### 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, respectively). The second is a request to register a seed treatment for leafy green vegetables (Crop Subgroup 4A). There is no petition number associated with 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 cloth ianidin 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 t hat 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 treatmen t 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 pelle tized lettuce seed are based on information from standard seed treatment of high

- acreage crops (e.g., corn, wheat, soybeans) and are considered to be extremely conservative when used to assess the lettuce

scenarios. Similarly, the assumptions used to assess multiple

- activity seed treatment scenarios result in very conservative estimates of exposure and risk. For these reasons, HED has determined that it is not appropriate in this case to apply an additional uncertain ty factor to account for the lack of the subchronic inhalation study.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The current tolerance enforcement method, a liquid chromatography tandem mass spectroscopy (LC

- MS/MS) method, is available to enforce tolerances for residues of clothian i 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, g roup 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. Compound

Common name Clothianidin Company experimental name TI

- 435, V

- 10066

IUPAC name (E)

- 1

- (2

- Chloro

- 1,3

- thiazol

- 5

- ylmethyl)

- 3

- methyl

- 2

- nitroguanidine

CAS name (E)

- N

- [(2

- Chloro

- 5

- thiazolyl)methyl]

- N’

- methyl

- N”

- nitroguanidine

CAS registry number 210880

- 92

- 5 (formerly 205510

- 53

- 8)

Chemical class Neonicotinoid

End

- use products V

- 10170 5 FS (EPA Reg. No

. 59639

- 151),

V

- 10170 2.13 SC (EPA Reg. No. 59639

- 150) Known impurities of concern None



### 3.2 Physical/Chemical Characteristics

The vapor pressure and octanol/water partition coefficient for clothianidin (Table 3.2) suggest that there is low potential for exposure to this chemical in the vapor phase and low potential for

bioaccumulation. The physicochemical properties of 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, pK

a at 20oC 11.09 Octanol/water partition coefficient, Log(K OW ) at 25oC 0.7

UV/visible absorption spectrum (Maximum, nm) 265.5 (acidic or neutral) 246.0 (basic) *PAI = Purified Active Ingredient; TGAI = technical grade active ingredient.

### 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, Type, and Equip. Max. Applic.

Rate

, 1

lb ai/A Max. No.

Applic. per

Season 2 Max. Seasonal

Applic. Rate

, lb ai/A PHI

, 3

days

EPA Reg. No. 59639

- 150

, V

- 10170 2.13 SC

Insecticide

, 23.60% ai

, Liquid Rice Foliar Application:

Ground + Aerial 0.075 1 0.075 Not Applicable

1 Rate = Maximum application rates as specified on proposed labels.

2 Maximum number of applications allowed on the proposed label.

3 PHI = Pre

- harvest Interval. For this use, application may not occur after tillering has initiated (BBCH Growth Stage 21).

Table 3.3.2. Proposed Application Rate of Clothianidin on Rice and Leafy Green Vegetable Seeds.

Product Vegetable Crops 1 App lication Method Max. Appl.

R ate

, 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 ag ricultural occupations may be exposed to clothianidin during handling of clothianidin

- containing products prior to application, during application, and during post

- application activities.

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

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.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 In take by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. 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 currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Clothianidin is a major 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 cotyledons of newly germinating seedlings and protects below

- and above

- ground plant parts from insect damage.

4.1 Toxicology Studies Available for Analysis

The toxicological database for clothianidin is complete, with the exception of a subchronic

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 i mmunotoxic 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 (monkeys) 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 backgro und 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 hydrolysis

.

In mic e, clothianidin was readily absorbed and excreted within 168 hours following a single low dose. Urine was the major route of excretion. Neither clothianidin nor its metabolites appeared to exhibit potential for bioaccumulation. Excretory patterns did 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 monkeys, absorption was calculated as 0.24% (±0.11%). This value was determined by adding the radioactivity recovered from urinary excretion, fecal excretion and from cage/pan/chair wash debris. Adjustment of the direct absorption determination was not necessary because recovery from the dermal dose was >90%. A value of 1% dermal absorption has been recommended as appropriate for use in risk assessment. This estimation takes into account any variability that woul d have likely occurred with testing several dose levels. The mouse single

- dose and rat single

- and multiple

- dose metabolism studies indicated that oral absorption was in the range of 90% or greater. Therefore, any extrapolation

from the oral to the derma l route using the dermal absorption factor is not likely to underestimate anticipated adverse effects.

4.3 Toxicological Effects

Clothianidin and its metabolites have relatively low (Category III or IV) acute toxicity via oral,

inhalation and dermal 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 II.

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

T he toxicological database lacks a subchronic inhalation study. Based on the use pattern, inhalation exposure is anticipated; therefore, a subchronic (21/28

- day) inhalation toxicit y 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 a nd 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 re production 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 stud ies is low and there

are no residual uncertainties for pre

- and/or postnatal toxicity because the observed effects are

well characterized and there are clear NOAELs/LOAELs determined for toxic effects seen

.

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

### 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 du rations, oral, dermal, and inhalation exposures may be aggregated because of the selection of a common endpoint for these routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

clothianidin is classified as ―Not Likely to be Carcinogenic to Humans.‖

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

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Dietary and Non

Occupational Human Health Risk Assessments. Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Acute Dietary Females age

13

- 49 NOAEL =

25 mg/kg/day 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

Acute 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, in halation) ―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 by 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 fairly consistent across plants, goats, hens, and rats, although the designation of major vs. minor metabolites varies depending on the test species.

5.1. 2 Residues of Concern Summary and Rationale

Table 5.1.2. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Crops except Leafy and Root/Tuber Vegetables: Parent Leafy and Root/Tuber Vegetables: Parent + TMG Parent

Rotational Crop Parent, TZNG, MNG Parent

Livestock Ruminant Parent, TZU, TZG, TZNG, ATMG

- Pyr Parent

Poultry Parent, TZU, TZG, TZNG, ATG

- Ac Parent Drinking Water Parent Not Applicable



### Based on the available metabolism studies, HED concluded that the nature of the residue has been adequately delineated, and that parent only is the residue of concern ( ROC ) to be used for the tolerance expression for primary crops. HED had previously determined that future new uses on root crops and/or leafy vegetables will require analysis for residues of TMG along with parent in field trial samples and that TMG should be included as a ROC for risk assessment if significant levels of TMG were 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, a nd expansion for crop groups 8 and 11 to include the 2010 definitions); rather, these requests are supported by previously submitted/reviewed data. In summary, the uses on rice resulted in no quantifiable residues ; the requested rate increase for 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 Louisiana

- that are currently under review by the Agency (MRID 48364804, MRID 48364803). The maximum

concentr ation at day zero, pre

- irrigation, was 210 ppb in the Louisiana plot cropped with rice. Clothianidin residues quickly dissipated to an average of 74.1 ppb three days after application, and further dissipated to 0.7 ppb 28 days after application. The Cali fornia plots show similar dissipation results with a maximum clothianidin concentration of 51.9 ppb at day zero, quickly dissipating to an average of 1.1 ppb ten days after application in the plots cropped with rice.

These interim results show that Tier I rice estimate may under estimate the initial exposure in the rice paddy soon after application, but it is a conservative estimate of clothianidin concentrations in release water shortly after application occurs.

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

Leafy vegetables (including brassica) (0.05 lb a.i./A) FIRST 4.0 ppb 2.2 ppb



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

### 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 ) rely on

tolerance

- level residues for all crops with registered and/or requested clothianidin uses. There

are a number of crops for which uses of both clothianidin and thiamethoxam have been registered. The labels for the various end

- use products containing these active ingredients prohibit the application of both active ingredients to the same crop during a growing cycle . Due to that restriction and the assumption of 100% crop treated, a single value reflecting the greatest clothianidin residue from either active ingredient has been used for crops listed for use with both active ingredients (versus combined estimates 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 analyses, the greatest exposure estimate is for the population subgroup Children 1

- 2 years old. Risk estimates for this subgroup are 24% aPAD and 21% cPAD. These estimates are well below HED’s level of concern (typically 100% of the PAD).

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

Table 5.4. 3. Summary of Dietary Exposure and Risk Estimates for Clothianidin.

Population Subgroup Acute (95 th Pecentile of Exposure) Chronic
Exposure, mg/day Risk, % aPAD Exposure, mg/day Risk, % cPAD

U.S. Population (total) 0.017373 7 0.006107 6
All infants (< 1 year) 0.054584 2 2 0.017497 1 8

Children 1

- 2 yrs 0.059972 2 4 0.020868 21

Children 3

- 5 yrs 0.04153 0 1 7 0.014497 1 5

Children 6

- 12 yrs 0.020012 8 0.007335 8

Youth 13

- 19 yrs 0.01223 0 5 0.004312 4

Adults 20

- 49 yrs 0.012257 5 0.004636 5
Adults 50+ yrs 0.01192 0 5 0.004882 5

Females 13

- 49 yrs 0.012765 5 0.004737 5 The population subgroup(s) with the highest exposure/risk estimates are shown in bold

.

### 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 t hat 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

- Type Spreader

Turf

Arena 0.5G Reg. No. 59639

- 156 0.67 0.00088 0.4

lb ai/A 0.5 A 0.00002233 0.00000293 0.0000253 440,000 3,300,000 390,000

Hose

- End Sprayer

Fruit trees & ornamentals

Arena 50 WDG Reg.No. 59639

- 156 39 0.0015 0.15

lb ai/gal.

5 gals 0.004875 0.00001875 0.004894 2000 520,000 2000

Hand

- Held Pump Sprayer

Fruit trees & ornamentals

Arena 50 WDG Reg.No. 59639

- 156 56 0.0038 0.0004 lb ai/gal. 0.0000187 0.000000126 0.000018 520,000 77,000,000 520,000

Hose

- End Sprayer

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 l b 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.) × a mount treated × DAF ( .01 ) ÷ body weight (60 kg).

5

. Inhalation dose (mg/kg/day) = inhalation unit exposur e (mg/lb ai) × application rate (lb ai./A or gal) × a mount 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

- mouth 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. H ED 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 days 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.

T here is the potential for postapplication dermal and oral exposure for children resulting from use of clothianidin on turf. A child's postapplication exposure assessment was not performed for use on ornamental tree trunks as children's contact with ornamentals is typically significantly less than turf. Therefore a turf postapplication exposure 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 resident ial exposure scenarios and t heir 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 always a pote ntial source of exposure to residents nearby spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for clothianidin . T he Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more informat ion 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 e valuation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides appli ed by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential post

- application exposure assessment was not performed to
address pesticide drift from neighboring treated agricultural fields, it is noted that residential exposure of children from use on turf and occupational exposure of flaggers during aerial application were assessed and were found to be not of concern

. Exposures from these scenarios are likely to be significantly greater than those associated with spray drift from agricultural applications of clothianidin. By extension, therefore, risks associated with spray drift of clothianidin are expected to be also not of concern.

7.0 Aggregate Exposure/Risk Characterization

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

Typically, HED does not consider residential exposures when assessing acute aggregate risk unless such exposures can be characterized as a series of single

- day exposures, which is not the case for clothianidin. Therefore, acute aggregate risk estimates for clothianidin are equivalent to the acute dietary risk estimates (Section 5 .4) and are below HED’s level of concern. There are no acute aggregate risk issues that would preclude granting the actions requested by the registrant.

7.2 Short

- and Intermediate

- Term Aggregate Risk

Short

- term aggregate assessments address exposures that may occur for durations of one to thirty days. Intermediate

- term assessments address exposures lasting from between thirty days to 6 months. In the case of clothianidin, the endpoints and doses for risk assessment are the same for

short

- and intermediate

- term exposures; therefore, separate assessments are not being conducted

for these two durations. O ral, dermal, and inhalation e ndpoints 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 a re 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 Combined 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 yrs.

3 Aggregate = Combined Residential + Dietary.

4 Aggregate MOE = short

- /intermediate

- term NOAEL (9.8 mg.kg.day) divided by the aggregate exposure. Value rounded to two significant figures.



### 7. 3 Chronic Aggregate Risk

Chronic aggregate risk assessments address exposures that are likely to occur, continuously, for greater than six months. In the case of clothianidin, residential exposures are not expected to

occur on a chronic 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 likely carcinogenic to humans.‖ Therefore, there is no cancer risk associated with exposure to clothianidin.

8.0 Cumulative Exposure/Risk Characterization

Clothianidin is a member of the neonicotinoid class of pesticides and is a major metabolite of another neonicotinoid, thiamethoxam. Structural similarities or common effects do not constitute a common mechanism of toxicity. Evidence is needed to establis h that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). Although clothianidin and thiamethoxam bind selectively to insect nicotinic acetylcholine receptors (nAChR), the specific binding site(s)/ receptor(s) for clothianidin, thiamethoxam and the other neonicotinoids are unknown at this time. Additionally, the commonality of the binding activity itself is uncertain, as preliminary evidence suggests that clothianidin operates by direct competitive inhibition, while thiamethoxam is a non

- competitive inhibitor. Furthermore, even if future research shows that neonicotinoids share a common binding activity to a specific site on insect nAChRs, there is not necessarily a relationship between this 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 notably 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 currently no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common 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 by 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 Pla nted 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 U nit 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 Baseli n e

plus gloves 37.6 0.219 0.075 1200 0.00056 0.00033 0.00089 11,000

Liquids for Ground

boom Application Baseline

plus gloves 37.6 0.219 0.075 200 9.4E

- 5 5.5E

- 5 0.00015 66,000

Applicator

### 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 U nit 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

. A cres 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 Treat ment 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 (m g/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 lay ers 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

- A pplication 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 previousl y 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 Fede ral 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 by 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 pest icides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

For seed treatments, a post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for seed treaters and secondary handlers (i.e.

, planters). It is expected that these exposure estimates would be protective of most post

- application inhalation exposure scenarios.

Dermal Post

- application Exposure

Foliar Treatments

For the foliar application to rice, the post

- application activity t hat involves the highest contact with foliage is scouting. The MOE associated with scouting foliarly 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 Type 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 III and IV. Acute toxicity category III or IV chemicals require a 12

- hour REI. Thus, the 12

- hour REI that appears on the labels for foliar

treatment s is adequate.

Seed Treatments

For seed treatments t here 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 registr ant 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 Die tary

(Food and Drinking Water) Exposure and Risk Assessments

.

D376358. S. Wang. 22 October 2010. Clothianidin: Occupational and Residential Exposure/

Risk Assessment for Proposed Seed T reatmen t 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 Acute Toxicity Profile

- Clothianidin Technical, Intermediates, and Metabolites

Test Material Guideline

No. Study Type MRID(s) Results Toxicity Category

Technical 870.1100 Acute oral

- rat 45422621 LD 50 > 5000 mg/kg IV

BN0230M

Metabolite 870.1100 Acute oral

- rat 45422628 LD 50 > 2000 mg/kg (♂+♀) III

BN0335E2

Metabolite 870.1100 Acute oral

- rat 45422623 LD 50 > 2000 mg/kg (♂+♀) III

MAI

Metabolite 870.1100 Acute oral

- rat 45422629 LD 50 = 758 mg/kg (♀) Males not more susceptible III

Clothianidin

- CCMT

Adduct Intermediate 870.1100 Acute oral

- rat 45422630 LD 50 > 2000 mg/kg (♂+♀) III

Clothianidin

Hexahydropyrimidine

Intermediate 870.1100 Acute oral

- rat 45422631 LD 50 > 2000 mg/kg (♂+♀) III

Clothianidin

- Triazan

Intermediate 870.1100 Acute oral

- rat 45422632 LD 50 > 2000 mg/kg (♂+♀) III

TMG Metabolite 870.1100 Acute oral

- rat 45422625 LD 50 < 550 mg/kg (♂)

LD 50 = 567 mg/kg (♀) II

TZMU Metabolite 870.1100 Acute oral

- rat 45422624 LD 50 = 1424 mg/kg (♂)

LD 50 = 1282 mg/kg (♀) III

TZNG Metabolite 870.1100 Acute oral

- rat 45422626 LD 50 > 1450 mg/kg (♂)

LD 50 = 1481mg/kg (♀) III

Technical 870.1100 Acute oral

- mouse 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 Acute dermal

- rat 45422634 LD 50 > 2000 mg/kg III

Technical 870.1300 Acute inhalation 45422636 LC 50 > 5.538 mg/L (♂+♀) IV

Technical 870.2400 Acute eye irritation 45422701 Slightly irritating to the eye IV

Clothianidin

- CCMT

Adduct Intermediate 870.2400 Acute eye irritation 45422814 Not irritating to the eye IV

Clothianidin

- Triazan

Intermediate 870.2400 Acute eye irritation 45422819 Not irritating to the eye IV

Technical 870.2500 Acute dermal

irritation 45422703 Not irritating to the skin IV

Clothianidin

- CCMT

Adduct Intermediate 870.2500 Acute dermal

irritation 45422813 Not irritating to the skin IV

Clothianidin

- Triazan

Intermediate 870.2500 Acute dermal

irritation 45422820 Not irritating to the skin IV

Technical 870.2600 Skin sensitization 45422705 Is not a sensitizer under conditions of study N/A

Clothianidin

- CCMT

Adduct Intermediate 870.2600 Skin sensitization 45422815 Is not a sensitizer under conditions of study N/A

Clothianidin

- Triazan

Intermediate 870.2600 Skin sensitization 45422821 Is a sensitizer under conditions of study N/A

### 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

- week) Acceptable/ guideline ppm=0, 150, 500 & 3000 mg/kg/day (M/F)=0/0, 9.0/10.9,
27.9/34.0, 202.0/254.2 NOAEL = 27.9/34.0 mg/kg/day (M/F)

LOAEL = 202.0/254.2 mg/kg/day (M/F)

based on decreased BW and BW gain.

870.3150 13

- 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

- r at ( 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

. Developmental NOAEL = 125 mg/kg/day (HDT) Developmental LOAEL = Not established

870.3700b Developmental

Toxicity

- r abbit ( 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

i ncreased incidences of clinical signs (scant feces and orange urine), mortalities, decreased food consumption, early delivery, abortion, and decreased body weight gain

. Developmental NOAEL = 25 mg/kg/day Developmental LOAEL = 75 mg/kg/day

based on premature deliver ies, 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/Systemic NOAEL = 31.2/36.8 mg/kg/day (M/F) Parental/Systemic LOAEL = 163.4/188.8 mg/kg/day (M/F) based on decreased body weight, body weight gain

, and absolute and

### 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

-

m ouse (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/

Carcin ogenicity,

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 mutagenic activity in bacteria ( S. typhimurium and E. coli ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay

Parent 45422733

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

870.5100 Gene Mutation

bacterial reverse mutation assay

Parent 45422734

(1999) Acceptable/

non

- guideline (only TA 1535 assayed) Only TA 1535 tested. No mutagenic activity in bacteria ( S. typhimurium ) under condtions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay

BN0335E2

metabolite 45422724

(2000) Acceptable/ guideline No mutagenic activity in bacteria ( S. typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay

TZMU

metabolite 45422725

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

870.5100 Gene Mutation

bacterial reverse

mutation assay methyl guanidine

intermediate 45422726

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

870.5100 Gene Mutation

bacterial reverse mutation assay

TZNG

metabolite 45422727

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

870.5100 Gene Mutation

bacterial reverse mutation assay

TMG

metabolite 45422728

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

870.5100 Gene Mutation

bacterial reverse mutation assay

BN0230M

metabolite 45422729

(2000) Acceptable/ guideline No mutagenic activity in bacteria ( S. typhimurium) under conditions of this assay.

870.5100 Gene Mutation 45422730 No mutagenic 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 mutagenic activity in bacteria ( S. typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay

TI 435

- Triazan

intermediate 45422822

(2000) Acceptable/ guideline No mutagenic activity in bacteria ( S. typhimurium ) under conditions of this assay.

870.5100 Gene Mutation

bacterial reverse mutation assay

TI 435

- CCMT

Adduct 45422816

(2000) Acceptable/ guideline No mutagenic activity in bacteria ( S. typhimurium ) under conditions of this assay.

870.5300 Gene Mutation

-

in vitro

mammalian cell gene mutation test (L5178Y

TK +/

- mouse lymphoma cells) 45422737 (2000)

Acceptable/ guideline Increases in mutant frequency with and

without S9 at dose levels that were cytotoxic. The observed response was primarily due to small colony formation, indicating clastogenic activity.

870.5300 Gene Mutation

-

in vitro

mammalian cell gene mutation test (V79

- HPRT Assay) 45422738

(1999) Acceptable/ guideline No increase in mutant frequency under the conditions of the study.

870.5300 Gene Mutation

– in vitro

mammalian cell gene mutation test (V79

- HPRT Assay) 46339001

(2003) Acceptable/ guideline There was no evidence of induced mutant colonies over background.

870.5375 Cytogenetics

-

in vitro

mammalian

chromosome

aberration test (CHL Cells)

Parent 45422736

(2000) Acceptable/ guideline Significant increases in frequency of cells

with structural aberrations. Predominant types were chromatid breaks and exchanges. There was, however, no clear indication of a

dose

- related response in either the presence

or absence of S9 activation.

870.5375 Cytogenetics

–

in vitro

mammalian

chromosome

aberration test (CHL Cells) 46339002

(2003) Acceptable/ guideline Clothianidin was clastogenic in the absence of S9 activation but only at precipitating concentrations. Some doubt regarding the relevance of this finding since clastogenicity was abolished when exogenous metabolic activation was incorporated into the test

### 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 Cytogenitics

-

mammalian erythrocyte

micronucleus

test
Parent 45422740

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

cond itions.

870.5395 Cytogenetics

-

mammalian erythrocyte

micronucleus

test

Parent 46339003

(2003) Acceptable/ guideline No significant increase in the frequency of MPCEs in bone marrow after any harvest in the test groups up to an overtly toxic dose for

this test system.

870.5550 Other Effects

-

DNA Repair

Test in B.

subtilis

Parent 45722735

(1990) Unacceptable/

non

- guideline (only single plates used) No potential for DNA damage under these

conditions.

870.5500 Other Effects

-

(UDS) in

Mammalian

Cells in Culture

Parent 45422739

(1999) Acceptable/

non

- guideline (only males used) No evidence (or a dose related positive response) that UDS was induced.

870.6200a Acute

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 was saturated. Following single or multiple

oral low doses (2.5 and 25mg/kg bw, respectively) of clothianidin, urinary

excretion accounted for 89.2

- 94.6% of the administered radioactivity suggesting that a multiple exposure regimen did not affect the absorption/excretion processes. Urinary

excretion 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

a bsorption in the high

- dose group. Neither clothianidin nor metabolites appear to undergo significant sequestration.
The metabolites identified (primarily oxidative demethylation products and cleavage products of the nitrogen

- carbon bond between the nitroimino and thiazolyl moieties) were consistent with Phase I processes. Extraction efficiencies appeared

to be 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 was the major route of excretion, accounting

for 92.4

- 93.7% of the administered

radioact ivity. 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)

- - 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 [ni troimino

- 14C]

- clothianidin the metabolism pathway proposed by the investigators was supported.

870.7600 Dermal

Penetration

– monkey 45868001 (2003)

Acceptable/

non

- guideline 6.13 μg/cm 2
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

-

mouse 445422823

(2000) Acceptable/

non

- guideline mg/kg=0, 12.5, 25, 50, 100, 200, 400 (single gavage dose) NOAEL = 25 mg/kg/day (M/F)

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

### 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. A cres 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 * applicat ion rate (lb ai/acre) * acres treated /day * dermal absorption rate (0.01) / body weight (60 kg).

e. 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).

f. Total dose (mg/kg/d ay ) = D ermal dose /day + i nhalation 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) Combined

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 800,000 Bagging Seeds

after Seed

treatment Single

Layer,

No

Gloves 0.0091 0.16 Rice 0.00075 718,000 0.0008152 0.0014336 0.0022488 4,400

Multiple Activities Worker 800,000 Multiple

Activities for

Seed treatment Single

Layer,

Gloves 0.042 1.6 Rice 0.00075 718,000 0.0037633 0.014337 0.01810 540

a Daily amounts treated values are based on ex posure 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 (cm 2 /hr) DAT 1 DFR 2 (ug/cm 2 ) 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 la nte d/day) Daily

Dermal

Dose b
(mg/kg/day) Daily

Inhalation

Dose c (mg/kg/day) Combined

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

Secondary Seed Handlers Secondary Seed

Handlers: planting seeds in

the field Single

Layer,

Gloves 0.25 3.4 Rice 0.00075 30,000 0.000936 0.0012729 0.0022089 4,400

a Daily amounts planted values are based on ex posure 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 /da y * 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 requi rements. For certain studies that review may have included review by 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.