[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: [email protected]. 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: 
[email protected].

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:
    [email protected]


    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