
EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION 

Docket ID Number: EPA-HQ-OPP-2012-0204

EPA Registration Division contact: Sidney Jackson, (703) 305-7610


Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number (PP#): 2E7988

	EPA has received a pesticide petition (PP), 2E7988 from IR-4,  500 College Road East, Suite 201W, Princeton, New Jersey, 08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of the combined residues of the insecticide imidacloprid, including its metabolites and degradates, in or on the following commodities:  Fish at 0.05 parts per million (ppm) and fish-shellfish, mollusc at 0.05 ppm.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition.  Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

      1. Plant metabolism.  The nature of the imidacloprid residue in plants and livestock is adequately understood.  The residues of concern are combined residues of imidacloprid and it metabolites containing the 6-chloropyridinyl moiety, all calculated as imidacloprid.

	2. Analytical method.   Adequate enforcement methodologies, Bayer Gas Chromatography/Mass Spectrometry (GC/MS) Method 00200 and Bayer GC/MS Method 00191, is available to enforce the tolerance expression.  The methods may be requested from: Chief, Analytical Chemistry Branch, Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755 - 5350; telephone number: (410) 305 - 2905; e-mail address:  residuemethods@epa.gov.
	3. Magnitude of residues.  Three residue field trials were conducted in Washington.  Approximately 0.5 lb ai/A (TRT 02, granular formulation) or 2.0 lb ai/A (TRT 03, flowable formulation) was applied to the treated plots in one broadcast application of either Mallet 0.5G (TRT 02) or Mallet 2F (TRT 03).  Oyster meat samples were collected 84 to 86 days following the application.  Additional samples were collected from WA43 at approximately 30 and 60 days.  A storage stability analysis demonstrated that the analytes remained stable in frozen oyster meat.  No residues above the LLMV of 0.05 ppm were observed  

B. Toxicological Profile

	1. A summary of the toxicological endpoints for imidacloprid used for human risk assessment can be found at http://www.regulations.gov in document ``Imidacloprid: Human-Health Risk Assessment,'' pages 16 - 17 in docket ID number EPA - HQ - OPP - 2008 - 0772.

C. Aggregate Exposure

	1. Dietary exposure.  In the Federal Register of April 28, 2010 (FRL-8818-5), EPA evaluated the dietary exposure to imidacloprid.  EPA considered exposure under the petitioned-for tolerances as well as all existing imidacloprid tolerances in (40CFR 180.472). EPA assessed dietary exposures from imidacloprid in food as follows: 
      i. Acute exposure.  Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide, if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a 1 - day or single exposure.  In estimating acute dietary exposure, EPA used food consumption information from the United States Department of Agriculture (USDA) 1994 - 1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII).  As to residue levels in food, EPA conducted an unrefined, acute dietary exposure assessment using tolerance-level residues and  assuming 100% crop treated (CT) for all registered and  proposed commodities for the general U.S. population and  various population subgroups. 
      ii. Chronic exposure.  In conducting the chronic dietary exposure assessment EPA used the food consumption data from the USDA 1994 - 1996 and 1998 CSFII. As to residue levels in food, EPA conducted a partially refined, chronic dietary exposure assessment using tolerance-level residues for all registered and proposed commodities and percent crop treated (PCT) for some registered commodities.
      iii. Cancer.  A cancer exposure assessment was not performed because imidacloprid is not carcinogenic.  On November 11, 1993, the Agency 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.

	i. Percent crop treated (PCT) Information.  Section 408(b)(2)(F) of FFDCA states that  the Agency may use data  on the actual percent of food treated for assessing chronic dietary risk only if:
      :: Condition a: The data used are reliable and provide a valid basis to show what percentage of the food derived from such crop is likely to contain the pesticide residue.
      :: Condition b: The exposure estimate does not underestimate exposure for any significant subpopulation group.
      :: Condition c: Data are available on pesticide use and food consumption in a particular area, the exposure estimate does not understate exposure for the population in such area.
      In addition, the Agency must provide for periodic evaluation of any estimates used. To provide for the periodic evaluation of the estimate of PCT as required by FFDCA section 408(b)(2)(F), EPA may require registrants to submit data  on PCT.
      The Agency used PCT information as follows:
      
                                   Commodity
                       Average percent Crop Treated Data
Almonds.....................
                                                                          <1
Apples.......................
                                                                             25
Artichoke...................
                                                                              5
Avocados...................
                                                                          <1
Blueberry...................
                                                                             10
Broccoli.....................
                                                                             50
Cabbage....................
                                                                             20
Cantaloupe................
                                                                             40
Cauliflower................
                                                                             50
Celery.......................
                                                                             10
Cherries.....................
                                                                             10
Cotton......................
                                                                             10
Cucumbers................
                                                                              5
Eggplant...................
                                                                             35
Field corn..................
                                                                        <2.5
Filberts (hazelnuts)......
                                                                          <1
Grapefruit.................
                                                                             10
Grapes......................
                                                                             30
Honeydew..................
                                                                             30
Lemons.....................
                                                                              5
Lettuce......................
                                                                             65
Oranges.....................
                                                                             10
Peaches......................
                                                                              5
Pears.........................
                                                                              5
Pecans........................
                                                                             10
Peppers......................
                                                                             30
                                   Commodity
                       Average percent Crop Treated Data
Potatoes.....................
                                                                             35
Prunes.......................
                                                                          <1
Pumpkin...................
                                                                             10
Soybeans...................
                                                                          <1
Spinach.....................
                                                                             20
Squash......................
                                                                             10
Strawberries...............
                                                                             10
Sugar beets................
                                                                          <1
Sweet corn.................
                                                                          <1
Tangerines.................
                                                                              5
Tobacco....................
                                                                             20
Tomatoes...................
                                                                             15
Walnuts.....................
                                                                          <1
Watermelon................
                                                                             15
      
      In most cases, EPA uses available data from the United States Department of Agriculture/National Agricultural Statistics Service (USDA/NASS), proprietary market surveys, and the National Pesticide Use Database for the chemical/crop combination for the most recent 6 years.  EPA uses an average PCT for chronic dietary risk analysis.  The average PCT figure for each existing use is derived by combining available public and private market survey data for that use, averaging across all observations, and rounding to the nearest 5%, except for those situations in which the average PCT is less than one.  In those cases, 1% is used as the average PCT and 2.5% is used as the maximum PCT.  EPA uses a maximum PCT for acute dietary risk analysis.  The maximum PCT figure  is the highest observed maximum value reported within the recent 6 years of available public and private market survey data for the existing use and  rounded up to the nearest multiple of 5%.
      The Agency believes that the three conditions discussed in Unit III.C.1.iv. 
have been met.  With respect to Condition a, PCT estimates are derived from Federal and private market survey data, which are reliable and have a valid basis.  The Agency is reasonably certain that the percentage of the food treated is not likely to be an underestimation.  As to Conditions b and c, regional consumption information and consumption information for significant subpopulations is taken into account through EPA's computer-based model for evaluating the exposure of significant subpopulations including several regional groups.  Use of this consumption information in EPA's risk assessment process ensures that EPA's exposure estimate does not understate exposure for any significant subpopulation group and allows the Agency to be reasonably certain that no regional population is exposed to residue levels higher than those estimated by the Agency.  Other than the data available through national food consumption surveys, EPA does not have available reliable information on the regional consumption of food to which imidacloprid may be applied in a particular area.


	ii. Drinking water.  The Agency used screening level water exposure models in the dietary exposure analysis and risk assessment for imidacloprid in drinking water.  These simulation models take into account data on the physical, chemical, and fate/transport characteristics of imidacloprid.  Further information regarding EPA drinking water models used in pesticide exposure assessment can be found at http://www.epa.gov/ oppefed1/models/water/index.htm.  Based on the First Index Reservoir Screening Tool (FIRST) and Screening Concentration in Ground Water (SCI- GROW) models, the estimated drinking water concentrations (EDWCs) of imidacloprid for acute exposures are estimated to be 36.0 parts per billion (ppb) for surface water and 2.09 ppb for ground water.  Modeled estimates of drinking water concentrations were directly entered into the dietary exposure model.  For acute dietary risk assessment, the water concentration value of 36.0 ppb was used to assess the contribution to drinking water.  For chronic dietary risk assessment, the water concentration of value 17.2 ppb was used to assess the contribution to drinking water.

	2. Non-dietary exposure.  The term ``residential exposure'' is used in this document to refer to non- occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and  tick control on pets).  Imidacloprid is currently registered for the following uses that could result in residential exposures:  Indoor and outdoor ornamental plantings, ornamental lawns and turf, pre- and post-construction termiticide applications, spot-on treatments for dogs and cats, and crack and crevice treatments.  Additionally, it is registered for use on mattresses for bed bug control.  EPA assessed residential exposure using the assumption that residential pesticide handlers (i.e., persons who might mix, load and, or apply a pesticide material) could be exposed to several formulations that contain imidacloprid.  The Agency also assessed post-application exposure for adults and children contacting surfaces, foliage, or pets that were treated with imidacloprid.  Residential exposures are expected to be short-term (i.e., 1 to 30 days) or intermediate-term (1 to 6 months) based upon the pest spectra, sites of application, methods of application, formulations and the retreatment intervals. Since the indoor crack and crevice and mattress scenarios resulted in the highest potential exposures, these assessments are protective of all residential exposures from imidacloprid.  

      3. Cumulative Effects  EPA has not found imidacloprid to share a common mechanism of toxicity with 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 assumed that imidacloprid does not have 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 EPA's website at http:// www.epa.gov/pesticides/cumulative.


D. Safety Determination

	1. Infants and Children. 
      1. In general.  In the Federal Register of April 28, 2010 (FRL-8818-5), the EPA specified that Section 408(b)(2)(C) of FFDCA provides that  EPA shall apply an additional tenfold (10X) margin of safety for infants and  children in the case of threshold effects to account for prenatal and  postnatal toxicity and the completeness of the database on toxicity and  exposure unless EPA determines based on reliable data that a different margin of safety will  be safe for infants and children.  This additional margin of safety is commonly referred to as the FQPA SF. In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor.  
      2. Prenatal and postnatal sensitivity.  There was no quantitative or qualitative evidence of increased susceptibility of rat and rabbit fetuses to in utero exposure in developmental studies.  There was no quantitative or qualitative evidence of increased susceptibility of rat offspring in the multi-generation reproduction study.  There was evidence of increased qualitative susceptibility in the rat developmental neurotoxicity study; however, the concern is low for the following reasons: 
      i. The effects in pups are well characterized with a clear NOAEL;
      ii. The pup effects occur in the presence of maternal toxicity with the same NOAEL for effects in both pups and dams; and
      iii. The doses and endpoints selected for regulatory purposes are protective of the pup effects noted at higher doses in the developmental neurotoxicity study. Therefore, there are no residual uncertainties for prenatal/postnatal toxicity in this study.
      3. Conclusion.  EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced to 1X for all exposure scenarios, except acute dietary (all populations).  That decision is based on the following findings:
      i. The toxicological database for imidacloprid is complete, with the exception of an immunotoxicity study.
      ii. The toxicology database for imidacloprid does not show any evidence of treatment-related effects on the immune system.  The overall weight of evidence suggests that this chemical does not directly target the immune system.  An immunotoxicity study is required as a part of new data requirements in 40 CFR part 158 for conventional pesticide registration; however, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that  currently used for overall risk assessment.  Therefore, a database uncertainty factor (UFDB) is not needed to account for lack of this study.
      iii. There is no evidence that imidacloprid results in increased susceptibility in utero to rats or rabbits in the prenatal developmental studies or in offspring in the 2 - generation reproduction study.
      iv. A developmental neurotoxicity study was performed with imidacloprid and well-defined NOAELs were achieved in the study.
      v. There was evidence of increased qualitative susceptibility in the rat developmental neurotoxicity study; however, the concern is low for reasons stated above.
      vi. There are no residual uncertainties for prenatal/postnatal toxicity.
      vii. 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.
      viii. The chronic food exposure assessment utilizes and proposed tolerance-level residues and %CT data 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.
      ix. The dietary drinking water assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide estimates of water concentrations which will not likely be exceeded.
      x. The residential handler assessment is based upon the residential standard operating procedures (SOPs) in conjunction with chemical-specific study data in some cases and Pesticide Handler Exposure Database (PHED) unit exposures in other cases.  The majority of the residential post-application assessment is based upon chemical-specific Turf Transfer Residue (TTR) data or other chemical-specific post-application exposure study data.  The chemical-specific study data as well as the surrogate study data used are reliable and also are not expected to underestimate risk to adults as well as to children.  In a few cases where chemical-specific data were not available, the SOPs were used alone.  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.
      A 3X FQPA SF was retained in the form of a UFL (uncertainty factor due to extrapolation from a LOAEL in the absence of a NOAEL) for the acute dietary (all populations) exposure scenario only, since a NOAEL was not observed in the relevant study for that exposure scenario (acute neurotoxicity study in rats).  A 3X uncertainty factor was judged to be adequate (as opposed to a 10X) for the following reasons:
      1. The LOAEL (42 mg/kg) is comparable to the LOAELs seen in adults in the developmental rat study (30 mg/kg/day) and the 2 - generation reproduction study [47/52 milligrams/ kilograms/day (mg/kg/day) (male/ female)] and in the offspring in the DNT study (55 mg/kg/day);
      2. The extrapolated NOAEL of 14 mg/kg (42/3 = 14) is comparable to the NOAEL of 20 mg/kg/day established in the offspring in the DNT; and,
      3. The neurotoxic effects in this study showed a good dose response which resulted in minimal effects on motor activity and locomotor activity at the LOAEL.


E. Safety Determination

      In the Federal Register of April 28, 2010 (FRL-8818-5), the EPA specified that EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD.  The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate SFs. EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs.  For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure.  Short-, intermediate, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable UFs is not exceeded.
      1. Acute risk.  An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumption of food and drinking water.  No adverse effect resulting from a single-oral exposure was identified and no acute dietary endpoint was selected.  Therefore, imidacloprid is not expected to pose an acute risk.  Using the exposure assumptions discussed in this unit for acute exposure, the acute dietary exposure from food and water to imidacloprid will occupy 70% of the aPAD for (children 1 to 2 years old) the population group receiving the greatest exposure.
      2. Chronic risk.  Using the exposure assumptions described in this unit for chronic exposure, EPA has concluded that chronic exposure to imidacloprid from food and  water will  utilize 32%  of the cPAD for (children 1 to 2 years  old) the population group receiving the greatest exposure.  Based on the explanation in Unit III.C.3., regarding residential use patterns, chronic residential exposure to residues of imidacloprid is not expected.
      3. Short-term risk.  Short-term aggregate exposure takes into account short-term residential exposure plus chronic exposure to food and  water (considered to be a background exposure level).  Imidacloprid is currently registered for crack and  crevice uses  and  bed bug uses  that  could result in short-term residential exposure and  the Agency has determined that  it is appropriate to aggregate chronic exposure through food and  water with short-term residential exposures to imidacloprid.  Using the exposure assumptions described in Unit III.C.3. for short-term exposures, EPA has concluded the combined short-term food, water, and residential exposures aggregated result in aggregate MOEs of 430 for adults and 170 for children.  Toddlers' residential short-term aggregate exposure includes dermal and inhalation exposure from the crack and crevice uses, dermal exposure from the bed-bug uses, and incidental oral exposure from hand-to-mouth contact with treated surfaces.  Adult short-term aggregate exposure includes dermal and inhalation exposure from indoor crack and crevice uses, and dermal exposure from the bed-bug uses.  These exposures were higher than those calculated for all other residential uses of imidacloprid.  Therefore, the crack and crevice and bed bug treatment exposure estimates were aggregated with the chronic dietary to provide a worst-case estimate of short- term aggregate risk for the U.S. population and children 1 to 2 years old.  The combined short-term residential MOEs for these scenarios were 580 for adults and 240 for children.
      4. Intermediate-term risk. Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level).  
      Imidacloprid is currently registered for crack  and  crevice uses  and  bed bug uses  that  could result in intermediate- term  residential exposure and  the Agency has determined that  it is appropriate to aggregate chronic exposure through food and  water with intermediate-term residential exposures to imidacloprid.
      Using the exposure assumptions described in Unit III.C.3. for short-term exposures, EPA has concluded the combined short-term food,  water, and residential exposures aggregated result in aggregate MOEs of 400 for adults and 150 for children.  Toddlers' residential intermediate-term aggregate exposure includes dermal and inhalation exposure from the crack and crevice uses, dermal exposure from the bed-bug uses, and incidental oral exposure from hand-to-mouth contact with treated surfaces.  Adult intermediate-term aggregate exposure includes dermal and inhalation exposure from indoor crack and crevice uses, and dermal exposure from the bed-bug uses.  These exposures were higher than those calculated for all other residential uses of imidacloprid.  Therefore, the crack and crevice and bed bug treatment exposure estimates were aggregated with the chronic dietary exposure to provide a worst-case estimate of intermediate-term aggregate risk for the U.S. population and children 1 to 2 years old.  The combined intermediate-term residential MOEs for these scenarios were 540 for adults and 260 for children.
      5. Aggregate cancer risk for U.S. population.  Based on the lack of evidence of carcinogenicity in mice and rats at doses that were judged to be adequate to assess the carcinogenic potential, imidacloprid was classified as ``not likely to be carcinogenic to humans,'' and is not expected to pose a cancer risk to humans. Therefore, a quantitative cancer risk assessment is not needed.
      6. Determination of safety. Based on these risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to imidacloprid residues.

F. International Tolerances

      There are no established Mexican, Canadian or Codex maximum residue limits (MRLs) for the proposed new uses.  


