Document ID: EPA-HQ-OPP-2007-1076-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-01-23T05:00Z

EPA Registration Division contact: [Marilyn Mautz, 703-305-6785]	

Arysta LifeScience North America Corporation

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
Arysta LifeScience North America Corporation, 15401 Weston Parkway,
Suite150, Cary NC 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 by establishing a tolerance for residues of
3-dodecyl-1,4-dihydro-1,4-dioxo-2-naphthyl acetate and its metabolite
2-dodecyl-3-hydroxy-1,4-naphthoquinone expressed as acequinocyl
equivalents in or on the grapes at  7 parts per million (ppm), in/on
grape juice at 0.05 parts per million (ppm) and  in/on raisins at 0.1
parts per million (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
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry                                       

	1. 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-1,4-naphthoquinone). The proposed tolerance
expression is the parent, acequinocyl and its hydroxy metabolite,
acequinocyl-OH.

	2. Analytical method. The analytical method to quantitate residues of
acequinocyl and acequinocyl-OH in/on fruit crops utilizes high pressure
liquid chromatography (HPLC) using mass spectrometric (MS/MS) detection.
The target limit of quantitation (LOQ) is 0.01 ppm.

	3. 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 residues expressed as acequinocyl equivalents in/on grapes were
0.6205 ppm, in/on raisins were 0.0383 ppm. The crop field trial data are
adequate to support the proposed tolerance of 1 ppm for the grapes, 0.05
ppm for grape juice and 0.1 ppm for raisins.

B. Toxicological Profile

	1. Acute toxicity.  Acequinocyl technical has low acute, dermal and
inhalation toxicity in laboratory animals. The oral LD50 (M/F) in the
rat and mouse was > 5000 mg/kg. The dermal LD50 (M/F) was > 2000 mg/kg.
The inhalation LC50 was reported as > 0.84 mg/l. 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.



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

	3. 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.
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 NOEL=150 mg/kg/day based on these signs.
Developmental NOEL=500 mg/kg/day based on increase in certain skeletal
variants that may be attributed to the observed maternal toxicity.

 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 NOEL=60 mg/kg/day based on reduction in maternal body weight
and 5 females were sacrificed at 120 mg/kg/day. Fetal NOEL=60 mg/kg/day
due to skeletal variations in the thoraco-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
NOEL=100 ppm (7.3 and 8.7 mg/kg/day). Systemic: Hemorrhage and swollen
body parts were seen at 800 and 1500 ppm in F1 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 F1
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.

	4. 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 the 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. NOEL=400 ppm (30.4 mg/kg/day for males and 32.2
mg/kg/day for females). ii. Mouse feeding study. Groups of CD-1 (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 NOEL 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 NOEL 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. NOEL=1000 mg/kg/day.

	5. 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. NOEL=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. NOEL=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-1(ICR)BR mice at 0, 20, 50, 150 or 500 ppm for 80
weeks. NOEL=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-1,4-naphthalenedione (acequinocyl-OH or
designated R1). Subsequent oxidation of the dodecyl chain yielded
butanoic and hexanoic acids, the only measurable identified urinary
metabolites. 2-(1,2-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.

	7. Metabolite toxicology. NA-Remove.

	8. 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 1 ppm for grapes, 0.05 ppm for
grape juice and 0.1 ppm for raisins along with the previously
established or proposed 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 grapes.  This chronic risk
assessment was conducted to assess dietary exposures from acequinocyl in
food using Exponent’s Dietary Exposure Evaluation Model – Food
Commodity Intake Database (DEEM™ FCID) 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;  and a chronic toxicological
endpoint of 2.7 mg/kg bw (NOAEL); 0.027 mg/kg bw (chronic RfD) from the
chronic mouse study.  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 grapes, the chronic dietary food
exposure estimates to acequinocyl are still much less than 100% of
chronic RfD. To be specific,  exposure from grapes has very little
effect on the estimated chronic dietary food exposure as can be seen
from the following: US population at 5.1%, females 13-49 at 3.3%,
children 3-5 at 16.8% and all infants (<1 year) at 14.0%. The most
highly exposed population was children 1-2 years at 25.5%. 

	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 T1/2: 14 minutes, soil
photolyis T1/2: 2 days, aerobic soil metabolism (4 soils) T1/2: <3 days,
aerobic aquatic metabolism T1/2: 0.39 day in water and sediment,
hydrolysis T1/2: pH4=74 days, pH7=2.2 days, pH9=1.3 hours. Acequinocyl
shows low soil mobility. The DWEC (Drinking Water Estimated
Concentration) for chronic exposures is estimated to be 0.24 ppb for
surface water and 0.003 ppb for ground water. These values are taken
directly from FR, Vol. 69, No. 139, 7/21/04, page 43529) and represent
results of the PRZM/EXAMS (surface water) and SCI-GROW models (ground
water) models, respectively since the proposed use on all tree nuts is
not expected to result in higher environmental concentrations than those
from the currently proposed uses.  To determine drinking water exposure,
DWLOCs (drinking  water levels of comparison) were calculated and used
as a point of comparison against the model estimates of the pesticide
concentration in drinking water. For acequinocyl, the chronic DWLOC
values were greater than the estimated concentration (DWEC) in surface
and ground water for each population group. Therefore, exposures to
acequinocyl in drinking water do not pose a significant human health
risk.

	2. Non-dietary exposure. The proposed expansion of the registration for
applications to grapes requires evaluation of occupational handler and
postapplication exposures and dietary exposures for consumers.  

Occupational Handler Exposure: Short-term MOEs for occupational handler
exposures are estimated to range from 3,900 to 530,000, depending on the
site and type of equipment used.  MOEs greater than 100 indicate a
reasonable certainty of no harm is anticipated for occupational handlers
making applications of Kanemite™ 15SC.  Based on the anticipated
occupational use patterns for acequinocyl products,  intermediate-term
(1 month to 6 months) and long-term (several months to lifetime)
exposures are not expected for occupational handlers of acequinocyl. 

Occupational Postapplication Exposure: Estimated MOEs range from 130 to
26,000, demonstrating a reasonable certainty of no harm for workers
re-entering treated crops on the day of application as soon as the
sprays have dried.  

Residential Handler exposure: MOEs for residential handler exposures
associated with all types of handheld equipment are estimated to range
from 2,900 to 430,000, depending on the type of equipment used.

Residential Postapplication exposures: Estimated MOEs are 2,900 for
youth and 2,600 for adults, demonstrating a reasonable certainty of no
harm for adults and youth engaging in postapplication activities in
treated ornamentals.

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

	1. U.S. population. The chronic dietary food exposure (including all
current and proposed uses) to acequinocyl was estimated at 5.1% of the
cRfD for the total US population. The calculated DWLOCs was 21,000 ppb
(short-term residential aggregate) and 900 ppb (long-term residential
aggregate) for the total US population. The surface and groundwater
DWECs for acequinocyl were estimated to be 0.24 ppb and 0.003 ppb,
respectively. Since the chronic DWECs are less than the DWLOCs for all
population subgroups, the chronic aggregate risk estimates are below the
level of concern.

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)nocyl were estimated to be 0.24 ppb and 0.003 ppb, respectively. Since
the chronic DWECs are less than the DWLOCs for all population subgroups
including infants, the chronic aggregate risk estimates are below the
level of concern.

F. International Tolerances

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

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