Document ID: EPA-HQ-OPP-2009-0289-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-08-19T04:00Z

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

Pursuant to section 408(d)(2) of the FFDCA, as amended by the Food
Quality Protection Act (FQPA), Interregional Research Project Number 4
(IR-4) has submitted the following summary of information, data and
rationales in support of this pesticide petition and authorization for
the summary to be published in the Federal Register in a notice of
receipt of the petition.  This summary was prepared by Nippon Soda Co.,
Ltd.   

EPA Registration Division contact: Laura Nollen

Interregional Research Project Number 4 (IR-4)

PP# 9E7544

EPA has received a pesticide petition (9E7544) from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540 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 by establishing tolerances for residues of the insecticide
acetamiprid,
N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine, in or on
the raw agricultural commodities fruit, small, vine climbing, except
fuzzy kiwifruit, subgroup 13-07F at 0.35 parts per million (ppm) and
tolerances with regional restrictions for clover, forage at 0.10 ppm;
clover, hay at 0.01 ppm and tea at 50 ppm.  This action also proposes to
delete the existing tolerance for grapes at 0.20 ppm since it will be
superseded by the proposed tolerance on subgroup 13-07F.  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..

Residue Chemistry-

1.  Plant Metabolism-  The metabolism of acetamiprid in plants is well
understood, having  been investigated in eggplant, apples, cabbage,
carrots, and cotton.  Metabolism in plants primarily involves
demethylation of the N-methyl group with subsequent hydrolysis of the
acetamidine function to give the N-acetyl compound.  This compound is
then hydrolyzed to the corresponding amine followed by oxidation to the
alcohol and acid.  Conjugation of the alcohol with glucose is also
significant.  Degradation of the side chain without loss of the N-methyl
group is seen in carrots since this is the major metabolic route in
soil. 

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 crops with methanol and analysis by LC/MS/MS methods. 
The limit of quantification (LOQ) and the limit of detection (LOD) for
the method are calculated to be 0.0076 ppm and 0.0025 ppm for clover
forage, respectively while the limit of quantification (LOQ) and the
limit of detection (LOD) for the method for clover hay are calculated to
be 0.0082 ppm and 0.0027 ppm, respectively.  The LOQ and LOD for grape
are calculated to be 0.0064 ppm and 0.0021 ppm, respectively.  The LOQ
and LOD for greenhouse-grown tomatoes was 0.0075 ppm and 0.0025,
respectively.

3.  Magnitude of Residues-  Magnitude of residue studies were conducted
in clover grown for seed.  Trials with applications at the maximum
proposed label use rate were conducted in Oregon (Region 11) and are
adequate for obtaining a regional use for acetamiprid on clover grown
for seed.

An existing cattle feeding study was conducted at dose levels adequate
to support the proposed new animal feed items and no revision to the
existing tolerances for the combined residues of acetamiprid
N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine and its
metabolite N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-acetamidine are
necessary.

Magnitude of residue studies at the maximum proposed label use rate were
conducted on grapes as the representative commodity for Crop Subgroup
13-07F (Fruit, small, vine, climbing, except fuzzy kiwifruit) in six
different crop residue regions throughout the US and Canada and are
adequate for obtaining an amended (increased) tolerance for the crop
subgroup.

Toxicological Profile-

1.  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. 

2.  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 S.
typhimurium and E. 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. 

C. Aggregate Exposure

1. Dietary-  Acute and chronic dietary analyses were previously
conducted to estimate exposure to potential acetamiprid residues.  Acute
dietary exposure estimates used food consumption information from the
USDA’s 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake
by Individuals (CSFII).  Anticipated residues derived from field trial
data for certain commodities (apples; broccoli; cabbage, celery;
grapefruit; grapes, lettuce; oranges; pears; peppers; spinach; tomatoes;
stone fruit; and cucurbits) were used and assumed residues present at
tolerance levels were used for all other commodities.  Percent crop
treated (PCT) information for some of the registered commodities
(apples, broccoli, celery, lettuce pears, grapefruit, grapes, oranges,
peppers, spinach, and tomatoes) was used but 100 PCT was assumed for all
other commodities.  For chronic exposure scenarios, tolerance level
residues were assumed in all previously registered food and 100 PCT for
all crops except apples and oranges.  Exposure estimates to drinking
water were previously made based on conservative tier one FIRST and
SCIGROW modeling.  Overall the additional dietary exposure from the use
of acetamiprid on clover grown for seed and an increase in the tolerance
level for Crop Subgroup 13-07F (Fruit, small, vine, climbing, except
fuzzy kiwifruit) is expected to remain within acceptable levels.  

2.  Food-  The acute dietary exposure estimates from food and water
previously occupied 35% of the acute Population Adjusted Dose (aPAD) at
the 99.9th percentile for children 1-2 years old, the population group
receiving the greatest exposure.  The acute RfD was based on the NOAEL
of 10 mg/kg/day in the developmental neurotoxicity study in rats.  Any
increase in acute dietary exposure from the use of acetamiprid on clover
grown for seed and an increase in tolerance level for Crop Subgroup
13-07F (Fruit, small, vine, climbing, except fuzzy kiwifruit) is
expected to remain within acceptable levels.  

Previously the chronic exposure to acetamiprid from food and water
utilized 35% of the chronic Population Adjusted Dose (cPAD) for children
1 to 2 years old, the population group with greatest exposure.  Any
increase in chronic dietary exposure from the use of actetamiprid on
clover grown for seed and an increase in tolerance level for Crop
Subgroup 13-07F (Fruit, small, vine, climbing, except fuzzy kiwifruit)
is expected to remain within acceptable levels.

The cPAD was based on the NOEL of 7.1 mg/kg/day in the chronic rat study
and an uncertainty factor of 100 to account for inter- and intra-species
variations.  In the Final Rule establishing tolerances for acetamiprid
on stone fruit, tree nuts, succulent legumes and cucurbits (Federal
Register, Vol. 72, No. 228 / Wednesday, November 28, 2007 / Page 67256),
EPA determined that reliable data show that it would be safe for infants
and children to reduce the FQPA safety factor to 1X.  

3.  Drinking Water-  Based on the First Index Reservoir Screening Tool
(FIRST) and Screening Concentration in Ground Water (SCI-GROW) models,
the previously estimated environmental concentrations (EECs) of
acetamiprid for acute exposures were 20.1 parts per billion (ppb) for
surface water and 1.6 ppb for ground water.  The EECs for chronic
exposures were estimated to be 4.9 ppb for surface water and 1.6 ppb for
ground water.  Modeled estimates of drinking water concentrations were
directly entered into the dietary exposure model.  For acute and chronic
dietary risk assessment the water concentration values of 20.1 ppb and
4.9 ppb, respectively, were used to assess the contribution to drinking
water.

4.  Non-dietary exposure-  Acetamiprid is registered for use as a
pre/post-construction termiticide, as a crack-and-crevice or spot spray
inside structures, and as a gel bait formulation for control of ants and
cockroaches in residential settings.  Homeowner handler exposure is not
expected since termiticide applications are made by professional Pest
Control Operators (PCOs) only and post-application exposure is not
expected since applications are below ground or in hard-to-reach
structure components.  Crack-and-crevice or spot sprays indoors are
restricted to PCO applicators only so there is no exposure to
residential handlers while post-application exposure is negligible due
to the limited surface area being treated.  Residential handlers may be
exposed dermally from the use of gel baits but inhalation exposure is
not expected due to the low vapor pressure of acetamiprid. 
Post-application exposure to gel baits is negligible due to the
unlikelihood of homeowners revisiting crack-and-crevice or spot areas
where baits are applied, the low vapor pressure of acetamiprid, the
incorporation of a bittering agent in the formulation, and the
incorporation of the gel in a bait station.

For aggregate food, drinking water, and residential short term
exposures, the Margin of Exposure (MOE) was calculated to be 900 for
adults 20 to 49 years old and 930 for adults 50 years and older who
apply gel bait acetamiprid products.  Adults were considered to be the
most likely to be exposed from residential uses of acetamiprid as well
as food and drinking water exposure.  Intermediate aggregate exposure
was determined to be the same as short term aggregate exposure since the
short term and intermediate term dermal exposures and endpoints for
acetamiprid are the same.  The dietary exposure pathway is the only
source of chronic exposure to acetamiprid.  Therefore chronic aggregate
exposure and risk estimate are equivalent to the chronic dietary and
risk estimate.

Therefore, there is reasonable certainty that no harm will result from
aggregate (food, drinking water, and residential) exposure to
acetamiprid residues.

 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-  Using the conservative assumptions described above
and based on the completeness and reliability of the toxicity data, it
is concluded that aggregate exposure from the existing and proposed uses
of acetamiprid will utilize < 100% of the acute Population Adjusted Dose
(aPAD) and < 100% of the chronic Population Adjusted Dose (cPAD) for the
U.S. Population.  These percentages are likely to be much less as more
realistic exposure data and models are developed.  EPA generally has no
concern for exposures below 100% of the aPAD and cPAD.  Drinking water
levels of comparison (DWLOCs) based on these exposure estimates are much
greater than conservative estimated concentrations, and would be
expected to be well below the 100% level.  Existing uses allowing
residential applications of acetamiprid both indoors and outdoors
resulted in short-term applicator exposure MOEs of greater than 1,500
and short-term post-application exposure MOEs of greater than 2,000 for
adult and toddler exposure scenarios.  For intermediate-term
post-application exposure following indoor applications, the MOEs for
adults and toddlers were greater than 2,500. Therefore, there is a
reasonable certainty that no harm will occur to the US Population from
aggregate exposure to acetamiprid.

2.  Infants and Children-.  In multi-generation reproduction and
teratology studies, no adverse effects on reproduction were observed in
either rats or rabbits.  In the long term feeding studies in rats and
mice there was no evidence of carcinogenicity.  Acetamiprid was not
mutagenic under the conditions of testing. There is no indication of
developmental neurotoxicity associated with acetamiprid.  Using the
conservative assumptions described in the exposure section above,  the
percent of the acute Population Adjusted Dose (aPAD) that may be used is
< 100% for children 1-2 years old (the most highly exposed infant and
children sub-group) and < 100% of the chronic Population Adjusted Dose
(cPAD).  As in the adult situation, drinking water levels of comparison
are much higher than the worst case drinking water estimated
concentrations and would be expected to use well below 100% of the RfD,
if they occur at all.  MOEs resulting from post-application exposure to
acetamiprid in residential areas are greater than 2,000.  Therefore,
there is a reasonable certainty that no harm will occur to infants and
children from aggregate exposure to residues of acetamiprid.

F.  International Tolerances- 

Acetamiprid is registered for use on food crops in several countries
outside the United States.