Document ID: EPA-HQ-OPP-2006-0902-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-15T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

November 28, 2006

				

MEMORANDUM

	SUBJECT:	Clothianidin:  Human Health Risk Assessment for Proposed Uses
on Grape, Sorghum, Potato, and Cotton (and for a Proposed Section 18
Exemption for Use on Sugar Beet).  PC Code:  044309; Petition Numbers: 
3F6792, 4F6869, 5F6908, 06OR040, 06WY01, 06CO03, and 06ND01; DP Numbers:
 D331226 and D326635.

Regulatory Actions:		Section 3 (Grape, Sorghum, Potato, Cotton)

Section 18 (Sugar Beet)

		Risk Assessment Type:	Single Chemical/Aggregate

	FROM:	Kelly M. Schumacher, Biologist

		Michael A. Doherty, Ph.D., Chemist

		William T. Drew, Chemist

		Shih-Chi Wang, Ph.D., Biologist

		Registration Action Branch 2

		Health Effects Division (7509P)

THROUGH: 	Richard A. Loranger, Ph.D., Branch Senior Scientist

		Registration Action Branch 2

		Health Effects Division (7509P)

TO:	Venus Eagle, RM 01

		Insecticide/Rodenticide Branch

		Registration Division (7505P)

		and

Stacey Groce/Anthony Britten, RM 05

		Risk Integration, Minor Use & Emergency Response Branch	

Registration Division (7505P)

	

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc148850239"  1.0	Executive
Summary	  PAGEREF _Toc148850239 \h  4  

  HYPERLINK \l "_Toc148850240"  2.0	Ingredient Profile	  PAGEREF
_Toc148850240 \h  9  

  HYPERLINK \l "_Toc148850241"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc148850241 \h  11  

  HYPERLINK \l "_Toc148850242"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc148850242 \h  11  

  HYPERLINK \l "_Toc148850243"  3.2	FQPA Considerations	  PAGEREF
_Toc148850243 \h  14  

  HYPERLINK \l "_Toc148850244"  3.3	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc148850244 \h  16  

  HYPERLINK \l "_Toc148850245"  3.3.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc148850245 \h  16  

  HYPERLINK \l "_Toc148850246"  3.3.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc148850246 \h  16  

  HYPERLINK \l "_Toc148850247"  3.3.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc148850247 \h  16  

  HYPERLINK \l "_Toc148850248"  3.3.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc148850248 \h  17  

  HYPERLINK \l "_Toc148850249"  3.3.5	Dermal Absorption	  PAGEREF
_Toc148850249 \h  17  

  HYPERLINK \l "_Toc148850250"  3.3.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc148850250 \h  17  

  HYPERLINK \l "_Toc148850251"  3.3.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc148850251 \h  18  

  HYPERLINK \l "_Toc148850252"  3.3.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc148850252 \h  18  

  HYPERLINK \l "_Toc148850253"  3.3.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc148850253 \h  19  

  HYPERLINK \l "_Toc148850254"  3.3.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc148850254 \h  19  

  HYPERLINK \l "_Toc148850255"  3.3.11	Summary of Toxicological Doses
and Endpoints for Clothianidin for Use in Human Risk Assessments	 
PAGEREF _Toc148850255 \h  19  

  HYPERLINK \l "_Toc148850256"  3.4	Endocrine disruption	  PAGEREF
_Toc148850256 \h  21  

  HYPERLINK \l "_Toc148850257"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc148850257 \h  21  

  HYPERLINK \l "_Toc148850258"  4.1	Incident Reports	  PAGEREF
_Toc148850258 \h  21  

  HYPERLINK \l "_Toc148850259"  4.2	National Health and Nutritional
Examination Survey (NHANES)	  PAGEREF _Toc148850259 \h  22  

  HYPERLINK \l "_Toc148850260"  4.3	Agricultural Health Study (AHS)	 
PAGEREF _Toc148850260 \h  22  

  HYPERLINK \l "_Toc148850261"  4.4	Other Pesticide Epidemiology
Published Literature	  PAGEREF _Toc148850261 \h  22  

  HYPERLINK \l "_Toc148850262"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc148850262 \h  22  

  HYPERLINK \l "_Toc148850263"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc148850263 \h  22  

  HYPERLINK \l "_Toc148850264"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc148850264 \h  22  

  HYPERLINK \l "_Toc148850265"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc148850265 \h  22  

  HYPERLINK \l "_Toc148850266"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc148850266 \h  22  

  HYPERLINK \l "_Toc148850267"  5.1.4	Analytical Methodology	  PAGEREF
_Toc148850267 \h  23  

  HYPERLINK \l "_Toc148850268"  5.1.5	Environmental Degradation	 
PAGEREF _Toc148850268 \h  23  

  HYPERLINK \l "_Toc148850269"  5.1.6	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc148850269 \h  24  

  HYPERLINK \l "_Toc148850270"  5.1.7	Drinking Water Residue Profile	 
PAGEREF _Toc148850270 \h  24  

  HYPERLINK \l "_Toc148850271"  5.1.8	Food Residue Profile	  PAGEREF
_Toc148850271 \h  25  

  HYPERLINK \l "_Toc148850272"  5.1.9	International Residue Limits	 
PAGEREF _Toc148850272 \h  26  

  HYPERLINK \l "_Toc148850273"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc148850273 \h  26  

  HYPERLINK \l "_Toc148850274"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc148850274 \h  27  

  HYPERLINK \l "_Toc148850275"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc148850275 \h  27  

  HYPERLINK \l "_Toc148850276"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc148850276 \h  28  

  HYPERLINK \l "_Toc148850277"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc148850277 \h  28  

  HYPERLINK \l "_Toc148850278"  6.1	Residential Handler Exposure	 
PAGEREF _Toc148850278 \h  28  

  HYPERLINK \l "_Toc148850279"  6.2.	Residential Post-application
Exposure	  PAGEREF _Toc148850279 \h  28  

  HYPERLINK \l "_Toc148850280"  6.3	Other (Spray Drift, etc.)	  PAGEREF
_Toc148850280 \h  29  

  HYPERLINK \l "_Toc148850281"  6.4	Exposure from Use of Tobacco	 
PAGEREF _Toc148850281 \h  30  

  HYPERLINK \l "_Toc148850282"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc148850282 \h  30  

  HYPERLINK \l "_Toc148850283"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc148850283 \h  30  

  HYPERLINK \l "_Toc148850284"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc148850284 \h  30  

  HYPERLINK \l "_Toc148850285"  7.3	Long-Term Aggregate Risk	  PAGEREF
_Toc148850285 \h  31  

  HYPERLINK \l "_Toc148850286"  7.4	Cancer Risk	  PAGEREF _Toc148850286
\h  31  

  HYPERLINK \l "_Toc148850287"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc148850287 \h  31  

  HYPERLINK \l "_Toc148850288"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc148850288 \h  32  

  HYPERLINK \l "_Toc148850289"  9.1	Short-/Intermediate-Term Handler
Risk	  PAGEREF _Toc148850289 \h  33  

  HYPERLINK \l "_Toc148850290"  9.1.1	Handler Risk from Crop Protection
Uses	  PAGEREF _Toc148850290 \h  33  

  HYPERLINK \l "_Toc148850291"  9.1.2	Handler Risk from Seed Treatment
Uses	  PAGEREF _Toc148850291 \h  34  

  HYPERLINK \l "_Toc148850292"  9.2	Short-/Intermediate-Term
Post-application Risk	  PAGEREF _Toc148850292 \h  37  

  HYPERLINK \l "_Toc148850293"  9.2.1	Post-application Risk from Crop
Protection Uses	  PAGEREF _Toc148850293 \h  37  

  HYPERLINK \l "_Toc148850294"  9.2.2	Post-application Risk from Seed
Treatment Uses	  PAGEREF _Toc148850294 \h  37  

  HYPERLINK \l "_Toc148850295"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc148850295 \h  40  

  HYPERLINK \l "_Toc148850296"  10.1	Toxicology	  PAGEREF _Toc148850296
\h  40  

  HYPERLINK \l "_Toc148850297"  10.2	Residue Chemistry	  PAGEREF
_Toc148850297 \h  40  

  HYPERLINK \l "_Toc148850298"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc148850298 \h  40  

  HYPERLINK \l "_Toc148850299"  References:	  PAGEREF _Toc148850299 \h 
41  

  HYPERLINK \l "_Toc148850300"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc148850300 \h  42  

  HYPERLINK \l "_Toc148850301"  A.2	Toxicity Profiles	  PAGEREF
_Toc148850301 \h  43  

 1.0	Executive Summary  TC \l1 "1.0	Ex

ecutive Summary 

Background

Clothianidin
[(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine] is a
systemic insecticide that belongs to the nitroguanidine sub-class of
neonicotinoid compounds, which have agonistic activity on nicotinergic
acetylcholine receptors (nAChR).  It enters through the roots and
cotyledons of newly germinating seedlings and protects below- and
above-ground plant parts from insect damage.  Clothianidin is currently
registered for use on corn, canola, pome fruit, tobacco, turf, and
ornamental plants.    SEQ CHAPTER \h \r 1 Tolerances are established for
residues of clothianidin in/on canola seed and corn commodities (0.01 to
0.10 ppm), in milk (0.01 ppm), and in/on pome fruit (1.0 ppm).    SEQ
CHAPTER \h \r 1  

Belay™ 16 WSG, a 16.0% active ingredient (a.i.) water-soluble granule,
at rates up to 0.20 lb a.i./A for soil applications to potatoes;
Clutch™ 50 WDG, a 50% a.i. water-dispersible granule, at up to 0.14 lb
a.i./A for foliar applications to potatoes; and Clutch™ 50 WDG at up
to 0.2 lb a.i./A for foliar applications to grapes.  Bayer CropScience
has requested the establishment of permanent tolerances in/on sorghum
grain, forage, and stover, as well as cottonseed and gin byproducts. 
The petitioner has proposed to use Poncho™ 600, a 48% a.i. flowable
concentrate, applied to sorghum as a seed treatment, at rates up to 0.25
lb a.i./100 lb seeds.  AE1283742™, a 14% a.i. flowable concentrate,
would be applied as a seed treatment to cotton at up to 0.15 lb a.i./100
lb seeds.  Finally, the states of Oregon, Wyoming, Colorado, and North
Dakota have requested a Section 18 emergency exemption for use of
Poncho™ 600 on sugar beet seeds at rates up to 6 lb a.i./100 lbs seed.

 

Hazard Characterization

Clothianidin does not appear to exhibit toxicity towards a consistent
specific target organ.  Decreases in body weight and body weight gain
were observed in rats, dogs, and mice.  In single dose studies, mice
(acute toxicity category II) appear more sensitive than rats (category
IV).  Clinical signs of neurotoxicity were exhibited in both mice
(decreased motor activity, tremors, and deep respirations at 50 mg/kg)
and rats (transient signs of decreased arousal, motor activity, and
locomotor activity at 100 mg/kg) in acute neurotoxicity studies
following exposure by gavage; however, no indications of neurotoxicity
were observed following dietary exposure in the subchronic neurotoxicity
study in rats.  In a developmental neurotoxicity study in rats,
decreased body weights, body weight gains, motor activity, and acoustic
startle response amplitude (females) were seen in offspring at doses
lower than those resulting in maternal toxicity.  Although the No
Observed Adverse Effect Levels (NOAELs) were similar for the subchronic
and chronic feeding studies in the rat, a greater spectrum of effects
was observed in the chronic study (decreased body weight, body weight
gain and food consumption plus additional observations in the liver,
ovary and kidney) versus the subchronic study (effects only on body
weight and food consumption).  In the rat, administration via the oral
route appears to be more toxic than via the dermal route.  In longer
term studies, dogs exhibited clinical signs of anemia.  The only
observed effects in mice following chronic dietary administration were
increases in vocalization and decreases in body weight and body weight
gain.  The Hazard Identification Assessment Review Committee (HIARC)
classified clothianidin as not likely to be carcinogenic to humans.  

There was no evidence of increased quantitative or qualitative
susceptibility of rat or rabbit offspring in developmental studies;
however, increased quantitative susceptibility of rat pups was seen in
both the reproduction and developmental neurotoxicity studies.    SEQ
CHAPTER \h \r 1 The degree of concern for both of these studies is low
because the observed effects are well characterized and there are clear
NOAELs and Lowest Observed Adverse Effect Level (LOAELs).  The NOAEL for
the effects of concern identified in the reproduction study (decreased
mean body weight gain and absolute thymus weights in pups, delayed
sexual maturation, and an increase in still births) is the basis for the
endpoint selected for the chronic dietary and short-, intermediate- and
long-term non-dietary risk assessments.

Dose Response Assessment and Food Quality Protection Act (FQPA) Decision

On November 14, 2002, the Health Effects Division (HED) Hazard
Identification Assessment Review Committee (HIARC) recommended that
testing be conducted to assess immune system function in adults and in
young animals following exposure during the period of organogenesis. 
This decision was based on evidence of decreased absolute and adjusted
organ weights of the thymus and spleen in multiple studies in the
clothianidin data base and on evidence of increased quantitative
susceptibility of juvenile rats, compared to adults, in the
two-generation reproduction study to these effects.  HIARC evaluated the
need for a database uncertainty factor (UFDB) for clothianidin in the
absence of the developmental immunotoxicity study, and they determined
that there is insufficient data to justify selection of an additional
safety factor for the protection of infants and children lower than the
default value of 10X for both single and repeated dose exposure
scenarios.  Therefore, they determined that a UFDB of 10X should be
applied to both single and repeated dose exposure scenarios (i.e., acute
and chronic RfDs, short- and intermediate-term incidental oral
exposures, and short-, intermediate-, and long-term dermal and
inhalation exposures resulting from residential uses of clothianidin) to
account for the lack of the developmental immunotoxicity study with
clothianidin.

A guideline immunotoxicity study conducted in adult rats has now been
reviewed by HED and shows no clothianidin-mediated immunotoxicity, in
the form of a T-cell dependent anti-SRBC-forming cell response, in
adults at doses lower than those resulting in generalized signs of
toxicity (e.g., decreases in body weight).  While the antibody response
was intact in adult rats in the presence of decreased lymphoid organ
weights in this study, it cannot be concluded that similar effects will
occur in offspring.  A developmental immunotoxicity (DIT) study is
required to evaluate the immune response of the offspring.  Because
results from the DIT could result in a more protective (i.e., lower)
regulatory endpoint, the 10X UFDB is applied to account for the lack of
this study.

Residue Chemistry

The nature of the residue has been adequately delineated in plants,
based on the acceptable corn, sugar beet, apple, and tomato metabolism
studies.  HED has determined that the parent compound is the only
residue of concern (ROC) in primary crops for both tolerance setting and
risk assessment purposes.  The nature of the residue in livestock is
also understood based on acceptable goat and hen metabolism studies. 
For ruminants, HED concluded that the ROCs for risk assessment include
parent and the metabolites TZU, TZG, TZNG, and ATMG-Pyruvate; for
poultry, HED concluded that the ROCs for risk assessment include parent
and the metabolites TZU, TZG, TZNG, and ATG-Acetate.  However, only
parent needs to be included in the tolerance expression.  

In general, adequate field trials, storage stability data, analytical
methods, and processing studies are available to support the proposed
new uses.  In addition, adequate enforcement methods are available. 
Although processing studies are not currently available for sugar beets,
for the purposes of the Section 18 emergency exemption, it is assumed
that clothianidin residues do not concentrate in sugar beet commodities
and that the tolerance set for sugar beet roots is protective for
residues found in the processed commodities.  However, processing
studies on sugar beets will be required to grant permanent registration
for use of clothianidin as a sugar beet seed treatment.

Dietary Exposure Assessment

el (DEEM-FCID™, Version 2.03).  Because clothianidin is a major
metabolite of the active ingredient thiamethoxam, residues of
clothianidin resulting from uses of thiamethoxam were accounted for in
these assessments.  The acute assessment is based on maximum residues of
clothianidin observed in clothianidin and thiamethoxam field trials and
assumes 100% crop treated (%CT).  The chronic assessment is based on
average residues from clothianidin and thiamethoxam field trials and
also assumes 100% crop treated.  This method of accounting for
thiamethoxam’s involvement in clothianidin exposure likely
overestimates that particular contribution to total exposure, as it
results in a potential “double counting” of clothianidin coming from
thiamethoxam for crops that have registered uses of both compounds.  The
empirical processing factor for apple juice was used for apple and pear
juice, and empirical factors were used for grape juice and raisins;
otherwise, DEEM default processing factors were used.  The analyses
include direct incorporation of estimated clothianidin residues in
drinking water.  For water, the highest acute estimate from conservative
models was used for both the acute and the chronic dietary exposure
analyses.

Based on these highly conservative assumptions, acute dietary risk
estimates at the 95th percentile of exposure are less than or equal to
45% of the acute population-adjusted dose (aPAD) for all population
subgroups.  Chronic dietary risk estimates are less than or equal to 16%
of the chronic population-adjusted dose (cPAD) for all population
subgroups.  Generally, HED is concerned when risk estimates exceed 100%
of the PAD; therefore, all acute and chronic dietary risk estimates are
below HED’s level of concern.

 TC \l2 "5.2  Dietary Exposure and Risk 

Residential Risk

No residential exposure to clothianidin is expected from the proposed
new uses addressed in this assessment.  Residential exposures to
clothianidin are expected solely from currently registered uses on
turfgrass.  A margin of exposure (MOE) of 1000 or more is sufficient to
protect adults and children from residential exposures to clothianidin. 
The residential risks associated with post-application exposure to
clothianidin residues on turfgrasses do not exceed HED’s level of
concern for the general U.S. population or any population subgroup.

Aggregate Risk

The acute aggregate assessment for clothianidin exposure includes only
food and water exposures.  Short- and intermediate-term aggregate
assessments were conducted based on food, water, and residential
exposures.  The long-term aggregate risk assessment includes only food
and water since no long-term exposure scenarios are expected from
residential uses of clothianidin.  Because clothianidin has been
classified as a “not likely human carcinogen”, a cancer aggregate
risk assessment is not required.  Estimates of acute, short-term,
intermediate-term, and long-term aggregate risks associated with the
registered and proposed uses of clothianidin do not exceed HED’s level
of concern for the general U.S. population or any population subgroup.

Occupational Risk

Occupational exposure assessments were conducted for both handler and
post-application exposures for both the proposed crop protection and
seed treatment uses.  Based on the frequency/interval of applications on
the crops and the seasonal nature of seed treatment operation, EPA
assumes that both application handlers and post-application workers
would be exposed for less than 6 months per year (short- and
intermediate-term exposures).  Therefore, long-term exposure assessments
are not required.

A margin of exposure (MOE) of 100 or more is sufficient to protect
workers from all of the handler and post-application occupational
exposures to clothianidin.  None of the risk estimates for any of the
occupational scenarios examined in this assessment exceed HED’s level
of concern.  Risk estimates for handlers performing crop protection uses
are below the level of concern at the baseline level (MOEs = 6,900 to
210,000).  Risk estimates calculated for the seed treatment handlers are
below the level of concern at the single-layer level (MOEs = 190 to
11,000).  Estimated risks calculated for post-application activities on
the day of application are below the level of concern (MOEs = 4,100 to
270,000).  All post-application risk estimates for seed planters are
below the level of concern at the single-layer level (MOEs = 3,300 to
58,000).

Environmental Justice Considerations

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
Surveys of Food Intake 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, nondietary 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 post-application
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.

Review of Human Research

This risk assessment does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

Recommendations

Based on the results of our assessment, HED recommends the establishment
of the following permanent tolerances for residues of clothianidin,
pending resolution of the deficiencies noted in Section 10 of this
document:

	Sorghum, grain, grain	0.01 ppm

	Sorghum, grain, forage	0.01 ppm

	Sorghum, grain, stover	0.01 ppm

	Cotton, undelinted seed	0.01 ppm

	Cotton, gin byproducts	0.01 ppm

	Grape	0.60 ppm

	Potato	0.05 ppm

	Potato, granules/flakes	0.08 ppm

	

  SEQ CHAPTER \h \r 1 A separate tolerance for raisins is not required. 
The registrant should submit a revised Section F to reflect these
changes.  

Furthermore, HED recommends approval of the emergency exemption request
for use of clothianidin on sugar beet seed in Oregon, Wyoming, Colorado,
and North Dakota and establishment of time-limited tolerances for
residues of clothianidin as follows:

Beet, sugar, roots	0.02 ppm

Beet, sugar, tops	0.02 ppm

Additional Data Needs

See Section 10.

2.0	Ingredient Profile

Clothianidin is a systemic insecticide that belongs to the
nitroguanidine sub-class of neonicotinoid compounds, which has agonistic
activity on nicotinergic acetylcholine receptors (nAChR).  It is a
metabolite of another neonicotinoid, thiamethoxam.  Clothianidin enters
through the roots and cotyledons of newly germinating seedlings and
protects below- and above-ground plant parts from insect damage.  

The chemical structure and nomenclature of clothianidin are presented in
Table 2.1, and the physicochemical properties of the technical grade of
clothianidin are presented in Table 2.2.  The end-use products
containing clothianidin as the active ingredient (a.i.) for the proposed
new uses include:  (1) Clutch™ 50 WDG insecticide (50.0% a.i.,
water-dispersible granule), (2) Belay™ 16 WSG insecticide (16.0% a.i.,
water-soluble granule), (3) Poncho™ 600 seed treatment insecticide
(48.0% a.i., liquid), and (4) AE1283742™ seed treatment insecticide
(14.1% a.i., liquid).  The proposed directions for the new uses of
clothianidin are summarized in Table 2.3.

Table 2.1.  Clothianidin Nomenclature.

Chemical Structure	

Empirical Formula	C6H8ClN5O2S

Common name	Clothianidin

Company experimental name	TM-444, TI-435, V-10066

IUPAC name
(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine

CAS name	[C(E)]-N-[(2-chloro-5-thiazolyl)
methyl]-N’-methyl-N”-nitroguanidine

CAS Registry Number	210880-92-5 (formerly 205510-53-8)

End-use product/EP	Clutch( 50 WDG, EPA Registration #66330-40

Belay( 16 WSG, EPA Registration #66330-52

Poncho( 600, EPA Registration #264-789

AE1283742, EPA Registration #264-XXX (not yet registered)

Chemical Class	Neonicotinoid (chloronicotinyl)

Known Impurities of Concern	None

Table 2. 2.  Physicochemical Properties of Clothianidin.

Parameter	Value	Reference

Molecular weight	249.7	MRID 45422301

Melting point/range ((C)	176.8

	pH at 23(C	6.24 (1% solution/suspension)

	Density (g/cm3) at 20(C	1.61 (PAI), 1.59 (TGAI)

	Water solubility (g/L) at 20°C	0.327

	Solvent solubility (g/L) at 25(C	n-Heptane 	<0.00104

Xylene	0.0128

1-Octanol	0.938

Dichloromethane	1.32

Ethyl Acetate	2.03

Methanol	6.26

Acetone	15.2

	Vapor pressure (Pa) at 25(C	1.3 x 10-10

	Dissociation constant (pKa) at 20(C	11.09

	Octanol/water partition coefficient (log KOW) at 25(C	0.7

	UV/visible absorption spectrum, maximum (nm)	265.5 (acidic, neutral
solutions)

246.0 (basic solution)

	 

Table 2.3.  Summary of Proposed Directions for New Uses of Clothianidin.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate	PHI (days)	Use Directions and Limitations

Grapes1,2

Drip-irrigation to soil; during fruit development; using chemigation.
16% WSG

[66330-52]	0.2 lb a.i./A	2	0.20 lb a.i./A	30	Do not apply 50% WDG
following soil application of 16% WSG.  A 14-day RTI is specified for
the foliar applications.  A minimum application volume is not specified.
 Regardless of formulation or application type, do not apply more than
0.20 lb a.i./A per season of clothianidin per crop.

Foliar broadcast; during fruit development; ground or aerial equipment.
50% WDG

[66330-40]	0.094 lb a.i./A	2	0.19 lb a.i./A	0

	Potatoes1,2

In-furrow to soil (at planting) or side-dress to soil (during hilling);
ground equipment.	16% WSG

[66330-52]	0.2 lb a.i./A	1	0.20 lb a.i./A	N/A	Do not apply 50% WDG
following soil application of 16% WSG. A 7-day RTI is specified for the
foliar applications.  A minimum application volume is not specified. 
Regardless of formulation or application type, do not apply more than
0.20 lb a.i./A/season of clothianidin per crop.

Foliar broadcast; during tuber development; ground or aerial equipment.
50% WDG

[66330-40]	0.047 lb a.i./A	3	0.14 lb a.i./A	14

	Sorghum1

Seed treatment; prior to planting; commercial seed-treatment equipment.
48% FC

[264-789]	0.25

lb a.i./100 lb seeds	1	0.25

lb a.i./100 lb seeds	N/A	For use by commercial seed treaters only.  Not
for use in farm applicators used at planting.  Treated seed must be
conspicuously colored.

Cotton1

Seed treatment; prior to planting; commercial seed-treatment equipment.
14% FC

[264-XXX]	0.15

lb a.i./100 lb seeds	1	0.15

lb a.i./100 lb seeds	N/A	For use by commercial seed treaters only.  Not
for use in farm applicators used at planting.  Treated seed must be
conspicuously colored.

Sugar Beet (Oregon, Wyoming, Colorado, and North Dakota)3

Seed treatment; prior to planting; commercial liquid or slurry treaters.
48% FC

[264-789]	6 lb a.i./100 lb seeds

[60 g a.i./1 kg seeds]	1	6 lb a.i./100 lb seeds

[60 g a.i./1 kg seeds]	N/A	For use by commercial seed treaters only. 
Not for use in farm applicators used at planting.  Treated seed must be
conspicuously colored.

1 Section 3 action

2 Both labels specify a 12-hour restricted entry interval (REI).  PBIs
for rotated crops are not specified.  

3 Section 18 action

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

3.1	Hazard and Dose-Response Characterization

The toxicology database for clothianidin is complete, with the exception
of a developmental immunotoxicity study.  The scientific quality is
relatively high, and the toxicity profile of clothianidin can be
characterized for most potential developmental, reproductive,
neurotoxic, carcinogenic, and mutagenic effects.  Clothianidin induces
some effects that are similar to other neonicotinoid insecticides,
particularly effects on the liver, hematopoietic system, and kidneys. 

With the exception of the TMG metabolite, most of the metabolites and
intermediates appear to be of similar toxicity to the parent technical
material in acute oral studies.  The TMG metabolite appears to be more
toxic.  In addition, the clothianidin-triazan intermediate tested as a
dermal sensitizer under the conditions of the study, whereas the parent
was not a dermal sensitizer.  

Acute neurotoxicity studies were conducted in both rats and mice
following exposure to clothianidin by gavage.  Comparing these two
studies, mice appear to be more sensitive than rats to the acute
neurotoxic effects of clothianidin when the compound is administered via
oral gavage.  In the acute neurotoxicity rat study, FOB effects,
including decreased arousal and decreased motor and locomotor activity,
were seen at the LOAEL on Day 0 in males.  Effects at dose levels above
the LOAEL in the rat study included tremors, slightly uncoordinated
gait, effects on pupil response and righting reflex, decreases in body
temperature, and ataxia.  In the acute neurotoxicity study in mice,
effects were also observed on Day 0 in males (no female mice were
tested), but they occurred at lower dose levels than those that produced
neurotoxic effects in rats.  Effects seen at the LOAEL in this mouse
study included transient signs of decreased spontaneous motor activity,
tremors, and deep respirations.  At higher dose levels, decreases in
reactivity, grooming, and muscle tone; prone position; staggering gait;
mydriasis; and hypothermia were observed in mice. 

In rats only, a subchronic neurotoxicity study was conducted following
dietary exposure to clothianidin.  In contrast to the acute
neurotoxicity study described previously, in which neurotoxic effects
were observed after gavage exposure, no indications of neurotoxicity
were noted in the subchronic study following dietary exposure.  Slightly
decreased food consumption, body weights, and body weight gains were the
only observed effects in the subchronic neurotoxicity study. 

 

In subchronic oral studies in rats and dogs, decreases in body weight
and body weight gain were observed in both species.  In addition, dogs
also displayed decreased white blood cells, albumin, and total protein,
as well as some anemia, and they appear to be more sensitive than rats
to the effects of clothianidin following subchronic oral exposure. 
Following subchronic exposures, male dogs are more sensitive than
females.  No effects were observed up to the limit dose in the 28-day
dermal study in rats. 

Chronic feeding studies were conducted in the dog, rat, and mouse. 
Anemia was observed in the dog.  In the rat, decreased body weight and
food consumption, ovary interstitial gland hyperplasia, increased
lymphohistiocytic infiltrate, and altered hepatocellular eosinophilic
foci of the liver were observed in females; decreased body weight and
food consumption, slightly increased incidences of pelvic
mineralization, and transitional cell hyperplasia in the kidney, mottled
livers, and altered hepatocellular eosinophilic foci in the liver were
observed in male rats.  In the mouse, decreases in body weight and body
weight gain in females and increases in vocalization in both sexes were
the only observed effects. 

A comparison of the subchronic and chronic feeding studies in the rats
shows that a wider spectrum of effects was observed in the chronic
study, even though the NOAELs and LOAELs in these two studies were
similar.  Thus, it appears that there may be more toxicity in rats when
exposure is over a longer period of time.  In contrast, administration
of clothianidin to the dog for a longer period of time does not appear
to result in any additional effects or effects at lower dose levels.

In the developmental neurotoxicity study, toxicity in the offspring was
observed at a lower dose level than the dose that caused toxicity in the
maternal animals.  Maternal effects included decreased body weights,
body weight gains, and food consumption.  Effects seen in the offspring
included decreased body weights, body weight gains, motor activity, and
acoustic startle response in the females.  

No quantitative or qualitative susceptibility was observed in either of
the developmental rat or rabbit studies.  In the rat, no developmental
toxicity was observed at the highest dose tested, although this dose
level induced decreases in body weight gain and food consumption in the
dams.  In the rabbit, premature deliveries, decreased gravid uterine
weights, an increase in litter incidence of a missing lobe of the lung,
and a decrease in the litter average for ossified sternal centra per
fetus were noted at a dose level in which maternal death, a decrease in
food consumption, and clinical signs (scant feces and orange urine) were
observed.  Since the developmental effects observed in the rabbit study
were seen in the presence of maternal toxicity, they are not considered
to be qualitatively more severe than the maternal effects.

Quantitative susceptibility was observed in the two-generation
reproduction study since the offspring NOAEL is lower than the parental
NOAEL.  The LOAEL for offspring toxicity is based on decreased body
weight gains, delayed sexual maturation (males), decreased absolute
thymus weights in F1 pups of both sexes, and an increase in stillbirths
in both generations.  The parental systemic LOAEL is based on decreased
absolute body weights and body weight gains with decreased absolute and
relative thymus weights in both sexes. 

 

In the rat chronic feeding/carcinogenicity study, an apparent increase
in thyroid c-cell tumors was observed in females.  In addition, an
increased incidence of hepatocellular carcinomas in males was examined
more closely.  A statistical analysis revealed that the increase in
thyroid c-cell tumors did not appear to be significant, especially when
carcinomas and adenomas are combined.  The increased incidence of
hepatocellular carcinomas at the low and high doses were just outside
historical control incidences for the same testing laboratory (only 2
studies) but were within the historical control range for the animal
supplier.  In addition, there was no dose-response.  Finally, there was
no continuum (i.e., no preneoplastic lesions and no adenomas).  There
was no evidence of an increase in tumors in mice.  Therefore,
clothianidin is classified as not likely to be carcinogenic to humans. 
Clothianidin is a major animal and plant metabolite of thiamethoxam. 
Thiamethoxam is not carcinogenic to male and female rats; however,
dietary administration of thiamethoxam is associated with increased
incidence of liver tumors in both sexes of mice.  The fact that
thiamethoxam induces liver tumors in mice and no tumors in rats supports
the argument that clothianidin is not likely to be carcinogenic to
humans because the apparent increases in tumors with clothianidin were
in a different species (rats) and because the tumor of higher potential
concern (thyroid) was not in the same target organ.

In the mutagenicity studies, none of the intermediates or metabolites
appeared to have genotoxic potential under the conditions of the
studies, but the studies for the technical material gave mixed results. 
Some of the batches of test material tested positively, and some tested
negatively.  The HIARC has requested that the composition of the test
materials used in the mutagenicity studies be investigated to determine
whether or not the differences in composition may have affected the
results from the studies.  Additional data on the composition of the
materials has been submitted and is currently under review.

In some of the toxicological studies, there was evidence of possible
effects on the immune system.  Decreased absolute and adjusted thymus
and spleen weights were observed in multiple studies.  In addition,
juvenile rats in the two-generation reproduction study appeared to be
more susceptible to these effects.  The thymus is involved in the
production of T cells, whose function is to recognize and respond to
foreign antigens.  The spleen serves an important function in clearing
the blood of infectious organisms.  Therefore, the HIARC recommends a
developmental immunotoxicity study.

In rats, clothianidin is readily absorbed and excreted within 96 hours
following a single low dose or repeated low doses, but at a high dose,
absorption became biphasic and was saturated.  The studies suggest that
a multiple exposure regimen did not affect the absorption/excretion
processes.  There was rapid absorption and distribution of administered
radioactivity to all organs and tissues followed by rapid excretion with
reduction to background levels in most tissues and organs within 24
hours.  There was a somewhat greater rate of absorption and elimination
in females.  Excretory patterns did not exhibit gender-related
variability but reflected the delayed absorption in the high-dose group.
 The metabolites identified (primarily oxidative demethylation products
and cleavage products of the nitrogen-carbon bond between the nitroimino
and thiazolyl moieties) were consistent with Phase I processes.

 

In mice, clothianidin is readily absorbed and excreted within 168 hours
following a single low dose.  Urine was the major route of excretion. 
Neither clothianidin nor its metabolites appeared to exhibit potential
for bioaccumulation.  Excretory patterns did not exhibit gender-related
variability.  The major metabolites in both urine and feces were the
parent compound (clothianidin) and TZNG
[N-(2-chlorothiazol-5-ylmethyl)-N’-nitroguanidine], which resulted
from N-demethylation of clothianidin.

A dermal absorption study with monkeys is available.  In this study,
dermal absorption was calculated at 0.24% (± 0.11%).  This value was
determined by adding the radioactivity recovered from urinary excretion,
fecal excretion, and from Cage/Pan/Chair Wash, Debris.  Adjustment of
the direct absorption determination was not necessary because recovery
from the dermal dose was >90%.  A value of 1% dermal absorption has been
recommended as appropriate for use in risk assessment.  This estimation
takes into account any variability that would have likely occurred with
testing several dose levels.  The mouse single dose and rat single and
multiple dose metabolism studies indicate that oral absorption is in the
range of 90% or greater.  Therefore, any extrapolation from the oral to
the dermal route using the dermal absorption factor is not likely to
grossly underestimate anticipated adverse effects.  TC \l2 "3.1	Hazard
and Dose-Response Characterization 

3.2	FQPA Considerations

For a complete history of the FQPA considerations associated with
clothianidin, refer to “Human Health Risk Assessment for Clothianidin.
 Proposal for Tolerance of Residues in/on Pome Fruit and the Use on
Tobacco, Turf, and Ornamental Plants” (D304499, W. Cutchin, 1/6/2005).

On November 14, 2002, the Health Effects Division (HED) Hazard
Identification Assessment Review Committee (HIARC) evaluated the
potential for increased susceptibility of infants and children from
exposure to clothianidin as required by the Food Quality Protection Act
(FQPA) of 1996.  While no quantitative or qualitative susceptibility was
observed in either of the developmental rat or rabbit studies, as
discussed in section 3.1, quantitative susceptibility was observed in
both the developmental neurotoxicity and reproduction rat studies.  In
the developmental neurotoxicity study, offspring toxicity (decreased
body weight gains, motor activity, and acoustic startle response) was
seen at a lower dose than the dose that caused maternal toxicity. 
However, HIARC determined that the degree of concern for the
developmental neurotoxicity study is low and there are no residual
uncertainties for pre- and/or postnatal toxicity because the observed
effects are well characterized and there are clear NOAELs/LOAELs. 

In the two-generation reproduction study, offspring toxicity (decreased
body weight gains, delayed sexual maturation in males, decreased
absolute thymus weights in F1 pups of both sexes, and an increase in
stillbirths in both generations) was seen at a lower dose than the dose
that caused parental toxicity.  Based on evidence of decreased absolute
and adjusted organ weights of the thymus and spleen in multiple studies
in the clothianidin data base and on evidence of increased quantitative
susceptibility of juvenile rats, compared to adults, in the
two-generation reproduction study to these effects, the HIARC
recommended that testing be conducted to assess immune system function
in adults and in young animals following exposure during the period of
organogenesis.  Additionally, HIARC determined that there is
insufficient data to justify selection of an additional safety factor
for the protection of infants and children lower than the default value
of 10X and that a UFDB of 10X should be applied to both single and
repeated dose exposure scenarios (i.e., acute and chronic RfDs, short-
and intermediate-term incidental oral exposures, and short-,
intermediate-, and long-term dermal and inhalation exposures resulting
from residential uses of clothianidin) to account for the lack of the
developmental immunotoxicity study (DIT) with clothianidin.  There are
no residual uncertainties for pre- and/or postnatal toxicity for the
two-generation reproduction study because the endpoint of concern is the
one that is being used for short, intermediate, and long term dietary
and non-dietary exposure risk assessments and because an additional
safety factor is applied for the lack of a DIT.  

A guideline immunotoxicity study conducted in adult rats has now been
reviewed by HED and shows no clothianidin-mediated immunotoxicity, in
the form of a T-cell dependent anti-SRBC-forming cell response, in
adults at doses lower than those resulting in generalized signs of
toxicity (e.g., decreases in body weight).  While the antibody response
was intact in adult rats in the presence of decreased lymphoid organ
weights in this study, it cannot be concluded that similar effects will
occur in offspring.  A developmental immunotoxicity (DIT) study is
required to evaluate the immune response of the offspring.  Because
results from the DIT could result in a more protective (i.e., lower)
regulatory endpoint, the 10X UFDB is applied to account for the lack of
this study (D318520, K. Schumacher, Draft).

In addition to the hazard data, the clothianidin risk assessment team
evaluated the quality of the exposure data and found no residual
uncertainties.  The acute dietary exposure assessment is based on
maximum residues of clothianidin observed in clothianidin and
thiamethoxam field trials and assumes 100% crop treated (%CT).  The
chronic assessment is based on average residues from clothianidin and
thiamethoxam field trials and also assumes 100% crop treated.  For
water, the highest acute estimate from conservative models was used for
both the acute and the chronic dietary exposure analyses.  By using
these conservative assessments, acute and chronic exposures/risks will
not be underestimated.  The residential exposure assessment utilizes
residential SOPs to assess post-application exposure to children as well
as incidental oral ingestion by toddlers.  The residential SOPs are
based on reasonable worst-case assumptions and will not likely
underestimate exposure/risk.  These assessments are unlikely to
underestimate the potential exposure to infants and children resulting
from the use of clothianidin.  Based on these data, the clothianidin
risk assessment team concluded that no additional safety factor is
needed to account for exposure considerations.

3.3	Hazard Identification and Toxicity Endpoint Selection

For a complete discussion of the endpoints, refer to “Human Health
Risk Assessment for Clothianidin.  Proposal for Tolerance of Residues
in/on Pome Fruit and the Use on Tobacco, Turf, and Ornamental Plants”
(D304499, W. Cutchin, 1/6/2005).

3.3.1	Acute Reference Dose (aRfD) - Females age 13-49

Study Selected:  Developmental toxicity study in rabbits

MRID Number:  45422713

Dose and Endpoint for Establishing aRfD:  25 mg/kg/day (NOAEL), based on
an increased litter incidence of a missing lobe of the lung observed at
75 mg/kg/day (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

The acute dietary endpoint for females in the 13 to 49 year age group is
based on an increased litter incidence of a missing lobe of the lung. 
This developmental effect is presumed to occur following a single oral
dose and is considered an appropriate endpoint for this population
subgroup.  Other effects observed at 75 mg/kg/day were premature
deliveries, decreased gravid uterine weights and decreased litter
average for ossified sternal centra per fetus; however, these are not
considered to be single dose effects.

3.3.2	Acute Reference Dose (aRfD) - General Population

Study Selected:  Special neurotoxicity/pharmacology study in mice and
rats

MRID Number:  45422823

Dose and Endpoint for Establishing aRfD:  25 mg/kg (NOAEL), based on
transient signs of decreased spontaneous motor activity, tremors, and
deep respirations observed at 50 mg/kg (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

The acute dietary endpoint for the general population is based on
transient signs of decreased spontaneous motor activity, tremors and
deep respirations in the mouse following a single oral dose.  This
endpoint is considered appropriate for the general population because
the effects were observed following a single dose and the route of
administration (oral) is appropriate for dietary considerations.  TC \l3
"3.5.2	Acute Reference Dose (aRfD) - General Population 

3.3.3	Chronic Reference Dose (cRfD) 

Study Selected:  Two-generation reproduction study in the rat

MRID Number:  45422714 through -16 

Dose and Endpoint for Establishing cRfD:  9.8 mg/kg (NOAEL), based on
decreased body weight gains and delayed sexual maturation, decreased
absolute thymus weights in F1 pups, and an increase in stillbirths in
both generations observed at 31.2 mg/kg (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

The chronic dietary endpoint is based on offspring effects in the
two-generation reproduction study:  decreased body weight gains and
delayed sexual maturation, decreased absolute thymus weights in F1 pups,
and an increase in stillbirths in both generations.  This endpoint is
considered

appropriate for chronic dietary exposure because the route of
administration (oral) is

appropriate for dietary considerations. The study and endpoint were
selected because they are

protective of effects observed in all the other available studies.

3.3.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected:  Two-generation reproduction study in the rat 

MRID Number:  45422714 through -16 

Dose and Endpoint for Risk Assessment:  9.8 mg/kg (NOAEL), based on
decreased body weight gains and delayed sexual maturation, decreased
absolute thymus weights in F1 pups and an increase in stillbirths in
both generations observed at 31.2 mg/kg (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

This endpoint is based on an oral study, which is the route of interest
for an incidental oral risk estimate. The study and endpoint were
selected because they are protective of effects observed in all the
other available studies. The endpoint is appropriate for all durations,
as the effect may be a result of either short- and/or longer-term
exposure.  In addition, it is appropriate for incidental oral exposure
because it is based on offspring effects from the reproduction study. 
TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

3.3.5	Dermal Absorption

Dermal Absorption Factor:  1%

A dermal absorption study with monkeys is available.  In a dermal
penetration study (MRID

45868001), TI-435 [Clothianidin] as the FS 600 formulation (10% a.i.)
[nitroimino- 14C] TI-

435) was administered to five male Rhesus monkeys.  Test material was
applied to a shaved area

(4 cm x 6 cm) of skin on the back of each animal.  The total dose was
contained in 100 ml of

test substance and was applied at a dose of 6.13 ug/cm2.  Animals were
exposed for 8 hours, and then the application sites were washed. 
Subjects were monitored for 120 hours. Urine and feces were collected
for the exposure period and the subsequent monitoring period.  TC \l3
"3.5.5	Dermal Absorption 

3.3.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  Two-generation reproduction study in the rat

MRID Number:  45422714 through -16 

Dose and Endpoint for Risk Assessment:  9.8 mg/kg (NOAEL), based on
decreased body weight gains and delayed sexual maturation, decreased
absolute thymus weights in F1 pups and an increase in stillbirths in
both generations observed at 31.2 mg/kg (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

This endpoint is based on an oral study. A dermal study is available;
however, the selected endpoint addresses potential effects on offspring,
which are not examined in the dermal study. Therefore, the study and
endpoint were selected because they are protective of effects observed
in all the available studies. The mouse single dose and rat single and
multiple dose metabolism studies indicate that oral absorption is in the
range of 90% or greater. Therefore, extrapolation from the oral to the
dermal route is not likely to grossly underestimate anticipated adverse
effects. The endpoint is appropriate for all durations as the effect may
be a result of either short- and/or longer-term exposure. A 1% dermal
absorption factor should be used for route-to-route extrapolation.

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

3.3.7	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  Two-generation reproduction study in the rat

MRID Number:  45422714 through -16 

Dose and Endpoint for Risk Assessment:  9.8 mg/kg (NOAEL), based on
decreased body weight gains and delayed sexual maturation, decreased
absolute thymus weights in F1 pups and an increase in stillbirths in
both generations observed at 31.2 mg/kg (LOAEL)

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments about Study/Endpoint/Uncertainty Factor:  

This endpoint is based on an oral study. No inhalation studies are
available. Therefore, an oral study is selected to estimate risk using a
route-to-route extrapolation. The study and endpoint were selected
because it is protective of effects observed in all the available
studies. The endpoint is appropriate for all durations as the effect may
be a result of either short- and/or longer-term exposure. Absorption via
inhalation is assumed to be equivalent to absorption via the oral route.

3.3.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.3.8.  Summary of Levels of Concern for Clothianidin 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	1000	1000	1000

Inhalation	1000	1000	1000

Incidental Oral	1000	1000	1000

3.3.9	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources:  oral, dermal, and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows: short-, intermediate- and long-term exposures (incidental oral,
dermal, and inhalation exposure) can be aggregated because of the use of
a common endpoint for oral, dermal (oral equivalent) and inhalation
(oral equivalent) routes of exposure.

3.3.10	Classification of Carcinogenic Potential

In accordance with the Draft 1999 Carcinogen Risk Assessment Guidelines,
the HIARC classified clothianidin as “not likely to be carcinogenic to
humans”. A statistical analysis showed that the increase in thyroid
c-cell tumors in female rats was not significant, especially when
carcinomas and adenomas are combined. The increased incidence of
hepatocellular carcinomas in male rats at the low and high doses are
just outside historical control incidences for the same testing
laboratory (only 2 studies) but are within the historical control range
for the animal supplier.  In addition, there was no dose-response and
there is no continuum (i.e. no preneoplastic lesions and no adenomas). 
Based on these factors, it was determined that there is no evidence of
carcinogenicity in rats. There is no evidence of carcinogenicity in
mice.  TC \l3 "3.5.10	Classification of Carcinogenic Potential 

3.3.11	Summary of Toxicological Doses and Endpoints for Clothianidin for
Use in Human Risk Assessments  TC \l3 "3.5.11	Summary of Toxicological
Doses and Endpoints for [Chemical] for Use in Human Risk Assessments 

Table 3.3.11a.  Toxicological Doses and Endpoints for Clothianidin for
Use in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

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

Acute Dietary (General Population, including Infants and Children)
NOAEL= 25 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Acute RfD = 0.025 mg/kg/day

aPAD = 0.025 mg/kg/day	Special neurotoxicity/

pharmacology study in mice and rats

LOAEL = 50 mg/kg based on transient signs of decreased spontaneous motor
activity, tremors and deep respirations. 

Acute Dietary

(Females 13-49 years of age)	NOAEL = 25 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Acute RfD = 0.025 mg/kg/day

aPAD = 0.025 mg/kg/day	Developmental rabbit study

LOAEL = 75 mg/kg/day based on an increased litter incidence of a missing
lobe of the lung

Chronic Dietary (All Populations)	NOAEL= 9.8 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Chronic RfD = 0.0098

mg/kg/day

cPAD = 0.0098 mg/kg/day	Two-generation reproduction study 

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations. 

Incidental Oral (All Durations)	NOAEL= 9.8 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Residential LOC for MOE = 1000	Two-generation reproduction study 

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations.

Dermal 

(All Durations)	NOAEL= 9.8  mg/kg/day

Dermal absorption rate = 17%	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Residential LOC for MOE = 1000	Two-generation reproduction study 

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations.

Inhalation

(All Durations)	NOAEL = 9.8 mg/kg/day

Inhalation absorption rate =  100%	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x

	Residential LOC for MOE = 1000	Two-generation reproduction study 

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” 

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).  UFDB = to account for the absence of key data (i.e.,
lack of a developmental immunotoxicity 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.

Table 3.3.11b.  Summary of Toxicological Doses and Endpoints for
Clothianidin 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 

(All Durations)	NOAEL=9.8 mg/kg/day

Dermal absorption rate = 17%	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Two-generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations.

Inhalation

(All Durations)	NOAEL=9.8 mg/kg/day

Inhalation absorption rate =  100%	UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Two-generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased mean body weight gain and
delayed sexual maturation, decreased absolute thymus weights in F1 pups
and an increase in stillbirths in both generations.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” 

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).  MOE = margin of exposure.  LOC = level of concern.

3.4	Endocrine disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

For clothianidin, effects which indicate potential endocrine disruption
include changes in the ovaries and/or ovarian weights in the rat, dog,
and mouse studies, changes in the testes and/or testicular weights in
rodents and dogs, possible delayed sexual maturation in the reproduction
and developmental neurotoxicity studies, increased adrenal weights with
congestion, and increased thyroid weights with noted cysts and adenomas.
 These effects have been well-characterized, with clear NOAELs/LOAELs,
and the doses and endpoints selected for clothianidin risk assessments
are considered protective.  

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, clothianidin may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

  TC \l1 "4.0	Public Health and Pesticide Epidemiology Data 

4.1	Incident Reports

There are currently no incident reports for clothianidin (H. Allender,
8/29/2006).

4.2	National Health and Nutritional Examination Survey (NHANES) 

Clothianidin is not currently included in the NHANES database (R. Allen,
8/23/2006).

4.3	Agricultural Health Study (AHS) 

Clothianidin is not currently included in the AHS database (R. Allen,
8/23/2006).

4.4	Other Pesticide Epidemiology Published Literature

No public health or epidemiology data were found for this chemical when
the National Library of Medicine TOXNET and PubMed databases were
searched (K. Schumacher, 8/29/2006  TC \l2 "4.4	Other Pesticide
Epidemiology Published Literature ).

5.0	Dietary Exposure/Risk Characterization

HED MARC Decision Memo (D282449, Y. Donovan, 4/25/2003)

HED Residue Chemistry Summary Document (D303473, W. Drew, 2/1/2006)

EFED Estimated Environmental Concentrations (D299401 and D301729, L.
Liu, 7/6/2004)

HED Dietary Exposure Memo (D326758, M. Doherty, 9/13/2006)

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

5.1.1	Metabolism in Primary Crops

Adequate plant metabolism studies are available reflecting the
application of [14C]-clothianidin as a seed treatment to corn and sugar
beets, as foliar applications to apples, and as soil and foliar
applications to tomatoes.  The metabolic profiles in the tested primary
crops were similar in that the highest level residue was the parent,
clothianidin, with the exception of mature sugar beet tops.  Based on
these metabolism studies, the Metabolism Assessment Review Committee
(MARC) concluded that the nature of the residue has been adequately
delineated, and that parent only is the residue of concern (ROC) to be
used in risk assessment and the tolerance expression for primary crops. 
However, the MARC also determined that future new uses on root crops
and/or leafy vegetables will require analysis of TMG along with parent
in field trial samples.    TC \l3 "5.1.1	Metabolism in Primary Crops 

5.1.2	Metabolism in Rotational Crops

Adequate confined and limited field rotational crop studies are
available to support the proposed maximum seasonal use rates on sorghum,
cotton, potatoes, and sugar beets.  The metabolism of clothianidin in
primary and rotational crops is similar.  The MARC concluded that
parent, TZNG, and MNG are the ROCs in rotational crops and that only
parent needs to be included in the tolerance expression.

5.1.3	Metabolism in Livestock

The nature of clothianidin residues in livestock is adequately
understood based on acceptable goat and hen metabolism studies.    TC
\l3 "5.1.3	Metabolism in Livestock For ruminants, the MARC concluded
that the ROCs for risk assessment include parent and the metabolites
TZU, TZG, TZNG, and ATMG-Pyruvate; for poultry, the MARC concluded that
the ROCs for risk assessment include parent and the metabolites TZU,
TZG, TZNG, and ATG-Acetate.  However, for purposes of tolerances, the
MARC recommended that only parent needs to be included in the tolerance
expression.  

5.1.4	Analytical Methodology

Adequate LC/MS/MS methods are available for both collecting data and
enforcing tolerances for clothianidin residues in plant (Bayer Methods
00552 and 109240-1) and animal (Bayer Method 00624) commodities.  The
validated limit of quantitation (LOQ) for clothianidin in plant
commodities is 0.010 ppm, except for wheat straw (0.020 ppm), and the
validated LOQs are 0.010 ppm in milk and 0.020 ppm in animal tissues. 
All three of these methods have been reviewed by BEAD’s Analytical
Chemistry Laboratory (ACL), approved for tolerance enforcement, and
forwarded to FDA for inclusion in PAM Volume II.  

In addition, Arvesta has submitted another LC/MS/MS method (Morse Method
#Meth-164) for enforcing tolerances and collecting data on residues of
clothianidin and TMG in grape and potato commodities.  This newer method
is similar to Method 00552 and involves extraction of residues with
acetonitrile/water, cleanup using solid phase extraction (SPE)
cartridges, and the separate analysis of clothianidin and TMG by
LC/MS/MS.  The validated LOQ for each analyte is 0.020 ppm in all grape
and potato matrices, except for potato chips and raisins (with LOQs of
0.040 ppm).  The method was adequately validated in conjunction with the
field trials and processing studies and has undergone a successful
independent laboratory validation (ILV) trial.  

Samples of sorghum and cotton commodities were analyzed for clothianidin
using an LC/MS/MS method developed by Bayer (Bayer Method 109240-1),
which is essentially Method 00552 with the use of an internal standard
for quantitation.  Methods 00552 and 109240-1 have been reviewed by the
Agency and approved for tolerance enforcement, as noted above.  The
validated LOQ for clothianidin residues is 0.010 ppm in sorghum forage,
stover, and grain; the LOQ is also 0.010 ppm in cottonseed and gin
byproducts.  This method was adequately validated in conjunction with
the field trials.    TC \l3 "5.1.4	Analytical Methodology 

Multiresidue method testing of clothianidin and its metabolites MNG,
TZG, TZNG, TZU, and ATMG-Pyr have been submitted (Residue Chemistry
Summary Document, D282446, Y. Donovan, 5/1/2003).  However, it was
determined that clothianidin and its major metabolites are not
adequately recovered using any of the multiresidue methods.  These data
were forwarded to the US FDA for further evaluation.  

5.1.5	Environmental Degradation

The fate and disposition of clothianidin in the environment suggest that
it is persistent and mobile, stable to hydrolysis, and has potential to
leach to ground water, as well as runoff to surface waters.  The high
persistence of clothianidin (aerobic soil metabolism and terrestrial
field dissipation half-lives ranging from half a year to several years)
may cause accumulation of the chemical in soils following repeated uses.
  TC \l3 "5.1.5	Environmental Degradation 

5.1.6	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.6.  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

Plants

	Primary Crop	Parent

(For Sugar Beet only:  Parent and TMG)	Parent

	Rotational Crop	Parent, TZNG, MNG	Parent

Livestock

	Ruminant	Parent, TZU, TZG, TZNG, ATMG-Pyr	Parent

	Poultry	Parent, TZU, TZG, TZNG, ATG-Ac	Parent

Drinking Water	Parent	Not Applicable

5.1.7	Drinking Water Residue Profile

EFED provided Tier I Estimated Drinking Water Concentrations (EDWCs) for
clothianidin in surface water and in ground water for use in human
health risk assessments.  The simulation model FIRST was used to
calculate the surface water EDWCs, and the SCI-GROW model was used to
calculate the groundwater EDWC.  No clothianidin monitoring data were
available.  Although clothianidin is a major metabolite of thiamethoxam
in plants and in animals, it was not found in environmental fate
studies.  Therefore, exposure to clothianidin in drinking water due to
thiamethoxam uses is not expected.  The MARC's decision on residues of
concern for thiamethoxam in drinking water is parent only.  For the
simulation models, the application rate of 0.4 lbs a.i./A for turfgrass
was used.  This rate is the highest of all the proposed and existing
uses.  The EDWCs for clothianidin in surface waters are 7.29 ppb for
acute risk calculations and 1.35 ppb for chronic risk and cancer risk
calculations.  Clothianidin EDWCs in groundwater are not expected to
exceed 5.84 ppb.  Typically, HED uses the higher of the surface or
groundwater estimates for each duration when assessing dietary risk
(e.g., 7.29 ppb from surface water for acute exposures and 5.84 ppb from
groundwater for chronic exposures).  As an added conservatism in this
chronic assessment, the acute 7.29 ppb EDWC from surface water was used
for both the acute and chronic analyses.

Table 5.1.7.  Summary of Estimated Surface Water and Groundwater
Concentrations for Clothianidin.

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	7.29	5.84

Chronic (non-cancer)	1.35	5.84

Chronic (cancer)	N/A	N/A

a From the Tier 1 FIRST model assuming a maximum applicate rate of 0.4
lb a.i./A, a Koc of 84, and a soil aerobic metabolic half-life of 744
days.

b From the SCI-GROW model. 

5.1.8	Food Residue Profile

The available field trial data are adequate and will support the
proposed use patterns for clothianidin on sorghum, cotton, grapes, and
potatoes.  The number and geographic distribution of the field trials
are adequate, and the appropriate samples were collected at the proposed
PHIs.  The samples were analyzed using adequate analytical methods and
the sample storage intervals are supported by the available storage
stability data.  The available field trial data support the proposed
tolerances of 0.01 ppm on sorghum and cotton commodities, 0.05 ppm on
potatoes, 0.08 ppm on potato granules/flakes, and 0.60 ppm on grapes.

To support the request for a Section 18 exemption for use on sugar beet
seeds, the registrant provided data from 12 sugar beet field trials
conducted in 2004, including 5 conducted in states or regions where the
seeds would be planted.  The number and location of these trials were
selected based on guidance provided by the EPA.  In these trials, a
formulation of 60 g clothianidin plus 16 g cyfluthrin as an emulsifiable
(in water) concentrate (Clothianidin + Cyfluthrin 600 EW) was applied as
a single seed treatment to sugar beet seeds at 6 lb clothianidin/100 lb
seeds.  Based on the seeding rates used at the various field trial sites
(52,870 to 71,320 seeds/A), the actual field use rates were equivalent
to 0.070 to 0.094 lb clothianidin/A (and 0.019 to 0.025 lb
cyfluthrin/A).  Duplicate composite samples of sugar beet roots and tops
were collected from each trial at crop maturity.  An LC/MS/MS method was
used to determine clothianidin and TMG residues in sugar beet roots and
tops.  The LOQ is 0.01 ppm for clothianidin residues and 0.01 for TMG
residues in sugar beet roots and tops.  For clothianidin, the highest
average field trial (HAFT) residues were 0.017 ppm in sugar beet roots
(maximum residue =  0.019 ppm) and 0.011 ppm in sugar beet tops (maximum
residue = 0.011 ppm).  For TMG, the HAFT residues were <0.01 ppm in
sugar beet roots (maximum residue = <0.01 ppm) and 0.024 ppm in sugar
beet tops (maximum residue = 0.026 ppm).  These field trial data support
tolerances of 0.02 ppm clothianidin on sugar beet roots and tops.  As
noted previously, the MARC recommended that TMG be considered a residue
of concern in sugar beets.  Since all TMG residues were below the LOQ
(0.01 ppm) in sugar beet roots, use of the 0.02 ppm tolerance for
clothianidin per se is adequate for dietary risk assessment.  Since
sugar beet tops are a minor animal feed and not used for food, the
quantifiable residues (maximum 0.026 ppm) of TMG in tops will not have a
significant impact on dietary risk.

Residue data from the available limited field rotational crop studies,
conducted at 0.7X to 0.9X the proposed maximum seasonal rates (0.20 lb
a.i./A), adequately support the current tolerances for inadvertent
residues in selected rotational crops.

The available processing data for sorghum, cotton, grapes, and potatoes
are adequate.  Samples were analyzed using adequate methodology and are
supported by the available storage stability data.  

For grapes, residues of clothianidin concentrated slightly in juice
(1.1X) and by 1.6X in raisins.  Based on the HAFT residues from the
grape field trials (0.277 ppm) and the above processing factor for
raisins, the maximum expected residues of clothianidin in raisins would
be 0.443 ppm.  As this residue level is below the recommended tolerance
of 0.60 ppm on grapes, a separate tolerance for raisins is not required.
 

For potatoes, processing factors determined from the two processing
studies were similar for each matrix.  Residues of clothianidin were
reduced in wet peel (0.5X), but concentrated in granules (2.3X) and
chips (1.4X).  Based on HAFT residues of 0.031 ppm for whole tubers, the
maximum expected residues in granules/flakes and chips would be 0.071
and 0.043 ppm, respectively.  As the maximum expected residue level in
chips is less than the recommended tolerance of 0.05 ppm on potatoes, a
separate tolerance is not required on chips.  Based on the maximum
expected residues in potato granules/flakes, HED is recommending a
tolerance be established at 0.08 ppm on this processed food.  

For sorghum, residues in three subsamples of grain harvested at maturity
were non-detectable (less than 0.003 ppm).  Considering that residues
were less than a third of the LOQ in grain treated at 2X the proposed
label’s maximum use rate, and that the application to sorghum is made
as a seed treatment, residue data on aspirated grain fractions derived
from sorghum are not required.  In addition, the Agency does not
currently require processing data on sorghum’s processed commodity,
flour.  

In cotton, residues in three samples of undelinted cottonseed (harvested
at maturity and ginned following treatment at 5X the proposed label’s
maximum use rate) were all less than the LOQ (0.010 ppm).  The
registrant (Bayer CropScience) submitted a request for waiver of the
requirement for a cotton processing study.  HED recommends that the
waiver be granted (no cotton processing data are required).  

Processing studies on sugar beets are not available.  For the purposes
of the Section 18 exemption for use of clothianidin on sugar beet seed,
it is assumed that clothianidin residues do not concentrate in sugar
beet commodities, considering that the majority of field trial values
were < LOQ.  As such, the tolerance set for sugar beet roots is
considered protective for residues found in the processed commodities. 
However, processing studies on sugar beets will be required to grant
permanent registration for use of clothianidin as a sugar beet seed
treatment.

The current tolerance for clothianidin residues in milk is adequate and
tolerances are not required for meat, meat-byproducts, or fat from
cattle, goat, hogs, horses, or sheep.  A poultry feeding study and
tolerances for residues in poultry tissues and eggs are not required at
the present time. 

5.1.9	International Residue Limits

Canadian maximum residue limits (MRLs) have been established for
residues of clothianidin at 0.01 mg/kg in milk, corn and canola.  As of
February 2006, there are no Canadian, Mexican, or Codex MRLs or
tolerances for cotton, sorghum, grapes, or potatoes.   TC \l3 "5.1.11
International Residue Limits 

5.2	Dietary Exposure and Risk

HED Dietary Exposure Memo (D326758, M. Doherty, 9/13/2006)

Acute and chronic dietary exposure and risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID™, Version
2.03).  Clothianidin has been classified as “not likely”
carcinogenic; therefore, a cancer dietary assessment is not needed. 
Clothianidin is a major metabolite of the active ingredient thiamethoxam
and residues of clothianidin coming from thiamethoxam were accounted for
in these assessments.  All registered, pending, and proposed uses of
thiamethoxam, as of the date of this memorandum, are included in these
assessments.  The acute assessment is based on maximum residues of
clothianidin observed in clothianidin and thiamethoxam field trials and
assumes 100% crop treated (%CT).  The chronic assessment is based on
average residues from clothianidin and thiamethoxam field trials and
also assumes 100% crop treated.  Assuming 100% crop treated in these
analyses results in a potential “double counting” of clothianidin
coming from thiamethoxam for crops that have registered uses of both
compounds, since the label for clothianidin does not permit application
of another "Group 4A" insecticide (e.g., thiamethoxam) following
application of clothianidin.  Therefore, this method of accounting for
thiamethoxam’s involvement in clothianidin exposure likely
overestimates that particular contribution to total exposure.  The
empirical processing factor for apple juice is used for apple and pear
juice, and empirical factors are used for grape juice and raisins;
otherwise, DEEM default processing factors are used.  The analyses
include direct incorporation of estimated clothianidin residues in
drinking water.  For water, the highest acute estimate from conservative
models was used for both the acute and the chronic dietary exposure
analyses.

Based on these highly conservative assumptions, acute dietary risk
estimates at the 95th percentile of exposure are less than or equal to
45% of the acute population-adjusted dose (aPAD) for all population
subgroups.  Chronic dietary risk estimates are less than or equal to 16%
of the chronic population-adjusted dose (cPAD) for all population
subgroups.  Generally HED is concerned when risk estimates exceed 100%
of the PAD; therefore, all acute and chronic dietary risk estimates are
below HED’s level of concern.

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

Table 5.2.1.  Summary of the Acute Dietary Exposure and Risk Estimates
for Clothianidin.

Population Subgroup	Acute PAD (mg/kg/day)	Acute Estimates

(95th Percentile)

Dietary Exposure (mg/kg/day)	% aPAD

General U.S. Population	0.025	0.002813	11

All Infants (< 1 year old)	0.025	0.007807	31

Children 1-2 years old	0.025	0.011229	45

Children 3-5 years old	0.025	0.007232	29

Children 6-12 years old	0.025	0.003083	12

Youth 13-19 years old	0.025	0.001409	6

Adults 20-49 years old	0.025	0.001902	8

Adults 50+ years old	0.025	0.002102	8

Females 13-49 years old	0.025	0.001976	8

  TC \l3 "5.2.1  Acute Dietary Exposure/Risk 

Chronic Dietary Exposure/Risk

Table 5.2.2.  Summary of the Chronic Dietary Exposure and Risk Estimates
for Clothianidin.

Population Subgroup	Chronic PAD (mg/kg/day)	Source of Clothianidin

Clothianidin	Thiamethoxam	Total

Dietary Exposure (mg/kg/day)	% cPAD	Dietary Exposure (mg/kg/day)	% cPAD
Dietary Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.0098	0.000370	4	0.000105	1	0.000475	5

All Infants (< 1 year old)	0.0098	0.001085	11	0.000179	2	0.001264	13

Children 1-2 years old	0.0098	0.001321	14	0.000263	3	0.001584	16

Children 3-5 years old	0.0098	0.000928	10	0.000223	2	0.001151	12

Children 6-12 years old	0.0098	0.000453	5	0.000142	2	0.000595	6

Youth 13-19 years old	0.0098	0.000225	2	0.000095	1	0.000320	3

Adults 20-49 years old	0.0098	0.000274	3	0.000084	1	0.000358	4

Adults 50+ years old	0.0098	0.000302	3	0.000085	1	0.000387	4

Females 13-49 years old	0.0098	0.000281	3	0.000081	1	0.000362	4

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The acute assessment is based on maximum residues of clothianidin
observed in clothianidin and thiamethoxam field trials and assumes 100%
crop treated.  The chronic assessment is based on average residues from
clothianidin and thiamethoxam field trials and also assumes 100% crop
treated.  TC \l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT)
Information 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

HED Occupational/Residential Exposure Memo, (D296176, M. Dow, 2/24/04)

HED Occupational/Residential Exposure Memo, (D309473, S. Wang, Draft)

Residential (non-occupational) exposure to clothianidin results solely
from the currently registered use of this compound on turfgrass.  Refer
to the risk assessment for use on turfgrass (D304499, W. Cutchin,
1/6/2005) or to the corresponding residential exposure assessment
(D296176, M. Dow, 2/24/2004) for more details.

6.1	Residential Handler Exposure

Although residential handler exposure is not expected from the currently
registered or proposed uses of clothianidin, due to the absence of
products registered or proposed for homeowner use, the exposure
estimates in Table 6.2 do include adult exposure from application with a
granular push-type spreader.  Therefore, this represents an overestimate
of total exposure. TC \l2 "6.1	Residential Handler Exposure 

6.2.	Residential Post-application Exposure

Based on the registered use patterns on turfgrasses, a number of
residential or recreational post-application exposures are possible.  In
a residential setting, a “homeowner” may be exposed during
application of the material to his or her lawn (although not in the case
of clothianidin, due to the absence of products registered or proposed
for homeowner use).  Further, the “homeowner” may also experience
post-application dermal exposure.  Toddlers may be exposed via
“hand-to-mouth” oral exposures and/or dermal exposures.  These
estimated exposures and risks are also presented.  “Aggregated”
exposures are presented for toddlers (i.e., hand-to-mouth turf +
hand-to-mouth soil + dermal post-application).  Hand-to-mouth ingestion
of granules is considered episodic in nature, that is, a “one-time”
event.  Therefore the exposure from ingestion of granules is not
combined with believed multiple exposures from “mouthing” of turf or
soil or from post-application dermal exposure.  Golfers may be exposed
to post-application residues, and estimates of adult and adolescent
golfer exposures are presented.

It is HED’s policy to routinely conduct screening level assessments
(based on standard values in the Residential SOPs) for children’s
incidental ingestion of granules, when a granular pesticide may be
applied in residential settings.  The screening-level assessment for
clothianidin resulted in an MOE of 250 and is a risk of concern.  Based
on information provided by Arysta (email from Doina Bujor dated
11/27/2006) on the particle volumes of the granular clothianidin
formulations, HED agrees that there is little exposure potential for
children’s incidental ingestion of clothianidin granules.  The
particle size is relatively small, and if used according to label
directions, it is unlikely that clothianidin granules would be
accessible to a child.

The MOEs for the residential post-application exposures/risks range from
1,300 to 490,000 (Table 6.2).  MOE values greater than 1000 are
considered adequate to protect adults and children from residential
post-application exposures to clothianidin.  The estimated MOEs are
based upon conservative assumptions and are >1000; therefore, the
estimated risks from residential post-application exposures do not
exceed HED’s level of concern.

Table 6.2.  Summary of Residential Exposure and Risk Estimates for
Clothianidin.

Activity	Exposure

(mg a.i./kg bw/day)	MOE

Toddler oral hand to mouth from contacting treated turf	0.0059	1700

Toddler incidental oral ingestion of treated soil	0.00002	490000

Adult dermal post applic turf contact	0.00108	9100

Adult combined dermal exposure = application + postapplication
application            0.000026

post-application +  0.00108	8900

Toddler dermal post applic turf contact	0.00155	6300

Toddler combined oral (except granules) and dermal exposures	treated
turf + treated soil + dermal

0.00747	1300

Adult golfer post app turf contact	0.000075	130000

Child golfer post app turf contact	0.000128	77000

6.3	Other (Spray Drift, etc.)

Spray drift is 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
clothianidin.  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 and risks associated with aerial as well as other
application types where appropriate.   TC \l2 "6.3	Other (Spray Drift,
etc.) 

It is noted that the 0.4 lb a.i./acre application rate for turf was
modeled to estimate post-application residential exposure of toddlers. 
As this rate is equal to or higher than many of agricultural application
rates, this scenario is protective of any exposure of farm children via
spray drift from agricultural clothianidin applications.

6.4	Exposure from Use of Tobacco

Exposure to clothianidin from use of tobacco has been addressed in a
previous risk assessment (D304499, W. Cutchin, 1/6/2005) and is not
re-examined in this document.

7.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources:  food, drinking water, and
residential exposures.  In an aggregate assessment, exposures from
dietary and residential sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED considers both the route and duration of exposure.

Short- and intermediate-term aggregate risk assessment is required for
clothianidin due to potential residential and/or recreational exposures
to residues on turfgrass.

7.1	Acute Aggregate Risk

Rather than using back-calculated drinking water levels of comparison
(DWLOCs), estimates of pesticide residues in drinking water were
incorporated directly into the dietary exposure analysis to assess
aggregate acute risk.  Therefore, the acute aggregate risk estimates are
equivalent to the acute dietary risk estimates provided in Table 5.2.1. 
The acute aggregate risks associated with the registered and proposed
uses of clothianidin do not exceed HED’s level of concern for the
general U.S. population or any population subgroup.

7.2	 TC \l2 "7.1	Acute Aggregate Risk  TC \l2 "7.1	Acute Aggregate Risk
Short- and Intermediate-Term Aggregate Risk

The HIARC has determined that, for clothianidin, the toxicological
effects are the same across oral, dermal, and inhalation routes of
exposure and has selected the same endpoint and dose for short- and
intermediate-term exposure scenarios.  Therefore, the exposures are
simply summed (combined/aggregated) for use in risk calculations. 
Short- and intermediate aggregate risk estimates range from an MOE of
1,100 for toddlers (food + water + treated turf + treated soil + dermal)
to 22,000 for youth golfers (food + water+ post-application treated
turf).  The short- and intermediate-term aggregate risks associated with
the registered and proposed uses of clothianidin do not exceed HED’s
level of concern for the general U.S. population or any population
subgroup.

Table 7.2.  Short- and Intermediate-Term Aggregate Risk Calculations for
Clothianidin.

Population	NOAEL

(mg/kg/day)	LOC1	Average

Food & Water Exposure

(mg/kg/day)	Residential Exposure2

(mg/kg/day)	Aggregate MOE [food, water, and residential]3

Toddler	9.8	1000	0.001584	0.007470	1100

Females 13-49	9.8	1000	0.000362	0.001106	6700

Adult (male)	9.8	1000	0.000475	0.001106	6200

Adult golfer	9.8	1000	0.000475	0.000075	18000

Youth golfer	9.8	1000	0.000320	0.000128	22000

1  The Level of Concern is based on the following uncertainty factors: 
10X for interspecies variability, 10X for intraspecies variability, and
10X for database uncertainty for the lack of a developmental
immunotoxicity study.

2  Residential Exposure = [oral exposure + dermal exposure + inhalation
exposure].  See Table 6.2.

3  Aggregate MOE = [NOAEL (Avg Food & Water Exposure +
Residential Exposure)]

7.3	Long-Term Aggregate Risk

Long-term residential exposure to clothianidin (i.e., >6 months) is not
considered likely to occur.  Estimates of pesticide residues in drinking
water were incorporated directly into the dietary exposure analysis to
assess aggregate chronic risk.  Therefore, the long-term aggregate risk
estimates are equivalent to the chronic dietary risk estimates provided
in Table 5.2.2.  As previously noted, clothianidin is a metabolite of
the active ingredient thiamethoxam and exposures to clothianidin due to
thiamethoxam uses were considered in the chronic dietary assessment. 
The long-term aggregate risks associated with clothianidin exposure
resulting from the registered and proposed uses of clothianidin and from
the registered uses of thiamethoxam do not exceed HED’s level of
concern for the general U.S. population or any population subgroup.

7.4	Cancer Risk

Clothianidin has been classified by HED HIARC as a “not likely human
carcinogen.”   A cancer aggregate risk assessment is not required.

8.0	Cumulative Risk Characterization/Assessment

Clothianidin is a member of the neonicotinoid class of pesticides and is
a metabolite of another neonicotinoid, thiamethoxam.  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 clothianidin is based on
unrelated effects in mammals, including changes in body and thymus
weights, delays in sexual maturation, and still births.  Additionally,
the most sensitive toxicological effect in mammals differs across the
neonicotinoids (e.g., testicular tubular atrophy with thiamethoxam;
mineralized particles in thyroid colloid with imidaclopid).  Thus, there
is currently no evidence to indicate that neonicotinoids share common
mechanisms of toxicity, and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the neonicotinoids.
 For information regarding EPA’s efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements concerning common
mechanism determinations and procedures for cumulating effects from
substances found to have a common mechanism released by EPA’s Office
of Pesticide Programs on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

Note that because clothianidin is a major metabolite of thiamethoxam,
EPA has combined exposure to clothianidin resulting both from
thiamethoxam use and from use of clothianidin as an active ingredient
and has compared this aggregate exposure estimate to relevant endpoints
for clothianidin.  EPA has taken the further conservative step of
assuming that, in instances where both thiamethoxam and clothianidin are
registered for use on a crop, both pesticides will, in fact, be used on
that crop. 

9.0	Occupational Exposure/Risk Pathway

HED Occupational/Residential Exposure Memo, (D309473, S. Wang, DRAFT)

The proposed new uses of clothianidin include:  (1) the uses of
Clutch™ 50 WDG insecticide (clothianidin 50.0%, water-dispersible
granule) and Belay™ 16 WSG insecticide (clothianidin 16.0%,
water-soluble granule) on potato and grape by ground equipment, and (2)
the uses of Poncho™ 600 seed treatment insecticide (clothianidin
48.0%, liquid) on sorghum and AE1283742™ seed treatment insecticide
(clothianidin 14.1%, liquid) on cotton.  Additionally, a Section 18
emergency exemption requests the use of Poncho™ 600 (clothianidin
48.0%, liquid) on sugar beet seeds in Oregon, Wyoming, Colorado, and
North Dakota.

The maximum application rates listed on the proposed labels provided by
the Registration Division were used for all exposure assessments.  For
crop protection uses, the maximum rates are:  0.047 lb a.i./A for potato
and 0.094 lb a.i./A for grape using Clutch 50 WDG; and 0.2 lb a.i./A for
both potato and grape using Belay 16 WSG.  For seed treatment uses, the
maximum rates are:  (1) 0.25 lb a.i./100 lbs seed for sorghum, (2) 0.15
lb a.i./100 lbs seed for cotton, and (3) 6 lb a.i./100 lbs sugar beet
seeds.

The number of exposure days per year was not provided.  Based on the
frequency/interval of applications on the crops and the seasonal nature
of seed treatment operation, EPA assumes that both application handlers
and post-application workers would be exposed for less than 6 months per
year (short- and intermediate-term exposures).  Long-term exposure is
not expected.

Since no chemical-specific data for assessing human exposures during
pesticide handling activities were submitted to the Agency in support of
the registration of the proposed new uses, HED used surrogate data from
the PHED Version 1.1 (PHED Surrogate Exposure Guide, 8/98) to assess
exposures for crop protection uses.  Defaults established by the HED
Science Advisory Council for Exposure were used for acres treated per
day and body weight.  For seed treatment uses, handler assessments were
based on the unit exposure data from the Science Advisory Council for
Exposure (Exposure SAC) Policy #14: Standard Operating Procedures (SOP)
for Seed Treatment (May 1, 2003).  The treating/planting data were
obtained from Exposure SAC Policy #15:  Amount of Seed Treated or
Planted Per Day (March 2, 2004) or from information provided through the
Registration Division.  For sugar beet seeds, the amount of seeds
treated per day in a commercial seed treatment facility was assumed to
be 8000 lbs/day, which is the rate previously used to assess handler
risk from sugar beet seed treatment (D303485, S. Wang, 6/3/2004).

The occupational post-application exposures/risks were calculated from
activity specific transfer coefficient (Tc) values from the HED Science
Advisory Council for Exposure Policy Number 3.1 (for crop use scenarios)
or from unit exposures given in the HED Science Advisory Council for
Exposure Policy Number 14 (for the seed planter scenario).  

9.1	Short-/Intermediate-Term Handler Risk

9.1.1	Handler Risk from Crop Protection Uses

Based upon the proposed crop protection use patterns, there are five
handler scenarios that are expected to result in the highest
occupational exposures:  1) Mixing/Loading Dry Flowable for Ground-boom
Applications, 2) Mixing/Loading Dry Flowable for Airblast Applications,
3) Mixing/Loading Dry Flowable for Chemigation, 4) Applying Sprays with
Ground-boom Equipment, and 5) Applying Sprays with Airblast Equipment.

A margin of exposure (MOE) of 100 or more is sufficient to protect
workers from all of the occupational handler exposures to clothianidin. 
Risk estimates calculated for handlers performing crop protection uses
are below the level of concern at the baseline level (MOEs = 6,900 to
210,000).  Summaries of the handler exposures/risks from crop protection
uses are presented in Table 9.1.1.   

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 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 judgment.

9.1.2	Handler Risk from Seed Treatment Uses

Based upon the proposed seed treatment use patterns, there are four
handler scenarios that are expected to result in the highest
occupational exposures:  1) Loading (Open)/Applying Liquid for Seed
Treatment, 2) Sewing Seeds after Seed Treatment, 3) Bagging Seeds after
Seed Treatment, and 4) Multiple Activities Worker for Seed Treatment.

An MOE of 100 or more is sufficient to protect workers from all of the
occupational handler exposures to clothianidin.  Risk estimates
calculated for the seed treatment handlers are below the level of
concern at the single-layer level (MOEs = 190 to 11,000).  Summaries of
the handler exposures/risks from seed treatment uses are presented in
Table 9.1.2.

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.

Table 9.1.1.  Short- and Intermediate-Term Handler Risk for Crop
Protection Uses of Clothianidin.

Exposure Scenario (Scenario #)	Mitigation Levela	Dermal Unit Exposureb
(mg/lb a.i.)	Inhalation Unit Exposurec   (ug/lb a.i.)	Crop	Application
Rate

(lb a.i./A)	Amount Treatedd

(A/day)	Daily

Dermal

Dosee (mg/kg/day)	Daily

Inhalation

Dosef (mg/kg/day)	Combined

Daily Doseg (mg/kg/day)	MOEh

Mixer/Loader

Dry Flowables for 

ground-boom 

application (1)	Baseline	0.066	0.77	Potato	0.047	80	0.000035	0.000041
0.000076

	130,000

Dry Flowables for 

airblast 

application (2)	Baseline	0.066	0.77	Grape	0.094	40	0.000035	0.000041
0.000076

	130,000

Dry Flowables for 

chemigation (3)	Baseline	0.066	0.77	Potato & Grape	0.2	350	0.00066
0.00077	0.00143

	6,900

Applicator

Sprays with 

ground-boom  (4)	Baseline	0.014	0.74	Potato	0.047	80	0.0000075	0.0000396
0.000047

	210,000

Sprays with 

airblast (5)	Baseline	0.36	4.5	Grape	0.094	40	0.00019	0.00024	0.00043

	23,000

a	Baseline consists of long-sleeve shirt, long pants, shoes, and socks
and no respirator.  PPE consists of long-sleeve shirt, long pants,
shoes, socks, chemical-resistant gloves, and no respirator.

b	Baseline Dermal Unit Exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading, and open cab tractors, as
appropriate.  

c	Baseline Inhalation Exposure represents no respiratory protection,
open mixing/loading, and open cab tractors, as appropriate.  

d	Daily acres treated values are from EPA estimates of acreage that
could be treated or volume handled in a single day for each exposure
scenario of concern, based on the application method and
formulation/packaging type.

e	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb a.i.) *
dermal absorption (0.01) * application rate (lb a.i./acre) * daily acres
treated /  body weight (70 kg).

f	Daily inhalation dose (mg/kg/d) = (unit exposure (µg/lb a.i.) *
(1mg/1000 µg) conversion * application rate (lb a.i./acre) * daily
acres treated / body weight (70 kg).

g	Combined daily dose = daily dermal dose + daily inhalation dose.

h	MOE = NOAEL (9.8 mg/kg/d) / combined daily dose.  UF = 100.



Table 9.1.2.  Short- and Intermediate-Term Handler Risk for Seed
Treatment Uses of Clothianidin.

Exposure Scenario (Scenario #)	Mitigation Level	Dermal Unit Exposure

(mg/lb a.i.)	Inhalation Unit Exposure   (ug/lb a.i.)	Seed Species
Application Rate

(lb a.i.  per lb seed)	Amount Treateda

(lb seed trt per day)	Daily

Dermal

Doseb

(mg/kg/day)	Daily

Inhalation

Dosec

(mg/kg/day)	Combined

Daily Dosed

(mg/kg/day)	MOEe

Loader/Applicator

Loading/Applying

Liquids for 

Seed Treatment (1)	Single-Layer, Gloves	0.023	0.00034	Sorghums	0.0025
718,000	0.0059	0.0087	0.0146	670

Cotton	0.0015	160,000	0.00079	0.0012	0.00199	4,900

Sugar Beet	0.06	8,000	0.0016	0.0023	0.0039	2,500

Sewer

Sewing Seeds after Seed treatment (2)	Single-Layer, 

No Gloves	0.0062	0.00023	Sorghums	0.0025	718,000	0.0016	0.0059	0.0075
1,300

Cotton	0.0015	160,000	0.00021	0.00079	0.001	9,800

Sugar Beet	0.06	8,000	0.00043	0.0016	0.00203	4,800

Bagger

Bagging Seeds after Seed treatment (3)	Single-Layer, 

No Gloves	0.0091	0.00016	Sorghums	0.0025	718,000	0.0023	0.0041	0.0064
1,500

Cotton	0.0015	160,000	0.00031	0.00055	0.00086	11,000

Sugar Beet	0.06	8,000	0.00062	0.0011	0.00172	5,700

Multiple Activities Worker

Multiple Activities for Seed treatment (4)	Single-Layer, Gloves	0.042
0.0016	Sorghums	0.0025	718,000	0.011	0.041	0.052	190

Cotton	0.0015	160,000	0.0014	0.0055	0.0069	1,400

Sugar Beet	0.06	8,000	0.0029	0.011	0.0139	700

a	Daily amounts treated values are based on the information provided
through the Registration Division. 

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb a.i.) *
dermal absorption (0.01) * application rate (lb a.i./lb seed) * daily
amounts treated /  body weight (70 kg).

c	Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb a.i.) *
application. rate (lb a.i./lb seed) * daily amounts treated / body
weight (70 kg).

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

e	MOE = NOAEL (9.8  mg/kg/d) / combined daily dose.  UF = 100.9.2
Short-/Intermediate-Term Post-application Risk

9.2.1	Post-application Risk from Crop Protection Uses

A summary of the anticipated post-application activities for the
proposed crop protection uses and their respective dermal transfer
coefficients (TCs), as well as the exposures/risks from these activities
are presented in Table 9.2.1.  An MOE of 100 or more is sufficient to
protect workers from all of the post-application occupational exposures
to clothianidin.  Estimated risks calculated for post-application
activities on the day of application are below the level of concern
(MOEs = 4,100 to 270,000).  

Table 9.2.1.  Short-Term Post-Application Risk for Crop Protection Uses
of Clothianidin.

  SEQ CHAPTER \h \r 1 Crop	Application Rate 

(lb a.i./A)	Work Activity	Transfer Coefficientsa (cm2/hr)
Post-application Dayb	DFRc

(ug/cm2)	Daily Dosed (mg/kg/day)	 MOE e 

Potato	0.047	irrigation, scouting, thinning, weeding immature plants 
300	0	0.105	0.00004	270,000

irrigation and scouting mature plants	1500	0	0.105	0.0002	54,000

hand harvesting	2500	0	0.105	0.0003	33,000

Grape	0.094	hedging, irrigation, scouting, hand weeding 	500	0	0.211
0.0001	81,000

scouting, training, tying	1000	0	0.211	0.0002	41,000

hand harvest, leaf pulling, thinning, pruning, training/tying	5000	0
0.211	0.0012	8,100

girding and cane turning	10000	0	0.211	0.0024	4,100

a	Transfer coefficient from Science Advisory Council for Exposure:
Policy Memo #003 "Agricultural Transfer Coefficients," 05/07/98.

b	Day after treatment represents approximately 12 hours following
application  when sprays have dried.

c	DFR = Application Rate (lb a.i./acre) x Fraction of active ingredient
that remains on the foliage when sprays have dried  x 4.54E8 µg/lb x
24.7E-9 acre/cm2.

d	Daily dose = DFR (µg/cm2) x TC (cm2/hr) x conversion factor (1
mg/1,000 µg) x exposure time (8 hrs/day) x dermal absorption (0.01) /
body weight (70 kg).

e	MOE = NOAEL (9.8 mg/kg/day) / daily dose (mg/kg/day).

							

The technical material has a Toxicity Category IV for eye
irritation/skin irritation, and a Category III for acute dermal
toxicity.  Per the Worker Protection Standard (WPS), a 12-hr restricted
entry interval (REI) is required.  The 12-hour REI appearing on the
labels is appropriate.

9.2.2	Post-application Risk from Seed Treatment Uses

The post-application exposure scenario for seed treatment consists of
the farmer purchasing bags of treated seed, placing the seed in the
hopper, and planting seed in the fields.  Post-application exposure
associated with seed treatment was calculated using unit exposures given
from the Science Advisory Council for Exposure Policy #14 (May 1, 2003)

An MOE of 100 or more is sufficient to protect workers from all of the
post-application occupational exposures to clothianidin.  All
post-application risk estimates for seed planters are below the level of
concern at the single-layer level (MOEs = 3,300 to 58,000).  These
exposure/risk values are presented in Table 9.2.2.

The post-application 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
judgment.

Table 9.2.2.  Short- and Intermediate-Term Post-Application Risk for
Seed Treatment Uses of Clothianidin.

Exposure Scenario	Mitigation Level	Dermal Unit Exposure

(mg/lb a.i.)	Inhalation Unit Exposure   (ug/lb a.i.)	Seed Species
Application Rate

(lb a.i.  per lb seed)	Amount Planteda

(lb seed pnted/day)	Daily

Dermal

Doseb

(mg/kg/day)	Daily

Inhalation

Dosec

(mg/kg/day)	Combined

Daily Dosed

(mg/kg/day)	MOEe

Planter

Post-application:

planting seeds in the field	Single-Layer, Gloves	0.25	0.00034	Sorghums
0.0025	800	0.000071	0.000097	0.00017	58,000

Cotton	0.0015	3,600	0.00019	0.00026	0.00045	22,000

Sugar Beet	0.06	1,200	0.0026	0.00035	0.00295	3,300

a	Daily amounts planted values are based on the information provided by
the Registrant through Registration Division. 

b	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb a.i.) *
dermal absorption (0.01) * application rate (lb a.i./lb seed) * daily
amounts treated /  body weight (70 kg).

c	Daily inhalation dose (mg/kg/d) = (unit exposure (mg/lb a.i.) *
application. rate (lb a.i./lb seed) * daily amounts treated / body
weight (70 kg).

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

e	MOE = NOAEL (9.8 mg/kg/d) / combined daily dose.  UF = 100.			10.0
Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and Label
Requirements 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

Developmental immunotoxicity study

10.2	Residue Chemistry

No major residue chemistry deficiencies were noted in the subject
petitions that would preclude the establishment of permanent tolerances
for clothianidin on sorghum, cotton, grapes, and potatoes; however, the
following labeling issues should be resolved prior to establishing
permanent tolerances.  

(1) Because the field trials supporting foliar applications of 50% WDG
did not include the use of any spray adjuvants, directions (for use on
grapes) on the label of the 50% WDG formulation should prohibit the use
of wetting agents or other adjuvants.  HED does not object to the use of
adjuvants on potatoes in light of the exaggerated-rate data from the
processing studies showing tuber residues below the recommended 0.05 ppm
tolerance.  Alternatively, HED would not object to conditional
registration of the 50% WDG formulation (for use on grapes) allowing the
adjuvants, contingent upon submission of data showing that residues,
with and without the use of such agents, are comparable.  

(2) Based on the current tolerances on rotational crops, the proposed
labels for potatoes should be amended to include a plant-back
restriction of 30 days for cereal grain crops, grasses, nongrass animal
feeds (such as alfalfa), soybeans, and dry beans.  A plant-back
restriction of 1 year is required for all other rotated crops.  If
plant-back intervals of less than 1 year are desired by the petitioner,
then extensive field rotational crop trials will be required.

  TC \l2 "10.2	Residue Chemistry 

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

None

References:

  TC \l1 "References: 

HED Clothianidin Risk Assessment (D304499, W. Cutchin, 1/6/2005)

HED DIT Waiver Request Memo (D318520, K. Schumacher, Draft)

HED MARC Decision Memo (D282449, Y. Donovan, 4/25/2003)

HED Residue Chemistry Summary Document (D303473, W. Drew, 2/1/2006)

EFED Estimated Environmental Concentrations (D299401 and D301729, L.
Liu, 7/6/2004)

HED Dietary Exposure Memo (D326758, M. Doherty, 9/13/2006)

HED Occupational/Residential Exposure Memo, (D309473, S. Wang, Draft)

HED Occupational/Residential Exposure Memo, (D296176, M. Dow, 2/24/2004)

HED Occupational/Residential Exposure Memo for Ipconazole (D303485, S.
Wang, 6/3/2004)Appendix A:  Toxicology Assessment  TC \l1 "Appendix A: 
Toxicology Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

The requirements (40 CFR 158.340) for food uses for clothianidin are in
Table 1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

yes	-

-

yes

yes

yes

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies

Developmental Immunotoxicity		

yes	

no

A.2	Toxicity Profiles

Table A.2.1 is identical to the acute toxicity profile table included in
the most recent risk assessment for clothianidin (D304499, W. Cutchin,
1/6/2005).  However, Table A.2.2 differs from the subchronic, chronic,
and other toxicity profile table provided in D304499 in that information
about an immunotoxicity study conducted in adult rats has been added.

Table A.2.1	Acute Toxicity Profile - Clothianidin Technical,
Intermediates, and Metabolites

  SEQ CHAPTER \h \r 1 Test Material	Guideline No.	Study Type	MRID(s)
Results	Toxicity Category

  SEQ CHAPTER \h \r 1 Technical	870.1100	Acute oral - rat	45422621	LD50
> 5000 mg/kg	IV

BN0230M  Metabolite	870.1100	Acute oral - rat	45422628	LD50 > 2000 mg/kg
(♂+♀)	III

BN0335E2 Metabolite	870.1100	Acute oral - rat	45422623	LD50 > 2000 mg/kg
(♂+♀)	III

MAI 

Metabolite	870.1100	Acute oral - rat	45422629	LD50 = 758 mg/kg (♀)

Males not more susceptible	III

Clothianidin-CCMT-

Adduct Intermediate	870.1100	Acute oral - rat	45422630	LD50 > 2000 mg/kg
(♂+♀)	III

Clothianidin-Hexahydropyrimidine Intermediate	870.1100	Acute oral - rat
45422631	LD50 > 2000 mg/kg (♂+♀)	III

Clothianidin-Triazan Intermediate	870.1100	Acute oral - rat	45422632
LD50 > 2000 mg/kg (♂+♀)	III

TMG Metabolite	870.1100	Acute oral - rat	45422625	LD50 < 550 mg/kg (♂)

LD50 = 567 mg/kg (♀)	II

TZMU Metabolite	870.1100	Acute oral - rat	45422624	LD50 = 1424 mg/kg
(♂)

LD50 = 1282 mg/kg (♀)	III

TZNG Metabolite	870.1100	Acute oral - rat	45422626	LD50 > 1450 mg/kg
(♂)

LD50 = 1481mg/kg (♀)	III

Technical	870.1100	Acute oral - mouse	45422622	LD50 = 389 mg/kg (♂; 

95% C.I. = 380-475)

LD50 = 465 mg/kg (♀;

95% C.I. =   SEQ CHAPTER \h \r 1 384-561)

LD50 = 425 mg/kg (♂+♀;

95% C.I. =   SEQ CHAPTER \h \r 1 380-475)	II

Technical	870.1200	Acute dermal - rat	45422634	LD50 > 2000 mg/kg	III

Technical	870.1300	Acute inhalation	45422636	LC50 >   SEQ CHAPTER \h \r
1 5.538 mg/L (♂+♀)	IV

Technical	870.2400	Acute eye irritation	45422701	  SEQ CHAPTER \h \r 1
Slightly irritating to the eye	IV

Clothianidin-CCMT- Adduct Intermediate	870.2400	Acute eye irritation
45422814	  SEQ CHAPTER \h \r 1 Not irritating to the eye	IV

Clothianidin-Triazan Intermediate	870.2400	Acute eye irritation	45422819
  SEQ CHAPTER \h \r 1 Not irritating to the eye	IV

Technical	870.2500	Acute dermal irritation	45422703	  SEQ CHAPTER \h \r
1 Not irritating to the skin	IV

Clothianidin-CCMT- Adduct Intermediate	870.2500	Acute dermal irritation
45422813	  SEQ CHAPTER \h \r 1 Not irritating to the skin	IV

Clothianidin-Triazan Intermediate	870.2500	Acute dermal irritation
45422820	  SEQ CHAPTER \h \r 1 Not irritating to the skin	IV

Technical	870.2600	Skin sensitization	45422705	  SEQ CHAPTER \h \r 1 Is
not a sensitizer under conditions of study	N/A

Clothianidin-CCMT- Adduct Intermediate	870.2600	Skin sensitization
45422815	  SEQ CHAPTER \h \r 1 Is not a sensitizer under conditions of
study	N/A

Clothianidin-Triazan Intermediate	870.2600	Skin sensitization	45422821	 
SEQ CHAPTER \h \r 1 Is a sensitizer under conditions of study	N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

Guideline No. 	Study Type	Results

870.3100

	90-Day oral toxicity - rat	NOAEL =   SEQ CHAPTER \h \r 1 27.9/34.0
mg/kg/day   SEQ CHAPTER \h \r 1 (M/F)    

LOAEL =   SEQ CHAPTER \h \r 1 202.0/254.2 mg/kg/day (M/F) 

based on   SEQ CHAPTER \h \r 1 decreased BW and BW gain.

870.3150

	90-Day oral toxicity - dog	NOAEL = 19.3/42.1 mg/kg/day (M/F) 

LOAEL = 40.9/61.8 mg/kg/day (M/F) based on thinness, decreased body
weight, body weight gain and anemia (1 M); and on decreased white blood
cells, albumin, and total protein (F).

870.3200

	21/28-Day dermal toxicity - rat	NOAEL = 1000 mg/kg/day (HDT)

LOAEL = Not established 

870.3700a

	Prenatal developmental in rodents - rat	Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 40 mg/kg/day based on decreased body weight gain and
food consumption.

Developmental NOAEL = 125 mg/kg/day (HDT)

Developmental LOAEL = Not established

870.3700b

	Prenatal developmental in nonrodents - rabbit	Maternal NOAEL = 25
mg/kg/day

Maternal LOAEL = 75 mg/kg/day based on increased incidences of clinical
signs (scant feces and orange urine), mortalities, decreased food
consumption, early delivery, abortion, and decreased body weight gain.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = 75 mg/kg/day based on premature deliveries,
decreased gravid uterine weights, an increased litter incidence of a
missing lobe of the lung, and decreased litter average for ossified
sternal centra per fetus.

870.3800

	Reproduction and fertility effects - rat	Parental/Systemic NOAEL =
31.2/36.8 mg/kg/day (M/F)

Parental/Systemic LOAEL = 163.4/188.8 mg/kg/day (M/F) based on decreased
body weight, body weight gain, and absolute and relative thymus weights.

Reproductive NOAEL = 31.2/188.8 mg/kg/day (M/F)

Reproductive LOAEL = 163.4/not established mg/kg/day (M/F) based on
decreased sperm motility and increased number of sperm with detached
heads in both generations.

Offspring NOAEL = 9.8/11.5 mg/kg/day (M/F)

Offspring LOAEL = 31.2/36.8 mg/kg/day (M/F) based on decreased body
weight gains and delayed sexual maturation (M), decreased absolute
thymus weights in F1 pups of both sexes, and an increase in stillbirths
in both generations.

870.4100a

	Chronic toxicity -rodents	See 870.4300, which includes requirements for
both 870.4100 and 870.4200.

870.4100b

	Chronic toxicity - dog	NOAEL = 46.4/40.1 mg/kg/day (M/F)

LOAEL = not established/52.9 mg/kg/day (M/F) based on clinical evidence
of anemia in females.

Note:  dose-related decreases in ALT activity observed in mid- and
high-dose males and females.

870.4200

	Carcinogenicity -mouse	NOAEL = 171.4/65.1 mg/kg/day (M/F)

LOAEL = 254.1/215.9 mg/kg/day (M/F) based on decreased body weight and
body weight gain; decreased food consumption and food efficiency in
males at the LOAEL. 

No evidence of carcinogenicity.

870.4300

	Combined chronic feeding/ carcinogenicity - rat	NOAEL = 82.0/32.5
mg/kg/day (M/F)

LOAEL = 156.5/97.8 mg/kg/day (M/F) based on decreased body weight and
food consumption and altered hepatocellular eosinophilic focus of the
liver in both sexes; ovary interstitial gland hyperplasia and increased
lymphohistiocytic infiltrate in females; and slightly increased
incidences of pelvic mineralization and transitional cell hyperplasia in
the kidney, mottled livers of males.

No evidence of carcinogenicity.

870.5100	Gene Mutation bacterial reverse mutation assay

Parent	  SEQ CHAPTER \h \r 1 Small, but significant increase in
frequency of  histidine revertants in  TA1535 strain treated at 1500 and
5000 ug/plate +/-S9; still present but weaker in its absence.   The
positive response was only reproducible at 5000 ug/plate +/-S9.
Clothianidin considered mutagenic under conditions of this test.

870.5100	Gene Mutation bacterial reverse mutation assay

Parent	No mutagenic activity in bacteria (Salmonella typhimurium and
Escherichia coli) under conditions of this assay.

870.5100	Gene Mutation bacterial reverse mutation assay

Parent	No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	Gene Mutation bacterial reverse mutation assay

Parent	Only TA 1535 tested.  No mutagenic activity in bacteria
(Salmonella typhimurium) under conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

BN0335E2 metabolite	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

TZMU metabolite 	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

methyl guanidine intermediate	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

TZNG metabolite	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

TMG metabolite	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

BN0230M metabolite	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

MAI metabolite	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation bacterial reverse mutation assay

N-Methylnitroguanidin intermediate	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation - bacterial reverse mutation assay

TI 435-Triazan intermediate	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5100	

Gene Mutation - bacterial reverse mutation assay

TI 435-CCMT-Adduct	

No mutagenic activity in bacteria (Salmonella typhimurium) under
conditions of this assay.

870.5300	

Gene Mutation - in vitro mammalian cell gene mutation test (L5178Y TK
+/- mouse lymphoma cells)

Parent	

Increases in mutant frequency with and without S9 at dose levels that
were cytotoxic.  The observed response was primarily due to small colony
formation, indicating clastogenic activity.

870.5300	

Gene Mutation - in vitro mammalian cell gene mutation test (V79-HPRT
Assay)

Parent	

No increase in mutant frequency under the conditions of the study.

870.5395	

Cytogenetics - mammalian erythrocyte micronucleus test

Parent	

Clothianidin is considered to be neither clastogenic nor aneugenic under
these test conditions.

870.5375	

Cytogenetics -  in vitro mammalian chromosome aberration test (CHL
Cells)

Parent	

Significant increases in frequency of cells with structural aberrations.
Predominant types were chromatid breaks and exchanges.  There was,
however, no clear indication of a dose-related response in either the
presence or absence of S9 activation.

870.5500	

Other Effects - DNA Repair Test in Bacillus subtillis

Parent	

No potential for DNA damage under these conditions.

870.5550	

Other Effects - (UDS) in Mammalian Cells in Culture

Parent	

No evidence (or a dose related positive response) that UDS was induced.

870.6200a

	Acute neurotoxicity screening battery - rat	NOAEL = Not established

LOAEL = 100 mg/kg/day based on FOB findings (decreased arousal, motor
activity, and locomotor activity).

870.6200b

I

J

¿

À

Á

Ä

Å

Ð

Õ

×

Ú

-

@

A



ž

À

Á

Ø

ù

ༀႄᄎ킄㄂$葞ฐ葠ː摧姖R᐀Ú

ø

hª

&



é

 

!

"

#

$

%

&

'

(

D

E

F

G

J

K

]

^

_

y

z

{

|

}

~



€

ž

ᄀ脈栖ތ"ࡕ洁H渄H甄Ĉᄔ脈栖ތ"䡭Ѐ䡮Ѐࡵἁž

Ÿ

 

£

¤

Æ

Ç

È

â

ã

ä

æ

ç

è

é

ê

ë

j¸

hÈ

hÈ

hÈ

h

h

h

&

ㄈ$摧‴É

h

萏ː萑ﴰ␱䀀Ħ葞ː葠ﴰ摧㕦	

㄀$摧䲢9

态ú摧枆»

态ú摧眃 

ô

ô

wpˆ

㄀$摧⟰³

H*

H*

gd

H*

萏ː萑ﴰ␱䀀Ħ葞ː葠ﴰ摧㕦	

㄀$摧㔥¥

Ž

³

´

C

D

㄀$摧洍 

&´

+

A

B

C

a

c

n

”

—

¡

Ã

ã

ä

hB

h

 h

h

&D

b

c

㄀$摧⚖o

è

¶

¶

l

n

␱䀀Ħ摧㕦	

摧媳v

	ï

	ï

ਁ砃愀϶x

摧媳v

摧媳v

	ï

	ï

ਁ砃愀϶x

摧媳v

摧媳v

	ï

	ï

ਁ砃愀϶x

摧媳v

摧媳v

	ï

	ï

ਁ砃愀϶x

摧媳v

摧媳v

	ï

	§

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧媳v

摧埦ä

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

”ÿ

n

¶

㄀$摧ᔵ»

”ÿ

n

¶

 h¿

h

h¿

h¿

h¿

 h¿

h¿

gdæWä

ਁ氃愀϶l

愀Ĥ摧埦ä

愀Ĥ摧埦ä

愀Ĥ摧埦ä

愀Ĥ摧埦ä

愀Ĥ摧埦ä

h‚

 h

h

h

h

h‚

萏ː萑ﴰ␱䀀Ȧ葞ː葠ﴰ摧㕦	

&

˜þ

˜þ

˜þ

˜þ

˜þ

옍)

&

&

&

¶

¶

¶

¶

kd

¶

¶

¶

¶

&

&

h,

˜þ

˜þ

h,

&

옍)

옍)

옍)

옍)

옍)

옍)

h‚

h‚

@

$

@

$

@

@

$

@

$

@

$

@

$

@

$

@

$

@

$

@

$

@

$

@

$

@

@

@

h‚

h‚

h‚

@

@

@

@

㐀ۖĀ̊e攃昀Ĵ̀

$

摧ᗰ

摧ᗰ

摧ᗰ

摧ᗰ

摧ᗰ

摧ᗰ

㐀ۖĀ̊e攃昀Ĵ

摧ᗰ

摧ᗰ

摧ᗰ

摧ᗰ̀LOAEL = 142 mg/kg/day based on decreased body weights, body
weight gains, and food consumption.

Offspring NOAEL = 12.9 mg/kg/day

Offspring LOAEL = 42.9 mg/kg/day based on decreased body weights, body
weight gains, motor activity, and acoustic startle response in females.

870.7485

	Metabolism and pharmacokinetics - rat	Overall recovery: 95-100%.
Readily absorbed and excreted within 96 hours following a single 2.5
mg/kg bw or repeated oral dose of 25 mg/kg bw, but at a dose of 250
mg/kg, absorption became biphasic and was saturated.  Following single
or multiple oral low doses (2.5 and 25mg/kg bw, respectively) of
clothianidin, urinary excretion accounted for 89.2-94.6% of the
administered radioactivity suggesting that a multiple exposure regimen
did not affect the absorption/excretion processes.  Urinary excretion
unaffected following single 250 mg/kg dose.  Excretion via the feces
accounted for the remainder of the administered radioactivity in all
treatment groups (3.8-8.6%). Rapid absorption and distribution of
administered radioactivity to all organs and tissues followed by rapid
excretion with reduction to background levels in most tissues and organs
within 24 hours. Somewhat greater rate of absorption  and elimination in
females.  Excretory patterns did not exhibit gender-related variability
but reflected the delayed absorption in the high-dose group.  Neither
clothianidin nor metabolites appear to undergo significant
sequestration. 

 The metabolites identified (primarily oxidative demethylation products
and cleavage products of the nitrogen-carbon bond between the nitroimino
and thiazolyl moieties) were consistent with Phase I processes. 
Extraction efficiencies appeared to be excellent and most components in
all of the matrices examined (urine, feces, and tissues) were adequately
quantified and characterized.  The available data, based upon studies
using both the nitroimino- and the thiazolyl-2-labeled clothianidin,
affirmed the metabolism pathway proposed by the investigators.

870.7485

	Metabolism and pharmacokinetics - mouse	Of the administered
radioactivity, 98.7-99.2% was recovered. Readily absorbed and excreted
within 168 hours following a single oral dose of 5 mg/kg body weight. 
Urine was the major route of excretion, accounting for 92.4-93.7% of the
administered radioactivity. Feces accounted for 5.0-6.8% of the
administered radioactivity.  Within 24 hours, 89.0-91.7 % of the
administered radioactivity was excreted in the urine and 4.9-6.2% was
excreted in the feces.  Residual radioactivity in any given tissue at
168 hours post-dose was considerably less than 1% of the administered
dose.  Therefore, neither clothianidin nor its metabolites appeared to
exhibit potential for bioaccumulation. Excretory patterns did not
exhibit gender-related variability. 

Both urinary and fecal metabolites were identified using TLC and
radioautography in conjunction with known standards and were quantified
by TLC/LSC .  The major metabolites in both urine and feces were the
parent compound (clothianidin) and TZNG
[N-(2-chlorothiazol-5-ylmethyl)-N-nitroguanidine] which resulted from
N-demethylation of clothianidin.  Extraction efficiencies were excellent
and most components in the urine and feces were adequately quantified
and characterized.  Based on the data from the oral administration of
[nitroimino-14C]-clothianidin the metabolism pathway proposed by the
investigators was supported.

870.7600	Dermal penetration - monkey	Dermal absorption as the sum of
urinary and fecal excretion and Cage/Pan/Chair Wash, Debris was 0.24 (+
0.11) as percent of dose. Adjustment of the direct absorption
determination was not necessary because recovery from the dermal dose
was >90%.  

A value of 1% dermal absorption was considered appropriate for use in
risk assessment.  This estimation takes into account any variability
that would have likely occurred with testing several dose levels.

870.7800	Immunotoxicity – rat (adults)	Immunotoxicity NOAEL = 253
mg/kg/day (M/F)

Immunotoxicity LOAEL = not established

At the highest dose tested, 253 mg/kg/day, a decrease in body weights,
body weight gains, and food consumption was noted in adult males and
females.

Non-guideline	Special Study:

Neurotoxicity and pharmacology - mouse	NOAEL = 25 mg/kg/day (M/F)

ent signs of decreased spontaneous motor activity, tremors, and deep
respirations.

 TC \l1 " Appendix D:  Review of Human Research 

	Page   PAGE  2  of   NUMPAGES  50