                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                 	OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION
	


MEMORANDUM

	Date:	1 February 2012

	SUBJECT:	Clothianidin  -  Human Health Risk Assessment for Requested Foliar Uses on Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit.  

PC Code:  044309
DP Barcode:  D387290, D389529
MRID Nos.:  48364801, 48364802, 48438001
Registration Nos.:  59639-150, 59639-151
Petition No.:  1F7832
Regulatory Action:  Section 3
Assessment Type:  Single Chemical, Aggregate
Registration Case No.:  7620
TXR No.:  None
CAS No.:  210880-92-5
Decision Nos.: 444551, 447268
40 CFR 180.586

	FROM:	Michael A. Doherty, Ph.D., Senior Chemist
		Alan Levy, Ph.D., Toxicologist
		Suku Oonnithan, Biologist
		Shih-Chi Wang, Ph.D., Biologist
		Risk Assessment Branch II
		Health Effects Division (7509P)

	THROUGH:	Margarita Collantes, Biologist
		Zaida Figueroa, Industrial Hygenist
		Elizabeth Holman, Chemist
		Karlyn Middleton, Toxicologist
		Richard A. Loranger, Senior Scientist
		Christina Swartz, Branch Chief
		Risk Assessment Branch II
		Health Effects Division (7509P)

	TO:	Marianne Lewis/Venus Eagle, RM 01
		Insecticide-Rodenticide Branch 
		Registration Division (7505P)





1.0  Executive Summary	4
2.0  HED Recommendations	4
2.1  Data Deficiencies/Conditions of Registration	4
2.2  Tolerance Considerations	5
2.2.1  Enforcement Analytical Method	5
2.2.2  International Harmonization	5
2.2.3  Recommended Tolerances	5
2.2.4  Revisions to Petitioned-For Tolerances	5
2.3  Label Recommendations	5
3.0  Introduction	6
3.1  Chemical Identity	6
3.2  Physical/Chemical Characteristics	6
3.3  Pesticide Use Pattern	7
3.4	Anticipated Exposure Pathways	7
3.5	Consideration of Environmental Justice	7
4.0	Hazard Characterization and Dose-Response Assessment	8
4.1	Toxicology Studies Available for Analysis	8
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	8
4.2.1	Dermal Absorption	9
4.3	Toxicological Effects	9
4.4	Safety factor for Infants and Children (FQPA Safety Factor)	9
4.4.1	Completeness of the Toxicology Database	10
4.4.2	Evidence of Neurotoxicity	10
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	10
4.4.4	Residual Uncertainty in the Exposure Database	11
4.5	Toxicity Endpoint and Point of Departure Selections	11
4.5.1	Dose-Response Assessment	11
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	11
4.5.3	Cancer Classification and Risk Assessment Recommendation	11
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	11
5.0	Dietary Exposure and Risk Assessment	13
5.1	Metabolite/Degradate Residue Profile	13
5.1.2	Residues of Concern Summary and Rationale	13
5.2	Food Residue Profile	13
5.3	Water Residue Profile	14
5.4	Dietary Risk Assessment	15
5.4.1	Description of Residue Data Used in Dietary Assessment	15
5.4.2	Percent Crop Treated Used in Dietary Assessment	15
5.4.3	Dietary Exposure and Risk Estimates	15
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	16
6.2	Residential Bystander Post-Application Inhalation Exposure	19
6.3	Spray Drift	19
7.0	Aggregate Exposure/Risk Characterization	20
7.1	Acute Aggregate Risk	20
7.2	Short- and Intermediate-Term Aggregate Risk	20
7.3	Chronic Aggregate Risk	21
7.4	Cancer Aggregate Risk	21
8.0	Cumulative Exposure/Risk Characterization	21
9.0	Occupational Exposure/Risk Characterization	22
9.1	Short- and Intermediate-Term Handler Risk	22
9.2	Short- and Intermediate-Term Post-Application Risk	25
10.0	References	26
Appendix A.  Toxicology Profile	27
A.1.  Toxicology Data Requirements	27
a The subchronic inhalation study is required.  HED has recommended that this study be called in to support registration review.  As discussed in Section 2.1, it is not being required to support the requested uses.	27
A.2.  Toxicity Profiles	28

1.0  Executive Summary

Valent U.S.A. Corporation, one of the registrants for clothianidin, has submitted two petitions regarding expanded uses of the insecticide.  The first, PP# 1F7832, requests the following three actions:  (1) register clothianidin for foliar and seed treatment uses on rice; (2) increase the application rate from 4 fl. oz/A/application to 6 fl. oz/A/application for vegetables; and (3) modify the crop listing for fruiting vegetables (Crop Group 8) and pome fruits (Crop Group 11) to include the most recent definitions for those crop groups (08-10 and 11-10, respectively).  The second is a request to register a seed treatment for leafy green vegetables (Crop Subgroup 4A).  There is no petition number associated with the second request (i.e., there are no tolerance actions associated with the request).  The end-use products for these actions are V-10170 5 FS (EPA Reg. No. 59639-151) for the seed treatment uses and V-10170 2.13 SC (EPA Reg. No. 59639-150) for the foliar uses.

HED has evaluated the toxicological and residue chemistry databases associated with clothianidin, and has determined that there are no human health risk issues that would preclude granting the requests.

2.0  HED Recommendations

Rice.  HED recommends granting the requested registrations and establishing a permanent tolerance for residues of clothianidin in/on rice, grain at 0.01 ppm.  Upon establishment of the permanent tolerance, the existing time-limited tolerance can be removed from the CFR.

Label Amendment  -  Foliar Application Rate to Vegetables.  HED recommends amending the submitted proposed label for V-10170 2.13 SC to allow applications of up to 6 fl. oz of product (0.1 lb a.i.) per acre per application.  The maximum allowable application per acre per season should not be increased.  The rate increase does not require changes to existing tolerance levels.

Expansion of Crops for Groups 8 and 11.  No new data have been submitted regarding this request.  Data requirements for these crop groups have already been met.  The revised definitions of these groups did not result in changes to the representative commodities relative to the previous definition.  HED recommends expanding the crops listed on the label to those defined as Crop Group 8-10 and Crop Group 11-10 in 40 CFR 180.41.  

Seed Treatment of Leafy Green Vegetables (Crop Subgroup 4A).  HED recommends amending the submitted proposed label for V-10170 5 FS to include crops in Crop Subgroup 4A.  Tolerances for residues of clothianidin in/on these crops are already established and are based on foliar applications.  No revisions to the current tolerances are necessary to accommodate the requested seed-treatment use.

2.1  Data Deficiencies/Conditions of Registration

There are no data deficiencies or conditions of registration associated with the requested actions.  The toxicological database for clothianidin lacks a subchronic inhalation study.  HED has recommended that this study be required to support registration review; it is not required at this time.  Currently, all inhalation margins of exposure (MOEs) associated with residential scenarios are greater than or equal to 170,000 and indicate that a subchronic inhalation study will have no significant impact on our conclusions that residential and aggregate risks are not of concern.  Occupational inhalation MOEs range from 340 to over 170,000.  The MOEs at the low end of the range are associated with secondary handlers of pelletized lettuce seed or multiple-activity seed treatment scenarios.  HED does not have inhalation unit exposure estimates that are specific to either low-acreage crops, such as lettuce, or pelletized seed treatment.  The unit exposure values used to assess inhalation exposure during secondary handling of pelletized lettuce seed are based on information from standard seed treatment of high-acreage crops (e.g., corn, wheat, soybeans) and are considered to be extremely conservative when used to assess the lettuce scenarios.  Similarly, the assumptions used to assess multiple-activity seed treatment scenarios result in very conservative estimates of exposure and risk.  For these reasons, HED has determined that it is not appropriate in this case to apply an additional uncertainty factor to account for the lack of the subchronic inhalation study.

2.2  Tolerance Considerations

2.2.1  Enforcement Analytical Method

The current tolerance enforcement method, a liquid chromatography tandem mass spectroscopy (LC-MS/MS) method, is available to enforce tolerances for residues of clothianidin.

2.2.2  International Harmonization

There are no international harmonization issues associated with these actions.

2.2.3  Recommended Tolerances

Granting the requests regarding the increased application rate to vegetables and the seed treatment of leafy green vegetables does not involve any changes to existing tolerances for residues of clothianindin.  For the requests regarding uses on rice, fruiting vegetables, and pome fruit, HED recommends the following changes in the Code of Federal Regulations:
      * 40 CFR 180.586(a)(1)
            o Add "Rice, grain" at 0.01 ppm to the tolerance table,
            o Change "Fruit, pome" to "Fruit, pome, group 11-10," and
            o Change "Vegetables, fruiting, group 8" to "Vegetables, fruiting, group 8-10."
      * 40 CFR 180.586(a)(2)
            o Remove this section completely as it is no longer needed.

2.2.4  Revisions to Petitioned-For Tolerances

None.

2.3  Label Recommendations

None.

3.0  Introduction

3.1  Chemical Identity

Table 3.1.  Clothianidin Nomenclature.
Compound
                                       
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)
Chemical class
Neonicotinoid
End-use products
V-10170 5 FS (EPA Reg. No. 59639-151), 
V-10170 2.13 SC (EPA Reg. No. 59639-150)
Known impurities of concern
None

3.2  Physical/Chemical Characteristics

The vapor pressure and octanol/water partition coefficient for clothianidin (Table 3.2) suggest that there is low potential for exposure to this chemical in the vapor phase and low potential for bioaccumulation.  The physicochemical properties of clothianidin do not provide much insight regarding the potential for dermal absorption of this compound.

Table 3.2.  Physicochemical Properties of Clothianidin.
Parameter
Value
Reference
Melting point, ºC
176.8
D335355, W. Drew, 10/16/07
Molecular wt.
249.68

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

Density, g/cm[3]
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 (at 25ºC)
1.3 x 10[-10] Pa, 9.75 x 10[-13] mm Hg

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  Pesticide Use Pattern

Table 3.3.1.  Proposed Use Pattern for Clothianidin as Foliar Treatments for Rice.
                          Reg. No., Form type, &
                                   AI or AE
                                     Crop
         Applic. Timing,                            Type, and Equip. 
                            Max. Applic. Rate, [1]
                                    lb ai/A
                        Max. No. Applic. per Season [2]
                          Max. Seasonal Applic. Rate,
                                    lb ai/A
                                   PHI, [3]
                                     days
      EPA Reg. No. 59639-150,             V-10170 2.13 SC  Insecticide, 
                               23.60% ai, Liquid
                                     Rice
Foliar Application: Ground + Aerial
                                     0.075
                                       1
                                     0.075
                                Not Applicable
[1] Rate = Maximum application rates as specified on proposed labels.
[2] Maximum number of applications allowed on the proposed label.
[3] PHI = Pre-harvest Interval.  For this use, application may not occur after tillering has initiated (BBCH Growth Stage 21). 

Table 3.3.2.  Proposed Application Rate of Clothianidin on Rice and Leafy Green Vegetable Seeds.
                                   Product  
                                   Vegetable 
                                    Crops 1
                              Application  Method
                          Max. Appl. Rate, mg ai/seed
                                No. of seeds/lb
                            (representative crops) 
                                   lb ai/lb
                                    of seed
                                 EPA Reg. No.
                                  59639-151,
                          V-10170 5 FS, Insecticide,
                               47.8% ai, Liquid
Rice (dry-seeded)
Commercial equipment utilizing standard liquid or slurry treaters
                                Not Applicable
                                Not Applicable
0.00075
                                       
Short-season crops (Parsley)
Liquid Open-Pour Mix/Load System 
0.05
454,000
0.05

Spinach group (Spinach)

0.15
45,360
0.015

Full-season crops (Head lettuce)
Pelletized 
0.4
480,000
0.42



1.5
                                       
1.59
[1] Representative crops that have seed weights in ExpoSAC Policy #15 are in parenthesis. 

3.4	Anticipated Exposure Pathways

Clothianidin is registered for use on a number of agricultural row and orchard crops, as well as turf and ornamental plants in a residential setting.  As a result of these uses, humans may be exposed to clothianidin in their diet and from activities on golf courses, lawns, and around home exteriors.  Application of clothianidin to agricultural crops may result in clothianidin migration to surface and/or groundwater sources of drinking water, making drinking water a potential pathway of exposure.  Persons involved in agricultural occupations may be exposed to clothianidin during handling of clothianidin-containing products prior to application, during application, and during post-application activities.

This risk assessment addresses these exposure pathways as well as the potential for aggregate exposures from multiple pathways. 

3.5	Consideration of Environmental Justice

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 from pesticide exposures to population subgroups 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 after 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.

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, with the exception of a subchronic inhalation study.  The scientific quality of the available studies 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 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 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 residues 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).

The toxicological database lacks a subchronic inhalation study.  Based on the use pattern, inhalation exposure is anticipated; therefore, a subchronic (21/28-day) inhalation toxicity study (870.3465) is required and will be called in to support registration review (D391496, M. Doherty et al., 8 December 2011).  As discussed in Section 2.1, a database-uncertainty factor is not being used to account for the lack of the subchronic inhalation study.   

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, and
	Developmental immunotoxicity study in rats.

4.4.2	Evidence of Neurotoxicity

Clothianidin was tested in the following 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 at the LOAEL; 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 observed included decreased body weights, body weight gains and food consumption at the high dose.  In offspring decreased body weights, body weight gains, motor activity and acoustic startle response were seen at a lower dose.

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 evidence of increased quantitative or qualitative susceptibility was observed in the developmental rat or rabbit studies, increased quantitative susceptibility was seen in both the developmental neurotoxicity and rat reproduction studies.  In both studies, offspring toxicity was seen at doses lower than doses that caused maternal toxicity.  However, HED determined that the degree of concern for the developmental neurotoxicity and reproduction studies 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 determined for toxic effects seen.

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), clothianidin is classified as "Not Likely to be Carcinogenic to Humans." 

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/pharmacology
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
LOC= 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
LOC= 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 toxicity considered equivalent to oral toxicity)
UFA= 10X
UFH= 10X
SFFQPA=1
LOC= 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).    FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  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
LOC= 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 toxicity considered equivalent to oral toxicity)
UFA= 10X
UFH= 10X
SFFQPA=1
LOC= 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).    FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  LOC = level of concern.  N/A = not applicable.
 
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 HED in 2003.  The clothianidin risk assessment team concurs with the previous findings 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.  

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
Crops except Leafy and Root/Tuber Vegetables: Parent 
Leafy and Root/Tuber Vegetables:  Parent + 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

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

The petitioner has submitted data, from studies conducted at an exaggerated rate, depicting residues of clothianidin in/on rice grain following foliar or seed treatment applications of clothianidin.  No new data were submitted to support the other requests (increased application rate for vegetables, seed treatment of leafy vegetables, and expansion for crop groups 8 and 11 to include the 2010 definitions); rather, these requests are supported by previously submitted/reviewed data.  In summary, the uses on rice resulted in no quantifiable residues; the requested rate increase for vegetables brings the application rate up to the level used in the field trials (reviewed in 2009); residues resulting from seed treatment of leafy vegetables are expected to be significantly less than those resulting from foliar application (a registered use pattern), without any increase to the overall field loading of clothianidin; and the expansions from Crop Group 8 to Crop Group 8-10 and from Crop Group 11 to Crop Group 11-10 are supported by the data submitted to originally register those uses and establish tolerances.

A full discussion of the residue chemistry evaluation can be found in D395799 (M. Doherty, 1 February 2012).

5.3	Water Residue Profile

Based on available data, clothianidin is persistent under most field and laboratory conditions and is mobile to highly mobile based on laboratory adsorption tests.  The Environmental Fate and Effects Division (EFED) has supplied HED with Tier I estimated drinking water concentrations (EDWC) for clothianidin in surface water resulting from foliar application to rice.  The assessment also addresses residues resulting from the seed treatment of leafy vegetables.  EDWCs from that use are significantly lower than those associated with the use on rice (Table 5.3).
      
EFED used the Tier I Rice Model (v 1.0) as a screening model to calculate the surface water EDWC resulting from a single foliar application of clothianidin to a flooded field (as proposed on the label).  This concentration represents the estimated concentration that would be expected in the release water downstream of the treated rice paddy.  FIRST (FQPA Index Reservoir Screening Tool, version 1.1, 01/01/07) was used to calculate the surface water EDWC resulting from a single foliar application to leafy vegetables.
      
The concentrations predicted in release water from rice paddies treated with clothianidin were compared to two (2) aquatic field dissipation studies - one in California, one in Louisiana - that are currently under review by the Agency (MRID 48364804, MRID 48364803).  The maximum concentration at day zero, pre-irrigation, was 210 ppb in the Louisiana plot cropped with rice.  Clothianidin residues quickly dissipated to an average of 74.1 ppb three days after application, and further dissipated to 0.7 ppb 28 days after application.  The California plots show similar dissipation results with a maximum clothianidin concentration of 51.9 ppb at day zero, quickly dissipating to an average of 1.1 ppb ten days after application in the plots cropped with rice.  These interim results show that Tier I rice estimate may under estimate the initial exposure in the rice paddy soon after application, but it is a conservative estimate of clothianidin concentrations in release water shortly after application occurs.

Table 5.3.  Tier I EDWCs for drinking water risk assessment based on the proposed clothianidin use on rice and leafy vegetables
Use (application rate, lbs a.i./A)
Model
                                     Acute
                                    Chronic
Surface water drinking water sources, downstream of rice paddy (0.084 lb a.i./A)
Tier I Rice Model (v1.0)
                                    72 ppb
                                  <72 ppb
Leafy vegetables (including brassica) (0.05 lb a.i./A)
FIRST
                                    4.0 ppb
                                    2.2 ppb

The EDWC of 72 ppb has been used to account for residues of clothianidin in both the acute and chronic dietary risk assessments.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary assessments (D395798, M. Doherty, 1 February 2012) rely on tolerance-level residues for all crops with registered and/or requested clothianidin uses.  There are a number of crops for which uses of both clothianidin and thiamethoxam have been registered.  The labels for the various end-use products containing these active ingredients prohibit the application of both active ingredients to the same crop during a growing cycle.  Due to that restriction and the assumption of 100% crop treated, a single value reflecting the greatest clothianidin residue from either active ingredient has been used for crops listed for use with both active ingredients (versus combined estimates from clothianidin and from thiamethoxam).  Generally, this assessment uses the established or recommended clothianidin tolerance for crops having tolerances for both compounds (Subgroup 13G, based on observed clothianidin residues in thiamethoxam strawberry field trials, being the exception).  For foods with thiamethoxam tolerances but without clothianidin tolerances, maximum residues of clothianidin observed in thiamethoxam field trials have been used in these assessments.

5.4.2	Percent Crop Treated Used in Dietary Assessment

Both the acute and chronic dietary assessments assumed that all crops with uses of either clothianidin or thiamethoxam were treated (i.e., 100% crop treated).

5.4.3	Dietary Exposure and Risk Estimates

The results of the screening-level dietary exposure assessments are summarized in Table 5.4.3.  For both the acute and chronic analyses, the greatest exposure estimate is for the population subgroup Children 1-2 years old.  Risk estimates for this subgroup are 24% aPAD and 21% cPAD.  These estimates are well below HED's level of concern (typically 100% of the PAD).

Clothianidin has been classified as "Not Likely to be Carcinogenic to Humans;" therefore, there are no cancer risks associated with exposure to clothianidin.

Table 5.4.3.  Summary of Dietary Exposure and Risk Estimates for Clothianidin.
Population Subgroup
                     Acute (95[th] Pecentile of Exposure)
                                    Chronic

                               Exposure, mg/day
                                 Risk, % aPAD
                               Exposure, mg/day
                                 Risk, % cPAD
U.S. Population (total)
0.017373
7
0.006107
6
All infants (< 1 year)
0.054584
22
0.017497
18
Children 1-2 yrs
0.059972
24
0.020868
21
Children 3-5 yrs
0.041530
17
0.014497
15
Children 6-12 yrs
0.020012
8
0.007335
8
Youth 13-19 yrs
0.012230
5
0.004312
4
Adults 20-49 yrs
0.012257
5
0.004636
5
Adults 50+ yrs
0.011920
5
0.004882
5
Females 13-49 yrs
0.012765
5
0.004737
5
The population subgroup(s) with the highest exposure/risk estimates are shown in bold.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are no new or proposed residential uses associated with this action.  This assessment provides the most recent residential exposure assessment which includes revised residential handler exposure estimates for use on turf (see assessments by G. Bangs, 12/1997, and M. Dow, D296176, 2/24/2004) and tree trunks (S. Wang, D375369, 9/30/2010).  No chemical specific unit exposure data were available for this assessment; therefore, the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (June 2011) and the Outdoor Residential Exposure Task Force (ORETF) study (MRID 44972201) unit exposures were used to estimate handler exposures.  HED's level of concern (LOC) is equal to a margin of exposure (MOE) of 100 for residential exposure.  

Handler dermal, inhalation and total exposure scenarios resulted in MOEs greater than 100 and therefore are not of concern.  Although a point of departure from an oral study was used to assess the handler inhalation risks, the calculated inhalation MOEs are all >170,000, thus providing a suitable margin of safety to account for any uncertainties in the route-to-route extrapolation.  Handler exposure and risk estimates are summarized in Table 6.1.  Residential postapplication exposure estimates for use of clothianidin on turf resulted in MOEs greater than 100 and, therefore, are not of concern.  HED does not assess postapplication exposure resulting from use on ornamental plants as it is not likely that individuals would have continuous contact with such sites on a regular basis.  Postapplication exposure resulting from treated ornamentals is expected to be minimal and protected by the broadcast turf scenario assessment.  Postapplication exposure and risk estimates are summarized in Table 6.2  








Table 6.1:  Residential Handler Exposure and Risk Estimates for Clothianidin
Scenario
                          Unit Exposure, [1] mg/lb ai
                             Application Rate [2]
                                       
                              Amount Treated [3]
                                Dose, mg/kg/day
                                    MOE [7]

                                    Dermal
                                  Inhalation
                                       
                                       
                                  Dermal [4]
                                Inhalation [5]
                                   Total [6]
                                    Dermal
                                  Inhalation
                                     Total
Granular Push-Type Spreader
Turf
Arena 0.5G 
Reg. No. 59639-156
0.67
0.00088
                                      0.4
                                    lb ai/A
0.5 A
0.00002233
0.00000293
0.0000253
440,000
3,300,000
390,000
Hose-End Sprayer
Fruit trees & ornamentals
Arena 50 WDG
Reg.No. 59639-156
39
0.0015
                                     0.15
                                  lb ai/gal.
5 gals
0.004875
0.00001875
0.004894
2000
520,000
2000
Hand-Held Pump Sprayer 
Fruit trees & ornamentals
Arena 50 WDG
Reg.No. 59639-156
56
0.0038
                                    0.0004
                                  lb ai/gal.

0.0000187
0.000000126
0.000018
520,000
77,000,000
520,000
Hose-End Sprayer
Lawn
Arena 50 WDG
Reg.No. 59639-156
11
0.017
                                      0.4
                                    lb ai/A
0.5 A
0.000367
0.0000566
0.000423
27,000
170,000
23,000
1.	All scenarios use Occupational Residential Exposure Task Force (ORETF) Study Data (MRID 449722-01)
2.	Label application rate = 0.4 lb ai/acre for turf ; 0.15 lb ai/gal. for tree trunks; and 0.0004 lb ai/gal for ornamentals
3.	Policy 12: Recommended Revision to the SOPs for Residential Exposure Assessment
4.	Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) x application rate (lb ai/A or gal.) x amount treated x DAF (.01) / body weight (60 kg).
5.	Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) x application rate (lb ai./A or gal) x amount treated / body weight (60 kg). 
6	Total Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day)
7.	MOE = NOAEL (9.8 mg/kg/day) / Dose (mg/kg/day)
   
Table 6.2:  Residential Postapplication Exposure and Risk Estimates for Clothianidin
                                   Lifestage
                      Postapplication Exposure Scenarios
                                    Dose[1]
                                    MOE[1]
                                     Adult
                                    Golfer
                                    Dermal
0.000075
130,000
                                       
                                       
                                  Inhalation
                                      NA
                                      NA
                                       
                                     Turf
                                    Dermal
0.00108
9,000
                                       
                                       
                                  Inhalation
                                      NA
                                      NA
                                     Child
                                     Turf
                                    Dermal
0.00155
6,300
                                       
                                       
                                  Inhalation
                                      NA
                                      NA
                                       
                                       
                                 Hand-to-mouth
0.0059
1,700
                                       
                                       
                                Soil Ingestion
0.00002
490,000
   1. M. Dow, D296176, 2/24/2004

Combined Residential Exposure Estimates

HED combines risk estimates resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and when similar toxicological effects occur from different routes of exposure.  HED reviewed all residential sources of exposure to determine which residential exposure scenarios would be appropriate to combine.
   
HED combined handler exposure resulting from treatment of residential lawns and ornamental tree trunks as it is probable that a homeowner would use the same pesticidal product to treat their lawn and ornamentals simultaneously on the same day.  However, HED did not combine exposure resulting from adult handler and postapplication exposure because of the conservative assumptions and inputs within each estimated exposure scenario.  The likelihood that a homeowner would treat their lawn and then repeatedly re-enter the treated site continuously for 30 days is minimal.  Furthermore, it is unlikely that a home owner would treat their lawn and then play golf on a course treated with the same pesticide on the same day.  HED believes that combining co-occurring exposures resulting from handler and postapplication exposure would result in an overestimate of adult exposure.  Therefore, HED selected the most conservative combined adult residential scenario, handler exposure (MOE = 1800) as the contributing source of adult residential exposure.  The adult combined handler exposure resulted in an MOE greater than HED's level of concern (LOC = MOE >= 100) and was not a risk of concern.
  
There is the potential for postapplication dermal and oral exposure for children resulting from use of clothianidin on turf.  A child's postapplication exposure assessment was not performed for use on ornamental tree trunks as children's contact with ornamentals is typically significantly less than turf.  Therefore a turf postapplication exposure assessment would be protective of postapplication exposure from ornamental uses.  The children's oral exposure is based on postapplication hand-to-mouth exposures only.  To include exposure from object-to-mouth and soil ingestion in addition to hand-to-mouth could result in a very conservative estimation of exposure as it would overestimate the potential of oral exposure.  Since the toxicological effects from the dermal and oral routes of exposure are the same, a total residential exposure assessment was conducted for children.  The total residential children's postapplication exposure assessment result in an MOE significantly greater than HED's LOC (MOE >=100) and is not a risk of concern. 

Table 6.2 summarizes the combined residential exposure scenarios and their risk estimates.


Table 6.3.  Combined Residential Exposure and Risk Estimates for Clothianidin
Combined Exposure Scenario
                                  Life-stage
                                 Total Handler
                                    MOE [1]
                                   Combined
                                Handler MOE [2]
                 Total Post-application Exposure, 3 mg/kg/day
                            Total Post-application 
                                    MOE [4]
Lawn/Turf
Spreader
Arena 0.5G [Reg. No. 59639-156]
                                     Adult
390,000
1800
0.00108
9,100
Lawn/Turf
Hose-End Sprayer
Arena 50 WDG [Reg.No. 59639-156]
                                     Adult
20,000

0.00108
9,100
Tree Trunk (Bark) Application
Hose-End Sprayer
Arena 50 WDG [Reg.No. 59639-156]
                                     Adult
2000

                                      NA
                                      NA
Tree Trunk (Bark) Application
Hand-Held Sprayer
Arena 50 WDG [Reg.No. 59639-156]
                                     Adult
520,000

                                      NA
                                      NA
Turf /Lawn
                                     Child
                                      NA
0.00745
1300
1.	From Table 6.1.
2.	1/(1/Total Handler MOE Arena 50 WDGTurf + 1/Total Handler MOE Arena 50 WDGTree Trunk Hose-End Sprayer)
3.	From Table 6.2.  For child, the total post-application exposure estimate is from dermal and hand-to-mouth exposures. 
4.	Total Postapplication MOE = NOAEL (9.8 mg/kg/day) / Total Postapplication Exposure (mg/kg/day)

6.2	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for clothianidin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (1.3 x 10[-10] Pa), and the low proposed use rate (not to exceed 0.2 lb a.i./A/season).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for clothianidin.

6.3	Spray Drift

Spray drift is always a potential source of exposure to residents nearby 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.

Although a quantitative residential post-application exposure assessment was not performed to address pesticide drift from neighboring treated agricultural fields, it is noted that residential exposure of children from use on turf and occupational exposure of flaggers during aerial application were assessed and were found to be not of concern.  Exposures from these scenarios are likely to be significantly greater than those associated with spray drift from agricultural applications of clothianidin.  By extension, therefore, risks associated with spray drift of clothianidin are expected to be also not of concern.

7.0	Aggregate Exposure/Risk Characterization

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

7.1	Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessing acute aggregate risk unless such exposures can be characterized as a series of single-day exposures, which is not the case for clothianidin.  Therefore, acute aggregate risk estimates for clothianidin are equivalent to the acute dietary risk estimates (Section 5.4) and are below HED's level of concern.  There are no acute aggregate risk issues that would preclude granting the actions requested by the registrant.

7.2	Short- and Intermediate-Term Aggregate Risk

Short-term aggregate assessments address exposures that may occur for durations of one to thirty days.  Intermediate-term assessments address exposures lasting from between thirty days to 6 months.  In the case of clothianidin, the endpoints and doses for risk assessment are the same for short- and intermediate-term exposures; therefore, separate assessments are not being conducted for these two durations.  Oral, dermal, and inhalation endpoints and doses for risk assessment are equal and were selected from the same study (two-generation reproduction study).  In order to assess aggregate risk, exposure estimates from residential sources (Section 6.3) are combined with the chronic exposure estimate from food and drinking water, which represents a background level of dietary exposure.  Aggregate exposures and risks are summarized in Table 7.2.  The level of concern for each exposure pathway is 100; thus, any MOE that is less than 100 indicates a potential risk of concern.  For clothianidin, all aggregate MOEs are greater than 100 and are not of concern to HED.  There are no short- or intermediate-term aggregate risk issues that would preclude granting the actions requested by the registrant.

Table 7.2.  Short- and Intermediate-Term Aggregate Exposure and Risk Estimates for Clothianidin.
Population Subgroup
                         Estimated Exposure, mg/kg/day
                               Aggregate MOE [4]

                           Combined Residential [1]
                                  Dietary [2]
                                 Aggregate [3]

Adults
0.0054
0.0049
0.0103
950
Children
0.0075
0.0145
0.0220
450
1 The value shown is the short-/intermediate-term NOAEL (9.8 mg/kg/day) divided by the MOE from Table 6.3.  For adults, the handler exposure estimate is greater than the post-application exposure estimate and is being used to assess aggregate exposure.
2 From Table 5.4.3.  Adult = Adults 50+ (highest adult exposure estimate). Children = Children 3-5 yrs.
3 Aggregate = Combined Residential + Dietary.
4 Aggregate MOE = short-/intermediate-term NOAEL (9.8 mg.kg.day) divided by the aggregate exposure.  Value rounded to two significant figures.

7.3	Chronic Aggregate Risk

Chronic aggregate risk assessments address exposures that are likely to occur, continuously, for greater than six months.  In the case of clothianidin, residential exposures are not expected to occur on a chronic basis; therefore, the chronic aggregate risk estimates are equivalent to the dietary risk estimates (Section 5.4.3) and are below HED's level of concern.  There are no chronic aggregate risk issues that would preclude granting the actions requested by the registrant.

7.4	Cancer Aggregate Risk

Clothianidin has been determined to be "not likely carcinogenic to humans."  Therefore, there is no cancer risk associated with exposure to clothianidin.

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 http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Characterization

9.1	Short- and Intermediate-Term Handler Risk

Based on the proposed use patterns, exposures may be of short- to intermediate-term durations.  Long-term exposure is not expected.  Both dermal and inhalation exposures are expected to be significant.  No chemical-specific data for assessing human exposure during pesticide occupational activities were submitted to the Agency in support of the proposed new uses.  Exposure estimates for foliar treatments were derived using data from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Outdoor Residential Exposure Task Force (ORETF) database. For seed treatments, exposure estimates were derived using data from the Science Advisory Council for Exposure (Exposure SAC) Policy #14: Standard Operating Procedures (SOP) for Seed Treatment (May 1, 2003) and the treating/planting data from the Exposure SAC Policy #15 & Policy # 14: Amount of Seed Treated or Planted Per Day (March 2, 2004).  For these assessments, female body weight (60 kg) was used since the doses for risk assessment are based on developmental endpoints.

Foliar Treatment on Rice 

Dermal and inhalation risks were combined, since the toxicological effects for the dermal and inhalations routes were the same.  MOEs for handler activities associated with foliar applications on rice, assuming PPE of single-layer + gloves, are greater than 100 and are not of concern (Table 9.1a).

Table 9.1a.  Short- and Intermediate-Term Occupational Exposure and Risk Estimates Associated with Foliar Application of Clothianidin on Rice.
Exposure Scenario
                                 PPE Level [1]
                         Unit Exposure, [2] ug/lb ai
                                 Appl.  Rate,
                                    lb ai/A
                          Acres  Treated per day [3]
                            Dose, [4,5,6] mg/kg/day
                                     Total
                                    MOE [7]


                                    Dermal
                                    Inhal.
                                       
                                       
                                    Dermal
                                    Inhal.
                                     Total

                                 Mixer/Loader
Liquids for Aerial Application
Baseline plus gloves
37.6
0.219
0.075
1200
0.00056
0.00033
0.00089
11,000
Liquids for Ground-boom Application 
Baseline plus gloves
37.6
0.219
0.075
200
9.4E-5
5.5E-5
0.00015
66,000
                                  Applicator
Sprays with Fix-Wing Aerial Equipment 
Enclosed cockpit
5.0
0.068
0.075
1200
0.00008
0.0001
0.00018
55,000
Sprays with Ground-boom Equipment 
Baseline plus gloves
16.1
0.34
0.075
200
0.00004
0.00009
0.00013
78,000
                                    Flagger
Flagging
Baseline plus gloves
12
0.35
0.075
350
0.00005
0.00015
0.00021
48,000
1.	PPE consists of long-sleeve shirt, long pants, shoes, and socks plus gloves.  
2.	Dermal and inhalation unit exposures are from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table.
3.	Acres treated values are from EPA estimates of acreage that could be treated in a day based on the appl. Method and formulation/packaging type.
4.	Dermal dose (mg/kg/day) =  unit dermal exposure (ug/lb ai) x (1 mg/1000 ug) conversion x application rate (lb ai/acre) x acres treated/day x dermal absorption rate (0.01) / body weight (60 kg).
5.	Inhalation dose (mg/kg/day) = unit exposure (ug/lb ai) x (1 mg/1000 ug) conversion x application rate (lb ai/acre) x acres treated/day / body weight (60 kg).
6.	Total dose (mg/kg/day) = Dermal dose/day + inhalation dose/day.
7.	Total MOE = NOAEL (9.8 mg/kg/day) / total dose/day.  

Primary Handlers for Seed Treatments on Rice and Leafy Vegetables

The dermal and inhalation exposures were combined to calculate a total MOE because the endpoint selected for both exposure routes is the same.  For seed-treatment activities on rice and leafy green vegetables, MOEs for all primary handler activities (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.  

Table 9.1b.  Occupational Handler Exposures and Risk Estimates Associated with Seed Treatment of Clothianidin:  Rice and Leafy Green Vegetables.
                             Seed Groups Treated 
                                      PPE
                                  Appl. rate
                                   lb ai/lb
                                   of seed 
                              Lbs. seeds treated
                                    per day
                                unit exposure, 
                               ug ai/lb ai [1]
                                     Dose,
                               mg/kg/day 2[,3,4]
                                    Total 
                                    MOE [5]
                                       
                                       
                                       
                                       
                                    Dermal
                                  Inhalation
                                    Dermal
                                  Inhalation
                                     Total
                                       
                               Loader/Treater  
Rice
B + G
0.00075
718,000
23
0.34
0.002061
0.003046
0.005107
1,900
Parsley

0.05
5,500
23
0.34
0.00105
0.00156
0.00261
3,800
Spinach 

0.015
5,500
23
0.34
0.00032
0.00047
0.00078
13,000
Lettuce [P]

0.42
500
23
0.34
0.00081
0.00119
0.002
4,900
Lettuce [P]

1.59
500
23
0.34
0.00305
0.00451
0.00755
1,300
                                    Bagger
Rice
B
0.00075
718,000
9.1
0.16
0.000815
0.001434
0.002249
4,400
Parsley

0.05
5,500
9.1
0.16
0.00042
0.00073
0.00115
8,500
Spinach 

0.015
5,500
9.1
0.16
0.00013
0.00022
0.00035
28,000
Lettuce [P]

0.42
500
9.1
0.16
0.00032
0.00056
0.00088
11,000
Lettuce [P]

1.59
500
9.1
0.16
0.00121
0.00212
0.00333
2,900
                                     Sewer
Rice
B
0.00075
718,000
6.2
0.23
0.000555
0.002061
0.002616
3,700
Parsley

0.05
5,500
6.2
0.23
0.00028
0.00105
0.00134
7,300
Spinach 

0.015
5,500
6.2
0.23
0.00009
0.00032
0.0004
24,000
Lettuce [P]

0.42
500
6.2
0.23
0.00022
0.00081
0.00102
9,600
Lettuce [P]

1.59
500
6.2
0.23
0.00082
0.00305
0.00387
2,500
                                Multiple Worker
Rice
B + G
0.00075
718,000
42
1.6
0.003763
0.014337
0.01810
540
Parsley

0.05
5,500
42
1.6
0.00193
0.00733
0.00926
1,100
Spinach 

0.015
5,500
42
1.6
0.00058
0.0022
0.00278
3,500
Abbreviation used: PPE= personal protective equipment; B = long-sleeved shirt, long pants and shoes with socks; G=gloves; MOE = margin of exposure; [P] = pelleted seed treatment. 
1.	Dermal and inhalation unit exposures are from ExpoSAC SOP #14.
2.	Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) x lbs of seeds treated/day x dermal unit exposure x 1 mg/1000ug x dermal absorption factor (1%)] / body wt (60 kg).  
3.	Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) x lbs of seeds treated/day x inhalation unit exposure x 1 mg/1000ug x inhalation absorption factor (100%)] / body wt (60 kg). 
4.	Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 
5.	Total MOE = NOAEL (9.8 mg/kg/day) / Total dose (mg/kg/day).

Secondary Handlers for Seed Treatments on Rice and Leafy Vegetables

Exposures to secondary handlers occur when bags of clothianidin treated seeds are transported to the field, poured into hoppers, and planted in the field.  Both dermal and inhalation exposures may result from handling treated seeds.  Use of pelletized seeds is expected to further reduce exposures to secondary handlers due to the multiple layers of coating of the seeds.  MOEs for these scenarios are all greater than 100 (Table 9.1c) and are not of concern.

Table 9.1c.  Exposures and Risk Estimates to Secondary Handlers From Planting Leafy Green Seeds Treated with Clothianidin.
                                  Seed Groups
                                    Treated
                                     PPE 
                                     A. R
                                   lb ai/lb
                                  of seed [1]
                                  Lbs. seeds 
                                    planted
                                  per day [2]
                                unit exposure, 
                                 ug ai/lb ai 
                                     Dose,
                              mg/kg/day 3[, 4, 5]
                                    Total 
                                    MOE [6]
                                       
                                       
                                       
                                       
                                    Dermal 
                                  Inhalation
                                    Dermal 
                                  Inhalation
                                     Total
                                       
Parsley  
Baseline*
0.05
480
250
3.4
0.001
0.00136
0.00236
4,200
Spinach  

0.015
1,200
250
3.4
0.00075
0.00102
0.00177
5,500
Lettuce [P]

0.42
320
250
3.4
0.0056
0.00762
0.01322
740
Lettuce [P]

1.59
320
250
3.4
0.0212
0.02883
0.05003
200
Abbreviation used: same as in Table 9.1b. 
* Gloves are required only when loading treated seeds into planter hopper.
[P] Pelleted seed 
1.	Application rates from Table 1  
2.	Pounds of seeds of leafy greens planted per day are from ExpoSAC's Policy # 15.
3.	Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) x lbs of seeds treated/day x dermal unit exposure x 1 mg/1000 ug x dermal absorption factor (1%)] / body wt (60 kg).  
4.	Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) x lbs of seeds treated/day x inhalation unit exposure x 1 mg/1000 ug x inhalation absorption factor (100%)] / body wt (60 kg). 
5.	Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 
6.	Total MOE = NOAEL (9.8 mg/kg/day) / total dose (mg/kg/day).

9.2	Short- and Intermediate-Term Post-Application Risk

In estimating post-application risk, HED has considered both dermal and inhalation routes of exposure.  

Inhalation Post-Application Exposure

For field foliar applications of clothianidin, as per the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (1.3 x 10[-10] Pa, 9.75 x 10[-13] mm Hg), and the low proposed use rate (0.075 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for clothianidin.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

For seed treatments, a post-application inhalation exposure assessment is not required as exposure is expected to be negligible.  Seed treatment assessments provide quantitative inhalation exposure assessments for seed treaters and secondary handlers (i.e., planters).  It is expected that these exposure estimates would be protective of most post-application inhalation exposure scenarios.

Dermal Post-application Exposure

Foliar Treatments

For the foliar application to rice, the post-application activity that involves the highest contact with foliage is scouting.  The MOE associated with scouting foliarly treated rice fields is 39,000 (Table 9.2) and is not of concern.

Table 9.2.  Summary of Occupational Post-Application Exposure and Risk Estimates Associated with Clothianidin Foliar Rice Treatments.
Crop
Treatment Type
Activity
Mitigation Level
Daily Dose, mg/kg/day [a]
MOE b
Rice
Foliar Broadcast
Scouting
Single Layer, Gloves
0.000246
40,000


Hand Weeding
Single Layer, Gloves
0.0000157
620,000
[a] Daily Dose from D397004, S. Wang, 30 January 2012.
[b] MOE = NOAEL (9.8 mg/kg/day) / Combined Daily Dose.  Level of concern = 100.

The Restricted Entry Interval (REI) is based on the acute toxicity of clothianidin technical material, which is classified in acute toxicity category III and IV.  Acute toxicity category III or IV chemicals require a 12-hour REI.  Thus, the 12-hour REI that appears on the labels for foliar treatments is adequate.

Seed Treatments

For seed treatments there is a possibility that farm workers may be exposed to residues of clothianidin if they enter fields that are planted with treated seeds of leafy greens to do irrigation and/or scouting.  The registrant has not submitted any chemical-specific postapplication exposure data to evaluate such risks.  HED's evaluation indicates that dermal exposure to postapplication workers is minimal due to the lack of dermal contact with planted seeds.  

The Worker Protection Standard (WPS) and Restricted Entry Interval (REI) contain requirements for protecting postapplication workers from dermal and inhalation exposures after application of a pesticide in the field.  However, WPS and REI are not required for pesticide formulations that are registered for seed treatment uses, because of the low potential for such exposures to postapplication workers.

10.0	References

D395799.  M. Doherty.  1 February 2012.  Clothianidin-Requested Foliar Uses on Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit  -  Evaluation of Residue Chemistry Data.

D395798.  M. Doherty.  1 February 2012.  Clothianidin Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments.

D376358.  S. Wang.  22 October 2010.  Clothianidin: Occupational and Residential Exposure/ Risk Assessment for Proposed Seed Treatment Use of Clothianidin on Rice.

D389737.  S. Oonnithan.  30 January 2012.  Clothianidin:  Occupational and Residential Exposure Assessment for the New Use as Seed Treatment of Leafy Greens.

D397004.  S. Wang.  30 January 2012.  Clothianidin: Occupational and Residential Exposure/Risk Assessment for Section 3 Registration of Foliar Use on Rice.
Appendix A.  Toxicology Profile

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    21- or 28-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                    yes[a]
                                      yes
                                      yes
                                      yes
                                       -
                                      no
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	
870.7800    Immunotoxicity..............................................................
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
Special Studies
         Developmental Immunotoxicity	
                                       
                                      yes
                                       
                                      yes
[a] The subchronic inhalation study is required.  HED has recommended that this study be called in to support registration review.  As discussed in Section 2.1, it is not being required to support the requested uses.

A.2.  Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Clothianidin Technical, Intermediates, and Metabolites
                                 Test Material
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
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. = 384-561)
LD50 = 425 mg/kg (♂+♀;
95% C.I. = 380-475)
                                      II
Technical
870.1200
Acute dermal - rat
                                   45422634
LD50 > 2000 mg/kg
                                      III
Technical
870.1300
Acute inhalation
                                   45422636
LC50 > 5.538 mg/L (♂+♀)
                                      IV
Technical
870.2400
Acute eye irritation
                                   45422701
Slightly irritating to the eye
                                      IV
Clothianidin-CCMT- Adduct Intermediate
870.2400
Acute eye irritation
                                   45422814
Not irritating to the eye
                                      IV
Clothianidin-Triazan Intermediate
870.2400
Acute eye irritation
                                   45422819
Not irritating to the eye
                                      IV
Technical
870.2500
Acute dermal irritation
                                   45422703
Not irritating to the skin
                                      IV
Clothianidin-CCMT- Adduct Intermediate
870.2500
Acute dermal irritation
                                   45422813
Not irritating to the skin
                                      IV
Clothianidin-Triazan Intermediate
870.2500
Acute dermal irritation
                                   45422820
Not irritating to the skin
                                      IV
Technical
870.2600
Skin sensitization
                                   45422705
Is not a sensitizer under conditions of study
                                      N/A
Clothianidin-CCMT- Adduct Intermediate
870.2600
Skin sensitization
                                   45422815
Is not a sensitizer under conditions of study
                                      N/A
Clothianidin-Triazan Intermediate
870.2600
Skin sensitization
                                   45422821
Is a sensitizer under conditions of study
                                      N/A


Table A.2.2.	  Subchronic, Chronic and Other Toxicity Profile  for Clothianidin
                                  Guide line
                                  Study Title
                                     MRID
                                    Results
870.3100
90-Day Oral Toxicity - rat (diet)
45422809
(2000)
45422708
(4-week)
Acceptable/
guideline
ppm=0, 150, 500  & 3000
mg/kg/day (M/F)=0/0, 9.0/10.9, 27.9/34.0, 202.0/254.2
NOAEL = 27.9/34.0 mg/kg/day (M/F)    
LOAEL = 202.0/254.2 mg/kg/day (M/F) 
based on decreased BW and BW gain.
870.3150
13-Week Oral Toxicity- dog (diet)
45422810
2000
45422808
2000
4-week
45422811
1998
palatability
Acceptable/
guideline
ppm=0, 325, 650, 1500 & 2250
mg/kg/day
(M/F)=0/0, 9.2/9.6, 19.3/21.2, 40.9/42.1, 58.2/61.8  
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
28-Day Dermal Toxicity - rat
45422707 (2000)
Acceptable/
guideline
mg/kg/day= 0, 100, 300 & 1000
NOAEL = 1000 mg/kg/day (HDT)
LOAEL = Not established
870.3700a
Developmental Toxicity- rat (gavage)
45422711 (1998)
45422710 (1998)
range-finding
Acceptable/
guideline
mg/kg/day=0, 10, 40 & 125
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
Developmental Toxicity- rabbit (gavage)
45422713 (1998)
45422712 (1998)
range-finding
Acceptable/
guideline
mg/kg/day=0, 10, 25, 75 & 100
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 (2- Generation)- rat (diet)
45422715 (2000)
45422714 (2000)
pilot
45422716
(2001)
supplemental
45422825 (1999)
rat feed
45422826
(1999)
rat feed
Acceptable/
guideline
ppm=0, 150, 500 & 2500
mg/kg/day
(M/F)=0/0, 9.8/10.7, 31.2/34.3,163.4/188.8
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.
870.4100
Chronic (1 year) - dog (diet)
45422717 (2000)
45422718
Acceptable/
guideline
ppm=0, 325, 650, 1500 & 2000
mg/kg/day (M/F)=0/0,  4.8/8.5, 16.6/15.0, 36.3/40.1, 46.4/52.9
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, 18-Month - mouse (diet)
45422721 (2000)
45422709
(1997)
4-week
45422722
(2001)
supplementary
Acceptable/
guideline
ppm=0,100, 350 or 1250
mg/kg/day
(M/F)=0/0, 13.5/17.0, 47.2/65.1, 171.4/215.9
In addition: 50/sex - 700 ppm (wk 1-4), 2000 (5-10), 2500 (11-34), 2000/1800 (M/F) 35-79 [254,1/322,3] 
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
Chronic/ Carcinogenicity, 2-Year-rat (diet) 
45422719 (2000)
45422720
(2001)
supplementary
Acceptable/
guideline
ppm (M/F)=0,  150, 500, 1500 & 3000
mg/kg/day
(M/F)=0/0, 8.1/9.7, 27.4/32.5, 82.0/97.8, 156.5/193.4
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
45422731 (2000)
Acceptable/
guideline
Small, but significant increase in frequency of histidine revertants in TA 1535 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
45422732
(1990)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium and E. coli) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
Parent
45422733
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
Parent
45422734
(1999)
Acceptable/
non-guideline
(only TA 1535 assayed)
Only TA 1535 tested. No mutagenic activity in bacteria (S. typhimurium) under condtions of this assay. 
870.5100
Gene Mutation bacterial reverse mutation assay
BN0335E2 metabolite
45422724
(2000)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
TZMU metabolite
45422725
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
methyl guanidine intermediate
45422726
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
TZNG metabolite
45422727
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
TMG metabolite
45422728
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
BN0230M metabolite
45422729
(2000)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
MAI metabolite
45422730
(1999)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial
reverse mutation assay
N=Methylnitroguanidin intermediate
45422812
(2001)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
TI 435-Triazan intermediate
45422822
(2000)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100
Gene Mutation bacterial reverse mutation assay
TI 435-CCMT-Adduct
45422816
(2000)
Acceptable/
guideline
No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5300
Gene Mutation - in vitro mammalian cell gene mutation test (L5178Y TK +/- mouse lymphoma cells)
45422737 (2000)
Acceptable/
guideline
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)
45422738
(1999)
Acceptable/
guideline
No increase in mutant frequency under the conditions of the study.
870.5300
Gene Mutation  -  in vitro mammalian cell gene mutation test (V79 - HPRT Assay)
46339001
(2003)
Acceptable/
guideline
There was no evidence of induced mutant colonies over background.
870.5375
Cytogenetics - in vitro mammalian chromosome aberration test (CHL Cells)
Parent
45422736
(2000)
Acceptable/
guideline
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.
870.5375
Cytogenetics  -  in vitro mammalian chromosome aberration test (CHL Cells)
Parent
46339002
(2003)
Acceptable/
guideline
Clothianidin was clastogenic in the absence of S9 activation but only at precipitating concentrations.  Some doubt regarding the relevance of this finding since clastogenicity was abolished when exogenous metabolic activation was incorporated into the test system and was confined to precipitating concentrations.
870.5395
Cytogenitics - mammalian erythrocyte micronucleus test
Parent
45422740
(2000)
Acceptable/
guideline
Clothianidin is considered to be neither clastogenic nor aneugenic under these test conditions.
870.5395
Cytogenetics - mammalian erythrocyte micronucleus test
Parent
46339003
(2003)
Acceptable/
guideline
No significant increase in the frequency of MPCEs in bone marrow after any harvest in the test groups up to an overtly toxic dose for this test system.
870.5550
Other Effects - DNA Repair Test in B. subtilis 
Parent
45722735
(1990)
Unacceptable/
non-guideline (only single plates used)
No potential for DNA damage under these conditions.
870.5500
Other Effects - (UDS) in Mammalian Cells in Culture
Parent
45422739
(1999)
Acceptable/
non-guideline
(only males used)
No evidence (or a dose related positive response) that UDS was induced.
870.6200a

Acute Neurotoxicity Screening Battery-rat (gavage)
45422801
 (2000)
45422802
(2000)
to establish NOEL
Acceptable/
guideline
mg/kg=0,100, 200 & 400
NOEL=0, 20, 40 & 60
NOAEL = 60 mg/kg
LOAEL = 100 mg/kg based on FOB findings (decreased arousal, motor activity, and locomotor activity).
870.6200b

Subchronic Neurotoxicity Study-rat (diet)
45422803 (2000)
45422825
(1999)
supplementary
Acceptable/
guideline
ppm (M/F)=0, 150, 1000 & 3000
mg/kg/day
(M/F)=0/0,9.2/10.6, 60.0/71.0, 177.0/200.1
NOAEL = 60.0/71.0 mg/kg/day (M/F)
LOAEL = 177.0/200.1 mg/kg/day (M/F) based on slightly decreased food consumption, body weights, and body weight gains.

No evidence of neurotoxicity.
870.6300

Developmental Neurotoxicity Study-rat
(diet)
445422804
(2000)
Acceptable/
non-guideline
(upgradable with FOB information)
ppm=0, 150, 500 & 1750
mg/kg/day
gestation=0, 12.9, 42.9, 142
lactation=0, 27.3, 90.0, 299.0
Maternal NOAEL = 42.9 mg/kg/day
Maternal 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 Study- rat

45422805 (2000)
45422806
 (2000)
Acceptable/
guideline
single dose=2.5 or 250mg/kg;
14-day repeated dose =25 mg/kg/day
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 Study  -  mice


45422807
(2000)
Acceptable/
non-guideline
single gavage dose of 5 mg/kg
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
45868001 (2003)
Acceptable/
non-guideline
6.13 ug/cm2
8 hour exposure

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 (adult) (diet)
46536502
(2004)
Acceptable/
guideline
ppm=0, 150, 500 & 3000
mg/kg/day
(M/F)=0/0, 13.8/14.0, 45.8/46.2, 252.8/253
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 were noted in adult males and females.
Non-guideline
Developmental Immunotoxicity study - rat
(diet)
47526501 (2008)
Acceptable/
non-guideline
ppm=0, 150, 500 & 2000
mg/kg/day
gestation=0, 10, 35, 121
lactation=0, 22, 68, 250
after weaning:
Assay 1=0/0, 28/26, 98/93,404/404
Assay 2=0/0, 28/27, 89/93, 338/398
No immunotoxicological adverse effects at any of the doses tested.
Non-guideline
Other Genotoxicity  -  Unscheduled DNA synthesis in primary rat hepatocytes
46339004
(2003)
Acceptable/
non-guideline
No evidence of DNA damage and repair in this test system, as determined by radioactive tracer procedures (nuclear silver grain counts).
Non-guideline
Special Study:
Neurotoxicity and pharmacology - mouse
445422823
(2000)
Acceptable/
non-guideline
mg/kg=0, 12.5, 25, 50, 100, 200, 400 (single gavage dose)
NOAEL = 25 mg/kg/day (M/F)
LOAEL = 50 mg/kg (M/F) based on transient signs of decreased spontaneous motor activity, tremors and deep respirations.


Appendix B.  Detailed Occupational Exposure and Risk Estimates.

Table B1.  Non-Cancer Occupational Exposure and Risk for Handlers Applying Clothianidin on Rice:  Foliar Treatment.  D397004, S. Wang, 30 January 2012.
                                       
                        Exposure Scenario (Scenario #)
                                       
                                      PPE
                                    Level a
                                       
                           unit exp.  (ug/lb ai) [b]
                                       
                                  Appl.  Rate
                                   (lb ai/A)
                                       
                                    Acres 
                                  Treated [c]
                                     / day
                                       
                                    Dermal
                             Dose [d] (mg/kg/day)
                                       
                                    Inhal.
                             Dose [e] (mg/kg/day)
                                       
                                 Total   Dose/
                                    day [f]
                                       
                          Sh. and Interm. term Total
                                    MOE [g]
                                       
                                       
                                    Dermal
                                    Inhal. 
                                       
                                       
                                       
                                       
                                       
                                       
                                 MIXER/LOADER
Liquids for Aerial Application (1)
                                   Baseline
                                     plus
                                    gloves
                                     37.6
                                     0.219
                                       
                                     0.075
                                     1200
                                    0.00056
                                    0.00033
                                    0.00089
                                    11,000
Liquids for Ground-boom Application (2)
                                   Baseline
                                     plus
                                    gloves
                                     37.6
                                     0.219
                                     0.075
                                      200
                                    9.4E-5
                                    5.5E-5
                                    0.00015
                                    66,000
                                  APPLICATOR
Sprays with Fix-Wing Aerial Equipment (3)
                               Enclosed cockpit
                                      5.0
                                     0.068
                                     0.075
                                     1200
                                    0.00008
                                    0.0001
                                    0.00018
                                    55,000
Sprays with Ground-boom Equipment (4)
                                   Baseline
                                     plus
                                    gloves
                                     16.1
                                     0.34
                                     0.075
                                      200
                                    0.00004
                                    0.00009
                                    0.00013
                                    78,000
                                    FLAGGER
Flagging (5)
                                   Baseline
                                     plus
                                    gloves
                                      12
                                     0.35
                                     0.075
                                      350
                                    0.00005
                                    0.00015
                                    0.00021
                                    48,000
a.  PPE consists of long-sleeve shirt, long pants, shoes, and socks plus gloves.  
b.  Dermal and inhalation unit exposures are from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table.
c.  Acres treated values are from EPA estimates of acreage that could be treated in a day based on the appl. method and formulation/packaging type.
d.  Dermal dose (mg/kg/day) =  unit dermal exposure (ug/lb ai) * (1 mg/1000 ug) conversion * application rate (lb ai/acre) * acres treated/day * dermal
     absorption rate (0.01) / body weight (60 kg).
e.  Inhalation dose (mg/kg/day) = unit exposure (ug/lb ai) * (1 mg/1000 ug) conversion * application rate (lb ai/acre) * acres treated/day / body weight (60 kg).
f.  Total dose (mg/kg/day) = Dermal dose/day + inhalation dose/day.
g.  Total MOE = NOAEL (9.8 mg/kg/day) / total dose/day. Since the dermal and inhalation NOAEL are the same for both short and intermediate-term exposure 
      durations, the corresponding risks are also the same and therefore.  
Table B2.  Occupational Exposure and Risk Estimates for Primary Handlers Applying Clothianidin on Rice:  Seed Treatment.  D376358, S. Wang, 22 October 2010.
Exposure Scenario
Mitigation Level
Dermal Unit Exposure (mg/lb ai)
Inhalation Unit Exposure   (ug/lb ai)
Seed Species
Application Rate
(lb ai  per lb seed)
Amount Treated[a]
(lb seed trt per day)
Daily
Dermal
Dose b (mg/kg/day)
Daily
Inhalation
Dose[c] (mg/kg/day)
Combined Daily Dose[d]  (mg/kg/day)
MOE[e]  
                               Loader/Applicator
Loading/Applying
Liquid  for 
Seed Treatment
Single Layer, Gloves
0.023
0.34
Rice
0.00075
718,000
0.002061
0.003046
0.005107
1,900
                                     Sewer
Sewing Seeds after Seed treatment
Single Layer, 
No Gloves
0.0062
0.23
Rice
0.00075
718,000
0.000555
0.002061
0.002616
3,700
                                    Bagger





800,000
Bagging Seeds after Seed treatment
Single Layer, 
No Gloves
0.0091
0.16
Rice
0.00075
718,000
0.0008152
0.0014336
0.0022488
4,400
                          Multiple Activities Worker





800,000
Multiple Activities for Seed treatment
Single Layer, Gloves
0.042
1.6
Rice
0.00075
718,000
0.0037633
0.014337
0.01810
540
a	Daily amounts treated values are based on exposure SAC Policy #15. 
b	Daily dermal dose (mg/kg/d) =  unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated /  body weight (70 kg).
c	Daily inhalation dose (mg/kg/d) = unit exposure (ug/lb ai) * 0.001 * application. rate (lb ai/lb seed) * daily amounts treated / body weight (60 kg).
d	Combined daily dose (mg/kg/d) =  Daily dermal dose (mg/kg/d) + Daily inhalation dose (mg/kg/d).
e	MOE = NOAEL (9.8  mg/kg/d) / combined daily dose.  UF = 100.



Table B3.  Occupational Exposures and Risk Estimates for Primary Handlers Applying Clothianidin to Leafy Green Vegetable Seeds.  D389737, S. Oonnithan, 30 January 2012.
                             Seed Groups Treated 
                                      PPE
                                  Appl. rate
                                   lb ai/lb
                                   of seed 
                              Lbs. seeds treated
                                    per day
                                    Dermal
                                  unit exp., 
                               ug ai/lb ai [1]
                                    Inhal.
                                  unit exp.,
                                ug ai/lb ai [1]
                                    Dermal
                                   dose/day
                                    mg/kg 2
                                    Inhal.
                                   dose/day
                                    mg/kg 3
                                     Total
                                   dose/day
                                    mg/kg 4
                                  Short-term
                                    Total 
                                    MOE [5]
                                Loader/Treater  
Parsley 
                                   Baseline
                                      + G
0.05
5,500
23
0.34
0.00105
0.00156
0.00261
3,800
Spinach 
                                       
0.015
5,500
23
0.34
0.00032
0.00047
0.00078
13,000
Lettuce **
                                       
0.42
500
23
0.34
0.00081
0.00119
0.002
4,900
Lettuce **
                                       
1.59
500
23
0.34
0.00305
0.00451
0.00755
1,300
                                    Bagger
Parsley 
                                   Baseline
0.05
5,500
9.1
0.16
0.00042
0.00073
0.00115
8,500
Spinach 
                                       
0.015
5,500
9.1
0.16
0.00013
0.00022
0.00035
28,000
Lettuce **
                                       
0.42
500
9.1
0.16
0.00032
0.00056
0.00088
11,000
Lettuce **
                                       
1.59
500
9.1
0.16
0.00121
0.00212
0.00333
2,900
                                     Sewer
Parsley 
                                   Baseline
0.05
5,500
6.2
0.23
0.00028
0.00105
0.00134
7,300
Spinach 
                                       
0.015
5,500
6.2
0.23
0.00009
0.00032
0.0004
24,000
Lettuce **
                                       
0.42
500
6.2
0.23
0.00022
0.00081
0.00102
9,600
Lettuce **
                                       
1.59
500
6.2
0.23
0.00082
0.00305
0.00387
2,500
                                Multiple Worker
Parsley 
                                   Baseline
                                      + G
0.05
5,500
42
1.6
0.00193
0.00733
0.00926
1,100
Spinach 
                                       
0.015
5,500
42
1.6
0.00058
0.0022
0.00278
3,500
Abbreviation used: Baseline PPE= long-sleeved shirt, long pants and shoes with socks, G=gloves, MOE = margin of exposure, PPE= personal protective equipment.  
**  Lettuce seeds are pelleted.
1.  Dermal and inhalation unit exposures are from ExpoSAC SOP #14.
2.  Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * dermal unit exposure * dermal absorption factor (1%)] / body wt (60 kg).  3.  Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * inhalation unit exposure * inhalation absorption factor (100%)] / body wt (60 kg). 
4.  Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 
5.  Total MOE = NOAEL (9.8 mg/kg/day) / Total dose (mg/kg/day).



 Table B4.  Post-application Exposure and Risk to Workers Scouting Clothianidin Treated Rice Fields: Foliar Treament.  D397004, S. Wang, 30 January 2012.
                        Transfer Coefficients (cm[2]/hr)
                                    DAT [1]
                                DFR 2 (ug/cm[2])
                              Dose (mg/kg/day) [3]
                                    MOE [4]
 75
 0
 0.168
 0.00025
 40,000
 1100
 0
 0.168
 0.0000157
 620,000
1.  DAT = Days after treatment.
2.  DFR = Dislodgeable Foliar Residue = application rate (lb ai/A) x (1- daily dissipation rate) [t] x 4.54E+8 ug/lb x  2.47E-8 A/cm2  x   20% DFR after initial treatment.
3.  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x 1% dermal absorption x 8 hrs/day]  body weight (60 kg).
4.  MOE = NOAEL/Daily Dose   ( Dermal NOAEL = 9.8 mg/kg/day).   

Table B5.  Exposures and Risk Estimates to Secondary Handlers From Planting Rice Seeds Treated with Clothianidin.  D376358, S. Wang, 22 October 2010.
Exposure Scenario
Mitigation Level
Dermal Unit Exposure (mg/lb ai)
Inhalation Unit Exposure   (ug/lb ai)
Seed  Category--Representative
Seed Species
Application Rate
(lb ai  per lb seed)
Amount Planted[a]
(lb seed planted/day)
Daily
Dermal
Dose b (mg/kg/day)
Daily
Inhalation
Dose[c] (mg/kg/day)
Combined Daily Dose[d] (mg/kg/day) 
MOE[e]  
                            Secondary Seed Handlers
Secondary Seed Handlers: planting seeds in the field
Single Layer, Gloves
0.25
3.4
Rice
0.00075
30,000
0.000936
0.0012729
0.0022089
4,400
a	Daily amounts planted values are based on exposure SAC Policy #15 or the information provided by the Registrant through Registration Division. 
b	Daily dermal dose (mg/kg/d) =  unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated /  body weight (70 kg).
c	Daily inhalation dose (mg/kg/d) = unit exposure (ug/lb ai) * 0.001* application. rate (lb ai/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.			

Table B6.  Exposures and Risk Estimates to Secondary Handlers From Planting Leafy Green Seeds Treated with Clothianidin.  D389737, S. Oonnithan, 30 January 2012.
                                  Seed Groups
                                    Treated
                                     PPE 
                                     A. R
                                   lb ai/lb
                                  of seed [1]
                                  Lbs. seeds 
                                    planted
                                  per day [2]
                                    Dermal
                                  unit exp., 
                                 ug ai/lb ai 
                                    Inhal.
                                  unit exp.,
                                 ug ai/lb ai 
                                     Derm.
                                   dose/day
                                    mg/kg 3
                                    Inhal.
                                   dose/day
                                    mg/kg 4
                                     Total
                                   dose/day
                                    mg/kg 5
                                    Total 
                                    MOE [6]
Parsley  
Baseline*
0.05
480
250
3.4
0.001
0.00136
0.00236
4,200
Spinach  

0.015
1,200
250
3.4
0.00075
0.00102
0.00177
5,500
Lettuce**

0.42
320
250
3.4
0.0056
0.00762
0.01322
740
Lettuce**

1.59
320
250
3.4
0.0212
0.02883
0.05003
200
Abbreviation used: same as in Table 7. 
*.  Gloves are required only when loading treated seeds into planter hopper.
**.  Pelleted seed. 
1.  Application rates from Table 1.  
2.  Pounds of seeds of leafy greens planted per day are from ExpoSAC's Policy # 15.
3.  Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * dermal unit exposure * dermal absorption factor (1%)] / body wt (60 kg).  4.  Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * inhalation unit exposure * inhalation absorption factor (100%)] / body wt (60 kg). 
5.  Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 
6.  Total MOE = NOAEL (9.8 mg/kg/day) / total dose (mg/kg/day).



Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force (ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
