Dinotefuran; Pesticide Tolerance, 14535-14546 [05-5620]
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Mailing Standards of the United States
Postal Service, Domestic Mail Manual,
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I
14535
Authority: 5 U.S.C. 552(a); 39 U.S.C. 101,
401, 403, 414, 416, 3001–3011, 3201–3219,
3403–3406, 3621, 3626, 5001.
§§ 111.1, 111.2, 111.3, and 111.4
[Amended]
2. Amend §§ 111.1, 111.2, 111.3, and
111.4 by removing the words ‘‘Domestic
Mail Manual’’ each time they appear,
and adding the words ‘‘Mailing
Standards of the United States Postal
Service, Domestic Mail Manual’’ in their
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I
3. Amend § 111.3(f) by adding the
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PART 111—GENERAL INFORMATION
ON POSTAL SERVICE
§ 111.3 Amendment to the Mailing
Standards of the United States Postal
Service, Domestic Mail Manual.
1. The authority citation for part 111
continues to read as follows:
*
I
*
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(f) * * *
*
*
Transmittal letter for issue
Dated
*
*
Premier Edition .................................................
*
*
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January 6, 2005 ................................................
*
*
[insert FR citation for this Final Rule].
§ 111.4
dinotefuran, [N-methyl-N′-nitro-N′′((tetrahydro-3furanyl)methyl)guanidine] alone in or
on cattle meat, fat, and meat byproducts
(mbyp); goat meat, fat, and mbyp; hog
meat, fat, and mbyp; horse meat, fat, and
mbyp; sheep meat, fat, and mbyp; and
milk. Mitsui Chemicals, Inc. requested
these tolerances under the Federal Food,
Drug, and Cosmetic Act (FFDCA), as
amended by the Food Quality Protection
Act of 1996 (FQPA).
119, Crystal Mall #2, 1801 S. Bell St.,
Arlington, VA. This docket facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The docket telephone number
is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT: Rita
Kumar, Registration Division (7505C),
Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001; telephone number:
(703) 308–8291; e-mail address:
kumar.rita@epa.gov.
[Amended]
4. Amend § 111.4 by removing ‘‘March
29, 1979’’ and adding ‘‘March 23, 2005’’
in its place.
I
Stanley F. Mires,
Chief Counsel, Legislative.
[FR Doc. 05–5360 Filed 3–22–05; 8:45 am]
BILLING CODE 7710–12–P
ENVIRONMENTAL PROTECTION
AGENCY
This regulation is effective
March 23, 2005. Objections and requests
for hearings must be received on or
before May 23, 2005.
DATES:
40 CFR Part 180
[OPP–2005–0003; FRL–7695–5]
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
SUMMARY: This regulation establishes
tolerances for combined residues of
dinotefuran, [N-methyl-N′-nitro-N′′((tetrahydro-3furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro3-furylmethyl)guanidine] and UF [1methyl-3-(tetrahydro-3furylmethyl)urea], expressed as
dinotefuran in or on vegetable, fruiting,
group 8; vegetable, cucurbit, group 9;
brassica, head and stem, subgroup 5A;
grape; grape, raisin; potato; potato,
chips; potato, granules/flakes; tomato,
paste; cotton, undelinted seed; cotton,
gin byproducts; and for residues of
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To submit a written
objection or hearing request follow the
detailed instructions as provided in
Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a
docket for this action under docket
identification (ID) number OPP–2005–
0003. All documents in the docket are
listed in the EDOCKET index at
https://www.epa.gov/edocket. Although
listed in the index, some information is
not publicly available, i.e., CBI or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available either
electronically in EDOCKET or in hard
copy at the Public Information and
Records Integrity Branch (PIRIB), Rm.
ADDRESSES:
Dinotefuran; Pesticide Tolerance
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SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by
this action if you are an agricultural
producer, food manufacturer, or
pesticide manufacturer. Potentially
affected entities may include, but are
not limited to:
• Crop production (NAICS 111), e.g.,
agricultural workers; greenhouse,
nursery, and floriculture workers;
farmers.
• Animal production (NAICS 112),
e.g., cattle ranchers and farmers, dairy
cattle farmers, livestock farmers.
• Food manufacturing (NAICS 311),
e.g., agricultural workers; farmers;
greenhouse, nursery, and floriculture
workers; ranchers; pesticide applicators.
• Pesticide manufacturing (NAICS
32532), e.g., agricultural workers;
commercial applicators; farmers;
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Federal Register / Vol. 70, No. 55 / Wednesday, March 23, 2005 / Rules and Regulations
greenhouse, nursery, and floriculture
workers; residential users.
This listing is not intended to be
exhaustive, but rather provides a guide
for readers regarding entities likely to be
affected by this action. Other types of
entities not listed in this unit could also
be affected. The North American
Industrial Classification System
(NAICS) codes have been provided to
assist you and others in determining
whether this action might apply to
certain entities. If you have any
questions regarding the applicability of
this action to a particular entity, consult
the person listed under FOR FURTHER
INFORMATION CONTACT.
B. How Can I Access Electronic Copies
of this Document and Other Related
Information?
In addition to using EDOCKET
(https://www.epa.gov/edocket/), you may
access this Federal Register document
electronically through the EPA Internet
under the ‘‘Federal Register’’ listings at
https://www.epa.gov/fedrgstr/. A
frequently updated electronic version of
40 CFR part 180 is available at E-CFR
Beta Site Two at https://
www.gpoaccess.gov/ecfr/. To access the
OPPTS Harmonized Guidelines
referenced in this document, go directly
to the guidelines at https://www.epa.gov/
opptsfrs/home/guidelin.htm/.
II. Background and Statutory Findings
In the Federal Register of July 2, 2003
FR 39547–39554) (FRL–7312–8), EPA
issued a notice pursuant to section
408(d)(3) of FFDCA, 21 U.S.C.
346a(d)(3), announcing the filing of two
pesticide petitions (PP 2F6427 and
3F6566) by Mitsui Chemicals, Inc.,
Chiyoda-ku, Tokyo, Japan. The petitions
requested that 40 CFR 180.603 be
amended by establishing tolerances for
combined residues of the insecticide
dinotefuran, [N-methyl-N′-nitro-N′′((tetrahydro-3furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro3-furylmethyl)guanidine] and UF [1methyl-3-(tetrahydro-3furylmethyl)urea], expressed as
dinotefuran as follows: (PP 3F6566) in
or on fruiting vegetables at 0.7 parts per
million (ppm); tomato paste at 1.0 ppm;
cucurbit at 0.5 ppm; head and stem
brassica vegetables at 1.4 ppm; grape at
0.8 ppm; raisin at 2.5 ppm; potato at
0.05 ppm; potato, chips at 0.10 ppm;
granules at 0.15 ppm; cattle, goat, hog,
horse and sheep fat, meat, and
byproducts, and milk at 0.05 ppm; and
(PP 2F6427) in or on cotton seed
undelinted at 0.2 ppm; and cotton gin
byproducts at 7.0 ppm. That notice
included a summary of the petition
prepared by Mitsui Chemicals Inc., the
registrant. One comment was received
from a private citizen, in support of this
notice.
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* * * .’’
EPA performs a number of analyses to
determine the risks from aggregate
exposure to pesticide residues. For
further discussion of the regulatory
requirements of section 408 of FFDCA
and a complete description of the risk
assessment process, see the final rule on
Bifenthrin Pesticide Tolerances in the
Federal Register of November 26, 1997
(62 FR 62961) (FRL–5754–7).
III. Aggregate Risk Assessment and
Determination of Safety
Consistent with section 408(b)(2)(D)
of FFDCA, EPA has reviewed the
available scientific data and other
relevant information in support of this
action. EPA has sufficient data to assess
the hazards of and to make a
determination on aggregate exposure,
consistent with section 408(b)(2) of
FFDCA, for tolerances for combined
residues of dinotefuran, [N-methyl-N′nitro-N′′-((tetrahydro-3furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro3-furylmethyl)guanidine] and UF [1methyl-3-(tetrahydro-3furylmethyl)urea], expressed as
dinotefuran on fruiting vegetables,
group 8 at 0.7 ppm; tomato paste at 1.0
ppm; cucurbit at 0.5 ppm; head and
stem brassica vegetables at 1.4 ppm;
grape at 0.8 ppm, raisin at 2.5 ppm,
potato at 0.05 ppm, potato, chips at 0.10
ppm, potato, granules/flakes at 0.15
ppm; cotton seed undelinted at 0.4 ppm,
cotton gin byproducts at 7.0 ppm; and
for residues of dinotefuran, [N-methylN′-nitro-N′′-((tetrahydro-3furanyl)methyl)guanidine] alone in or
on cattle meat, fat, and meat byproducts
(mbyp) at 0.05 ppm; goat meat, fat, and
mbyp at 0.05 ppm; hog meat, fat, and
mbyp at 0.05 ppm; horse meat, fat, and
mbyp at 0.05 ppm; sheep meat, fat, and
mbyp 0.05 ppm; and milk at 0.05 ppm.
EPA’s assessment of 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 dinotefuran are
discussed in Table 1 of this unit as well
as the no observed adverse effect level
(NOAEL) and the lowest observed
adverse effect level (LOAEL) from the
toxicity studies reviewed.
TABLE 1.—SUBCHRONIC, CHRONIC, AND OTHER TOXICITY
Guideline No.
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Results
90-Day oral toxicity in rats
870.3100
Study Type
NOAEL: 38/384 (M/F) mg/kg/day
LOAEL: 384 (M) mg/kg/day based on adrenal histopathology; 1,871 (F) mg/kg/day
based on decreased body weight/body weight gain, changes in hematology/clinical
chemistry, changes in organ weights, and adrenal histopathology
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TABLE 1.—SUBCHRONIC, CHRONIC, AND OTHER TOXICITY—Continued
Guideline No.
Study Type
Results
870.3100
90-Day oral toxicity in
mice
NOAEL: 4,442/5,414 (M/F) mg/kg/day
LOAEL: 10,635/11,560 (M/F) mg/kg/day, based on decreased body weight, body
weight gain
870.3150
90-Day oral toxicity in
dogs
NOAEL: 307/not determined (M/F) mg/kg/day
LOAEL: 862 (M) mg/kg/day, based on body weight gain, hemorrhagic lymph nodes;
<59 (F), based on decreased body weight, body weight gain
870.3200
28-Day dermal toxicity
(rats)
Systemic
NOAEL: 1,000 mg/kg/day
LOAEL: not determined (no effects seen)
Dermal:
NOAEL: 1,000 (M), ≤200 (F) mg/kg/day
LOAEL: not determined/≤1,000 (M/F) mg/kg/day based on lack of effects in males,
increase in acanthosis/hyperkeratosis in high dose females (lower doses not evaluated histopathologically)
870.3465
28-Day inhalation toxicity
(rat)
NOAEL:<0.22 (M) mg/L, 0.22 (F) mg/L
LOAEL: decreased body weight gain, food consumption (M); increased clinical signs
(protruding eyes) (F)
870.3700
Prenatal developmental
toxicity study (rats)
Maternal
NOAEL: 300 mg/kg/day
LOAEL: 1,000 mg/kg/day based on decreased body weight gain and food consumption
Developmental
NOAEL: 1,000 mg/kg/day
LOAEL: not determined (no effects seen)
870.3700
Prenatal developmental
toxicity study (rabbits)
Maternal
NOAEL: 52 mg/kg/day
LOAEL: 125 mg/kg/day based on decreased body weight gains, food consumption,
and necropsy findings
Developmental
NOAEL: 300 mg/kg/day
LOAEL: >300 mg/kg/day (no effects seen)
870.3800
Reproduction and fertility
effects (rats)
Parental/systemic
NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822/907 (M/F) mg/kg/day, based on decreased food consumption, weight
gain in males, soft feces in females, and decreasedspleen weights in both sexes
Reproductive (tentative)
NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822/907 (M/F) mg/kg/day, based on decreased uterine weights and microscopic alterations in the uterus and vagina of F0 females, decreased numbers of
primordial follicles in F1 females, altered estrous cyclicity in F0 and F1 females,
increase in abnormal sperm morphology in F0 and F1 males, decreased testicular
sperm count in F0 males, and decreased sperm motility in F1 males
Developmental
NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822–935/907–1005 (M/F) mg/kg/day based on decreased body weights,
body weight gains, and spleen weights in F1 and F2 males and females, decreased thymus weights in F2 males and females, and decreased forelimb grip
strength (F1 males) or hindlimb grip strength (F1 females)
870.4100
Chronic toxicity (rats)
See 870.4300 combined chronic toxicity/carcinogenicity (rats)
870.4100
Chronic toxicity (dogs)
NOAEL: >20/22 (M/F) mg/kg/day
LOAEL: 20/108 (M/F) mg/kg/day based on decreased thymus weight, decreased
food efficiency, body weight, and body weight gain in females, decreased thymus
weight in males
870.4200
Carcinogenicity (rats)
See 870.4300 combined chronic toxicity/carcinogenicity (rats)
870.4200
Carcinogenicity (mice)
NOAEL: <3 (M), <4 (F) mg/kg/day
LOAEL: 3/4 (M/F) mg/kg/day based on decreased spleen weights at week 79 terminal sacrifice in males and increased ovarian weights at week 53 in females
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TABLE 1.—SUBCHRONIC, CHRONIC, AND OTHER TOXICITY—Continued
Guideline No.
Study Type
Results
870.4300
Combined chronic toxicity/
carcinogenicity (rats)
NOAEL: 99.7/127.3 (M/F) mg/kg/day
LOAEL: 991/1,332 (M/F) mg/kg/day based on decreased body weight gain, food efficiency in females, increased incidences of kidney pelvic mineralization and ulceration in males
870.5100
Bacterial reverse mutation
test
Negative. ± S9 up to 16,000 µg/plate
870.5100
Bacterial reverse mutation
test
Negative, ± S9 up to limit dose of 5,000 µg/plate
870.5300
In vitro mammalian cell
gene mutation test
Negative, ± S9 up to 2002 µg/mL (mouse lymphoma L5178Y cells)
870.5375
In vitro mammalian chromosome aberration test
Negative for clastogenic/aneugenic activity up to 2000 µg/mL (CHL/IU cells)
870.5395
In vivo mammalian
cytogenics -micronucleus assay
Negative at oral doses up to 1,080 mg/kg/day for 2 days
870.6200
Acute neurotoxicity
screening battery
NOAEL: 750 (M), 325 (F) mg/kg/day
LOAEL: 1,500 (M), 750 (F) mg/kg/day based on decreased motor activity on day 1
870.6200
Subchronic neurotoxicity
screening battery
NOAEL: 33/40 (M/F) mg/kg/day
LOAEL: 327/400 (M/F) mg/kg/day based on increased motor activity during week 2
870.7485
Metabolism and pharmacokinetics (rats)
Absorption was >90% regardless of dose. The radiolabel was widely distributed
through the body and was completely excreted within 168 hours of treatment.
Urine was the primary elimination route, accounting for 88–99.8%. Excretion into
the urine was rapid, being 84–99% complete within 24 hours of treatment. Absorption of the radioactivity was linear within the dose range of 50 and 1,000 mg/kg.
Elimination of radioactivity was fast for all groups with a T1/2 ranging from 3.64 to
15.2 hours for the low and high doses, respectively. Radioactivity was rapidly
transferred from maternal blood to milk and widely distributed in the fetal tissues.
The Cmax for milk and fetal tissues was detected 0.5 hours after maternal treatment. The concentrations of radioactivity in fetal tissue and maternal milk declined
quickly and were below detection limits 24 hours post-treatment. After IV or oral
treatment, 75–93% of the administered radiolabeled test material, or nearly 93–
97% of total urinary radiolabel, was excreted unchanged in the urine. The parent
compound was also the primary component in the plasma, milk, bile, feces, and
most tissues collected 4–8 hours after treatment and at both dose levels. Less
than 10% of the parent compound was metabolized into numerous minor metabolites that were not well resolved by High Performance Liquid Chromotography
(HPLC) or 2D-TLC. For all parameters measured in this study, no sex - or doserelated differences or label position effects were found.
Special study
Neonatal rat metabolism
study (12-day old rat
pups)
After a single oral 50 mg/kg dose of (G-14C) MTI-446 to 12-day old rats, absorption
was high (absorption could not be adequately determined but may have approached 80%) and the radiolabel was widely distributed within the body. Approximately 32–36% of the administered dose was excreted within 4 hours of treatment. Urine was the primary elimination route as indirectly evidenced by finding
high radioactive areas in the kidneys and bladder by whole body autoradiography.
No areas of tissue sequestration were found and no gender-related differences
were identified. The test material was essentially not metabolized, the parent compound accounting for >97% of the radiolabel in the excreta, plasma, kidneys, and
stomach, and nearly 61–83% in intestines (and contents), and liver.
B. Toxicological Endpoints
The dose at which no adverse effects
are observed (the NOAEL) from the
toxicology study identified as
appropriate for use in risk assessment is
used to estimate the toxicological level
of concern (LOC). However, the lowest
dose at which adverse effects of concern
are identified (the LOAEL) is sometimes
used for risk assessment if no NOAEL
was achieved in the toxicology study
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selected. An uncertainty factor (UF) is
applied to reflect uncertainties inherent
in the extrapolation from laboratory
animal data to humans and in the
variations in sensitivity among members
of the human population as well as
other unknowns. An UF of 100 is
routinely used, 10X to account for
interspecies differences and 10X for
intraspecies differences.
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Three other types of safety or
uncertainty factors may be used:
‘‘Traditional uncertainty factors;’’ the
‘‘special FQPA safety factor;’’ and the
‘‘default FQPA safety factor’’. By the
term ‘‘traditional uncertainty factor,’’
EPA is referring to those additional
uncertainty factors used prior to FQPA
passage to account for database
deficiencies. These traditional
uncertainty factors have been
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incorporated by the FQPA into the
additional safety factor for the
protection of infants and children. The
term ‘‘special FQPA safety factor ’’
refers to those safety factors that are
deemed necessary for the protection of
infants and children primarily as a
result of the FQPA. The ‘‘default FQPA
safety factor’’ is the additional 10X
safety factor that is mandated by the
statute unless it is decided that there are
reliable data to choose a different
additional factor (potentially a
traditional uncertainty factor (UF) or a
special FQPA safety factor).
For dietary risk assessment (other
than cancer) the Agency uses the UF to
calculate an acute or chronic reference
dose (aRfD or cRfD) where the RfD is
equal to the NOAEL divided by an UF
of 100 to account for interspecies and
intraspecies differences and any
traditional UFs deemed appropriate
(RfD = NOAEL/UF). Where a special
FQPA safety factor or the default FQPA
safety factor is used, this additional
factor is applied to the RfD by dividing
the RfD by such additional factor. The
acute or chronic Population Adjusted
Dose (aPAD or cPAD) is a modification
of the RfD to accommodate this type of
safety factor.
For non-dietary risk assessments
(other than cancer) the UF is used to
determine the LOC. For example, when
100 is the appropriate UF (10X to
account for interspecies differences and
10X for intraspecies differences) the
LOC is 100. To estimate risk, a ratio of
the NOAEL to exposures (margin of
exposure (MOE) = NOAEL/exposure) is
calculated and compared to the LOC.
The linear default risk methodology
(Q*) is the primary method currently
used by the Agency to quantify
carcinogenic risk. The Q* approach
assumes that any amount of exposure
will lead to some degree of cancer risk.
A Q* is calculated and used to estimate
risk which represents a probability of
14539
occurrence of additional cancer cases
(e.g., risk). An example of how such a
probability risk is expressed would be to
describe the risk as one in one hundred
thousand (1 x 10-5), one in a million (1
x 10-6), or one in ten million (1 x 10-7).
Under certain specific circumstances,
margin of exposure (MOE) calculations
will be used for the carcinogenic risk
assessment. In this non-linear approach,
a ‘‘point of departure’’ is identified
below which carcinogenic effects are
not expected. The point of departure is
typically a NOAEL based on an
endpoint related to cancer effects
though it may be a different value
derived from the dose response curve.
To estimate risk, a ratio of the point of
departure to exposure (MOEcancer = point
of departure/exposures) is calculated.
A summary of the toxicological
endpoints for dinotefuran used for
human risk assessment is shown in the
following Table 2.
TABLE 2.—SUMMARY OF TOXICOLOGICAL DOSE AND ENDPOINTS FOR DINOTEFURAN FOR USE IN HUMAN RISK
ASSESSMENT
Special FQPA SF and Level
of Concern for Risk Assessment
Exposure/Scenario
Dose Used in Risk Assessment, UF
Acute dietary (General population including infants and
children)
NOAEL = 125 mg/kg/day
UF = 100
Acute RfD = 1.25 mg/kg/day
FQPA SF = 1
aPAD = acute RfD ÷ FQPA
SF = 1.25 mg/kg/day
Developmental toxicity study in rabbits
LOAEL = 300 mg/kg/day based on clinical signs
in does (prone position, panting, tremor, erythema) seen following a single dose.
Chronic dietary (All populations)
LOAEL= 20 mg/kg/day
UF = 1,000
Chronic RfD = 0.02 mg/kg/
day
FQPA SF = 1
cPAD = chronic RfD ÷ FQPA
SF = 0.02 mg/kg/day
Chronic toxicity study in dogs
LOAEL = 20 mg/kg/day based on decreased
thymus weight in males
Short-term incidental oral (1
to 30 days)
NOAEL= 33 mg/kg/day
Residential LOC for MOE =
100
Occupational = NA
Subchronic neurotoxicity study in rats
LOAEL = 327 mg/kg/day based on increased
motor activity during week 2
Intermediate-term incidental
oral (1 to 6 months)
NOAEL= 22 mg/kg/day
Residential LOC for MOE
=100
Occupational = NA
Chronic toxicity study in dogs
LOAEL = 108 mg/kg/day based on decreased
body weight and body weight gain in females
Short-term dermal (1 to 30
days)
No quantitation required.
Residential LOC for MOE =
NA
Occupational LOC for MOE
= NA
No quantitation required. No systemic toxicity
was seen at the limit dose in a 28-day dermal
toxicity study in which neurotoxicity was evaluated. No developmental toxicity concerns.
Intermediate-term dermal (1
to 6 months)
Oral study NOAEL = 22 mg/
kg/day (dermal absorption
rate = 30%)
Residential LOC for MOE =
100
Occupational LOC for MOE
=100
Chronic toxicity study in dogs
LOAEL = 108 mg/kg/day based on decreased
body weight and body weight gain in females
Long-term dermal (>6
months)
Oral study LOAEL = 20 mg/
kg/day (dermal absorption
rate = 30%)
Residential LOC for MOE =
1,000
Occupational LOC for MOE
= 1,000
Chronic toxicity study in dogs
LOAEL = 20 mg/kg/day based on decreased
thymus weight in males
Short-term inhalation (1 to 30
days)
Inhalation study LOAEL= 60
mg/kg/day
Residential LOC for MOE =
1,000
Occupational LOC for MOE
= 1,000
28-day Inhalation toxicity study in rats
LOAEL = 60 mg/kg/day based on decreased
body weight gain in males
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Study and Toxicological Effects
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TABLE 2.—SUMMARY OF TOXICOLOGICAL DOSE AND ENDPOINTS FOR DINOTEFURAN FOR USE IN HUMAN RISK
ASSESSMENT—Continued
Exposure/Scenario
Dose Used in Risk Assessment, UF
Special FQPA SF and Level
of Concern for Risk Assessment
Study and Toxicological Effects
Intermediate-term inhalation
(1 to 6 months)
Inhalation study LOAEL = 60
mg/kg/day
Residential LOC for MOE
=1,000
Occupational LOC for MOE
= 1,000
28-day Inhalation toxicity study in rats
LOAEL = 60 mg/kg/day based on decreased
body weight gain in males
Long-term inhalation (>6
months)
Oral study LOAEL= 20 mg/
kg/day (inhalation absorption rate = 100%)
Residential LOC for MOE =
1,000
Occupational LOC for MOE
= 1,000
Chronic toxicity study in dogs
LOAEL = 20 mg/kg/day based on decreased
thymus weight in males
Cancer (oral, dermal, inhalation)
NA
NA
Not required; no evidence of carcinogenicity.
UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of
concern, NA = Not applicable.
C. Exposure Assessment
1. Dietary exposure from food and
feed uses. Tolerances have been
established (40 CFR 180.603) for the
combined residues of dinotefuran and
its metabolites, in or on a variety of raw
agricultural commodities. Risk
assessments were conducted by EPA to
assess dietary exposures from
dinotefuran in food as follows:
i. Acute exposure. Acute dietary risk
assessments are performed for a fooduse pesticide, if a toxicological study
has indicated the possibility of an effect
of concern occurring as a result of a 1day or single exposure.
In conducting the acute dietary risk
assessment EPA used the DEEMTM
software with the FCID, which
incorporates food consumption data as
reported by respondents in the U.S.
Department of Agriculture (USDA)
1994–1996 and 1998 Nationwide
Continuing Surveys of Food Intake by
Individuals (CSFII), and accumulated
exposure to the chemical for each
commodity. The following assumptions
were made for the acute exposure
assessments: The dietary risk analyses
incorporated tolerance level residues
and assumed 100% of the crops had
been treated with dinotefuran. The
acute risk estimates are below the
Agency’s level of concern (< 100%
aPAD) for the general U.S. population
and all population subgroups.
ii. Chronic exposure. In conducting
the chronic dietary risk assessment EPA
used the DEEMTM software with the
FCID, which incorporates food
consumption data as reported by
respondents in the USDA 1994–1996
and 1998 CSFII, and accumulated
exposure to the chemical for each
commodity. The following assumptions
were made for the chronic exposure
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assessments: The dietary risk analyses
incorporated tolerance level residues
and assumed 100% of the crops had
been treated with dinotefuran. The
chronic risk estimates are below the
Agency’s level of concern (<100%
cPAD) for the general U.S. population
and all population subgroups.
iii. Cancer. Dinotefuran is classified
as ‘‘not likely to be a carcinogen,’’
therefore, an exposure assessment for
quantifying cancer risk was not
conducted.
2. Dietary exposure from drinking
water. The Agency lacks sufficient
monitoring exposure data to complete a
comprehensive dietary exposure
analysis and risk assessment for
dinotefuran in drinking water. Because
the Agency does not have
comprehensive monitoring data,
drinking water concentration estimates
are made by reliance on simulation or
modeling taking into account data on
the physical characteristics of
dinotefuran.
The Agency uses the FQPA Index
Reservoir Screening Tool (FIRST) or the
Pesticide Root Zone Model/Exposure
Analysis Modeling System (PRZM/
EXAMS), to produce estimates of
pesticide concentrations in an index
reservoir. The SCI-GROW model is used
to predict pesticide concentrations in
shallow ground water. For a screeninglevel assessment for surface water EPA
will use FIRST (a Tier 1 model) before
using PRZM/EXAMS (a Tier 2 model).
The FIRST model is a subset of the
PRZM/EXAMS model that uses a
specific high-end runoff scenario for
pesticides. Both FIRST and PRZM/
EXAMS incorporate an index reservoir
environment, and both models include
a percent crop treated (PCT) area factor
as an adjustment to account for the
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maximum PC coverage within a
watershed or drainage basin.
None of these models include
consideration of the impact processing
(mixing, dilution, or treatment) of raw
water for distribution as drinking water
would likely have on the removal of
pesticides from the source water. The
primary use of these models by the
Agency at this stage is to provide a
screen for sorting out pesticides for
which it is unlikely that drinking water
concentrations would exceed human
health levels of concern.
Since the models used are considered
to be screening tools in the risk
assessment process, the Agency does
not use estimated environmental
concentrations (EECs), which are the
model estimates of a pesticide’s
concentration in water. EECs derived
from these models are used to quantify
drinking water exposure and risk as a
%RfD or %PAD. Instead, drinking water
levels of comparison (DWLOCs) are
calculated and used as a point of
comparison against the model estimates
of a pesticide’s concentration in water.
DWLOCs are theoretical upper limits on
a pesticide’s concentration in drinking
water in light of total aggregate exposure
to a pesticide in food, and from
residential uses. Since DWLOCs address
total aggregate exposure to dinotefuran
they are further discussed in the
aggregate risk sections below.
Based on the FIRST and SCI-GROW
models, the EECs of dinotefuran for
acute exposures are estimated to be 76
parts per billion (ppb) for surface water
and 5.1 ppb for ground water. The EECs
for chronic exposures are estimated to
be 21 ppb for surface water and 5.1 ppb
for ground water.
3. From non-dietary exposure. The
term ‘‘residential exposure’’ is used in
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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).
Dinotefuran is currently registered for
use on the following residential nondietary sites: Professional turf
management, professional ornamental
production, residential indoor, and
lawn. The risk assessment was
conducted using the following
residential exposure assumptions:
Outdoor uses for turf farms, golf
courses, residential lawns, and
ornamentals.
There is a potential for exposure to
homeowners in residential settings
during the application of products
containing dinotefuran. There is also a
potential for exposure from entering
areas previously treated with
dinotefuran such as lawns where
children might play, or golf courses and
home gardens that could lead to
exposures for adults. As a result, risk
assessments were previously discussed
for both residential handler and
postapplication scenarios in the final
rule for setting tolerance on leafy
vegetables in the Federal Register of
September 17, 2004 (69 FR 55963)
(FRL–7368–1). The proposed new
agricultural uses of dinotefuran do not
add any additional residential
exposures or risks.
The risks from the combined
exposures of adults applying
dinotefuran to residential lawns and
then being dermally exposed from
postapplication activities on the treated
lawn do not exceed the Agency’s level
of concern. Children’s combined risks
from activities on treated lawns do not
exceed the Agency’s level of concern.
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.’’
Unlike other pesticides for which EPA
has followed a cumulative risk approach
based on a common mechanism of
toxicity, EPA has not made a common
mechanism of toxicity finding as to
dinotefuran and any other substances
and dinotefuran 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 dinotefuran has a
common mechanism of toxicity with
other substances. For information
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regarding EPA’s efforts to determine
which chemicals have a common
mechanism of toxicity and to evaluate
the cumulative effects of such
chemicals, see the policy statements
released by EPA concerning common
mechanism determinations and
procedures for cumulating effects from
substances found to have a common
mechanism on EPA’s web site at http:/
/www.epa.gov/pesticides/cumulative/.
D. Safety Factor for Infants and
Children
1. In general. Section 408 of FFDCA
provides that EPA shall apply an
additional tenfold margin of safety for
infants and children in the case of
threshold effects to account for prenatal
and postnatal toxicity and the
completeness of the 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. Margins of safety are
incorporated into EPA risk assessments
either directly through use of a MOE
analysis or through using uncertainty
(safety) factors (UFs) in calculating a
dose level that poses no appreciable risk
to humans. In applying this provision,
EPA either retains the default value of
10X when reliable data do not support
the choice of a different factor, or, if
reliable data are available, EPA uses a
different additional safety factor value
based on the use of traditional UFs and/
or special FQPA safety factors, as
appropriate.
2. Prenatal and postnatal sensitivity.
Prenatal developmental toxicity studies
in rats and rabbits provided no
indication of increased susceptibility
(qualitative or quantitative) of rat or
rabbit fetuses to in utero exposure to
dinotefuran. There was no indication of
increased (quantitative) susceptibility in
the fetuses as compared to parental
animals in the two generation
reproduction study. Qualitative
susceptibility was observed in the
reproduction study; however, the degree
of concern is low because the observed
effects are well characterized (decreased
body weight, decreased thymus weight,
and decreased grip strength) and there
are clear NOAELs/LOAELs.
3. Conclusion. Although there is
generally low concern and no residual
uncertainties for prenatal and/or
postnatal toxicity resulting from
exposure to dinotefuran, some
uncertainty is raised by a deficiency in
the data (a lack of a NOAEL in the
chronic dog study) and the need for a
developmental immunotoxicity study
(DIT).
The absence of a NOAEL for the
chronic dog study and the need for a
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14541
DIT study generate some uncertainty
regarding the protectiveness of chronic
regulatory endpoints and long-term
levels of concern. Accordingly, EPA
does not have reliable data supporting
adoption of a safety factor other than the
default additional 10X factor as
specified in FFDCA section 408(b)(2)(C).
The chronic endpoint and long-term
level of concern have therefore, been
generated using an overall safety/UF of
1,000 (representing 100X for
interspecies and intraspecies variation
and an additional 10X pursuant to
FFDCA section 408(b)(2)(C).
The Agency does not have similar
concerns regarding acute, short-term,
and intermediate-term risk assessments
for several reason. First, the absence of
a NOAEL only occurred in a chronic
study. Second, reliable data show that
the DIT is unlikely to result in a NOAEL
for acute, short-term, or intermediateterm effects that is lower than the
NOAELs currently being used to assess
the risk from such effects. EPA has
required a DlT study with dinotefuran
based on the changes in the thymus
weight in offspring in the reproduction
study and in adult rats and dogs. There
is, however, little evidence to support a
direct effect of dinotefuran on immune
function. This is because lymphoid
organ weight changes can be secondary
to generalized toxicity (e.g., reductions
in body weight, body weight gain, and/
or food efficiency). In the reproduction
study, decreased thymus weights were
seen in offspring in the presence of
decreased body weight only at the Limit
Dose (10,000 ppm). In the 1-year dog
study, decrease in thymus weight was
seen in the absence of other toxicity,
however, no decrease in thymus weight
was seen in the subchronic study in
dogs which was conducted at higher
doses (i.e., the results of the 1-year
study was not supported by the results
of the 90-day study).
Further, the only evidence on
dinotefuran’s potential immunological
effect is found in studies with prolonged
exposure. In the reproduction study, the
effect of concern i.e, decrease in thymus
weight in only 1-generation (F2) was
seen only following approximately 13–
weeks of exposure to the parental
animals at close to the limit dose (1,000
mg/kg). Similarly, thymus effects in the
chronic dog study were only observable
after long-term exposures, but were not
seen in the 90-day dog study.
Finally, it is clear that the DIT study,
which is performed in the rat, will have
to be conducted at high doses (close to
the limit dose) to elicit a potential single
dose effect and this will result in a
potential NOAEL higher than that
currently used for various risk
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assessments. As noted, in the rat
reproduction study, effects only
occurred at doses close to the limit dose
(1,000 mg/kg/day). The limit dose is the
maximum dose recommended for
testing in the Series 870 Health Effects
Harmonized Test Guidelines; toxic
effects occurring only at or near the
limit dose are of less concern for human
health since they may be specifically
related to the high dose exposure and
may not occur at the much lower doses
to which humans are exposed.
Additionally, in the acute neurotoxicity
study in the rat, the LOAEL was 750
mg/kg/day in females and 1,500 mg/kg/
day in males based on reductions in
motor activity indicating that high doses
are required to elicit dinotefuraninduced toxicity in rats.
The NOAELs in the critical studies
selected for acute dietary (125 mg/kg/
day), short-term incidental oral (33 mg/
kg/day), and intermediate-term
incidental oral and dermal (22 mg/kg/
day) exposure scenarios are lower than
the offspring NOAEL (241 mg/kg/day) in
the reproduction study. Therefore, EPA
is confident that the doses selected for
these risk assessments will address the
concerns for the thymus weight changes
seen in the offspring in the reproduction
study and will not underestimate the
potential risk from exposure to
dinotefuran.
The Agency believes there are reliable
data showing that the regulatory
endpoints are protective of children
despite the need for a development
neuorotoxicity (DNT) study. DNT data
received and reviewed for other
compounds in this chemical class
(neonicotinoids) including thiacloprid,
clothianidin, and imidacloprid, indicate
that the results of the required DNT
study will not likely impact the
regulatory doses selected for
dinotefuran.
In addition, the acute and chronic
dietary food exposure assessment
Default body weights and drinking
water consumption values vary on an
individual basis. This variation will be
taken into account in more refined
screening-level and quantitative
drinking water exposure assessments.
Different populations will have different
DWLOCs. Generally, a DWLOC is
calculated for each type of risk
assessment used: Acute, short-term,
intermediate-term, chronic, and cancer.
When EECs for surface water and
ground water are less than the
calculated DWLOCs, EPA concludes
with reasonable certainty that exposures
to the pesticide in drinking water (when
considered along with other sources of
exposure for which EPA has reliable
data) would not result in unacceptable
levels of aggregate human health risk at
this time. Because EPA considers the
aggregate risk resulting from multiple
exposure pathways associated with a
pesticide’s uses, levels of comparison in
drinking water may vary as those uses
change. If new uses are added in the
future, EPA will reassess the potential
impacts of residues of the pesticide in
drinking water as a part of the aggregate
risk assessment process.
1. Acute risk. Using the exposure
assumptions discussed in this unit for
acute exposure, the acute dietary
exposure from food to dinotefuran will
occupy 1.2% of the aPAD for the U.S.
population, 1.2% of the aPAD for
females 13 to 49 years old, 1.3% of the
aPAD for infants <1 year old, and 2.9%
of the aPAD for children 1 to 2 years
old. In addition, there is potential for
acute dietary exposure to dinotefuran in
drinking water. After calculating
DWLOCs and comparing them to the
EECs for surface water, and ground
water, EPA does not expect the
aggregate exposure to exceed 100% of
the aPAD, as shown in the following
Table 3.
utilized proposed tolerance level
residues and 100% crop treated
information for all commodities. By
using these screening-level assessments,
acute and chronic exposure/risks will
not be underestimated. Furthermore, the
dietary drinking water assessment (Tier
1 estimates) uses values generated by
models and associated modeling
parameters which are designed to
provide conservative, health protective,
high-end estimates of water
concentrations. Finally, the residential
assessment for children’s
postapplication exposures is based upon
maximum application rates in
conjunction with chemical-specific
study data and are not expected to
underestimate risk.
E. Aggregate Risks and Determination of
Safety
To estimate total aggregate exposure
to a pesticide from food, drinking water,
and residential uses, the Agency
calculates DWLOCs which are used as a
point of comparison against EECs.
DWLOC values are not regulatory
standards for drinking water. DWLOCs
are theoretical upper limits on a
pesticide’s concentration in drinking
water in light of total aggregate exposure
to a pesticide in food and residential
uses. In calculating a DWLOC, the
Agency determines how much of the
acceptable exposure (i.e., the PAD) is
available for exposure through drinking
water e.g., allowable chronic water
exposure (mg/kg/day) = cPAD - (average
food + residential exposure). This
allowable exposure through drinking
water is used to calculate a DWLOC.
A DWLOC will vary depending on the
toxic endpoint, drinking water
consumption, and body weights. Default
body weights and consumption values
as used by the EPA’s Office of Water are
used to calculate DWLOCs: 2 liter (L)/
70 kg (adult male), 2L/60 kg (youth and
adult female), and 1L/10 kg (child).
TABLE 3.—AGGREGATE RISK ASSESSMENT FOR ACUTE EXPOSURE TO DINOTEFURAN
aPAD /(mg/
kg/day)
Population/Subgroup
Surface
Water EEC/
(ppb)
%aPAD/
(Food)
Ground
Water EEC/
(ppb)
Acute
DWLOC
(ppb)
U.S. population
1.25
1.2
76
5.1
43,000
All infants (<1 year old)
1.25
1.3
76
5.1
12,000
Children (1–2 years old)
1.25
2.9
76
5.1
12,000
Females (13–49 years old)
1.25
1.2
76
5.1
37,000
2. Chronic risk. Using the exposure
assumptions described in this unit for
chronic exposure, EPA has concluded
that exposure to dinotefuran from food
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will utilize 21% of the cPAD for the
U.S. population, 18% of the cPAD for
infants <1 year old, and 54% of the
cPAD for children 1 to 2 years old, and
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20% of the cPAD for females 13 to 49
years old. Based on the use pattern,
chronic residential exposure to residues
of dinotefuran does not exceed the
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Agency’s level of concern, as discussed
in Unit III.E.3. below. In addition, there
is potential for chronic dietary exposure
to dinotefuran in drinking water. After
calculating DWLOCs and comparing
them to the EECs for surface water, and
ground water, EPA does not expect the
aggregate exposure to exceed 100% of
14543
the cPAD, as shown in the following
Table 4.
TABLE 4.—AGGREGATE RISK ASSESSMENT FOR CHRONIC (NON-CANCER) EXPOSURE TO DINOTEFURAN
Population Subgroup
cPAD (mg/kg/day)
Surface
Water EEC
(ppb)
%cPAD (FOOD)
Ground
Water EEC
(ppb)
Chronic
DWLOC
(ppb)
U.S. population
0.02
21
21
5.1
550
All infants (<1 year old)
0.02
18
21
5.1
160
Children (1–2 years old)
0.02
54
21
5.1
90
Females (13–49 years old)
0.02
19
21
5.1
490
3. Short-term risk. Short-term
aggregate exposure takes into account
residential exposure plus chronic
exposure to food and water (considered
to be a background exposure level).
Dinotefuran is currently registered for
uses that could result in short-term
residential exposure. Short-term and
intermediate-term aggregate risk
assessments based on exposure from
oral, inhalation, and dermal routes were
considered. However, the toxicological
effects for oral and inhalation routes of
exposure are different (i.e.,
neurotoxicity for oral and decrease in
body weight for inhalation); and
therefore, these exposure scenarios have
not been combined. Also, because no
systemic toxicity was seen at the limit
dose in a 28-day dermal toxicity study,
no quantification of short-term dermal
risk is required. Therefore, a short-term
aggregate risk assessment was not
performed for dinotefuran. An
intermediate-term aggregate risk
assessment was performed as a
screening level assessment, which will
apply to short-term aggregate risk.
4. Intermediate-term risk.
Intermediate-term aggregate exposure
takes into account residential exposure
plus chronic exposure to food and water
(considered to be a background
exposure level).
Dinotefuran is currently registered for
use(s) that could result in intermediate-
term residential exposure and the
Agency has determined that it is
appropriate to aggregate chronic food
and water and intermediate-term
exposures for dinotefuran. An
intermediate-term aggregate risk
assessment was performed as a
screening level assessment for adults
and children.
For children, the children’s subgroup
with the highest estimated chronic
dietary exposure (children 1–2 years
old) was aggregated with residential
exposures to children playing on treated
lawns (dermal and oral hand-to-mouth
exposures) in order to calculate the
worst case intermediate-term aggregate
risk to children. The reciprocal MOE
method was used to conduct the
intermediate-term aggregate risk
assessment for children, since the level
of concern MOEs are identical for all
MOEs in the calculation.For adults, the
aggregate risk index method was used,
since level of concern MOEs are not
identical for all types of exposure in the
calculation.
i. Intermediate-term aggregate risk for
children. The child subgroup with the
highest estimated chronic dietary
exposure (children 1–2 years old) was
used to calculate the intermediate-term
aggregate risk, including chronic dietary
(food and drinking water) and
residential and oral exposures. Based on
the toxicity endpoint information, all
acceptable MOEs are 100, and an
intermediate-term oral endpoint for
incidental ingestion residential
exposure was identified. Therefore, the
intermediate-term incidental oral
endpoint (NOAEL) was used to
incorporate dietary (food and water),
and residential incidental ingestion
exposures in the aggregate risk
assessment. An intermediate-term
residential exposure scenario was
identified and includes dermal and
incidental oral exposure routes. To
complete the aggregate intermediateterm exposure and risk assessment,
chronic dietary (food and drinking
water) and residential dermal and oral
exposures must be included.
For children’s combined exposure on
turf, the total MOE was estimated to be
590. The average (chronic) dietary
exposure for the highest exposed child
subgroup (children 1–2 years old) was
estimated to be 0.011 mg/kg/day. The
reciprocal MOE equation is solved for
MOE water to determine the
DWLOCIntermediate-term for children.
Compared with the Estimated Drinking
Water Concentrations (EDWCs), EPA’s
calculated aggregate intermediate-term
DWLOC does not exceed the Agency’s
level of concern for the subgroup
population of children 1 to 2 years old.
The aggregate risk assessment for
intermediate-term exposure to children
is summarized in the following Table 5.
TABLE 5.—AGGREGATE RISK ASSESSMENT FOR INTERMEDIATE-TERM EXPOSURE OF CHILDREN TO DINOTEFURAN
NOAEL/mg/
kg/day
Population
Children (3–5
years old)
Max Exposure2
mg/kg/
day
Target
MOE1
22
100
Average
Food Exposure
mg/kg/
day
Residential Exposure3 mg/
kg/day
0.011
0.037
0.22
Aggregate
MOE
(food &
residential)4
460
Max
Water Exposure5
mg/kg/
day
Ground
Water
EEC6 µg/
L
Surface
Water
EEC6 µg/
L
IntermediateTerm
DWLOC7
µg/L
0.17
5.1
21
1,700
1
The target MOE of 100 is based on the standard inter- and intra-species safety factors, 10x for intra-species variability and 10x for inter-species extrapolation.
2 Maximum exposure (mg/kg/day) = NOAEL/Target MOE
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Residential exposure to children playing on treated lawns (combined dermal + oral hand-to-mouth + oral object-to-mouth + oral soil inges-
tion)
4
5
6
7
Aggregate MOE = [NOAEL/(Avg. Food Exposure + Residential Exposure)]
Maximum Water Exposure (mg/kg/day) = Target Maximum Exposure - (Food Exposure + Residential Exposure)
The use site producing the highest level was used; i.e., turf.
DWLOC (µg/L) = [Maximum water exposure (mg/kg/day) x body weight (10 kg)]/[Water exposure (1L) x 10-3 mg/µg]
ii. Intermediate term aggregate risk for
adults. For adults, the worst case
intermediate-term aggregate risk
assessment includes the following
scenarios: (1) Dermal and inhalation
exposures to residential handlers (i.e.
M/L/A of liquids to lawns by hose-end
sprayers); (2) dermal postapplication
exposures on treated lawns;, and (3) oral
dietary exposures (i.e. food + drinking
water). Based on the toxicity endpoint
information, the acceptable MOEs are
not all identical. The intermediate-term
inhalation endpoint has a UF/MOE of
1,000, because a NOAEL was not
reached and a LOAEL was used instead,
while the assessments for incorporating
food, water and dermal exposures have
UFs/MOEs of 100. In this case, the
aggregate risk index (ARI) method was
used to calculate DWLOC values for the
adult aggregate intermediate-term risk
assessment.
The highest estimated average
(chronic) dietary exposure for adults
occurred with the general U.S.
population (i.e. 0.0042 mg/kg/day). The
adult residential combined risks from
dermal (ARI = 17) and inhalation (ARI
= 970) exposures to residential handlers
and dermal postapplication exposures
(ARI = 12) on treated lawns were
combined.
The intermediate-term aggregate risk
including drinking water exposure can
be calculated using the ARI method for
aggregating exposure. The equations are
solved for MOEwater to determine the
DWLOC Intermediate-term for adults.
Compared with the EDWCs, EPA’s
calculated aggregate intermediate-term
DWLOC does not exceed Agency’s level
of concern for the general U.S.
population. The aggregate risk
assessment for intermediate-term
exposure to adults is summarized in the
following Table 6.
TABLE 6.—AGGREGATE RISK ASSESSMENT FOR INTERMEDIATE-TERM EXPOSURE OF ADULTS TO DINOTEFURAN.
Residential ARIs3
Population
Target
ARI1
Applicators
ARI Food2
Inhalation
Exposure
970
Dermal Exposure
Females (14–49
years old)
1
116
Postapplic
ation Dermal Exposure
Max Water
Exposure
ARI4
12
17
Ground
Water
EDWC5 µ/
L
Surface
Water
EDWC µ/L
IntermediateTerm
DWLOC6
µ/L
5.1
21
5,600
1.18
1
ARI (Aggregate Risk Index) = MOE Calculated/MOEAceeptable
2 ARIFood = [22 / 0.0019] / 100 = 116
ARIdermal = MOEcalculated/100 and, ARIinhal = MOE inhal/1,000
4 ARI
Water = 1/[1/1- (1/ARIResidential aplicator dermal) + (1/ARIResidential applicator inhalation) + (1/ARIPostapplication dermal)]
5 The use site producing the highest level was used; i.e. turf.
6 DWLOC (µ/L) = [Maximum water exposure (mg/kg/day) x body weight (60 kg)]/[Water exposure (2 L) x 10-3 mg/µg] where Maximum water
exposure = NOAEL (22) / [ARIWater (1.18) x 100] = 0.1866 mg/kg/day
2
3
IV. Other Considerations
A livestock enforcement method is
needed to enforce the proposed
tolerances of dinotefuran on milk, meat,
and meat byproducts. The Liquid
Chromatography (LC)/MS/MS method,
which was used for the analysis of
samples collected from the cow feeding
study, may be used for tolerance
enforcement. The independent
laboratory validation and
radiovalidation data are currently under
review by the Agency.
A. Analytical Enforcement Methodology
B. International Residue Limits
Adequate enforcement methodology
for plant commodities (High
Performance Liquid Chromatography
(HPLC)/Mass Spectrometry (MS); HPLC/
Ultraviolet (UV); and HPLC/MS/MS) is
available to enforce the tolerance
expression. The methods may be
requested from: Chief, Analytical
Chemistry Branch, Environmental
Science Center, 701 Mapes Rd., Ft.
Meade, MD 20755–5350; telephone
number: (410) 305–2905; e-mail address:
residuemethods@epa.gov.
There are currently no established
Codex, Canadian, or Mexican maximum
residue limits for residues of
dinotefuran in/on plant or livestock
commodities.
5. Aggregate cancer risk for U.S.
population. Dinotefuran is not expected
to pose a cancer risk.
6. Determination of safety. Based on
these risk assessments, EPA concludes
that there is a reasonable certainty that
no harm will result to the general
population, and to infants and children
from aggregate exposure to dinotefuran
residues.
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14:14 Mar 22, 2005
Jkt 205001
V. Conclusion
Therefore, the tolerance is established
for combined residues of dinotefuran,
[N-methyl-N′-nitro-N′′-((tetrahydro-3furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro3-furylmethyl)guanidine] and UF [1-
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Fmt 4700
Sfmt 4700
methyl-3-(tetrahydro-3furylmethyl)urea], expressed as
dinotefuran, in or on vegetable, fruiting,
group 8 at 0.7 ppm; vegetable, cucurbit,
group 9 at 0.5 ppm; Brassica, head and
stem, subgroup 5A at 1.4 ppm; grape at
0.9 ppm; grape, raisin at 2.5 ppm; potato
at 0.05 ppm; potato, chips at 0.1 ppm;
potato, granules/flakes at 0.15 ppm;
tomato, paste at 1.0 ppm; cotton,
undelinted seed at 0.4 ppm; cotton, gin
byproducts at 8.0 ppm; and for residues
of dinotefuran alone in or on cattle,
meat at 0.5 ppm; cattle, fat at 0.05 ppm;
cattle meat byproducts (mbyp) at 0.05
ppm; goat, meat at 0.05 ppm; goat, fat
at 0.05 ppm; goat mbyp at 0.05 ppm;
hog, meat at 0.05 ppm; hog, fat at 0.05
ppm; hog mbyp at 0.05 ppm; horse,
meat at 0.05 ppm; horse, fat at 0.05
ppm; horse, mbyp at 0.05 ppm; milk at
0.05 ppm; sheep, meat at 0.05 ppm;
sheep, fat at 0.05 ppm; and sheep, mbyp
at 0.05 ppm.
E:\FR\FM\23MRR1.SGM
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Federal Register / Vol. 70, No. 55 / Wednesday, March 23, 2005 / Rules and Regulations
VI. Objections and Hearing Requests
Under section 408(g) of FFDCA, as
amended by FQPA, any person may file
an objection to any aspect of this
regulation and may also request a
hearing on those objections. The EPA
procedural regulations which govern the
submission of objections and requests
for hearings appear in 40 CFR part 178.
Although the procedures in those
regulations require some modification to
reflect the amendments made to FFDCA
by FQPA, EPA will continue to use
those procedures, with appropriate
adjustments, until the necessary
modifications can be made. The new
section 408(g) of FFDCA provides
essentially the same process for persons
to ‘‘object’’ to a regulation for an
exemption from the requirement of a
tolerance issued by EPA under new
section 408(d) of FFDCA, as was
provided in the old sections 408 and
409 of FFDCA. However, the period for
filing objections is now 60 days, rather
than 30 days.
A. What Do I Need to Do to File an
Objection or Request a Hearing?
You must file your objection or
request a hearing on this regulation in
accordance with the instructions
provided in this unit and in 40 CFR part
178. To ensure proper receipt by EPA,
you must identify docket ID number
OPP–2005–0003 in the subject line on
the first page of your submission. All
requests must be in writing, and must be
mailed or delivered to the Hearing Clerk
on or before May 23, 2005.
1. Filing the request. Your objection
must specify the specific provisions in
the regulation that you object to, and the
grounds for the objections (40 CFR
178.25). If a hearing is requested, the
objections must include a statement of
the factual issues(s) on which a hearing
is requested, the requestor’s contentions
on such issues, and a summary of any
evidence relied upon by the objector (40
CFR 178.27). Information submitted in
connection with an objection or hearing
request may be claimed confidential by
marking any part or all of that
information as CBI. Information so
marked will not be disclosed except in
accordance with procedures set forth in
40 CFR part 2. A copy of the
information that does not contain CBI
must be submitted for inclusion in the
public record. Information not marked
confidential may be disclosed publicly
by EPA without prior notice.
Mail your written request to: Office of
the Hearing Clerk (1900L),
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001. You may also deliver
VerDate jul<14>2003
14:14 Mar 22, 2005
Jkt 205001
your request to the Office of the Hearing
Clerk in Suite 350, 1099 14th St., NW.,
Washington, DC 20005. The Office of
the Hearing Clerk is open from 8 a.m.
to 4 p.m., Monday through Friday,
excluding legal holidays. The telephone
number for the Office of the Hearing
Clerk is (202) 564–6255.
2. Copies for the Docket. In addition
to filing an objection or hearing request
with the Hearing Clerk as described in
Unit VI.A., you should also send a copy
of your request to the PIRIB for its
inclusion in the official record that is
described in ADDRESSES. Mail your
copies, identified by docket ID number
OPP–2005–0003, to: Public Information
and Records Integrity Branch,
Information Resources and Services
Division (7502C), Office of Pesticide
Programs, Environmental Protection
Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460–0001. In person
or by courier, bring a copy to the
location of the PIRIB described in
ADDRESSES. You may also send an
electronic copy of your request via email to: opp-docket@epa.gov. Please use
an ASCII file format and avoid the use
of special characters and any form of
encryption. Copies of electronic
objections and hearing requests will also
be accepted on disks in WordPerfect
6.1/8.0 or ASCII file format. Do not
include any CBI in your electronic copy.
You may also submit an electronic copy
of your request at many Federal
Depository Libraries.
B. When Will the Agency Grant a
Request for a Hearing?
A request for a hearing will be granted
if the Administrator determines that the
material submitted shows the following:
There is a genuine and substantial issue
of fact; there is a reasonable possibility
that available evidence identified by the
requestor would, if established resolve
one or more of such issues in favor of
the requestor, taking into account
uncontested claims or facts to the
contrary; and resolution of the factual
issues(s) in the manner sought by the
requestor would be adequate to justify
the action requested (40 CFR 178.32).
VII. Statutory and Executive Order
Reviews
This final rule establishes a tolerance
under section 408(d) of FFDCA in
response to a petition submitted to the
Agency. The Office of Management and
Budget (OMB) has exempted these types
of actions from review under Executive
Order 12866, entitled Regulatory
Planning and Review (58 FR 51735,
October 4, 1993). Because this rule has
been exempted from review under
Executive Order 12866 due to its lack of
PO 00000
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Fmt 4700
Sfmt 4700
14545
significance, this rule is not subject to
Executive Order 13211, Actions
Concerning Regulations That
Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May
22, 2001). This final rule does not
contain any information collections
subject to OMB approval under the
Paperwork Reduction Act (PRA), 44
U.S.C. 3501 et seq., or impose any
enforceable duty or contain any
unfunded mandate as described under
Title II of the Unfunded Mandates
Reform Act of 1995 (UMRA) (Public
Law 104–4). Nor does it require any
special considerations under Executive
Order 12898, entitled Federal Actions to
Address Environmental Justice in
Minority Populations and Low-Income
Populations (59 FR 7629, February 16,
1994); or OMB review or any Agency
action under Executive Order 13045,
entitled Protection of Children from
Environmental Health Risks and Safety
Risks (62 FR 19885, April 23, 1997).
This action does not involve any
technical standards that would require
Agency consideration of voluntary
consensus standards pursuant to section
12(d) of the National Technology
Transfer and Advancement Act of 1995
(NTTAA), Public Law 104–113, section
12(d) (15 U.S.C. 272 note). Since
tolerances and exemptions that are
established on the basis of a petition
under section 408(d) of FFDCA, such as
the tolerance in this final rule, do not
require the issuance of a proposed rule,
the requirements of the Regulatory
Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply. In addition, the
Agency has determined that this action
will not have a substantial direct effect
on States, on the relationship between
the national government and the States,
or on the distribution of power and
responsibilities among the various
levels of government, as specified in
Executive Order 13132, entitled
Federalism (64 FR 43255, August 10,
1999). Executive Order 13132 requires
EPA to develop an accountable process
to ensure ‘‘meaningful and timely input
by State and local officials in the
development of regulatory policies that
have federalism implications.’’ ‘‘Policies
that have federalism implications’’ is
defined in the Executive Order to
include regulations that have
‘‘substantial direct effects on the States,
on the relationship between the national
government and the States, or on the
distribution of power and
responsibilities among the various
levels of government.’’ This final rule
directly regulates growers, food
processors, food handlers and food
retailers, not States. This action does not
E:\FR\FM\23MRR1.SGM
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14546
Federal Register / Vol. 70, No. 55 / Wednesday, March 23, 2005 / Rules and Regulations
alter the relationships or distribution of
power and responsibilities established
by Congress in the preemption
provisions of section 408(n)(4) of
FFDCA. For these same reasons, the
Agency has determined that this rule
does not have any ‘‘tribal implications’’
as described in Executive Order 13175,
entitled Consultation and Coordination
with Indian Tribal Governments (65 FR
67249, November 6, 2000). Executive
Order 13175, requires EPA to develop
an accountable process to ensure
‘‘meaningful and timely input by tribal
officials in the development of
regulatory policies that have tribal
implications.’’ ‘‘Policies that have tribal
implications’’ is defined in the
Executive Order to include regulations
that have ‘‘substantial direct effects on
one or more Indian tribes, on the
relationship between the Federal
Government and the Indian tribes, or on
the distribution of power and
responsibilities between the Federal
Government and Indian tribes.’’ This
rule will not have substantial direct
effects on tribal governments, on the
relationship between the Federal
Government and Indian tribes, or on the
distribution of power and
responsibilities between the Federal
Government and Indian tribes, as
specified in Executive Order 13175.
Thus, Executive Order 13175 does not
apply to this rule.
VIII. Congressional Review Act
The Congressional Review Act, 5
U.S.C. 801 et seq., as added by the Small
Business Regulatory Enforcement
Fairness Act of 1996, generally provides
that before a rule may take effect, the
agency promulgating the rule must
submit a rule report, which includes a
copy of the rule, to each House of the
Congress and to the Comptroller General
of the United States. EPA will submit a
report containing this rule and other
required information to the U.S. Senate,
the U.S. House of Representatives, and
the Comptroller General of the United
States prior to publication of this final
rule in the Federal Register. This final
rule is not a ‘‘major rule’’ as defined by
5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection,
Administrative practice and procedure,
Agricultural commodities, Pesticides
and pests, Reporting and recordkeeping
requirements.
VerDate jul<14>2003
14:14 Mar 22, 2005
Jkt 205001
Dated: February 25, 2005.
Lois Rossi,
Director, Registration Division, Office of
Pesticide Programs.
(b) Section 18 emergency exemptions.
[Reserved]
(c) Tolerances with regional
registrations. [Reserved]
(d) Indirect or inadvertent residues.
[Reserved]
Therefore, 40 CFR chapter I is
amended as follows:
I
[FR Doc. 05–5620 Filed 3–22–05; 8:45 am]
PART 180—[AMENDED]
BILLING CODE 6560–50–S
1. The authority citation for part 180
continues to read as follows:
I
Authority: 21 U.S.C. 321(q), 346a and 371.
ENVIRONMENTAL PROTECTION
AGENCY
2. Section 180.603 is revised to read as
follows:
40 CFR Part 180
§ 180.603 Dinotefuran; tolerances for
residues.
Mesotrione; Pesticide Tolerance
I
(a) General. (1) Tolerances are
established for the combined residues of
Dinotefuran, [N-methyl-N′-nitro-N′′((tetrahydro-3furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro3-furylmethyl)guanidine] and UF [1methyl-3-(tetrahydro-3furylmethyl)urea], expressed as
dinotefuran.
Parts per
million
Commodity
Brassica, head and stem, subgroup 5A ...............................
Cotton, undelinted seed ...........
Cotton, gin byproducts .............
Grape ........................................
Grape, raisin .............................
Potato .......................................
Potato, chips .............................
Potato, granules/flakes .............
Tomato, paste ...........................
Vegetable, fruiting, group 8 ......
Vegetable, cucubit, group 9 .....
Vegetable, leafy, except Brassica, group 4 .........................
1.4
0.4
8.0
0.9
2.5
0.05
0.1
0.15
1.0
0.7
0.5
5.0
(2) Tolerances are established for
residues of dinotefuran N-methyl-N′nitro-N′′-tetrahydro-3furanyl)methyl)guanidine in/on the
following commodities:
Parts per
million
Commodity
Cattle, fat ..................................
Cattle, mbyp .............................
Cattle, meat ..............................
Goat, fat ....................................
Goat, mbyp ...............................
Goat, meat ................................
Hog, fat .....................................
Hog, mbyp ................................
Hog, meat .................................
Horse, fat ..................................
Horse, mbyp .............................
Horse, meat ..............................
Milk ...........................................
Sheep, fat .................................
Sheep, mbyp ............................
Sheep, meat .............................
PO 00000
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0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
[OPP–2005–0049; FRL–7703–1]
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
SUMMARY: This regulation establishes
tolerances for residues of mesotrione in
or on sweet corn. Syngenta Crop
Protection Inc. requested these
tolerances under the Federal Food,
Drug, and Cosmetic Act (FFDCA), as
amended by the Food Quality Protection
Act of 1996 (FQPA).
DATES: This regulation is effective
March 23, 2005. Objections and requests
for hearings must be received on or
before May 23, 2005.
ADDRESSES: To submit a written
objection or hearing request follow the
detailed instructions as provided in
Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a
docket for this action under docket
identification (ID) number OPP–2005–
0049. All documents in the docket are
listed in the EDOCKET index at
https://www.epa.gov/edocket. Although
listed in the index, some information is
not publicly available, i.e., CBI or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available either
electronically in EDOCKET or in hard
copy at the Public Information and
Records Integrity Branch (PIRIB), Rm.
119, Crystal Mall #2, 1801 S. Bell St.,
Arlington, VA. This docket facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The docket telephone number
is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT:
Joanne Miller, Registration Division
(7505C), Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460; telephone number: (703)
E:\FR\FM\23MRR1.SGM
23MRR1
]]>Agencies
[Federal Register Volume 70, Number 55 (Wednesday, March 23, 2005)]
[Rules and Regulations]
[Pages 14535-14546]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-5620]
=======================================================================
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-2005-0003; FRL-7695-5]
Dinotefuran; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: This regulation establishes tolerances for combined residues
of dinotefuran, [N-methyl-N'-nitro-N''-((tetrahydro-3-
furanyl)methyl)guanidine] and its metabolites DN [1-methyl-3-
(tetrahydro-3-furylmethyl)guanidine] and UF [1-methyl-3-(tetrahydro-3-
furylmethyl)urea], expressed as dinotefuran in or on vegetable,
fruiting, group 8; vegetable, cucurbit, group 9; brassica, head and
stem, subgroup 5A; grape; grape, raisin; potato; potato, chips; potato,
granules/flakes; tomato, paste; cotton, undelinted seed; cotton, gin
byproducts; and for residues of dinotefuran, [N-methyl-N'-nitro-N''-
((tetrahydro-3-furanyl)methyl)guanidine] alone in or on cattle meat,
fat, and meat byproducts (mbyp); goat meat, fat, and mbyp; hog meat,
fat, and mbyp; horse meat, fat, and mbyp; sheep meat, fat, and mbyp;
and milk. Mitsui Chemicals, Inc. requested these tolerances under the
Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food
Quality Protection Act of 1996 (FQPA).
DATES: This regulation is effective March 23, 2005. Objections and
requests for hearings must be received on or before May 23, 2005.
ADDRESSES: To submit a written objection or hearing request follow the
detailed instructions as provided in Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a docket for this action under docket
identification (ID) number OPP-2005-0003. All documents in the docket
are listed in the EDOCKET index at https://www.epa.gov/edocket. Although
listed in the index, some information is not publicly available, i.e.,
CBI or other information whose disclosure is restricted by statute.
Certain other material, such as copyrighted material, is not placed on
the Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available either electronically
in EDOCKET or in hard copy at the Public Information and Records
Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1801 S.
Bell St., Arlington, VA. This docket facility is open from 8:30 a.m. to
4 p.m., Monday through Friday, excluding legal holidays. The docket
telephone number is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Rita Kumar, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-8291; e-mail address: kumar.rita@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.
Potentially affected entities may include, but are not limited to:
Crop production (NAICS 111), e.g., agricultural workers;
greenhouse, nursery, and floriculture workers; farmers.
Animal production (NAICS 112), e.g., cattle ranchers and
farmers, dairy cattle farmers, livestock farmers.
Food manufacturing (NAICS 311), e.g., agricultural
workers; farmers; greenhouse, nursery, and floriculture workers;
ranchers; pesticide applicators.
Pesticide manufacturing (NAICS 32532), e.g., agricultural
workers; commercial applicators; farmers;
[[Page 14536]]
greenhouse, nursery, and floriculture workers; residential users.
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Access Electronic Copies of this Document and Other
Related Information?
In addition to using EDOCKET (https://www.epa.gov/edocket/), you may
access this Federal Register document electronically through the EPA
Internet under the ``Federal Register'' listings at https://www.epa.gov/
fedrgstr/. A frequently updated electronic version of 40 CFR part 180
is available at E-CFR Beta Site Two at https://www.gpoaccess.gov/ecfr/.
To access the OPPTS Harmonized Guidelines referenced in this document,
go directly to the guidelines at https://www.epa.gov/opptsfrs/home/
guidelin.htm/.
II. Background and Statutory Findings
In the Federal Register of July 2, 2003 FR 39547-39554) (FRL-7312-
8), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21
U.S.C. 346a(d)(3), announcing the filing of two pesticide petitions (PP
2F6427 and 3F6566) by Mitsui Chemicals, Inc., Chiyoda-ku, Tokyo, Japan.
The petitions requested that 40 CFR 180.603 be amended by establishing
tolerances for combined residues of the insecticide dinotefuran, [N-
methyl-N'-nitro-N''-((tetrahydro-3-furanyl)methyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro-3-furylmethyl)guanidine] and UF
[1-methyl-3-(tetrahydro-3-furylmethyl)urea], expressed as dinotefuran
as follows: (PP 3F6566) in or on fruiting vegetables at 0.7 parts per
million (ppm); tomato paste at 1.0 ppm; cucurbit at 0.5 ppm; head and
stem brassica vegetables at 1.4 ppm; grape at 0.8 ppm; raisin at 2.5
ppm; potato at 0.05 ppm; potato, chips at 0.10 ppm; granules at 0.15
ppm; cattle, goat, hog, horse and sheep fat, meat, and byproducts, and
milk at 0.05 ppm; and (PP 2F6427) in or on cotton seed undelinted at
0.2 ppm; and cotton gin byproducts at 7.0 ppm. That notice included a
summary of the petition prepared by Mitsui Chemicals Inc., the
registrant. One comment was received from a private citizen, in support
of this notice.
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* * *
.''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 of FFDCA and a complete
description of the risk assessment process, see the final rule on
Bifenthrin Pesticide Tolerances in the Federal Register of November 26,
1997 (62 FR 62961) (FRL-5754-7).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of and to
make a determination on aggregate exposure, consistent with section
408(b)(2) of FFDCA, for tolerances for combined residues of
dinotefuran, [N-methyl-N'-nitro-N''-((tetrahydro-3-
furanyl)methyl)guanidine] and its metabolites DN [1-methyl-3-
(tetrahydro-3-furylmethyl)guanidine] and UF [1-methyl-3-(tetrahydro-3-
furylmethyl)urea], expressed as dinotefuran on fruiting vegetables,
group 8 at 0.7 ppm; tomato paste at 1.0 ppm; cucurbit at 0.5 ppm; head
and stem brassica vegetables at 1.4 ppm; grape at 0.8 ppm, raisin at
2.5 ppm, potato at 0.05 ppm, potato, chips at 0.10 ppm, potato,
granules/flakes at 0.15 ppm; cotton seed undelinted at 0.4 ppm, cotton
gin byproducts at 7.0 ppm; and for residues of dinotefuran, [N-methyl-
N'-nitro-N''-((tetrahydro-3-furanyl)methyl)guanidine] alone in or on
cattle meat, fat, and meat byproducts (mbyp) at 0.05 ppm; goat meat,
fat, and mbyp at 0.05 ppm; hog meat, fat, and mbyp at 0.05 ppm; horse
meat, fat, and mbyp at 0.05 ppm; sheep meat, fat, and mbyp 0.05 ppm;
and milk at 0.05 ppm. EPA's assessment of 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 dinotefuran are
discussed in Table 1 of this unit as well as the no observed adverse
effect level (NOAEL) and the lowest observed adverse effect level
(LOAEL) from the toxicity studies reviewed.
Table 1.--Subchronic, Chronic, and Other Toxicity
----------------------------------------------------------------------------------------------------------------
Guideline No. Study Type Results
----------------------------------------------------------------------------------------------------------------
870.3100 90-Day oral toxicity in NOAEL: 38/384 (M/F) mg/kg/day
rats LOAEL: 384 (M) mg/kg/day based on adrenal
histopathology; 1,871 (F) mg/kg/day based
on decreased body weight/body weight gain,
changes in hematology/clinical chemistry,
changes in organ weights, and adrenal
histopathology
----------------------------------------------------------------------------------------------------------------
[[Page 14537]]
870.3100 90-Day oral toxicity in NOAEL: 4,442/5,414 (M/F) mg/kg/day
mice LOAEL: 10,635/11,560 (M/F) mg/kg/day, based
on decreased body weight, body weight gain
----------------------------------------------------------------------------------------------------------------
870.3150 90-Day oral toxicity in NOAEL: 307/not determined (M/F) mg/kg/day
dogs LOAEL: 862 (M) mg/kg/day, based on body
weight gain, hemorrhagic lymph nodes; <59
(F), based on decreased body weight, body
weight gain
----------------------------------------------------------------------------------------------------------------
870.3200 28-Day dermal toxicity Systemic
(rats) NOAEL: 1,000 mg/kg/day
LOAEL: not determined (no effects seen)
Dermal:
NOAEL: 1,000 (M), <=200 (F) mg/kg/day
LOAEL: not determined/<=1,000 (M/F) mg/kg/
day based on lack of effects in males,
increase in acanthosis/hyperkeratosis in
high dose females (lower doses not
evaluated histopathologically)
----------------------------------------------------------------------------------------------------------------
870.3465 28-Day inhalation toxicity NOAEL:<0.22 (M) mg/L, 0.22 (F) mg/L
(rat) LOAEL: decreased body weight gain, food
consumption (M); increased clinical signs
(protruding eyes) (F)
----------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental Maternal
toxicity study (rats) NOAEL: 300 mg/kg/day
LOAEL: 1,000 mg/kg/day based on decreased
body weight gain and food consumption
Developmental
NOAEL: 1,000 mg/kg/day
LOAEL: not determined (no effects seen)
----------------------------------------------------------------------------------------------------------------
870.3700 Prenatal developmental Maternal
toxicity study (rabbits) NOAEL: 52 mg/kg/day
LOAEL: 125 mg/kg/day based on decreased
body weight gains, food consumption, and
necropsy findings
Developmental
NOAEL: 300 mg/kg/day
LOAEL: >300 mg/kg/day (no effects seen)
----------------------------------------------------------------------------------------------------------------
870.3800 Reproduction and fertility Parental/systemic
effects (rats) NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822/907 (M/F) mg/kg/day, based on
decreased food consumption, weight gain in
males, soft feces in females, and
decreasedspleen weights in both sexes
Reproductive (tentative)
NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822/907 (M/F) mg/kg/day, based on
decreased uterine weights and microscopic
alterations in the uterus and vagina of F0
females, decreased numbers of primordial
follicles in F1 females, altered estrous
cyclicity in F0 and F1 females, increase
in abnormal sperm morphology in F0 and F1
males, decreased testicular sperm count in
F0 males, and decreased sperm motility in
F1 males
Developmental
NOAEL: 241/268 (M/F) mg/kg/day
LOAEL: 822-935/907-1005 (M/F) mg/kg/day
based on decreased body weights, body
weight gains, and spleen weights in F1 and
F2 males and females, decreased thymus
weights in F2 males and females, and
decreased forelimb grip strength (F1
males) or hindlimb grip strength (F1
females)
----------------------------------------------------------------------------------------------------------------
870.4100 Chronic toxicity (rats) See 870.4300 combined chronic toxicity/
carcinogenicity (rats)
----------------------------------------------------------------------------------------------------------------
870.4100 Chronic toxicity (dogs) NOAEL: >20/22 (M/F) mg/kg/day
LOAEL: 20/108 (M/F) mg/kg/day based on
decreased thymus weight, decreased food
efficiency, body weight, and body weight
gain in females, decreased thymus weight
in males
----------------------------------------------------------------------------------------------------------------
870.4200 Carcinogenicity (rats) See 870.4300 combined chronic toxicity/
carcinogenicity (rats)
----------------------------------------------------------------------------------------------------------------
870.4200 Carcinogenicity (mice) NOAEL: <3 (M), <4 (F) mg/kg/day
LOAEL: 3/4 (M/F) mg/kg/day based on
decreased spleen weights at week 79
terminal sacrifice in males and increased
ovarian weights at week 53 in females
----------------------------------------------------------------------------------------------------------------
[[Page 14538]]
870.4300 Combined chronic toxicity/ NOAEL: 99.7/127.3 (M/F) mg/kg/day
carcinogenicity (rats) LOAEL: 991/1,332 (M/F) mg/kg/day based on
decreased body weight gain, food
efficiency in females, increased
incidences of kidney pelvic mineralization
and ulceration in males
----------------------------------------------------------------------------------------------------------------
870.5100 Bacterial reverse mutation Negative. S9 up to 16,000
test [mu]g/plate
----------------------------------------------------------------------------------------------------------------
870.5100 Bacterial reverse mutation Negative, S9 up to limit dose
test of 5,000 [mu]g/plate
----------------------------------------------------------------------------------------------------------------
870.5300 In vitro mammalian cell Negative, S9 up to 2002 [mu]g/
gene mutation test mL (mouse lymphoma L5178Y cells)
----------------------------------------------------------------------------------------------------------------
870.5375 In vitro mammalian Negative for clastogenic/aneugenic activity
chromosome aberration up to 2000 [mu]g/mL (CHL/IU cells)
test
----------------------------------------------------------------------------------------------------------------
870.5395 In vivo mammalian Negative at oral doses up to 1,080 mg/kg/
cytogenics -micronucleus day for 2 days
assay
----------------------------------------------------------------------------------------------------------------
870.6200 Acute neurotoxicity NOAEL: 750 (M), 325 (F) mg/kg/day
screening battery LOAEL: 1,500 (M), 750 (F) mg/kg/day based
on decreased motor activity on day 1
----------------------------------------------------------------------------------------------------------------
870.6200 Subchronic neurotoxicity NOAEL: 33/40 (M/F) mg/kg/day
screening battery LOAEL: 327/400 (M/F) mg/kg/day based on
increased motor activity during week 2
----------------------------------------------------------------------------------------------------------------
870.7485 Metabolism and Absorption was >90% regardless of dose. The
pharmacokinetics (rats) radiolabel was widely distributed through
the body and was completely excreted
within 168 hours of treatment. Urine was
the primary elimination route, accounting
for 88-99.8%. Excretion into the urine was
rapid, being 84-99% complete within 24
hours of treatment. Absorption of the
radioactivity was linear within the dose
range of 50 and 1,000 mg/kg. Elimination
of radioactivity was fast for all groups
with a T1/2 ranging from 3.64 to 15.2
hours for the low and high doses,
respectively. Radioactivity was rapidly
transferred from maternal blood to milk
and widely distributed in the fetal
tissues. The Cmax for milk and fetal
tissues was detected 0.5 hours after
maternal treatment. The concentrations of
radioactivity in fetal tissue and maternal
milk declined quickly and were below
detection limits 24 hours post-treatment.
After IV or oral treatment, 75-93% of the
administered radiolabeled test material,
or nearly 93-97% of total urinary
radiolabel, was excreted unchanged in the
urine. The parent compound was also the
primary component in the plasma, milk,
bile, feces, and most tissues collected 4-
8 hours after treatment and at both dose
levels. Less than 10% of the parent
compound was metabolized into numerous
minor metabolites that were not well
resolved by High Performance Liquid
Chromotography (HPLC) or 2D-TLC. For all
parameters measured in this study, no sex
or dose-related differences or label
position effects were found.
----------------------------------------------------------------------------------------------------------------
Special study Neonatal rat metabolism After a single oral 50 mg/kg dose of (G-
study (12-day old rat 14C) MTI-446 to 12-day old rats,
pups) absorption was high (absorption could not
be adequately determined but may have
approached 80%) and the radiolabel was
widely distributed within the body.
Approximately 32-36% of the administered
dose was excreted within 4 hours of
treatment. Urine was the primary
elimination route as indirectly evidenced
by finding high radioactive areas in the
kidneys and bladder by whole body
autoradiography. No areas of tissue
sequestration were found and no gender-
related differences were identified. The
test material was essentially not
metabolized, the parent compound
accounting for >97% of the radiolabel in
the excreta, plasma, kidneys, and stomach,
and nearly 61-83% in intestines (and
contents), and liver.
----------------------------------------------------------------------------------------------------------------
B. Toxicological Endpoints
The dose at which no adverse effects are observed (the NOAEL) from
the toxicology study identified as appropriate for use in risk
assessment is used to estimate the toxicological level of concern
(LOC). However, the lowest dose at which adverse effects of concern are
identified (the LOAEL) is sometimes used for risk assessment if no
NOAEL was achieved in the toxicology study selected. An uncertainty
factor (UF) is applied to reflect uncertainties inherent in the
extrapolation from laboratory animal data to humans and in the
variations in sensitivity among members of the human population as well
as other unknowns. An UF of 100 is routinely used, 10X to account for
interspecies differences and 10X for intraspecies differences.
Three other types of safety or uncertainty factors may be used:
``Traditional uncertainty factors;'' the ``special FQPA safety
factor;'' and the ``default FQPA safety factor''. By the term
``traditional uncertainty factor,'' EPA is referring to those
additional uncertainty factors used prior to FQPA passage to account
for database deficiencies. These traditional uncertainty factors have
been
[[Page 14539]]
incorporated by the FQPA into the additional safety factor for the
protection of infants and children. The term ``special FQPA safety
factor '' refers to those safety factors that are deemed necessary for
the protection of infants and children primarily as a result of the
FQPA. The ``default FQPA safety factor'' is the additional 10X safety
factor that is mandated by the statute unless it is decided that there
are reliable data to choose a different additional factor (potentially
a traditional uncertainty factor (UF) or a special FQPA safety factor).
For dietary risk assessment (other than cancer) the Agency uses the
UF to calculate an acute or chronic reference dose (aRfD or cRfD) where
the RfD is equal to the NOAEL divided by an UF of 100 to account for
interspecies and intraspecies differences and any traditional UFs
deemed appropriate (RfD = NOAEL/UF). Where a special FQPA safety factor
or the default FQPA safety factor is used, this additional factor is
applied to the RfD by dividing the RfD by such additional factor. The
acute or chronic Population Adjusted Dose (aPAD or cPAD) is a
modification of the RfD to accommodate this type of safety factor.
For non-dietary risk assessments (other than cancer) the UF is used
to determine the LOC. For example, when 100 is the appropriate UF (10X
to account for interspecies differences and 10X for intraspecies
differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to
exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and
compared to the LOC.
The linear default risk methodology (Q*) is the primary method
currently used by the Agency to quantify carcinogenic risk. The Q*
approach assumes that any amount of exposure will lead to some degree
of cancer risk. A Q* is calculated and used to estimate risk which
represents a probability of occurrence of additional cancer cases
(e.g., risk). An example of how such a probability risk is expressed
would be to describe the risk as one in one hundred thousand (1 x
10-5), one in a million (1 x 10-6), or one in ten
million (1 x 10-7). Under certain specific circumstances,
margin of exposure (MOE) calculations will be used for the carcinogenic
risk assessment. In this non-linear approach, a ``point of departure''
is identified below which carcinogenic effects are not expected. The
point of departure is typically a NOAEL based on an endpoint related to
cancer effects though it may be a different value derived from the dose
response curve. To estimate risk, a ratio of the point of departure to
exposure (MOEcancer = point of departure/exposures) is
calculated.
A summary of the toxicological endpoints for dinotefuran used for
human risk assessment is shown in the following Table 2.
Table 2.--Summary of Toxicological Dose and Endpoints for Dinotefuran for Use in Human Risk Assessment
----------------------------------------------------------------------------------------------------------------
Special FQPA SF and
Exposure/Scenario Dose Used in Risk Level of Concern for Study and Toxicological
Assessment, UF Risk Assessment Effects
----------------------------------------------------------------------------------------------------------------
Acute dietary (General population NOAEL = 125 mg/kg/day FQPA SF = 1 Developmental toxicity
including infants and children) UF = 100............... aPAD = acute RfD / FQPA study in rabbits
Acute RfD = 1.25 mg/kg/ SF = 1.25 mg/kg/day. LOAEL = 300 mg/kg/day
day. based on clinical
signs in does (prone
position, panting,
tremor, erythema) seen
following a single
dose.
----------------------------------------------------------------------------------------------------------------
Chronic dietary (All populations) LOAEL= 20 mg/kg/day FQPA SF = 1 Chronic toxicity study
UF = 1,000............. cPAD = chronic RfD / in dogs
Chronic RfD = 0.02 mg/ FQPA SF = 0.02 mg/kg/ LOAEL = 20 mg/kg/day
kg/day. day. based on decreased
thymus weight in males
----------------------------------------------------------------------------------------------------------------
Short-term incidental oral (1 to 30 NOAEL= 33 mg/kg/day Residential LOC for MOE Subchronic
days) = 100 neurotoxicity study in
Occupational = NA...... rats
LOAEL = 327 mg/kg/day
based on increased
motor activity during
week 2
----------------------------------------------------------------------------------------------------------------
Intermediate-term incidental oral (1 NOAEL= 22 mg/kg/day Residential LOC for MOE Chronic toxicity study
to 6 months) =100 in dogs
Occupational = NA...... LOAEL = 108 mg/kg/day
based on decreased
body weight and body
weight gain in females
----------------------------------------------------------------------------------------------------------------
Short-term dermal (1 to 30 days) No quantitation Residential LOC for MOE No quantitation
required. = NA required. No systemic
Occupational LOC for toxicity was seen at
MOE = NA. the limit dose in a 28-
day dermal toxicity
study in which
neurotoxicity was
evaluated. No
developmental toxicity
concerns.
----------------------------------------------------------------------------------------------------------------
Intermediate-term dermal (1 to 6 Oral study NOAEL = 22 Residential LOC for MOE Chronic toxicity study
months) mg/kg/day (dermal = 100 in dogs
absorption rate = 30%) Occupational LOC for LOAEL = 108 mg/kg/day
MOE =100. based on decreased
body weight and body
weight gain in females
----------------------------------------------------------------------------------------------------------------
Long-term dermal (>6 months) Oral study LOAEL = 20 Residential LOC for MOE Chronic toxicity study
mg/kg/day (dermal = 1,000 in dogs
absorption rate = 30%) Occupational LOC for LOAEL = 20 mg/kg/day
MOE = 1,000. based on decreased
thymus weight in males
----------------------------------------------------------------------------------------------------------------
Short-term inhalation (1 to 30 days) Inhalation study LOAEL= Residential LOC for MOE 28-day Inhalation
60 mg/kg/day = 1,000 toxicity study in rats
Occupational LOC for LOAEL = 60 mg/kg/day
MOE = 1,000. based on decreased
body weight gain in
males
----------------------------------------------------------------------------------------------------------------
[[Page 14540]]
Intermediate-term inhalation (1 to 6 Inhalation study LOAEL Residential LOC for MOE 28-day Inhalation
months) = 60 mg/kg/day =1,000 toxicity study in rats
Occupational LOC for LOAEL = 60 mg/kg/day
MOE = 1,000. based on decreased
body weight gain in
males
----------------------------------------------------------------------------------------------------------------
Long-term inhalation (>6 months) Oral study LOAEL= 20 mg/ Residential LOC for MOE Chronic toxicity study
kg/day (inhalation = 1,000 in dogs
absorption rate = Occupational LOC for LOAEL = 20 mg/kg/day
100%) MOE = 1,000. based on decreased
thymus weight in males
----------------------------------------------------------------------------------------------------------------
Cancer (oral, dermal, inhalation) NA NA Not required; no
evidence of
carcinogenicity.
----------------------------------------------------------------------------------------------------------------
UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL =
lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference
dose, MOE = margin of exposure, LOC = level of concern, NA = Not applicable.
C. Exposure Assessment
1. Dietary exposure from food and feed uses. Tolerances have been
established (40 CFR 180.603) for the combined residues of dinotefuran
and its metabolites, in or on a variety of raw agricultural
commodities. Risk assessments were conducted by EPA to assess dietary
exposures from dinotefuran in food as follows:
i. Acute exposure. Acute dietary risk assessments are performed for
a food-use pesticide, if a toxicological study has indicated the
possibility of an effect of concern occurring as a result of a 1-day or
single exposure.
In conducting the acute dietary risk assessment EPA used the
DEEMTM software with the FCID, which incorporates food
consumption data as reported by respondents in the U.S. Department of
Agriculture (USDA) 1994-1996 and 1998 Nationwide Continuing Surveys of
Food Intake by Individuals (CSFII), and accumulated exposure to the
chemical for each commodity. The following assumptions were made for
the acute exposure assessments: The dietary risk analyses incorporated
tolerance level residues and assumed 100% of the crops had been treated
with dinotefuran. The acute risk estimates are below the Agency's level
of concern (< 100% aPAD) for the general U.S. population and all
population subgroups.
ii. Chronic exposure. In conducting the chronic dietary risk
assessment EPA used the DEEMTM software with the FCID, which
incorporates food consumption data as reported by respondents in the
USDA 1994-1996 and 1998 CSFII, and accumulated exposure to the chemical
for each commodity. The following assumptions were made for the chronic
exposure assessments: The dietary risk analyses incorporated tolerance
level residues and assumed 100% of the crops had been treated with
dinotefuran. The chronic risk estimates are below the Agency's level of
concern (<100% cPAD) for the general U.S. population and all population
subgroups.
iii. Cancer. Dinotefuran is classified as ``not likely to be a
carcinogen,'' therefore, an exposure assessment for quantifying cancer
risk was not conducted.
2. Dietary exposure from drinking water. The Agency lacks
sufficient monitoring exposure data to complete a comprehensive dietary
exposure analysis and risk assessment for dinotefuran in drinking
water. Because the Agency does not have comprehensive monitoring data,
drinking water concentration estimates are made by reliance on
simulation or modeling taking into account data on the physical
characteristics of dinotefuran.
The Agency uses the FQPA Index Reservoir Screening Tool (FIRST) or
the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/
EXAMS), to produce estimates of pesticide concentrations in an index
reservoir. The SCI-GROW model is used to predict pesticide
concentrations in shallow ground water. For a screening-level
assessment for surface water EPA will use FIRST (a Tier 1 model) before
using PRZM/EXAMS (a Tier 2 model). The FIRST model is a subset of the
PRZM/EXAMS model that uses a specific high-end runoff scenario for
pesticides. Both FIRST and PRZM/EXAMS incorporate an index reservoir
environment, and both models include a percent crop treated (PCT) area
factor as an adjustment to account for the maximum PC coverage within a
watershed or drainage basin.
None of these models include consideration of the impact processing
(mixing, dilution, or treatment) of raw water for distribution as
drinking water would likely have on the removal of pesticides from the
source water. The primary use of these models by the Agency at this
stage is to provide a screen for sorting out pesticides for which it is
unlikely that drinking water concentrations would exceed human health
levels of concern.
Since the models used are considered to be screening tools in the
risk assessment process, the Agency does not use estimated
environmental concentrations (EECs), which are the model estimates of a
pesticide's concentration in water. EECs derived from these models are
used to quantify drinking water exposure and risk as a %RfD or %PAD.
Instead, drinking water levels of comparison (DWLOCs) are calculated
and used as a point of comparison against the model estimates of a
pesticide's concentration in water. DWLOCs are theoretical upper limits
on a pesticide's concentration in drinking water in light of total
aggregate exposure to a pesticide in food, and from residential uses.
Since DWLOCs address total aggregate exposure to dinotefuran they are
further discussed in the aggregate risk sections below.
Based on the FIRST and SCI-GROW models, the EECs of dinotefuran for
acute exposures are estimated to be 76 parts per billion (ppb) for
surface water and 5.1 ppb for ground water. The EECs for chronic
exposures are estimated to be 21 ppb for surface water and 5.1 ppb for
ground water.
3. From non-dietary exposure. The term ``residential exposure'' is
used in
[[Page 14541]]
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).
Dinotefuran is currently registered for use on the following
residential non-dietary sites: Professional turf management,
professional ornamental production, residential indoor, and lawn. The
risk assessment was conducted using the following residential exposure
assumptions: Outdoor uses for turf farms, golf courses, residential
lawns, and ornamentals.
There is a potential for exposure to homeowners in residential
settings during the application of products containing dinotefuran.
There is also a potential for exposure from entering areas previously
treated with dinotefuran such as lawns where children might play, or
golf courses and home gardens that could lead to exposures for adults.
As a result, risk assessments were previously discussed for both
residential handler and postapplication scenarios in the final rule for
setting tolerance on leafy vegetables in the Federal Register of
September 17, 2004 (69 FR 55963) (FRL-7368-1). The proposed new
agricultural uses of dinotefuran do not add any additional residential
exposures or risks.
The risks from the combined exposures of adults applying
dinotefuran to residential lawns and then being dermally exposed from
postapplication activities on the treated lawn do not exceed the
Agency's level of concern. Children's combined risks from activities on
treated lawns do not exceed the Agency's level of concern.
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.''
Unlike other pesticides for which EPA has followed a cumulative
risk approach based on a common mechanism of toxicity, EPA has not made
a common mechanism of toxicity finding as to dinotefuran and any other
substances and dinotefuran 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 dinotefuran has a
common mechanism of toxicity with other substances. For information
regarding EPA's efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA concerning common
mechanism determinations and procedures for cumulating effects from
substances found to have a common mechanism on EPA's web site at http:/
/www.epa.gov/pesticides/cumulative/.
D. Safety Factor for Infants and Children
1. In general. Section 408 of FFDCA provides that EPA shall apply
an additional tenfold margin of safety for infants and children in the
case of threshold effects to account for prenatal and postnatal
toxicity and the completeness of the 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. Margins of safety are
incorporated into EPA risk assessments either directly through use of a
MOE analysis or through using uncertainty (safety) factors (UFs) in
calculating a dose level that poses no appreciable risk to humans. In
applying this provision, EPA either retains the default value of 10X
when reliable data do not support the choice of a different factor, or,
if reliable data are available, EPA uses a different additional safety
factor value based on the use of traditional UFs and/or special FQPA
safety factors, as appropriate.
2. Prenatal and postnatal sensitivity. Prenatal developmental
toxicity studies in rats and rabbits provided no indication of
increased susceptibility (qualitative or quantitative) of rat or rabbit
fetuses to in utero exposure to dinotefuran. There was no indication of
increased (quantitative) susceptibility in the fetuses as compared to
parental animals in the two generation reproduction study. Qualitative
susceptibility was observed in the reproduction study; however, the
degree of concern is low because the observed effects are well
characterized (decreased body weight, decreased thymus weight, and
decreased grip strength) and there are clear NOAELs/LOAELs.
3. Conclusion. Although there is generally low concern and no
residual uncertainties for prenatal and/or postnatal toxicity resulting
from exposure to dinotefuran, some uncertainty is raised by a
deficiency in the data (a lack of a NOAEL in the chronic dog study) and
the need for a developmental immunotoxicity study (DIT).
The absence of a NOAEL for the chronic dog study and the need for a
DIT study generate some uncertainty regarding the protectiveness of
chronic regulatory endpoints and long-term levels of concern.
Accordingly, EPA does not have reliable data supporting adoption of a
safety factor other than the default additional 10X factor as specified
in FFDCA section 408(b)(2)(C). The chronic endpoint and long-term level
of concern have therefore, been generated using an overall safety/UF of
1,000 (representing 100X for interspecies and intraspecies variation
and an additional 10X pursuant to FFDCA section 408(b)(2)(C).
The Agency does not have similar concerns regarding acute, short-
term, and intermediate-term risk assessments for several reason. First,
the absence of a NOAEL only occurred in a chronic study. Second,
reliable data show that the DIT is unlikely to result in a NOAEL for
acute, short-term, or intermediate-term effects that is lower than the
NOAELs currently being used to assess the risk from such effects. EPA
has required a DlT study with dinotefuran based on the changes in the
thymus weight in offspring in the reproduction study and in adult rats
and dogs. There is, however, little evidence to support a direct effect
of dinotefuran on immune function. This is because lymphoid organ
weight changes can be secondary to generalized toxicity (e.g.,
reductions in body weight, body weight gain, and/or food efficiency).
In the reproduction study, decreased thymus weights were seen in
offspring in the presence of decreased body weight only at the Limit
Dose (10,000 ppm). In the 1-year dog study, decrease in thymus weight
was seen in the absence of other toxicity, however, no decrease in
thymus weight was seen in the subchronic study in dogs which was
conducted at higher doses (i.e., the results of the 1-year study was
not supported by the results of the 90-day study).
Further, the only evidence on dinotefuran's potential immunological
effect is found in studies with prolonged exposure. In the reproduction
study, the effect of concern i.e, decrease in thymus weight in only 1-
generation (F2) was seen only following approximately 13-weeks of
exposure to the parental animals at close to the limit dose (1,000 mg/
kg). Similarly, thymus effects in the chronic dog study were only
observable after long-term exposures, but were not seen in the 90-day
dog study.
Finally, it is clear that the DIT study, which is performed in the
rat, will have to be conducted at high doses (close to the limit dose)
to elicit a potential single dose effect and this will result in a
potential NOAEL higher than that currently used for various risk
[[Page 14542]]
assessments. As noted, in the rat reproduction study, effects only
occurred at doses close to the limit dose (1,000 mg/kg/day). The limit
dose is the maximum dose recommended for testing in the Series 870
Health Effects Harmonized Test Guidelines; toxic effects occurring only
at or near the limit dose are of less concern for human health since
they may be specifically related to the high dose exposure and may not
occur at the much lower doses to which humans are exposed.
Additionally, in the acute neurotoxicity study in the rat, the LOAEL
was 750 mg/kg/day in females and 1,500 mg/kg/day in males based on
reductions in motor activity indicating that high doses are required to
elicit dinotefuran-induced toxicity in rats.
The NOAELs in the critical studies selected for acute dietary (125
mg/kg/day), short-term incidental oral (33 mg/kg/day), and
intermediate-term incidental oral and dermal (22 mg/kg/day) exposure
scenarios are lower than the offspring NOAEL (241 mg/kg/day) in the
reproduction study. Therefore, EPA is confident that the doses selected
for these risk assessments will address the concerns for the thymus
weight changes seen in the offspring in the reproduction study and will
not underestimate the potential risk from exposure to dinotefuran.
The Agency believes there are reliable data showing that the
regulatory endpoints are protective of children despite the need for a
development neuorotoxicity (DNT) study. DNT data received and reviewed
for other compounds in this chemical class (neonicotinoids) including
thiacloprid, clothianidin, and imidacloprid, indicate that the results
of the required DNT study will not likely impact the regulatory doses
selected for dinotefuran.
In addition, the acute and chronic dietary food exposure assessment
utilized proposed tolerance level residues and 100% crop treated
information for all commodities. By using these screening-level
assessments, acute and chronic exposure/risks will not be
underestimated. Furthermore, the dietary drinking water assessment
(Tier 1 estimates) uses values generated by models and associated
modeling parameters which are designed to provide conservative, health
protective, high-end estimates of water concentrations. Finally, the
residential assessment for children's postapplication exposures is
based upon maximum application rates in conjunction with chemical-
specific study data and are not expected to underestimate risk.
E. Aggregate Risks and Determination of Safety
To estimate total aggregate exposure to a pesticide from food,
drinking water, and residential uses, the Agency calculates DWLOCs
which are used as a point of comparison against EECs. DWLOC values are
not regulatory standards for drinking water. DWLOCs are theoretical
upper limits on a pesticide's concentration in drinking water in light
of total aggregate exposure to a pesticide in food and residential
uses. In calculating a DWLOC, the Agency determines how much of the
acceptable exposure (i.e., the PAD) is available for exposure through
drinking water e.g., allowable chronic water exposure (mg/kg/day) =
cPAD - (average food + residential exposure). This allowable exposure
through drinking water is used to calculate a DWLOC.
A DWLOC will vary depending on the toxic endpoint, drinking water
consumption, and body weights. Default body weights and consumption
values as used by the EPA's Office of Water are used to calculate
DWLOCs: 2 liter (L)/70 kg (adult male), 2L/60 kg (youth and adult
female), and 1L/10 kg (child). Default body weights and drinking water
consumption values vary on an individual basis. This variation will be
taken into account in more refined screening-level and quantitative
drinking water exposure assessments. Different populations will have
different DWLOCs. Generally, a DWLOC is calculated for each type of
risk assessment used: Acute, short-term, intermediate-term, chronic,
and cancer.
When EECs for surface water and ground water are less than the
calculated DWLOCs, EPA concludes with reasonable certainty that
exposures to the pesticide in drinking water (when considered along
with other sources of exposure for which EPA has reliable data) would
not result in unacceptable levels of aggregate human health risk at
this time. Because EPA considers the aggregate risk resulting from
multiple exposure pathways associated with a pesticide's uses, levels
of comparison in drinking water may vary as those uses change. If new
uses are added in the future, EPA will reassess the potential impacts
of residues of the pesticide in drinking water as a part of the
aggregate risk assessment process.
1. Acute risk. Using the exposure assumptions discussed in this
unit for acute exposure, the acute dietary exposure from food to
dinotefuran will occupy 1.2% of the aPAD for the U.S. population, 1.2%
of the aPAD for females 13 to 49 years old, 1.3% of the aPAD for
infants <1 year old, and 2.9% of the aPAD for children 1 to 2 years
old. In addition, there is potential for acute dietary exposure to
dinotefuran in drinking water. After calculating DWLOCs and comparing
them to the EECs for surface water, and ground water, EPA does not
expect the aggregate exposure to exceed 100% of the aPAD, as shown in
the following Table 3.
Table 3.--Aggregate Risk Assessment for Acute Exposure to Dinotefuran
----------------------------------------------------------------------------------------------------------------
Surface Ground
Population/Subgroup aPAD /(mg/ %aPAD/ Water EEC/ Water EEC/ Acute DWLOC
kg/day) (Food) (ppb) (ppb) (ppb)
----------------------------------------------------------------------------------------------------------------
U.S. population 1.25 1.2 76 5.1 43,000
----------------------------------------------------------------------------------------
All infants (<1 year old) 1.25 1.3 76 5.1 12,000
----------------------------------------------------------------------------------------------------------------
Children (1-2 years old) 1.25 2.9 76 5.1 12,000
----------------------------------------------------------------------------------------
Females (13-49 years old) 1.25 1.2 76 5.1 37,000
----------------------------------------------------------------------------------------------------------------
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to
dinotefuran from food will utilize 21% of the cPAD for the U.S.
population, 18% of the cPAD for infants <1 year old, and 54% of the
cPAD for children 1 to 2 years old, and 20% of the cPAD for females 13
to 49 years old. Based on the use pattern, chronic residential exposure
to residues of dinotefuran does not exceed the
[[Page 14543]]
Agency's level of concern, as discussed in Unit III.E.3. below. In
addition, there is potential for chronic dietary exposure to
dinotefuran in drinking water. After calculating DWLOCs and comparing
them to the EECs for surface water, and ground water, EPA does not
expect the aggregate exposure to exceed 100% of the cPAD, as shown in
the following Table 4.
Table 4.--Aggregate Risk Assessment for Chronic (Non-Cancer) Exposure to Dinotefuran
----------------------------------------------------------------------------------------------------------------
Surface Ground
Population Subgroup cPAD (mg/kg/day) %cPAD (FOOD) Water EEC Water EEC Chronic
(ppb) (ppb) DWLOC (ppb)
----------------------------------------------------------------------------------------------------------------
U.S. population 0.02 21 21 5.1 550
-------------------
