Document ID: EPA-HQ-OPP-2009-0812-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-11-17T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF CHEMICAL SAFETY AND

                                                                        
                      POLLUTION PREVENTION

MEMORANDUM

Date:		26-AUG-2010

SUBJECT:	Acequinocyl; Human-Health Risk Assessment for Proposed Section
3 Uses on Fruiting Vegetables, Hops, Okra, and Edible-Podded Beans.

PC Code:  006329	DP Barcode:  D368425 

Decision No.:  417967	Registration No.:  66330-38

Petition No.:  9E7598	Regulatory Action:  Section 3

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  7621

TXR No.:  NA	CAS No.:  57960-19-7

MRID No.:  NA	40 CFR:  §180.599

FROM:	Sarah J. Levy, Chemist

		Anwar Y. Dunbar, Ph.D., Pharmacologist

		Allison Nowotarski, Biologist

Registration Action Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

THROUGH:	Dana M. Vogel, Branch Chief 

		George F. Kramer, Ph.D., Branch Senior Chemist

RAB1/HED (7509P)

TO:		B. Madden/S. Jackson, Risk Manager (RM05)

Registration Division (RD) (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational/residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the registered and proposed uses for acequinocyl on fruiting
vegetables, hops, okra, and edible-podded beans.  

A summary of the estimated human health risks resulting from the
registered and proposed uses for acequinocyl are provided in this
document.  The risk assessment, residue chemistry data review, and
dietary exposure assessment were provided by Sarah Levy (RAB1), the
hazard characterization was provided by Anwar Dunbar, the
occupational/residential exposure assessment was provided by Allison
Nowotarski (RAB1), and the drinking water exposure assessment was
provided by Iwona Maher of the Environmental Fate and Effects Division
(EFED).

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F, and submission of
analytical reference standards to the EPA National Pesticide Standards
Repository, there are no residue chemistry issues that would preclude
granting a permanent registration for the requested uses of acequinocyl
or establishment of tolerances for residues of acequinocyl and
acequinocyl-OH as follows: 

Vegetable, fruiting, group 8	0.70 ppm

Okra	0.70 ppm

Bean, edible podded	0.25 ppm

Hop, dried cones	4.0 ppm

Registration should be conditional pending resolution of the following
deficiencies:

Toxicology

An Immunotoxicity Study.

Acute and Subchronic Neurotoxicity Studies.

A 28-Day Inhalation Study.

Note to PM:  According to HED’s Interim Guidance on Tolerance
Expressions (5/27/09, S. Knizner), the tolerance expression for
acequinocyl should be revised to state:

“Tolerances are established for residues of acequinocyl, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below 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, in or on the commodity.

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc270591971"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc270591971 \h  4  

  HYPERLINK \l "_Toc270591972"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc270591972 \h  8  

  HYPERLINK \l "_Toc270591973"  2.1  Identification of Active Ingredient
  PAGEREF _Toc270591973 \h  8  

  HYPERLINK \l "_Toc270591974"  2.2  Structural Formula of Acequinocyl
and Acequinocyl-OH	  PAGEREF _Toc270591974 \h  8  

  HYPERLINK \l "_Toc270591975"  2.3  Physical and Chemical Properties of
Acequinocyl	  PAGEREF _Toc270591975 \h  8  

  HYPERLINK \l "_Toc270591976"  3.0  HAZARD CHARACTERIZATION/FQPA
CONSIDERATIONS	  PAGEREF _Toc270591976 \h  9  

  HYPERLINK \l "_Toc270591977"  3.1  Hazard Profile	  PAGEREF
_Toc270591977 \h  9  

  HYPERLINK \l "_Toc270591978"  3.2  FQPA Considerations	  PAGEREF
_Toc270591978 \h  11  

  HYPERLINK \l "_Toc270591979"  3.3  Dose-Response Assessment	  PAGEREF
_Toc270591979 \h  12  

  HYPERLINK \l "_Toc270591980"  3.4  Endocrine Disruption	  PAGEREF
_Toc270591980 \h  14  

  HYPERLINK \l "_Toc270591981"  3.5  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc270591981 \h  15  

  HYPERLINK \l "_Toc270591982"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc270591982 \h  15  

  HYPERLINK \l "_Toc270591983"  4.1  Summary of Proposed Uses	  PAGEREF
_Toc270591983 \h  16  

  HYPERLINK \l "_Toc270591984"  4.2  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc270591984 \h  17  

  HYPERLINK \l "_Toc270591985"  4.2.1  Residue Profile	  PAGEREF
_Toc270591985 \h  17  

  HYPERLINK \l "_Toc270591986"  4.3  Water Exposure/Risk Pathway	 
PAGEREF _Toc270591986 \h  19  

  HYPERLINK \l "_Toc270591987"  4.4  Dietary Exposure Analyses	  PAGEREF
_Toc270591987 \h  20  

  HYPERLINK \l "_Toc270591988"  4.4.1  Chronic Dietary Exposure Analysis
  PAGEREF _Toc270591988 \h  21  

  HYPERLINK \l "_Toc270591989"  4.5  Residential/Non-Occupational
Exposure Pathway	  PAGEREF _Toc270591989 \h  21  

  HYPERLINK \l "_Toc270591990"  4.5.1  Residential Handler Exposure/Risk
  PAGEREF _Toc270591990 \h  22  

  HYPERLINK \l "_Toc270591991"  4.5.2  Residential Post-application
Exposure/Risk	  PAGEREF _Toc270591991 \h  23  

  HYPERLINK \l "_Toc270591992"  4.5.3  Spray Drift	  PAGEREF
_Toc270591992 \h  24  

  HYPERLINK \l "_Toc270591993"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc270591993 \h  24  

  HYPERLINK \l "_Toc270591994"  5.1  Acute Aggregate Risk	  PAGEREF
_Toc270591994 \h  24  

  HYPERLINK \l "_Toc270591995"  5.2  Short-Term Aggregate Risk	  PAGEREF
_Toc270591995 \h  25  

  HYPERLINK \l "_Toc270591996"  5.3  Intermediate-Term Aggregate Risk	 
PAGEREF _Toc270591996 \h  25  

  HYPERLINK \l "_Toc270591997"  5.4  Long-Term Aggregate Risk	  PAGEREF
_Toc270591997 \h  25  

  HYPERLINK \l "_Toc270591998"  5.5  Cancer Risk	  PAGEREF _Toc270591998
\h  25  

  HYPERLINK \l "_Toc270591999"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc270591999 \h  25  

  HYPERLINK \l "_Toc270592000"  7.0  OCCUPATIONAL EXPOSURE AND RISK
ASSESSMENT	  PAGEREF _Toc270592000 \h  26  

  HYPERLINK \l "_Toc270592001"  7.1  Occupational Handler Exposure/Risk	
 PAGEREF _Toc270592001 \h  26  

  HYPERLINK \l "_Toc270592002"  7.2  Post-application Exposure/Risk	 
PAGEREF _Toc270592002 \h  28  

  HYPERLINK \l "_Toc270592003"  7.3  REI	  PAGEREF _Toc270592003 \h  31 

  HYPERLINK \l "_Toc270592004"  8.0  RESIDUE CHEMISTRY AND TOXICOLOGY
DEFICIENCIES	  PAGEREF _Toc270592004 \h  31  

  HYPERLINK \l "_Toc270592005"  8.1  Residue Chemistry	  PAGEREF
_Toc270592005 \h  31  

  HYPERLINK \l "_Toc270592006"  8.2  Toxicology	  PAGEREF _Toc270592006
\h  31  

  HYPERLINK \l "_Toc270592007"  8.3  Occupational and Residential
Exposure	  PAGEREF _Toc270592007 \h  31  

  HYPERLINK \l "_Toc270592008"  APPENDIX:  Toxicity Profile Tables and
Metabolites.	  PAGEREF _Toc270592008 \h  32  

 1.0  EXECUTIVE SUMMARY

Acequinocyl is a quinoline-type miticide that is currently registered
for use on greenhouse, shadehouse, ornamental, floral, foliage, nursery
crops, grapes, tree nuts, pome fruits, citrus fruits, pistachios, and
strawberries, as well as for use on landscape ornamentals in and around
residences, businesses, public property, schools, interiorscapes, and
other non-production areas by commercial applicators and homeowners. 
Acequinocyl is currently registered to Arysta Lifescience North America
Corporation as a 15% suspension-concentrate (SC) formulation.

Under PP#9E7598, the Interregional Research Project No.4 (IR-4), on
behalf of the Agricultural Experiment Station of AZ, CA, CO, FL, ID, NC,
NJ, NY, OK, OR, TN, TX, VA, and WA, is requesting for the establishment
of tolerances for the combined residues of the insecticide acequinocyl,
2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione, and its metabolite,
2-dodecyl-3-hydroxy-1,4-naphthoquinone, expressed as acequinocyl
equivalents in/on the following commodities:

Vegetable, fruiting, group 8	0.70 ppm

Okra	0.70 ppm

Bean, edible podded	0.25 ppm

Hop, dried cones	3.5 ppm

™ 15 SC Miticide, a 1.25 pounds per gallon (lb/gal) SC formulation. 
Up to two foliar applications are proposed for a maximum seasonal rate
of 0.6 lb active ingredient per acre (ai/A), with a 7-day preharvest
interval (PHI), except for okra for which a 1-day PHI is proposed.

Hazard Assessment:  Acequinocyl has low acute toxicity via the oral,
dermal, and inhalation routes (Toxicity Categories III and IV).  No
ocular or dermal irritation was noted.  Acequinocyl is not a dermal
sensitizer.  Acequinocyl is a known Vitamin K antagonist; therefore, it
is thought to produce its adverse effects by disrupting the blood
coagulation system as indicated by increased prothrombin time, increased
activated partial thromboplastin time, and internal hemorrhages.  

In a subchronic oral toxicity study, a 28-day dermal toxicity study, and
a chronic feeding/oncogenicity study (all in the rat), acequinocyl
increased prothrombin and activated partial thromboplastin times. 
Although clotting factors were not measured in some studies (i.e.,
rat/rabbit developmental toxicity study, mouse subchronic/chronic
toxicity study, and 2-generation reproduction rat study), internal
hemorrhages were observed.  In the combined chronic
toxicity/oncogenicity study in rats, enlarged eyeballs were observed. 
Hepatotoxicity in the mouse was evidenced by histopathology and
increased liver enzymes.  

In both rat and rabbit developmental toxicity studies, acequinocyl
increased the number of resorptions.  Developmental effects (i.e.,
resorptions) occurred at a dose that was higher than or the same as the
dose that caused maternal toxicity.  In the 2-generation reproduction
toxicity study in the rat, there was no evidence of reproductive
toxicity, though there were notable toxic effects observed in offspring
that were not observed in adults including swollen body parts,
protruding eyes, clinical signs, delays in pupil development and
increased mortality occurring mainly after weaning.  A clear
no-observable-adverse-effect level (NOAEL) was observed for these
effects. 

There was no evidence of carcinogenic potential in either the rat or
mouse carcinogenicity study, indicating that acequinocyl is "not likely"
to be carcinogenic to humans.  There was no concern for mutagenic
activity as indicated by several mutagenicity studies.

Dose-Response Assessment and FQPA Decision:  The HED Hazard
Identification Assessment Review Committee (HIARC) met on October 14,
2003, to select endpoints for risk assessments and to evaluate the
potential for increased susceptibility of infants and children.  The
Committee recommended the Food Quality Protection Act (FQPA) Safety
Factor (SF) for increased susceptibility of infants and children be
reduced to 1X because there are no residual uncertainties for pre-
and/or post-natal toxicity.  In April 2010, HED’s RAB1 toxicology team
re-evaluated the previously determined endpoints to incorporate any
newly submitted data, changes in use patterns, and changes in exposure
scenarios.  For a detailed explanation of the endpoints and rationale,
see Section 3.3.

Dietary Exposure (Food + Drinking Water):  The HED Metabolism Assessment
Review Committee (MARC) determined that the residues of concern in the
dietary exposure and risk assessment are acequinocyl and acequinocyl-OH
(also referred to as R1) for both tolerance expression and risk
assessment purposes.  In addition, for liver and kidney,
2-hydroxy-3-hexanoic acid-1,4 naphthalenedione (AKM-15) was also
included, but for risk assessment purposes only.  For the aquatic
exposure modeling, both parent and metabolite (acequinocyl-OH)
concentrations were estimated in the surface and ground water to address
the toxicity concerns associated with the acequinocyl-OH degradate.  The
1-in-10-year peak concentrations of acequinocyl ranged from 0.18 (CA
citrus) to 5.57 (FL nursery plants except roses) ppb.  The 60-day
concentrations of acequinocyl ranged from 0.04 to 1.26 ppb.  

™), Version 2.03, which uses food consumption data from the U.S.
Department of Agriculture’s (USDA’s) Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998. Tolerance-level
residues, DEEM( ver. 7.76 default processing factors, and 100 percent
crop treated (%CT) data were used in the chronic dietary assessment.  An
acute dietary assessment was not conducted for acequinocyl because an
endpoint of concern attributable to a single dose was not identified;
therefore, an acute reference dose (aRfD) was not established.  A cancer
dietary assessment was not conducted because acequinocyl was classified
as not likely to be carcinogenic to humans.

For the chronic dietary assessment, the general U.S. population and all
population subgroups have risk estimates which were not of concern to
HED.  The chronic dietary risk assessment shows that the chronic dietary
risk estimates do not exceed HED’s level of concern [(LOC) i.e., <100%
of the chronic population-adjusted dose (cPAD)].  For the general U.S.
population, the exposure for food and water utilized 9.8% of the cPAD. 
The chronic dietary risk estimate for the highest exposed population
subgroup, children 1-2 years old, is 45% of the cPAD.

Residential Exposure/Risk:  Acequinocyl is currently registered for use
on landscape ornamentals in and around residences, businesses, public
property, schools, interiorscapes, and other non-production areas by
commercial applicators and homeowners.  All risks for residential
handlers are above the target MOE of 100 and do not exceed HED’s LOC. 
Post-application exposure is not anticipated with the proposed uses.  

Occupational Exposure Estimates:  Occupational handler and
postapplication exposure is expected from the proposed uses of
acequinocyl.  No chemical-specific handler exposure data were submitted
in support of this Section 3 registration.  It is the  policy of the HED
to use data from the Pesticide Handlers Exposure Database (PHED) Version
1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess
handler exposures for regulatory actions when chemical-specific
monitoring data are not available (HED Science Advisory Council for
Exposure (ExpoSAC) Draft Standard Operating Procedure (SOP) #7, dated
1/28/99). 

All risks for occupational handlers are above the target margin of
exposure (MOE) of 100 with the use of gloves, and do not exceed the LOC
as the proposed labels already require the use of protective gloves as
personal protective equipment.  There are no risks of concern for all
occupational post-application activities associated with the proposed
uses. 

Acequinocyl is classified in Toxicity Category III for acute dermal and
acute inhalation.  It is classified in Toxicity Category IV for primary
eye irritation and primary skin irritation and it is not a dermal
sensitizer.  Therefore, the Worker Protection Standard (WPS) interim
restricted-entry interval (REI) of 12 hours is adequate to protect
agricultural workers from post-application exposures to acequinocyl.  

Aggregate Exposure Assessment:  Acute and cancer aggregate-risk
assessments were not performed because no appropriate endpoint was
available to determine the aRfD for the general population or any
population subgroup, and acequinocyl is classified as “Not likely to
be Carcinogenic to Humans,” respectively.  Intermediate- and long-term
aggregate assessments were not performed since the use pattern is not
expected to result in residential handler or postapplication exposure of
more than 30-day duration.  

A chronic aggregate exposure risk assessment was assessed by
incorporating the drinking water directly into the dietary-exposure
assessment.  As the chronic dietary exposure estimates are not of
concern to HED for the general U.S. population or any population
subgroup, the chronic aggregate risk is not of concern for these
populations.  An aggregate risk assessment was performed for short-term
aggregate exposure (food + drinking water + residential exposure)
because there are residential uses.  Short-term aggregate exposures and
risk estimates were calculated for adults and the aggregate MOEs are
>100 and are, therefore, not of concern to HED.  

Environmental Justice Considerations:  Potential areas of environmental
justice concerns, to the extent possible, were considered in this
human-health risk assessment, in accordance with U.S. Executive Order
12898, "Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations,"
http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf
).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under CSFII and are used
in pesticide risk assessments for all registered food uses of a
pesticide.  These data are analyzed and categorized by subgroups based
on age, season of the year, ethnic group, and region of the country. 
Additionally, OPP is able to assess dietary exposure to smaller,
specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant.  Whenever appropriate, non-dietary
exposures based on home use of pesticide products and associated risks
for adult applicators and for toddlers, youths, and adults entering or
playing on treated areas postapplication are evaluated.  Further
considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure to bystanders and farm workers as well as
lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research:  Past acequinocyl risk assessments rely in
part on data from studies in which adult human subjects were
intentionally exposed to a pesticide to determine their dermal and
inhalation exposure.  Many such studies, involving exposure to many
different pesticides, comprise generic pesticide exposure databases such
as PHED, the Outdoor Residential Exposure Task Force (ORETF) Database,
and the Agricultural Reentry Task Force (ARTF) Database.  EPA has
reviewed all the studies supporting these multi-pesticide generic
exposure databases, and has found no clear and convincing evidence that
the conduct of any of them was either fundamentally unethical or
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted.  All applicable requirements of
EPA’s Rule for the Protection of Human Subjects of Research (40 CFR
Part 26) have been satisfied, and there is no regulatory barrier to
continued reliance on these studies.

Recommendation for Tolerances and Registration:  Pending submission of
revised Sections B and F, and submission of analytical reference
standards to the EPA National Pesticide Standards Repository, there are
no residue chemistry issues that would preclude granting a permanent
registration for the requested uses of acequinocyl or establishment of
tolerances for residues of acequinocyl and acequinocyl-OH as follows: 

Vegetable, fruiting, group 8	0.70 ppm

Okra	0.70 ppm

Bean, edible podded	0.25 ppm

Hop, dried cones	4.0 ppm

Registration should be conditional pending resolution of the following
deficiencies:

Toxicology

An Immunotoxicity Study.

Acute and Subchronic Neurotoxicity Studies.

A 28-Day Inhalation Study.

Note to PM:  According to HED’s Interim Guidance on Tolerance
Expressions (S. Knizner, 5/27/09), the tolerance expression for
acequinocyl should be revised to state:

“Tolerances are established for residues of acequinocyl, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below 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, in or on the commodity.

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

Provided below are the physical/chemical properties for acequinocyl;
they include product chemistry data.  Most of this information was
obtained from the acequinocyl “Pesticide Fact Sheet;” 9/26/03 ( 
HYPERLINK "http://www.epa.gov/opprd001/factsheets/acequinocyl.pdf" 
http://www.epa.gov/opprd001/factsheets/acequinocyl.pdf ).

2.1  Identification of Active Ingredient

Registrant:			Arysta Lifescience North America Corporation

Trade Names:			Kanemite( (EPA Reg. #: 66330-38)

CAS Chemical Name:		2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione

CAS Registry No.: 		57960-19-7

Common Name:		Acequinocyl

PC Code:			006329

Pesticide Type:		Miticide

Chemical Family:		Quinoline

Target Pests:			Tetranychus, Panonychus and Eutetranychus spp of mites

Formulation:			Product- Kanemite™ 15 SC; 1.25 lb ai/gal

Types of Formulations:	Technical (96.8% ai); End-Use Product (15.8%)

Empirical Formula:		C24H32O4

Molecular Weight:		384.5

2.2  Structural Formula of Acequinocyl and Acequinocyl-OH

Acequinocyl	Acequinocyl-OH

2.3  Physical and Chemical Properties of Acequinocyl

These physical and chemical properties are for the end-use product
unless otherwise noted.  

6.69 μg/L at 200C (technical)	

Octanol/Water Partition Coefficient (Log Kow):	(6.2 (technical)

Melting Point:		59.6(C (technical)

Density:		1.13 g/cm3

Acequinocyl is a liquid at room temperature, thus, any losses due to
volatilization/sublimation are expected to be minimal.

3.0  HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

The existing toxicological database for acequinocyl is complete and
supports the establishment of permanent tolerances for residues of
acequinocyl in/on the raw agricultural commodities (RACs) resulting from
the proposed uses.  The toxicity profile tables also may be found in the
Appendix, Tables A-1 and A-2.  The following documents support the
hazard characterization of acequinocyl:

Acequinocyl.  2nd Report of the Hazard Identification Assessment Review
Committee (HIARC).  Meeting Date:  October 14, 2003.  TXR No. 0052234. 
P. Terse; 11/13/04.

Acequinocyl.  Report of the Hazard Identification Assessment Review
Committee.  Meeting Date:  July 15, 2003.  TXR No. 0052075.  R. Fricke;
8/14/03.  

3.1  Hazard Profile

Acequinocyl binds to the Qo center at Complex III in the mitochondria of
mite cells and, thereby, exerts its miticidal action by inhibiting
electron transfer.  Acequinocyl possesses moderate activity against
plant mitochondrial complex III, in contrast to much higher activity
against an insect mitochondrial complex III.  There is a lack of
information regarding whether or not acequinocyl inhibits the mammalian
mitochondrial electron transfer system.  

Acequinocyl has low acute toxicity via the oral, dermal, and inhalation
routes.  No ocular or dermal irritation was noted.  Acequinocyl is not a
dermal sensitizer.  Acequinocyl is a known Vitamin K antagonist and,
therefore, is thought to disrupt blood coagulation.  This mechanism is
supported by effects observed in the database.  

In the rat subchronic oral toxicity study, the primary effects included
pallor, swelling of the eyes and limbs, decreased motor activity,
piloerection, reddish urine, increased activated partial thromboplastin
time, increased prothrombin time, and internal hemorrhages.  In the
mouse subchronic oral toxicity study, effects included pallor, sunken
eyes, labored/irregular breathing, hunched posture, piloerection, weight
loss, and hepatic vacuolization (blood coagulation profile was not
evaluated in this study).  In the dog subchronic oral toxicity study,
toxic effects included reduced body weight gains, reduced food
efficiency, decreased total protein, increased triglyceride levels,
elevated platelet counts, elevated reticulocytes, increased prothrombin
time, and decreased liver and heart weights (absolute).  In the rat
28-day dermal toxicity study, the primary effects were red-stained
treated skin area, increased prothrombin time, increased activated
partial prothromboplastin time, increased fibrinogen levels, and
increased heart weights (absolute and relative to the body weight).

In the rat chronic oral studies, toxic effects included enlarged
eyeballs, increased prothrombin time, and increased activated partial
thromboplastin time.  In the mouse chronic oral toxicity study,
hepatotoxicity was indicated by increased liver enzyme levels (alanine
and aspartate aminotransferase), increased liver weight, hepatocyte
vacuolization, and hepatocyte fatty deposition (blood clotting was not
evaluated in this study).  In the dog chronic toxicity study, effects
included elevated prothrombin time, increased reticulocyte/platelet
count, reduced body weight gain, and reduced food efficiency.   

In the rat prenatal developmental toxicity study, maternal toxicity
resulted in pale eyes, piloerection, red vaginal discharge, and internal
hemorrhage at the lowest-observable adverse effects level (LOAEL; 500
mg/kg/day), whereas developmental toxicity was indicated by increased
resorptions and fetal variations (750 mg/kg/day).  In the rabbit,
maternal toxicity produced body weight loss, reduced fecal output,
reduced food consumption, pale lungs/liver, internal hemorrhaging, hair
loss, and blood-stained urine (120 mg/kg/day).  The developmental
toxicity study in rabbits identified an increased number of complete
resorptions (120 mg/kg/day). 

In the rat two-generation reproductive toxicity study, both the maternal
and reproductive toxicity LOAELs were not observed, however the LOAEL
for parental males was 58.9/69.2 mg/kg/day based on hemorrhagic effects.
 The offspring systemic LOAEL was also 58.9 mg/kg/day.  Though the
offspring LOAEL was similar to that of parental male’s, there were
effects specific to the pups which in addition to the hemorrhagic
effects noted in both generations, included swollen body parts,
protruding eyes, clinical signs, delays in pupil development and
increased mortality occurring mainly after weaning. 

Previously, HED’s HIARC concluded that exposure to acequinocyl does
not pose a neurotoxicity concern.  First, acequinocyl is a known Vitamin
K antagonist; neurotoxic compounds of similar structure were not
identified.  Second, although two studies showed effects that could be
indicative of neurotoxicity, HIARC considered these as secondary because
they were observed at very high doses.  In the 2-generation reproduction
study, significant reduction in startle response in F2 pups was observed
in the mid- and high- dose groups (58.9/69.2 mg/kg/day and 111.2/133.5
mg/kg/day).  However, other functional development tests (such as a
pupillary reflex test at 21 days post partum, an open field exploration
test at 35-48 days post partum and a water maze test with a learning
phase and a memory phase at 35-48 days post partum) that were performed
on pups did not show significant differences as compared to control
values even at the highest dosage level.  In the rat subchronic oral
toxicity study, neurotoxicity signs, such as decreased motor activity,
piloerection and hunched posture, were observed at the high dose
(252.7/286.0 mg/kg/day), but in the presence of clinical signs including
wasting, swelling of the orbit and limbs, pallor, and reddish urine. 
Furthermore, all rats in this 252.7/286.0 mg/kg/day (3200 ppm) group
died or were sacrificed moribund in the first three weeks of treatment.

There was no evidence of carcinogenic potential in either the rat or
mouse carcinogenicity study, indicating that acequinocyl is "not likely"
to be carcinogenic to humans.

There was no concern for mutagenic activity as indicated by several
mutagenicity studies, including a bacterial (Salmonella, E. coli)
reverse mutation assay, an in vitro mammalian chromosomal aberration
assay, an in vivo mouse bone marrow micronucleus assay, and a bacterial
DNA damage or repair assay.

Acequinocyl exhibits marginal absorption into the plasma (13-16% for the
10 mg/kg low dose and 8-9% for the 500mg/kg high dose) and relatively
rapid and complete excretion (24 hours for the low dose and 72 hours for
the high dose), primarily via the bile and feces (82.6%) in rat.
Absorption is saturated at the high dose.  Plasma kinetic data revealed
peak plasma concentrations occurring at 2-6 hours following a single or
14-day repeated low dose and at approximately 24 hours for the high dose
group.  The elimination half-life is about 4.4-6.5 hours for the single
day low dose group.  Acequinocyl undergoes nearly complete metabolism to
hydrolysis products and a glucuronide conjugate.  There was no evidence
for selective tissue accumulation or sequestration.  

In feces and the bile, the components identified were:  (1) parent
compound; (2) 2-hydroxy-3-dodecyl-1, 4-naphthalenedione
(acequinocyl-OH); (3) 2-(1,2-dioxotetradecyl)-benzoic acid (AKM-18); (4)
conjugated acequinocyl-OH; (5) 2-hydroxy-3-butanoic
acid-1,4-naphthalenedions; and (AKM-14) (6) 4 naphthalenedione (AKM-15).
 The structures for these metabolites may be found in the Appendix,
Table A-3.  

 

The major urinary metabolites included:  (1) 2-hydroxy-3-hexanoic
acid-1; 4 naphthalenedione (AKM-15); and (2) 2-hydroxy-3-butanoic
acid-1,4-naphthalenedions (AKM-14).   Neither the parent compound nor
the hydroxy metabolite (acequinocyl-OH) was observed in the urine.  

The major components detected in plasma were:  (1) parent compound; (2)
acequinocyl-OH; (3) conjugated acequinocyl-OH; (4) AKM-14; and (5)
AKM-15.  

3.2  FQPA Considerations

HED’s RAB1 risk assessment team concluded that based on toxicological
considerations and the residue assumptions used in the dietary and
residential exposure analyses, the FQPA SF may be reduced to 1X.  This
recommendation is based on the following considerations:

There are no residual uncertainties for pre- and post-natal toxicity.

There is potential evidence of neurotoxicity or neuropathology in the
2-generation reproduction study as well as the rat subchronic
neurotoxicity study, however these toxicities are not considered to be
primary effects since they occur in the presence of more severe systemic
effects in both studies.  Therefore, although an acute and subchronic
neurotoxicity studies are now required as a part of new data
requirements in the 40CFR §158 for conventional pesticide registration,
the agency does not believe that conducting these studies will result in
a lower point of departure (POD) than that currently used for overall
risk assessment, and therefore, a database uncertainty factor (UFDB) is
not needed to account for lack of these studies.  

There is no evidence of increased susceptibility of rat or rabbit
fetuses to in utero exposure to acequinocyl.  In the 2-generation
reproduction study, more severe effects were observed in the offspring,
however these effects were observed at the same doses as parental
effects, and a clear NOAEL was established which is being used in
endpoint selection.

The toxicology database for acequinocyl does not show any evidence of
treatment-related effects on the immune system.  The overall weight of
evidence suggests that this chemical does not directly target the immune
system.  An immunotoxicity study is required as a part of new data
requirements in the 40 CFR Part 158 for conventional pesticide
registration; however, the Agency does not believe that conducting a
functional immunotoxicity study will result in a lower POD than that
currently in use for overall risk assessment, and therefore, a UFDB is
not needed to account for the lack of this study.

A 28-day inhalation study is not available; however, the EPA has
determined that the additional FQPA SF is not needed.  Residential
inhalation risk was estimated by calculating exposure using the Agency's
Residential SOPs.  For chemicals with low vapor pressure (7.5 x 10-5
mmHg or below for outdoor uses at 20-300C), these standard assumptions
are expected to overestimate the exposure via the inhalation route. 
Acequinocyl is such a compound (1.69 x 10-11 mmHg at 250C) and exposure
through the inhalation route is expected to be minimal.  Therefore, the
risk estimate is conservative and is considered protective and the
additional FQPA SF is not needed. 

Since all calculated inhalation MOEs for residential handlers are
significantly greater than HED’s LOC (MOE >100), the lack of an
inhalation study will not impact the FQPA SF.

The dietary food and drinking water exposure assessments will not
underestimate the potential exposures for infants and children; and the
residential use (ornamentals) is not expected to result in
post-application exposure to infants and children.

The dietary drinking water assessment utilizes model-generated water
concentration values and associated modeling parameters that are
designed to provide conservative, health-protective, high-end estimates
of water concentrations that will not likely be exceeded.

3.3  Dose-Response Assessment

Tables 3.3.1 and 3.3.2 provide the toxicity endpoints used in this risk
assessment.  

Table 3.3.1.  Summary of Toxicological Doses and Endpoints for
Acequinocyl for Use in Dietary, Occupational, and Residential Exposure
Risk Assessments.

Exposure/

Scenario	POD	Uncertainty/FQPA SF	RfD, PAD, LOC 	Study and Toxicological
Effects

Acute Dietary (General Population, including Infants and Children)	N/A
N/A	N/A	An endpoint of concern (effect) attributable to a single dose
was not identified in the database.  Quantification of acute risk to
general population including infants and children is not required.

Chronic Dietary (All Populations)	NOAEL = 2.7 mg/kg/day	UFA = 10x

UFH =10x

FQPA SF = 1X

	cPAD = cRfD = 0.027 mg/kg/day 

	18-month carcinogenicity study in mice;

LOAEL = 7.0 mg/kg/day based on clinical chemistry and microscopic
nonneoplastic lesions (brown pigmented cells and perivascular
inflammatory cells in liver).

Short- (1-30 days) and Intermediate-(1-6 months) Term Dermal	Dermal
NOAEL = 200 mg/kg/day	UFA = 10x

UFH =10x

	LOC (occupational/

residential) = 

MOE <100 

	28-day dermal study in rats;

LOAEL = 1000 mg/kg/day based on increased clotting factor times.

Short- (1-30 days) Term Inhalation

	Oral NOAEL=60 mg/kg/day

(inhalation absorption rate=100%)	UFA= 10x

UFH=10x

	LOC (occupational/

residential) = 

MOE <100 

	Developmental toxicity study in rabbits;

Maternal LOAEL = 120 mg/kg/day based on clinical signs (hematuria,
reduced fecal output, body weight loss, and reduced food consumption)
and gross necropsy findings (pale lungs and liver, hemorrhaging uterus,
fluid in the cecum, fur in the stomach, blood stained vaginal opening,
blood-stained urinary bladder contents/urine).

Intermediate- 

(1-6 months) Term Inhalation

	Oral NOAEL = 16 mg/kg/day

(inhalation absorption rate=100%)	UFA = 10x

UFH = 10x

	LOC (occupational/

residential) = 

MOE <100 

	Subchronic toxicity in mice;

LOAEL = 81 mg/kg/day based on hepatocyte vacuolation.

Cancer (oral, dermal, inhalation)   	Classification:  “Not likely to
be Carcinogenic to Humans.”

1  UF = uncertainty factor, UFA = extrapolation from animal to human
(interspecies), UFH = potential variation in sensitivity among members
of the human population (intraspecies), FQPA SF = FQPA Safety Factor,
NOAEL = no-observed-adverse-effect level, LOAEL =
lowest-observed-adverse-effect level, RfD = reference dose (a = acute, c
= chronic), PAD = population-adjusted dose, MOE = margin of exposure,
LOC = level of concern, N/A = Not Applicable, UFDB = database
uncertainty factor, UFL = uncertainty factor for lack of a NOAEL.

2   15% Dermal-absorption factor – derived from dermal-penetration
study.

Acute Dietary Endpoint:  The aRfD for the general population, including
infants and children, was not established because an endpoint of concern
attributable to a single dose was not identified.  Therefore, this
assessment is not necessary.

Chronic Dietary Endpoint:  The chronic reference dose (cRfD) of 0.027
mg/kg/day was determined on the basis of the chronic carcinogenicity
study in mice.  An UF of 100 (10-fold for interspecies extrapolation and
10-fold for intraspecies variability) was applied to the NOAEL of 2.7
mg/kg/day to derive the cRfD.  The LOAEL of 7.0 mg/kg/day is based on
clinical chemistry and microscopic non-neoplastic lesions (brown
pigmented cells and perivascular inflammatory cells) in the liver.  The
FQPA SF of 1X is applicable for chronic dietary risk assessment. 
Therefore, the cPAD is equal to the RfD and is 0.027 mg/kg/day.  The
lowest NOAEL in the database was derived from this study, and this study
is thus appropriate for the chronic reference dose.  It is also
appropriate for both the expected duration of exposure and the route of
exposure.

Short- and Intermediate-Term Incidental Oral Endpoints:  Since there are
no residential uses under consideration in the current risk assessment,
where there may be potential short- or intermediate term incidental oral
exposures, these risk assessments were not performed.

Dermal Absorption:  No dermal absorption factor was necessary for the
short- and intermediate-term dermal assessments since the endpoint was
based on a dermal study.  However, HIARC selected a dermal absorption
rate of 15% for the long-term dermal assessment.  The dermal penetration
study yielded absorptions of 12.23%, 19.75% and 14.77% at 168 hours
(doses were 0.1, 0.01, and 0.001 mg/cm2, respectively).  Because a
higher dermal absorption value (20%) was observed at the mid-dose than
observed at the lowest dose (15%), HIARC selected a 15% dermal
absorption value that was based on the average absorption values at the
three doses at 168 hours (7 days).

Short- and Intermediate-Term Dermal Endpoints:  The short- and
intermediate-term dermal endpoints are based on increased clotting
factor times seen in the rat 28-day dermal toxicity study at the LOAEL
of 1000 mg/kg/day (NOAEL = 200 mg/kg/day).  This study is ideal for this
exposure scenario because it is the route specific study, it matches the
durations of exposure (1-30 days and 1-6 months), and it is consistent
with the mechanism of action for this active ingredient.  The LOC for
occupational exposure is for a MOE of <100.

Short-Term Inhalation Endpoint:  The short-term inhalation endpoint is
based on the maternal NOAEL of 60 mg/kg/day in the developmental study
in rabbits.  The NOAEL of 60 mg/kg/day was based on clinical signs
(hematuria, reduced fecal output, body weight loss, and reduced food
consumption) and gross necropsy findings (pale lungs and liver,
hemorrhaging uterus, fluid in the cecum, fur in the stomach, blood
stained vaginal opening, blood-stained urinary bladder contents/urine)
at the LOAEL of 120 mg/kg/day.  Because HIARC selected an oral NOAEL for
short-term inhalation exposure assessment, a conservative 100% oral
equivalent inhalation absorption factor is assumed.  This study is
relevant for the duration of exposure and is protective of pregnant
females from the above mentioned effects, which are consistent with
mechanism of action for this active ingredient.  

Intermediate-Term Inhalation Endpoint:  The intermediate-term inhalation
endpoint is based on hepatocyte vacuolization seen in the 90-day oral
study in mice observed at the LOAEL of 81 mg/kg/day (NOAEL = 16
mg/kg/day).  Because HIARC selected an oral NOAEL for intermediate-term
inhalation exposure assessment, a conservative 100% oral equivalent
inhalation absorption factor is assumed.  This study is relevant for the
duration of exposure (90-days).  The LOC for occupational exposure is
for a MOE of <100.

  

Long-Term Dermal and Inhalation Endpoints:  Since the uses under
consideration in the current risk assessment do not include long-term
dermal or inhalation exposures, long-term dermal and inhalation risk
assessments were not performed.

Based on the available toxicity database and the Agency's current
practices, the inhalation risk for acequinocyl was assessed using an
oral toxicity study.  The Agency sought expert advice and input on
issues related to this route-to-route extrapolation approach (i.e., the
use of oral toxicity studies for inhalation risk assessment) from its
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific
Advisory Panel (SAP) in December 2009.  The Agency received the SAP’s
final report on March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, re-examine and develop new policies and procedures for
conducting inhalation risk assessments, including route-to-route
extrapolation of toxicity data.  If any new policies or procedures are
developed, then the Agency may revisit the need for an inhalation
toxicity study for acequinocyl and/or a re-examination of the inhalation
toxicity risk assessment.

3.4  Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations.  Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data.  Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Acequinocyl was not among the group of 58 pesticide active ingredients
on the initial list to be screened under the EDSP.  Under FFDCA sec.
408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:    HYPERLINK
"http://www.epa.gov/endo/"  http://www.epa.gov/endo/ 

3.5  Recommendation for Aggregate Exposure Risk Assessments

Since short- and intermediate-term inhalation endpoints are based on
oral studies, dietary exposure will be aggregated to inhalation exposure
for all populations/durations.   

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

Please refer to the following documents for detailed considerations of
the material summarized in this section: 

PP#: 9E7598.  Acequinocyl.  Petition for Use on Fruiting Vegetables,
Hops, Okra, and Edible-Podded Beans.  Summary of Analytical Chemistry
and Residue Data.  D369100.  S. Levy, 8/25/10.

 PP#: 9E7598.  Acequinocyl.  Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk Assessment for the Section 3
Registration Action Use on Fruiting Vegetables, Hops, Okra, and
Edible-Podded Beans.  D369101.  S. Levy, 8/25/10.

 Acequinocyl: Occupational and Residential Exposure/Risk Assessment for
Proposed Use on Fruiting    Vegetables Crop Group 8 (Tomatoes &
Peppers), Edible Podded Beans, Hops, and Okra.  DP Barcode:  369099.  A.
Nowotarski.  6/10/10.

Acequinocyl and its Degradate, Acequinocyl-OH (R1), Drinking Water
Assessment in Support of IR-4 New Uses Registration for Fruiting
Vegetables (Crop Group 8), Okra, Edible Podded Beans, and Hops. D368426
and 368579.  I. Maher et al., 4/29/10.

Acequinocyl is a quinoline type miticide registered for use in the U.S.
on pome fruits, citrus fruits, grapes, tree nuts, pistachios, and
strawberries for the control of various phytophagous mite species. 

 

Under PP#9E7598, the Interregional Research Project No.4 (IR-4), on
behalf of the Agricultural Experiment Station of AZ, CA, CO, FL, ID, NC,
NJ, NY, OK, OR, TN, TX, VA, and WA, is requesting for the establishment
of tolerances for the combined residues of the insecticide acequinocyl,
2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione, and its metabolite,
2-dodecyl-3-hydroxy-1,4-naphthoquinone, expressed as acequinocyl
equivalents in/on the following commodities:

Vegetable, fruiting, group 8	0.70 ppm

Okra	0.70 ppm

Bean, edible podded	0.25 ppm

Hop, dried cones	3.5 ppm

4.1  Summary of Proposed Uses

The petitioner provided a draft label for Kanemite  SEQ CHAPTER \h \r 1
™ 15 SC Miticide (EPA Reg. No. 66330-38), a 1.25 lb/gal SC formulation
of acequinocyl.  The acequinocyl formulation, which is currently
registered for use on several fruit and nut crops, is proposed for use
on fruiting vegetables, okra, edible-podded beans and hops.  Table 4.1.1
provides a summary of the proposed use patterns.

Table 4.1.1.  Summary of Proposed Directions for Use of Acequinocyl.

Commodity	Trade Name (EPA Reg. No.)	Application Timing, Type, Equipment
Application Rate

(lb ai/A)	Maximum Number Applications

Per Season	Maximum Seasonal Application Rate

(lb ai/A)	PHI1

(days)	Use Directions and Limitations1

Fruiting vegetable crop group 8 (tomato and pepper)	Kanemite™  15 SC
Ground	0.3 	2	0.6	7	

RTI:  21 days, 

minimum GPA:  100

Edible podded bean

	Hop

	Okra

1

	1  PHI = preharvest interval, RTI = retreatment interval, GPA = gallons
of water volume per acre.

General label restrictions include:  (i) do not apply through any type
of irrigation system; (ii) do not apply by air; (iii) do not apply
within 75 feet of aquatic areas; and (iv) not for indoor residential
use.  The product may be combined with most commonly used pesticides
with the exception of strongly alkaline material, which can reduce
activity; combination with Phos-ethyl (fosetyl) is prohibited. 
Broad-spectrum insect control may be obtained by tank-mixing the SC
acequinocyl product with other miticide/insecticide products; a
spray-mix compatibility and phytotoxicity trial under local conditions
should first be conducted.  A 12-hour REI is specified.  No rotational
crop restrictions are specified on the label.  The label requires
applicators and other handlers to wear long-sleeved shirt and long
pants, chemical-resistant gloves, and shoes plus socks.

Conclusions:  The proposed use directions are adequate to allow for
evaluation of the submitted residue data relative to the proposed uses. 
The proposed uses are generally supported by the submitted field trial
data; however, the data for fruiting vegetables supports a 1-day PHI for
all fruiting vegetables.  The petitioner may reduce the proposed PHI for
fruiting vegetables from 7 days to 1 day, based on field trial data. 
The submitted fruiting vegetable data do support the 1-day PHI proposed
for okra.  

Furthermore, the submitted field trial data reflect applications made
without the use of a spray adjuvant.  A revised Section B should be
submitted incorporating an adjuvant-use restriction.  An adequate
confined rotational crop study was previously submitted, reflecting the
maximum proposed use pattern for rotated crops (fruiting vegetables and
edible-podded beans).  These data support a 30-day plant-back interval
(PBI) for all non-labeled crops.  A revised Section B should be
submitted incorporating the rotational crop restriction.

4.2  Dietary Exposure/Risk Pathway

4.2.1  Residue Profile

Nature of the Residue-Plants:  The nature of acequinocyl residues in
apples, oranges, and eggplants is understood based on the previously
submitted and reviewed metabolism studies.  In these crops, the
metabolism of acequinocyl involves the loss of the acetyloxy moiety to
form acequinocyl-OH, the opening of the quinone ring to form AKM-18, and
the subsequent degradation of the quinone ring to yield polar
metabolites that degrade to phthalic acid.  For purposes of risk
assessment and the tolerance expression, HED has determined that the
residues of concern in these commodities include parent and
acequinocyl-OH (Memo, S. Levy, 07-JAN-2004; DP# 297872).

Nature of the Residue-Livestock:  There are no livestock feedstuffs
associated with the proposed crop uses addressed herein.  Therefore, no
livestock metabolism data, enforcement methods, storage stability data,
or feeding studies are required to support this petition.

Magnitude of the Residue-Plants:  The submitted magnitude of the residue
data for tomatoes, peppers, edible-podded beans, and hops are adequate. 
The field trials reflect the proposed use patterns and an adequate
number of field trials were conducted in major crop growing regions. 
The submitted field trial data reflect applications made without the use
of a spray adjuvant.  A revised Section B should be submitted
incorporating an adjuvant-use restriction.  The Agency’s tolerance
spreadsheet as specified by the Guidance for Setting Tolerances Based on
Field Trial Data SOP (August 2009 version) was used to determine the
appropriate tolerance levels.  The field trial data will support
tolerances of:  0.70 ppm for fruiting vegetables; 0.70 ppm for okra;
0.25 ppm for edible-podded beans; and 4.0 ppm for dried hop cones.

It is noted that the proposed PHI for fruiting vegetables is 7 days
whereas the field trials reflect a 1-day PHI.  Residue decline trials
for tomato and pepper demonstrate that residues generally decline with
later sampling intervals; therefore, the proposed/recommended tolerance
will likely overestimate anticipated residues of acequinocyl and
acequinocyl-OH in/on fruiting vegetables.  The available data support
the proposed tolerances for fruiting vegetables, okra, and edible-podded
beans; however, the proposed tolerance for hop dried cones is too low.

Magnitude of the Residue in Processed Food and Feed:  An adequate tomato
processing study is available and supports the proposed use on fruiting
vegetables.  The tomato processing study is adequate.  The results
indicate that residues of acequinocyl and acequinocyl-OH did not
concentrate in paste and puree processed from tomato fruits bearing
quantifiable residues of acequinocyl.  No tolerances are required for
tomato processed matrices.  

Residue Analytical Method for Crops:  There are adequate residue
analytical methods for enforcing tolerances for acequinocyl residues of
concern in/on the proposed/registered plant commodities.  These methods
include two high-performance liquid chromatography methods with tandem
mass-spectroscopy detection (HPLC/MS/MS) for determining residues in/on
fruit and nut commodities (Morse Methods Meth-133, Revision #4 and
Meth-135, Revision #3  SEQ CHAPTER \h \r 1 ) (Memo, S. Levy, 8/25/10;
DP#: 380302).  For each of these methods, residues are extracted with
hexane or acetonitrile (ACN)/water and cleaned up by solvent
partitioning, gel-permeation chromatography (GPC) and/or silica-gel
solid-phase extraction (SPE).  

Residue data from the current field trial and processing studies were
obtained using the approved enforcement methods, Meth-135 (tomato,
pepper and hops) and Meth-133 (snap beans) with minor modifications. 
The methods are adequate for data collection based on acceptable method
validation and concurrent method recovery data for tomato and its
processed matrices, pepper, and snap beans.  However, the
data-collection method yielded consistently low recoveries (~53%) for
acequinocyl-OH in dried hop cones; therefore, residues of the metabolite
from the hop field trials were corrected for low recoveries.  The
validated limit of quantitation (LOQ) was 0.010 ppm for acequinocyl and
0.025 ppm for acequinocyl-OH in/on tomato and pepper; 0.020 ppm each for
acequinocyl and acequinocyl-OH in/on edible-podded beans; and 0.10 ppm
for acequinocyl in/on hop dried cones.  

The available analytical standards for acequinocyl and acequinocyl-OH at
the EPA National Pesticide Standards Repository (personal communication
with Dallas Wright, ACB, 4/30/10) expired on 4/19/10 and 4/20/10,
respectively.  This is a deficiency.  The petitioner should either
recertify the lot in the repository and send in an updated certificate
of analysis (COA), or submit new standards (different lot #) if the
previous lots will not be recertified.

The data requirements for multiresidue (MRM) methods are fulfilled. 
Certain MRM protocols resulted in acceptable recoveries.  The MRM
testing data have been forwarded to the U.S. Food and Drug
Administration (FDA) for further evaluation (Memo, S. Levy, 2/18/04;
DP#: 298917).

Storage Stability in Plants:  The submitted concurrent storage stability
data for tomato, snap bean, and hops is adequate to support the storage
intervals and conditions incurred by the field trial studies.  In
addition, the concurrent storage stability data for the parent
acequinocyl is adequate to support the sample storage intervals and
conditions for the pepper field trials and tomato processing studies. 
It is noted that zero-day data were not provided.  IR-4 is reminded that
storage stability studies should always include a zero-day sampling
interval to establish the residue levels present at the time samples are
placed into storage [see OPPTS 860.1380(d)(6)(i)].  

The concurrent storage stability data indicate problems with the
stability of acequinocyl-OH in peppers and processed tomato paste and
puree.  Because zero-day samples were not analyzed, determination of
residue levels present at the time samples were placed in frozen storage
could not be made.  In addition, an insufficient number of time points
were analyzed in order to establish how much of the residue
(acequinocyl-OH) was lost at various time points.  

However, because residues of acequinocyl-OH in the pepper field trial
were <10% of the parent value or were <LOQ, correction for 51% decline
would not affect the results.  Furthermore, in the tomato processing
study, because there were quantifiable residues of the parent in the RAC
and residues of acequinocyl-OH in the RAC were nonquantifiable, HED
believes that any concentration of acequinocyl-OH residues would not
significantly increase the total residue level. Therefore, HED is not
requesting additional storage stability data at this time.  

Confined Accumulation in Rotational Crops:  An adequate confined
rotational crop study was previously submitted.  These data reflect the
maximum proposed use pattern for rotated crops (fruiting vegetables and
edible-podded beans); the results indicate that residues of acequinocyl
do not accumulate in rotated crops.  These data support a 30-day PBI for
all non-labeled crops.

Proposed and Recommended Tolerances:  The proposed and recommended
tolerances for the combined residues of acequinocyl are listed below in
Table 4.2.1.1 (a revised Section F should be submitted).  There are no
established or proposed Codex, Canadian, or maximum residue limits
(MRLs) for acequinocyl.

The field trial data for tomato and pepper are considered adequate to
support a crop group tolerance.  The tomato, bell pepper and non-bell
pepper datasets were separately entered into the tolerance spreadsheet
(rev. 8/09) in the Agency’s Guidance for Setting Pesticide Tolerances
Based on Field Trial Data; see Appendix I.  The proposed tolerance (0.70
ppm) for the fruiting vegetable group 8 is appropriate.  No tolerances
are required for tomato paste or puree.

Okra has been recommended to be added as a member of the fruiting
vegetable group 8; however, until okra has been officially added to the
crop group, a separate tolerance is required.  The tomato and pepper
field trial data will support the proposed tolerance (0.70 ppm) for
okra. 

The snap bean and hop dried cone data are adequate, and were entered
into the tolerance spreadsheet to determine the appropriate tolerances;
see Appendix I.  The proposed tolerance (0.25 ppm) for edible-podded
beans is appropriate; however, the tolerance proposed for hop dried
cones is too low and should be increased to 0.40 ppm.

The proposed and HED-recommended tolerances are listed in Table 4.2.1.1.

Table 4.2.1.1.  Tolerance Summary for Acequinocyl.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments; 

Correct Commodity Definition

Vegetable, fruiting, group 8	0.70	0.70

	Okra	0.70	0.70

	Bean, edible podded	0.25	0.25

	Hop, dried cones	3.5	4.0

	

4.3  Water Exposure/Risk Pathway

Environmental Fate Assessment:  Acequinocyl appears to undergo fairly
rapid transformation in most aquatic and terrestrial environments. It
undergoes hydrolysis with a half-life of a few hours to less than 2 days
under neutral and alkaline pH conditions.  However, it is stable at
acidic pH conditions.  Photodegradation in water appears to be the main
route of degradation in aquatic environments, with half-lives occurring
in less than 15 minutes in sterile lab and river water. Acequinocyl also
undergoes fast degradation in terrestrial environments.  The half-lives
for aerobic biotransformation on soil are less than 2 days under
laboratory conditions and under field conditions, acequinocyl applied to
bare plots dissipated with half-lives ranging from 2 hrs in California
to 14 hours in New York. 

Acequinocyl can reach surface water via spray drift and less likely via
runoff.  Due to its high Kd values it is expected to exhibit low
mobility in soil and low potential to leach into groundwater. Once
acequinocyl has entered surface water, it is not likely to persist as it
will hydrolyze to form hydroxy-acequinocyl (also known as OH-AKD 023,
2-hydroxy-3-dodecyl-1,4-napthelenedione (HDNQ), and R-1).

Surface and Ground Water Estimated Drinking Water Concentrations
(EDWCs):  There are no drinking water monitoring data available for
acequinocyl or its metabolite acequinocyl-OH (R1), the residues of
concern.  Groundwater and surface water estimated drinking water
concentrations (EDWCs) were generated for acequinocyl using the
Screening Concentration in Ground Water (SCI-GROW) and Pesticide Root
Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) models,
respectively.  Two approaches were used in performing the drinking water
assessment for the proposed acequinocyl uses.  In Approach #1,
acequinocyl was conservatively assumed to be stable to all routes of
degradation to account for the uncertainties associated with the
environmental fate data.  In Approach #2, total (acequinocyl +
acequinocyl-OH) residues were modeled with the assumption that the
metabolite acequinocyl-OH (referred to as the R1 degradate in this
assessment) is of toxicological concern.  The highest PRZM-EXAMS surface
water modeling estimates were obtained for the Pennsylvania tomato
scenario for the chronic values.  The modeled EDWCs for ground and
surface water are summarized in Table 4.3.1.

Table 4.3.1.  Ground and Surface Water EDWCs for Acequinocyl.

Approach #1 and #2

Groundwater EDWC for Acequinocyl + R1 (ppb)	Surface Water

	Approach #1

Acequinocyl	Approach #2

Acequinocyl + R1

	1-in-10-Year Chronic Mean Concentration (ppb)	1-in-10-Year Chronic Mean
Concentration (ppb)

0.0036	2.45	0.29

Since the surface water EDWCs are higher than the groundwater EDWC, HED
selected the surface water value for use in the chronic dietary
assessment.  The EDWC derived via Approach #1 represents the upper-bound
value (2.45 ppb) while that derived via Approach #2 represents the
lower-bound value (0.29).  The 2.45 ppb value was used in the dietary
modeling as this value assures a conservative assessment.

4.4  Dietary Exposure Analyses

An acute dietary assessment was not conducted for acequinocyl because an
endpoint of concern attributable to a single dose was not identified;
therefore, an aRfD was not established and an acute dietary assessment
is not necessary.  A cancer dietary assessment was not conducted because
acequinocyl was classified as not likely to be carcinogenic to humans.

An acequinocyl chronic dietary exposure assessment was conducted using
the DEEM-FCID™, Version 2.03, which incorporates consumption data from
USDA’s CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are based on
the reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (i.e., apple pie)
are linked to EPA-defined food commodities (i.e., apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups.  Based on analysis of the 1994-96, 98 CSFII
consumption data, which took into account dietary patterns and survey
respondents, HED concluded that it is most appropriate to report risk
for the following population subgroups: the general U.S. population, all
infants (<1 year old), children 1-2, children 3-5, children 6-12, youth
13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (i.e., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

4.4.1  Chronic Dietary Exposure Analysis

The DEEM-FCID™ analysis estimates the dietary exposure of the U.S.
population and various population subgroups.  The chronic dietary
exposure assessment (using tolerance level residues and 100% CT
information for all registered and proposed uses) was conducted for the
general U.S. population and various population subgroups.  Drinking
water was incorporated directly into the dietary assessment using the
chronic concentration for surface water generated by the PRZM/EXAMS
model.  The highest chronic surface water value (i.e., most
conservative) of 2.45 ppb was used for this assessment.  

This assessment concludes that the chronic dietary exposure estimates
are not of concern to HED for the general U.S. population (9.8% cPAD)
and all population subgroups.  The most highly exposed population
subgroup is children 1-2 years old at 45% of the cPAD.  The use of
anticipated residues (ARs), empirical processing factors, and % CT data
would refine further HED’s exposure and risk estimates; however,
refinement is not needed at this time.

Table 4.4.1.1.  Summary of Dietary (Food and Drinking Water) Exposure
and Risk for Acequinocyl.

Population Subgroup	Chronic Dietary1

	Dietary Exposure

(mg/kg/day)	% cPAD

U.S. Population (total)	0.002657	9.8

All Infants (< 1 year old)	0.005584	21

Children 1-2 years old	0.012193	45

Children 3-5 years old	0.008046	30

Children 6-12 years old	0.003657	14

Youth 13-19 years old	0.001855	6.9

Adults 20-49 years old	0.001758	6.5

Adults 50+ years old	0.001811	6.7

Females 13-49 years old	0.001808	6.7

1  Chronic dietary endpoint of 0.027 mg/kg/day applies to the general
U.S. population and all population subgroups.  The values for the
highest exposed population for each type of risk assessment should be
bolded.

4.5  Residential/Non-Occupational Exposure Pathway

Acequinocyl is currently registered for use on landscape ornamentals in
and around residences, businesses, public property, schools,
interiorscapes, and other non-production areas by commercial applicators
and homeowners.  The last residential exposure assessment was conducted
in September of 2007 (Memo, K. Lowe, 9/6/07, D332006, 337473) and showed
no risks of concern to HED (i.e., MOEs >100).  The assessment provided
in this document reflects changes to the short- and intermediate-term
dermal and inhalation endpoints.

4.5.1  Residential Handler Exposure/Risk

There is potential for residential handler exposure from the registered
uses on landscape ornamentals in and around residences, businesses,
public property, schools, interiorscapes, and other non-production areas
by commercial applicators and homeowners.  Homeowner handlers are
expected to complete all tasks associated with the use of a pesticide
product including mixing and loading (if needed), and application. Based
upon the proposed use pattern, the following residential handler
scenarios have been assessed:

Mixing/loading.applying liquids with low-pressure handwand (ORETF- fruit
trees and ornamentals); and

Mixing/loading/applying liquids with hose-end sprayer (ORETF- fruit
trees and ornamentals).

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available from the ORETF. 
Homeowner handler assessments are based on the assumption that
individuals are wearing shorts, short-sleeved shirts, socks, and shoes. 
Residential handler exposure scenarios are considered to be short-term
only, due to infrequent use patterns associated with homeowner products.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula: 

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/gallon) x Amount Handled (gal/day)

Where:  

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data or from ORETF data;

Application Rate		=	Normalized application rate (lb ai/gal); and

	Daily Area Treated 	=	Normalized amount handled (gal/day). 

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula: 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg bw/day);

Daily Exposure 			=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body Weight 			= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE = NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 4.5.1.1 presents the exposure/risks for residential handler
short-term dermal and inhalation exposures at baseline.  Based on
HED’s residential handler assessment, there are no risks of concern
for residential handlers (i.e., MOEs >100).

Table 4.5.1.1.  Residential Handler Dermal and Inhalation Exposures and
Risks.

Dermal and

Inhalation Unit Exposures 

(mg/lb ai)	Application Rate

(lb ai/gallon)1	Amount Handled Daily 

(gallons)2	Doses (mg/kg/day)3	MOEs4

Mixer/Loader/Applicator – Liquid with Low-Pressure Handwand
(ORETF--fruit trees and ornamentals)

Dermal

Baseline5: 56	0.00125	5	Dermal

Baseline: 0.005	Dermal

Baseline:  40,000

Inhalation

Baseline6: 0.0026

	Inhalation

Baseline: 2.3E-07	Inhalation

Baseline:  2.6E8

Mixer/Loader/Applicator – Liquid with Hose-End Sprayer (ORETF-- fruit
trees and ornamentals)

Dermal

Baseline: 39	0.00125	100	Dermal

Baseline: 0.07	Dermal

Baseline:  2,900

Inhalation

Baseline: 0.0016

	Inhalation

Baseline: 2.9E-06	Inhalation

Baseline:   2.1E7

1	Application rates are the maximum application rates determined from
proposed labels for acequinocyl.

2	Amount handled per day values are HED estimates of acres treated per
day based on ExpoSAC SOP #9 “Standard Values for Daily Acres Treated
in Agriculture,” industry sources, and HED estimates.

3	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/gal) x
Amount Handled (gal/day) x %Absorption (100% dermal and 100% inhalation)
/ Body weight (70 kg).  

4	MOE = NOAEL/Dose; where the short-term dermal NOAEL = 200 mg/kg/day
and short-term inhalation NOAEL = 60 mg/kg/day.

5	Baseline Dermal:  short-sleeve shirt, short pants, and no gloves.

6	Baseline Inhalation:  no respirator.

4.5.2  Residential Post-application Exposure/Risk

Dermal:  With respect to the registered residential uses on landscape
ornamentals, current HED policy (see ExpoSAC minutes from 8/19/99 and
10/11/01) specifies that no significant dermal post-application exposure
is anticipated from landscape ornamentals, either by residents or
professional applicators; therefore, no residential dermal
post-application assessment was conducted.

Inhalation:  Based on the Agency's current practices, a quantitative
residential post-application inhalation exposure assessment (including
bystander exposure) was not performed for acequinocyl at this time. 
However, volatilization of pesticides may be a potential source of
post-application inhalation exposure to individuals nearby to pesticide
applications.  The Agency sought expert advice and input on issues
related to volatilization of pesticides from its FIFRA SAP in December
2009.  The Agency received the SAP’s final report on March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, develop policies and procedures, to identify the need for
and, subsequently, the way to incorporate post-application inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative post-application inhalation exposure assessment for
acequinocyl.

4.5.3  Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for acequinocyl.
 The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices (see
the Agency’s Spray Drift website for more information at
http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical
by chemical basis, the Agency is now requiring interim mitigation
measures for aerial applications that must be placed on product
labels/labeling.  The Agency has completed its evaluation of the new
database submitted by the Spray Drift Task Force, a membership of U.S.
pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT® computer model to its
risk assessments for pesticides applied by air, orchard airblast and
ground hydraulic methods.  After the policy is in place, the Agency may
impose further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard, or the risks themselves can be aggregated.  When
aggregating exposures and risks from various sources, HED considers both
the route and duration of exposure.

5.1  Acute Aggregate Risk

An endpoint of concern was not identified to quantify acute-dietary risk
to the general population or to any population subgroup.  Since an acute
dietary endpoint was not identified, an acute hazard does not exist and
an acute aggregate assessment was not performed.  

5.2  Short-Term Aggregate Risk

Short-term aggregate risk is made up of dietary and non-dietary sources
of exposure.  Since acequinocyl has a residential use on ornamentals,
adult residential handler exposure is expected.  Short-term aggregate
risk is made up of average dietary exposures from food and drinking
water sources, and dermal and inhalation residential exposures.  The
adult 50+ years old population is the highest exposed adult population
and can be considered protective of the other adult populations groups;
therefore, this sub-population is shown below in Table 5.2.1, as well as
the general U.S. population.

Dietary (food and drinking water) exposure is based on a Tier 1
(unrefined) chronic dietary exposure assessment (see Table 4.4.1.1). 
Residential exposure estimates are conservative estimates due to the
standard assumptions that were built into the calculations.  Residential
exposure estimates were taken from Table 4.5.1.1.  The short-term
aggregate risk calculations for both the general U.S. population and the
adults 50+ years old sub-population are shown below in Table 5.2.1 and
are not of concern to HED.  

Table 5.2.1.  Short-Term Aggregate Risk Calculations.

Population	Dietary MOE1	Residential Dermal MOE2	Residential Inhalation
MOE2	Aggregate

MOE3

U.S. Population	23,000	2,900	21,000,000	2,600

Adults 50+ years old	33,000	2,900	21,000,000	2,700

1  Dietary MOE = short-term oral NOAEL (60 mg/kg/day) ( chronic dietary
exposure.

2  Residential MOEs are from Table 4.5.1.1.  The “liquid with hose-end
sprayer handler” scenario was used as the MOEs for this scenario are
lower (i.e., more conservative) than the “liquid with low-pressure
handwand handler” scenario.

3  Aggregate MOE (dietary and residential) =
1(((1(MOEdietary)+(1(MOEdermal)+(1(MOEinhalation); LOC = 100.

5.3  Intermediate-Term Aggregate Risk

Intermediate-term aggregate risk was not calculated since the use
pattern is not expected to result in residential handler or
postapplication exposure of more than 30-day duration.  

5.4  Long-Term Aggregate Risk

Chronic (long-term) aggregate risk is made up only of dietary sources;
therefore, the chronic exposure estimates provided in the chronic
dietary exposure analysis represents chronic aggregate exposure.  

 

5.5  Cancer Risk

Aggregate cancer risk was not calculated because acequinocyl is not
considered to be a carcinogen.

6.0  CUMULATIVE RISK

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 acequinocyl and any other
substances and acequinocyl does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that acequinocyl has a common mechanism
of toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/." 
http://www.epa.gov/pesticides/cumulative/. 

7.0  OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT

The proposed uses are on agricultural crops; therefore, there is the
potential for occupational handler and post-application exposure. 
Please refer to the following document for detailed considerations of
the material summarized in this section: 

Acequinocyl: Occupational and Residential Exposure/Risk Assessment for
Proposed Use on Fruiting Vegetables Crop Group 8 (Tomatoes & Peppers),
Edible Podded Beans, Hops, and Okra.  DP Barcode: 369099.  A.
Nowotarski.  6/9/10.

7.1  Occupational Handler Exposure/Risk

Potential occupational exposure scenarios include:  1) mixing/loading
liquids in support of groundboom operations, and 2) applicators using
open-cab groundboom equipment.  Application through irrigation or aerial
systems is prohibited. 

No chemical-specific data are available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in PHED (8/1998).
 For pesticide handlers, it is HED standard practice to present
estimates of dermal exposure for “baseline”; that is, for workers
wearing a single layer of work clothing consisting of a long-sleeved
shirt, long pants, shoes plus socks, and no protective gloves, as well
as for “baseline” and the use of protective gloves or other
personal-protective equipment (PPE) as might be necessary.  The proposed
product label involved in this assessment directs applicators and other
handlers to wear long-sleeved shirt and long pants, socks, shoes, and
chemical-resistant gloves made of waterproof material. 

Daily handler exposures are estimated for each applicable handler task
with the application rate, the area treated in a day, and the applicable
unit exposure using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/area) x Daily Area Treated (area/day)

Where:

Daily Exposure		=	Amount (mg ai/day) inhaled that is available for
inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data;

Application Rate		=	Normalized application rate based on a logical unit
treatment, such as acres; and

Daily Area Treated 	=	Normalized application area based on a logical
unit treatment such as acres (A/day).

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate inhalation absorption factor using the following formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100)) / Body Weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg body weight/day);

Daily Exposure 		=	Amount (mg ai/day) deposited on surface of skin that
is available for dermal absorption, or the amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body Weight 			= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Based on the use pattern and information provided on the labels, (i.e.,
2 applications per season and 21-day RTI), short- and intermediate-term
exposures are expected and were assessed.  Long-term exposures are not
expected; therefore, a long-term assessment was not conducted. 

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using an MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 7.1.1 provides a summary of the estimated exposures and risks to
occupational pesticide handlers.  An MOE ≥100 is adequate to protect
occupational pesticide handlers.  Since all the estimated MOEs are >100
with baseline protection, the proposed uses are not of concern for HED. 

Table 7.1.1.  Occupational Dermal and Inhalation Exposures and Risks.

Crop or Target	App. Rate (lb ai/A)1	Area Treated Daily or Amount Handled
(A/day)2	Dermal and Inhalation Unit Exposures (mg/lb ai)	Short- and
Intermediate-term Doses (mg/kg/day)5	MOEs6	Combined

MOEs7

	Short-term	Int.-term	

Short-term

	

Int.-term

Mixing/Loading Liquid Concentrates for Groundboom Applications (PHED)

Fruiting vegetable crop group 8 (tomato and pepper)	0.3 	80	Dermal

Baseline3: 2.9

	Dermal

Baseline: 0.15

	Dermal

Baseline: 

1300

	

1,300

	

1,300

Edible podded bean

	Inhalation

Baseline4: 0.0012	

Inhalation

Baseline: 0.00041

 	Inhal.

Baseline: 

150,000 	Inhal.

Baseline: 

39,000

Hop

Okra

Applying Sprays via Groundboom Equipment

Fruiting vegetable crop group 8 (tomato and pepper)	0.3	80	Dermal

Baseline: 0.014	Dermal

Baseline: 0. 00072	Dermal

Baseline: 

280,000	

130,000	

51,000

Edible podded bean

	Inhalation

Baseline: 0.00074	Inhalation

Baseline:  

0.00025	

Inhal.

Baseline: 240,000	

Inhal.

Baseline: 63,000

Hop

Okra

1	Application rates are the maximum application rates determined from
proposed labels for acequinocyl.

2	Amount handled per day values are HED estimates of acres treated per
day based on ExpoSAC SOP #9 “Standard Values for Daily Acres Treated
in Agriculture,” industry sources, and HED estimates.

3	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves.

4	Baseline Inhalation: no respirator.

5	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre or
lb ai/gallon) x Area Treated (acres/day) or Amount Handled (gallons) /
Body weight (kg).  

6	MOE = NOAEL/dose; where the short- and intermediate-term dermal NOAEL
= 200 mg/kg/day; short-term inhalation NOAEL = 60 mg/kg/day;
intermediate-term inhalation NOAEL = 16 mg/kg/day.

7	Combined MOE = NOAEL (xx mg/kg/day) / Combined dermal + inhalation
dose (mg/kg/day).

7.2  Post-application Exposure/Risk

Dermal:  HED expects that post-application dermal exposure will occur
since acequinocyl is applied as a foliar spray.  Post-application
exposure is expected to be short-term based on information provided on
the proposed label.  In addition, since the short and intermediate-term
points of departure are the same, short-term risk estimates are
protective of intermediate term exposures.  Post-application exposures
have been assessed using dermal transfer coefficients (TCs) from HED’s
ExpoSAC Policy Number 3.1 “Agricultural Transfer Coefficients”
(August, 2000).  Table 7.2.1 summarizes the scenarios assessed.  In
addition, the following assumptions were used in the calculations: 

Exposure Duration			=	8 hours per day

Body Weight				=	70 kg

Dislodgeable Foliar Residue (DFR)	=	No DFR data are available for
acequinocyl for the proposed uses. Therefore, this assessment uses
HED’s default assumption that 20% of the application rate is available
on Day 0 (i.e., 12 hours after application) and the residue dissipates
at a rate of 10% per day.

Table 7.2.1.  Anticipated Post-application Activities and Dermal TCs.

Proposed Crops	Policy Crop Group Category	Application Rate (lb ai/A)	TCs
(cm2/hr)	Activities

Tomato	Fruiting vegetable group 8	0.3	1000	Pruning (hand), staking,
thinning, training, tying

	700	Irrigation, scouting

	500	Weeding (hand)

Bell Pepper

0.3	1000	Harvest (hand), staking, tying

	700	Irrigation, scouting

	500	Weeding (hand), thinning

Chili Pepper

0.3	1000	Harvest (hand), pruning (hand), thinning

	700	Irrigation, scouting

	500	Weeding (hand)

Okra

0.3	1000	Harvest (hand), staking, tying

	700	Irrigation, scouting, pruning (hand)

	500	Weeding (hand), thinning 

Hops	Bunch/bundle	0.3	2000	Harvest (hand and mech), stripping, training

	1300	Scouting

	100	Irrigation, weeding (hand)

Edible-Podded Bean	Field/ row crop, low/ medium	0.3	2500	Harvest (hand)

	1500	Irrigation, scouting

	100	Weeding (hand), thinning

Equations/Calculations:

Daily dermal exposures were calculated on each post-application day
after application using the following equation:

Daily Dermal Doset  =  [DFRt (µg/cm2) x 0.001 mg/µg x TC (cm2/hr) x DA
x ET (hrs)]  /  BW (kg)

Where,

		DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm2);

		TC	=	transfer coefficient (cm2/hr);

		DA	=	dermal absorption factor (100%);

	     	ET	=	exposure time (8 hr/day); and

		BW	=	body weight (70 kg).

Once daily exposures are calculated, the calculation of daily absorbed
dose and the resulting MOEs use the same algorithms that are described
above for the handler exposures.  These calculations are completed for
each day or appropriate block of time after application.

HED has determined that short-term dermal risk estimates are not of
concern (i.e., MOEs >100) on the day of treatment (i.e., Day 0) for all
post-application exposure activities.  Table 7.2.2 presents a summary of
occupational dermal post-application risks associated with use of
acequinocyl.

Table 7.2.2.  Post-application Risk Estimates for Acequinocyl.

Crop

Grouping	Application  Rate

(lb ai/A)	TC

(cm2/hr)	DFR (ug/cm2)	Days After Treatment

	MOE1

Fruiting vegetable group 8	0.3	1000	0.67

	0

(12 hours)	2600

700

	3700

500

	5200

Bunch/

bundle	0.3	2000	0.67	0

(12 hours)	1300

1300

	2000

100

	26000

Field/row crop,

Low/

medium	0.3	2500	0.67	0

(12 hours)	1000

1500

	1700

100

	26000

The information in the table is based on proprietary and non-proprietary
data.

1  NOAEL/Daily Dose (Short-term NOAEL = 200 mg/kg/day).

Inhalation:  Based on the Agency's current practices, a quantitative
occupational postapplication inhalation exposure assessment was not
performed for acequinocyl at this time.  However, there are multiple
potential sources of postapplication inhalation exposure to individuals
performing postapplication activities in previously treated fields. 
These potential sources include volatilization of pesticides and
resuspension of dusts and/or particulates that contain pesticides.  The
Agency sought expert advice and input on issues related to
volatilization of pesticides from its FIFRA SAP in December 2009.  The
Agency received the SAP’s final report on 3/2/10
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report as well as
available postapplication inhalation exposure data generated by the
Agricultural Reentry Task Force and may, as appropriate, develop
policies and procedures, to identify the need for and, subsequently, the
way to incorporate occupational postapplication inhalation exposure into
the Agency's risk assessments.  If new policies or procedures are put
into place, the Agency may revisit the need for a quantitative
occupational postapplication inhalation exposure assessment for
acequinocyl.

7.3  REI 

Acequinocyl is classified in Toxicity Category III for acute dermal and
acute inhalation.  It is classified in Toxicity Category IV for primary
eye irritation and primary skin irritation and it is not a dermal
sensitizer.  Therefore, the WPS interim REI is adequate to protect
agricultural workers from post-application exposures to acequinocyl.  

8.0  RESIDUE CHEMISTRY AND TOXICOLOGY DEFICIENCIES

8.1  Residue Chemistry

Revised Section F.

Revised Section B.

Analytical reference standards for the acequinocyl and acequinocyl-OH
must be submitted to the EPA National Pesticide Standards Repository.

8.2  Toxicology

An Immunotoxicity Study.

Acute and Subchronic Neurotoxicity Studies.

A 28-Day Inhalation Study.

8.3  Occupational and Residential Exposure

None.

cc: S. Levy (RAB1); A. Dunbar; A. Nowotarski

RDI:  RAB1 Branch (09-JUN-2010); RAB1 Chemists (09-JUN-2010)

S. Levy: S10953: PY1:703-305-0783; 7509P:RAB1

APPENDIX:  Toxicity Profile Tables and Metabolites.

Table A-1.  Acute Toxicity of Acequinocyl.

Guideline

No.	Study Type	MRID #(s)	Results	Toxicity Category

870.1100

(81-1)	Acute Oral (rat)	45435011	LD50 > 5000 mg/kg	IV

870.1200

(81-2)	Acute Dermal	45435012	LD50 > 2000 mg/kg	III

870.1300

(81-3)	Acute Inhalation	45435013	LC50 > 0.84 mg/L	III

870.2400

(81-4)	Primary Eye Irritation	45435014	Not an eye irritant	IV

870.2500

(81-5 )	Primary Skin Irritation	45435015	Not a dermal irritant	IV

87.2600

(81-6)	Dermal Sensitization	45435016	Not a dermal sensitizer	N/A

Table A-2.  Toxicity Profile for Acequinocyl.

Guideline No.; 

Study Type	MRID (year); Doses; Classification	Results

870.3100 

90-Day Oral Toxicity Rodents-MOUSE     	45673701 (1995); 

0, 100, 500, 1000 ppm

M:  0, 16, 81, 151 mg/kg/day 

F:  0, 21, 100, 231 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 16/21 mg/kg/day; LOAEL (M/F) = 81/100
mg/kg/day based on hepatocyte vacuolization.

870.3100 

90-Day Oral Toxicity Rodents-RAT	45531904 (1998);

0, 100, 400, 1600, 3200 ppm; 

M: , 7.6, 30.4, 119.5, 252.7 mg/kg/day 

F:  0, 8.3, 32.2, 129.2, 286.0 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 30.4/32.2 mg/kg/day; LOAEL (M/F )=
119.5/129.2 mg/kg/day based on increased prothrombin times in males and
increased activated partial thromboplastin times in both sexes.

870.3150 

90-Day Oral Toxicity Nonrodents-DOG	45531905 (1995);

0, 40, 160, 640, 1000 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 40/40 mg/kg/day; LOAEL (M/F) =
160/160 mg/kg/day based on decreased body-weight gains and reduced food
efficiencies in males and for female beagle dogs based on increased
platelet counts.

870.3200

28-Day Dermal Toxicity-RAT	45531906 (1999); 

0, 40, 200, 1000 mg/kg/day 

Acceptable/Guideline	Systemic NOAEL = 200 mg/kg/day; LOAEL = 1000
mg/kg/day based on increased clotting factor times (increased
prothrombin time, increased activated partial prothromboplastin time,
increased fibrinogen levels).

Dermal NOAEL = 1000 mg/kg/day; 

LOAEL = not established.

870.3700a 

Prenatal Developmental in Rodents-RAT	45531908, 45651706 (1995); 

0, 50, 150, 500, 750 mg/kg/day

Acceptable/Guideline 

	Maternal NOAEL = 150 mg/kg/day; LOAEL = 500 mg/kg/day based on signs of
internal hemorrhage and increased incidence of clinical signs (pale
eyes, piloerection, red vaginal discharge).

Developmental NOAEL = 500 mg/kg/day mg/kg/day; LOAEL = 750 mg/kg/day
based on increased resorptions. 

870.3700b 

Prenatal Developmental in Nonrodents-RABBIT  	45531907, 45651705 (1995);

0, 30, 60, 120 mg/kg/day 

Acceptable/Guideline

	Maternal NOAEL = 60 mg/kg/day; LOAEL = 120 mg/kg/day based on
treatment-related clinical signs leading to premature sacrifice
(hematuria, reduced fecal output, body weight loss, and reduced food
consumption) and gross necropsy findings (pale lungs and liver,
hemorrhaging uterus, fluid in the cecum, fur in the stomach, blood
stained vaginal opening, blood-stained urinary bladder contents/urine,
and hair loss).

   

Developmental NOAEL = 60 mg/kg/day; LOAEL = 120 mg/kg/day based upon
increased number of complete resorptions.

870.3800 

2-Generation Reproduction and Fertility-RAT	45531909 (1997);

0, 100, 800, 1500 ppm;

M:  0, 7.3, 58.9, 111.2 mg/kg/day 

F:  0, 8.7, 69.2, 133.5 mg/kg/day

Acceptable/Guideline

	Parental NOAEL (M/F):  111.2/ 133.5 mg/kg/day; 

LOAEL (M/F) = not established 

Offspring NOAEL (M/F):  7.3-8.2/8.7 mg/kg/day; LOAEL (M/F) = 58.9/69.2
based on hemorrhagic effects, swollen body parts, protruding eyes,
clinical signs, delays in pupil development and increased mortality post
weaning.

Reproductive NOAEL (M/F):  124/136 mg/kg/day; LOAEL (M/F) = not
established.

870.4100b 

Chronic Toxicity-DOG

	45531910 (1996); 

0, 5, 20, 80, 320 mg/kg/day 

Acceptable/Guideline	NOAEL (M/F) = 80/80 mg/kg/day.

LOAEL (M/F) = 320/320 mg/kg/day based on premature sacrifice
(inappetence, body-weight loss).

870.4300

Chronic/ Carcinogenicity-MOUSE

	45531911 (1994);

0, 20, 50, 150, 500 ppm ;

M:  0, 2.7, 7.0, 20.3, 66.0 mg/kg/day 

F:  0, 3.5, 8.7, 26.3, 86.00 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 2.7/3.5 mg/kg/day.

LOAEL (M/F) = 7.0/8.7 mg/kg/day based on clinical chemistry and
microscopic non-neoplastic lesions (brown pigmented cells and
perivascular inflammatory cells in liver).

870.4300 

Chronic/

Carcinogenicity-RAT 	45531912 (1997);

0, 50, 200, 800 or 1600 ppm;

M:  0, 2.25, 9.02, 36.41, 74.00 mg/kg/day 

F:  0, 2.92, 11.61, 46.2, 93.56 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 2.25/46.20 mg/kg/day

LOAEL (M/F) = 9.02/93.56 mg/kg/day based on enlarged eyeballs in male
and female rats (coagulopathy).

870.5100

Gene Mutation	45435101 (1998);

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瑹ᣡ¬਀19.5, 39.1, 78.1, 156, 313, 625, 1250, 2500 or 5000 μg/plate
in the presence and absence of mammalian metabolic activation (S9-mix)
and additionally at 9.77 μg/plate without S9-mix. 

Acceptable/Guideline	There was no evidence of induced mutant colonies
over background.

870.5300

Gene Mutation	45435102 (1998);

5-7 doses ranging from 10-320 μg/mL

Acceptable/Guideline	There was no clear evidence of biologically-
significant induction of mutant colonies over background.

870.5375

Chromosome Aberration	45435103 (1998);

0, 150, 300, 600 or 1200 μg/mL for 24 or 48 hours without metabolic
activation (S9-mix) and to concentrations of 0, 481, 963, 1925 or 3850
μg/mL (highest concentration is equivalent to 10mM) for 6 hours with
S9-mix.  

Acceptable/Guideline	There was no evidence of chromosome aberrations
induced over background.

870.5395

Mammalian Erythrocyte Micronucleus Test in MICE	45435104 (1993);

0, 1250, 2500 or 5000 mg/kg body weight

Acceptable/Guideline	There was no statistically-significant increase in
the frequency of micronucleated polychromatic erythrocytes in mouse bone
marrow at any dose or harvest time.

870.7485

Metabolism-RAT	45435105, 45531913 (1997); 

single oral doses of 10 or 500 mg/kg (phenyl label) or 10 mg/kg (dodecyl
label), and 14-day repeated 10 mg/kg dose (phenyl label).

Acceptable/Guideline	Acequinocyl exhibits marginal absorption,
relatively rapid and complete excretion primarily via the bile and
feces, and undergoes nearly complete metabolism to hydrolysis products
and a glucuronide conjugate.  There was no evidence for selective tissue
accumulation or sequestration of 2023 (acequinocyl) or its metabolites
in rats.

870.7600

Dermal Penetration-RAT 	45435106(2000); 

0, 0.001, 0.01, 0.1, 1.0 mg/cm2

Acceptable/Guideline	Percent of dose absorbed decreased with exposure
concentration indicating that saturation of absorption at/or about the
high dose.  Absorption at 168 hours was 12.23%, 19.75%, and 14.77% for
the 0.1, 0.01, and 0.001 mg/cm2 dose groups, respectively.

Table A-3.  Structures of Acequinocyl and Its Metabolites.

Common Name/Code	Chemical Name	Chemical Structure

Acequinocyl	2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione	

Acequinocyl-OH

(Metabolite R1)	2-dodecyl-3-hydroxy-1,4-naphthalenedione	

AKM-15	2-hydroxy-3-hexanoic acid-1, 4 naphthalenedione	

Acequinocyl	Human-Health Risk Assessment	DP# 368425

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