Document ID: EPA-HQ-OPP-2012-0626-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-09-28T04:00Z

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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 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.]

	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,
tolerance-level 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

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
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/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
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.

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.

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 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 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.

	

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 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 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.

≥ 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.

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