[Federal Register Volume 75, Number 218 (Friday, November 12, 2010)]
[Rules and Regulations]
[Pages 69353-69360]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-28499]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

 [EPA-HQ-OPP-2007-0504; FRL-8845-6]


Isoxaben; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for residues of 
isoxaben in or on almond, hulls; grape; nut, tree, group 14; and 
pistachio. Dow AgroSciences requested these tolerances under the 
Federal Food, Drug, and Cosmetic Act (FFDCA).

DATES: This regulation is effective November 12, 2010. Objections and 
requests for hearings must be received on or before January 11, 2011, 
and must be filed in accordance with the instructions provided in 40 
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: EPA has established a docket for this action under docket 
identification (ID) number EPA-HQ-OPP-2007-0504. All documents in the 
docket are listed in the docket index available at http://www.regulations.gov. Although listed in the index, some information is 
not publicly available, e.g., Confidential Business Information (CBI) 
or other information whose disclosure is restricted by statute. Certain 
other material, such as copyrighted material, is not placed on the 
Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available in the electronic 
docket at http://www.regulations.gov, or, if only available in hard 
copy, at the OPP Regulatory Public Docket in Rm. S-

[[Page 69354]]

4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, 
VA. The Docket Facility is open from 8:30 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays. The Docket Facility telephone 
number is (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: Susan Stanton, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 305-5218; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
Potentially affected entities may include, but are not limited to those 
engaged in the following activities:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).
    This listing is not intended to be exhaustive, but rather to 
provide a guide for readers regarding entities likely to be affected by 
this action. Other types of entities not listed in this unit could also 
be affected. The North American Industrial Classification System 
(NAICS) codes have been provided to assist you and others in 
determining whether this action might apply to certain entities. If you 
have any questions regarding the applicability of this action to a 
particular entity, consult the person listed under FOR FURTHER 
INFORMATION CONTACT.

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of EPA's 
tolerance regulations at 40 CFR part 180 through the Government 
Printing Office's e-CFR site at http://www.gpoaccess.gov/ecfr. To 
access the harmonized test guidelines referenced in this document 
electronically, please go to http://www.epa.gov/ocspp and select ``Test 
Methods and Guidelines.''

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an 
objection to any aspect of this regulation and may also request a 
hearing on those objections. You must file your objection or request a 
hearing on this regulation in accordance with the instructions provided 
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify 
docket ID number EPA-HQ-OPP-2007-0504 in the subject line on the first 
page of your submission. All objections and requests for a hearing must 
be in writing, and must be received by the Hearing Clerk on or before 
January 11, 2011. Addresses for mail and hand delivery of objections 
and hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing that does not contain any CBI for inclusion in the public 
docket. Information not marked confidential pursuant to 40 CFR part 2 
may be disclosed publicly by EPA without prior notice. Submit a copy of 
your non-CBI objection or hearing request, identified by docket ID 
number EPA-HQ-OPP-2007-0504, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public 
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania 
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P), 
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South 
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only 
accepted during the Docket Facility's normal hours of operation (8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays). 
Special arrangements should be made for deliveries of boxed 
information. The Docket Facility telephone number is (703) 305-5805.

II. Summary of Petitioned-For Tolerance

    In the Federal Register of August 1, 2007 (72 FR 42072) (FRL-8138-
1), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 
U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 
7F7222) by Dow AgroSciences, 9330 Zionsville Road, Indianapolis, IN 
46268. The petition requested that 40 CFR part 180 be amended by adding 
a section for the herbicide, isoxaben, and establishing tolerances 
therein for residues of isoxaben, N-[3-(1-ethyl-1-methylpropyl)-5-
isoxazolyl]-2, 6-dimethoxybenzamide, in or on almond, hulls at 0.35 
parts per million (ppm); grape; grape, juice; and grape, raisin at 0.01 
ppm; and nut, tree, group 14 and pistachio at 0.03 ppm. That notice 
referenced a summary of the petition prepared by Dow AgroSciences, the 
registrant, which is available in the docket, http://www.regulations.gov. There were no comments received in response to the 
notice of filing.
    Based upon review of the data supporting the petition, EPA has 
reduced the tolerances for nut, tree, group 14 and pistachio from 0.03 
ppm to 0.02 ppm and increased the tolerance for almond, hulls from 0.35 
ppm to 0.40 ppm. EPA has also determined that the proposed tolerances 
for grape, juice and grape, raisin are not needed. Finally, EPA has 
revised the requested tolerance expression in accordance with current 
policy. The reasons for these changes are explained in Unit IV.C.

III. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a 
reasonable certainty that no harm will result from aggregate exposure 
to the pesticide chemical residue, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information.'' This includes exposure through drinking water and in 
residential settings, but does not include occupational exposure. 
Section 408(b)(2)(C) of FFDCA requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance and to ``ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue * * 
*.''
    Consistent with section 408(b)(2)(D) of FFDCA, and the factors 
specified in section 408(b)(2)(D) of FFDCA, EPA has reviewed the 
available scientific data and other relevant information in support of 
this action. EPA has sufficient data to assess the hazards of and to 
make a determination on aggregate exposure for isoxaben including 
exposure resulting from the tolerances established by this action. 
EPA's assessment of exposures and risks associated with isoxaben 
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

[[Page 69355]]

concerning the variability of the sensitivities of major identifiable 
subgroups of consumers, including infants and children.
    Isoxaben is of low acute toxicity when administered orally, 
dermally, or via inhalation. It is not a dermal sensitizer or skin 
irritant and causes only minor transient irritation to the eye.
    The primary target organs identified for isoxaben in repeated-dose 
studies are the liver and kidney. Although liver effects were observed 
in all species tested (rat, dog, mouse), adverse changes were only 
observed in the mouse following chronic oral exposure. These effects 
included histopathology and increased blood alkaline phosphatase and 
alanine aminotransferase activities at high doses. In the dog and rat, 
liver effects were considered adaptive and consisted of enlargement, 
hepatocellular hypertrophy and induction of hepatic microsomal enzymes. 
Increased incidence and severity of nephropathy was observed in the rat 
following chronic (2-year) exposure. No adverse renal effects were 
reported in the dog or mouse. There was no indication of neurotoxicity 
or immunotoxicity in the available studies, which generally tested up 
to or above the limit dose.
    No maternal or developmental effects were seen in the rabbit or rat 
developmental studies. In the rat reproductive toxicity study, two 
matings (a and b generations) per F0 and F1 parental generations were 
conducted, plus two additional matings (F2c and 
F3a) to examine developmental effects on gestation day 20. 
Effects included a decrease in corpora lutea, resulting in a decrease 
in the mean number of implantations and mean live fetuses per litter. 
Nursing pups showed decreased body weight gain at the highest dose 
tested. An increase in the incidence of several malformations 
(exencephaly, microphthalmia/coloboma and hydroureter) was seen in the 
F2b, F2c and F3a mating generations at 
the limit dose of 1,000 milligrams/kilogram/day (mg/kg/day highest dose 
tested (HDT)), but not in the F1a, F1b or 
F2a offspring. The relationship of these findings to 
treatment is unclear because an examination of the genealogy of these 
offspring suggests a possible heritable component. A large percentage 
of the affected litters were the result of either cousin matings or had 
in common F0 progenitors derived from several F0 litters from the 
supplier. However, because the relationship to treatment could not be 
ruled out, the malformations were considered a possible treatment-
related effect.
    No effects of treatment were reported in a 21-day repeated-
application dermal toxicity study in the rabbit. This is consistent 
with relatively low dermal absorption (<=11% of administered dose) 
observed in a dermal penetration study in the monkey and the low oral 
toxicity observed in subchronic oral studies in the rat, mouse and dog.
    Isoxaben is classified as having ``Suggestive Evidence of 
Carcinogenic Potential'' based on an increased incidence of benign 
liver tumors observed in male and female mice at the high dose only. 
EPA has concluded that the chronic risk assessment, based on the 
chronic RfD/PAD, is protective of potential carcinogenicity for the 
following reasons. The liver tumors were observed only in one species 
(mice), were not malignant, and were observed in the presence of liver 
toxicity at dietary levels exceeding the limit dose (1,000 mg/kg/day). 
The chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/
day in the rat, which is more than 200-fold lower than the dose at 
which tumors were observed in the mouse and, therefore, protective of 
potential carcinogenicity.
    Specific information on the studies received and the nature of the 
adverse effects caused by isoxaben as well as the no-observed-adverse-
effect-level (NOAEL) and the lowest-observed-adverse-effect-level 
(LOAEL) from the toxicity studies can be found at http://www.regulations.gov in the document ``Isoxaben. Human Health Risk 
Assessment for the First Food Uses of the Herbicide on Grapes, Tree 
Nuts and Pistachio'' at page 50 in docket ID number EPA-HQ-OPP-2007-
0504.

B. Toxicological Points of Departure/Levels of Concern

    Once a pesticide's toxicological profile is determined, EPA 
identifies toxicological points of departure (POD) and levels of 
concern to use in evaluating the risk posed by human exposure to the 
pesticide. For hazards that have a threshold below which there is no 
appreciable risk, the toxicological POD is used as the basis for 
derivation of reference values for risk assessment. PODs are developed 
based on a careful analysis of the doses in each toxicological study to 
determine the dose at which no adverse effects are observed (the NOAEL) 
and the lowest dose at which adverse effects of concern are identified 
(the LOAEL). Uncertainty/safety factors are used in conjunction with 
the POD to calculate a safe exposure level--generally referred to as a 
population-adjusted dose (PAD) or a reference dose (RfD)--and a safe 
margin of exposure (MOE). For non-threshold risks, the Agency assumes 
that any amount of exposure will lead to some degree of risk. Thus, the 
Agency estimates risk in terms of the probability of an occurrence of 
the adverse effect expected in a lifetime. For more information on the 
general principles EPA uses in risk characterization and a complete 
description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
    A summary of the toxicological endpoints for isoxaben used for 
human risk assessment is shown in Table 1 of this unit.

   Table 1--Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Human Health Risk Assessment
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                                        Point of departure and
          Exposure/scenario               uncertainty/safety     RfD, PAD, LOC for risk  Study and toxicological
                                               factors                 assessment                effects
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Acute dietary (All Populations,        Not Applicable.........  Not Applicable.........  An appropriate endpoint
 including Females 13-50 years of                                                         was not identified
 age, Infants and Children).                                                              that could occur
                                                                                          following a single
                                                                                          exposure.
Chronic dietary (All populations)....  NOAEL= 5.0 mg/kg/day     Chronic RfD = 0.05 mg/   Chronic oral toxicity/
                                        UFA = 10x UFH = 10x      kg/day cPAD = 0.05 mg/   carcinogenicity in the
                                        FQPA SF = 1x.            kg/day.                  rat. LOAEL = 50.7 mg/
                                                                                          kg/day based on renal
                                                                                          toxicity in males.
Incidental oral short-term (1 to 30    Not Applicable.........  Not Applicable.........  An appropriate endpoint
 days).                                                                                   was not identified for
                                                                                          short-term oral
                                                                                          exposures.

[[Page 69356]]

 
Incidental oral intermediate-term (1   NOAEL= 200 mg/kg/day     LOC for MOE = 100......  Reproductive toxicity
 to 6 months).                          UFA= 10x.                                         in the rat (oral).
                                       UFH= 10x FQPA SF = 1x..                            Offspring LOAEL =
                                                                                          1,000 mg/kg/day based
                                                                                          on decreased body
                                                                                          weight gain in F1
                                                                                          females on Day 70.
                                                                                         One year dietary study
                                                                                          in the rat (co-
                                                                                          critical supporting
                                                                                          study). LOAEL = 625 mg/
                                                                                          kg/day based on
                                                                                          decreased body weight
                                                                                          gain in females during
                                                                                          the first six months
                                                                                          with a NOAEL of 62.5
                                                                                          mg/kg/day.
Dermal short-term (1 to 30 days).....  Not Applicable.........  Not Applicable.........  An appropriate endpoint
                                                                                          was not identified for
                                                                                          short-term dermal
                                                                                          exposures.
Dermal intermediate-term (1 to 6       Not Applicable.........  Not Applicable.........  An appropriate endpoint
 months).                                                                                 was not identified for
                                                                                          intermediate-term
                                                                                          dermal exposures.
Inhalation short-term (1 to 30 days).  Inhalation (or oral)     LOC for MOE = 100......  Reproductive toxicity
                                        study NOAEL= 200 mg/kg/                           in the rat (oral).
                                        day (inhalation                                   LOAEL = 1,000 mg/kg/
                                        absorption rate =                                 day based on increased
                                        100%).                                            incidence of
                                       UFA = 10x..............                            malformations.
                                       UFH = 10x..............
                                       FQPA SF = 1x...........
Inhalation intermediate-term (1 to 6   Inhalation (or oral)     LOC for MOE = 100......  Reproductive toxicity
 months).                               study NOAEL = 200 mg/                             in the rat (oral).
                                        kg/day (inhalation                                LOAEL = 1,000 mg/kg/
                                        absorption rate =                                 day based on decreased
                                        100%).                                            body weight gain in F1
                                       UFA = 10x..............                            females on Day 70,
                                       UFH = 10x..............                            decreased F2 pup
                                       FQPA SF = 1x...........                            weights, gestation
                                                                                          survival and live pups/
                                                                                          litter, and increased
                                                                                          incidence of
                                                                                          malformations.
                                                                                         One year dietary study
                                                                                          in the rat (co-
                                                                                          critical supporting
                                                                                          study). LOAEL = 625 mg/
                                                                                          kg/day based on
                                                                                          decreased body weight
                                                                                          gain in females during
                                                                                          the first six months
                                                                                          with a NOAEL of 62.5
                                                                                          mg/kg/day.
                                      --------------------------------------------------------------------------
Cancer (Oral, dermal, inhalation)....  Classification: Suggestive Evidence of Carcinogenic Potential, based on
                                        increased incidence of hepatocellular adenomas in male and female mice.
                                        The chronic risk assessment, based on the chronic RfD/PAD, is considered
                                        protective of potential carcinogenicity; a separate exposure assessment
                                        to evaluate cancer risk is unnecessary.
----------------------------------------------------------------------------------------------------------------
UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members
  of the human population (intraspecies). FQPA SF = Food Quality Protection Act Safety Factor. PAD = population
  adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of
  concern. LOAEL = lowest observed adverse effect level. NOAEL = no observed adverse effect level.

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. In evaluating dietary 
exposure to isoxaben, EPA considered exposure under the petitioned-for 
tolerances. There are no tolerances currently established for isoxaben. 
EPA assessed dietary exposures from isoxaben in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk 
assessments are performed for a food-use pesticide, if a toxicological 
study has indicated the possibility of an effect of concern occurring 
as a result of a 1-day or single exposure. No such effects were 
identified in the toxicological studies for isoxaben; therefore, a 
quantitative acute dietary exposure assessment is unnecessary.
    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment EPA used the food consumption data from the USDA 1994-1996 
and 1998 Continuing Surveys of Food Intakes by Individuals (CSFII). As 
to residue levels in food, EPA assumed that residues are present in all 
commodities at the tolerance level and that 100% of commodities are 
treated with isoxaben. DEEMTM 7.81 default concentration 
factors were used to estimate residues of isoxaben in processed 
commodities.
    iii. Cancer. Based on the data summarized in Unit III.A., EPA 
classified isoxaben as having ``Suggestive Evidence of Carcinogenic 
Potential'' but determined that the chronic risk assessment will be 
protective of both non-cancer and cancer effects. Therefore, a separate 
exposure assessment to evaluate cancer risk is unnecessary.
    iv. Anticipated residue and percent crop treated (PCT) information. 
EPA did not use anticipated residue or PCT information in the dietary 
assessment for isoxaben. Tolerance level residues and 100% CT were 
assumed for all food commodities.

[[Page 69357]]

    2. Dietary exposure from drinking water. The residues of concern in 
drinking water following applications of isoxaben include isoxaben and 
its degradates hydroxyisoxaben (N-[3-(1-hydroxyl-1-methylpropyl)-5-
isoxazoyl]-2,6-dimethoxy-benzamide); dimethoxybenzamide (2,6-
dimethoxybenzamide); methoxyphenylpyrimidinol (6-(1-ethyl-1-
methylpropyl)-2-(2-hydroxy-6-methoxyphenyl)-4-pyrimidinol); and AEM 
hexenoylisoxaben (N-[3-amino-4-ethyl-4-methyl-2-hexenoyl]-2,6-
dimethoxybenzamide). The Agency used screening level water exposure 
models in the dietary exposure analysis and risk assessment for 
isoxaben and its degradates in drinking water. These simulation models 
take into account data on the physical, chemical, and fate/transport 
characteristics of isoxaben and its degradates. Further information 
regarding EPA drinking water models used in pesticide exposure 
assessment can be found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the First Index Reservoir Screening Tool (FIRST) and 
Screening Concentration in Ground Water (SCI-GROW) models, the 
estimated drinking water concentrations (EDWCs) of isoxaben and its 
degradates for chronic exposures for non-cancer assessments (the only 
dietary exposure scenario of concern for isoxaben) are estimated to be 
120 parts per billion (ppb) for surface water and 43.6 ppb for ground 
water.
    Modeled estimates of drinking water concentrations were directly 
entered into the dietary exposure model. For chronic dietary risk 
assessment, the water concentration of value 120 ppb was used to assess 
the contribution to drinking water.
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., for lawn and garden pest control, indoor pest control, 
termiticides, and flea and tick control on pets). Isoxaben is currently 
registered for the following uses that could result in residential 
exposures: Home lawns, recreational turf areas and ornamental 
plantings. EPA assessed residential exposure using the following 
assumptions: There is a potential for exposure of homeowners applying 
products containing isoxaben on home lawns (i.e., residential handler 
exposure). There is also a potential for post-application exposure of 
adults and children entering lawn and recreation areas which have been 
treated with isoxaben and for bystander exposure of adults and children 
in areas adjacent to pesticide applications.
    For residential handlers, dermal and inhalation exposures of short-
term duration are expected. Since EPA did not identify an endpoint of 
concern for dermal exposures, only short-term inhalation exposures were 
assessed.
    The following types of residential exposure may occur following 
applications of isoxaben on lawns and recreational turf areas: Short- 
and intermediate-term dermal and inhalation exposure of adults and 
children entering treated areas; short-term incidental oral hand-to-
mouth and/or object-to-mouth exposure of children playing on treated 
turf; short- and intermediate-term incidental oral exposure of children 
ingesting soil from treated areas; and episodic oral exposure of 
children ingesting pesticide granules following applications of 
granular isoxaben formulations on lawns. Post-application inhalation 
exposures are expected to be negligible due to the low volatility of 
isoxaben, label recommendations for incorporation of the product (by 
rainfall or irrigation) after application, and the types of application 
equipment used to apply isoxaben (i.e., isoxaben is not applied using 
air blast or aerial equipment that would increase the potential for 
inhalation exposure). EPA did not identify an endpoint of concern for 
acute or short-term oral exposures or for short- or intermediate-term 
dermal exposures. Therefore, in its post-application exposure 
assessment for isoxaben, EPA assessed only intermediate-term oral 
exposure of children ingesting treated soil. EPA does not typically 
consider soil ingestion to occur over intermediate-term durations, 
i.e., from 1-6 months, largely due to use patterns and the fact that 
residues are removed by precipitation or through microbial degradation 
in soil. In the case of isoxaben, the Agency estimated incidental oral 
exposure from ingestion of soil because the use pattern calls for 
repeat applications and the environmental fate data indicate that 
isoxaben is persistent in the soil. EPA conducted a conservative 
assessment of potential intermediate-term oral risk from soil ingestion 
using an application rate of 3.0 lb ai/A, equivalent to 3X the maximum 
single rate of 1.0 lb ai/A. The higher rate was assumed to account for 
build-up in the soil due to the pesticide's persistence.
    Bystander exposure of adults and children is possible on areas 
adjacent to application sites. EPA's concern for bystander exposures is 
low based on several considerations:
    i. Low acute toxicity of isoxaben via the inhalation route of 
exposure;
    ii. Label recommendations for incorporation of the product (by 
rainfall or irrigation) after application;
    iii. Isoxaben's low volatility; and
    iv. The types of application equipment used to apply isoxaben 
(i.e., isoxaben is not applied using air blast or aerial equipment that 
would increase the potential for inhalation exposure).
    In addition, EPA notes that MOEs calculated for residential 
handlers of isoxaben are very high, ranging from 2.9 million to 28 
million (See Unit III.E.3.). Bystander exposures of both adults and 
children are expected to be substantially lower than residential 
handler exposures, resulting in even higher MOEs and lower risk for 
bystanders. For these reasons, EPA's concern for bystander exposure of 
adults and children is low, and a quantitative assessment of bystander 
exposure and risk is considered unnecessary.
    Further information regarding EPA standard assumptions and generic 
inputs for residential exposures may be found at http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
    4. Cumulative effects from substances with a common mechanism of 
toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when 
considering whether to establish, modify, or revoke a tolerance, the 
Agency consider ``available information'' concerning the cumulative 
effects of a particular pesticide's residues and ``other substances 
that have a common mechanism of toxicity.''
    EPA has not found isoxaben to share a common mechanism of toxicity 
with any other substances, and isoxaben does not appear to produce a 
toxic metabolite produced by other substances. For the purposes of this 
tolerance action, therefore, EPA has assumed that isoxaben does not 
have 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 EPA's Web site at http://www.epa.gov/pesticides/cumulative.

D. Safety Factor for Infants and Children

    1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA 
shall apply an additional tenfold (10X) 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 database on toxicity 
and exposure unless EPA determines based on reliable data that a 
different margin of safety will be safe for infants and children. This 
additional margin of

[[Page 69358]]

safety is commonly referred to as the FQPA Safety Factor (SF). In 
applying this provision, EPA either retains the default value of 10X, 
or uses a different additional safety factor when reliable data 
available to EPA support the choice of a different factor.
    2. Prenatal and postnatal sensitivity. The pre- and postnatal 
toxicity database for isoxaben includes guideline rat and rabbit 
developmental toxicity studies and a three-generation reproduction 
toxicity study in rats. There was no maternal or developmental toxicity 
observed in the developmental studies in rats and rabbits. Increased 
qualitative susceptibility was observed in the rat reproductive 
toxicity study as decreased live pups/litter and decreased gestation 
survival in F2b litters (relative to body weight effects in 
mothers).
    3. Conclusion. EPA has determined that reliable data show the 
safety of infants and children would be adequately protected if the 
FQPA SF were reduced to 1X. That decision is based on the following 
findings:
    i. The toxicity database for isoxaben is largely complete, missing 
only acute and subchronic neurotoxicity studies, an immunotoxicity 
study and a subchronic inhalation study. EPA has determined that an 
additional uncertainty factor is not needed to account for the lack of 
these studies for the following reasons:
     There is no evidence in the existing studies that isoxaben 
targets either the nervous system or the immune system.
     EPA's concern for inhalation toxicity from subchronic 
exposures is low, based on isoxaben's low vapor pressure and frequency 
of application.
     Overall, the toxicity of isoxaben is low. The available 
oral studies of short-term (e.g., developmental toxicity) or subchronic 
exposure duration indicated no toxicity up to the limit dose. Effects 
observed in adult animals (decreased body weight) at exposures of 
intermediate-term duration were minimal, and malformations seen in 
offspring in the rat reproduction study were of uncertain relationship 
to treatment. The endpoints were assumed by EPA to be treatment-
related, a conservative assumption intended to ensure the risk 
assessment is protective of potential effects.

Based on these considerations, EPA does not expect the required studies 
to provide lower points of departure than those currently selected for 
risk assessment, and an additional uncertainty factor is not needed to 
account for the lack of these studies.
    ii. There is no evidence of neurotoxicity in the available 
toxicology database and no evidence of developmental toxicity in either 
the rat or rabbit developmental toxicity studies at doses up to the 
limit dose. Based on these considerations, there is no need for a 
developmental neurotoxicity study or additional UFs to account for 
neurotoxicity.
    iii. There was no evidence of increased susceptibility in the rat 
and rabbit developmental toxicity studies. Although increased 
qualitative susceptibility was observed in the rat reproductive 
toxicity study as decreased live pups/litter and decreased gestation 
survival in F2b litters (relative to body weight effects in 
mothers), EPA's concern for qualitative susceptibility is low. 
Offspring effects were seen only at the limit dose in later generations 
and not observed in the developmental studies. Additionally, since 
there is evidence that observed malformations were due in part to 
heritable factors, the relationship of these effects to treatment is 
unclear. There are low concerns for effects on offspring viability, 
because they were only observed at the limit dose and may have been 
secondary to effects on the dams. The endpoints and points of departure 
selected for risk assessment are protective of these effects.
    iv. There are no residual uncertainties identified in the exposure 
databases. The dietary food exposure assessments were performed 
assuming tolerance-level residues and 100% crop treated for all 
commodities. EPA made conservative (protective) assumptions in the 
ground and surface water modeling used to assess exposure to isoxaben 
in drinking water. EPA used similarly conservative assumptions to 
assess postapplication exposure of children as well as incidental oral 
exposure of toddlers. These assessments will not underestimate the 
exposure and risks posed by isoxaben.

E. Aggregate Risks and Determination of Safety

    EPA determines whether acute and chronic dietary pesticide 
exposures are safe by comparing aggregate exposure estimates to the 
acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer risks, EPA 
calculates the lifetime probability of acquiring cancer given the 
estimated aggregate exposure. Short-, intermediate-, and chronic-term 
risks are evaluated by comparing the estimated aggregate food, water, 
and residential exposure to the appropriate PODs to ensure that an 
adequate MOE exists.
    1. Acute risk. An acute aggregate risk assessment takes into 
account acute exposure estimates from dietary consumption of food and 
drinking water. No adverse effect resulting from a single oral exposure 
was identified and no acute dietary endpoint was selected. Therefore, 
isoxaben is not expected to pose an acute risk.
    2. Chronic risk. Using the exposure assumptions described in this 
unit for chronic exposure, EPA has concluded that chronic exposure to 
isoxaben from food and water will utilize 17% of the cPAD for infants, 
less than 1 year old, the population group receiving the greatest 
exposure. Based on the explanation in Unit III.C.3., regarding 
residential use patterns, chronic residential exposure to residues of 
isoxaben is not expected.
    3. Short-term risk. Short-term aggregate exposure takes into 
account short-term residential exposure plus chronic exposure to food 
and water (considered to be a background exposure level). Isoxaben is 
currently registered for uses that could result in short-term 
residential exposure, and the Agency has determined that it is 
appropriate to aggregate chronic exposure through food and water with 
short-term residential exposures to isoxaben.
    Using the exposure assumptions described in this unit for short-
term exposures, EPA has concluded the combined short-term food, water, 
and residential exposures result in an aggregate MOE of 82,000 for 
adults. The MOE for adults includes chronic exposure from food and 
water plus short-term residential handler exposure of adult females, 
based on the worst-case granular push-type applicator scenario. Because 
EPA's level of concern for isoxaben is a MOE of 100 or below, this MOE 
is not of concern. For children, no short-term oral or dermal endpoints 
of concern were identified, and residential post-application inhalation 
exposure is expected to be negligible. Therefore, EPA relies on the 
chronic dietary risk assessment discussed in Unit III.E.2. for 
evaluating children's short-term risk from isoxaben.
    4. Intermediate-term risk. Intermediate-term aggregate exposure 
takes into account intermediate-term residential exposure plus chronic 
exposure to food and water (considered to be a background exposure 
level). Isoxaben is currently registered for uses that could result in 
intermediate-term residential exposure, and the Agency has determined 
that it is appropriate to aggregate chronic exposure through food and 
water with intermediate-term residential exposures to isoxaben.
    Using the exposure assumptions described in this unit for 
intermediate-

[[Page 69359]]

term exposures, EPA has concluded that the combined intermediate-term 
food, water, and residential exposures result in an aggregate MOE of 
51,000 for children. The MOE for children includes chronic exposure 
from food and water plus intermediate-term oral exposure of children 
ingesting treated soil. Because EPA's level of concern for isoxaben is 
a MOE of 100 or below, the MOE for children is not of concern. For 
adults, no intermediate-term dermal endpoint of concern was identified, 
and residential post-application inhalation exposure is expected to be 
negligible. Therefore, EPA relies on the chronic dietary risk 
assessment discussed in Unit III.E.2. for evaluating adults' 
intermediate-term risk from isoxaben.
    5. Aggregate cancer risk for U.S. population. As explained in Unit 
III.A., risk assessments based on the endpoint selected for chronic 
risk assessment are considered to be protective of any potential 
carcinogenic risk from exposure to isoxaben. Based on the results of 
the chronic risk assessment discussed above in Unit III.E.2., EPA 
concludes that isoxaben is not expected to pose a cancer risk.
    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, or to infants and children from aggregate 
exposure to isoxaben residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

    Adequate enforcement methodology (high-performance liquid 
chromatography with tandem mass spectromectric detection (LC/MS/MS), 
method GRM 02.26.S.1) is available to enforce the tolerance expression. 
The method may be requested from: Chief, Analytical Chemistry Branch, 
Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350; 
telephone number: (410) 305-2905; e-mail address: 
[email protected].

B. International Residue Limits

    In making its tolerance decisions, EPA seeks to harmonize U.S. 
tolerances with international standards whenever possible, consistent 
with U.S. food safety standards and agricultural practices. EPA 
considers the international maximum residue limits (MRLs) established 
by the Codex Alimentarius Commission (Codex), as required by FFDCA 
section 408(b)(4). The Codex Alimentarius is a joint U.N. Food and 
Agriculture Organization/World Health Organization food standards 
program, and it is recognized as an international food safety 
standards-setting organization in trade agreements to which the United 
States is a party. EPA may establish a tolerance that is different from 
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain 
the reasons for departing from the Codex level.
    The Codex has not established a MRL for isoxaben.

C. Revisions to Petitioned-For Tolerances

    Based on the maximum residue of 0.015 ppm observed in field trials 
with almonds and pecans, the proposed tolerances for nut, tree, group 
14 and pistachio were reduced from 0.03 ppm to 0.02 ppm. The proposed 
tolerance for almond hulls was increased from 0.35 ppm to 0.40 ppm 
based on analysis of the field trial data using the Agency's Tolerance 
Spreadsheet in accordance with the ``Guidance for Setting Pesticide 
Tolerances Based on Field Trial Data.'' EPA has also determined that, 
since the tolerance for grape will cover residues in/on grape juice and 
raisins, separate tolerances are not needed for these commodities.
    Finally, EPA is revising the requested tolerance expression to 
clarify the chemical moieties that are covered by the tolerances and 
specify how compliance with the tolerances is to be measured. The 
revised tolerance expression makes clear that the tolerances cover 
residues of the herbicide isoxaben, including its metabolites and 
degradates, but that compliance with the specified tolerance levels is 
to be determined by measuring only isoxaben N-[3-(1-ethyl-1-
methylpropyl)-5-isoxazolyl]-2, 6-dimethoxybenzamide, in or on the 
commodities.

V. Conclusion

    Therefore, tolerances are established for residues of isoxaben, 
including its metabolites and degradates, in or on almond, hulls at 
0.40 ppm; grape at 0.01 ppm; nut, tree, group 14 at 0.02 ppm; and 
pistachio at 0.02 ppm. Compliance with these tolerances is to be 
determined by measuring only isoxaben N-[3-(1-ethyl-1-methylpropyl)-5-
isoxazolyl]-2, 6-dimethoxybenzamide, in or on the commodities.

VI. Statutory and Executive Order Reviews

    This final rule establishes tolerances under section 408(d) of 
FFDCA in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993). Because this final rule has been 
exempted from review under Executive Order 12866, this final rule is 
not subject to Executive Order 13211, entitled Actions Concerning 
Regulations That Significantly Affect Energy Supply, Distribution, or 
Use (66 FR 28355, May 22, 2001) or Executive Order 13045, entitled 
Protection of Children from Environmental Health Risks and Safety Risks 
(62 FR 19885, April 23, 1997). 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., nor does it require any 
special considerations under Executive Order 12898, entitled Federal 
Actions to Address Environmental Justice in Minority Populations and 
Low-Income Populations (59 FR 7629, February 16, 1994).
    Since tolerances and exemptions that are established on the basis 
of a petition under section 408(d) of FFDCA, such as the tolerance in 
this final rule, do not require the issuance of a proposed rule, the 
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et 
seq.) do not apply.
    This final rule directly regulates growers, food processors, food 
handlers, and food retailers, not States or tribes, nor does this 
action alter the relationships or distribution of power and 
responsibilities established by Congress in the preemption provisions 
of section 408(n)(4) of FFDCA. As such, the Agency has determined that 
this action will not have a substantial direct effect on States or 
tribal governments, on the relationship between the national government 
and the States or tribal governments, or on the distribution of power 
and responsibilities among the various levels of government or between 
the Federal Government and Indian tribes. Thus, the Agency has 
determined that Executive Order 13132, entitled Federalism (64 FR 
43255, August 10, 1999) and Executive Order 13175, entitled 
Consultation and Coordination with Indian Tribal Governments (65 FR 
67249, November 9, 2000) do not apply to this final rule. In addition, 
this final rule does not 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).
    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).

[[Page 69360]]

VII. Congressional Review Act

    The Congressional Review Act, 5 U.S.C. 801 et seq., generally 
provides that before a rule may take effect, the agency promulgating 
the rule must submit a rule report 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: October 29, 2010.
Steven Bradbury,
Director, Office of Pesticide Programs.

0
Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

0
1. The authority citation for part 180 continues to read as follows:

    Authority:  21 U.S.C. 321(q), 346a and 371.


0
2. Add Sec.  180.650 to subpart C to read as follows:


Sec.  180.650  Isoxaben; tolerances for residues.

    (a) General. Tolerances are established for residues of the 
herbicide isoxaben, including its metabolites and degradates, in or on 
the commodities in the table below. Compliance with the tolerance 
levels specified below is to be determined by measuring only isoxaben, 
N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2, 6-dimethoxybenzamide, in 
or on the commodity.

------------------------------------------------------------------------
                                                             Parts per
                        Commodity                             million
------------------------------------------------------------------------
Almond, hulls...........................................            0.40
Grape...................................................            0.01
Nut, tree, Group 14.....................................            0.02
Pistachio...............................................            0.02
------------------------------------------------------------------------

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

[FR Doc. 2010-28499 Filed 11-10-10; 8:45 am]
BILLING CODE 6560-50-P