UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION


MEMORANDUM

Date:		7-MAR-2013

SUBJECT:	Imidacloprid.  Section 3 Request for use on Oyster Beds in Washington (WA), and Section 18 Emergency Exemption Request for use on Sugarcane in Louisiana (LA).  Human-Health Risk Assessment.  

PC Code:  129909  
DP Barcodes:  D399719 and D407172
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
TXR 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-pyridinyl)methyl]-N-nitro-2-imidazolidinimine) on oyster beds in Willapa Bay and Grays 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, residue chemistry data review, dietary exposure assessment, and occupational exposure assessment (sugarcane use) were provided by Jennifer Tyler (RAB1); the hazard characterization and endpoint selection by Chester Rodriguez (RAB1); the occupational exposure assessment (oyster bed use) and residential exposure assessment by Matthew Crowley (CEB); and the drinking water exposure assessment by José Melendez of the Environmental Fate and Effects Division (EFED).

                               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	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	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 Analysis	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 Bystander 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.  Physical/Chemical Properties.	45

1.0	Executive Summary

Background:  Imidacloprid 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 whitefly).  It is a member of the pyridylmethylamine class of compounds.  Its mode of action involves disruption of the nervous system by acting as an inhibitor at nicotinic acetylcholine receptors.  Imidacloprid blocks the signals that are induced by acetylcholine at the post-synaptic membrane, resulting in normal nerve function impairment.

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 currently established for the combined residues of imidacloprid and its metabolites containing the 6-chloropyridinyl moiety, 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 oyster beds to control burrowing shrimp.  IR-4 has requested to add this use to the following labels:  Protector[(R)] 0.5G [a granular (G) product containing 0.5% imidacloprid as the active ingredient (ai); EPA Reg. No. xxx-xxx], and Protector[(R)] 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-chloropyridinyl moiety, all expressed as the parent, in/on fish at 0.05 ppm, and fish-shellfish, mollusc at 0.05 ppm.

IN ADDITION, THE LOUISIANA 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 systems were the nervous system and the thyroid.  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, increased 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 toxicity 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 thyroid 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-generation 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 body 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 assays.  

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 evaluation.  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 observed 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 offspring neurotoxic effects and the accompanying 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 in 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 uncertainties in the exposure 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 oyster 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 analyses 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; Ver. 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 and proposed commodities, and %CT information for some commodities).  The results indicate that the acute (95[th] percentile) and chronic dietary exposure estimates are below HED's LOC for the general U.S. population and all other population subgroups.  For both acute and chronic assessments, the most highly exposed population subgroup is children 1-2 years old at 74% of the aPAD and 28% of the cPAD, respectively.  

Residential (Non-Occupational) Exposure Assessment:  The proposed use of imidacloprid on oyster beds in WA can result in residential exposure via potential contact with residues in oyster-bed water or sediment during recreational swimming.  In addition, imidacloprid has several   registered uses which may result in residential exposure.  Based on these registered use patterns, there is a potential for short-term dermal and inhalation handler; and short-term dermal, inhalation, and incidental oral post-application exposure.  There is also the potential for 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).  

The equations and inputs for the post-application exposures due to the oyster bed use were generally developed from 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 resulting 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 scenarios:  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 pathways 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 oyster beds and sugarcane.  For the proposed oyster bed use, HED has determined that risk estimates are not a concern (i.e., MOE >100) 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 individuals in enclosed cockpits.

For the proposed use of imidacloprid on oyster 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., during oyster 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.  The 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 Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 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 data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0	HED Recommendations

HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registration and establishment of the tolerances 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 chromatography/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 chromatography/ultraviolet (HPLC/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).

Bayer 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 by these methods.  The results of the MRM testing for imidacloprid were forwarded to FDA for inclusion in the Pesticide Analytical 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 exemptions]
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-chloropyridinyl 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:  The residue chemistry data support the time-limited tolerances for the combined residues of imidacloprid and its metabolites containing the 6-chloropyridinyl 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 MRLs 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[(R)] 0.5G (EPA Reg. No. xxx-xxx), and Protector[(R)] 2F (EPA Reg. No. xxx-xxx) labels.


3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Test Compound Nomenclature.
Chemical Structure

Common Name
Imidacloprid
Company Experimental Name
Imidacloprid
IUPAC Name
(EZ)-1-(6-chloro-3-pyridylmethyl)-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[(R)] 2F (EPA Reg. No. xxx-xxx)
Protector[(R)] 0.5G (EPA Reg. No. xxx-xxx)

3.2	Physical/Chemical Characteristics
THE PHYSICAL 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.  Imidacloprid has a low octanol water partition coefficient (0.57); therefore, it is not expected to bioaccumulate in lipophilic matrices.  It is highly soluble in water (1.54 g/L), which, coupled with its low octanol water coefficient, 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 treated plants regardless of the method of application. 

3.3	Pesticide Use Pattern
PP#2E7988:  The petitioner has submitted draft labels for the Protector[(R)] 0.5G (EPA Reg. No. xxx-xxx), and Protector[(R)] 2F (EPA Reg. No. xxx-xxx).  A summary of the proposed use patterns 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 addition, the label for the granule formulation directs users to wear a dust mask.  The proposed label specifies a 12-hour REI.


TABLE 3.3.1.  SUMMARY OF PROPOSED DIRECTIONS FOR USE OF IMIDACLOPRID ON OYSTER BEDS.
                                   Use Site
                           Trade Name (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)
                                  Oyster beds
                         Protector[(R)] 0.5G (xxxxx-xx)
 Drop/rotary spreader; Tractor-drawn spreader; Belly grinder
 Helicopter
                                      0.5
                                      0.5
                                      30
                                       1
                                      NA
                                      NA
                                       
                               Protector[(R)] 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 during 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 imidacloprid 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 Name (EPA Reg. No.)
                             Application Equipment
                                  App.  Rate
                                   (lb ai/A)
                            Max. Seasonal App. Rate
                                   (lb ai/A)
                                Minimum PHI[1]
                                    (days)
                                  Max. # App.
                                     Min.
                                    GPA[2]
                                    RTI[3]
                                    (days)
                                   Sugarcane
                           Admire[(R)] Pro (264-758)
 Aerially
                                   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. Simoneaux 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 oyster beds to control ghost shrimp, and the proposed Section 18 Emergency Exemption request for the use of imidacloprid on sugarcane in LA.
3.4	Anticipated Exposure Pathways
RD HAS REQUESTED AN ASSESSMENT OF HUMAN-HEALTH RISK TO SUPPORT THE PROPOSED NEW USE OF IMIDACLOPRID 1) on oyster beds of Willapa Bay and Grays 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 oyster 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 oyster beds and sugarcane.  In addition, for the proposed use on sugarcane, there is a possibility of post-application dermal exposure to occupational workers when reentering field previously 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 conducted (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, particularly for the dietary and residential 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 Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, 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 analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 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 bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.


4.0	Hazard Characterization and Dose-Response Assessment

4.1	Mode of Action

Imidacloprid is a systemic insecticide effective against the larval, nymphal, and adult insect stages.  Its postulated insecticidal mode of action involves inhibition at nicotinic acetylcholine receptors, resulting in nerve function impairment.  Some 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 selection, 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 guideline 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 recovered 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 between 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 highest 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.  However, a dermal-absorption factor (DAF) of 7.2% has been previously 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 toxicity study in rabbits.

4.5	Summary of Toxicological Effects

The main targets of toxicity following oral administration of imidacloprid in mammalian systems were the nervous system and the thyroid.  The most sensitive species tested was the rat.  Evidence of neurotoxicity was reported in the rat ACN as changes in clinical signs and FOB measurements including decreased motor and locomotor activities, tremors, gait abnormalities, increased 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 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 thyroid colloid of rats, body weight decrements in mice, and no toxic effects in dogs.  No other thyroid effects were measured in the rat study.

In prenatal developmental toxicity studies in rats and rabbits, there were developmental effects at dose levels that also produced maternal toxicity.  In the rat study, there was a slight increase in the incidence of wavy ribs at a dose level higher than that causing deficit in maternal body-weight 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 wavy 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 recently submitted immunotoxicity study in rats, there were no immunotoxic effects reported at the highest dose level tested.  The only treatment-related effects were limited to deficits in body weights 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 systemic) 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," by all routes 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 assays.

4.6	SF 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.


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:  developmental toxicity studies in rats and rabbits; two-generation 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 acetylcholine 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 system were reported in any other studies in the imidacloprid database.  

4.6.3	Evidence of Sensitivity/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 (body-weight 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-weight 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.

4.0.4 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 exposures/risks will not be underestimated.

The chronic dietary food exposure assessment utilizes existing and proposed tolerance-level residues and % CT data verified by the Biological and Economics Analysis 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 models and associated 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 residential SOPs in conjunction with PHED unit exposures.  The residential SOPs are based upon reasonable worst-case assumptions and are not expected to underestimate risk.  These assessments of exposure are not likely to underestimate the resulting estimates of 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 study 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 only 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 effects (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 combined UF of 100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  Thus, the acute reference dose (aRfD) and aPAD are equivalent 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 thyroid 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 study.  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 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/day. 

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 study at the LOAEL of 30 mg/kg/day (NOAEL = 10 mg/kg/day).  The NOAEL of 30 mg/kg/day is comparable to the extrapolated NOAEL of 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 thyroid 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 study.  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 toxicology 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 LOAEL of 30 mg/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 wavy 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 LOAEL of 72 mg/kg/day from a rabbit 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 thyroid colloids (postulated reservoirs in the thyroid 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 previously estimated for imidacloprid (Memo, G. Kramer et al., 16-MAR-2009; D375406) yielding 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 study 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 wavy ribs.  Although a 4-week rat inhalation toxicity study was performed and no toxic effects were observed (no LOAEL 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 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 thyroid colloids (postulated reservoirs in the thyroid 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).  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 individual exposures can be combined if they have the same toxicological effects.  For short- and intermediate-exposure, dermal and inhalation exposures can be combined 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 (thyroid toxicity) from the rat chronic toxicity study.

4.7.3	Cancer Classification

Imidacloprid has been classified as a Group E chemical, "Evidence of non-carcinogenicity for humans," by 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.  Imidacloprid: Summary of Toxicological Endpoints and Points of Departure for Residential Human-Health Risk Assessment.
                                   Exposure
                                   Scenario
                       Dose Used in Risk Assessment, SFs
                         RfD, LOC for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary
(all populations)
LOAEL = 42 mg/kg/day

UFA = 10X
UFH = 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

UFA = 10X
UFH = 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

UFA = 10X
UFH = 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

UFA = 10X
UFH = 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

UFA = 10X
UFH = 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
UFA = 10X
UFH = 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

UFA = 10X
UFH = 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

UFA = 10X
UFH = 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 mineralized particles in thyroid colloid in males.
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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  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 oyster beds were reviewed by HED in a memo dated 7-MAR-2012 (Memo, J. Tyler; D400189).  The EDWCs were provided by EFED (Memo, J. Melendez; 22-JULY-2009).  The acute and chronic dietary exposure assessment was completed in a HED memorandum dated 7-MAR-2012 (Memo, J. Tyler; D400187).

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 Review Committee (MARC) in 1993 (Memo, F. Griffith, 25-JUN-1993, TXR#:  0050886).  The nature of imidacloprid residues in plants and livestock is adequately understood.  The residue of concern in plants and livestock is imidacloprid and its metabolites containing the 6-chloropyridinyl moiety, all expressed as the parent, as specified in 40 CFR §180.472.  In a meeting on 18-DEC-2002, the HED MARC 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; D287400).

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 oyster beds.  However, the registrant recently 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 oyster beds.  The ChemSAC determined that the proposed tolerance for residues of imidacloprid and its metabolites containing the 6-chloropyridinyl 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.  Total residues of imidacloprid were less than limit of quantitation [LOQ, defined as the lowest level of method validation, LLMV (0.05 ppm)] in/on oyster meat harvested 26-86 days following either a single application of Mallot[(R)] 0.5G at an application rate of 0.50 lb ai/A; or Mallot 2F[(R)] at an application rate of 2.0 lb ai/A.  Samples were analyzed for total imidacloprid residues using an acceptable method, and the study is supported by adequate storage stability data.  For oysters, the Organization for Economic Co-operation and Development (OECD) tolerance-calculation procedures could not be used to calculate a possible tolerance as residues of imidacloprid were <LOQ in/on all samples of oyster meat.  Therefore, the tolerance of 0.05 ppm for fish-shellfish, mollusc is appropriate.

PP#12LA11:  No residue 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, molasses.

The recommended 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 imidacloprid 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 PHI of 45 days.  The results of previously 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 previously submitted sugarbeet processing study indicate that total residues of imidacloprid do not concentrate in sugar (0.025X), but do concentrate in molasses (8.3X) (Memo, F. Griffith, 16-MAY-1995; D212683).  Therefore, a tolerance of 50 ppm (6.0-ppm tolerance x 8.3) is necessary for 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 oyster bed use as EFED 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 memo 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.  Estimated Tier 1 EDWCs of Imidacloprid in Drinking Water.
Drinking Water Source (Model Used)
Use (Rate modeled)
EDWC (ppb)
Groundwater (SCI-GROW)
Citrus (0.5 lb ai/A)
Acute and Chronic
2.09
Surface water (FIRST

Acute
36.0


Chronic
17.2


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 directly in the acute and chronic dietary assessments using the acute (peak) and chronic (annual average) concentrations for surface water generated by the FIRST model, respectively.
 
 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%; eggplant: 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%; soybeans (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 highly exposed population subgroup, children 1-2 years old, at 74% of the aPAD.  The acute assessment was highly conservative, using several upper-end assumptions.  Additional 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 that 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 estimated 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 order 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) Exposure and Risk for Imidacloprid.
                              Population Subgroup
                       Acute Dietary (95[th] Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/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 oyster beds in Washington State's Willapa Bay and Grays 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 oyster bed water or sediment during recreational swimming, or in the case of subsistence fishermen or local Native American tribes, collecting oysters.  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 Grays Harbor (Memo, J. Dawson, 14-MAR-2003: D287532).  There are no residential uses associated with the proposed Section 18 Emergency Exemption use on sugarcane.

For the purposes of evaluating aggregate (dietary and non-dietary) exposure for the proposed uses, 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-crevice 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.  Generally, 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).  Risks 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.

The registered and proposed residential uses were evaluated by HED and reviewed by the HED Science Advisory Council for Exposure (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 professionally 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 uses, 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 existing imidacloprid uses is based on the following scenarios:  

   * Mixing/loading/applying liquid formulations for use with manually-pressurized handwands in indoor settings (bed-bug treatments and crack-and-crevice treatments);
   * Mixing/loading/applying liquid formulations for use with hose-end sprayers on lawns and gardens;
   * Mixing/loading/applying 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/applying granule formulations to lawns and gardens using a push-type/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 exposure for residential handlers to be short-term (1-30 days) 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 using 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.

Table 6.1 below provides a summary of residential handler risk estimates from existing residential uses of imidacloprid, updated using the 2012 Residential SOPs and policy changes for body weigh assumptions.  Short-term risk estimates for residential handlers are not of concern (MOEs >100).


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 (mg/lb ai)
Inhalation Unit Exposure (mg/lb ai)
Maximum Application Rate[1]
Area Treated or Amount Handled Daily[2]
Dermal
Inhalation
Total






Dose (mg/kg/day)[3]
MOE[4]
Dose (mg/kg/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 ft[2]
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 ft[2]
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
0.0021
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 gallons/day) x DAF (%) / BW (kg).
[4] Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
[5] Inhalation Dose = Inhalation 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 = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).
[7] Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1 / [(1/Dermal MOE) + (1/Inhalation MOE)].
6.2	Post-Application Exposure and Risk Estimates

As a result of both the proposed use on oyster 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 treated with imidacloprid.

Based on the proposed use pattern, only 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 reviewed 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 by EPA as a screening tool to conduct exposure assessments of pesticides found in swimming 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 assessment 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 Grays Harbor intertidal oyster beds:
   o       Ingestion of water during recreational swimming (both adults and children 3<6 years old);
   o       Dermal exposure during recreational swimming (both adults and children 3<6 years old);
   o       Dermal exposure to oyster bed sediment while collecting/harvesting oysters (adults) and playing (children 3<6 years old);
   o       Inhalation exposure during recreational swimming and/or collecting/harvesting oysters (both adults and children 3<6 years old); and,
   o       Incidental ingestion of sediment via hand-to-mouth activities (children 3<6 years old only).

   * As a result of existing residential uses:
   o             Dermal exposure from contact with treated turf (both adults and children 11<16, 6<11, and 1<2 years 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);
   o             Dermal exposure from contact with treated mattresses (bed-bug treatments) and indoor surfaces (both adults and children 1<2 years old)  -  updated from most recent risk assessment (Memo, K. Lowe, 17-FEB-2009; D367396);
   o             Dermal exposure from contact with treated pets (both adults and children 1<2 years 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 years 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 years old)  -  updated from most recent risk assessment (Memo, K. Lowe, 17-FEB-2009; D367396);
   o             Incidental ingestion from contact with treated turf (children 1<2 years old only)  -  updated from most recent risk assessment (Memo, G. Kramer et al., 16-MAR-2009; D375406);
   o             Incidental 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             Incidental ingestion from contact with treated pets (children 1<2 years old only)  -  updated from most recent risk assessments (Memos, G. Kramer et al., 16-MAR-2009, D375406 (spot-on); K. Lowe, 17-FEB-2009; D367396 (collar)); and,
   o             Incidental ingestion from contact with treated wood (children 1<2 years 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 years old, etc.) selected for each post-application scenario as a result of the registered uses are based on an analysis provided as Appendix A in the 2012 Residential SOPs.  The lifestages (adults and children 3<6 years old) selected for the post-application scenarios as a result of the proposed oyster bed use are based on the expected potential for individuals to be in oyster beds and the activities they will conduct.  In the case of Native American 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 only 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 the proposed use of imidacloprid on oyster 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 assumptions.

Table 6.2.1.  Residential Post-application Non-cancer Exposure and Risk Estimates from the Proposed Use of Imidacloprid to Control Burrowing Shrimp.[1]
Use/Target
Lifestage
Post-application Exposure Scenario
Dose
(mg/kg-day)
MOE
Combined Routes
(X indicates included in Combined MOE)
Combined MOE
WA State Willapa Bay and Grays Harbor Intertidal Oyster Beds
Adult 
Dermal (water)
Swimming
5.6E-06
1,800,000
X
59,000


Dermal (sediment)
Oyster 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
X


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 (LT) 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, especially day after day for up to 30 days.  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, the 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 oyster bed use is low, thus risk estimates are not 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 Imidacloprid.
                          Combined Exposure Scenario
                                   Lifestage
                               Exposure Scenario
                               Route of Exposure
                                     Dose
                              Combined Total Dose
                                  (mg/kg-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 years old aggregate assessment, the recommended residential exposure scenario is contacting treated pets following application of pet collars.
Table 6.4.  Recommendations for the Residential Exposures for the Imidacloprid Aggregate Assessment.[1]
                                   Lifestage
                        Handler Exposure (mg/kg/day)[2]
               Residential Handler Total Exposure (mg/kg/day)[3]
                         Residential Handler Total MOE
                   Post-application Exposure (mg/kg/day)[4]
            Residential Post-application Total Exposure (mg/kg/day)
                      Residential Post-application MOE[5]
                                       
                                    Dermal
                                  Inhalation
                                       
                                       
                                    Dermal
                                  Inhalation
                                     Oral
                                       
                                       
                           Short-/Intermediate-Term
                                     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] For adults, residential 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] Post-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).

6.5	Residential Bystander Post-application Inhalation Exposure

Post-application inhalation exposure while swimming in intertidal oyster beds was assessed for the proposed use of imidacloprid.  However, bystander inhalation exposure was not assessed for the existing agricultural uses 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 IV) 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-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for the existing uses of imidacloprid.

6.6	Spray Drift

Spray drift is always 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 by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray-drift-management practices to reduce off-target drift with specific products with significant risks associated with drift.

Note that an application 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 likely protective of any exposure via spray drift from the proposed oyster-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 quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  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 intermediate-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 protective of the longer-term exposures.   A cancer aggregate risk assessment was not performed because imidacloprid is not carcinogenic.  All potential exposure pathways were assessed in the aggregate risk assessment. 

7.1	Acute Aggregate Risk

The acute aggregate 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 separately.  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.

60.2 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 dermal 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.  

For adults, the combined dermal post-application exposures from contacting treated lawns and gardens resulted in the highest short-term exposure (exposure = 0.037 mg/kg/day; MOE = 270 see Table 6.4).  For children, the combined dermal and hand-to-mouth exposure 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.

Table 7.2.  Short-Term Aggregate Risk Calculations.
                                  Population
                               NOAEL (mg/kg/day)
                                    LOC[1]
                     Max Allowable Exposure[2] (mg/kg/day)
            Average Food and Drinking Water Exposure (mg/kg/day)[3]
                      Residential Exposure (mg/kg/day)[4]
                         Total Exposure (mg/kg/day)[5]
                Aggregate MOE (food, water, 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 days 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 water 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-case 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 contacting 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 = 700; 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. population 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.

Table 7.4.  Chronic Aggregate Risk Calculations.
                                  Population
                          Chronic/Long-Term Scenario
                                       
                               NOAEL (mg/kg/day)
                                    LOC[1]
                     Max Allowable Exposure[2] (mg/kg/day)
            Average Food and Drinking Water Exposure (mg/kg/day) 3
                      Residential Exposure (mg/kg/day)[4]
                         Total Exposure (mg/kg/day)[5]
                Aggregate MOE (food, water, 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.

6.0 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 produce a toxic metabolite produced by 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 determine 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/.

7.0 Occupational Exposure/Risk Characterization

Based on the proposed application scenarios and toxicological considerations, non-cancer occupational handler (dermal and inhalation) assessments were conducted for the proposed uses on oyster beds and sugarcane; and occupational post-application (dermal) assessments were conducted for the proposed sugarcane use.  The proposed Section 3 use on oyster 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 task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the anticipated use patterns, potential occupational handler exposure scenarios include:  

   * As a result of the proposed Section 3 use on oyster 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 Applications of the granule formulation using tractor-drawn spreaders;
         o Flagging for aerial applications of the granule and diluted liquid formulation;
         o Mixing/loading/applying the liquid formulation with a backpack sprayer; and,
         o Loading/applying the granule formulation 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             Flagging 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 Grays Harbor in Washington State) and the limit of one application per acre per year.  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.  Long-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 information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

Occupational handler exposure assessments are completed by HED using different levels of risk mitigation.  Typically, HED uses a tiered approach.  The lowest tier is designed as the "baseline" exposure scenario (i.e., long-sleeve shirt, long pants, shoes, socks, no respirator).  If risk estimates are of concern at baseline attire, then increasing levels of PPE (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 systems) 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 controls 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 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.

PP#2E7988:  Table 9.1.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers resulting from the use on oyster beds.  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) 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 LOC (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).  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 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 National 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 strongly encourages the use of the engineering control system 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 timely and appropriate.
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]
                          Maximum Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                               Mitigation Level
                               Mitigation Level
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/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 = Inhalation 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 = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day).
[8] Total MOE = 1/(1/Dermal MOE + 1/Inhalation MOE). 
Table 9.1.2.  Short-Term Occupational Exposure and Risk Estimates for Imidacloprid Applications to Sugarcane in LA.
                                    Crop or
                                    Target
                               Unit Exposure[1]
                              (ug ai/lb handled)
                              Application Rate[2]
                                   (lb ai/A)
                               Units Treated[3]
                                    (A/day)
                              Avg. Daily Dose[4]
                               (mg ai/kg 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 September 2001.
  [4] Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated * Absorption 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 + Inhalation 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 previously 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 type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

For the proposed Section 3 use of imidacloprid on oyster 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 oyster harvesting) 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-application dermal exposures are expected.  

9.2.1	Dermal Post-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 on 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 duration 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 activities, and are not of concern.
 
Table 9.2.1.  Summary of Short-term Occupational Post-application Risk Estimates.
                                   Crop/Site
                         Transfer Coefficient (cm2/hr)
                          Application Rate (lb ai/A)
                             DFR on Day 0 (ug/cm2)
                                 Day 0 ST MOE2
                         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 ug/lb x 2.47E-8 acre/cm2.
[2] MOE = POD (NOAEL, 10 mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR (ug/cm[2]) x TC x 0.001 mg/ug 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 primarily 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 pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for imidacloprid.


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 Comments 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[(R)]).

F. Griffith, 18-JUN-1993, D187911, PP# 3F4169 - Imidacloprid (Confidor[(R)]) on Apples, Cottonseed, Potatoes, Meat, Milk, Poultry, and Eggs. Review of the Analytical Method and Petitioner's February 5, 1993 Letter.

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[(R)]).

F. Griffith, 20-SEP-1993, D185148, Imidacloprid (Confidor(R)) on Apples, Cottonseed, Potatoes, Meat, Milk, Poultry, and Eggs.  Review of Residue Data and Analytical Method.

F. Griffith, 1-JUN-1994, D202113, Imidacloprid (Admire(R)) on Apples, Cotton-seed, Potatoes, Meat, Milk, poultry, and Eggs. Evaluation of the Tolerance Method Validation Report.

F. Griffith, 8-JUN-1994, D200233, Imidacloprid (Admire(R)) 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, Imidacloprid (Admire(R)) on the Fruiting Vegetables and Brassica (Cole) Leafy Vegetables Crop Groups, Lettuce, Grapes and Grape Processed Commodities, Tomato Processed Commodities, Meat, Milk, Poultry, and Eggs. Review of the Residue Data and Analytical Method.

F. Griffith, 16-MAY-1995, D212683, Imidacloprid (Gaucho(R)) on barley, wheat, and sugarbeets following seed treatment. Review of the January 19, March 8 and 28, 1995 Amendments.

F. Griffith, 8-JUN-1995, D213252, Imidacloprid (Admire(R)) on Citrus Fruits Crop Group and Pecans. Review of the Residue Data and Analytical Method.
F. Griffith, 18-DEC-1995, D221591, Imidacloprid (Admire(R)) in citrus fruits crop group; and apples, cottonseed and potatoes. Evaluation of the Tolerance Method Validation Report.

F. Griffith, 29-FEB-1996, D217632, Imidacloprid 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 Vegetables (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. Lowe, 17-FEB-2009, D367396, Imidacloprid: 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 Human 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; D287400, IMIDACLOPRID; 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 Oyster 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 Oyster 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 Louisiana.







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: RAB1
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
                             LD50 = 424 mg/kg (M)
                            LD50 >450 mg/kg (F)
                                      II
                                     81-2
                                 Acute Dermal
                                   42055332
                              LD50 >5000 mg/kg
                                      IV
                                     81-3
                               Acute Inhalation
                                   42256317
                               LC50 >5.33 m/L
                                      IV
                                     81-4
                            Primary Eye Irritation
                                   42055334
                              Not an eye irritant
                                      IV
                                     81-5 
                            Primary Skin Irritation
                                   42055335
                             Not a dermal irritant
                                      IV
                                     81-6
                             Dermal Sensitization
                                   42055336
                            Not a dermal sensitizer
                                      N/A

Table A.2.  Toxicity Profile of Imidacloprid 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
F0 (M/F): 0, 8.1/8.8, 20.1/22.1, or 56.7/62.8 mg/kg/day
F1 (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 F0 males and females and F1 females and decreased gestational weight gain by F1 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.
870.4100a
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
Carcinogenicity (mice)
42256335 (1991)
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
NOAEL = Males:  208 mg/kg/day; Females:  274 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 carcinogenicity.
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 carcinogenicity.
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.
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
Lact.:  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 body-weight gain during lactation.
Offspring NOAEL = 20 mg/kg/day.
LOAEL = 55 mg/kg/day based on decreased body weight and body-weight 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 IV.
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 or IV dose.
42256358 (1990)
42256359 (1990)
Acceptable/guideline



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 amount 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.  Dechlorination 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, 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 differences 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 penetration
NA
NA





Appendix B.  Physical/Chemical Properties.

Table B1.  Physicochemical Properties of Imidacloprid.
Parameter
                                     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 law 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
                                       
Hydrolysis 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)



