Proquinazid; Pesticide Tolerances, 18810-18815 [2014-07563]
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highest residues; the OECD tolerancecalculation procedure does not permit
this.
C. Revisions to Petitioned-for Tolerances
For pepper and eggplant, the available
data indicate that residues may be
greater than the proposed 0.6 ppm
tolerance. Using the OECD tolerancecalculation procedure, EPA determined
that a tolerance of 1.5 ppm is
appropriate for both pepper and
eggplant. Based on the highest-average
field-trial residue and an average tomato
paste processing factor of 2.94x, the
Agency concluded that a tomato, paste
tolerance of 1.2 ppm should be
established.
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V. Conclusion
Therefore, tolerances are established
for residues of metaflumizone, (E and Z
isomers; 2-[2-(4-cyanophenyl)-1-[3(trifluoromethyl)phenyl]ethylidene]-N[4-(trifluoromethoxy)phenyl]
hydrazinecarboxamide) and its
metabolite 4-{2-oxo-2-[3(trifluoromethyl)phenyl]ethyl}benzonitrile, in or on eggplant at 1.5
ppm; pepper at 1.5 ppm; tomato at 0.60
ppm; and tomato, paste at 1.2 ppm.
VI. Statutory and Executive Order
Reviews
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). 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 FFDCA section 408(d), such as
the tolerances in this final rule, do not
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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 FFDCA section 408(n)(4). 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) (2 U.S.C. 1501 et seq.).
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) (15 U.S.C. 272 note).
VII. Congressional Review Act
Pursuant to the Congressional Review
Act (5 U.S.C. 801 et seq.), 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 action 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: March 28, 2014.
Lois Rossi,
Director, Registration Division, Office of
Pesticide Programs.
Therefore, 40 CFR chapter I is
amended as follows:
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PART 180—[AMENDED]
1. The authority citation for part 180
continues to read as follows:
■
Authority: 21 U.S.C. 321(q), 346a and 371.
2. In § 180.657:
a. Add alphabetically the
commodities to the table in paragraph
(a).
■ b. Add footnote 1 to the table in
paragraph (a).
The additions read as follows:
■
■
§ 180.657 Metaflumizone; tolerances for
residues.
(a) General. * * *
Parts per
million
Commodity
*
*
*
*
Eggplant 1 ..................................
*
*
*
*
*
Pepper 1 ....................................
Tomato 1 ....................................
Tomato, paste 1 .........................
*
1.5
1.5
0.60
1.2
1 There are no U.S. registrations as of April
4, 2014.
*
*
*
*
*
[FR Doc. 2014–07559 Filed 4–3–14; 8:45 am]
BILLING CODE 6560–50–P
ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 180
[EPA–HQ–OPP–2012–0164; FRL–9903–11]
Proquinazid; Pesticide Tolerances
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
This regulation establishes
tolerances for residues of proquinazid in
or on grape and raisin. DuPont Crop
Protection requested these tolerances
under the Federal Food, Drug, and
Cosmetic Act (FFDCA).
DATES: This regulation is effective April
4, 2014. Objections and requests for
hearings must be received on or before
June 3, 2014, and must be filed in
accordance with the instructions
provided in 40 CFR part 178 (see also
Unit I.C. of the SUPPLEMENTARY
INFORMATION).
SUMMARY:
The docket for this action,
identified by docket identification (ID)
number EPA–HQ–OPP–2012–0164, is
available at https://www.regulations.gov
or at the Office of Pesticide Programs
Regulatory Public Docket (OPP Docket)
in the Environmental Protection Agency
Docket Center (EPA/DC), EPA West
ADDRESSES:
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Bldg., Rm. 3334, 1301 Constitution Ave.
NW., Washington, DC 20460–0001. The
Public Reading Room is open from 8:30
a.m. to 4:30 p.m., Monday through
Friday, excluding legal holidays. The
telephone number for the Public
Reading Room is (202) 566–1744, and
the telephone number for the OPP
Docket is (703) 305–5805. Please review
the visitor instructions and additional
information about the docket available
at https://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Lois
Rossi, Registration Division (7505P),
Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave. NW., Washington,
DC 20460–0001; telephone number:
(703) 305–7090; email address:
RDFRNotices@epa.gov.
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. The following
list of North American Industrial
Classification System (NAICS) codes is
not intended to be exhaustive, but rather
provides a guide to help readers
determine whether this document
applies to them. Potentially affected
entities may include:
• Crop production (NAICS code 111).
• Animal production (NAICS code
112).
• Food manufacturing (NAICS code
311).
• Pesticide manufacturing (NAICS
code 32532).
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 https://www.ecfr.gov/cgi-bin/textidx?&c=ecfr&tpl=/ecfrbrowse/Title40/
40tab_02.tpl.
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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–2012–0164 in the subject line on
the first page of your submission. All
objections and requests for a hearing
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must be in writing, and must be
received by the Hearing Clerk on or
before June 3, 2014. 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 (excluding
any Confidential Business Information
(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 the non-CBI copy of your
objection or hearing request, identified
by docket ID number EPA–HQ–OPP–
2012–0164, by one of the following
methods:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the online
instructions for submitting comments.
Do not submit electronically any
information you consider to be CBI or
other information whose disclosure is
restricted by statute.
• Mail: OPP Docket, Environmental
Protection Agency Docket Center (EPA/
DC), (28221T), 1200 Pennsylvania Ave.
NW., Washington, DC 20460–0001.
• Hand Delivery: To make special
arrangements for hand delivery or
delivery of boxed information, please
follow the instructions at https://
www.epa.gov/dockets/contacts.htm.
Additional instructions on
commenting or visiting the docket,
along with more information about
dockets generally, is available at
https://www.epa.gov/dockets.
II. Summary of Petitioned-For
Tolerance
In the Federal Register of May 2, 2012
(77 FR 25954) (FRL–9346–1), EPA
issued a document pursuant to FFDCA
section 408(d)(3), 21 U.S.C. 346a(d)(3),
announcing the filing of a pesticide
petition (PP 1E7972) by DuPont Crop
Protection, Stine Haskell Research
Center, P.O. Box 30, Newark, DE 19714–
0030. The petition requested that 40
CFR 180.674 be amended by
establishing tolerances for residues of
the fungicide proquinazid, 6-Iodo-2propoxy-3-propyl-3H-quinazolin-4-one,
in or on imported commodities to
include grape at 0.5 parts per million
(ppm) and raisin at 1.0 ppm. That
document referenced a summary of the
petition prepared by DuPont Crop
Protection., the registrant, which is
available in the docket, https://
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
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changed one of the requested
commodity names from raisin; to grape,
raisin; and added a significant figure to
the numerical grape tolerance. 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 FFDCA section
408(b)(2)(D), and the factors specified in
FFDCA section 408(b)(2)(D), EPA has
reviewed the available scientific data
and other relevant information in
support of this action. EPA has
sufficient data to assess the hazards of
and to make a determination on
aggregate exposure for proquinazid
including exposure resulting from the
tolerances established by this action.
EPA’s assessment of exposures and risks
associated with proquinazid 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.
Proquinazid has no significant acute
toxicity via the oral, dermal, or
inhalation routes of exposure. It is not
an eye or skin irritant and does not
cause skin sensitization. Based on the
results of a 28-day dermal study in rats
(as well as the dermal lethal dose (LD)
study), proquinazid is poorly absorbed
through the skin.
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The liver and thyroid are the primary
target organs for proquinazid. In
rodents, body weight/body weight gain
reductions, increased liver and thyroid
organ weights, hypertrophy/
hyperplasia, liver enzyme induction,
and thyroid hormone changes were seen
across varying durations and routes of
exposure in rodents but not in dogs. In
the 90-day oral rat study, the low dose
effects of proquinazid are characterized
primarily by altered thyroid hormones
and associated follicular cell
hypertrophy in the thyroid. Decrements
in body weight and nutritional
parameters, as well as histopathological
changes in the liver (including
hypertrophy) were observed at higher
doses. In a 28-day oral rat study,
hypertrophy of the thyroid and liver
was completely reversible after a 6 week
recovery period. In chronic rodent
studies, non-neoplastic effects in both
mice and rats included thyroid
follicular hyperplasia and hypertrophy,
with associated thyroid hormone
changes (only investigated in rats), and
some marked hepatic lesions, i.e.,
necrosis and hyperplasia (including
oval cell hyperplasia in rats). In
addition, chronic exposure in rats led to
increases in the incidence of liver and
thyroid tumors. The mode of action for
the thyroid tumors in rats involves early
changes in liver enzyme regulation that
lead to dis-regulation of thyroid
hormone homeostasis thyroid follicular
hypertrophy/hyperplasia, and thyroid
follicular adenoma formation. Mode of
action data were submitted on the
thyroid follicular cell tumors observed
in male rats and the
cholangiocarcinomas observed in female
rats. The hypothesized mode of action
(i.e., non-genotoxic) for each tumor type
(i.e, the thyroid and
cholangiocarcinoma) was supported by
adequate studies that clearly identified
the sequence of key events, doseresponse concordance, and temporal
relationship to the tumor types. No
treatment-related tumors were observed
in male or female mice. The overall
weight-of-evidence was considered
sufficient to demonstrate that
proquinazid thyroid follicular tumors
are the result of an anti-thyroidal mode
of action and that a carcinogenic
response would not be expected at
doses below the threshold for changes
in liver enzyme regulation leading to
dis-regulation of thyroid hormone
homeostasis. The data also shows that
rats are substantially more sensitive
than humans to the development of
thyroid follicular cell tumors in
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response to thyroid hormone imbalance.
Proquinazid induced
cholangiocarcinomas in female rats only
at doses that produced marked liver
toxicity and oval cell hyperplasia
microscopically. In contrast, in both
male and female rats, doses that
produced less severe or no
hepatotoxicity or oval cell proliferation
did not produce chlolangiocarcinomas.
Therefore, at high enough doses,
proquinazid can cause these
biochemical and histopathological
effects in livers of rodents but is
unlikely to be carcinogenic at doses
below those causing these changes. In
contrast, in both male and female rats,
doses that produced less severe or no
hepatoxicity or oval cell proliferation
did not produce cholangiocarcinomas.
Therefore, at high enough doses,
proquinazid can cause these
biochemical and histopathological
effects in livers of rodents but is
unlikely to be carcinogenic at doses
below those causing these changes.
Therefore, the Agency determined that
quantification of risk using a non-linear
approach (i.e., reference dose (RfD) will
adequately protect for all chronic
toxicity, including carcinogenicity, that
could result from exposure to
proquinazid.
There is no mutagenicity concerns
from in vivo or in vitro genetic toxicity
assays. Proquinazid was not found to be
immunotoxic. No evidence of increased
quantitative or qualitative susceptibility
was seen following in utero exposure to
proquinazid with rats or rabbits in the
prenatal developmental studies or in
young rats in the 2-generation
reproduction study. The 2-generation rat
reproduction study resulted in no
effects on reproduction or fertility. The
offspring effects (decreases in F1 pup
weight during lactation) occurred at the
same dose which caused parental effects
(thyroid hypertrophy, reduced body
weight gain, and food consumption).
Evidence of developmental delays were
observed in developmental toxicity
studies in rabbits and rats and were
characterized by reduced fetal weight
and an increased incidence of retarded
ossification and patent ductus
arteriosus, respectively. These
developmental effects occurred in the
presence of maternal toxicity and were
considered of equal toxicity.
There is limited evidence for
neurotoxicity following oral exposures
to proquinazid. Following a single
exposure, evidence for neurotoxicity at
the lowest observed adverse effect level
(LOAEL) was limited to decreased
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motor activity in both sexes with no
behavioral or neuropathology changes.
At doses above the study LOAEL other
effects including decreased grip strength
and food splay were observed.
Following repeated (dietary) exposures,
there were no treatment-related clinical
signs of neurotoxicity, behavioral
changes or neuropathology. Specific
information on the studies received and
the nature of the adverse effects caused
by proquinazid as well as the no
observed adverse effect level (NOAEL)
and the LOAEL from the toxicity studies
can be found at https://
www.regulations.gov in document
‘‘Proquinazid: Human Health Risk
Assessment for the Tolerance on
Imported Grapes’’ dated September
2013 at pages 23 through 35 in docket
ID number EPA–HQ–OPP–2012–0164.
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
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 https://www.epa.gov/
pesticides/factsheets/riskassess.htm.
A summary of the toxicological
endpoints for proquinazid used for
human risk assessment is shown in
Table 1. of this unit. Because only oral
exposure are anticipated for imported
grapes, no other endpoints are relevant
such as dermal and inhalation
exposures.
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TABLE 1—SUMMARY OF TOXICOLOGICAL DOSES AND ENDPOINTS FOR PROQUINAZID FOR USE IN HUMAN HEALTH RISK
ASSESSMENT
Point of departure
and uncertainty/safety factors
RfD, PAD, LOC for
risk assessment
Study and toxicological effects
Acute dietary (General population including infants and
children).
NOAEL = 50 mg/kg/
bw UFA = 10x.
UFH = 10x
FQPA SF = 10x
UFDB
Acute RfD = aPAD =
0.050 mg/kg/bw.
Acute Neurotoxicity Study-Rat.
LOAEL = 100 mg/kg/bw based on decreased motor activity
seen in females on day 1.
Chronic dietary (All populations)
NOAEL= 1.2 mg/kg/
day.
UFA = 13x
UFH = 10x
FQPA SF = 10x
UFDB
Chronic RfD = cPAD Chronic Toxicity/Carcinogenicity Study-Rat.
= 0.004 mg/kg/day. LOAEL = 12 mg/kg/day based on increases in non-neoplastic
liver lesions and changes in thyroid hormones and thyroid
pathology.
Cancer (Oral, dermal, inhalation).
A non linear approach (i.e., RfD will adequately protect for all chronic toxicity, including carcinogenicity, that
could result from exposure to proquinazid. The cPAD for proquinazid will protect for carcinogenic effects because it is below the level that caused changes in liver enzyme regulation and liver toxicity.
Exposure/scenario
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FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest observed adverse effect level. mg/kg/bw = milligram/kilogram/body
weight. NOAEL = no observed adverse effect level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFDB = to account for the absence of data or other data deficiency. UFH =
potential variation in sensitivity among members of the human population (intraspecies).
C. Exposure Assessment
1. Dietary exposure from food and
feed uses. In evaluating dietary
exposure to proquinazid, EPA
considered exposure under the
petitioned-for tolerances as well as all
existing proquinazid tolerances in 40
CFR 180.674. EPA assessed dietary
exposures from proquinazid 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.
Such effects were identified for
proquinazid. In estimating acute dietary
exposure, EPA used food consumption
information from the United States
Department of Agriculture (USDA)
2003–2008 National Health and
Nutrition Examination Survey, What We
Eat in America (NHANES/WWIA). As to
residue levels in food, EPA used
tolerance level residues and 100%
percent crop treated (PCT). Default
processing factors were used for grape
juice. The Agency considers these to be
highly conservative assessments.
ii. Chronic exposure. In conducting
the chronic dietary exposure assessment
EPA used the food consumption data
from the USDA 2003–2008 NHANES/
WWEIA. As to residue levels in food,
EPA used tolerance level residues and
100% PCT.
iii. Cancer. Quantification of risk
using a non-linear approach (i.e., RfD
will adequately protect for all chronic
toxicity, including carcinogenicity,
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which could result from exposure to
proquinazid. Cancer risk was assessed
using the same exposure estimates as
discussed in Unit III.C.1.ii., chronic
exposure.
iv. Anticipated residue and PCT
information. EPA did not use
anticipated residue and/or PCT
information in the dietary assessment
for proquinazid. Tolerance level
residues and/or 100% CT were assumed
for all food commodities.
2. Dietary exposure from drinking
water. There is no drinking water
exposure in the U.S. associated with the
establishment of an import tolerance.
3. From non-dietary exposure. The
term ‘‘residential exposure’’ is used in
this document to refer to nonoccupational, non-dietary exposure
(e.g., for lawn and garden pest control,
indoor pest control, termiticides, and
flea and tick control on pets).
Proquinazid is not registered for any
specific use patterns that would result
in residential exposure.
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 proquinazid to
share a common mechanism of toxicity
with any other substances, and
proquinazid does not appear to produce
a toxic metabolite produced by other
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substances. For the purposes of this
tolerance action, therefore, EPA has
assumed that proquinazid 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 https://
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
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.
No evidence of increased quantitative or
qualitative susceptibility was seen
following in utero exposure to
proquinazid with rats or rabbits in the
prenatal developmental studies or in
young rats in the 2-generation
reproduction study. The 2-generation rat
reproduction study resulted in no
effects on reproduction or fertility. The
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offspring effects (decreases in F1 pup
weight during lactation) occurred at the
same dose which caused parental effects
(thyroid hypertrophy, reduced body
weight gain, and food consumption).
Evidence of developmental delays were
observed in developmental toxicity
studies in rabbits and rats were
characterized by reduced fetal weight
and an increased incidence retarded
ossification and paten ductus arteriosus,
respectively. These developmental
effects occurred in the presence of
maternal toxicity. For the rats, the
developmental effects were seen in the
presence of clear maternal toxicity,
including a marked reduction in body
weight gain after adjustment for uterine
contents and were considered to be of
equal severity.
3. Conclusion. In determining
whether there are reliable data to amend
or remove the presumptive 10X FQPA
safety factor, EPA considered the
following factors:
i. The toxicity database for
proquinazid required by 40 CFR Part
158 is complete. However, there
remains some uncertainty regarding the
potential for proquinazid effects on the
thyroid in the young. Effects on the
thyroid (manifested as changes in
hormones, weight, and histopathology)
following proquinazid exposure were
consistently observed in adult animals
(rats) following subchronic and chronic
exposures. Thyroid effects, however,
were not assessed in studies involving
neo- or postnatal animals, and EPA is
lacking data showing the comparative
effect of proquinazid on the thyroid in
adult and neo- and postnatal animals.
ii. There is only limited evidence that
proquinazid is a neurotoxic chemical
and there is no need for a
developmental neurotoxicity study or
additional UFs to account for
neurotoxicity. There is limited evidence
for neurotoxicity following oral
exposures to proquinazid. Following a
single exposure, evidence for
neurotoxicity at the LOAEL was limited
to decreased motor activity in both
sexes with no behavioral or
neuropathology changes. At doses above
the study LOAEL other effects including
decreased grip strength and foot splay
were observed. Following repeated
(dietary) exposures, there were no
treatment-related clinical signs of
neurotoxicity, behavioral changes, or
neuropathology.
iii. As discussed in Unit III.D.2., there
is no evidence that proquinazid results
in increased susceptibility with in utero
rats or rabbits in the prenatal
developmental studies or in young rats
in the 2-generation reproduction study.
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iv. There are no residual uncertainties
identified in the exposure databases.
The dietary food exposure assessments
were performed based on 100% CT and
tolerance-level residues. Drinking water
is not a factor because this is an import
tolerance assessment. These
assessments will not underestimate the
exposure and risks posed by
proquinazid.
Despite the lack of any indication of
sensitivity in the young and the very
conservative exposure assessment, EPA
has determined that it lacks reliable data
to choose a FQPA safety factor other
than the default value of 10X given (1)
the absence of data on thyroid effects on
the young, including comparative
thyroid data on adults and the young,
and (2) the fact that thyroid effects were
the most sensitive effect seen in adult
animals. At the same time, after
considering all of the data on
proquinazid toxicity and exposure, EPA
has also determined that application of
a FQPA safety factor of 10X, in
conjunction with inter- and intraspecies
safety factors, will result in a risk
assessment that protects the safety of
infants and children. Although there is
some uncertainty as to whether the
young might have greater sensitivity to
proquinazid’s thyroid effects due to the
absence of comparative thyroid data,
two developmental studies and a
reproduction study have otherwise
shown no indication of sensitivity in the
young to proquinazid. Additionally, the
exposure assessment provides an extra
margin of safety given that it is based on
the conservative assumption that all
grapes, and all food products derived
from grapes (e.g., raisins, grape juice,
wine), consumed in the United States
bear residues of proquinazid at the
appropriate tolerance level. This
assumption is particularly conservative
here because proquinazid is not
registered for use in the United States.
Taking into account all of these
considerations, EPA concludes that no
safety factor in addition to the inter- and
intraspecies factors, and the default
FQPA safety factor is needed to protect
the safety of infants and children.
residential exposure to the appropriate
PODs to ensure that an adequate MOE
exists.
1. Acute risk. Using the exposure
assumptions discussed in this unit for
acute dietary exposure from food to
proquinazid will occupy 18% of the
aPAD for children 1–2 years old, the
population group receiving the greatest
exposure.
2. Chronic risk. Using the exposure
assumptions described in this unit for
chronic exposure, EPA has concluded
that chronic exposure to proquinazid
from food will utilize 47% of the cPAD
for children 1–2 years old the
population group receiving the greatest
exposure. There are no residential uses
for proquinazid. Based on the
explanation in Unit III.C.3., regarding
residential use patterns, chronic
residential exposure to residues of
proquinazid is not expected.
3. Aggregate cancer risk for U.S.
population. The cPAD of 0.004 mg/kg/
day will be protective of both noncancer and cancer effects, including rat
tumors (liver, thyroid, and
cholangiocarcinomas). As discussed in
Unit III.E., aggregate exposure to
proquinazid is below the cPAD.
4. 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 proquinazid
residues.
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
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
United Nations Food and Agriculture
Organization/World Health
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IV. Other Considerations
A. Analytical Enforcement Methodology
Adequate enforcement methodology
(gas chromatography with electron
capture detection) is available to enforce
the proposed tolerances for residues of
proquinazid on grape commodities.
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;
email address: residuemethods@
epa.gov.
B. International Residue Limits
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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 proquinazid. However, the
tolerances established in this rule are
harmonized with Canadian MRLs.
C. Revisions to Petitioned-For
Tolerances
The Agency is changing the proposed
commodity definition for raisins from
raisin to grape, raisin. The change in the
commodity definition is to make the
tolerance consistent with Agency
naming-conventions for commodities
and crop groups. No changes are
recommended for the proposed
tolerance levels, but the grape tolerance
is being revised from 0.5 to 0.50 to
correct the number of significant figures.
V. Conclusion
Therefore, tolerances are established
for residues of proquinazid in or on
grape at 0.50 ppm and grape, raisin 1.0
ppm.
TKELLEY on DSK3SPTVN1PROD with RULES
VI. Statutory and Executive Order
Reviews
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). 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).
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Since tolerances and exemptions that
are established on the basis of a petition
under FFDCA section 408(d), such as
the tolerance in this final rule, do not
require the issuance of a proposed rule,
the requirements of the Regulatory
Flexibility Act (RFA) (5 U.S.C. 601 et
seq.), do not apply.
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 FFDCA section 408(n)(4). 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) (2 U.S.C. 1501 et seq.).
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) (15 U.S.C. 272 note).
VII. Congressional Review Act
Pursuant to the Congressional Review
Act (5 U.S.C. 801 et seq.), 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 action 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.
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Dated: March 25, 2014.
Marty Marnell,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is
amended as follows:
PART 180—[AMENDED]
1. The authority citation for part 180
continues to read as follows:
■
Authority: 21 U.S.C. 321(q), 346a and 371.
■
2. Add § 180.674 to read as follows:
§ 180.674 Proquinazid; tolerances for
residues.
(a) General. Tolerances are
established for residues of the fungicide,
proquinazid, including its metabolites
and degradates, in or on the
commodities listed in the following
table. Compliance with the tolerance
levels specified in the following table is
to be determined by measuring only
proquinazid, [6-Iodo-2-propoxy-3propyl-3H-quinazolin-4-one), in or on
the following commodities:
Commodity
Parts per
million
Grape 1 ................................
Grape, raisin 1 .....................
1 No
0.50
1.0
U.S. registrations for Proquinazid.
(b) Section 18 emergency exemptions.
[Reserved]
(c) Tolerances with regional
registrations. [Reserved]
(d) Indirect or inadvertent residues.
[Reserved]
[FR Doc. 2014–07563 Filed 4–3–14; 8:45 am]
BILLING CODE 6560–50–P
ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 180
[EPA–HQ–OPP–2011–0110; FRL–9400–3]
Imazapic; Pesticide Tolerances
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
This regulation establishes a
tolerance for residues of imazapic in or
on soybean, seed. BASF Corporation
requested this tolerance under the
Federal Food, Drug, and Cosmetic Act
(FFDCA).
DATES: This regulation is effective April
4, 2014. Objections and requests for
hearings must be received on or before
June 3, 2014, and must be filed in
accordance with the instructions
provided in 40 CFR part 178 (see also
Unit I.C. of the SUPPLEMENTARY
INFORMATION).
SUMMARY:
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[Federal Register Volume 79, Number 65 (Friday, April 4, 2014)]
[Rules and Regulations]
[Pages 18810-18815]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-07563]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[EPA-HQ-OPP-2012-0164; FRL-9903-11]
Proquinazid; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: This regulation establishes tolerances for residues of
proquinazid in or on grape and raisin. DuPont Crop Protection requested
these tolerances under the Federal Food, Drug, and Cosmetic Act
(FFDCA).
DATES: This regulation is effective April 4, 2014. Objections and
requests for hearings must be received on or before June 3, 2014, 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: The docket for this action, identified by docket
identification (ID) number EPA-HQ-OPP-2012-0164, is available at https://www.regulations.gov or at the Office of Pesticide Programs Regulatory
Public Docket (OPP Docket) in the Environmental Protection Agency
Docket Center (EPA/DC), EPA West
[[Page 18811]]
Bldg., Rm. 3334, 1301 Constitution Ave. NW., Washington, DC 20460-0001.
The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
Public Reading Room is (202) 566-1744, and the telephone number for the
OPP Docket is (703) 305-5805. Please review the visitor instructions
and additional information about the docket available at https://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Lois Rossi, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone
number: (703) 305-7090; email address: RDFRNotices@epa.gov.
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.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
Crop production (NAICS code 111).
Animal production (NAICS code 112).
Food manufacturing (NAICS code 311).
Pesticide manufacturing (NAICS code 32532).
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 https://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.
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-2012-0164 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
June 3, 2014. 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 (excluding any Confidential Business Information (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 the non-CBI copy of your objection or hearing
request, identified by docket ID number EPA-HQ-OPP-2012-0164, by one of
the following methods:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be CBI or other
information whose disclosure is restricted by statute.
Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC
20460-0001.
Hand Delivery: To make special arrangements for hand
delivery or delivery of boxed information, please follow the
instructions at https://www.epa.gov/dockets/contacts.htm.
Additional instructions on commenting or visiting the docket, along
with more information about dockets generally, is available at https://www.epa.gov/dockets.
II. Summary of Petitioned-For Tolerance
In the Federal Register of May 2, 2012 (77 FR 25954) (FRL-9346-1),
EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C.
346a(d)(3), announcing the filing of a pesticide petition (PP 1E7972)
by DuPont Crop Protection, Stine Haskell Research Center, P.O. Box 30,
Newark, DE 19714-0030. The petition requested that 40 CFR 180.674 be
amended by establishing tolerances for residues of the fungicide
proquinazid, 6-Iodo-2-propoxy-3-propyl-3H-quinazolin-4-one, in or on
imported commodities to include grape at 0.5 parts per million (ppm)
and raisin at 1.0 ppm. That document referenced a summary of the
petition prepared by DuPont Crop Protection., the registrant, which is
available in the docket, https://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
changed one of the requested commodity names from raisin; to grape,
raisin; and added a significant figure to the numerical grape
tolerance. 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 FFDCA section 408(b)(2)(D), and the factors
specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available
scientific data and other relevant information in support of this
action. EPA has sufficient data to assess the hazards of and to make a
determination on aggregate exposure for proquinazid including exposure
resulting from the tolerances established by this action. EPA's
assessment of exposures and risks associated with proquinazid 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.
Proquinazid has no significant acute toxicity via the oral, dermal,
or inhalation routes of exposure. It is not an eye or skin irritant and
does not cause skin sensitization. Based on the results of a 28-day
dermal study in rats (as well as the dermal lethal dose (LD) study),
proquinazid is poorly absorbed through the skin.
[[Page 18812]]
The liver and thyroid are the primary target organs for
proquinazid. In rodents, body weight/body weight gain reductions,
increased liver and thyroid organ weights, hypertrophy/hyperplasia,
liver enzyme induction, and thyroid hormone changes were seen across
varying durations and routes of exposure in rodents but not in dogs. In
the 90-day oral rat study, the low dose effects of proquinazid are
characterized primarily by altered thyroid hormones and associated
follicular cell hypertrophy in the thyroid. Decrements in body weight
and nutritional parameters, as well as histopathological changes in the
liver (including hypertrophy) were observed at higher doses. In a 28-
day oral rat study, hypertrophy of the thyroid and liver was completely
reversible after a 6 week recovery period. In chronic rodent studies,
non-neoplastic effects in both mice and rats included thyroid
follicular hyperplasia and hypertrophy, with associated thyroid hormone
changes (only investigated in rats), and some marked hepatic lesions,
i.e., necrosis and hyperplasia (including oval cell hyperplasia in
rats). In addition, chronic exposure in rats led to increases in the
incidence of liver and thyroid tumors. The mode of action for the
thyroid tumors in rats involves early changes in liver enzyme
regulation that lead to dis-regulation of thyroid hormone homeostasis
thyroid follicular hypertrophy/hyperplasia, and thyroid follicular
adenoma formation. Mode of action data were submitted on the thyroid
follicular cell tumors observed in male rats and the
cholangiocarcinomas observed in female rats. The hypothesized mode of
action (i.e., non-genotoxic) for each tumor type (i.e, the thyroid and
cholangiocarcinoma) was supported by adequate studies that clearly
identified the sequence of key events, dose-response concordance, and
temporal relationship to the tumor types. No treatment-related tumors
were observed in male or female mice. The overall weight-of-evidence
was considered sufficient to demonstrate that proquinazid thyroid
follicular tumors are the result of an anti-thyroidal mode of action
and that a carcinogenic response would not be expected at doses below
the threshold for changes in liver enzyme regulation leading to dis-
regulation of thyroid hormone homeostasis. The data also shows that
rats are substantially more sensitive than humans to the development of
thyroid follicular cell tumors in response to thyroid hormone
imbalance. Proquinazid induced cholangiocarcinomas in female rats only
at doses that produced marked liver toxicity and oval cell hyperplasia
microscopically. In contrast, in both male and female rats, doses that
produced less severe or no hepatotoxicity or oval cell proliferation
did not produce chlolangiocarcinomas. Therefore, at high enough doses,
proquinazid can cause these biochemical and histopathological effects
in livers of rodents but is unlikely to be carcinogenic at doses below
those causing these changes. In contrast, in both male and female rats,
doses that produced less severe or no hepatoxicity or oval cell
proliferation did not produce cholangiocarcinomas. Therefore, at high
enough doses, proquinazid can cause these biochemical and
histopathological effects in livers of rodents but is unlikely to be
carcinogenic at doses below those causing these changes. Therefore, the
Agency determined that quantification of risk using a non-linear
approach (i.e., reference dose (RfD) will adequately protect for all
chronic toxicity, including carcinogenicity, that could result from
exposure to proquinazid.
There is no mutagenicity concerns from in vivo or in vitro genetic
toxicity assays. Proquinazid was not found to be immunotoxic. No
evidence of increased quantitative or qualitative susceptibility was
seen following in utero exposure to proquinazid with rats or rabbits in
the prenatal developmental studies or in young rats in the 2-generation
reproduction study. The 2-generation rat reproduction study resulted in
no effects on reproduction or fertility. The offspring effects
(decreases in F1 pup weight during lactation) occurred at
the same dose which caused parental effects (thyroid hypertrophy,
reduced body weight gain, and food consumption). Evidence of
developmental delays were observed in developmental toxicity studies in
rabbits and rats and were characterized by reduced fetal weight and an
increased incidence of retarded ossification and patent ductus
arteriosus, respectively. These developmental effects occurred in the
presence of maternal toxicity and were considered of equal toxicity.
There is limited evidence for neurotoxicity following oral
exposures to proquinazid. Following a single exposure, evidence for
neurotoxicity at the lowest observed adverse effect level (LOAEL) was
limited to decreased motor activity in both sexes with no behavioral or
neuropathology changes. At doses above the study LOAEL other effects
including decreased grip strength and food splay were observed.
Following repeated (dietary) exposures, there were no treatment-related
clinical signs of neurotoxicity, behavioral changes or neuropathology.
Specific information on the studies received and the nature of the
adverse effects caused by proquinazid as well as the no observed
adverse effect level (NOAEL) and the LOAEL from the toxicity studies
can be found at https://www.regulations.gov in document ``Proquinazid:
Human Health Risk Assessment for the Tolerance on Imported Grapes''
dated September 2013 at pages 23 through 35 in docket ID number EPA-HQ-
OPP-2012-0164.
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 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 https://www.epa.gov/pesticides/factsheets/riskassess.htm.
A summary of the toxicological endpoints for proquinazid used for
human risk assessment is shown in Table 1. of this unit. Because only
oral exposure are anticipated for imported grapes, no other endpoints
are relevant such as dermal and inhalation exposures.
[[Page 18813]]
Table 1--Summary of Toxicological Doses and Endpoints for Proquinazid for Use in Human Health Risk Assessment
----------------------------------------------------------------------------------------------------------------
Point of departure
Exposure/scenario and uncertainty/ RfD, PAD, LOC for Study and toxicological effects
safety factors risk assessment
----------------------------------------------------------------------------------------------------------------
Acute dietary (General population NOAEL = 50 mg/kg/bw Acute RfD = aPAD = Acute Neurotoxicity Study-Rat.
including infants and children). UFA = 10x. 0.050 mg/kg/bw. LOAEL = 100 mg/kg/bw based on
UFH = 10x........... decreased motor activity seen in
FQPA SF = 10x....... females on day 1.
UFDB................
----------------------------------------------------------------------------------------------------------------
Chronic dietary (All populations) NOAEL= 1.2 mg/kg/day Chronic RfD = cPAD Chronic Toxicity/Carcinogenicity
UFA = 13x........... = 0.004 mg/kg/day. Study-Rat.
UFH = 10x........... LOAEL = 12 mg/kg/day based on
FQPA SF = 10x....... increases in non-neoplastic liver
UFDB................ lesions and changes in thyroid
hormones and thyroid pathology.
------------------------------------------------------------------------------
Cancer (Oral, dermal, inhalation) A non linear approach (i.e., RfD will adequately protect for all chronic
toxicity, including carcinogenicity, that could result from exposure to
proquinazid. The cPAD for proquinazid will protect for carcinogenic effects
because it is below the level that caused changes in liver enzyme regulation
and liver toxicity.
----------------------------------------------------------------------------------------------------------------
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest observed adverse effect level. mg/kg/bw =
milligram/kilogram/body weight. NOAEL = no observed adverse effect level. PAD = population adjusted dose (a =
acute, c = chronic). RfD = reference dose. UF = uncertainty factor. UFA = extrapolation from animal to human
(interspecies). UFDB = to account for the absence of data or other data deficiency. UFH = potential variation
in sensitivity among members of the human population (intraspecies).
C. Exposure Assessment
1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to proquinazid, EPA considered exposure under the petitioned-
for tolerances as well as all existing proquinazid tolerances in 40 CFR
180.674. EPA assessed dietary exposures from proquinazid 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.
Such effects were identified for proquinazid. In estimating acute
dietary exposure, EPA used food consumption information from the United
States Department of Agriculture (USDA) 2003-2008 National Health and
Nutrition Examination Survey, What We Eat in America (NHANES/WWIA). As
to residue levels in food, EPA used tolerance level residues and 100%
percent crop treated (PCT). Default processing factors were used for
grape juice. The Agency considers these to be highly conservative
assessments.
ii. Chronic exposure. In conducting the chronic dietary exposure
assessment EPA used the food consumption data from the USDA 2003-2008
NHANES/WWEIA. As to residue levels in food, EPA used tolerance level
residues and 100% PCT.
iii. Cancer. Quantification of risk using a non-linear approach
(i.e., RfD will adequately protect for all chronic toxicity, including
carcinogenicity, which could result from exposure to proquinazid.
Cancer risk was assessed using the same exposure estimates as discussed
in Unit III.C.1.ii., chronic exposure.
iv. Anticipated residue and PCT information. EPA did not use
anticipated residue and/or PCT information in the dietary assessment
for proquinazid. Tolerance level residues and/or 100% CT were assumed
for all food commodities.
2. Dietary exposure from drinking water. There is no drinking water
exposure in the U.S. associated with the establishment of an import
tolerance.
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). Proquinazid is not
registered for any specific use patterns that would result in
residential exposure.
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 proquinazid to share a common mechanism of
toxicity with any other substances, and proquinazid does not appear to
produce a toxic metabolite produced by other substances. For the
purposes of this tolerance action, therefore, EPA has assumed that
proquinazid 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 https://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 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. No evidence of increased
quantitative or qualitative susceptibility was seen following in utero
exposure to proquinazid with rats or rabbits in the prenatal
developmental studies or in young rats in the 2-generation reproduction
study. The 2-generation rat reproduction study resulted in no effects
on reproduction or fertility. The
[[Page 18814]]
offspring effects (decreases in F1 pup weight during
lactation) occurred at the same dose which caused parental effects
(thyroid hypertrophy, reduced body weight gain, and food consumption).
Evidence of developmental delays were observed in developmental
toxicity studies in rabbits and rats were characterized by reduced
fetal weight and an increased incidence retarded ossification and paten
ductus arteriosus, respectively. These developmental effects occurred
in the presence of maternal toxicity. For the rats, the developmental
effects were seen in the presence of clear maternal toxicity, including
a marked reduction in body weight gain after adjustment for uterine
contents and were considered to be of equal severity.
3. Conclusion. In determining whether there are reliable data to
amend or remove the presumptive 10X FQPA safety factor, EPA considered
the following factors:
i. The toxicity database for proquinazid required by 40 CFR Part
158 is complete. However, there remains some uncertainty regarding the
potential for proquinazid effects on the thyroid in the young. Effects
on the thyroid (manifested as changes in hormones, weight, and
histopathology) following proquinazid exposure were consistently
observed in adult animals (rats) following subchronic and chronic
exposures. Thyroid effects, however, were not assessed in studies
involving neo- or postnatal animals, and EPA is lacking data showing
the comparative effect of proquinazid on the thyroid in adult and neo-
and postnatal animals.
ii. There is only limited evidence that proquinazid is a neurotoxic
chemical and there is no need for a developmental neurotoxicity study
or additional UFs to account for neurotoxicity. There is limited
evidence for neurotoxicity following oral exposures to proquinazid.
Following a single exposure, evidence for neurotoxicity at the LOAEL
was limited to decreased motor activity in both sexes with no
behavioral or neuropathology changes. At doses above the study LOAEL
other effects including decreased grip strength and foot splay were
observed. Following repeated (dietary) exposures, there were no
treatment-related clinical signs of neurotoxicity, behavioral changes,
or neuropathology.
iii. As discussed in Unit III.D.2., there is no evidence that
proquinazid results in increased susceptibility with in utero rats or
rabbits in the prenatal developmental studies or in young rats in the
2-generation reproduction study.
iv. There are no residual uncertainties identified in the exposure
databases. The dietary food exposure assessments were performed based
on 100% CT and tolerance-level residues. Drinking water is not a factor
because this is an import tolerance assessment. These assessments will
not underestimate the exposure and risks posed by proquinazid.
Despite the lack of any indication of sensitivity in the young and
the very conservative exposure assessment, EPA has determined that it
lacks reliable data to choose a FQPA safety factor other than the
default value of 10X given (1) the absence of data on thyroid effects
on the young, including comparative thyroid data on adults and the
young, and (2) the fact that thyroid effects were the most sensitive
effect seen in adult animals. At the same time, after considering all
of the data on proquinazid toxicity and exposure, EPA has also
determined that application of a FQPA safety factor of 10X, in
conjunction with inter- and intraspecies safety factors, will result in
a risk assessment that protects the safety of infants and children.
Although there is some uncertainty as to whether the young might have
greater sensitivity to proquinazid's thyroid effects due to the absence
of comparative thyroid data, two developmental studies and a
reproduction study have otherwise shown no indication of sensitivity in
the young to proquinazid. Additionally, the exposure assessment
provides an extra margin of safety given that it is based on the
conservative assumption that all grapes, and all food products derived
from grapes (e.g., raisins, grape juice, wine), consumed in the United
States bear residues of proquinazid at the appropriate tolerance level.
This assumption is particularly conservative here because proquinazid
is not registered for use in the United States. Taking into account all
of these considerations, EPA concludes that no safety factor in
addition to the inter- and intraspecies factors, and the default FQPA
safety factor is needed to protect the safety of infants and children.
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. Using the exposure assumptions discussed in this
unit for acute dietary exposure from food to proquinazid will occupy
18% of the aPAD for children 1-2 years old, the population group
receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that chronic exposure to
proquinazid from food will utilize 47% of the cPAD for children 1-2
years old the population group receiving the greatest exposure. There
are no residential uses for proquinazid. Based on the explanation in
Unit III.C.3., regarding residential use patterns, chronic residential
exposure to residues of proquinazid is not expected.
3. Aggregate cancer risk for U.S. population. The cPAD of 0.004 mg/
kg/day will be protective of both non-cancer and cancer effects,
including rat tumors (liver, thyroid, and cholangiocarcinomas). As
discussed in Unit III.E., aggregate exposure to proquinazid is below
the cPAD.
4. 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 proquinazid residues.
IV. Other Considerations
A. Analytical Enforcement Methodology
Adequate enforcement methodology (gas chromatography with electron
capture detection) is available to enforce the proposed tolerances for
residues of proquinazid on grape commodities.
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; email address:
residuemethods@epa.gov.
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 United Nations
Food and Agriculture Organization/World Health
[[Page 18815]]
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 proquinazid. However, the
tolerances established in this rule are harmonized with Canadian MRLs.
C. Revisions to Petitioned-For Tolerances
The Agency is changing the proposed commodity definition for
raisins from raisin to grape, raisin. The change in the commodity
definition is to make the tolerance consistent with Agency naming-
conventions for commodities and crop groups. No changes are recommended
for the proposed tolerance levels, but the grape tolerance is being
revised from 0.5 to 0.50 to correct the number of significant figures.
V. Conclusion
Therefore, tolerances are established for residues of proquinazid
in or on grape at 0.50 ppm and grape, raisin 1.0 ppm.
VI. Statutory and Executive Order Reviews
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). 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 FFDCA section 408(d), such as the tolerance in this
final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.), do not apply.
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 FFDCA section 408(n)(4). 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) (2 U.S.C. 1501 et seq.).
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) (15 U.S.C. 272 note).
VII. Congressional Review Act
Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.),
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 action 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: March 25, 2014.
Marty Marnell,
Acting Director, Office of Pesticide Programs.
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. 180.674 to read as follows:
Sec. 180.674 Proquinazid; tolerances for residues.
(a) General. Tolerances are established for residues of the
fungicide, proquinazid, including its metabolites and degradates, in or
on the commodities listed in the following table. Compliance with the
tolerance levels specified in the following table is to be determined
by measuring only proquinazid, [6-Iodo-2-propoxy-3-propyl-3H-
quinazolin-4-one), in or on the following commodities:
------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Grape \1\............................................... 0.50
Grape, raisin \1\....................................... 1.0
------------------------------------------------------------------------
\1\ No U.S. registrations for Proquinazid.
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 2014-07563 Filed 4-3-14; 8:45 am]
BILLING CODE 6560-50-P