i

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 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 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., 14th FL., New York, NY 10005 requesting, 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 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.

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 has been developed

which involves extraction of acetamiprid from various matrices with solvents and

analysis by LC/MS/MS methods. An analytic method to determine acetamiprid 

residue in citrus currently exists, as provided in MRIDs 44988525 and 44988526.]
2

3. Magnitude of residues. Twelve residue field trials looking at various rates, 

PHIs, and number of applications of acetamiprid were conducted in Europe on 

oranges (5 trials), tangerines (5 trials) and lemons (2 trials). According 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 acetamiprid tolerance for citrus in the United States needs to increase 

from 0.5 ppm to 1.0 ppm. For the chronic dietary exposure analysis, tolerancelevel residues were assumed for all commodities (registered, pending and 

proposed), resulting in a conservative estimate of potential exposures. For the 

acute dietary exposure analysis, 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 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 10 mg/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 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 LD50 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/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 LD50 for F5688 11% ME in the rat was 1035 mg/kg. The acute dermal LD-50 for 
3

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.

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 

Gazel in the rat was >2000 mg/kg. The acute inhalation (4 hour exposure, nose 

only) in the rat resulted in a LC-50 of >3.5 mg/l. Gazel is not considered a 

primary eye irritant, dermal irritant or a skin sensitizer.

2. Genotoxicty.

Genetic Toxicity for Technical Acetamiprid- 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.

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
4

test article was administered orally by 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. 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.
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-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.

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 corn 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/feed 

handling establishments and an increased tolerance on citrus (this petition). 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 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 years old are the highest exposed population subgroup for both acute and 

chronic exposure scenarios. Acute exposure constituted 46.04% of the acute 
6

population adjusted dose (aPAD) and chronic exposure constituted 14.1% 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 soybeans and food/feed 

handling establishments (Federal Register, Vol. 77, No. 60 I Wednesday, March 

28, 2012 I Page 18712), 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 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 Wednesday, 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 SCIGROW. 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 residential exposure from the registered 

termiticide/insecticide use is considered negligible for handler and postapplication 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 accidental ingestion. Lastly, homeowner 

MOEs from potential handler and post application exposure to the residential use 
7

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 postapplication 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 registrations 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 analysis.

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 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 infants and 

children from aggregate exposure to acetamiprid residues.

F. International Tolerances

There are no Codex or Mexican maximum residue levels (MRLs) established on 

the commodity associated with this petition. Canada has established an MRL for 

acetamiprid on citrus fruits at 0.5 ppm.