410) 305-2905; e-mail address:
residuemethods@epa.gov.
B. International Residue Limits
There are currently no established Codex, Canadian, or Mexican
maximum residue limits (MRLs) for topramezone.
V. Conclusion
Therefore, the tolerance is established for residues of
topramezone, [3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-
(methylsulfonyl)phenyl](5-hydroxy-1-methyl-1H-pyrazol-4-yl)methanone,
in or on cattle, kidney at 0.05 ppm; cattle, liver at 0.15 ppm; corn,
field, forage at 0.05 ppm; corn, field, grain at 0.01 ppm; corn, field,
stover at 0.05 ppm; corn, pop, grain at 0.01 ppm; corn, pop, stover at
0.05 ppm; corn, sweet, forage at 0.05 ppm; corn, sweet, kernal plus cob
with husks removed at 0.01 ppm; corn, sweet, stover at 0.05 ppm; goat,
kidney at 0.05 ppm; goat, liver at 0.15 ppm; horse, kidney at 0.05 ppm;
horse, liver at 0.15 ppm; sheep, kidney at 0.05 ppm; and sheep, liver
at 0.15 ppm, respectively.
VI. Objections and Hearing Requests
Under section 408(g) of FFDCA, as amended by 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 FFDCA by FQPA, EPA
will continue to use those procedures, with appropriate adjustments,
until the necessary modifications can be made. The new section 408(g)
of 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 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 OPP-2005-0156 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 October
11, 2005.
1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the
[[Page 46418]]
grounds for the objections (40 CFR 178.25). If a hearing is requested,
the objections must include a statement of the factual issue(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 (1900L),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001. You may also deliver your request to the
Office of the Hearing Clerk in Suite 350, 1099 14\th\ St., NW.,
Washington, DC 20005. The Office of the Hearing Clerk is open from 8
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Office of the Hearing Clerk is (202) 564-6255.
2. 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 ADDRESSES. Mail your
copies, identified by docket ID number OPP-2005-0156, 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 ADDRESSES. You may also send an electronic copy of
your request via e-mail to: opp-docket@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 issue(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
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 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) (Public Law
104-4). Nor does it require any special considerations under Executive
Order 12898, entitled Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations (59 FR 7629,
February 16, 1994); or OMB review or any Agency action under Executive
Order 13045, entitled Protection of Children from Environmental Health
Risks and Safety Risk (62 FR 19885, April 23, 1997). This action does
not involve any technical standards that would require Agency
consideration of voluntary consensus standards pursuant to section
12(d) of the National Technology Transfer and Advancement Act of 1995
(NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272 note). Since
tolerances and exemptions that are established on the basis of a
petition under section 408(d) of FFDCA, such as the tolerance in this
final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply. In addition, the Agency has determined that this
action will not have a substantial direct effect on States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government, as specified in Executive Order 13132, entitled Federalism
(64 FR 43255, August 10, 1999). Executive Order 13132 requires EPA to
develop an accountable process to ensure ``meaningful and timely input
by State and local officials in the development of regulatory policies
that have federalism implications.'' ``Policies that have federalism
implications'' is defined in the Executive order to include regulations
that have ``substantial direct effects on the States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government.'' This final rule directly regulates growers, food
processors, food handlers and food retailers, not States. This action
does not alter the relationships or distribution of power and
responsibilities established by Congress in the preemption provisions
of section 408(n)(4) of FFDCA. For these same reasons, the Agency has
determined that this rule does not have any ``tribal implications'' as
described in Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 6,
2000). Executive Order 13175, requires EPA to develop an accountable
process to ensure ``meaningful and timely input by tribal officials in
the development of regulatory policies that have tribal implications.''
``Policies that have tribal implications'' is defined in the Executive
order to include regulations that have ``substantial direct effects on
one or more Indian tribes, on the relationship between the Federal
Government and the Indian tribes, or on the distribution of power and
responsibilities between the Federal Government and Indian tribes.''
This rule will not have substantial direct effects on tribal
governments, on the relationship between the Federal Government and
Indian tribes, or on the distribution of power and responsibilities
between the Federal Government and Indian tribes, as specified in
Executive Order 13175. Thus, Executive Order 13175 does not apply to
this rule.
VIII. Congressional Review Act
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
[[Page 46419]]
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 this final rule in the Federal Register. This
final rule is not a ``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: July 26, 2005.
James Jones,
Director, Office of Pesticide Programs.
0
Therefore, 40 CFR part 180 is amended as follows:
PART 180--[AMENDED]
0
1. The authority citation for part 180 continues to read as follows:
Authority: 21 U.S.C. 321(q), 346a and 371.
0
2. Section 180.612 is added to read as follows:
Sec. 180.612 Topramezone; tolerances for residues.
(a) General. (1) Tolerances are established for residues of the
herbicide topramezone, [3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-
(methylsulfonyl)phenyl](5-hydroxy-1-methyl-1H-pyrazol-4-yl)methanone,
in or on the following raw agricultural commodities:
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Cattle, kidney............................................. 0.05
Cattle, liver.............................................. 0.15
Corn, field, forage........................................ 0.05
Corn, field, grain......................................... 0.01
Corn, field, stover........................................ 0.05
Corn, pop, grain........................................... 0.01
Corn, pop, stover.......................................... 0.05
Corn, sweet, forage........................................ 0.05
Corn, sweet, kernel plus cob with husks removed............ 0.01
Corn, sweet, stover........................................ 0.05
Goat, kidney............................................... 0.05
Goat, liver................................................ 0.15
Horse, kidney.............................................. 0.05
Horse, liver............................................... 0.15
Sheep, kidney.............................................. 0.05
Sheep, liver............................................... 0.15
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 05-15604 Filed 8-9-05; 8:45 am]
BILLING CODE 6560-50-S