Document ID: EPA-HQ-OPP-2009-0737-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-23T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     Office of Chemical Safety

 and Pollution Prevention

Date:  May 3, 2010

MEMORANDUM

	SUBJECT:	Thiamethoxam – Human health risk assessment for new seed
treatment use on onions, dry bulb, eliminating the current geographic
use restrictions for the foliar treatment of barley, and review of other
conditional registration data. 

PC Code:  060109	DP Barcodes:  D373596/D375248

Decision Nos.:  D415289	Registration Nos.:  100-938, 100-1294

Petition No.: 9F7582 	Regulatory Action:  Amended Section 3

Risk Assessment Type:  Single Chemical Aggregate	Case No.:  None

TXR No.:  None	CAS No.:  153719-23-4

MRID No.:  None	40 CFR:  180.565

    FROM:       	Dennis McNeilly, Chemist/Risk Assessor

		William T. Drew, Chemist

		Shih-Chi Wang, Biologist

		Risk Assessment Branch II (RAB2)

		Health Effects Division (7509P)

THROUGH:	Alan Levy, Ph.D., Toxicologist

		Suku Oonnithan, Biologist

		Risk Assessment Branch II (RAB2)

		Health Effects Division (7509P)

			&

		Richard Loranger, Ph.D., Senior Chemist

		Christina Swartz, Branch Chief

		Risk Assessment Branch II (RAB2)

		Health Effects Division (7509P)

	TO:	Julie Chao/Venus Eagle, Team 01

		Insecticide/Rodenticide Branch

		Registration Division (7505P)

Table of Contents

`  TOC \f \h  

  HYPERLINK \l "_Toc260812005"  1.0  Executive Summary	  PAGEREF
_Toc260812005 \h  4  

  HYPERLINK \l "_Toc260812006"  2.0  Ingredient Profile	  PAGEREF
_Toc260812006 \h  7  

  HYPERLINK \l "_Toc260812007"  2.1  Summary of Proposed Uses	  PAGEREF
_Toc260812007 \h  8  

  HYPERLINK \l "_Toc260812008"  2.2  Structure and Nomenclature	 
PAGEREF _Toc260812008 \h  9  

  HYPERLINK \l "_Toc260812009"  2.3  Physical and Chemical Properties	 
PAGEREF _Toc260812009 \h  10  

  HYPERLINK \l "_Toc260812010"  3.0  Hazard Characterization/Assessment	
 PAGEREF _Toc260812010 \h  11  

  HYPERLINK \l "_Toc260812011"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc260812011 \h  11  

  HYPERLINK \l "_Toc260812012"  3.1.1	Database Summary	  PAGEREF
_Toc260812012 \h  11  

  HYPERLINK \l "_Toc260812013"  3.1.1.1	Studies available and considered
  PAGEREF _Toc260812013 \h  11  

  HYPERLINK \l "_Toc260812014"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc260812014 \h  11  

  HYPERLINK \l "_Toc260812015"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc260812015 \h  12  

  HYPERLINK \l "_Toc260812016"  3.1.2	Toxicological Effects	  PAGEREF
_Toc260812016 \h  12  

  HYPERLINK \l "_Toc260812017"  3.1.3	Dose-response	  PAGEREF
_Toc260812017 \h  15  

  HYPERLINK \l "_Toc260812018"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc260812018 \h  15  

  HYPERLINK \l "_Toc260812019"  3.3	FQPA Considerations	  PAGEREF
_Toc260812019 \h  16  

  HYPERLINK \l "_Toc260812020"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc260812020 \h  16  

  HYPERLINK \l "_Toc260812021"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc260812021 \h  16  

  HYPERLINK \l "_Toc260812022"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc260812022 \h  17  

  HYPERLINK \l "_Toc260812023"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc260812023 \h  17  

  HYPERLINK \l "_Toc260812024"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc260812024 \h  18  

  HYPERLINK \l "_Toc260812025"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc260812025 \h  18  

  HYPERLINK \l "_Toc260812026"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc260812026 \h  18  

  HYPERLINK \l "_Toc260812027"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc260812027 \h  18  

  HYPERLINK \l "_Toc260812028"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc260812028 \h  19  

  HYPERLINK \l "_Toc260812029"  3.4	Safety Factor for Infants and
Children	  PAGEREF _Toc260812029 \h  19  

  HYPERLINK \l "_Toc260812030"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc260812030 \h  20  

  HYPERLINK \l "_Toc260812031"  3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc260812031 \h  20  

  HYPERLINK \l "_Toc260812032"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc260812032 \h  20  

  HYPERLINK \l "_Toc260812033"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc260812033 \h  20  

  HYPERLINK \l "_Toc260812034"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc260812034 \h  22  

  HYPERLINK \l "_Toc260812035"  3.5.5	Dermal Absorption	  PAGEREF
_Toc260812035 \h  23  

  HYPERLINK \l "_Toc260812036"  3.5.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc260812036 \h  23  

  HYPERLINK \l "_Toc260812037"  3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc260812037 \h  23  

  HYPERLINK \l "_Toc260812038"  3.5.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc260812038 \h  24  

  HYPERLINK \l "_Toc260812039"  3.5.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc260812039 \h  24  

  HYPERLINK \l "_Toc260812040"  3.5.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc260812040 \h  25  

  HYPERLINK \l "_Toc260812041"  3.5.11	Summary of Toxicological Doses
and Endpoints for Use in Human Risk Assessments	  PAGEREF _Toc260812041
\h  25  

  HYPERLINK \l "_Toc260812042"  3.6	Endocrine disruption	  PAGEREF
_Toc260812042 \h  29  

  HYPERLINK \l "_Toc260812043"  4.0  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc260812043 \h  29  

  HYPERLINK \l "_Toc260812044"  5.0  Dietary Exposure/Risk
Characterization	  PAGEREF _Toc260812044 \h  30  

  HYPERLINK \l "_Toc260812045"  5.1  Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc260812045 \h  30  

  HYPERLINK \l "_Toc260812046"  5.3  Drinking Water Residue Profile	 
PAGEREF _Toc260812046 \h  31  

  HYPERLINK \l "_Toc260812047"  5.4  Food Residue Profile	  PAGEREF
_Toc260812047 \h  33  

  HYPERLINK \l "_Toc260812048"  5.5  International Residue Limits	 
PAGEREF _Toc260812048 \h  34  

  HYPERLINK \l "_Toc260812049"  5.6  Dietary Exposure and Risk	  PAGEREF
_Toc260812049 \h  34  

  HYPERLINK \l "_Toc260812050"  5.6.1  Anticipated Residue and Percent
Crop Treated (%CT) Information	  PAGEREF _Toc260812050 \h  36  

  HYPERLINK \l "_Toc260812051"  6.0  Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc260812051 \h  36  

  HYPERLINK \l "_Toc260812052"  6.1  Other (Spray Drift, etc.)	  PAGEREF
_Toc260812052 \h  39  

  HYPERLINK \l "_Toc260812053"  7.0  Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc260812053 \h  39  

  HYPERLINK \l "_Toc260812054"  7.1  Acute Aggregate Risk	  PAGEREF
_Toc260812054 \h  40  

  HYPERLINK \l "_Toc260812055"  7.2  Short-Term Aggregate Risk	  PAGEREF
_Toc260812055 \h  40  

  HYPERLINK \l "_Toc260812056"  7.3  Intermediate-Term Aggregate Risk	 
PAGEREF _Toc260812056 \h  41  

  HYPERLINK \l "_Toc260812057"  7.4  Long-Term Aggregate Risk	  PAGEREF
_Toc260812057 \h  42  

  HYPERLINK \l "_Toc260812058"  7.5  Cancer Risk	  PAGEREF _Toc260812058
\h  42  

  HYPERLINK \l "_Toc260812059"  8.0  Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc260812059 \h  42  

  HYPERLINK \l "_Toc260812060"  9.0  Occupational Exposure/Risk Pathway	
 PAGEREF _Toc260812060 \h  43  

  HYPERLINK \l "_Toc260812061"  9.1  Short- and Intermediate-Term
Handler Risk	  PAGEREF _Toc260812061 \h  43  

  HYPERLINK \l "_Toc260812062"  5.2.2  Post-application	  PAGEREF
_Toc260812062 \h  48  

  HYPERLINK \l "_Toc260812063"  9.2  Short-Term Postapplication Risk	 
PAGEREF _Toc260812063 \h  48  

  HYPERLINK \l "_Toc260812064"  10.0  Regulatory Recommendations and
Data Needs	  PAGEREF _Toc260812064 \h  49  

  HYPERLINK \l "_Toc260812065"  10.1  Toxicology	  PAGEREF _Toc260812065
\h  50  

  HYPERLINK \l "_Toc260812066"  10.2  Residue Chemistry	  PAGEREF
_Toc260812066 \h  50  

  HYPERLINK \l "_Toc260812067"  10.3  Occupational and Residential
Exposure	  PAGEREF _Toc260812067 \h  50  

  HYPERLINK \l "_Toc260812068"  References	  PAGEREF _Toc260812068 \h 
51  

 

1.0  Executive Summary  TC \l1 "1.0  Executive Summary 

Thiamethoxam is a broad spectrum nitroguanidine insecticide which
belongs to the pesticidal class of compounds known as the neonicotinoids
(Group 4A; Insecticide Resistance Action Commitee).  It has activity
against sucking and chewing insects on a wide variety of crops. 
Thiamethoxam appears to interfere with the nicotinic acetylcholine
receptors of the insect’s nervous system, but the specific receptor
site is unknown at this time.  It does not inhibit cholinesterase or
interfere with sodium channels and, therefore, has a different mode of
action than organophosphate, carbamate, and pyrethroid insecticides.

This risk assessment addresses the requested new use for thiamethoxam as
a seed treatment on dry bulb onions.  It is proposed for seed treatment
of dry bulb onions at 0.05-0.20 mg ai/seed.  In conjunction with the
proposed use, Syngenta requests the establishment of a permanent
tolerance for residues of thiamethoxam and its metabolite, CGA-322704
(clothianidin), in/on onions, as listed below.  

Onion, dry bulb	0.03 ppm

In addition, Syngenta has submitted a response to data gaps previously
identified by HED (D281702; M. Doherty; 17 April 2007) for the
conditional registration of thiamethoxam on several crops:  1) a
revision of the currently approved enforcement method, Method AG-675, to
include the full extraction steps for plant and livestock commodities,
including the microwave extraction step for liver; 2) a new poultry
feeding study, in which liver samples are analyzed using the  modified
enforcement method, along with validation data; and, 3) residue decline
data for barley.

Thiamethoxam’s major metabolite is CGA-322704, which is also the
registered active ingredient clothianidin.  A new chlothianidin dietary
assessment and risk assessment accounting for clothianidin residues on
onion, dry bulb resulting from thiamethoxam application is not necessary
since chlothianidin is currently registered for use on Vegetable, bulb
group 3-07, which includes onion, dry bulb (0.45 ppm tolerance).

Databases for toxicology, residue chemistry, and
occupational/residential exposure are sufficient for purposes of human
health risk assessment.  An immunotoxicity study, a new requirement
under 40 CFR Part 158 as a part of the data requirements for
registration of a pesticide (food and non-food uses), is needed to
complete the database.  Any registrations granted should be made
conditional upon receipt and review of those data.  In addition, there
are label modifications and tolerance revisions that should be completed
prior to registration or establishment of tolerances (see section 10).

In mammals, thiamethoxam shows toxicological effects primarily in the
liver, kidney, testes, and hematopoietic system (blood cellular system).
 In addition, developmental neurological effects were observed in rats. 
The developmental effect is being used to assess risks associated with
acute exposures to thiamethoxam, and the liver and testicular effects
are the basis for assessing longer term exposures.  It is classified as
“not likely to be carcinogenic to humans.”  The selected endpoints
and points of departure for risk assessment from the available data are
protective of all toxicological effects, including potential immunotoxic
effects, observed in the database for all population groups, and,
therefore, the Health Effects Division (HED) has reduced the FQPA Safety
Factor to account for sensitivity of infants and children from 10X to
1X.

Based on the available toxicity database and the Agency's current
practices, short- and intermediate-term inhalation risks for
thiamethoxam were assessed using an oral toxicity study.  The Agency is
in the process of evaluating a March, 2010 Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) report
and may, as appropriate, re-examine and develop new policies and
procedures for conducting inhalation risk assessments, including
route-to-route extrapolation of toxicity data.  If any new policies or
procedures are developed, the Agency may revisit the need for an
inhalation toxicity study for thiamethoxam and/or a re-examination of
the inhalation toxicity risk assessment.

The submitted field trial data for thiamethoxam on dry bulb onions are
acceptable, and support the proposed use of Cruiser® 70WS as a
pre-plant seed treatment.  Based on the maximum combined thiamethoxam
residues of concern (ROCs) of <0.026 ppm in 1X-treated samples, HED
recommends a tolerance of 0.03 ppm.

The submitted field trial data for thiamethoxam on barley confirm that
the total thiamethoxam residues do not increase in barley matrices with
later sampling intervals than the established 21-day precutting interval
for barley hay, or the 21-day pre-harvest interval (PHI) for barley
grain and straw.  The additional trials also support a registration of
Actara®, a 25% ai water-dispersable granule (WDG) formulation, and the
removal of the current geographical limitations on the foliar treatment
of barley.  The available residue data support the established
tolerances for the combined thiamethoxam ROCs for barley grain at 0.30
ppm, and 0.40 ppm for both barley hay and straw.

Syngenta has submitted a revised version of the current enforcement
method.  The full extraction steps for plant and livestock commodities,
including the microwave extraction step for liver, have been
incorporated, as previously requested by HED, as a condition of
registration.  Syngenta has submitted method validation data for the
revised method, i.e., Method GRM.009.04A.  No Independent Laboratory
Validation (ILV) data have been submitted, nor will ILV data be
required, because the method is a revised version of an existing
enforcement method.

The poultry feeding study is adequate, and fulfills the requirement for
liver data analyzed by the modified enforcement method.  HED concludes
that residues in eggs and poultry meat, fat, and meat byproducts remain
a 40CFR §180.6[a][3] situation (there is no expectation of finite
residues in these commodities).  As a result, tolerances are not
required.  This conclusion may be reevaluated, if and when, additional
poultry feedstuffs are proposed in the future.  

HED has assessed dietary (food + drinking water) as well as various
non-dietary “residential” exposures.  The dietary exposure estimates
are based on highly conservative, health-protective assumptions
regarding residue levels in food and water as well as the extent to
which crops are treated with thiamethoxam.  Risk estimates associated
with dietary exposure are below HED’s level of concern for all
population subgroups, including those of infants and children. 
Exposures in a residential setting may occur following application of
thiamethoxam to turf and/or indoor crack and crevice treatment. 
Therefore, HED has assessed dermal and incidental oral (hand-to-mouth)
exposures.  Risk estimates for these exposures are below HED’s level
of concern for the assessed population subgroups.  Similarly, highly
conservative estimates of aggregate risk (combined risk from dietary and
non-dietary exposures) are below HED’s level of concern for all
population subgroups.  Given the existing and proposed use patterns for
thiamethoxam as well as the health-protective assumptions throughout
this risk assessment, it is unlikely that any geographic, ethnic, or
socioeconomic population will have increased exposure relative to the
standard population subgroups assessed by OPP.

HED has assessed occupational exposures to thiamethoxam.  Primary and
secondary handler exposure associated with the use of Cruiser® 70WS
(packaged in water soluble bags) to treat bulb onion seeds were assessed
for mixing and loading seed treatment systems.  With the exception of
the multiple activities scenario using HED’s standard assumption
regarding the amount of seed treated per day (5,500 lbs treated/day,
MOE=59), the potential occupational exposures/risks resulting from the
proposed use do not exceed the HED level of concern (MOEs range from 300
to 7,400).  

The MOE of 59 for the multiple activities scenario is a very
conservative estimate.  It is based on a single layer plus gloves
protection (the proposed label also requires dust mask and coveralls).  
In addition, the MOE of 59 for the multiple activities scenario is based
on the unit of exposure for a liquid product, and the proposed product
is a wettable power packaged in water soluble packets (an engineering
control measure which can provide more than 50% reduction in exposures);
therefore, this MOE probably over estimates the risk.

HED believes that this MOE probably over estimates the risk; however,
until data/information are available to further refine the actual
exposure/risk, HED recommends that the label limit the pounds of
formulated product used per handler to 260 lbs per day.  If the maximum
amount of Cruiser® 70WS Insecticide that can be used to treat bulb
onion seed in a seed treatment facility is limited to 260 lbs per
production line per 8-hour work shift (based on ca. 3,000 lbs seeds
treated per day) the MOE for multiple activities worker is 110.  This
requires that a worker performing tasks associated with seed treatment
production, have exposure limited to 260 lbs. of formulated product (for
Cruiser® 70WS) per day.  This limitation should be reflected on the
label.

All MOEs for secondary seed handlers (i.e., those who plant treated
seed) are greater than 100 wearing a single layer of clothing plus
gloves, with MOEs ranging from 190 to 310.  

Exposures related to indoor residential activities have been combined
with chronic dietary exposure estimates to assess the worst-case short-
and intermediate-term aggregate exposures.  The indoor crack and crevice
scenario has higher exposure for both adults and children than the
exposure levels in the turf scenario and has been used for the aggregate
exposure assessment.  The short-term aggregate MOEs range from 370 to
500, while intermediate-term aggregate MOEs range from 370 to 540. 
Since these are greater than 100, they represent aggregate risk
estimates that are below HED’s level of concern.

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).  As a part of
every pesticide risk assessment, OPP considers a large variety of
consumer subgroups according to well-established procedures.  In line
with OPP policy, HED estimates risks to population subgroups from
pesticide exposures that are based on patterns of that subgroup’s food
and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, non-dietary exposures based on home use of pesticide
products and associated risks for adult applicators and for toddlers,
youths, and adults entering or playing on treated areas postapplication
are evaluated.  Further considerations are currently in development as
OPP has committed resources and expertise to the development of
specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), the Outdoor Residential Task Force (ORETF) and
Agricultural Reentry Task Force (ARTF) have been determined to require a
review of their ethical conduct.  They have received that review and
have been determined to be ethical.

  

HED is recommending for the establishment of a permanent tolerance on
bulb onion, as shown in Table 10, and for conditional registration of
thiamethoxam for the requested uses, pending receipt and review of the
data requested in Section 10.  The existing barley tolerances are
adequate and do not need to be modified.  Prior to granting the
registration or establishing the new tolerance, HED recommends that
revisions to the proposed label be completed.  These items are also
described in Section 10.

2.0  Ingredient Profile  TC \l1 "2.0  Ingredient Profile 

Thiamethoxam is a broad spectrum nitroguanidine insecticide which
belongs to the pesticidal class of compounds known as the
neonicotinoids.  It has activity against sucking and chewing insects on
a wide variety of crops.  It appears to interfere with the nicotinic
acetylcholine receptors of the insect’s nervous system, but the
specific receptor site is unknown at this time.  It does not inhibit
cholinesterase or interfere with sodium channels and, therefore, has a
different mode of action than organophosphate, carbamate, and pyrethroid
insecticides.

The chemical structure and nomenclature of thiamethoxam and its
regulated metabolite, CGA-322704, are presented in Table 2.2.  The
physicochemical properties of the technical grade of thiamethoxam are
presented in Table 2.3.  The metabolite CGA-322704 is the active
ingredient clothianidin (PC Code 044309).

2.1  Summary of Proposed Uses  TC \l2 "2.1  Summary of Proposed Uses 

The product proposed for use on dry bulb onions is Cruiser® 70WS (EPA
Reg. No. 100-1294), a wettable powder formulation of thiamethoxam
containing 70% ai, packaged in water soluble bags.  It is proposed for
use as a seed treatment of dry bulb onions.  The proposed use directions
on dry bulb onions are presented in Table 2.1.  

For barley, the most recent product label for Actara® Insecticide (EPA
Reg. No. 100-938, approved 6 October 2009), a 25% ai WDG formulation,
was examined, along with a Syngenta-provided thiamethoxam label
registered under a Special Local Needs Registration (SLN CO 090004). 
HED’s review of previous barley data submissions (D281702; M. Doherty;
17 April 2007) required the revision of the product label to restrict
use of the product to the states of ID, ND, OR, SD and WA, based on the
available residue data.  The requested label revision has been made. 
However, it is now Syngenta’s intention to expand the use of
thiamethoxam on all major barley growing regions without the geographic
restriction.  The registered use directions on barley are also presented
in Table 2.1.

Table 2.1  Summary of Proposed Use Directions on Dry Bulb Onions, and
Registered Use

                                                                
Directions on Barley.  

Use Timing; Type; and Equipment	Product

[Registration Number]	Single Use Rate	Maximum Uses per Season	Maximum
Seasonal Use Rate	PHI

(Days)	Use Directions and Limitations

Dry Bulb Onion 

Seed treatment	Cruiser® 70WS

[100-1294]

Packaged in water-soluble bags.	0.05-0.20 mg ai/seed	1 (Implied)	0.18

lb ai/A 1	Not specified	The label restricts any soil or foliar
application of products containing thiamethoxam to crops grown from seed
treated with Cruiser® 70WS.  

Barley

Foliar spray;

ground/aerial	Actara®

[100-938]

	0.0625 lb ai/A	2	0.125 lb ai/A	21	Use ground (minimum spray volume of
10 GPA) or aerial (5 GPA) equipment.  Minimum retreatment interval (RTI)
is 7 days.  

Note:  Use of Actara® on barley is currently restricted to crops grown
in ID, ND, OR, SD and WA.  The SLN registration for CO090004 is
restricted to crops grown in CO.  The registrant wants to remove this
use restriction.

1. The draft label specifies a maximum seasonal use rate of 0.18 lb ai/A
(or 81.6 g ai/A), based on a maximum 	seeding rate of 406,000 seeds/A.  

 

Rotational crop restrictions:  There are no rotational crop restrictions
listed in the submitted label for Cruiser® 70WS.  For the Actara®
Insecticide label, the following rotational crop restrictions are
established:  Treated areas may be replanted immediately following
harvest, or as soon as practical following the last application with any
crops listed on this label or to barley, canola, cotton, cucurbit
vegetables, legume vegetables, oilseeds (rapeseed, Indian rapeseed,
Indian mustard seed, field mustard seed, black mustard seed, flax seed,
safflower seed, crambe seed and borage seed), sorghum, sunflower, and
wheat.  Any cover crop planted for erosion control or soil improvement
may be planted as soon as practical following the last application. 
However, the cover crop may not be grazed or harvested for food or feed.
 For all other crops, a 120-day PBI must be observed.  

Conclusions:  The submitted use directions for bulb onions are
sufficient to allow for evaluation of the submitted residue data
relative to the proposed use patterns.  However, the product label for
Cruiser® 70WS (EPA Reg. #100-1294) should be revised to specify that
only registered crops may be replanted immediately following harvest, or
as soon as practical following the last application.  For all other
crops, a 120-day PBI should be observed.

The submitted use directions for barley are also adequate to evaluate
Syngenta’s request to expand the foliar use of thiamethoxam to all
major barley growing regions, without geographic restriction.

2.2  Structure and Nomenclature  TC \l2 "2.2  Structure and Nomenclature

Table 2.2.  Nomenclature.

Chemical structure	

Empirical Formula	C8H10ClN5O3S

Common name	Thiamethoxam

Company experimental name	  SEQ CHAPTER \h \r 1 CGA 293343

IUPAC name	  SEQ CHAPTER \h \r 1
3-(2-chloro-1,3-thiazol-5-ylmethyl)-5-methyl-1,3,5-oxadiazinan-4-ylidene
(nitro)amine

CAS name	  SEQ CHAPTER \h \r 1
3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-nitro-4H-1,3,5-oxa
diazin-4-imine

CAS registry number	  SEQ CHAPTER \h \r 1 153719-23-4

End-use product (EP)	70% WS formulation in water soluble bags (Cruiser®
70WS; EPA Reg. No. 100-1294)

25% WG formulation (Actara® Insecticide; EPA Reg. No. 100-938)

2 lb/gal FlC formulation (Platinum® Insecticide; EPA Reg. No. 100-939)

40% WG formulation (Centric® 40WG Insecticide; EPA Reg. No. 100-1147)

2 lb/gal FlC formulation (Actara® 240 SC Insecticide; EPA File Symbol
100-RELN)

47.6% liquid formulation (Cruiser® Insecticide; EPA Reg. No. 100-941)

0.22% granular formulation (Flagship® Insecticide; EPA File Symbol
100-OAN)

0.33% granular formulation (Meridian® Insecticide; EPA File Symbol
100-OAR)

25% WG formulation (Meridian™ Insecticide; EPA File Symbol 100-OUG)

Chemical Class	Neonicotinoid, Group 4A

Known Impurities of Concern	None

Chemical structure of CGA-322704 metabolite	

N-[(2-chloro-5-thiazoyl)methyl]-N’-methyl-N”-nitroguanidine

Common Name 	Clothianidin

2.3  Physical and Chemical Properties  TC \l2 "2.3  Physical and
Chemical Properties 

Table 2.3.  Physicochemical Properties of Thiamethoxam.  

Parameter	Value	Reference

Melting point/range	139.1°C	PMRA Regulatory Note (REG2001-03) on
Thiamethoxam, 2/9/01

pH	4.7 (1% solution in water)

	Density	1.57 g/cm3

	Water solubility	4.1 g/L (25°C)

	Solvent solubility	Solvent

acetone

dichloromethane

ethyl acetate

hexane

methanol

octanol

toluene	Solubility (g/L)

48

110

7.0

<1 mg/L

13

0.62

0.68

	Vapor pressure	2.7 x 10-9  Pa (20°C)

6.6 x 10-9  Pa (25°C)

	Dissociation constant, pKa	No dissociation within the pH range 2–12

	Octanol/water partition coefficient, Log(KOW)	0.13 (25°C)

	UV/visible absorption spectrum	Not available

	

Thiamethoxam is a solid under ambient conditions and has a low
volatility.  The compound has relatively low solubility in nonpolar
organic solvents and its octanol/water partition coefficient suggests
that accumulation of thiamethoxam in fatty tissues is unlikely to occur.

3.0  Hazard Characterization/Assessment  TC \l1 "3.0  Hazard
Characterization/Assessment 

3.1  Hazard and Dose-Response Characterization  TC \l2 "3.1  Hazard and
Dose-Response Characterization 

3.1.1  Database Summary  TC \l3 "3.1.1	Database Summary 

The toxicological database for thiamethoxam is sufficient for purposes
of human health risk assessment.  The scientific quality is relatively
high and the toxicity profile of thiamethoxam can be characterized for
most effects, including potential carcinogenic, mutagenic,
developmental, and neurotoxic.  The doses and endpoints for use in human
health risk assessments are summarized in Tables 3.5.12a and 3.5.12b,
below.  Recent changes to 40 CFR Part 158 make immunotoxicity testing
(870.7800) required for pesticide registration.  The study was required
in conjunction with a previous risk assessment for proposed uses of
thiamethoxam (9/25/2008), and remains a datagap and condition of
registration.  Despite the lack of the immunotoxicity study, HED has not
retained a database uncertainty factor (UFDB) for the lack of the study,
because the doses and endpoints for risk assessment are considered to be
protective of potential immunotoxicity.

3.1.1.1  Studies available and considered  TC \l4 "3.1.1.1	Studies
available and considered 

The following studies were submitted in support of thiamethoxam
registration:  acute and subchronic neurotoxicity; subchronic feeding
studies in rats, mice and dogs; a subchronic dermal study in rats;
chronic/carcinogenicity in rats; carcinogenicity in mice; a chronic
study in dogs; developmental studies in rats and rabbits; developmental
neurotoxicity; two reproduction studies in rats; mutagenicity battery;
and metabolism.  In addition, in conjunction with the update of the
cancer classification in 2005, a number of studies were submitted to
support the mode of action for carcinogenicity.

3.1.1.2  Mode of action, metabolism, toxicokinetic data  TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data 

Thiamethoxam has activity against sucking and chewing insects.  It is a
broad spectrum insecticide which belongs to the neonicotinoid class of
compounds.  While laboratory data indicate that thiamethoxam interferes
with the nicotinic acetyl choline receptors of the insect’s nervous
system, the specific binding site/receptor(s) is unknown at this time. 
Although imidacloprid, also a neonicotinoid insecticide, is also known
to interfere with nicotinic acetyl choline receptors, thiamethoxam
appears to function at a different location.  Thiamethoxam does not
inhibit cholinesterase or interfere with sodium channels and, therefore,
has a different mode of action than organophosphate, carbamate and
pyrethroid insecticides.  Thiamethoxam is reported to have excellent
acropetal translocation in the xylem and no basipetal movement in the
phloem.

In an in vitro nicotinic receptor binding study, thiamethoxam had
essentially no affinity for either mammalian nicotinic acetyl choline
receptor subtype and was considered inactive.  This thiamethoxam binding
affinity study to rat forebrain α4β2 and α7-type nicotinic receptors
was considered Acceptable/Non-Guideline.

In rats, thiamethoxam is absorbed rapidly and extensively, and is widely
distributed, followed by very rapid elimination, mostly in the urine
(84-95%).  The half-life times from tissues ranged from 2-6 hours.  The
major biotransformation reaction is cleavage of the oxadiazine ring to
form the corresponding nitroguanidine compound (i.e., chlothianidin, the
regulated metabolite in plants and livestock).  In mice, approximately
72% of the administered dose is excreted in the urine, while 19% is
excreted in the feces.  The predominant components are unchanged parent
(33-41% of administered dose) and two other metabolites (8-12% and 9-18%
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.  

3.1.1.3 Sufficiency of studies/data  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

Data are sufficient for FQPA evaluation, toxicity endpoint selection and
dose-response evaluation.  In accordance with the revised part 158
toxicology data requirements, an immunotoxicity study should be
submitted.  To date, this study has not been received.  However, HED has
concluded that a 10X UFDB is not needed to account for the lack of the
required immunotoxicity study.

3.1.2  Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

Acutely, technical thiamethoxam is slightly toxic to rats and moderately
toxic to mice via the oral route (Toxicity Category III); it is of low
toxicity to rats via the dermal (Toxicity Category III) and inhalation
routes (Toxicity Category IV).  It is not irritating to the skin and
minimally irritating to the eye, and is not a dermal sensitizer.

The database on thiamethoxam indicates that the primary targets for this
chemical are the liver, testes, kidney, and hematopoietic system.  In
addition, effects on the thyroid (rats and dogs) and the adrenal gland
(rats) are seen in the short-term studies.

The liver effects occur across species, sexes and routes of
administration.  In the rat, inflammatory cell infiltration and necrosis
of single hepatocytes are observed in the 28-day dermal study and
hepatocellular hypertrophy and lymphohistiocytic infiltration of the
liver are observed in the subchronic oral studies.  Chronic oral
exposure induces an increase in the incidence of foci of cellular
alteration in females.  In rats, there was no evidence of liver tumors
at the dose levels tested.  Females appear to be more sensitive than
males for liver effects in rats.  In the mouse, the following effects
were observed in oral studies:  hepatocellular hypertrophy, necrosis of
single hepatocytes, lymphocytic infiltration (subchronic and chronic),
apoptosis, induction of microsomal enzymes, Kupffer cell pigmentation
(subchronic), Kupffer cell hyperplasia, increased incidence of foci of
cellular alteration, and increased mitotic activity (chronic).  Male
mice are more sensitive to the liver pathology than are females. 
Chronic dosing also results in the development of benign and malignant
liver tumors in both sexes of mice.  An increase in the number of
animals with multiple tumors is also observed; however, treatment does
not affect the latency to tumor formation nor lethality resulting from
the observed tumors.  The incidence of non-neoplastic and neoplastic
pathology is increased at the same dose level, i.e., there is no clear
departure point between doses that induce tumors and other systemic
toxic effects.  In both rats and mice, there appears to be increasing
severity of effects with increasing dose.  In rats, the lowest dose at
which an effect is observed in the liver does not appear to decrease
significantly with increasing length of exposure to the test material. 
Due to dose spacing, it is not possible to determine if this is the case
in the mouse, which appears to be the most sensitive species.

Testicular effects are observed in the rat and dog.  They consist of
decreased testes weights, increased incidence and severity of
seminiferous tubular atrophy and sperm abnormalities at low dose levels
in the rat; decreased testes weights associated with microscopic
evidence of reduction in spermatogenesis and occurrence of spermatic
giant cells in the testes at toxic dose levels in the subchronic dog
study; and atrophy of the seminiferous tubules at minimally to
moderately toxic dose levels in the chronic dog study.  Testicular
effects were noted in both of the 2-generation reproduction studies. 
The effects in the rat are only observed in the F1 males in the
two-generation reproduction study and are not observed at any other
time.  In both studies, there is evidence of increased quantitative
susceptibility for male pups.  Reproductive effects in males appear in
the F1 generation in the form of increased incidence and severity of
testicular tubular atrophy in one study and sperm abnormalities in the
other study.  While the testicular effects observed in the two studies
differ, the findings of the two studies support each other and are
consistent relative to observed thiamethoxam toxicity.  These effects
are being used as the basis for risk assessment because they are
observed at very low dose levels.  It is anticipated that they may be
observed after either intermediate-term or chronic exposure,
particularly when exposure occurs in utero.

n attributed by the study authors to accumulation of α2u-globulin, a
protein that is unique to male rats, in the proximal convoluted tubules.
 The observed pathology is consistent with α2u-globulin mediated kidney
toxicity.  Collectively, special studies submitted demonstrate an
increase in accumulation of α2u-globulin in conjunction with the
observance of hyaline droplets in some dose groups as compared to lower
levels observed in controls.   

Hematological effects are observed in the rat, dog and mouse with the
dog being the most sensitive species.  Both sexes appear to be affected;
although the male appears to be more affected in the rodent and the
female more affected in the dog.  In the rat, increased spleen weights,
increases in the incidence and severity of hemosiderosis and/or
extramedullary hematopoiesis are observed in both the subchronic and
chronic studies.  In the mouse, a slight reduction in erythrocytes,
hemoglobin and hematocrit, accompanied by increased mean corpuscular
volume and mean corpuscular hemoglobin are observed in the subchronic
feeding study at very high dose levels.  In the dog, leukopenia and
slight microcytic anemia are observed in the subchronic oral study.

Thyroid effects in the rat (thyroid follicular cell hypertrophy) and dog
(increase in thyroid weight) may be due to induction of microsomal
enzymes in the liver, which in turn affect the
hypothalamus-pituitary-thyroid-liver homeostatic process for regulation
of thyroid hormones.  Evidence of this is the presence of hepatocellular
hypertrophy in several species.  The adrenal effects observed in the
subchronic rat studies generally consist of fatty change and
inflammatory cell infiltration of the adrenal cortex.

Alanine aminotransferase (ALT) levels are significantly decreased in the
dog and companion animal studies.  While the toxicological significance
of this observation is unclear, there is no doubt regarding its
association to treatment with thiamethoxam.  It has been proposed that
the decreases in ALT activity may be caused by either interference with
or suppression of in vivo concentrations of pyridoxal phosphate (vitamin
B6, a cofactor necessary for ALT activity) or by direct suppression of
ALT synthesis.  If thiamethoxam interferes with vitamin B6, it could
have significant implications regarding potential adverse developmental
effects.

Developmental/Reproductive Effects:  In the developmental studies, there
is no quantitative or qualitative evidence of increased 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.  

Two reproduction studies are available.  In both studies, there is
evidence of increased quantitative susceptibility for male pups. 
Reproductive effects in males appear in the F1 generation in the form of
increased incidence and severity of testicular tubular atrophy in one
study and sperm abnormalities in the other study.  While the testicular
effects observed in the two studies differ, the findings of the two
studies support each other and are consistent relative to observed
thiamethoxam toxicity.  

Carcinogenicity and Mutagenicity:  Thiamethoxam induces hepatocellular
adenomas and carcinomas in male and female Tif:MAGf (SPF) mice.  The HED
Cancer Assessment Review Committee (June 13, 2005) concluded that the
mouse liver tumors 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 sustained increase in cell
replication rates.   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.  The CARC 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.  Quantification of carcinogenic potential is not required.
 The submitted mutagenicity studies are adequate and indicate that
thiamethoxam is not mutagenic.

3.1.3  Dose-response  TC \l3 "3.1.3	Dose-response 

The database on thiamethoxam indicates the primary targets for this
chemical are the liver, testes, kidney, and hematopoietic system.  The
testicular effects are considered to be toxicologically significant and
occur at low doses, and therefore most of the endpoints for risk
assessment are based on these effects.

 α2u-globulin, a protein that is unique to male rats, and, therefore,
these 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.  While these effects could be potential
indication of immunotoxicity, HED concluded that the leukopenia was
associated with an anemic response, as opposed to direct immunotoixicty.
 The decreases in spleen weight occurred at very high doses, and were
not statistically significant.  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.

3.2  Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

In rats, thiamethoxam is rapidly and extensively absorbed, widely
distributed, and very rapidly eliminated, mostly in urine.  The highest
tissue concentrations are in skeletal muscle (10-15% of administered
dose).  The half-life times from tissues ranged from 2-6 hours.  Very
low tissue residues were reported after 7 days.  Within 24 hours,
approximately 84-95% of the administered dose was excreted in urine,
while 2.5-6% was excreted in the feces. Most was excreted as unchanged
parent (70-80% of  dose).  The major biotransformation reaction is
cleavage of the oxadiazine ring to form the corresponding nitroguanidine
compound (CGA-322704).  Enterohepatic circulation is negligible.

In mice, approximately 72% of the administered dose was excreted in the
urine and 19% was excreted in feces.  Small but measurable amounts were
detected in expired air (approximately 0.2% of dose).  Parent (33-41% of
administered dose) and 2 predominant metabolites: 8-12% and 9-18% of
administered dose were found.  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 30-60% of the
administered dose was excreted as metabolites.

3.3  FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1  Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

The database for evaluating in utero or postnatal susceptibility is
adequate for the purpose of the current risk assessment, and for
evaluating the need for an FQPA safety factor.  However, the database is
not complete because the required immunotoxicity study has not been
submitted.  The following acceptable studies are available:

	Developmental toxicity studies in rats and rabbits

	Two two-generation reproduction studies in rats

	Developmental neurotoxicity study in rats

3.3.2  Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of
Neurotoxicity 

Thiamethoxam was tested in acute, 90-day and developmental neurotoxicity
studies.  In the acute neurotoxicity study, drooped palpebral closure,
lower rectal temperature, increased forelimb grip strength (males only)
and decreased locomotor activity were observed 2-3 hours after dosing. 
Effects at a higher dose included abnormal body tone, ptosis, impaired
respiration, tremors, longer latency to first step in the open field,
crouched-over posture, gait impairment, hypo-arousal, decreased number
of rears, uncoordinated landing during the righting reflex test, slight
lacrimation (females only) and higher mean average input stimulus value
in the auditory startle response test (males only).  These effects were
no longer evident at the 1 week and 2 week post-dosing examinations.  In
addition to these findings, 3 females were found dead within the first 2
days after treatment. There were no treatment-related histopathological
findings noted in the central or peripheral nervous system at any dose
level tested.

In the 90-day neurotoxicity study, there were no treatment-related
systemic or neurotoxicological effects observed at any dose level tested
up to 95 mg/kg bw/day in males and 216.4 mg/kg bw/day in females.  In
addition, no treatment-related histopathological findings were noted in
the central or peripheral nervous systems.  The subchronic mammalian
neurotoxicity study was not tested at sufficiently high dose levels;
however, a new study is not required at this time because no
neuropathology was observed at the dose levels tested, and the weight of
the evidence from the other toxicity studies indicates that there is no
reason for concern.

In the developmental neurotoxicity study, there was no evidence of
neurotoxicity in the dams exposed up to 298.7 mg/kg/day; a dose that was
associated with decreases in body weight gain and food consumption.  In
pups exposed to 298.7 mg/kg/day, there were significant reductions in
absolute brain weight and size (i.e., length and width of the cerebellum
was less in males on day 12, and there were significant decreases in
Level 3-5 measurements in males and in Level 4-5 measurements in females
on day 63).

The following evidence of neurotoxicity was observed in other oral
studies.  In the 28-day dog study there was a decrease in absolute but
not relative brain weight in females at 43 mg/kg/day.  This does not
appear in either the 90-day study (up to 50 mg/kg/day) or the chronic
dog study (up to 45 mg/kg/day).  In the mouse carcinogenicity study,
there was an increase in relative brain weight in high dose males that
was attributed to reduction in body weight gain.  In the rat
chronic/carcinogenicity study, there was a slight increase in incidence
of brain effects in high dose males.  Microscopically, this increase was
associated with hydrocephalus and pressure atrophy which was secondary
to pituitary adenomas. The increased incidence of brain effects is not
likely due to a neuronal tissue malformation but, rather, secondary to a
pituitary adenoma.  

3.3.3  Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

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.  An increase in
qualitative susceptibility was based upon reduced brain weight and size
in male and female pups at the highest dose tested; whereas, effects in
dams were limited to decreased body weight gain and food consumption.

3.3.4  Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

Two acceptable reproduction studies are available.  In both studies,
there is evidence of increased quantitative susceptibility for male
pups.  Reproductive effects in males appear in the F1 generation in the
form of increased incidence and severity of testicular tubular atrophy
in one study and sperm abnormalities in the other study.  HED has
determined that there is evidence of increased quantitative
susceptibility for male pups (NOAEL: 0.6 mg/kg/day for increased
incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared
to the parents (NOAEL: 1.8 mg/kg/day for hyaline changes in renal
tubules at 61 mg/kg/day).

In another two-generation reproductive study, there was quantitative
evidence of increased susceptibility.  In this study, the NOAEL for
reproductive effects is 1.2 mg/kg/day based upon sperm abnormalities,
and the LOAEL is 3 mg/kg/day.  The study is classified as
acceptable-non-guideline and is useful for risk assessment, even though
additional information pertaining to the study has been requested.  HED
does not believe the outstanding information will impact the NOAEL
identified for sperm abnormalities in this study.

Histopathology findings from the 1998 study cannot be combined with data
from the new reproduction study due to differences in histopathology
reporting criteria which may affect both incidence and severity of
reported testicular lesions and may make comparison to the previous
study or other historical control data (where such criteria were not
applied) inappropriate at this time.  While the testicular effects
observed in the two reproductive studies differ, the findings support
each other and are consistent relative to observed thiamethoxam
toxicity.  Although histopathological effects (tubular atrophy) were not
observed in the more recent 2004 study at low dose levels, the
observation of reduced sperm production would be expected to co-occur
with the tubular atrophy that was observed in the 1998 study.

3.3.5  Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

None.

3.3.6  Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1  Determination of Susceptibility  TC \l4 "3.3.6.1	Determination
of Susceptibility 

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; however, there was
increased qualitative susceptibility because the effects in the pups
(reduced brain weight and significant changes in brain morphometric
measurements) were considered to be more severe than findings in the
dams (decreased body weight gain and food consumption).

There is evidence of increased quantitative susceptibility for male pups
in both two-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 a more recent two-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) for the most
sensitive subgroup (pups) observed in the toxicological database.

3.3.6.2  Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC \l4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility 

There is low concern for an increase in quantitative susceptibility in
the rats or rabbits since developmental and offspring toxicity occurred
at dose levels equal to or higher than the doses where parental toxicity
was observed in three studies (rat developmental, rabbit developmental
and rat developmental neurotoxicity).  There is also low concern for the
increased qualitative susceptibility observed in the DNT study because
the doses and endpoints selected for risk assessment are protective of
the effects in the offspring.  As noted previously, the Agency selected
the NOAEL for testicular effects in F1 pups based on two reproductive
toxicity studies for risk assessment to be protective of all sensitive
subpopulations.

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 an increase in forelimb
grip strength.  However, 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.

3.3.7  Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.7	Recommendation for a Developmental Neurotoxicity Study 

A developmental neurotoxicity study has been requested, received, and
reviewed by the Agency (see Section 3.3.2).

3.4  FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety
Factor for Infants and Children 

The toxicity database for thiamethoxam is not complete because the
required immunotoxicity study has not been submitted.  The available
data for thiamethoxam show the potential for immunotoxic effects,
including changes in spleen weight and leukopenia.  However, HED
concluded that the leukopenia was associated with an anemic response as
opposed to direct immunotoxicity.  In addition, the reduced spleen
weights were observed at high doses, and were not statistically
significant.  Based on these considerations, HED previously concluded
that an additional database uncertainty factor (UFDB) was not needed to
account for the lack of the immunotoxicity study.

HED further recommends that the 10X FQPA safety factor for the
protection of infants and children be reduced to 1X.  There is no
quantitative or qualitative evidence of increased susceptibility of rat
or rabbit fetuses to in utero exposure to thiamethoxam in the
developmental toxicity studies.  The developmental NOAELs are either
higher than or equal to the maternal NOAELs.  There was no evidence of
increased quantitative susceptibility in the DNT study in rats.

 

Although there is evidence of increased quantitative susceptibility for
male pups of both two- generation reproductive studies, NOAELs and
LOAELs were established in these studies, and HED selected the NOAEL for
testicular effects in F1 pups as the basis for risk assessment.  HED has
confidence that the NOAEL selected for risk assessment is protective of
the most sensitive effect (testicular) for the most sensitive subgroup
(pups) observed in the toxicological database.

 

In addition, the NOAELs selected for risk assessment are protective of
all toxicological effects observed in the database including
treatment-related changes in the adrenal gland, thyroid, testes and
ovaries.  Thus, HED believes the FQPA safety factor should be reduced to
1X.

The dietary food exposure assessment is not likely to underestimate
exposure/risk.  The dietary drinking water assessment utilizes water
concentration values generated by models and associated modeling
parameters that are designed to provide conservative, health protective,
high-end estimates of water concentrations which will not likely be
exceeded.  The residential exposure assessment was conducted using
standard, health-protective assumptions.

3.5  Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.5.1
Acute Reference Dose (aRfD) - Females age 13-49 

A separate aRFD is not being used for females age 13-49.  Females in
this age group will be assessed using the aRFD for the general
population (see 3.5.2).

3.5.2  Acute Reference Dose (aRfD) - General Population  TC \l3 "3.5.2
Acute Reference Dose (aRfD) - General Population 

Study Selected:  Developmental Neurotoxicity Study—rat	  (OPPTS
870.6300)

MRID No.:  46028202, 46028201

Dose and Endpoint for Establishing aRfD:  Developmental NOAEL = 34.5
mg/kg/day based on delayed sexual maturation in male pups, and reduced
brain morphometric measurements LOAEL = 298.7 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors:  The endpoint chosen was
presumed to occur following a single exposure and could be relevant for
all populations, including children.  The endpoint is based on the most
sensitive effect in the most sensitive subpopulation (pups).  Although
the toxicological effects occurred in pups, it is not known if these
effects resulted from pre- or post-natal dosing, and therefore the
endpoint is relevant to all populations, and is considered to be
protective.  An UF of 100 was applied to account for inter-species
extrapolation (10x) and intra-species variation (10x).

	Acute RfD =    34.5 mg/kg/day (NOAEL)   = 0.35 mg/kg/day

			              100 (UF)

3.5.3  Chronic Reference Dose (cRfD)   TC \l3 "3.5.3	Chronic Reference
Dose (cRfD) 

Study Selected:  Two 2-Generation Reproduction Toxicity Studies—rat
(OPPTS 870.3800)

MRID No.:  44718707; 46402902, 46402904, 46402906

Dose and Endpoint for Establishing the cRfD:  The Agency selected both
two-generation reproductive studies as co-critical.  The NOAEL of 1.2
mg/kg/day is based on sperm abnormalities in the F1 males observed after
in utero and post-natal exposure in the rat reproduction study at 3
mg/kg/day.  In the other two-generation reproduction study, the NOAEL of
0.6 mg/kg/day and LOAEL of 1.8 mg/kg/day are based on testicular atrophy
in F1 males.  The higher NOAEL was selected from these two studies based
on the rationale detailed below in “Comments on
Study/Endpoints/Uncertainty Factors.”  While the testicular effects
observed in the two reproductive studies differ, the findings support
each other and are consistent relative to observed thiamethoxam
toxicity.  Although histopathological effects (tubular atrophy) were not
observed in the more recent 2004 study at low dose levels, the
observation of reduced sperm production would be expected to co-occur
with the tubular atrophy that was observed in the 1998 study.

Uncertainty Factor(s):  An UF of 100 was applied to account for
inter-species extrapolation (10x) and intra-species variation (10x).

Comments on Study/Endpoint/Uncertainty Factors:  The endpoint is based
on the most sensitive effect observed in offspring.  The endpoint is
appropriate because effects were observed after subchronic exposure and
are thus likely to be observed after chronic exposure.

Although the NOAEL of 1.2 mg/kg/day is very close to the LOAEL of 1.8
mg/kg/day for testicular effects, the Agency has confidence that the
NOAEL is protective.  The NOAEL of 1.2 mg/kg/day is based on the 2004
study for significant reductions in the number of sperm in the right
testes of F1 males at 3 mg/kg/day.  This endpoint is considered
conservative and protective because there was no dose-response
relationship and these findings were not observed in the F0 males.  Most
of the other sperm parameters were not significantly altered until much
higher dose levels of 155 mg/kg/day.  Although some sperm abnormalities
were noted in the 1998 study, such as decreased sperm motility, even at
0.6 mg/kg/day, there was no dose-response relationship, there was high
variability among all groups and there were no treatment-related effects
on sperm count or sperm morphology.  Based on a special complementary
study conducted to evaluate this finding, HED concluded the sperm
effects in this study were likely due to technical error and not
treatment-related.  However, based on consideration of both reproductive
studies, the Agency believes that it is appropriate to select a NOAEL of
1.2 mg/kg/day for these sperm effects for use in risk assessment.

The LOAEL of 1.8 mg/kg/day is based on testicular atrophy in F1
generation males.  In the 2004 study, testicular lesions were marginal
even at much higher dose levels of 155 mg/kg/day where there was an
increase in incidence but not severity of testicular lesions.  The
difference in the two studies may possibly be due to different grading
criteria, and also differences in histopathological evaluation
protocols.  The 1998 study only evaluated one slice per testis.  The
2004 study evaluated 4 slices per testis, calculated an average
numerical grade and reported only marginal testicular lesions at 155
mg/kg/day.  Therefore, HED believes the LOAEL of 1.8 mg/kg/day for
testicular atrophy is likely to be conservative and protective because
of the findings of the 2004 study.

Although there are no indications of effects on other reproductive
parameters (i.e. mating, gestation, fertility and viability), similar
effects were observed in a second species (dog) after subchronic
exposure.  Due to the high fecundity of rats, the lack of effects on
other reproductive parameters is not necessarily an indication that the
testicular effects would not be a problem in humans.  Since no data are
available to indicate how the testicular effects occur, whether or not
they can be considered an endocrine effect, or whether or not they can
definitively be considered adverse, the testicular effects were selected
to provide a conservative approach for assessment of risk to humans.  In
addition, it is not known whether the observed effects are due to
exposure to either the male or female or both parents in the study. 
Therefore, the endpoint will be applied to the general population.

The Agency recognizes that this endpoint may not be relevant for young
children that are sexually immature.  However, this endpoint was
determined to be conservative and health-protective for use in risk
assessment.

	Chronic RfD =    1.2 mg/kg/day (NOAEL)   = 0.012 mg/kg/day

			              100 (UF)

3.5.4  Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected:  90-day Oral Toxicity —dog  (OPPTS 870.3150)

MRID No.:  44718702

Dose and Endpoint for  Risk Assessment:  The incidental oral endpoint
(all durations) of 8.23 mg/kg/day is 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; decreased cholesterol and phospholipid
levels, testis weights, spermatogenesis, and spermatic giant cells in
testes (males) that occurred at 32 mg/kg/day in males and 33.9 mg/kg/day
in females.

 Comments on Study/Endpoint:  The Agency recognizes that some of the
observed effects in this study (i.e., testicular and ovarian effects)
may not be relevant for young children that are sexually immature. 
However, these effects occurred along with other more toxicologically
relevant findings for children, and thus this endpoint was determined to
be conservative and health-protective for use in risk assessment.

s protective of the effects noted in rats and mice.  In addition, the
renal effects in the rat study are most likely attributed to
accumulation of α2u-globulin, and thus are not relevant to humans.

3.5.5  Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

Dermal Absorption Factor:  5%.

HED recommends use of a 5% dermal absorption factor based on an
evaluation of in vivo dermal absorption data for two formulated products
containing thiamethoxam and an in vivo dermal absorption study in the
rat using technical thiamethoxam.  The 5% dermal absorption value
represents the maximum amount absorbed for all dose groups for either
formulation tested in the most recent study.

3.5.6  Dermal Exposure (Short-, Intermediate- and Long-Term) Adults  TC
\l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  Two 2-Generation Reproduction Toxicity Studies—rat
(OPPTS 870.3800)

MRID No.:  44718707; 46402902, 46402904, 46402906

Dose and Endpoint for Risk Assessment:  The dermal endpoint for adults,
all durations (1.2 mg/kg/day) is based on sperm abnormalities and
testicular effects observed after in utero and post-natal exposure in
the rat reproduction studies (see comments from the chronic dietary
section above).  

Comments on Study/Endpoint:  Although a 28-day dermal toxicity study in
rats is available, HED selected a reproductive NOAEL because the
reproductive parameters are not evaluated in the dermal toxicity study
and thus the consequences of these effects cannot be ascertained for the
dermal route of exposure.  Since an oral toxicity study was selected, a
5% dermal absorption factor is recommended.

3.5.7  Dermal Exposure (Short-, Intermediate- and Long-Term) Children
Age 1 to 6 Years   TC \l3 "3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term) 

Study Selected:  28-Day Dermal Toxicity Study—rat (OPPTS 870.3200)

MRID No.:  44710402

Dose and Endpoint for Risk Assessment:  The dermal endpoint (children
1-6, all durations) of 60 mg/kg/day is based on increased plasma
glucose, triglyceride levels, and alkaline phosphatase activity as well
as inflammatory cell infiltration in the liver and necrosis of single
hepatocytes in females at 250 mg/kg/day.

Comments on Study/Endpoint  The Agency selected the dermal toxicity
study to assess young children because the testicular effects observed
in the two-generation rat reproduction study are not relevant for young
children that are sexually immature.  Because a route-specific toxicity
study was selected, a dermal absorption factor is not necessary when
assessing dermal exposure to children.

3.5.8  Inhalation Exposure (Short-, Intermediate- and Long-Term)   TC
\l3 "3.5.8	Level of Concern for Margin of Exposure 

Based on the available toxicity database and the Agency's current
practices, short- and intermediate-term inhalation risks for
thiamethoxam were assessed using an oral toxicity study.  The Agency
sought expert advice and input on issues related to this route to route
extrapolation approach (i.e. the use of oral toxicity studies for
inhalation risk assessment) from its Federal Insecticide, Fungicide, and
Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The
Agency received the SAP’s final report on March 2, 2010 (  HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/" 
http://www.epa.gov/scipoly/SAP/meetings/2009/  120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, re-examine and develop new policies and procedures for
conducting inhalation risk assessments, including route to route
extrapolation of toxicity data.  If any new policies or procedures are
developed, the Agency may revisit the need for an inhalation toxicity
study for thiamethoxam and/or a re-examination of the inhalation
toxicity risk assessment.

Study Selected:  Two 2-Generation Reproduction Toxicity Studies—rat 
(OPPTS 870.3800)

MRID No.:  44718707, 46402902, 46402904, 46402906

Dose and Endpoint for Risk Assessment:  NOAEL of 1.2 mg/kg/day is based
on sperm abnormalities and testicular effects observed after in utero
and post-natal exposure in the rat reproduction studies (see comments
from the chronic dietary endpoint section above).

Comments about the Study/Endpoint:  Since no data are available to
indicate how much exposure will induce the effects, the effects are
considered to be appropriate for all exposure durations.  Other than
acute toxicity, no inhalation studies are available.  Therefore, the
reproductive endpoint is selected for inhalation exposure.  Inhalation
absorption is assumed to be 100% of oral absorption.  The Agency
recognizes that this endpoint may not be relevant for young children
that are sexually immature.  However, based on the use pattern and
physical-chemical characteristics, the Agency does not anticipate
inhalation exposure to young children.

3.5.9  Level of Concern for Margin of Exposure  TC \l3 "3.5.9
Recommendation for Aggregate Exposure Risk Assessments 

Table 3.5.9   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential Exposure

Dermal	100	100	100

Inhalation	100	100	100

Incidental Oral	100	100	100

3.5.10  Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.10	Classification of Carcinogenic Potential 

According to FQPA (1996), when there are potential residual exposures to
a pesticide, an aggregate risk assessment must consider exposures from 3
major routes: oral, dermal, and inhalation. 

Similar endpoints were selected for short-, intermediate- and long-term
exposures via oral, dermal and inhalation routes, so they may be
aggregated.  The endpoints are protective of adverse testicular, liver
and hematological effects, which appear to be the most sensitive effects
of thiamethoxam exposure via oral and dermal exposure.

3.5.11  Classification of Carcinogenic Potential  TC \l3 "3.5.11	Summary
of Toxicological Doses and Endpoints for Use in Human Risk Assessments 

Thiamethoxam induces hepatocellular adenomas and carcinomas in male and
female mice.  These findings served as the basis for HED’s conclusion
that thiamethoxam was likely to be carcinogenic to humans; furthermore,
HED recommended using a linear low dose extrapolation for assessing
cancer risk.  The registrant subsequently conducted a number of studies
to support a mode of action for carcinogenicity in mice.  These studies
were evaluated, and the Cancer Assessment Review Committee (CARC) 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.  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 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
3000 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.

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March, 2005), the CARC re-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 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.

3.5.12  Summary of Toxicological Doses and Endpoints for Thiamethoxam
for Use in Human Health Risk Assessments.

Table 3.5.12a.  Toxicological Doses and Endpoints for Thiamethoxam for
Use in Dietary and Residential Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

All populations including infants and children 	NOAEL =  34.5 mg/kg/day
UFA= 10x

UFH= 10x

SFFQPA=1

 	aRfD=0.35 mg/kg/day

aPAD=0.35 mg/kg/day	Rat Developmental Neurotoxicity study 

LOAEL = 298.7 mg/kg/day based on delayed sexual maturation in male pups,
and reduced brain morphometric measurements.

Chronic Dietary

All populations including infants and children	NOAEL= 1.2 mg/kg/day
(MRID 46402904) 	UFA= 10x

UFH= 10x

SFFQPA=1	cRfD=0.012 mg/kg/day

cPAD=0.012 mg/kg/day	2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on increased incidence and severity of
tubular atrophy in testes of F1 generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm
abnormalities in F1 males.

Incidental Oral (all durations)	NOAEL= 8.23 mg/kg/day	UFA= 10x

UFH= 10x

SFFQPA=1	MOE= 100 (residential)	90-day Dog study 

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 NOAEL= 1.2

 mg/kg/day

(dermal absorption rate = 5%)	UFA= 10x

UFH= 10x

SFFQPA=1	MOE= 100 (residential)	2-Generation reproduction study LOAEL =
1.8 mg/kg/day based on increased incidence and severity of tubular
atrophy in testes of F1 generation males. 

2-Generation reproduction study 

LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm
abnormalities in F1 males.

Dermal (all durations) (infants/

children 1-6 yrs)	Dermal Study

NOAEL=60 mg/kg/day	UFA= 10x

UFH= 10x

SFFQPA=1	MOE= 100 (residential)	Rat 28-Day Dermal Toxicity Study

LOAEL = 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. 

Inhalation (all durations)

	Oral study NOAEL= 1.2 mg/kg/day

(inhalation absorption rate = 100% of oral absorption)	UFA= 10x

UFH= 10x

SFFQPA=1	MOE= 100 (residential)	2-Generation reproduction study LOAEL =
1.8 mg/kg/day based on increased incidence and severity of tubular
atrophy in testes of F1 generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm
abnormalities in F1 males.

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.   Quantification
of cancer risk is not required.   

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

Table 3.5.12b.  Summary of Toxicological Doses and Endpoints for
Thiamethoxam for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal

Short-term

(1-30 days) and Intermediate-term (1-6 months)	Oral study NOAEL= 1.2

 mg/kg/day

(dermal absorption rate = 5%)	UFA= 10x

UFH= 10x	MOE= 100 (occupational)	2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on increased incidence and severity of
tubular atrophy in testes of F1 generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm
abnormalities in F1 males.

Inhalation

Short-term

(1-30 days) and Intermediate-term (1-6 months)	Oral study NOAEL= 1.2

 mg/kg/day

(inhalation absorption factor = 100%)	UFA= 10x

UFH= 10x

	MOE= 100 (occupational)	2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on increased incidence and severity of
tubular atrophy in testes of F1 generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm
abnormalities in F1 males.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

3.6  Endocrine disruption  TC \l2 "3.6	Endocrine disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Thiamethoxam is not among the group of 58 pesticide active ingredients
on the initial list to be screened under the EDSP.  Under FFDCA sec.
408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:  http://www.epa.gov/endo/.

4.0  Public Health and Pesticide Epidemiology Data  TC \l1 "4.0  Public
Health and Pesticide Epidemiology Data 

None.

5.0  Dietary Exposure/Risk Characterization  TC \l1 "5.0  Dietary
Exposure/Risk Characterization 

5.1  Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

References:	44939802.der.doc (Cucumber)

		45093709.der.doc (Tobacco)

		45093711.der.doc (Tobacco)

		45093713.der.doc (Potato)

		45093714.der.doc (Lettuce)

		  SEQ CHAPTER \h \r 1 MARC Decision Memo:  D258614, 8/31/99, G.J.
Herndon

Residue Chemistry Memo D252021, 3/30/00, G.J. Herndon (PP#9F5046)

		  SEQ CHAPTER \h \r 1 Residue Chemistry Memo D265079, 5/8/00, G.J.
Herndon (PP#9F5051)

  SEQ CHAPTER \h \r 1 

Data have been submitted and reviewed depicting the metabolism of
thiamethoxam in numerous crops and the environment.  HED has determined
that the plant and livestock residues of concern for purposes of
tolerance enforcement and risk assessment are the combined residues of
thiamethoxam and clothianidin (CGA-322704) (see Table 5.1).  For a
complete discussion of metabolism in crops and livestock, including
chemical names and structures, see the Residue Chemistry Summary
Document (D281702, M. Doherty, March 2007).

Table 5.1.  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression for Compliance Monitoring

Plants	Primary Crop	Thiamethoxam + clothianidin	Thiamethoxam +
clothianidin

	Rotational Crop	Not Applicable	Not Applicable

Livestock	Ruminant	Thiamethoxam + clothianidin	Thiamethoxam +
clothianidin

	Poultry	Thiamethoxam + clothianidin	Thiamethoxam + clothianidin

Drinking Water	Thiamethoxam	Not Applicable

Analytical Methodology

References:  Residue Chemistry Memo D252021; G.J. Herndon; 30 March 2000

	          SEQ CHAPTER \h \r 1 Residue Chemistry Memo D265079; G.J.
Herndon; 8 May 2000

	        Residue Chemistry Memo D271516; M. Doherty; 29 May 2001

	          SEQ CHAPTER \h \r 1 Residue Chemistry Memo D281702; M.
Doherty; 17 April 2007

        Residue Chemistry Memo D367065; W. Drew; 3 May 2010

The   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 HPLC Method AG-675 with
UV or MS detection was previously submitted in conjunction with
thiamethoxam petitions.  Method AG-675 has been determined to be
adequate for enforcing tolerances for residues of thiamethoxam and
CGA-322704 in crop and livestock commodities.  Syngenta has submitted a
revised Method AG-675, i.e., Method GRM.009.04A.  The full extraction
steps for plant and livestock commodities, including the microwave
extraction step for liver, have been incorporated, as previously
requested by HED as a condition of registration.  The LOQs of Method
GRM.009.04A have been established at 0.01 ppm each for residues of
thiamethoxam, CGA-322704 and CGA-265307.  Syngenta has submitted method
validation data for Method GRM.009.04A.  No ILV data have been
submitted, nor will ILV data be required, because the method is a
revised version of an existing enforcement method.  Although the
addition of a microwave extraction step is a significant change to the
method, residues of thiamethoxam, CGA-322704 and CGA-265307 are likely
to be low in livestock commodities.  In addition, the extensive cleanup
procedures after the microwave extraction step are very similar to the
cleanup procedures used for the Polytron extract of livestock commodity
samples in Method AG-675, which has been adequately validated by the
Analytical Chemistry Branch (ACB).  

The various data-collection methods, used for analysis of samples taken
from the magnitude of the residue studies discussed in this action, are
based on either Methods AG-675 or GRM.009.04A.  Method recoveries from
concurrent analysis of samples were within the generally recognized
acceptable range of 70-120%.

5.3  Drinking Water Residue Profile TC \l2 "5.3  Drinking Water Residue
Profile 

Reference:  EFED Memo D368072, C. Koper, 2 February 2010

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 groundwater.

The drinking water residues used in these dietary risk assessments were
provided by EFED (D368072, C. Koper, 2 February 2010), and incorporated
directly into the dietary assessments.  Water residues were incorporated
in DEEM-FCID via entry into the food categories “water, direct, all
sources” and “water, indirect, all sources.”  The estimated
drinking water concentrations (EDWCs) in surface water are 0.13177 ppm
and 0.01131 ppm for acute and chronic scenarios, respectively. 
Typically, HED uses the higher of the surface or groundwater estimates
for each duration when assessing dietary risk.  

The EDWCs were incorporated into the acute and chronic thiamethoxam
assessments.  Clothianidin, a major metabolite of thiamethoxam in plants
and livestock, is not a significant degradate of thiamethoxam in surface
or groundwater sources of drinking water. 

A Tier II screening-level drinking water assessment was conducted for
the proposed seed treatment of dry bulb onions.  EFED also evaluated
carrots, leafy vegetables and Brassica (cole) leafy vegetables because
previous assessments on these commodities were conducted at a lower
application rate.  

For surface water, the EDWCs for the crops modeled in this assessment
did not exceed the previous EDWCs for rice reported in the previous
drinking water assessment (D363202) dated 07 April 2009. The reported
acute concentration of 131.77 µg/L, annual mean (chronic) concentration
of 11.31 µg/L and the highest 30 year annual average concentration of
11.31 µg/L from the rice model are higher than the calculated EDWCs 
(see Table 5.3) for the various uses.  Therefore, the current EDWCs for
surface water do not supersede the drinking water concentrations
previously estimated for this chemical (D363202, F. Khan, 7 April 2009).

For groundwater, based on the proposed highest annual use rate for leafy
vegetables, the SCI-GROW model concentration of thiamethoxam was 3.42
µg/L.  This value was compared to 7.94 µg/L reported for grapes in the
previous drinking water assessment (D329467) dated 10 January 2007. 
However, further review of this assessment revealed that the aerobic
soil metabolism half-life input value was incorrect causing an incorrect
groundwater EDWC value.  The 90th upper percentile on the mean was used
instead of the mean half-life value.  Given that there were less than
four half-life values in the data set, the value was re-calculated based
on the mean half-life value, as specified in the SCI-GROW input guidance
embedded within the model.  The correct EDWC is 4.14 µg/L.  Since 3.42
µg/L is less than 4.14 µg/L, the current EDWC does not supersede the
recalculated estimated drinking water concentration for groundwater.

The acute scenario EDWC in surface water (0.13177 ppm) was obtained via
exposure modeling which utilized a modified Tier I Rice Model and the
Provisional Cranberry Model.  This model and its description are
available at the EPA internet website via the web link,   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  

Table 5.3. Tier II Estimated Drinking Water Concentrations (EDWCs)
resulting from applications of Thiamethoxam.

Drinking Water Source (model)	Use

Scenario 

(modeled rate)	1-in-10 year acute (µg/L)	1-in-10 year chronic (µg/L)
30- year average (µg/L)

Surface Water (PRZM/EXAMS)	Dry Bulb Onions:

CA Onion

GA Onion

(1 app. X 0.18 lbs ai/acre)	

0.94

12.25

	

0.15

0.92	

0.03

0.26

	Carrots:

FL Carrots 

(1 app. X 0.22 lbs ai/acre)	

9.25	

0.53	

0.36

	Brassica (Cole) Leafy Vegs:

CA Cole Crop

(1 app. X 0.22 lbs ai/acre)	

7.90	

1.06	

0.44

	Leafy Vegetables:

CA Lettuce (1 run)

(2 app. X 0.133 lbs. ai/acre)

CA Lettuce (2 runs)

(1 app. X 0.133 lbs. ai/acre)

(1 app. X 0.133 lbs. ai/acre)	

12.19

11.85

5.86	

2.07

1.84

0.71	

1.03

0.64

0.39

Tail water 

	Rice

(0.173 lbs ai/A/year)	131.771,2	11.311,3	11.311,3

	Cranberry

(0.188 lbs ai/A/year)	54.752	4.503	4.503

Groundwater 

(SCI-GROW)	Leafy Vegetables:

(0.22 lbs a.i./acre)

	

3.42	

3.42	

3.42

	Grape

(0.266 lb ai/A)	4.14	4.14	4.14

Bold text denotes maximum estimated EDWC values.  All values adjusted
with percent crop area factor of 0.87 (maximum area within a watershed
that may be planted with a modeled crop).

1 = Recommended EDWCs for surface water 

2 = EDWCs based on day 1 

3 = EDWCs based on average of 365days

Monitoring Data

The registrant has conducted small-scale prospective groundwater studies
in several locations in the US to investigate the mobility of
thiamethoxam in a vulnerable hydrogeological setting.  A review of those
data (Amer Al-Mudallal, D339099, 4/18/06) 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.

5.4  Food Residue Profile  TC \l2 "5.4  Food Residue Profile 

Reference:  Residue Chemistry Memo D367065; W. Drew; 3 May 2010

Onion, dry bulb.  The submitted field trial data for thiamethoxam on dry
bulb onions are acceptable, and support the proposed use of Cruiser®
70WS for pre-plant seed treatment.   A large percentage (86%) of the
residue values for onions were below the combined LOQ of 0.022 ppm;
therefore, the tolerance harmonization spreadsheet was not used to
determine the tolerance.  Based on the maximum combined thiamethoxam
ROCs of <0.026 ppm in 1X-treated samples, HED recommends a tolerance of
0.03 ppm.  

Barley.  Syngenta has submitted additional barley field trial data in
response to a data gap identified by HED (D281702; M. Doherty; 17 April
2007) during its review of initial data to support the registration of
Actara® Insecticide on barley.  The submitted field trial data for
thiamethoxam on barley are adequate, and fulfill the requested residue
decline data.  They confirm that the total thiamethoxam residues do not
increase in barley matrices with later sampling intervals than the
established 21-day precutting interval for barley hay, or the 21-day PHI
for barley grain and straw.  The additional trials also support the
Section 3 registration of Actara® foliar use on barley without
geographical restrictions on foliar use.  The aggregate of residue data
support the established tolerances for the combined thiamethoxam ROCs
for barley grain at 0.30 ppm, and 0.40 ppm for both barley hay and
straw.

Poultry.  A new poultry feeding study with thiamethoxam was conducted. 
Four treatment groups of fifteen laying hens each were dosed with
thiamethoxam at 0, 0.2, 0.6, and 2 ppm in the feed for 28 consecutive
days.  Hens were sacrificed 20-24 hours after the treated feed was
replaced with untreated feed, and composite samples of skin (with
attached fat), peritoneal fat, liver and muscle were collected and only
the liver samples were analyzed.  

Liver samples were analyzed for residues of thiamethoxam and its
metabolites CGA-322704 and CGA-265307 using HPLC/MS/MS Method
GRM.009.04A which is a modification of the current tolerance enforcement
method and includes microwave extraction.  This method is adequate for
data collection based on acceptable method recoveries.  The validated
LOQ is 0.01 ppm for each analyte in poultry liver.  

The maximum storage duration from collection to analysis was 56 days for
poultry liver.  The available storage stability data for eggs and beef
tissues are adequate to support the storage durations and conditions of
the poultry feeding study samples.  

Residues of thiamethoxam, CGA-322704, and CGA-265307 were each below the
LOQ (<0.01 ppm) in all liver samples from the 0.2- and 0.6-ppm dose
groups.  For the 2.0-ppm dose group, thiamethoxam residues were all
below the method LOQ (<0.01 ppm), CGA-322704 residues were <0.01-0.01
ppm (two samples measured 0.01 ppm), and CGA-265307 residues were 0.01
ppm.

Conclusions:  The new poultry feeding study is adequate, and fulfills
the requirement for liver data analyzed by the modified enforcement
method.  A dietary burden of 0.245 ppm was recently calculated (D281702;
M. Doherty; 17 April 2007) for poultry.   Given that the projected
thiamethoxam ROC at the 1X feeding level will be <LOQ, HED concludes
that residues in eggs and poultry meat, fat, and meat byproducts remain
a 40CFR §180.6[a][3] situation (there is no expectation of finite
residues in these commodities).  As a result, tolerances are not
required.  This conclusion will be reevaluated, if and when, new poultry
feed items are proposed in the future.

5.5  International Residue Limits TC \l2 "5.5  International Residue
Limits 

There are no international residue limits that affect HED’s
recommendations at this time.  There are no CODEX or Mexican maximum
residue limits (MRLs) for thiamethoxam.  Canada has established an MRL
of 0.02 mg/kg for residues of thiamethoxam and CGA-322704 in all food
crops, and is transitioning to specific commodity MRLs (all at 0.02
mg/kg) on a variety of crops including various cereal grains, peas and
beans, soybeans, sweet corn, and sunflower.

5.6  Dietary Exposure and Risk TC \l2 "5.6  Dietary Exposure and Risk 

Reference:  D375247, D. McNeilly, 3 May 2010

Acute and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which
uses food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  The analyses were performed to evaluate Section 3 requests
for new uses on onions dry bulb and removal of the geographical
limitations for the foliar treatment of barley.

A new chlothianidin dietary assessment and risk assessment accounting
for clothianidin residues on onion, dry bulb resulting from thiamethoxam
application is not necessary, since chlothianidin is registered for use
on Vegetable, bulb group 3-07, which includes onion, dry bulb (0.45 ppm
tolerance) and on Cereal grain group 15, except rice (0.01 ppm
tolerance).

There is available information indicating that thiamethoxam and
clothianidin have different toxicological effects in mammals and should
be assessed separately; however, in conducting these assessments,
residues of clothianidin coming from thiamethoxam were combined with
residues of thiamethoxam.  The total residue was then used to estimate
dietary exposure and risk.  Clothianidin, a major metabolite of
thiamethoxam in plants and livestock, is not a significant degradate of
thiamethoxam in surface or groundwater sources of drinking water. 

The acute dietary assessment is based on tolerance level residues of
thiamethoxam and clothianidin and assumes 100% crop treated for all
commodities.  The chronic dietary assessment is based on tolerance level
residues and anticipated residues from thiamethoxam field trials.  The
chronic assessment assumes that 100% of crops with registered or
requested uses of thiamethoxam are treated.

The drinking water residues used in these dietary risk assessments were
provided by EFED (D368072, C. Koper, 2 Feb 2010 and D363202, F. Khan, 7
April 2009), and incorporated directly into the dietary assessments. 
Water residues were incorporated in DEEM-FCID via entry into the food
categories “water, direct, all sources” and “water, indirect, all
sources.”  The estimated drinking water concentrations (EDWCs) in
surface water are 0.132 ppm and 0.0113 ppm for acute and chronic
scenarios, respectively.  For groundwater, based on the proposed highest
annual use rate for grape, the SCI-GROW model concentration of
thiamethoxam was 4.14 µg/L (Table 5.6.a).  Typically, HED uses the
higher of the surface or groundwater estimates for each duration when
assessing dietary risk.

Table 5.6.a. Tier I estimated drinking water concentrations (EDWCs)
resulting from applications of thiamethoxam.

Drinking water source (model)	Use 

(modeled rate)	Acute

 (µg/L)	Chronic

(µg/L)	Cancer Chronic (µg/L)

Tail water 

	Rice

(0.173 lbs ai/A/year)	131.771,2	11.311,3	11.311,3

	Cranberry

(0.188 lbs ai/A/year)	54.752	4.503	4.503

Groundwater (SCIGROW)	Leafy Vegetables:

(0.22 lbs a.i./acre)

	

3.42	

3.42	

3.42

	Grape

(0.266 lb ai/A)	4.14	4.14	4.14

1 = Recommended EDWCs for surface water 

2 = EDWCs based on day 1 

3 = EDWCs based on average of 365days 

These assumptions result in conservative, health-protective estimates of
exposure (Table 5.6.b).  Risk estimates for acute and chronic dietary
exposure for all assessed population subgroups are below HED’s level
of concern (generally 100% of the aPAD or cPAD).

Table 5.6.b.  Summary of Estimated Dietary (Food + Drinking Water)
Exposure

and Risk for Thiamethoxam.

Population Subgroup	aPAD, mg/kg	Acute Estimates 

(95th percentile)	cPAD, mg/kg/day	Chronic Estimates

Exposure, mg/kg	Risk, % aPAD

Exposure, mg/kg/day	Risk, % cPAD

U.S. Population	0.35	0.018088	5.2	0.012	0.002795	23

All infants

 (< 1 year)	0.35	0.033163	9.5	0.012	0.003002	25

Children 1-2 yrs	0.35	0.032980	9.5	0.012	0.005065	42

Children 3-5 yrs	0.35	0.026607	7.6	0.012	0.004446	37

Children 6-12 yrs	0.35	0.018827	5.4	0.012	0.003196	27

Youth 13-19 yrs	0.35	0.014308	4.1	0.012	0.002308	19

Adults 20-49 yrs	0.35	0.016273	4.7	0.012	0.002567	21

Adults 50+ yrs	0.35	0.016610	4.8	0.012	0.002625	22

Females 13-49 yrs	0.35	0.016146	4.6	0.012	0.002595	22

The population subgroup with the highest estimated exposure/risk is
bolded.

5.6.1  Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l3 "5.6.1  Anticipated Residue and Percent Crop Treated (%CT)
Information 

Reference:  D375247, D. McNeilly, 3 May 2010

The dietary assessment is a screening-level assessment using tolerance
level residues for the acute analysis.  Tolerance level and anticipated
residues (calculated from field trial data) for selected commodities
(discussed in detail in D364256/D364257, D. McNeilly, June 30, 2009)
were used in the chronic assessment.  The chronic assessment anticipated
residues were average residues from crop field trial data.  100% crop
treated was assumed for both the acute and chronic analyses.

6.0  Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0  Residential (Non-Occupational) Exposure/Risk Characterization 

Reference:  Thiamethoxam: Occupational and Residential Exposure
Assessment for Section 3 Registration, M. Collantes; July 24, 2009;
D359207

Handler

  Optigard ™ is formulated as a suspension concentrate which contains
21.6% of the active ingredient thiamethoxam and is applied as a 0.05%
and/or 0.1% dilution for spot or crack and crevice treatment.  The
registered label indicates that thiamethoxam is to be applied by
commercial applicators only; therefore, an assessment for homeowner
applicator exposure was not performed.

Postapplication Exposure

There is a potential for exposure from entering areas previously treated
with thiamethoxam that could lead to exposures for adults and children. 
 Postapplication residential scenarios were assessed using the HED Draft
Standard Operating Procedures (SOPs) for Residential Exposure
Assessments (12/18/97), and the Revisions to the Standard Operating
Procedures (SOPs) for Residential Exposure Assessment (Science Advisory
Council for Exposure Policy 12, Revised February 22, 2001).  The level
of concern (LOC) for the margin of exposure (MOE) is 100 for all
residential uses.

Post-application dermal exposure can result from pesticide residue
transferring to the skin of individuals who contact previously treated
indoor surfaces (e.g., carpets, floors, furniture, and other surfaces)
during standard activities such as recreation, housework or other
occupant activities.  Such exposure is assumed to occur for adults and
toddlers.  All postapplication dermal scenarios resulted in MOEs greater
than 100 and are not of concern to HED.  A summary of the dermal
postapplication exposure and risks are included in Table 6.a.

Table 6.a.:  Postapplication Dermal Exposure for Children and Adults for
0.1% and 0.05% Sprays for Crack and Crevice

Surface	Population

Subgroup	ISR 1 (µg/cm2)	CF	TC 2 (cm2/hr)	ED 3 (hrs)	Dermal Absorption
(mg/kg/day)	BW (kg)	Dermal Dose 4 (mg/kg/day)	NOAEL  (mg/kg/day)	MOE 5

carpet	adult	0.025

	0.001	16,700	8	0.05	60	0.00278	1.2	430

	child

	6,000

1	15	0.08	60	750

vinyl	adult	0.05

16,700	4	0.05	60	0.00278	1.2	430

	child

	6,000

1	15	0.08	60	750

1.  ISR = indoor surface transferable residues = deposition residue (0.5
ug/cm2) x fraction of residue available for transfer from

     carpet vs. hard surface  (0.05/0.1)  

2.  Tc = transfer coefficient based on HED Residential SOPs

3.  ED =exposure duration based on HED Residential SOPs

4.  Dose = ISR (ug/cm2) x 0.001 (mg/ug) x Tc (cm2/hr) x ED (hrs/day) x
dermal absorption for adults only (mg/kg/day) 

BW (kg)

5.  Adult MOE = NOAEL (1.2 mg/kg/day)	Child MOE = NOAEL (60 mg/kg/day)

       	 Dermal Dose				 Dermal Dose

Oral non-dietary ingestion exposures also were assessed for children
(i.e. hand-to-mouth) for indoor crack and crevice use.  The
hand-to-mouth transfer scenario assumes that pesticide residues are
transferred to the skin of children during postapplication contact with
treated indoor areas and are subsequently ingested as a result of
hand-to-mouth transfer.  In conducting this assessment for thiamethoxam,
HED used standard assumptions with respect to the frequency of mouthing
events for both short- and intermediate-term durations, as well hand
surface area, the saliva extraction factor, and the duration of time
spent on indoor surfaces.  The hand-to-mouth transfer postapplication
exposure assessment resulted in oral MOEs greater than 100 for all
scenarios, and therefore oral postapplication risks are not of concern
to HED.  Table 6.b summarizes the MOEs for hand-to-mouth transfer of
pesticide residues from indoor crack and crevice use.

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for thiamethoxam at
this time primarily because it has a very low vapor pressure (6.6 x 10-9
@ 25oC), inhalation exposure is expected to be negligible as a result of
indoor crack and crevice use.  However, volatilization of pesticides may
be a potential source of postapplication inhalation exposure to
individuals nearby to pesticide applications.  The Agency sought expert
advice and input on issues related to volatilization of pesticides from
its Federal Insecticide, Fungicide, and Rodenticide Act Scientific
Advisory Panel (SAP) in December 2009.  The Agency received the SAP’s
final report on March 2, 2010 (  HYPERLINK
"http://www.epa.gov/scipoly/SAP /meetings/2009/" 
http://www.epa.gov/scipoly/SAP /meetings/2009/  120109meeting.html). 
The Agency is in the process of evaluating the SAP report and may, as
appropriate, develop policies and procedures to identify the need for
and, subsequently, the way to incorporate postapplication inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative postapplication inhalation exposure assessment for
thiamethoxam.

Table 6.b.:  Postapplication Oral Exposure for Children for 0.1% and
0.05% Sprays for Crack and Crevice

Surface	ISR 1 (µg/cm2)	SA2

(cm2)	FQ3   (event/hr)	ED4   (hrs)	SE5	CF6	Oral Dose7 (mg/kg/day)	MOE8

Short –term

carpet	0.025	20	20	8	0.5	0.001

	0.0026	3100

vinyl	0.05

	4

Intermediate-term

carpet	0.025	20	9.5	8	0.5	0.001	0.00126	6500 

vinyl	0.05

	4

  1. ISR = indoor surface transferable residues = deposition residue
(0.5 ug/cm2) x fraction of residue available for

      transfer from carpet vs. hard surface  (0.05/0.1)  2. Surface
area.

  3. Frequency of hand-to-mouth events.  4. Exposure duration.  5.
Saliva extraction factor.  6. Conversion factor (mg/µg).

  7. Oral Dose = (ISR x SA x FQ x ED x SE x CF1)/(BW 15 kg)   8. Oral
MOE = NOAEL (8.23 mg/kg/day)/Oral dose.		   

Combined Residential Risk Estimates

In the previous 2007 thiamethoxam residential assessment, a combined
residential assessment was performed for turf dermal and oral
postapplication exposure of toddlers only.  A more recent 2009
assessment (D365272, D. McNeilly, 6 August 2009) evaluated an indoor
crack and crevice product and provided a revised combined residential
assessment based on indoor crack and crevice use.  These exposures and
risks were greater than exposure/risk from the use on lawns.  Therefore,
the indoor exposures should be used in an aggregate assessment in order
to be protective.

		

HED combined all non-dietary sources of post application exposure to
obtain an estimate of potential combined exposure which could be used
for the aggregate assessment.  These scenarios consisted of adult and
toddler dermal postapplication exposure and oral (hand-to-mouth)
exposures for toddlers.  All postapplication scenarios resulted in
combined MOEs greater than 100 and were not of concern to HED.  Table
6.c provides a summary of the combined residential indoor crack and
crevice exposures and risks.

 Table 6.c.  Combined Residential Exposure and Risk Estimates from
Indoor Crack and Crevice Use

Postapplication

Scenarios	Daily Dose

(mg/kg/day) 1	MOE 2	Combined

MOE 3

Short-term

Adult Dermal – indoor surface	0.00278	430	430

Toddler Dermal - indoor surface	0.08	750	

610

Hand-to-Mouth	0.0026	3100

	Intermediate-term

Adult Dermal - indoor surface	0.0278	430	430

Toddler Dermal - indoor surface	0.08	750	

680

Hand-to-Mouth	0.001267	6500

		1 Daily Dose = see Tables 6.a. and 6.b.  	2 Adult Dermal MOE = NOAEL
(1.2 mg/kg/day)	 

       	                                                                
                       Dermal Dose					

       Child Dermal MOE = NOAEL (60 mg/kg/day)

   	                        Dermal Dose

       Child Oral MOE = NOAEL (8.23 mg/kg/day)

       	                  Oral Dose					       	 

	3 Toddler Combined MOE = 1/ [(1/MOEDermal) + (1/MOEHand-to-Mouth)]

6.1  Other (Spray Drift, etc.) TC \l2 "6.1  Other (Spray Drift, etc.) 

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
thiamethoxam.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling.  The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products having significant risks
associated with drift.

7.0  Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0 
Aggregate Risk Assessments and Risk Characterization 

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.  Given the existing and proposed use
patterns for thiamethoxam as well as the health-protective assumptions
throughout this risk assessment, it is unlikely that any geographic,
ethnic, or socioeconomic population will have increased exposure
relative to the standard population subgroups assessed by OPP.

7.1  Acute Aggregate Risk TC \l2 "7.1  Acute Aggregate Risk 

In examining acute aggregate risk, HED has assumed that the only pathway
of exposure relevant to that time frame is dietary exposure.  Therefore,
the acute aggregate risk is composed of exposures to thiamethoxam
residues in food and drinking water and is equivalent to the acute
dietary risk discussed in Section 5.6.  As noted in that section, the
acute risk estimates are well below HED’s level of concern for all
population subgroups.

7.2  Short-Term Aggregate Risk TC \l2 "7.2  Short-Term Aggregate Risk 

References:   D375247, D. McNeilly, 3 May 2010

                    D359207, M. Collantes; 24 July 2009

Short-term exposures (1 to 30 days of continuous exposure) may occur as
a result of entering indoor areas previously treated with a thiamethoxam
indoor crack and crevice product.  Exposures related to indoor
activities (Table 6.c) have been combined with chronic dietary exposure
estimates (as an estimate of background dietary exposure; Table 5.6.b)
to assess the worst-case short-term aggregate exposure.  The indoor
crack and crevice scenario has higher exposure for both adults and
children than the exposure levels in the turf scenario.  The short-term
aggregate MOEs range from 370 to 500 (Table 7.2).  Since these are
greater than 100, they represent aggregate risk estimates that are below
HED’s level of concern.

Table 7.2.  Estimates of Short-term Aggregate Risks for Thiamethoxam

Population Subgroup	Margins of Exposure (MOEs)

	Dietary Aggregate1	Dermal 2	Hand-to-Mouth 2	Total Short-Term

 Aggregate 3

General U.S. population	2,900	

430	–	

380

All infants	2,700	750	3,100	500

Children 1-2 yrs	1,600	750	3,100	440

Children 3-5 yrs	1,900	750	3,100	460

Children 6-12 yrs	2,600	430	–	370

Youth 13-19 yrs	3,600	430	–	380

Adults 20-49 yrs	3,200	430	–	380

Adults 50+ yrs	3,100	430	–	380

Females 13-49 yrs	3,200	430	–	380

1  Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷
Chronic Dietary (Food + Water) Exposure (mg/kg/day; from Table 5.6.b). 
Values are rounded to 2 significant figures.

2  Indoor crack and crevice exposure (which has higher exposure than
residential turf) from Table 6c.  Hand-to-mouth is appropriate for
infant and children population subgroups only.  

3 Total Aggregate MOE = 1/[(1/MOEDietary) + (1/MOEDermal) + (1/MOEHtM)].
 Values rounded to 2 significant figures.

7.3  Intermediate-Term Aggregate Risk TC \l2 "7.3  Intermediate-Term
Aggregate Risk 

Intermediate-term exposures (30 to 180 days of continuous exposure) may
occur as a result of entering indoor areas previously treated with a
thiamethoxam indoor crack and crevice product.  Exposures related to
indoor activities (Table 6.c) have been combined with chronic dietary
exposure estimates (as an estimate of background dietary exposure; Table
5.6.b) to assess the worst-case intermediate-term aggregate exposure. 
The indoor crack and crevice scenario has higher exposure for both
adults and children than the exposure levels in the turf scenario.  The
intermediate-term aggregate MOEs range from 370 to 540 (Table 7.3). 
Since these are greater than 100, they represent intermediate-term
aggregate risk estimates that are below HED’s level of concern.

The difference between short- and intermediate-term aggregate risk is
the frequency of hand-to-mouth events for children.  For short-term
exposure there are 20 events per hour and for intermediate-term exposure
there are 9.5 events per hour (see Table 6.b).  The doses and end-points
for short- and intermediate-term aggregate risk are the same.   

Table 7.3.  Estimates of Intermediate-term Aggregate Risks for
Thiamethoxam

Population Subgroup	Margins of Exposure (MOEs)

	Dietary Aggregate1	Dermal 2	Hand-to-Mouth 2	Total Intermediate-Term

Aggregate 3

General U.S. population	2,900	430	–	380

All infants	2,700	750	6,500	540

Children 1-2 yrs	1,600	750	6,500	480

Children 3-5 yrs	1,900	750	6,500	500

Children 6-12 yrs	2,600	430	–	370

Youth 13-19 yrs	3,600	430	–	380

Adults 20-49 yrs	3,200	430	–	380

Adults 50+ yrs	3,100	430	–	380

Females 13-49 yrs	3,200	430	–	380

1  Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷
Chronic Dietary (Food + Water) Exposure

  (mg/kg/day; from Table 5.6.b).  Values are rounded to 2 significant
figures.  2  Indoor crack and crevice exposure (which has

  higher exposure than residential turf) from Table 6c.  Hand-to-mouth
is appropriate for infant and children population subgroups

  only.  3 Total Aggregate MOE = 1/[(1/MOEDietary) + (1/MOEDermal) +
(1/MOEHtM)].  Values rounded to 2 significant figures.

7.4  Chronic Aggregate Risk TC \l2 "7.4  Long-Term Aggregate Risk 

In examining chronic aggregate risk, HED has assumed that the only
pathway of exposure relevant to that time frame is dietary exposure. 
Therefore, chronic aggregate risk is composed of exposures to
thiamethoxam residues in food and drinking water and is equivalent to
the chronic dietary risk discussed in Section 5.6.  As noted in that
section, the chronic risk estimates are below HED’s level of concern
for all population subgroups.

7.5  Cancer Risk TC \l2 "7.5  Cancer Risk 

Thiamethoxam has been classified as “not likely to be carcinogenic to
humans.”  As such, the risk of cancer from thiamethoxam is not of
concern.  The chronic risk assessment would be protective for any
potential cancer effects. 

8.0  Cumulative Risk Characterization/Assessment  TC \l1 "8.0 
Cumulative Risk Characterization/Assessment 

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 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 imidacloprid).  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   HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

9.0  Occupational Exposure/Risk Pathway  TC \l1 "9.0  Occupational
Exposure/Risk Pathway 

Reference:  Shih-Chi Wang, D372848, 3 May 2010

Seed Treatment (Onion, dry bulb)

The Cruiser® 5 70WS formulation of thiamethoxam is labeled for use in
commercial seed treatment facilities only.  Two seed treatment methods
were assessed, 300 lbs of seeds per day by pelletizing method and 5,500
lbs of seeds per day by film coating method.

Reference:  Margarita Collates, D332064; March, 2007

Barley (not a new use, the request is to remove the current geographical
limitations on the foliar treatment of barley) 

Actara® Insecticide, a 25% WDG formulation of thiamethoxam labeled for
foliar insect control use on leafy, fruiting, and root vegetables,
berries, pome and stone fruits, barley and a number of other crops and
turf, sod farm and ornamentals, was previously assessed for occupational
and residential exposures.

9.1  Short- and Intermediate-Term Handler Risk  TC \l2 "9.1  Short- and
Intermediate-Term Handler Risk 

This assessment covers commercial handlers-loader/applicator, sewer,
bagger, and multiple activities worker for seed treatment use on bulb
onions.  Thiamethoxam is to be applied only in commercial seed treatment
facilities.  HED generally relied on the seed treatment SOPs #14 and
#15, and standard assumptions, etc. to evaluate occupational exposure.

Based on application rate and label information, exposure is expected to
occur for short- and intermediate-term durations.  HED considers MOEs of
less than 100 to indicate a risk of concern for occupational exposure to
thiamethoxam.  In addition, doses and endpoints for assessing
occupational risk are based on the same studies for all durations for
both dermal and inhalation exposures; therefore, the short-term and
intermediate-term risk assessments are equivalent.

HED has evaluated the proposed seed treatment use of thiamethoxam on
bulb onions.  With the exception of the multiple activities scenario,
using HED’s standard assumption for the amount of seed treated per day
(5,500 lbs treated/day), the potential occupational exposures/risks
resulting from the proposed use do not exceed HED’s level of concern. 
That is, with the exception of the multiple activities scenario,
occupational margins of exposure (MOEs) are greater than the level of
concern (LOC) of 100.  The default assumption of 5,500 lbs treated per
day resulted in an MOE of 59 for the multiple activities scenario.

HED believes that this multiple activities scenario MOE probably over
estimates the risk, however until data/information are available to
further refine the actual exposure/risk, HED recommends that the label
limit the pounds of formulated product used per handler to 260 lbs per
day.  If the maximum amount of CRUISER® 70WS Insecticide that can be
used to treat bulb onion seed in a seed treatment facility is limited to
260 lbs per production line per 8-hour work shift (based on ca. 3,000
lbs seeds treated per day) the MOE for multiple activities worker is
110.  This requires that a worker performing tasks associated with seed
treatment, limit exposure to 260 lbs. of formulated product (for
Cruiser® 5 70WS) per day.  This limitation should be reflected on the
label.

Seed Treatment (Onion, dry bulb)

Primary Handler Exposure

With the exception of the multiple activities scenario using HED’s
standard assumption regarding the amount of seed treated per day (5,500
lbs treated/day, MOE=59), the potential occupational exposures/risks
resulting from the proposed use do not exceed the HED level of concern
(MOEs range from 300 to 7,400).  

According to the proposed label, the loader/applicator must wear
personal protective equipment (PPE) consisting of a single layer of
clothing plus chemical-resistant gloves and dust mask; workers
conducting sewer and bagger activities must wear a single layer of
clothing plus chemical-resistant gloves.  The multiple task workers must
wear (1) a single layer of clothing, (2) chemical-resistant gloves, (3)
dust mask, and (4) chemical-resistant coveralls.  Thus, the MOE of 59
for the multiple activities scenario is a very conservative estimate
because it was based on single layer plus gloves protection.  If the
dust mask and coveralls are added to the single layer plus gloves
protection when conducting the exposure assessment, exposure from the
multiple task workers may be not of concern.  However, data are not
available to evaluate this scenario.

In addition, the MOE of 59 for the multiple activities scenario is based
on the unit of exposure for liquid product, and the product being
evaluated here is a wettable powder packaged in water soluble packets
(considered as an engineering control measure which can provide more
than 50% reduction in exposure); therefore this MOE is not of concern.  
 

N瑯㩥†桔⁥楳湧晩捩湡散漠⁦獵湩⁧慷整⁲潳畬汢⁥
慰正瑥⁳湩攠灸獯牵⁥敲畤瑣潩㩮

●   PHED unit exposure for mixing/loading liquid product 

      = 0.023 + 0.0012 = 0.0242 mg/lb ai handled

●   PHED unit exposure for mixing/loading water soluble packet product

      = 0.0098 + 0.00024 = 0.01004 mg/lb ai handled       

A summary of the exposures and risks for seed treatment handlers is
presented in Table 9.1.a.

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures.  The uncertainties associated with this assessment
stem from the assumptions regarding that amount of chemical handled and
the amount of seed treated per day.  The estimated exposures are
believed to be reasonable high-end estimates based on observations from
field studies and professional judgment.

Barley

The short- and intermediate-term occupational exposure and risk
resulting from the use of Actara® Insecticide on barley applied by
aerial and groundboom equipment were previously found to be not of
concern (MOE = 180-1200).  

Table 9.1.a.  Thiamethoxam Non-Cancer Risk for Seed-Treatment Handlers.

Exposure Scenario (Scenario #)	

Mitigation Level	

Dermal Unit Exposure (mg/lb ai)	

Inhalation Unit Exposure   (mg/lb ai)	

Seed Species	

Application Rate

(lb ai  per lb seed)	

Amount Treateda

(lb seed trt per day)	

Daily

Dermal

Dose b (mg/kg/day)	

Daily

Inhalation

Dosec (mg/kg/day)	

Combined Daily Dosed  (mg/kg/day)	

MOEe  

Loader/Applicator

Loading/Applying

Water soluble bags  for Seed Treatment (1)	Single Layer, Gloves	0.0098
0.00024	Onion (bulb)	0.06	5,500	0.002695	0.00132	0.004015	300

300	0.00015	0.000072	0.000222	5,400

Sewer

Sewing Bags after Seed treatment (2)	Single Layer, 

No Gloves	0.0062	0.00023	Onion (bulb)	0.06	5,500	0.001705	0.001265
0.00297	400

300	0.000093	0.000069	0.000162	7,400

Bagger

Bagging Seeds after Seed treatment (3)	Single Layer, 

No Gloves	0.0091	0.00016	Onion (bulb)	0.06	5,500	0.002503	0.00088
0.003383	360

300	0.000136	0.000048	0.000184	6,500

Multiple Activities Worker

Multiple Activities for Seed treatment (4)	Single Layer, Gloves	0.042
0.0016	Onion (bulb)	0.06	5,500	0.01155	0.0088	0.02035	59

300	0.000631	0.00048	0.001111	1,100

a	Daily amounts treated values are based on exposure SAC Policy #15 or
the information provided by the Registrant through Registration
Division.  5,500 for film-coated treatment, 

                  300 for pelletizing treatment. 

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) *
dermal absorption (0.05) * application rate (lb ai/lb seed) * daily
amounts treated]/ body weight (60 kg).

c	Daily inhalation dose (mg/kg/d) = [unit exposure (mg/lb ai) *
application. rate (lb ai/lb seed) * daily amounts treated]/ body weight
(60 kg).

d	Combined daily dose (mg/kg/d) =  Daily dermal dose (mg/kg/d) + Daily
inhalation dose (mg/kg/d).

e	MOE = NOAEL (1.2  mg/kg/d) / combined daily dose.  UF = 100.



Table 9.1.b.  Thiamethoxam Non-Cancer Risk for Secondary Seed Handlers.

Exposure Scenario (Scenario #)	

Mitigation Level	

Dermal Unit Exposure (mg/lb ai)	

Inhalation Unit Exposure   (mg/lb ai)	

Seed Species	

Application Rate

(lb ai  per lb seed)	

Amount Planteda

(lb seed pnted/day)	

Daily

Dermal

Dose b (mg/kg/day)	

Daily

Inhalation

Dosec (mg/kg/day)	

Combined Daily Dosed (mg/kg/day) 	

MOEe  

Secondary Seed Handlers

Secondary Seed Handlers: planting seeds in the field	Single Layer,
Gloves	0.25	0.00342	Onion (bulb)	0.06	400	0.005	0.00136	0.00636	190

240	0.003	0.000816	0.003816	310

a	Daily amounts planted values are based on exposure SAC Policy #15 or
the information provided by the Registrant through Registration
Division. 

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) *
dermal absorption (0.05) * application rate (lb ai/lb seed) * daily
amounts treated]/ body weight (60 kg).

c	Daily inhalation dose (mg/kg/d) = [unit exposure (mg/lb ai) *
application. rate (lb ai/lb seed) * daily amounts treated]/ body weight
(60 kg).

d	Combined daily dose (mg/kg/d) =  Daily dermal dose (mg/kg/d) + Daily
inhalation dose (mg/kg/d).

e	MOE = NOAEL (1.2 mg/kg/d) / combined daily dose.  UF = 100.			

Secondary Seed Handlers  tc \l2 "5.2.2  Post-application  

The exposure scenario for secondary seed handlers from treated seeds
consists of the farmer purchasing bags of treated seeds, placing the
seeds in the hopper, and planting seeds in fields.  The exposure
associated with handling treated seeds was calculated using unit
exposures given in the HED Exposure Science Advisory Council (ExpoSAC)
SOP #14 (May 1, 2003).

Secondary Seed Handler’s Exposure and Risk

All MOEs for secondary seed handlers are greater than 100 and do not
exceed HED’s level of concern at the single layer plus gloves level of
mitigation (190 or 310).  A summary of the exposure/risk values is
presented in Table 9.1.b.

    

The secondary seed handler’s exposure estimates in this assessment are
based on a central tendency estimate of unit exposure, upper-percentile
assumptions for the application rate, and a conservative estimate of
exposure frequency; and are assumed to be representative of high-end
exposures.  The uncertainties associated with this assessment stem from
the use of surrogate exposure data (e.g., differences in use scenario
and data confidence) and assumptions regarding that amount of chemical
handled.  The estimated exposures are believed to be reasonable high-end
estimates based on observations from field studies and professional
judgement.

9.2  Short- and Intermediate-Term Postapplication Risk  TC \l2 "9.2 
Short-Term Postapplication Risk 

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for thiamethoxam at
this time primarily because it has a very low vapor pressure (6.6 x 10-9
@ 25oC), inhalation exposure is expected to be negligible as a result of
indoor crack and crevice use.  However, volatilization of pesticides may
be a potential source of postapplication inhalation exposure to
individuals nearby to pesticide applications.  The Agency sought expert
advice and input on issues related to volatilization of pesticides from
its Federal Insecticide, Fungicide, and Rodenticide Act Scientific
Advisory Panel (SAP) in December 2009.  The Agency received the SAP’s
final report on March 2, 2010 (  HYPERLINK
"http://www.epa.gov/scipoly/SAP /meetings/2009/" 
http://www.epa.gov/scipoly/SAP /meetings/2009/  120109meeting.html). 
The Agency is in the process of evaluating the SAP report and may, as
appropriate, develop policies and procedures to identify the need for
and, subsequently, the way to incorporate postapplication inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative postapplication inhalation exposure assessment for
thiamethoxam.

Since no quantitative postapplication assessment was completed for
treated seeds, the restricted entry interval (REI) is based on the acute
toxicity of thiamethoxam technical material which is classified as
Category IV for acute dermal toxicity and for skin and eye irritation
potential.  The default restricted-entry interval is 12 hours for active
ingredients classified as acute toxicity categories III or IV for these
routes of exposure.  In accordance with the Worker Protection Standard
(WPS), for purposes of seed treatment, once the seeds are planted,
workers can enter during the REI, provided they do not contact the
soil/media subsurface that contains the treated seeds.  Therefore, HED
concurs with the 12-hour REI on the proposed label for seed treatment. 
HED recommends that the Registration Division ensure that appropriate
language is placed on the product label to require the label on treated
seed to include the restricted-entry interval following the planting of
treated seed. (Note:  HED does not have transfer coefficients to assess
postapplication dermal exposures to pesticides in the soil.)

Potential postapplication dermal exposure to workers entering Actara®
Insecticide treated fields of barley to do scouting and irrigation were
previously assessed (D332064, Margarita Collates; March, 2007).  All
scenarios resulted in MOEs greater than 100 and therefore are not of
concern.   

10.0  Regulatory Recommendations and Data Needs  TC \l1 "10.0 
Regulatory Recommendations and Data Needs 

HED recommends that the tolerance expression be revised as follows: 
Tolerances are established for residues of the insecticide thiamethoxam,
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only thiamethoxam
(3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-nitro-4H-1,3,5-ox
adiazin-4-imine) and its metabolite CGA-322704 [ N
-(2-chloro-thiazol-5-ylmethyl) - N '-methyl- N '-nitro-guanidine],
calculated as the stoichiometric equivalent of thiamethoxam, in or the
commodities, as shown in Table 10.

The submitted residue data for dry bulb onions are adequate.  Because a
large percentage (86%) of the residue values for onions were below the
combined LOQ of 0.022 ppm, the tolerance harmonization spreadsheet was
not used to determine an appropriate tolerance.  Instead, the maximum
residue value (0.026 ppm) from the crop field trials was used to
determine a tolerance.  The recommended tolerance in dry bulb onion is
0.03 ppm (see Table 10, below). 

 

The established tolerances for barley commodities were reassessed
following submission of additional crop field trial data (including
residue decline data).  The aggregate of residue data support the
Section 3 registration of Actara® Insecticide on barley.  They also
confirm that the established tolerances for the combined thiamethoxam
ROCs in/on barley grain at 0.30 ppm, and barley hay and straw at 0.40
ppm each are adequate.  

There are no Codex or Mexican MRLs established for residues of
thiamethoxam in/on the crops associated with this assessment.  Canada
has established an MRL of 0.02 mg/kg for residues of thiamethoxam and
CGA-322704 in all food crops, and is transitioning to specific commodity
MRLs (all at 0.02 mg/kg) on a variety of crops including various cereal
grains, peas and beans, soybeans, sweet corn, and sunflower.  

Table 10	Tolerance Summary for Thiamethoxam.  

Commodity	Proposed/Established Tolerance (ppm)	Recommended Tolerance
(ppm)	Comments; Correct Commodity Definition

Onion, bulb	0.03	0.03	Adequate dry bulb onion residue data are
available. 

Barley, grain	0.30	0.30	The established barley commodity tolerances
remain adequate following evaluation of additional data.  

Barley, hay	0.40	0.40

	Barley, straw	0.40	0.40

	

10.1  Toxicology  TC \l2 "10.1  Toxicology 

870-7800 Immunotoxicity Study

The petitioner should submit, as a condition of registration, an
immunotoxicity study.  This study is now required under the new 40 CFR
Part 158 data requirements, and was required in conjunction with the
previous risk assessment.  The study remains a data gap for
thiamethoxam.

Route to Route Extrapolation Approach

Based on the available toxicity database and the Agency's current
practices, short- and intermediate-term inhalation risks for
thiamethoxam were assessed using an oral toxicity study.  The Agency
sought expert advice and input on issues related to this route to route
extrapolation approach (i.e. the use of oral toxicity studies for
inhalation risk assessment) from its Federal Insecticide, Fungicide, and
Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The
Agency received the SAP’s final report on March 2, 2010 (  HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009" 
http://www.epa.gov/scipoly/SAP/meetings/2009  /120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, re-examine and develop new policies and procedures for
conducting inhalation risk assessments, including route to route
extrapolation of toxicity data.  If any new policies or procedures are
developed, the Agency may revisit the need for an inhalation toxicity
study for thiamethoxam
湡⽤牯愠爠ⵥ硥浡湩瑡潩⁮景琠敨椠桮污瑡潩⁮潴楸楣
祴爠獩⁫獡敳獳敭瑮മㄍ⸰′删獥摩敵䌠敨業瑳祲–䍔
尠㉬∠〱㈮†敒楳畤⁥桃浥獩牴ᕹ഍㘸⸰㈱〰䐠物捥楴
湯⁳潦⁲獕൥

 h

!

#

0

<

>

?

N

‹

©

ª

¬

¯

°

´

µ

º

¼

Å

Æ

È

Ø

hŽ

hŽ

‚

ª

Æ

é

	

+

„

Þ

	

-

)

*

+

,

-

I

J

K

L

b

c

d

~



€

‚

ƒ

„

…

†

¢

£

 £

¤

¥

¼

½

¾

Ø

Ù

Ú

Û

Ü

Ý

Þ

ß

à

ü

ý

þ

ÿ

 Þ

ô

jŸ

j"

j“

 h

 h?

 h?

 h?

 h?

h

 h

 h

 h

 h

 h

H*

{

|

¸

Ò

Ó

Ž

£

¸

»

Ó

N

hO

hO

騀䈋逘$騆

퀀ࠂ䀇

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

	@

퀀ࠂ䀇

	@

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

摧✾=

 h

 h

h

퀀ࠂ䀇

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

	@

	@

	@

퀀ࠂ䀇

퀀ࠂ䀇

	@

	@

퀀ࠂ䀇

”ÿs	8

摧䯵1

摧䯵1

摧䯵1

摧䯵1

愀Ĥ摧䯵1

摧䯵1

摧䯵1

摧䯵1

摧䯵1

愀Ĥ摧䯵1

摧䯵1

摧憛o

摧多î

hõ$

摧砻5	㜀$␸䠀$摧浿ô

摧砻5

 hu

hõ$

 hu

ô

h

h

h

hõ$

h

摧捺\

Ѐ

Ѐ

Ѐ

Ѐ

Ѐ

h

h

摧࠮æ

hÎX

 h

Ѐ

Ѐ

Ѐ

yt

Ѐ

Ѐ

Ѐ

Ѐ

Ѐ

Ѐ

h

㄀$ᨀ

摧汤z

+

@

G

O

\

a

g

p

x

…

†

‡

ˆ

‰

Š

Š

‹

Œ

˜

¡

ª

°

±

·

¸

Ý

ì

ö

ý

	

!

"

=

>

i

~

„

‹

˜

£

«

²

º

½

¾

¿

À

Á

Â

Ã

Ä

È

Ñ

Ù

â

è

é

Ff

h?

 h

摧ἑ¹

The product label for Cruiser® 70WS (EPA Registration #100-1294) should
be revised to specify that only registered crops may be replanted
immediately following harvest, or as soon as practical following the
last application.  For all other crops, a 120-day PBI should be
observed.

10.3  Occupational and Residential Exposure  TC \l2 "10.3  Occupational
and Residential Exposure 

860.1200 Directions for Use --  Use Limitation

 

HED believes that this multiple activities scenario MOE over estimates
the risk, however until data/information are available to further refine
the actual exposure/risk, HED recommends that the label limit the pounds
of formulated product used per handler to 260 lbs.  If the maximum
amount of CRUISER® 70WS Insecticide that can be used to treat bulb
onion seed in a seed treatment facility is limited to 260 lbs per day
(based on ca. 3,000 lbs seeds treated per 8 hour day) the MOE for
multiple activities worker is 110.  This requires that a worker
performing tasks associated with seed treatment limit exposure to 260
lbs. of formulated product (for Cruiser® 70WS) per day.  This
limitation should be reflected on the label.  

References:  TC \l1 "References 

D371848.  Thiamethoxam: Occupational and Residential Exposure/Risk
Assessment for Proposed Section 3 Registration for Seed Treatment Use on
Bulb Onions.  Shih-Chi Wang; 3 May 2010.

D368072.  Tier II Drinking Water Exposure Assessment to Establish a
Tolerance of Thiamethoxam on Onion Seed.  Christopher M. Koper; February
2, 2010.   

Thiamethoxam.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration as a
Seed Treatment on Onion, Dry Bulb.  Dennis McNeilly; 3 May 2010.

D367065.  Thiamethoxam.  Petition to Establish a Permanent Tolerance for
Residues of the Insecticide Resulting from Food/Feed Use as a Seed
Treatment on Bulb Onions.  Response to Data Gaps from Conditional
Registration of Various Food/Feed Crops (as Specified in HED Memo
D281702; M. Doherty; 17 April 2007).  Summary of Analytical Chemistry
and Residue Data.  William Drew; 3 May 2010.

D329466.  Thiamethoxam Human Health Risk Assessment for Proposed New
Uses or Revised Uses on Artichoke, Barley, Brassica Vegetables,
Bushberry, Caneberry, Cotton, Cranberry, Cucurbit Vegetables, Fruiting
Vegetables, Hops, Juneberry, Leafy Vegetables, Legume Vegetables,
Lingonberry, Mint, Oilseed Crops, Pecan, Pome Fruit, Potato Seed Pieces,
Root Vegetables (Except Sugarbeet), Salal, Stone Fruit, Strawberry,
Tobacco, Tuberous and Corm Vegetables, and Turf.  Michael Doherty, 22
May 2007.

D364256.  Thiamethoxam.  Acute and Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk Assessments for the Section 3
Registration of Thiamethoxam on Rice, Sugar Beets, and Tropical Fruits. 
Dennis McNeilly, June 30, 2009.

ExpoSAC Policy 14: Standard Operating Procedures (SOPs) for Seed
Treatment, May 1, 2003.

ExpoSAC Policy 15:   SEQ CHAPTER \h \r 1 Amount of Seed Treated or
Planted per Day, March 2, 2004.

HED Draft Standard Operating Procedures (SOP’s) for Residential
Exposure Assessments (12/18/97), and the Revisions to the Standard
Operating Procedures (SOP’s) for Residential Exposure Assessment
(Science Advisory Council for Exposure Policy 12, Revised February 22,
2001).

Thiamethoxam                                                            
                                       D373596/D375248

 PAGE   

Page   PAGE  3  of   NUMPAGES  51