[Federal Register Volume 63, Number 30 (Friday, February 13, 1998)]
[Rules and Regulations]
[Pages 7299-7305]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-3750]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300617; FRL-5771-1]
RIN 2070-AB78
Benoxacor; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of
benoxacor (4-(dichloroacetyl)-3,4-dihydro-3-methyl-2H-1,4-benzoxazine
at 0.01 part per million (ppm) when used as an inert ingredient
(safener) in pesticide formulations containing metolachlor in or on raw
agricultural commodities for which tolerances have been established for
metolachlor. It also removes time limitations for residues of benoxacor
on the same commodities that expire on February 14, 1998. Novartis Crop
Protection, Incorporated requested this tolerance under the Federal
Food, Drug and Cosmetic Act (FFDCA), as amended by the Food Quality
Protection Act of 1996 (Pub. L. 104-170).
DATES: This regulation is effective February 13, 1998. Objections and
requests for hearings must be received by EPA on or before April 14,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300617], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300617], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: [email protected]. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300617]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Kerry B. Leifer, Registration
Division (7505W), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e-mail address: Rm. 4W17, Crystal
Station #1, 2800 Crystal Drive, Arlington, VA, (703) 308-8811, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: In the Federal Register of June 30, 1992 (57
FR 29031), EPA established time-limited tolerances under section 408 of
the FFDCA 21 U.S.C. 346a(d) for residues of benoxacor at 0.01 ppm when
used as an inert ingredient (safener) in pesticide formulations
containing metolachlor in or on raw agricultural commodities for which
tolerances have been established for metolachlor. These time-limited
tolerances expired on December 1, 1996. In the Federal Register of
November 5, 1996 (61 FR 56954) (FRL-5572-8), EPA issued a notice
pursuant to section 408 of FFDCA 21 U.S.C. 346a(e) announcing the
filing of pesticide petition (PP7E3489) for tolerances by Novartis Crop
Protection, Incorporated, P.O. Box 18300, Greensboro, NC 27419. This
notice included a summary of the petition prepared by Novartis, the
petitioner. There were no comments received in response to the notice
of filing.
The petition requested that 40 CFR 180.460 be amended to extend the
time-limited tolerances for residues of benoxacor at 0.01 ppm when used
as an inert ingredient (safener) in pesticide formulations containing
metolachlor in or on raw agricultural commodities for which tolerances
have been established for metolachlor from December 1, 1996, to
December 1, 1998. On February 21, 1997 (62 FR 7941) (FRL-5583-4), EPA
established time-limited tolerances for benoxacor at 0.01 ppm when used
as an inert ingredient (safener) in pesticide formulations containing
metolachlor in or on raw agricultural commodities for which tolerances
have been established for metolachlor with an expiration date of
February 14, 1998.
[[Page 7300]]
In the Federal Register of November 21, 1997 (62 FR 62304) (FRL-
5755-4), EPA issued a notice pursuant to section 408 of FFDCA 21 U.S.C.
346a(e) announcing the filing of pesticide petition (PP7E3489) for
tolerances by Novartis Crop Protection, Incorporated (formerly Ciba
Crop Protection), P.O. Box 18300, Greensboro, NC 27419. This notice
included a summary of the petition prepared by the petitioner. There
were no comments received in response to the notice of filing.
The petition requested that the time limitation for tolerances
established for residues of benoxacor at 0.01 ppm when used as an inert
ingredient (safener) in pesticide formulations containing metolachlor
in or on raw agricultural commodities for which tolerances have been
established for metolachlor be removed based upon the chronic toxicity
and oncogenicity data submitted as a condition of registration.
The basis for the time-limited tolerances that expire February 14,
1998, was given in the February 21, 1997 issue of the Federal Register
(62 FR 7941). These time-limited tolerances were predicated on the
expiration of pesticide product registrations that were made
conditional due to the lack of certain chronic/oncogenicity data. The
rationale for using time-limited tolerances was to encourage pesticide
manufacturers to comply with the conditions of registration in a timely
manner. There is no regulatory requirement to make tolerances time-
limited due to the conditional status of a product under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) as amended. It is
current EPA policy to no longer establish time limitations on
tolerances if none of the conditions of registration have any bearing
on human dietary risk. The current petition action meets that condition
and thus the expiration dates associated with the crop tolerances are
being deleted.
I. Risk Assessment and Statutory Findings
New 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. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health. An uncertainty factor (sometimes
called a ``safety factor'') of 100 is commonly used since it is assumed
that people may be up to 10 times more sensitive to pesticides than the
test animals, and that one person or subgroup of the population (such
as infants and children) could be up to 10 times more sensitive to a
pesticide than another. In addition, EPA assesses the potential risks
to infants and children based on the weight of the evidence of the
toxicology studies and determines whether an additional uncertainty
factor is warranted. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100% or less of the RfD) is
generally considered acceptable by EPA. EPA generally uses the RfD to
evaluate the chronic risks posed by pesticide exposure. For shorter
term risks, EPA calculates a margin of exposure (MOE) by dividing the
estimated human exposure into the NOEL from the appropriate animal
study. Commonly, EPA finds MOEs lower than 100 to be unacceptable. This
100-fold MOE is based on the same rationale as the 100-fold uncertainty
factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute,'' ``short-term,''
``intermediate term,'' and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of FQPA,
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from
food, water, and residential uses when reliable data are available. In
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all
three sources are not typically added because
[[Page 7301]]
of the very low probability of this occurring in most cases, and
because the other conservative assumptions built into the assessment
assure adequate protection of public health. However, for cases in
which high-end exposure can reasonably be expected from multiple
sources (e.g. frequent and widespread homeowner use in a specific
geographical area), multiple high-end risks will be aggregated and
presented as part of the comprehensive risk assessment/
characterization. Since the toxicological endpoint considered in this
assessment reflects exposure over a period of at least 7 days, an
additional degree of conservatism is built into the assessment; i.e.,
the risk assessment nominally covers 1-7 days exposure, and the
toxicological endpoint/NOEL is selected to be adequate for at least 7
days of exposure. (Toxicity results at lower levels when the dosing
duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.The
TMRC is a ``worst case'' estimate since it is based on the assumptions
that food contains pesticide residues at the tolerance level and that
100% of the crop is treated by pesticides that have established
tolerances. If the TMRC exceeds the RfD or poses a lifetime cancer risk
that is greater than approximately one in a million, EPA attempts to
derive a more accurate exposure estimate for the pesticide by
evaluating additional types of information (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
Percent of crop treated estimates are derived from federal and
private market survey data. Typically, a range of estimates are
supplied and the upper end of this range is assumed for the exposure
assessment. By using this upper end estimate of percent of crop
treated, the Agency is reasonably certain that exposure is not
understated for any significant subpopulation group. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations
including several regional groups, to pesticide residues. For this
pesticide, the most highly exposed population subgroup, non-nursing
infants less than one year old, was not regionally based.
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action, EPA has sufficient data to assess the hazards of benoxacor
and to make a determination on aggregate exposure, consistent with
section 408(b)(2), for a tolerance for residues of benoxacor when used
as an inert ingredient (safener) in pesticide formulations containing
metolachlor in or on raw agricultural commodities for which tolerances
have been established for metolachlor at 0.01 ppm. EPA's assessment of
the dietary exposures and risks associated with establishing the
tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by benoxacor are
discussed below.
1. Acute toxicity. A rat acute oral study with an LD50
>5,000 milligram/kilogram (mg/kg), a rabbit acute dermal study with an
LD50 >2,010 mg/kg, a rat inhalation study with an
LC50 >2,000 mg/liter, a primary eye irritation study in the
rabbit showing moderate eye irritation, a primary dermal irritation
study in the rabbit showing benoxacor is not a skin irritant, and a
skin sensitization study which showed benoxacor to be a skin sensitizer
in the Guinea pig. Results of a dermal absorption study show a maximum
of 55.7% of benoxacor is absorbed by the rat following a 24-hour dermal
exposure.
2. Genotoxicity. Benoxacor did not induce point mutations in vitro
at limit (cytotoxic) concentrations in a Salmonella /mammalian
microsome test or show any mutagenic activity in the Chinese hamster
V79 mammalian point mutation test and is neither clastogenic nor
aneugenic in the Chinese hamster at doses up to the limit dose of 5,000
mg/kg. Benoxacor did not induce unscheduled DNA synthesis in isolated
rat hepatocytes at cytotoxic concentrations up to 20 micrograms/ml.
3. Subchronic toxicity--i. Dogs. In a subchronic feeding study in
dogs (5 dogs/sex/dose), benoxacor was administered at doses of 0, 0.25,
1, 5, 50, 150, or 400 milligram/kilograms/day (mg/kg/day) for 90 days.
The NOEL was 5 mg/kg/day and the lowest observed effect level (LOEL) 50
mg/kg/day based on increased liver and gallbladder weights.
ii. Mice. In a subchronic feeding study, CD-1 mice were
administered dietary concentrations of 0, 50, 500, 2,000, and 6,000 ppm
(approximately 0, 7.14, 70.7, 290, and 1,100 mg/kg/day for males and 0,
9.53, 99.8, 382, and 1,470 mg/kg/day for females) of benoxacor for 13
weeks. The systemic toxicity NOEL was 500 ppm (70.7 and 99.8 mg/kg/day
in males and females respectively) and the systemic toxicity LOEL was
2,000 ppm (290 and 382 mg/kg/day in males and females respectively)
based on increased incidence of renal cortex fibrosis and
calcifications in males, and increases in water consumption, platelet
counts, and liver and kidney weights in both males and females.
iii. Rats. In a subchronic feeding study in rats, six groups of 15
male and 15 female Sprague Dawley rats were fed benoxacor at dietary
concentrations of approximately 0, 0.5, 5, 15, 50, or 300 mg/kg/day for
13 weeks. The NOEL was 5 mg/kg/day and the LOEL was 15 mg/kg/day based
on increased incidence of kidney nephrosis.
[[Page 7302]]
4. Dermal toxicity study. In a 21-day dermal toxicity study,
benoxacor was repeatedly applied daily to the shaved skin of 5 male and
5 female New Zealand white rabbits at dose levels of 0, 1, 500, or
1,010 mg/kg for 6/hours/day . The NOEL was >1,010 mg/kg/day.
5. Developmental toxicity study--i. Rabbits. In an oral
developmental toxicity study, rabbits were administered benoxacor at
doses of 0, 0.5, 2.5, 12.5,and 62.5 mg/kg/day. The systemic maternal
NOEL was 12.5 mg/kg/day and the systemic maternal LOEL was 62.5 mg/kg/
day based on decreased consumption values. The developmental toxicity
NOEL was 12.5 mg/kg/day and the developmental toxicity LOEL was 62.5
mg/kg/day based on increased frequency of vertebral anomalies with or
without associated rib anomalies.
ii. Rats. In an oral developmental toxicity study, rats were
administered benoxacor at doses of 0, 1, 100, and 400 mg/kg/day. The
systemic maternal NOEL was 100 mg/kg/day and the systemic maternal LOEL
was 400 mg/kg/day based on increased maternal gross pathology findings,
and decreased body weight gain. The developmental toxicity NOEL was 100
mg/kg/day and the developmental toxicity LOEL was 400 mg/kg/day based
on decreased fetal weight, number of live fetuses, decreased uterine
weight and increased early resorptions, and fetal visceral variations,
malformations, and skeletal variations.
6. Reproductive toxicity study. In a two-generation reproduction
study, Sprague-Dawley rats were fed in the diet with benoxacor at doses
of 0, 10, 50, 100, 500, and 1,000 ppm for two generations. For
parental/systemic toxicity, the NOEL was 50 ppm (3.55 mg/kg/day in the
male and 4.51 mg/kg/day in the females) and the LOEL was 500 ppm (34.84
mg/kg/day in males and 41.21 mg/kg/day in females) based on decreased
body weight and body weight gain in both sexes and both generations.
For reproductive toxicity the NOEL was 50 ppm (3.55 mg/kg/day in the
male and 4.51 mg/kg/day in the female) and the LOEL was 500 ppm (34.84
mg/kg/day in males and 41.21 mg/kg/day in females) based on decreased
pup body weight on lactation day 21 in both generations.
7. Chronic toxicity study. In a 52-week feeding study, benoxacor
was administered orally to male and female beagle dogs (4/sex/group) at
doses of 0, 1, 5, 40, or 80 mg/kg/day. The NOEL was 5 mg/kg/day and the
LOEL was 40 mg/kg/day based upon decreases in mean body weight gain in
males and increases in adjusted liver and kidney weights and increased
lipofuscin deposition in the kidney in both sexes.
8. Carcinogenicity study. In a carcinogenicity study, CD-1 mice
were fed benoxacor (50/sex/group) at dietary levels of 0, 10, 30, 600,
and 1,200 ppm (0, 1.2, 3.7, 75, and 167 mg/kg/day for males and 0, 1.6,
4.7, 93, and 201 mg/kg/day for females) for 18 months. There was
evidence of carcinogenicity at the two highest doses tested.
Statistically (p<0.05) significant increases of squamous cell
papillomas and combined papillomas/carcinomas were seen in the
nonglandular stomach (forestomach) in both sexes at the highest dose
tested. There were also statistically significant positive trends for
carcinomas in male mice and for papillomas and combined papilloma/
carcinoma in both sexes. For chronic toxicity, the NOEL was 30 ppm (3.7
mg/kg/day and 4.7 mg/kg/day in males and females, respectively) and the
systemic LOEL was 600 ppm (75 mg/kg/day and 93 mg/kg/day in males and
females, respectively) based on increased liver/body weight ratios in
both sexes. The NOEL for mouse forestomach tumors was 3.7 mg/kg/day in
males and 4.7 mg/kg/day in females with tumors occurring at 75 and 93
mg/kg/day in males and females. Dosing was considered adequate to
assess the carcinogenic potential of benoxacor based on body weight
reduction in males, treatment-related increased liver/body weight
ratios in both sexes, and other treatment-related increased incidences
of tumor and nontumor findings in the forestomach.
9. Chronic/oncogenicity study. In a combined chronic/oncogenicity
study, Crl:CD BR rats (70 /sex/group) were fed benoxacor dosed at
dietary levels of 0, 10, 50, 500, and 1,000 ppm (0, 0.4, 2.0, 20.6, and
41 mg/kg/day for males and 0, 0.6, 2.8, 28.2, and 59 mg/kg/day for
females) for two years. Statistically significant (p<0.01) increasing
trends were seen in male rats for forestomach squamous cell papillomas
and papillomas and/or carcinomas combined. There was also a
statistically significant (p<0.05) increasing trend for forestomach
squamous cell carcinomas in male rats. There were significant
differences in the pair-wise comparisons of the male high-dose group
with the controls for forestomach squamous cell papillomas (p<0.05) and
for papillomas and/or carcinomas combined (p<0.01). Statistically
significant (p<0.01) increasing trends, and differences in the pair-
wise comparisons of the high-dose group with the controls, were seen in
female rats for forestomach squamous cell papillomas and papillomas
and/or carcinomas combined. For chronic toxicity, the NOEL was 10 ppm
(0.4 mg/kg/day and 0.6 mg/kg/day in males and females, respectively)
and the systemic LOEL is 50 ppm (2.0 mg/kg/day in males) based on
centrolobular hepatic enlargements with or without hepatocytic
vacuolation in male rat livers. At a dose level of 2.6 mg/kg/day,
hyperkeratosis of the forestomach in females was observed. The NOEL for
rat forestomach tumors was 20.6 mg/kg/day in males and 28.2 in females
with tumors occurring at 41 and 59 mg/kg/day in males and females.
B. Toxicological Endpoints
1. Acute toxicity. An acute dietary risk assessment for the general
population, including infants and children, is not required because no
treatment-related effects attributable to a single exposure (dose) were
seen in oral studies conducted with benoxacor.
2. Short- and intermediate-term toxicity. A short- and
intermediate-term risk assessment is not required for benoxacor. There
was no systemic toxicity at 1,010 mg/kg/day (highest dose tested) in a
21-day dermal toxicity study in rabbits.
3. Chronic toxicity. EPA has established the RfD for benoxacor at
0.004 mg/kg/day. This RfD is based on a 2-year feeding study in rats
with a NOEL of 0.4 mg/kg/day. An uncertainty factor of 100 was used in
calculating the RfD to account for interspecies extrapolation and
intra-species variability.
4. Carcinogenicity. EPA's Health Effects Division Carcinogenicity
Peer Review Committee (CPRC) has determined that, in accordance with
the EPA proposed Guidelines for Carcinogenic Risk Assessment (April 23,
1996), benoxacor's carcinogenic potential be characterized as ``cannot
be determined, but suggestive'' based on increases in forestomach
tumors in both sexes of mice and rats. The consensus of the CPRC was
that these tumors have little or no relevance to humans. For cancer
risk assessment purposes, the CPRC recommended using a threshold (MOE)
approach based on the most sensitive precursor forestomach lesions. It
was further recommended that the NOEL for rat forestomach lesions of
0.4 mg/kg/day be used as the point of departure for MOE calculations.
C. Exposures and Risks
1. From food and feed uses. Tolerances have been established (40
CFR 180.460) for the residues of benoxacor in or on a variety of raw
agricultural commodities. Risk assessments were conducted by EPA to
[[Page 7303]]
assess dietary exposures and risks from benoxacor as follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. Since there are no acute toxicological
concerns for benoxacor, an acute dietary risk assessment was not
required.
ii. Chronic exposure and risk. For the purpose of assessing chronic
dietary exposure from benoxacor, EPA considered the proposed benoxacor
tolerance of 0.01 ppm and the raw agricultural commodities for which
tolerances have been established for metolachlor. There are no other
established U.S. tolerances for benoxacor, and there are no other
registered uses for benoxacor on food or feed crops in the United
States. In conducting this exposure assessment, EPA assumed tolerance
level residues and 100% crop treated, resulting in a large
overestimation of dietary exposure and protective of any chronic
dietary exposure scenario. Further, regional consumption information is
taken into account through EPA's computer-based model for evaluating
the exposure of significant subpopulations including several regional
groups. Review of this regional data allows the Agency to be reasonably
certain that no regional population is exposed to residue levels higher
than those estimated by the Agency. Based on the chronic dietary
exposure TMRC's of 0.000205 mg/kg/day for the U.S. population and
0.000828 mg/kg/day for the most highly exposed population subgroup
(non-nursing infants less than one year old), this chronic dietary risk
assessment resulted in the use of 5.13% of the RfD for the U.S.
population and 20.7% of the RfD for the most highly exposed population
subgroup. A cancer dietary MOE was calculated to be 1,950.
2. From drinking water. For the purposes of assessing chronic
exposure in drinking water, EPA has considered the registered uses and
the available data on persistence and mobility for benoxacor. The
Agency has determined through a qualitative risk assessment that the
physical and chemical characteristics of benoxacor are such that it is
not expected to impact water resources. While benoxacor is mobile, it
is not persistent (half-life in soil of 49 days under aerobic
conditions and 70 days anaerobically). In light of these findings, EPA
believes that benoxacor's use will not impact ground water or surface
water resources, and therefore, is not expected to lead to exposure to
humans through drinking water. If new uses are added in the future, OPP
will reassess the potential impacts of benoxacor on drinking water as a
part of the aggregate risk assessment process.
3. From non-dietary exposure. All registered metolachlor products
to which benoxacor is added as a safener are commercial agricultural
products not registered for residential use. The potential for non-
occupational exposure to benoxacor by the general population is
therefore unlikely except for the potential residues in food crops
discussed above.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' The Agency believes that ``available
information'' in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
EPA does not have, at this time, available data to determine
whether benoxacor 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,
benoxacor 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 benoxacor has a common mechanism of toxicity
with other substances.
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. Since there are no acute toxicological concerns for
benoxacor, EPA has no cause for concern for acute aggregate exposure.
2. Chronic risk. Using the TMRC exposure assumptions described
above, EPA has concluded that aggregate chronic exposure to benoxacor
from food and water will utilize 5.13% of the RfD for the U.S.
population. The major identifiable subgroup with the highest aggregate
exposure is non-nursing infants less than one year old (utilizing 20.7%
of the RfD). EPA generally has no concern for exposures below 100% of
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. EPA does not expect the aggregate exposure to
exceed 100% of the RfD. EPA concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to benoxacor
residues.
E. Aggregate Cancer Risk for U.S. Population
The carcinogenic risk from food uses of benoxacor for the general
U.S. population was calculated by comparing the dietary exposure from
benoxacor to the NOEL identified for use with the cancer risk
assessment. Based on the NOEL selected by the CPRC for cancer risk
characterization of 0.4 mg/kg/day, the cancer risk was estimated to
result in a MOE of 1,950 contributed through all the published, pending
and new uses for benoxacor. Based upon the extreme conservatism of the
dietary exposure estimates and the fact that tumors were
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observed only at dose levels far in excess of the selected NOEL, this
MOE is at a level which the Agency does not consider raising a concern
for excess lifetime cancer.
F. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children--i. In general. In
assessing the potential for additional sensitivity of infants and
children to residues of benoxacor, EPA considered data from
developmental toxicity studies in the rat and rabbit and a 2-generation
reproduction study in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure gestation. Reproduction
studies provide information relating to effects from exposure to the
pesticide on the reproductive capability of mating animals and data on
systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre- and post-natal toxicity and the
completeness of the database 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 MOE analysis or through using uncertainty (safety)
factors in calculating a dose level that poses no appreciable risk to
humans. In either case, EPA generally defines the level of appreciable
risk as exposure that is greater than 1/100 of the NOEL in the animal
study appropriate to the particular risk assessment. This 100-fold
uncertainty (safety) factor/MOE (safety) is designed to account for
inter-species extrapolation and intra-species variability. EPA believes
that reliable data support using the 100-fold uncertainty factor rather
than the 1,000-fold margin/factor, when EPA has a complete data base
under existing guidelines and when the severity of the effect in
infants or children, the potency or unusual toxic properties of a
compound, or the quality of the exposure data do not raise concerns
regarding the adequacy of the standard margin/factor.
ii. Developmental toxicity studies. See Toxicological Profile in
Unit II.A. of this preamble.
iii. Reproductive toxicity study. See Toxicological Profile in Unit
II.A. of this preamble.
iv. Pre- and post-natal sensitivity. There is no evidence of
increased sensitivity to young rats or rabbits following pre- or post-
natal exposure to benoxacor.
v. Conclusion. The toxicological data base for evaluating pre- and
post-natal toxicity for benoxacor is complete with respect to current
data requirements. Because both developmental and reproductive effects
occurred in the presence of parental (systemic) toxicity, these data do
not suggest an increased pre- or post-natal sensitivity of children and
infants to benoxacor exposure. Based on the above, EPA concludes that
reliable data support use of a 100-fold MOE/uncertainty factor, rather
than the standard 1,000-fold margin/factor to protect infants and
children. EPA concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
benoxacor residues.
2. Acute risk. Since there are no acute toxicological concerns for
benoxacor, EPA has no cause for concern for acute aggregate exposure.
3. Chronic risk. Using the conservative exposure assumptions
described above, EPA has concluded that aggregate exposure to benoxacor
from food will range from 3.69% of the RfD for females 13+ years, to
20.7% of the RfD for non-nursing infants less than one year old. EPA
generally has no concern for exposures below 100% of the RfD because
the RfD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health. EPA does not expect the aggregate exposure to exceed 100% of
the RfD. EPA concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
benoxacor residues.
4. Cancer risk. Carcinogenic risk to infants and children from food
uses of benoxacor is addressed under Aggregate Cancer Risk for U.S.
Population under Unit II.E. of this preamble.
III. Other Considerations
A. Metabolism In Plants and Animals
The metabolism of benoxacor in plants and animals is adequately
understood for purposes of these tolerances.
B. Analytical Enforcement Methodology
Adequate enforcement methodology, GC/NPD, is available to enforce
the tolerance expression. An analytical methodology for the
determination of benoxacor and its metabolites in plant and animal
commodities (Ciba Analytical Method AG536(C)) is available from: Calvin
Furlow, Public Information and Records Integrity Branch, Information
Resources and Services Division (7502C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location and telephone number: Rm. 119FF, CM#2, 1921 Jefferson
Davis Hwy., Arlington, VA 22202, (703) 305-5229.
C. Magnitude of Residues
The magnitude of the residue in plants is adequately understood for
the purposes of these tolerances.
D. International Residue Limits
No Codex Maximum Residue Levels have been established for residues
of benoxacor on commodities for which a tolerance for metolachlor
exist.
IV. Conclusion
Therefore, the tolerances are established for benoxacor (4-
(dichloroacetyl)-3,4-dihydro-3-methyl-2H-1,4-benzoxazine) at 0.01 ppm
when used as an inert ingredient (safener) in pesticide formulations
containing metolachlor in or on raw agricultural commodities for which
tolerances have been established for metolachlor.
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance regulation issued by EPA under
new section 408(e) and (l)(6) as was provided in the old section 408
and in section 409. However, the period for filing objections is 60
days, rather than 30 days. EPA currently has procedural regulations
which govern the submission of objections and hearing requests. These
regulations will require some modification to reflect the new law.
However, until those modifications can be made, EPA will continue to
use those procedural regulations with appropriate adjustments to
reflect the new law.
Any person may, by April 14, 1998, file written objections to any
aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's
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contentions on such issues, and a summary of any evidence relied upon
by the requestor (40 CFR 178.27). A request for a hearing will be
granted if the Administrator determines that the material submitted
shows the following: There is genuine and substantial issue of fact;
there is a reasonable possibility that available evidence identified by
the requestor would, if established, resolve one or more of such issues
in favor of the requestor, taking into account uncontested claims or
facts to the contrary; and resolution of the factual issues in the
manner sought by the requestor would be adequate to justify the action
requested (40 CFR 178.32). Information submitted in connection with an
objection or hearing request may be claimed confidential by marking any
part or all of that information as CBI. Information so marked will not
be disclosed except in accordance with procedures set forth in 40 CFR
part 2. A copy of the information that does not contain CBI must be
submitted for inclusion in the public record. Information not marked
confidential may be disclosed publicly by EPA without prior notice.
VI. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number [OPP-300617] (including any comments and data submitted
electronically). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The public
record is located in Room 119 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
Electronic comments may be sent directly to EPA at:
[email protected].
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
This final rule establishes tolerances under FFDCA section 408(d)
in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since these tolerances and exemptions that are
established on the basis of a petition under FFDCA section 408(d), such
as the tolerances in this final rule, do not require the issuance of a
proposed rule, the requirements of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels, or expanding exemptions
might adversely impact small entities and concluded, as a generic
matter, that there is no adverse economic impact. The factual basis for
the Agency's generic certification for tolerance actions published on
May 4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This rule is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: February 10, 1998.
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. 346a and 371.
2. Section 180.460 is revised to read as follows:
Sec. 180.460 Benoxacor; tolerances for residues.
(a) General . Tolerances are established for residues of the inert
ingredient (safener) benoxacor (4-(dichloroacetyl)-3,4-dihydro-3-
methyl-2H-1,4-benzoxazine) at 0.01 ppm when used in pesticide
formulations containing metolachlor in or on raw agricultural
commodities for which tolerances have been established for metolachlor.
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 98-3750 Filed 2-12-98; 8:45 am]
BILLING CODE 6560-50-F