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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: Jennifer Urbanski, tel. no. (703) 347**  **- 0156**  **INSTRUCTIONS: Please utilize this ou**  **tline 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 c/o Nisso America Inc. Petition number 2F8060 EPA has received a pesticide petition ( 2F8060 ) from Nippon Soda Co., Ltd. c/o Nisso America Inc., 88 Pine St., 14 th FL ., New York, NY 10005 request ing, 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 ( Options (pick one) 1. by establishing a tolerance for residues of Acetamiprid in or on the raw agricultural commodity Citrus Fruits, Crop Group 10 and Citrus, dried pulp, at 1.0 and 2.4 parts per million (ppm) , respectively . EPA has determined that the petition contains data or information regarding th e 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 petit ion. A. Residue Chemistry 1. Plant metabolism. 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 residue s. As a result, a method has been developed which involves extraction of acetamiprid from various matrices with solvents and anal ys is by

L C/MS/MS methods. An anal yt ic method to determine acetamiprid residue in citrus currently exists, as provided in MRI Ds 44988525 and 44988526. ]2 3. Magnitude of residues. Twelve residue field trials looking at various rates, PHI s, and number of applications of acetamiprid were conducted in Europe on oranges (5 trials), tangerines (5 trials) and lemons (2 trials). Accordi ng to the European Food Safety

Authority

(EFSA), a citrus crop group tolerance of 1 ppm is supported by

these data and is established in the EU. To accommodate international trade of citrus crops that are being treated with acetamiprid in Europe, the acet amiprid tolerance for citrus in the United States needs to increase from 0.5 ppm to 1.0 ppm. For the chronic dietary exposure anal ys is, tolerance level residues were assumed for all commodities (registered, pending and proposed), resulting in a conservati ve estimate of potential exposures. For the acute dietary

exposure analy sis, EPA policy permits the use of mean residues in acute assessments only

for blended foods (e.g., oils, grains, beans, etc.), and distributions of data from the field trial studies were used for non - blended and partially blended foods (EPA, 1999). For conservatism, tolerance - level (1.0 ppm) residues were assumed for citrus fruit imported from Europe. B. Toxicological Profile 1. Acute toxicity. Acute Toxicity

for Technical Acetamipr id - 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 L C - 50 for acetamiprid was greater than 1.15 mg/L, the highest attainable concentration. Acetamiprid was not irritating to the ey es or skin and was not considered to be a sensitizing agent. The NOEL for acute neurotoxicity was 10 mg/kg and no evidence of neuropathy was noted. Acute Toxicity

for For mulated Acetamiprid 70WP - The acute oral LD - 50 for Acetamiprid 70WP was 944 mg/kg for fe male Sprague - Dawley rats and 1107 mg/kg for male rats. The acute dermal LD - 50 for formulated acetamiprid was greater than 2000mg/kg in rats. The acute inhalation L C - 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 fo rmulated 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 L C - 50 of >0.51 mg/1. 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 for3 F5688 11% ME in the rat was >5000 mg/kg. The acute inhalation (4 hour exposure, nose only) in the rat resulted in a L C - 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. Acute Toxicity

for Formulated Acetamiprid Justice Insecticide - The acute oral LD - 50 for Justice in the rats was 439 mg/kg. The acute dermal LD - 50 for Justice in the rat was >5000 mg/kg. The acute inhalation (4 hour exposure, nose only) in the rat resulted in a LC - 50 of >5.05 mg/l. Ocular administration of Justice in the rabbit produced mild irritation. Justice is not considered a dermal irritant nor is it considered a skin sensitizer. Acute Toxicity

for Formulated Acetamiprid Gazel Insecticide - The acute oral LD - 50 for Justice in the rats was 1000 - 2000 mg/kg. The acute dermal LD - 50 for Ga zel in the rat was >2000 mg/kg. The acute inhalation (4 hour exposure, nose only) in the rat resulted in a L C - 50 of >3.5 mg/l. Gazel is not considered a primary ey e irritant, dermal irritant or a skin sensitizer. 2. Genotoxicty. Genetic Toxicity

for Technical Acetamiprid - Based on the weight of the evidence provided b y 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 ty ph imurium 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 sy nthesis (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 cy totoxic dose levels; no ef

fect 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 tox icity. Inthe multi - generation rat reproduction stud y a NOELof 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 ter atology study the developmental NOEL was 50 mg/kg/day (maternal NOEL of 16 mg/kg/day based on decreased bod y weight and food consumption) and in the rabbit teratology

study the developmental NOEL was 30 mg/kg/day (maternal NOELof 15 mg/kg/day

based on dec reased bod y 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. The4 test article was administered orall y b y gavage to Cri: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. F 0 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 w as exhibited at dose levels of 2.5 and 10 mg/kg/day . F 1 developmental toxicity was expressed at a dose level of 45 mg/kg/day by earl y postnatal mortality and reduced post - weaning bod y 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 F 1 males and females without concomitant effects in other functional endpoints (FOB), neuropathology or brain morphometry . Based on the results of this study , the NOA EL for maternal toxicity , developmental toxicity and developmental neurotoxicity is considered to be 10 mg/kg/day . 4. Subchronic toxicity. Inthe 3 - month dog feeding study a NOEL of 800 ppm (32 mg/kg/day

for both males and females) was established base d 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 respectivel y for male and female rats) was established based on liver cell hy pertrophy at a dose of 800 ppm. In the 3 - month mouse feeding stud y a NOEL of 400 ppm (53.2 and 64.6 mg/kg/day respectivel y for male and female mice) was established based on increased liver/bod y weight ratio and decreased cholesterol in females at 800 ppm. A 13 week dietary

neurotoxicity

study for a cetamiprid established a NOEL of 200 ppm (14.8 and 16.3 mg/kg for male and female rats) based on reduced bod y 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 1 000 mg/kg/day caused no sy stemic toxicity , dermal irritation or histomorphological lesions in either sex tested. 5. Chronic toxicity. Inthe 1 - year dog stud y, the NOELwas established at 600 ppm (20 and 21 mg/kg/day for male and female dogs, respectivel y) based on growth retardation and decreased food consumption at a dose of 1500 ppm.5 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 - ye ar 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 meta bolism. 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 a s part of the total toxic residue in plants, therefore no tolerance is being requested b y 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 s ys tem. Developmental toxicity

studies in rats and rabbits and a reproductive study in rats gave no indication that acetamiprid has an y effects on endocrine function. The chr onic feeding studies also did not show any long - term effects related to endocrine s ys tems. C. Aggregate Exposure 1. Dietary exposure. Acute and chronic dietary analy ses were previousl y 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 corn vegetable crop group, cucurbit crop group, stone fruit crop grou p, tree nut crop group (including pistachio) berries, bulb vegetables, succulent legumes (excluding so ybeans), clover, tea, so ybeans, food/feed handling establishments and an increased tolerance on citrus (this petition). The assessment also included anti cipated 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 increased tolerance of acetamiprid in or on citrus 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 y ears old are the highest exposed population subgroup for both acute and chronic exposure scenarios. Acute exposure constituted 46.04% o f the acute6 population adjusted dose (aPAD) and chronic exposure constituted 14.1% of the chronic population adjusted dose (cPAD). The aPAD was based on the NOELof 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 soy beans and food/feed handling establishments (Fede ral Register, Vol. 77, No. 60 I Wednesday , March 28, 2012 I Page 18712), EPA concluded that reliable data show the safet y of infants and children would be adequatel y protected if the FQPA safet y factor was reduced to 1X. Any increase in acute and chronic dietary exposure from the increased tolerance of acetamiprid in or on citrus is expected to be negligible and therefore the exposure would be less than the aPAD and cPAD (e.g., less than 100%) and would remain within acceptable levels. 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 acetamiprid pesticide tolerance Final Rule found in the Federal Register/ Vol.77, No. 60 Wednesd ay , March 28, 2012. 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 95.2 ppb for acute exposures and 26.6 ppb for chronic exposure while the ground water EDWC was 0.035 ppb. The proposed tolerance increase of acetamiprid on citrus is not expected to increase the EDWC values as the proposed increase in the tolerance is to accommodate the use of the product overseas. 2. Non
- dietary exposure . Acetamiprid is registered for the following residential non - dietary

sites: pre - and post - construction termiticide/insecticide in subterranean 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 resid ential 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 ty picall y 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 f ormulation to reduce the potential for accidental ingestion. Lastl y, homeowner MOEs from potential handler and post application exposure to the residential use7 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 use of crack & crevice treatments of acetamiprid in indoor food/feed handling establishments resulted in MOEs ≥ 473 for children and MOEs ≥ 680 for adults. Similarly , a risk assessment of incidental non - dietary

ingestion exposure to children from crack & crevice treatment of acetamiprid in indoor areas resulted in MOEs ≥ 1420. The previous acetamiprid registratio ns meet acceptable levels of non - dietary exposure. The proposed tolerance increase in citrus is to accommodate fruit being treated overseas and imported to the US so no additional non - dietary exposure is expected. 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 anal ys is. E. Safety Determination 1. U.S. population. Based on assessments estimating the aggregate risk from the current uses of acetamiprid and the incremental exposure and risk from the proposed tolerance increase for Citrus fruits, Crop Group 10 and Citrus, dried pulp, there remains reasonable certainty that no harm will result to the general population from aggregate exposure to acetamiprid residues. 2. Infants and children . Based on assessments estimating the aggregate risk from the current uses of acetam iprid and the incremental exposure and risk from the proposed tolerance increase for Citrus fruits, Crop Group 10 and Citrus, dried pulp, there remains reasonable certainty that no harm will result to infants and children from aggregate exposure to acetami prid residues. F. International Tolerances There are no Codex or Mexican maximum residue levels (MRL s) established on the commodity

associated with this petition. Canada has established an MRLfor acetamiprid on citrus fruits at 0.5 ppm.