Document ID: EPA-HQ-OPP-2011-0403-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-03-28T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[Nippon Soda Co., Ltd.]

[0F7812]

	EPA has received a pesticide petition ([0F7812]) from [Nippon Soda Co., Ltd.], [c/o Nisso America Inc., 45 Broadway, Suite 2120, New York, NY, 10006] 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
[acetamiprid] in or on the raw agricultural commodity [food/feed handling establishments] at [0.05] parts per million (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 supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. [The metabolism of acetamiprid in plants is well understood, having been investigated in eggplant, apples, cabbage, carrots, and cotton.]

	2. 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 toxic residues.  As a result a method was developed that involves extraction of acetamiprid from composite meals with a solvent followed by a decantation and filtration and finally analysis by a LC/MS/MS method.  The limit of quantification (LOQ) and the limit of detection for the method are calculated to be 0.05 ppm and 0.01 ppm for composite meals, respectively.  The method was reliable for composite meal analyses with an overall average recovery of 93 +- 14%.]

	3. Magnitude of residues. [Magnitude of residue was determined in a test designed to simulate a representative worst-case exposure of various stored covered and uncovered food products to spot or crack & crevice treatment of acetamiprid in a restaurant, warehouse, food processing plant or other food/feed handling establishment.  The trial was conducted as specified in the Residue Chemistry Guideline OPPTS 860.1460 with applications at both 2X and 8X maximum label use rate.  No residue was detected in any composite meal that was analyzed.]

B. Toxicological Profile

   	1. Acute toxicity.  [Acute Toxicity for Technical Acetamiprid- The acute oral LD-50 for acetamiprid was 146 mg/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 LC-50 for acetamiprid was greater than 1.15 mg/L, the highest attainable concentration.  Acetamiprid was not irritating to the eyes or skin and was not considered to be a sensitizing agent. The NOEL 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 1107mg/kg for male rats.  The acute dermal LD-50 for formulated acetamiprid was greater than 2000mg/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 F4688 50 WSP  -  The acute oral LD-50 for F4688 50 WSP in the rat was 550 mg/kg.  The acute dermal LD-50 for F4688 50 WSP in the rabbit was >2000 mg/kg.  The acute inhalation (4 hour exposure) in the rat resulted in a LC-50 of >0.51 mg/l.  Ocular administration of F4688 50 WSP in the rabbit produced irritation which cleared within 72 hours.  F4688 50 WSP is not considered a dermal irritant nor is it considered a skin sensitizer.
   Acute Toxicity for Formulated Acetamiprid F5688 11% ME  -  The acute oral LD-50 for F5688 11% ME in the rat was 1035 mg/kg.  The acute dermal LD-50 for F5688 11% ME in the rat was >5000 mg/kg.  The acute inhalation (4 hour exposure, nose only) in the rat resulted in a LC-50 of >2.2 mg/l.  Ocular administration of F5688 11% ME in the rabbit produced mild irritation.  F5688 is not considered a dermal irritant nor is it considered a skin sensitizer.]

	2. 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 non-clastogenic in an in vivo chromosomal aberration study in rat bone marrow.  It also was negative in an in vivo mouse bone marrow micronucleus assay.]

   	3. Reproductive and developmental toxicity. [In the multi-generation rat reproduction study a NOEL of 100 ppm was established based on decreased body weight gains and a reproduction NOEL of 800 ppm (highest dose tested) was established for reproductive performance and fertility. In the rat teratology study the developmental NOEL was 50 mg/kg/day (maternal NOEL of 16 mg/kg/day based on decreased body weight and food consumption) and in the rabbit teratology study the developmental NOEL was 30 mg/kg/day (maternal NOEL 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 NOEL 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 NOEL 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 NOEL 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 NOEL 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.]

   	5. Chronic toxicity. [In the 1-year dog study, the NOEL 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 NOEL 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 NOEL 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.]

	6. Animal metabolism. [The metabolism of acetamiprid is well understood and the primary animal metabolite is IM-2-1.]

	7. 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.]

	8. 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.]

	9. 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 no-observed-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 analyses were previously conducted to estimate exposure to potential acetamiprid residues in/on the following crops:  cole crop group, 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, and tea.  The assessment also included anticipated residues in meat, milk, poultry, and eggs.  Exposure estimates to drinking water were made based on conservative FIRST and SCI-GROW modeling.  The additional dietary exposure from the use of proposed spot or crack & crevice treatments of acetamiprid in food/feed handling establishments is expected to be negligible and remain within acceptable levels.]

   	i. Food. [Based on the current labeled uses and using field trial data, percent crop-treated values, various empirical processing factors, and including estimated drinking water concentrations (EDWC), both acute and chronic dietary risk estimates for all population subgroups do not indicate a risk of concern.  Children 1-2 years old are the highest exposed population subgroup for both acute and chronic exposure scenarios.  Acute exposure constituted 43% of the acute population adjusted dose (aPAD) and chronic exposure constituted 15% of the chronic population adjusted dose (cPAD). The aPAD was based on the NOEL of 10 mg/kg/day in the developmental neurotoxicity study in rats and an uncertainty factor of 100.  The cPAD was based on the NOEL of 7.1 mg/kg/day in the chronic rat study and an uncertainty factor of 100.  An uncertainty factor of 100 was used because in the Final Rule establishing tolerances for acetamiprid on clover, grapes, and tea (Federal Register, Vol. 75, No. 27 / Wednesday, February 10, 2010 / Page 67256), EPA concluded that reliable data show the safety of infants and children  would be adequately protected if the FQPA safety factor was reduced to 1X. 
   
Any increase in acute and chronic dietary exposure from the use of spot or crack & crevice treatments of actetamiprid in food/feed handling establishments is expected to be negligible and therefore the aPAD and cPAD would remain within acceptable levels (e.g., <= 100%).]

   	ii. Drinking water. [Estimated drinking water residues were incorporated directly into the EPA's dietary assessment for the current labeled uses as mentioned in the most recent acetamprid pesticide tolerance Final Rule found in the Federal Register/ Vol.75, No. 27/ Wednesday, February 10, 2010.  Acute and chronic estimates of drinking water concentrations (EDWCs) in surface water were generated using the screening mechanistic model FIRST.  Ground water concentration estimates were generated using the screening regression model SCI-GROW.  The EDWC for surface water was 20.1 ppb for acute exposures and 4.9 ppb for chronic exposure while the ground water EDWC was 0.0016 ppb.  
   
The proposed use of spot or crack & crevice applications of acetamiprid indoors in food/feed handling establishments is not expected to increase the EDWC values.]

   	2. Non-dietary exposure. [Acetamiprid is registered for the following residential non-dietary sites:  pre- and post-construction termiticide/insecticide in subterranean or hard-to-reach structure components and building perimeters, indoor and outdoor crack & crevice or spot treatments of gel baits, and a Ready to Use (RTU) and concentrate formulations for homeowner use outdoors on fruit, vegetables and ornamentals.  The residential exposure from the registered termiticide/insecticide use is considered negligible for handler and post-application exposure due to the label restriction limiting handlers to licensed individuals (e.g., Pest Control Operators) and to the application target site being typically inaccessible.  Post-application exposure to the gel bait formulation is considered negligible due to the crack & crevice or spot application method, the low vapor pressure of acetamiprid, and the use of a bittering agent in the formulation to reduce the potential for incidental ingestion.  Lastly, homeowner MOEs from potential handler and post-application exposure to the residential use products are well within the acceptable range (i.e., > 100).  Using EPA's HED SOP for Residential Exposure Assessments (5/5/00), an assessment of post-application dermal exposure and risk from the proposed use of crack & crevice treatments of acetamprid in indoor food/feed handling establishments resulted in MOEs >= 473 for children and MOEs >= 680 for adults.  Similarly, a risk assessment of incidental nondietary ingestion exposure to children from crack & crevice treatment of acetamiprid in indoor areas resulted in MOEs >= 1420.
   
    With the existing uses acetamiprid, the acute aggregate risk is equal to the acute dietary exposure via food and drinking water and is estimated at 43% of the aPAD for the population group potentially receiving the greatest exposure, children 1 to 2 years old.  The incremental exposure from the proposed spot or crack & crevice applications of acetamiprid in food/feed handling establishments is expected to be negligible and therefore does not pose an acute aggregate risk concern.
    
     In the Final Rule establishing new tolerances for acetamiprid published in the February 10, 2010 Federal Register, EPA concluded that the combined short-term and intermediate-term food, water, and residential aggregated exposures result in an aggregate MOE of 270 for toddlers, the population group receiving the greatest combined short-term and intermediate-term risk (from the combine dermal and incidental oral postapplication exposures following indoor crack and crevice treatments).  MOEs greater than 100 are considered acceptable. The incremental exposure from the proposed spot or crack & crevice applications of acetamiprid in food/feed handling establishments is expected to be negligible and therefore does not pose a short- and intermediate-term aggregate risk concern.
    
    Chronic aggregate risk is estimated through the food and drinking water exposure pathways which are the only source of chronic exposure to acetamiprid (e.g., 180+ consecutive days).  Therefore the current chronic aggregate exposure and risk estimates are equivalent to the chronic dietary risk estimate which is 15% of the cPAD for the population group potentially receiving the greatest exposure, children 1 to 2 years old.  The incremental exposure associated with the proposed spot and crack & crevice treatment of acetamiprid in food/feed handling establishments is expected to be negligible and therefore does not pose a chronic risk concern.]

D. 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.]

E. Safety Determination

	1. U.S. population. [Based on assessments estimating the aggregate risk from the current uses of acetamiprid and the negligible incremental exposure and risk from the proposed spot or crack & crevice use in food/feed handling establishments, there is a reasonable certainty that no harm will result to the U.S. general population from aggregate exposure to acetamiprid residues.]

	2. Infants and children. [Based on assessments estimating the aggregate risk from the current uses of acetamiprid and the negligible incremental exposure and risk from the proposed spot or crack & crevice use in food/feed handling establishments, there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to acetamiprid residues.]

F. International Tolerances

	[Acetamiprid is registered for use on food crops in several countries outside the United States.  There are no Codex, Canadian or Mexican maximum residue levels (MRLs) establish on the commodity (i.e., food/feed handling establishments) associated with this petition.]