Document ID: EPA-HQ-OPP-2010-0619-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-08-11T04:00Z

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<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING >

<EPA Registration Division contact: Laura Nollen, (703) 305-7390>

<<<<Interregional Research Project Number 4 (IR-4)>>>>

<Petition Number 0E7738>

<	EPA has received a pesticide petition, PP 0E7738, from 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 by establishing tolerances
for the combined residues of the insecticide avermectin B1(a mixture of
avermectins containing greater than or equal to 80% avermectin B1a (5-O-
demethyl avermectin A1) and less than or equal to 20% avermectin B1b
(5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1))
and its delta-8,9-isomer in or on the raw agricultural commodities
onion, bulb, subgroup 3-07A at 0.01 parts per million (ppm); chive,
fresh leaves at 0.01 ppm; chive, dried leaves at 0.07 ppm; and bean,
dry, seed at 0.01 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.   SEQ CHAPTER \h \r 1 The metabolism of abamectin
in plants is adequately understood and the residues of concern include
the parent insecticide abamectin (also referred to as avermectin B1
which is a mixture of a minimum of 80% avermectin B1a and a maximum of
20% avermectin B1b) and the delta 8,9-isomer of the B1a and of the B1b
components of the parent insecticide.>

<	2. Analytical method. The analytical methods involve homogenization,
filtration, partition, and cleanup with analysis by high performance
liquid chromotography (HPLC)-fluorescence detection. The methods are
sufficiently sensitive to detect residues at or above the tolerances
proposed. All methods have undergone independent laboratory validation
as required by PR Notice 96–

1.>

<	3. Magnitude of residues. Bulb Onions: Eight residue field trials were
conducted in California, Colorado, New Mexico, New York, Ohio, Oregon,
Texas, and Washington. Three foliar applications totaling  approximately
0.057 lb ai/A of abamectin were applied to the treated plots (except in
one California trial, where four foliar applications totaling  0.076 lb
ai/A was applied.  . Commercially mature dry bulb onions were collected
approximately 30 days after the last application. The maximum combined
avermectin B1a and 8,9-Z avermectin B1a residue from dry bulb onions was
0.0026 ppm in the New York trial. In all other samples the residues were
below the lowest limit of method validation (LLMV). There were no
residues of avermectin B1b greater than the LLMV.

Chives: Three residue field trials were conducted in New Jersey,
Washington, and Maryland. Three foliar applications totaling 
approximately 0.057 lb abamectin /A was applied to the treated plots.  .
Commercially mature fresh chive leaves were collected approximately 6
(±1) days after the last application.  At the Washington site, one
treated and one untreated fresh chive sample was collected 7 days after
the final application and dried in a drying cabinet for 2 days before
collection. An additional fresh chive harvest was conducted at the
Washington site approximately 13 days after the final application to
support the possibility of adding chive to the existing tolerance for
the Herb crop subgroup (except chives).. The maximum combined avermectin
B1a and 8,9-Z avermectin B1a residue found in the Maryland trial at a 6
±1 day PHI in fresh chives leaves was 0.00247 ppm,. Another sample,
found in the Washington fresh chives trial, contained a combined
avermectin B1a and 8,9-Z avermectin B1a residue of 0.00216 ppm. The
maximum combined avermectin B1a and 8,9-Z avermectin B1a residue from
dried chives leaves was 0.0101 ppm, found in the Washington trial. In
all other samples fresh and dry, the residues were below the LLMV. 
There were no residues of avermectin B1b greater than the LLMV.

Dry Beans: Twelve field trials were conducted with dry beans in
California, Idaho, Washington, Ohio, North Dakota, Wisconsin, and New
Jersey. A total of approximately 0.057 lb ai/A of abamectin was applied
to the treated plots in three foliar applications. Commercially mature
dry beans were collected approximately 6 (±1) days after the final
application. The maximum combined avermectin B1a and 8,9-Z avermectin
B1a residue in dry beans ,found in a California trial, was 0.004 ppm,.
In all other samples the residues were below the LLMV. There were no
residues of avermectin B1b greater than the LLMV.>

<B. Toxicological Profile>

<	1. Acute toxicity.  The database includes the following studies with
Syngenta’s technical abamectin products:

Abamectin Technical:  

i. A rat acute oral study with an LD50 of 13.6 mg/kg.

ii. A rat acute oral study with an LD50 of 214-232 mg/kg.

iii. A rabbit acute dermal study with an LD50 of 2000 mg/kg.

iv. A rat acute inhalation study with an LC50 of 0.21 mg/L (nose only).

v. A primary eye irritation study in rabbits which showed no irritation.

vi. A primary skin irritation study in rabbits which showed slight
irritation.

vii. A dermal sensitization study (Buehler) in guinea pigs which was
negative.

Abamectin Technical II

A rat acute oral study with an LD50 of 372.5  mg/kg

ii. A rat acute dermal study with an LD50 of >200 mg/kg but <2000 mg/kg 

A rat acute inhalation study with an LC50 of >0.0518 mg/L (nose only)

v. A primary eye irritation study in rabbits which showed no irritation.

vi. A primary skin irritation study in rabbits which showed slight
irritation.

vii.  A dermal sensitization study (Buehler) in guinea pigs with
Abamectin Technical supports the registration of this technical.

>

<	2. Genotoxicty. The Ames assays> conducted with and without metabolic
activation were both negative. The V–79 mammalian cell mutagenesis
assays conducted with and without metabolic activation did not produce
mutations. In an alkaline elution/rat hepatocyte assay, abamectin was
found to induce single strand DNA breaks without significant toxicity in
rat hepatocytes treated in vitro at doses greater than 0.2 millimole per
liter (mM). This in vitro dose of 0.2 mM is biologically unobtainable in
vivo, due to the toxicity of the compound. However, at these potentially
lethal doses, in vivo treatment did not induce DNA single strand breaks
in hepatocytes. In the mouse bone marrow assay, abamectin was not found
to induce chromosomal damage. There are also, many studies and a great
deal of clinical and followup experience with regard to ivermectin, a
closely similar human and animal drug.

<	3. Reproductive and developmental toxicity. In a 2-generation study in
rats> the NOAEL was established at 0.12 mg/kg/day in pups based upon
retinal folds, decreased body weight (bwt), and mortality. The NOAELs
for systemic and reproductive toxicity were 0.4 mg/kg/day. In the
1-generation reproduction study in rats with the delta 8,9-isomer, the
NOAEL was 0.4 mg/kg/day and the lowest observed adverse effect level
(LOAEL) was greater than 0.4 mg/kg/day highest dose tested (HDT). In an
oral developmental toxicity study in rabbits the maternal NOAEL was 1.0
mg/kg/day based upon decreased body weights and tremors. The fetal NOAEL
was 1.0 mg/kg/day based upon clubbed feet. In an oral developmental
toxicity study in rats the maternal and fetal NOAEL was 1.6 mg/kg/day,
the HDT. In an oral developmental toxicity study the maternal NOAEL in
CF-1 mice that expressed P-glycoprotein was greater than 1.5 mg/kg/day,
the highest and only dose tested. No cleft palates were observed in
fetuses that expressed normal levels of P-glycoprotein, but fetuses with
low or no levels of P-glycoprotein had increased incidence of cleft
palates. In a developmental neurotoxicity study in rats the maternal
NOAEL was 0.4 mg/kg/day, the HDT, and the offspring NOAEL was 0.12
mg/kg/day with an offspring LOAEL of 0.2 mg/kg/day based on slight pup
body weight loss. In a second developmental neurotoxicity study in rats
the maternal NOAEL was 0.4 mg/kg/day, the HDT, and the offspring NOAEL
was 0.2 mg/kg/day with an offspring LOAEL of 0.4 mg/kg/day based on
decreased body weight in both sexes. There was no evidence of
neurotoxicity in the offspring.

<	4. Subchronic toxicity. Subchronic toxicity studies included the
following:

i. A rat 14–week oral toxicity study with a NOAEL of 0.4 mg/kg/day,
the HDT.

ii. A dog 12–week feeding study with a NOAEL of 0.5 mg/kg/day based
upon mydriasis.

iii. A dog 18–week oral study with a NOAEL of 0.25 mg/kg/day based
upon mortality.>

<	5. Chronic toxicity. A rat 53–week carcinogenicity feeding study was
negative for carcinogenicity, with a NOAEL of 1.5 mg/kg/day based upon
tremors. A CD–1 mouse 94–week carcinogenicity feeding study was
negative for carcinogenicity, with a NOAEL of 4 mg/kg/day based upon
decreased body weights. A dog 53–week chronic feeding study resulted
in a NOAEL of 0.25 mg/kg/day based upon mydriasis.>

<	6. Animal metabolism. Rats were given oral doses of 0.14 or 1.4 mg/kg
bwt/day of abamectin or 1.4 mg/kg bwt/day of the delta 8,9 isomer. Over
7–days, the percentages excreted in urine were 0.3–1% of the
administered dose of abamectin and 0.4% of the dose of the isomer. The
animals eliminated 69–82% of the dose of abamectin and 94% of the dose
of isomer in feces. In rats, goats, and cattle, unchanged parent
compound accounted for up to 50% of the total radioactive residues in
tissues. The 24-hydroxymethyl derivative of abamectin was found in rats,
goats, and cattle treated with the compound and in rats treated with the
delta 8,9 isomer, and the 3’’-O-demethyl derivative was found in
rats and cattle administered abamectin and in rats administered the
isomer.>

<	7. Metabolite toxicology. There are no metabolites of concern based on
a differential metabolism between plants and animals. The potential
hazard of the 24-hydroxymethyl or the 3’’-O-demethyl animal
metabolites was evaluated in toxicology studies with abamectin
photolytic break-down product, the delta 8,9-isomer.>

<	8. Endocrine disruption. [There is no evidence that abamectin is an
endocrine disrupter. Evaluation of the rat multigenerational study
demonstrated no effect on the time to mating or on the mating and
fertility indices, suggesting no effects on the estrous cycle, on mating
behavior, or on male or female fertility at doses up to 0.4 mg/kg/day,
the HDT. Furthermore, the range finding study demonstrated no adverse
effect on female fertility at doses up to 1.5 mg/kg/day, the HDT.
Similarly, chronic and subchronic toxicity studies in mice, rats, and
dogs did not demonstrate any evidence of toxicity to the male or female
reproductive tract, or to the thyroid or pituitary (based upon organ
weights and gross and histopathologic examination). In the developmental
studies, the pattern of toxicity observed does not seem suggestive of
any endocrine effect. Finally, experience with ivermectin in breeding
animals, including sperm evaluations in multiple species, shows no
adverse effects suggestive of endocrine disruption.>

C.  Aggregate Exposure

	1. Dietary Exposure.  Acute and chronic Tier III dietary exposure
evaluations were made for abamectin using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.03) from Exponent.  All
consumption data for these assessments was taken from the USDA’s
Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96
consumption database and the Supplemental CSFII children’s survey
(1998) consumption database.  These Tier III assessments included all
currently registered Section 3 foliar crop uses including:  apples,
avocado, celeriac, citrus fruit (Crop Group 10), cotton, cucurbits (Crop
Group 9), fruiting vegetables (Crop Group 8), grapes, herbs (crop
subgroup 19A, except chives), hops, leafy vegetables except Brassica
(Crop Group 4), mint (peppermint and spearmint), pears, pistachios,
stone fruit (Crop Group 12), strawberries, tree nuts (Crop Group 14),
and tuberous and corm vegetables (Crop Group 1C).  Section 18 registered
uses include bean (lima, seed) and dry bulb onions.  Abamectin is
currently registered for seed treatment (ST) uses on corn, cotton,
cucurbits, and tomatoes, as a food handling establishment use
(Whitmire), a cattle ear-tag use; a seed treatment use on soybeans is
pending.  Proposed uses include an IR-4 foliar uses on chives, dry beans
(seed), and dry bulb onions.  Percent of crop treated values were
conservatively estimated to be 100% for the proposed use on dry beans. 
For these exposure assessments, residue data were taken from field trial
data where abamectin was applied at the maximum intended use rate and
samples were harvested at the minimum pre-harvest interval (PHI) to
obtain maximum residue values.  Drinking water estimates were
incorporated directly into the dietary exposure assessment using the
higher of the estimated drinking water concentrations (EDWCs) for
surface and ground water.  All consumption data for these assessments
were taken from the USDA’s Continuing Survey of Food Intake by
individuals (CSFII) with the 1994-96 consumption database and the
Supplemental CSFII children’s survey (1998) consumption database.  

i.  Food   Acute Exposure.  The abamectin acute dietary (food only) risk
assessment was performed for all population subgroups with an acute
reference dose of 0.005 mg/kg-bw/day based on a 12-week dose-range
finding study in dogs with a No Observed Adverse Effect Level (NOAEL) of
0.5 mg/kg-bw/day and an uncertainty factor of 100X.  The 100-fold safety
factor includes intra- and interspecies variations and no additional
FQPA safety factors were included in these acute assessments.  For the
purpose of the aggregate risk assessment, exposure values were expressed
in terms of margin of exposure (MOE), which was calculated by dividing
the NOAEL by the exposure for each population subgroup.  In addition,
exposure was also expressed as a percent of the acute reference dose
(%aRfD).  Acute (food only) exposure to the U.S. population resulted in
a MOE of 660 (15.1% of the acute RfD of 0.005 mg/kg-bw/day).  The most
sensitive sub-population was children (1-2 years old) with a MOE of 367
(27.2% of the aRfD).  Since the benchmark MOE for this assessment was
100 and since the EPA generally has no concern for exposures below 100%
of the aRfD, Syngenta believes that there is a reasonable certainty that
no harm will result from dietary (food only) exposure to residues
arising from the current and proposed uses for abamectin.

Chronic Exposure.  The abamectin chronic dietary (food only) risk
assessment was performed for all population subgroups with a chronic
reference dose of 0.0004 mg/kg-bw/day based on combined data from three
reproduction studies and two developmental neurotoxicity studies with a
No Observed Adverse Effect Level (NOAEL) of 0.12 mg/kg-bw/day and an
uncertainty factor of 300X.  The 300-fold safety factor includes intra-
and interspecies variations (100X) and the additional FQPA safety
factors of 3X for the steepness of the dose-response curve and the
severity of effects.  For the purpose of the aggregate risk assessment,
exposure values were expressed in terms of margin of exposure (MOE),
which was calculated by dividing the NOAEL by the exposure for each
population subgroup.  In addition, exposure was also expressed as a
percent of the chronic reference dose (%RfD).  Chronic (food only)
exposure to the U.S. population resulted in a MOE of 2,344 (12.8% of the
chronic RfD of 0.0004 mg/kg-bw/day).  The most sensitive sub-population
was children (1-2 years old) with a MOE of 677 (44.3% of the chronic
RfD).  Since the benchmark MOE for this assessment was 300 and since the
EPA generally has no concern for exposures below 100% of the RfD,
Syngenta believes that there is a reasonable certainty that no harm will
result from dietary (food only) exposure to residues arising from the
current and proposed uses for abamectin.

Cancer.  Abamectin is considered “not likely to be a human
carcinogen”.  Therefore, no cancer risk assessment was performed for
abamectin.

ii.  Drinking Water.  Another potential source of abamectin exposure to
the general population is from residues in drinking water.  Estimated
Drinking Water Concentrations (EDWCs) are made by reliance on simulation
or modeling taking into account data on the physical characteristics and
environmental fate of abamectin.  For this assessment the proposed uses
of abamectin on bulb onion, beans (dry) and chives, as well as all
existing uses were evaluated using the Tier 2 Model, PRZM/EXAMS Shell
(PE5) for surface water and the Tier 1 model SCI-GROW (v 2.3) for
groundwater.

For surface water the highest EDWCs resulted from the proposed use for
dry beans.  PRZM/EXAMS calculated a surface water acute EDWC of 0.993
ppb and a chronic EDWC of 0.358 ppb.  For ground water the currently
registered use for cucurbits provided higher EDWCs than the proposed
uses.  For the groundwater model, the cucurbits application parameters
consisted of one seed treatment at 0.066 lb a.i./A (adjusted for 6%
desorption from seed) followed by three aerial applications at 0.019 lb
a.i./A with application intervals of 7 days.  This provided an EDWC
(acute and chronic) of 0.00184 ppb.

Since the surface water EDWCs exceed the ground water EDWC, the surface
water values should be used for comparison purposes and are considered
protective for any ground water concentration concerns.

Acute Exposure from Drinking Water.  The acute EDWC of 0.993 ppb was
used to calculate the acute drinking water exposure values for the U.S.
Population and population subgroups.  Acute drinking water exposure to
the U.S. population resulted in a MOE of 25,000 (0.4% of the aRfD of
0.005 mg/kg/day, Benchmark MOE = 100).  The most sensitive
sub-population was children (3 - 5 years old) with a MOE of 20,833 (0.5%
of the aRfD of 0.005 mg/kg/day, Benchmark MOE = 100).  Since the
Benchmark MOE for this assessment is 100 and since EPA generally has no
concern for exposures below 100% of the aRfD, Syngenta believes that
there is a reasonable certainty that no harm will result from acute
drinking water exposure to residues arising from the current and
proposed uses for abamectin.

Chronic Exposure from Drinking Water.  The chronic EDWC of 0.358 ppb was
used to calculate the chronic drinking water exposure values for the
U.S. Population and population subgroups.  Chronic drinking water
exposure to the U.S. Population resulted in a MOE of 15,000 (Benchmark
MOE = 300; 2.0% of the cRfD of 0.0004 mg/kg/day).  The most sensitive
sub-population was infants (<1 year old) with a MOE of 5,000 (6.0% of
the cRfD of 0.0004 mg/kg/day, Benchmark MOE = 300).  Since the Benchmark
MOE for this assessment is 300 and since EPA generally has no concern
for exposures below 100% of the cRfD, Syngenta believes that there is a
reasonable certainty that no harm will result from chronic dietary
(drinking water) exposure to residues arising from the current and
proposed uses for abamectin.

2.  Non-Dietary Exposure.  A residential exposure and risk assessment
was performed for abamectin using the endpoints and uncertainty factors
established by the EPA in a recent assessment (March 11, 2009). 
Residential exposure and risk assessments were performed for granular
abamectin baits used to treat lawns and for indoor abamectin-based crack
and crevice products.  As such, residential assessments included handler
exposure for adults and post-application exposure risks for adults and
children.  The highest predicted exposure for adults mixing, loading and
applying product by belly grinder application to turf resulted in a
combined (dermal plus inhalation) short-term margin of exposure (MOE) of
60,550.  The post-application dermal exposure to adults following use of
granules on lawns is MOE = 402,379.  Children’s post-application
dermal plus non-dietary oral aggregate exposure to abamectin from lawn
products had a short-term MOE of 48,192.  Incidental ingestion of
granules on treated lawns by children was compared to the acute dietary
NOAEL and had a MOE of 65,563.  The highest predicted exposure for
adults applying dust to crack and crevices resulted in a combined
(dermal plus inhalation) short-term MOE of 1,976,285.  The
post-application dermal exposure to adults following use of a dust
formulation had a MOE of 1,796,407.  Post-application dermal plus
non-dietary oral exposure from abamectin use in dust products are
acceptable (short-term aggregate MOE = 288,462, intermediate-term
aggregate MOE = 483,871) for children re-entering indoor carpeted areas
following crack and crevice treatments.  Other formulations for similar
crack and crevice products are expected to have less migration from the
treated area and thus, to result in lower risk from dermal, oral, and
inhalation post application exposure.  The MOEs for all residential
scenarios for children do not exceed the EPA’s level of concern
(Benchmark MOE of 300) and there is a reasonable certainty that no harm
will result from the residential uses of abamectin.

D.  Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”.  Unlike other pesticides for which EPA
has followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding as to
abamectin and any other substances and abamectin does not appear to
produce a toxic metabolite produced by other substances.  Therefore,
Syngenta has not assumed that abamectin has a common mechanism of
toxicity with other substances. 

E.  Safety Determination

	1.  U.S. Population.  The acute dietary exposure analysis (food plus
drinking water) showed that exposure from all registered and proposed
abamectin crop uses result in a MOE of 643 (15.5% of the aRfD, Benchmark
MOE = 100) for the general U.S. population.  The chronic dietary
exposure analysis (food plus drinking water) showed that exposure from
all registered and proposed abamectin crop uses result in a MOE of 2,043
(14.7% of the chronic RfD, Benchmark MOE = 300) for the general U.S.
population.  Based on the completeness and reliability of the toxicity
data supporting these petitions, Syngenta believes that there is a
reasonable certainty that no harm will result from aggregate exposure to
residues arising from all current and proposed abamectin uses, including
anticipated dietary exposure from food, water, and all other types of
non-occupational exposures.  

	2. Infants and children.  The acute dietary exposure analysis (food
plus drinking water) showed that exposure from all registered and
proposed abamectin uses result in a MOE of 363 (27.5% of the aRfD) for
children one to years old (the most sensitive population subgroup).  The
chronic dietary exposure analysis (food plus drinking water) showed that
exposure from all registered and proposed abamectin uses result in a MOE
of 637 (47.1% of the cRfD) for children one to years old (the most
sensitive population subgroup).  Since all aggregate MOEs were above the
Benchmark MOEs and because the EPA has no concern for exposures
resulting in a MOE above the Benchmark MOE, Syngenta believes that there
is a reasonable certainty that no harm will result to any population
subgroup from aggregate exposure to residues arising from all current
and proposed abamectin uses, including anticipated dietary exposure from
food, drinking water and all other types of non-occupational exposures.

F.  International Tolerances

	Codex has established an abamectin Maximum Residue Level (MRL) of 0.02
ppm for peppers.  The fruiting vegetable tolerance of 0.02 ppm for
abamectin is harmonized with Codex.  International MRLs for abamectin
have been established for various agricultural commodities in a number
of countries including Argentina, Australia, Belgium, Brazil, Canada,
Czech Republic, Estonia, France, Germany, Greece, Hungary, Israel,
Italy, Japan, Korea (South), Malaysia, Mexico, Netherlands, New Zealand,
Poland, Portugal, Russia, , Serbia and Montenegro, Slovak Republic,
South Africa, Spain, Switzerland, Taiwan, and the United States.

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