Thiamethoxam; Pesticide Tolerance

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: June 22, 2007 (Volume 72, Number 120)]
[Rules and Regulations]
[Page 34401-34409]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22jn07-15]

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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[EPA-HQ-OPP-2006-0523; FRL-8133-6]

AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for combined residues
of thiamethoxam and its metabolite (CGA-322704) in or on artichoke, globe;
caneberry subgroup 13-A, hop, dried cones; grape; grape, raisin; brassica,

[[Page 34402]]

head and stem, subgroup 5-A; brassica, leafy greens, subgroup 5-B;
vegetable, leafy, except brassica group 4. Additionally, tolerance
levels for barley, grain; barley, hay and barley, straw will be
amended. Interregional Research Project Number 4 (IR-4) and Syngenta
Crop Protection Inc. requested these tolerances under the Federal Food,
Drug, and Cosmetic Act (FFDCA).

DATES: This regulation is effective June 22, 2007. Objections and
requests for hearings must be received on or before August 21, 2007,
and must be filed in accordance with the instructions provided in 40
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: EPA has established a docket for this action under docket
identification (ID) number EPA-HQ-OPP-2006-0523. To access the
electronic docket, go to http://www.regulations.gov, select ``Advanced
Search,'' then ``Docket Search.'' Insert the docket ID number where
indicated and select the ``Submit'' button. Follow the instructions on
the regulations.gov web site to view the docket index or access
available documents. All documents in the docket are listed in the
docket index available in regulations.gov. Although listed in the
index, some information is not publicly available, e.g., Confidential
Business Information (CBI) or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available in the electronic docket at http://www.regulations.gov, or,
if only available in hard copy, at the OPP Regulatory Public Docket in
Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr.,
Arlington, VA. The Docket Facility is open from 8:30 a.m. to 4 p.m.,
Monday through Friday, excluding legal holidays. The Docket Facility
telephone number is (703) 305-5805.

FOR FURTHER INFORMATION CONTACT: Barbara Madden, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 305-6463; e-mail address: madden.barbara@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 those
engaged in the following activities:
• Crop production (NAICS code 111), e.g., agricultural
workers; greenhouse, nursery, and floriculture workers; farmers.
• Animal production (NAICS code 112), e.g., cattle ranchers
and farmers, dairy cattle farmers, livestock farmers.
• Food manufacturing (NAICS code 311), e.g., agricultural
workers; farmers; greenhouse, nursery, and floriculture workers;
ranchers; pesticide applicators.
• Pesticide manufacturing (NAICS code 32532), e.g.,
agricultural workers; commercial applicators; farmers; greenhouse,
nursery, and floriculture workers; residential users.
This listing is not intended to be exhaustive, but rather to
provide a guide for readers regarding entities likely to be affected by
this action. Other types of entities not listed in this unit could also
be affected. The North American Industrial Classification System
(NAICS) codes have been provided to assist you and others in
determining whether this action might apply to certain entities. If you
have any questions regarding the applicability of this action to a
particular entity, consult the person listed under FOR FURTHER
INFORMATION CONTACT.

B. How Can I Access Electronic Copies of this Document?

In addition to accessing an electronic copy of this Federal Register
document through the electronic docket at http://www.regulations.gov,
you may access this Federal Register document electronically through the
EPA Internet under the ``Federal Register'' listings at
http://www.epa.gov/fedrgstr. You may also access a frequently updated
electronic version of EPA's tolerance regulations at 40 CFR part 180
through the Government Printing Office's pilot e-CFR site at
http://www.gpoaccess.gov/ecfr.

C. Can I File an Objection or Hearing Request?

Under section 408(g) of the FFDCA, any person may file an objection
to any aspect of this regulation and may also request a hearing on
those objections. You must file your objection or request a hearing on
this regulation in accordance with the instructions provided in 40 CFR
part 178. To ensure proper receipt by EPA, you must identify docket ID
number EPA-HQ-OPP-2006-0523 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 as required by 40 CFR part 178 on or
before August 21, 2007.
In addition to filing an objection or hearing request with the
Hearing Clerk as described in 40 CFR part 178, please submit a copy of
the filing that does not contain any CBI for inclusion in the public
docket that is described in ADDRESSES. Information not marked
confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA
without prior notice. Submit this copy, identified by docket ID number
EPA-HQ-OPP-2006-0523, by one of the following methods:
• Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
• Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
• Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket's normal hours of operation (8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays). Special
arrangements should be made for deliveries of boxed information. The
Docket Facility telephone number is (703) 305-5805.

II. Petition for Tolerance

In the Federal Register of July 12, 2006 (71 FR 39316) (FRL-8074-
3), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21
U.S.C. 346a(d)(3), announcing the filing of pesticide petitions (PP
6E7060, 0F6142, and 9F5051) Interregional Research Project Number 4
(IR-4), 681 U.S. Highway #1 South, North Brunswick, NJ 08902-
3390 and Syngenta Crop Protection Inc., P.O. Box 18300, Greensboro, NC
27419-8300. These petitions requested that 40 CFR 180.565 be amended by
establishing a tolerance for combined residues of the insecticide,
thiamethoxam [3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-
nitro-4H-1,3,5-oxadiazin-4-imine and its metabolite [N-(2-chloro-
thiazol-5-ylmethyl)-N'-methyl-N'-nitro-guanidine] in or on the
following commodities:
PP 6E7060: Caneberry subgroup 13-A at 0.30 parts per million (ppm);
hops at 0.1 ppm; globe artichoke at 0.4 ppm and amend the existing
tolerance levels for barley, grain at 0.3 ppm; barley, hay at 0.4 ppm;
and barley, straw at 0.4 ppm.
PP 0F6142: Grapes at 0.15 ppm; grape, juice at 0.20 ppm; and
raisins at 0.30 ppm.

[[Page 34403]]

PP 9F5051: Vegetable, leafy, except brassica, group 4 at 2.0 ppm;
brassica, leafy greens, subgroup 5-B at 2.0 ppm; brassica, head and
stem, subgroup 5-A at 1.0 ppm.
That notice referenced a summary of the petitions prepared by
Syngenta Crop Protection Inc., the registrant, which is available to
the public in the docket, http://www.regulations.gov. Comments were
received on the notice of filing. EPA's response to these comments is
discussed in Unit IV.C.
Based upon review of the data supporting the petitions, EPA has
determined tolerance levels for artichoke, grape, caneberry subgroup
13-A, brassica head and stem subgroup 5-A, brassica leafy greens
subgroup 5-B, vegetable leafy except brassica group 4 should be
modified and a tolerance for grape juice should not be established. The
reason for these changes is explained in Unit V.
EPA is also deleting several established tolerances in Sec.
180.565(b) that are no longer needed. The tolerance deletions under
Sec. 180.565(b) are time-limited tolerances established under section
18 emergency exemptions that are superceded by the establishment of
general tolerances for thiamethoxam and its metabolite under Sec.
180.565(a).
The revisions to Sec. 180.565(b) are as follows:
1. Delete the time-limited tolerance for artichoke, globe at 0.40
ppm. A tolerance for artichoke, globe at 0.45 ppm is established by
this action under Sec. 180.565(a).
2. Delete the time-limited tolerances for bean, dried at 0.02 ppm
and bean, succulent at 0.02 ppm as these tolerances have expired and
are no longer in force.
3. Delete the time-limited tolerance for hops at 0.10 ppm. A
tolerance for hop, dried cones at 0.10 ppm is established by this
action under Sec. 180.565(a).

III. Aggregate Risk Assessment and Determination of Safety

Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of the 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 the 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. . .
.'' These provisions were added to the FFDCA by the Food Quality
Protection Act (FQPA) of 1996.
Consistent with section 408(b)(2)(D) of FFDCA, and the factors
specified in section 408(b)(2)(D) of FFDCA, EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of and to
make a determination on aggregate exposure for the petitioned-for
tolerances for combined residues of the insecticide, thiamethoxam [3-
[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-nitro-4H-1,3,5-
oxadiazin-4-imine and its metabolite [N-(2-chloro-thiazol-5-ylmethyl)-
N'-methyl -N'-nitro-guanidine] on artichoke, globe at 0.45 ppm; barley,
grain at 0.30 ppm; barley, hay at 0.40 ppm; barley, straw at 0.40 ppm;
Brassica, head and stem, subgroup 5-A at 4.5; brassica, leafy greens,
subgroup 5-B at 3.0 ppm; caneberry subgroup 13-A at 0.35 ppm; grape at
0.20 ppm; grape, raisin at 0.30 ppm; hop, dried cones at 0.10 ppm; and
vegetable, leafy except Brassica, group 4 at 4.0 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. Specific information on the studies received and the nature
of the adverse effects caused by thiamethoxam as well as the no-
observed-adverse-effect-level (NOAEL) and the lowest-observed-adverse-
effect-level (LOAEL) from the toxicity studies can be found at
http://www.regulations.gov. The referenced document is available in the
docket established by this action, which is described under ADDRESSES,
and is identified as EPA-HQ-OPP-2006-0523-0003 in that docket.
The database for thiamethoxam indicates 4 primary targets for this
pesticide: The liver, testes, kidney, and hematopoietic system. The
testicular effects are considered to be toxicologically significant
effects and most of the endpoints for risk assessment are based on
these effects. In the liver, enzyme induction and hepatocellular
hypertrophy in and of themselves are not necessarily considered adverse
effects. However, other effects were associated with these observations
that are considered to be toxicologically significant. These include
necrosis of single hepatocytes, foci of cellular alteration, apoptosis,
Kupffer cell infiltration, pigmentation and hyperplasia, and benign and
malignant liver tumors. The majority of the kidney effects may be
attributed to accumulation of [alpha]2u-globulin, a protein that is
unique to males rats (it is noted that 1 high-dose female in the
reproduction study also had similar effects). If the effects in male
rats are related to accumulation of [alpha]2u-globulin, then these
particular kidney effects are not relevant to humans. The hematological
effects are observed in three species. These include increased spleen
weights, increases in the incidence and severity of hemosiderosis and/
or extramedullary hematopoiesis and a slight reduction in erythrocytes,
hemoglobin and hematocrit. In the dog, leukopenia and slight microcytic
anemia have been observed. These effects are not considered to be as
significant as the testicular, liver, and kidney effects. They often
appear at very high dose levels and the changes are not dramatic.
The final rule published in the Federal Register of January 5, 2006
http://www.epa.gov/fedrgstr/EPA-PEST/2005/January/Day-05/p089.htm)
reported that the EPA had classified thiamethoxam as ``likely
carcinogen for humans'' based on increased incidence of hepatocellular
adenomas and carcinomas in male and female mice. Quantification of risk
based on most potent unit was based on male mouse liver adenoma and/or
carcinoma combined tumor rate. The upper bound estimate of unit risk,
Q1* was calculated as 3.77 x 10-2 in human equivalents.
EPA re-evaluated this determination based on new data submitted by
the registrant indicating the mode of action for the mouse liver
tumors. EPA agreed with the registrant that a plausible mode of action
has been established for the development of liver tumors in a mouse
bioassay with thiamethoxam. EPA concluded that the liver tumors in the
mouse arise through a non-genotoxic mode of action characterized by a
series of key events that include: Perturbation of cholesterol
biosynthesis, hepatotoxicity, cell death (both as single cell necrosis
and apoptosis) and a

[[Page 34404]]

sustained increase in cell replication rates. Neither the key events
nor an increase in liver tumors are seen in rats fed on diets
containing up to 3,000 ppm thiamethoxam. The key metabolites, CGA330050
and CGA265307, responsible for the key events in the mouse are not
formed in sufficient quantities in the rat and explain the lack of a
carcinogenic response in this species.
A sufficient amount of active metabolite must be produced along
with persistent exposure to the active metabolite to lead to the
hepatotoxic/regenerative proliferative/neoplastic response in the
mouse. Limited human in vitro metabolism studies suggest that humans
are more similar to the rat compared to the mouse in producing the
active metabolite. The rat does not develop tumors following treatment
with thiamethoxam. Thus, the mouse appears to be uniquely sensitive to
this mode of action. Because of the threshold nature of the mode of
action and the unique sensitivity of the mouse, it is concluded that
humans are unlikely to be at risk for developing tumors following
exposures to thiamethoxam.
After considering EPA's Final Guidelines for Carcinogen Risk
Assessment, the Agency classified thiamethoxam as ``Not Likely to be
Carcinogenic to Humans'' based on convincing evidence that a non-
genotoxic mode of action for liver tumors was established in the mouse
and that the carcinogenic effects are a result of a mode of action
dependent on sufficient amounts of a hepatotoxic metabolite produced
persistently. Although humans are qualitatively capable of producing
the active metabolite, thiamethoxam is unlikely to pose a cancer risk
to humans unless sufficient amounts of metabolites are persistently
formed to drive a carcinogenic response. Lastly, the non-cancer
(chronic) assessment is sufficiently protective of the key events
(perturbation of liver metabolism, hepatotoxicity/regenerative
proliferation) in the animal mode of action and, thus, cancer is not an
issue. Thus, quantification of carcinogenic potential is not required.
In assessing the human health risks associated with the existing
and proposed uses of thiamethoxam, EPA has included exposure to
thiamethoxam as well as its metabolite CGA-322704 when evaluating
exposure from the dietary (food only) pathway. This approach was
developed when the Agency received the first food-use request for
registration of thiamethoxam and determined that the CGA-322704
metabolite/degradate, as well as the parent compound, are residues of
concern in food; no exposure to CGA-322704 in drinking water was
considered likely following application of thiamethoxam. At the time,
toxicological information regarding CGA-322704 was not available, and
it was assumed that thiamethoxam and this metabolite are
toxicologically equivalent for estimation of dietary risk.
Subsequently, the Agency received a petition requesting
registration of the insecticide clothianidin. Upon review of that
petition, the Agency discovered that CGA-322704 and clothianidin are
identical. With the registration of clothianidin uses, the Agency now
has a complete toxicological database for both thiamethoxam and CGA-
322704 (referred to in the remainder of this rule as clothianidin).
While some of the toxic effects observed following sing with the two
active ingredients are similar, the available information indicate that
thiamethoxam and clothianidin have different toxicological effects in
mammals and should be assessed separately. A separate risk assessment
of clothianidin has been completed in conjunction with the registration
of clothianidin. The most recent assessment, which provides details
regarding the toxicology of clothianidin are discussed in the final
rule published in the Federal Register of December 13, 2006
(http://www.epa.gov/EPA-PEST/2006/December/Day-13/p20898.htm).

B. Toxicological Endpoints

For hazards that have a threshold below which there is no
appreciable risk, the toxicological level of concern (LOC) is derived
from the highest dose at which no adverse effects are observed (the
NOAEL) in the toxicology study identified as appropriate for use in
risk assessment. However, if a NOAEL cannot be determined, the lowest
dose at which adverse effects of concern are identified (the LOAEL) is
sometimes used for risk assessment. Uncertainty/safety factors (UF) are
used in conjunction with the LOC to take into account 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. Safety is assessed for acute and chronic
risks by comparing aggregate exposure to the pesticide to the acute
population adjusted dose (aPAD) and chronic population adjusted dose
(cPAD). The aPAD and cPAD are calculated by dividing the LOC by all
applicable uncertainty/safety factors. Short-, intermediate, and long-
term risks are evaluated by comparing aggregate exposure to the LOC to
ensure that the margin of exposure (MOE) called for by the product of
all applicable uncertainty/safety factors is not exceeded.
For non-threshold risks, the Agency assumes that any amount of
exposure will lead to some degree of risk and estimates risk in terms
of the probability of occurrence of additional adverse cases.
Generally, cancer risks are considered non-threshold. For more
information on the general principles EPA uses in risk characterization
and a complete description of the risk assessment process, see
http://www.epa.gov/fedrgstr/EPA-PEST/1997/November/Day-26/p30948.htm.

A summary of the toxicological endpoints for thiamethoxam used for
human risk assessment is shown in the Table of this unit .

Summary of Toxicological Dose and Endpoints for Thiamethoxam for Use in Human Risk Assessment
----------------------------------------------------------------------------------------------------------------
Dose Used in Risk
Assessment, Special FQPA SF and
Exposure/Scenario Interspecies and Level of Concern for Study and Toxicological
Intraspecies and any Risk Assessment Effects
Traditional FQPA, SF
----------------------------------------------------------------------------------------------------------------
Acute Dietary (All Populations NOAEL = 34.5 mg/kg/day Special FQPA SF = 1X Rat Developmental
including females 13-50 years of SF = 100X.............. aPAD = acute RfD Neurotoxicity study
age, infants and children) Acute RfD = 0.35 mg/kg/ Special FQPA. LOAEL = 298.7 mg/kg/day
day. SF = 0.35 mg/kg/day.... based on delayed
sexual maturation in
male pups, and reduced
brain morphometric
measurements.
----------------------------------------------------------------------------------------------------------------

[[Page 34405]]

Chronic Dietary (All populations) NOAEL= 1.2 mg/kg/day Special FQPA SF = 1X 2-Generation
SF = 100X.............. cPAD = chronic RfD/ Reproduction study
Chronic RfD = 0.012 mg/ Special FQPA SF = LOAEL = 1.8 mg/kg/day
kg/day. 0.012 mg/kg/day. based on increased
incidence and severity
of tubular atrophy in
testes of F1
generation males.
2-Generation
Reproduction study
LOAEL = 3 in males
based on sperm
abnormalities in F1
males. No LOAEL was
determined for
females.
----------------------------------------------------------------------------------------------------------------
Incidental Oral (All durations) NOAEL = 8.23 mg/kg/day LOC for MOE = 100 90-day Dog study
(Residential) LOAEL= 32 (males) 33.9
(females) mg/kg/day
based on slightly
prolonged prothrombin
times and decreased
plasma albumin and A/G
ratio (both sexes);
decreased calcium
levels and ovary
weights and delayed
maturation in the
ovaries (females);
decreased cholesterol
and phospholipid
levels, testis
weights,
spermatogenesis, and
spermatic giant cells
in testes (males).
----------------------------------------------------------------------------------------------------------------
Dermal (All durations) (Adults) Oral study LOC for MOE = 100 2-Generation
(Residential) NOAEL= 1.2 mg/kg/day (Residential) Reproduction study
(dermal absorption LOAEL = 1.8 mg/kg/day
rate = 5%). based on increased
incidence and severity
of tubular atrophy in
testes of F1
generation males.
2-Generation
Reproduction study
(46402904)
LOAEL = 3 in males
based on sperm
abnormalities in F1
males. No LOAEL was
determined for
females.
----------------------------------------------------------------------------------------------------------------
Dermal (All durations) (Infants/ Dermal study LOC for MOE = 100 Rat 28-Day Dermal
children 1-6 years old) NOAEL = 60 mg/kg/day (Residential) Toxicity study
(Residential) (dermal absorption LOAEL = 250 (females)
rate = 5%. mg/kg/day based on
increased plasma
glucose, triglyceride
levels, and alkaline
phosphatase activity
and inflammatory cell
infiltration in the
liver and necrosis of
single hepatocytes in
females.
----------------------------------------------------------------------------------------------------------------
Inhalation (All durations) Oral study LOC for MOE = 100 2-Generation
(Residential) NOAEL = 1.2 mg/kg/day (Residential) Reproduction study
(inhalation absorption LOAEL = 1.8 mg/kg/day
rate = 100%). based on increased
incidence and severity
of tubular atrophy in
testes of F1
generation males.
2-Generation
Reproduction study
(46402904)
LOAEL = 3 in males
based on sperm
abnormalities in F1
males. No LOAEL was
determined for
females.
----------------------------------------------------------------------------------------------------------------
Cancer (oral, dermal, inhalation) ``Not Likely to be Carcinogenic to Humans'' based on convincing evidence
that a non-genotoxic mode of action for liver tumors was established in
the mouse and that the carcinogenic effects are a result of a mode of
action dependent on sufficient amounts of a hepatotoxic metabolite
produced persistently. Quantification of cancer risk is not required.
----------------------------------------------------------------------------------------------------------------

C. Exposure Assessment

1. Dietary exposure from food and feed uses. In evaluating dietary
exposure to thiamethoxam, EPA considered exposure under the petitioned-
for tolerances as well as all existing thiamethoxam tolerances in (40
CFR 180.565). EPA assessed dietary exposures from thiamethoxam in food
as follows:
For both acute and chronic exposure assessments EPA combined
residues of clothianidin coming from thiamethoxam with residues of
thiamethoxam per se. As discussed above, thiamethoxam's major
metabolite is CGA-322704, which is also the registered active
ingredient clothianidin. There is available information indicating that
thiamethoxam and clothianidin have different toxicological effects in
mammals and should be assessed separately, however, these exposure
assessments for this action incorporated the total residue of
thiamethoxam and clothianidin to estimate dietary exposure. This
aggregation of thiamethoxam and clothianidin began with the initial
assessment of thiamethoxam, prior to the requested registration of
clothianidin as an active ingredient, and is being maintained in this
action for historical purposes. In future assessments, as time and
resources allow, the EPA will provide a rationale for the separate
analysis of risks coming from thiamethoxam and clothianidin, and will
conduct separate evaluations of exposure and risk for each chemical.
The combining of these residues, as was done in these assessments,
results in highly

[[Page 34406]]

conservative estimates of dietary exposure and risk.
i. Acute exposure. Quantitative acute dietary exposure and risk
assessments are performed for a food-use pesticide, if a toxicological
study has indicated the possibility of an effect of concern occurring
as a result of a 1-day or single exposure. In estimating acute dietary
exposure, EPA used food consumption information from the USDA 1994-1996
and 1998 Nationwide Continuing Surveys of Food Intake by Individuals
(CSFII). As to residue levels in food, EPA assumed maximum residues of
thiamethoxam and clothianidin observed in the thiamethoxam field
trials. It was also assumed that 100% of crops with registered or
requested uses of thiamethoxam are treated.
ii. Chronic exposure. In conducting the chronic dietary exposure
assessment EPA used the food consumption data from the USDA 1994-1996
and 1998 Nationwide CSFII. As to residue levels in food, EPA assumed
maximum residues of thiamethoxam and clothianidin observed in the
thiamethoxam field trials. It was also assumed that 100% of crops with
registered or requested uses of thiamethoxam are treated.
A complete listing of the inputs used in these assessments can be
found in the document titled Thiamethoxam Acute and Chronic Aggregate
Dietary and Drinking Water Exposure and Risk Assessments for FIFRA
Section 3 Registration available in the docket established by this
action EPA-HQ-OPP-2006-0523.
iii. Cancer. A quantitative cancer exposure assessment is not
necessary because EPA concluded that thiamethoxam is ``Not Likely to be
Carcinogenic to Humans'' based on convincing evidence that a non-
genotoxic mode of action for liver tumors was established in the mouse
and that the carcinogenic effects are a result of a mode of action
dependent on sufficient amounts of a hepatotoxic metabolite produced
persistently. Therefore, the Agency concluded that thiamethoxam is not
expected to pose a carcinogenic risk and an exposure assessment
pertaining to cancer risk is not necessary.
2. Dietary exposure from drinking water. Thiamethoxam is expected
to be persistent and mobile in terrestrial and aquatic environments.
These fate properties suggest that thiamethoxam has a potential to move
into surface water and shallow ground water.
The Agency lacks sufficient monitoring data to complete a
comprehensive dietary exposure analysis and risk assessment for
thiamethoxam 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 environmental fate characteristics of thiamethoxam. Further
information regarding EPA drinking water models used in pesticide
exposure assessment can be found at
http://www.epa.gov/oppefed1/models/water/index.htm.
Based on the Pesticide Root Zone Model/Exposure Analysis Modeling
System (PRZM/EXAMS) and Screening Concentrations in Groundwater (SCI-
GROW) models, the estimated environmental concentrations (EECs) of
thiamethoxam for acute exposures are estimated to be 12.26 parts per
billion (ppb) for surface water and 7.94 ppb for ground water. The EECs
for chronic exposures are estimated to be 1.29 ppb for surface water
and 7.94 ppb for ground water.
The registrant has conducted small-scale prospective ground water
studies in several locations in the U.S. to investigate the mobility of
thiamethoxam in a vulnerable hydrogeological setting. A review of those
data shows that generally residues of thiamethoxam as well as CGA-
322704 are below the limit of quantitation (0.05 ppb). When
quantifiable residues are found, they are sporadic and at low levels.
The maximum observed residue levels from any monitoring well were 1.0
ppb for thiamethoxam and 0.73 ppb for CGA-322704. These values are well
below the modeled estimates summarized above, indicating that the
modeled estimates are, in fact, protective of what actual exposures are
likely to be.
Modeled estimates of drinking water concentrations were directly
entered into the dietary exposure model. For both the acute and chronic
assessments the acute EEC of 12.26 ppb (0.0123 ppm) was used as a
worst-case estimate of exposure via drinking water.
3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets).
Thiamethoxam is registered for use on turfgrass on golf courses,
residential lawns, commercial grounds, parks, playgrounds, athletic
fields, landscapes, interiorscapes and sod farms. Thiamethoxam is
applied by commercial applicators only. Therefore, exposures resulting
from homeowner applications were not assessed. However, entering areas
previously treated with thiamethoxam could lead to exposures for adults
and children. As a result, risk assessments have been completed for
postapplication scenarios. Short-term exposures (1 to 30 days of
continuous exposure) may occur as a result of activities on treated
turf. There are no use patterns for thiamethoxam that indicate
intermediate-term (1 to 6 months of continuous exposure) or chronic
non-dietary exposures are likely to occur.
Dermal exposures were assessed for adults and children. Oral non-
dietary ingestion exposures (i.e. soil ingestion, and hand-/object-to-
mouth) were assessed for children as well. Since all postapplication
scenarios occur outdoors the potential for inhalation exposure is
negligible and therefore does not require an inhalation exposure
assessment. For purposes of this assessment exposure from residential
lawns is used to represent the worst case scenario for both dermal and
oral postapplication exposure.
Postapplication dermal exposure resulting from contact with treated
turf was assessed using the HED Standard Operating Procedures for
Residential Exposure and a chemical-specific turf transfer residue
(TTR) study.
4. Cumulative effects from substances with a common mechanism of
toxicity. Section 408(b)(2)(D)(v) of the 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.''
Thiamethoxam is a member of the neonicotinoid class of pesticides
and produces, as a metabolite, another neonicotinoid, clothianidin.
Structural similarities or common effects do not constitute a common
mechanism of toxicity. Evidence is needed to establish that the
chemicals operate by the same, or essentially the same sequence of
major biochemical events (EPA, 2002). Although clothianidin and
thiamethoxam bind selectively to insect nicotinic acetylcholine
receptors (nAChR), the specific binding site(s)/receptor(s) for
clothianidin, thiamethoxam, and the other neonicotinoids are unknown at
this time. Additionally, the commonality of the binding activity itself
is uncertain, as preliminary evidence suggests that clothianidin
operates by direct competitive inhibition, while thiamethoxam is a non-
competitive inhibitor. Furthermore, even if future research shows that
neonicotinoids share a common binding activity to a

[[Page 34407]]

specific site on insect nicotinic acetylcholine receptors, there is not
necessarily a relationship between this pesticidal action and a
mechanism of toxicity in mammals. Structural variations between the
insect and mammalian nAChRs produce quantitative differences in the
binding affinity of the neonicotinoids towards these receptors, which,
in turn, confers the notably greater selective toxicity of this class
towards insects, including aphids and leafhoppers, compared to mammals.
While the insecticidal action of the neonicotinoids is neurotoxic, the
most sensitive regulatory endpoint for thiamethoxam is based on
unrelated effects in mammals, including effects on the liver, kidney,
testes, and hematopoietic system. Additionally, the most sensitive
toxicological effect in mammals differs across the neonicotinoids
(e.g., testicular tubular atrophy with thiamethoxam; mineralized
particles in thyroid colloid with imidaclopid). Thus, there is
currently no evidence to indicate that neonicotinoids share common
mechanisms of toxicity, and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the
neonicotinoids. 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
concerning common mechanism determinations and procedures for
cumulating effects from substances found to have a common mechanism
released by EPA's Office of Pesticide Programs on EPA's website 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 (10X) tenfold margin of safety for infants and children
in the case of threshold effects to account for prenatal and postnatal
toxicity and the completeness of the data base on toxicity and exposure
unless EPA determines based on reliable data that a different margin of
safety will be safe for infants and children. This additional margin of
safety is commonly referred to as the FQPA safety factor. 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 FQPA
safety factor value based on the use of traditional uncertainty/safety
factors and/or special FQPA safety factors, as appropriate.
2. Prenatal and postnatal sensitivity. In the developmental
studies, there is no evidence of increased quantitative or qualitative
susceptibility of rat or rabbit fetuses to in utero exposure to
thiamethoxam. The developmental NOAELs are either higher than or equal
to the maternal NOAELs. The toxicological effects in fetuses do not
appear to be any more severe than those in the dams or does. In the rat
developmental neurotoxicity study, there was no quantitative evidence
of increased susceptibility.
There is evidence of increased quantitative susceptibility for male
pups in both 2-generation reproductive studies. In one study, there are
no toxicological effects in the dams whereas for the pups, reduced
bodyweights are observed at the highest dose level, starting on day 14
of lactation. This contributes to an overall decrease in bodyweight
gain during the entire lactation period. The reproductive effects in
males appear in the F1 generation in the form of increased incidence
and severity of testicular tubular atrophy (see developmental/
reproductive section). These data are considered to be evidence of
increased quantitative susceptibility for male pups (increased
incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared
to the parents (hyaline changes in renal tubules at 61 mg/kg/day; NOAEL
is 1.8 mg/kg/day).
In the more recent 2-generation reproduction study, the most
sensitive effect was sperm abnormalities at 3 mg/kg/day (the NOAEL is
1.2 mg/kg/day) in the F1 males. This study also indicates increased
susceptibility for the offspring for this effect.
Although there is evidence of increased quantitative susceptibility
for male pups in both reproductive studies, NOAELs and LOAELs were
established in these studies and the Agency selected the NOAEL for
testicular effects in F1 pups as the basis for risk assessment. The
Agency has confidence that the NOAEL selected for risk assessment is
protective of the most sensitive effect (testicular effects) for the
most sensitive subgroup (pups) observed in the toxicological
database.Due to the finding of quantitative sensitivity in the
reproduction studies, the EPA conducted a degree of concern analysis to
assess the residual uncertainties for prenatal and/or postnatal
susceptibility. The Agency concluded that there is low concern for an
increased susceptibility in the young given:
i. There was no increased sensitivity (qualitative or quantitative)
in the rat developmental, rabbit developmental and rat developmental
neurotoxicity studies; and
ii. There was a clear NOAEL identified for the effects in pups in
the rat reproduction studies where sensitivity was seen; and
iii. The Agency selected this NOAEL as the basis for risk assessment.
3. Conclusion. The final rule published in the Federal Register of
January 5, 2006 (http://www.epa.gov/fedrgstr/EPA-PEST/2005/January/Day-05/
p089.htm) reported that the EPA had determined that the 10X special
safety factor to protect infants and children should be retained for
thiamethoxam based on the following factors: Effects on endocrine
organs observed across species; the significant decrease in alanine
amino transferase levels in the companion animal studies and in the dog
studies; the mode of action of this chemical in insects (interferes
with the nicotinic acetyl choline receptors of the insect's nervous
system); the transient clinical signs of neurotoxicity in several
studies across species; and the suggestive evidence of increased
quantitative susceptibility in the rat reproduction study.
Since that determination the EPA has received and reviewed a
Developmental Neurotoxicity (DNT) study in rats and an additional
Reproduction study in rats. Taking the results of these studies into
account, EPA has determined that reliable data show that it would be
safe for infants and children to reduce the FQPA safety factor to 1X.
That decision is based on the following findings:
i. The toxicity database for thiamethoxam is complete.
ii. For the reasons discussed above, there is low concern for an
increased susceptibility in the young.
iii. Although there is evidence of neurotoxicity after acute
exposure to thiamethoxam at doses of 500 mg/kg/day including drooped
palpebral closure, decrease in rectal temperature and locomotor
activity and increase in forelimb grip strength, no evidence of
neuropathology was observed. These effects occurred at doses at least
14-fold and 416-fold higher than the doses used for the acute, and
chronic risk assessments, respectively; thus, there is low concern for
these effects since it is expected that the doses used for regulatory
purposes would be protective of the effects noted at much higher doses.
iv. There are no residual uncertainties identified in the exposure
databases. The dietary food exposure assessments were performed based
on assumption that the maximum residues of thiamethoxam and
clothianidin observed in the thiamethoxam field

[[Page 34408]]

trials were remaining on crops. Although there is available information
indicating that thiamethoxam and clothianidin have different
toxicological effects in mammals and should be assessed separately, the
residues of each have been combined in these assessments to ensure that
the estimated exposures of thiamethoxm do not underestimate actual
potential thiamethoxam exposures. An assumption of 100% crop treated
was made for all foods evaluated in the assessments. For both the acute
and chronic assessments the acute EEC of 12.26 ppb (0.0123 ppm) was
used as a worst-case estimate of exposure via drinking water. Compared
to the results from small-scale prospective ground water studies where
the maximum observed residue levels from any monitoring well were 1.0
ppb for thiamethoxam and 0.73 ppb for CGA-322704, the modeled estimates
are protective of what actual exposures are likely to be. Similarly
conservative Residential SOPs as well as a chemical-specific turf
transfer residue (TTR) study were used to assess post-application
exposure to children as well as incidental oral exposure of toddlers.
These assessments will not underestimate the exposure and risks posed
by thiamethoxam.

E. Aggregate Risks and Determination of Safety

Safety is assessed for acute and chronic risks by comparing
aggregate exposure to the pesticide to the acute population adjusted
dose (aPAD) and chronic population adjusted dose (cPAD). The aPAD and
cPAD are calculated by dividing the LOC by all applicable uncertainty/
safety factors. For linear cancer risks, EPA calculates the probability
of additional cancer cases given aggregate exposure. Short-,
intermediate, and long-term risks are evaluated by comparing aggregate
exposure to the LOC to ensure that the margin of exposure (MOE) called
for by the product of all applicable uncertainty/safety factors is not
exceeded.
1. Acute risk. Using the exposure assumptions discussed in this
unit for acute exposure, the acute dietary exposure from food and water
to thiamethoxam will occupy 3% of the aPAD for children 1-2 years old,
the population group receiving the greatest exposure.
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to
thiamethoxam from food and water will utilize 42% of the cPAD for
children 1-2 years old, the population group with greatest exposure.
Based on the use patterns proposed, chronic residential exposure to
residues of thiamethoxam is not expected.
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).
Thiamethoxam is currently registered for use that could result in
short-term residential exposure and the Agency has determined that it
is appropriate to aggregate chronic food and water and short-term
exposures for thiamethoxam. The level of concern for the margin of
exposure (MOE) is 100 for all residential uses (i.e., MOEs less than
100 indicate potential risks of concern). Using the exposure
assumptions described in this unit for short-term exposures, EPA has
concluded that food, water, and residential exposures aggregated result
in aggregate MOEs of 730 through 2,800 for all exposure scenarios
(dermal exposures, and oral non-dietary ingestion) for infants,
children and adults.
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). There are no
use patterns for thiamethoxam that indicate intermediate-term (1 to 6
months of continuous exposure) exposures are likely to occur.
5. Aggregate cancer risk for U.S. population. The Agency has
classified thiamethoxam as not likely to be a human carcinogen based on
convincing evidence that a non-genotoxic mode of action for liver
tumors was established in the mouse and that the carcinogenic effects
are a result of a mode of action dependent on sufficient amounts of a
hepatotoxic metabolite produced persistently. Thiamethoxam is not
expected to pose a cancer risk.
6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, or to infants and children from aggregate
exposure to thiamethoxam residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

Adequate enforcement methodology (high-performance liquid
chromatography/ultraviolet (HPLC/UV) or mass spectrometry (MS) is
available to enforce the tolerance expression. The method may be
requested from: Chief, Analytical Chemistry Branch, Environmental
Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350; telephone
number: (410) 305-2905; e-mail address: residuemethods@epa.gov.

B. International Residue Limits

There are no CODEX or Mexican maximum residue limits (MRLs) for
thiamethoxam. A number of Canadian MRLs exist for this chemical and are
in accord with U.S. tolerances. The new/revised tolerances established
by this rule have been derived using the NAFTA Tolerance Harmonization
Spreadsheet.

C. Response to Comments

Several comments were received from a private citizen objecting to
establishment of these tolerances. The Agency has received similar
comments from this commenter on numerous previous occasions. Refer to
Federal Register 70 FR 37686 (June 30, 2005), 70 FR 1354 (January 7,
2005), 69 FR 63096-63098 (October 29, 2004) for the Agency's response
to these objections. In addition, the commenter noted several adverse
effects seen in animal toxicology studies with thiamethoxam and claims
because of these effects no tolerance should be approved. EPA has
found, however, that there is a reasonable certainty of no harm to
humans after considering these toxicological studies and the exposure
levels of humans to thiamethoxam.

V. Conclusion

Based upon review of the data supporting and use of the NAFTA
Tolerance Harmonization Spreadsheet the EPA has determined that
tolerance levels for the following crops should be changed as follows:
Artichoke, globe from 0.40 ppm to 0.45 ppm; caneberry subgroup 13-A
from 0.30 ppm to 0.35 ppm; grape from 0.15 ppm to 0.20 ppm; brassica,
head and stem, subgroup 5-A from 1.0 ppm to 4.5 ppm; brassica, leafy
greens, subgroup 5-B from 2.0 ppm to 3.0 ppm; and vegetable, leafy,
except brassica from 2.0 ppm to 4.0 ppm. EPA has also determined that a
separate tolerance for grape juice is not needed since any residues in
grape juice are not expected to exceed the grape tolerance of 0.20 ppm.
Therefore, tolerances are established for the combined residues of
thiamethoxam [3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl- N -
nitro-4H-1,3,5-oxadiazin-4-imine and its metabolite [N-(2-chloro-
thiazol-5-ylmethyl)-N'-methyl-N'-nitro-guanidine] on artichoke, globe
at 0.45 ppm; barley, grain at 0.30 ppm; barley, hay at 0.40 ppm;
barley, straw at 0.40 ppm; brassica, head and stem, subgroup 5-A at
4.5; brassica, leafy greens, subgroup

[[Page 34409]]

5-B; caneberry subgroup 13-A at 0.35 ppm; grape at 0.20 ppm; grape,
raisin at 0.30 ppm; hop, dried cone at 0.10 ppm; and vegetable, leafy
except brassica, group 4 at 4.0 ppm.

VI. 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, 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) or Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997). This final rule does not contain any information collections
subject to OMB approval under the Paperwork Reduction Act (PRA), 44
U.S.C. 3501 et seq., nor does it require any special considerations
under Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994).
Since tolerances and exemptions that are established on the basis
of a petition under section 408(d) of FFDCA, such as the tolerance in
this final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply.
This final rule directly regulates growers, food processors, food
handlers and food retailers, not States or tribes, nor does this action
alter the relationships or distribution of power and responsibilities
established by Congress in the preemption provisions of section
408(n)(4) of FFDCA. As such, the Agency has determined that this action
will not have a substantial direct effect on States or tribal
governments, on the relationship between the national government and
the States or tribal governments, or on the distribution of power and
responsibilities among the various levels of government or between the
Federal Government and Indian tribes. Thus, the Agency has determined
that Executive Order 13132, entitled Federalism (64 FR 43255, August
10, 1999) and Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (59 FR 22951, November 6,
2000) do not apply to this rule. In addition, This rule does not impose
any enforceable duty or contain any unfunded mandate as described under
Title II of the Unfunded Mandates Reform Act of 1995 (UMRA) (Public Law
104-4).
This action does not involve any technical standards that would
require Agency consideration of voluntary consensus standards pursuant
to section 12(d) of the National Technology Transfer and Advancement Act
of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272 note).

VII. Congressional Review Act

The Congressional Review Act, 5 U.S.C. 801 et seq., generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report to each House of the Congress and to
the Comptroller General of the United States. EPA will submit a report
containing this rule and other required information to the U.S. Senate,
the U.S. House of Representatives, and the Comptroller General of the
United States prior to publication of this final rule in the Federal
Register. This final rule is not a ``major rule'' as defined by 5
U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

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

Dated: June 6, 2007.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

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

PART 180--AMENDED

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

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

• 2. Section 180.565 is amended as follows:
• i. In paragraph (a) by alphabetically adding commodities to the table;
• ii. In paragraph (a) by revising the entries for Barley, grain; Barley,
hay and Barley, straw in the table;
• iii. In paragraph (b) by removing the entries for Artichoke, globe;
Bean, dry , seed; Bean, succulent; and Hops in the table.
The amendment read as follows:

Sec. 180.565 Thiamethoxam; tolerances for residues.

(a) * * *

------------------------------------------------------------------------
Parts per
Commodity million
------------------------------------------------------------------------
Artichoke, globe........................................... 0.45
Barley, grain.............................................. 0.30
Barley, hay................................................ 0.40
Barley, straw.............................................. 0.40
* * * * *
Brassica, head and stem, subgroup 5-A...................... 4.5
Brassica, leafy greens, subgroup 5-B....................... 3.0
* * * * *
Caneberry subgroup 13-A.................................... 0.35
* * * * *
Grape...................................................... 0.20
Grape, raisin.............................................. 0.30
* * * * *
Hop, dried cones........................................... 0.10
* * * * *
Vegetable, leafy, except brassica, group 4................. 4.0
------------------------------------------------------------------------

* * * * *
[FR Doc. E7-11794 Filed 6-21-07; 8:45 am]
BILLING CODE 6560-50-S

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