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isoxadifen-ethyl (AE F122006) Time-Limited Pesticide Tolerance 6/01


ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-301135; FRL-6786-1]
RIN 2070-AB78


Isoxadifen-ethyl; Time-Limited Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: This regulation establishes time-limited tolerances for
combined residues of the safener isoxadifen-ethyl in or on rice, grain;
rice, straw; rice, hulls; and rice, bran. Aventis CropScience requested
this tolerance under the Federal Food, Drug, and Cosmetic Act (FFDCA),
as amended by the Food Quality Protection Act (FQPA) of 1996. The
tolerance will expire on June 21, 2004.

DATES: This regulation is effective June 21, 2001. Objections and
requests for hearings, identified by docket control number OPP-301135,
must be received by EPA on or before August 20, 2001.

ADDRESSES: Written objections and hearing requests may be submitted by
mail, in person, or by courier. Please follow the detailed instructions
for each method as provided in Unit VI. of the SUPPLEMENTARY
INFORMATION. To ensure proper receipt by EPA, your objections and
hearing requests must identify docket control number OPP-301135 in the
subject line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By mail: Vera Soltero, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (703) 308-9359; and e-mail address:
soltero.vera@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural
producer, food manufacturer, or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:


------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS Codes         Potentially
                                                       Affected Entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

[[Page 33180]]

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

    1. Electronically.You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations,'' ``Regulations and Proposed Rules,'' and then look up the
entry for this document under the ``Federal Register--Environmental
Documents.'' You can also go directly to the Federal Register listings
at http://www.epa.gov/fedrgstr/. To access the OPPTS Harmonized
Guidelines referenced in this document, go directly to the guidelines
at http://www.epa.gov/opptsfrs/home/guidelin.htm. A frequently updated
electronic version of 40 CFR part 180 is available at http://
www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180_00.html, a
beta site currently under development.
    2. In person. The Agency has established an official record for
this action under docket control number OPP-301135. The official record
consists of the documents specifically referenced in this action, and
other information related to this action, including any information
claimed as Confidential Business Information (CBI). This official
record includes the documents that are physically located in the
docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period is available for
inspection in the Public Information and Records Integrity Branch
(PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy.,
Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The PIRIB telephone number is (703) 305-5805.

II. Background and Statutory Findings

    In the Federal Registers of June 9, 1999 (64 FR-30997) (FRL-6082-6)
and June 30, 2000 (65 FR-40632) (FRL-6592-6), EPA issued notices
pursuant to section 408 of the FFDCA, 21 U.S.C. 346a as amended by the
FQPA of 1996 (Public Law 104-170) announcing the filing of a pesticide
petition (PP 9E5060) for tolerance by Aventis CropScience, P.O. Box
12014, 2 T.W. Alexander Dr., Research Triangle Park, NC 27709. These
notices included a summary of the petition prepared by Aventis
CropScience, the petitioner. There were no comments received in
response to these notices of filing.
    The petition requested that 40 CFR 180.570 be amended by
establishing a tolerance for the combined residues of the safener
isoxadifen-ethyl, (ethyl 5,5-diphenyl-2-isoxazoline-3-carboxylate, CAS
No. 163520-33-0) and its metabolites: 4,5-dihydro-5,5-diphenyl-3-
isoxazolecarboxylic acid and -hydroxy--
benezenepropanenitrile, in or on rice, grain; and rice, straw at 0.050
and 0.20 part per million (ppm) respectively. The Agency determined
that the tolerance levels should be raised and that tolerances for two
additional rice commodities are appropriate due to the lack of a rice
processing study. Thus, the tolerance levels for the safener
isoxadifen-ethyl and its metabolites for the following commodities are:
rice, grain; rice, straw; rice, hulls; and rice, bran at 0.10, 0.25,
0.50, and 0.80 ppm respectively. The tolerances will expire on June 21,
2004.
    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).

III. 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 and to
make a determination on aggregate exposure, consistent with section
408(b)(2), for a tolerance for the combined residues of isoxadifen-
ethyl and its metabolites on rice, grain; rice, straw; rice, hulls; and
rice, bran at 0.10, 0.25, 0.50, and 0.80 ppm respectively. EPA's
assessment of exposures and risks associated with establishing the
tolerances follow.

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 on 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 isoxadifen-ethyl
are discussed in the following Table 1 as well as the no observed
adverse effect level (NOAEL) and the lowest observed adverse effect
level (LOAEL) from the toxicity studies reviewed.

            Table 1.--Subchronic, Chronic, and Other Toxicity
------------------------------------------------------------------------
        Guideline No.             Study Type             Results
------------------------------------------------------------------------
870.3100                       90-Day oral       NOAEL = 19.8 miligram/
                                toxicity mouse    killogram/day(mg/kg/
                                                  day) in males, 254 mg/
                                                  kg/day in females
                                                 LOAEL = 191 mg/kg/day
                                                  in males, 573 mg/kg/
                                                  day infemales based on
                                                  pathological changes
                                                  in the liverconsisting
                                                  of hepatocellular
                                                  hypertrophy,
                                                  hepatocellularvacuolat
                                                  ion and fatty deposits
                                                  in liver (males and
                                                  females).
------------------------------------------------------------------------

870.3100                       90-Day oral       NOAEL = 13.8 mg/kg/day
                                toxicity          in males, 333.2mg/kg/
                                rodents- rat      day in females highest
                                                  dose tested (HDT)
                                                 LOAEL = 137.9 mg/kg/day
                                                  in males based on
                                                  decreasedbody weight
                                                  and body weight gain.
------------------------------------------------------------------------
870.3150                       90-Day oral       NOAEL = 1.2 mg/kg/day
                                toxicity in       in males, 6.5mg/kg/day
                                nonrodents-dog    in females.
                                                 LOAEL = 6.1 mg/kg/day
                                                  in males, and 47.5 mg/
                                                  kg/day infemales based
                                                  on slight fat deposits
                                                  in the collecting
                                                  ductsof the kidney and
                                                  aspermia (males) and
                                                  decreased bodyweight
                                                  gain, differences in
                                                  various hematological
                                                  parameters,and
                                                  moderate fat deposits
                                                  in the collecting
                                                  ducts of the kidneys
                                                  (females).
------------------------------------------------------------------------
870.3200                       28-Day dermal     NOAEL= 1,000 mg/kg/day
                                toxicity          LOAEL= not established
------------------------------------------------------------------------
870.3700a                      Prenatal          Maternal NOAEL = 120 mg/
                                developmental     kg/day
                                in rodents-rat   LOAEL = 1,000 mg/kg/day
                                                  based on mortality,and
                                                  reduced body weight,
                                                  body weight gain and
                                                  food consumption.
                                                 Developmental NOAEL =
                                                  15 mg/kg/day
                                                 LOAEL = 120 mg/kg/day
                                                  based on increased
                                                  incidence ofbent
                                                  scapula.
------------------------------------------------------------------------
870.3700b                      Prenatal          Maternal NOAEL = 50 mg/
                                developmental     kg/day
                                in nonrodents-   LOAEL = 500 mg/kg/day
                                rabbit            based on mortality.
                                                 Developmental NOAEL =
                                                  50 mg/kg/day
                                                 LOAEL = 500 mg/kg/day
                                                  based on increased
                                                  litterincidence of
                                                  fused, aplastic,
                                                  dislocated or
                                                  fragmentedcaudal
                                                  vertebrae centers.
------------------------------------------------------------------------
70.3800                        Reproduction and  Parental/Systemic NOAEL
                                fertility         = 12.6 mg/kg/dayin
                                effects- rat      males, 16.7 mg.kg.day
                                                  in females
                                                 LOAEL = 249.8 mg/kg/day
                                                  in males, 346.5 mg/kg/
                                                  day infemales based on
                                                  decreased body weight
                                                  and body weightgain
                                                  and increased kidney
                                                  lesions in males and
                                                  females.
                                                 Reproductive NOAEL 249.8 mg/kg/day
                                                  in males, 346.5mg/kg/
                                                  day in females
                                                 LOAEL = not established
                                                 Offspring NOAEL = 12.6
                                                  mg/kg/day in males,
                                                  16.7mg/kg/day in
                                                  females
                                                 LOAEL = 249.8 mg/kg/day
                                                  in males, 346.5 mg/kg/
                                                  day in females based
                                                  on decreased body
                                                  weight in male pups
                                                  and delayed sexual
                                                  maturation in males
                                                  and females.
------------------------------------------------------------------------
870.4100b                      Chronic toxicity  NOAEL = 3.3 mg/kg/day
                                dogs              in males, 3.6mg/kg/day
                                                  in females
                                                 LOAEL = 24 mg/kg/day
                                                  based on increased
                                                  bloodcreatinine in
                                                  females, decreased
                                                  urinary specific
                                                  graviy inboth sexes,
                                                  increased partial
                                                  thromboplastin time in
                                                  bothsexes, and
                                                  increased incidence
                                                  and severity of
                                                  straighttubule
                                                  vacuolation in the
                                                  kidney of both sexes.
------------------------------------------------------------------------
870.4200                       Carcinogenicity   NOAEL = 84 mg/kg/day in
                                rats              males, 118mg/kg/day in
                                                  females
                                                 LOAEL = 171 mg/kg/day
                                                  in males, 249 mg/kg/
                                                  day infemales based on
                                                  decreases in body
                                                  weight and bodyweight
                                                  gain for both sexes,
                                                  proteinaceous plugs in
                                                  theurinary bladder of
                                                  males and increased
                                                  severity ofprogressive
                                                  nephropathy in
                                                  females.
                                                 No evidence of
                                                  carcinogenicity
------------------------------------------------------------------------
870.4300                       Carcinogenicity   NOAEL = 16.6 mg/kg/day
                                mice              in males, 202.5 mg/kg/
                                                  day in females
                                                 LOAEL = 169.6 mg/kg/day
                                                  in males, 407.3 mg/kg/
                                                  day infemales based on
                                                  significant decreased
                                                  survival in males and
                                                  females.
                                                 No evidence of
                                                  carcinogenicity
------------------------------------------------------------------------
870.5265                       Gene mutation     Non-mutagenic when
                                                  tested yp to
                                                  5,000g/plate,
                                                  in presence and
                                                  absence of activation,
                                                  inS.typhimurium
                                                  strains TA98, TA1000,
                                                  TA1535 and TA1537and
                                                  E.coli strain WP2uvra.
------------------------------------------------------------------------
870.5300                       Cytogenetics      Non-mutagenic at the
                                                  HGPRT locus inChinese
                                                  hamster (CH) lung V79
                                                  cells tested up to
                                                  cytotoxicconcentration
                                                  s or limit of
                                                  solubility, in
                                                  presence andabsence of
                                                  activation.
------------------------------------------------------------------------
870.5375                       Chromosome        Did not induce
                                aberration        structural
                                                  chromosomeaberration
                                                  in CH lung V79 cell
                                                  cultures in theabsence
                                                  of activation, but did
                                                  induce increased
                                                  levels ofnumerical
                                                  aberrations, in
                                                  presence of
                                                  activation.
------------------------------------------------------------------------
870.5395                       Micronucleus      Non-mutagenic in mouse
                                                  bone
                                                  marrowmicronucleus
                                                  assay up to 200 mg/kg.
------------------------------------------------------------------------
870.5550                       Unscheduled DNA   There was no evidence
                                synthesis         that unschedulesDNA
                                                  synthesis, as
                                                  determined by
                                                  radioactive
                                                  tracerprocedures
                                                  (nuclear silver grain
                                                  counts) was induced in
                                                  ratsexposed up to
                                                  2,000 mg/kg (limit
                                                  dose).
------------------------------------------------------------------------
870.7485                       Metabolism and    Absorption was 46% in
                                pharmacokinetic   males and 82%
                                s                 infemales. Urinary
                                                  excretion was the
                                                  primary route
                                                  ofelimination. Fecal
                                                  excretion was greater
                                                  in males thanfemales.
                                                  The free acid and
                                                  hydroxy free acid were
                                                  theprincipal
                                                  components detected in
                                                  excreta.
------------------------------------------------------------------------

B. Toxicological Endpoints

    The dose at which no observed adverse effect level (NOAEL) from the
toxicology study identified as appropriate for use in risk assessment
is used to estimate the toxicological level of concern (LOC). However,
the lowest dose at which adverse effects of concern are identified (the
LOAEL) is sometimes used for risk assessment if no NOAEL was achieved
in the toxicology study selected. An uncertainty factor (UF) is applied
to reflect uncertainties inherent in the extrapolation from laboratory
animal data to humans and in the variations in sensitivity among
members of the human population as well as other unknowns. An UF of 100
is routinely used, 10X to account for interspecies differences and 10X
for intraspecies differences.
    For dietary risk assessment (other than cancer) the Agency uses the
UF to calculate an acute or chronic reference dose (acute RfD or
chronic RfD) where the RfD is equal to the NOAEL divided by the
appropriate UF (RfD = NOAEL/UF). Where an additional safety factor is
retained due to concerns unique to the FQPA, this additional factor is
applied to the RfD by dividing the RfD by such additional factor. The
acute or chronic Population Adjusted Dose (aPAD or cPAD) is a
modification of the RfD to accommodate this type of FQPA Safety Factor.
    For non-dietary risk assessments (other than cancer) the UF is used
to determine the LOC. For example, when 100 is the appropriate UF (10X
to account for interspecies differences and 10X for intraspecies
differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to
exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and
compared to the LOC.

   Table 2.--Summary of Toxicological Dose and Endpoints for isoxadifen-ethyl for Use in Human Risk Assessment
----------------------------------------------------------------------------------------------------------------
                                                                 FQPA SF* and Level of
          Exposure Scenario               Dose Used in Risk Concern for Risk     Study and Toxicological
                                            Assessment, UF Assessment                Effects
----------------------------------------------------------------------------------------------------------------
Acute dietaryfemales 13-50 years of    NOAEL = 15 mg/kg/day     FQPA SF = 3X             Developmental toxicity
 age                                   UF = 100...............  aPAD = acute RfD           rat
                                       Acute RfD = 0.15 mg/kg/   . LOAEL = 120 mg/kg/
                                        day.                    FQPA SF = 0.05 mg/kg/     daybased on increased
                                                                 day. incidence of bent
scapula.
----------------------------------------------------------------------------------------------------------------
Chronic dietaryall populations         NOAEL = 3.3 mg/kg/day    FQPA SF = 1X             Subchronic toxicity
                                       UF = 100...............  cPAD = chronic RfD        (feeding) -
                                       Chronic RfD = 0.033 mg/   . dog;chronic toxicity
                                        kg/day.                 FQPA SF = 0.033 mg/kg/    (feeding) - dog
                                                                 day. LOAEL = 6.1 mg/kg/day
based on fat deposits
incollecting ducts of
nephron (males).
----------------------------------------------------------------------------------------------------------------
Short-termdermal (1 to 7 days)         Oral study NOAEL= 13.8   LOC for MOE = 100        90-Day feeding study -
 (occupational)                         mg/kg/day (occupational)           rat
                                        (dermalabsorption rate LOAEL = 137.9 mg/kg/day
                                        = 14%) based on decreased
bodyweight and body
weight gain after 8
days of exposure
(males).
----------------------------------------------------------------------------------------------------------------
Intermediate-termdermal (1 week to     Oral study NOAEL = 3.3   LOC for MOE = 100        Subchronic toxicity
 several months) occupational)          mg/kg/day (dermal (feeding) - dog (co-
                                        absorption rate = 14%) critical);
chronictoxicity
(feeding) - dog
LOAEL = 6.1 mg/kg/day
based on fat deposits
in collecting ducts of
nephron (males).
----------------------------------------------------------------------------------------------------------------
Short-term inhalation(1 to 7 days)     Oral study               LOC for MOE = 100        90-Day feeding study -
 (occupational)                        NOAEL=13.8 mg/kg/day rat
                                        (inhalation absorption LOAEL = 137.9 mg/kg/
                                        rate = 100%). daybased on decreased
body weight and body
weight gainafter 8
days of exposure
(males).
----------------------------------------------------------------------------------------------------------------
Intermediate-terminhalation (1 week    Oral study NOAEL = 3.3   LOC for MOE = 100        Subchronic toxicity
 to several months) (occupational)      mg/kg/day(inhalation (feeding) - dogco-
                                        absorption rate = critical); chronic
                                        100%) toxicity (feeding) -
dog
LOAEL = 6.1 mg/kg/day
based on fat deposits
incollecting ducts of
nephron (males).
----------------------------------------------------------------------------------------------------------------
Cancer (oral, dermal, inhalation)      Cancer classification    Risk assessment not      No evidence of
                                        (``not likely'') required.                carcinogenicity
----------------------------------------------------------------------------------------------------------------
* The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique
  to the FQPA.

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. There are no permanent
or time-limited tolerances for isoxadifen-ethyl. Tolerances are
unnecessary for ruminant or poultry commodities at this time. Risk
assessments were conducted by EPA to assess dietary exposures from
isoxadifen-ethyl in food as follows:
    i. Acute exposure. 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. The Dietary Exposure Evaluation Model (DEEM)
analysis evaluated in the individual food consumption as reported by
respondents in the USDA 1989-1992 nationwide Continuing Surveys of Food
Intake by Individuals (CSFII) and accumulated exposure to the chemical
for each commodity. The following assumptions were made for the acute
exposure assessments. A copnservative acute analysis was performed
using tolerance level residues, default processing factors, and
assuming 100% of the crops were. No anticipated residues were used. In
addition, to account for the lack of rotational crop data, a value of
0.25 ppm for soybean seed was used inthe DEEM analysis along
with maximum theoretical concentration factors for soybean meal (2.2X),
hulls (11.3X), and oil (12.0X).
    For acute dietary risk, the Agency's level of concern is > 100%
aPAD. The acute dietary exposure estimate for the females 13-50 years
old subgroup, at the 95th percentile of exposure, is 5%
aPAD,which is below the Agency's level of concern.
    ii. Chronic exposure. In conducting this chronic dietary risk
assessment the DEEM analysis evaluated the individual food
consumption as reported by respondents in the USDA 1989-1992 nationwide
CSFII and accumulated exposure to the chemical for each commodity. The
chronic dietary exposure analysis made use of the same assumptions that
went into the acute dietary previously described. For chronic dietary
risk, the Agency's level of concern is >100% cPAD. Dietary exposure
estimates for representative population subgroups are presented below:

 Table 3.--Summary of Results from Chronic DEEM Analysis of Isoxadifen-
                                  ethyl
------------------------------------------------------------------------
                                   Exposure (mg/kg/
            Subgroup                     day)               % cPAD
------------------------------------------------------------------------
U.S. population (total)           0.001297            4
------------------------------------------------------------------------
All infants (< 1-year old)        0.005080            15
------------------------------------------------------------------------
Children 1-6 years old            0.002458            7
------------------------------------------------------------------------
Children 7-12 years old           0.001952            6
------------------------------------------------------------------------
Females 13-50 years old           0.001001            3
------------------------------------------------------------------------
Males 13-19 years old             0.001483            5
------------------------------------------------------------------------
Males 20+ years old               0.001035            3
------------------------------------------------------------------------
Seniors 55+ years old             0.000854            3
------------------------------------------------------------------------

    The results of the chronic analysis indicate that for all
population subgroups the estimated chronic dietary risk associated with
the uses of isoxadifen-ethyl is below the Agency's level of concern.
    iii. Cancer. After consideration of the Agency's ``Proposed
Guidelines for Carcinogen Risk Assessment (April 10, 1996),'' EPA has
classified isoxadifen-ethyl as ``not likely to be a human carcinogen.''
This classification is based on the lack of evidence of carcinogenicity
in mice and rats. Therefore, a cancer risk analysis is not necessary.
    2. Dietary exposure from drinking water. The Agency lacks
sufficient monitoring exposure data to complete a comprehensive dietary
exposure analysis and risk assessment for isoxadifen-ethyl in drinking
water. Because the Agency does not have comprehensive monitoring data,
drinking water concentration estimates are made by reliance on
simulation or modeling taking into account data on the physical
characteristics of isoxadifen-ethyl.
    The Agency uses the Generic Estimated Environmental Concentration
(GENEEC) or the Pesticide Root Zone/Exposure Analysis Modeling System
(PRZM/EXAMS) to estimate pesticide concentrations in surface water and
Screening Concentrations in Ground Water (SCI-GROW), which predicts
pesticide concentrations in ground water. In general, EPA will use
GENEEC (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a
screening-level assessment for surface water. The GENEEC model is a
subset of the PRZM/EXAMS model that uses a specific high-end runoff
scenario for pesticides. GENEEC incorporates a farm pond scenario,
while PRZM/EXAMS incorporate an index reservoir environment in place of
the previous pond scenario. The PRZM/EXAMS model includes a percent
crop (PC) area factor as an adjustment to account for the maximum PC
coverage within a watershed or drainage basin.
    None of these models include consideration of the impact processing
(mixing, dilution, or treatment) of raw water for distribution as
drinking water would likely have on the removal of pesticides from the
source water. The primary use of these models by the Agency at this
stage is to provide a coarse screen for sorting out pesticides for
which it is highly unlikely that drinking water concentrations would
ever exceed human health levels of concern.
    Since the models used are considered to be screening tools in the
risk assessment process, the Agency does not use estimated
environmental concentrations (EECs) from these models to quantify
drinking water exposure and risk as a %RfD or %PAD. Instead drinking
water levels of comparison (DWLOCs) are calculated and used as a point
of comparison against the model estimates of a pesticide's
concentration in water. DWLOCs are theoretical upper limits on a
pesticide's concentration in drinking water in light of total aggregate
exposure to a pesticide in food, and from residential uses. Since
DWLOCs address total aggregate exposure to isoxadifen-ethyl they are
further discussed in the aggregate risk sections below.
    Based on the GENEEC and SCI-GROW models, the estimated
environmental concentrations (EECs) of isoxadifen-ethyl for acute
exposures are estimated to be 80 parts per billion (ppb) for surface
water and 5 ppb for ground water. The EECs for chronic exposures are
estimated to be 40 ppb for surface water and 5 ppb for ground water. It
has been determined that the 56-day GENEEC model estimate would
routinely overestimate drinking water residues by at least a factor of
three. Therefore, the chronic exposure estimate for surface water (40
ppb) was divided by 3 in Table 5 below.
    3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets). There are no
residential uses of isoxadifen-ethyl.
    4. Cumulative exposure to substances with a 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 isoxadifen-ethyl 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,
isoxadifen-ethyl 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 isoxadifen-ethyl has a common
mechanism of toxicity with other substances. For information regarding
EPA's efforts to determine which chemicals have a common mechanism of
toxicity and to evaluate the cumulative effects of such chemicals, see
the final rule for Bifenthrin Pesticide Tolerances (62 FR 62961,
November 26, 1997).

D. Safety Factor for Infants and Children

    1. Safety factor for infants and children--i.  In general. 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 prenatal and postnatal toxicity and the completeness of the
data base on toxicity and exposure unless EPA determines that a
different margin of safety will be safe for infants and children.
Margins of safety are incorporated into EPA risk assessments either
directly through use of a margin of exposure (MOE) analysis or through
using uncertainty (safety) factors in calculating a dose level that
poses no appreciable risk to humans.
    ii. Prenatal and postnatal sensitivity. Based in the available
data, both quantitative and qualitative evidence of increased
susceptibility was observed following in utero isoxadifen-ethyl
exposure to rats. In the prenatal rat developmental toxicity study, the
developmental toxicity NOAEL/LOAEL of 15/120 mg/kg/day occurs below
level of the maternally toxic NOAEL/LOAEL of 120/1,000 mg/kg/day. This
finding established the quantitative susceptibility for isoxadifen-
ethyl. Additionally, the developmental effect observed (increased
incidence of bent scapula) is considered more severe and permanent that
the maternal effects of reduced body weight, body weight gain and food
consumption. The finding established the qualitative susceptibility for
isoxadifen-ethyl. However, there was no evidence of increased
susceptibility in the rabbit prenatal toxicity study or following
prenatal/postnatal exposure in the 2-generation reproduction study.
    iii. Conclusion. EPA determined that the 10X safety factor would be
reduced to 3X because the toxicology data base is complete; a
developmental neurotoxicity study was not required; the dietary (food
and drinking water) exposure assessments will not underestimate the
potential exposures for infants and children; and there are currently
no residential uses.
    The FQPA safety factor for isoxadifen-ethyl is applicable to
females 13-50 population subgroup for acute dietary risk assessment
since there is concern for increased susceptibility of the young, as
demonstrated in the prenatal developmental study in rats.

E. Aggregate Risks and Determination of Safety

    To estimate total aggregate exposure to a pesticide from food,
drinking water, and residential uses, the Agency calculates DWLOCs
which are used as a point of comparison against the model estimates of
a pesticide's concentration in water (EECs). DWLOC values are not
regulatory standards for drinking water. DWLOCs are theoretical upper
limits on a pesticide's concentration in drinking water in light of
total aggregate exposure to a pesticide in food and residential uses.
In calculating a DWLOC, the Agency determines how much of the
acceptable exposure (i.e., the PAD) is available for exposure through
drinking water e.g., allowable chronic water exposure (mg/kg/day) =
cPAD - (average food + residential exposure). This allowable exposure
through drinking water is used to calculate a DWLOC.
    A DWLOC will vary depending on the toxic endpoint, drinking water
consumption, and body weights. Default body weights and consumption
values as used by the USEPA Office of Water are used to calculate
DWLOCs: 2L/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg
(child). Default body weights and drinking water consumption values
vary on an individual basis. This variation will be taken into account
in more refined screening-level and quantitative drinking water
exposure assessments. Different populations will have different DWLOCs.
Generally, a DWLOC is calculated for each type of risk assessment used:
acute, short-term, intermediate-term, chronic, and cancer.
    When EECs for surface water and ground water are less than the
calculatedDWLOCs, EPA concludes with reasonable certainty that
exposures to the pesticide in drinking water (when considered along
with other sources of exposure for which EPA has reliable data) would
not result in unacceptable levels of aggregate human health risk at
this time. Because EPA considers the aggregate risk resulting from
multiple exposure pathways associated with a pesticide's uses, levels
of comparison in drinking water may vary as those uses change. If new
uses are added in the future, EPA will reassess the potential impacts
of residues of the pesticide in drinking water as a part of the
aggregate risk assessment process.
    1. Acute risk. The acute dietary exposure analysis assumed
tolerance level residues and 100% crop treated for all proposed
commodities, in addition to estimating from possible contributions from
soybeans based on the rotational crop use. Using the exposure
assumptions discussed in this unit for acute exposure, the acute
dietary exposure from food to isoxadifen-ethyl will occupy 5% of the
aPAD for females 13 years and older. In addition, there is potential
for acute dietary exposure to isoxadifen-ethyl in drinking water. The
EECs for surface and ground water are less than the DWLOC. Thus, EPA
does not expect the aggregate exposure to exceed 100% of the aPAD, as
shown in Table 4:

                                       Table 4.--Aggregate Risk Assessment for Acute Exposure to isoxadifen-ethyl
--------------------------------------------------------------------------------------------------------------------------------------------------------
Surface Water EEC   Ground Water EEC
                   Population Subgroup                        aPAD (mg/kg)       %aPAD (Food)          (ppb)              (ppb) Acute DWLOC (ppb)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females 13-50years old 0.050                  5                 80                  5 14,000
--------------------------------------------------------------------------------------------------------------------------------------------------------

    2. Chronic risk. The chronic exposure analysis assumed tolerance
level residues and 100% crop treated for all commodities, in addition
to estimating from possible contributions from soybeans based on the
rotational crop use. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to
isoxadifen-ethyl from food will utilize 4% of the cPAD for the U.S.
population, 15% of the cPAD for all infants and 7% of the cPAD for
children 1-6 years old. There are no residential uses for isoxadifen-
ethyl that result in
chronic residential exposure to isoxadifen-ethyl. In addition, there is
potential for chronic dietary exposure to isoxadifen-ethyl in drinking
water. The EECs for surface and ground water are less than the DWLOC.
Thus, EPA does not expect the aggregate exposure to exceed 100% of the
cPAD, as shown in Table 5:

                                Table 5.--Aggregate Risk Assessment for Chronic (Non-Cancer) Exposure to isoxadifen-ethyl
--------------------------------------------------------------------------------------------------------------------------------------------------------
Surface Water EEC   Ground Water EEC    Chronic DWLOC
                   Population Subgroup                       cPAD mg/kg/day      %cPAD (Food)          (ppb)              (ppb) (ppb)
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. population 0.033                  4                 13                  5 1100
--------------------------------------------------------------------------------------------------------------------------------------------------------
All infants (1 year old) 0.033                 15                 13                  5 280
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (1-6 years old) 0.033                  7                 13                  5 310
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (7-12 years old) 0.033                  6                 13                  5 310
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females (13-50 years old) 0.033                  3                 13                  5 960
--------------------------------------------------------------------------------------------------------------------------------------------------------
Males (13-19 years old) 0.033                  5                 13                  5 1100
--------------------------------------------------------------------------------------------------------------------------------------------------------
Males (20+ years old) 0.033                  3                 13                  5 1100
--------------------------------------------------------------------------------------------------------------------------------------------------------
Seniors (55+ years old) 0.033                  3                 13                  5 1100
--------------------------------------------------------------------------------------------------------------------------------------------------------

    3. Short-term risk. Short-term aggregate exposure takes into
account residential exposure plus chronic exposure to food and water
(considered to be a background exposure level). Isoxadifen-ethyl is not
registered for use on any sites that would result in residential
exposure. Therefore, no short-term risk assessment was performed.
    4. Intermediate-term risk. Intermediate-term aggregate exposure
takes into account residential exposure plus chronic exposure to food
and water (considered to be a background exposure level). Isoxadifen-
ethyl is not registered for use on any sites that would result in
residential exposure. Therefore, no intermediate-term risk assessment
was performed.
    5. Aggregate cancer risk for U.S. population. The Agency has
classified isoxadifen-ethyl as ``not likely to be a carcinogen.''
Therefore, an aggregate cancer risk assessment was not performed.
    6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, and to infants and children from aggregate
exposure to combined residues of isoxadifen-ethyl and its metabolites.

IV. Other Considerations

A. Analytical Enforcement Methodology

    The petitioner proposed using a multiresidue method (MRM) for
enforcement of tolerances of isoxadifen-ethyl residues and its
metabolites on rice. Data were submitted pertaining to the behavior of
isoxadifen-ethyl using FDA MRM protocols (PAM Vol 1). Residues of the
parent compound were recovered from rice using Protocol E, Method 303.
There were also quantitative recoveries of 4,5-dihydro-5,5-diphenyl-3-
isoxazolecarboxylic acid (metabolite 1) using protocol B. No results
concerning the behavior of metabolite -hydroxy-
benezenepropanenitrile (metabolite 2) in rice using the multiresidue
protocols were reported.
    The petitioner also submitted an Independent Laboratory Validation
(ILV) for the parent and metabolite 2 in rice grain, using gas
chromatography with a mass-selective detector (GC/MSD). Validation of
this method was successful.
    At this time there is not one analytical method that can detect the
parent and both metabolites in rice. However, if a situation should
arise, then the Agency could perform both the MRM and the GC/MSD
methods which would detect residues of isoxadifen-ethyl and both its
metabolites in rice.
    The Agency is requiring the petitioner to resubmit the analytical
method and an ILV for the parent and both of the metabolites to satisfy
the requirement for an enforcement analytical method. Following
successful Agency validation of the MRM and the enforcement analytical
methods, and review and evaluation of the other required data, the
Agency will consider establishing permanent tolerances.

B. International Residue Limits

    There are no CODEX, Canadian, or Mexican tolerances/MRLs for
isoxadifen-ethyl residues.

C. Conditions

    The following data are required to establish permanent tolerances
for isoxadifen-ethyl: Confined/field accumulation in rotational crops
study; rice processed commodity study; successful method validation of
the analytical enforcement method; and adequate storage stability data.
Additionally, as a condition of registration, rotational crops are
limited to soybeans and there will be a 9-month plantback interval for
isoxadifen-ethyl in rice agricultural commodities.

V. Conclusion

    Therefore, the time-limited tolerances are established for combined
residues of isoxadifen-ethyl, and its metabolites, in or on rice,
grain; rice, straw; rice, hulls; and rice, bran at 0.10, 0.25, 0.50 and
0.80 ppm respectively.

VI. Objections and Hearing Requests

    Under section 408(g) of the FFDCA, as amended by the FQPA, any
person may file an objection to any aspect of this regulation and may
also request a hearing on those objections. The EPA procedural
regulations which govern the submission of objections and requests for
hearings appear in 40 CFR part 178. Although the procedures in those
regulations require some modification to reflect the amendments made to
the FFDCA by the FQPA of 1996, EPA will continue to use those
procedures, with appropriate adjustments, until the necessary
modifications can be made. The new section 408(g) provides essentially
the same process for persons to ``object'' to a regulation for an
exemption from the requirement of a tolerance issued by EPA under new
section 408(d), as was provided in the old FFDCA sections 408 and 409.
However, the period for filing objections is now 60 days, rather than
30 days.

A. What Do I Need to Do to File an Objection or Request a Hearing?

    You must file your objection or request a hearing on this
regulation in accordance with the instructions provided in this unit
and in 40 CFR part 178. To ensure proper receipt by EPA, you must
identify docket control number OPP-301135 in the subject line on the
first page of your submission. All requests must be in writing, and
must be mailed or delivered to the Hearing Clerk on or before August
20, 2001.
    1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the grounds for
the objections (40 CFR 178.25). If a hearing is requested, the
objections must include a statement of the factual issues(s) on which a
hearing is requested, the requestor's contentions on such issues, and a
summary of any evidence relied upon by the objector (40 CFR 178.27).
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
information that does not contain CBI must be submitted for inclusion
in the public record. Information not marked confidential may be
disclosed publicly by EPA without prior notice.
    Mail your written request to: Office of the Hearing Clerk (1900),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460. You may also deliver your request to the Office
of the Hearing Clerk in Rm. C400, Waterside Mall, 401 M St., SW.,
Washington, DC 20460. The Office of the Hearing Clerk is open from 8
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Office of the Hearing Clerk is (202) 260-4865.
    2. Tolerance fee payment. If you file an objection or request a
hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or
request a waiver of that fee pursuant to 40 CFR 180.33(m). You must
mail the fee to: EPA Headquarters Accounting Operations Branch, Office
of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please
identify the fee submission by labeling it ``Tolerance Petition Fees.''
    EPA is authorized to waive any fee requirement ``when in the
judgement of the Administrator such a waiver or refund is equitable and
not contrary to the purpose of this subsection.'' For additional
information regarding the waiver of these fees, you may contact James
Tompkins by phone at (703) 305-5697, by e-mail at tompkins.jim@epa.gov,
or by mailing a request for information to Mr. Tompkins at Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    If you would like to request a waiver of the tolerance objection
fees, you must mail your request for such a waiver to: James Hollins,
Information Resources and Services Division (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460.
    3. Copies for the docket. In addition to filing an objection or
hearing request with the Hearing Clerk as described in Unit VI.A., you
should also send a copy of your request to the PIRIB for its inclusion
in the official record that is described in Unit I.B.2. Mail your
copies, identified by docket control number OPP-301135, to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
In person or by courier, bring a copy to the location of the PIRIB
described in Unit I.B.2. You may also send an electronic copy of your
request via e-mail to: opp-docket@epa.gov. Please use an ASCII file
format and avoid the use of special characters and any form of
encryption. Copies of electronic objections and hearing requests will
also be accepted on disks in WordPerfect 6.1/8.0 or ASCII file format.
Do not include any CBI in your electronic copy. You may also submit an
electronic copy of your request at many Federal Depository Libraries.

B. When Will the Agency Grant a Request for a Hearing?

    A request for a hearing will be granted if the Administrator
determines that the material submitted shows the following: There is a
genuine and substantial issue of fact; there is a reasonable
possibility that available evidence identified by the requestor would,
if established resolve one or more of such issues in favor of the
requestor, taking into account uncontested claims or facts to the
contrary; and resolution of the factual issues(s) in the manner sought
by the requestor would be adequate to justify the action requested (40
CFR 178.32).

VII. Regulatory Assessment Requirements

    This final rule establishes a tolerance 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) (Public Law 104--4). Nor
does it require any 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 OMB review or any other Agency action under
Executive Order 13045, entitled Protection of Children from
Environmental Health Risks and Safety Risks (62 FR 19885, April 23,
1997). This action does not involve any technical standards that would
require Agency consideration of voluntary consensus standards pursuant
to section 12(d) of the National Technology Transfer and Advancement
Act of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272
note). Since tolerances and exemptions that are established on the
basis of a petition under FFDCA section 408(d), such as the tolerance
in this final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply. In addition, the Agency has determined that this
action will not have a substantial direct effect on States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government, as specified in Executive Order 13132, entitled Federalism
(64 FR 43255, August 10, 1999). Executive Order 13132 requires EPA to
develop an accountable process to ensure ``meaningful and timely input
by State and local officials in the development of regulatory policies
that have federalism implications.'' ``Policies that have federalism
implications'' is defined in the Executive Order to include regulations
that have`` substantial direct effects on the States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government.'' This final rule directly regulates growers, food
processors, food handlers and food retailers, not States. This action
does not alter the relationships or distribution of power and
responsibilities established by Congress in the preemption provisions
of FFDCA section 408(n)(4). For these same reasons, the Agency has
determined that this rule does not have any ``tribal implications'' as
described in Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 6,
2000). Executive Order 13175, requires EPA to develop an accountable
process to ensure ``meaningful and timely input by tribal officials in
the development of regulatory policies that have tribal implications.''
``Policies that have tribal implications'' is defined in the Executive
Order to include regulations that have ``substantial direct effects on
one or more Indian tribes, on the relationship between the Federal
government and the Indian tribes, or on the distribution of power and
responsibilities between the Federal government and Indian tribes.''
This rule will not have substantial direct effects on tribal
governments, on the relationship between the Federal government and
Indian tribes, or on the distribution of power and responsibilities
between the Federal government and Indian tribes, as specified in
Executive Order 13175. Thus, Executive Order 13175 does not apply to
this rule.

VIII. 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 this final rule in the Federal Register. This final
rule is not a ``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.


    Dated: June 11, 2001.
Peter Caulkins,
Acting Director, Registration Division, 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. 321(q), 346(a) and 371.

    2. Section 180.570 is added to read as follows:


Sec. 180.570  Isoxadifen-ethyl; tolerances for residues.

    (a) General. Tolerances to expire on June 21, 2004 are established
for residues of isoxadifen-ethyl (ethyl 5,5-diphenyl-2-isoxazoline-3-
carboxylate, CAS No. 163520-33-0) and its metabolites: 4,5-dihydro-5,5-
diphenyl-3-isoxazolecarboxylic acid and -hydroxy--
benezenepropanenitrile when in the commodities listed below. This
safener will be used only in conjunction with the active ingredient
fenoxaprop-p-ethyl, at a rate of 0.17 pound of safener per pound of
active ingredient.

----------------------------------------------------------------------------------------------------------------
Expiration/Revocation
               Commodity                              Parts per million                           Date
----------------------------------------------------------------------------------------------------------------
Rice, bran............................ 0.80 ppm  June 21, 2004
Rice, grain........................... 0.10 ppm  June 21, 2004
Rice, hulls........................... 0.50 ppm  June 21, 2004
Rice, straw........................... 0.25 ppm  June 21, 2004
----------------------------------------------------------------------------------------------------------------

    (b) Section 18 emergency exemptions. [Reserved]
    (c) Tolerances with regional registrations. [Reserved]
    (d) Indirect or inadvertent residues. [Reserved]

[FR Doc. 01-15613 Filed 6-20-01; 8:45 am]