Page 1 of 45 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** 7 - MAR - 2013 **SUBJECT: Imidacloprid.**  Section 3 Request for use on Oy ster Beds in Washington (WA),

and Section 18 Emergency Exemption Request for use on Sugarcane in Louisiana (LA). **Hum an**  **- Health Risk Assessment.**  **PC Code:** 129909 **DP Barcode s**  **:** D 399719 and D 407172 **Decision Nos.:** 461091 and 472398 **Registration No. :**  xxx - xxx, xxx - xxx , 264 - 758 **Petition Nos .:**  2E7988 and 12LA11 **Regulatory Action:** Section 3 Registration **Risk Assessment Type :**  Single Chemical Aggregate **Case No.:** 7605 **T XR No.:**  **NA CAS No.:**  138261 - 41 - 3 **MRID No.: NA 40 CFR:**  §180.472 **FROM:** Jennifer R. Tyler, Chemist

Chester E. Rodriguez, Ph.D., Toxicologist Risk Assessment Branch 1 (RAB1) /Health Effects Division (HED; 7509P) Matthew Crowley , Biologist Chemistry

and Exposure Branch (CEB)/HED (7509P) **THROUGH:** George F. Kramer, Ph.D., Branch Senior Scientist

Dana M. Vogel, Deputy Division Director RAB1/HED (7509P) **TO:** Sidney

Jackson/Barbara Madden Tawanda Maignan/Debra Rate Registration Division (RD; 7505P) The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the following: 1) the Section 3 request for the use of the active ingredient (ai) imidacloprid (1 - [(6 - chloro - 3 - py ridinyl)methyl] - N - nitro - 2 - imidazolidinimine) on oyster beds in Willapa Bay and Gray s Harbor in WA; and 2) the Section 18 Emergency

Exemption request for the use of imidacloprid on sugarcane in LA . A summary of the findings and an assessment of human - health risk resulting from the aforementioned uses are provided in this document. The risk assessment, res idue chemistry data review, dietary

exposure assessment , and occupational exposure assessment (sugarcane use) were provided b y J ennifer Tyler (RAB1); the hazard characterization and endpoint selection by Chester Rodriguez (RAB1); the occupational exposure assessment (o ys ter bed use) andImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 2 of 45 residential exposure assessment by Matthew Crowley

(CEB); and the drinking water exposure assessment by

Jo sé Melendez of the Environmental Fate and Effects Division (EFED).Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 3 of 45 **Table of Contents** 1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 HED Recommendations ................................ ................................ ................................ ....... 7 2.1 Data Deficiencies ................................ ................................ ................................ ............. 7 2.2 Tolerance Considerations ................................ ................................ ................................ . 7 2.3 Label Recommendations ................................ ................................ ................................ .. 8 3.0 Introduction ................................ ................................ ................................ .......................... 9 3.1 Chemical Identity ................................ ................................ ................................ ............. 9 3.2 Phy s ical/Chemical Characteristics ................................ ................................ ................... 9 3.3 Pesticide Use Pattern ................................ ................................ ................................ ........ 9 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 11 3.5 Consideration of Environmental Justice ................................ ................................ ........ 11 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 12 4.1 Mode of Action ................................ ................................ ................................ .............. 12 4.2 Toxicology

Studies Available for Analy sis ................................ ................................ ... 12 4.3 Absorption, Distribution, Metabolism, & Excretion (ADME) ................................ ...... 12 4.4 Dermal Absorption ................................ ................................ ................................ ......... 12 4.5 Summary

of Toxicological Effects ................................ ................................ ................ 12 4.6 SF for Infants and Children (FQPA SF) ................................ ................................ ........ 13 4.7 Toxicity

Endpoint and Point of Departure Selections ................................ .................... 15 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 18 5.1 Residues of Concern Summary and Rationale ................................ ............................... 18 5.2 Food Residue Profile ................................ ................................ ................................ ...... 18 5.3 Water Residue Profile ................................ ................................ ................................ .... 19 5. 4 Dietary

Risk Assessment ................................ ................................ ................................ 20 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ .... 21 6.1 Residential Handler Exposure and Risk Estimates ................................ ........................ 22 6.2 Post - Application Exposure and Risk Estimates ................................ ............................. 24 6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios) ......................... 27 6.4 Residential Risk Estimates for Use in Aggregate Assessment ................................ ...... 28 6.5 Residential By stan der Post - application Inhalation Exposure ................................ ........ 30 6.6 Spray

Drift ................................ ................................ ................................ ...................... 30 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 30 7.1 Acute Aggregate Risk ................................ ................................ ................................ .... 31 7.2 Short - Term Aggregate Risk ................................ ................................ ........................... 31 7.3 Intermediate - Term Aggregate Risk ................................ ................................ ................ 32 7.4 Chronic Aggregate Risk ................................ ................................ ................................ . 32 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 33 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 33 9.1 Handler Exposure and Risk Estimates ................................ ................................ ........... 33 9.2 Post - Application Exposure and Risk Estimates ................................ ............................. 37 10.0 References ................................ ................................ ................................ .......................... 39 Appendix A. Toxicology Profile and Executive Summaries. ................................ ...................... 41 Appendix B. Phy sical/Chemical Properties. ................................ ................................ ................ 45Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 4 of 45 **1.0 Executive Summary**  **Background:** Im idacloprid is an insecticide registered for uses on a variety of crops for the control of aphids, cucumber beetles, and whiteflies (including sweet potato or silverleaf whitef ly). It is a member of the py ridylmethylamine class of compounds. Its mode of action involves disruption of the nervous s ys tem by acting as an inhibitor at nicotinic acetyl choline receptors. Imidacloprid blocks the signals that are induced b y acetyl choline at the post - sy naptic membrane, resulting in normal nerve function impairm ent. Imidacloprid is registered for use on several agricultural products, ornamental turf/plant products, seed treatments, pet care products, as well as structural pest products. Tolerances are currentl y established for the combined residues of imidaclop rid and its metabolites containing the 6 - chlorop yridinylmoiety , all expressed as the parent, under 40 CFR §180.472 in/on various plant and livestock commodities. The Interregional Research Project No. 4 (IR - 4) has submitted a petition (PP# 2E7988) for the use of imidacloprid on oy ster beds to control burrowing shrimp. IR - 4 has requested to add this use to the following labels: Protector® 0.5G [a granular (G) product containing 0.5% imidacloprid as the active ingredient (ai); EPA Reg. No. xxx - xxx], and Protector® 2F [a flowable concentrate (F) formulation containing 21.4% imidacloprid as the ai; EPA Reg. No. xxx - xxx]. In conjunction with this petition, tolerances have been requested for the combined residues of imidacloprid and its metabolites containing the 6 - chloropy ridinyl moiety, all expressed as the parent, in/on fish at 0.05 ppm, and fish - shellfish, mollusc at 0.05 ppm. In addition, the L ouisiana Department of Agriculture and Forestry ( LDAF) has submitted a Section 18 Emergency

Exemption request for the use of imidacloprid on sugarcane in LA. **Hazard Assessment :**  The main targets of toxicity following oral administration of imidacloprid in mammalian sy stems were the nervous s ys tem and the thy roid. The most sensitive species tested was the rat. Evidence of neurotoxicity was reported in the rat acute neurotoxicity (ACN) study as changes in clinical signs and functional - observation battery (FOB) measurements, including decreased motor and locomotor activities, tremors, gait abnormalities, increase d righting reflex impairments and body temperature, decreased number of rears and response to stimuli, and decreases in forelimb and hindlimb grip strength. Also, in a rat developmental neurotoxicity

(DNT) study

where imidacloprid was administered to pregnant/lactating dams in the diet, there were decreases in offspring motor activity measurements and a small but statistically

significant decrease in the caudate/putamen width in the brain of female pups. No neurotoxic effects were reported in any other to xicity study including the rat subchronic neurotoxicity

study . Long - term dietary

exposure to imidacloprid in a rat chronic toxicity study resulted in an increased incidence of mineralized particles in the thy roid colloid, and there were no effects reported in the rabbit dermal or rat inhalation studies. There was no evidence of increased qualitative or quantitative susceptibility in either rats or rabbits based on the results of prenatal developmental toxicity studies or a two - generati on reproductive toxicity

studies in rats. In the rat DNT study , however, the neurotoxic offspring effects noted above occurred in the presence of only maternal food consumption and bodyImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 5 of 45 weight gain, indicating increased qualitative susceptibility in the young, though a clear no observed - adverse - effect level (NOAEL) was established. There was no evidence of carcinogenic potential in either the rat chronic toxicity /carcinogenicity or mouse carcinogenicity studies, and imidacloprid was not genotoxic in a variety of assay s. **Food Quality Protection Act (FQPA) Decision:** The RAB1 risk assessment team recommends that the FQPA Safety

Factor (SF) be reduced to 1X for all exposure scenarios, except for the acute dietary

endpoint for all populations for which the FQPA SF has been reduced to 3X because of the lack of NOAEL in the critical study selected (rat ACN). This decision was based on the following (see Section 4.6 for more detail): The existing toxicology

database for imidacloprid is adequate for FQPA SF e valuation . The following acceptable studies are available: developmental study in rats and rabbits; 2 - generation reproduction study in rats; ACN and subchronic neurotoxicity (SCN) studies in rats; and DNT study in rats. Evidence of neurotoxicity was obse rved in the ACN and DNT studies, but not the SCN study or any other studies in the imidacloprid database. There was increased qualitative susceptibility in the rat DNT study . However, the concern is low because a clear NOAEL was established for the offsp ring neurotoxic effects and the accompanyi ng maternal food consumption and body weight decrements. Further, there was no evidence of increased susceptibility (quantitative or qualitative) based on the results of the pre natal developmental toxicity study i n rats and rabbits and rat two - generation reproductive toxicity study . Therefore, there are no residual uncertainties for pre - /post - natal toxicity in this study . There are no residual uncertai nties in the expos ure database . **Residue Chemistry and Drinking Water Assessments:**  The residue chemistry and drinking water databases are adequate to assess potential human exposure to imidacloprid. Adequate residue chemistry

data have been submitted to support the proposed use on oy ster beds as well as the proposed tolerances on fish and fish, shellfish - mollusc . No residue data have been submitted in support of the proposed Section 18 Emergency Exemption use on sugarcane. However, previously- submitted residue data are adequate to support the proposed use and time - limited tolerances on sugarcane, cane and sugarcane, molasses. EFED provided Tier 1 estimated drinking water concentrations (EDWCs) for surface water [using FQPA Index Reservoir Screening Tool (FIRST)] and groundwater [using Screening Concentration in Ground Water (SCI - GROW)] for imidacloprid and its degradates (imidacloprid urea, imidacloprid guanidine, and imidacloprid olefin). **Dietary (Food and Drinking Water) Exposure Assessment** : Acute and chronic dietary (food and drinking water) exposure anal ys es were conducted for the general U.S. population and various population subgroups using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM - FCID; V er. 3.16). For acute and chronic dietary risk estimates, HED’s level of concern (LOC) is for estimates that exceed 100% acute population adjusted dose (aPAD) or chronic population - adjusted dose (cPAD) , respectively . The acute dietary exposure assessment was unrefined ( assuming tolerance - level residues and assuming 100% crop treated ( CT ) for all registered and proposed commodities) , and the chronic dietary exposure assessment was partially refined (using tolerance - level residues for all registered andImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 6 of 45 prop osed commodities, and %CT information for some commodities). The results indicate that the acute (95 th percentile) and chronic dietary exposure estimates ar e below HED’s LOC for the general U.S. population and all other population subgroups . For both acute and chronic assessments, the most highl y exposed population subgrou p is children 1 - 2 years old at 74% of the aPAD and 28% of the cPAD , respectivel y . **Residential (Non**  **- Occupational)**  **Exposure Assessment :**  The proposed use of imidacloprid on oy ster be ds in WA can result in residential exposure via potential contact with residues in oy ster bed water or sediment during recreational swimming . In addition, imidacloprid has several registered uses which may result in residential exposure . Based on the se registered use patterns, there is a potential for short - term dermal and inhalation handler ; and short - term dermal, inhalation, and incidental oral post - applic ation exposure . There is also the potential for intermediate - and long - term exposures from the p et collar use, as it presents the potential for prolonged exposure via a continuous source and frequent contact (i.e., playing with pets). The equations and inputs for the post - application exposures due to the oy ster bed use were generall y developed fro m HED’s SWIMODEL V 3.0, and using updated body- weight information. All potential residential exposures from existing uses were re - evaluated utilizing the 2012 Residential standard operating procedures (SOPs) and policy changes on body weight. The resulti ng margins of exposure ( MOEs ) were all ≥140; and, therefore, do not exceed HED’s LOC. **Aggregate Exposure Scenarios and Risk Conclusions** : For the proposed uses, human - health aggregate risk assessments have been conducted for the following exposure scenari os: acute aggregate exposure (food + drinking water), short - term aggregate exposure (food + drinking water + residential), and chronic aggregate exposure (food + drinking water + residential). Although there are intermediate - term residential exposures, an intermediate - term aggregate was not quantitatively

assessed since (1) the short - and intermediate - term PODs are the same and (2) the short - term aggregate provides a worst - case estimate of residential exposure. For these reasons, the short - term aggregate is protective of the longer - term exposures. A cancer aggregate risk assessment was not performed because there is no evidence that imidacloprid is carcinogenic. All potential exposure pathway s were assessed in the aggregate risk assessment as a conservative, health - protective measure. All aggregate risk estimates are not of concern to HED for the scenarios listed above. **Occupational Handler and Post**  **- application**  **Exposure Estimates** : Occupational short - term dermal and inhalation handler exposures are expected for individuals involved in applications of imidacloprid to oy ster beds and sugarcane . For the proposed oy ster bed use, HED has determined that risk estimates are not a concern (i.e., MOE >10 0) with baseline attire and chemical - resistant gloves (as required on the label). For the proposed sugarcane use, HED has determined that risks are not a concern with baseline attire. For aerial applications, no risks of concern were identified for indiv iduals in enclosed cockpits. For the proposed use of imidacloprid on oy ster beds, the extent of post - application exposure is expected to be non - occupational in nature. Thus, any formal occupational post - application dermal or inhalation exposures (e.g., d uring o ys ter harvesting) is adequately covered in the residential exposure assessment. Based on the proposed Section 18 Emergency Exemption use of imidacloprid on sugarcane , occupational post - application dermal exposures are expected. TheImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 7 of 45 short - term post - application assessments resulted in MOEs of 100 or greater on “day 0” (immediately

after application) for all exposure activities, and are not of concern. The 12 - hour restricted entry

interval (REI) is adequate for the proposed use patterns. **Review of H**

**uman 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 Pesticide Handlers Exposure Database Version 1.1 (PH ED 1.1) ; Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and Agricultural Reentry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of d ata sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html . **2.0 HED**  **Recommendations** HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registratio n and establishment of the tol erances listed in Section 2.2.2. In addition, the databases support a Section 18 Emergency Exemption request and the establishment of time - limited tolerances listed in Section 2.2.2. HED is not recommending for any additional data or label modifications in conjunction with this petition. **2.1 Data Deficiencies**  No additional data are required to support the proposed use. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate enforcement methods are available for determination of imidacloprid residues of concern in plant [Bayer gas chromatograph y/mass spectrometry (GC/MS) Method 00200] and livestock commodities (Bayer GC/MS Method 00191). These methods have undergone successful EPA petition method validations (PMVs), and the registrant has fulfilled the remaining requirements for additional raw data, method validation, independent laboratory validation (ILV), and an acceptable confirmatory method [high - performance liquid chromatograph y/ultraviolet (HPL C/UV) Method 00357] (Memos, F. Griffith, 18 - JUN - 1993 , D187911; 1 - JUN - 1994 , D202113; 8 - JUN - 1994 , D200233; 8 - JUN - 1995 , D213252; and 18 - DEC 1995 , D221591). Baye r Corporation previously submitted adequate multiresidue (MRM) recovery data for imidacloprid and the metabolites 5 - hydroxy imidacloprid, imidacloprid olefin, des nitro imidacloprid, and 6 - chloronicotinic acid ( 6 - CNA) through Food and Drug Administration (FDA) Protocols A through E (Memos, F. Griffith, 18 - JUN - 1993 , D187911; 15 - JUN - 1993 , D193027; 8 - JUN - 1994 , D200233; and 22 - JUN - 1994 , D194206). Imidacloprid and its metabolites were not recoverable b y these methods. The results of the MRM testing for imidacloprid were forwardedImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 8 of 45 to FDA for inclusion in the Pesticide Anal ytical Method Volume I (PAM I) (Memo, F. Griffith, 15 - JUL - 1993 , D193005). **2.2. 2**  **Recommended Tolerances Table 2.2.2. Tolerance Summary for Imidacloprid.**  **Commodity Proposed** 

**Tolerance (ppm)**  **Currently**

**Established Tolerance (ppm)**  **Recommended**

**Tolerance ( ppm)**  **Comments**

**( correct commodity definition**  **) 2E7988**  **[§180.472(a) General]** fish 0.05 - 0.05 fish - shellfish, mollusc 0.05 - 0.05 **12LA11 [§180.472(b) Section 18 emergency exem** **ptions]** sugarcane, cane - - 6.0 sugarcane, molasses - - 50 **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances PP# 2E7988**  : The residue chemistry data support the proposed tolerances for the combined residues of imidacloprid and its metabolites containing the 6 - chlorop yridinyl moiety, all expressed as the parent, in/on fish at 0.05 ppm, and fish - shellfish, mollusc at 0.05 ppm. No revisions to the proposed tolerances are necessary . **PP# 12LA11**  : T he residue chemistry data support the time - limited tolerances for the combined residues of imidacloprid and its metabolites containing the 6 - chlorop yridinyl moiety, all expressed as the parent, in/on sugarcane, cane at 6.0 ppm; and sugarcane, molasses at 50 ppm. **2.2.4 International Harmonization**  There are currently

no established Codex, Canadian, or Mexican maximum residue limits (MRLs ) for imidacloprid on fish, molluscs , or sugarcane . Therefore, harmonization of MRL s and U.S. tolerances is not an issue at this time. **2.3 Label Recommendations**  HED is not recommending for any changes to the Protector® 0.5G (EPA Reg . No. xxx - xxx), and Protector® 2F (EPA Reg. No. xxx - xxx) labels.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 9 of 45 **3.0 In**  **troduction 3.1**  **Chemical Identity Table 3.1. Test Com** **pound Nom enclature.**  Chemical Structure

Common Name Imidacloprid Com pany Experimental Name Imidacloprid IUPAC Name (EZ ) - 1 - (6 - chloro - 3 - py

ridylmethyl) -N

- nitroimidazolidin 2 - ylideneamine CAS Name 1 - [(6 - chloro - 3 - pyridinyl)methyl] -N - nitro - 2 - imidazolidinimine CAS # 138261 - 41 - 3 End - use Products (EUP) Protector ® 2F (EPA Reg. No. xxx - xxx) Protector ® 0.5G (EPA Reg. No. xxx - xxx) **3.2 Physical/Chemical Characteristics**  The phy sical and chemical properties, as well as a summary of relevant environmental fate parameters are detailed in Appendix B. Imidacloprid has a low vapor pressure (10 - 7 mPa); therefore, it is not a volatile pesticide. The low Henry's law constant (6.5X10 - 11 atm m 3 /mole) also indicates that it has a low potential of volatizing from water. Im idacloprid has a low octanol water partition coefficient (0.57) ; therefore, it is not expected to bioaccumulate in lipophilic matrices. It is highl y soluble in water (1.54 g/L) , which, coupled with its low octanol water coef ficient, suggests a potential to leach to ground water, as well as transport to surface water via runoff. In view of its environmental fate properties including persistence for many months in soil and water, imidacloprid, will translocate throughout treat ed plants regardless of the method of application. **3.3 Pesticide Use Pattern**  **PP#2E7988** : The petitioner has submitted draft labels for the Protector ® 0.5G (EPA Reg . No. xxx - xxx), and Protector® 2F (EPA Reg. No. xxx - xxx). A summary of the proposed use p atterns are detailed in Table 3.3.1. The proposed imidacloprid labels direct mixers, loaders, applicators and other handlers to wear a long - sleeved shirt, long pants, shoes plus socks and chemical resistant gloves. In additi on, the label for the granule formulation directs users to wear a dust mask. The proposed label specifies a 12 - hour REI . N

N N C l C

H 2 N O 2N

HImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 10 of 45 **Table 3.3.1. Summary of Proposed Directions for Use of Imidacloprid on Oyster Beds. Use**  **Site Trade** 

**Nam e**  **(EPA Reg. No.)**  **Application Equipment App.**  **Rate (lb**  **ai/A) Max.**  **Seasonal App.**  **Rate (lb ai/A)**  **PHI 1** 

**(days) Max.** 

**# App.**  **Min.**

**GPA 2**  **RTI 3** 

**(days)** Oy ster beds Protector ®

0.5G (xxxxx - xx) Drop/rotary spreader ;

Tractor - draw

n spreader ; Belly grinder Helicopter 0.5 0.5 30 1 NA NA Protector ® 2F (xxxxx - xx) Groundboom ,

Helicopter , Backpack 0.5 0.5 30 1 ground: 5 air: 2 Restrictions:  Not for sale to any persons other than a member of the Willapa - Greys Harbor Oyster Growers Association.  A single application/year is allowed.  No adjuvants or surfactants allowed.  Aerial applications must be made on beds exposed at low tide.  Applications from a floating platform or boat may be made under water using a calibrated granular applicator.  All application must be made between April 15 and December 15. Do not apply aerially durin g Federal Holidays.  During aerial applications, all public access areas and public boat launches within 1⁄4 mile radius of bed shall be posted. 1. PHI = pre - harvest interval. 2. GPA = gallons of water per acre. 3. RTI = retreatment interval. **PP# 12LA11**  : LDAF has submitted proposed use directions for the use of imidacloprid on sugarcane in LA. A maximum of 20,000 A can be treated under the requested Crisis Exemption. A summary

of the proposed use patterns are detailed in Table 3.3.2. The proposed im idacloprid product labels direct mixers, loaders, applicators and other handlers to wear a long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves. In addition, the label for the granule formulation directs users to wear a dust mask . The proposed label specifies a 12 - hour REI. **Table 3.3.2. Summary of Proposed Directions for Use of Imidacloprid on Sugarcane in LA. Use Site**  **Trade**

**Nam e (EPA**  **Reg. No.) Application** 

**Equipment App.** 

**Rate (lb ai/A)**  **Max.**

**Seasonal App. Rate**  **(lb ai/A) Minim**  **um**

**PHI 1**  **(days) Max. #** 

**App. Min.**  **GPA 2**  **RTI 3**  **(days)** Sugarcane Admire ® Pro

(264 - 758) Aeriall y 0.06 - 0.08 0.16 36 2 NS NS 1. PHI = pre - harvest interval. The minimum PHI was provided in an email dated 11/19/12 (personal communication between B. Simon eaux to T. Maignan). 2. GPA = gallons of water per acre. 3. RTI = retreatment interval. HED Conclusions: The use directions provided by the petitioner are adequate to allow evaluation of the residue data relative to the proposed Section 3 use of imidacloprid on oy ster beds to control ghost shrimp, and the proposed Section 18 Emergency Exemption request for th e use of imidacloprid on sugarcane in LA.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 11 of 45 **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human - health risk to support the proposed new use of imidacloprid 1) on oy ster beds of Willapa Bay and Gray s Harbor in Washington State to control burrowing shrimp , and 2) on sugarcane in LA . Humans may be exposed to imidacloprid in food and drinking water since imidacloprid may be applied directly

to growing crops and oy ster beds, and applications may

result in imidacloprid reaching surface and ground water sources of drinking water. There are numerous registered residential uses of imidacloprid; therefore, human exposure in residential or non - occupational settings may occur. In an occupational setting, applicators may

be exposed while handling the pesticide prior to application, as well as during application to oy ster beds and sugarcane. In addition, f or the proposed use on sugarcane , there is a possibility

of post - application dermal exposure to occupational workers when reentering field previ ously

treated with imidacloprid. The most recent human - health risk assessment for imidacloprid was conducted in 2009 (Memo, G. Kramer et al. , 16 - MAR - 2009; D375406) . A human - health Scoping Document in support of Registration Review was also recently condu cted (Memo, J. Tyler, 3 - DEC - 2008; D353984). This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of imidacloprid, but also considers the existing uses as well, particularl y for the dietary

and residentia l exposure assessments. **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 ri sk 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 a nd 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 U.S. Department of Agriculture’s National Health and Nutrition Examination Sur vey , What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . 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 product s and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 12 of 45 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Mode of A**  **ction** Imidacloprid is a s ys temic insecticide effective against the larval, ny mphal, and adult insect stages. It s postulated insecticidal mode of action involves inhibition at nicotinic acetyl choline receptors, resulting in nerve function impairment. Som e of the toxic effects reported in mammals are also consistent with a neurotoxic mode of action. **4.2 Toxicology Studies Available for Analysis**  The toxicological database for imidacloprid is adequate for characterization of its hazard, toxicity endpoint s election, and FQPA consideration. In the most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR - 2009; D375406), the only toxicity data gap noted was an immunotoxicity

study as part of the revised 40 CFR §158 data requirements. Since then, a guidelin e 28 - day

rat immunotoxicity

study has been submitted and reviewed by the Agency . The results of the study are included in this hazard characterization. **4.3 Absorption, Distribution, Metabolism, & Excretion (ADME)**  Following oral administration in the rat, 14 C - methylene - radiolabeled imidacloprid was rapidly absorbed with a time to maximum plasma concentration of 1.1 - 2.5 hours post - dose. Absorption was also extensive based on the extent of urinary (70 - 80% of recove red radioactivity) and biliary (~31.8% based on studies with bile - fistulated animals) excretion of radioactivity . Plasma elimination was biphasic with an estimated primary plasma clearance half - life of 3 hours and a secondary , minor half

- life ranging betw een 26 - 118 hours. Urine was the primary route of excretion. Total tissue burden after 48 hours was approximately 0.5% of the administered radioactivity . Though retention of radioactivity was minimal, liver, kidney , lung, skin, and plasma showed the high est levels. Other less significant sites of radioactivity were the brain and testes. There were two major routes of biotransformation for imidacloprid. The first included an oxidative cleavage of the parent compound followed by dechlorination to give 6 - CNA. The second route included the hydroxylation of imidazolidine. There were no significant differences in ADME processes between sexes or dose levels tested. **4.4 Dermal Absorption**  There is no dermal absorption study available for imidacloprid. Howev er, a dermal - absorption factor (DAF) of 7.2% has been previousl y estimated based on the ratio of the maternal lowest observed - adverse - effect level (LOAEL) of 72 mg/kg bw/day from a rabbit developmental toxicity study and the NOAEL from a dermal - specific to xicity study in rabbits. **4.5 Summary of Toxicological Effects**  The main targets of toxicity following oral administration of imidacloprid in mammalian sy stems were the nervous s ys tem and the thy roid. The most sensitive species tested was the rat. Evidence of neurotoxicity was reported in the rat ACN as changes in cl inical signs and FOB measurements including decreased motor and locomotor activities, tremors, gait abnormalities, increased righting reflex impairments and body temperature, decreased number of rears andImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 13 of 45 response to stimuli, and decreases in forelimb and hindlimb grip strength. Also, in a rat DNT study where imidacloprid was administered to pregnant/lactating dams in the diet, there were decreases in offspring motor activity measurements and a small but statistically significant decrease in the caudate/putamen width in the brain of female pups. No neurotoxic effects were reported in any other toxicity study including the rat subchronic neurotoxicity study. Long - term exposure to imidacloprid resulted in an increased incidence of mineralized particles in the thy roid colloid of rats, body

weight decrements in mice, and no toxic effects in dogs. No other thy roid effects were measured in the rat study . In prenatal developmental toxicity studies in rats and rabbits, there were developmental effects at dose le vels that also produced maternal toxicity . In the rat study , there was a slight increase in the incidence of wav y ribs at a dose level higher than that causing deficit in maternal bodyweight gain. Developmental effects in the rabbit occurred at the same dose as severe maternal toxicity including deaths and body- weight deficits. Developmental effects in rabbits included abortions, total litter resorptions, increased post - implantation loss due to increased late resorptions, decreased fetal weights, and an increased incidence of wav y ribs in the high - dose group. In the rat two - generation reproductive toxicity study , there were decreases in pup body weights reported in both litters of each generation at the same dose level as parental effects manifested as decreased premating and gestational body- weight gain. In a recentl y submitted immunotoxicity study in rats, there were no immunotoxic effects reported at the highest dose level tested. The onl y treatment - related effects were limited to deficits in body w eights and food consumption at the highest dose tested. No toxic effects were identified at the limit dose of 1000 mg/kg bw/day in a dermal toxicity study in rabbits. In a rat 4 - week inhalation toxicity study , there were no effects reported (either portal of entry or sy stemic) at the highest concentration tested. There was no evidence of carcinogenic potential in either the rat chronic toxicity /carcinogenicity or mouse carcinogenicity studies. The RfD/Peer Review Committee classified imidacloprid as a Group E chemical, “Evidence of non - carcinogenicity for humans,” b y all rout es of exposure based upon lack of evidence of carcinogenicity in rats and mice (11/10/1993) . There was also no concern for mutagenicity across a host of genotoxicity assay s. **4. 6**  **S F**  **for Infants and Children (FQPA SF)** The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios, except for the acute dietary endpoint for all populations for which the FQPA SF has been reduced to 3X because of the lack of a NOAEL in the critical study (the rat ACN). The rationale is provided below.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 14 of 45 **4.6.1 Completeness of the Toxicology Database**  The existing toxicology

database for imidacloprid is complete and adequate for FQPA SF evaluation. The following studies are available for consideration: d evelopmental toxic ity studies in rats and rabbits; two - g eneration reproductive toxicity study in rats ; ACN and SCN studies in rats , and DNT study in rats . **4.6 .2**  **Evidence of Neurotoxicity** The neurotoxic potential of imidacloprid has been addressed given its postulated insecticidal neurotoxic mode of action, involving nerve function impairment through inhibition at nicotinic acetyl choline receptors. Evidence of neurotoxicity was observed in the ACN and DNT studies but not the SCN study

as previously

described in the toxicological effects section of this document. No signs of effects on the nervous s ys tem were reported in any other studies in the imidacloprid database. **4.6.3 Evidence of S**  **ensitivity/Susceptibility in the Developing or Young Animal** There is no evidence of increased susceptibility (quantitative or qualitative) based on the results of pre - natal developmental toxicity studies in rats and rabbits and the rat two - generation reproductive toxicity

study where developmental effects were observed at the same or higher doses than those causing maternal effects. In the rat DNT study, however, there is evidence of increased qualitative susceptibility, but the concern is low since: 1) the effects in pups (bodyweight deficits, decreased motor activity , and small decrease in female caudate/putamen width) are well - characterized with a clear maternal NOAEL ; 2) the pup effects occurred at the same dose as maternal toxicity

(decreased body- we ight gain and food consumption); and 3) the doses and endpoints selected for regulatory purposes are protective of the pup effects noted at higher doses in the DNT study . Therefore, there are no residual uncertainties for pre - /post - natal toxicity in this study . **4.6.4 Residual Uncertainty in the Exposure Database**  The acute dietary

food exposure assessment utilizes existing and proposed tolerance - level residues and 100% CT information for all commodities. By using these screening - level assessments, actual expos ures/risks will not be underestimated. The chronic dietary

food exposure assessment utilizes existing and proposed tolerance - level residues and % CT data verified b y the Biological and Economics Anal ys is Division (BEAD) for several existing uses. For all proposed uses, 100% CT is assumed. The chronic assessment is somewhat refined and based on reliable data and will not underestimate exposure/risk. The dietary

drinking water assessment utilizes water concentration values generated by model s and associat ed modeling parameters, which are designed to provide conservative, health protective, high - end estimates of water concentrations which will not likely be exceeded. The residential handler and post - application exposure assessments are based upon the resid ential SOPs in conjunction with PHED unit exposures. The residential SOPs are based upon reasonable worst - case assumptions and are not expected to underestimate risk. TheseImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 15 of 45 assessments of exposure are not likel y to underestimate the resulting estimates o f risk from exposure to imidacloprid. **4.7 Toxicity Endpoint and Point of Departure Selections**  **4.7.1 Dose**  **- Response Assessment**  Table 4.7.4 summarizes the toxicological doses and endpoints selected for human - health risk assessment . Acute Dietary Endpoint ( all populations) : The acute endpoint for all populations (including females of childbearing age) was based on decreased motor and locomotor activity in females in the rat acute neurotoxicity s tudy at the LOAEL of 42 mg/kg/day . An FQPA SF of 3X was retained in the form of a database uncertainty factor (UF) for lack of a NOAEL . The database UF of 3X was judged as adequate (as opposed to 10X) because the effect (decreased motor and locomotor activity) shows a good dose response with minimal change as compared to the control group at the LOAEL of 42 mg/kg/day , and statistical significance was onl y achieved at the next higher dose of 151 mg/kg/day . Furthermore, the LOAEL of 42 mg/kg/day is comparable to the LOAEL of 55 mg/kg/day for offspring effect s (which includes decreased motor activity) in the rat DNT study, and the extrapolated NOAEL of 14 mg/kg/day (42/3 = 14) is comparable to and more protective than the NOAEL of 20 mg/kg/day established in the DNT for offspring effects. The standard combine d UF of 100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation. Thus, the acute reference dose (aRfD) and aPAD are e quivalent at 0.14 mg/kg/day since the FQPA SF is in the form of a database uncertainty (lack of NOAEL) rather than increased susceptibility in the young. Chronic Dietary (all populations ) : This endpoint was based on the increased incidence of mineralized particles in thy roid coll oids in male rats at the LOAEL of 16.9 mg/kg/day (NOAEL = 5.7 mg/kg/day) in a combined chronic toxicity /carcinogenicity

rat study . The standard combined UF of 100X was applied to account for interspecies (10X) and intraspecies (10X) extrapolation. The FQ PA SF was not retained for this exposure scenario since the toxicology database is adequate and there were no residual uncertainties for pre - and or post - natal susceptibility . Thus, the chronic reference dose (cRfD) and cPAD are equivalent at 0.057 mg/kg/d ay . Incidental Oral [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : This endpoint was based on decreased maternal body- weight gain observed in the rat prenatal developmental toxicity s tudy at the LOAELof 30 mg/kg/day (NOAEL= 10 mg/kg/day). The NOAEL of 30 mg/kg/day is comparable to the e xtrapolated NOAELof 14 mg/kg/day from the rat ACN study also evaluated for this endpoint. An MOE of 100 based on interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. Incidental Oral [long- term (>6 months) ] : This endpoint was based on the increased incidence of mineralized particles in thy roid colloids in male rats at the LOAEL of 16.9 mg/kg/day (NOAEL = 5.7 mg/kg/day) in a combined chronic toxicity /carcinogenicity

rat stu dy . The standard combined UF of 100x was applied to account for interspecies (10X) and intraspecies (10X) extrapolation. The FQPA SF was not retained for this exposure scenario since the toxicologyImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 16 of 45 database is complete and there were no residual uncertainties for pre - and or post - natal susceptibility . Dermal [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : This endpoint was based on decreased maternal body - weight gain observed in the rat prenatal developmental toxicity study at the L OAEL of 30 m g/kg/day (NOAEL = 10 mg/kg/day). This point of departure (POD) is higher than the LOAEL of 100 mg/kg/day (NOAEL = 30 mg/kg/day) for developmental effects based on an increase incidence of wav y ribs. Although a 21 - day rabbit dermal toxicity

study was performed and no toxic effects were observed, such studies are based on non - pregnant adult animals and do not account for potential developmental effects. A DAF of 7.2% has been previously estimated based on the ratio of the LOAELof 72 mg/kg/day from a rabb it developmental toxicity study and the NOAEL of 1000 mg/kg/day from a dermal specific toxicity

study in rabbits. An MOE of 100 based on interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. Dermal [long (>6 months) - term ] : Because of the duration of this exposure scenario, this endpoint was based on the chronic toxicity /carcinogenicity

study in rats. As noted above, the effects consisted of an increased incidence of mineralized particles in thyro id colloids (postulated reservoirs in the th yroid gland for production and storage of thyroid hormones) in male rats at the LOAEL of 16.9 mg/kg/day (NOAEL = 5.7 mg/kg/day). A DAF of 7.2% was previousl y estimated for imidacloprid ( Memo, G. Kramer et al. , 16 - MAR - 2009; D375406 ) yie lding a dermal - equivalent dose (DED) of ≈ 81 mg/kg/day . An MOE of 100 which includes interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. Inhalation [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : This endpoint was based on decreased maternal body- weight gain observed in the rat prenatal developmental toxicity s tudy at the LOAEL of 30 mg/kg/day (NOAEL = 10 mg/kg/day). This POD is higher than the offspring LOAEL of 100 mg/kg/day (NOAEL = 30 mg/kg/day) based on an increase incidence of wav y ribs. Although a 4 - week rat inhalation toxicity study was performed and no toxic effects were observed (no L OAEL identified), such studies are based on non - pregnant adult animals and do not account for potential developmental effects. 100% absorption is being assumed via this route of exposure. An MOE of 100 based on interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. Inhalation [long (>6 months) - term ] : Because of the duration of this exp osure scenario, this endpoint was based on the chronic toxicity /carcinogenicity

study in rats. As noted above, the effects consisted of an increased incidence of mineralized particles in thyro id colloids (postulated reservoirs in the th yroid gland for pro duction and storage of th yroid hormones) in male rats at the LOAEL of 16.9 mg/kg/day (NOAEL = 5.7 mg/kg/day). An MOE of 100 which includes interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. **4.7.2 Recommendation for**  **Combining Routes of Exposure for Risk Assessment** When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources, oral, dermal and inhalation, and determine whether the in dividual exposures can be combined if they have the same toxicological effects. For short - and intermediate - exposure, dermal and inhalation exposures can be combinedImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 17 of 45 because the same endpoint (maternal body weight gain deficits) is being used. Similarly , for long - term exposures, oral, dermal and inhalation endpoints can be combined because of the use of the same endpoint (th yroid toxicity ) from the rat chronic toxicity study . **4.7.3 Cancer Classification**  Imidacloprid has been classified as a Group E chemi cal, “Evidence of non - carcinogenicity for humans,” b y the HED RfD/Peer Review Committee (11/10/93). **4.7.4 Summary of Points of Departure and Toxicity Endpoints Used In Human**  **- Health**  **Risk Assessment Table 4.7.4. Im** **idacloprid: Summary of Toxicological Endp oints and Points of Departure for Residential Human**  **- Health**  **Risk Assessment. Exposure**  **Scenario Dose Used in Risk** 

**Assess me**  **nt, SFs RfD, LOC for Risk**  **Assess me**  **nt Study and Toxicological Effects**  Acute Dietary (all populations) LOAEL = 42 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 3X aRfD = aPAD = 0.14 mg/kg Acute neurotoxicity

– rat LOAEL = 42 mg/kg/day , based upon the decrease in motor and locomotor activities observed in females. Chronic Dietary (All populations) NOAEL = 5.7 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X cRfD = cPAD = 0.057 mg/kg/day Combined chronic toxicity/carcinogenicity

– rat LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized particles in thyroid colloid in males. Incidental Oral [Short- (1 - 30 days) & Intermediate (1 - 6 months) terms] NOAEL = 10 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X LOC for MOE = 100 Prenatal developmental toxicity

– rat LOAEL = 30 mg/kg/day based on decreased maternal body weight gain. Incidental Oral [Long - Term (> 6 months)] NOAEL = 5.7 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X LOC for MOE = 100 Combined chronic toxicity/carcinogenicity

– rat LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized particles in thyroid colloid in males. Dermal [Short- (1 - 30 days) & Intermediate (1 - 6 months) terms] NOAEL = 10 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X DAF = 7.2% LOC for MOE = 100 Prenatal developmental toxicity

– rat LOAEL = 30 mg/kg/day based on decreased maternal body weight gain Dermal [Long - Term (> 6 months)] NOAEL = 5.7 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X (DAF = 7.2%) LOC for MOE = 100 Combined chronic toxicity/carcinogenicity

– rat LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized particles in thyroid colloid in males. Inhalation [Short- (1 - 30 days) & Intermediate (1 - 6 months) terms] NOAEL = 10 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X (Assumed 100% absorption) LOC for MOE = 100 Prenatal developmental toxicity

– rat LOAEL = 30 mg/kg/day based on decreased maternal body weight gain Long - Term Inhalation (>6 months) NOAEL = 5.7 mg/kg/day

UF A = 10X UF H = 10X FQPA SF = 1X (Assumed 100% absorption) LOC for MOE = 100 Combined chronic toxicity/carcinogenicity

– rat LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineraliz ed particles in thyroid colloid in males.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 18 of 45 **Table 4.7.4. Im idacloprid: Summary of Toxicological Endp**  **oints and Points of Departure for Residential Human -**  **Health Risk Assessment.**  **Exposure Scenario**  **Dose Used in Risk**

**Assess me**  **nt, SFs RfD, LOC for Risk**  **Assess me**  **nt Study and Toxicological Effects**  Cancer (oral, dermal, inhalation) Classified as Group E, “Evidence of non - carcinogenicity for humans.” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed - adverse - effect level. LOAEL = lowest - observed - adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  The residue chemistry

data submitted in support of the proposed Section 3 use on oy ster beds were reviewed b y HED in a memo dated 7 - MAR - 201 2 (Memo , J. Tyler; D400189) . The EDWCs were provided by EFED (Memo, J. Melendez; 22 - JULY - 2009 ). The acute and chronic dietary exposure assessment was comple ted in a HED memorandum dated 7 - MAR - 2012 (Memo , J. Tyler; D 400187 ). **5.1 Residues of Concern Summary and**  **Rationale** Data concerning the metabolism of imidacloprid in apples, potatoes, tomatoes, eggplant, cottonseed, field corn, tobacco, ruminants, and poultry have been submitted and reviewed (Memos, F. Griffith, 20 - SEP - 1993 , D185148; 8 - JUN - 1994 , D200233; and 29 - FEB - 1996 , D217632). The results of the aforementioned plant and livestock metabolism studies were presented to the HED Metabolism Assessment Rev iew Committee (MARC) in 1993 (Memo, F. Griffith, 25 - JUN - 1993 , TXR#: 0050886). The nature of imidacloprid r esidues in plants and livestock is adequatel y understood. The residue of concern in plants and livestock is imidacloprid and its metabolites containing the 6 - chloropy ridinyl moiety, all expressed as the parent, as specified in 40 CFR §180.472. Ina meeti ng on 18 - DEC - 2002 , the HED MAR C recommended that for surface water risk assessment, degradates of concern should be parent and the three degradates: imidacloprid urea, imidacloprid guanidine, and imidacloprid olefin (Memo, J. Tyler, 13 - JAN - 2003 ; D28740 0 ). **5.2 Food Residue Profile**  **PP# 2E7988** : No magnitude of the residue in fish or nature of the residue in fish studies were submitted in support of the proposed use on oy ster beds . However, the registrant recentl y submitted a waiver request for both studies. The request was presented to the HED Science Advisory Council for Chemistry

(ChemSAC) on 23 - FEB - 2011, and the ChemSAC agreed with the rationale for the waiver (ChemSAC Minutes). Therefore, data demonstrating the magnitude of the residue or nature of the residue in fish are not necessary to support the proposed use on oy ster beds. The ChemSAC determined that the proposed tolerance for residues of imidacloprid and its metabolites containing the 6 - chlorop yridinyl moiety, all expressed as the parent , in/on fish at 0.05 ppm is appropriate. The submitted magnitude of the residue study in oysters was conducted in accordance with OPPTS Guideline 860.1400, and the data are adequate to support the proposed use. TotalImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 19 of 45 residues of imidacloprid were less th an limit of quantitation [L OQ, defined as the lowest level of method validation, LLMV (0.05 ppm)] in/on oyster meat harvested 26 - 86 day s following either a single application of Mallot ® 0.5G at an application rate of 0.50 lb ai/A; or Mallot 2F ® at an appli cation rate of 2.0 lb ai/A. Samples were analyzed for total imidacloprid residues using an acceptable method, and the study is supported b y adequate storage stability data. For o ys ters, the Organization for Economic Co - operation and Development (OECD) to lerance - calculation procedures could not be used to calculate a possible tolerance as residues of imidacloprid were <LOQ in/on all samples of oy ster meat. Therefore, the tolerance of 0.05 ppm for fish - shellfish, mollusc is appropriate. **PP# 12LA11**  : No res idue chemistry data were submitted in support of the proposed Section 18 Emergency

Exemption request for the use of imidacloprid on sugarcane in LA. In connection with this Section 18, time - limited tolerances should be established at 6.0 ppm in or on sugarcane, cane and at 50 ppm for sugarcane, molass es. The re commended tolerance level of 6.0 ppm for sugarcane , cane is based on the established tolerance level for leaf petioles, subgroup 4B (Memo, Y. Donovan, 23 - MAR - 1999 ; D242320). According to current im idacloprid labels, soil - directed application may be made to leaf petioles, subgroup 4B at a maximum application rate of 0.38 lb ai/A, and a minimum PHIof 45 day s. The results of previousl y submitted celery crop field trial study indicate that the highest residue level of imidacloprid on treated celery is 5.62 ppm following a single soil sidedress application at a rate of 0.5 lb ai/A. In addition, the results of a previousl y submitted sugarbeet processing study indicate that total residues of imidacloprid do not concentrate in sugar (0.025 X ) , but do concentrate in molas ses (8. 3X ) (Memo, F. Griffith, 16 - MAY - 1995 ; D212683). Therefore, a tolerance of 50 ppm (6. 0 - ppm tolerance x 8.3) is necessary f or sugarcane, molasses. A separate tolerance for sugar is not needed; however, a reduction factor of 0.025X was applied to sugarcane, sugar (6.0 ppm x 0.025 = 0.15 ppm) in the acute and chronic dietary exposure assessment. **5.3 Water Residue Profile**  EFED provided Tier 1 EDWCs for surface water (using FIRST) and groundwater (using SCI GROW) for imidacloprid and its degradates (imidacloprid urea, imidacloprid guanidine, and imidacloprid olefin). EDWCs were not provided for the proposed o ys ter bed use as EF ED does not expect any

impacts on drinking water from this particular use (personal communication between M. Barrett and C. Smith, 1 -NOV - 2012). Therefore, the EDWCs provided in 2009 were incorporated used in this risk assessment. The EDWCs in the 2009 me mo were calculated based on a maximum application rate of 0.5 lb ai/A/season. The acute and chronic EDWCs in surface water are 36.0 ppb and 17.2 ppb of imidacloprid, based on applications of the chemical to citrus. The SCI - GROW generated groundwater EDWC is 2.09 ppb of imidacloprid. **Table 5.3. Estim ated Tier 1 EDWCs of Imidacloprid in Drinking Water.**  **Drinking Water Source (Model Used) Use (Rate m**  **odeled) EDWC (ppb)**  Groundwater (SCI - GROW) Citrus (0.5 lb ai/A) Ac ute and Chronic 2.09 Surface water (FIRST Ac ute 36.0 Chronic 17.2Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 20 of 45 **5.4 Dietary Risk Assessment**  Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the DEEM - FCID (Ver. 3.16), which uses food consumption data from the USDA’s NHANES/WWEIA. This dietary survey was conducted from 2003 to 2008. **5. 4.1**  **Description of Residue and Percent Crop Treated Data Used in Dietary Assessment**  The acute dietary

exposure assessment was unrefined, using tolerance - level residues and assuming 100% CT for all registered and proposed commodities. The chronic dietary exposure assessment was partially

refined using tolerance - level residues for all registered and proposed commodities, and % CT information for some commodities. Exposure to drinking water was incorporated directl y in the acute and chronic dietary assessments using the acute (peak) and chronic (annual average) concentrations for surface water generated b y the FIRST model, respectivel y. In a memo dated 2 - AUG - 2012, the BEAD provided updated estimated % CT information for several commodities ( Memo, J. Alsadek, D403995). For the chronic assessment, the following average weighted % CT information was used: almonds: <1 % ; apples: 30 % ; artichokes: 5 % ; avocados: <1 % ; beans, green: 5 % ; blueberries: 10 % ; broccoli: 55 % ; cabbage: 25%; caneberries: 10%; cantaloupe: 40%; carrots: <1%; cauliflower: 50%; celery : 10%; cherries: 15%; corn (seed treatment): <2.5%; cotton: 5%; cotton (seed treatment): 5%; cucumbers: 5%; dry beans/peas: <1%; eg gplant: 60%; filberts (hazelnuts): <2.5%; grapefruit: 25%; grapes: 30%; honeydew: 30%; lemons: 5%; lettuce: 65%; onions: <1%; oranges: 20%; peaches: 5%; peanuts: <1%; pears: 5%; peas, green: <2.5%; pecans: 15%; peppers: 15%; pistachios: <1%; potatoes: 35%; prunes: <1%; pumpkin: 10%; sorghum (seed treatment): 15%; soy beans (seed treatment): 5%; spinach: 20%; squash: 15%; strawberries: 10%; sugar beets: <2.5%; sweet corn: <1%; tangerines: 10%; tobacco: 25%; tomatoes: 25%; walnuts: 5%; watermelon: 20%; wheat ( seed treatment): 10%. **5.4.2 Acute Dietary Risk Assessment**  An unrefined (using tolerance - level residues and assuming 100% CT for all registered and proposed commodities) acute dietary exposure assessment was conducted for the general U.S. population and various population subgroups. This assessment indicates that the acute dietary exposure estimates are below HED’s LOC , <100% aPAD, at the 95 th exposure percentile for the general U.S. population and all other population subgroups. The acute dietary exposure is estimated for the U.S. population at 28 % of the aPAD and the most highl y exposed population subgroup, children 1 - 2 years old, at 74% of the aPAD. The acute assessment was highly conservative, using several upper - end assumptions. Ad ditional refinements, such as inclusion of anticipated residues (ARs ) and %CT data could be made in order to refine the acute assessment. However, HED is confident that the assessment does not underestimate risk to the general U.S. population or any population subgroup. **5.4.3 Chronic Dietary Risk Assessment**  A partially

refined (using tolerance - level residues for all registered and proposed commodities and %CT data for some commodities) chronic dietary exposure assessment was conducted for the general U.S. population and various population subgroups. This assessment concludes thatImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 21 of 45 the chronic dietary

exposure estimates are below HED’s LOC (<100% cPAD) for the general U.S. population and all population subgroups. The chronic dietary exposure is estim ated for the U.S. population at 8.3 % of the cPAD and the most highly exposed population subgroup, children 1 - 2 years old, at 28% of the cPAD . Additional refinements, such as inclusion of ARs and % market - share data for the proposed uses could be made in o rder to refine the chronic assessment. However, HED is confident that the assessment does not underestimate risk to the general U.S. population or any

population subgroup. **5.4.4 Summary Table**  **Table 5.4.4 . Summary of Dietary**  **(Food and Drinking Water) Ex** **posure and Risk for Imidacloprid. Population Subgroup**  **Acute Dietary (95 th**  **Percentile) Chronic Dietary**  **Dietary Exposure (m**  **g/kg/day) % aPAD**  **Dietary Exposure (m**  **g/kg/day) % cPAD**  General U.S. Population 0.038591 28 0.004707 8.3 All Infants (<1 year old) 0.080374 57 0.007691 13 **Children 1 -**  **2 years old** 0.103801 74 ***** 0.016205 28 ***** Children 3 - 5 years old 0.081638 58 0.011274 20 Children 6 - 12 years old 0.044966 32 0.006225 11 Youth 13 - 19 years old 0.026992 19 0.003594 6.3 Adults 20 - 49 years old 0.025911 18 0.003754 6.6 Adults 50 - 99 years old 0.025662 18 0.003812 6.7 Females 13 - 49 years old 0.025875 18 0.003725 6.5 *The subpopulation(s) with the highest risk estimates. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  The proposed use of imidacloprid on oy ster beds in Washington State’s Willapa Bay and Gray s Harbor is not expected to result in residential handler exposure (professionally applied), but can result in residential post - application exposures via potential contact with residues in the oy ster bed water or sediment during recreational swimming, or in the case of subsistence fishermen or local Native American tribes, collecting o ys ters. These scenarios are consistent with the human health risk assessment for an identical use pattern

– applications of carbaryl to control burrowing shrimp in Willapa Bay

and Gray s Harbor ( Memo, J. Dawson, 14 - MAR - 2003: D287532 ). There are no residential uses associated with the proposed Section 18 Emerg ency Exemption use on sugarcane. For the purposes of evaluating aggregate (dietary and non - dietary) exposure for th e proposed use s , imidacloprid has a variety of existing residential uses that should be considered, including residential lawns and gardens, indoor uses for bed bugs and crack - and - crev ice treatments, pet uses (spot - on treatment and collars), and pre - and post - construction termiticide and wood preservative uses. Short - term dermal and inhalation handler exposures are expected. Generall y, short - term dermal, inhalation, and incidental oral post - application exposures are expected, with the exception of intermediate - and long - term exposures from the pet collar use, as it presents the potential for prolonged exposure via a continuous source and frequent contact (i.e., playing with pets). Ris ks from these uses have been re - evaluated to reflect updates to HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ) along with policy

changes for body

weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for imidacloprid.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 22 of 45 The registered and proposed residential uses were evaluated by HED and reviewed by

the HED Science Advisory

Council for Exp osure (ExpoSAC; Memo, M. Crowley , 6 - MAR - 2012, D400191). **6.1 Residential Handler Exposure**  **and Risk Estimates** HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. As the new use is expected to be professionall y applied, residential handler exposure is not expected. For exposure to professional applicators as a result of the new use, see Section 9.1. Unlike the proposed use s , however, existing residential uses, considered for the purposes of the aggregate risk assessment, are expected to result in residential handler exposure. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED than occupational pesticide applicators as homeowners are assumed to complete all elements of an application without use of any protective equipment. Risks from these uses have been estimated in past human - health risk assessments; however, have been re - evaluated to reflect updates to HED’s 2012 Residential SOPs and policy changes for body weight assumptions. The quantitative exposure/risk assessment developed for residential handlers for exist ing imidacloprid uses is based on the following scenarios:

 Mixing/loading/appl yi ng liquid formulations for use with manually- pressurized handwands in indoor settings (bed - bug treatments and crack - and - crevice treatments);  Mixing/loading/appl yi ng liquid f ormulations for use with hose - end sprayers on lawns and gardens;  Mixing/loading/appl yi ng liquid formulations for use with a bucket or watering can to treat plant stems and tree trunks;  Applications to gardens using a ready- to - use (RTU) trigger - spray bottle ;  Loading/appl yi ng granule formulations to lawns and gardens using a push - ty pe/rotary spreader;  Applications of potting spikes and potting mediums to garden plants; and,  Applications of spot - on treatments and collars to pets. HED expects the duration of e xposure for residential handlers to be short - term (1 - 30 day s) in duration. Assessing exposures and risks resulting from residential uses is very similar to assessing occupational exposures and risks, except that a tiered approach for personal protection u sing increasing levels of personal - protective equipment ( PPE ) is not used in residential handler risk assessments. Homeowner handler assessments are based on the assumption that individuals are wearing shorts, short - sleeved shirts, socks, and shoes. Tabl e 6.1 below provides a summary of residential handler risk estimates from existing residential uses of imidacloprid, updated u sing the 2012 Residential SOPs and policy changes for body weigh assumptions . Short - term risk estimates for residential handlers are not of concern (MOEs >100).Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 23 of 45 **Table 6.1. Residential Handler Non -**  **cancer Exposure and Risk Estimates for Existing Residential Uses of Imidacloprid.**  **Exposure Scenario MOE Level**  **of Concern Dermal Unit** 

**Exposure (m**  **g/lb ai) Inhalation** 

**Unit Exposure**  **(m g/lb ai)**  **Ma xim**  **um**

**Application Rate**  **1 Area Treated or** 

**Am ount**  **Handled Daily 2**  **Dermal Inhalation**  **Total**

**Dose (m**  **g/k g/day)**  **3 MOE**  **4 Dose**  **(m g/k** **g/day) 5**  **MOE 6**  **MOE 7**  Indoors (bed bug and crack- and crevice treatments) 100 69 1.1 0.008 lb ai/gallon 0.5 gallons 0.00025 40,000 5.5E - 05 180,000 33,000

Gardens /Trees Hose - end

sprayer 100 58 0.0014 0.5 lb ai/acre 1200 ft2 0.00072 14,000 2.4E - 07 41,000,000 14,000 Watering can 100 58 0.0014 0.25 lb ai/gallon 1 gallon 0.013 770 4.4E - 06 2,300,000 770 Potting medium 100 160 0.38 0.00288 lb ai/container 1 container 0.00041 24,000 1.4E - 05 730,000 23,000 Potting spikes 100 160 0.38 0.00011 lb ai/spike 10 spikes 0.00016 63,000 5.2E - 06 1,900,000 61,000 Trigger spray bottle 100 85.1 0.061 0.000189 lb ai/bottle 2 bottles 0.000029 350,000 2.9E - 07 35,000,000 340,000 Rotary spreader 100 0.81 0.0026 0.4 lb ai/acre 1200 ft2 0.000008 1,200,000 3.6E - 07 28,000,000 1,200,000 Pets Spot - on 100 120 Negligible 0.001 lb ai/pet 2 pets 0.00022 46,000 NA NA NA

Collar 100 120 Negligible 0.0099 lb ai/pet 2 pets 0.0 0 21 4,700 NA NA NA Lawns /Turf Hose - end

sprayer 100 13.4 0.022 0.5 lb ai/acre 0.5 acres 0.003 3,300 6.9E - 05 150,000 3,200 Rotary spreader 100 0.81 0.0026 0.4 lb ai/acre 0.5 acres 0.00015 69,000 6.5E - 06 1,500,000 66,000 1 See Table 4.2 for assessment reference. 2 Based on 2012 Residential SOPs. Departures from the SOP include the gardens/trees: watering - can scenario (per label, 1 gallon of solution treats 20 trees), the potting - medium scenario (per label, 1 container = 20 lbs), and the potting - spike scenario (10 spikes considered a reasonable use estimate). 3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or g allons/day) x DAF (%) / BW (kg). 4 Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal D ose (mg/kg/day). 5 Inhalation Dose = I

nhalation Unit Exposure (mg/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (kg). 6 Inhalation MOE = I

nhalation NOAEL (mg/kg/day) / I nhalation Dose (mg/kg/day). 7 Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + I nhalation Dose) **OR** Total MOE = 1 / [(1/Dermal MOE) + (1/I nhalation MOE)] .Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 24 of 45 **6.2 Post**  **- Application Exposure**  **and Risk Estimates** As a result of both the proposed use on o ys ter beds and from existing residential uses, there is the potential for post - application exposure for individuals exposed as a result of being in an environment that has been previously treate d with imidacloprid. Based on the proposed use pattern, onl y short - term post - application dermal, incidental oral, and inhalation exposures to imidacloprid residues in oyster bed water and sediment are expected . This assessment mimics those scenarios revi ewed for an identical use pattern for the ai carbaryl (Memo, J. Dawson, 14 - MAR - 2003; D287532). The equations and inputs are generally derived from SWIMODEL 3.0, developed b y EPA as a screening tool to conduct exposure assessments of pesticides found in sw imming pools and spas and EPA’s Risk Assessment Guidance for Superfund

– Part E, Supplemental Guidance for Dermal Risk Assessment (“RAGS - E”). For the registered residential uses , in general, short - term dermal, inhalation, and incidental oral post - application exposures are expected. Intermediate - and long - term dermal, incidental oral and inhalation exposures are expected from the pet collar use, as it presents the potential for prolonged exposure via a continuous source and frequent contact (i.e., playing with pets). These risks were estimated in previous assessments (listed below, where applicable) but have been re evaluated here using the updated 2012 Residential SOPs and policy changes for body

weight assumptions. The quantitative exposure/risk assess ment for residential post - application exposure is based on the following scenarios:

 As a result of the proposed use to control burrowing shrimp in Washington State’s Willapa Bay

and Gray s Harbor intertidal o ys ter beds: o In gestion of water during recreation al swimming (both adults and children 3<6 ye ars old); o Dermal exposure during recreational swimming (both adults and children 3<6 ye ars old); o Dermal exposure to o ys ter bed sediment while collecting/harvesting o ys ters (adults) and playing (children 3<6 ye ars old); o Inhalation exposure during recreational swimming and/or collecting/harvesting oy sters (both adults and children 3<6 years old); and, o In cidental ingestion of sediment via hand - to - mouth activities (children 3<6 years old only).

 As a result of existin g residential uses: o Dermal exposure from contact with treated turf (both adults and children 11<16, 6<11, and 1<2 ye ars old)

– updated from most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR - 2009; D375406); o Dermal exposure from contact with treated gardens and trees (adults and children 6<11 years old)

– updated from most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR - 2009; D375406);Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 25 of 45 o Dermal exposure from contact with treated mattresses (bed - bug treatm ents) and indoor surfaces (both adults and children 1<2 ye ars old)

– updated from most recent risk assessment (Memo, K. L owe, 17 - FEB - 2009; D367396); o Dermal exposure from contact with treated pets (both adults and children 1< 2 ye ars old)

– updated from most recent risk assessments (Memos, G. Kramer et al. , 16 - MAR - 2009, D375406 (spot - on); K. Lowe, 17 - FEB - 2009; D367396 (collar)); o Dermal exposure from contact with treated wood (both adults and children 1<2 ye ars old)

– updated from most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR - 2009; D375406); o Inhalation exposure following mattress treatments and indoor crack- and - crevice treatments (both adults and children 1<2 ye ars old)

– updated from most recent risk assessment (Me mo, K. L owe, 17 - FEB - 2009; D367396); o In cidental ingestion from contact with treated turf (children 1<2 ye ars old only)

– updated from most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR 2009; D375406 ); o In cidental ingestion from contact with treated indoor surfaces (children 1<2 years old only)

– updated from most recent risk assessment (Memo, K. Lowe, 17 - FEB 2009; D367396); o In cidental ingestion from contact with treated pets (children 1<2 ye ars old only)

– updated from most recent risk assessments (M emos, G. Kramer et al. , 16 - MAR 2009, D375406 (spot - on); K. L owe, 17 - FEB - 2009; D367396 (collar)); and, o In cidental ingestion from contact with treated wood (children 1<2 ye ars old only)

– updated from most recent risk assessment (Memo, G. Kramer et al. , 16 - MAR 2009; D375406 ). The lifestages (e.g., adults, children 1<2 ye ars old, etc.) selected for each post - application scenario as a result of the registered uses are based on an anal ys is provided as Appendix A in the 2012 Residential SOPs. The lifestages (ad ults and children 3<6 years old) selected for the post application scenarios as a result of the proposed o yster bed use are based on the expected potential for individuals to be in oy ster beds and the activities they will conduct. In the case of Native Am erican tribes and subsistence fishermen, it could be the case that families participate in these activities; thus, young children are considered as well. These lifestages are not the onl y lifestages that could be potentially exposed for these post - application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially

exposed lifestages. Table 6.2.1 below provides a summary of residential post - application risk estimates from th e proposed use of imidacloprid on oy ster beds. Table 6.2.2 below provides a summary of residential post - application risk estimates from existing residential uses of imidacloprid, updated using the 2012 Residential SOPs and policy changes for body

weight a ssumptions.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 26 of 45 **Table 6.2.1. Residential Post**  **- application Non**  **- cancer Exposure and Risk Estimates from** **the Proposed Use of Imidacloprid to Control Burrowing Shrim** **p. 1**  **Use/Target Lifestage**  **Post -**  **application Exposure**

**Scenario Dose**  **(m g/k** **g -**  **day) MOE**  **Combined Routes**  **(X indicates included in Combined MOE)**  **Combined MOE** WA State Willapa Bay and Grays Harbor Intertidal Oy ster Beds Adult Dermal (water) Swimming 5.6E - 06 1,800,000 X 59,000

Dermal (sediment) Oy ster

Harvesting 1.2E - 04 85,000 X Ingestion (water) 4.5E - 05 220,000 X Inhalation 3.7E - 09 2,700,000,000 X Children 3<6 years Dermal (water) Swimming 7.3E - 06 1,400,000 X 2,600

Dermal (sediment) Playing in

oyster bed 2.4E - 03 4,200 X Ingestion (water) 3.5E - 04 28,000 X Hand to Mouth (sediment) 1.1E - 03 8,800 X Inhalation 8.2E - 09 1,200,000,000 X 1 All MOEs represent short - term risk estimates. Intermediate - and long - term exposures are not expected from this use. **Table 6**  **.2.2 .**  **Residential Post -**  **application Non**  **- cancer**  **Exposure and Risk Estimates for Existing Residential**  **Uses of Imidacloprid .**  **1** Use/Target Lifestage Post - application Exposure Scenario Dose (mg/kg - day) MOE 5 Combined Routes (X indicates included in Combined MOE) Combined

MOE

Turf (spray application) 2 Adult Dermal High - contact (playing) 0.014 740 -- NA Mowing 0.00026 36,000 -- Golfing 0.0011 9,400 -- Child 11<16 Dermal Mowing 0.00032 32,000 -- NA

Golfing 0.0012 8,100 -- Child 6<11 Dermal Golfing 0.0015 6,900 -- NA Child 1<2 Dermal (high - contact

play) 0.027 370 X 290 Hand to Mouth 0.0076 1,300 X Object to Mouth 0.00023 43,000 -- Incidental Soil Ingestion 1.7E - 05 590,000 -- Gardens/ Trees (spray application) 2 Adult Dermal 0.023 430 -- NA

Child 6<11 Dermal 0.016 630 -- NA

Indoor Bed bug (mattress) Adult Dermal 0.00059 17,000 -- NA

Child 1<2 Dermal 0.0013 7,400 -- NA Crack- and crevice Adult Dermal (playing on carpet) 3 0.00088 11,000 X 6,200 Inhalation 0.0007 14,000 X Child 1<2 Dermal (playing on

carpet) 3 0.00085 12,000 X 1,800 Inhalation 0.003 3,400 X Hand to Mouth (playing on carpet) 3 0.0018 5,700 XImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 27 of 45 **Table 6.2.2.**  **Residential Post -**  **application Non**  **- cancer**  **Exposure and Risk Estimates for Existing Residential**  **Uses of Imidacloprid. 1**  Use/Target Lifestage Post - application Exposure Scenario Dose

(mg/kg - day) MOE 5 Combined Routes (X indicates included in Combined MOE) Combined

MOE

Pets Spot - on Adult Dermal (playing with small cat) 4 0.0055 1,800 -- NA Child 1<2 Dermal

(playing with small cat) 0.0139 720 X 630 Hand to Mouth (playing with small cat) 4 0.0019 5,200 X

Collar Adult ST/IT Dermal (playing with small cat) 4 0.0028 3600 -- NA LT Dermal (playing with small cat) 4 0.0028 2000 -- NA

Child 1<2 ST/IT Dermal

(playing with small cat) 4 0.0071 1,400 X 1,200 Hand to Mouth (playing with small cat) 4 0.00098 10,000 X

LT Dermal (playing with small cat) 4 0.0071 800 X 700 Hand to Mouth (playing with small cat) 4 0.00098 5,800 X Wood Preservative / Termiticide Adult Dermal (playing on deck) 0.0184 540 -- NA Child 1<2 Dermal

(playing on deck) 0.042 240 X 140 Hand to Mouth (playing on deck) 0.028 360 X 1 See Appendix A for calculations and inputs. 2 Risk estimates presented only in this table for spray applications, as risks from uses of granule formulations are lower. 3 Risk estimates presented only in this table from contacting treated carpets, as risks from contacting other surfaces are lower. 4 Risk estimates presented only in this table from contacting small cats, as risks from other treated pets are lower. 5 MOEs are for short - term exposures only except for the pet collar which presents risks for short - /intermediate - term (ST/IT) and long - term (L T) exposures. **6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)**  Because of the potential likelihood for some uses to occur on the same day or over the same exposure duration, risks from some imidacloprid residential uses are combined to determine whether their co - occurrence presents a risk of concern. Residential handler and post - application scenarios are generally

not combined. Although there is potential for the same individual (i.e., adult) to apply

a pesticide in and around the home and be exposed by reentering a treated area in the same day , this is an unlikely exposure scenario, especiall y day after day for up to 30 day s. Combining both of these exposure scenarios would also be inappropriate because of the conservative nature of each individual assessment. There may

be post - application residential exposure scenarios for a particular pesticide which could be combined for purposes of an aggregate exposure assessment. For imidacloprid, theImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 28 of 45 outdoor treatments of lawns and gardens have a reasonable probability of co - occurring as do the indoor bed - bug and crack - and - crevice treatments. The likelihood of any of the existing residential uses to co - occur with exposures from the proposed oy ster bed use is low, thus risk estimates are no t presented. Table 6.3 presents combined risks for these scenarios, using a similar equation as shown in Section 6.2.1 and 6.2.2. **Table 6.3. Non**  **- Cancer Residential Combined (Multiple Exposure Scenarios) Exposure and Risk Estimates for**  **Im idacloprid.**  **Combined Exposure**  **Scenario Lifestage**  **Exposure Scenario Route of**  **Exposure Dose**  **Combined Total Dose**  **(m g/k** **g -**  **day) Combined Total** 

**MOEs** Outdoor Scenario (Turf/Garden) Adult Handler: Turf - Sprays Dermal 0.003 0.016 620 Inhalation 6.9E - 05 Handler: Garden - Sprays Dermal 0.013 Inhalation 4.4E - 06 Adult Post - application: Turf -

Sprays Dermal 0.014 0.037 270 Post - application: Garden

- Sprays Dermal 0.023

Bedbug Scenario Adult Post - application: Perimeter Dermal 0.00088 0.0022 4,500 Post - application: Mattress Dermal 0.00059 Post - application: Perimeter/Mattress Inhalation 0.0007 Child Post - application:

Perimeter Dermal 0.00085 0.0069 1,500

Hand to Mouth 0.0018 Post - application: Mattress Dermal 0.0013 Post - application: Perimeter/Mattress Inhalation 0.003 **6.4 Residential Risk Estimates for Use in Aggregate Assessment**  The residential scenarios listed below should be used for the aggregate (dietary + non - dietary) assessment. Table 6.4 presents the risk estimates.

 The recommended residential exposure for use in the short - term adult aggregate assessment reflects combined dermal post - application exposures from contacting treated lawns and gardens. For the long - term adult aggregate assessment, the recommended residential exposure scenario is contacting treated pets following applications of pet collars.  The recommended residential exposure for use in the short - term children 1<2 years old aggregate assessment reflects combined dermal and hand - to - mouth exposures from contacting treated wood surfaces (e.g., playing on decks). For the long - term children 1<2 ye ars old aggregate assessment, the recommended residential exposure scenario is contacting treated pets following application of pet collar s.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 29 of 45 **Table 6.4. Recommendations for the Residential Exposures for the Im idacloprid Aggregate Assessment.**  **1 Lifestage**  **Handler Exposure (mg/kg/day) 2**  **Residential Handler Total**  **Exposure (m**  **g/kg/day) 3**  **Residential**

**Handler Total MOE**  **Post -**  **application Exposure (m**  **g/kg/day) 4**  **Residential Post**  **- application**  **Total Exposure (m**  **g/kg/day) Residential** 

**Post**   ** application** **MOE 5**  **Derm al**  **Inhalation Derm**  **al Inhalation**  **Oral Short**  **- /Intermediate**  **- Ter**  **m** Adult 0.016 0.0001 0.016 620 0.037 N/A N/A 0.037 **270** Child 1<2 N/A N/A N/A N/A 0.042 N/A 0.028 0.07 **140 Long**  **- Term**  Adult N/A N/A N/A N/A 0.0028 N/A N/A 0.0028 **2,000** Child 1<2 N/A N/A N/A N/A 0.0071 N/A 0.00098 0.0081 **700** 1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 2 Handler exposure is the combined lawn and garden uses presented in Section 5.3

– this was the handler scenario with the highest exposures. 3 F or adults, r esidential total exposure combines the highest dermal and inhalation exposures (Table 5.1.1, 5.2.1, 5 .2.2, and 5.2.3), where applicable. For children, total residential exposure combines high - end post application incidental oral AND dermal exposure, where applicable (Table 5.2.1, 5.2.2, 5.3.1). 4 Total MOE = 1 / (1/Dermal MOE) + (1/Inhalation MOE). 5 Pos t - application exposure represents high - end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration. 6 Total MOE = 1 / (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental oral MOE).Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 30 of 45 **6.5 Residential Bystander**  **Post -**  **application Inhalation Exposure** Post - application inhalation exposure while swimming in intertidal oy ster beds was assessed for the proposed use of imidacloprid. However, b ys tander inhalation exposure was not assessed for the existing agricultural us es of imidacloprid. Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed at this time primarily because of the low acute inhalation toxicity (Toxicity Category I V) and low vapor pressure (4 x 10 - 7 mmHg). However, volatilization of pesticides may be a source of post application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - applicati on 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 the existing uses of imidacloprid. **6.6 Spray Dr**  **ift** 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, could also be a potential source of exposure from the ground application method employed for imidacloprid . 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). The Agency has completed its evaluation of the new database submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is dev eloping a policy on how to appropriatel y apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast , and ground h ydraulic methods. After the policy is in place, the Agency

may impose further refi nements in spray- drift - management practices to reduce off - target drift with specific products with significant risks associated with drift. Note that an ap plication rate of 0.5 lb ai/A was used in the updated assessment of the existing lawn/turf registration to estimate post - application residential exposure of children. As this rate is equal to or higher than the registered and proposed uses, the exposures resulting from direct application to lawns/turf are likel y protective of any exposure via spray drift from the proposed oy ster - bed use. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate pesticide 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 quantitativeImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 31 of 45 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. In the case of imidacloprid, aggregate risk assessments were performed for acute aggregate exposure (food + drinking water), short - term aggregate exposure (food + drinking water + residential), and chronic aggregate exposure (food + drinking water + residential ). Although there are intermediate - term residential exposures, an intermedi ate - term aggregate was not quantitatively assessed since (1) the short - and intermediate - term points of departure are the same and (2) the short - term aggregate represents worst - case residential exposures. For these reasons, the short - term aggregate is pro tective of the longer - term exposures. A cancer aggregate risk assessment was not performed because imidacloprid is not carcinogenic. All potential exposure pathway s were assessed in the aggregate risk assessment. **7.1 Acute Aggregate Risk**  The acute ag gregate risk assessment takes into account exposure estimates from dietary consumption of imidacloprid (food and drinking water). The dermal, inhalation, and incidental oral exposures resulting from short - term residential applications are assessed separat ely . The acute dietary

exposure estimates are below HED’s LOC (<100% aPAD) at the 95th exposure percentile for the general U.S. population (28% of the aPAD) and all other population subgroups (see Table 5.4.4 ). The most highly- exposed population subgroup is children 1 - 2 years old, at 74 % of the aPAD. Therefore, the acute aggregate risk associated with the proposed use of imidacloprid does not exceed HED’s LOC for the general U.S. population or any population subgroups. **7.2 Short**  **- Term Aggregate Risk**  The short - term aggregate risk assessment estimates risks likely to result from 1 - to 30 - day exposures to imidacloprid residues from food, drinking water, and residential pesticide uses. High - end estimates of residential exposure are used, and average values are used for food and drinking water exposures. Short - term aggregate risk assessments are necessary for both adults and children as there is potential for both short - term d ermal and inhalation handler exposure, and short - term post application exposure from the residential uses of imidacloprid. For the short - term aggregate risk assessment, potential residential post - application exposures were combined with food and drinking water exposures. F or adults, the combined dermal post - application exposures from contacting treated lawns and gardens resulted in the highest short - term expo sure (exposure = 0.037 mg/kg/day ; MOE = 270 see Table 6.4 ). For children, the combined dermal and hand - to - mouth expo sure from contacting treated wood surfaces resulted in the highest short - term exposure (exposure= 0.07 mg/kg/day , MOE = 140; see Table 6.4). Therefore, these short - term exposure estimates were aggregated with the chronic dietary

(food) to provide a worst - case estimate of short - term aggregate risk for the general U.S. population and children 1 - 2 years old (the child population subgroup with the highest estimated chronic dietary food exposure) (see Table 5.4.4 ). As the short - term aggregate MOEs are greater than 100, risks are not of concern.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 32 of 45 **Table 7.2. Short -**  **Term Aggregate Risk Calculations. Population**  **NOAEL**

**( mg** **/k g/day** **) LOC**  **1 Ma** **x Allowable**  **Exposure 2**  **( mg** **/k g/day** **) Average Food** 

**and Drinking**  **Water Exposure**  **( mg** **/k g/day** **) 3**  **Residential**

**Exposure (**  **mg /k** **g/day )**  **4 Total** 

**Exposure (**  **mg /k** **g/day )**  **5 Aggregate** 

**MOE (food, wa** **ter, and residential)**  **6** Adults 10 100 0.1 0.004707 0.037 0.041707 240 Children 1 - 2 years old 10 100 0.1 0.016205 0.07 0.086205 120 1 The level of concern (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation. 2 Maximum Exposure (mg/kg/day) = NOAEL/LOC. 3 Avg. Dietary Exposure. See Table 5.4.4 . 4 Residential Exposure = Dermal exposure for adults and Oral + Dermal exposure for children.. See Table 6.4. 5 Total exposure = Avg. Dietary Exposure + Residential Exposure. 6 Aggregate MOE = NOAEL ÷ Total Exposure. **7.3 Intermediate**  **- Term Aggregate Risk**  The intermediate - term aggregate risk assessment estimates risks likely to result from 30 day s to 6 months exposure to imidacloprid residues from food, drinking water, and residential pesticide uses. High - end estimates of residential exposure are used, and average values are used for food and drinking w ater exposures. Although there is potential for intermediate - term residential exposure from the registered pet collar use, an intermediate - term aggregate assessment is not required. The short - and intermediate - term toxicological endpoints are the same, and the exposures assessed in the short term aggregate (adults - combined dermal post - application exposures from contacting treated lawns and gardens; and children - combined dermal and hand - to - mouth from contacting treated wood surfaces) provide a worst - cas e estimate of short - term residential exposure. Therefore, the estimates of risk for short - term duration exposures are protective of those for intermediate - term duration exposures. **7.4 Chronic Aggregate Risk**  The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of imidacloprid (food and drinking water) and long - term residential uses. High - end estimates of residential exposure are used, and average values are used for food and drinking water exposures. Based on the proposed and existing use patterns, there is potential for long - term residential exposure from the pet - collar use, as it presents the potential for prolonged exposure via a continuous source and frequent contact (i.e., playing with pets). For adults, the dermal post application exposure from co ntacting treated pets resulted in a long - term exposure of 0.0028 mg/kg/day

(MOE = 2 ,000 ; see Table 6.4 ). For children, the combined dermal and hand - to mouth from contacting treated pets resulted in a combined long - term exposure of 0.0081 mg/kg/day

(MOE = 7 00 ; see Table 6.4 ). Therefore, these long - term exposure estimates were aggregated with the chronic dietary (food) to provide a worst - case estimate of chronic aggregate risk for the general U.S. p opulation and children 1 - 2 years old (the child population subgroup with the highest estimated chronic dietary food exposure) (see Table 7.4). As the chronic aggregate MOEs are greater than 100, risks are not of concern.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 33 of 45 **Table 7.4. Chronic Aggregate Ris k Calculations.**  **Population Chronic/Long**  **- Term Scenario** 

**NOAEL (**  **mg /k** **g/day )**  **LOC 1**  **Ma x**  **Allowable Exposure**  **2 (**  **mg /k** **g/day )**  **Average Food**

**and Drinking**  **Water Exposure**  **( mg** **/k g/day** **) 3**  **Residential**

**Exposure (**  **mg /k** **g/day )**  **4 Total** 

**Exposure (**  **mg /k** **g/day )**  **5 Aggregate** 

**MOE (food, wa** **ter, and residential)**  **6** Adults 5.7 100 0.057 0.004707 0.0028 0.007507 760 Children 1 - 2 years old 5.7 100 0.057 0.016205 0.0081 0.024305 230 1 The level of concern (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC. 3 Avg. Dietary Exposure. See Table 5.4.4 . 4 Residential Exposure = Dermal exposure for adults and Oral + Dermal exposure for children. See Table 6.4. 5 Total exposure = Avg. Dietary Exposure + Residential Exposure. 6 Aggregate MOE = NOAEL ÷ Total Exposure. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to imidacloprid and any other substances and imidacloprid does not appear to p roduce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that imidacloprid has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to deter mine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  Based on the proposed application scenario s and toxicological considerations, non - can cer occupational handler (dermal and inhalation) assessment s were conducted for the proposed uses on oy ster beds and sugarcane; and occupational post - application (dermal) assessments were conducted for the proposed sugarcane use. The proposed Section 3 us e on oy ster beds and Section 18 Emergency

Exemption use on sugarcane were evaluated by HED and were reviewed by the HED ExpoSAC ( Memo, M. Crowley , 6 - MAR - 2012, D400191 ; and J. Tyler, 7 - MAR 2012; D407182 ). **9.1 Handler**  **Exposure and Risk Estimates** HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner specific to each application event.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 34 of 45 Based on the anticipated use patterns, potential occupational handler exposure scenarios include:

 As a result of the proposed Section 3 use on o ys ter beds: o Mixing/loading the liquid formulation to support aerial and groundboom applications; o Mixing/loading the granule formulation to support aerial and tractor - drawn spreader applications; o Applications of the granule and diluted liquid formulation using aerial equipment; o Applications of the diluted liquid formulation with groundboom sprayers; o Ap plications of the granule formulation using tractor - drawn spreaders; o Flagging for aerial applications of the granule and diluted liquid formulation; o Mixing/loading/appl yi ng the liquid formulation with a backpack sprayer; and, o Loading/appl yi ng the granule f ormulation with a belly

grinder or rotary

spreader.

 As a result of use on the proposed Section 18 Emergency Exemption on sugarcane: o Mixing/loading liquids to support aerial applications, o Applying liquids with enclosed cockpit aerial equipment, and o Flagg ing to support aerial applications. For the proposed use of imidacloprid to control burrowing shrimp, only short - term exposures are expected due to the limited geographical area of the applications (Willapa Bay and Gray s Harbor in Washington State) and the limit of one application per acre per ye ar. As a result, it is unlikely that an individual would make repeated daily applications for 1 - 6 months for this use. Short term exposure is also anticipated for the proposed sugarcane use as the use directions limit application to 2 per crop cycle. However, the short - and intermediate - term toxicological endpoints are the same; therefore, the estimates of risk for short - term duration exposures are protective of those for intermediate - term duration exposures. L ong - term exposures are not expected; therefore, a long - term assessment was not conducted. The average adult body weight of 80 kg was used for estimating dermal and inhalation doses. No chemical - specific handler exposure data were submitted in support of this Section 3 registration. 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 PHED 1.1, the AHETF database, the ORETF database, or other registrant - submitted occupational 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 info rmation 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 . Occupational handler exposure assessments are completed by HED using different levels of risk mitigation. Ty

pically , HED uses a tiered approach. The lowest tier is designed as the “baseline ”Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 35 of 45 exposure scenario (i.e., long - sleeve shirt, long pants, shoe s, socks, no respirator). If risk estimates are of concern at baseline attire, then increasing levels of P PE (i.e., gloves, respirators) are evaluated. If risk estimates remain a concern with maximum PPE, then engineering controls (i.e., enclosed cabs or cockpits, water - soluble packaging, and closed mixing/loading s ys tems) are evaluated. This approach is used to ensure that the lowest level of risk mitigation that provides adequate protection is selected, since the addition of PPE and engineering control s involves an additional expense to the user and (in the case of PPE) also involves an additional burden to the user due to decreased comfort and dexterity and increased heat stress and respiratory stress. The proposed imidacloprid product labels direct m ixers, loaders, applicators and other handlers to wear a long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves. In addition, the label for the granule formulation directs users to wear a dust mask. **PP#2E7988** : Table 9 .1 .1 provides a summary of the estimated exposures and risks to oc cupational pesticide handlers resulting from the use on oy ster beds. All dermal and inhalation risk estimates for occupational handlers are above the L OC (MOEs > 100) with baseline protection (i .e., long - sleeve shirt, long pants, shoes, and socks) and chemical - resistant gloves . Only engineering control data (i.e., enclosed cockpits) are available for aerial application scenarios. All dermal and inhalation risk estimates for occupational aerial applicators are above the L OC (MOEs >100) with baseline clothing and enclosed cockpits . **PP# 12LA11**  : Table 9.1.2 provides a summary of the estimated exposures and risks to occupational pesticide handlers resulting from the use on sugarcane. For the scenarios where baseline data are available, all dermal and inhalation risk estimates for occupational handlers are above the LOC (MOEs >100) with baseline protection (i.e., long - sleeve shirt, long pants, shoes, and socks) . Onl y engineering control data (i.e., enclosed cockpits) are available for aerial application scenarios. All dermal and inhalation risk estimates for occupational aerial applicators are above the LOC (MOEs >100) with baseline clothing and enclosed cockpits . The Agency

has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly

used as indicated by

the 1998 Nati onal Agricultural Aviation Association (NAAA) survey

of their membership. It appears, however, flaggers are still used in approximately

10 - 15% of aerial application operations. In cases like these, the Agency strongl y encourages the use of the engineerin g control sy stem but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and will consider those results as are timel y and appropriate.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 36 of 45 **Table 9.1.1. Short -**  **Term Occupational Exposure and Risk Estimates for Imidacloprid Applications to WA Oyster Beds.**  **Exposure Scenario Dermal Unit**  **Exposure (ug/lb ai) 1**  **Inhalation Unit Exposure (ug/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area** 

**Treated or Am**  **ount Handled**  **Daily 3**  **Dermal Inhalation**  **Total Mitigation Level**  **Mitigation Level Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose**

**(m g/k** **g/day) 6**  **MOE 7**  **MOE 8**  Mixer/Loader Granules Aerial applications 6.9 [Baseline, CR gloves] 1.7 [No respirator] 0.5 lb ai/acre 1200 acres 0.0037 2,700 0.0128 780 610 Tractor - drawn spreader applications 200 acres 0.00062 16,000 0.00213 4,700 3,600 Liquids Aerial applications 37.6 [Baseline, CR gloves] 0.219 [No respirator] 1200 acres 0.0203 490 0.00164 6,100 450 Groundboom applications 200 acres 0.0034 3,000 0.00027 36,000 2,800 Applicator Granules Aerial applications 1.7 [Engineering control (enclosed cockpit)] 1.3

[Engineering control (enclosed cockpit)] 0.5 lb ai/acre 1200 acres 0.00092 11,000 0.00975 1,000 920 Tractor - drawn spreader applications 7.2

[Baseline, CR gloves] 1.2 [No respirator] 200 acres 0.00065 15,000 0.0015 6,700 4,600 Liquids Aerial applications 5 [Engineering control (enclosed cockpit)] 0.068

[Engineering control (enclosed cockpit)] 1200 acres 0.0027 3,700 0.00051 20,000 3,100 Groundboom applications 16.1 [Baseline, CR gloves] 0.34 [No respirator] 200 acres 0.0015 6,900 0.000085 190,000 5,400

Flagger Granules Aerial applications 2.73 [Baseline, CR gloves] 0.15 [No respirator] 0.5 lb ai/acre 350 acres 0.00189 23,000 0.00033 30,000 13,000 Liquids Aerial applications 12 [Baseline, CR gloves] 0.35 [No respirator] 350 acres 0.00043 5,300 0.00077 13,000 3,800 Mixer/loader/Applicator Liquids Backpack sprayer 8260 [Baseline, CR gloves] 2.58 [No respirator] 0.1 lb

ai/gallon 40 gallons 0.0297 340 0.000129 78,000 340 Granules Belly grinder 9300 [Baseline, CR gloves] 62 [No respirator] 0.5 lb ai/acre 1 acre 0.00419 2,400 0.000388 26,000 2,200 Rotary spreader 240

[Baseline, CR gloves] 10 [No respirator] 5 acres 0.00054 19,000 0.000313 32,000 12,000 1 Unit exposures from PHED/ORETF/AHETF/etc. See: http://www.epa.gov/pesticides/science/handler- exposure - data.html . Baseline = single - layer (SL) of clothing (long - sleeve shirt, long pants, shoes/socks). CR = chemical - resistant. 2 Based on proposed labels. 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (%) / BW (kg). 5 Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (kg). 7 Inhalation MOE = I

nhalation NOAEL (mg/kg/day)/ I nhalation Dose (mg/kg/day). 8 Total MOE = 1/(1/Dermal MOE + 1/I nhalation MOE).Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 37 of 45 **Table 9.1.2. Short**  **- Term** **Occupational Exposure and Risk Estimates for Imidacloprid Applications to Sugarcane in LA.**  **Crop or Target**  **Unit Exposure 1** 

**(μg ai/lb handled) Application**  **Rate 2**  **(lb ai/A) Units** 

**Treated 3**  **(A/day) Avg. Daily Dose**  **4**

**(m g ai/k** **g bw/day) Short**  **- term**  **MOEs 5**  **Total**

**MOE 6**  **Mixer/Loader –**  **Liquid –**  **Aerial Applications** Sugarcane Dermal

Baseline 6 : 220 0.08 1200 Dermal Baseline: 0.019 Dermal

Baseline: 530 520 Inhalation Baseline: 0.219 Inhalation Baseline: 0.00026 Inhalation

Baseline: 38,000 **Applicator –**  **Aerial Applications** Sugarcane Dermal

Eng. Control 8 : 5.0 0.08 1200 Dermal Baseline: 0.00432 Dermal

Baseline: 23,000 19,000 Inhalation Eng. Control: 0.065 Inhalation Baseline: 0.000082 Inhalation Baseline: 120,000 **Flagger** Sugarcane Dermal

Baseline: 11 0.08 350 Dermal Baseline: 0.00028 Dermal

Baseline: 36,000 25,000 Inhalation Baseline: 0.35 Inhalation Baseline: 0.00012 Inhalation

Baseline: 82,000 1 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” March, 2012. 2 Application Rate. = Taken from proposed use information. 3 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, revised 25 Septem ber 2001. 4 Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated * Absorpt ion factor (dermal only = 7.2%)  80 kg Body Weight. 5 MOE = Margin of Exposure = NOAEL  ADD . NOAEL = 10 mg/kg bw/day (dermal), 10 mg/kg bw/day (inhalation). 6 Total MOE = NOAEL  (Combined Dermal + I nhalation Dose). 7 Baseline = Long - sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation) . 8 Engineering Control = enclosed cockpit and baseline attire (long - sleeve shirt, long pants, shoes, and socks). **9.2 Post**  **- Application Exposure and Risk Estimates**  HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter pre viously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure. For the proposed Section 3 use of imidacloprid on oy ster beds, the extent of post - application exposure is expected to be non - occupational in nature. Thus, any occupational post - application dermal or inhalation exposures (e.g., during o ys ter harvestin g) are adequately covered by

the residential post - application assessment in Section 6 .2. Based on the proposed Section 18 Emergency

Exemption use of imidacloprid on sugarcane , occupational post - applicati on dermal exposures are expected . **9.2.1 Dermal P**  **ost -**  **application Exposure and Risk Estimates** HED expects that post - application exposure will occur since imidacloprid is applied as a foliar spray . Post - application exposure is expected to be short - term based on information provided onImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 38 of 45 the label (a maximum of 2 applications per crop cycle). However, the short - and intermediate term toxicological endpoints are the same; therefore, the estimates of risk for short - term duration exposures are protective of those for intermediate - term durati on exposures. 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 “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post app - exposure - data.html . A summary

of the post - application MOEs and respective reentry intervals is provided in Table 9.2.1. The short - term post - application assessments for sugarcane resulted in MOEs of 100 or greater on “day

0” (immediately

after application) for all exposure activ ities, and are not of concern. **Table 9.2.1. Summary of Short**  **- term**  **Occupational Post -**  **application Risk Estimates. Crop/Site**  **Transfer Coefficient**

**(cm 2**  **/hr )**  **Application Rate (lb ai/A)**  **DFR on Day**

**0 (ug/cm 2)**  **Day 0 ST**

**MOE 2**  **Day X at which**

**ST MOE ≥ LOC**  Sugarcane 70 (hand weeding) 0.08 0.224 88,000 0

1100 (scouting) 5,600 0 17,600 (hand harvesting) 350 0 1 DFR = AR x F x (1 - D) t x 4.54E8 μg/lb x 2.47E - 8 acre/cm 2

. 2 MOE = POD (NOAEL, 10 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day x 7.2 % dermal absorption]  body weight 80 kg adult). **9.2.2 Inhalation Post**  **- application Exposure**  **and Risk Estimates** Based on the Agency's current practices, a quantitative inhalation post - application inhalation exposure assessment was not performed at this time primaril y because of the low acute inhalation toxicity

(Toxicity Category IV) and low vapor pressure (4 x 10 - 7 mmHg) . However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated areas. These potential sources include volatilization of pes ticides 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 FIFRA 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 i n the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and may , as appropriate, develop polici es 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 f

or a quantitative occupational post - application inhalation exposure assessment for imidacloprid.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 39 of 45 **10.0 References**  J. Alsadek, 2 - AUG - 2012, D403995, Usage Report Package in Support of Registration for the Insecticide Imidacloprid (129099). M. Crowley , 6 - MAR - 2013, D400191, Occupational and Residential Exposure Assessment for a Proposed Use to Control Burrowing Shrimp in Oyster Beds. J. Dawson, 14 - MAR - 2003, D287532, Carbaryl: Revised HED Risk Assessment - Phase 5 - Public Comment Period, Error Correction C omments Incorporated. Y. Donovan, 23 - MAR - 1999 , D242320 , PP# 8F04940. Imidacloprid - Proposal for Tolerances of Residues in/on Citrus Crop group and Processed Commodities; in/on Leafy Petiole Vegetables: Residue Chemistry

Review. F. Griffith, 15 - JUN - 1993 , D193027, Multiresidue Method (MRM) Validation Data For Imidacloprid (Confidor ® ) . F. Griffith, 18 - JUN - 1993 , D187911, PP# 3F4169 - Im idacloprid (Confidor ® ) on Apples, Cottonseed, Potatoes, Meat, Milk, Poultry, and Eggs. Review of the Analy tical Me thod and Petitioner's February 5, 1993 L etter. F. Griffith, 25 - JUN - 1993 , TXR# 0050886 , Metabolism Committee Meeting Held on June 22, 1993: Metabolism of Imidacloprid. F . Griffith, 15 - JUL - 1993, D193005 , Multiresidue Method (MRM) Validation Data for Imidacloprid (Confidor ® ). F. Griffith, 20 - SEP - 1993, D 185148, Im idacloprid (Confidor®) on Apples, Cottonseed, Potatoes, Meat, Milk, Poultry , and Eggs. Review of Residue Data and Anal ytical Method. F. Griffith, 1 - JUN - 1994 , D202113, Im idacloprid (Admire®) on Apples, Cotton - seed, Potatoes, Meat, Milk, poultry , and Eggs. Evaluation of the Tolerance Method Validation Report. F. Griffith, 8 - JUN - 1994 , D200233, Im idacloprid (Admire®) on Apples, Potatoes, Cottonseed, Meat, Milk, Poultry , and Eggs. Review of the March 1 and April 11, 1994, Amendments. F. Griffith, 22 - JUN - 1994 , D194206 , Im idacloprid (Admire®) on the Fruiting Vegetables and Brassica (Cole) Leafy

Vegetables Crop Groups, Lettuce, Grapes and Grape Processed Commoditie s, Tomato Processed Commodities, Meat, Milk, Poultry , and Eggs. Review of the Residue Data and Anal yt ical Method. F. Griffith, 16 - MAY - 1995 , D212683 , Im idacloprid (Gaucho®) on barley , wheat, and sugarbeets following seed treatment. Review of the January 19, March 8 and 28, 1995 Amendments.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 40 of 45 F. Griffith, 8 - JUN - 1995 , D213252, Im idacloprid (Admire®) on Citrus Fruits Crop Group and Pecans. Review of the Res idue Data and Anal ytical Method. F. Griffith, 18 - DEC - 1995, D221591 , Im idacloprid (Admire®) in citrus fru its crop group; and apples, cottonseed and potatoes. Evaluation of the Tolerance Method Validation Report. F. Griffith, 29 - FEB - 1996, D217632 , Im idacloprid on Tobacco. Amended Registration Request and the February

26, 1996 Amendment. G. Kramer et al. , 16 - MAR - 2009, D375406 , Revised Human - Health Risk Assessment for Proposed Section 3 Seed Treatment Uses on Bulb Vegetables (Crop Group 3); Cereal Grains (Crop Group 15); Root and Tuber Vegetables, Except Sugar Beet (Crop Subgroup 1B); Tuberous and Corm Vegetabl es (Crop Subgroup 1C); Leafy Vegetables, Except Brassica (Crop Subgroup 4A); Brassica Vegetables (Crop Group 5); Fruiting Vegetables (Crop Group 8); Cucurbit Vegetables (Crop Group 9), and Residential Crack and Crevice and Bed - Bug Uses. K. L owe, 17 - FEB - 20 09, D367396 , Im idacloprid: Occupational and Residential Risk Assessment for Proposed Bed Bug Use and an Assessment for a Crack and Crevice Use. J. Melendez , 22 - JULY - 2009 , Tier I Estimated Environmental Concentrations of Imidacloprid for the Use in the Hum an Health Risk Assessment, Registration of a New Product for Seed Treatment, Sepresto 75WS, and New Use on Bulb Vegetables (Crop Group 3) for GAUCHO 550SC. J. Tyler, 13 - JAN - 2003; D28740 0, IM IDACLOPRID; Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Decision Document . J. Tyler, 3 - DEC - 2008; D353984, Imidacloprid. Human Health Assessment Scoping Document in Support of Registration Review. J. Tyler; 7 - MAR - 2013; D400189, Section 3 Requests for Use on Oy ster Beds. J. Tyler; 7 - MAR - 2013; D400187, Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for Use on Oy ster Beds; and the Section 18 Emergency Exemption Request for Use on Sugarcane in Louisiana (LA). J. Tyler, 7 - MAR - 2013; D407182, Occupational Exposure Assessment to Support a Section 18 Request for the use of Imidacloprid on Sugarcane in L ouisiana.

cc: J. Tyler RDI : risk assessment team (12/12/12); RAB1 (12/19 /12); G. Kramer (12/ 17 /12); C. Smith (12/17 /13 ) J. Tyler: S - 10943: Potomac Yard 1 (PY1): (703) 305 - 5564: 7509P: RAB1Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 41 of 45 **Appendix A. Toxicology Profile and Executive Summaries .**  **Table A.1. Acute Toxicity of Imidacloprid. Guideline No.**  **Study Type MRID #(s)**  **Results Toxicity Category**  81 - 1 Acute Oral 42055331 LD 50 = 424 mg/kg (M) LD 50 >450 mg/kg (F) II 81 - 2 Acute Dermal 42055332 LD 50 >5000 mg/kg IV 81 - 3 Acute I nhalation 42256317 LC 50 >5.33 m/L IV 81 - 4 Primary Eye Irritation 42055334 Not an eye irritant IV 81 - 5 Primary Skin I rritation 42055335 Not a dermal irritant IV 81 - 6 Dermal Sensitization 42055336 Not a dermal sensitizer N/A **Table A.2. Toxicity Profile of Im idacloprid Technical.**  **Guideline No./ Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3100 90 - Day oral toxicity rodents (rats) NA NA 870.3150 90 - Day oral toxicity (nonrodents) NA NA 870.3200 21/28 - Day dermal toxicity (rabbits) 42256329 (1990) Acceptable/guideline 0 or 1000 mg/kg/day 6 hr/day, 5 d/week NOAEL = 1000 mg/kg/day (HDT) . LOAEL = not identified . 870.3250 90 - Day dermal toxicity NA NA 870.3465 4 - Week inhalation toxicity (rat) 42273001 (1989) Acceptable/guideline 0, 0.0055, 0.035, or 0.191 mg/L/day, 6 hr/day, 5 d/week for 4 weeks NOAEL = 0.191 mg/L/day (HDT) . LOAEL = not identified . 870.3700a Prenatal developmental toxicity (rats) 42256338 (1992) Acceptable/guideline F: 0, 10, 30, or 100 mg/kg/day **Maternal** NOAEL = 10 mg/kg/day . LOAEL = 30 mg/kg/day based on decreased body- weight gain and decreased corrected body- weight gain. **Developmental** NOAEL = 30 mg/kg/day . LOAEL = 100 mg/kg/day based on a slight increase in the incidence of wavy ribs. 870.3700b Prenatal developmental toxicity (rabbits) 42256339 (1992) Acceptable/guideline F: 0, 8, 24, or 72 mg/kg/day **Maternal** NOAEL = 24 mg/kg/day . LOAEL = 72 mg/kg/day based on maternal deaths and decreased maternal absolute body weights, body- weight gains, and food consumption. **Developmental** NOAEL = 24 mg/kg/day . LOAEL = 72 mg/kg/day based on abortion, total litter resorptions, increased post - implantation loss due to increased late resorptions, decreased fetal weights, and very low incidences of skeletal alterations. 870.3800 Reproduction and fertility effects (rats) 42256340 (1990) Acceptable/guideline 0, 100, 250, or 700 ppm F 0 (M/F): 0, 8.1/8.8, 20.1/22.1, or 56.7/62.8 mg/kg/day F 1 (M/F): 0, 6.4/7.2, 16.5/18.9, or 47.3/52.3 mg/kg/day **Parental/Systemic** NOAEL = 16.5 mg/kg/day . LOAEL = 47.3 mg/kg/day based on decreased premating weight gain by F 0 males and females and F 1 females and decreased gestational weight gain by F 1 females. **Reproductive** NOAEL = 47.3 mg/kg/day (HDT) . LOAEL = not identified . **Offspring** NOAEL = 16.5 mg/kg/day . LOAEL = 47.3 mg/kg/day based on decreased pup body weights in both litters of both generations. 870.41 00a Chronic toxicity (rodents) NA; see 870.4300 NA 870.4100b Chronic toxicity (dogs) 42273002 (1989) Acceptable/guideline 0, 200, 500, or 1250/2500 ppm M/F: 0, 6.1, 15, or 41(first 16 wks.), then 72 mg/kg/d NOAEL = 72 mg/kg/day (HDT) . LOAEL = not identified .

870.4200a Carcinogenicity (rats) NA; see 870.4300 NA 870.4200b 42256335 (1991) NOAEL = Males: 208 mg/kg/day; Females: 274 mg/kg/day .Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 42 of 45 **Table A.2. Toxicity Profile of Im idacloprid Technical.**  **Guideline No./ Study Type MRID No. (year)/**  **Classification /Doses Results**  Carcinogenicity (mice) Acceptable/guideline with 42256336 0, 100, 330, or 1000 ppm M: 0, 20, 66, or 208 mg/kg/day F: 0, 30, 104, or 274 mg/kg/day 42256336 (1991) 0 or 2000 ppm M: 0 or 414; F: 0 or 424 mg/kg/day LOAEL = Males: 414 mg/kg/day; Females: 424 mg/kg/day based on decreased body weights, food consumption and water intake. **No evidence of carcinogeni city.** 

870.4300 Combined Chronic/carcinogenicity (rats) 42256331 (1989) Acceptable/guideline with 42256332 0, 100, 300, or 900 ppm M: 0, 5.7, 16.9, or 51.3 mg/kg/day F: 0, 7.6, 24.9, or 73.0 mg/kg/day 42256332 (1991) 0 or 1800 ppm M: 0 or 102.6; F: 0 or 143.7 mg/kg/day NOAEL = Males: 5.7 mg/kg/day; Females: 7.6 mg/kg/day . LOAEL = Males: 16.9 mg/kg/day; Females: 24.9 mg/kg/day based on thyroid toxicity (increased incidence of mineralized particles in thyroid colloid) in males. **No evidence of carcinoge nicity.** 

870.5100 Bacterial reverse mutation 42256341 Acceptable/guideline Negative for inducing reverse mutation in bacteria exposed to doses up to 5000 ug/plate. 870.5100 Bacterial reverse mutation 42256343 Acceptable/guideline Negative up to 12,500 ug/plate. 870.5100 Bacterial reverse mutation 42256363 Acceptable/guideline Negative up to 5500 ug/plate. 870.5300 In vitro mammalian cell gene mutation 42256342 Acceptable/guideline Negative for inducing forward mutation in Chinese Hamster Ovary (CHO) (mammalian) cells treated up to 1222 ug/mL. 870.5300 In vitro mammalian cell gene mutation 42256364 Acceptable/guideline Negative up to 2000 ug/mL. 870.5300 In vitro mammalian cell gene mutation 42256365 Acceptable/guideline Negative up to 2000 ug/mL. 870.5375 In vitro mammalian chromosome abberation (HL) 42256345 Acceptable/guideline Positive at 500 ug/mL - S9 and 1300 ug/mL +S9, both cytotoxic doses . 870.5375 In vitro mammalian chromosome abberation (CHV79) 42256370 Acceptable/guideline Negative up to 1000 ug/mL. 870.5375 In vitro mammalian chromosome abberation (CHO) 42256371 Acceptable/guideline Negative up to 1000 ug/mL. 870.5380 Mammalian germ cell chromosome abberation (mouse) 42256348 Unacceptable/guideline Negative, but only tested up to 80 mg/ml. 870.5385 Mammalian bone marrow chromosome aberration (chinese hamster) 42256344 Acceptable/guideline Negative for chromosome breakage up to 2000 ug/mL. 870.5395 Mammalian micronucleus (mouse) 42256347 Unacceptable/guideline Negative, but only tested up to 80 mg/kg. 870.5395 Mammalian micronucleus (mouse) 42256366 Acceptable/guideline Negative up to 50 mg/kg IP, toxic dose. 870.5395 Mammalian micronucleus (mouse) 42256367 Unacceptable/guideline Negative up to 80 mg/kg IP, a non - toxic dose. 870.5395 Mammalian micronucleus (mouse) 42256368 Unacceptable/guideline Negative up to 100 mg/kg PO, a non - toxic dose. 870.5395 Mammalian micronucleus (mouse) 42256369 Acceptable/guideline Negative up to 160 mg/kg PO, toxic dose.Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 43 of 45 **Table A.2. Toxicity Profile of Im idacloprid Technical.**  **Guideline No./ Study Type MRID No. (year)/**  **Classification /Doses Results**  870.5500 DNA damage/repair REC assay 41156351 Acceptable/guideline Negative up to 5000 ug/disc, the limit of solubility, with or without activation. 870.5550 Unscheduled DNA synthesis (RPH) 42256352 Acceptable/guideline Negative up to 750 ug/mL, a cytotoxic dose. 870.5575 Mitotic gene conversion 42256353 Acceptable/guideline Negative for crossing - over in yeast cells exposed with/without activation to precipitating levels of test article (5,000 - 10,000 ug/mL). 870.5550 Unscheduled DNA synthesis (RPH) 42256372 Acceptable/guideline Negative up to cytotoxic doses (1333 ug/mL). 870.5900 In vitro sister chromatid exchange (CHO) 42256349 Acceptable/guideline Positive at 500 ug/mL - S9 and 2000 ug/mL +S9, both cytotoxic doses. 870.5900 In vitro sister chromatid exchange (CHO) 47256350 Acceptable/guideline Negative at cytotoxic doses of 400 ug/mL - S9 and 1250 ug/mL +S9. 870.59.15 In vivo sister chromatid exchange (chinese hamster bone marrow) 42256346 Acceptable/guideline Negative up to 2000 mg/kg. 870.6200a Acute neurotoxicity screening battery rat 43170301 (1994) 43285801 (1994) Acceptable/guideline 0, 42, 151, or 307 mg/kg NOAEL = not identified. LOAEL = 42 mg/kg based on decreased motor and locomotor activities observed in females. 870.6200b Subchronic neurotoxicity screening battery rat 43286401 (1994) Minimum 0, 150, 1000, or 3000 ppm M: 0, 9.3, 63.3, or 196 mg/kg/day F: 0, 10.5, 69.3, or 213 mg/kg/day NOAEL = 9.3 mg/kg/day. LOAEL = 63.3 mg/kg/day based on decreased body- weight gain.

870.6300 Developmental neurotoxicity (rat) 45537501 (2001) Acceptable/non - guideline 0, 100, 250, or 750 ppm Gest.: 0, 8.0 - 8.3, 19.4 - 19.7, or 54.7 - 58.4 mg/kg/day La ct.: 0, 12.8 - 19.5, 30.0 - 45.4, or 80.4 - 155.0 mg/kg/day **Maternal** NOAEL = 20 mg/kg/day. LOAEL = 55 mg/kg/day based on decreased food consumption and bodyweight gain during lactation. **Offspring** NOAEL = 20 mg/kg/day. LOAEL = 55 mg/kg/day based on decreased body weight and bodyweight gain, decreased motor activity and decreased caudate/putamen width in females. 870.7485 Metabolism and pharmacokinetics rat 42256354 (1990) 42256356 (1987) M&F: 1.0 or 20.0 mg/kg (labeled) as single oral dose or 1.0 mg/kg unlabeled orally followed by 1.0 mg/kg single oral dose (labeled) or 1.0 mg/kg (labeled) single dose I V . M: 20.0 mg/kg single oral dose or 1.0 mg/kg single duodenal dose . 42256357 (1991) M&F: 1.0 mg/kg single oral dose . M: 1.0 or 150 mg/kg single oral dose 42256373 (1990) . M: 1.0 or 150 mg/kg single oral dose or 80.0 mg/kg single oral dose after 1 year 1800 ppm . 42256355 (1987) M: 1.0 mg/kg single oral Methylene - labeled imidacloprid was rapidly absorbed with approximately 90% of the administered dose being eliminated within 24 hours and 96% within 48 hours. There were no biologically significant differences between sexes, dose levels, or route of administration. Urinary excretion was the major route of elimination (70 - 80% of recovered radioactivity), with a lesser am ount eliminated in feces (17 - 25% of recovered radioactivity). Biliary excretion was a major contributor to fecal radioactivity (36.6% vs. 4.8% of recovered radioactivity in bile - fistulated animals). Total tissue burden after 48 hours accounted for only approximately 0.5% of the recovered radioactivity, with major sites of accumulation being the liver, kidney, lung, skin, and plasma and minor sites being the brain and testes. Maximum plasma concentration occurred between 1.1 and 2.5 hours, and elimination half - lives (calculated from two exponential terms) were 3 and 26 - 118 hours. There were two major evident routes of biotransformation. The first included an oxidative cleavage of the parent compound to give 6 - CNA and its glycine conjugate. Dechlorinatio n of this metabolite formed the 6 -hydroxynicotinic acid and its mercapturic acid derivative. The second included the hydroxylation of imidazolidine followed by elimination of water of the parent compound to give NTN 35884. In a comparison between [methylene 14 C]imidacloprid and [imidazolidine 4,5 - 14 C]imidacloprid, the rates of excretion were similar; however, the renal portion was higher with the imidazolidine - labeled test material. The imidazolidine - labeled test material also demonstrated higher accumulation in the tissues, with the major sites of accumulation being the liver, kidney,Imidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 44 of 45 **Table A.2. Toxicity Profile of Im idacloprid Technical.**  **Guideline No./ Study Type MRID No. (year)/**  **Classification /Doses Results**  or IV dose . 42256358 (1990) 42256359 (1990) Acceptable/guideline lung, and skin, and the minor sites being brain and muscle. In a comparison between [methylene 14 C]imidacloprid and WAK 3839, there were no significant difference s in the absorption, distribution, and excretion of the total radioactivity. More radioactivity was found in the tissues of the animals receiving imidacloprid at the 1.0 and 150.0 dose levels. The major sites of accumulation of WAK 3839 included lung, renal fat, liver, and kidney, with minor sites being the testis and brain. WAK 3839 was formed during pretreatment (chronic oral dosing) of imidacloprid; however, the proposed metabolic pathways of the two compounds were different. 870.7600 Dermal penetrat ion NA NAImidacloprid Human - Health Risk Assessment DP# s 399719 and 407172

Page 45 of 45 **Appendix B. Physical/Chemical Properties** . **Table B1. Physicochem ical Properties of Im** **idacloprid. Param**  **eter Value**  **Reference** Molecular Weight 255.7 PP#6E7116; W. Cutchin, 14 - May - 2007; DP#s: 332757, 333517, & 334153 The Pesticide Manual Twelfth Edition (2000) pH 5 to 11 Water solubility (g/L at 23°C) 1.54 Solvent solubility (g/L at 20°C) Dichloromethane: 55, Isopropanol: 1.2, Toluene: 0.68, n - hexane:

<0.1 Vapor pressure (mPa at 20°C) 4 x 10 - 7 Octanol/water partition coefficient, log KOW (25°C) 0.57 (21 ° C) Henry’s la w constant (@20 ° C) 6.5x10 - 11 atm m3/mole Cal - EPA Soil Half - life (or other relevant information from EFED Drinking water assessment) R.Parker, 13 - April - 2007; DP#s: 334029, 334030, 332756, 333122,

333123, 333125, 333126, 330568, 330569 Hydroly sis half

- life @ pH 7 Stable Photolysis half

- life, distilled water (days) 0.2 Photolysis half

- life, soil (days) 39 Aerobic soil half

- life (days) 359 Aerobic aquatic metabolism half - life (days) 27 Soil leaching (KOC , mL/g) 178 (132 - 256)