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ENVIRONMENTAL PROTECTION AGENCY
Environmental Protection Agency
CFR Citation: 40 CFR Part 180
RIN ID: RIN 2070-AB78
OPP ID: [OPP-301087; FRL-6758-1]
NOTICE: RULES
ACTION: Pesticides; tolerances in food, animal feeds, and raw agricultural commodities:
DOCUMENT ACTION: Final rule.
SUBJECT CATEGORY: Thiamethoxam; Pesticide Tolerance
DATES: This regulation is effective December 21, 2000. Objections and requests hearings, identified by docket control number OPP301087, must be received by EPA on or before February 20, 2001.
DOCUMENT SUMMARY: This regulation establishes tolerances for combined residues of thiamethoxam and its metabolite in or on barley, canola, cotton, sorghum, wheat, milk, and the meat and meat byproducts of cattle, goats, hogs, horses, and sheep. Novartis Crop Protection, Inc. requested this tolerance under the Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality Protection Act of 1996.
SUMMARY: Thiamethoxam,
SUPPLEMENTAL INFORMATION
I. General InformationA. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Examples of Categories NAICS codes potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing
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 the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http://www.epa.gov/. To access this document, on the Home Page select ``Laws and Regulations'', ``Regulations and Proposed Rules,'' and then look up the entry for this document under the ``Federal RegisterEnvironmental Documents.'' You can also go directly to the Federal Register listings at http://www.epa.gov/fedrgstr/. To access the OPPTS Harmonized Guidelines referenced in this document, go directly to the guidelines at http://www.epa.gov/opptsfrs/home/guidelin.htm. [[Page 80344]]
2. In person. The Agency has established an official record for this action under docket control number OPP301087. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 3055805. II. Background and Statutory Findings
In the Federal Register of May 5, 1999 (64 FR 24153) (FRL60727), EPA issued a notice pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food Quality Protection Act of 1996 (FQPA) (Public Law 104170) announcing the filing of a pesticide petition (9F5046 and 9F5051) for tolerance by Novartis Crop Protection, P. O. Box 18300 Greensboro, NC 274198300. This notice included a summary of the petition prepared by Novartis Crop Protection, the registrant. There were no comments received in response to the notice of filing.
The petitions requested that 40 CFR part 180 be amended by establishing tolerances for the combined residues of the insecticide thiamethoxam, ([3[(2chloro5thiazolyl)methyl]tetrahydro5methylN nitro4H1,3,5oxadiazin4imine) and its CGA322704 metabolite (N(2 chlorothiazol5ylmethyl)N'methylN'nitroguanidine) in or on the raw agricultural commodity rapeseed (canola), tuberous and corm vegetables crop subgroup, barley grain, sorghum grain, sorghum forage, sorghum stover, wheat grain, wheat hay, wheat straw, and milk at 0.02 ppm; barley straw at 0.03 ppm; barley hay at 0.05 ppm; undelinted cottonseed at 0.10 ppm; cucurbit vegetables crop group, and pome fruit crop group at 0.20 ppm; fruiting vegetables crop group at 0.25 ppm; wheat forage at 0.50 ppm; tomato paste at 0.80 ppm; head and stem Brassica vegetables crop subgroup at 1.00 ppm; cotton gin byproducts at 1.50 ppm; leafy vegetables crop group, and leafy Brassica greens crop subgroup at 2.00 parts per million (ppm). In addition, meat of cattle, goats, hogs, horses, and sheep at 0.02 ppm and meat byproducts of cattle, goats, hogs, horses, and sheep at 0.02 ppm.
Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue....''
EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. For further discussion of the regulatory requirements of section 408 and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997) (FRL57547).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure, consistent with section 408(b)(2), for tolerances for the combined residues of thiamethoxam and its metabolite in or on barley grain at 0.02 ppm; barley hay at 0.05 ppm; barley straw at 0.03 ppm; undelinted cottonseed at 0.10 ppm; cotton gin byproducts at 1.5 ppm; sorghum forage at 0.02 ppm; sorghum grain at 0.02 ppm; sorghum stover at 0.02 ppm; wheat forage at 0.50 ppm; wheat grain at 0.02 ppm; wheat hay at 0.02 ppm; wheat straw at 0.02 ppm; milk at 0.02 ppm; meat of cattle, goats, hogs, horses, and sheep at 0.02 ppm; meat byproducts of cattle, goats, hogs, horses, and sheep at 0.02 ppm respectively. 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 thiamethoxam are
discussed in the following Table 1 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 90Day oral NOAEL = 1.74
toxicity rat (males), 92.5
(females) mg/kg/
day LOAEL = 17.64
(males), 182.1
(females) mg/kg/
day based on
increased
incidence of
hyaline change of
renal tubular
epithelium
(males), fatty
change in adrenal
gland of females,
liver changes in
females, all at
the LOAEL. [[Page 80345]]
870.3100 90Day oral NOAEL = 1.41
toxicity mouse (males), 19.2
(females) mg/kg/
day LOAEL = 14.3
(males), 231
(females) mg/kg/
day based on
increased
incidence of
hepatocellular
hypertrophy. At
higher dose
levels: decrease
in body weight and
body weight gain,
necrosis of
individual
hepatocytes,
pigmentation of
Kupffer cells, and
lymphocytic
infiltration of
the liver in both
sexes; slight
hematologic
effects and
decreased absolute
and relative
kidney weights in
males; and ovarian
atrophy, decreased
ovary and spleen
weights, and
increased liver
weights in
females.
870.3150 90Day oral NOAEL = 8.23
toxicity dog (males), 9.27
(females) mg/kg/
day LOAEL = 32.0
(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 occurrence of
spermatic giant
cells in testes
(males).
870.3200 28Day dermal NOAEL = 250
toxicity rat (males), 60
(females) mg/kg/
day LOAEL = 1,000
(males), 250
(females) 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 and
hyaline change in
renal tubules and
a very slight
reduction in body
weight in males.
At higher dose
levels in females,
chronic tubular
lesions in the
kidneys and
inflammatory cell
infiltration in
the adrenal cortex
were observed.
870.3700a Prenatal Maternal NOAEL = 30
developmental mg/kg/day LOAEL =
rat 200 mg/kg/day
based on decreased
body weight, body
weight gain, and
food consumption.
Developmental
NOAEL = 200 mg/kg/
day LOAEL = 750 mg/
kg/day based on
decreased fetal
body weight and an
increased
incidence of
skeletal
anomalies.
870.3700b Prenatal Maternal NOAEL = 50
developmental mg/kg/day LOAEL =
rabbit 150 mg/kg/day
based on maternal
deaths,
hemorrhagic
uterine contents
and hemorrhagic
discharge,
decreased body
weight and food
intake during the
dosing period.
Developmental
NOAEL = 50 mg/kg/
day LOAEL = 150 mg/
kg/day based on
decreased fetal
body weights,
increased
incidence of post
implantation loss
and a slight
increase in the
incidence of a few
skeletal anomalies/
variations.
870.3800 Reproduction and Parental/Systemic
fertility effects NOAEL = 1.84
rat (males), 202.06
(females) mg/kg/
day LOAEL = 61.25
(males), not
determined
(females) mg/kg/
day based on
increased
incidence of
hyaline change in
renal tubules in
F
870.4300 Combined chronic NOAEL = 21.0
carcinogenicity (males), 50.3
rat (females) mg/kg/
day LOAEL = 63.0
(males), 155
(females) mg/kg/
day based on
increased
incidence of
lymphocytic
infiltration of
the renal pelvis
and chronic
nephropathy in
males and
decreased body
weight gain,
slight increase in
the severity of
hemosiderosis of
the spleen, foci
of cellular
alteration in
liver and chronic
tubular lesions in
kidney in females.
No evidence of
carcinogenicity.
870.5100 870.5265 Gene mutation in No evidence of gene
S. typhimurium mutation when
and E. coli tested up to 5,000
870.7485 Metabolism and Approximately 72%
pharmacokinetics of administered
mouse dose excreted in
the urine; 19%
excreted in feces.
Small but
measurable amount
detected in
expired air
(approximately
0.2% of dose).
Predominant
metabolites:
unchanged parent
(3341% of
administered dose;
2 other
metabolites: 812%
and 918% of
administered dose.
These are the same
structures that
were most commonly
observed in rat
excreta, however
the proportions
are quite
different in mouse
excreta. One
additional
significant
metabolite (mouse
R6) was isolated
from feces
samples. Between
3060% of the
administered dose
was excreted as
metabolites.
870.7600 Dermal penetration Estimates of dermal
rat absorption were
based on the sum
of radioactivity
in skin test site,
urine, feces,
blood, and
carcass.
Percentage dermal
absorption is
27.0, highest mean
dermal absorption
value across all
groups. This value
is considered to
represent the
potential
cumulative dermal
absorption of test
material that
might occur after
a 10 hour dermal
exposure. As the
study design did
not permit
analysis of the
fate of skin bound
residues, residues
at skin site were
included in
determination of
dermal absorption.
Hepatic cell NOAEL = 16 (males),
proliferation 20 (females) mg/kg/
study mouse day LOAEL = 72
(males), 87
(females) mg/kg/
day based on
proliferative
activity of
hepatocytes. At
higher dose
levels, increases
in absolute and
relative liver
wts, speckled
liver,
hepatocellular
glycogenesis/fatty
change,
hepatocellular
necrosis,
apoptosis and
pigmentation were
observed.
Replicative DNA NOAEL = 711 mg/kg/
synthesis in 28 day (highest dose
day feeding study tested) LOAEL =
male rat not established.
Immunohistochemica
l staining o liver
sections from
control and high
dose animals for
proliferating cell
nuclear antigen
gave no indication
for a treatment
related increase
in the fraction of
DNA synthesizing
hepatocytes in S
phase. CGA 293343
did not stimulate
hepatocyte cell
proliferation in
male rats.
Special study to NOAEL = 17 (males),
assess liver 20 (females) mg/kg/
biochemistry in day LOAEL = 74
mouse (males), 92
(females) mg/kg/
day based on
marginal to slight
increases in
absolute and
relative liver
weights, a slight
increase in the
microsomal protein
content of the
livers, moderate
increases in the
cytochrome P450
content, slight to
moderate increases
in the activity of
several microsomal
enzymes, slight to
moderate induction
of cytosolic
glutathione S
transferase
activity.
Treatment did not
affect peroxisomal
fatty acid Beta
oxidation. 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.
For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (acute RfD or chronic RfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factor is retained due to concerns unique to the FQPA, 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 FQPA Safety Factor.
For nondietary 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 is expressed as 1 x 106 or one in a million).
Under certain specific circumstances, MOE calculations will be used for
the carcinogenic risk assessment. In this nonlinear 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 (MOE
[[Page 80348]]
assessment is shown in the following Table 2:
Table 2.Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Human Risk Assessment
FQPA SF* and Level of
Exposure Scenario Dose Used in Risk Concern for Risk Study and Toxicological
Assessment, UF Assessment Effects
Acute Dietary general population NOAEL = 100 mg/kg/day FQPA SF = 10 aPAD = Acute mammalian
including infants and children UF = 100 Acute RfD = 1 acute RfD FQPA SF = neurotoxicity study in
mg/kg/day 0.1 mg/kg/day the rat LOAEL = 500 mg/
kg/day based on
treatmentrelated
neurobehavioral
effects observed in
the FOB and LMA
testing (drooped
palpebral closure,
decreased rectal
temperature and
locomotor activity,
increased forelimb
grip strength)
Chronic Dietary all populations NOAEL= 0.6 mg/kg/day UF FQPASF = 10 cPAD = 2Generation
= 100 Chronic RfD = chronic RfD FQPA SF = reproduction study
0.006 mg/kg/day 0.0006 mg/kg/day LOAEL = 1.8 mg/kg/day
based on increased
incidence and severity
of tubular atrophy in
testes of F
C. Exposure Assessment
1. Dietary exposure from food and feed uses. The dietary exposure is based on the combined residues of thiamethoxam and its metabolite in or on the following raw agricultural commodities: barley, canola, cotton, sorghum, wheat, milk, and the meat and meat byproducts of cattle, goats, hogs, horses, and sheep. Risk assessments were conducted by EPA to assess dietary exposures from thiamethoxam and its metabolite 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 one day
or single exposure. The Dietary Exposure Evaluation Model (DEEM) [[Page 80349]]
analysis evaluated the individual food consumption as reported by
respondents in the USDA 19891992 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: tolerence level residues and 100% crop treated.
ii. Chronic exposure. In conducting this chronic dietary risk assessment the Dietary Exposure Evaluation Model (DEEM) analysis evaluated the individual food consumption as reported by respondents in the USDA 19891992 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 chronic exposure assessments: percent crop treated (based on projected market shares) and anticipated residues (Tier 3).
iii. Cancer. The dietary exposure for determining cancer risk is based on the chronic exposure explained in the previous paragraph using the same assumptions.
Section 408(b)(2)(E) authorizes EPA to use available data and information on the anticipated residue levels of pesticide residues in food and the actual levels of pesticide chemicals that have been measured in food. If EPA relies on such information, EPA must require that data be provided 5 years after the tolerance is established, modified, or left in effect, demonstrating that the levels in food are not above the levels anticipated. Following the initial data submission, EPA is authorized to require similar data on a time frame it deems appropriate. As required by section 408(b)(2)(E), EPA will issue a data callin for information relating to anticipated residues to be submitted no later than 5 years from the date of issuance of this tolerance.
Section 408(b)(2)(F) states that the Agency may use data on the actual percent of food treated for assessing chronic dietary risk only if the Agency can make the following findings: Condition 1, that the data used are reliable and provide a valid basis to show what percentage of the food derived from such crop is likely to contain such pesticide residue; Condition 2, that the exposure estimate does not
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