Document ID: EPA-HQ-OPP-2010-0217-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-11T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF CHEMICAL SAFETY AND

                                                                        
                   POLLUTION PREVENTION

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	28 October 2010

	SUBJECT:	Clothianidin – Human Health Risk Assessment of the Requested
Experimental Use Permit as a Rice Seed Treatment.  

 

PC Code:  044309	DP Barcodes:  D376087

Decision Nos.:  426468	Registration Nos.:  59639-EUP-XX

Risk Assessment Type:  Single Chemical, Aggregate 	Regulatory Action: 
Experimental Use Permit

Petition No.:  0G7682	Case No.:  NA

TXR No.:  NA	CAS No.:  210880-92-5

MRID No.:  See MRID Summary Table	40 CFR:  180.586

	FROM:	Michael A. Doherty, Ph.D., Senior Chemist

		Shih-Chi Wang, Ph.D., Biologist  SEQ CHAPTER \h \r 1 

		Risk Assessment Branch II

		Health Effects Division (7509P)

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

		Christina Swartz, Branch Chief

		Risk Assessment Branch II

		Health Effects Division (7509P)

	TO:	John Hebert (RM 07)

		Insecticide/Rodenticide Branch			  SEQ CHAPTER \h \r 1   SEQ CHAPTER
\h \r 1 

		Registration Division

MRID Summary Table

MRID No.	Study Type	Comments

47955201	Petition Volume

	47955202	Petition Volume

	47955203	860.1500 Rice

860.1520 Polished rice, hulls and bran 	New DERs; 47955203.de1.doc and
47955203.de2.doc

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc276025678"  1.0	Executive
Summary	  PAGEREF _Toc276025678 \h  4  

  HYPERLINK \l "_Toc276025679"  2.0	HED Recommendations	  PAGEREF
_Toc276025679 \h  4  

  HYPERLINK \l "_Toc276025680"  2.1	Data Needs	  PAGEREF _Toc276025680
\h  5  

  HYPERLINK \l "_Toc276025681"  2.2	Tolerance Considerations	  PAGEREF
_Toc276025681 \h  5  

  HYPERLINK \l "_Toc276025682"  2.2.1	Enforcement Analytical Method	 
PAGEREF _Toc276025682 \h  5  

  HYPERLINK \l "_Toc276025683"  2.2.2	International Harmonization	 
PAGEREF _Toc276025683 \h  5  

  HYPERLINK \l "_Toc276025684"  2.2.3	Recommended Tolerances	  PAGEREF
_Toc276025684 \h  5  

  HYPERLINK \l "_Toc276025685"  2.2.4	Revisions to Petitioned-For
Tolerances	  PAGEREF _Toc276025685 \h  5  

  HYPERLINK \l "_Toc276025686"  2.3	Label Recommendations	  PAGEREF
_Toc276025686 \h  5  

  HYPERLINK \l "_Toc276025687"  2.3.1	Recommendations from Residue
Reviews	  PAGEREF _Toc276025687 \h  5  

  HYPERLINK \l "_Toc276025688"  2.3.2	Recommendations from Occupational
Assessment	  PAGEREF _Toc276025688 \h  6  

  HYPERLINK \l "_Toc276025689"  2.3.3	Recommendations from Residential
Assessment	  PAGEREF _Toc276025689 \h  6  

  HYPERLINK \l "_Toc276025690"  3.0	Ingredient Profile	  PAGEREF
_Toc276025690 \h  6  

  HYPERLINK \l "_Toc276025691"  3.1	Structure and Nomenclature	  PAGEREF
_Toc276025691 \h  6  

  HYPERLINK \l "_Toc276025692"  3.2	Physical/Chemical Characteristics	 
PAGEREF _Toc276025692 \h  6  

  HYPERLINK \l "_Toc276025693"  3.3	Summary of Existing/Proposed Uses	 
PAGEREF _Toc276025693 \h  7  

  HYPERLINK \l "_Toc276025694"  4.0	Hazard Characterization and
Dose-Response Assessment	  PAGEREF _Toc276025694 \h  7  

  HYPERLINK \l "_Toc276025695"  4.1	Toxicology Studies Available for
Analysis	  PAGEREF _Toc276025695 \h  8  

  HYPERLINK \l "_Toc276025696"  4.2	Absorption, Distribution,
Metabolism, & Elimination (ADME)	  PAGEREF _Toc276025696 \h  8  

  HYPERLINK \l "_Toc276025697"  4.2.1	Dermal Absorption	  PAGEREF
_Toc276025697 \h  8  

  HYPERLINK \l "_Toc276025698"  4.3	Toxicological Effects	  PAGEREF
_Toc276025698 \h  9  

  HYPERLINK \l "_Toc276025699"  4.4	Safety factor for Infants and
Children (FQPA Safety Factor)	  PAGEREF _Toc276025699 \h  9  

  HYPERLINK \l "_Toc276025700"  4.4.1	Completeness of the Toxicology
Database	  PAGEREF _Toc276025700 \h  9  

  HYPERLINK \l "_Toc276025701"  4.4.2	Evidence of Neurotoxicity	 
PAGEREF _Toc276025701 \h  9  

  HYPERLINK \l "_Toc276025702"  4.4.3	Evidence of
Sensitivity/Susceptibility in the Developing or Young Animal	  PAGEREF
_Toc276025702 \h  10  

  HYPERLINK \l "_Toc276025703"  4.4.4	Residual Uncertainty in the
Exposure Database	  PAGEREF _Toc276025703 \h  10  

  HYPERLINK \l "_Toc276025704"  4.5	Toxicity Endpoint and Point of
Departure Selections	  PAGEREF _Toc276025704 \h  10  

  HYPERLINK \l "_Toc276025705"  4.5.1	Dose-Response Assessment	  PAGEREF
_Toc276025705 \h  10  

  HYPERLINK \l "_Toc276025706"  4.5.2	Recommendation for Combining
Routes of Exposures for Risk Assessment	  PAGEREF _Toc276025706 \h  10  

  HYPERLINK \l "_Toc276025707"  4.5.3	Cancer Classification and Risk
Assessment Recommendation	  PAGEREF _Toc276025707 \h  10  

  HYPERLINK \l "_Toc276025708"  4.5.4	Summary of Points of Departure and
Toxicity Endpoints Used in Human Risk Assessment	  PAGEREF _Toc276025708
\h  11  

  HYPERLINK \l "_Toc276025709"  4.6	Endocrine Disruption	  PAGEREF
_Toc276025709 \h  12  

  HYPERLINK \l "_Toc276025710"  5.0	Dietary Exposure and Risk Assessment
  PAGEREF _Toc276025710 \h  13  

  HYPERLINK \l "_Toc276025711"  5.1	Metabolite/Degradate Residue Profile
  PAGEREF _Toc276025711 \h  13  

  HYPERLINK \l "_Toc276025712"  5.1.2	Residues of Concern Summary and
Rationale	  PAGEREF _Toc276025712 \h  14  

  HYPERLINK \l "_Toc276025713"  5.2	Food Residue Profile	  PAGEREF
_Toc276025713 \h  15  

  HYPERLINK \l "_Toc276025714"  5.3	Water Residue Profile	  PAGEREF
_Toc276025714 \h  16  

  HYPERLINK \l "_Toc276025715"  5.4	Dietary Risk Assessment	  PAGEREF
_Toc276025715 \h  16  

  HYPERLINK \l "_Toc276025716"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc276025716 \h  17  

  HYPERLINK \l "_Toc276025717"  6.1	Spray Drift	  PAGEREF _Toc276025717
\h  18  

  HYPERLINK \l "_Toc276025718"  7.0	Aggregate Exposure/Risk
Characterization	  PAGEREF _Toc276025718 \h  18  

  HYPERLINK \l "_Toc276025719"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc276025719 \h  18  

  HYPERLINK \l "_Toc276025720"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc276025720 \h  18  

  HYPERLINK \l "_Toc276025721"  7.3	Chronic Aggregate Risk	  PAGEREF
_Toc276025721 \h  19  

  HYPERLINK \l "_Toc276025722"  7.4	Cancer Aggregate Risk	  PAGEREF
_Toc276025722 \h  19  

  HYPERLINK \l "_Toc276025723"  8.0	Cumulative Exposure/Risk
Characterization	  PAGEREF _Toc276025723 \h  19  

  HYPERLINK \l "_Toc276025724"  9.0	Occupational Exposure/Risk
Characterization	  PAGEREF _Toc276025724 \h  20  

  HYPERLINK \l "_Toc276025725"  9.1	Short- and Intermediate-Term Handler
Risk	  PAGEREF _Toc276025725 \h  20  

  HYPERLINK \l "_Toc276025726"  9.2	Short- and Intermediate-Term
Post-Application Risk	  PAGEREF _Toc276025726 \h  20  

  HYPERLINK \l "_Toc276025727"  10.0	Incidents	  PAGEREF _Toc276025727
\h  21  

  HYPERLINK \l "_Toc276025728"  11.0	Environmental Justice
Considerations	  PAGEREF _Toc276025728 \h  21  

  HYPERLINK \l "_Toc276025729"  12.0	References	  PAGEREF _Toc276025729
\h  21  

 

1.0	Executive Summary

Clothianidin,
(E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine, is
a broad spectrum, systemic neonicotinoid insecticide (Group 4A
insecticide) with numerous tolerances.  Valent U.S.A. Corporation (the
petitioner) has submitted a petition (PP# 0G7682) requesting an
Experimental Use Permit (EUP) for use of a flowable suspension
clothianidin formulation containing 5 lbs a.i./gal (NipsIt INSIDE®
Insecticide; EPA Experimental Use Permit No. 59639-EUP-XX) as a seed
treatment for the control of various insects on rice at a maximum rate
of 75 g a.i./100 kg seed. The proposed use is for dry-seeded rice using
drill planters only.  The petitioner is proposing a time-limited
tolerance for residues of clothianidin in/on rice grain at 0.01 ppm.

The Health Effects Division (HED) has reviewed the available
toxicological, residue chemistry, and occupational/residential exposure
information relevant for this assessment.

The toxicological database for clothianidin is complete.  The available
data indicate that there are no consistent specific target organs in
mammals.  The majority of studies show decreases in body weights and
body weight gains.  More severe developmental (missing lobe of the lung
in the rabbit) and neurological effects in rats and mice are
attributable to exposure to clothianidin; these effects serve as the
basis for acute risk assessments.  Effects on body weight gain, delayed
sexual maturation, decreased thymus weights, and an increase in
stillbirths are the basis for assessing short-, intermediate-, and/or
long-term (chronic) exposures.  Based on the completeness of the
database, the observed effects, and the endpoints used for risk
assessment, the FQPA Safety Factor has been reduced to 1X, leaving the
100X safety factor to account for within-species (10X) and
across-species (10X) variability.  Clothianidin has been classified as
not likely to be carcinogenic to humans.

The available residue chemistry data are sufficient for purposes of
evaluating this EUP.  The recommended tolerance level is based on seed
treatment uses on corn and wheat, which show residues below the limit of
quantitation (0.01 ppm) in/on corn kernels and wheat grain.  Processing
studies with rice show that residues are unlikely to concentrate in
processed commodities as a result of this seed-treatment use.

Aggregate risk estimates, incorporating exposures from drinking water,
dietary food, and non-dietary sources indicate that human health risks
from clothianidin are below the Agency’s level of concern.  Similarly,
risks associated with occupational activities involving this use are
below the Agency’s level of concern.  Thus, there are no human health
risk issues which would preclude granting the EUP or establishing
time-limited tolerances.

2.0	HED Recommendations

HED recommends in favor of granting the EUP for the rice seed treatment
use of clothianidin described herein and for establishing a time-limited
tolerance at 0.01 ppm for residues of clothianidin in/on rice, grain. 
HED further recommends that the petitioner collect the data described in
Section 2.1 as part of the use program in order to support a future
petition for a Section 3 registration and establishment of permanent
tolerances.

2.1	Data Needs

As part of the experimental use program, the petitioner should evaluate
residues of clothianidin in rice commodities, including processed
commodities from rice grown from treated seed, to ensure establishment
of appropriate tolerance levels if a future Section 3 registration is
sought on rice.  HED also encourages the petitioner to monitor residues
of clothianidin in the rice-field water in order to evaluate the need
for any restrictions regarding the use of that water.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An acceptable analytical method is available to enforce the proposed
tolerance.  The method involves extraction of residues with
acetonitrile/water, cleanup using solid phase extraction (SPE)
cartridges, and analysis of clothianidin by LC/MS/MS.  The method has
been validated to a limit of quantitation (LOQ) of 0.02 ppm in grape and
potato matrices (except for potato chips and raisins at 0.04 ppm).  The
method was adequately validated to an LOQ of 0.01 ppm in conjunction
with rice field trials and processing studies, and has undergone a
successful independent laboratory validation (ILV) trial.

2.2.2	International Harmonization

There are currently no established or proposed Codex, Canadian, or
Mexican maximum residue limits (MRLs) for clothianidin in/on rice. 
Therefore, harmonization with international MRLs is not an issue with
this petition.  An International Residue Limit Status Sheet is attached.

2.2.3	Recommended Tolerances

Table 2.2.3. 	Tolerance Summary for Clothianidin

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

Rice grain	0.01	0.01	Rice, grain

2.2.4	Revisions to Petitioned-For Tolerances

HED’s recommended tolerance level is in accord with that proposed by
the petitioner.

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

Prior to granting the EUP, HED recommends that the EUP label be modified
to specify that the tail water from rice fields planted in
clothianidin-treated rice may not be used to irrigate crops.  Note that
the proposed label already states that the product may not be used in
areas where aquaculture practices are in place.

2.3.2	Recommendations from Occupational Assessment

None

2.3.3	Recommendations from Residential Assessment

None

3.0	Ingredient Profile

3.1	Structure and Nomenclature

Table 3.1.	Clothianidin Nomenclature.

Chemical Structure	

Common name	Clothianidin

Company experimental name	TI-435, V-10066

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

CAS name
(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)	5 lb/gal FlC (NipsIt INSIDE® Insecticide; EPA
Experimental Use Permit No. 59639-EUP-XX)

Chemical Class	Insecticide (Neonicotinoid)

Known Impurities of Concern	None

3.2	Physical/Chemical Characteristics

Table 3.2.	Physicochemical Properties of Clothianidin.

Parameter	Value	Reference

Molecular wt.	249.68	D335355, W. Drew, 10/16/07

Melting point (ºC)	176.8

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

	Density (g/cm3)	1.61 (PAI)*, 1.59 (TGAI)

	Water solubility (g/L at 20ºC)	0.327

	Solvent solubility (g/L at 25ºC)	Acetone	15.2	Dichloromethane	1.32

Ethyl acetate	2.03	Heptane 	<0.00104

Methanol	6.26	Octanol	0.938

Xylene	0.0128

	Vapor pressure (Pa at 20ºC)	1.3 x 10-10

	Dissociation constant, pKa at 20ºC	11.09

	Octanol/water partition coefficient, Log(KOW) at 25ºC	0.7

	UV/visible absorption spectrum (Maximum, nm)	265.5 (acidic or neutral)

246.0 (basic)

	*PAI = Purified Active Ingredient; TGAI = technical grade active
ingredient.

3.3	Summary of Existing/Proposed Uses

The petitioner has submitted an application for an Experimental Use
Permit (EUP) for use of the 5 lbs/gal FlC formulation (V-10170 5 FS; EPA
Reg. No. 59639-151) as a rice seed treatment, under the name NipsIt
INSIDE Insecticide.  The proposed use is for seed treatment only when
rice seed is dry-seeded using drill planters.  Seed applications, at a
maximum use rate of 75 g a.i./100 kg seed, will be made using commercial
seed treating equipment at rice seed treatment facilities between the
months of February to April 2011 and February to April, 2012. The
proposed maximal acreages to be treated are 20,000 acres for Arkansas,
10,000 acres for Texas, 5,000 acres for Louisiana, and 5,000 acres for
Mississippi. The flowable suspension formulation is not to be used as a
rice seed treatment in areas where rice/crawfish aquaculture practices
are in place, or in or near fish farm, shrimp, prawn, or crab pond or
nursery operations. In addition, application of the flowable suspension
formulation is not to be followed by a spray treatment of another
neonicotinoid insecticide. The formulation is slurried with water and a
seed colorant, and applied using commercial seed treatment equipment. 
The proposed use directions are summarized below in Table 3.  HED has
recommended that the label be modified regarding the rice-field tail
water (see Section 2.3).

Table 3.3.	Summary of Directions for Use of Clothianidin Seed Treatment.

Applic. Timing, Type, and Equip.	Form.

[EPA Reg. No.]	Application Rate 1	Use Directions and Limitations

Rice

Seed treatment using commercial seed treatment equipment only	5 lb/gal
FlC

[59639-151]	75 g a.i./100 kg seed

or

0.075 lb a.i./100 lb seed

(0.11 lb a.i./A)	Limited to use in AR, LA, MS, and TX

Do not use treated seed for food, feed or oil processing.

Rotational Crop Restrictions:

Immediate Plant-back: Canola, cotton, corn (field, pop and sweet),
fruiting vegetables (including curcubits), leafy vegetables (including
Brassica vegetables), rapeseed, sorghum, soybean, sugarbeet, tuberous
and corm vegetables

30-Day Plant-back: Cereal grains (except corn and sorghum), dry beans,
grasses, non-grass animal feeds, root and tuber vegetables (except
tuberous and corm vegetables)

8-month Plant-back: Sugarcane

12-month Plant-back: any crops without an earlier plant-back interval

The application rate expressed on a lb a.i./A basis was calculated by
the reviewer using the maximum seed treatment rate and the maximum
planting rate (150 lbs seed/A) from the ExpoSAC SOP 15 memo (3/2/2004). 
The Petitioner used a planting rate of 120 lb seed/A, resulting in an
application rate of 0.09 lb a.i./A.

4.0	Hazard Characterization and Dose-Response Assessment

Clothianidin is a major metabolite of the active ingredient thiamethoxam
and 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.

4.1	Toxicology Studies Available for Analysis

The toxicological database for clothianidin is complete.  The scientific
quality is relatively high and the toxicity profile of clothianidin can
be characterized for most effects, including potential carcinogenic,
mutagenic, developmental and reproductive, neurotoxic and immunotoxic
effects.  The following studies were submitted: acute and subchronic
neurotoxicity; subchronic in rats, mice and dogs; subchronic dermal,
chronic/carcinogenicity in rats; carcinogenicity in mice; chronic in
dogs; developmental in rats and rabbits; developmental neurotoxicity;
reproduction; mutagenicity battery; metabolism (rats and mice); dermal
penetration (monkeys) and immunotoxicity as well as developmental
immunotoxicity.

4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)

In rats, clothianidin was readily absorbed and excreted within 96 hours
following a single 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
primarily via the urine (>89% of dose) and to a lesser extent, the
feces, 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 of oxidation, reduction and hydrolysis.

 

In mice, clothianidin was 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.

4.2.1	Dermal Absorption

In a dermal absorption study in monkeys, absorption was calculated as
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 indicated that oral absorption was 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
underestimate anticipated adverse effects.

4.3	Toxicological Effects

Clothianidin and its metabolites have relatively low (Category III or
IV) acute toxicity via oral, inhalation and dermal routes of exposure in
the rat and there is no evidence of dermal sensitization or eye
irritation with the exception of the clothianidin-triazan intermediate,
which is a dermal sensitizer.  The other exceptions were for technical
clothianidin and the TMG metabolite via the oral route in the rat both
of which were toxicity Category II.

Clothianidin induces some effects that are similar to other
neonicotinoid insecticides, particularly on the liver, hematopoietic
system and kidneys.  For a complete description of toxicological
effects, see D355373 (M. Doherty et al., 13 August 2009).

4.4	Safety factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA safety factor for the protection of
infants and children be reduced to 1X.

4.4.1	Completeness of the Toxicology Database

The database for evaluating in utero or postnatal susceptibility is
adequate for evaluation of the FQPA safety factor.  The following
acceptable studies are available:

	Developmental toxicity studies in rats and rabbits

	Two-generation reproduction study in rats

	Developmental neurotoxicity study in rats

	Developmental immunotoxicity study in rats

4.4.2	Evidence of Neurotoxicity

Clothianidin was tested in the following three rat neurotoxicity
studies: acute, 90-day and developmental.  In addition, a
neurotoxicity/pharmacology single dose study was performed in mice. 

In the acute neurotoxicity study, decreased arousal, motor activity and
locomotor activity were observed; however, in the subchronic study, the
LOAEL was based on decreased body weights, body weight gains and food
consumption with no evidence of neurotoxicity.

In the developmental neurotoxicity study, the maternal effects included
decreased body weights, body weight gains and food consumption; whereas,
in the offspring, decreased body weights, body weight gains, motor
activity and acoustic startle response in females were observed at a
lower dose than the dose required to induce effects in the dams.

In the single dose mouse study, transient signs of decreased spontaneous
motor activity, tremors and deep respirations were observed.

No signs of neurotoxicity were observed in the remainder of the toxicity
studies.

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young
Animal

While no increased quantitative or qualitative susceptibility was
observed in either of the developmental rat or rabbit studies, increased
quantitative susceptibility was observed in both the developmental
neurotoxicity and rat reproduction 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 what caused maternal toxicity.  However, HED 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 dose lower than that
which caused parental toxicity.

Immunotoxicity and developmental immunotoxicity studies were performed
and neither showed any changes in the immune system parameters examined.

4.4.4	Residual Uncertainty in the Exposure Database

The assessment for clothianidin is based on high-end assumptions
regarding dietary and non-dietary exposures.  As such, the exposure
assessment is unlikely to underestimate actual exposures to
clothianidin.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

For a complete discussion of the dose-response assessment and the points
of departure for use in risk assessment, please see D355373, M. Doherty
et al., 13 August 2009.

4.5.2	Recommendation for Combining Routes of Exposures for Risk
Assessment

For all durations, oral, dermal, and inhalation exposures may be
aggregated because of the selection of a common endpoint for these
routes of exposure.

4.5.3	Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March, 2005), the clothianidin is classified 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 were 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 was no evidence of
carcinogenicity in rats.  There was no evidence of carcinogenicity in
mice.

4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in
Human Risk Assessment

Table 4.5.4.1.  Summary of 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	Level of Concern for Risk Assessment	Study and
Toxicological Effects

Acute Dietary

Females age 

13-49 	NOAEL =  

25 mg/kg/day	UFA = 10X

UFH = 10X

SFFQPA =1

 	aRfD=0.25 mg/kg/day

aPAD=0.25 mg/kg/day	Rabbit developmental  study 

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

Acute Dietary

General population	NOAEL = 

25 mg/kg/day	UFA = 10X

UFH = 10X

SFFQPA  = 1	aRfD = 0.25

mg/kg/day

aPAD 0.25

mg/kg/day	Special neurotoxicity/pharmacol

study in mice 

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

Chronic Dietary

All populations including infants and children	NOAEL= 

9.8 mg/kg/day  	UFA = 10X

UFH = 10X

SFFQPA =1	cRfD=0.098 mg/kg/day

cPAD=0.098 mg/kg/day	2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups and
increased stillbirths in both generations

Incidental Oral (short and intermediate term)	NOAEL= 

9.8 mg/kg/day	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 	2-Generation reproduction study 

LOAEL= 31.2  mg/kg/day based on decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups 

Dermal (all durations) 	Oral study NOAEL= 

9.8 mg/kg/day

(dermal absorption = 1%)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 	2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on  decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups and
increased stillbirths in both generations

Inhalation (all durations)

	Oral study NOAEL= 

9.8 mg/kg/day

(inhalation absorption = 100% of oral absorption)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups and
increased stillbirths in both generations

Cancer (oral, dermal, inhalation)	“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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

Table 4.5.4.2.  Summary of Toxicological Doses and Endpoints for
Clothianidin for Use in Occupational Human Health Risk Assessments.

Exposure/

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

Dermal (all durations) (Adults)	Oral study NOAEL= 

9.8 mg/kg/day

(dermal absorption = 1%)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 	2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on  decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups and
increased stillbirths in both generations

Inhalation (all durations)

	Oral study NOAEL= 

9.8 mg/kg/day

(inhalation absorption = 100% of oral absorption)	UFA= 10X

UFH= 10X

SFFQPA=1	MOE= 100 	2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed
sexual maturation, decreased absolute thymus weights in F1 pups and
increased stillbirths in both generations

Cancer (oral, dermal, inhalation)	“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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

4.6	Endocrine Disruption

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

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

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

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

5.0	Dietary Exposure and Risk Assessment 

5.1	Metabolite/Degradate Residue Profile

The metabolism of clothainidin in primary crops, rotational crops,
livestock, and rats was evaluated by the Metabolism Assessment Review
Committee (MARC) in 2003.  The clothianidin risk assessment team concurs
with the findings of the MARC regarding the residues of concern for risk
assessment and tolerance enforcement (Table 5.1.2).

The metabolism of clothianidin is complex, with a few major (> 10% of
the total radioactive residues) and numerous minor metabolites.  The
list of terminal residues is fairly consistent across plants, goats,
hens, and rats, although the designation of major vs. minor metabolites
varies depending on the test species.  



Table 5.1.1.  Overview of clothianidin metabolic profile in plant and
animal matrices.

Residue1	Rat	Hen	Goat	Corn	Sugar Beet	Rotational Crops	Apple	Tomato

Clothianidin	(	(	(	(	(	(	(	(

ACT**	(

	ATG-Ac

(*

ATG-Pyr

(

ATMG-Pyr

	(*

	ATMT

(

CTCA**	(

	(

MG	(

(	(	(	(	(

	MNG	(	(	(	(	(	(*	(	(

MTCA**	(

	NTG	(	(	(	(	(	(	(

	THMN	(

(

	THMN-Glc

	(

	TMG	(	(	(	(	(* (tops)	(	(

	TMHG

	(

	TMT

(

TZG	(	(*	(*

	TZMU	(

(	(	(	(	(

	TZNG	(	(*	(*	(	(	(*	(	(

TZU	(	(*	(*	(	(	(	(

	UREA	(	(	(

	* 	major metabolites

**	ACT, MTCA, CTCA did not show up in hen and goat because only the
nitroimino label was used.  There are also no acute studies with these
metabolites.

1 TZMU = N-(2-Chlorothiazol-5-ylmethyl)-N’-methylurea

TZNG = N-(2-Chloro-5-thiazolylmethyl)-N’-nitroguanidine

THMN = Thiazolyl hydroxy methyl nitroguanidine

TZU = N-(2-Chlorothiazol-5-ylmethyl) urea

TMG = N-(2-Chloro-5-thiazolylmethyl)-N’-methylguanidine

MNG = N-Methyl-N’-nitroguanidine

MG = Methyl guanidine

NTG = Nitroguanidine

ATMG-Pyruvate =
N’-[(2-chlorothiazol-5-ylmethylamino)(methylamino)methylene]-2-oxoprop
ano hydrazide

ATG-Acetate = N’-[amino(2-chlorothiazol-5-ylmethylamino)methylene]
acetohydrazide

5.1.2	Residues of Concern Summary and Rationale

Table 5.1.2.  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	Leafy and Root/Tuber Vegetables:  Parent + TMG

Other crops: Parent	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

Based on the available metabolism studies, HED concluded that the nature
of the residue has been adequately delineated, and that parent only is
the residue of concern (ROC) to be used for the tolerance expression for
primary crops.  HED had previously determined that future new uses on
root crops and/or leafy vegetables will require analysis for residues of
TMG along with parent in field trial samples and that TMG should be
included as a ROC for risk assessment if significant levels of TMG were
observed.  In a previous submission, residues of TMG were shown to occur
in leafy vegetables at levels approximately 10-fold below those of
clothianidin.

5.2	Food Residue Profile

Although the petitioner supplied field trials conducted with rice, the
data from those trials are not appropriate for residue levels associated
with this EUP.  The rice trials were conducted with foliar applications
rather than with clothianidin-treated seed.

The petitioner has requested that a temporary tolerance for rice, grain
be established based on residue data from on-going wheat trials (seed
treatment) and from registered seed treatment uses on sorghum and corn. 
In addition, the petitioner has supplied information from an on-going
aquatic dissipation study in rice.  The wheat trials and the aquatic
dissipation study have not yet been submitted to the Agency for review.

As noted above, the submitted field trial data on rice are not
appropriate for evaluating a seed-treatment use.  Likewise, the sorghum
trials do not support the use pattern for rice due to the difference in
the field-equivalent application rate (0.026 lb a.i./A for sorghum vs.
0.11 lb a.i./A for rice).  The data from the corn trials support a 0.01
ppm tolerance on rice grain, and the information from the ongoing
aquatic dissipation study provides further evidence that residues are
expected to be low in the rice plants (although there is the issue of
the long PHI and there is not enough available information to determine
to what degree the rice plant itself may be diluting residues in the
grain).  Valent is currently conducting a wheat seed treatment residue
trial with NipsIt INSIDE.  To date, with a 1x application rate (60 g
a.i./100 kg seed), the residue levels in wheat grain from 22 locations
have been less than the LOQ of 0.01 ppm.  A 5x application rate (300 g
a.i./100 kg) was used at one location, and the residue level in the
wheat grain is also less than the LOQ of 0.01 ppm.  Information
regarding the planting rate was not provided; therefore OPP cannot
determine the field equivalent rate in terms of pounds a.i./A.

Based on the available data and the nature of the application, elevated
residues of clothianidin are not expected in processed rice commodities.
 The available data support a 0.01-ppm time-limited tolerance for
residues of clothianidin in/on rice grain which will cover residues in
other regulated rice commodities.

5.3	Water Residue Profile

The Environmental Fate and Effects Division (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 (J. Meléndez, D360266, 4 August 2009).  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 thiamethoxam environmental fate studies.  Therefore, exposure
to clothianidin in drinking water due to thiamethoxam uses is not
expected.  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 scenarios and 1.35 ppb for chronic
risk.  Clothianidin EDWCs in groundwater are not expected to exceed 5.88
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 5.88 ppb from groundwater for
chronic exposures).  EFED has confirmed that the requested experimental
seed-treatment use on rice will not result in higher EDWCs than those
previously provided.

Table 5.3.  Summary of Estimated Surface Water and Groundwater
Concentrations for Clothianidin.

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

Acute	7.29	5.88

Chronic (non-cancer)	1.35	5.88

a From the Tier I FIRST model.  Input parameters are based on use of
clothianidin on turf grass.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.4 lb
ai/A, a Koc of 84, and a half-life of 744 days.

5.4	Dietary Risk Assessment

As previously noted, clothianidin is a metabolite of thiamethoxam.  When
assessing thiamethoxam, a separate assessment is conducted for
clothianidin in order to take into account residues of clothianidin
coming from thiamethoxam.  In assessing use of thiamethoxam on rice,
residue estimates of 0.01 ppm in/on rice commodities were included in
the clothianidin assessment.  Therefore, new dietary exposure estimates
are not required to assess risks associated with this EUP.  The most
recent clothianidin dietary assessment (M. Doherty, D364363, 11 August
2009) is based on tolerance-level residue levels and an assumption that
100% of registered crops are treated.  Exposure and risk estimates from
that assessment are summarized in Table 5.4, below.

Table 5.4.  Summary of Dietary Exposure and Risk Estimates for
Clothianidin (from M. Doherty, D364363, 11 August 2009).

Population Subgroup	Acute (95th Pecentile of Exposure)	Chronic

	Exposure, mg/day	Risk, % aPAD	Exposure, mg/day	Risk, % cPAD

U.S. Population (total)	0.015019	6	0.004582	5

All infants (< 1 year)	0.048266	19	0.012680	13

Children 1-2 yrs	0.057317	23	0.018429	19

Children 3-5 yrs	0.039089	16	0.012188	12

Children 6-12 yrs	0.018014	7	0.005801	6

Youth 13-19 yrs	0.011055	4	0.003194	3

Adults 20-49 yrs	0.010157	4	0.003229	3

Adults 50+ yrs	0.010121	4	0.003438	4

Females 13-49 yrs	0.010797	4	0.003325	3

The population subgroup(s) with the highest exposure/risk estimates are
shown in bold.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

The non-occupational/residential exposure/risk assessment is based on
the HED’s previous assessment (M. Dow, D296176, 24 February 2004). 
The results of this assessment are summarized as follow:

There is a registered use for clothianidin on turf and, therefore,
residential and recreational post-application exposures are possible.

Although residential handler exposure is not expected from the currently
registered uses of clothianidin, owing to the absence of products
registered for homeowner use, the exposure estimates in Table 6 (below)
do include adult exposure from commercial application to turfgrass via
granular push-type spreader as well as from a basal bark application to
ornamental trees.  This represents an overestimate of total exposure
from registered uses.  HED also recently assessed a pending ornamental
tree use where residents could be exposed as applicators (S. Wang,
D375369, 30 September 2010).  The residential handler MOE for this use
was 2600, which is not of concern.

The MOEs for the residential post-application exposures/risks range from
1,300 to 490,000 (Table 6.0).  MOE values greater than 100 are
considered adequate to protect adults and children from residential
non-dietary post-application exposures to clothianidin.  The estimated
MOE’s are based upon conservative assumptions and are >1000;
therefore, the estimated risks from residential non-dietary
post-application exposures do not exceed HED’s level of concern.

Table 6.0.  Summary of Residential Post-Application Exposure and Risk
Estimates.

Activity	Exposure (Dose)

mg a.i./kg bw/day	MOE

Adult dermal application to turf	0.000026	370,000

Adult dermal post-application turf contact	0.00108	9,100

Adult golfer post-application turf contact	0.000075	130,000

Adult basal bark application (from S. Wang, D375369, 30 September 2010)
0.003798	2,600

Adult combined	0.004979	1,900

Toddler oral hand to mouth from contacting treated turf	0.0059	1,700

Toddler incidental oral ingestion of treated soil	0.00002	490,000

Toddler dermal post-application turf contact	0.00155	6,300

Toddler combined	0.00747	1,300

6.1	Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
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 (see the Agency’s Spray Drift website for more information
at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a
chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling.  The Agency has completed its evaluation of the
new database submitted by the Spray Drift Task Force, a membership of
U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

It is noted that the 0.4 lb ai/acre application rate for turf was
modeled to estimate postapplication 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.

7.0	Aggregate Exposure/Risk Characterization

As noted above, dietary and residential exposure estimates associated
with this EUP have already been addressed by previous assessments. 
Therefore, aggregate risk estimates have not changed from those
developed previously.  Results from the previous assessment are
summarized in the sections below.

7.1	Acute Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that
constitute an acute exposure scenario; therefore, acute aggregate
exposure and risk estimates are equivalent to the acute dietary exposure
and risk estimates summarized in Table 5.4 and are below HED’s level
of concern.

7.2	Short- and Intermediate-Term Aggregate Risk

All of the short- and intermediate-term aggregate MOEs are greater than
100 (Table 7.2) and, therefore, represent risks that are below HED’s
level of concern.

Table 3.  Summary of the Short- and Intermediate-Term Aggregate Exposure
and Risk Estimates for Clothianidin.

Population Subgroup	Total Residential Exposure, mg/kg/day	Chronic
Dietary Exposure, mg/kg/day	Aggregate Exposure1, mg/kg/day	MOE2

U.S. Population (total)	0.004979	0.004582	0.009561	10,00

All infants (< 1 year)	0.00747	0.012680	0.020150	480

Children 1-2 yrs	0.00747	0.018429	0.025899	380

Children 3-5 yrs	0.00747	0.012188	0.019658	500

Children 6-12 yrs	0.004979	0.005801	0.010780	910

Youth 13-19 yrs	0.004979	0.003194	0.008173	1,200

Adults 20-49 yrs	0.004979	0.003229	0.008208	1,200

Adults 50+ yrs	0.004979	0.003438	0.008417	1,200

Females 13-49 yrs	0.004979	0.003325	0.008304	1,200

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

1 Aggregate Exposure = Residential Exposure + Chronic Dietary Exposure

2 Aggregate MOE = NOAEL (9.8 mg/kg/day) ÷ Aggregate Exposure
(mg/kg/day)

7.3	Chronic Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that
constitute a long-term exposure scenario; therefore, long-term aggregate
exposure and risk estimates are equivalent to the chronic dietary
exposure and risk estimates summarized in Table 5.2 and are below
HED’s level of concern.

7.4	Cancer Aggregate Risk

Clothianidin has been classified as “not likely to be carcinogenic to
humans.”  Therefore, cancer risk is not a concern for this chemical.

8.0	Cumulative Exposure/Risk Characterization

Clothianidin is a member of the neonicotinoid class of pesticides and is
a major 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 nAChRs, 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 (such as testicular tubular atrophy with thiamethoxam,
and mineralized particles in thyroid colloid with imidacloprid).  Thus,
there is currently no evidence to indicate that neonicotinoids share
common mechanisms of toxicity, and EPA is not following a cumulative
risk approach based on a common mechanism of toxicity for the
neonicotinoids.  For information regarding EPA’s efforts to determine
which chemicals have a common mechanism of toxicity, and to evaluate the
cumulative effects of such chemicals, see the policy statements
concerning common mechanism determinations, and procedures for
cumulating effects from substances found to have a common mechanism,
released by OPP 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.  Labeling for formulations containing either of these
compounds specifies that other neonicotinoid insecticides are not to be
applied during the growing season (i.e., a crop treated with
clothianidin will not be treated with thiamethoxam).  Therefore, the
assumption of 100% crop treated for both the acute and chronic dietary
assessments obviates the need to account for potential uses of both
chemicals on a given crop.

9.0	Occupational Exposure/Risk Characterization

The number of exposure days per year was not provided as part of the
petition.  Based on the frequency/interval of applications in typical
seed treatment operations, EPA assumes that both application handlers
and secondary seed handlers would be exposed for less than 6 months per
year (short- and intermediate-term exposures).  Long-term exposures are
not expected.

9.1	Short- and Intermediate-Term Handler Risk

The 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) and
based on the treating/planting data from the Exposure SAC Policy #15 &
Policy # 14: Amount of Seed Treated or Planted Per Day (March 2, 2004). 
 

All MOEs calculated for commercial seed treatment handlers
(loader/applicator, sewer, bagger, and multiple activities seed
treatment workers) are greater than 100 at the baseline level (single
layer + gloves for loader/applicator and multiple activities worker;
single layer + no gloves for sewer and bagger) and therefore do not
exceed HED’s level of concern.  Handler exposure and risk estimates
are summarized in Table 9, below.

9.2	Short- and Intermediate-Term Post-Application Risk

Occupational post-application risk for seed treatments is assessed for
workers planting treated seeds (secondary seed handlers).  The MOE for
secondary seed handlers is also greater than 100 (Table 9) at the
baseline level (single layer + gloves) and does not exceed HED’s level
of concern.  

Based on the Agency's current practices, a quantitative occupational
post-application inhalation exposure assessment was not performed for
clothianidin at this time.

Table 9.  Summary of Occupational Exposure and Risk Estimates Associated
with Rice Seed Treatment with Clothianidin.

Activity	Mitigation Level	Combined Daily Dose, mg/kg/day a	MOE b

Seed-Treatment Handlers

Loading/Applying Liquid	Single Layer, Gloves	0.00511	1,900

Bagging Treated Seeds	Single Layer, No Gloves	0.00225	4,400

Sewing Bags of Treated Seeds	Single Layer, No Gloves	0.00262	3,700

Multiple Activities	Single Layer, Gloves	0.0181	540

Secondary Seed Handlers (Post-Application)

Planting Seeds	Single Layer, Gloves	0.00221	4,400

a Combined Daily Dose = Daily dermal dose + daily inhalation dose (from
D376358, S. Wang, 22 October 2010).

b MOE = NOAEL (9.8 mg/kg/day) ÷ Combined Daily Dose.  Level of concern
= 100.

10.0	Incidents

No public health or epidemiological data were used for this risk
assessment.

11.0	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," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food 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.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
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.

12.0	References

D355373.  Clothianidin: Human Health Risk Assessment for Proposed Uses
on Berries (Group 13-07H), Brassica Vegetables (Group 5), Cotton,
Cucurbit Vegetables (Group 9), Fig, Fruiting Vegetables (Group 8), Leafy
Green Vegetables (Group 4A), Peach, Pomegranate, Soybean, Tree Nuts
(Group 14), and Tuberous and Corm Vegetables (Group 1C).  Memorandum
from M. Doherty et al., to K. Davis.  13 August 2009.

D376357.  Clothianidin; Petition for Time-Limited Tolerance and
Experimental Seed Treatment Use on Rice.  Summary of Analytical
Chemistry and Residue Data.  Memorandum from M. Doherty to J. Hebert. 
28 October 2010.

D364363.  Clothianidin Acute and Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk Assessments.  Memorandum from M.
Doherty to M. Doherty, D. McNeilly, and K. Davis.  11 August 2009.

D296176.  CLOTHIANIDIN - Exposure/Risk Assessment for the Proposed New
Uses of Clothianidin on Turfgrass, Landscape Ornamentals and Tobacco. 
Memorandum from M. Dow to C. Swartz. 24 February 2004.

D376358.  Clothianidin: Occupational and Residential Exposure/Risk
Assessment for Proposed Seed treatment Use of Clothianidin on Rice. 
Memorandum from S. Wang to J. Hebert.  22 October 2010.

Clothianidin Human Health Risk Assessment	DP No. 376087

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