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Isoxaflutole (Rhone-Poulenc).
September 23, 1998. Pesticide
Tolerance Petition.
Final Rule. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/September/Day-23/p25449.htm
[Federal Register: September 23, 1998 (Volume 63, Number 184)]
[Rules and Regulations]
[Page 50773-50784]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23se98-13]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300713; FRL-6029-3]
RIN 2070-AB78
Isoxaflutole; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes a tolerance for combined residues
of isoxaflutole [5-cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethyl
benzoyl) isoxazole] and its metabolites 1-(2-methylsulfonyl-4-
trifluoromethylphenyl)-2-cyano-3-cyclopropyl propan-1,3-dione and 2-
methylsulphonyl-4-trifluoromethyl benzoic acid, calculated as the
parent compound, in or on field corn, grain; field corn, fodder; field
corn, forage; and establishes 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-cyclopropyl propan-
1,3-dione, calculated as the parent compound, in or on the meat of
cattle, goat, hogs, horses, poultry, and sheep; liver of cattle, goat,
hogs, horses and sheep; meat byproducts (except liver) of cattle, goat,
hogs, horses, and sheep; fat of cattle, goat, hogs, horses, poultry,
and sheep; liver of poultry; eggs; and milk. Rhone-Poulenc Ag Company
requested this tolerance under the Federal Food, Drug and Cosmetic Act
(FFDCA), as amended by the Food Quality Protection Act of 1996 (Pub. L.
104-170).
DATES: This regulation is effective September 23, 1998. Objections and
requests for hearings must be received by EPA on or before November 23,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300713], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300713], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: opp-docket@epamail.epa.gov. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300713]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Joanne I. Miller,
Registration Division [7505C], Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Crystal Mall #2,
1921 Jefferson Davis Hwy., Arlington, VA, 703-305-6224, e-mail:
miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: In the Federal Register of February 26, 1997
(62 FR 8737)(FRL-5585-2), EPA, issued a notice pursuant to section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e)
announcing the filing of a pesticide petition (PP) 6F4664 for tolerance
by Rhone-Poulenc Ag Company, P.O. Box 12014, 2 T.W. Alexander Drive,
Research Triangle Park, NC 27709. This notice included a summary of the
petition prepared by Rhone-Poulenc Ag Company, the registrant. There
were no comments received in response to the notice of filing.
In the Federal Register of July 27, 1998 (63 FR 40119)(FRL-6017-3),
EPA issued a notice pursuant to section 408 of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e) announcing the filing of an
amended pesticide petition for this tolerance petition. The revised
petition requested that 40 CFR part 180 be amended by establishing
tolerances for combined residues of the herbicide isoxaflutole [5-
cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethyl benzoyl) isoxazole]
and
[[Page 50774]]
its metabolites 1-(2-methylsulfonyl-4-trifluoromethylphenyl)-2-cyano-3-
cyclopropyl propan-1,3-dione (RPA 202248) and 2-methylsulphonyl-4-
trifluoromethyl benzoic acid (RPA 203328), calculated as the parent
compound, in or on field corn, grain at 0.20 part per million (ppm);
field corn, fodder, at 0.50 ppm, field corn, forage at 1.0 ppm; and by
establishing a tolerance for combined residues of the herbicide
isoxaflutole [5-cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethyl
benzoyl) isoxazole] and its metabolite RPA 202248, calculated as the
parent compound, in or on the meat of cattle, goat, hogs, horses,
poultry, and sheep at 0.20 ppm, liver of cattle, goat, hogs, horses and
sheep at 0.50 ppm, meat byproducts (except liver) of cattle, goat,
hogs, horses, and sheep at 0.1 ppm, fat of cattle, goat, hogs, horses,
poultry, and sheep at 0.20 ppm, liver of poultry at 0.3 ppm, eggs at
0.01 ppm and milk at 0.02 ppm.
I. Risk Assessment and Statutory Findings
Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure. Section 408(b)(2)(C)
requires EPA to give special consideration to exposure of infants and
children to the pesticide chemical residue in establishing a tolerance
and to ``ensure that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to the pesticide
chemical residue. . . .''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 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).
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of
isoxaflutole and to make a determination on aggregate exposure,
consistent with section 408(b)(2), for the tolerances described above.
EPA's assessment of the dietary exposures and risks associated with
establishing the tolerances follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by isoxaflutole are
discussed below.
1. Several acute toxicology studies places the technical-grade
herbicide in Toxicity Category III.
2. In a 21-day dermal toxicity study in rats, eight CD rats/sex/
group were treated topically with dosages of either 10, 100 or 1,000
milligrams/kilogram/day (mg/kg/day) of isoxaflutole 8 hours per day for
21 days. The test material was applied using 0.5% w/v methylcellulose
in purified water daily at a volume-dosage of 2 ml/kg bodyweight.
Treatment-related marginal increase in relative liver weight was
observed in both sexes of rats at 1,000 mg/kg/day. This finding was
considered as an adaptive response to isoxaflutole treatment. There
were no differences between the control and treated groups in any of
the other parameters measured. The systemic toxicity Lowest Observable
Adverse Effect Level (LOAEL) is greater than 1,000 mg/kg/day for males
and females; the systemic toxicity no observable effect level (NOEL) is
1,000 mg/kg or greater for males and females. The dermal toxicity LOAEL
is greater than 1,000 mg/kg/day for males and females; the dermal
toxicity NOEL is 1,000 mg/kg/day or greater for males and females.
3. In a 28-day oral subchronic toxicity study, RPA 203328 (a
metabolite of isoxaflutole) was administered in the diet to male and
female Charles River France, Sprague-Dawley rats (10/sex/dose) at
dosage levels of 0, 150, 500, 5,000, or 15,000 ppm (0, 11.14, 37.57,
376.96 or 1,117.79 mg/kg/day in males and 12.68, 42.70, 421.53 or
1,268.73 mg/kg/day in females, respectively) for 28 days. Among males,
a slightly lower urinary pH at 15,000 ppm and minimally higher urinary
refractive index at 500 and 15,000 ppm were noted. In the absence of
adverse effects on other parameters, these changes were considered as a
normal physiological response to ingestion of an acidic compound. There
were no compound related adverse effects on survival, clinical signs,
body weight, food consumption, clinical chemistry, hematology, and
gross or microscopic pathology. The LOAEL is greater than 1,117.79 mg/
kg/day in males and 1,268.73 mg/kg/day in females (15,0000 ppm). The
NOEL for both sexes is 1,117.79 mg/kg/day in males and 1,268.73 mg/kg/
day in females (15,000 ppm).
4. In a chronic toxicity study, isoxaflutole was administered to
five beagle dogs/sex/dose in the diet at dose levels of 0, 240, 1,200,
12,000, or 30,000 ppm (0, 8.56, 44.81, and 453 mg/kg/day, respectively,
for males; 0, 8.41, 45.33, 498, or 1,254 mg/kg/day, respectively, for
females) for 52 weeks. The 52-week mean intake value for males in the
30,000 ppm treatment group was not available because all dogs in that
group were sacrificed after 26 weeks due to severe chronic reaction to
the test substance. The LOAEL is 453 mg/kg/day for males; 498 mg/kg/day
for females (12,000 ppm), based on reduced weight gains compared to
controls and intravascular hemolysis with associated clinical chemistry
and histopathological findings. The NOEL is 44.81 mg/kg/day for males;
45.33 mg/kg/day for females (1,200 ppm).
5. In a combined chronic toxicity/carcinogenicity study,
isoxaflutole was continuously administered to 75 Sprague-Dawley rats/
sex/dose at dietary levels of 0, 0.5, 2, 20 or 500 mg/kg/day for 104
weeks. An additional 20 rats/sex/group were treated for 52 weeks, after
which 10 rats/sex/group were sacrificed and the remainder were held for
a maximum of 8 weeks without treatment in order to assess reversibility
of treatment-related changes. Evidence of systemic toxicity observed at
500 mg/kg/day in one or both sexes included: abnormal gait, limited use
of limbs, lower body weight gains and food consumption, decreased food
efficiency during the first 14 weeks of the study, elevated cholesterol
levels throughout the 104-week study, increased absolute and relative
liver weights, and thyroid hyperplasia. Increased incidence of
periacinar hepatocytic hypertrophy, portal tract (senile) bile duct
changes, focal cystic degeneration of the liver was observed in males
at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity,
gross necropsy changes in eyes, corneal lesions, degeneration of
sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day
and higher doses and in females at 500 mg/
[[Page 50775]]
kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid,
ocular, and nervous system toxicity in males and liver toxicity in
females. The chronic NOEL is 2.0 mg/kg/day.
Under the conditions of this study, isoxaflutole induced benign
and malignant tumors of the liver in both sexes at 500 mg/kg/day
hepatocellular adenomas (in 14/75 in males and 29/74 in females vs. 2/
75 and 4/74 in the control group rats) and hepatocellular carcinomas
(17/75 and 24/74 vs. 5/75 and 0/74 in the controls, respectively).
Combined incidences of liver adenoma/carcinoma in males and females
were 31/75 and 46/74, respectively, with animals bearing carcinomas in
the majority. Thyroid follicular adenomas occurred with increased
frequency in 500 mg/kg/day males (15/75 vs 3/74 in controls). The above
tumor incidences exceeded the historical incidence of these tumors for
this strain in this laboratory. The study demonstrated that
isoxaflutole is carcinogenic to rats at a dose of 500 mg/kg/day. The
chemical was administered at a dose sufficient to test its carcinogenic
potential. At 500 mg/kg/day, there were alterations in most of the
parameters measured including clinical signs of toxicity, body weight
gain, food consumption, food conversion efficiency, and clinical as
well as post-mortem pathology. Thyroid stimulating hormone (TSH) was
not measured in this study. However, in a separate special study
investigating the mechanism of action of isoxaflutole on the thyroid,
tested at the same doses as this study, TSH was indirectly measured
since there was a significant reduction in T4 level and thyroid gland
weights were significantly increased. These results were sufficient to
support the hypothesis that isoxaflutole may have induced thyroid
tumors in male rats through a disruption in the thyroid-pituitary
hormonal feedback mechanisms.
6. In a 78-week carcinogenicity study, isoxaflutole was fed in
diet to 64 or 76 mice/sex/dose at dose levels of 0, 25, 500, or 7,000
ppm daily (means of 0, 3.2, 64.4, or 977.3 mg/kg/day, respectively, for
males; and 0, 4.0, 77.9, or 1,161.1 mg/kg/day, respectively, for
females). Interim sacrifices were made at 26 weeks (12 mice/sex at the
0 and 7,000 pm doses) and at 52 weeks (12 mice/sex at all dose levels).
Isoxaflutole had no significant effect on the survival of animals.
Systemic signs of toxicity in the treated groups included: decreased
body weight gain in both sexes at 500 ppm and 7,000 ppm and for females
at 25 ppm group; food consumption was unaffected except food efficiency
was lower for both sexes at 7,000 ppm during the first 14 weeks of the
study; absolute and relative/body liver weights were significantly
increased in both sexes at 7,000 ppm and at 500 ppm relative liver
weight was increased in males at 52 weeks and in females at 78 weeks;
gross necropsy at 78-week sacrifice revealed increased occurrences of
liver masses in both sexes at 7,000 ppm; non-neoplastic lesions of the
liver occurred at 52-week sacrifice in males at 500 ppm and in males
and females at 7,000 ppm. At termination, the 500 ppm group males
exhibited increased incidence of hepatocyte necrosis. At 7,000 ppm,
significant increase in non-neoplastic lesions in both sexes included
periacinar hepatocytic hypertrophy, necrosis, and erythrocyte-
containing hepatocytes. In addition, males at the high dose had
pigment-laden hepatocytes and Kupffer cells, basophilic foci, and
increased ploidy; extramedullary hemopoiesis in the spleen was noted in
both sexes; increase incidences of hepatocellular adenoma and carcinoma
were observed in both sexes at 7,000 ppm in the 52-week and 78-week
studies.
Among scheduled and unscheduled deaths in the 78-week study, there
were significant occurrences of hepatocellular adenomas in 27/52 males
(52%) and 15/52 females (29%), and carcinomas in 17/52 males (33%) and
4/52 females (8%; non-significant). The incidences of these tumors
exceeded the corresponding historical incidence with this species, in
this laboratory. Combined adenoma and carcinoma incidences at 7,000 ppm
were 73% for males and 35% for females. At 500 ppm, the incidences of
17% adenomas and 15% carcinomas in males and 2% adenomas in females
were not statistically significant, but exceeded the means for
historical controls. The 52- and 78-week studies revealed a dose-
related decrease in the first occurrence of carcinomas in males; the
earliest carcinomas were observed at 78, 71, 52, and 47 weeks at the 0
through 7,000 ppm doses. There were no carcinomas in females up to 78
weeks at 0, 25, or 500 ppm, although, the earliest finding at 7,000 ppm
was at 60 weeks.
The LOAEL for this study is 64.4 mg/kg/day for males and 77.9 mg/
kg/day for females (500 ppm), based on decreased body weight gains,
increased liver weights, and increased incidences of histopathological
liver changes. The NOEL is 3.2 mg/kg/day for males and 4.0 mg/kg/day
for females (25 ppm). Although body weight was decreased marginally in
females at 25 ppm, there were no corroborating findings of toxicity at
this dose. Under conditions of this study, isoxaflutole appears to
induce hepatocellular adenomas and carcinomas in male and female CD-1
mice. The chemical was tested at doses sufficient to measure its
carcinogenic potential.
7. In a developmental toxicity study isoxaflutole was administered
to 25 female Sprague-Dawley rats by gavage at dose levels of 0, 10,
100, or 500 mg/kg/day from gestational days 6-15, inclusive. Maternal
toxicity, observed at 500 mg/kg/day, was manifested as an increased
incidence of salivation; decreased body weight, weight gain, and food
consumption during the dosing period. The maternal LOAEL is 500 mg/kg/
day, based on increased incidence of clinical signs and decreased body
weights, body weight gains and food consumption. The maternal NOEL is
100 mg/kg/day.
Developmental toxicity, observed at 100 and 500 mg/kg/day, were
manifested as increased incidences of fetuses/litters with various
anomalies: growth retardations (decreased fetal body weight; increased
incidence of delayed ossification of sternebrae, metacarpals and
metatarsals). In addition, an increased incidence of vertebral and rib
anomalies and high incidence of subcutaneous edema were observed at 500
mg/kg/day. The incidences of these anomalies were higher than the
concurrent control values and in some cases exceeded the range for
historical controls. The LOAEL for developmental toxicity is 100 mg/kg/
day, based on decreased fetal body weights and increased incidences of
skeletal anomalies. The developmental NOEL is 10 mg/kg/day.
8. In a developmental toxicity study, isoxaflutole was administered
to 25 female New Zealand White Rabbits by gavage at dose levels of 0,
5, 20, or 100 mg/kg/day from gestational days 6-19, inclusive. Maternal
toxicity, observed at 100 mg/kg/day, was manifested as increased
incidence of clinical signs (little diet eaten and few feces) and
decreased body weight gain and food consumption during the dosing
period. The maternal LOAEL is 100 mg/kg/day, based on increased
incidence of clinical signs, decreased body weight gains and food
consumption. The maternal NOEL is 20 mg/kg/day.
Developmental toxicity, observed at 5 mg/kg/day consisted of
increased incidence of 27th pre-sacral vertebrae. Additional findings
noted at 20 and 100 mg/kg/day were manifested as increased number of
postimplantation loss and late resorptions, as well as growth
retardations in the form of generalized reduction in skeletal
ossification, and increased incidence of 13 pairs of ribs.
[[Page 50776]]
At 100 mg/kg/day, an increased incidence of fetuses with incisors not
erupted was also observed. Incidences of these anomalies, on a litter
basis, were higher than the concurrent control values and in some cases
exceeded the range for historical controls. The LOAEL for developmental
toxicity is 5 mg/kg/day, based on increased incidence of fetuses with
27th pre-sacral vertebrae. The developmental NOEL was not established.
9. In a 2-generation reproduction study, isoxaflutole was
administered to Charles River Crl:CD BR VAF/Plus rats (30/sex/group) at
nominal dietary levels of 0, 0.5, 2, 20 or 500 mg/kg/day (actual levels
in males: 0, 0.45, 1.76, 17.4 or 414 mg/kg/day; females: 0, 0.46, 1.79,
17.7 or 437 mg/kg/day, respectively). Evidence of toxicity was observed
in the male and female parental rats of both generations: at 20 and 500
mg/kg/day, increased absolute and relative liver weights associated
with liver hypertrophy was observed; at 500 mg/kg/day (HDT), decreased
body weight, body weight gain and food consumption during premating and
gestation, and increased incidence of subacute inflammation of the
cornea of the eye in F<INF>0</INF> adults as well as keratitis in
F<INF>1</INF> adults were reported. There were no other systemic
effects that were attributed to treatment, nor was there any
indication, at any treatment level, of an effect on reproductive
performance of the adults. Treatment-related effects were observed in
F<INF>1</INF> and F<INF>2</INF> offspring: at 20 and 500 mg/kg/day,
reduction in pup survival was noted; at 500 mg/kg/day, decrease in body
weights of F<INF>1</INF> and F<INF>2</INF> pups throughout lactation,
increased incidence of chronic keratitis, low incidence of inflammation
of the iris, as well as retinal and vitreous bleeding in F<INF>2</INF>
pups and weanlings were observed. Necropsy of F<INF>1</INF> and
F<INF>2</INF> pups culled on day 4 revealed an increased number of pups
with no milk in the stomach and underdeveloped renal papillae. The
Systemic LOAEL is 17.4 mg/kg/day for males and females, based upon
increased liver weights and hypertrophy and the Systemic NOEL is 1.76
mg/kg/day for males and females. The Reproductive LOAEL is greater than
437 mg/kg/day, based on lack of reproductive effects and the
Reproductive NOEL is greater than or equal to 437 mg/kg/day.
10. For parent isoxaflutole, in a Salmonella typhimurium reverse
gene mutation assay, independently performed tests were negative in
S.typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 up to
insoluble doses (<gr-thn-eq> 500 <greek-m>g/plate +/- S9) and was non-
cytotoxic. In a mouse lymphoma L5178Y forward gene mutation assay,
independently performed tests were negative up to insoluble
(<gr-thn-eq> 150 <greek-m>g/ml +/-S9) or soluble (<ls-thn-eq> 75
<greek-m>g/ml +/-S9) doses. An in vitro cytogenetic assay in cultured
human lymphocytes tested negative up to insoluble concentrations
(<gr-thn-eq> 300 <greek-m>g/ml -S9; 600 <greek-m>g/ml +S9) and was non-
cytotoxic. A mouse micronucleus assay tested negative in male or female
CD-1 mice up to the highest administered oral gavage dose (5,000 mg/
kg). No evidence of an overt toxic response in the treated animals or a
cytotoxic effect on the target cells was observed.
For the major metabolite RPA 202248, in a Salmonella typhimurium
reverse gene mutation assay, independently performed plate
incorporation or preincubation modification to the standard plate
incorporation tests were negative in S. typhimurium strains TA1535,
TA1537, TA98, TA100 and TA102 up to the highest dose assayed (5,000
<greek-m>g/plate +/- S9).
For the minor metabolite RPA 203328, in a Salmonella typhimurium
reverse gene mutation assay, independently performed plate
incorporation tests were negative in S. typhimurium strains TA1535,
TA1537, TA98, and TA100 up to cytotoxic doses (<gr-thn-eq> 2,500
<greek-m>g/plate +/- S9). In an In vivo mouse micronucleus assay, male
mice were orally dosed with 500, 1,000, or 2,000 mg/kg RPA 203328 (99%)
administered in 0.5% methylcellulose at a constant volume of 10 ml/kg.
There was no indication of a clastogenic and/or aneugenic effect
associated with administration of RPA 203328 under the conditions of
this assay, which included administration of a limit dose (2,000 mg/kg)
with sacrifice times of 24 and 48 hours. In a Chinese hampster ovary/
Hypoxanthine guanine phophoribosyl transferase (CHO/HGPRT) forward
mutation assay with duplicate cultures and a confirmatory assay, two
independently performed CHO cell HGPRT forward gene mutation assays
used duplicate cultures of RPA 203328 that were assayed at
concentrations of 84.5 - 2,700 <greek-m>g/ml -S9 (initial and
confirmatory trials) and 338 - 2,700 <greek-m>g/ml +S9 (initial trial)
and 675 - 2,700 <greek-m>g/ml (confirmatory trial). In the assays,
there was no indication of cytotoxicity <plus-minus>S9 at the highest
dose level of 2,700 <greek-m>g/ml. Although there were a few sporadic
instances of statistically significant elevations in mutation
frequency, these were not dose-related and were generally below the 15
x 10<SUP>-6</SUP> required for a positive response except in one case
(a value of 15.8 x 10<SUP>-6</SUP>). Overall, there was no evidence
of any increase in mutation frequency resulting from exposure to RPA
203328. In an In vitro cytogenetics assay in cultured Chinese hamster
ovary cells (CHO), CHO cells were analyzed from cultures exposed to RPA
203328 (99.0%) at 931, 1,330, 1,900 and 2,710 <greek-m>g/ml
<plus-minus> S9 in an initial trial (3-hr exposure, followed by wash
and 15-hr incubation, then 2-hr exposure to colcemid, followed by
fixation). In the confirmatory trial, cells were exposed to
concentrations of 924, 1,320, 1,890 and 2,700 <greek-m>g/ml
<plus-minus> S9(-S9: 17.8-hr exposure to RPA 203328, followed by 2-hr
exposure to colcemid; +S9, same schedule as in the first trial). No
effect on mitotic indices was observed at the highest dose level +S9 in
either trial. The positive controls induced the expected high yield of
cells with chromosome aberrations. There was, however, no evidence that
RPA 203328 induced a clastogenic response at any dose or harvest time.
11. In a metabolism study, <SUP>14</SUP>C-isoxaflutole was
administered to groups (five/sex/dose) of male and female Sprague-
Dawley (CD) rats by gavage at a single low oral dose (1 mg/kg),
repeated low oral dose (1 mg/kg/day as a final dose in a 15 day repeat
dose series), and a single high dose (100 mg/kg). In addition,
pharmacokinetics in blood was investigated using 2 groups of 10 rats
(five/sex/dose) that received a single oral dose of 1 or 100 mg/kg of
<SUP>14</SUP>C-isoxaflutole. Urine and feces were collected at 24, 48,
96, 120, 144, and 168 hours after dosing, and tissues were collected at
168 hours post-dosing. Metabolite analysis was performed on the urine
and feces of all dose groups, and on the liver samples of the two low
dose group male and female rats.
<SUP>14</SUP>C-isoxaflutole was rapidly and extensively absorbed
and metabolized. RPA 202248, a major metabolite, a diketonitrile
derivative, represented 70% or more of the radioactivity excreted in
the urine and feces from the two low dose groups. The other minor
metabolite, RPA 203328, was more polar. Elimination was rapid and dose-
dependent. The mean total recovery ranged from 98.09% to 99.84% (mean
99.21%). Urinary elimination (males: 61.16% to 66.65%, females: 58.80%
to 67.41%) was predominant in the two low dose groups while the major
portion of radiolabel was excreted via the feces (males: 62.99%,
females: 55.23%) in the high dose group. The higher fecal elimination
possibly resulted from the saturation of absorption resulting in
elimination of unchanged parent compound. The majority of the
radiolabel was eliminated in the first 24 and 48 hours for the low and
the high dose groups, respectively. The extensive systemic clearance of
the radiolabel was
[[Page 50777]]
reflected in the low levels of radioactivity found in tissues at 168
hours post-dosing. For the two low dose groups, liver (0.172 to 0.498
ppm) and kidneys (0.213 to 0.498 ppm) accounted for the major portion
of the administered dose found in tissues. In the high dose group, the
highest level of radioactivity was found in decreasing order in blood,
plasma, liver, and kidney. Sex-related differences were observed in the
excretion and distribution pattern among high dose rats. The
elimination half-lives were similar among single low and high dose
groups, with an estimated mean blood half-life of 60 hours. No sex
differences were observed in the metabolism of <SUP>14</SUP>C-
isoxaflutole.
12. In an acute neurotoxicity study, CD rats (10/sex/group)
received a single oral gavage administration of isoxaflutole in 0.5%
aqueous methylcellulose at doses of 0 (vehicle only), 125, 500 or 2,000
mg/kg body weight. No treatment-related effects were observed on
survival, body weight, body weight gain or food consumption. There were
significant decreases in landing foot splay measurements in males at
2,000 mg/kg during functional observational battery (FOB) tests
indicating impairment of neuromuscular function. At 500 mg/kg, males
exhibited significant decreases in landing foot splay measurements on
day 15. The LOAEL was 500 mg/kg based on significant decreases in
landing foot splay on day 15. The NOEL was 125 mg/kg.
In a subchronic neurotoxicity study, isoxaflutole was administered
to CD rats (10/sex/group) at dietary levels of 0, 25, 250 or 750 mg/kg/
day for 90 days. Treatment-related effects observed in high-dose males
consisted of decreases in body weight and body weight gain. The LOAEL
was established at 25 mg/kg/day based on significant decreases in mean
hind limb grip strength in male rats at 25 mg/kg/day (LDT) during both
trials at week 13 as well as a non significant decrease in mean
forelimb grip strength at week 13.
13. In a dermal absorption study <SUP>14-</SUP>C-
Isoxaflutole(99.7%) as a 1% carboxy methylcellulose aqueous suspension
was administered to male Crl:CDBR rats (4/dose) as a single dermal
application at 0.865, 7.32 or 79 mg/cm<SUP>2</SUP>. Dermal absorption
was measured after 0.5, 1, 2, 4, 10 and 24 hours of exposure. At the
lowest dose, 3.46% was absorbed at 10 hours and 4.42% was absorbed at
24 hours. All other doses showed less than 1% absorbed at 24 hours.
14. EPA determined that plant tolerances should be established in
terms of isoxaflutole and its metabolites RPA 202248 and RPA 203328.
EPA also decided that the residues of concern in drinking water are
isoxaflutole and its metabolites RPA 202248 and RPA 203328. Structural
activity relationship (SAR) and mutagenicity data on RPA 203328 were
submitted and reviewed and EPA concluded that RPA 203328 does not pose
a special toxicological concern as to carcinogenic toxicity. However,
the proposed analytical enforcement method for plants involves
hydrolysis of isoxaflutole to RPA 202248, conversion of RPA 202248 to
RPA 203328, and then derivatization of RPA 203328 to a methyl ester for
gas chromatography (GC) analysis. Therefore, even though there may not
be concerns with RPA 203328 for carcinogenic toxicity, it will be
included in the dietary (food) risk assessment for food commodities.
However, RPA 203328 will not be included in an aggregate cancer risk
assessment.
Because there is increased sensitivity to offspring and RPA 203328
is a rat metabolite the Metabolism Committee concluded that the
registrant should perform a developmental toxicity study in rats using
RPA 203328 to further characterize the toxicity of RPA 203328. Until
review of a developmental study on RPA 203328 the Agency will not
exclude RPA 203328 from risk assessments based on a developmental
endpoint.
B. Toxicological Endpoints
1. Acute toxicity. EPA identified the developmental LOAEL of 5 mg/
kg/day from the developmental toxicity study in rabbits as the acute
dietary endpoint to be used for risk assessments for the subpopulation
females (13+). The LOAEL is based on increased incidence of fetuses
with 27th pre-sacral vertebrae; a NOEL was not established. The fetal
incidence of this anomaly was dose-depended and exceeded the concurrent
as well as the historical control incidences. Also at the next higher
dose (20 mg/kg/day) there was an increased incidence of fetuses with
reduced ossification. It was noted that the developmental anomalies
occurred below the dose that caused maternal toxicity (100 mg/kg/day).
Because of the use of a LOAEL, an uncertainty factor of 3X in addition
to the conventional safety factor of 100X to account for inter- and
intra-species variations was applied for this risk assessment. EPA also
determined that for acute dietary risk assessment for the subpopulation
females (13+), the 10X safety factor for the protection of infants and
children (as required by FQPA) should be retained. Thus, a MOE of 3,000
is required for this subgroup.
EPA also identified the NOEL of 125 mg/kg/day from the acute
neurotoxicity study as the endpoint of concern to be used in acute
dietary risk assessment for the general population including infants
and children. The NOEL is based on significant decreases in landing
foot splay on day 15. EPA determined that for acute dietary risk
assessment for the general population, the 10X safety factor to protect
infants and children (as required by FQPA) should be retained. Thus, a
MOE of 1,000 is required for the general population including infants
and children, and includes the conventional 100X safety factor and 10X
safety factor for FQPA.
The conclusion to retain the 10X FQPA safety factor was based on
the following factors:
There is increased sensitivity of rat and rabbit fetuses as
compared to maternal animals following in utero exposures in prenatal
developmental toxicity studies. In both species, the developmental
effects were seen at doses which were not maternally toxic. (i.e.,
developmental NOELs were less than the maternal NOELs). In rats,
increased sensitivity manifested as growth retardation characterized as
decreased fetal body weight and increased incidence of delayed
ossification of sternebrae, metacarpals and metatarsals. In rabbits,
increased sensitivity was manifested as fetuses with increased pre-
sacral vertebrae at the lowest dose tested as well as fetuses with
increased incidences of skeletal anomalies at the next two higher doses
tested; also a NOEL for developmental toxicity was not established in
this study.
There is also concern for the developmental neurotoxic potential of
isoxaflutole. This is based on the demonstration of neurotoxicy in
functional observational battery (FOB) measurements in the acute and
subchronic neurotoxicity as well as evidence of neuropathology in the
combined chronic toxicity/carcinogenicity studies.
Finally, a developmental neurotoxicity study is required based on
the evidence of neurotoxicity as well as the lack of assessment of
susceptibility of the offspring in functional/neurological development
in the standard developmental/reproduction toxicity studies. An
evaluation of the neurotoxicity studies by EPA identified significant
neurobehavioral findings, supported by neuropathology observed in the
chronic study in rats following long term exposure. With this
information considered in the weight-of-the-evidence evaluation, EPA
determined that a developmental
[[Page 50778]]
neurotoxicity study in rats with isoxaflutole will be required.
2. Short - and intermediate - term toxicity. EPA did not select
doses or endpoints for these risk assessments due to the lack of dermal
or systemic toxicity in the 21-day dermal toxicity study in rats
following repeated dermal applications at doses up to and including
1,000 mg/kg/day (Limit-Dose).
3. Chronic toxicity. EPA has established the RfD for isoxaflutole
at 0.002 mg/kg/day. This RfD is based on a NOEL of 2 mg/kg/day based on
hepato, thyroid, ocular and neurotoxicity in males as well as
hepatotoxicity in females at 20 mg/kg/day (LOAEL) following dietary
administration of Isoxaflutole (99.2%) at 0, 0.5, 2, 20 or 500 mg/kg/
day for 104 weeks to male and female Sprague-Dawley rats. An
uncertainty factor of 1,000 was used to account for the protection of
infants and children (as required by FQPA) including the potential for
increased sensitivity to fetuses following in utero exposure, and
inter- and intra-species variations.
4. Carcinogenicity. In accordance with the EPA proposed Guidelines
for Carcinogenic Risk Assessment (April 23, 1996), isoxaflutole was
characterized as ``likely to be a human carcinogen,'' based on
statistically significant increases in liver tumors in both sexes of
mice and rats, and statistically significant increases in thyroid
tumors in male rats. Also, the liver tumors in male mice had an early
onset.
Administration of isoxaflutole in the diet to CD-1 mice for 78
weeks resulted in statistically significant increases in hepatocellular
adenomas and combined adenoma/carcinoma in both sexes at the highest
dose (7,000 ppm, equivalent to 977.3 mg/kg/day for males; 1,161.1 mg/
kg/day for females). There were also positive significant trends for
hepatocellular adenomas, carcinomas and combined adenoma/carcinoma in
both sexes. In male mice there was also a statistically significant
increase in hepatocellular carcinomas at the highest dose with a
positive significant trend and, at the 53-week sacrifice, there was
evidence of early onset for hepatocellular adenomas. The incidences of
hepatocellular tumors exceeded that for historical controls in both
sexes. The CPRC agreed that the highest dose in this study was adequate
and not excessive.
Administration of isoxaflutole in the diet to Sprague-Dawley rats
for 2 years resulted in statistically significant increases in
hepatocellular adenomas, carcinomas and combined adenoma/carcinoma in
both sexes at the highest dose (500 mg/kg/day). There were also
positive significant trends for hepatocellular carcinomas, adenomas and
combined adenoma/carcinoma in both sexes. The incidences of
hepatocellular adenomas and carcinomas exceeded that for historical
controls in both sexes.
In male rats there was also a statistically significant increase
in thyroid follicular cell adenomas, carcinomas and combined adenoma/
carcinoma at the highest dose, and positive significant trends for
these adenomas and combined adenoma/carcinoma. The incidences of
thyroid adenomas and carcinomas exceeded that of historical controls in
male rats. The CPRC agreed that the highest dose in the rat study was
adequate and not excessive.
There was no evidence of mutagenicity in the studies submitted and
no structurally related analogs could be identified, since isoxaflutole
is a member of a new class of chemicals.
Studies submitted by the registrant to show a mechanistic basis for
the liver tumors were considered to be suggestive, but not convincing.
The mechanistic evidence presented for the thyroid tumors appeared to
be scientifically plausible and consistent with EPA current policy.
EPA decided that for the purpose of risk characterization, a non-
linear MOE approach be applied to the most sensitive precursor lesion
in the male rat thyroid, and that a linear low-dose extrapolation be
applied for the tumors of the rat liver. The NOEL of 2 mg/kg/day in
males from a 104 week combined chronic toxicity/carcinogenicity study
in rats was used for the non-linear MOE cancer risk assessment. The
endpoint of concern and LOAEL was 20 mg/kg/day based on thyroid
hyperplasia. Tumors first appear in this study at the 500 mg/kg/day
dose.
It was later decided that there was no reason not to include the
results from the 78-week feeding/carcinogenicity study in mice when
determining the Q<INF>1</INF>* to be used for risk assessment for the
linear low-dose extrapolation. A Q<INF>1</INF>* was developed for the
female mouse liver, female rat liver, male mouse liver and male rat
liver and the Q<INF>1</INF>* with the highest unit of potency used for
risk assessment.
The four resulting estimates of unit potency were 3.55 x
10<SUP>-3</SUP> for female CD-1 mouse liver, 3.84 x 10<SUP>-3</SUP>
for female rat liver, 1.14 x 10<SUP>-2</SUP> for male CD-1 mouse
liver, and 5.27 x 10<SUP>-3</SUP> for male rat liver. The unit risk,
Q<INF>1</INF>* (mg/kg/day)<SUP>-1</SUP> of isoxaflutole, based upon
male mouse liver (adenomas and or carcinomas) tumors is 1.14 x
10<SUP>-2</SUP> in human equivalents, converted from animals to humans
by use of the 3/4's scaling factor (1994, Tox--Risk, 3.5-K.Crump). The
dose levels used in the 79 week mouse study were 0, 3.2, 64.4 or 977.3
mg/kg/day of isoxaflutole. The corresponding tumor rates for the male
mice were 13/47, 15/50, 14/48 or 38/49.
C. Exposures and Risks
1. From food and feed uses. No previous tolerances have been
established for the combined residues of isoxaflutole and its
metabolites. Risk assessments were conducted by EPA to assessed dietary
exposures from isoxaflutole as follows:
Section 408(b)(2)(E) authorizes EPA to use available data and
information on the anticipated residue levels of pesticide residues in
food and the actual levels of pesticide chemicals that have been
measured in food. If EPA relies on such information, EPA must require
that data be provided 5 years after the tolerance is established,
modified, or left in effect, demonstrating that the levels in food are
not above the levels anticipated. Following the initial data
submission, EPA is authorized to require similar data on a time frame
it deems appropriate. As required by section 408(b)(2)(E), EPA will
issue a data call-in for information relating to anticipated residues
to be submitted no later than 5 years from the date of issuance of this
tolerance.
Section 408(b)(2)(F) states that the Agency may use data on the
actual percent of food treated for assessing chronic dietary risk only
if the Agency can make the following findings: (1) that the data used
are reliable and provide a valid basis to show what percentage of the
food derived from such crop is likely to contain such pesticide
residue; (2) that the exposure estimate does not underestimate exposure
for any significant subpopulation group; and (3) if data are available
on pesticide use and food consumption in a particular area, the
exposure estimate does not understate exposure for the population in
such area. In addition, the Agency must provide for periodic evaluation
of any estimates used. To provide for the periodic evaluation of the
estimate of percent crop treated as required by the section
408(b)(2)(F), EPA may require registrants to submit data on percent
crop treated.
The Agency used percent crop treated (PCT) information as follows:
A routine chronic dietary exposure analysis for field corn was
based on 34% of the crop treated. These estimates were derived from
market projections for the end of a 5-year period after the initial
registration. Although percent of crop is expected to be significantly
less
[[Page 50779]]
in initial years of registration, 34% of the market share is considered
to be the highest percentage attainable after 5 years and is considered
to be conservative. At the end of the 5-year period, EPA will require
that data be provided to demonstrate that the percent of corn treated
is not above the level anticipated (34%).
The Agency believes that the three conditions listed in Unit
II.C.1.(1)-(3) above have been met. With respect to Unit II.C.1.(1),
EPA finds that the percent of crop treated information described above
is conservative and will be reassessed at the end of 5 years after
initial registration. As to Unit II.C.1.(2) and (3), regional
consumption information and consumption information for significant
subpopulations is taken into account through EPA's computer-based model
for evaluating the exposure of significant subpopulations including
several regional groups. Use of this consumption information in EPA's
risk assessment process ensures that EPA's exposure estimate does not
understate exposure for any significant subpopulation group and allows
the Agency to be reasonably certain that no regional population is
exposed to residue levels higher than those estimated by the Agency.
Other than the data available through national food consumption
surveys, EPA does not have available information on the consumption of
food bearing isoxaflutole in a particular area.
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1 day or single exposure. As discussed in the Toxicological
Endpoints section, separate acute dietary endpoints of concern were
identified for use in risk assessment for females 13+ as compared to
the general population including infants and children. The appropriate
MOEs for acute dietary risk assessment are 3,000 for females 13+ and
1,000 for the general population including infants and children.
The Dietary Risk Evaluation System (DRES) detailed acute analysis
estimates the distribution of single-day exposures for the overall U.S.
population and certain subgroups. The analysis evaluates individual
food consumption as reported by respondents in the USDA 1977-78
Nationwide Food Consumption Survey (NFCS) and accumulates exposure to
the chemical for each commodity. Each analysis assumes uniform
distribution of isoxaflutole in the commodity supply.
The MOE is a measure of how close the high end exposure comes to
the NOEL (LOAEL for females 13+) and is calculated as the ratio of the
NOEL to the exposure (NOEL/exposure = MOE). For these acute dietary
risk assessments, use of isoxaflutole on corn, anticipated residues
were used since corn is a blended commodity. The high end MOE for the
subgroup of females, 13+ was 10,000, and is no cause for concern given
the need for a MOE of 3,000. The high end MOEs for the remaining
populations all exceed 125,000, and demonstrate no acute dietary
concern given the need for a MOE of 1,000 for the general population
including infants and children.
ii. Chronic exposure and risk. a. Chronic non-cancer risk. A DRES
chronic exposure analysis was performed using a RfD of 0.002 mg/kg/day,
tolerance level residues and 100 percent crop treated information to
estimate the Theoretical Maximum Residue Contribution, and anticipated
residues to estimate exposure for the general population and 22
subgroups. Using tolerance level residues and assuming 100 percent crop
treated, non-nursing infants (< 1 year old ) is the subgroup that
utilized the greatest percentage of the RfD at 81%. By refining the
chronic dietary risk assessment assuming 34 percent of the corn crop
treated and incorporating anticipated residues for corn, animal RACs
and processed commodities, less than 1 percent of the RfD is utilized
for the general population and 1 percent of the RfD for nursing
infants, the subgroup that accounts for the greatest percentage of the
RfD.
The refined chronic dietary risk assessment is considered a
reasonable estimate of risk since anticipated residues and percent crop
treated estimates were incorporated. Based on the risk estimates
calculated in this analysis, the chronic (non-cancer) dietary risk from
use of isoxaflutole on corn does not exceed EPA's level of concern.
b. Carcinogenic risk. Refined dietary risk assessments for cancer
were conducted using anticipated residues for isoxaflutole in corn and
animal RACs and processed commodities including the metabolites RPA
207048 and RPA 205834, as well as percent crop treated information. The
results of these risk assessments are reported below.
As discussed in the Toxicological Endpoints section above, a non-
linear MOE methodology was applied for the estimation of human cancer
risk. The NOEL of 2 mg/kg/day in males from a 104 week combined chronic
toxicity/carcinogenicity study in rats is the endpoint to be used for
the non-linear MOE cancer risk assessment. Cancer MOEs are estimated by
dividing the carcinogenic NOEL by the chronic exposure. The assessment
was conducted for the total U.S. population only. Using this approach,
the upper bound cancer risk was calculated and resulted with a MOE of
250,000.
A linear low-dose extrapolation (Q<INF>1</INF>*) was also applied
for the tumors of the rat liver. It later was decided that there was no
reason not to include the results from the 78-week feeding/
carcinogenicity study in mice when determining the Q<INF>1</INF>* to be
used for risk assessment. The unit risk, Q<INF>1</INF>* (mg/kg/
day)<SUP>-1</SUP> of isoxaflutole, based upon male mouse liver
(adenomas and or carcinomas) tumors is 1.14 x 10<SUP>-2</SUP> in
human equivalents. Using the linear approach and a Q<INF>1</INF>* of
0.0114 resulted in an upper bound cancer risk of 9.3 x
10<SUP>-8</SUP>. This linear risk estimate, for use of isoxaflutole on
corn, is below EPA's level of concern for life time cancer risk.
2. From drinking water. Parent isoxaflutole is not expected to
persist in surface water or to reach ground water. However, the
metabolites RPA 202248, and RPA 203328 are expected to reach both
ground and surface water, where they are expected to persist and
accumulate.
EPA estimated exposure for isoxaflutole and its metabolites RPA
202248 and RPA 203328 for both surface and ground water based on
available modeling. Since there are no registered uses for isoxaflutole
in the United States, there are no monitoring data to compare against
the modeling. Environmental concentrations for surface water were
estimated using Tier 2 modeling from EPA'a Pesticide Root Zone Model
(PRZM)/EXAMS. The acute and chronic groundwater concentrations were
estimated using the SCI-GROW model. For surface water, the maximum
concentrations were used for acute risk calculations, the annual means
(1-10 years) for chronic risk calculations. For ground water, the SCI-
GROW numbers for each compound were used for acute, chronic, and cancer
risk assessment.
If residues of isoxaflutole reach water resources, they will be
primarily associated with the aqueous phase with minimal adsorption to
sediment because of their low adsorption coefficients. Standard
coagulation-flocculation and sedimentation processes used in water
treatment are not expected to be effective in removing isoxaflutole
residues, based on their adsorption coefficients. The use of GAC
(Granular Activated Carbon) is also not expected to be effective in
removing isoxaflutole
[[Page 50780]]
residues because of low binding affinity to organic carbon.
i. Acute exposure and risk. Drinking water levels of concern
(DWLOC) were calculated for acute exposures to isoxaflutole in surface
and ground water for females 13+, the general population and children
(1-6 years old). Relative to an acute toxicity endpoint, the acute
dietary food exposure (from the DRES analysis) was subtracted from the
ratio of the acute NOEL to the appropriate MOE to obtain the acceptable
acute exposure to isoxaflutole in drinking water. DWLOCs were then
calculated from this acceptable exposure using default body weights (70
kg for general population, 60 kg for females and 10 kg for children)
and drinking water consumption figures (2 liters general population and
females and 1 liter for children). Based on these calculations EPA's
DWLOC for acute dietary risk is 4,200 parts per billion (ppb) for the
general population, 1,200 ppb for children (1-6 years old) and 36 ppb
for females 13+.
For acute dietary risk estimated maximum concentrations of
isoxaflutole and its metabolites RPA 202248 and RPA 203328 were used.
In surface water, isoxaflutole and its metabolites RPA 202248 and RPA
203328 are estimated to be 0.4 ppb, 2.0 ppb, and 10.0 ppb,
respectively. Estimated maximum concentrations of isoxaflutole and its
metabolites RPA 202248 and RPA 203328 in ground water are 0.00025 ppb,
0.23 ppb and 6.1 ppb, respectively. The maximum estimated
concentrations of isoxaflutole and its metabolites RPA 202248 and RPA
203328 in surface and ground water were less than EPA's levels of
concern for acute exposure in drinking water for the general
population, females 13+ and children. Therefore, EPA concludes with
reasonable certainty that residues of isoxaflutole and its metabolites
RPA 202248 and RPA 203328 in drinking water do not contribute
significantly to the aggregate acute human health risk at the present
time.
ii. Chronic exposure and risk-- a. Chronic non-cancer risk. EPA
has calculated DWLOC for chronic (non-cancer) exposures to isoxaflutole
in surface and ground water. To calculate the DWLOC for chronic
exposures relative to a chronic toxicity endpoint, the chronic dietary
food exposure (from DRES) was subtracted from the RfD (0.002 mg/kg/day)
to obtain the acceptable chronic (non-cancer) exposure to isoxaflutole
in drinking water. DWLOCs were then calculated from this acceptable
exposure using default body weights (70 kg for males, 60 kg for females
and 10 kg for children) and drinking water consumption figures (2
liters males and females and 1 liter children). Based on this
calculation EPA's DWLOC for chronic (non-cancer) risk is 70 ppb for
males, 60 ppb for females and 19 ppb for children.
Estimated annual average concentrations of isoxaflutole and its
metabolites RPA 202248 and RPA 203328 in surface water are 0.01 ppb,
1.7 ppb and 9.3 ppb, respectively. Estimated annual average
concentrations of isoxaflutole and its metabolites RPA 202248 and RPA
203328 in ground water are 0.00025 ppb, 0.23 ppb and 6.1 ppb,
respectively. For the purposes of the screening level assessment, the
maximum and average annual concentrations in ground water are not
believed to vary significantly. The estimated annual average
concentrations of isoxaflutole and its metabolites RPA 202248 and RPA
203328 in surface and ground water were less than EPA's levels of
concern for chronic (non-cancer) exposure in drinking water. Therefore,
EPA concludes with reasonable certainty that residues of isoxaflutole
and its metabolites RPA 202248 and RPA 203328 in drinking water do not
contribute significantly to the aggregate chronic (non-cancer) human
health risk at the present time.
b. Carcinogenic risk. A non-linear cancer aggregate risk
assessment has not been conducted since the point of departure for non-
linear cancer risk assessment (2 mg/kg/day) is the same endpoint as the
RfD and the aggregate cancer linear risk assessment using the Q* is
considered more restrictive. Therefore, to calculate the DWLOC for
chronic exposures relative to a carcinogenic toxicity endpoint, the
chronic (cancer) dietary food exposure (from the DRES analysis) was
subtracted from the ratio of the negligible cancer risk (1 x
10<SUP>-6</SUP>) to the recommended linear low-dose extrapolation
(Q<INF>1</INF>*, 1.14 x 10<SUP>-2</SUP> ) to obtain the acceptable
chronic (cancer) exposure to isoxaflutole in drinking water. DWLOCs
were then calculated from this acceptable exposure using default body
weights (70 kg) and drinking water consumption figures (2 liters).
Based on this calculation EPA's DWLOC for carcinogenic risk is 3.1 ppb.
As stated in the Toxicological Profile section, Unit II.A. above,
RPA 203328 does not have to be included in an aggregate cancer risk
assessment. Estimated annual mean concentrations of isoxaflutole and
its metabolite RPA 202248 in surface water are 0.01 ppb and 1.7 ppb,
respectively. Estimated annual average concentrations of isoxaflutole
and its metabolites RPA 202248 in ground water are 0.00025 ppb and 0.23
ppb, respectively. The estimated concentrations of isoxaflutole and its
metabolite RPA 202248 in ground and surface water were less than EPA's
levels of concern. Therefore, EPA concludes with reasonable certainty
that residues of isoxaflutole and its metabolite RPA 202248 in drinking
water do not contribute significantly to the aggregate cancer human
health risk at the present time.
3. From non-dietary exposure. There are no registered or proposed
residential uses for isoxaflutole.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.''
EPA does not have, at this time, available data to determine
whether isoxaflutole has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
isoxaflutole does not appear to produce a toxic metabolite produced by
other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that isoxaflutole has a common mechanism of
toxicity with other substances. For information regarding EPA's efforts
to determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see the Final Rule
for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26,
1997)(FRL-5754-7).
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. Separate acute dietary endpoints of concern were
identified for use in risk assessment for females 13+ as compared to
the general population including infants and children. The appropriate
MOEs for acute dietary risk assessment are 3,000 for females 13+ and
1,000 for the general population including infants and children. For
these acute dietary risk assessments, use of isoxaflutole on corn,
anticipated residues were used since corn is a blended commodity. The
high end MOE for the subgroup of females, 13+ was 10,000, and is no
cause for concern given the need for a MOE of 3,000. The high end MOEs
for the remaining populations all exceed 125,000, and
[[Page 50781]]
demonstrate no acute dietary concern given the need for a MOE of 1,000
for the general population including infants and children.
DWLOC's were calculated for acute exposures to isoxaflutole in
surface and ground water for females 13+, the general population and
children (1-6 years old). Relative to an acute toxicity endpoint, the
acute dietary food exposure (from the DRES analysis) was subtracted
from the ratio of the acute NOEL to the appropriate MOE to obtain the
acceptable acute exposure to isoxaflutole in drinking water. Based on
these calculations EPA's DWLOC for acute dietary risk is 4,200 ppb for
the general population, 1,200 ppb for children (1-6 years old) and 36
ppb for females 13+. For acute dietary risk estimated maximum
concentrations of isoxaflutole and its metabolites RPA 202248 and RPA
203328 were used. In surface water, isoxaflutole and its metabolites
RPA 202248 and RPA 203328 are estimated to be 0.4 ppb, 2.0 ppb, and
10.0 ppb, respectively. Estimated maximum concentrations of
isoxaflutole and its metabolites RPA 202248 and RPA 203328 in ground
water are 0.00025 ppb, 0.23 ppb and 6.1 ppb, respectively. The maximum
estimated concentrations of isoxaflutole and its metabolites RPA 202248
and RPA 203328 in surface and ground water were less than EPA's levels
of concern for acute exposure in drinking water for the general
population, females 13+ and children. Therefore, EPA concludes with
reasonable certainty that residues of isoxaflutole and its metabolites
RPA 202248 and RPA 203328 in drinking water do not contribute
significantly to the aggregate acute human health risk at the present
time.
2. Chronic risk. Using the ARC exposure assumptions described
above, EPA has concluded that aggregate exposure to isoxaflutole from
food will utilize 1% of the RfD for the U.S. population. The major
identifiable subgroup with the highest aggregate exposure is discussed
below. EPA generally has no concern for exposures below 100% of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. Despite the potential for exposure to isoxaflutole in
drinking water and from non-dietary, non-occupational exposure, EPA
does not expect the aggregate exposure to exceed 100% of the RfD. EPA
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to isoxaflutole residues.
3. Short- and intermediate-term risk. Short- and intermediate-term
aggregate exposure takes into account chronic dietary food and water
(considered to be a background exposure level) plus indoor and outdoor
residential exposure. There are no proposed residential uses for
isoxaflutole. Therefore, short and intermediate aggregate risks are
adequately addressed by the chronic aggregate dietary risk assessment.
4. Aggregate cancer risk for U.S. population. Using the linear
approach and a Q<INF>1</INF>* of 0.0114 resulted in an upper bound
cancer risk of 9.3 x 10<SUP>-8</SUP>. This linear risk estimate, for
use of isoxaflutole on corn, is below EPA's level of concern for life
time cancer risk. To calculate the DWLOC for chronic exposures relative
to a carcinogenic toxicity endpoint, the chronic (cancer) dietary food
exposure (from the DRES analysis) was subtracted from the ratio of the
negligible cancer risk (1 x 10<SUP>-6</SUP>) to the recommended
linear low-dose extrapolation (Q<INF>1</INF>*, 1.14 x
10<SUP>-2</SUP>) to obtain the acceptable chronic (cancer) exposure to
isoxaflutole in drinking water. DWLOCs were then calculated from this
acceptable exposure using default body weights (70 kg) and drinking
water consumption figures (2 liters). Based on this calculation EPA's
DWLOC for carcinogenic risk is 3.1 ppb. Estimated annual mean
concentrations of isoxaflutole and its metabolite RPA 202248 in surface
water are 0.01 ppb and 1.7 ppb, respectively. Estimated annual average
concentrations of isoxaflutole and its metabolites RPA 202248 in ground
water are 0.00025 ppb and 0.23 ppb, respectively. The estimated
concentrations of isoxaflutole and its metabolite RPA 202248 in ground
and surface water were less than EPA's levels of concern. Therefore,
EPA concludes with reasonable certainty that no harm will result from
aggregate exposure to residues of isoxaflutole and its metabolites.
5. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to isoxaflutole residues.
E. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children-- i. In general. In
assessing the potential for additional sensitivity of infants and
children to residues of isoxaflutole, EPA considered data from
developmental toxicity studies in the rat and rabbit and a two-
generation reproduction study in the rat. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from maternal pesticide exposure gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre-and post-natal toxicity and the
completeness of the data base unless EPA determines that a different
margin of safety will be safe for infants and children. Margins of
safety are incorporated into EPA risk assessments either directly
through use of a margin of exposure (MOE) analysis or through using
uncertainty (safety) factors in calculating a dose level that poses no
appreciable risk to humans. EPA believes that reliable data support
using the standard uncertainty factor (usually 100 for combined inter-
and intra-species variability)) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor.
ii. Pre- and post-natal sensitivity. As described in the
Toxicological Endpoints section, Unit II.B. above, EPA has determined
that the 10X safety factor to protect infants and children (as required
by FQPA) should be retained based on the increased sensitivity of rat
and rabbit fetuses as compared to maternal animals following in utero
exposures in prenatal developmental toxicity studies, the concern for
the developmental neurotoxic potential of isoxaflutole, and the lack of
assessment of susceptibility of the offspring in functional/
neurological development in the standard developmental/reproduction
toxicity studies. Thus, a safety factor of 1,000 is required for
infants and children, and includes the conventional 100X safety factor
and 10X safety factor for FQPA.
2. Acute risk. The appropriate MOEs for acute dietary risk
assessment is 1,000 for infants and children. For the acute dietary
risk assessment, use of isoxaflutole on corn, anticipated residues were
used since corn is a blended commodity. The high end MOE for infants
and children exceed 125,000, and demonstrate no acute dietary concern
given the need for a MOE of 1,000. DWLOC's were then calculated for
acute exposures to isoxaflutole in surface and ground water. Relative
to an acute toxicity endpoint, the acute
[[Page 50782]]
dietary food exposure (from the DRES analysis) was subtracted from the
ratio of the acute NOEL to the appropriate MOE to obtain the acceptable
acute exposure to isoxaflutole in drinking water. Based on these
calculations, EPA's DWLOC for acute dietary risk is 1200 ppb for
children (1-6 years old). For acute dietary risk, estimated maximum
concentrations of isoxaflutole and its metabolites RPA 202248 and RPA
203328 were used. In surface water, isoxaflutole and its metabolites
RPA 202248 and RPA 203328 are estimated to be 0.4 ppb, 2.0 ppb, and
10.0 ppb, respectively. Estimated maximum concentrations of
isoxaflutole and its metabolites RPA 202248 and RPA 203328 in ground
water are 0.00025 ppb, 0.23 ppb and 6.1 ppb, respectively. The maximum
estimated concentrations of isoxaflutole and its metabolites RPA 202248
and RPA 203328 in surface and ground water were less than EPA's levels
of concern for acute exposure in drinking water for infants and
children. Therefore, EPA concludes with reasonable certainty that
residues of isoxaflutole and its metabolites RPA 202248 and RPA 203328
in drinking water do not contribute significantly to the aggregate
acute risk to infants and children at the present time.
3. Chronic risk. Using the exposure assumptions described above,
EPA has concluded that aggregate exposure to isoxaflutole from food
will utilize 1% of the RfD for infants and children. EPA generally has
no concern for exposures below 100% of the RfD because the RfD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health.
Despite the potential for exposure to isoxaflutole in drinking water,
EPA does not expect the aggregate exposure to exceed 100% of the RfD.
4. Short- or intermediate-term risk. There are no proposed
residential uses for isoxaflutole. Therefore, short and intermediate
aggregate risks are adequately addressed by the chronic aggregate
dietary risk assessment.
5. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to isoxaflutole
residues.
III. Other Considerations
A. Metabolism in Plants and Animals
The nature of the residue in plants is adequately understood. The
major terminal residues of regulatory concern are the parent compound,
isoxaflutole and its metabolites, RPA 202248 and RPA 203328. The nature
of the residue in ruminants is also considered to be understood. The
major terminal residues of regulatory concern are the parent compound,
isoxaflutole and it metabolite, RPA 202248.
B. Analytical Enforcement Methodology
For plants, a modification of the gas chromatography/mass
spectrometry detection (GC/MSD) method is used involving hydrolysis of
residues of isoxaflutole to RPA 202248, conversion of RPA 202248
residues to RPA 203328, and then derivatization of RPA 203328 to a
methyl ester for GC analysis. The limit of quantitation (LOQ) is 0.01
ppm. For animals, isoxaflutole is converted to RPA 202248 by base
hydrolysis. RPA 202248 is with high performance liquid chromatography.
The LOQ is 0.01 ppm for milk and eggs; 0.40 ppm for beef and poultry
liver, 0.20 ppm for beef and poultry muscle and fat; and 0.20 ppm for
beef kidney.
Adequate enforcement methodology is available to enforce the
tolerance expression. The method may be requested from: Calvin Furlow,
PRRIB, IRSD (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Rm 101FF, Crystal Mall #2, 1921
Jefferson Davis Hwy., Arlington, VA 22202, (703-305-5229).
C. Magnitude of Residues
Residues of isoxaflutole and its metabolites are not expected to
exceed the established tolerance levels in the raw agricultural
commodities or on animal commodities as a result of this use.
D. International Residue Limits
There is neither a Codex proposal, nor Canadian or Mexican limits
for residues of isoxaflutole and its metabolites in corn.
E. Rotational Crop Restrictions
An accumulation study on confined rotational crops was submitted.
Isoxaflutole was applied to outdoor plots at a rate of 200 g a.i./
hectare (0.18 lbs. ai/A) using preplant incorporation or preemergence
application to separate plots. Lettuce, sorghum and radishes were
planted 34 days after treatment; mustard, radishes and wheat were
planted 123 days after treatment; and lettuce, sorghum and radishes
were planted 365 days after treatment. All crops were harvested when
mature. Immature samples of wheat and sorghum forage, radish roots and
foliage and mustard or lettuce were also taken. The highest residue
levels were seen in 34 days after treatment sorghum forage (0.13-0.24
ppm).
The petitioner has provided stability data only for the parent and
two metabolites instead of investigating the stability of the
metabolite profile present in the samples at harvest. Further, the data
submitted indicate that isoxaflutole was extensively metabolized to RPA
202248 and RPA 203328 during storage. As RPA 202248 and RPA 203328 were
the only metabolites identified and these metabolites are determined in
the proposed enforcement method, the petitioner will not be required to
repeat the confined rotational crop study. Due to uncertainties in the
composition of the samples at harvest, EPA will base its conclusions
from this study on the total radioactive residue. The results of this
study show that residues are 0.01 ppm or greater in all crops at the
12-month plantback interval. Field accumulation studies in rotational
crops are required to determine the appropriate plantback intervals
and/or the need for rotational crop tolerances. Until limited field
trial data are submitted, reviewed and found acceptable, crop rotation
restrictions are required. The end-use product label should contain a
statement limiting the planting of rotational crops to 6 months after
application.
IV. Conclusion
Therefore, tolerances are established for combined residues of
isoxaflutole [5-cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethyl
benzoyl) isoxazole] and its metabolites RPA 202248 and RPA 203328,
calculated as the parent compound, in field corn, grain at 0.20 ppm;
field corn, fodder, at 0.50 ppm, field corn, forage at 1.0 ppm; and
tolerances are established 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-cyclopropyl propan-1,3-dione,
calculated as the parent compound, in or on the meat of cattle, goat,
hogs, horses, poultry, and sheep at 0.20 ppm, liver of cattle, goat,
hogs, horses and sheep at 0.50 ppm, meat byproducts (except liver) of
cattle, goat, hogs, horses, and sheep at 0.1 ppm, fat of cattle, goat,
hogs, horses, poultry, and sheep at 0.20 ppm, liver of poultry at 0.3
ppm, eggs at 0.01 ppm and milk at 0.02 ppm.
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance
[[Page 50783]]
regulation issued by EPA under new section 408(e) and (l)(6) as was
provided in the old section 408 and in section 409. However, the period
for filing objections is 60 days, rather than 30 days. EPA currently
has procedural regulations which govern the submission of objections
and hearing requests. These regulations will require some modification
to reflect the new law. However, until those modifications can be made,
EPA will continue to use those procedural regulations with appropriate
adjustments to reflect the new law.
Any person may, by November 23, 1998, file written objections to
any aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27). A request for a hearing
will be granted if the Administrator determines that the material
submitted shows the following: There is genuine and substantial issue
of fact; there is a reasonable possibility that available evidence
identified by the requestor would, if established, resolve one or more
of such issues in favor of the requestor, taking into account
uncontested claims or facts to the contrary; and resolution of the
factual issues in the manner sought by the requestor would be adequate
to justify the action requested (40 CFR 178.32). Information submitted
in connection with an objection or hearing request may be claimed
confidential by marking any part or all of that information as
Confidential Business Information (CBI). Information so marked will not
be disclosed except in accordance with procedures set forth in 40 CFR
part 2. A copy of the information that does not contain CBI must be
submitted for inclusion in the public record. Information not marked
confidential may be disclosed publicly by EPA without prior notice.
VI. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number [OPP-300713] (including any comments and data submitted
electronically). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The public
record is located in Room 119 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
Electronic comments may be sent directly to EPA at:
opp-docket@epamail.epa.gov.
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
A. Certain Acts and Executive Orders
This final rule establishes tolerances under FFDCA section 408(d)
in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
B. Executive Order 12875
Under Executive Order 12875, entitled Enhancing Intergovernmental
Partnerships (58 FR 58093, October 28, 1993), EPA may not issue a
regulation that is not required by statute and that creates a mandate
upon a State, local or tribal government, unless the Federal government
provides the funds necessary to pay the direct compliance costs
incurred by those governments. If the mandate is unfunded, EPA must
provide to the Office of Management and Budget (OMB) a description of
the extent of EPA's prior consultation with representatives of affected
State, local and tribal governments, the nature of their concerns,
copies of any written communications from the governments, and a
statement supporting the need to issue the regulation. In addition,
Executive Order 12875 requires EPA to develop an effective process
permitting elected officials and other representatives of State, local
and tribal governments ``to provide meaningful and timely input in the
development of regulatory proposals containing significant unfunded
mandates.''
Today's rule does not create an unfunded federal mandate on State,
local or tribal governments. The rule does not impose any enforceable
duties on these entities. Accordingly, the requirements of section 1(a)
of Executive Order 12875 do not apply to this rule.
C. Executive Order 13084
Under Executive Order 13084, entitled Consultation and Coordination
with Indian Tribal Governments (63 FR 27655, May 19,1998), EPA may not
issue a regulation that is not required by statute, that significantly
or uniquely affects the communities of Indian tribal governments, and
that imposes substantial direct compliance costs on those communities,
unless the Federal government provides the funds necessary to pay the
direct compliance costs incurred by the tribal governments. If the
mandate is unfunded, EPA must provide OMB, in a separately identified
section of the preamble to the rule, a description of the extent of
EPA's prior consultation
[[Page 50784]]
with representatives of affected tribal governments, a summary of the
nature of their concerns, and a statement supporting the need to issue
the regulation. In addition, Executive Order 13084 requires EPA to
develop an effective process permitting elected and other
representatives of Indian tribal governments ``to provide meaningful
and timely input in the development of regulatory policies on matters
that significantly or uniquely affect their communities.''
Today's rule does not significantly or uniquely affect the
communities of Indian tribal governments. This action does not involve
or impose any requirements that affect Indian Tribes. Accordingly, the
requirements of section 3(b) of Executive Order 13084 do not apply to
this rule.
In addition, since tolerances and exemptions that are established
on the basis of a petition under FFDCA section 408(d), such as the
tolerances in this final rule, do not require the issuance of a
proposed rule, the requirements of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions published on May
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This rule is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: September 11, 1998.
Stephen L. Johnson,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. By adding Sec. 180.537 to read as follows:
Sec. 180.537 Isoxaflutole; tolerances for residues.
(a) General. (1) Tolerances are established for 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-cyclopropyl propan-
1,3-dione (RPA 202248) and 2-methylsulphonyl-4-trifluoromethyl benzoic
acid (RPA 203328), calculated as the parent compound, in or on the
following raw agricultural commodities:
------------------------------------------------------------------------
Parts
Commodity per
million
------------------------------------------------------------------------
Field corn, fodder............................................. 0.50
Field corn, forage............................................. 1.0
Field corn, grain.............................................. 0.20
------------------------------------------------------------------------
(2) Tolerances are established 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-cyclopropyl propan-
1,3-dione (RPA 202248), calculated as the parent compound, in or on the
following raw agricultural commodities:
------------------------------------------------------------------------
Parts
Commodity per
million
------------------------------------------------------------------------
Cattle, fat.................................................... 0.20
Cattle, liver.................................................. 0.50
Cattle, meat................................................... 0.20
Cattle, meat byproducts (except liver)......................... 0.10
Eggs........................................................... 0.01
Goat, fat...................................................... 0.20
Goat, liver.................................................... 0.50
Goat, meat..................................................... 0.20
Goat, meat byproducts (except liver)........................... 0.10
Hogs, fat...................................................... 0.20
Hogs, liver.................................................... 0.50
Hogs, meat..................................................... 0.20
Hogs, meat byproducts (except liver)........................... 0.10
Horses, fat.................................................... 0.20
Horses, liver.................................................. 0.50
Horses, meat................................................... 0.20
Horses, meat byproducts (except liver)......................... 0.10
Milk........................................................... 0.02
Poultry, fat................................................... 0.20
Poultry, liver................................................. 0.30
Poultry, meat.................................................. 0.20
Sheep, fat..................................................... 0.20
Sheep, liver................................................... 0.50
Sheep, meat.................................................... 0.20
Sheep, meat byproducts (except liver).......................... 0.10
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 98-25449 Filed 9-22-98; 8:45 am]
BILLING CODE 6560-50-F