### Clothianidin Human Health Risk Assessment **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A** **GENCY**

MEMORANDUM Date: 2 7 September 2012 SUBJECT: Clothianidin

– Aggregate Human Health Risk Assessment of New Uses on

Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and Tolerance for Pepper and Eggplant (Crop Subgroup 8 PC Code: 044309 Decision Nos.: 455249, 459388 Petition No.: 2F8008, 1E7923 Risk Assessment T ype: T XR No.: None MRID No.: NA 

### FROM: Michael A. Doherty, Ph.D., Chemist Suku Oonnithan, Ph.D., Biologist Edward Scollon, Ph.D., Toxicologist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Zaida Figu e roa, Industrial Hygenist

Linnea Hansen, Toxicologist Elizabeth Holman, Chemist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) TO: Marianne Lewis/Venus Eagle Insecticide/Rodenticide Branch Registration Division (7505P) Barbara Madden Risk Integration, Minor Use, and Emergency Response Branch Registration Division (7505P) Clothianidin Human Health Risk Assessment DP No. D395348

Page 1 of 52 **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A** **GENCY WA** **SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND** 

**POLLUTION PREVENTION**



### September 2012

Aggregate Human Health Risk Assessment of New Uses on Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and Tolerance for Pepper and Eggplant (Crop Subgroup 8
- 10B). DP Barcode s : D395348, 455249, 459388 Registration No. : 59639 2F8008, 1E7923 Regulatory Action: Section 3 Assessment T ype: Single Chemical, Aggregate Case No.: 7620 CAS No.: 210880 - 92 40 CFR 180.586 

### Michael A. Doherty, Ph.D., Chemist Suku Oonnithan, Ph.D., Biologist Edward Scollon, Ph.D., Toxicologist Risk Assessment Branch II Health Effects Division (7509P)

roa, Industrial Hygenist Linnea Hansen, Toxicologist Elizabeth Holman, Chemist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) Marianne Lewis/Venus Eagle (RM 01) Insecticide/Rodenticide Branch Registration Division (7505P) Risk Integration, Minor Use, and Emergency Response Branch Registration Division (7505P) DP No. D395348 **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A** **GENCY**
**OFFICE OF CHEMICAL SAFETY AND**

**POLLUTION PREVENTION**



### Aggregate Human Health Risk Assessment of New Uses on Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and D395348, D 397647 59639 - 150, 59639 - 152 Section 3 92 - 5

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 2 of 52 1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 HED Recommendations ................................ ................................ ................................ ....... 4 2.1 Data Deficiencies/Conditions of Registration ................................ ................................ 4 2.2 Tolerance Considerations ................................ ................................ ................................ 4 2.2.1 Enforcement Anal ytical Method ................................ ................................ ................. 4 2.2.2 International Harmonization ................................ ................................ ....................... 5 2.2.3 Recommended Tolerances ................................ ................................ .......................... 5 2.2.4 Revisions to Petitioned
- For Tolerances ................................ ................................ ...... 5 2.3 Label Recommendations ................................ ................................ ................................ . 6 2.3.1 Re commendations from Residue Reviews ................................ ................................ . 6 2.3.2 Recommendations from Occupational and Residential Assessments ........................ 6 3.0 Introduction ................................ ................................ ................................ .......................... 6 3.1 Chemical Identity ................................ ................................ ................................ ............ 6 3.2 Phy sical/Chemical Characteristics ................................ ................................ .................. 6 3.3 Pesticide Use Pattern ................................ ................................ ................................ ....... 7 3.4 Anticipated Exposure Pathways ................................ ................................ ..................... 8 3.5 Consideration of Environmental Justice ................................ ................................ ......... 8 4.0 Hazard Characterization and Dose
- Response Assessment ................................ .................. 9 4.1 Toxicology

Studies Available for Analy sis ................................ ................................ .... 9 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................ .... 9 4.2.1 Dermal Absorption ................................ ................................ ................................ .... 10 4.3 Toxicological Effects ................................ ................................ ................................ .... 10 4.4 Safety

factor for Infants and Children (FQPA Safety Factor) ................................ ...... 12 4.4.1 Completeness of the Toxicology Database ................................ ............................... 13 4.4.2 Evidence of Neurotoxicity ................................ ................................ ........................ 13 4.4.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ........... 13 4.4.4 Residual Uncertainty in the Exposure Database ................................ ....................... 14 4.5 Toxicity

Endpoint and Point of Departure Selections ................................ .................. 14 4.5.1 Endpoint Selection ................................ ................................ ................................ .... 14 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment .......... 16 4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ 16 4.5.4 Summary

of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment ................................ ................................ ................................ ............................ 17 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 18 5.1 Metabolite/Degradate Residue Profile ................................ ................................ .......... 18 5.2 Food Residue Profile ................................ ................................ ................................ ..... 19 5.3 Water Residue Profile ................................ ................................ ................................ ... 20 5.4 Dietary

Risk Assessment ................................ ................................ .............................. 20 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ....... 20 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ .................. 21 5.4.3 Acute and Chronic Dietary Risk Estimates ................................ .............................. 21 5.4.4 Dietary

Exposure and Risk Estimate Summary Table ................................ .............. 22 6.0 Residential (Non
- Occupational) Exposure/Risk Characterization ................................ .... 22 6.1 Residential Handler Exposure ................................ ................................ ....................... 22 6.2 Post - Application Exposure ................................ ................................ ........................... 23 6.3 Combined Exposure ................................ ................................ ................................ ...... 24

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 3 of 52 6.4 Residential By stander Post
- Application Inhalation Exposure ................................ ...... 25 6.5 Spray

Drift ................................ ................................ ................................ .................... 25 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 26 7.1 Acute Aggregate Risk ................................ ................................ ................................ ... 26 7.2 Short
- and Intermediate
- Term Aggregate Risk ................................ ............................. 26 7.3 Chronic Aggregate Risk ................................ ................................ ................................ 27 7.4 Cancer Aggregate Risk ................................ ................................ ................................ . 27 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 27 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 28 9.1 Short
- and Intermediate
- Term Handler Risk ................................ ................................ 28 9.2 Short
- and Intermediate
- Term Post - Application Risk ................................ .................. 29 9.2.1 Dermal Post
- Application Risk ................................ ................................ .................. 29 9.2.2 Inhalation Post
- Application Risk ................................ ................................ .............. 30 10.0 References ................................ ................................ ................................ .......................... 31 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 32 A.1. Toxicology

Data Requirements ................................ ................................ ....................... 32 A.2. Toxicity

Profiles ................................ ................................ ................................ ............... 33 A.3. En dpoint Selection ................................ ................................ ................................ ........... 42 Appendix B. Metabolism Summary Table ................................ ................................ ................... 45 Appendix C. Physical/Chemical Properties ................................ ................................ ................. 46 Appendix D. Review of Human Research ................................ ................................ ................... 47 Appendix E. Occupational Exposure/Risk Summary Tables ................................ ...................... 48 Appendix F. Summary

of Relevant International Residue Limits for Cl othianidin. ................... 52

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 4 of 52 **1.0 Executive Summary**  The Registration Division (RD) requested that the Health Effects Division (HED) conduct an exposure and risk assessment for a revision to the pre
- harvest interval (PHI) for Crop Subgroup 8 - 10B (peppers and eggplant) proposed b y Valent BioSciences and for the IR4 (Inter- Regional Project #4) proposed new uses on strawberry , pistachio, and citrus (Crop Group 10
- 10) , and use on tea without a U.S. registration. This assessment takes into account previously registered uses on other crops and in residential use s ites . The toxicological database for clothianidin is largely complete; the only

missing study

is the subchronic (28
- day) inhalation toxicity study . HED has determined that the study is required and has requested its submission during registration review. Pending the results of the study , a 10X database uncertainty factor has been retained for residential and occupational inhalation exposure assessments. The residue chemistry database for clothianidin is complete. HED has evaluated the available hazard and residue chemistry data to derive risk estimates associated with dietary , residential, and occupational exposure. HED’s aggregate risk assessment is based on screening
- level assumptions and the resulting estimated exposure levels likely overestimate actual exposures that may occur. Sentinel aggregate risk indices (ARIs) are 1.21 for children aged 1
- 2 years old and 6.9 for adults, and are not of concern. Similarly , occupational ARIs are not of concern, ranging from 1.1 to 660. Even with the conservative, health
- protective assumptions, aggregate and occupational risk estimates are below HED’s level of concern for all scenarios and population groups. There are no human health risk issues that would preclude granting the requested label amendment and ne w uses, and establishing permanent tolerances as described below . **2.0 HED Recommendations**  **2.1 Data Deficiencies/Conditions of Registration**  A 28 - day inhalation toxicity study in rats is required, based on weight of evidence considerations, including the available toxicity data and the potential for exposure to clothianidin via the inhalation route. The study has been requested under registration review. **2.2 Tolerance Considerations**  **2.2.1 Enforce**  **ment Analytical Method** Adequate methods, based on solvent extraction and L C - MS/MS separation, identification, and quantification, are available for plant (Morse Method #Meth
- 164 - modified, RM
- 39C - 1, or Baye r Method 00552) and livestock (Bayer Method 0062 4) matrices. The LOQ for clothianidin in plant commodities is 0.01 ppm, except for wheat straw (0.02 ppm), and the validated LOQs are 0.01 ppm in milk and 0.02 ppm in animal tissues. Clothianidin and its major metabolites are not adequatel y recovered using any of the FDA multiresidue methods.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 5 of 52 **2.2.2 International Harmonization**  There are no Canadian or Codex M ax imum Residue Limits (M RL s ) for clothianidin that are relevant to th e recommended tolerances. Codex MRL s (see Appendix F) are in place for tea, strawberry , citrus, and fruiting vegetables; however, the MRLs are based on clothianidin derived from treatment with thiamethoxam rather than treatment with clothianidin. Therefore, it is not appropriate to harmonize U.S. tolerances with the Codex MRL s. The Pest Management Regulatory Agency (PMRA) of Health Canada intends to establish an MRLfor residues in Crop Subgroup 13
- 07G (low
- growing berries) at 1.5 ppm . Strawberry is the representative crop for this subgroup ; therefore, in terms of strawberry , the residue level will be harmonized. HED is not recommending for the entire subgroup because the requested use was on strawberry

only . With respect to Crop Subgroup 8
- 10B, the new tolerance for this subgroup is considerabl y greater than the existing Crop Group 8 tolerance. The new tolerance will result in regulatory action levels for this subgroup being out of harmonization with PMRA. **2.2.3 Recommended Tolerances**  Table 2.2.3. Summary of Requested and Recommended Tolerances for Residues of Clothianidin. Commodity Tolerance, ppm Comments/Corrections Requested Recommended Vegetable, fruiting, peppers and eggplant, Subgroup 8
- 10B 0.7 0.80 Upon establishment of this tolerance, the existing tolerance listing for vegetables, fruiting, Group 8 should be revised to Vegetable, fruiting, group 8
- 10, except pepper/eggplant subgroup 8
- 10B Pistachio 0.01 0.01 -- Straw berry 1.4 1.50 -- Tea , dried 50 70 -- Fruit, citrus, Group 10
- 10 0.5 0. 6 0 -- Citrus, dried pulp 1 -- A tolerance for this processed commodity is not necessary. 

### 2.2.4 **Revisions to Petitioned -**  **For Tolerances** HED is recommending tolerance levels for Subgroup 8
- 10B (peppers and eggplant) , strawberry , tea, and citrus (including dried citrus pulp ) that are different from those requested by the petitioners. In the case of Subgroup 8
- 10B , strawberry , and citrus , the difference is likely due to the petitioners’ use of the NAFTA MRL calculation procedures rather than the OECD MRL calculation procedure s. The recommended tolerance for residues in/on tea appears to include a broader scope of data th an was used to derive the petitioned
- for tolerance. HED has determined that a separate tolerance for the processed commodity dried citrus pulp is not necessary . Although residues concentrate in dried citrus pulp, it is anticipated that they would not exceed the recommended tolerance level for the whole fruit.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 6 of 52 **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews** 

 RD should ensure that the res trictions listed on the proposed label regarding use of adjuvants and restrictions on aerial application reflect all of the recent revisions/recommendations that were made by HED outside of these petitions (e.g., see M. Doherty, D 404897, 13 August 2012; M. Doherty , D405080, 5 September 2012) .  Update the rotational crop restrictions to include strawberry as a crop suitable for immediate plant back.  Revise the labels to ensure that for all crops , the maximum amount of active ingredient applied per season is g eneric for clothianidin and not specific to any one particular end
use product or ty

pe of application being made.  HED notes that the maximum seasonal foliar use rate for V
- 10170 2.13 SC on strawberry (0.1 lb a.i./A) differs from the maximum seasonal use rate for the Arena product (0.2 lb a.i./A). HED recommends that RD ensure that these differences are intended by the petitioner. The available residue data support a maximum seasonal application rate of 0.2 lb a.i./A to strawberry , irrespective of formul ation ty pes . **2.3.2 Recommendations from Occupational**  **and Residential Assessment**  **s** None. **3.0 Introduction**  **3.1 Chemical Identity**  Table 3.1. Clothianidin Nomenclature. Parent Com

pound

Common name Clothianidin Com pany experimental name TI - 435, V - 10066 IUPAC name (E)
- 1 - (2
- Chloro
- 1,3 - thiazol
- 5 - ylmethyl)
- 3 - methyl
- 2 - nitroguanidine CAS name (E)
-N - [(2
- Chloro
- 5 - thiazolyl)methyl]
-N’ - methyl
-N” - nitroguanidine CAS registry number 210880 - 92 - 5 (formerly 205510
- 53 - 8) Molecular wt. 249.68 End
- use product (EP) 50% WDG (Arena ® 50 WDG; EPA Reg. No. 59639 - 152) 2.13 lb/gal FlC (V
- 10170 2.13 SC; EPA Reg. No. 59639 - 150) 

### 3.2 **Physical/Chemical Characteristics** Appendix C summarizes the phy sical and chemical properties of clothianidin. Based on the available data, clothianidin has a low vapor pressure and exposure to this chemical in the vapor S N N

H N NH Cl C

H 3 N O 2

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 7 of 52 phase is not expected. The octanol/water partitioning coefficient is also quite low, indicating that clothianidin is unlikely

to accumulate in fatty

tissues. **3.3 Pesticide Use Pattern**  Table 3.3. Summary of Directions for Use of Clothianidin. Appl. timing, ty pe, and (equip.) Form ul ation [EPA Reg. No.] Max. Single

Appl. rate ( lb ai/A) Max. N o.

of A ppl. / S eason Max .

S easonal A ppl. Rate (lb ai/A) PHI

(days) Use D irections

and L imitations Straw berry Foliar, ground or aerial (FWA, ground boom and air
-blast sprayers) Arena ® 50 WDG [59639 - 152] 0.05 - 0.2 4 0.2 1 RTI=7 days Soil broadcast, pre
- or at transplanting, in
- furrow , band or bed, transplant water drench, drip/trickle irrigation (back pack and MPHG) 0.15 - 0.2 1 0.2 21 RTI=Not applicable Foliar, ground or aerial (FWA, ground boom and air
-blast sprayers) V - 10170 2.13 SC [59639 - 150] 0.05 - 0.1 2 0.1 1 RTI=7 days Soil in
- furrow , band, drench, drip or trickle irrigation (back pack and MPHG) 0.15 - 0.2 1 0.2 21 RTI=not applicable Citrus fruit Foliar, ground or aerial (aircraft, and air
-blast sprayer) V - 10170 2.13 SC [59639 - 150] 0.05 - 0.1 4 0.2 1 RTI=14 days Soil in
- furrow , band, drench, drip or trickle irrigation (back
pack and MPHG) 0.15 - 0.2 1 0.2 21 RTI=not applicable Basal bark spray (back
-pack) 0.1 for 2
- 4 ft. and 0.2 for 4 - 8 ft. trees 1 0.2 1 RTI=not applicable Nectarine Foliar, post bloom ground (air blast sprayer) V - 10170 2.13 SC [59639 - 150] 0.05 - 0.1 4 0.2 21 RTI=10 days

Pistachio Foliar, ground or aerial (FWA and air blast sprayer) V - 10170 2.13 SC [59639 - 150] 0.05 - 0.1 4 0.2 21 RTI=10 days

Tea
Foliar NS 1.8 1 NS 7 Use patterns are implied from the field trial application parameters Peppers and Eggplant (Crop Subgroup 8
- 10B) * Foliar Arena ® 50 WDG [59639 - 152] 0.05 - 0.1 4 0.2 1 RTI=10 days Soil in
- furrow , band, drench, drip or trickle irrigation (back
0.15 - 0.2 1 0.2 NS Apply at planting

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 8 of 52 Table 3.3. Summary of Directions for Use of Clothianidin. Appl. timing, ty pe, and (equip.) Form ul ation [EPA Reg. No.] Max. Single

Appl. rate ( lb ai/A) Max. N o.

of A ppl. / S eason Max .

S easonal A ppl. Rate (lb ai/A) PHI

(days) Use D irections

and L imitations pack and MPHG) Foliar V - 10170 2.13 SC [59639 - 150] 0.05 - 0.067 3 0.2 1 RTI = 7 days Soil broadcast, pre
- or at transplanting, in
- furrow , band or bed, transplant water drench, drip/trickle irrigation (back pack and MPHG) 0.15 - 0.2 1 0.2 NS Apply at planting Abbreviations used: MPHG= mechanically pressurized hand gun , PHI = Preharvest interval, RTI= re - treatment interval , NS=not specified . * Uses on peppers and eggplant are already registered, with a PHI of 7 days. This entry reflects the requested label amendment to reduce the PHI to 1 day. 

### The personal protective equipment (PPE) requirements proposed for applicators and other handlers include : long
- sleeved shirt and long pants, socks plus shoes, and chemical
- resistant gloves . The Restricted Entry Interval (REI) is 12 hours . The PPE and REI on both labels are appropriate based on the acute toxicity and estimated handler exposures and risks for clothianidin . **3.4 Anticipated Exposure Pathways**  Clothianidin is registered for use on numerous agricultural crops as well as on re sidential turf , and there is also an indoor use to control bed bugs . Exposure to clothianidin may occur from ingestion of residues in/on foods and in drinking water , and via the dermal and inhalation routes for adults using clothianidin products in occupational and residential settings. Finally , incidental oral ingestion can occur for toddlers playing in areas previousl y treated with clothianidin (e.g., turf and indoor surfaces). **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
. As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the Dept. of Health and Human Services under the National Health and Nutrition Examination Surveys and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non
- dietary

exposures based on home use of pesticide products and associated risks

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 9 of 52 for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - applic ation are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Toxicology Studies Available for Analysis**  Appendix A summarizes the toxicity profile for clothianidin. The toxicity database is largel y complete, and the following studies are available: acute, subchronic, and developmental neurotoxicity ; subchronic oral in rats, mice and dogs; subchronic dermal, chronic/carcinogenicity in rats; carcinogenicity

in mice; chronic in dogs; developmental in rats and rabbits; 2
- generation reproduction in the rat; mutagenicity battery ; metabolism (rats and mice); dermal penetration (monkey s); 28
- day

immunotoxicity

as well as developmental immunotoxicity in the rat ; and a special neurotoxicity

and pharmacology

study in mice. A complete battery of mutagenicity studies w as also conducted with clothianidin and several metabolites. The only missing toxicology

study is a subchronic ( 28 - day) inhalation study , which HED has determined is required , based on weight
- of
- evi dence considerations . **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  The ADME of clothianidin was examined in single
- dose studies in rats (2.5 and 250 mg/kg) and mice (5 mg/kg) and a 14
- day repeated
- dose study

in the rat (25 mg/kg/day) using radiolabeled chemical. The rate of absorption, route of excretion, and nature of metabolism was similar across species and gender. Following an oral dose, greater than 90% of the administered dose is excreted in the urine within the first 24 hours . At 250 mg/kg/day , there was a lag in urinary clearance, taking up to 48 hours to excrete 90% of the administered dose (AD). The lag indicates saturation of the absorption mechanism at this high dose. The remaining 5
- 6% of the AD is eliminated via the feces. Females absorbed slightly greater amounts of the administered dose in the rat; 90% for males and 95% for females in the 2.5 mg/kg group. However, females also had a slightl y greater clearance rate so there was not a greater net accumulation in the females. Females were only tested at the 2.5 - mg/kg dose. The time
- to - peak plasma concentrations in the rat (T max

### ) were 1.5 and 2.7 hours for the 2.5 and 25 mg/kg dose groups, respectivel y. Following absorption, clothianidin is distributed throughout the body. Although the organs associated with the absorption and elimination systems ( i.e. , bladder, kidney, liver, and nasal mucosa) initially

demonstrate elevated levels, none of the tissues examined contained residue levels >1% of the administered 24 h ours after dosing in the rat. Therefore, bioaccumulation is not a concern. Parent was the most abundant residue indentified in the urine , at 30% AD in the mouse and 55
- 74% in the rat. Three metabolites were identified as major (> 10% AD), with several additional

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 10 of 52 metabolites identified at <10% AD. The major metabolites were the result of demethyl ation of the parent or cleavage products of the nitrogen
- carbon bond between the nitroimino and thiazolyl moieties. **4.2.1 Dermal Absorp**  **tion** A dermal penetration study was conducted in monkey s , using the undiluted FS 600 formulation of clothianidin ( 10% ai ) . The e xposure duration was 8 hours and the subjects were monitored for 120 hours. Dermal absorption was estimated based on the sum of the administered dose measured in fecal and urinary excretions. Dermal penetration was low at 0.24% of the administered dose. A value of 1% dermal absorption has been recommended as appropriate for use in risk assessment (K. Schumacher, D331226, 28 No vember 2006) . **4.3 Toxicological Effects**  The insecticidal mode of action of clothianidin is agonism of the nic o tinic acetyl choline receptor, leading to overstimulation of the central nervous system and death. In mammals, the toxic effects of clothianidin appear to be much less specific and involve multiple organ s ys tems. The primary effects as indicated by

the toxicity

database are on the liver, hematopoietic system and kidney s. Liver, body

weight changes , thy

roid effects and neurotoxicity are all commo nly observed in toxicity

studies of other neonicotinoids. A cute neurotoxicity

studies were conducted in rats and mice following exposure by gavage. In the acute neurotoxicity

rat study , FOB effects, including decreased arousal as well as decreased motor and locomotor activity , were seen at the lowest observed adverse effect level ( LOAE L) on Day 0 in males. Effects at dose levels above the LOAEL in the rat study included tremors, slightly uncoordinated gait, effects on pupil response and righting reflex, and decreases in both temperature and ataxia. In the acute neurotoxicity study in mice, effects were also observed on Day 0 in males (no female mice were tested), but occurred at lower doses than those that produced neurotoxic effects in rats. Effects se en at the L OAEL in the mouse study included transient signs of decreased spontaneous motor activity, tremors and deep respirations. At higher dose levels, decreases in reactivity, grooming and muscle tone , prone position , staggered gait , mydriasis, and hypothermi a were observed . In subchronic oral studies in rats and dogs, decreases in body weight and body

weight gain were observed. In addition, dogs also displayed decreased white blood cell s, albumin and total protein, as well as some anemia, and they appeared to be more sensitive than rats. Male dogs were more sensitive than females. Neurotoxicity was not observed in the subchronic n eurotoxicity

study . No effects were observed up to the limit dose in the 28
- day dermal study

in rats. Chronic feeding studies were conducted in the dog, rat and mouse. Anemia was the onl y adverse effect observed in the dog , and was onl y found in females at the highest dose tested. In the rat, decreased body weight and food consumption, interstitial gland hyp erplasia in the ovary , increased ly

mphohistiocy

tic infiltrate and altered hepatocellular eosinophil ic foci of the liver were observed in females; decreased body weight and food consumption, slightly increased

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 11 of 52 incidences of pelvic mineralization, and transitional cell hyperplasia in the kidney, mottled livers, and altered hepatocellular eosinophilic foci in the liver were observed in male rats. In the mouse, decreases in body weight and body weight gain in females and increases in vocalization in both sexes were the only observed effects. A comparison of the subchronic and chronic feeding studies in rats showed that a wider spectrum of effects was observed in the chronic study, even though the no observed adverse effect levels (NOAELs ) and LOAELs in these two studies were similar. Thus, it appears that there may be more toxicity

in rats when exposure is over a longer period of time. In contrast, administration to the dog for a longer period of time does not appear to result in any additional effects or eff

ects at lower doses. No increased quantitative or qualitative susceptibility was observed in the developmental rat or rabbit studies. In the rat, no developmental toxicity was observed at the highest dose tested, although this dose induced decreases in b ody weight gain and food consumption in the dams. In the rabbit, premature deliveries, decreased gravid uterine weights, an increase in litter incidence of a missing lobe of the lung and decreased ossification of the sternum were noted at a dose level at which maternal death, a decrease in food consumption and clinical signs (scant feces and orange urine) were observed. The developmental effects in this study are not considered to be quantitatively

more severe than the maternal effects because they occurred at the same dose and they are not considered to be qualitatively more severe because death occurred in the dams. There was an increase in quantitative susceptibility in the developmental neurotoxicity and reproductive toxicity studies ; offspring effect s were observed in the absence of maternal toxicity . In the DNT, maternal effects observed at the high
- dose included decreased body weights, body weight gains and food consumption. Effects seen in the offspring observed at the mid
- dose included decreased body weights, body weight gains, motor activity and acoustic startle response in females. In the two
- generation reproduction study , the LOAEL for offspring toxicity is based on decreased body weight gains, delayed sexual maturation (mal es), decreased absolute thy mus weights in F1 pups of both sexes, and an increase in stillbirths in both generations at the mid
dose. The parental s ys temic L OAEL is based on decreased absolute body weights and body weight gains with decreased absolute and relative thy mus weights in both sexes observed at the high
- dose. Clothianidin is classified as not likely to be carcinogenic to humans. In the rat chronic carcinogenicity

study , an apparent increase in thy roid c
- cell tumors was observed in females. A s tatistical analysis revealed that the increase in these tumors did not appear to be significant, especiall y when carcinomas and adenomas were combined. Increased incidence s of hepatocellular carcinomas at the low and high doses were just outside historical control incidences for the same testing laboratory (onl y 2 studies) but were within the historical control range for the animal supplier. In addition, there was no dose
- response and no continuum ( i.e. , no preneoplastic lesions and no adenomas). There w as no evidence of an increase of tumors in mice. In the mutagenicity studies, none of the intermediates or metabolites appeared to have genotoxic potential under the conditions of the studies, but the studies for the technical material gave mixed

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 12 of 52 results. Some of the batches of test material were positive and some were negative. HED had requested that the composition of the test materials used in the mutagenicity studies be investigated to determine whether or not the differences in composition may have affected the results from the studies. To address the request, additional mutagenicity studies were performed and it was determined that there was no concern because clothianidin was neither clastogenic nor aneugenic in the mouse bone marrow micro nucleus assay up to a toxic oral dose (100 mg/kg); also, there was no induction of unscheduled DNA sy nthesis (UDS) in the livers of Wistar male mice when administered at the limit dose of 2000 mg/kg. In some of the toxicity

studies, there was evidence of possible effects on the immune sy stem. Decreased absolute and relative thy mus and spleen weights were observed in multiple studies. In addition, juvenile rats in the two
- generation reproduction study appeared to be more susceptible to these effects. The thy mus is involved in the production of T cells, whose function is to recognize and respond to foreign antigens. The spleen serves an important function in clearing the blood of infectious organisms. A guideline immunotoxicity study showed no evidence o f clothianidin
- mediated immunotoxicity in adult rats, in the form of a T
- cell dependent anti
- Sheep Red Blood Cell (SRBC) forming cell response, at doses lower than those resulting in generalized signs of toxicity ( e.g. , decreases in body

weight). However, since effect in the offspring occurred at lower doses in the two
- generation study , HED concluded that the lack of effects on immunotoxicity in adults did not alleviate concerns for immunotoxicity in the offspring. A developmental immunotoxicity study was required and demonstrated no increased susceptibility

with respect to immunotoxicity . Clothianidin and numerous metabolites were examined for acute toxicity . Acute toxicity via oral, inhalation and dermal routes of exposure in the rat is relativel y low (Category III or IV). Only technical clothianidin in the mouse and the TMG metabolite in the rat via the oral route were toxicity

Category I I. There is no evidence of dermal sensitization or eye irritation with the exception of the clothianidin
- triazan intermediate, which is a dermal sensitizer. **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  HED recommends that the FQPA SF of 10X be reduced to 1X for dermal and oral exposure pathway s based on the following considerations : (1) the toxicology data base is complete (with the exception of an inhalation study) and includes developmental neurotoxicity , immunotoxicity and developmental immunotoxicity studies ; (2) HED characterized the degree of concern for the quantitative susceptibility observed in the clothianidin 2 - generation reproduction and DNT studies as low based on the clear NOAEL s for the offspring effect s and the selection of regulatory

doses that are protectiv e of th o se effects ; ( 3) the rat is the most sensitive species tested, and the NOAEL and L OAEL selected from the 2 - generation reproduction study in rats are protective of effects observed in other species throughout the toxicology database; (4 ) there are no residual uncertainties for pre
- and/or post
- natal toxicity, since the submitted developmental immunotoxicity study indicated no evidence of susceptib i lity ; (5) HED is regulating the use of clothianidin based upon the most sensitive offspring effects observed in the reproduction toxicity

study , and therefore the risk assessm ent is protective of these and other effects that occurred at higher doses ; ( 6 ) the exposure databases (dietary food, drinking water, and residential) are complete ; and ( 7 ) the risk assessment for each potential exposure scenario

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 13 of 52 includes all metabolites and/or degradates of concern and does not underestimate potential exposure and risk for infants or children. In the absence of the required inhalation toxicity study , HED is recommending the 10X FQPA factor be retained as a data base uncertainty factor for assessing inhalation exposure and risk only , for both adults and children . **4.4.1 Completeness of the Toxicology Database**  Acceptable guideline studies for developmental , reproductive toxicity and neurotoxicity (including DNT) are available for FQPA assessment . Immunotoxicity studies in rats and mice have also been submitted and reviewed. A subchronic inhalation study remains outstanding and is considered a data deficiency ( TXR 0055320 ). **4.4.2 Evidence of Neurotoxicity**  Neurotoxicity

was observed in acute neurotoxicity studies in the rat and mouse. Neurotoxicity was observed on the day

of dosing and was not observed in subsequent evaluations. In the rat, decreased arousal and motor activity were observed at the LOAEL of 100 mg/kg (NOAEL 60 mg/kg). Effects at dose levels above the LOAEL in the rat study included tremors, slightl y uncoordinated gait, effects on pupil response and righting reflex, and decreases in both temperature and ataxia . In the mouse, transient signs of decreased spontaneous motor activity , tremors and deep respirations were observed at the L OAEL 50 mg/kg (NOAEL25 mg/kg) . At higher dose levels, decreases in reactivity ; grooming and muscle tone; prone position; staggered gait; mydriasis; and hypother mia were observed . In the developmental neurotoxicity study , toxicity in the offspring was observed at a lower dose level than the dose that caused toxicity in the maternal animals. Maternal effects included decreased body weights, body weight gains, and food consumption. Effects seen in the offspring included decreased body weights, body weight gains, motor activity , and acoustic startle response in the females. Neurotoxicity was not observed in the subchronic neurotoxicity study with a high dose of 17 7/200 mg/kg/day (M/F) or any other study

in the toxicity

database. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There is no residual concern for increased qualitative or quantitative susceptibility in the rat or rabbit developmental toxicity studies. In the two
- generation reproduction developmental neurotoxicity studies in the rat, there was increased quantitative susceptibility as the offspring NOAELs were below the parental NOAELs. However, clear NOAELs were identified for the offspring effects. There were indications of potential immunotoxicity in the database. D ecreased absolute and relative thymus and spleen weights were observed in multiple studies. Juvenile rats in the two
generation reproduction study appeared to be more susceptible to the se effects, indicating a concern for qualitative susceptibility . However, a guideline immunotoxicity study showed no evidence of clothianidin
- mediated immunotoxicity in adult rats, and a developmental

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 14 of 52 immunotoxicity

study demonstrated no susceptibility wi th respect to immunotoxicity . Therefore, the residual concern for immunotoxicity in adults and offspring is reduced. Since there is evidence of increased qua nti tative susceptibility

of the young following exposure to clothianidin in the rat reproduction study and the DNT study , HED performed a degree of concern anal ys is to: 1) determine the level of concern for the effects observed when considered in the context of all available toxicity data; and, 2) identify

any resi dual uncertainties after establishing toxicity

endpoints and traditional uncertainty factors to be used in the clothianidin risk assessment. If residual uncertainties are identified, HED examines whether the residual uncertainties can be addressed b y a FQ PA safety factor, and if so, what factors should be retained. Considering the overall toxicity profile and the endpoints and doses selected for the clothianidin risk assessment, HED characterized the degree of concern for the effects observed in the cloth ianidin 2 - generation reproduction and DNT studies as low , noting that there are clear NOAEL s for the offspring effect s and regulatory doses were selected to be protectiv e of these effects. No other residual uncertainties were identified with respect to su sceptibility . HED believes that the endpoints and doses selected for clothianidin are protective of adverse effects in both offspring and adults. **4.4.4 Residual Uncertainty in the Exposure Database**  In the absence of the 28
- day inhalation study , there is uncertainty about potential portal of entry effects occurring via the inhalation route of exposure, and HED is recommending retaining the 10X FQPA factor as a database uncertainty factor for the inhalation route of exposure only, pending submission of the required study (Hazard and Science Policy Council, 23 March 2012, TXR# 0055320) . HED has used conservative assumptions in the dietary exposure assessment, including the use of 100% crop treated assumptions , tolerance
- level residue values, and upper
- bound estimates of potential exposure through drinking water. In addition, the residential exposure assessment was conducted such that residential exposure and risk will not be underestimated. The aggregate exposure and risk estimates presented in this asse ssment are expected to over
- estimate actual exposure and risk expected based on the current and proposed use patterns, and no risk estimates of concern were identified. **4.5 Toxicity Endpoint and Point of Departure Selections**  Based on the use pattern and the toxicological profile of clothianidin , HED selected endpoints and doses for acute and chronic dietary risk assessment and non - occupational and occupational exposures (i.e., incidental oral, dermal, or inhalation). For occupational handlers and workers re entering treated areas, HED selected endpoints and doses for dermal and inhalation exposure and risk assessment. **4.5.1 Endpoint Selection** 

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 15 of 52 The acute dietary

endpoints and dose selected for risk assessment were based on single dose effects observed in the toxicity database; separate endpoints were selected for females 13
- 49 and the general US population including infants and children. For all other exposure scenarios, including incidental oral, dermal and inhalation, HED relied on the endpoint and dose selected from the 2
- generation reproduction toxicity study. Because effects seen in the reproduction study can occur as the result of a single exposure at a critical junction during pregnancy or from multiple exposures throughout pregnancy and lactation, the NOAEL for offspring effects observed in the reproduction study was selected as the dose for all durations of exposure. The dose selected for risk assessment is also the most sensitive for repeated exposures, and is protective of all other effects in the datab a se. Acute Dietary

Endpoint for Females 13
- 49: The endpoint used for establishing the aPAD for females 13
- 49 was selected from the developmental study in the rabbit. An aPAD of 0.25 mg/kg/day

was derived f

rom a NOAEL of 25 mg/kg/day and a 100 - f

old factor that included 10x for inter
- species extrapolations, 10x for intra
- species variations, and a 1x FQPA SF. The LOAEL of 75 mg/kg/day was based on increased litter incidence of a missing lobe of the lung. This endpoint is appropriate for the acute dietary exposure assessment because it could be the result of a single exposure at a critical junction during pregnancy or from multiple exposures throughout pregnancy , it is an appropriate route of exposure (oral) , and it is protective of developing offspring . Acute Dietary

Endpoint for the General Population: The endpoint used for establishing the aPAD for the general population was selected from the acute neurotoxicity study in rats. An aPAD of 0.25 mg/kg/day was derived from a NOAELof 25 mg/kg/day and a 100
- fold factor that included 10x for inter
- species extrapolations, 10x for intra
- species variations, and a 1x FQPA SF. The LOAEL of 50 mg/kg was based on transient signs of spontaneous motor activity, tremors, and deep respirations observed on D ay 1. Similar signs of neurotoxicity were observed in the acute neurotoxicity study in the rat at 100 mg/kg, with a NOAEL of 60 mg/kg. This endpoint is appropriate for the acute dietary exposure assessment because it is the result of a single dose, is an appropriate route of exposure (oral) and is protective of the general population. Although the developmental toxicity study in the rat had a lower maternal NOAEL of 10 mg/kg/day

(LOAEL 40 mg/kg/day), this study was not chosen for endpoint selection because the NOAEL is considered to be artificiall y low due to dos e spacing and because the effects (decreased body weight and food consumption) were not the result of acute exposure . Chronic Dietary : The endpoint used for establishing the cPAD was selected from the 2 - generation reproduction study in the rat. A cPAD of 0.0 1 mg/kg/day was derived from a NOAEL of 9.8 mg/kg/day and a 100 - fold factor that included 10x for inter
- species extrapolation, 10x for intra
- species variability , and a 1x FQPA SF. The LOAEL of 31.2 mg/kg was based on decreased body weight gains, de layed sexual maturation, decreased thy mus weights in F1 pups, and increased stillbirths in both generations. This study had the lowest NOAEL resulting from repeated dose exposure in the database. In cidental Oral : The endpoint used for assessing short
- term incidental oral exposure w as selected from the 2 - generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day , and the level of concern (LOC) is an MOE of 100 ( 10x for inter
- species extrapolation, 10x for intra
-

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 16 of 52 species variab ility , and a 1x FQPA SF ) . The effects observed at the LOAEL of 31.2 mg/kg have been described above (see chronic dietary). The study , dose and endpoint were selected because of the exposure duration and because selection of the offspring effects is prote ctive of the population of concern, developing children. Dermal (All Durations) : The endpoint used for assessing all durations of dermal exposure w as selected from the 2 - generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day , and the L OC i s an MOE of 100 ( 10x for inter
- species extrapolation, 10x for intra
- species variability , and a 1x FQPA SF ) . The effects observed at the LOAEL of 31.2 mg/kg have been described above (see chronic dietary) . The study was selected because of the exposure duration, and because it is protective of the population of the most sensitive population, developing children. Although a dermal (route specific) toxicity study in rat s was submitted, no effects were seen at the highest dose tested of 1000 mg/kg/day . Use of the route
- specific study for dermal risk assessment would not be protective of the offspring effects observed in both the DNT and the 2
- generation reproduction studies because the dermal study does not evaluate reproduction and developmental parameters . Since the dermal endpoint was selected from an oral study , a 1% dermal absorption factor (DAF) is used to determine dermal exposure and risk. Inhalation (All Durations) : The endpoint used for assessing all durations of inhalation exposure w as selected from the 2 - generation reproduction study in the rat. The NOAELis 9.8 mg/kg/day , and the LOC is an MOE of 1000 ( 10x for inter
- species extrapolation, 10x for intra
- species variability , a 1 0 x FQPA SF for residential scenarios, and a 10x database uncertainty factor for occupational scenarios ) . The effects observed at the LOAEL of 31.2 mg/kg have been described above . The study was selected because of the exposure duration, and because it is protective of the most sensitive population, developing children. No route - specific information is available for the inhalation toxicity of clothianidin . In the absence of a route
- specific study , the NOAEL and LOAEL from an oral study have been use d for risk assessment (i.e., inhalation toxicity is assumed to be equivalent to oral toxicity ). **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  HED has chosen a single endpoint and dose from the 2 - generation reproduction study for assessing exposure via incidental oral, dermal and inhalation routes . Therefore, these routes of exposure can be combined in the risk assessment . **4.5.3 Cancer Classification and Risk Assessment Recommendation**  Clothianidin is classified as “not likel y to be carcinogenic to humans.” There was no treatment
related increase in tumor incidences in treated mice when compared to controls. In the rat, there was an increase in thyroid c
- cell tumors in female that did not appear to be significant, especiall y when carcinomas and adenomas are combined. There was an increase incidence of hepatocellular carcinomas in male rats at the low and high doses just outside historical control incidences for the same testing laboratory (onl y 2 studies) but within the historical control range for the animal supplier. In addition, there was no dose
- response. Finall y, there was no continuum (i.e. no preneoplastic lesions and no adenomas). Clothianidin was positive for the

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 17 of 52 gene mutation bacterial reverse mutation assay at the highest dose tested. However, clothianidin and several metabolites were negative in the remaining mutagenicity studies. **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** Table 4.5 .4 a . 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 (L OC) for Risk Assessment Study and Toxicological Effects
Ac ute Dietary Females age 13 - 49 NOAEL =

25 mg/kg/day UF A = 10X

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

mg/kg/day aPAD=0.25 mg/kg/day Rabbit developmental study

LOAEL = 75 mg/kg/day based on increased litter incidence of a missing lobe of the lung Ac ute Dietary General population NOAEL =

25 mg/kg/day UF A = 10X

UF H = 10X SF FQPA = 1 X 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 X 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
- term) NOAEL=

9.8 mg/kg/day UF A= 10X

UF H= 10X SF FQPA=1 X MOE= 10 0

(residential) 2 - Generation reproduction study

LOAEL= 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups Dermal (all durations) Oral study

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

UF H= 10X SF FQPA=1 X MOE= 100

(residential) 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 = oral toxicity) UF A= 10X

UF H= 10X SF FQPA=10X for lack of subchronic inhalation study MOE= 1000

(residential) 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 C arcinogenic 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). UF DB = to account for the absence of key data .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 18 of 52 SF FQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Table 4.5 .4 b . 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 (L OC) for Risk Assessment Study and Toxicological Effects

Dermal (all durations) (Adults) Oral study

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

UF H= 10X MOE= 100

(occupational) 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 = oral toxicity) UF A= 10X

UF H= 10X UF DB = 10X MOE= 1000

(occupational) 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 wi th lower environmentally relevant human exposures. NOAEL = no observed 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 s ensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key data . MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

### 5.0 **Dietary Exposure and Risk Assessment 5.1**  **Metabolite/Degradate Residue Profile** D262541, Y. Donovan, 2 February 2000 

### Previous risk assessments have described the available metabolism data to support use of clothianidin on a number of agricultural crops. Appendix B summarizes the results of the av ailable metabolism studies. Based on the se results , HED concluded that the nature of the residue has been adequately delineated, and that parent onl y is the residue of concern ( ROC ) to be used for the tolerance expression for primary crops and livestock c ommodities . HED had previously determined that future new uses on root crops and/or leafy vegetables will require anal ys is for residues of the metabolite TMG along with parent in field trial samples , and that TMG should be included as a ROC for risk asses sment if significant levels of TMG were observed . Table 5.1. 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

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 19 of 5 2 Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression. Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Leafy and Root/Tuber Vegetables: Parent + TMG Other crops: Parent Parent Rotational Crop Parent, TZNG, MNG Parent Livestock Ruminant Parent, TZU, TZG, TZNG, ATMG - Py r Parent Poultry Parent, TZU, TZG, TZNG, ATG - Ac Parent Drinking Water Parent Not Applicable 

### 5.2 **Food Residue Profile** D39 7689 , M . Doherty , 26 September 2012 D39 9953 , M . Doherty , 26 September 2012 

### Adequate field trial data have been submitted to support the requested uses on strawberry , citrus, and tea, as well as the requested PHI reduction and tolerance increase for peppers and eggplant ( Crop Subgroup 8
- 10B ). Inaddition, HED has adequate data to determine the potential for concentration of residues in citrus processed commodities; the data indicate concentration occurs only in dried citrus pulp. Adequate data are available from representative tree nut commodities to translate the existing tolerance for residues in/on tree nuts to pistachio. The data are summarized in the tables below. Table 5.2.1. Summary of Residue Data for Clothianidin in/on Bell and Non
- Bell Peppers Following a 1
- Day PHI. Pepper Type Variety Trial Location Application Rates, g a.i./A Clothianidin Residues,

ppm Average Residue ± Std. Dev., ppm Bell Hunter Tift, GA 44.54 + 45.16 0.085, 0.123 0.104 ± 0.027

Heritage Barnwell, SC 45.42 + 45.30 0.068, 0.049 0.059 ± 0.013 Green Bell Seminole, FL 45.05 + 44.75 0.094, 0.083 0.089 ± 0.008 Revolution Martin County, FL 46.34 + 46.49 0.048, 0.034 0.041 ± 0.010 McCabi Yuma, AZ 46.38 + 45.89 0.122, 0.127 0.125 ± 0.004 Cal Wonder Tulare County, CA 45.21 + 46.30 0.198, 0.225 0.212 ± 0.019 Non - Bell Mesilla Seminole, FL 44.4 + 45.2 0.312, 0.282, 0.311 0.302 ± 0.017

Dulce Yuma, AZ 46.9 + 47.3 0.069, 0.082, 0.114 0.088 ± 0.023 Conch Tift, GA 45.4 + 45.1 0.019, 0.015, 0.021 0.018 ± 0.003 Summary of Clothianidin Residue Data for Straw berry , Citrus, and Tea . Commodity Application

Rate, lb a.i./A PHI,

days n Clothianidin, ppm

Min. Max. LAFT HAFT Median Mean Std. Dev. Straw berry 0.2 1 10 0.096 1.170 0.103 1.120 0.258 0.327 0.301 Grapefruit 0.2 1 7 0.010 0.346 0.010 0.281 0.047 0.084 0.098 Lemon 0.2 1 7 0.022 0.201 0.034 0.176 0.094 0.105 0.050 Orange 0.2 1 13 0.005 0.269 0.008 0.219 0.057 0.083 0.066 Tea 0.9

– 1.8 3 - 7 12 2.14 38.0 2.15 37.55 13.95 15.21 11.76 Summary of Residues and Processing Factors from the Orange Processing Study. Commodity Residues (ppm) [Average] P rocessing Factor 1

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 20 of 52 Fruit 0.223 0.236 [0.242] 0.267 _ Oil < 0.005 < 0.005 [<0.005] < 0.005 <0.02 Juice 0.006 0.007 [0.006] 0.006 0.03X Dried P ulp 0.417 0.406 [0.406] 0.396 1. 6 8 X
1 Processing factor from RAC, calculated from the average residues . 

### 5.3 **Water Residue Profile** Based on available data, clothianidin is persistent under most field and laboratory conditions and is mobile to highly

mobile based on laboratory adsorption tests . The Environmental Fate and Effects Division (EFED) ha s supplied HED with Tier I estimated drinking water concentrations (EDWC) for clothianidin in surface water resulting from foliar application to rice (R. Baris, 15 September 2011, D393235) . EFED has confirmed that it is the appropriate value to use in this assessment (e
- mail from R. Baris; 16 July 2012, 3:12:46 pm). EFED used the Tier I Rice Model (v 1.0) as a screening model to calculate the surface water EDWC resulting from a single foliar application of clothianidin to a flooded field (as proposed on the label) . This concentration represents the estimated concentration that would be expected in the release water downstream of the treated rice paddy . For the previous risk assessment in which HED also evaluated the use of clothianidin on leafy vegetables, the 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 applicatio n to leafy vegetables , as shown in the table below . Potential residues in drinking water associated with the currently proposed uses would likely be much lower than those predicted using the Tier I Rice Model. Table 5.3. Tier I EDWCs for drinking water risk assessment based on the proposed clothianidin use on rice and leafy vegetables Use (application rate, lbs a.i./A) Model Ac ute Chronic Surface water drinking water sources, dow nstream of rice paddy (0.084 lb a.i./A) Tier I Rice Model (v1.0) 72 ppb < 72 ppb Leafy vegetables (including brassica) (0.05 lb a.i./A) FIRST 4.0 ppb 2.2 ppb 

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

risk assessments. **5.4 Dietary Risk Assessment**  D39769 0 , M . Doherty , 26 September 2012 

### 5.4.1 **Description of Residue Data Used in Dietary Assessment**

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 21 of 52 The acute and chronic assessments rel y on tolerance
- level residues (40 CFR 180.586) for all crops with registered and/or requested clothianidin uses. For crops exc ept leafy vegetables, the residue of concern for risk assessment purposes is the parent compound. For root crops and leafy vegetables, the residues of concern are the parent compound and the TMG metabolite. Field trial data show no detectable residues of TMG in root crops and that TMG does not exceed 10% of the parent compound residue level in leafy vegetables. A factor of 1.1 (entered into the model as Adjustment Factor 1) has been incorporated into the assessment for leafy vegetables to account for the presence of TMG. For livestock commodities, the residues of concern are the parent compound as well as the metabolites TZU, TZG, TZNG, ATMG
- py ruvate, and ATG
acetate. Milk is currently the onl y livestock
- derived commodity with a tolerance for clothianidin. A factor of 1.5, which is based on metabolism data, has been incorporated into the assessment to account for the residues of concern in milk. There are a number of crops for which uses of both clothianidin and thiamethoxam have been registered. The labels for the various end
- use products containing these active ingredients prohibit the application of both active ingredients to the same crop during a growing cycle. Due to that restriction and the assumption of 100% crop treated, a single value reflecting the greatest clothianidin residue from either active ingredient has been used for crops listed for use with both active ingredients (versus combined estimates from clothianidin and from thiamethoxam). Generally , this assessment uses the established o r recommended clothianidin tolerance for crops having tolerances for both compounds. For foods with thiamethoxam tolerances but without clothianidin tolerances, maximum residues of clothianidin observed in thiamethoxam residue trials have been used in the se assessments. These include meats, meat b y- products, artichoke, tropical fruits, coffee, hop, and mint (the estimate for residue in coffee was updated from 0.01 ppm to 0.04 ppm to reflect new data from recentl y submitted thiamethoxam field trials). Orange processing study data show that clothianidin does not concentrate in citrus oil or juice. Relative to the whole fruit, there is a modest increase in residues in pulp (1.8X). These empirical processing factors, as well as those derived previously , have been included in these anal ys es. Complete listings of the residue estimates, metabolite factors, and processing factors used in these anal ys es may

be found in Attachment 1. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  HED assumed 100% crop treated for all food items in the dietary assessment for both acute and chronic exposure durations. **5.4.3 Acute**  **and Chronic Dietary Risk**  **Estimates** The acute and chronic assessments are based on highl y conservative, health
- protective assumptions regardin g residue levels in food and percentage of crops treated. Likewise, the estimated concentration in drinking water is highly conservative, especially given that it represents residues in rice paddy tail water and no adjustment was made to take into account the portion of the watershed that would be cropped to rice. The anal ys es resulting from these assumptions should be considered screening
- level analyses that likely overestimate actual dietary

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 22 of 52 exposure to clothianidin. All risk estimates (Table 5.4.4) are below HED’s level of concern (<100% of the aPAD and cPAD) . There are no dietary

exposure or risk considerations that would preclude making the label amendment shortening the PHI for Crop Subgroup 8
- 10B, registering the clothianidin end
- use products as requested, and establishing tolerances commensurate with those registration actions. **5.4. 4**  **Dietary Exposure and Risk Estimate Summary Table**  Table 5.4.4. Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Clothianidin. Population Subgroup Ac ute (95 th Percentile) Chronic Exposure, mg/kg/day % aPAD Exposure, mg/kg/day % cPAD ARI Total US Population 0.020913 8 0.007458 8 13.1 All Infants 0.051461 21 0.016683 17 5.87 **Children 1 -**  **2 years old 0.069586**  **28 0.027256**  **28** 3.60 Children 3 - 5 years old 0.048260 19 0.018444 19 5.31 Children 6
- 12 years old 0.024264 10 0.009165 9 10.7 Youth 13
- 19 years old 0.014341 6 0.005346 6 18.3 Adults 20
- 49 years old 0.015090 6 0.005822 6 16.8 Adults 50
- 99 years old 0.014403 6 0.006109 6 16.0 Female 13 - 49 years old 0.015390 6 0.005974 6 16.4 The population subgroup(s) with the highest exposure/risk estimates are shown in **bold** . 1 ARI = Aggregate Risk Index. ARI values <1 indicate a potential risk of concern. ARI = NOAEL (9.8 mg/kg/day) ÷ Exposure ÷ LOC (Oral LOC = 100). 

### 6.0 **Residential (Non -**  **Occupational) Exposure/Risk Characterization** D397691, S. Oonnithan, 27 September 2012 

### The use of clothianidin on turf, ornamental plants, and/or indoor surfaces may result in human exposure in a residential se tting. Such exposures may occur during application of products containing clothianidin (handler exposure) as well as following application (post
- application exposure) and are expected to be of short
- term (1
- 30 day s ) duration . HED assessed exposure and developed risk estimates for numerous residential handler and post
- application scenarios using the 2012 residential SOPs ( M. Collantes , D397724, 15 August 2012) . Th ose assessments are based on conservative estimates of e xposure and the results are summarized in Tables 4 and 5. **6.1 Residential Handler Exposure**  For clothianidin, residential handler risk estimates are considered to be of potential concern when the dermal MOE is less than 100, the inhalation MOE is less than 1000, and/or the aggregate risk index (ARI), reflecting combined dermal and inhalation exposure, is less than one. As shown in Table 6.1, the residential handler risk estimates are not of concern (ARIs range from 11 to 990) .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 23 of 52 Table 6.1. Summary of Residential Handler Exposure and Risk Estimates for Clothianidin. M. Collantes D397724, 15 August 2012.
Use Site Application Method Form ulation Activity Exposure Estimate, mg/kg/day (MOE) ARI 1 Dermal Inhalation Turf Push
- Ty

pe Spreader Arena 0.5G Mixing/ Loading/ Applying 2.3x10 - 5

(420,000) 7.5x10 - 6

(1,300,000) 990 Turf Belly Grinder Arena 0.5G Loading/ Applying 5.7x10 - 4

(17,000) 6.2x10 - 6

(1,600,000) 160 Tree Trunk Manually Pressurized

Handwand Arena 50 WDG Mixing/ Loading/ Applying 6.8x10 - 3

(1,400) 2.0x10 - 4

(50,000) 11 Lawns Hose - End Sprayer Arena 50 WDG Mixing/ Loading/ Applying 3.8x10 - 4

(25,000) 6.4x10 - 5

(150,000) 96 Fruit Trees Hose - End Sprayer Arena 50 WDG Mixing/ Loading/ Applying 1.4 x 10 - 3

(7,100) 3.3 x 10 - 6

(2,900,000) 69 Indoor Surfaces (Bed Bug) Manually Pressurized

Handwand File Symbol 73049 - UIE Mixing/ Loading/

Applying 1.7x10 - 4

(58,000) 2.7x10 - 4

(36,000) 34 Indoor Surfaces (Bed Bug) Paintbrush File Symbol 73049 - UIE Applying 1.1x10 - 3 (9,000) 4.9x10 - 5

(200,000) 62 1 ARI is calculated as the NOAEL ÷ Σ (Exposure i × LOC), where Exposure i is each exposure source being included in the ARI calculation and LOC is the product of the applicable safety factors (100 for dermal and oral exposures and 1000 for inhalation exposures) . 

### 6.2 **Post -** **Application Exposure** There is potential for post - application dermal and inhalation exposure for adults and children resulting from use of clothianidin on residential turf , ornamentals (i.e., trees) , and indoor surfaces. There is also potential for incidental oral post
- application exposure for children. Table 6.2 provides a summary

of the post
- application exposure estimates and calculated ARIs. As shown in Table 6.2, the residential post
- application ri sk estimates are not of concern (ARIs range from 1.9 to 490).

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 24 of 52 Table 6.2. Summary of Residential Post
- Application Exposure and Risk Estimates for Clothianidin. M. Collantes D397724, 15 August 2012. Use Site Life Stage Exposure Estimate, mg/kg/day (MOE) ARI 1 Hand
- to Mouth Object
- to Mouth Soil

Ingestion Dermal Inhalation Turf
- WDG Adult NA NA NA 1.7x10 - 3 (5,600) NA 56 Child 1
- 2 years old 6.2x10 - 3

(1,600) 1.9x10 - 4

(52,000) 1.4x10 - 5

(720,000) 2.9x10 - 3

(3,300) 11 Pick
- Your - Own Tree Crop

– Apples and Pears Adult NA NA NA 22,000 NA 220

Child 6<11 yrs 49,000 490 Child 1
- 2 years old NA NA Bed Bug

– Carpet Adult NA NA NA 3.9x10 - 3 (2,500) 7.1x10 - 10

(1.4x10 10 ) 25 Child 1
- 2 years old 4.9x10 - 2

(200) 7.0x10 - 3

(1,500) NA 3.3x10 - 3 (3,000) 2.5x10 - 9

(3.9X10 9 ) 1.9 Bed Bug

– Hard Surface Adult NA NA NA 1.3x10 - 3 (7,500) 7.1x10 - 10

(1.4x10 10 ) 75 Child 1
- 2 years old 1.6x10 - 2

(600) 4.0x10 - 3

(2,200) NA 2.2x10 - 3 (4,500) 2.5x10 - 9

(3.9X10 9 ) 5.4 Bed Bug

– Mattress Adult NA NA NA 6.9x10 - 4 (14,000) 7.1x10 - 10

(1.4x10 10 ) 140 Child 1
- 2 years old NC NC NA 1.6x10 - 3 (6,200) 2.5x10 - 9

(3.9X10 9 ) 61 1 ARI values reflect combined oral, dermal, and inhalation exposure estimates identified by bold text; object
- to mo uth and soil ingestion are not included due to the conservatism in the hand
- to - mouth estimate. ARI is calculated as the NOAEL ÷ Σ (Exposure i × LOC), where Exposure i is each exposure source being included in the ARI calculation and LOC is the product of the applicable safety factors (100 for dermal and oral exposures and 1000 for inhalation exposures). NA = Not Applicable . NC = Not Calculated . Th ese exposure pathways are considered to be not relevant. In the case of bed bug mattress treatments, the activities are expected to be much less frequent for sleeping children. Exposures via these activities are addressed by hard surface and carpet scenarios. 

### 6.3 **Combined Exposure** HED combines risk estimates resulting from separate residential exposure scenarios when it is likely they can occur simultaneously based on the use
- pattern and the behavior associated with the exposed life stage . Although there is potential for adult exposure resulting from both applying the product and post
- application activities, HED did not combine exposure estimates from adult handler and post
- application activities because of the conservative assumptions and inputs within each exposure scenario. Although Table 6.2 provides the estimates MOEs for object
- to - mouth and soil ingestion, the combined children’s exposure includes onl y the hand
- to - mouth exposure for the incidental oral exposure component . To include exposure from object
- to - mouth and soil ingestion in addition to hand
- to - mouth would overestimate incidental oral exposure s for purposes of estimating combined residential exposure . For purposes of performing an aggregate assessment, HED sele cted the worst
- case adult and children exposure scenarios. The treatment of tree trunks using a manually
- pressurized

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 25 of 52 handwand presents the worst
- case exposure estimate for adults (ARI=11) , while the bed bug scenario presents the worst
- case exposure estimates for children 1 to < 2 yr s old (ARI=1.8) . A summary of the residential exposure scenarios for the aggregate assessment is provided in Table 6.3. Table 6 .3 . Residential Exposure Scenario and Risk Estimates for Aggregate Assessment. Scenario Life S tag e Scenario Scenario ARI 1 Com

bined ARI 2 Handler Scenarios Tree Trunk Adult Manually Pressurized Handwand 11 11 Lawns Adult Hose - End Sprayer 96 40 Fruit Trees Adult Hose - End Sprayer 69 Post - Application Scenarios Bed Bug Adult Perimeter (Carpet) 25 21 Mattress 140 Children 1 to < 2 years old Perimeter (Carpet) 1.9 1. 8 Mattress 61 1 Scenario ARIs are from Tables 4 and 5 for handler and post
- application exposures, respectively. 2 Com bined ARI = 1 ÷Σ (1 ÷ARI Scenario ), where ARI Scenario is the ARI for each scenario being included in the combined ARI. 

### 6.4 **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 IV), low vapor pressure ( 1.3x10 - 10 

### Pa , 9.75x10 - 13 

### mmHg), and the low proposed use rate (not to exceed 0.2 lb a.i./A/season). However, volatilization of pes ticides may

be a source of post
- application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodentic ide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post
application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post
- application inhalation exposure assessment for clothianidin. Although a quantitative bystander risk assessment was not conducted, post - application inhalation assessments were conducted to evaluate uses of clothianidin within a residential dwelling and risk estimates were not of concern. It is anticipated that these exposures are greater than those that would occur for residential by standers and are , there fore, protective of by stander exposures that may occur . **6.5 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, coul d also be a

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 26 of 52 potential source of exposure from the ground application method employed for clothianidin . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measure s for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift manag ement practices to reduce off
- target drift with specific products with significant risks associated with drift. Although a quantitative residential post
- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an assessment for clothianidin was performed for inhalation exposure to flaggers and the risk was not of concern (ARI = 27 , Table 9.1 ). This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post
- application inhalation exposure scenarios
. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticid e exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute Aggregate Risk**  Ty pically , HED does not consider residential exposures when assessing acute a ggregate 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**  In estimating aggregate risk, HED has considered the combined residential ARI s (Table 6.3) and the dietary

exposure ARIs in Table 5.4.4. The aggregate ARIs (Table 7 .2 ) are the worst
- case risk estimates for each life stage. The aggregate ARIs are all greater than 1 and indicate that aggregate risks are not of concern.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 27 of 52 Table 7 .2 . Aggregate Risk Estimates for Clothianidin . Life S tage Residential Combined ARI 1 Dietary ARI 1 Aggregate ARI 2 Adult 11 1 6.0 6. 5 Children 1 to < 2 years old 1.8 3.60 1.2 1 Residential Combined ARIs are the minimum ARI for each life stage from Table 6 .3 ; Dietary ARIs are from Table 5.4.4 . The adult dietary ARI is from the population subgroup Adults 50
- 9 9 years old and is the most conservative ARI from any of the adult
- only s ubgroups. 2 Aggregate ARI = 1 ÷ (1 ÷ARI Residential + 1 ÷ARI Dietary) 

### 7. **3 Chronic Aggregate Risk**  Chronic aggregate risk assessments address exposures that are likely to occur, continuously , for greater than six months. In the case of clothianidin, residential exposures are not expected to occur on a chronic basis; therefore, the chronic aggregate risk estimates are equivalent to the dietary risk estimates (Section 5.4.3) and are below HED’s level of concern. There are no chronic aggregate risk issues that would preclude granting the actions requested by the registrant. **7. 4**  **Cancer Aggregate Risk** Clothianidin is classified as “Not Likel y to be Carcinogenic to Humans;” therefore, cancer risk is not a concern. **8.0 Cumulative Exposure/Risk Characterization**  Clothianidin is a member of the neonicotinoid class of pesticides and is a major metabolite of another neonicotinoid, thiamethoxam. Structural similarities or common effects do not constitute a common mechanism of toxicity . Evidence is needed to establis h that the chemicals operate b y the same, or essentially the same, sequence of major biochemical events (EPA, 2002). Although clothianidin and thiamethoxam bind selectivel y to insect nicotinic acetylcholine receptors (nAChR), the specific binding site(s)/receptor(s) for clothianidin, thiamethoxam and the other neonicotinoids are unknown at this time. Additionally , the commonality of the binding activity itself is uncertain, as preliminary evidence suggests that clothianidin operates by direct competitive inhibition, while thiamethoxam is a non
- competitive inhibitor. Furthermore, even if future research shows that neonicotinoids share a common binding activity to a specific site on insect nAChRs, there is not necessaril y a relationship between this pestici dal action and a mechanism of toxicity

in mammals. Structural variations between the insect and mammalian nAChRs produce quantitative differences in the binding affinity of the neonicotinoids towards these receptors which, in turn, confers the notabl y gre ater selective toxicity of this class towards insects, including aphids and leafhoppers, compared to mammals. While the insecticidal action of the neonicotinoids is neurotoxic, the most sensitive regulatory endpoint for clothianidin is based on unrelated effects in mammals, including changes in body and thymus weights, delays in sexual maturation, and still births. Additionally, the most sensitive toxicological effect in mammals differs across the neonicotinoids (such as testicular tubular atrophy with th iamethoxam, and mineralized particles in thyroid colloid with imidacloprid). Thus, there is currentl y no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common me chanism of toxicity for the neonicotinoids. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity, and to evaluate the cumulative effects of such chemicals, see

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 28 of 52 the policy statements concerning common mec hanism determinations, and procedures for cumulating effects from substances found to have a common mechanism, released b y OPP on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9.0 Occup**  **ational Exposure/Risk Characterization** D397691, S. Oonnithan, 27 September 2012 

### 9.1 **Short -**  **and Intermediate**  **- Term Handler Risk**  HED has assumed that both short
- and intermediate
- term occupational exposures may occur. Short
- term exposures (1
- 30 day s) are l ikely to occur for many

occupational exposure scenarios. Certain application scenarios (e.g., aerial application) are likel y to be conducted b y contract applicators whose exposure may extend into an intermediate
- term (1
- 6 months) duration. Chemical
- speci fic data for estimating occupational exposure to clothianidin were not submitted. It is the policy

of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical
- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, or other registrant
- submitted oc cupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler
- exposure - table.pdf), which, along with additional information on HED policy on use of surrogate data , including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler
- exposure data.html
. D ermal and inhalation exposure s were calculat ed for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The product labels for Arena ® 

### 50 WDG and V
- 10170 2.13 SC recommend applicators and other handlers must wear long
- sleeved shirt and long pants, shoes plus socks and chemical
resistant gloves made of any waterproof material. Occupational handler exposure and risk estimates are summarized in Table 9.1. Since the short
and intermediate
- term endpoints and PODs are the same for each route of exposure , only short
term exposure s w ere estimated , and are considered protective of intermediate
- term exposure and risk . Estimated exposure and risk associated with the new foliar and/or soil treatments on citrus fruit trees, pistachio, and strawberry resulted in ARI s of 1.1 to 660 for mix ers/loaders, applicators, and flaggers, assuming baseline PPE plus gloves, engineering controls such as enclosed cockpit, and open cabs. These estimated risks are not of concern. For aerial uses of Arena ® 

### 50 WDG and V
- 10170 2.13 C formulations, the estim ated ARI s for mixers/loaders, applicators, and flaggers ranged from 1 .1 to 260, assuming use of baseline clothing plus gloves and an enclosed cockpit (engineering controls) for aerial applications .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 29 of 52 Table 9.1. Summary of Occupational Handler Exposure and Risk Estimates for Clothianidin . Scenario Crop Dermal Dose, mg/kg/day Inhalation

Dose, mg/kg/day Dermal

MOE 1 Inhalation

MOE 2 Com

bined ARI 3 Mixer/Loader Arena WDG, Aerial Straw berry 0.00052 0.00909 18721 1078 1.1 Arena WDG, Groundboom Straw berry 0.00012 0.00208 81904 4717 5 V - 10170 2.13 SC, Aerial Straw berry , Citrus, Pistachio 0.00019 0.00011 51383 88219 75 V - 10170 2.13 SC, Ground boom Straw berry 0.00004 0.00003 224801 385959 330 V - 10170 2.13 SC, Air blast Citrus 0.00002 0.00001 449601 77918 660 Applicator Arena WDG, Aerial Straw berry 0.00005 0.00007 193200 142059 130 Arena WDG, Groundboom Straw berry 0.00004 0.00008 262500 124301 110 V - 10170 2.13 SC, Aerial Straw berry , Citrus, Pistachio 0.00003 0.00003 386400 284118 260 V - 10170 2.13 SC, Ground boom Straw berry 0.00002 0.00004 525000 248603 240 V - 10170 2.13 SC, Air blast Citrus, Nectarine, Pistachio 0.00092 0.00027 10632 35382 27 Flagger V - 10170 2.1 SC & Arena WDG All crops 0.00012 0.00036 80500 27600 27 Mixer/Loader/Applicator V - 10170 2.1 SC & Arena WDG , Soil broadcast, Backpack Straw berry , Citrus; dilution =0.02 lb a.i./gal 0.00096 0.00003 10223 327616 78

V - 10170 2.1 SC & Arena WDG , Soil drench, MPHG Straw berry , Citrus; dilution = 0.004 lb a.i./gal 0.000226 0.000226 43000 43000 39

1 Dermal MOE = NOAEL (9.8 mg/kg/day) ÷ Dermal Exposure. 2 Inhalation MOE = NOAEL (9.8 mg/kg./day) ÷ Inhalation Exposure. 3 ARI (Aggregate Risk Index) = 1 ÷ [(1 ÷ Dermal MOE) + (1÷ Inhalation MOE)] 

### 9.2 **Short -**  **and Intermediate**  **- Term Post** **- Application Risk**  **9.2.1 Dermal Post**  **- A** **pplication Risk** Chemical
- specific dislodgeable foliar residue data have not been submitted for clothianidin . Therefore, this assessment uses HED’s default assumption that 25% of the application is

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 30 of 52 available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day . It is the policy

of HED to use the best available data to assess post
- application exposure. Sources of generic post
- application data, used as surrogate data in the absence of chemical
specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post - application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3 which, along with additional information about the ARTF data, can be found at the Agency website. The post
- application dermal exposures and risks resulting from foliar applications of clothianidin on citrus fruit, nectarine, pistachio, and strawberry are summarized in Table 9 .2.1 . The short
and intermediate
- term post - application dermal MOEs ranged from 8,400 to 22,0 00 are not of concern at the LOC of ≥ 100 . The post - application dermal exposures resulting from soil
- directed applications of clothianidin on citrus and strawberry and trunk treatment on citrus were not assessed as there are n o surrogate transfer coefficients available for broadcast, band, in
- furrow, soil drench, or tree trunk applications. However, dermal post
- application exposure s for workers from such treatments are expected to be minimal because workers do not come in contact with the treated surfaces . Therefore, post
- application risk s for these uses are not of concern. Table 9.2.1. Post
- application Dermal Exposures and Risks Resulting from Foliar Use of Clothianidin on Citrus, Nectarine, Pistachio, and Strawberry. Crop Activities Appl. Rate (lb ai/A) Estimated

DFR (ug/cm2 ) 1 Transfer

Coefficient (cm 2/hr) 2 Dermal

Dose 3 (mg/kg/day) Short
- term

Dermal MOE 4 Citrus fruits Fruit harvesting 0.1 0.280 1,400 0.000454 22,000 Nectarine Thinning of fruits 3,600 0.00117 8,400 Pistachio Harvesting 1,400 0.000454 22,000 Straw berry Harvesting, training 0.2 0.561 1,100 0.000715 14,000 1 . Dislodgeable Foliar Residue (DFR) = Appl ication Rate (lb ai/A) * (1
- Daily D issipation Rate) t * Co nv . F actor ( 4.54E+8 μg/lb ) * Co nv . F actor ( 2.47E - 8 A/cm 2 ) * Residue T ransfer Rate (20% default) after treatment. 2 . Transfer coefficient (TC) from ExpoSAC Policy #3, June 3, 2011. 3. D ermal D ose (mg/kg/day) = [DFR * T C * Co nv . F actor ( 0.001 mg/μg ) * Dermal A bsorption F actor (1%) * 8 hrs/day] / Body W eight (6 9 kg). 4 . MOE = S hort
- term D ermal NOAEL ( 9.8 mg/kg/day) / D ermal D ose (mg/kg/day). 

### 9.2.2 **Inhalation Post -** **A pplication Risk**  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 IV), low vapor pressure ( 1.3x10 - 10 

### Pa, 9.75 x10 - 13 

### mm Hg) and low application rate s (0. 2 lb ai/A). However, there are multiple potential sources of post
application inhalation exposure to individuals performing post
- application activities in previously

treated fields. These s ources 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 F IFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 31 of 52 scipoly/SA P/meetings/ 2009/120109meeting.html) . The Agency is in the process of evaluating the SAP report as well as available post
- application inhalation exposure data generated b y the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way

to incorporate occupational post
- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post
- application inhalation exposure assess ment for clothianidin . Although a quantitative post
- application inhalation exposure assessment was not performed for clothianidin , HED has assessed inhalation exposure and risk for occupational flaggers resulting from aerial applications and the risk was not of concern (ARI = 27 , Table 9.1 ). Inhalation exposure for flaggers is likely to result in higher exposure than th at from post
- application activities performed in the treated field . Therefore, it is expected that the flagger inhalation exposure estimates would be protective of most occupational post
- application inhalation exposure scenarios. **10.0 References**  D397689 . M. Doherty . 26 September 2012 . Clothianidin

– New Uses on Strawberry, Pistachio,

Citrus, and Tea. Evaluation of Residue Chemistry Data. D397690. M. Doherty. 26 September 2012 . Clothianidin

– Acute and Chronic Dietary Exposure and Risk Estimates for Requested Amended Registration on Peppers and New Uses on Strawberry , Citrus, Pistachio, and Tea. D397691 . S. Oonnithan . 27 September 2012 . Clothianidin. Occupational Exposure Assessment

for New Uses on Citrus, Nectarine, Pistachio, and Strawberry ; and Label Amendments to Add Aerial Application. D399953 . M. Doherty . 26 September 2012 . Clothianidin

– Proposed Label Amendments:

Reduction in PHIfor Crop Subgroup 8
- 10B (Peppers and Eggplant) and Change in Tolerance. D397724. M. Collantes. 15 August 2012. Clothianidin: Occupational and Residential

Exposure and Risk Assessment to Support the Proposed Bed Bug Treatment. TXR# 0055320. J. Van Alstine. 23 March 2012. Clothianidin: Summary of Hazard and

Science Policy

Council (HASPOC) Meeting of March 8, 2012: Recommendation on the need for a 28
- day

inhalation study .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 32 of 52 **Appendix A. Toxicology Profile and Executive Summaries A.1. T**  **oxicology Data Requirements** The requirements (40 CFR 158.340) for food uses for clothianidin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Test Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. **870.3465 21 -**  **or 28 -**  **Day Inhalation ................................**  **.............** yes yes yes no **yes a**  yes

yes yes

- **no** 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation
- mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen) ................................ ..... 870.6100b 90
- Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90
- Day

Neuro. Screening Battery (rat) .......................... 870.6300 Develop. Neuro ................................ .............................. no no yes yes yes -

- yes yes yes 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity.............................................................. yes yes yes yes

yes yes Special Studies

Developmental Immunotoxicity ................................ .. yes yes a The subchronic inhalation study is required. HED has recommended that this study be called in to support registration review.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 33 of 52 **A.2. Toxicity Profiles** Table A.2.1 . Acute Toxicity Profile
- Clothianidin Technical, Intermediates, and Metabolites . Test Material Guideline

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

Technical 870.1200 Ac ute dermal
- rat 45422634 LD 50 > 2000 mg/kg III Technical 870.1300 Ac ute inhalation 45422636 LC 50 > 5.538 mg/L ( ♂+♀) IV Technical 870.2400 Ac ute eye irritation 45422701 Slightly irritating to the eye IV Clothianidin
- CCMT Adduct Intermediate 870.2400 Ac ute eye irritation 45422814 Not irritating to the eye IV Clothianidin
- Triazan Intermediate 870.2400 Ac ute eye irritation 45422819 Not irritating to the eye IV Technical 870.2500 Ac ute dermal irritation 45422703 Not irritating to the skin IV Clothianidin
- CCMT Adduct Intermediate 870.2500 Ac ute dermal irritation 45422813 Not irritating to the skin IV Clothianidin
- Triazan Intermediate 870.2500 Ac ute dermal irritation 45422820 Not irritating to the skin IV Technical 870.2600 Skin sensitization 45422705 Is **not** a sensitizer under conditions of study N/A Clothianidin
- CCMT Adduct Intermediate 870.2600 Skin sensitization 45422815 Is **not** a sensitizer under conditions of study N/A Clothianidin
- Triazan Intermediate 870.2600 Skin sensitization 45422821 **Is** a sensitizer under conditions of study N/A

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 34 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results 870.3100 90 - Day

Oral Toxicity
- rat (diet) 45422809

(2000) 45422708 (4
- we ek) Acceptable/ guideline ppm=0, 150, 500 & 3000 mg/kg/day (M/F)=0/0, 9.0/10.9, 27.9/34.0, 202.0/254.2 **NOAEL** = 27.9/34.0 mg/kg/day (M/F) **LOAEL** = 202.0/254.2 mg/kg/day (M/F) based on decreased BW and BW gain.

870.3150 13 - W eek Oral

Toxicity
- d og ( diet) 45422810

2000 45422808 2000 4 - week 45422811 1998 palatability Acceptable/ guideline ppm=0, 325, 650, 1500 & 2250 mg/kg/day (M/F)=0/0, 9.2/9.6, 19.3/21.2, 40.9/42.1, 58.2/61.8 **NOAE L =**  19.3/42.1 mg/kg/day (M/F) **LOAEL =** 40.9/61.8 mg/kg/day (M/F) based on thinness, decreased body weight, body weight gain and anemia (1 M); and on decreased white blood cells , albumin, and total protein (F).

870.3200 28 - Day

Dermal Toxicity
- rat 45422707 (2000)

Acceptable/ guideline mg/kg/day= 0, 100, 300 & 1000 **NOAEL** = 1000 mg/kg/day (HDT) **LOAEL** = Not established 870.3700a Developmental

Toxicity
- rat ( g avage) 45422711 (1998)

45422710 (1998) range - finding Acceptable/ guideline mg/kg/day=0, 10, 40 & 125 **Maternal NOAEL**  = 10 mg/kg/day **Maternal LOAEL**  = 40 mg/kg/day based on decreased body weight gain and food consumption . **Developm ental**  **NOAEL** = 125 mg/kg/day (HDT) **Developm ental**  **LOAEL** = Not established 870.3700b Developmental

Toxicity
- rabbit ( g avage) 45422713 (1998)

45422712 (1998) range - finding Acceptable/ guideline mg/kg/day=0, 10, 25, 75 & 100 **Maternal NOAEL**  = 25 mg/kg/day **Maternal LOAEL**  = 75 mg/kg/day based on increased incidences of clinical signs (scant feces and orange urine), mortalities, decreased food consumption, early delivery, abortion, and decreased body weight gain . **Developm ental**  **NOAEL** = 25 mg/kg/day **Developm ental**  **LOAEL** = 75 mg/kg/day based on premature deliveries, decreased gravid uterine weights, an increased litter incidence of a missing lobe of the lung , and decreased litter average for ossified sternal centra per fetus. 870.3800 Reproduction

(2
- Generation)
- rat (diet) 45422715 (2000)

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

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 35 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results supplemental 45422825 (1999) rat feed 45422826 (1999) rat feed Acceptable/ guideline ppm=0, 150, 500 & 2500 mg/kg/day (M/F)=0/0, 9.8/10.7, 31.2/34.3,163.4/188.8 relative thymus weights . **Reproductive NOAEL**  = 31.2/188.8 mg/kg/day (M/F) **Reproductive LOAEL**  = 163.4/not established mg/kg/day (M/F) based on decreased sperm motility and increased number of sperm with detached heads in both generations . **Offspring NOAEL**  = 9.8/11.5 mg/kg/day (M/F) **Offspring LOAEL**  = 31.2/36.8 mg/kg/day (M/F) based on decreased body weight gains and delayed sexual maturation (M), decreased absolute thymus weights in F1 pups of both sexes , and an increase in stillbirths in both gener ations. 870.4100 Chronic ( 1 year)

- d og (diet) 45422717 (2000)

45422718 Acceptable/ guideline ppm=0, 325, 650, 1500 & 2000 mg/kg/day (M/F)=0/0, 4.8/8.5, 16.6/15.0, 36.3/40.1, 46.4/52.9 **NOAEL** = 46.4/40.1 mg/kg/day (M/F) **LOAEL** = not established/52.9 mg/kg/day (M/F) based on clinical evidence of anemia in females . Note: dose
- related decreases in ALT activity observed in mid
- and high
- dose males and females. 870.4200 Carcinogenicity,

18 - Month
- mouse (diet) 45422721 (2000)

45422709 (1997) 4 - week 45422722 (2001) supplementary Acceptable/ guideline ppm=0,100, 350 or 1250 mg/kg/day (M/F)=0/0, 13.5/17.0, 47.2/65.1, 171.4/215.9 In addition: 50/sex
- 700 ppm (wk 1 - 4), 2000 (5
- 10), 2500 (11
- 34), 2000/1800 (M/F) 35
- 79 [254,1/322,3] **NOAEL =**  171.4/65.1 mg/kg/day (M/F) **LOAEL =**  254.1/215.9 mg/kg/day (M/F ) based on decreased body weight and body weight gain; decreased food consumption and food efficiency in males at the LOAEL. **No evidence of carcinogenicity.**

870.4300 Chronic/

Carcinogenicity, 2 - Year - rat (diet) 45422719 (2000)

45422720 (2001) supplementary Acceptable/ guideline ppm (M/F)=0, 150, 500, 1500 & 3000 mg/kg/day (M/F)=0/0, 8.1/9.7, 27.4/32.5, 82.0/97.8, 156.5/193.4 **NOAEL** = 82.0/32.5 mg/kg/day (M/F) **LOAEL** = 156.5/97.8 mg/kg/day (M/F) based on decreased body weight and food consumption and altered hepatocellular eosinophilic focus of the liver in both sexes; ovary interstitial gland hyperplasia and increased lymphohistiocytic infiltrate in females; and slightly increased incidences of pelvic mineralization and transitional cell hyperplasia in the kidney, mottled livers of males . **No evidence of carcinogenicity.**

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 36 of 52 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 con sidered mutagenic under conditions of this test. 870.5100 Gene Mutation

bacterial reverse mutation assay **Parent** 45422732

(1990) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium and E. coli) under conditions of this assay. 870.5100 Gene Mutation

bacterial reverse mutation assay **Parent** 45422733

(1999) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay. 870.5100 Gene Mutation

bacterial reverse mutation assay **Parent** 45422734

(1999) Acceptable/ non - guideline (only TA 1535 assayed) Only TA 1535 tested. No mutagenic activity in bacteria (S. typhimurium ) under conditions of this assay. 870.5100 Gene Mutation

bacterial reverse mutation assay **BN0335E2 metabolite**  45422724

(2000) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

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

(1999) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

bacterial reverse mutation assay **methyl guanidine**  **intermediate** 45422726

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

870.5100 Gene Mutation

bacterial reverse mutation assay **TZNG** metabolite 45422727

(1999) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

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

(1999) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

bacterial reverse mutation assay **BN0230M metabolite**  45422729

(2000) Acceptable/ guideline No mutagenic activity in bacteria (S. typhimurium) under conditions of this assay.
870.5100 Gene Mutation 45422730 No m utagenic activity in bacteria (S.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 37 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results

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

Acceptable/ guideline typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

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

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

870.5100 Gene Mutation

bacterial reverse mutation assay **TI 435 -**  **Triazan intermediate**  45422822

(2000) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5100 Gene Mutation

bacterial reverse mutation assay **TI 435**  **- CCMT**  **** **Adduct** 45422816

(2000) Acceptable/ guideline No m utagenic activity in bacteria (S. typhimurium ) under conditions of this assay.
870.5300 Gene Mutation
-

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

Acceptable/ guideline Increases in mutant frequency with and without S9 at dose levels that were cy totoxic. The observed response was primarily due to small colony formation, indicating clastogenic activity. 870.5300 Gene Mutation
-

in vitro mamma lian cell gene mutation test (V79
- HPRT Assay) 45422738

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

870.5300 Gene Mutation

– in vitro mammalian cell gene mutation test (V79
- HPRT Assay) 46339001

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

870.5375 Cy

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

(2000) Acceptable/ guideline Significant increases in frequency of cells with structural aberrations. Predominant ty pes were chromatid breaks and exchanges. There was, however, no clear indication of a dose
- related response in either the presence or absence of S9 activation. 870.5375 Cy

togenetics

– in vitro mammalian chromosome aberration test (CHL Cells) 46339002

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

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 38 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results

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

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

(2000) Acceptable/ guideline Clothianidin is considered to be neither clastogenic nor aneugenic under these test conditions.
870.5395 Cy

togenetics
- mammalian erythrocyte micronucleus test **Parent** 46339003

(2003) Acceptable/ guideline No significant increase in the frequency of MPCEs in bone marrow

after any harvest in the test groups up to an overtly toxic dose for this test system. 870.5550 Other Effects
-

DNA Repair Test in B. subtilis **Parent** 45722735

(1990) Unacceptable/ non - guideline (only single plates used) No potential for DNA damage under these conditions.
870.5500 Other Effects
-

(UDS) in Mammalian Cells in Culture **Parent** 45422739

(1999) Acceptable/ non - guideline (only males used) No evidence (or a dose related positive response) that UDS was induced.
870.6200a Ac ute

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

( 2000 ) 45422802 (2000) to establish NOEL Acceptable/ guideline mg/kg=0,100, 200 & 400 NOEL=0, 20, 40 & 60 **NOAEL** = 60 mg/kg **LOAEL** = 100 mg/kg based on FOB findings (decreased arousal, motor activity, and locomotor activity).

870.6200b Subchronic

N eurotoxicity Study
- rat (diet) 4 5422803 (2000)

45422825 (1999) supplementary Acceptable/ guideline ppm (M/F)=0, 150, 1000 & 3000 mg/kg/day (M/F)=0/0,9.2/10.6, 60.0/71.0, 177.0/200.1 **NOAEL** = 60.0/71.0 mg/kg/day (M/F) **LOAEL** = 177.0/200.1 mg/kg/day (M/F) based on slightly decreased food consumption , body weights, and body weight gains. No evidence of neurotoxicity.
870.6300 Developmental

N eurotoxicity Study
- rat (diet) 445422804

(2000) Acceptable/ non - guideline (upgradable with FOB information) ppm=0, 150, 500 & 1750 mg/kg/day gestation=0, 12.9, 42.9, 142 lactation=0, 27.3, 90.0, 299.0 **Maternal NOAEL**  = 42.9 mg/kg/day **Maternal LOAEL**  = 142 mg/kg/day based on decreased body weights, body weight gains, and food consumption . **Offspring NOAEL**  = 12.9 mg/kg/day **Offspring LOAEL**  = 42.9 mg/kg/day based on decreased body weights, body weight gains, motor activity, and acoustic startle response in females .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 39 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results 870.7485 Metabolism

S tudy
- rat 45422805 (2000)

45422806 (2000) Acceptable/ guideline single dose=2.5 or 250mg/kg; 14 - day repeated dose =25 mg/kg/day Overall recovery: 95
- 100%. Readily absorbed and excreted within 96 hours following a single 2.5 mg/kg bw or repeated oral dose of 25 mg/kg bw, but at a dose of 250 mg/kg, absorption became biphasic and wa s saturated. Following single or multiple oral low doses (2.5 and 25mg/kg bw, respectively) of clothianidin, urinary excretion accounted for 89.2
- 94.6% of the administered radioactivity suggesting that a multiple exposure regimen did not affect the absorption/excretion processes. Urinary excretion unaffec ted following single 250 mg/kg dose. Excretion via the feces accounted for the remainder of the administered radioactivity in all treatment groups (3.8
- 8.6%). Rapid absorption and distribution of administered radioactivity to all organs and tissues follow ed by rapid excretion with reduction to background levels in most tissues and organs within 24 hours. Somewhat greater rate of absorption and elimination in females. Excretory patterns did not exhibit gender
- related variability but reflected the delayed absorption in the high
- dose group. Neither clothianidin nor metabolites appear to undergo significant sequestration. The metabolites identified (primarily oxidative demethylation products and cleavage products of the nitrogen
- carbon bond between the nitroimino and thiazolyl mo ieties) were consistent with Phase I processes. Extraction efficiencies appeared to be excellent and most components in all of the matrices examined (urine, feces, and tissues) were adequately quantified and characterized. The available data, based upon studies using both the nitroimino
- and the thiazolyl
- 2 - labeled clothianidin, affirmed the metabolism pathway proposed by the investigators. 870.7485 Metabolism

Study

– mice 45422807

(2000) Acceptable/ non - guideline single gavage dose of 5 mg/kg Of the administered radioactivity, 98.7
- 99.2% was recovered. Readily absorbed and excreted within 168 hours following a single oral dose of 5 mg/kg body weight. Urine wa s the major route of excretion, accounting for 92.4
- 93.7% of the administered radioactivity. Feces accounted for 5.0
- 6.8% of the administered radioactivity. Within 24 hours, 89.0
- 91.7 % of the administered radioactivity was excreted in the uri ne and 4.9 - 6.2% was excreted in the feces.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 40 of 52 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 hours post
- dose was considerably less than 1% of the administered dose. Therefore, neither clothianidin nor its metabolites appeared to exhibit potential for bio accumulation. Excretory patterns did not exhibit gender
- related variability. Both urinary and fecal metabolites were identified using TLC and radioautography in conjunction with known standards and were quantified by TLC/LSC . The major metabolites in both urine and feces were the parent compound (clothianidin) and TZNG [N - (2
- chlorothiazol
- 5 - ylmethyl)
-N - nitroguanidine] which resulted from N
demethylation of clothianidin. Extraction efficiencies were excellent and most components in the urine and feces we re adequately quantified and characterized. Based on the data from the oral administration of [nitroimino
- 14C] - clothianidin the metabolism pathway proposed by the investigators was supported. 870.7600 Dermal

Penetration

– mo nkey 45868001 (2003)

Acceptable/ non - guideline 6.13 μg/cm2 8 hour exposure Undiluted FS 600 formulation of clothianidin (10% ai) 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. D395348

Page 41 of 52 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin . Guide line Study Title MRID Results 98/93,404/404 Assay 2=0/0, 28/27, 89/93, 338/398 Non - guideline Other

Genotoxicity

– Unscheduled DNA synthesis in primary rat hepatocytes 46339004

(2003) Acceptable/ non - guideline No evidence of DNA damage and repair in this test system, as determined by radioactive tracer procedures (nuclear silver grain counts). Non - guideline Special Study:

Neurotoxicity and pharmacology
- mo use 45422823

(2000) Acceptable/ non - guideline mg/kg=0, 12.5, 25, 50, 100, 200, 400 (single gavage dose) **NOAEL** = 25 mg/kg/day (M/F) **LOAEL** = 50 mg/kg (M/F) based on transient signs of decreased spontaneous mo tor activity, tremors and deep respirations.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 42 of 52 **A .**  **3. Endpoint Selection**  **Acute Reference Dose (aRfD) -**  **General Population**  Studies Selected : Special Neurotoxicity /Pharmacology

study in Mice ( MRID 45422823 ) Dose and Endpoint for Risk Asses sment : NOAEL = 25 mg/kg/day (both studies) based on transient signs of spontaneous motor activity , tremors, and deep respirations observed on D ay 1 at 50 mg/kg/day . **mg/kg 0.25**  **RfD Acute**  

 (UF) 100 mg/kg 25 

### Comments about Study

/Endpoint/Uncertainty Factors : These endpoints and dose were selected because the oral route of exposure is relevant to dietary risk assessment and the duration of exposure is relevant to acute dietary risk. Similar signs of neurotoxicity were obser

ved in the acute neurotoxicity

study in the rat at 100 mg/kg, with a NOAEL of 60 mg/kg. Although the developmental toxicity

study in the rat had a lower maternal NOAEL of 10 mg/kg/day (LOAEL 40 mg/kg/day), this study was not chosen for endpoint selection because the NOAEL is considered to be artificially low due to dose spacing. The standard uncertainty factors (100x) were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies extrapolation). **Acute Referenc e Dose (aRfD)** 
**– Females 13**  **- 49**  Studies Selected : Developmental Study in the Rabbit (MRID 45422713, 45422712) Dose and Endpoint for Risk Assessment : NOAEL = 25 mg/kg/day (both studies) based on increased litter incidences of a missing lobe of th e lung observed on Day 1 at 75 mg/kg/day . **mg/kg 0.25**  **RfD Acute**  

 (UF) 100 mg/kg 25 

### Comments about Study

/Endpoint/Uncertainty Factors : The endpoint and dose were selected because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of exposure is relevant to acute dietary risk and 3) they

are protective of potential offspring effects. Based on the available data, HED determined that changes in organ development can occur as the result of a single expo sure at a critical junction during pregnancy or from multiple exposures throughout pregnancy

and lactation. The standard uncertainty factors (100x) were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies e xtrapolation).

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 43 of 52 **Chronic Reference Dose (cRfD )**  Studies Selected : 2 - Generation Reproduction Study in the Rat (MRID 45422715, 45422714) Dose and Endpoint for Risk Assessment : NOAEL = 9.8 mg/kg/day based on decreased body weights gains, delayed sexual maturation, decreased thy mus weights in F1 pups, and increased stillbirths in both generations at the LO AEL of 31.2 mg/kg/day . **mg/kg/day 0.01**  **RfD Chronic**  

 (UF) 100 mg/kg/day 8 . 9 

### Comments about Study

/Endpoint/Uncertainty Factors : This endpoint and dose was selected because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of exposure is relevant to chronic risk scenarios, and 3) it is the lowes t endpoint in the toxicology database and is therefore protective of both chronic effects and potential qualitative sensitivity of offspring . The standard uncertainty factors were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies extrapolation). **Incidental Oral Exposure Short**  **- and Intermediate** **- Term Incidental Exposure (1**  **- 30 days**  **and 1 -**  **6 months )**  Studies Selected : 2 - Generation Repro duction Study in the Rat (MRID 45422715, 45422714) Dose and Endpoint for Risk Assessment : NOAEL = 9.8 mg/kg/day based on decreased body weights gains,, delayed sexual maturation, decreased thy mus weights in F1 pups, and increased stillbirths in both generations at the LO AEL of 31.2 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors : The NOAE L and LOAEL from the 2 - generation reproduction study were selected for the short
- and intermediate
- term incidental oral risk assessment because they are protective of developmental effects present in rat pups observed in the presence of less severe maternal effects at similar doses. The standard uncertainty factors (100x) were applied (10x for intraspecies variability and 10x for interspecies extrapolation). **Dermal Exposure All Durations**  Studies Selected : 2 - Generation Reproduction Study in the Rat (MRID 45422715, 45422714) Dose and Endpoint for Risk Assessment : NOAEL = 9.8 mg/kg/day based on decreased body weights gains, delayed sexual maturation, decreased thy mus weights in F1 pups, and increased stillbirths in both generations at the LO AEL of 31.2 mg/kg/day .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 44 of 52 Comments about Study

/Endpoint/Uncertainty Factors : Although a dermal (route specific) toxicity study in rat s was submitted, no effects were seen at the highest dose tested of 1000 mg/kg/day . Use of the route
- specific study for dermal risk assessment would not be protective of the offspring effects observed in both the DNT and the 2
- generation reproduction studies because reproduction and developmental parameters were not evaluated . Since the dermal endpoint is based on an oral study , a 1% dermal absorption factor (DAF) is used to determine dermal exposure and risk. The standard uncertainty factors (100x) w ere applied (10x for intraspecies variability

and 10x for interspecies extrapolation). **Inhalation Exposure Short**  **- and Intermediate** **- Term Inhalation Exposures**  **(1 -** **30 days and 1 -**  **6 mont hs)**  Studies Selected : 2 - Generation Reproduction Study in the Rat (MRID 45422715, 45422714) Dose and Endpoint for Risk Assessment : NOAEL = 9.8 mg/kg/day based on decreased body weights gains,, delayed sexual maturation, decreased thy mus weights in F1 pups, and increased stillbirths in both generations at the LO AEL of 31.2 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors : The study was selected because it is of an appropri ate exposure length and it is protective of the most sensitive population, developing children. No route - specific information is available for the inhalation toxicity of clothianidin . In the absence of a route
- specific study , the NOAEL and LOAEL from an oral study are used to estimate inhalation exposure and the associated risk (i.e., inhalation toxicity is assumed to be equivalent to oral toxicity). In this case, the NOAELand LOAEL from the 2
- generation reproduction study were selected because the duration is appropriate for short
- and intermediate
term exposures and it is protective of potential effects in offspring. Because effects seen in the reproduction study can occur as the result of a single exposure at a critical junction during pregnancy

or f rom multiple exposures throughout pregnancy and lactation, the NOAEL for offspring effects observed in the reproduction study was selected as the dose for all durations of exposure scenarios. The standard uncertainty factors were applied to all exposure sc enarios (10x for intraspecies variability and 10x for interspecies extrapolation). Inthe absence of the required inhalation toxicity

study , HED is recommending the 10X FQPA factor be retained as a database uncertainty factor for assessing inhalation expo sure and risk under the FQPA . Similarly, a 10X database uncertainty

factor should be applied to non
- FQPA assessments (e.g., occupational assessments).

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 45 of 52 **Appendix B. Metabolism Summary Table** Table B1 . Overview of clothianidin metabolic profile in plant and animal matrices. Residue Rat Hen Goat Corn Sugar Beet Rotational

Crops Apple Tomato Clothianidin         ACT**  AT G - Ac  * AT G - Py r  AT MG - Py

r  * AT MT  CTCA**   MG       MNG       *   MTCA**  NTG        THMN   THMN - Glc  TMG      * (tops)   TMHG  TM T  TZG   *  * TZMU       TZNG   *  *    *   TZU   *  *     UREA    

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

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 46 of 52 **Appendix C. Physical/Chemical Properties Physicochemical Properties of Clothianidin.**  Parameter Value Reference Melting point (oC) 176.8 D335355, W. Drew , 10/16/07 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 (Pa at 20oC) 1.3 x 10 - 10 Dissociation constant, pKa at 20oC 11.09 Octanol/water partition coefficient, Log(KOW) at 25oC 0.7 UV/visible absorption spectrum (Maximum, nm) 265.5 (acidic or neutral) 246.0 (basic) PAI = Purified Active Ingredient; TGAI = technical grade active ingredient.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 47 of 52 **Appendix D. Review of Human Research** This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the P esticide Handlers’ Exposure Database ( HED , version 1.1) , are subject to ethics review pursuant to 40 CFR 26, hav e received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review b y the HSRB. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticid es/science/handler
- exposure - data.html and http://www.epa.gov/pesticides/science/post
- app - exposure - data.html.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 48 of 52 **Appendix E. Occupational Exposure/Risk Summary Tables T**  **able E1.**  **Occup at**  **ional Exposures and Risks Resulting from Use of Clothianidin on Proposed New Crops.**  **Scen. #**  **Scenario 1**  **Crop & Appl.**  **rate (lb ai/A or lb ai/gal)**  **2 Area**  **t reated** 

**or gal// day**  **3 Source of** 

**Unit exp. & PPE**  **4 Derm**  **al**

**UE 5**  **μg/lb ai Inhal.** 

**UE 5**  **μg/lb ai Derm**  **al**

**D ose**  **6 mg/kg/day**  **Inhal.**

**D ose**  **6 mg/kg/day**  **Short -**  **term**

**Derm al**  **MOE 7**  **Short -**  **term**

**Inhal. MOE**  **7 Combined** 

**Short -**  **term ARI**  **8 MIXER/LOADER**  1 Arena WDG Aerial Straw berry (0.2) 350 AHETF B+G 51.6 8.96 0.00052 0.00909 18,721 1,078 1.1 2 Arena WDG, Ground boom Straw berry (0.2) 80 AHETF B+G 51.6 8.96 0.00012 0.00208 81,904 4,717 5 8, 14, 23 V - 10170 2.13 SC, Aerial Straw berry (0.1) Citrus (0.1) Pistachio (0.1) 350 AHETF B+G 37.6 0.219 0.00019 0.00011 51,383 88,219 75 9 V - 10170 2.13 SC, Ground boom Straw berry (0.1) 80 AHETF B+G 37.6 0.219 0.00004 0.00003 224,801 385,959 330 15, 21, 24 V - 10170 2.13 SC, Air blast Citrus (0.1)

Nectarine (0.1) Pistachio (0.1) 40 AHETF B+G 37.6 0.219 0.00002 0.00001 449,601 77,918 660

**APPLICATOR** 3 Arena WDG Aerial Straw berry (0.2) 350 AHETF Closed cockpit 5.0 0.068 0.00005 0.00007 193,200 142,059 130 4 Arena WDG, Ground boom Straw berry (0.2) 80 AHETF B+G+ open cab 16.1 0.34 0.00004 0.00008 262,500 124,301 110 10, 16, 25 V - 10170 2.13 SC, Aerial Straw berry (0.1) Citrus (0.1) Pistachio (0.1) 350 AHETF Closed cockpit 5.0 0.068 0.00003 0.00003 386,400 284,118 260 11 V - 10170 2.13 SC, Gr. boom Straw berry (0.1) 80 AHETF B+G+ open cab 16.1 0.34 0.00002 0.00004 525,000 248,603 240 17, 22, 26 V - 10170 2.13 SC, Air blast Citrus (0.1)

Nectarine (0.1) Pistachio (0.1) 350 AHETF B+G+ open cab 1,590 4.71 0.00092 0.00027 10,632 35,382 27

**FLAGGER** 7, 27 V - 10170 2.1 SC & Arena WDG All crops

(0.2) 350 PHED B+G 12 0.35 0.00012 0.00036 80,500 27,600 27

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 49 of 52 **T able**  **E1. Occup**  **at ional Exposures and Risks Resulting from** **Use of Clothianidin on Proposed New Crops. Scen.**  **# Scenario**  **1 Crop**  **& Appl. rate (lb ai/A or**  **lb ai/gal) 2**  **Area t**  **reated**

**or gal// day**  **3 Source of** 

**Unit exp. & PPE**  **4 Derm**  **al**

**UE 5**  **μg/lb ai Inhal.** 

**UE 5**  **μg/lb ai Derm**  **al**

**D ose**  **6 mg/kg/day**  **Inhal.**

**D ose**  **6 mg/kg/day**  **Short -**  **term**

**Derm al**  **MOE 7**  **Short -**  **term**

**Inhal. MOE**  **7 Combined** 

**Short -**  **term ARI**  **8 MIXER / LOADER / APPLICATOR**  5, 12, 18, 19 Arena WDG and V - 10170 2.1 SC Soil broadcast Backpack Straw berry (0.2), Citrus (0.2) dilution = 0.02 lb ai/gal 40

gal/day B+G 8,260 2.58 0.00096 0.00003 10,223 327,616 78 6, 13, 20 Arena WDG and V - 10170 2.1 SC Soil drench MPHG Straw berry (0.2), Citrus (0.2) , dilution = 0.004 lb ai/gal 1000

gal/day B+G 390 3.9 0.000226 0.000226 43,000 43,000 39 Abbreviations used: AHETF = agricultural handler exposure task force database, ARI = aggregate risk index, B = baseline PPE ( long
- sleeved shirt, long pants, shoes and socks, and no respirator), G = chemical resistant gloves, MOE = mar gin of exposure, MPHG = mechanically pressurized handgun, PHED = pesticide handler exposure database, PPE = personal protective equipment, and UE = unit exposure. 1 . Exposure scenarios are from Table 6. 2. For soil broadcast and drench applications and citrus trunk treatments an application rate of 0.2 lb ai/A was proposed. The diluent volume used for back
-pack sprayer was 10 gal/A and at an application rate of 0.2 lb ai/A, the conc. of clothianidin in the spray mix amounted to 0.02 lb ai/gal. The corresponding numbers for MPHG used for soil drench was 50 gal/A at 0.004 lb ai/gal. 3. Area treated per day assumptions are from ExpoSAC (SOP No. 9.1). The spray volumes used per day for backpack and mechani cally pressurized handgun were assumed to be 40 and 1000 gal/day, respectively. 4. # Source of unit exposures may be proprietary. 5 . From http://www.epa.gov/pesticides/science/handler
- exposure - data.html 

### . F or backpack sprayer, same unit dermal and inhalation unit exposures were used for both WDG and SC formulations. 6. Dermal dose (mg/kg/day) = [Appl. Rate (lb ai/A or lb ai/gal) * Area Treated (acres or spray vol. /day) * Dermal Unit E xp. * Conversion F actor (μg/lb ai* 0.001) * Dermal A

bsorption Factor (1.0%)] / Body wt. (69 kg). Inhalation D ose (mg/kg/day) = [Appl. Rate (lb ai/A or lb ai/gal) * Area T reated (acres or amount treated/day) * Inhal. Unit E xp. * Conversion Factor (μg/lb ai *0.001) * Inhalati on A bsorption Factor (100%)] / Body wt. (69 kg). 7. Short
- term D ermal MOE = Short
- term D ermal NOAEL (9.8 mg/kg/day) / Dermal D ose (mg/kg/day). Short
- term I nhalation MOE = Short
- term I nhalation NOAEL (9.8 mg/kg/day) / Inhalation D ose (mg/kg/day). 8. S hort
- term

ARI = 1/[(1/( S hort
- term D ermal MOE/100) + (1/( S hort
- term I nhalation MOE/1000)]. The intermediate
- term ARI is the same as the short
- term , because of the same endpoints and doses for both exposure durations.

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 50 of 52 **Table E2 . Occupational**  **Exposures and Risks Resulting from Aerial Applications of Arena**  **® WDG and V**  **- 10170 2.13 SC Form** **ulations of Clothianidin on Selected Crops.**  **Scen. #**  **Scenario Used**  **1 Crop**  **s 2**  **(Appl. Rate**  **lb ai/A) 3**  **A rea** 

**t reated/**  **day (A)**  **PPE & UE**

**Database 4**  **Derm al** 

**UE 5**  **μg/lb ai**  **Inhal.**

**UE 5**  **μg/lb ai Derm**  **al**

**dose 6**  **mg/kg/day Inhal.** 

**dose 6**  **mg/kg/day Short**  **- term** 

**Derm al**  **MOE 7**  **Short -**  **term**

**Inhal. MOE**  **7 Combined** 

**Short -**  **term ARI**  **8 MIXER & LOADER**  1 Aerial Arena WDG All crops 0.1 350 AHETF B+G 51.6 8.96 0.00026 0.00454 37,442 2,156 2.1 2 Aerial V - 10170 2.13 SC Brassica

leafy
- and leafy veg. 0.067 350 AHETF B+G 37.6 0.219 0.00013 0.00007 76,691 131,670 110
3 Fruiting veg.,

pe ach, pomegranate, and tree nuts 0.1 350 AHETF B+G 37.6 0.219 0.000 19 0.000 11 51 , 383 88 , 219 75 **APPLICATOR & FLAGGER** 4 Applying by aerial All crops 0.1 350 AHETF closed cockpit 5.0 0.068 0.0000 3 0.00 0 0 3 386 , 4 00 284 , 118 260 5 Flagging PHED, B+G 12.0 0.35 0.000 0 6 1 0.00018 161,000 55,200 53 1. Exposure scenarios are from Table 6. 2. The crops include Brassica leafy
- , fruiting
- and leafy vegetables, peach, pomegranate, and tree nuts. 3. The proposed application rate for Brassica
- and l eafy vegetables is only 0.067 lb ai/A. Since all other crops have the rate at 0.1 lb ai/A , the exposures for applicator and flagger were estimated at the higher rate. 4, 5, 6, 7, and 8 are the same as in Table 7 .

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 51 of 52 **Table E3. P**  **ost -**  **application Derm**  **al Exposures and Risks**  **Resulting from Foliar Use of Clothianidin on**  **Citrus, Nectarine, Pistachio, and Strawberry. Crop**  **Activit ies**  **Appl. Rate (lb ai/A)**  **Estimated**

**DFR (ug/cm** **2 )**  **1 Transfer** 

**Coefficient (cm** **2 /hr)**  **2 Derm**  **al**

**Dose 3**  **(m g/kg/day)**  **Short -**  **term**

**Derm al**  **MOE 4**  Citrus fruits Fruit harvesting 0.1 0.280 1,400 0.000454 22,000 Nectarine Thinning of fruits 3,600 0.00117 8,400 Pistachio Harvesting 1,400 0.000454 22,000 Straw berry Harvesting, training 0.2 0.561 1,100 0.000715 14,000 1 . Dislodgeable Foliar Residue (DFR) = Appl ication Rate (lb ai/A) * (1
- Daily D issipation Rate) t * Co nv . F actor ( 4.54E+8 μg/lb ) * Conv . F actor ( 2.47E - 8 A/cm2 ) * Residue T ransfer Rate (20% default) after treatment. 2 . Transfer coefficient (TC) from ExpoSAC Policy #3, June 3, 2011. 3. D ermal d ose (mg/kg/day) = [DFR * T C * Co nv . F actor ( 0.001 mg/μg ) * Dermal A bsorption F actor (1%) * 8 hrs/day] / Body W eight (6 9 kg). 4: MOE = S hort
- term D ermal NOAEL ( 9.8 mg/kg/day) / D ermal D ose (mg/kg/day).

### Clothianidin Human Health Risk Assessment DP No. D395348

Page 52 of 52 **Appendix F. Summary of Relevant**  **International Residue Limits for Clothianid in**  **.**



## Clothianidin (044309; 11 September 2012) Summary of US and International Tolerances and Maximum Residue Limits . Residue Definition : US Canada Mexico 2 

### Codex 3,4 

### 40 CFR 180.586: Plant/Livesto c k: clothianidin, ( E )
- N - [(2
- Chloro
- 5 -thiazolyl)methyl]
- N' - methyl
- N" -nitroguanidine [C(E )]
- N - [(2
- chloro
- 5 - thiazolyl)methyl]
- N' - methyl
N"-nitroguanidine clothianidin. The residue is not fat
- soluble. Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex 3,4 

### Tea (import only) 70 0.7 Tea, green, black (black, fermented and dried) (T) Strawberry 1.5 0 0.07 berries and other small fruits (except grapes) (c, T) Fruit, Citrus, Group 10
- 10 0. 60 0.07 citrus fruits (T) Pistachio 0.01 Pepper and Eggplant (Crop Subgroup 8
- 10B) 0.8 0 0.05 fruiting vegetables other than cucurbits (T) 0.5 peppers chili, dried Completed: M. Negussie; 09/13/2012
1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC. 4 The source of the residue; T
- thiamethoxam; C
- clothianidin