Document ID: EPA-HQ-OPP-2014-0740-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-12T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2014-0740

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

Interregional Research Project Number 4 
Pesticide Petition Number: 4E8307
EPA has received a pesticide petition number (PP#) 4E8307 from the Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters,  Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450  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 180.578 (c) by establishing tolerances with a regional registration for residues of the insecticide acetamiprid (1E)-N-[(6-chloro-3-pyridinyl)methyl]-N'-cyano-N-methylethanimidamide, including its metabolites and degradates, to be determined by measuring only acetamiprid in or on the raw agricultural commodities: clover forage at 0.3 part per million (ppm) and clover hay at 1.5 ppm. In addition, the petitioner proposes that upon approval of the above-mentioned tolerances to remove existing tolerances at 40 CFR 180.578 (c) that are superseded by this action for Clover, forage at 0.10 ppm, and Clover, hay at 0. 01 ppm.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 
 
 Plant metabolism. The metabolism of acetamiprid in plants is well understood, having been investigated in eggplant, apples, cabbage, carrots, and cotton. 
 
 Analytical method. Based upon the metabolism of acetamiprid in plants and the toxicology of the parent and metabolites, quantification of the parent acetamiprid is sufficient to determine residues of concern for enforcement purposes.  As a result a method was developed that involves extraction of acetamiprid from crop matrices with a solvent followed by a decantation and filtration and finally analysis by a liquid chromatography (LC)/mass spectroscopy (MS)/MS method.   For clover matrices, the respective limits of detection (LOD) and limits of quantitation (LOQ) were:  forage -- 0.0025 ppm and 0.0069  -  0.0075 ppm, and hay-0.0012  -  0.0035 ppm and 0.0035  -  0.0104 ppm.  The lowest level of method validation (LLMV) for each clover matrix was 0.01 ppm for acetamiprid.   Based on acceptable recoveries, the analytical method was reliable for the tested matrices. 
 
 Magnitude of residues. Magnitude of residue was determined in a tests designed to simulate a representative worst-case exposure.  The trials were conducted as specified in the Residue Chemistry Guidelines.   
 
Separate magnitude of the residue studies with clover were conducted by the IR-4 Project in the U.S. in 2006, 2010, and 2012. 
Acetamiprid, the active ingredient in ASSAIL(R) 30 SG, is used on clover for control of clover aphid (Nearctaphis bakeri) and pea aphid (Acyrthosiphon pisum) on clover.  In 2009, the results from three clover trials, conducted in Oregon in 2006, were submitted to EPA to obtain a tolerance (MRID 47716901).  The Health Effects Division of EPA ruled that because all three of the clover field trials were conducted at the same site within two weeks of each other, it did not consider them to be three separate trials; thus, they ruled that two additional clover field trials reflecting the same use pattern utilized in the submitted studies were required as a condition of registration.  To satisfy this condition, two trials were conducted for this study during the 2010 growing season, both in Oregon (Region 11).   
 
At each 2010 trial, one foliar broadcast application of ASSAIL(R)t30 SG at a rate of approximately 0.075 lb ai/A was targeted at 30 (+/-3) days before the harvest of forage samples.  A nonionic surfactant spray additives was added to the spray mixture.  The actual applications were made at 29-32 days before the harvest of the forage samples.  Additionally, hay samples were cut at a normal harvest time and allowed to dry in the field (in a hoophouse) and the hay samples then collected. 
 
Sample analysis for residues of acetamiprid was conducted by the IR-4 North Central Research Center, Michigan State University, 3900 Collins Road, Lansing, MI.  The method used for analysis was an adaptation of the analytical method "KP-216R1, Preliminary LC/MS/MS Analytical Method for the Determination of AssailTM 70WP Insecticide (Acetamiprid) in Crop Matrices", by Fenn Li and Paul Reibach, Cerexagri Company, Sep 06, 2003.   
 
The nature of the residues of acetamiprid is adequately understood and an acceptable analytical method is available for enforcement purposes.   
 
The maximum storage intervals for clover forage and hay samples in this study were 519 days and 516 days, respectively.  Storage stability samples of clover forage and hay fortified at 0.10 ppm acetamiprid were analyzed after 509 days and 510 days, respectively and yielded recoveries that averaged 96% and 72%, respectively.  The validated sensitivity of the method is 0.01 ppm in clover forage and hay.   
 
The results from the two trials conducted in 2010 show that the maximum residue in clover forage and hay following a total application of approximately 0.075 lb ai/A and a pre-harvest interval (PHI) of 29-32 days was 0.117 ppm in forage and 0.70 ppm in hay. 
 
The two trials performed in 2010 however, produced forage and hay samples that were either sampled sooner or dried faster than the original 2006 trials.  Additional trials were thus conducted in 2012 to bridge the 2006 and 2010 trials and support the original request for a regional pesticide registration and also provide data to support a shorter PHI for hay samples.   
 
At each 2012 trial, one foliar broadcast application of ASSAIL(R) 30 SG at a rate of approximately 0.075 lb ai/A was targeted at 30 (+/-3) days before the harvest of forage samples.  A nonionic surfactant spray additive was added to the spray mixture. The actual applications were made at 27-30 days before the harvest of the forage samples. Additionally, forage samples were cut at 27-30 days (a normal harvest time) and also at 50  - 53 days and these cuttings allowed to dry in an open air greenhouse and the dried hay samples collected.   
 
As with the 2010 trials, sample analysis for residues of acetamiprid was conducted by the 
IR-4 North Central Region Laboratory, Michigan State University, 3900 Collins Road, 
Lansing, MI.  The method used for analysis was an adaptation of the analytical method 
"KP-216R1, Preliminary LC/MS/MS Analytical Method for the Determination of 
AssailTM 70WP Insecticide (Acetamiprid) in Crop Matrices", by Fenn Li and Paul Reibach, Cerexagri Company, Sep 06, 2003. The validated sensitivity of the method is 0.01 ppm in clover forage and hay.  
 
The maximum storage intervals for clover forage and hay samples in the 2012 trials were 247 days and 245 days, respectively, and within the timeframe showing stability of residues determined with the 2010 study samples.   
 
The results from the two trials from 2012 show that the maximum residue in clover forage and hay following a total application of approximately 0.075 lb ai/A and a preharvest interval (PHI) of 27-30 days was 0.169 ppm in forage (approx. 30 days) and 0.763 ppm in hay (approx. 30 days) and 0.116 ppm in hay (approx. 50 days). 
 
B. Toxicological Profile 
 
 1. Acute toxicity.  Acute Toxicity for Technical Acetamiprid- The acute oral lethal dose (LD)-50 for acetamiprid was 146 milligram (mg)/kilogram (kg) for female Sprague-Dawley rats and 217 for male rats.  
The acute dermal LD-50 for acetamiprid was greater than 2000 mg/kg in rats.  The acute 4 hour inhalation lethal concentration (LC)-50 for acetamiprid was greater than 1.15 mg/Liter (L), the highest attainable concentration.  Acetamiprid was not irritating to the eyes or skin and was not considered to be a sensitizing agent. The no-observed adverse-effect level (NOAEL for acute neurotoxicity was 10mg/kg and no evidence of neuropathy was noted.   
Acute Toxicity for Formulated Acetamiprid 70WP-The acute oral LD-50 for Acetamiprid 
70WP was 944 mg/kg for female Sprague-Dawley rats and 1107 mg/kg for male rats.  The acute dermal LD-50 for formulated acetamiprid was greater than 2000 mg/kg in rats. The acute inhalation LC-50 (four hour) for Acetamiprid 70WP was determined to be greater than 2.88 mg/L, the highest attainable concentration.  Acetamiprid 70WP was concluded to be a mild eye irritant and slight skin irritant.  There were no indications of skin sensitization for the formulated product. 
Acute Toxicity for Formulated Acetamiprid 30 SG  -  The acute oral LD-50 for Acetamiprid 30 SG was 805 mg/kg for female Sprague-Dawley rats and 886 mg/kg for male rats.  The acute dermal LD-50 for the formulation was greater than 200 mg/kg in rats.  An acute inhalation toxicity test was waived for the formulation due to the nonrespirable particle size of the formulation.  Acetamiprid 30 SG was found to be a moderate eye irritant and mild skin irritant.  There were no indications of skin sensitization for the formulated product. 
 
 Genotoxicty. [Based on the weight of the evidence provided by a complete test battery, acetamiprid is neither mutagenic nor genotoxic.  The compound was found to be devoid of mutagenic activity (with and without metabolic activation) in Salmonella typhimurium and Escherichia coli (Ames assay).  Acetamiprid was also not mutagenic in an in vitro mammalian cell gene mutation assay on Chinese hamster ovary (CHO) cells (HPRT locus, with and without metabolic activation).  Acetamiprid did not induce unscheduled DNA synthesis (UDS) in either rat liver primary cell cultures or in mammalian liver cells in vivo.  In an in vitro chromosomal aberration study using CHO cells, acetamiprid was positive when tested under metabolic activation at cytotoxic dose levels; no effect was detected without metabolic activation.  Acetamiprid was nonclastogenic in an in vivo chromosomal aberration study in rat bone marrow.  It also was negative in an in vivo mouse bone marrow micronucleus assay. 
 
 Reproductive and developmental toxicity. In the multi-generation rat reproduction study a NOAEL of 100 ppm was established based on decreased body weight gains and a reproduction NOAEL of 800 ppm (highest dose tested) was established for reproductive performance and fertility. In the rat teratology study the developmental NOAEL was 50 mg/kg/day (maternal NOAEL of 16 mg/kg/day based on decreased body weight and food consumption) and in the rabbit teratology study the developmental NOAEL was 30 mg/kg/day (maternal NOAEL of 15 mg/kg/day based on decreased body weight and food consumption).  In both the rat and rabbit studies there were no fetotoxic or teratogenic findings. 
    
A developmental neurotoxicity study in rats with acetamiprid was conducted.  The test article was administered orally by gavage to Crl:CD(SD)IGS BR rats once daily from gestation day 6 through lactation day 21 inclusive at dosage levels of 2.5, 10, and 45 mg/kg/day.  One female in the 45 mg/kg/day group died during parturition on gestation day 23, following delivery of one pup.  All other females survived to the scheduled necropsies.  No adverse clinical signs were noted.  F0 maternal toxicity was expressed at a dose level of 45 mg/kg/day by a single mortality and reductions in body weight gain and food consumption.  No maternal toxicity was exhibited at dose levels of 2.5 and 10 mg/kg/day.  F1 developmental toxicity was expressed at a dose level of 45 mg/kg/day by early postnatal mortality and reduced post-weaning body weights.  No developmental toxicity was exhibited at dose levels of 2.5 and 10 mg/kg/day.  Deficits in auditory startle response occurred in the 45 mg/kg/day group F1 males and females without concomitant effects in other functional endpoints (FOB), neuropathology or brain morphometry.  Based on the results of this study, the NOAEL for maternal toxicity, developmental toxicity and developmental neurotoxicity is considered to be 10 mg/kg/day. 
 
 4. Subchronic toxicity. In the 3-month dog feeding study a NOAEL of 800 ppm (32 mg/kg/day for both males and females) was established based on growth retardation and decreased food consumption.  
In the 3-month rat feeding study a NOAEL of 200 ppm (12.4 and 14.6 mg/kg/day respectively for male and female rats) was established based on liver cell hypertrophy at a dose of 800 ppm. 
In the 3-month mouse feeding study a NOAEL of 400 ppm (53.2 and 64.6 mg/kg/day respectively for male and female mice) was established based on increased liver/body weight ratio and decreased cholesterol in females at 800 ppm.  
A 13 week dietary neurotoxicity study for acetamiprid established a NOAEL of 200 ppm (14.8 and 16.3 mg/kg for male and female rats) based on reduced body weight and food consumption decreases at 800 ppm.  There was no evidence of neurotoxicity.   
A 21 day dermal study in rabbits at dose levels up to 1000 mg/kg/day caused no systemic toxicity, dermal irritation or histomorphological lesions in either sex tested. 
 
Chronic toxicity. In the 1-year dog study, the NOAEL was established at 600 ppm (20 and 21 mg/kg/day for male and female dogs, respectively) based on growth retardation and decreased food consumption at a dose of 1500 ppm.  
In the 18-month mouse study the NOAEL was established at 130 ppm (20.3 and 25.2 mg/kg/day for male and female mice) based on growth retardation and hepatic toxicity at 400 ppm. 
In the 2-year rat study the NOAEL was 160 ppm (7.1 and 8.8 mg/kg/day for male and female rats) based on growth retardation and hepatic toxicity.  There were no indications of carcinogenicity in either the rat or mouse chronic studies. 
 
 Animal metabolism.  The metabolism of acetamiprid is well understood and the primary animal metabolite is IM-2-1. 
 
 Metabolite toxicology.  Testing of IM-2-1 demonstrated that it is significantly less toxic than the parent acetamiprid and it is not being considered as part of the total toxic residue in plants, therefore no tolerance is being requested by the registrant.  The acute oral LD50 of IM-2-1 is 2543 mg/kg for male rats and 1762 mg/kg for female rats. 
 
 Endocrine disruption.  Acetamiprid does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system.  Developmental toxicity studies in rats and rabbits and a reproductive study in rats gave no indication that acetamiprid has any effects on endocrine function.  The chronic feeding studies also did not show any long-term effects related to endocrine systems. 
 
 Immunotoxicity.  Dietary administration of acetamiprid to CD-1 mice at concentrations up to 900 ppm for four weeks caused a non-specific toxic response at 300 ppm in females and 900 ppm in both sexes but there was no effect on the immune function, as assessed by the measurement of antigen-specific, T-cell dependent antibody formation.  The no-observed-effect level in mice for immunotoxicity by acetamiprid was therefore greater than 900 ppm (i.e., >128 mg/kg/day in males and > 157 mg/kg/day in females).  Dietary administration of acetamiprid to Sprague Dawley rats at concentrations up to 900 ppm for four weeks caused a non-specific toxic response at 300 ppm in males and 900 ppm in both sexes but there was no effect on the immune function, as assessed by the measurement of antigen-specific, T-cell dependent antibody formation.  The noobserved-effect level in rats for immunotoxicity by acetamiprid was therefore greater than 900 ppm (i.e., >62.9 mg/kg/day in males and > 67.7 mg/kg/day in females). 
 
C. Aggregate Exposure 
 
 	1. Dietary exposure.  Acute and chronic dietary exposure analyses were conducted by the Agency (Health Effects Division (HED) memo, March 7, 2013) to estimate exposure to potential acetamiprid residues in/on the following crops: asparagus, leafy and head cole crop groups and turnip greens, citrus crop group, fruiting vegetable crop group, pome fruit crop group, grapes, leafy vegetables, canola oil, mustard seed, cotton, tuberous and corm vegetable crop group, cucurbit crop group, stone fruit crop group, tree nut crop group (including pistachio), berries, bulb vegetables, succulent legumes (excluding soybeans), clover, tea, soybeans, food handling establishments, and sweet corn.  The assessment also included residues in meat, milk, poultry, and eggs using the currently established tolerance levels for these commodities.  Exposure estimates from drinking water were made based on conservative FQPA Index Reservoir Screening Tool (FIRST) and Screening Concentration in Ground Water (SCI-GROW) modeling.   
 
The additional dietary exposure from the use of acetamiprid on clover is expected to remain within acceptable levels since the dietary assessment was unrefined with assumptions of 100% crop treated and tolerance-level crop residues for all existing and proposed uses. 
 
 	i. Food.  Tolerance-level and 100% crop treated values were used to estimate chronic and acute dietary exposure to potential residue of acetamiprid in food.   Chemical-specific processing factors were used for processed commodities.  In the absence of chemical-specific processing factors, Dietary Exposure Evaluation Model (DEEM)[TM] Version 7.81 default processing factors were used where appropriate. 
 
Chronic dietary exposures to acetamiprid were compared against a chronic population adjusted dose (cPAD) of 0.071 mg/kg bw/day.  The cPAD is based on the chronic no NOAEL of 7.1 mg/kg bw/day from a chronic toxicity/oncogenicity study in rats and an uncertainty factor of 100.  No FQPA safety factor is necessary, so the cPAD is identical to the chronic reference dose (cRfD). 
 
Chronic exposure (food + drinking water) was conservatively estimated for the overall US population and select population subgroups.  Chronic exposure for the overall US population was estimated to be 0.009604 mg/kg bw/day, representing 14% of the cPAD.  Exposure for the most highly exposed population subgroup, children 1-2 years old, was calculated to be 0.04261 mg/kg bw/day, or 60% of the cPAD.  
 
Acute dietary exposure to potential acetamiprid residues was compared against the 
NOAEL of 10 mg/kg bw/day from the developmental neurotoxicity study in rats.  Based on the acute NOAEL and an uncertainty factor of 100, the acute Reference Dose (aRfD) is 0.1 mg/kg bw/day.  No FQPA safety factor is necessary so the acute population adjusted dose (aPAD) is identical to the aRfD. 
 
Results of the conservative acute dietary (food + water) exposure analysis demonstrate that exposure at the 95[th] percentile is less than the aPAD for all population groups.  For the general US population, the 95[th] percentile exposure is 0.024916 mg/kg/day or 25% of the aPAD.  For the most highly exposed population subgroup, children 1-2 years old, acute dietary exposure at the 95[th] percentile of exposure was calculated to be 0.067723 mg/kg/day and represents 68% of the aPAD. 
 
 	ii. Drinking water.  Residues in surface water were estimated by EPA using the FIRST model and were 95.2 ppb for acute exposure and 26.6 ppb for chronic exposure.  The ground water concentration was estimated to be 0.035 ppb using the SCI-GROW model.  The surface and ground water estimates were based on a use for acetamiprid as a scatter bait for fly control (i.e. maximum use pattern) and it is assumed that the clover use would not be associated with higher concentrations in water.  The surface water estimates of 26.6 ppb and 95.2 ppb were used in the chronic and acute dietary assessments, respectively, because they provide the most conservative estimates of dietary exposure via acetamiprid residues in water.   
 
The use of acetamiprid on clover is not expected to increase the Estimated Drinking Water Concentration (EDWC) values. 
 
 	2. Non-dietary exposure.  Residential post-application exposures and margins of exposure (MOEs) for children , 3-6 years contacting acetamiprid residues following indoor crack & crevice application were estimated by EPA in 2013 (March 20, 2013 HED memo) and was above 100.  Aggregate MOEs for children, 1-2 years were estimated to be 120 for both the short- (1 to 30 days) and intermediate-term (1 to 6 months) scenarios.  MOEs greater than 100 indicate that aggregate exposures for toddlers are not of concern. 
 
 Cumulative Effects 
 
 A determination has not been made that acetamiprid has a common mechanism of toxicity with other substances.  Acetamiprid does not appear to produce a common toxic metabolite with other substances.  A cumulative risk assessment was therefore not performed for this analysis. 
 
 Safety Determination 
 
 U.S. population.  Based on assessments estimating the aggregate risk from the current uses of acetamiprid and the use on clover there is a reasonable certainty that no harm will result to the U.S. general population from aggregate exposure to acetamiprid residues. 
 
 Infants and children.  Based on assessments estimating the aggregate risk from the current uses of acetamiprid and the potential exposure from clover there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to acetamiprid residues. 
 
 International Tolerances 
 
 Acetamiprid is registered for use on food crops in several countries outside the United States.  Codex Maximum Residue Limits (MRLs) are established for acetamiprid.