Document ID: EPA-HQ-OPP-2011-0449-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-05-02T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                 	OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION
                                                                               
MEMORANDUM

Date:		30-NOV-2011

SUBJECT:	Acequinocyl; Human-Health Risk Assessment for Proposed Section 3 Uses on Succulent Soybean Vegetable; Succulent Shelled Beans; Cowpea Forage; Caneberry Subgroup 13-07A; Melon Subgroup 9A; Cucumber, Cherry; Low-Growing Berry Subgroup 13-07G; and Small Fruit Vine Climbing, Except Fuzzy Kiwifruit, Subgroup 13-07F.

PC Code:  006329
DP Barcode:  D389519 
Decision No.:  448205
Registration No.:  66330-38
Petition No.:  1E7864
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
		Kelly M. Lowe, Environmental Scientist
            Risk Assessment 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/L. Nollen, 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 succulent soybean vegetables, succulent shelled beans, cowpea forage, caneberry subgroup 13-07A, melon subgroup 9A, cucumber, cherry; low-growing berry subgroup 13-07G, and small fruit vine climbing, except fuzzy kiwifruit, subgroup 13-07F.  Note that the cucumber and caneberry field trial data were a joint-review with Canada.

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 Kelly Lowe (RAB1), and the drinking water exposure assessment was provided by Michael Lowit of the Environmental Fate and Effects Division (EFED).

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F, there are no toxicological, residue chemistry, or occupational/residential issues that would preclude granting a conditional registration for the requested uses of acequinocyl.  Permanent tolerances should be established for residues of acequinocyl, including its metabolites and degradates, in or on the commodities listed 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:

Soybean, vegetable, succulent .......................................................
0.25 ppm
Low growing berry subgroup 13-07G[1] ..............................................
0.50 ppm
Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit[1] ... 
1.6 ppm
Bean, succulent shelled.................................................................................
0.30 ppm
Cowpea, forage...........................................................................
6.0 ppm
Cowpea, hay.................................................................................
18 ppm
Caneberry subgroup 13-07A............................................................
4.0 ppm
Melon subgroup 9A........................................................................
0.15 ppm
Cucumber......................................................................................
0.15 ppm
Cherry, tart.................................................................................
1.0 ppm
Cherry, sweet..............................................................................
0.50 ppm
Meat byproducts of cattle, goat, horse and sheep[1] ...........................
0.02 ppm
[1]  Note to RD:  With the establishment of these tolerances, the following tolerances should be removed:  strawberry; grape; and liver of cattle, goat, horse, and sheep.

Registration should be conditional pending resolution of the following deficiencies:

Toxicology
   * An Immunotoxicity Study.
   * Acute and Subchronic Neurotoxicity Studies.
   * A 28-Day Inhalation Study.
                               TABLE OF CONTENTS
                                       
1.0  EXECUTIVE SUMMARY	4
2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	8
2.1  Identification of Active Ingredient	8
2.2  Structural Formula of Acequinocyl and Acequinocyl-OH	8
2.3  Physical and Chemical Properties of Acequinocyl	8
3.0  HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS	9
3.1  Hazard Profile	9. 
3.2  FQPA Considerations	11
3.3  Dose-Response Assessment	12
3.4  Recommendation for Aggregate Exposure Risk Assessments	14
4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION	15
4.1  Summary of Uses	16
4.2  Dietary Exposure/Risk Pathway	17
4.2.1  Residue Profile	17
4.3  Water Exposure/Risk Pathway	20
4.4  Dietary Exposure Analyses	21
4.4.1  Chronic Dietary Exposure Analysis	22
4.5  Residential/Non-Occupational Exposure Pathway	23
4.5.1  Short-term Residential Handler Risk	23
4.5.2  Short-term Residential Post-application Risk	23
4.5.3  Spray Drift	23
	4.5.4  Residential Bystander Post-application Inhalation Exposure	24
5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	24
5.1  Acute Aggregate Risk	24
5.2  Short-Term Aggregate Risk	24
5.3  Intermediate-Term Aggregate Risk	26
5.4  Long-Term Aggregate Risk	26
5.5  Cancer Risk	26
6.0  CUMULATIVE RISK	26
7.0  OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT	26
7.1  Short- and Intermediate-term Occupational Handler Risk	27
7.2  Short- and Intermediate-term Occupational Post-application Risk	29
8.0  RESIDUE CHEMISTRY AND TOXICOLOGY DEFICIENCIES	31
8.1  Residue Chemistry	31
8.2  Toxicology	31
8.3  Occupational and Residential Exposure	31
APPENDIX:  Toxicity Profile Tables and Metabolites.	32

1.0  EXECUTIVE SUMMARY

Acequinocyl is a quinoline-type miticide that is currently registered for the use in the U.S. on a number of raw agricultural commodities (RACs) for the control of various phytophagous mite species.  Acequinocyl is also registered for use in/on greenhouses, shadehouses, ornamental, floral, foliage, nursery crops, 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% soluble-concentrate (SC) formulation.

Under PP#1E7864, the Interregional Research Project No.4 (IR-4), on behalf of the Agricultural Experiment Station of TX, CA, OR, PA, GA, NM, OK, TN, UT, MI, FL, and AZ, is requesting for the establishment of tolerances for combined residues of the insecticide acequinocyl, 2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione, and its metabolite, 2-dodecyl-3-hydroxy-1,4-naphthoquinone (acequinocyl-OH), expressed as acequinocyl equivalents in/on the following commodities:

   Soybean, vegetable, succulent	0.25 ppm
   Low growing berry subgroup 13-07G	0.4 ppm
   Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit	1.6 ppm
   Bean, succulent shelled	0.15 ppm
   Cowpea, forage	9.0 ppm
   Caneberry subgroup 13-07A	4.5 ppm
   Melon subgroup 9A	0.06 ppm
   Cucumber	0.15 ppm
   Cherry	0.8 ppm

The end-use product proposed for use on the aforementioned proposed crops is Kanemite[(TM)] 15 SC Miticide a 1.25 pounds (lb)/gallon (gal) SC formulation (alternate brand names:  Shuttle(TM) 15 SC Miticide, and Shuttle(TM) O Miticide).  Up to two foliar, postemergent, ground applications are proposed for a maximum seasonal rate of 0.6 lb active ingredient (ai)/acre (A), with a 1-day preharvest interval (PHI), except for succulent shelled beans and cherries for which a 7-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 Food Quality Protection Act (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 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):  A chronic aggregate dietary (food + drinking water) exposure and risk assessment was conducted for acequinocyl using the Dietary Exposure Evaluation Model (DEEM-FCID[(TM)]), 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 that 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 + drinking water utilized 13% of the cPAD.  The chronic dietary risk estimate for the highest exposed population subgroup, children 1-2 years old, is 55% 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.  The last residential exposure risk assessment was conducted in June 2010 (Memo, A. Nowotarski; D369099).  All risks for residential handlers were above the target margin of exposure (MOE) of 100 and did not exceed the LOC.  Post-application residential exposure was not anticipated for the registered uses, and, therefore, a quantitative residential post-application assessment was not conducted.  HED has determined that the proposed uses will result in negligible residential exposure.  
Occupational Exposure Estimates:  The occupational handler assessment was completed assuming the maximum label application rate for each crop.  Based on the activity use pattern, the duration of exposure is expected to be short-term (1 to 30 days) and intermediate-term (1 to 6 months) for occupational scenarios; long-term exposures (greater than 6 months) are not anticipated based on the proposed use pattern.  For the dermal route of exposure, the same points of departure (PODs) were chosen for short-term and intermediate-term exposures; therefore, risks are the same for all durations of exposure.  For the inhalation route of exposure, different PODs were chosen for short-term and intermediate-term exposure durations.  The proposed label requires a long-sleeved shirt, long pants, shoes plus socks, and chemical-resistant gloves as dermal personal-protective equipment (PPE) for all applicators and other handlers.  

Occupational handler dermal and inhalation risk estimates were calculated.  For occupational handlers, dermal and inhalation MOEs above 100 do not exceed HED's LOC.  All risk estimates for occupational handlers are above the target MOE of 100 with the use of gloves, and do not exceed the LOC as the proposed labels already require the use of gloves as PPE. 

Occupational dermal post-application risk estimates were calculated using available chemical-specific dislodgeable foliar residue (DFR) data.  There were no risks of concern for all occupational post-application activities associated with the proposed uses.  Since no risks of concern were identified, the restricted-entry interval (REI) is based on the acute toxicity of the active ingredient.  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 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 post-application 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 the general U.S. population and females 13-49 years old (this sub-population is the highest exposed adult population and can be considered protective of the other adult populations groups).  The aggregate MOEs are >100, therefore, they do not exceed HED's level of concern.  

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 post-application 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:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re-entry Task Force (ARTF) database; and MRIDs 454286-19, 456516-11, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Recommendation for Tolerances and Registration:  Pending submission of revised Sections B and F, there are no toxicological, residue chemistry, or occupational/residential exposure issues that would preclude granting a conditional registration for the requested uses of acequinocyl.  Permanent tolerances should be established for residues of acequinocyl, including its metabolites and degradates, in or on the commodities listed 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:

Soybean, vegetable, succulent .........................................................
 0.25 ppm
Berry, low growing, subgroup 13-07G[1] .............................................
 0.50 ppm
Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13-07F[1]... 
 1.6 ppm
Bean, succulent shelled.................................................................................
0.30 ppm
Cowpea, forage..............................................................................
6.0 ppm
Cowpea, hay.................................................................................
18 ppm
Caneberry subgroup 13-07A............................................................
4.0 ppm
Melon subgroup 9A........................................................................
0.15 ppm
Cucumber......................................................................................
0.15 ppm
Cherry, tart....................................................................................
1.0 ppm
Cherry, sweet.................................................................................
0.50 ppm
Meat byproducts of cattle, goat, horse and sheep[1] ..............................
0.02 ppm
  Note to RD:  With the establishment of these tolerances, the following tolerances should be removed:  strawberry; grape; and liver of cattle, goat, horse, and sheep.
Registration should be conditional pending resolution of the following deficiencies:

Toxicology
   * An Immunotoxicity Study.
   * Acute and Subchronic Neurotoxicity Studies.
   * A 28-Day Inhalation Study.

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

Provided below are the physical/chemical properties for acequinocyl.  Most of this information was obtained from the acequinocyl "Pesticide Fact Sheet;" 9/26/03 (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[(TM)] 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.  

Appearance:	
Pale yellow
Physical State:	
Liquid Suspension
Vapor Pressure:
1.69 x 10-9 pascals at 25[0]C (technical)
Water Solubility:
6.69 μg/L at 20[0]C (technical)	
Octanol/Water Partition Coefficient (Log Kow):
6.2 (technical)
Melting Point:	
59.6C (technical)
Density:	
1.13 g/cm[3]

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 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.  2[nd] Report of the HIARC.  Meeting Date:  October 14, 2003. P. Terse, 13-NOV-2004; TXR No. 0052234.
 * Acequinocyl.  Report of the HIARC.  Meeting Date:  July 15, 2003.  R. Fricke, 14-AUG-2003; TXR No. 0052075.  

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 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.  

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.

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 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 Standard Operating Procedures (SOPs).  For chemicals with low vapor pressure (7.5 x 10[-5] mmHg or below for outdoor uses at 20-30[0]C), 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 25[0]C) 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 affect the FQPA SF.
    *       The dietary food (tolerance-level residues, 100% crop treated) and drinking water exposure (modeled) 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

Table 3.3.1 provides 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.[1]
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-term 
(1-30 days) incidental oral

NOAEL=60 mg/kg/day

UFA = 10x
UFH =10x

LOC (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-term 
(1-6 months) incidental oral
NOAEL = 16 mg/kg/day

UFA = 10x
UFH =10x

LOC (residential) = 
MOE <100 

Subchronic toxicity in mice;
LOAEL = 81 mg/kg/day based on hepatocyte vacuolization.
Short- (1-30 days) and Intermediate-term (1-6 months) 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-term (1-30 days) 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 vacuolization.
Cancer (oral, dermal, inhalation)   
Classification:  "Not likely to be Carcinogenic to Humans."
    [1]  Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  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.

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 derived from 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 generate 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-Term Incidental Oral Endpoint:  The short-term incidental endpoint was derived from the development rabbit study where the maternal NOAEL was 60 mg/kg bw/day.  The maternal LOAEL was 120 mg/kg bw/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).  This study is relevant for the duration of exposure, and is protective of the populations of concern.  

Intermediate-Term Incidental Oral Endpoint: The intermediate-term incidental or 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).based upon hepatocyte vacuolization observed in male and female mice at the LOAEL of 81/ 100  mg/kg/day.  The endpoint is appropriate for the route, duration of exposure (1-6 months) and populations of concern.  Corneal effects seen in rats at 800 ppm (36.41 mg/kg/day and 46.20 mg/kg/day for male and female, respectively) would also be protected by this dose (NOAEL, 16 mg/kg/day).
  
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/cm[2], 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  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#: 1E7864.  Petition for Use on Succulent Soybean Vegetable; Succulent Shelled Beans; Cowpea Forage; Caneberry Subgroup 13-07A; Melon Subgroup 9A; Cucumber, Cherry; Low-Growing Berry Subgroup 13-07G; and Small Fruit Vine Climbing, Except Fuzzy Kiwifruit, Subgroup 13-07F.  Summary of Analytical Chemistry and Residue Data. S. Levy, 30-NOV-2011; D389989.
    * PP#: 1E7864.  Acequinocyl.  Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Use on Succulent Soybean Vegetable; Succulent Shelled Beans; Cowpea Forage; Caneberry Subgroup 13-07A; Melon Subgroup 9A; Cucumber; Cherry; Low-Growing Berry Subgroup 13-07G; and Small Fruit Vine Climbing, Except Fuzzy Kiwifruit, Subgroup 13-07F. S. Levy, 30-NOV-2011; D389990.
    * Acequinocyl: Occupational and Residential Exposure/Risk Assessment for Proposed Use on Succulent soybean; Low growing berry subgroup 13-07G; Small fruit vine climbing (except fuzzy kiwifruit, subgroup 13-07F); Succulent bean; Cowpea forage; Caneberry (subgroup 13-07A); Melon (subgroup 9A); Cucumber (greenhouse and field), and Cherry.  K. Lowe, 30-NOV-2011; D389991.  
    * Acequinocyl:  Drinking Water Assessment to Support Proposed New IR-4 Uses (Succulent Soybean Vegetable, Low Growing Berry, Small Fruit Vine Climbing - Except Fuzzy Kiwifruit, Succulent Shelled Beans, Cowpea Forage, Caneberry, Melon, Cucumber, and Cherry).  M. Lowit et al., 07-SEP-2011; D389520.

Acequinocyl is a quinoline-type miticide registered for use in the U.S. on a number of RACs for the control of various phytophagous mite species. 
 
Under PP#1E7864, the IR-4, on behalf of the Agricultural Experiment Station of TX, CA, OR, PA, GA, NM, OK, TN, UT, MI, FL, and AZ, is requesting for the establishment of tolerances for combined residues of the insecticide acequinocyl and its metabolite, 2-dodecyl-3-hydroxy-1,4-naphthoquinone (acequinocyl-OH), expressed as acequinocyl equivalents in/on the following commodities:

   Soybean, vegetable, succulent	0.25 ppm
   Low growing berry subgroup 13-07G	0.4 ppm
   Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit	1.6 ppm
   Bean, succulent shelled	0.15 ppm
   Cowpea, forage	9.0 ppm
   Caneberry subgroup 13-07A	4.5 ppm
   Melon subgroup 9A	0.06 ppm
   Cucumber	0.15 ppm
   Cherry	0.8 ppm

No new data were submitted to support tolerances on succulent soybean vegetables, low-growing berry 13-07G crop subgroup, or small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit.  The petitioner has requested that existing tolerances be expanded to their respective crops or crop groups.

4.1  Summary of Uses

The petitioner provided a draft label for Kanemite[(TM)] 15 SC Miticide (EPA Reg. No. 66330-38), a 1.25 lb/gal SC formulation of acequinocyl.  This acequinocyl formulation is currently registered for use on several fruit and nut crops, 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.
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                       Use Directions and Limitations[1]
                            Bean, succulent shelled
Postemergence, foliar;
Ground only; Groundboom
                                1.25 lb/gal SC
                                  [66330-38]
                                      0.3
                                       2
                                      0.6
                                       7
Minimum spray volume of 30 gal/A; minimum RTI of 14 days.  Do not allow grazing on cowpea forage within 7 days of last treatment.
                           Caneberry subgroup 13-07A
Postemergence, foliar;
Ground only; Groundboom
                                1.25 lb/gal SC
                                  [66330-38]
                                      0.3
                                       2
                                      0.6
                                       1
Minimum spray volume of 50 gal/A; minimum RTI of 21 days.
                               Melon subgroup 9A
Postemergence, foliar;
Ground only; Groundboom
                                1.25 lb/gal SC
                                  [66330-38]
                                      0.3
                                       2
                                      0.6
                                       1
Minimum spray volume of 30 gal/A; minimum RTI of 21 days.
                                   Cucumber
Postemergence, foliar; Ground only; Groundboom (field); Handheld sprayers (greenhouse)
                                1.25 lb/gal SC
                                  [66330-38]
                                 0.3 or 0.1[2]
                                       2
                                      0.6
                                       1
Minimum spray volume of 30 gal/A; minimum RTI of 21 days.  The use of an adjuvant or surfactant is prohibited.
                                    Cherry
Postemergence, foliar;
Ground only; Airblast
                                1.25 lb/gal SC
                                  [66330-38]
                                      0.3
                                       2
                                      0.6
                                       7
Minimum spray volume of 40 gal/A; for optimal control, use a minimum of 150 gal/A; minimum RTI of 14 days.  Do not use in alternate row middle applications.
[1]  RTI = retreatment interval.
[2]  Label indicates a minimum of 30 gal/A.  Application rate = 0.3 lb ai/A / 30 gal/A = 0.01 lb ai/gal.

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.  The label requires applicators and other handlers to wear a long-sleeved shirt and long pants and shoes plus socks, plus chemical-resistant gloves.

Rotational crop restrictions are as follows:  food and feed crops not listed on the proposed label must not be planted within 30 days of the last Kanemite[(TM)] 15 SC application.

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 supported by the submitted field trial data.  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.  The available data support a 30-day PBI for all non-labeled crops, which is reflected on the proposed label.

4.2  Dietary Exposure/Risk Pathway

4.2.1  Residue Profile

Nature of the Residue:  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, the HED Metabolism Assessment Review Committee (MARC) has determined that the residues of concern in these commodities include parent and acequinocyl-OH (Memo, S. Levy, et al., 07-JAN-2004; D297872).

The qualitative nature of acequinocyl residues in ruminants is understood based on an adequate goat metabolism study (Memo, S. Levy, 10-MAR-2004; D284757).  The metabolism of acequinocyl in goats appears to involve the loss of the acetyloxyl moiety to form acequinocyl-OH and partial cleavage of the dodecyl side chain to form AKM-15.  Opening and degradation of the quinone ring was also evidenced by the presence of AKM-18 and phthalic acid.  The MARC concluded that for tolerance expression, the residues of concern in livestock commodities include parent and acequinocyl-OH.  For risk assessment purposes, the residues of concern in livestock commodities are parent and acequinocyl-OH (for liver and kidney, metabolite AKM-15 is to be included as well (Memo, S. Levy, et al., 07-JAN-2004; D297872). 

Metabolism data on poultry are not required at the present time as none of the proposed or existing uses of acequinocyl are on crops having regulated poultry feedstuffs.

Magnitude of the Residue-Plants:  IR-4 submitted adequate field trial data in support of the proposed uses on succulent shelled beans, caneberry, cantaloupe, cherry, and cucumber.  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 prohibiting the addition of adjuvants to the spray solution.  The Organization for Economic Co-operation and Development (OECD) maximum residue limit (MRL) calculator was used to determine the appropriate tolerance levels.  The field trial data will support tolerances of:  0.30 ppm for residues in/on bean, succulent shelled; 6.0 ppm for residues in/on cowpea, forage; 18 ppm for residues in/on cowpea, hay; 4.0 ppm for residues in/on caneberry subgroup 13-07A; 0.15 ppm for residues in/on melon subgroup 9A; 1.0 ppm for residues in/on cherry, tart; 0.50 ppm for residues in/on cherry, sweet; and 0.15 ppm for residues in/on cucumber.  A revised Section F should be submitted. 

No new data were submitted to support tolerances on succulent soybean vegetables, low-growing berry 13-07G crop subgroup, or small fruit climbing vine subgroup 13-07F, except fuzzy kiwifruit.  However, existing established tolerances in 40 CFR §180.599 should be extended to support these crop group tolerances.  HED recommends that that the tolerance for residues at in/on edible-podded beans should be extended to soybean, vegetable, succulent; the tolerance for residues in/on strawberries should be extended to the low-growing berry 13-07G subgroup; and the tolerance for residues in/on grapes should be extended to small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit.  See Table 4.2.1.1 for details.

There are no processed food/feed items associated with the proposed uses.  Therefore, data requirements for this guideline are not relevant to this tolerance petition.

Magnitude of the Residue-Livestock:  Based on the potential dietary exposure of livestock to acequinocyl residues from the current and proposed uses, the dietary burden was re-evaluated.  The re-evaluated dietary burden indicates that the currently established tolerance level of 0.02 ppm for residues in cattle, goat, horse, and sheep fat are appropriate.  Furthermore, the 0.02-ppm residue level is sufficient to cover residues of the additional metabolite (AKM-15) of concern in ruminant liver and kidney.  The established 0.02-ppm residue level in cattle, goat, horse, and sheep liver is appropriate; however, the commodity definition should be changed to "meat byproducts" rather than "liver."  With the establishment of the cattle, goat, horse, and sheep tolerance in meat byproducts, RD should remove the tolerance (40 CFR §180.599) for liver.  Furthermore, the meat byproducts tolerance of 0.02 ppm is adequate to cover residues in the kidney of cattle, goats, horses, and sheep.  A revised Section F should be submitted.

Residue Analytical Method for Crops:  There are adequate residue analytical methods for enforcing tolerances for acequinocyl residues of concern in/on the proposed/registered commodities.  These methods include two high-performance liquid chromatography methods with tandem mass-spectroscopy detection (HPLC/MS/MS) for determining residues in/on plant commodities (Morse Methods Meth-135 and #Meth-133, revision #3).  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).  In the current field trials, residues of acequinocyl and acequinocyl-OH were determined using a modified version of Morse Method #Meth-133, revision #3.  The method limit of quantitation (LOQ; based on the lowest level of method validation (LLMV)) for succulent shelled beans was 0.02 ppm for each analyte.  The LOQs (based on the LLMV) for cantaloupe were 0.015 ppm for acequinocyl, and 0.01 ppm for acequinocyl-OH.  For cherries, cucumbers, and caneberries, the LOQ (based on the LLMV) was 0.01 for each analyte.  The method was adequately validated in conjunction with the analysis of field trial samples.  

Analytical reference standards for acequinocyl and acequinocyl-OH are currently available at the EPA National Pesticide Standards Repository (electronic communication with Theresa Cole, 31-OCT-2011) with expiration dates of June, 2012.  
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, 18-FEB-2004; D298917).

Storage Stability in Plants:  The submitted concurrent storage stability data for the subject crops are adequate to support the storage intervals and conditions incurred by the field trial studies. 

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, which is reflected on the proposed label.

Proposed and Recommended Tolerances:  There are currently no established Codex, Canadian, or Mexican MRLs for acequinocyl residues in/on cucumbers or caneberries.  Data for these crops were jointly reviewed by the U.S. and Canada.  The data support tolerance levels of 0.15 ppm and 0.40 ppm, respectively.  These levels are harmonized between the U.S. and Canada.
  
Canada has a MRL of 0.5 ppm for residues in/on strawberries.  The OECD Calculator shows that the data support a tolerance of 0.40 ppm for residues in/on the low-growing berry subgroup 13-07G (which includes strawberries); however, in order to harmonize with Canada, HED recommends establishing a tolerance of 0.50 ppm for residues in this subgroup.  Canada also has a MRL for residues of 0.02 ppm in/on meat byproducts of cattle, goat, horse, and sheep.  HED is recommending for the same tolerance level as Canada; therefore, harmonization will not be an issue.  The proposed and HED-recommended tolerances are listed in Table 4.2.1.1.

The petitioner should submit a revised Section F with the appropriate commodity definitions and/or HED-recommended tolerance levels listed in Table 4.2.1.1.  Furthermore, the Section F should state the following (as it appears in 40 CFR §180.599):  "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."  A revised Section F should be submitted.

Table 4.2.1.1.  Tolerance Summary for Acequinocyl.
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
Comments; 
Correct Commodity Definition
Soybean, vegetable, succulent
                                     0.25
                                     0.25
Established edible-podded bean tolerance extended to soybean, vegetable, succulent.
Low-growing berry subgroup 
13-07G
                                      0.4
                                     0.50
Established strawberry tolerance extended for a subgroup tolerance.  With establishment of this subgroup tolerance, the strawberry tolerance should be removed.
Berry, low growing, subgroup 13-07G
Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit
                                      1.6
                                      1.6
Established grape tolerance extended for a subgroup tolerance.  With establishment of this subgroup tolerance, the grape tolerance should be removed.
Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13-07F
Bean, succulent shelled
                                     0.15
                                     0.30

Cowpea, forage
                                      9.0
                                      6.0

Cowpea, hay
                                      --
                                      18

Caneberry subgroup 13-07A
                                      4.5
                                      4.0

Melon subgroup 9A
                                     0.06
                                     0.15

Cucumber
                                     0.15
                                     0.15

Cherry
                                      0.8
                                      1.0
Cherry, tart

                                      --
                                     0.50
Cherry, sweet
Liver of cattle, goat, horse, and sheep[1]
                                      --
                                     0.02
Meat byproducts of cattle, goat, horse and sheep
[1]  A tolerance of 0.02 ppm is already established under 40 CFR §180.599; however, the commodity definition should be changed to meat byproducts to cover residues in liver and kidney.

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 R-1).

Surface and Ground Water Estimated Drinking Water Concentrations (EDWCs):  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.  There are no drinking water monitoring data available for either acequinocyl or acequinocyl-OH.  Groundwater EDWCs were generated for acequinocyl using the Screening Concentration in Ground Water (SCI-GROW) Model.  Surface water EDWCs were generated using the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) model for all proposed uses except cranberry (cranberries are part of the low growing berries subgroup, 13-07G).  Cranberry harvesting may involve field flooding and PRZM/EXAMS is not currently parameterized to assess this type of scenario; therefore, cranberry was assessed using the provisional cranberry model (note that since the provisional cranberry model only uses a one year simulation, the highest 30-year annual average concentration is not available for the cranberry scenario).

Similar to previous drinking water assessments provided by EFED, two approaches were used in performing the drinking water assessment for 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 half-lives of acequinocyl and R1 are valid and the total toxic residues were modeled to address toxicity concerns with R1.  The EDWCs are summarized below in Table 4.3.1.  Surface water EDWCs for the proposed uses are higher than those previously reported for both approaches.  The ground water EDWC for the current assessment is the same as the last assessment.

Table 4.3.1.  Recommended EDWCs of Acequinocyl Derived from the Previous Uses.
                         Drinking water source (model)
                           Proposed Use/Scenario[3]
                 EDWCs from Surface Water Sources (ug/L)[1,2]

                                  Approach 1
                      (assume no acequinocyl degradation)
                                  Approach 2
                         (combined acequinocyl and R1)

                              1-in-10-year acute
                             1-in-10-year chronic
                                 30-year mean
                              1-in-10-year acute
                             1-in-10-year chronic
                                 30-year mean
Surface water
(PRZM/EXAMS)
Cherry/MI cherry
                                6.69 (25.89)[4]
                                     6.69 
                                  (17.84)[4]
                                6.69 (10.19)[4]
                                     5.59
                                     0.42
                                     0.26
Surface water
(PRZM/EXAMS)
Small fruit (vine climbing, except fuzzy kiwifruit, 13-07F)/NY grape
                                6.69 (23.12)[4]
                                     6.69 
                                  (15.34)[4]
                                     6.69 
                                   (9.57)[4]
                                     4.22
                                     0.38
                                     0.27
Surface water
(Provisional Cranberry Model)
Cranberry/Provisional Cranberry Model
                                     4.24
                                     3.75
                                      --
                                    3.81[5]
                                    1.36[5]
                                      --
Groundwater (SCIGROW)
All proposed uses
                                 3.6 x 10[-3]
                               <3.6 x 10[-3]
                               <3.6 x 10[-3]
                                 3.6 x 10[-3]
                               <3.6 x 10[-3]
                               <3.6 x 10[-3]
[1]   Bolded values are the recommended EDWCs by EFED.
[2]   A default PCA of 0.87 was applied.
[3]   Maximum of 2 applications of 0.3 lb ai/A for all proposed uses.
[4]   EDWC (shown in parentheses) exceeds the solubility limit of acequinocyl (6.69 ug/L at 20°C); therefore, the recommended EDWC is 6.69 ppb.  
[5]   Based on a one-year simulation; 1-10-year calculation is not applicable.

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 (6.69 ppb) while that derived via Approach #2 represents the lower-bound value (1.36 ppb).  The 6.69 ppb value was used in this dietary assessment 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[(TM)], 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[(TM)] 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.  DEEM ver. 7.81 default processing factors were used with the exception of those for grape juice and raisins.  As residues were reduced in both grape juice (<0.02x) and raisin (0.15x), separate tolerances are not required for these commodities.  The DEEM ver. 7.81 default processing factors for juice and raisin were set to 1 as concentration was shown not to occur (Memo, S. Levy, 05-SEP-2007; DP#: 342805).
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 6.69 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 (13% cPAD) and all population subgroups.  The most highly exposed population subgroup is children 1-2 years old at 55% 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 + Drinking Water) Exposure and Risk for Acequinocyl.
 Population Subgroup
                               Chronic Dietary[1]
 
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
 U.S. Population (total)
                                    0.003627
                                       13
 All Infants (<1 year old)
                                    0.006513
                                       24
 Children 1-2 years old
                                    0.014761
                                       55
 Children 3-5 years old
                                    0.010370
                                       38
 Children 6-12 years old
                                    0.005172
                                       19
 Youth 13-19 years old
                                    0.002825
                                       11
 Adults 20-49 years old
                                    0.002525
                                      9.4
 Adults 50+ years old
                                    0.002473
                                      9.2
 Females 13-49 years old
                                    0.002563
                                      9.5
 [1] Chronic dietary POD of 0.027 mg/kg/day applies to the general U.S. population and all population subgroups.  The values for the highest exposed population are bolded.

4.5  Residential/Non-Occupational Exposure Pathway

4.5.1  Short-term Residential Handler 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.  Residential handler exposure from applying acequinocyl to trees and ornamentals with handheld equipment was assessed in June 2010 (A. Nowotarski, D369099).  All MOEs were >100 and are not of concern to HED (see Table 4.5.1.1). 

Table 4.5.1.1.  Summary of Residential Handler Exposure and Risk.
                                   Scenario
                     Residential Handler Dose (mg/kg/day)
                            Residential Handler MOE
  Mixer/Loader/Applicator  -  Liquid Formulation with Low-Pressure Handwand 
                                    Dermal
                               Baseline:  0.005
                                       
                                  Inhalation
                              Baseline:  2.3E-07
                                    Dermal
                               Baseline:  40,000
                                       
                                  Inhalation
                              Baseline:  2.6E+08
                                       
                                       
                                       
Mixer/Loader/Applicator  -  Liquid Formulation with Hose-End Sprayer (ORETF-- fruit trees and ornamentals)
                                    Dermal
                                Baseline:  0.07
                                       
                                  Inhalation
                              Baseline:  2.9E-06
                                    Dermal
                               Baseline:  2,900
                                       
                                  Inhalation
                              Baseline:  2.1E+07
                                       
                                       
                                       

4.5.2  Short-term Residential Post-application Risk

Post-application exposure was not anticipated for the registered residential uses; and therefore, a quantitative post-application assessment was not conducted.  

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[(R)] 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.

4.5.4  Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment 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.

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 hazard does not exist, 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 females 13-49 years old population is the highest exposed adult population and can be considered protective of the other adult populations groups; therefore, this population subgroup 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 females 13-49 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 MOE[1]
                           Residential Dermal MOE[2]
                         Residential Inhalation MOE[2]
                                   Aggregate
                                    MOE[3]
                                U.S. Population
                                    17,000
                                     2,900
                                  21,000,000
                                     2,500
                            Females 13-49 years old
                                    23,000
                                     2,900
                                  21,000,000
                                     2,600
[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((1MOEdietary)+(1MOEdermal)+(1MOEinhalation); 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 post-application 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 (see Table 4.4.1.1) 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 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 Succulent soybean; Low growing berry subgroup 13-07G; Small fruit vine climbing (except fuzzy kiwifruit, subgroup 13-07F); Succulent bean; Cowpea forage; Caneberry (subgroup 13-07A); Melon (subgroup 9A); Cucumber (greenhouse and field), and Cherry.  K. Lowe, 30-NOV-2011; D389991.
7.1  Short- and Intermediate-term Occupational Handler Risk

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 

1) Mixing/loading liquids in support of groundboom operations, 
2) Applicators using open-cab groundboom equipment,
3) Mixing/loading/applying liquids via backpack sprayers,
4) Mixing/loading/applying liquids via mechanically-pressurized handgun, and 
5) Mixing/loading/applying liquids via manually pressurized handwand. 

For pesticide handlers, HED presents estimates of dermal exposure for "baseline" (i.e., 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 PPE, as might be necessary.  The acequinocyl product labels direct mixers, loaders, applicators, and other handlers to wear long-sleeved shirt and long pants, chemical-resistant gloves, and shoes plus socks.  

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the PHED (Version 1.1), the AHETF database, the ORETF database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.  

Typically, HED completes short- and intermediate-term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate-term scenarios.  Based on use data and label instructions, HED believes that occupational exposures may occur over a single day or up to weeks at a time for many of the use-patterns and that intermittent exposure over several weeks may also occur.  Some applicators may apply these products over a period of weeks, because they are commercial applicators who are completing multiple pesticide applications for multiple clients.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.  

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.  Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Acequinocyl (with baseline protection).  
                               Exposure Scenario
                                Crop or Target
                              Application Rate2 
                    Area Treated or Amount Handled Daily[3]
                          Unit Exposure (mg/lb ai)[1]
                              Dose (mg/kg/day)[4]
                     Short- and Intermediate-term MOEs[5]
                                       
                                       
                                       
                                       
                              Baseline[6] Dermal 
                            Baseline[6] Inhalation 
                               Baseline Dermal 
                             Baseline Inhalation 
                               Baseline Dermal 
                             Baseline Inhalation 
                                 Mixer/Loader
              Mixing/Loading Liquids for Groundboom Applications
                                   soybeans
                                     0.3 
                                    lb ai/A
                                      200
                                     acres
                                     0.22
                                   0.000219
                                     0.19
                                    0.00019
                                     1,100
                                  ST: 320,000
                                  IT: 85,000
                                       
 small fruit and berry, succulent bean, cowpea forage, melon, cucumber (field)
                                      0.3
                                    lb ai/A
                                      80
                                     acres
                                     0.22
                                   0.000219
                                     0.075
                                   0.000075
                                     2,700
                                  ST: 800,000
                                  IT: 210,000
               Mixing/Loading Liquids for Airblast Applications
                                   cherries
                                      0.3
                                    lb ai/A
                                      40
                                     acres
                                     0.22
                                   0.000219
                                     0.038
                                   0.000038
                                     5,300
                                 ST: 1,600,000
                                  IT: 430,000
                                  Applicator
                   Applying Sprays via Groundboom Equipment
                                   soybeans
                                      0.3
                                    lb ai/A
                                      200
                                     acres
                                    0.0786
                                    0.00034
                                     0.067
                                    0.00029
                                     3,000
                                  ST: 210,000
                                  IT: 55,000
                                       
 small fruit and berry, succulent bean, cowpea forage, melon, cucumber (field)
                                      0.3
                                    lb ai/A
                                      80
                                     acres
                                    0.0786
                                    0.00034
                                     0.027
                                    0.00012
                                     7,400
                                  ST: 510,000
                                  IT: 140,000
                    Applying Sprays via Airblast Equipment
                                   cherries
                                      0.3
                                    lb ai/A
                                      40
                                     acres
                                     1.77
                                    0.00471
                                      0.3
                                    0.00081
                                      660
                                  ST: 74,000
                                  IT: 20,000
                            Mixer/Loader/Applicator
             Mixing/Loading/Applying Liquids with Backpack Sprayer
                             Greenhouse cucumbers
                                     0.01 
                                 lb ai/gallon
                                  40 gallons
                                     13.2
                                     0.14
                                     0.075
                                    0.0008
                                     2,700
                                  ST: 75,000
                                  IT: 20,000
      Mixing/Loading/Applying Liquids with Manually-pressurized Handwand
                                       
                                       
                                  40 gallons
                                      100
                                     0.03
                                     0.57
                                    0.00017
                                      350
                                  ST: 350,000
                                  IT: 93,000
 Mixing/Loading/Applying Liquids with Mechanically-pressurized Handgun Sprayer
                                       
                                       
                                 1000 gallons
                                      3.5
                                     0.12
                                      0.5
                                     0.017
                                      400
                                   ST: 3,500
                                    IT: 930
1.  Unit Exposures are taken from "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (September 26, 2011).  
2.  Applic. Rate. = Maximum rate listed on proposed Kanemite label (Reg. No. 66330-38).
3.  Units Treated are taken from "Standard Values for Daily Acres Treated in Agriculture"; ExpoSAC SOP No. 9.1.  Revised September 25, 2001.
4.  Dose (mg/kg/day) = Unit Exposure (mg/lb ai) * Application Rate * Area treated or Amount handled  Body Weight (70 kg).  
5.  MOE = NOAEL  Dose.  NOAEL = 200 (dermal), 60 (short-term inhalation), or 16 (intermediate-term inhalation) mg/kg bw/day.
6.  Baseline = Long-sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation). 
7.2  Short- and Intermediate-term Occupational Post-application Risk

Dermal

HED expects that post-application exposure will occur since acequinocyl is applied post-emergence as a foliar spray.  Post-application exposure is expected to be short- and intermediate-term based on information provided on proposed labels (e.g., maximum of two sprays per season at a rate of 0.3 lb ai/A).  The POD for the dermal route of exposure is the same for short- and intermediate-term exposure durations, so the risk estimate is protective of both durations of exposure.  It is not anticipated that there would be long-term exposure from the greenhouse cucumber use since the label recommends that the proposed product not be used in successive applications to avoid resistance issues.  

The following inputs and assumptions were used in the post-application exposure calculations:

   * Exposure Duration:  8 hours per day
   * Body Weight:  70 kg
   * Dermal TCs from the Science Advisory Council for Exposure (ExpoSAC) Policy Number 3.  
   * Chemical-specific DFR data 
         o Chrysanthemums in greenhouses (MRID 454286-19)
         o Apples (MRID 456516-11)
 
It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients," are presented in the "ExpoSAC Policy 3" (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Chemical-specific DFR data were available for acequinocyl; however, the data were not for the currently proposed crops.  Since DFR data are not available for the specific crops currently proposed for acequinocyl, the available data were used as surrogates.  Based on a review of the available data, it was decided that the DFR data for chrysanthemums in greenhouses would be used as a surrogate for cucumbers in greenhouses, and the DFR data for apples would be used for all other proposed field crops.  

All agricultural crop scenarios resulted in MOEs greater than 100 on day 0 and are not of concern.  Table 7.2.1 presents the risk estimates for all crops for the highest transfer coefficient associated with that crop; this represents the activities with the highest estimated risk. 

Table 7.2.1:  Dermal Post-application Exposure and Risk Using Chemical-Specific DFR Data.
                                   Crop Group
                                 Proposed Crop
               Highest Transfer Coefficient for Crop (cm[2]/hr) 
                            and Associated Activity
                              Days after Treatment
                                 Study Test Site
                            Chemical-specific DFR[1]
                                   (ug/cm[2])
                                 Dermal Dose[2]
                                  (mg/kg/day)
                                     MOE[3]
                           Field/row crop, low/medium
                Succulent soybean, succulent bean, cowpea forage
                                     1,900 
                             (irrigation; hand set)
                                       0
                                       CA
                                     0.217
                                     0.047
                                     4,200
                                        
                                        
                                        
                                        
                                       NY
                                     0.613
                                     0.130
                                     1,500
                                        
                                        
                                        
                                        
                                       WA
                                     0.435
                                     0.094
                                     2,100
                                   Berry, low
                      Low growing berries subgroup 13-07G
                                     1,900 
                             (irrigation; hand set)
                                       0
                                       CA
                                     0.217
                                     0.047
                                     4,200
                                        
                                        
                                        
                                        
                                       NY
                                     0.613
                                     0.130
                                     1,500
                                        
                                        
                                        
                                        
                                       WA
                                     0.435
                                     0.094
                                     2,100
                                  Vine trellis
                         Small fruit, subgroup 13-07F,
                         Caneberry crop subgroup 13-07A
                                    19,300 
                              (girdling, turning)
                                       0
                                       CA
                                     0.217
                                     0.480
                                      420
                                        
                                        
                                        
                                        
                                       NY
                                     0.613
                                      1.4
                                      150
                                        
                                        
                                        
                                        
                                       WA
                                     0.435
                                     0.960
                                      210
                              Vegetable, cucurbit
                               Melon subgroup 9A,
                                Cucumber (field)
                                     1,900 
                             (irrigation; hand set)
                                       0
                                       CA
                                     0.217
                                     0.047
                                     4,200
                                        
                                        
                                        
                                        
                                       NY
                                     0.613
                                     0.130
                                     1,500
                                        
                                        
                                        
                                        
                                       WA
                                     0.435
                                     0.094
                                     2,100
                             Vegetable, greenhouse
                             Cucumber (greenhouse)
                                     1,200
 (Hand harvesting, Pinching, Pollination, Hand pruning, Scouting, Turning, Tying/Training, Hand weeding, Propagating)
                                       0
                                       CA
                                     0.617
                                     0.085
                                     2,400
                          Tree, "fruit," deciduous
                                     Cherry
                                     3,600 
                                (thinning fruit)
                                       0
                                       CA
                                     0.217
                                     0.089
                                     2,200
                                        
                                        
                                        
                                        
                                       NY
                                     0.613
                                     0.250
                                      790
                                        
                                        
                                        
                                        
                                       WA
                                     0.435
                                     0.180
                                     1,100
1  Chemical-specific DFR = measured chrysanthemum DFR data for greenhouse cucumbers and predicted apple DFR data for all other crops.  Application rate in studies = proposed application rate; therefore, no adjustment of the DFR data was necessary.
2  Dermal Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x 8 hrs/day]  body weight (70 kg).
3  MOE = NOAEL (200 mg/kg/day)/ Dermal Dose (mg/kg/day). 

Inhalation 
Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for acequinocyl at this time.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated areas.  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, and 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 as well as available post-application 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 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 occupational post-application inhalation exposure assessment for acequinocyl.

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 of 12 hours is adequate to protect agricultural workers from post-application exposures to acequinocyl.  The proposed label lists a REI of 12 hours. 

8.0  RESIDUE CHEMISTRY AND TOXICOLOGY DEFICIENCIES

8.1  Residue Chemistry

    * Revised Section F.
    * Revised Section B.
       
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 (RAB1); K. Lowe (RAB1)
RDI:  RAB1 Branch (23-NOV-2011); RAB1 Chemists (09-NOV-2011)
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; 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);

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 MOUSE
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/cm[2]

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/cm[2] 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-18
                     2-(1,2-dioxotetradecyl)-benzoic acid
                                       
                                    AKM-15
                2-hydroxy-3-hexanoic acid-1, 4 naphthalenedione
                                       
                                       
                                    AKM-14
                2-hydroxy-3-butanoic acid-1,4-naphthalenedions