Document ID: EPA-HQ-OPP-2009-0812-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-01-15T05:00Z

Docket ID #:  EPA-HQ-OPP-2009-0812

COMPANY NOTICE OF FILING

EPA Registration Division contact: Sidney Jackson, 703-305-7610 

Interregional Research Project Number 4 (IR-4) and Arysta LifeScience
North America LLC

PP# 9E7598

EPA has received a pesticide petition (9E7598) from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540, in cooperation with Arysta LifeScience North
America LLC, 15401 Weston Parkway, Suite l50, Cary, N.C., 27513
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 180.599 by
revising the tolerance expression to read tolerances are established for
the residues of the insecticide acequinocyl, including its metabolites
and degradates. Compliance with the tolerance levels specified is to be
determined by measuring only the sum of acequinocyl
2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione, and its metabolite
2-dodecyl-3-hydroxy-1,4-naphthoquinone, calculated as the stoichiometric
equivalent of acequinocyl and by establishing a tolerance for the
residues of acequinocyl, including its metabolites and degradates in or
on fruiting, vegetables, group 8 at 0.7 parts per million (ppm), okra at
0.7 ppm, bean, edible podded at 0.25 ppm and hop, dried cone at 3.5 ppm.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.

A.	Residue Chemistry

Plant metabolism. The nature of the residues of acequinocyl in plants is
adequately understood based on three crops; apples, oranges and
eggplant. The major residue in all plant metabolism studies is
acequinocyl. A minor but significant metabolite is acequinocyl-OH
(2-dodecyl-3-hydroxy-l,4-naphthoquinone). The proposed tolerance
expression is the parent, acequinocyl and its hydroxy metabolite,
acequinocyl-OH.

Analytical method. The analytical method to quantitate residues of
acequinocyl and acequinocyl-OH in/on fruit crops utilizes high pressure
liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS)
detection for fruiting vegetables crop group 8 (tomatoes and peppers)
and LC/MS/MS for snap-bean, edible podded and hop, dried cones. The
lowest level for method validation (LLMV) was 0.01 ppm for acequinocyl
and 0.025 ppm for acequinocyl-OH.

Magnitude of residues. The proposed use of acequinocyl calls for a
maximum of 2 applications per season at 0.3 lb a.i. per acre per
application (maximum 0.6 lb a.i. per acre per season), with a 21-day
interval between applications. The pre-harvest interval is 7 days. The
maximum residue for each commodity is shown in the following table.

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Sample Type	Acequinocyl    

Maximum Residue (ppm)	Acequinocyl-OH

Maximum Residue (ppm)

Tomato Fruit	0.20	< 0.025

Tomato Paste	0.05	< 0.025

Tomato Puree	0.04	< 0.025

Non-Bell Peppers	0.2950	0.0429

Bell Peppers	0.564	0.0430

Snap Beans	0.19	0.03

Hops	2.53	0.735

The crop field trial data are adequate to support the proposed
tolerances requested in Section F of the petition.

B.	Toxicological Profile

1. Acute toxicity. Acequinocyl technical has low acute, dermal and
inhalation toxicity

in laboratory animals. The oral lethal dose (LD)50 male/female (M/F) in
the rat and mouse was > 5000 milligram per kilogram (mg/kg). The dermal
LD50 (M/F) was > 2000 mg/kg. The inhalation lethal concentration (LC)50
was reported as > 0.84 mg/1. In the eye and dermal irritation studies,
acequinocyl technical was not an eye or skin irritant to rabbits and was
not a skin sensitizer in guinea pigs.

Genotoxicty. Acequinocyl was found to be negative in the Ames reverse
mutation, mouse lymphoma, Chinese hamster lung (CHL) chromosome
aberration and mouse micronucleus assays.

Reproductive and developmental toxicity. i. Rat teratology. Acequinocyl
technical was administered by oral gavage to pregnant Sprague Dawley
rats at dose levels of 0, 50,150, 500 or 750 mg/kg/day on gestation days
7-17. Common signs in the descendants included vaginal discharge,
pallor, pale eyes, hypoactivity, piloerection, slow or irregular
breathing, intra-uterine hemorrhage and blood stained stomach and/or
intestinal contents. Maternal no-observed adverse effect level
(NOAEL)=150 mg/kg/day based on these signs. Developmental NOAEL=500
mg/kg/day based on an increase in certain skeletal variants that may be
attributed to the observed maternal toxicity.  

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ii. Rabbit teratology. Groups of New Zealand white rabbits received
acequinocyl technical by gavage at doses of 0, 30, 60 or 120 mg/kg/day.
Maternal NOAEL=60 mg/kg/day based on reduction in maternal body weight
and 5 females were sacrificed at 120 mg/kg/day. Fetal NOAEL=60 mg/kg/day
due to skeletal variations in the thoracic-lumbar ribs. 

iii. Rat reproduction study. Acequinocyl technical was fed to two
generations of male and female Sprague Dawley rats at dietary
concentrations of 0,100, 800, or 1500 ppm (0, 7.3, 59 or 111 mg/kg/day
for males and 0, 8.7, 69 or 134 mg/kg/day for females). Systemic and pup
NOAEL=100 ppm (7.3 and 8.7 mg/kg/day). Systemic: Hemorrhage and swollen
body parts were seen at 800 and 1500 ppm in Fl males. At 800 and 1500
ppm, treatment related clinical signs, hemorrhagic effects, subcutaneous
bleeding on body parts and/or cranium and/or brain were seen in the Fl
pups. At 800 and 1500 ppm toxicity seen in F2 pups included subcutaneous
bleeding on body parts and/or cranium and/or brain at weaning.

Subchronic toxicity. i. Rat feeding study. Fischer rats received
acequinocyl technical

at dietary concentrations of 0, 100, 400, 1600 or 3200 ppm (0, 7.57,
30.4, 120, 253 mg/kg/day,

respectively for males and 0, 8.27, 32.2,129, 286 mg/kg/day,
respectively for females) for 13

consecutive weeks. Treatment related yellow brown urine in all animals
of both sexes at 400

ppm suggested the presence of a metabolite of the test material.
Macroscopic examination

on the surviving animals revealed no treatment related abnormalities. At
3200 and 1600

ppm, macroscopic and microscopic examination of the mortalities revealed
hemorrhaging of

muscle and other organs. NOAEL = 400 ppm (30.4 mg/kg/day for males and
32.2 mg/kg/day for

females).

 ii. Mouse feeding study. Groups of CD-I (ICR) BR mice received
acequinocyl

technical by oral route at concentrations of 0, 100, 500, 1000 or 1500
ppm (0,16,81,151, 295

mg/kg/day respectively for males and 0, 21, 100, 231, 342 mg/kg/day
respectively for females)

for 13 weeks. At 100 ppm, there were hepatic histopathological lesions
and an increase in

relative liver weight. A clear NOAEL for both sexes was not determined. 

iii. Dog feeding study. Acequinocyl technical was administered via
gelatin capsule to male and female beagle dogs at dose levels of 0, 40,
160, 640 or 1000 mg/kg/day once a day 7 days a week for 13 weeks. At 40,
160 and 640 mg/kg/day colored feces were observed in both sexes.  At 160
and 640 mg/kg/day, treatment related decrease in body weight gain in
males and an increase platelet count for females was observed.
Macroscopic and microscopic examinations on the surviving animals
revealed no treatment related abnormalities. A clear NOAEL was not
determined.  

iv. 28-day dermal toxicity. Groups of Sprague Dawley rats received daily
dermal applications of acequinocyl technical at doses of 0, 40, 200 or
1000 mg/kg/day for 6 hours/day for 28 days followed by a 14 day
treatment free period only in the high dose group. There were no
macroscopic findings. Red staining occurred on the back of the animals
and was only seen in the morning after dosing. There was no evidence of
systemic toxicity. NOAEL=1000 mg/kg/day.

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Chronic toxicity. i. Dog feeding study. Beagle dogs were dosed by
capsule at 0,5,20,

80 or 320 mg/kg/day for 1 year with acequinocyl technical. Minor
disturbances in platelet

counts were observed in both sexes at 80 and 320 mg/kg/day. There were
no treatment

related macroscopic histopathological findings. Colored feces and/or
abnormally stained

sawdust were observed for all treatment groups. Varying degrees of
discoloration of the

urine was observed for animals receiving 20 mg/kg/day or more. The
discoloration was

considered to be attributable to a colored metabolite of the test
substance. NOAEL = 20

mg/kg/day.

ii Rat feeding/oncogenicity study. Groups of F344 rats received
acequinocyl technical at dietary levels of 0, 50, 200, 800 or 1600 ppm
(0, 2.25, 9.02, 36.4, 74.0 mg/kg/day for males and 0, 2.92, 11.6, 46.3,
93.6 mg/kg/day for females) for 2 years. The NOAEL = 200 ppm (9.02 and
11.6 mg/kg/day for males and females, respectively). Corneal
abnormalities and hypertrophy of the eye were observed in 800 ppm and
1600 ppm males and 1600 ppm females. At 800 ppm and 1600 ppm, PT was
observed to be longer in males and shorter in females and APTT longer in
females. Reddish brown urine was observed in both males and females.
There was no incidence of tumors.

iii. Mouse oncogenicity study. Acequinocyl technical was administered in
the diet of Crl:CD-l(ICR)BR mice at 0, 20, 50, 150 or 500 ppm for 80
weeks. NOAEL=20 ppm (lowest dose tested equal to 2.7 and 3.5 mg/kg/day
in males and females respectively), based on brown pigmented cells. At
50 and 500 ppm in both sexes, there was an increase incidence of fatty
hepatocytes. Other associated findings were increased liver weight,
slight increase in pale livers or pale areas within livers. Glomerular
amyloidosis was statistically increased in the 150 and 500 ppm males.
Yellow brown urine was consistently found in both sexes at high dose.
There was no increase in the incidence of tumors.

6.	Animal metabolism. Sprague Dawley rats were dosed orally with
acequinocyl

labeled 14C-phenyl or 14C-dodecyl. Both labels were used in the single
low dose (10 mg/kg)

study. The high dose (500 mg/kg) and 14-day repeat dose studies (10
mg/kg/day) were

conducted with 14C-phenyl acequinocyl only. Excretion was rapid, with
most of the dose in

the feces. Less than 15% of the radioactivity was found in the urine.
Absorption was about

25-42% based on the bile duct cannulation studies, which found 20-33% of
the administered

dose in bile, plus 5-9% in urine plus cage wash. Acequinocyl was not
detected in urine and was only a minor component (1-2%) in the feces.
The major fecal metabolite (12-36%) was the 2-hydroxy-3-dodecyl-l,
4-naphthalenedione (acequinocyl-OH or designated Rl). Subsequent
oxidation of the dodecyl chain yielded butanoic and hexanoic acids, the
only measurable identified urinary metabolites. 2-(l,
2-dioxotetradecyl)-benzoic acid comprised 19-40% of the radioactivity in
the feces. There were no remarkable differences in metabolite
disposition due to gender and no effect of pre-dosing for 2 weeks. The
large dose slowed transit time and reduced absorption.

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Endocrine disruption. A standard battery of toxicity tests have been
conducted on acequinocyl. No effects were seen to indicate that
acequinocyl has an effect on the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. The tolerance of 0.7 ppm for fruiting vegetables
crop group 8 (tomatoes and peppers) and okra, 0.25 ppm for edible podded
beans and 3.5 ppm for hops along with the previously established
tolerances for acequinocyl were incorporated into the aggregate exposure
results presented below. An aggregate risk assessment was conducted to
include the potential chronic dietary exposure from applications of
acequinocyl on these crops. This chronic risk assessment was conducted
to assess dietary exposures from acequinocyl in food using DEEM FCIDTM
and the following input parameters: tolerance level residues;
consumption data from the USDA 1994-1996 and 1998 Continuing Survey of
Food Intakes by Individuals (CSFII); 100 percent crop treated for all
commodities; default processing factors for all commodities, if
applicable; and a chronic toxicological endpoint of 2.7 mg/kg body
weight(bw) (NOAEL); 0.027 mg/kg bw(chronic reference dose (cRfD)) from
the chronic mouse study. Tolerance values used in the new Tier I DEEM
analysis for current registered uses were obtained from the most recent
EPA human health assessments (FR Notice, April 2, 2008).  Please note
that EPA has determined that there is no endpoint of concern
attributable to a single dose and, therefore, an acute reference dose
(aRfD) was not established. Therefore, no acute exposure assessment is
necessary (FR, Vol. 69, No. 139, 7/21/04, page 43528).

i. Food. The previous chronic dietary food exposure estimates to
acequinocyl were all less than 100% of chronic RfD.  When the previous
risk assessment is revised to include tomatoes, peppers, okra,
snap-beans, and hops, the chronic dietary food exposure estimates to
acequinocyl are still not a concern for the US population as a whole or
for any population subgroup.  The new chronic dietary exposure estimate
for the US population is 12.4% of the cPAD, indicating that there is
plenty of room in the risk cup even with the addition of these proposed
new crops.  The previous DEEM analysis without these new proposed IR-4
uses indicated 7.4% of the cPAD for the total US population (Levy,
2007).  The most highly exposed population subgroup is children aged 1-2
years old at 52.6% of the cPAD; this compares to 41% of the cPAD without
the addition of the new proposed IR-4 uses.  

In order to determine which of the registered and proposed commodities
were driving the revised dietary risk assessment, a critical commodity
contribution analysis was conducted for two subpopulation groups,
children 1-2 years old and children 3-5 years old.  This analysis
identified (a) crop groups with greater than 5% of the total exposure
contribution; and (b) those foods or food-forms within the crop groups
contributing more than 1% of the total exposure.  For both of these
subpopulations, the grape crop group (includes fresh grapes, grape juice
and raisins) was the largest contributor.  For children 1-2, this food
group contributed 33.7% of the total exposure; for children 3-5, the
contribution was 30.5% of the total exposure.  The next highest
contributor to the 1-2 year olds was the pome fruit grouping, with apple
juice being the highest 

Individual contributor.  The pome fruit group contributed 31.8% and
26.9% of total exposure for children aged 1-2 and 3-5, respectively. 
The third highest crop group contributor was the fruiting vegetables,
with fresh tomatoes, tomato sauce, and tomato puree being the highest
individual food contributors within that crop group.  This group
accounted for 21.9% and 28.3% of total exposure for children aged 1-2
and 3-5, respectively.

ii. Drinking water. The available environmental fate data indicate that
acequinocyl does not persist in the environment nor does it have the
ability to leach into groundwater resources. Acequinocyl degrades
rapidly in the environment. Aqueous photolyis, Tl/2 = 14 minutes, soil
photolyis, Tl/2 = 2 days, aerobic soil metabolism (4 soils) Tl/2 = <3
days, aerobic aquatic metabolism Tl/2 = 0.39 day in water and sediment,
hydrolysis Tl/2 = 74 days (pH4), = 2.2 days (pH7), =1.3 hours (pH9).
Acequinocyl shows low soil mobility.  Drinking water data was
incorporated directly into the DEEM dietary assessment under “drinking
water” for both direct and indirect sources using the chronic
concentration of parent-only (acequinocyl) residues modeled from surface
water using PRZM-EXAMS by EPA and used in their revised human health
risk assessment (Levy, S., 2007).  This was a very conservative estimate
because it was assumed that acequinocyl was stable to all routes of
degradation.  As a result, this model produced the highest estimated
drinking water concentration (EDWC), 2.73 part per billion (ppb), which
was considered to be the most protective.  Using these considerations,
exposures to acequinocyl in drinking water do not pose a significant
human health risk. 

iii. Non-dietary exposure. The proposed expansion of the registration
for applications to fruiting vegetables crop group 8 (tomatoes,
peppers), okra, edible podded beans, and hops requires evaluation of
occupational handler and postapplication exposures and dietary exposures
for consumers.

a. Occupational Handler Exposure: The following handler scenarios were
evaluated:

1. Mix/load liquid open-pour for groundboom applications

2. Mix/load liquid open-pour for airblast applications

3. Application by groundboom, open-cab

4. Application by airblast, open-cab

Exposure data from PHED were used to assess dermal and inhalation risks.
 All short-term and intermediate-term occupational risks were acceptable
(margin of exposure (MOE)s exceeded 100; short-term MOEs ranged from
4,866 to 51,330 and intermediate-term MOEs ranged from 20,700 to
291,300). 

Based on the anticipated occupational use patterns for acequinocyl
products, long-term (several months to lifetime) exposures are not
expected for occupational handlers of acequinocyl.

b. Occupational Postapplication Exposure: Since re-entry activities
occur after the sprays have dried, post-application inhalation exposures
are not assessed.  Post-application exposures to acequinocyl are
expected to be of short-term duration only (1 to 30 days) based on the
limited use pattern.  Short-term dermal post-application exposures were
assessed against the NOAEL for short-term dermal exposures (200
mg/kg/day).  For fruiting vegetables, okra, edible podded beans and
hops, the risks are not of concern (MOEs > 100) on day 0 for all
potential re-entry activities.  As such, the REI of 12 hours is
appropriately protective.  The highest exposure potential is in hops
with high contact activities such as training, stripping and harvesting;
the margin of exposure associated with these high contact activities is
942, well above the level of concern of 100.

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c. Residential Handler exposure: Residential handler risks were
calculated by EPA in the 2007 Human Health Risk Assessment document
(Levy, S., 2007).  Two scenarios, mixing/loading and applying liquids by
low-pressure hand-wand and mixing/loading and applying liquids with a
hose-end sprayer, were identified and evaluated for short-term
residential risks.  Based on the EPA residential handler assessment,
there are no risks of concern for residential handlers (MOEs > 100). 
The lowest MOE, 2,900, was associated with dermal exposure when using
the hose-end sprayer.

d. Residential Postapplication exposures: Current EPA policy indicates
that there is no significant post-application exposure to treated
residential ornamentals; therefore, no residential re-entry risk
assessment was performed.

In summary, all residential and occupational exposure scenarios are
associated with a reasonable certainty of no harm for the US population
and all subpopulations.

D.	Cumulative Effects

There is no information available to indicate that toxic effects
produced by acequinocyl are cumulative with those of any other compound.

E.	Safety Determination

U.S. population. . The chronic dietary food and drinking water exposure
(including all current and proposed uses) to acequinocyl was estimated
at 12.4% of the cPAD for the total US population. The calculated chronic
dietary risks included contributions of modeled residues from drinking
water (direct and indirect, all sources).  The groundwater EDWC for
acequinocyl was estimated to be 0.0036 ppb, while surface water EDWCs
were estimated to be 0.37 and 2.73 ppb, using two different approaches
(Levy, 2007).  The most conservative value, 2.73 ppb, was chosen for use
in the chronic dietary assessment. Acequinocyl concentrations in the
source surface water are not expected to exceed 2.73 ppb in chronic
scenarios due to the conservative high-end assumptions used in the
model. The Tier 1 chronic dietary risk assessment took into account
tolerance-level residues, 100% crop treated, and a drinking water
modeled concentration of 2.73 ppb. The result of this assessment
indicated exposures to the general US population were not of concern. 

Infants and children. The chronic dietary food exposure to acequinocyl
was estimated at 22.5% of cPAD for all infants (<1 year), and 52.6% of
cPAD for children 1-2 years (most highly exposed). The calculated
chronic dietary risks included contributions of modeled residues from
drinking water (direct and indirect, all sources).  The most
conservative value, 2.73 ppb obtained from PRZM-EXAMS surface water
model, was chosen for use in the chronic dietary assessment. Acequinocyl
concentrations in the source surface water are not expected to exceed
the EDWC of 2.73 ppb in chronic scenarios due to the conservative
high-end assumptions used in the model.  The Tier 1 chronic dietary risk
assessment took into account tolerance-level residues, 100% crop
treated, and a drinking water modeled concentration of 2.73 ppb. The
result 

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of this assessment indicated exposures to the most exposed
subpopulation, children aged 1 to 2 years, were not of concern. 

F.	International Tolerances

To date, no Codex, Canadian or Mexican tolerances exists for
acequinocyl.

REFERENCES:

Levy, Sarah.  Amendment to PP#s 6F7040 and #7F176.  Human Health Risk
Assessment for the Proposed Uses of Acequinocyl on Grapes, the Tree Nut
Crop Group, and Residential Sites (Ornamentals). December 12, 2007.

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