### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

MEMORANDUM Date: 1 February

2012 SUBJECT: Clothianidin

– Human Health Risk Assessment for

Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit PC Code: 044309 MRID Nos.: 48364801, 48364802, 48438001 Petition No.: 1F7832 Assessment Type: Single Chemical, Aggregate T XR No.: None Decision Nos.: 444551, 447268 

### 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 Hy genist Elizabeth Holman, Chemist Karl yn Middleton, Toxicologist Richard A. Loranger, Senior Scientist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) TO: Marianne Lewis/V Insecticide
- Rodenticide Branch Registration Division (7505P) UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WA SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION



### Human Health Risk Assessment for Requested Foliar Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit DP Barcode: D387290, MRID Nos.: 48364801, 48364802, 48438001 Registration Nos. : 59639 Petition No.: 1F7832 Regulatory Action: Section 3

Single Chemical, Aggregate Registration Case No.: 7620 CAS No.: 210880
- 92
- 5 Decision Nos.: 444551, 447268 40 CFR 180.586 

### A. Doherty, Ph.D., Senior Chemist Alan Levy, Ph.D., Toxicologist Suku Oonnithan, Biologist Chi Wang, Ph.D., Biologist Risk Assessment Branch II Health Effects Division (7509P) Margarita Collantes, Biologist Zaida Figueroa, Industrial Hy genist Elizabeth Holman, Chemist Karl yn Middleton, Toxicologist Richard A. Loranger, Senior Scientist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) Marianne Lewis/V enus Eagle, RM 01

Rodenticide Branch Registration Division (7505P) UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION



### Requested Foliar Uses on Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit
. D387290, D389529 : 59639
- 150, 59639
- 151 Regulatory Action: Section 3 Registration Case No.: 7620

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 2 of 41 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 Analy tical 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 L abel Recommendations
................................ ................................ ................................ ...... 5 3.0 Introduction
................................ ................................ ................................ .............................. 6 3.1 Chemical Identity
................................ ................................ ................................ ................. 6 3.2 Phy sical/Chemical Characteristics
................................ ................................ ....................... 6 3.3 Pesticide Use Pattern
................................ ................................ ................................ ............ 7 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 7 3.5 Consideration of Environmental Justice
................................ ................................ ......... 7 4.0 Hazard Characterization and Dose
- Response Assessment
................................ .................. 8 4.1 Toxicology

Studies Available for Analy sis
................................ ................................ .... 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
................................ .................. 1 5 5.4.3 Dietary

Exposure and Risk Estimates
................................ ................................ ....... 15 6.0 Residential (Non
- Occupational) Exposure/Risk Characterization
................................ .... 16 6.2 Residential By stander 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 3 of 41 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 reque sted uses.
................................ ................................ ................................ ....... 27 A.2. Toxicity

Profiles
................................ ................................ ................................ ............... 28

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 4 of 41 **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, respectivel y). The second is a request to register a seed treatment for leafy green vegetables (Crop Subgroup 4A). There is no petition number associated with th e second request ( i.e., there are no tolerance actions a ssociated 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 toxicolog ical and residue ch emistry 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 thes e crop groups have already been met. The revised definition s 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 acco mmodate 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 5 of 41 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 n ot 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, soy beans) 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 t andem mass spectroscop y (L C
- MS/MS) method, is available to enforce tolerances for residues of clothiani din. **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 do es 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 6 of 41 **3.0 Introduction**  **3.1 Chemical Identity**  T able 3. 1. Clothianidin Nomenclature. Com pound

Common name Clothianidin Com pany 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 phy sicochemical properties of clothiani din 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 , 9.7 5 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) *P AI = Purified Active Ingredient; TGAI = technical grade active ingredient. S N N

H N NH Cl C

H 3 N O 2

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 7 of 41 **3.3 Pesticide Use Pattern**  Table 3.3.1. Proposed Use Pattern for Clothianidin as Foliar Treatment s for Rice. Reg. No., Form type, & AI or AE Crop Applic. Timing, Ty pe, 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 App lication 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, l awns, 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 pathway s as well as the potential for aggregate exposures from multiple pathway s. **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 L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pd f . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 8 of 41 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 b y Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additional ly , 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 associate d risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas after application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers 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 metabo lite 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 an d cotyl edons 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 inh alation 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 rabbit s; developmental neurotoxicity ; reproduction; mutagenicity battery ; metabolism (rats and mice); dermal penetration (monkey s) and immunotoxicity as well as developmental immunotoxicity
. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  In rat s, 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 abso rption/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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 9 of 41 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 hydrol ys is
. In mic e, clothianidin was readil y 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 no t 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 Absorp**  **tion** In a dermal absorption study in monkey s, absorption was calculated as 0.24% (±0.11%). This value was determined b y 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 woul d have likel y 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 relativel y low (Category III or IV) acute toxicity

via oral, inhalation and dermal rout es 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 metabo lite via the oral route in the rat , both of which were toxicity Category I I. Clothianidin induces some effects that are similar to other neonicotinoid insecticides, particularl y on the liver, hematopoietic sy stem and kidneys. For a complete description o f 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 inhal ation 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 10 of 41 **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 mate rnal effects observed included decreased body weights, body weight gains and food consumption at the high dose
. In o ffspring 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 sy stem parameters examined.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 11 of 41 **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 expos ure 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 Likel y 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
Ac ute Dietary Females age 13
- 49 NOAEL =

25 mg/kg/day UF A = 10X

UF H = 10X SF FQPA =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 Ac ute Dietary General population NOAEL =

25 mg/kg/day UF A = 10X

UF H = 10X SF FQPA = 1 aRfD = 0.25

mg/kg/day aPAD 0.25 mg/kg/day **Special neurotoxicity/pharmacol ogy** 

**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 UF A = 10X

UF H = 10X SF FQPA =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 UF A= 10X

UF H= 10X SF FQPA=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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 12 of 41 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

weights in F1 pups Dermal (all durations) Oral study

NOAEL= 9.8 mg/kg/day (dermal absorption = 1%) UF A= 10X

UF H= 10X SF FQPA=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) UF A= 10X

UF H= 10X SF FQPA=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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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. T able 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%) UF A= 10X

UF H= 10X SF FQPA=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) UF A= 10X

UF H= 10X SF FQPA=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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 13 of 41 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 met abolism of clothainidin in primary crops, rotational crops, livestock, and rats was evaluated b y HED in 2003. The clothianidin risk assessment team concurs with the previous findings regarding the residues of concern for risk assessment and tolerance enfo rcement (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 fairl y 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
- Py r 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 adequatel y delineated, and that parent only is the residue of concern ( ROC ) to be used for the tolerance expression for primary crops. HED had previousl y determined that future new uses on root crops and/or leafy vegetables will require anal ys is 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 observe d
. 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 b y previously submitted/reviewed data. In summary , the uses on rice resulted in no quantifiable residues ; the requested rate increase for vegetabl es brings the application rate up to the level used in the field

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 14 of 41 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 patt ern) , without any

increase to the overall field loading of clothianidin; and the expansion s 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 D3 95799 (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 mobi le 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 vegetable s . 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 w ater downstream of the treated rice paddy
. FIRST ( FQPA Index Reservoir Screening Tool, version 1. 1 , 0 1 /01/0 7) 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 L ouisiana
- that are currentl y under review by the Agency

(MRID 48364804, MRID 48364803). The maximum concentr ation at day

zero, pre - irrigation, was 210 ppb in the L ouisiana 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 day s after application. The Cali fornia plots show similar dissipation results with a maximum clothianidin concentration of 51.9 ppb at day zero, quickl y 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 wate r risk assessment based on the proposed clothianidin use on rice and leafy vegetables Use (application rate, lbs a.i./A) Model Ac ute Chronic Surface water drinking water sources, dow nstream 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 15 of 41 **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 ) rel y 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 fro m 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 f ield 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 anal ys es, 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 Likel y 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 Ac ute (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 2 2 0.017497 1 8 **Children 1 -**  **2 yrs 0.059972**  **2 4**  **0.020868 21**  Children 3
- 5 y

rs 0.04153 0 1 7 0.014497 1 5 Children 6
- 12 y

rs 0.020012 8 0.007335 8 Youth 13
- 19 y

rs 0.01223 0 5 0.004312 4 Adults 20
- 49 y

rs 0.012257 5 0.004636 5 Adults 50+ yrs 0.01192 0 5 0.004882 5 Females 13
- 49 y

rs 0.012765 5 0.004737 5 The population subgroup(s) with the highest exposure/risk estimates are shown in **bold**
.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 16 of 41 **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 (Jun e 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 d ermal , 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 > 17 0,00 0 , thus providing a suitable margin of safety

to account for any

uncertainties in the route
- to - route extrapolation. Handler exposure and risk e s timates 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 e s timates are summarized in Table 6.2

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 17 of 41 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
- Ty

pe 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 Pum

p 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 L awn 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 Revisio n to the SOPs for Residential Exposure Assessment 4
. Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) × application rate (lb ai/A or gal.) × amo unt treated × DAF ( .01 ) ÷ body weight (60 kg). 5
. Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) × application rate (lb ai./A or gal) × amo unt treated ÷ body weight ( 6 0 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 - mo uth 0.0059 1,700 Soil Ingestion 0.00002 490,000 1. M. Dow , D296176, 2/24/2004

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 18 of 41 **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 assumpti ons 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 day s is minimal. Furthermore, it is unlikely that a home owner would treat th eir 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 ty pically significantly

less than turf. Therefore a turf postapplication exposure ass essment 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 condu cted 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 summ arizes the combined residential exposure scenarios and their risk estimates
.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 19 of 41 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 9,1 00 Lawn/Turf Hose
- End Sprayer Arena 50 WDG [ Reg.No. 59639
- 156 ] Adult 20,000 0.00108 9,1 00 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 WDG Turf + 1/Total Handler MOE Arena 50 WDG Tree 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**  **- A** **pplication 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 i ts 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 inhalatio n 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 alway s a potential source of exposure to residents nearb y spraying operations. This is particularl y 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 L ead 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 20 of 41 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 appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides appli ed b y 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 likel y 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 th e 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**  Ty pically , 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 day s. Intermediate
- term assessments address exposures lasting from between thirty day s 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. O ral, 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 l evel 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 21 of 41 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 E stimates for Clothianidin
. Population Subgroup Estimated Exposure, mg/kg/day Aggregate MOE 4 Com bined Residential 1 Dietary 2 Aggregate 3 Adult s 0.0 054 0.0049 0.0 103 95 0 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 y rs. 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 basi s; 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 regi strant. **7. 4**  **Cancer Aggregate Risk** Clothianidin has been determined to be “not likel y 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 establis h that the chemicals operate b y the same, or essentially the same, sequence of major biochemical events (EPA, 2002). Although clothianidin and thiamethoxam bind selectivel y 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 necessaril y a relationship between this pestici dal 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 notabl y gre ater 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 22 of 41 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 th iamethoxam, and mineralized particles in thyroid colloid with imidacloprid). Thus, there is currentl y no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common me chanism 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 mec hanism determinations, and procedures for cumulating effects from substances found to have a common mechanism, released b y OPP on EPA’s website at http://www.epa.gov/pesticides/cumulative/
. **9.0 Occup**  **ational Exposure/Risk Characterization 9.1**  **Short -**  **and Intermediate**  **- Term Handler Risk**  Based on the proposed use pattern s , exposure s may be of short
- to intermediate
- term durations
. Long
- term exposure is not expected. Both dermal and inhalation exposures are expected to be significant. N o 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 derive d 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 Treate d 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 tox icological 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 E xp osure, 2 μg/lb ai Appl.

Rate , lb ai/A Acres

Treated per day 3 Dose , 4,5,6 mg/kg/d ay Total MOE 7 Dermal Inhal. Dermal Inhal. Total

Mixer/Loader Liquids for Aerial Application Baselin e

plus gloves 37.6 0.219 0.075 1200 0.00056 0.00033 0.00089 11,000 Liquids for Ground
boom A pplication Baseline

plus gloves 37.6 0.219 0.075 200 9.4E
- 5 5.5E
- 5 0.00015 66,000 Applicator

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 23 of 41 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 E xp osure, 2 μg/lb ai Appl.

Rate , lb ai/A Acres

Treated per day 3 Dose , 4,5,6 mg/kg/d ay Total MOE 7 Dermal Inhal. Dermal Inhal. Total Sprays with Fix
Wing Aerial Equipment Enclosed

c ockpit 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 inh alation 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
. M ethod and formulation/packaging type. 4
. D ermal dose (mg/kg/d ay) = unit dermal exposure (μg/lb ai) × (1 mg/1000 μg) conversion × application rate (lb ai/acre) × acres treated/day × dermal absorption rate (0.01) ÷ body weight (60 kg). 5
. I nhalation dose (mg/kg/d ay) = unit exposure (μg/lb ai) × (1 mg/1000 μg) conversion × application rate (lb ai/acre) × acres treated/day ÷ body weight (60 kg). 6
. Total dose (mg/kg/d ay) = D ermal dose/day + i nhalation 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 ( loade r/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 therefo re, 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 Vegetable s . Seed Groups Treated PPE Appl. rate

lb ai/lb of seed Lbs. seeds

treated per day unit exp osure ,

μg 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 24 of 41 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) = [ A ppl. rate (lb ai/lb of seed) × lbs of seeds treated/day × dermal unit exposure × 1 mg/1000μg × dermal absorption factor (1%) ] ÷ body wt (60 kg)
. 3. Inhalation dose (mg/kg/day) = [ A ppl. rate (lb ai/lb of seed) × lbs of seeds treated/day × inhalation unit exposure × 1 mg/1000μg × 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. M OEs for these scenarios are all greater than 100 (Tabl e 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 exp osure ,

μg ai/lb ai D ose , mg/kg/day 3 , 4, 5 Total MOE 6 Dermal Inhalation Dermal Inhalation Total Parsley B aseline* 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) = [ A ppl. rate (lb ai/lb of seed) × lbs of seeds treated/day × dermal unit exposure × 1 mg/1000 μg × dermal absorption factor (1%) ] ÷ body wt (60 kg)
. 4. Inhalation dose (mg/kg/day) = [ A ppl. rate (lb ai/lb of seed) × lbs of seed s treated/day × inhalation unit exposure × 1 mg/1000 μg × 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).

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 25 of 41 **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), l ow 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 evalu ating the SAP report as well as available post
- application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporat e 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 c lothianidin
. 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). Itis 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 foliarl y treated rice fields is 3 9,000 (Table 9.2) and is not of concern. Table 9.2. Summary of Occupational Post
- Application Exposure and Risk Estimates Associated with Clothianidin

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 26 of 41 Foliar Rice Treatments. Crop Treatment T ype Activity Mitigation Level Daily Dose, mg/kg/day a MOE b Rice Foliar Broadcast Scouting Single Layer, Gloves 0.000 246 40 ,000 Hand Weeding Single Layer, Gloves 0.00001 57 62 0,000 a Daily Dose from D 397004, 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 I II and IV. Acute toxicity category III or IVchemicals require a 12
- hour REI. Thus, the 12
- hour REI that appears on the labels for foliar treatment s 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 Regis tration of Foliar Use on Rice.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 27 of 41 **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) guidel ine 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 28 of 41 **A.2. Toxicity Profiles** Table A.2.1 Ac ute Toxicity Profile
- Clothianidin Technical, Intermediates, and Metabolites Test Material Guideline

No. Study T ype MRID(s) Results Toxicity Category Technical 870.1100 Ac ute oral
- rat 45422621 LD 50 > 5000 mg/kg IV BN0230M Metabolite 870.1100 Ac ute oral
- rat 45422628 LD 50 > 2000 mg/kg ( ♂+♀) III BN0335E2 Metabolite 870.1100 Ac ute oral
- rat 45422623 LD 50 > 2000 mg/kg ( ♂+♀) III MAI Metabolite 870.1100 Ac ute oral
- rat 45422629 LD 50 = 758 mg/kg ( ♀) Males not more susceptible III Clothianidin
- CCMT
Adduct Intermediate 870.1100 Ac ute oral
- rat 45422630 LD 50 > 2000 mg/kg ( ♂+♀) III Clothianidin
Hexahydropyrimidine Intermediate 870.1100 Ac ute oral
- rat 45422631 LD 50 > 2000 mg/kg ( ♂+♀) III
Clothianidin
- Triazan Intermediate 870.1100 Ac ute oral
- rat 45422632 LD 50 > 2000 mg/kg ( ♂+♀) III TMG Metabolite 870.1100 Ac ute oral
- rat 45422625 LD 50 < 550 mg/kg ( ♂) LD 50 = 567 mg/kg ( ♀) II TZMU Metabolite 870.1100 Ac ute oral
- rat 45422624 LD 50 = 1424 mg/kg ( ♂) LD 50 = 1282 mg/kg ( ♀) III TZNG Metabolite 870.1100 Ac ute oral
- rat 45422626 LD 50 > 1450 mg/kg ( ♂) LD 50 = 1481mg/kg ( ♀) III Technical 870.1100 Ac ute oral
- mo use 45422622 LD 50 = 389 mg/kg ( ♂; 95% C.I. = 380
- 475) LD 50 = 465 mg/kg ( ♀; 95% C.I. = 384
- 561 ) LD 50 = 425 mg/kg ( ♂+♀; 95% C.I. = 380
- 475 ) II

Technical 870.1200 Ac ute dermal
- rat 45422634 LD 50 > 2000 mg/kg III Technical 870.1300 Ac ute inhalation 45422636 LC 50 > 5.538 mg/L ( ♂+♀) IV Technical 870.2400 Ac ute eye irritation 45422701 Slightly irritating to the eye IV Clothianidin
- CCMT
Adduct Intermediate 870.2400 Ac ute eye irritation 45422814 Not irritating to the eye IV Clothianidin
- Triazan Intermediate 870.2400 Ac ute eye irritation 45422819 Not irritating to the eye IV Technical 870.2500 Ac ute dermal irritation 45422703 Not irritating to the skin IV Clothianidin
- CCMT
Adduct Intermediate 870.2500 Ac ute dermal irritation 45422813 Not irritating to the skin IV Clothianidin
- Triazan Intermediate 870.2500 Ac ute 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

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 29 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results 870.3100 90
- Day

Oral Toxicity
- r at (diet) 45422809

(2000) 45422708 (4
- we ek) 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
- W eek Oral

Toxicity
- d og ( 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 **NOAE L =**  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 p rotein (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 ( g avage) 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
. **Developm ental**  **NOAEL** = 125 mg/kg/day (HDT) **Developm ental**  **LOAEL** = Not established 870.3700b Developmental

Toxicity
- rabbit ( g avage) 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
. **Developm ental**  **NOAEL** = 25 mg/kg/day **Developm ental**  **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)
- r at (diet) 45422715 (2000)

45422714 (2000) pilot 45422716 (2001) **Parental/System ic**  **NOAEL** = 31.2/36.8 mg/kg/day (M/F) **Parental/System ic**  **LOAEL** = 163.4/188.8 mg/kg/day (M/F) based on decreased body weight, body weight gain , and absolute and

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 30 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results 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 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 gener ations. 870.4100 Chronic ( 1 year)

- d og (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
- r at (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 ki dney, mottled livers of males
. **No evidence of carcinogenicity.**

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 31 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results 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 μg/plate +/
- S9; still present but weaker in its absence. The positive response was only reproducible at 5000 μg/plate +/
- S9. Clothianidin considered mutagenic under conditions of this test. 870.5100 Gene Mutation

bacterial reve rse mutation assay **Parent** 45422732

(1990) Acceptable/ guideline No m utagenic 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 m utagenic 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 m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay **TZ MU**  **metabolite** 45422725

(1999) Acceptable/ guideline No m utagenic 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 m utagenic 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 m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay **TM G**  **metabolite** 45422728

(1999) Acceptable/ guideline No m utagenic 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 m utagenic activity in bacteria (S. typhimurium) under conditions of this assay.

870.5100 Gene Mutation 45422730 No m utagenic activity in bacteria (S.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 32 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results

bacterial reverse mutation assay **MAI metabolite**  (1999)

Acceptable/ guideline typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay **N=Methylnitro guanidin**  **intermediate** 45422812

(2001) Acceptable/ guideline No m utagenic 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 m utagenic 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 m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.

870.5300 Gene Mutation
-

in vitro mammalian cell gene mutation test (L5178Y TK +/
- mo use lymphoma cells) 45422737 (2000)

Acceptable/ guideline Increases in mutant frequency with and without S9 at dose levels that were cy totoxic. 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 Cy

togenetics
- in vitro mammalian chromosome aberration test (CHL Cells) **Parent** 45422736

(2000) Acceptable/ guideline Significant increases in frequency of cells with structural aberrations. Predominant ty pes 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 Cy

togenetics

– in vitro mammalian chromosome aberration test (CHL Cells) 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 wa s abolished when exogenous metabolic activation was incorporated into the test

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 33 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results

**Parent** system and was confined to precipitating concentrations. 870.5395 Cy

togenitics
- mammalian erythrocyte micronucleus test **Parent** 45422740

(2000) Acceptable/ guideline Clothianidin is considered to be neither clastogenic nor aneugenic under these test conditions.

870.5395 Cy

togenetics
- 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 Ac ute

N eurotoxicity S creening B attery - rat (gavage) 4 5422801

( 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

N eurotoxicity Study
- rat (diet) 4 5422803 (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

N eurotoxicity 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
.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 34 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results 870.7485 Metabolism

S tudy
- 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 wa s 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 unaffec ted 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 follow ed 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 mo ieties) were consistent with Phase I processes. Extraction efficiencies appeared to be excelle nt 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 metab olism 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 wa s 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 35 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results Residual radioactivity in any given tissue at 168 hour s 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 feca l 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

– mo nkey 45868001 (2003)

Acceptable/ non - guideline 6.13 μg/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, bo dy 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, No immunotoxicological adverse effects at any of the doses tested.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 36 of 41 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin Guide line Study Title MRID Results 98/93,404/404 Assay 2=0/0, 28/27, 89/93, 338/398 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
- mo use 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 mo tor activity, tremors and deep respirations.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 37 of 41 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. (μg/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 inh alation 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. D ermal dose (mg/kg/d ay) = unit dermal exposure (μg/lb ai) * (1 mg/1000 μg) conversion * application rate (lb ai/acre) * acres treated/day * dermal absorption rate (0.01) / body weight (60 kg). e. Inhalation dose (mg/kg/d ay) = unit exposure (μg/lb ai) * (1 mg/1000 μg) conversion * application rate (lb ai/acre) * acres treated/day / body w eight ( 60 kg). f. Total dose (mg/kg/d ay) = D ermal 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 corre sponding risks are also the same and therefore.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 38 of 41 Table B2. Occupational Exposure and Risk Estimates for Primary Handlers Applying Clothianidin on Rice: Seed Treatment. D376358, S. Wang, 22 October 2010. Exposure Scenario Mitigatio

n Level Dermal

Unit Exposur e (mg/lb ai) Inhalatio

n Unit Exposur e (μg/lb ai) Seed Species Applicati on 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) Com

bined Daily Dose d (mg/kg/day) MOE e

Loader/Applicator Loading/Applyin g 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 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 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 ( μ g/lb ai) * 0.001 * application. rate (lb ai/lb seed) * daily amounts treated / body weight ( 6 0 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 39 of 41 Table B3. Occupational Exposures and Risk Estimates for Primary Handlers Applying Clothianidin to Leafy Green V egetable 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., μg ai/lb ai 1 Inhal.

unit exp., μg 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 #1 4. 2. Dermal dose (mg/kg/day) = [ A ppl. 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) = [ A ppl. 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).

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 40 of 41 Table B4. Post
- application Exposure and Risk to Workers Scouting Clothianidin Treated Rice Fields : Foliar Treament
. D397004, S. Wang, 30 January 2012
. Transfer Coefficients (cm2/hr) DAT 1 DFR 2 (ug/cm2 ) Dose (mg/kg/day) 3 MOE 4

75 0 0.168 0.000 25 40 ,000 1 1 00 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/ μ g 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 (μg/lb ai) Seed

Category
-- Representative Seed Species Applicatio

n Rate (lb ai per lb seed) Amount

Planted a (lb seed p lante d/day) Daily

Dermal Dose b (mg/kg/day) Daily

Inhalation Dose c (mg/kg/day) Com

bined 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 ( μ g/lb ai) * 0.001 * application. rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg). d Co mbined 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.

### Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 41 of 41 Table B6. Exposures and Risk Estimates to Secondary Handlers From Planting Leafy Green Seeds T reated 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., μg ai/lb ai Inhal.

unit exp., μg 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. 0 15 1,200 250 3.4 0.00 0 75 0.0 0 102 0.0 0 177 5 , 50 0 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) = [ A ppl. 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) = [ A ppl. 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 sub jects 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 Resid ential 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 b y the Human Studie s 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.