[Federal Register Volume 62, Number 38 (Wednesday, February 26, 1997)]
[Notices]
[Pages 8737-8740]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-4628]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-701; FRL-5585-2]
Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition
proposing the establishment of a tolerance for residues of isoxaflutole
in or on field corn. This notice contains a summary of the petition
prepared by the petitioner, Rhone-Poulenc Ag Company.
DATES: Comments, identified by the docket control number [PF-701], must
be received on or before, March 28, 1997.
ADDRESSES: By mail, submit written comments to Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St. SW.,
Washington, DC 20460. In person, bring comments to Rm. 1132, CM#2, 1921
Jefferson Davis Highway, Arlington, VA 22202.
Comments and data may also be submitted electronically by sending
electronic mail (e-mail) to: opp-docket@epamail.epa.gov. Electronic
comments must be submitted as an ASCII file avoiding the use of special
characters and any form of encryption. Comments and data will also be
accepted on disks in WordPerfect in 5.1 file format or ASCII file
format. All comments and data in electronic form must be identified by
the docket number [PF-701]. Electronic comments on this notice may be
filed online at many Federal Depository Libraries. Additional
information on electronic submissions can be found in Unit II of this
document.
Information submitted as a comments concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Joanne Miller, Product Manager (PM)
23, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC. Office
location, telephone number and e-mail address: Rm. 237, Crystal Mall
#2, 1921 Jefferson Davis Highway, Arlington, VA, 703-305-6224, e-mail:
miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP
6F4664) from Rhone-Poulenc Ag Company, P.O. Box 12014, 2 T.W. Alexander
Drive, Research Triangle Park, NC 27709, proposing pursuant to section
408(d) of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C.
346a(d), to amend 40 CFR part 180 by establishing a tolerance for the
combined residues of the herbicide isoxaflutole [5-cyclopropyl-4-(2-
methylsulfonyl-4-trifluoromethyl benzoyl) isoxazole] and its
metabolites 1-(2-methylsulfonyl-4-trifluoromethylphenyl)-2-cyano-3-
cyclopropylpropan-1,3-dione and 2-methylsulphonyl-4-trifluoromethyl
benzoic acid, calculated as the parent compound, in or on the raw
agricultural commodity field corn at 0.20 parts per million (ppm),
field corn, fodder, at 0.50 ppm, field corn, forage at 1.0 ppm; and
[[Page 8738]]
establishing a tolerance for combined residues of the herbicide
isoxaflutole [5-cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethyl
benzoyl)isoxazole] and its metabolite 1-(2-methylsulfonyl-4-
trifluoromethylphenyl)-2-cyano-3-cyclopropylpropan-1,3-dione,
calculated as the parent compound, in or on the liver of cattle, goat,
hogs, horses, poultry and sheep at 0.40 ppm, meat byproducts (except
liver) of cattle, goat, hogs, horses, and sheep at 0.2 ppm and milk at
0.02 ppm. The proposed analytical method is gas chromatography. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2); however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petitions. Additional data may be
needed before EPA rules on the petitions.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act (FQPA) Rhone-Poulenc included in the
petition a summary of the petition and authorization for the summary to
be published in the Federal Register in a notice of receipt of the
petition. The summary represents the views of Rhone-Poulenc; EPA is in
the process of evaluating the petition. As required by section
408(d)(3) EPA is including the summary as a part of this notice of
filing. EPA may have made minor edits to the summary for the purpose of
clarity.
I. Petition Summary
A. Isoxaflutole Uses
Isoxaflutole is the first compound in a new class of isoxazole
herbicides. Weeds found resistant to other herbicides are not cross
resistant to isoxaflutole. The unique mode of action, which disrupts
pigment biosynthesis in susceptible plants, of isoxaflutole provides
excellent selective control for a wide spectrum of grass and broadleaf
weeds at low use rates.
Isoxaflutole will be used on field corn to control broadleafs
(including Kochia, lambsquarters, mallow, mustard, nightshade, pigweed,
ragweed, smartweed, velvetleaf, and waterhemp); grasses (including
barnyardgrass, cupgrass, foxtails, Panicum and wild proso millet).
Isoxaflutole will be applied in either conventional, conservation
tillage, or no-till crop management systems and may be applied either
pre-plant, pre-plant incorporated or preemergence for use in field corn
production. The product controls emerging weeds and also has
postemergent burn-down activity to small exposed weeds. Application
rates for isoxaflutole alone range from 0.035 to 0.14 pounds active
ingredient per acre dependent on soil texture. Combinations of
isoxaflutole with up to one-half rates of other herbicides improves
control of several annual grasses and dramatically reduces total
herbicide volume usage in comparison with current agronomic practices.
Applications can be made up to 14 days before planting field corn in
either conventional or no-till situations. Isoxaflutole is formulated
as a 75 percent water dispersible granule and will be marketed under
the trade name of ``BALANCE''.
B. Isoxaflutole Safety
Rhone-Poulenc Ag Company has submitted 41 separate toxicology
studies in support of tolerances for isoxaflutole. According to Rhone-
Poulenc, isoxaflutole is not acutely toxic and produces minimal skin
and eye irritation. Further, isoxaflutole is not genotoxic, teratogenic
nor a reproductive toxin.
The following mammalian toxicity studies have been conducted to
support the tolerance of isoxaflutole:
A rat acute oral study with an LD50 of greater than 5,000
milligrams/kilogram (mg/kg).
A rabbit acute dermal LD50 of greater than 2,000 mg/kg.
A rat acute inhalation of LC50 of greater than 5.23 milligram/
litre (mg/L).
A primary eye irritation study in the rabbit which showed minimal
irritation.
A primary dermal irritation study in the rabbit which showed
minimal irritation.
A primary dermal sensitization study in the guinea pig which showed
no sensitization.
An acute neurotoxicity study conducted in rats administered a
single dose at 0, 125, 500 or 2,000 mg/kg with a no observed effect
level (NOEL) of 2,000 mg/kg (limit dose) and no treatment-related
effects at any dose.
A 90-day subchronic neurotoxicity study in rats administered at
dose levels of 0, 25, 250 or 750 milligrams/kilogram of body weight per
day (mg/kg bwt/day) with NOEL of 750 mg/kg/day. This dose is also the
Lowest Effect Level (LEL) for non-neurotoxic effects based on a
significant decrease in mean body weight gain.
A 12-month feeding study in dogs administered at levels of 0, 240,
1,200, 12,000 or 30,000 ppm with NOEL of 1,200 ppm based on slight
changes in liver and kidney weights in the absence of any associated
histopathological changes.
A 24-month chronic feeding/oncogenicity study in rats administered
at levels of 0.5, 2, 20 or 500 mg/kg bwt/day) with an overall NOEL of
2.0 mg/kg/day based on non-neoplastic changes in the cornea, sciatic
nerve, thigh muscle, thyroid and liver observed at 20 mg/kg/day. An
increased incidence of hepatocellular adenomas and carcinomas was
observed at 500 mg/kg bwt/day for males and females. In addition, most
of the 500 mg/kg/day males with liver tumors also had follicular cell
adenomas in the thyroid.
An oncogenicity study in mice administered 0, 25, 500 and 7,000 ppm
with a NOEL of 25 ppm based on a slight effect on liver weight and body
weight gain at the LEL of 500 ppm. An increased incidence of
hepatocellular adenomas and carcinomas was observed at 7,000 ppm in
both sexes. Increased liver weight, non-neoplastic cellular changes in
the liver, and amyloidosis in the duodenum, ileum, jejunum, kidneys,
heart ventricle, mesenteric lymph node, and thyroid were also observed
at 7,000 ppm.
A developmental toxicity study in rats administered at doses of 0,
10, 100 or 500 mg/kg bwt/day on gestation days 6 through 15 with a
maternal NOEL of 100 mg/kg/day based on salivation and lower body
weight, body weight gain and food consumption observed at 500 mg/kg/day
and a fetal NOEL of 10 mg/kg/day based on growth retardation and
increased incidences of vertebral and rib anomalies and subcutaneous
edema observed at 100 mg/kg/day.
A developmental toxicity study in rabbits administered at levels of
0, 5, 20 or 100 mg/kg bwt/day on gestation days 6 through 19 with a
maternal NOEL of 20 mg/kg/day based on no weight gain and decreased
food consumption observed at 100 mg/kg/day and fetal NOEL of 5 mg/kg/
day based on growth retardation and increased incidences of rib and
vertebral anomalies noted at 20 mg/kg/day.
A 2 generation reproduction study in rats fed at dose levels of 0,
0.5, 2, 20 or 500 mg/kg bwt/day with a NOEL for postnatal development
and parental toxicity of 2 mg/kg/day based on increased liver weight
and hepatocellular hypertrophy in F0 and F1 adults and a slightly lower
viability index for F1 pups at 20 mg/kg/day. No adverse effects on
mating or fertility indices and gestation, live birth or weaning
indices were noted in any generation.
Mutagenicity--Ames Assay. Negative with and without metabolic
activation.
Mouse lymphoma. Negative with and without metabolic activation.
[[Page 8739]]
In-vivo Mouse Micronucleus Assay. Negative.
In-vitro Cytogenetics Human Lymphocyte Assay. Negative in the
presence and absence of metabolic activation.
A metabolism study in the rat which demonstrates that the majority
of the total radioactivity (TRR) is excreted within 24 to 48 hours
through the urine and feces. Isoxaflutole is metabolized primarily via
hydrolysis to the 1-(2-methylsulfonyl-4-trifluoromethylphenyl)-2-cyano-
3-cyclopropylpropan-1,3-dione (RPA 202248) followed by either reduction
of the cyanonitrile group to form RPA 205834 or further hydrolysis to
2-methylsulphonyl-4-trifluoromethyl benzoic acid (RPA 203328). The RPA
202248 is the major metabolite excreted while RPA 203328 is the most
polar. Thus, the acute oral toxicity and mutagenic potential of these
two metabolites were assessed.
In the acute oral toxicity studies, RPA 203328 had an oral
LD50 greater than 5,000 mg/kg while RPA 202248 had an oral
LD50 greater than 2,000 mg/kg in fasted rats. At 5,000 mg/kg, RPA
202248 produced 40 percent mortality in both male and female rats. In
Ames assays, both RPA 202248 and RPA 203328 were found to be devoid of
mutagenic activity in the absence and presence of metabolic activation.
In the 28-day rat study, RPA 203328 was administered continuously
in the diet at levels of 0, 150, 500, 5,000, and 15,000 ppm (10 rats/
sex/group). No mortalities or treatment-related clinical signs were
observed during the study. No effects were observed on body weight,
food consumption, hematology, clinical chemistry, urinalysis, or
ophthalmoscopy. Further, no changes in organ weight or histopathology
were noted at any level. The NOEL of 15,000 ppm is equivalent to 1,120
mg/kg/day in males and 1,270 mg/kg/day in females.
C. Chronic Dietary Effects
Based upon all available data, the lowest NOEL of 2.0 mg/kg/day was
observed in the chronic rat study. Using this NOEL and a safety factor
of 100, a theoretical Reference Dose (RfD) of 0.02 mg/kg/day is
obtained. The only pending registration for isoxaflutole is for use in/
on field corn. A chronic dietary risk assessment using the maximum
residue limits proposed in this petition, and a 100 percent crop
treated shows that this use represents 1.8, 4.8, 5.3, and 3.3 percent
of the RfD for the whole U.S. population, for non-nursing infants less
than 1 year old, for children aged 1 to 6 years, and for children aged
7 to 12 years, respectively. Realizing that isoxaflutole is likely to
achieve only a 25 percent market share at maturity, less than 1.5
percent of the RfD is reached for all segments of the population. Thus,
Rhone-Poulenc believes that the anticipated dietary exposure to
isoxaflutole is well below the theoretical RfD of 0.02 mg/kg/day and is
negligible for all segments of the population including infants and
children.
Isoxaflutole presents a minimal acute hazard. The acute oral NOEL
is at least 1,000-fold higher than lowest chronic NOEL of 2 mg/kg/day
indicating that acute exposure is unlikely to constitute any
significant dietary risk. Further, as field corn is generally not
directly consumed, no significant acute dietary exposure is likely to
occur.
D. Aggregate Exposure
The FQPA of 1996 lists three other potential sources of exposure to
the general population that must be addressed. These are pesticides in
drinking water, exposure from non-occupational sources, and the
potential cumulative effect of pesticides with similar toxicological
modes of action. These exposures for isoxaflutole are discussed below.
1. Drinking water. There is no established maximum contaminant
level (MCL) or health advisory level (HAL) for isoxaflutole nor its
primary metabolite, 1-(2-methylsulphonyl-4-trifluoromethylphenyl)-2-
cyano-3-cyclopropane-1,3-dione. In the field dissipation study, the
half-life for isoxaflutole was up to 3.0 days and for 1-(2-
methylsulphonyl-4-trifluoromethylphenyl)-2-cyano-3-cyclopropane-1,3-
dione was 16 days under actual field conditions. Residues were only
found in the uppermost depths (above 12 inches). Based upon the data
generated by this study, isoxaflutole and its primary metabolite have a
low potential for reaching groundwater. Under actual use conditions,
neither compound is expected to be present at toxicologically
significant concentrations in ground water due to the low application
rate (maximum use rate 0.14 lbs. per acre) and the low acute toxicity
of each compound. Therefore, Rhone-Poulenc does not anticipate the
presence of isoxaflutole residues in drinking water.
2. Non-occupational exposure. Isoxaflutole is being proposed for
use on field corn only at this time. Thus, non-occupational exposure to
isoxaflutole via dermal or inhalation routes does not exist and dietary
exposure is the only consideration for risk assessment purposes.
3. Common mechanism of action. No other pesticides have been
identified which inhibit 4-HPPDase. The thyroid and liver tumors
observed with isoxaflutole in the rodent studies are most likely
indirectly related to a significant induction of the hepatic microsomal
enzymes PROD, BROD, and UDPGT. While hepatic microsomal enzyme
induction in rodents is likely to be produced by many other pesticides,
there is no data to indicate that these effects would be cumulative
with any other pesticide. Considering the rapid elimination of
isoxaflutole in the animal metabolism study, the effects associated
with isoxaflutole are unlikely to be cumulative with any other
compound. Further, considering the known sensitivity of the rat to the
development of thyroid lesions in response to an imbalance of thyroid
hormones and rodents to the development of liver tumors in response to
the induction of microsomal enzymes, occurrence of these tumors via
these mechanisms in rodent studies have little if any practical
relevance for human cancer or risk assessment. Epidemiological studies
support the position that neither thyroid tumors observed in rats due
to an imbalance of thyroid hormones or liver tumors observed in rodents
exposed to inducers of microsomal enzyme activity are likely to occur
in humans.
Therefore, only the potential risks associated with exposure to
isoxaflutole are considered for this assessment.
E. Determination of Safety for Infants and Children
Developmental toxicity (delayed ossification and rib and vertebral
anomalies) were observed in the developmental toxicity studies. The
NOELs were 10 mg/kg/day in rats and 5 mg/kg/day in rabbits. In a 2-
generation reproduction study, pups from the high dose group of 500 mg/
kg/day had significantly lower weights and a slightly lower viability
index for both F1 and F2 litters and corneal lesions for F2 litters.
Parental systemic toxicity for this dose group consisted of lower
weight gain and food consumption, corneal lesions, increased liver
weight, and hepatocellular hypertrophy. In addition, a slightly lower
viability index was noted for F1 pups from the 20 mg/kg/day dose group
but not for F2 pups. Parental systemic toxicity at 20 mg/kg/day
included increased liver weight and hepatocellular hypertrophy.
Considering the conservative exposure assumptions in setting the
tolerances and the dietary risk assessment assuming 100 percent crop
treated, less than 5.5 percent of the RfD is utilized for non-nursing
infants,
[[Page 8740]]
children 1 to 6 years old, and children 7 to 12 years old. No non-
occupational sources of exposure exist for isoxaflutole. Therefore,
based upon the completeness and reliability of the toxicity data and
the conservative exposure assessment, Rhone-Poulenc believes that there
is a reasonable certainty that no harm will result to infants and
children from exposure to the residues of isoxaflutole and no
additional uncertainty factor is warranted.
F. Estrogenic Effects
No evidence of estrogenic or androgenic effects were noted in any
study. No adverse effects on mating or fertility indices and gestation,
live birth, or weaning indices were noted in the 2-generation rat
reproduction study. An imbalance of thyroid hormones related to the
induction of UDPGT was noted in rats. However, considering species
differences in the half-life of thyroid hormones in rodent versus
primates (12 to 24 hours in rat compared to 5 to 9 days in humans) and
differences in the responsiveness of thyroid cells to TSH, thyroid
hormone levels in humans are unlikely to be affected by the extremely
low levels of isoxaflutole residues that might be present in food.
Therefore, Rhone-Poulenc believes that isoxaflutole is not likely to
cause any endocrine effects in most species including humans.
G. Chemical Residue
The nature of the residue of isoxaflutole in plants and animals is
considered understood. In plants, the metabolism proceeds through the
hydrolysis of the isoxazole ring to form the primary degradate, 1-(2-
methylsulphonyl-4-trifluoromethylphenyl)-2-cyano-3-cyclopropane-1,3-
dione, and further hydrolysis yields the second metabolite, 2-
methylsulphonyl-4-trifluromethyl benzoic acid. In animals the metabolic
pathway is very similar and the metabolites formed are primarily the 1-
(2-methylsulphonyl-4-trifluoromethylphenyl)-2-cyano-3-cyclopropane-1,3-
dione with two other toxicologically insignificant minor degradates.
An analytical method is available for detecting and measuring
levels of isoxaflutole in field corn with a limit of quantitation of
0.01 ppm. The method involves hydrolysis of isoxaflutole to a methyl
ester for gas chromatography analysis.
A total of 32 field corn trials were conducted in 13 different
states. The maximum residues were 0.88 ppm in forage, 1.1 ppm in
silage, 0.40 ppm in fodder and 0.11 ppm in grain. Based on these data,
the proposed tolerance levels are adequate to cover residues likely to
be present from the proposed use of isoxaflutole. Isoxaflutole residues
do not appear to concentrate in corn processed commodities. Therefore,
no food additive tolerances are being proposed for these processed
commodities.
In animal feeding studies, quantifiable residues in the cow were
observed only in liver (up to 0.8 ppm), kidney (up to 0.2 ppm) and milk
(up to 0.03 ppm) at the 46 ppm (10X) dietary burden level. No residues
were observed in fat or muscle. In poultry, quantifiable residues were
observed only in the liver (up to 0.6 ppm) at the highest dose level of
1.8 ppm (10X dietary burden). No residues of isoxaflutole nor its
primary metabolite, 1-(2-methylsulphonyl-4-trifluoromethylphenyl)-2-
cyano-3-cyclopropane-1,3-dione, were observed in eggs, meat, fat or
muscle. Based on these data and the expected (1X) dietary burden in
animal feed, the proposed tolerance levels are adequate to cover
residues likely to be present in animal tissues resulting from the corn
feed items of the animal's diet.
II. Public Record
EPA invites interested persons to submit comments on this notice of
filing. Comments must bear a notification indicating the docket control
number [PF-701].
A record has been established for this notice under docket control
numbers [PF-701] (including comments and data submitted electronically
as described below). A public version of this record, including
printed, paper versions of electronic comments, which does not include
any information claimed as CBI, is available for inspection from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
public record is located in Rm. 1132 of the Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2,
1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this notice, as well as the public version,
as described above will be kept in paper form. Accordingly, EPA will
transfer all comments received electronically into printed, paper form
as they are received and will place the paper copies in the official
record which will also include all comments submitted directly in
writing. The official record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental Protection, Administrative practice and procedure,
Agricultural commodities, Pesticide and pest, Reporting and
recordkeeping requirements.
Dated: February 11, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-4628 Filed 2-25-97; 8:45 am]
BILLING CODE 6560-50-F
